EUT Congress News Monday 23 March 2015

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30th Anniversary Congress of the European Association of Urology

Monday, 23 March 2015

Madrid, 20-24 March 2015

High-risk PCa: Better curative therapy remains elusive Maitland: Treatment can induce resistance in prostate cancer

By Joel Vega

Marcus Graefen (DE) and Francesco Montorsi (IT). “I really do not know…we do not have randomized data,” said Bossi replying to the query whether radiotherapy is less toxic than surgery. Graefen, on the other hand, said surgery is the only uni-modal therapy with a realistic chance of cure. “Moreover the results on urinary continence are comparable to low and intermediate-risk disease.”

Experts examined yesterday controversies, treatment insights and uncertainties in multi-modal approaches in prostate cancer during Plenary Session 2 with some speakers underscoring the lack of convincing data and others reiterating the message that, at best, patients with aggressive prostate cancer can only be assured of limited survival benefit.

“There are multiple mechanisms of resistance, and the resistance is at the cellular and genetic levels. Some resistance are induced by treatment and some are preexisting (and rapid),” said Prof. Norman Maitland (GB).

In the session chaired by Profs. Manfred Wirth (DE) and Arnulf Stenzl (DE), among the topics discussed were chemotherapy in hormone sensitive patients, ways to better identify low-risk patients, the roles of surgery and radiotherapy in high-risk patients, and and Maitland’s state-of-the-art lecture on biological resistance of cancer stem cells.

Profs. Manfred Wirth (l) and Arnulf Stenzl confer during Plenary Session 2

“The combination of standard androgen deprivation therapy (ADT) and six cycles of docetaxel significantly improved overall survival compared to standard ADT alone in men with hormone sensitive prostate cancer,” said Christopher Sweeney (USA). He added: “The benefit in patients with a high volume of metastases is clear and justifies the treatment burden, and they need to be chemo-fit.

Discussant Jacques Irani (FR) also conceded he would recommend the ADT-docetaxel combination to those with high-volume, metastatic disease, but noted he would await the publication of confirmative results such as those from the STAMPEDE trial.

In the same session the benefits or drawbacks of radiotherapy were examined by Alberto Bossi (FR),

Maitland gave a well-received state-of-the-art lecture regarding why anti-androgen therapies in prostate cancer fail to offer a better curative treatment. He explained that aside from the mechanisms of resistance to androgen receptor inhibition, the cancer stem cells, over time and treatment, undergo resistance.

“Anti-androgen treatments shrink tumours but their effects are time-limited,” warned Maitland. He noted that although using aggressive therapy may provide a brief respite with patient’s mortality extended for a limited period, the disease recur at a later stage.

Trends in bladder cancer treatment Thematic Session 6: New developments in diagnostics and treatment

By Monique van Hout Bladder cancer is a common urological malignancy but is much more complex compared to others because of multiple mutations in cells. Moreover, treatment is expensive because of the high risk of recurrence and the cost of cystoscopies.

tumour parts. The disadvantages are that it can be time consuming to collect urine samples and that they are non-homeostatic due to varying concentrations, pH value and content. In the future, urine samples can be used for identifying prognostic and surveillance biomarkers.

During Thematic Session 6, dedicated to bladder cancer, novel findings in diagnostics and treatment with BCG were discussed. Prof. Torben Orntoft (DK) presented his work on searching for biomarkers in body fluids. Since bladder cancers consist of different populations, traditional biopsies are less reliable and liquid biopsies may be more useful. Orntoft suggested urine as a potential option for liquid biopsy.

Related to this, Prof. Christopher Probert (GB) presented his work on sniffing cancer- or how dogs have demonstrated the ability to smell cancer and how, based on this principle, his team has developed a device which can identify the presence of cancerous tissue by analysing urine. By using gas chromatography–mass spectrometry (GCMS), the device distinguishes bladder cancer from controls in 95% of cases.

The advantages are that collecting a urine sample is non-invasive and that it represents all, or close to all,

Prof. Dr. Maximilian Burger (DE) and Dr. Kay Thomas (GB) debated whether or not BCG is still the gold

Patient-centered approach

standard in bladder cancer treatment. Burger argued that it is the gold standard based on three arguments: the data supporting BCG may be old, but it is solid; to date there is no effective alternative, although some important study data are coming out soon. He added that BCG is a true and effective therapy for bladder cancer.

Thomas, in turn, noted that response rates of BCG are low when it is used as a single agent. Instead, she made a case for a combined regime with BCG and mitomycin C (MMC). She presented data which show that BCG works better in combination with MMC and results in a reduced recurrence rate, although there is no difference in disease progression.

A show of hands and a vote for combined therapy

hand and explained that he believes change is coming After the debate, a show of hands revealed that Thomas but added that “to date, the data of combined had convinced the majority of the audience to consider treatment are not convincing,” and thus BCG remains switching to combined therapy. Even Burger raised his his treatment of choice.

Experience the Universa advantage.

By Loek Keizer

“One in three of all prostate cancer survivors was not satisfied with the information received.

Satisfaction with information provision is Despite best efforts, patients are still not entirely satisfied with the information that they receive from positively associated with HRQoL and illness their doctors, and research shows that this may affect perception. These results emphasize the need for better patient information provision, which may their quality of life. favourably impact HRQoL and illness perception This is one conclusion drawn by Ms. Romy Lamers (NL) among prostate cancer survivors,” said Lamers. in her poster on the dissatisfaction with information provision, part of Sunday’s Poster Session 30 which Also in attendance was Prof. Bertrand Tombal (BE) “At the bigger sessions about prostate cancer put patient concerns on the frontline. surgery, the results that relate to patient QoL A cross-sectional study was performed in 2011 among might be overstated a bit. At sessions like this, 999 patients, diagnosed with prostate cancer between when results come from people who are not in 2006-2009, as registered in the Eindhoven Cancer charge of the surgery, the results can be quite Registry (10 hospitals). All patients received a different.” questionnaire on health-related quality of life (HRQoL) (Full story on EAU-Europa UOMO alliance on (EORTC QLQ-C30 and QLQ-PR25), Brief Illness Perception Questionnaire (B-IPQ) and level of satisPage 3). faction with information provision (QLQ-INFO25-scale).

Monday, 23 March 2015

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Measuring and improving prostate cancer care

Today’s Industry Sessions

Crowdsourcing assessment of technical skill

Industry sessions, all starting at 17:45 hrs

Cracking the biomarker market

By Alba Leon

By Joel Vega

Cracking the code of refractory OAB: When, who and how?

ALLERGAN Room N101-102

Medical coverage in the United States presents unique challenges related to costs. They can be tackled through enabling partnerships between the medical community and insurance companies, but most importantly, by thinking out of the box.

Modern thinking in the management of male LUTS - but don’t forget the history ASTELLAS Room Stockholm

The current biomarker research field is humming with activity but the numbers and frequency of new biomarkers coming in doesn’t always translate to efficient clinical use, prompting researchers to ask if their efforts are worth the long and tedious process.

One example of collaboration to improve prostate cancer care through joint efforts is the MUSIC Project, currently being implemented in Michigan.

“Why are the latest markers not used? We expect the breakthrough marker, but we’re not very good at marker research,” said Guido Jenster (NL) during his Plenary Session 2 presentation where the theme focused on identifying low-risk prostate cancer patients.

The main goals of the MUSIC project are the measurement of peri-operative morbidity, analysis of patient-reported functional outcomes, and the assessment of technical skills.

He introduced his overview presentation by noting the current biomarker market is crowded with various types of markers which can be categorized as risk, diagnostic, prognostic, predictive and monitoring markers, implying there is no lack or scarcity in this research field.

“We were not measuring winners or losers, but measuring to improve,” said David Miller (US).

Technical skills assessment can become a performance measurement and can be used for resident evaluation. Eventually, this could lead to hospital credentialing, hiring and board certification.

Most importantly, it can lead to collaborative learning, and improvement.

“Unfortunately, our battle with molecular biomarkers has not been won,” he added. “The situation with biomarkers are still complex; markers today do have a clinical value but they come at a cost,” Jenster said,

Assessments are costly, so the group tried a new approach: what if the ‘wisdom of the crowd’ could help lower the costs while maintaining the quality of the evaluation? They turned to crowdsourcing.

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

The crowd provided very detailed and useful feedback, despite lack of medical training. Therefore, video assessment by peers or the crowd is feasible and this approach shows that even the non-specialist group is able to identify measurable differences in

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

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

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surgical techniques from medical professionals. In order to establish crowdsourcing as an assessment tool these preliminary results should, and will, be confirmed with a larger sample size, and the skill scores correlated with perioperative and functional outcomes.

He underscored that real test for a marker is its practical and efficient use in the clinical setting.

“Added clinical value- this is where our real value comes in,” said Jenster as he urged to pursue their goals.

“Undoubtedly, better skills will lead to improved patient care and more effective and efficient healthcare, which will ultimately benefit physicians, patients and payers,” said Miller.

“Be patient, persistent and supportive. PCa is a complex disease and good markers are difficult to find,” he said. “Get involved in collecting patient samples and test promising markers and assays.”

or old standard?

By Monique van Hout

By Alba Leon

Much research has been done on new treatment modalities for patients with metastatic castrationresistant prostate cancer (mCRPC) but the cross resistance between these therapies needs to be understood better.

The Thematic Session on Male Lower Urinary Tract Symptoms (LUTS) attracted a big audience for state-of-the-art lectures on the most current issues and treatments of LUTS.

An elevated neutrophil to lymphocyte ratio (NLR) may be related to lower PSA response in men treated with abiraterone but it appears to not have any predictive value for patients treated with taxanes. NLR is readily available and cheap and Van Soest argued that it should be included in prognostic nomogrammes and could be used for risk stratification in clinical trials.

Gleason score and duration of initial ADT may also be considered in treatment selection for mCRPC patients. Van Soest: “There is an urgent need for prospective, large-scale studies so that we can change the one-size-fits-all treatment for men with mCRPC into a personalised approach.”

Mr. Derek Rosario (GB) talked about the important issue of QoL for patients treated with ADT. As session chairman Prof. Bertrand Tombal (BE) pointed out: “Hormonal therapy is no sugar pill; QoL matters.” Rosario mentioned that although QoL is a

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“New technologies are laborious and expensive, and progress almost always comes in small steps,” he added.

Quality of life issues in patients undergoing ADT

Another relative new topic of research is the quality of life (QoL) for patients receiving androgendeprivation therapy (ADT). Dr. Robert van Soest (NL) gave an up-to-date overview of data on potential predictive biomarkers which may reveal the mechanisms of cross resistance. He said AR-V7 expression in circulating tumour cells is associated with primary cross resistance in abiraterone and enzalutamide, but not in treatment with taxanes.

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David Miller presents MUSIC results

mCRPC looks at novel research RP: Gold standard

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

Disclaimer

Seventy-six video clips from 12 different stages of robotic prostatectomies were recorded and shown to at least four expert reviewers, and between 30 and 55 online crowd-sourced reviewers. The results were surprising: “We got 1,500 valid crowd scores in less than nine hours, and a strong correlation between crowd and expert grades,” Miller added. This was especially true for the rank order of lower scoring surgeons.

Regarding prostate cancer, Jenster reiterated that since this disease is heterogenous, multi-focal and adaptable, it this further complicates the scenario.

Jean-Nicolas Cornu (FR) highlighted the latest research and advances in endoscopic surgical options to treat benign obstructions. He presented current evidence on open prostatectomy, Holmium Laser Enucleation of the prostate (HoLEP), and Greenlight vaporisation, stressing that there is still little evidence for other lasers, bipolar TURP and bipolar enucleation as viable treatment options.

Dr. Van Soest discusses potential predictive biomarkers for CRPC

very individual concept, there are scientific measures to study it. “Unfortunately, there aren’t many studies out there yet,” Rosario said before going through available data.

It is clear that androgen withdrawal results in non-beneficial effects and limiting exposure to ADT will improve QoL. Pharmaceutical interventions can improve adverse events but there are no data on whether or not this improves QoL. Exercise or physical activities have shown to have a positive impact on fatigue, a common side effect.

None of the other domains showed to be affected by exercise and long-term patient adherence is a problem. Discussing the possible impact of treatment on QoL and other forms of patient education are beneficial for patients’ expectations and a doctorpatient dialogue is important.

Cornu acknowledged that while there is Level 1 evidence for HoLEP, the treatment is not available everywhere, and that comparative data on treatment that include a long-term follow up for Greenlight vaporisation and HoLEP are still necessary. In his assessment new techniques for surgery can also be used for the treatment of prostates with a large volume, which until very recently was only done with open prostatectomy.

“The field is moving rapidly, and open prostatectomy is quickly changing from the gold standard, to the old standard,” according to Cornu.

Cosimo De Nunzio (IT) underscored the role of patient-centred therapy in treating male LUTS. He advocated a shift from a disease-centred approach, where the tumour is central, to a new paradigm where the patient and his needs, as well as those of his family, come first. This could “improve drug adherence, and reduce issues related to doctorshopping,” said De Nunzio.

Monday, 23 March 2015

EAU, Europa UOMO: renewed partnership A ‘win-win-win’ situation for the EAU, patients and society Congress news. . . . . . . . . . . . . . . . . . . . . . . . 1

By Loek Keizer The EAU and Europa UOMO (EUomo), Europe’s largest prostate cancer patient organization have formally renewed their partnership during the congress . The main aim of the continued collaboration is to improve public awareness on prostate diseases in general, and prostate cancer in particular, across Europe.

The collaboration also benefits the EAU by allowing direct and close interaction with an established European patient organisation, enabling it to evaluate patient awareness and attitudes to prevention, diagnosis and the treatment of prostatic diseases.

Together with EUomo, the EAU can establish a broad front with patients’ and nurses’ organisations towards expected government measures. The EAU could also harness EUomo’s affiliates to act as a patient group sounding board for new initiatives.

Surgical approaches to advanced kidney tumors . . . . . . . . . . . . . . . . . . . . . . . . 4 Management of recurrent UTI: Running out of antibiotics . . . . . . . . . . . . . . . 5 Redefining stone-free. . . . . . . . . . . . . . . . . . . 6 Prostate cancer incidence and mortality. . . . . 7

The new partnership will also optimize the doctor-patient dialogue and collaboration in healthcare development in Europe.

How to select patients for PET/CT or PET/MRI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Managing testicular cancer. . . . . . . . . . . . . . 10

EUomo Strategic Consultant, and former Chairman Prof. Louis Denis (BE) said: “Together with the EAU, we are a family. We have to sit down together and work out what the best way is to serve science for the EAU, achieve optimal treatment for the patient, cost-efficiency for society as a whole.”

Optimizing TURP. . . . . . . . . . . . . . . . . . . . . . . 11 Testicular sparing surgery- cautiously moving ahead . . . . . . . . . . . . . . . . . . . . . . . 13 Varicocele treatment and fertility. . . . . . . . . 14 Imaging in prostate cancer. . . . . . . . . . . . . . 15

Benefits for EUomo include access to the latest information on optimal surgical and medical treatment in urology. Active involvement in EAU activities, such as Guidelines, the Annual Congress and Masterclasses is another advantage for the patient organisation. EUomo can also use the EAU’s online platforms to reach a larger public.

Erectile dysfunction: future treatment strategies. . . . . . . . . . . . . . 17 Managing Balanitis Sclerotica Obliterans. . . 19 Post-chemotherapy RPLND: In whom? . . . . . 20 Twitter in urology: Benefits and caveats. . . . 21 Global threat of antibiotic resistance: No time to lose. . . . . . . . . . . . . . . . . . . . . . . 23

“We have to work with organisations like the EAU to educate patients to ask the right questions at the right time. The EAU can certainly help. Patients need the help of urologists to achieve that, through patient-oriented education and guidelines,” said EUomo Chairman Ken Mastris (GB).

“With EAU backing, we can extend our presence into Central and Eastern Europe, where patients are perhaps still under-represented and not as empowered as in Western Europe.”

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

EU Focus. . . . . . . . . . . . . . . . . . . . . . . . . . . 24 European Board of Urology introduces EBU-Medbook . . . . . . . . . . . . . . . . . . . . . . . 24

BUSY DAY The second day of the Technical Exhibition saw a big number of visitors at IFEMA, Feria de Madrid where around 150 companies are exhibiting the latest medical equipment and technology. At least 2,000 people are participating in the three-day exhibit. Visitors have until today to view and check out cutting-edge technologies and new trends in the medical industry.

EAUN develops standards in guidelines. . . . 24 STEPS: Five years of fostering collaboration in onco-urology. . . . . . . . . . . . 26 ESU Course 31 - Infectious diseases . . . . . . . 27

Day 3 Award Gallery

First Prize Best Abstract by a Resident: A. Grenabo-Bergdahl (Gothenburg, Sweden)

Second Prize Best Abstract by a Resident: T. Arends (Nijmegen, The Netherlands)

Third Prize Best Abstract by a Resident: Y. Wang (Munich, Germany)

First Video Prize: S. Secco (Milan, Italy)

Second Video Prize: R. Papalia (Rome, Italy)

Third Video Prize: A. Hoznek (Creteil, France)

ESTU-René Küss Prize 2015: C.D. Vera Donoso (Valencia, Spain)

European Urology Resident’s Corner Award: J. Leow (Boston, United States of America)

European Urology Resident’s Corner Award: N. Kroeger (Calgary, Canada)

Second Prize for the Best Abstract (Oncology): A. Feber (London, United Kingdom)

Best Booth Award 2015: K. Jones and M. Moss of Astellas Pharma Europe Ltd.

EUSP Best Scholar Award 2015: C. Rönnau (Greifswald, Germany)

Monday, 23 March 2015

EUT Congress News

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Surgical approaches to advanced kidney tumors Radical nephrectomy has high mortality rates but offers long-term survival Prof. Vsevolod Matveev N. N. Blokhin Cancer Research Center Moscow (RU)

Twenty patients (55.5%) had one adjacent organ resected, nine (25%) had two, and seven (19.5%) patients had three adjacent organs removed. The most common organ resected included diaphragm, psoas, spleen, colon, pancreas, and duodenum. Final pathology confirmed direct tumor invasion (stage T4) in 28 (77.8%) of 36 patients, while eight (22.2%) were downstaged to T3a.

All 36 patients underwent extended lymphadenectomy performed at the time of nephrectomy with nine (25%) having node positive Renal cell carcinoma (RCC) represents 2% to 3% of all disease. Six (16.7%) patients had positive surgical cancers, with the highest incidence occurring in margins on final pathology.

Western countries. During the last two decades there has been an annual increase of about 2% in Postoperative complications were reported in 29 incidence both worldwide and in most European patients (80.5%). The most common surgical countries1. complications were ileus (27.8%) and pancreatitis (8.3%). Other major complications included In 2012, there were approximately 84,400 new cases coagulopathy (16.7%), pneumonia (5.6%), acute renal of RCC and 34,700 kidney cancer related deaths within failure (5.6%), multiorgan failure (5.6%), and sepsis the European Union2. Despite recent achievements in (2.8%). One patient (2.8%) required reoperation for targeted therapy, RCC remains a disease largely small bowel obstruction. There were four (11.1%) managed by surgical measures even in cases of locally postoperative deaths within 28 days after surgery. advanced and metastatic tumor.

Median overall, cancer-specific, and recurrence free Complete removal of all tumor sites gives a chance for survival of 36 patients after radical nephrectomy with cure and should be attempted whenever possible. adjacent structures resection was 18.4, 19.0, and 10.9 Rapidly evolving targeted therapy provides a viable months, respectively. Five and 10-year cancer specific treatment option in case of disease recurrence and survival was 29.4 and 15.7%, respectively. We failed to progression, thus, justifying an aggressive surgical identify any prognostic factor significantly associated approach in patients with advanced disease. with long-term outcome. There was a tendency for a decreased survival in patients with Radical nephrectomy with adjacent organ resections pT4 (p=0,504), pN+ (p=0,169), G3 (p=0,060), and Invasion of adjacent organs in patients with RCC is those having sarcomatoid features (p=0,047) on final rare. The decision to operate on large, locally pathology. advanced tumors is often controversial given the complexity of surgery, high complications rate and Surgical management of RCC with IVC invasion poor long-term prognosis similar to patients with RCC has a natural tendency to extend into the renal metastatic disease3. The rationale for aggressive vein and inferior vena cava (IVC). Intracaval extension surgical approach in patients with clinically T4 RCC is occurs in 10% of RCC. A subpopulation of 1% has to provide palliation, possible downstaging, extension into the right atrium8. Complete surgical cytoreduction and survival advantage in selected removal of all tumor provides the only chance of cure cases. and or considerable palliation.

The majority of patients with large renal masses present with either local or systemic symptoms from their tumor. Removal of the tumor provides significant palliation in patients with pain, hematuria, fever, and some paraneoplastic syndromes. True pathologic involvement of adjacent organs by RCC cannot be reliably predicted preoperatively. A proportion of patients clinically suspected of having T4 RCC are downstaged4,5, and therefore can benefit from radical nephrectomy with adjacent organ resection.

Most classifications divide tumor thombi into four types based on the upper extent of the thrombus and relation to hepatic veins and diaphragm9. Precise identification of the extent of the thrombus is crucial for planning surgery. From the practical point of view it is important to subdivide supradiaphragmatic thrombi into intrapericardial and intra-atrial.

A total of 463 patients underwent surgery for RCC with IVC tumor thrombus from 1980 to 2012 at N. N. Blokhin Cancer Research Center. Median age of the cohort was 57 years (range 16-82 years). Distant Large tumor size and stage T4 is associated with a very high likelihood of developing metastatic disease3. metastases were present at the time of thrombectomy in 31.3% (145) of the patients. Twelve Data supporting radical nephrectomy with adjacent organ resection in this cohort can be extrapolated patients underwent nephrectomy elsewhere with from the studies demonstrating a survival advantage tumor thrombus left in place. Five (1.1%) patients for patients with metastatic disease who had received preoperative targeted therapy. Tumor thrombus extended above the diaphragm (level IV) undergone cytoreductive nephrectomy followed by in 85 (18.3%) patients. Type III retrohepatic adjuvant immunotherapy6. The role of cytoreductive nephrectomy in targeted therapy era is not defined yet thrombus was diagnosed in 82 (17.7%) cases. and is being assessed in two randomized trials.

Overall, 167 patients had advanced type III-IV tumor However, the survival benefit has been demonstrated thrombi of IVC. in retrospective studies7.

A large proportion of patients had associated (bland We reviewed our institutional experience with radical or tumor) thrombosis of infrarenal IVC 46(9.9%), contralateral renal vein 22(4.8%), Iliac veins 24(5.2%), nephrectomy in 348 patients with locally advanced (stage T3a or T4) RCC without venous invasion and no deep veins of lower extremities 23(4.9%), and major hepatic veins 19 (4.1%). distant metastasis. Thirty six patients (10.3%) underwent radical nephrectomy with concomitant Depending on the level of the tumor thrombus and resection of at least one adjacent organ. The median tumor size was 15 cm. Histological examination of the the extent of occlusion, 100 (21.6%) patients removed specimen revealed conventional clear cell presented with signs of IVC occlusion including caput medusa, lower extremity edema, ileofemoral carcinoma in 22 (61.1%) patients, chromophobe RCC in 4 (11.1%), and clear cell carcinoma with evidence of thrombosis, Budd-Chiary syndrome, varicocele, sarcomatoid features in 10 (27.8%). pulmonary embolization and syncopy.

Figure 1: Exposing the retrohepatic and subdiaphragmatic segments of IVC

Figure 2: Transdiaphragmatic approach to intrapericardial segment of IVC (the tourniquet on intrapericardial IVC)

25 patients underwent resection of distant metastases either as a separate procedure prior or after radical nephrectomy, or simultaneously with RN and thrombectomy. Metastatic sites included lungs, bone, liver, adrenal, contralateral kidney, soft tissues, cervical lymph nodes and salivary gland.

achieve a complete tumor removal and prevent possible complications a circumferential segmental IVC resection/cavectomy was performed in 49 (10.6%) of 463 cases (Figure 4).

Surgical technique A midline abdominal incision was used as a surgical approach for the majority of cases (99.6%), with additional sternotomy in 10 cases when cardiopulmonary bypass (CPB) was required.

The control of IVC varied according to the level of tumour thrombus. For the subhepatic thrombi the infrahepatic IVC was isolated with tourniquet loops, the IVC wall was incised on the lateral side, and the thrombus was extracted with blunt and sharp dissection from the vessel wall and circumferential excision of the ostium of renal vein. For tumour thrombi with minor extension to the retrohepatic segment of IVC, the accessory hepatic veins from the caudate lobe of the liver were ligated and divided. As a result of this manoeuvre, 3-5 cm of additional IVC was obtained, which allowed positioning of vascular clamp above the upper extent of the thrombus.

For massive thrombi reaching the level of main hepatic veins or intrapericardial thrombi mobilisation of the right lobe of the liver was performed. After ligating right adrenal and several short hepatic veins, the right lobe of the liver was rotated medially which provided an excellent exposure of the retrohepatic and subdiaphragmatic segments of IVC (Figure 1). The tourniquets were placed around the infrarenal IVC and renal vein(s). The hepatoduodenal ligament was isolated and used to control the hepatic circulation.

IVC above the upper level of the thrombus was controlled at its intrapericardial level through a limited diaphragmatic incision (Figure 2). After clamping of the infrarenal IVC and the renal vein(s) with Pringle manoeuvre, the retrohepatic IVC was incised. After completion of evacuation of the thrombus from the intrapericardial and retrohepatic sector the upper part of IVC incision was repaired with a running suture and a Satinsky clamp was positioned below hepatic veins in order to restore hepatic circulation and venous blood return to the right atrium as soon as possible. After restoring hepatic circulation a removal of subhepatic part of the thrombus was continued. The IVC was flushed with heparinised saline and evaluated for residual fragments.

The advantages of approaching the intrapericardial IVC through a diaphragmatic incision are that complete local control of the IVC can be obtained without sternotomy which makes the procedure less traumatic and avoids the undesirable effects of cardiopulmonary bypass. A similar technique can be used in cases of intraatrial thrombus on the condition that intraatrial part of the thrombus is mobile.

In 10 cases of massive intra-atrial thrombus, we used CPB (Figure 3). The main advantages of CPB include prevention of pulmonary embolization (PE) with the fragments of tumor thrombus and maintenance of adequate blood pressure despite an excessive blood loss. Cardioplegia with hypothermia is not usually necessary during thrombectomy. In most of the cases8 partial or parallel CPB was sufficient for performing thrombectomy. The disadvantages of CPB include complexity of the procedure, and need for systemic heparinisation.

Figure 3: A tumor thrombus within incised right atrium

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EUT Congress News

Figure 4: Right kidney tumor en block with IVC segment

In cases of true invasion of IVC wall with the tumor thrombus, the complete extraction of it becomes hardly achievable. The fragmentation of the thrombus increases the risk of tumor embolization. In order to

Replacement after circular IVC resection is controversial. The decision to replace IVC depends on such factors as level of the resected segment (more indicated for suprarenal than infrarenal segments), degree of IVC obstruction (more indicated for partial than complete obstruction), and resulting findings i.e., symptoms, collateral circulation, and intraoperative hemodynamic status after tumor and IVC resection, and renal function. Small defects of suprarenal IVC can be repaired with a patch graft. IVC grafting can be performed in selected cases. The disadvantages of IVC replacement include the risk of thrombosis and infection.

Radical nephrectomy with removal of thrombus from the IVC is associated with major perioperative morbidity with major complication rate of 34% and mortality reaching 10%10. Serious complications were registered in 19% in our series. Perioperative 90-day mortality of the whole cohort was 6.9%. In patients with advanced type III-IV thrombi perioperative mortality reached 11%.

Independent predictors of perioperative mortality in multivariant analysis included level of the thrombus, thrombosis of the contralateral renal vein, lactic acidosis and creatinine clearance < 60ml. In our logistic regression model patients with one or two unfavourable factors had the risk of perioperative mortality between 3% and 6.4%, while patients with four factors had a risk to die of 75% within 90 days after surgery.

The majority of tumors were clear cell histology (92.4%). 26.3% of patients had positive lymphnodes on final pathology. Overall five and 10-year survival rates of the whole cohort was 62.7% and 45.2%; CSS 67% and 57%, respectively. In subgroup of patients with type III and IV trombi five-year OS was 46% but in patients without distant metastasis it reached 57%.

OS was significantly associated with the presence of ascites, PE before surgery, invasion of sinus fat, type III-IV thrombi, contralateral RV thrombosis and presence of distant metastases. With regard to the risk of death from kidney cancer, pulmonary embolism before surgery, residual tumor, contralateral vein thrombosis and presence of distant metastasis were associated with a significantly increased risk of cancer-specific mortality.

Conclusion Radical nephrectomy (RN) with thrombectomy in patients with advanced IVC tumor thrombi is associated with high morbidity and mortality rates but provides long-term survival. The use of cardiopulmonary bypass should be limited to cases of large intraatrial thrombi. The role of cytoreductive surgery in M1 patients requires further investigation.

Although patients who presented with metastases have a poor prognosis, with appearance of new targeted therapies, the long-term survival of these patients will likely improve further.

Editorial Note: Due to space constraints the Reference List has been excluded. Interested readers can email a request for the complete list at EUT@uroweb.org.

Monday, 23 March 10.30-12.00: Thematic Session 13 Surgery in advanced and metastatic RCC State-of-the-art lecture

Monday, 23 March 2015

Management of recurrent UTI: Running out of antibiotics Public education on antibiotic overuse and misuse is crucial in managing UTI Prof. Robert Pickard Newcastle University Newcastle upon Tyne (GB)

Recurrent urinary tract infection (rUTI) defined as at least three infections in 12 months or two infections in six months, is a common health problem for women throughout the world with an approximate prevalence of 120 per 100,000.

The well-recognised symptoms of cystitis, including urinary frequency, dysuria, lower abdominal discomfort and urine odour, may not be lifethreatening but have a considerable detrimental effect on a woman’s ability to undertake her normal working, social and family life.

Systemic symptoms such as fever and loin pain are uncommon, challenging the previous perception that untreated cystitis inevitably leads to ascending infection and pyelonephritis. Although men are infrequently affected by rUTI, the prevalence is thought to be increasing particularly associated with the surge in trans-rectal biopsy of the prostate.

populations in the gut, skin and vagina needed to maintain well-being is also an increasing concern for women affected by rUTI. Local changes in resistance patterns of Escherichia coli The capacity of uropathogenic strains of E. coli to undergo genotypic and phenotypic change establishing resistance mechanisms against antibiotics commonly used against UTI is well established. Mechanisms include environmental pressure driving over-population by an existing resistant clone, horizontal gene transfer by plasmids and direct DNA acquisition, and vertical genotypic modification by environmentally advantageous mutations. The resistance mechanisms may be acquired within the gut reservoir, during initial colonisation of the vagina and urethra, or during the course of an active infection.

The first clinically relevant change was the expression Figure 2: Fluoroquinolone consumption in Europe 2013 measured as number of defined daily doses (DDD) from ECDC

by E. coli of β-lactamase which started in the 1980’s and has led to more than 90% of community acquired strains being resistance to penicillins, such as ampicillin, previously commonly prescribed for UTI. This lead to trimethoprim and trimethoprimsulfamethoxazole being increasingly used but resistance amongst E. coli UTI strains quickly developed in the 1990’s with now 35-75% are resistant to these drugs, according to geographical location.‘

The development of the fluoroquinolone class of antibiotics typified by ciprofloxacin licensed in 1987 was hailed as a major breakthrough in the treatment “Misuse and overuse of of UTI with excellent bioavailability and Gram antimicrobials is one of the world’s negative bacteriocidal activity from oral dosing. As high resistance rates discouraged use of standard most pressing public health agents, fluoroquinolones were increasingly prescribed Figure 3: Resistance rates for Escherichia coli against ciprofloxacin in Europe 2013 from ECDC for treatment of community-acquired UTI in the late problems. All urologists must 1990’s and in the first decade of this century, despite respond to the problem...” regulatory guidance to restrict use to healthand 3). The main concerns are the increasing threatening infections.

Current clinical management consumption of antibiotics despite the increasing For many years the standard management options for There were, for example, 20 million office threat of multi-resistance and the endemic presence women with recurrent UTI after exclusion of relevant of highly resistant strains of E. coli. prescriptions for ciprofloxacin issued in the United structural abnormalities of the urinary tract and States during 2010. Unfortunately, but perhaps modification of any lifestyle precipitants have been unsurprisingly, E. coli has come out on top again with What do urologists need to do? antibiotic prophylaxis or self-start short course Antibiotic stewardship an increasing proportion of UTI strains acquiring antibiotic therapy. The effectiveness of these options Antibiotic stewardship is a coordinated program that evolved or plasmid-carried mutations to the gyrase has been demonstrated by Cochrane meta-analysis of gene giving resistance to fluoroquinolones during the promotes the appropriate use of antibiotics, improves multiple randomised controlled trials. last decade. This has resulted in a step back to use of patient outcomes, reduces microbial resistance, and decreases the spread of infections caused by older antibiotics such as nitrofurantoin and For example, once daily prophylaxis with agents such fosfomycin which whilst being less effective are less multidrug-resistant organisms. Although currently as nitrofurantoin, trimethoprim, trimethoprimmost programmes are focused on the hospital prone to inducing resistance. sulfamethoxazole, cefalexin and ciprofloxacin environment, similar principles apply to community decrease the risk of UTI by 85% with a number prescribing.

Trimethroprim is also favoured, balancing the high needed to benefit of 2.2. In general three-day rate of laboratory resistance against seemingly better treatment courses of agents such as trimethoprim, the clinical effectiveness. In addition, agents with some There are a number of components to antibiotic β-lactams cefalexin or co-amoxyclav, and protection against β-lactamase such as co-amoxyclav, stewardship which urologists treating people with UTI ciprofloxacin are sufficient to resolve symptoms and cefelexin and pivmecillinam are recommended for use need to be engaged with. The first priority is to reduce achieve microbiological cure. or avoid antibiotic use where possible. This requires in some countries. Increasingly clinicians require up knowledge of and enthusiasm for effective alternative to date knowledge about local sensitivity patterns to However it should be noted that treatment of cystitis treatments to prevent or treat UTI such as vaginal guide their recommendation of specific agents. with an appropriate course of antibiotic reduces oestrogen therapy and methanamine.

Despite these recent improvements in prescribing, symptom duration by an average of one to two days resistance levels to most agents continue to climb compared to simple measures such as analgesia and (Figure 1).

Secondly, urologists must adhere to local, national high fluid intake without taking antibiotics. and international guidance documents such as the EAU Guideline on Infections in Urology. These Drivers for change documents set out best practice for the agent, dosage In recent years, several factors have prompted and duration of therapy to be used in specific patients, clinicians and healthcare policy makers to circumstances. Thirdly, urologists should lead the call for a change to the ‘routine’ antibiotic-based education of patients, such as women suffering rUTI, management options given to women with both other healthcare professionals such as primary care sporadic cystitis and rUTI. Women affected by rUTI are physicians and colleagues regarding the necessity of increasingly concerned as to the possible harms of safeguarding antibiotic effectiveness. Finally, taking frequent course of antibiotics or continuous urologists should contribute to audit, research and Figure 1: Cumulative increase in proportion of resistant prophylaxis. Clinicians are concerned with the rising service delivery change to reduce the threat of levels of resistance of the most frequent uropathogen, Escherichia coli isolates 2000-2010 antimicrobial resistance.

Escherichia coli (E. coli), seen in their practice area, Current research and policy makers are concerned with the public Better diagnostics health threat of expanding carriage of multi-resistant Public health threats Healthcare policy makers are increasingly concerned E. coli amongst national and international There is much interest in developing near patient about the contribution of indiscriminate antibiotic use testing to enable two important changes to clinical populations. for minor self-limiting infections such as UTI to the care pathways. First, a number of techniques can development and spread of carriage of multi-resistant achieve rapid species identification from a spot urine Patient harm from antibiotic treatment organisms, particularly E. coli and Clostridium difficile sample, although resistance pattern testing has not Increased publicity and media coverage of the downside of antibiotic treatment have meant that from both national and international perspectives. It is yet been achieved. recognised that there are a number of other pressures women increasingly ask about alternatives. Harms including widespread antibiotic use in agriculture and The expectation is that such tests will allow may result from agent-specific side effects such as increasing travel between continents. nausea and gastro-intestinal symptoms from immediate directed antibiotic prescribing rather than relying on empiric prescription of broad spectrum nitrofurantoin and trimethoprim, and vaginal In Europe data collection and advice on this is issue is drugs whilst culture and sensitivity results are candidiasis (thrush) from cefelexin. co-ordinated by the European Centre for Disease awaited. The second development is the Prevention and Control (ECDC) although any action is establishment of better urinary biomarkers that can Women considering becoming pregnant may also be the responsibility of individual nations. These data predict when asymptomatic or minimally symptomatic worried of possible effects on the developing foetus. have shown that resistant rates to ciprofloxacin tend bacteriuria transitions to active and healthIncreased information on the detrimental effect of antibiotic treatment on ‘healthy’ commensal bacterial to correlate with antibiotic usage nationally (Figures 2 threatening infection. This development will reduce Monday, 23 March 2015

ineffective use of antibiotics particularly in the elderly population.

New antibiotics A number of new agents within existing classes of antibiotics are under trial but are likely to suffer the same fate in terms of E. coli resistance as existing members of each class. The only two completely new agents are targeted at treatment of tuberculosis and Clostridium difficile. The urgent healthcare need and the high costs of drug development are leading governments in the United States and Europe to incentivise drug companies to continue development in this area mainly by encouraging partnership with academic laboratories.

Alternative antimicrobial interventions A number of agents have proven activity to prevent or treat UTI. These include symptom management with analgesia and potassium citrate whist the infection clears naturally, vaginal oestrogen supplementation and methanamine hippurate as an orally administered urinary antiseptic. In addition, some evidence suggests that oral treatment with an adjuvant, UroVaxom and with the sugar, D-mannose can give benefit.

Harnessing the innate immune response The body’s defence against uropathogens is mediated by the innate immune system with no evidence that adaptive immunity plays a role even in rUTI. The innate system consists of epithelial receptors, mainly of the Toll-like receptor (TLR) family that recognise bacterial ligands and initiate a cellular response leading to gene transcription.

The main products are anti-microbial peptides such as defensins which are secreted into the urine to directly kill invading bacteria and cytokines that attract a further line of defence in the form of activated polymorphonuclear leucocytes and macrophages. Emerging knowledge of mechanisms of activation and signal transduction raises the possibility that these processes can be harnessed in order to enhance the innate response. This will be particularly effective for individuals with a genetic susceptibility to UTI such as TLR-5 polymorphism.

Consistent use of guidelines Misuse and overuse of antimicrobials is one of the world’s most pressing public health problems. All urologists must respond to the problem chiefly by having knowledge of and consistent application of relevant clinical guidelines.

Education of patients and colleagues regarding the long-term harm of antibiotic overuse and misuse is also an imperative. Given the history of human endeavour and the strength of ongoing research it is likely that solutions will be found but this is more likely to concern enhancing our own innate immunity rather than development of different antibiotics.

Further reading EAU Guideline document on urological infections: http://www.uroweb.org/gls/pdf/19%20Urological%20 infections_LR.pdf European Centre of Disease Prevention and Control: http://www.ecdc.europa.eu/en/Pages/home.aspx Centres for Disease Control and Prevention: http:// www.cdc.gov/ UK Government Report on Threat of Antibiotic Resistance: https://www.gov.uk/government/ publications/chief-medical-officer-annual-reportvolume-2 References Hooton TM. Uncomplicated urinary tract infection. N Engl J Med 2012;366:1028-37.

Gupta K, Trautner BW. Diagnosis and management of recurrent urinary tract infections in non-pregnant women. BMJ 2013;346:f3140 Beerepoot MAJ, Geerlings SE, van Haarst EP, van Charante EM, ter Riet G. Non-antibiotic prophylaxis for recurrent urinary tract infections: A systematic review and meta-analysis of randomized controlled trials. J Uol 2013; 190: 1981-1989.

Godaly G, Ambite I, Svanborg C. Innate immunity and genetic determinants of urinary tract infection susceptibility. Curr Opin Infect Dis. 2015; 28: 88-96.

Monday, 23 March 07.30-11.00: Plenary Session 3 Functional urology: Hot topics below the belt State-of-the-art lecture

EUT Congress News

5

Redefining stone-free Adapting a modern definition and a new scoring system are needed to clarify what is stone-free Prof. Sven Lahme Head of Department of Urology Center for minimally invasive Therapy – robotic-assisted Surgery Siloah St. Trudpert Klinikum Pforzheim (DE) The aim of active stone treatment is to render the patient stone-free. Depending on the stone composition and the morphology of the urinary tract, the stone-free status affects the long-term results and the recurrence rate.

The stone clearance also depends on the treatment modality used. Endoscopic procedures allow the complete removal of urinary calculi, while the extracorporeal shock wave lithotripsy (SWL) often leaves residual stone fragments.

Concerning the definition of stone-free there is no generally accepted definition in the literature.

Approximately a third of publications dealing with the results of stone treatment, do not provide any information about the stone-free status. In a meta-analysis of 249 publications seven different definitions of stone clearance were found1.

Need to define the stone-free status The stone-free status of a patient depends on many factors: stone composition, type of treatment modality and the time between active stone treatment and evaluation of stone clearance.

be defined, but also the method of determining the stone-free status.

Definition of stone-free in the age of SWL Since SWL, ureterorenoscopy (URS) and percutaneous nephrolithotomy (PCNL) had been introduced different definitions of stone-free had been published.

Table 1: Definition of stonefree (SFR) level2 stonefree rate (SFR) level Size of stone detected

Evaluation modality

SFR

0

no stones

USS, CT, XR

0U, 0C or 0X

1

≤ 1mm

1U, 1C or 1X

2

≤ 2mm

2U, 2C or 2X

3

≤ 3mm

3U, 3C or 3X

In addition, the imaging modalities used to determine the stone-free rate were defined differently.

4 ≤ 4mm Depending on the author, patients were classified as free of stones if they had residual fragments <1mm, <2 mm, <3mm or <4mm. The method of assessment of the new technical possibilities, it is now possible to the stone-free rate was ultrasound, KUB or nonenhanced computer tomography. remove the stones completely so that no residual stones are remaining.

In the age of SWL the most common definition of Formerly accepted residual stones with a diameter of “stone-free” was residual fragments <4 mm. An accepted method for evaluating the stone-free status <4mm can be removed endoscopically under vision today. Thus, the problem arises to what extent the was ultrasound, KUB and non enhanced CT scan. current definition of stone clearance in the age of endourology still makes sense.

“There is a good reason to use a differentiated definition of stonefree, that is based on the size of residual fragments...”

Definition of stone-free in the age of endourology Due to the further miniaturization of endoscopic instruments, for example, in the form of Mini-PCNL, and the development of small diameter flexible endoscopes stone treatment has undergone a fundamental change in the last 15 years. Almost every part of the urinary tract is endoscopically accessible with low morbidity. Today active stone treatment is nowadays carried out more and more primary endoscopically.

New definition for stone clearance Considering the variety of methods for the removal of urinary stones and the methods used to evaluate the stone-free status, it seems difficult to develop a universal definition that is universally applicable.

Therefore, it seems advisable to establish a scoring system for the stone-free status, similar to the well-known scoring systems of complications. This system allows a precise classification of treatment results.

In addition, this scoring system enables an easy adaptation to different treatment modalities. It is obvious that residual stone of <2mm is an acceptable treatment result of SWL, while this may not be appropriate for patients who were treated by means of flexible URS. Somani et al. have recently proposed an appropriate scoring system (Table 1).

Furthermore, the stone-free status depends on the definition of stone-free. A generally accepted The EAU Guidelines have undergone a change in this definition of stone-free alone is required in order to achieve a better comparability of studies. In this respect, which allows a primary endoscopic treatment The stone-free level is calculated by the size of AZ_TUR_133.4x194.3_EAU_2015_Layout 1 17.02.15 13:06 Seite 1 residual fragments and an additional letter, depending on stone size and localization. Based on case, not only the size of residual fragment should

4U, 4C or 4X

which describes the imaging modality to evaluate the stone-free status. The future will show whether a better comparability of studies can be achieved by this differentiated definition of the stone-free status.

Adapting a modern definition A modern definition of stone clearance should be adapted to the needs of the modern endourological treatment modalities. There is a good reason to use a differentiated definition of stone-free, that is based on the size of residual fragments and the method used to determine the stone-free status. A new scoring system, which describes the stone-free status of the patient by a stone-free level could be a step in the right direction.

References 1. Deters LA, Jumper CM, Steinberg PL, Pais VM (2011) Evaluating the definition of “stone free status” in contemporary urologic literature, Clin Nephrol 76 (5): 354-7 2. Somani BK, Desai M, Traxer O, Lahme S (2014) Stonefree rate (SFR): a new proposal for defining levels of SFR, Urolithiasis 42: 95

Tuesday, March 24 08.00-12.30: Plenary Session Controversies in stone management State-of-the-art lecture

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EUT Congress News

e 2 at th th G 1 o o B , d r id Hall 9 ! in M a E AU th 24th , 2015 – 0 2 h c r Ma

Monday, 23 March 2015

Prostate cancer incidence and mortality Medical resources – a key factor in regional differences around the world inclusion in the monograph (as a result, no African countries were included). I also obtained countryspecific data on various health indicators and development indices from the World Bank database.

Prof. Anssi Auvinen School of Health Sciences University of Tampere Tampere (FI)

Any attempts to understand the natural history of prostate cancer (PC) based on the current incidence rates and outcomes are futile because of the abundance of the reservoir of indolent lesions detected by PSA testing and biopsies, causing noise that blurs the signal, i.e., the biological process.

Studies of natural history therefore become analyses of unnatural or cultural history of PC and PSA. Population-based analyses restricted to aggressive PC are difficult because data by Gleason grade or TNM stage are unfortunately not available from populationbased cancer registries with few exceptions.

Prostate cancer occurrence by continent Age-standardised PC incidence by continent ranges from roughly 100 in Oceania and North America to 50-60 in Europe and Latin America to 10-20 in Africa and Asia (Globocan). As is well-established, variation in PC mortality is considerably less striking, and the highest death rates (17 per 100,000) are reported from Latin America and Africa, closely followed by Oceania, Europe and North America (10-13 per 100,000), with substantially lower rates from Asia (4 per 100,000).

Correlates of international differences in prostate cancer incidence and mortality I examined age-standardised PC incidence data for the years 2003-2007 from 49 countries included in the Cancer Incidence in Five Continents, Vol X, with inclusion criterion of more than one region covered by a cancer registry with quality sufficient for meriting

Regression analysis of the international PC incidence data showed that the best predictor of the prostate cancer incidence was health care expenditure [Proportion of variance explained (R2=0.6)]. The association was largely driven by the data from European countries, comprising a third of the observations. However, it remained significant also after adjustment for continent (North America and Australasia were combined, due to small number of observations, while East and West Europe were analysed separately).

Western European countries, including Austria, Belgium, Finland, France and Germany, with survival up to 97% in the U.S (Allemani et al. 2014).

Does this indicate that medicine is practiced at the optimal level and has overcome prostate cancer in these countries? All patients cured and deaths from the disease Prostate cancer incidence world map prevented, appears as ideal. Unfortunately, a more likely explanation is that this is due to treatment question what country-level features are linked to PC Other correlates of PC incidence were gross national incidence, even if not applicable at individual level. of non-disease, a condition that would not have product (GNP, R2 0.27) and density of personal computers (R2 0.34). These can hardly be regarded as resulted in disease progression and death even in the These limitations are unlikely to change the conclusion that we are unable to distinguish prostate absence of any intervention, as indicated by the risk factors of PC, but reflect characteristics in the results achieved by active surveillance (Bul et al. cancer as a disease (with potentially serious increasingly prostate-oriented society. Interestingly, consequences) from a mere histological pattern 2013). when entering health care expenditure and either of associated with elevated PSA, a non-disease. As long these two attributes in the model, only health care as this is the case, prostate cancer will remain a Discussion remained significantly associated with PC incidence. major medical and public health challenge.

Secondary schooling, mobile phone density, mortality, The findings of these analyses confirm the view that the driver of PC incidence is not so much lifestyle, life expectancy were also associated with PC References incidence, but less strongly (while population growth genetic or other risk factors, but medical resources. was not). Similar results were obtained with Box-Cox PC can therefore be regarded largely as an iatrogenic Allemani C, Weir HK, Carrera H, et al. Global surveillance for disease. transformed rates. cancer survival 1995-2009. Lancet 2014 (E-publication) Strikingly, prostate cancer mortality exhibited no obvious correlation with any of the country indicators, which confirms the view that prostate cancer incidence and mortality are completely distinct phenomena. An interpretation that only mortality reflects a biological process, while incidence is mainly driven by medical culture, i.e., a wide pattern of practices and procedures, including PSA testing.

Prostate cancer survival An international comparison of survival among patients with PC, the CONCORD2 study showed five-year survival rates exceeding 90% for several

The medical profession appears to follow the principle of “what can be done, should be done.”

It can be due to either an effort to live up to the messianic expectations for the physicians (either prevalent among the public or perceived by the physician and mainly projected to the patients) or alternatively driven by defensive practice of medicine, based on a misconception that only omissions can constitute malpractice and not actions.

This exercise was based on an ecological analysis and is therefore subject to a wealth of shortcomings and uncertainties, but it does cast some light on the

Bul M, Zhu X, Valdagnani R, et al. Active surveillance for low-risk prostate cancer world-wide: the PRIAS study.

Eur Urol 2013;63:597-603 Forman D, Bray F, Brewster D, et al. (Eds). Cancer Incidence in Five Continents, Vol X. IARC, Lyon (http://ci5.iarc.fr) Ferlay J, Soerjomataram I, Ervik M, et al. GloboCan 2012 v1.0.

Cancer incidence and mortality worldwide. IARC, Lyon (globocan.iarc.fr)

Monday, 23 March 10.30-12.00: Thematic Session 14 Prostate cancer epidemiology State-of-the-art lecture

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EUT Congress News

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

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

Intervene early with Xofigo

®

30% REDUCED

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

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

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

a

Updated analysis.1

b

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

c

Essential Information Xofigo 1000 kBq/mL solution for injection (Refer to full Summary of Product Characteristics before prescribing).

• Composition1: Active ingredient: radium Ra 223 dichloride (radium-223 dichloride, 1000 kBq/mL, corresponding to 0.53 ng radium-223 at the reference date). Each vial contains 6 mL of solution (6.0 MBq radium-223 dichloride at the reference date). Excipients1: Water for injections, sodium citrate, sodium chloride, hydrochloric acid, dilute.

• Indication: Treatment of adults with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastases. Xofigo should be administered only by persons authorised to handle radiopharmaceuticals in designated clinical settings.

• Contraindications: There are no known contraindications.

• Warnings and Precautions: Bone marrow suppression, notably thrombocytopenia, neutropenia, leukopenia and pancytopenia, has been reported. Haematological evaluation of patients must be performed at baseline and prior to every dose. In case there is no recovery in values for absolute neutrophil count (ANC) and haemoglobin within 6 weeks after the last administration of Xofigo despite receiving standard of care, further treatment with Xofigo should only be continued after careful benefit/risk evaluation. Patients with evidence of compromised bone marrow reserve e.g. following prior cytotoxic chemotherapy and/or radiation treatment (EBRT) or patients with advanced diffuse infiltration of the bone (EOD4; “superscan”), should be treated with caution as an increased incidence of haematological adverse reactions such as neutropenia and thrombocytopenia has been observed. Limited available data indicate that patients receiving chemotherapy after Xofigo had a similar haematological profile compared to patients receiving chemotherapy after placebo. Crohn’s disease and ulcerative colitis: due to the faecal excretion of Xofigo, radiation may lead to aggravation of acute inflammatory bowel disease, therefore Xofigo should only be administered to these patients after a careful benefit-risk assessment. In patients with untreated imminent or established spinal cord compression, treatment with standard of care, as clinically indicated, should be completed before starting or resuming treatment with Xofigo. In patients with bone fractures, orthopaedic stabilisation of fractures should be performed before starting or resuming treatment with Xofigo. In patients treated with bisphosphonates and Xofigo, an increased risk of development of osteonecrosis of the jaw (ONJ) cannot be excluded. In the phase III study, cases of ONJ have been reported in 0.67% patients (4/600) in the Xofigo arm compared to 0.33% patients (1/301) in the placebo arm. However, all patients with ONJ were also exposed to prior or concomitant bisphosphonates and prior chemotherapy. Xofigo contributes to a patient’s overall long-term cumulative radiation exposure and therefore may be associated with

an increased risk of cancer and hereditary defects. No cases of Xofigo-induced cancer have been reported in clinical trials in follow-up of up to three years. Depending on the volume administered, this medicinal product can contain up to 2.35 mmol (54 mg) sodium per dose.

• Undesirable effects: Very common: thrombocytopenia, diarrhoea, vomiting, nausea; Common: neutropenia, pancytopenia, leukopenia, injection site reactions; Uncommon: lymphopenia.

• Classification for supply: Medicinal product subject to restricted medical prescription.

• Marketing Authorisation Holder: Bayer Pharma AG. 13342 Berlin. Germany.

• Date of revision of the underlying Prescribing Information: November 2013.

References: 1. Xofigo® (radium Ra 223 dichloride) solution for injection Summary of Product Characteristics (SmPC), Bayer Pharma AG, 13342 Berlin, Germany, 2013. 2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

This medicinal product is subject to additional monitoring.

Este medicamento está sujeto a seguimiento adicional, es prioritaria la notificación de sospechas de reacciones adversas asociadas a este medicamento.

Xofigo is not currently reimbursed in Spain. Information is correct at time of printing (1 February 2015). En el momento de imprimir este material (1 de Febrero de 2015) Xofigo no está comercializado en España.

To learn more, visit www.xofigo.com.

Please see Summary of Product Characteristics available at the Bayer HealthCare booth (FO2) in Hall 9.

La ficha técnica del producto está disponible en el stand de Bayer HealthCare (FO2) en el pasillo 9.

1

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

© 2015 Bayer Pharma AG. February 2015. L.ES.SM.02.2015.0344

L.ES.SM.02.2015.0344_Global_EAU_Ad_FR.indd 1

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How to select patients for PET/CT or PET/MRI Larger series of PET/CT studies needed to determine clinical value Prof. Dr. Igle Jan de Jong Head Department of Urology University Medical Center Groningen Groningen (NL)

The highest results are obtained using a hybrid PET/ CT system. In a comparison between the common used nomograms of Briganti and of Kattan, the PET/ CT showed higher specificity and accuracy than the nomograms. A pairwise comparison of the areas under the curve (AUCs) showed no statistical differences between PET/CT and the two nomograms4.

Improvement in experience amongst nuclear medicine physicians and larger series are needed before choline PET/CT can be routinely used in nodal staging5.

Hybrid imaging like PET/CT, SPECT/CT and PET/MRI is becoming the standard of care in staging of cancers including prostate cancer. For many tumors FDG PET/ CT is routinely used based on increased expression of the Glucose-1 transporter in cancer tissue.

Although the number of studies is limited with choline PET/CT, the detection of bone metastases is slightly superior to the routinely used bone scintigraphy, thus offering a single-step staging in prostate cancer patients at risk for metastases.

Recently, new prostate cancer-specific tracers for However, not all cancers overexpress the Glucose-1, imaging of prostate cancer with PET have been so in addition tumor-specific tracers have been reported, e.g., 18FACBC, 68Ga-PSMA and 18F developed for targeted imaging using, e.g. antibodies, DHT. Since clinical studies are limited and use of hormones or peptides. In prostate cancer, choline is these tracers is still experimental, no recommendation can be made on a clinical value the most common used tracer labeled with either a carbon-11 or fluor-18 isotope. at present.

Choline uptake is increased in prostate cancer for the up-regulated choline kinase in the Kennedy pathway.

Choline is also a component of cell membranes but so far no relation has been proven between proliferation and choline uptake. In addition, choline is not a cancer specific tracer and uptake is known in benign tissue and in inflammatory lymph nodes.

Recently, more prostate cancer-specific tracers have become available for clinical use. In this report, the current status of imaging of prostate cancer is described from a clinical point of view focusing on the questions which patient, which hybrid system and which tracer to select.

“The clinical value of PET/CT in metastatic prostate cancer is not yet determined. Many studies are ongoing on the use of PET/CT...”

Primary tumor For detection of the primary tumor and initial staging of prostate cancer, the importance of bioimaging over morphological imaging only has become evident using the multiparameter MRI. The localization and characterization of tumor tissue in the prostate using DWI, DCE and/or spectroscopy has brought MRI to set the new standard.

Addition of molecular imaging using 11C-choline PET/ CT with a pre specified SUV value did not show any additional value to T2MRI or to multiparameter MRI using whole mount prostatectomy specimens as reference1,2. First series on the use of a hybrid PET/ MRI system did show improvement in detection of primary prostate cancer as well as improved correlation with Gleason score after guided biopsies compared to a hybrid PET/CT.

Based on the current status and experience, the selection for choline PET/CT in primary prostate cancer is limited to men with Gleason 7 or higher prostate cancer and/or initial PSA levels of 20 ug/L or higher or T3. A preferably 11C-choline PET/CT can be used for the non-invasive assessment of nodal and/or bone metastases. But this would be only of use in those cases where first-line local treatment would be changed on identifying (multiple) nodal metastases.

Recurrent tumor Recurrent prostate cancer after initial local treatment is the most used and studied area of PET/ CT. Not surprisingly most studies have been performed using choline as tracer. In two recent meta-analyses the outcome of choline-PET and PET/ CT in biochemical failure were studied6,7. In both studies a large group of clinical cohort studies were re-analyzed with sample sizes of 1555 and 1055, respectively. A pooled sensitivity and specificity for localization of the disease (local recurrence, lymph nodes or bone metastases) of 85.6% and 92.6% were calculated.

The role of PSA level at initiation of the choline-PET/ CT clearly influences the detection rates in recurrent prostate cancers after surgery versus radiotherapy due to the differences in definition of recurrent prostate cancer, i.e., post-surgery PSA >0.2 ng/ml versus PSA nadir+2 ng/ml after radiotherapy. With recurrent prostate cancer after radical surgical treatment already diagnosed by a PSA level of 0,2 ng/ ml, the added clinical value of choline-PET/CT imaging in patients with such low PSA levels remains limited. Salvage radiotherapy will start at PSA levels of 0.2-0.3 ng/ml at which level the sensitivity of any type of imaging will be too low for detecting low volume tumor.

The importance of PSA levels and especially PSA kinetics as factors on the tumor detection rates of For staging of lymph nodes in primary prostate cancer, PET/CT are generally known. A total PSA level at time choline PET and PET/CT have been used and studied of PET of more than 2ug/L, PSA-doubling time of less for more than a decade in a number of centers in than six months and PSA-velocity of more than one or Europe. In a recent systematic review of the literature more than 2 ng/ml/yr are strong predictive factors for and meta-analysis, the results of 10 clinical cohorts a positive choline PET/CT scan. Recently, a pooled have been presented and showed a large variation cohort of 1,000 patients with recurrent prostate cancer between different centers and between the two tracers surgery or radiotherapy using 18F choline PET/CT was carbon-11 versus fluor-18 labeled choline3. In centers reported8. of excellence, choline PET/CT reached sensitivities between 60-80% in detection of pelvic lymph nodes In line with other series the fluorcholine PET/CT scan but other centers showed much lower sensitivities. was able to localize the site of recurrence in 2/3 This is partly due to the size of the metastases patients. Also in corroboration with earlier studies, a identified as reference in the different series. clear relation of between the detection rate of disease and PSA levels and PSA velocity was Clearly, the resolution of PET/CT systems provides a reported. Detection rate of 79% was seen if the PSA lower border detection of approximately 4-5 mm. The at time of PET/CT was >2 ng/ml. Detection rates calculated specificities of choline PET/CT were equally dropped to 31% and 43% when PSA at time of PET/ high amongst all 10 centers that reported on their CT was below 1 ng/ml or between one and two results and not different between carbon-11 or respectively. An additional finding was the effect of fluor-18 choline. initial Gleason on the detection rates. The rates were the highest in those patients who were initially For men harboring low-risk prostate cancer there is diagnosed with a Gleason score of 7 or higher in a no indication for staging with PET/CT for the low multivariate analysis even in men with a PSA level incidence of metastases and subsequent yield. For between 1 and 2 ng/ml. men with intermediate-high risk prostate cancer choline PET/CT can be used in centers with proven Accurate localization of recurrence experience. For this indication carbon-11choline PET/ With many salvage treatment options available in CT showed a pooled sensitivity of 58 % and a pooled recurrent prostate cancer after radiotherapy, accurate specificity of 94% compared to fluor-18 choline PET/ localization of the site of recurrence is the key to CT of 40% and 86% respectively. success or failure. At present the accuracy of choline Monday, 23 March 2015

11 C-choline PET/CT transversal image of a 69 year old male with a biochemical recurrence after EBRT plus adjuvant ADT in 2006 for a cT2 Gleason 4+5 pN0 M0 adenocarcinoma of the prostate. The 11C-choline PET/CT was made at a PSA level of 3,9 ng/ml and showed a local recurrent tumor which invades the left seminal vesicle up to the level of the anterior rectal wall.

PET/CT in recurrent prostate cancer is adequate to select patients for local salvage of the prostate but limited in use for guiding procedures like salvage lymphadenectomy, salvage EBRT or focal ablation.

In comparison with MRI choline, PET/CT was superior in detection of lymph node and bone metastases but MRI was superior in defining the local recurrent tumor.

For the selection of patients with recurrent prostate cancer a choline PET/MRI (if available) or PET/CT is recommended after radiotherapy (external beam or brachytherapy) with a PSA of 2 or higher, a short PSA doubling time or an initial Gleason 7 or higher prostate cancer. There is no indication for imaging at PSA levels below 1 ng/ml excluding the majority of men with recurrent prostate cancer after surgical treatment.

The clinical value of PET/CT in metastatic prostate cancer is not yet determined. Many studies are ongoing on the use of PET/CT for the evaluation of treatment in metastatic and castrate resistant prostate cancer using different radiotracers like FDG, choline, 18FACBC, 68Ga-PSMA and 18F DHT. Results are still limited and larger series have to be awaited before any recommendation can be made on their clinical value.

Due to space constraints the reference list has been excluded. Interested readers can email at EUT@uroweb.org for the complete list.

Monday, 23 March 10.30-12.00: Thematic Session 12 Imaging in prostate cancer State-of-the-art lecture

Tumour MicroEnvironment

It’s time to change the way we think about prostate cancer

Date of Preparation: February 2015

GSK Sponsored Symposium

How, why, when risk stratification in newly diagnosed BPH patients with moderate symptoms

Please scan this QR-Code with your mobile device to create a calendar event.

Date of Preparation 02 /15 CEM/Pharma/0001/15b

Saturday 21 March 18:00-19:30 Stockholm Room Ficha Técnica disponible en el stand Full SmPC available at the booth

EUT Congress News

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Managing testicular cancer Who benefits from adjuvant treatment in stage I testicular cancer?

Dr. Noboru Hara Division of Urology Department of Regenerative and Transplant Medicine Graduate School of Medical and Dental Sciences Niigata University Niigata (JP)

16% of men with this condition still experience disease relapse during surveillance7; risk-stratification for men with stage I seminoma is still a matter of concern in their management.

Testicular cancer is histopathologically classified into seminoma and nonseminoma. After an orchiectomy, the most feasible therapeutic option is determined with risk assessment based on the pathological diagnosis and clinical staging.

An international retrospective study enrolling 638 men reported that a primary tumor size of > 4 cm and rete testis invasion were factors associated with an increased risk of relapse; relapse rates were 31.5, 15,9 and 12% in those with both, one, and neither risk factor, respectively8. Aparicio and associates prospectively studied 314 men with stage I seminoma managed according to risk-adapted criteria. In their trial, those with a tumor diameter of less than 4 cm and no rete testis involvement were managed with surveillance; 6% of these patients still showed relapse9.

Nonseminoma is more likely to metastasize, and is associated with a poorer prognosis compared with seminoma at the same stage. Surveillance has recently been regarded as a management of choice for most patients with stage I seminoma, and treatment and follow-up strategies vary according to the clinicopathological characteristics of stage I nonseminoma1,2. However, risk factors associated with relapse still remain controversial in both entities.

Most recently, however, the SWENOTECA group performed a prospective study, and reported that a tumor size > 4 cm and rete testis invasion were independent factors associated with a higher risk of relapse during surveillance10. In 389 patients who selected surveillance in this prospective study, the relapse rate was 2.9% in men without risk factors, whereas it was 21.7 % in those with either or both risk factors.

Kollmannsberger et al. most recently reported that the five-year disease-specific survival rate reached 99.7% (95% CI: 99.24 to 99.93%) in 1,139 and 1,344 men with stage I nonseminoma and seminoma managed with active surveillance, respectively, the majority of whom were treated between 1998 and 20103. On the other hand, patients with some risk factors managed with surveillance require more intensive follow-up protocols.

Adjuvant carboplatin therapy with AUC7 has been regarded as an effective option to prevent relapse in men with stage I seminoma. Oliver et al., based on a randomized trial recruiting 1,477 patients (885 and 560 patients in the radiotherapy and carboplatin arm, respectively; median follow-up: four years), reported that relapse-free survival rates were similar between the two groups, and 4% of the carboplatin group showed disease relapse5.

For men with stage I nonseminoma, National Comprehensive Cancer Network (NCCN) guidelines recommended active surveillance after orchiectomy with chest radiography, general examinations, and measurement of serum tumor markers such as alpha-fetoprotein (AFP) and beta-human choriogonadotropin (β-hCG) every one to two months for the first year, every two months for the second year, every three months for the third year, every four months for the fourth year, biannually in the fifth year, and annually thereafter; abdominal-pelvic CT every three to four months for the first year, every four to six months in the second year, every six to 12 months for the third and fourth years, annually for the fifth year, and annually or biennially thereafter. Additionally, the quality-of-life of men managed with surveillance may possibly be impaired due to distress and anxiety, since adjuvant therapy markedly reduces the frequency of relapse1,4,5.

This study was designed for unselected patients, and outcomes stratified according to the disease risk were unknown. In the aforementioned SWENOTECA study, 675 patients received adjuvant carboplatin therapy. In patients without risk factors, the relapse rate was 2.7%, similar to that in those followed by surveillance (2.9%), and it was 9.4% in those with either or both risk factors.

In clinical practice, decision-making for selecting surveillance or adjuvant therapy in men with stage I testicular cancer is thus done according to the institutional policy or with informed consent and on a case-by-case basis. This presentation introduces recent approaches for this challenging problem in the application of adjuvant treatment for patients with stage I testicular cancer.

Stage I seminoma A recent surveillance based on the National Cancer Data Base (NCDB) jointly sponsored by the American College of Surgeons and American Cancer Society reported management trends for stage I testicular seminoma after orchiectomy (34,067 patients registered between January 1, 1998 and December 31, 2011). In 1998, 70.8% of the patients received adjuvant radiotherapy, 1.5% underwent chemotherapy, and 23.7% were managed with surveillance.

These proportions were not changed until 2005 and, thereafter, surveillance and adjuvant chemotherapy increased and radiotherapy decreased. By 2011, 54.0% of the patients were managed with surveillance, and 28.8 and 16.0% received radiotherapy and chemotherapy, respectively. Thus, surveillance has also become the mainstay for men with stage I seminoma in the United States6, and the option of adjuvant radiotherapy has been removed from European guidelines due to the long-term toxicity, represented by the risk of radiation-induced secondary cancers1,2.

The SWENOTECA group concluded that patients with no risk factors should be managed by surveillance, and that adjuvant carboplatin therapy has a relatively modest effect on the prevention of relapse in the subgroup mainly comprising those with high-risk disease.

Stage I nonseminoma It also remains controversial how patients with stage I nonseminoma should be managed. Twenty-five to 30% of men with stage I nonseminoma managed by surveillance have been reported to be diagnosed with relapse after orchiectomy, and adjuvant chemotherapy has been the therapeutic standard for those with elevated tumor marker levels at diagnosis and/or a highly malignant histopathology11.

Lymphovascular invasion and predominant embryonal carcinoma are generally considered to be histopathological risk factors11, and the former has been of greater prognostic value; about one-third of the patients show lymphovascular invasion and about 50% of them develop relapse3,5. A Danish populationbased study with 1,226 stage I nonseminoma patients (median follow-up time: 180 months) reported that the one-, two-, and five-year relapse rates were 24.9, 29.4, and 30.6%, respectively, and 70% of the relapses occurred in patients with lymphovascular invasion12. In this study, the 15-year cause-specific survival rate was 99.1%.

Regarding adjuvant chemotherapy for men with testicular stage I nonseminoma, a large prospective population-based study with risk-stratification has recently been published by the SWENOTECA group; 517 patients with stage I nonseminoma were treated with adjuvant chemotherapy with one course of bleomycin, etoposide, and cisplatin (BEP)4.

Adjuvant chemotherapy was recommended for patients with lymphovascular invasion in the primary tumor, and those without lymphovascular invasion selected surveillance or adjuvant chemotherapy. In this study, 258 men (50%) were diagnosed with According to the EAU guidelines on testicular cancer lymphovascular invasion, and eight of them (3.2%) 2011, about 15–20% of patients with stage I seminoma experienced relapse (median follow-up: 7.9 years; develop metastasis after orchiectomy, commonly in 95% CI: 1.6 – 6.4), whereas four relapses occurred in the retroperitoneum. This relapse rate was presented 255 men without lymphovascular invasion (1.6%). The referring to a report published in 19982. Based on a five-year overall and cause-specific survival rates recent prospective population-based study, about were 99.0 and 100%, respectively.

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EUT Congress News

The 10-year overall and cause-specific survival rates were 96.9 and 99.6%, respectively. The SWENOTECA group concluded that patients with lymphovascular invasion should be informed about one course of adjuvant BEP as well as extent of salvage therapy for relapse following surveillance, and additionally proposed that one course of adjuvant BEP is also a therapeutic option for men without lymphovascular invasion.

New approaches Advances in diagnostic technology possibly lead to the more accurate detection of micrometastasis in men with testicular cancer. However, there is no evidence to support the application of functional imaging modalities, represented by fluorodeoxyglucose positron emission tomography (FDG-PET), for the identification of micrometastasis in men with stage I disease. Also, some studies have examined the detection of circulating tumor cells in men with testicular cancer, but its ability to detect their micrometastasis is quite limited13.

Conclusions Although a definite conclusion cannot be drawn, a primary tumor size of >4 cm and rete testis invasion are associated with an increased risk for relapse in men with stage I seminoma, and lymphovascular invasion is a risk factor of relapse in those with stage I nonseminoma.

With surveillance based on an intensive follow-up protocol, their long-term cause-specific survival rate is considered to be close to 100%, but for men having stage I seminoma and nonseminoma with the above-mentioned risk factors, one course of adjuvant carboplatin and BEP therapy are options, respectively.

2. Albers P, Albrecht W, Algaba F, et al.; European Association of Urology. EAU guidelines on testicular cancer: 2011 update. Eur Urol 2011;60:304–19.

3. Kollmannsberger C, Tandstad T, Bedard PL, et al. Patterns of Relapse in Patients With Clinical Stage I Testicular Cancer Managed With Active Surveillance. J Clin Oncol 2014. pii: JCO.2014.56.2116.

4. Tandstad T, Ståhl O, Håkansson U, et al.; SWENOTECA. One course of adjuvant BEP in clinical stage I nonseminoma mature and expanded results from the SWENOTECA group. Ann Oncol 2014;25:2167–72.

5. Oliver RT, Mason MD, Mead GM, et al.; MRC TE19 collaborators and the EORTC 30982 collaborators.

Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial.

Lancet 2005;366:293–300.

6. Gray PJ, Lin CC, Sineshaw H, Paly JJ, Jemal A, Efstathiou JA. Management trends in stage I testicular seminoma: Impact of race, insurance status, and treatment facility.

Cancer 2014. doi: 10.1002/cncr.29094.

7. Tandstad T, Smaaland R, Solberg A, et al. Management of seminomatous testicular cancer: a binational prospective population-based study from the Swedish norwegian testicular cancer study group. J Clin Oncol 2011;29:719–25.

8. Warde P, Specht L, Horwich A, et al. Prognostic factors for relapse in stage I seminoma managed by surveillance: a pooled analysis. J Clin Oncol 2002; 20:4448–52.

9. Aparicio J, Germà JR, García del Muro X, et al.; Second Spanish Germ Cell Cancer Cooperative Group: Risk-adapted management for patients with clinical stage I seminoma: the Second Spanish Germ Cell Cancer Cooperative Group study. J Clin Oncol 2005;23:8717–23.

The reference list has been shortened due to space constraints. Interested readers can request for the complete list at EUT@uroweb.org.

References 1. Beyer J, Albers P, Altena R, et al. Maintaining success, reducing treatment burden, focusing on survivorship: highlights from the third European consensus conference on diagnosis and treatment of germ-cell cancer. Ann Oncol 2013;24:878–88.

Monday, 23 March 10.30-12.00: Thematic Session 15 Testicular cancer State-of-the-art lecture

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

Alternative approaches to individualised care

in prostate and bladder cancers M. Ribal (Spain)

Do we have new markers beyond PSA for diagnosing primary prostate cancer?

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

Y. Loriot (France)

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

J.A. Witjes (The Netherlands)

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

TOPIC OF THE YEAR 2015

The Bladder Cancer Topic of the Year was voted on and announced during the IPSEN-sponsored EAU 2015 Symposium.

If you would like further details regardingthe selected Topic of the Year, please visit the IPSEN booth.

Monday, 23 March 2015

Optimizing TURP Laser devices pose a challenge but reducing complications is key to maintain TURP’s gold-standard role Prof. Aurelien Descazeaud Professor of Urology Limoges University Hospital Limoges (FR)

For more than 60 years, transurethral resection of the prostate (TURP) has been the undisputed reference standard for men with lower urinary tract symptoms (LUTS) due to benign prostatic enlargement (BPE) and benign prostatic obstruction (BPO).

This role has been increasingly challenged by the development of medical and of minimally invasive treatment options, such as laser procedures. Two conditions are required to keep TURP as a gold standard: minimizing morbidity and enhancing functional outcomes.

What are functional outcomes and complication rates of TURP in the 21th century?

In a meta-analysis including 67 monopolar TURP (mTURP) studies published in 1997-2007 (Mayer BJUI 2012), mean patient age was 67 years. Mean pre-operative prostate volume was 47.6 g. Mean resected prostate tissue was 25.8 g, with a resection time of 38.5 minutes. Hospital stay was 3.6 days and initial catheterization duration was 2.5 days.

Post-operative urinary retention rate was 6.8%. In the 2000-2005 period, Rassweiler (Rassweiler 2006) reported a large series of TURP procedures in which transfusion rate was 0.4%, trans urethral resection (TUR) syndrome incidence was 0.0%, clot retention occurred in 2%, and urinary tract infection rate was 1.7%. Urinary retention rate was 3%. Early urge incontinence occurred in up to 30-40% of patients; however, late iatrogenic stress incontinence was rare (<0.5%).

resection, resulting in persisting obstruction. The long-term data of the Veterans Affairs Cooperative Trial (watchful waiting vs TURP) suggest that early TURP provides a better long-term outcome than patients who were initially randomized to watchful waiting and were then crossed over to TURP [Flanigan J Urol 1998]. It has been suggested that progressive detrusor failure resulting from prolonged BPO is responsible for this observation. It has also been suggested that alpha blockers therapy delays time of surgery without affecting the progressive nature of the disease (VelaNavarrete BJUi 2005).

Retrograde ejaculation occurs in up to 90% of cases and might be avoided if the tissue at the veru montanum is spared (Rassweiler 2006, Lourenco 2008). For example, the last technique was reported in a series of 87 BPH patients. Antegrade ejaculation was preserved in 79 of 87 (90.8%) patients at three months (ref Alloussi).

Erectile dysfunction was found to be unchanged following TURP in two systematic meta-analyses (Lourenco 2008).

Sophisticated lasers have increasingly challenge the role of the more traditional TURP

TUR syndrome: the wide application of bipolar TURP will most largely abandon the risk of TUR syndrome in the future. In mTURP, the procedure should not be longer than one hour, and should be disrupted in case of perforation of capsular veins.

Prolonged urinary incontinence: Urologists should keep in mind the causes of urinary incontinence after TURP: sphincteric incontinence (30%), detrusor overactivity Mortality rate was 0-0.25%. The major late (20%), mixed incontinence (30%), residual adenoma complications were urethral strictures (2.2-9.8%) and (5%), bladder neck contracture (5%), and urethral bladder neck contractures (0.3-9.2%). The retreatment stricture (5%). Sphincter lesions should be avoided as rate range was 3-14.5% after five years. In a recent veru montanum limit is respected. analysis of 20 contemporary RCTs published between Bleeding remains the major intraoperative 2005 and 2009 and a maximum follow-up of five complication. Technical improvements of highyears, TURP resulted in an improvement of mean Qmax by +162%, mean reduction of mean IPSS was frequency generators and instrumentation (continuous-flow instruments, video-TURP) resulted 70%, mean quality of life scores improved by 69%, in a significant decrease in the transfusion rate and mean PVR urine decreased by 77% [Ahyai Eur 2010 ]. Altogether, this data suggests that TURP has a (Rassweiler 2006). Risk of bleeding is associated with preoperative infection and urinary retention very good efficiency in the 21st century. because of the congested gland, prostate volume, and resection time. In case of significant peri- and How to minimize morbidity Urinary tract infection (UTI) risk factors for postoperative bleeding, balloon compression postoperative are perioperative bacteria, longer (tension of a 500-cm3 bottle) is the method of duration of the procedure, pre- operative indwelling choice. The use of 5ARI to decrease bleeding risk catheters, prolonged hospital stay, and discontinuation was discussed but is not a recommendation of the catheter drainage. The systematic reviews by (Donohue 2002).

Berry et al (Berry 2002) and Qiang et al (Kiang 2005) included 32 and 28 RCTs, respectively, with 21 RCTs How to optimize functional outcome reviewed in both studies. They concluded that Limited versus radical resection: Aagaard et al. antibiotic prophylaxis gives a significant decrease in (Aagaard 1994) reported on the long-term post-TURP bacteriuria, post-TURP fever, sepsis, and outcome (10-yr follow-up) of patients treated by the need for additional antibiotics post-TURP. There either total (ie, radical) or minimal (English was a trend suggesting higher efficacy for a short Channel) TURP. The decrease in urinary symptoms course (< 72 hours) of antibiotic prophylaxis than for a and improvements in Qmax and PVR were single-dose regimen (Kiang 2005). comparable in both groups; however, the treatment failure rate within 10 years was higher In summary, there is high evidence that the use of in the minimal (23%) compared to the total (7%) prophylactic antibiotics in TURP decreases bacteriuria TURP arm. Despite the higher long-term failure rate of minimal TURP, this study suggests that and clinical infectious complications. radical TURP is not necessary in all patients.

Urethral strictures have two main reasons related to location: meatal strictures, usually because of the TUIP: A meta-analysis of short- and long-term data from 10 RCTs comparing TUIP with TURP found similar relationship between the diameter of the instrument LUTS improvements and lower but not significant and the meatus; and bulbar strictures resulting from mechanical trauma and insufficient current isolation. improvements in Qmax for TUIP patients with small Preventive measures include generous application of prostates but without enlarged prostate median lobes gel (also during the procedure, when resection time is (Lourenco 2010). The need for reoperation was more prolonged), minimal mechanical movement of the common after TUIP (18.4%) than after TURP (7.2%) resectoscope in situ, and avoidance of high-cutting whereas morbidity was lower following TUIP versus currents (Marszalek 2009).

TURP (Lourenco 2010). Therefore, TUIP should be discussed in patients with prostate volume bellow Bladder neck stenosis is more likely in smaller glands. 30ml.

Trans-urethral incision of the prostate (TUIP) should be considered in patients with prostate volume Prostate size limit: No studies on the optimal cut-off smaller than 30g (Marszalek 2009). value are available, but the rate of complications increases with size (Reich 2008). The upper limit Urinary retention after catheter removal is usually depends on the experience of the surgeon and is attributed to detrusor failure rather than incomplete mostly suggested as 80 ml.

Monday, 23 March 2015

Bipolar TURP: In a recent systematic review, 40 independent RCTs evaluating bipolar devices were identified (Cornu 2014). Among the parameters analyzed, the following significantly favored bipolar TURP: transfusion rate, hemoglobin loss, sodium decrease, immediate acute urinary retention, clot retention, catheterization time, immediate reoperation rate, TUR syndrome, and length of stay.

Bipolar enucleation: Geavlete et al. reported a series of 140 BPH patients with prostate volume >80 mL operated by bipolar enucleation. Maximum flow rate and BPH tissue removal were similar with standard transvesical prostatectomy. The authors concluded that bipolar enucleation patients may benefit from significantly reduced complications, shorter convalescence and satisfactory follow-up symptom scores and voiding parameters (Geavlete 2013).

In a RCT including 100 patients with prostate volume >80ml, bipolar enucleation was found as effective as transvesical prostatectomy, with the advantage of endoscopy (Ou 2013). Eighty patients with benign prostatic hyperplasia and a prostate of larger than 70 ml were randomly assigned to prostate bipolar transurethral resection or bipolar enucleation. For large volume benign prostatic hyperplasia, bipolar enucleation of the prostate was associated with less blood loss, shorter hospital stay and catheterization time than bipolar transurethral resection of the prostate.

Moreover, bipolar enucleation seemed to be superior at long-term follow-up with fewer reoperations necessary (Zhu 2013). Finally, 180 BPH patients were equally and randomly assigned to undergo bipolar enucleation and bTURP. Compared with bTURP, bipolar enucleation had a higher incidence rate of short-term urinary incontinence in the treatment of BPH, but not that of genuine incontinence, with similar severity and recovery time (Liu 2014). Overall, bipolar enucleation seems to be an interesting development of bipolar technique for large volume prostates.

Bipolar vaporization: Good hemostasis properties for bipolar vaporization were reported (Delongchamps 2007). The technique is still being evaluated.

Optimizing TURP In the 21st century, laser devices challenge TURP. Therefore, TURP has to be optimized to remain the gold standard. Optimizing TURP requires, firstly, knowing what the functional results of TURP should be, and secondly, how to minimize complications.

New developments of TURP such as bipolar enucleation might also help in optimizing TURP. References Mayer EK, Kroeze SG, Chopra S, et al. Examining the ‘gold standard’: a comparative critical analysis of three

consecutive decades of monopolar transurethral resection of the prostate (TURP) outcomes. BJU Int. 2012 Ahyai SA, Gilling P, Kaplan SA, et al. Meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic enlargement.

Eur Urol 2010;58:384–97.

Rassweiler J, Teber D, Kuntz R, et al. Complications of transurethral resection of the prostate (TURP)—incidence, management, and prevention. Eur Urol 2006;50: 969–80.

Oelke M, Bachmann A, Descazeaud A, et al. European Association of Urology. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction.

Eur Urol. 2013 Jul;64(1):118-40.

Berry A, Barratt A. Prophylatic antibiotic use in transurethral prostatic resection: a meta-analysis. J Urol 2002; 167:571–7.

Qiang W, Jianchen W, MacDonald R, et al. Antibiotic prophylaxis for transurethral prostatic resec- tion in men with preoperative urine containing less than 100,000 bacteria per ml: a systematic review. J Urol 2005;173:1175–81.

Marszalek M, Ponholzer A, Pusman M, et al. Trans urethral resection of the prostate. Eur Urol supp 8. 2009, 505-512 Flanigan RC, Reda DJ, Wasson JH, et al. 5-year outcome of surgical resection and watchful waiting for men with moderately sympto- matic benign prostatic hyperplasia.

A department of Veterans Affairs Cooperative Study. J Urol 1998;160:12–7.

Vela-Navarrete R, Gonzalez-Enguita C, Garcia-Cardoso JV, et al. The impact of medical therapy on surgery for benign prostatic hyper- plasia: a study comparing changes in a decade (1992– 2002). BJU Int 2005;96:1045–8.

Lourenco T, Pickard R, Vale L, et al. Benign Prostatic Enlargement Team. Alternative approaches to endoscopic ablation for benign enlarge- ment of the prostate: systematic review of randomised controlled trials. BMJ 2008;337:a449, a 1662.

Alloussi SH, Lang C, Eichel R, et al. Ejaculation-preserving transurethral resection of prostate and bladder neck: short- and long-term results of a new innovative resection technique. J Endourol. 2014 Jan;28(1):84-9.

Donohue JF, Sharma H, Abraham R, et al. Transurethral prostate resection and bleeding: a randomized, placebo controlled trial of role of finasteride for decreasing operative blood loss. J Urol 2002;168:2024–6.

Aagard J, Jonler M, Fuglsig S, et al. Total transurethral versus minimal transurethral resection of the prostate—a 10-year fol- low-up study of urinary symptoms, uroflowmetry and residual volume. Br J Urol 1994;74:333–6.

Lourenco T, Shaw M, Fraser C, et al. The clinical effectiveness of transurethral incision of the prostate: a systematic review of randomised controlled trials. World J Urol 2010;28:23–32.

Reich O, Gratzke C, Bachmann A, et al. Morbidity, mortality and early outcome of transurethral resection of the prostate: a pro- spective multicenter evaluation of 10,654 patients. J Urol 2008;180:246–9.

Cornu JN, Ahyai S, Bachmann A, et al. A Systematic Review and Meta-analysis of Functional Outcomes and Complications Following Transurethral Procedures for Lower Urinary Tract Symptoms Resulting from Benign Prostatic Obstruction: An Update. Eur Urol. 2014 Jun 24.

In press.

Geavlete B, Stanescu F, Iacoboaie C, et al. Bipolar plasma enucleation of the prostate vs open prostatectomy in large benign prostatic hyperplasia cases - a medium term, prospective, randomized comparison. BJU Int. 2013 May;111(5):793-803.

Ou R, Deng X, Yang W, et al. Transurethral enucleation and resection of the prostate vs transvesical prostatectomy for prostate volumes >80 mL: a prospective randomized study. BJU Int. 2013 Jul;112(2):239-45.

Zhu L, Chen S, Yang S, et al.. Electrosurgical enucleation versus bipolar transurethral resection for prostates larger than 70 ml: a prospective, randomized trial with 5-year followup. J Urol. 2013 Apr;189(4):1427-31.

Liu JF, Liu CX, Tan ZH, et al. Transurethral bipolar plasmakinetic enucleation and resection versus transurethral bipolar plasmakinetic resection of the prostate for BPH: a randomized controlled trial on the incidence of postoperative urinary incontinence.

Zhonghua Nan Ke Xue. 2014 Feb;20(2):165-8.

Delongchamps NB, Robert G, de la Taille A, et al. Surgical management of BPH in patients on oral anticoagulation: transurethral bipolar plasma vaporization in saline versus transurethral monopolar resection of the prostate.

Can J Urol. 2011 Dec;18(6):6007-12.

Monday, 23 March 07.30-11.00: Plenary Session3 Functional urology: Hot topics below the belt

EUT Congress News

11

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Testicular sparing surgery- cautiously moving ahead Urologists need to closely examine the pros and cons of organ-sparing for testicular lesions

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Nathan Lawrentschuk Associate Professor University of Melbourne Austin Hospital and Peter MacCallum Cancer Centre Melbourne (AU)

The role of organ-sparing surgery has dramatically increased within uro-oncology- particularly for renal cancer, leading us to challenge extirpative organ removal in other malignancies.

In concert with this has been the realization that testicular lesions discovered on ultrasound are increasingly benign. This has required a rethink in how we manage some patients with testicular lesions.

Canada headed by Prof Michael Jewett where 27 men were identified: 17 (63%) had malignancy (9 seminoma; 3 teratoma; 1 embryonal; 3 Leydig cell; 1 CIS) whilst 10 (37%) were benign. Frozen section was accurate and no positive margins were reported with all stage 1 tumors. CIS was found in nine (53%) patients. No perioperative complications were recorded. Management post partial orchiectomy was predominantly observation (12/17). For the remaining 5/17 two patients had completion orchiectomy for local recurrence (one chemotherapy); a CIS-only and seminoma patient chose radiation, whilst one required RPLND (teratoma). The remaining five CIS patients were surveilled. 31% required testosterone substitution. All patients were disease-free at a median follow-up of 5.7years with no local recurrences.

The technique of partial orchiectomy is well established- isolate, clamp cord (some insist on cooling), excision, frozen section and then completion or replacement. Informed consent is paramount. The ideal principles for testis sparing surgery are outlined in Table 1 and Figure 2 below.

The potential advantages of organ-sparing testicular surgery are: 1) Preventing removal of whole organ for a benign lesion- often the benign lesion may be a Table 1: Principles for partial orchiectomy. “surprise” - one not predicted from history, examination or serial imaging but increasingly suspected. This is particularly relevant in the • Informed consent discussing radical solitary testis or where bilateral lesions occur orchiectomy as the “gold standard” (See Figure 1); • CIS and subsequent risks and treatment 2) Preservation of androgen function in the majority. need discussion Certainly the options for androgen replacement • Solitary testicles have best indication are now many and varied, but they do not in most • Bilateral- choose the better testis to operate instances replicate normal human physiology; on first 3) The possibility of observation, salvage surgery or • 2cm upper limit of lesion size although for radiation (especially in the case of carcinoma in polar lesions this may be extended to 3cm situ or CIS [TIS]) remains where an organ-sparing based on remaining testis parenchyma approach has been utilized; • Polar locations are favorable for surgery 4) Cosmesis is maintained with psychological impact • Androgen function and need for of removal avoided; and supplementation discussed 5) Preservation of fertility is less well documented • Consider measuring testosterone but possible. preoperatively • Surgical and pathological experience In general the risks of partial orchiectomy are positive necessary margins, or remaining CIS, the possibility of a missed synchronous small lesion, or metachronous lesions developing in the remnant testis. The latter two are much more of a concern with embryonal cancer or Cases of solitary testicular lesions or bilateral lesions more aggressive tumors where metastases are more are the most obvious and least contentious for likely. CIS may be dealt with by observation, radiation organ-sparing. They are illustrative of the advantages or completion orchiectomy. of partial orchiectomy. Although by no means would partial orchiectomy be considered “standard care”3 it does have a role and this is because the need for Overall the number of series describing organ preservation or testis-sparing surgery is small.1,2 securing “benignity” is somewhat diminished in The largest adult series we published from Toronto, these cases as discussed already.

Figure 1: Completion orchidectomy on the contralateral testicle (Photo: N. Lawrentschuk)

Organ preservation Certainly the ideal target groups are those where there is a high suspicion that the lesion is benign, but there is also a role for organ preservation where a lesion is unexpectedly found to be benign. However, if malignancy (particularly seminoma, which is most common), occurs, the stakes are less if adequate removal with a margin is obtained (i.e. one may continue to observe). The most contentious group is those men that have a normal contralateral testicle where there is no real functional loss if one testicle is removed. This would be an “elective” indication perhaps, rather than a “relative” indication as discussed in men with a solitary testis or bilateral lesions. Finally, children form a special group and small series have been supportive of the benign nature of most testicular tumors, provided markers are negative,2 but again this area is under development and requires more data.

Our approach as with other malignancies is one of risk stratification, with the goal of cancer control where a malignancy exists being paramount. Focus remains on sub-groups of patients who would benefit from organ preservation. The key when deciding to pursue the possibility of organ-sparing surgery is similar in all groups: 1. Does the lesion’s behavior appear benign? Slow or no growth with any characteristic features on history or ultrasound to suggest a benign lesion, with tumor markers negative.

2. Is the patient in a sub-group where benign lesions are more common? Sub-fertility. We now know it is likely the majority of men presenting with infertility and lesions of 5m (mm?) or less are extremely unlikely to harbor malignancy and should undergo active surveillance.4 Alternatively, if surgery is warranted they are ideal candidates for partial orchiectomy.

LC.

Organ-sparing approaches for testicular masses. Zuniga A, Lawrentschuk N, Jewett MA. Nat Rev Urol. 2010 Aug;7(8):454-64. doi: 10.1038/nrurol.2010.100

Monday, 23 March 2015

8:58 AM

3. Do you have a plan if the lesion is malignant? (based on frozen section or upon final pathology).

Further treatment options are completion orchidectomy, observation (e.g. in a solitary testis), or radiation. A good example: if CIS remains as a field change, or focally within the remnant testicle, we have the opportunity to observe, irradiate or go on to completion orchiectomy.

4. Are the issues of fertility with sperm cryopreservation and consideration of testicular supplementation accounted for and understood?

Urologists need to maintain a focused view on the outcomes, advantages and disadvantages of organ-sparing for testicular lesions. In this context, organ-sparing surgery remains an option in men with relative indications to reduce morbidity. However, the approach is potentially associated with a small risk recurrence, the need for adjuvant treatment and androgen substitution. Clearly a definite benefit of PO is that a significant proportion of our patients with suspicious testicular lesions will not have GCT and may be managed definitively with an organ-sparing approach.

Furthermore, endocrine function may be maintained in the majority, along with the psychological and cosmetic benefits of having the native testicle remain.

One would not pursue PO in men with a normal contralateral testicle unless our index of suspicion for a benign lesion is high (e.g. using serial observation and imaging of a small lesion in a man with no risk factors for GCT); they are in a sub-group with a likely benign lesion (sub-fertile men with small lesions of stable size) and until longer-term data from multiple centres is available.

References 1. Lawrentschuk N, Zuniga A, Grabowksi AC, Rendon RA, Jewett MA. Partial orchiectomy for presumed malignancy in patients with a solitary testis due to a prior germ cell tumor: a large North American experience. The Journal of urology 2011; 185(2): 508-13.

2. Bujons A, Sfulcini JC, Pascual M, Feu OA, Garat JM, Villavicencio H. Prepubertal testicular tumours and efficacy of testicular preserving surgery. BJU international 2011; 107(11): 1812-6.

3. Zuniga A, Lawrentschuk N, Jewett MA. Organ-sparing approaches for testicular masses. Nature reviews Urology 2010; 7(8): 454-64.

4. Toren PJ, Roberts M, Lecker I, Grober ED, Jarvi K, Lo KC. Small incidentally discovered testicular masses in infertile men--is active surveillance the new standard of care? The Journal of urology 2010; 183(4): 1373-7.

Monday, 23 March 10.30-12.00: Thematic Session 15 Testicular Cancer State-of-the-art lecture

EUT Congress News

13

Varicocele treatment and fertility Role of varicocele repair in men with non-obstructive azoospermia Dr. Marij DinkelmanSmit Department of Urology Erasmus Medical Center Rotterdam (NL)

After years of debate, the benefit of surgical repair of clinical varicoceles in terms of improvement of sperm parameters and increased spontaneous pregnancy rates in infertile men with oligospermia is now well documented1.

Although the exact pathophysiology of testicular failure caused by varicocele remains unclear, it has been shown that clinical hallmarks of impaired spermatogenesis significantly improve as a result of varicocele repair in selected patients. Specifically, the significant postoperative decrease in sperm DNA fragmentation following varicocele repair in a majority of patients, indicates that varicocelectomy may reverse the detrimental effect of a varicocele on the spermatogenesis2.

Non-obstructive azoospermia (NOA) is the most extreme feature in the clinical spectrum of testicular failure in male infertility. Among the etiologies of testicular failure are testicular dysgenesis syndrome, genetic disorders, testicular torsion, exposure to gonadotoxins and varicocele.

The incidence of NOA in men attending infertility clinics varies among institutions; concomitant varicoceles are estimated to be present in 5-15% of men with NOA. Testicular sperm extraction (TESE) in combination with intracytoplasmatic sperm injection (ICSI) is a widely available treatment modality for NOA. Because specialized laboratories successfully perform TESE and ICSI even when only very few testicular sperm are harvested from testicular biopsies, a gradual shift can be observed in the use of very low numbers of viable sperm in ejaculated semen samples (cryptozoospermia) for ICSI. In the past, ICSI would not have seemed feasible in these cryptozoospermic cases.

In their quest to offer patients with cryptozoospermia ICSI treatment and to optimize sperm retrieval rates in patients with NOA, urologists have a renewed interest in varicocele repair as a means to induce or maximize spermatogenesis in severe male infertility.

Unfortunately, history seems to repeats itself, and again the benefit of varicocelectomy, this time indicated for men with NOA and cryptozoospermia, is controversial.

This overview aims to discuss the best available evidence and divergent views on the recovery of motile sperm in ejaculates of previously azoospermic men after varicocelectomy and the improvement of testicular sperm retrieval rates in patients with NOA following varicocele repair.

Varicocelectomy Six non-randomized studies that included between 15 and 30 patients each, found that varicocelectomy induces spermatogenesis in men with NOA to the extent that low numbers of sperm reappear in the ejaculate in 20-55% of cases3-8. It should, however, be

• • •

Clinical varicocele Azoo- or cryptozoospermia 2 centrifuged semen pellets

taken into account that not all studies included NOA patients with azoospermia in at least two centrifuged semen sample pellets.

methodology are warranted to establish evidence-based treatment algorithms to select responders and identify clinically relevant outcome parameters like testicular sperm retrieval rate and ICSI outcome.

This inclusion criterion is important because cryptozoospermia can alternate azoospermia in repeat semen samples in the absence of intervention in up to 20% of patients. In the first postoperative semen analysis, motile sperm recovery is described in 32-46% following microsurgical inguinal varicocelectomy in studies that included centrifuged pellets.

However, two out of four studies described a relapse to azoospermic state or intermittent recovery six to nine months after the induction of spermatogenesis by varicocelectomy3,8. Based on these data, one can argue that the recovery of motile sperm after varicocele repair is only temporarily effective.

On the other hand, only trials that randomize for varicocele repair or no intervention and that study multiple semen samples before and after randomization will adequately answer if varicocelectomy is a clinically relevant therapy for patients with cryptozoospermia.

“...there seems to be a benefit of varicocele repair for patients with NOA. Varicocelectomy may result in the appearance of spermatozoa in the ejaculate.”

Interestingly, two meta-analyses concluded that the best results of varicocele repair in patients with NOA are observed in men with hypospermatogenesis or maturation arrest at spermatid stage, compared to Sertoli cell only9,10.

Five studies that evaluated the diagnostic value of testicular biopsy performed simultaneously with varicocele repair in 90 NOA patients were included in the most recent meta-analysis.

Testicular histopathology revealed hypospermatogenesis in 33%, maturation arrest in 29% and Sertoli cell only in 38% of cases. Following varicocele repair, in only one out of 34 patients with Sertoli cell only, motile sperm were recovered in a postoperative semen analysis.

These results can be interpreted that a diagnostic biopsy in patients with NOA can select for non-responders to varicocelectomy in up to 50% of patients.

Treatment algorithm A treatment algorithm suggests simultaneous TESE, cryopreservation of retrieved testicular sperm and diagnostic testicular biopsy in patients with NOA, clinical varicocele and normal genetic screening.

In this algorithm, proceeding with varicocele repair is indicated in patients with more advanced patterns of spermatogenesis and a female partner younger than 35 years. Patients with histopathological diagnosis of early maturation arrest or Sertoli cell only can be treated with TESE-ICSI if testicular sperm were retrieved during testicular biopsy9.

Although this treatment algorithm appears intuitive, several arguments can be opposed. In NOA testicular histology is often heterogeneous and may not be well reflected by a single biopsy. This is supported by microsurgical sperm retrieval rates of 20% in Sertoli cell only patients (own series). The results of the meta-analysis should also be

References

“‘Mixed atrophy’ in azoospermia” (25X) Photo: EUT Archives

interpreted cautiously because it is based on small, flawed, non-randomized trials.

Finally, a practical challenge of this treatment algorithm is that eligible patients and their partners will need to refrain from upfront TESE-ICSI using cryopreserved testicular sperm to embark on varicocele repair with unclear outcome.

3.

4.

An alternative application of varicocelectomy in patients with NOA is to improve the outcome of TESE. The best 5. available evidence for this approach is presented in four observational studies that compared sperm retrieval rates in 529 untreated and treated patients with a concomitant NOA and a clinical varicocele11-14.

6.

A significantly increased sperm retrieval rate in favor of varicocele therapy was observed in three out of four studies. Sperm retrieval rates in patients with varicocele repair ranged from 53-60%, compared to 25-60% in patients with untreated varicocele. It should be mentioned that the study that found no differences in TESE sperm retrieval rate included subclinical varicoceles in their analysis.

“Two out of three studies that compared TESE-ICSI outcome in treated and untreated patients concluded that varicocelectomy significantly increased clinical pregnancy rate.”

Two out of three studies that compared TESE-ICSI outcome in treated and untreated patients concluded that varicocelectomy significantly increased clinical pregnancy rate.

Female age was not significantly different between treatment groups or studies. It should be noted only one study was performed prospectively and none of the studies were randomized. The interval between varicocele repair and TESE varied considerably between studies and ranged from two months post-varicocele repair to 15 years following surgical treatment.

Benefit In summary, there seems to be a benefit of varicocele repair for patients with NOA. Varicocelectomy may result in the appearance of spermatozoa in the ejaculate. Also, varicocele repair prior to TESE may enhance sperm retrieval.

However, randomized controlled, adequately powered, multicenter trials with rigorous

• • •

Varicocelectomy Testicular histology TESE + cryopreservation sperm

•

No intervention

7.

8.

9.

10.

11.

12.

13.

14.

1. Kroese, A.C., N.M. de Lange, J.A. Collins, and J.L. Evers, Varicocele surgery, new evidence. Hum Reprod Update, 2013. 19(4): p. 317.

2. Smit, M., J.C. Romijn, M.F. Wildhagen, J.L. Veldhoven, R.F. Weber, and G.R. Dohle, Decreased sperm DNA fragmentation after surgical varicocelectomy is associated with increased pregnancy rate. J Urol, 2010. 183(1): p. 270-4.

Abdel-Meguid, T.A., Predictors of sperm recovery and azoospermia relapse in men with nonobstructive azoospermia after varicocele repair. J Urol, 2012. 187(1): p.

222-6.

Cakan, M. and U. Altug, Induction of spermatogenesis by inguinal varicocele repair in azoospermic men. Arch Androl, 2004. 50(3): p. 145-50.

Cocuzza, M., R. Pagani, R.I. Lopes, K.S. Athayde, A.M. Lucon, M. Srougi, and J. Hallak, Use of subinguinal incision for microsurgical testicular biopsy during varicocelectomy in men with nonobstructive azoospermia. Fertil Steril, 2009. 91(3): p. 925-8.

Esteves, S.C. and S. Glina, Recovery of spermatogenesis after microsurgical subinguinal varicocele repair in azoospermic men based on testicular histology. Int Braz J Urol, 2005. 31(6): p. 541-8.

Lee, J.S., H.J. Park, and J.T. Seo, What is the indication of varicocelectomy in men with nonobstructive azoospermia? Urology, 2007. 69(2): p. 352-5.

Pasqualotto, F.F., B.P. Sobreiro, J. Hallak, E.B. Pasqualotto, and A.M. Lucon, Induction of spermatogenesis in azoospermic men after varicocelectomy repair: an update. Fertil Steril, 2006.

85(3): p. 635-9.

Elzanaty, S., Varicocele repair in non-obstructive azoospermic men: diagnostic value of testicular biopsy - a meta-analysis. Scand J Urol, 2014. 48(6): p. 494-8.

Weedin, J.W., M. Khera, and L.I. Lipshultz, Varicocele repair in patients with nonobstructive azoospermia: a meta-analysis. J Urol, 2010. 183(6): p. 2309-15.

Haydardedeoglu, B., T. Turunc, E.B. Kilicdag, U. Gul, and T. Bagis, The effect of prior varicocelectomy in patients with nonobstructive azoospermia on intracytoplasmic sperm injection outcomes: a retrospective pilot study.

Urology, 2010. 75(1): p. 83-6.

Inci, K., M. Hascicek, O. Kara, A.V. Dikmen, T. Gurgan, and A. Ergen, Sperm retrieval and intracytoplasmic sperm injection in men with nonobstructive azoospermia, and treated and untreated varicocele. J Urol, 2009. 182(4): p.

1500-5.

Schlegel, P.N. and J. Kaufmann, Role of varicocelectomy in men with nonobstructive azoospermia. Fertil Steril, 2004. 81(6): p. 1585-8.

Zampieri, N., L. Bosaro, C. Costantini, S. Zaffagnini, and G. Zampieri, Relationship between testicular sperm extraction and varicocelectomy in patients with varicocele and nonobstructive azoospermia. Urology, 2013. 82(1): p. 74-7.

Monday, 23 March 10.30-12.00: Thematic Session 17 Andrology hot topics State-of-the-art lecture

ICSI using ejaculatory sperm • 2 semen analysis centrifuged semen pellets TESE

TESE -ICSI

Figure: proposed randomized controlled trial treatment algorithm to evaluate the effect of varicocelectomy on the recurrence of sperm in the ejaculate of patients with Non-obstructive azoospermia or cryptozoospermia, the predictive value of testicular histopathology and outcome parameters TESE sperm retrieval rate and ICSI results Randomized controlled trial treatment algorithm

14

EUT Congress News

Monday, 23 March 2015

Imaging in prostate cancer What is new in lymph node staging?

Prof. Günter Janetschek Dept. of Urology Paracelsus Medical University Salzburg (AT)

There are several situations where imaging for the lymph nodes of the prostate is of interest: 1: Preoperatively for clinical staging; 2. Intraoperatively to identify the lymph nodes draining the prostate; and 3: To search for the cause of a PSA relapse.

Clinical staging Exact clinical staging is a prerequisite to develop a risk-adapted treatment plan for intermediate and high-risk prostate cancer (PCa). This includes investigation of the lymph node status. CT and MRI are equally effective – or rather ineffective - therefore.

The positive predictive value is about 50%, whereas the negative predictive value is clearly higher with 96% (Wang 2006).

It is therefore very likely that a positive finding is due to lymph node metastases. However, small metastases in the range of a few millimetres cannot be detected at all. MRI is increasingly used for local staging of the prostate, therefore replacing CT also for lymph node staging.

There are some other alternatives. PET/CT is rarely used for this indication. 18F-FDG, the most common tracer for PET/CT imaging, is not effective in the detection of prostate cancer. Other tracers such as 18F-choline, 11C-choline, 11C-acetate, and 18F-fluoride have a much higher detection rate for prostate cancer.

“A PSA relapse following curative treatment for PCa may be due to lymph node metastases, but the discrimination from other possible locations of the relapse is usually difficult.”

A recently published metaanalysis reports a sensitivity of 49.2%, and a specificity of 95% for 11C/18F-choline PET/CT (Evangelista 2012). Our own experience seems even worse. An 11C-choline PET-CT was performed in 20 patients prior to extended lymph node dissection and sentinel node dissection.

Metastases were found in 10 (50%). The choline PET-CT was true positive in one patient only (10% of patients. with metastases), false positive in two, false negative in nine, and true negative in eight. The largest lymph node metastasis not detected was 8mm in size (Häcker 2006).

More promising results have recently been reported using a (68Ga)gallium PSMA ligand as radiopharmaceutical for the PET-CT. Initial studies demonstrated a higher contrast of the PET signal and therefore an improved diagnostic accuracy (AfsharOromieh 2013, Hellwig 2014).

However, experience is limited so far. Further improvement may be achieved by replacing PET/CT by PET/MRI (Wetter 2014).

More than 10 years ago, there was a report on the use of high-resolution MRI with lymphotrophic

superparamagnetic nanoparticles for the detection of otherwise undetectable lymph node metastases in patients with prostate cancer.

This new imaging modality identified all patients with lymph node metastases, and a node-by-node analysis had a significantly higher sensitivity than conventional MRI (Harisinghani 2003). However, these nanoparticles were commercially not available until very recently. They are now used in the Netherlands again, and may hopefully be available in the rest of Europe soon.

Pelvic node dissection In clinically localized intermediate- and high risk PCa, staging must be done by pelvic node dissection, since it is the only reliable staging method, given the significant limitations of preoperative imaging in the detection of small (<5 mm) metastases (EAU Guidelines 2014).

Figure 1a: presacral right lymph node package

However, it should be realized that extended lymph node dissection – the gold standard – has a false negative rate of at least 10% (Weckermann 2007), and sensitivity and specificity are as low as 80.5% and 60.5%, respectively (Janetschek, Hruby, unpublished data).

The false negative rate may be decreased by increasing the template (super-extended PLND), but this results in a very low specificity and positive predictive value of 30.2% and 9.0%, since many nodes are removed which are not linked to the prostate at all. Also, the complication rate will rise substantially. There is only one way out of this dilemma – the performance of a targeted lymph node dissection, so that only the lymph nodes draining the prostate are removed.

Sentinel node dissection, which is routine in breast cancer since many years, is such a targeted lymph node dissection. The lymph nodes are marked by a radioactive tracer –Technetium 99m – and detected intra-operatively by a gamma probe. This method delineates the lymphatic drainage of the targeted organ, but it cannot discriminate if there is cancer in the nodes or not.

Figure 1b: lymph node package marked by indocyanine green (ICG)

Therefore, histologic examination of these targeted nodes is an integral part of sentinel node dissection.

Wawroschek has introduced sentinel node dissection to PCa in 1999, and we were the first to perform it by means of laparoscopy (Jeschke 2005).

The latest EAUN guidelines publication is now online!

As an evolution of the method, we have replaced the radioactive tracer Tc 99m by fluorescence provided by indocyanine-green (ICG), which has many advantages (Jeschke 2012) (Figure 1).

Visit www.eaun.uroweb.org/nursing-guidelines for a free download or to order a printed copy

In addition to the lymph nodes, the lymphatic vessels also become visible. As a next step, we have left the sentinel concept to now remove all the nodes marked by fluorescence. In the meantime, we have learned to perform a fusion biopsy using the data from a multi-parametric MRI.

ide lines for Evide nce-based Gu gical Health Care Best Practice in Urolo

This new technology allows us to place the tracer directly in and around the tumour so that we specifically remove the lymph nodes of the cancer. We expect that specificity will increase substantially.

European Association of Urology Nurses

Another group had started to perform ICG-navigatedPO Box 30016 6803 AA Arnhem sentinel lymph node dissection at around the same The Netherlands T +31 (0)26 389 0680 time as we did. However, they do not use free ICG but F +31 (0)26 389 0674 ICG bound to a colloid together with Tc 99m (van dereaun@uroweb.org Poel 2011). This attachment to the colloid does not www.eaun.uroweb.org allow visualization of the lymphatic vessels.

PSA relapse A PSA relapse following curative treatment for PCa may be due to lymph node metastases, but the discrimination from other possible locations of the relapse is usually difficult.

European Association of Urology Nurses

drawMD Urology Health, Inc. Created using

Monday, 23 March 2015

e Images © Copyright Visibl

Imaging for lymph nodes is helpful when searching for the cause of a PSA relapse

bacillus Calmette -Gu with mitomycin C or ve bladder cancer asi inv in non-muscle

2015

In this situation, a PET/CT is most helpful. With PSA values <1 ng/ml, the detection rate is low and between 5% to 40% (Picchio 2011). With higher PSA levels the detection rate raises up to 25% to 90%.

Therefore PET/CT may be used as a guide for individualized treatment of recurrence.

Monday, 23 March 10.30-12.00: Thematic Session 12 Imaging in prostate cancer State-of-the-art lecture

tion Intravesical inst illa érin

European Association of Urology Nurses

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Erectile dysfunction Future treatment strategies should focus on a holistic approach Prof. Tom Lue UCSF Medical Center San Francisco California (USA)

Erectile dysfunction is not an “all or none” phenomenon. Endothelial dysfunction and penile end-organ disease represent the two ends of the spectrum of “organic” changes associated with erectile dysfunction.

Among all causes, aging is undoubtedly the most important contributing factor. Other causes such as diabetes mellitus, hypertension, hyperlipidemia, androgen deficiency, chronic systemic diseases cause “premature” aging of the penile tissue.

Advancing age and deterioration of the underlying diseases gradually affect the neuro-vascular supply resulting in alteration of tunica albuginea, elastic and collagen fibers, endothelial lining, and corporeal smooth muscle leading to end-organ failure.

The current recommendation of diagnosis is a patient-centered, goal directed approach. A detailed history is important in establishing diagnosis and identifying curable/reversible causes as well as any contraindication to PDE5I therapy.

The current therapeutic approaches, including PDE5I, intracavernous or transurethral therapy, vacuum device, and penile prosthesis are effective in providing functional erection to more than 90% of patients.

Treatment of choice Generally speaking, the phosphodiesterase type 5 inhibitors (PDE5Is) are the treatment of choice for mild cases while intracavernous injections are for

the moderate ones. Those with severe venoocclusive disorder are usually left with the choice between vacuum erection device and penile prosthesis. The current treatment options are mostly for symptomatic relief. A better understanding of the molecular mechanisms involved in the progression from mild to severe disease is urgently needed so that the prevention and treatment of ED can be improved.

ED is part of the aging process, accelerated by diabetes, hypertension, vascular disease, neural degeneration, hyperlipidemia, endocrine disorders and aggravated by psychological factors.

The current therapeutic approach does not address the accelerating and aggravating factors. From a population health point of view, our future research needs to be redirected to a holistic approach instead of a fragmented care.

Stem cells represent great promise for regenerative medicine. Depending on the source of the cells, two broad categories have generally been recognized: the embryonic stem cells (ESCs) and the adult stem cells (ASCs). ESCs hold the ability to differentiate into any cell type, whereas ASCs have the capacity to give rise only to cells of a given germ layer. Stem cell therapy is a promising option for ED cases not responsive or partially responsive to PDE5Is. Intracavernous injection is the most commonly used method for stem cell delivery. The issue of allogeneic versus autologous stem cell source also needs to be further clarified.

Among the different stem cells used, adipose- derived stem cell (ADSC) represents the most widely and easiest stem cells to work with. But, whether cultured ADSC or stromal vascular fraction (non-cultured ADSC mixture) is a better choice needs to be answered through additional comparative studies.

immediate and delayed injections had similar long-term positive treatment outcome in animal model of cavernous injury. The dosage of stem cells requires further testing as the currently chosen doses of half million to two million cells in the rat were arbitrary. All these tasks are important in order to develop the stem cells therapy as a better option for ED. Potential therapies Gene therapy has gained renewed interest recently following reports of success in patients with Parkinson’s disease, epidermolulysis bullosa, Leber congenital amaurosis type 2, and choroideremia.

A phase 1 clinical trial of single-dose corpus cavernosum injection of human Maxi-K naked DNA was reported by Melman and associates in 2007, but no further study was reported.

Low energy shock wave (LESW) therapy has emerged as a “restorative” therapy for patients with vasculogenic ED who also failed PDE5i therapy. In these patients, LESW seems to improve penile circulation and improve erectile function after several weeks of treatment.

In basic research of other organs, LESW appears to have several interesting effects such as recruitment of stem cells, angiogenesis, as well as anti-oxidative and analgesic effect. More research is needed to confirm these effects in the penis.

Monday, 23 March 7.30-11.00: Plenary Session 3 Functional urology: Hot topics below the belt American Urological Association (AUA) lecture

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Timing of stem cell injection represents another issue despite the demonstration that both

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New to the European Urology Family

Editor-in-Chief: J. Catto Co-Editors: A. Briganti and S.F. Shariat Associate Editors: G. Giannarini and T. Klatte

europeanurology.com 18

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Monday, 23 March 2015

Managing Balanitis Xerotica Obliterans (BXO) Close follow-up care is crucial to quickly diagnose malignant changes Dr. Rados P. Djinovic Sava Perovic Foundation Center for GenitoUrinary Reconstructive Surgery Belgrade (RS )

Lichen Sclerosus (LS) is a chronic, progressive, sclerosizing inďŹ&#x201A;ammatory dermatosis of the genital skin of unknown origin and pathogenesis.1 It occurs in the genital area and may cause scarring of the skin and urethral epithelium with consequent urinary and sexual problems.

Male genital lichen sclerosus, known as balanitis xerotica obliterans [BXO], occurs most frequently in persons who are uncircumcised and who are of middle age. It was described for the first time in 1928 by Stuhmer as a lichen sclerosus and atrophicus.2 In 1995, the American Academy of Dermatology recommended the term Lichen Sclerosus.3 One study revealed that 51 (98%) of 52 patients clinically diagnosed with penile lichen sclerosus were uncircumcised.4 It can be also found in children, with incidence higher than previously reported.5-7 Additionally, the incidence of BXO is high in boys with phimosis.8 It is thought to be the reason for circumcision in humans from ancient times. The disease is usually asymptomatic early in its course, but can present with soreness, pruritus, burning, hypoesthesia of the glans, difficulty in retracting the foreskin or decreased urinary stream.

Erogenic sensation can be decreased with unpleasant hypersensitivity and painful erections in uncircumcised patients.

patients with hypospadias.12-16 Influence on sexual life can vary from hypersensitivity with premature ejaculation (in phimotic prepuce) to anorgasmia due to decreased sensitivity in circumcised men.

Diagnosis Although obvious in majority of cases, definitive diagnosis can be established only by skin or urethral epithelium biopsy and histological examination.

Barbali et al showed that LS involvement of the urethral meatus is a prognostic factor for spread through fossa navicularis and penile urethra. They did not find involvement of the bulbar urethra in any patient.17 In differential diagnosis one should always consider the following conditions: balanitis circumscripta plasmacellularis, candidiasis, erythroplasia of Queyrat (bowen disease of the glans penis), lichen planus, psoriasis, plaque, reactive arthritis and vitiligo.

Complications As the disease progresses, urinary retention may be sufficient to lead to retrograde damage to the posterior urethra, bladder, and kidneys. Longstanding BXO resulting in renal impairment in a child that led to a persistent but improved renal impairment after circumcision has been noted.18

From left photo, Figures 6, 7a, 7b

BXO.22 Postoperatively, it is important to have regular follow-up to observe any changes in the involved areas suggestive of malignancy.

to prevent its shrinkage. Second stage is done six or more months later by simple tubularization of the neourethral plate (Figure 7c, d).

In both un-circumcised and circumcised patients where preputial skin is adherent to the glans their sharp surgical separation should be done, leaving wounded surfaces on both sides (Figure 5). Intensive post-operative application of the ointment is very important to prevent re-adhesion â&#x20AC;&#x201C;- in the first 10-14 days neutral or antibiotic ones, and after initial epitethelization some potent corticosteroid ointment is useful for a few months.

For pan-urethral strictures caused

by BXO it is still not sure if the disease affects the bulbar part or is a consequence of repeated dilations and chronic infection caused by residual urine.10 They are usually treated by long inlay of buccal mucosa, Figure 7c: Tubularization of preferably placed neourethral plate dorsally.

Approach can be combined perineal and penile or only perineal using penile eversion technique. In older patients with severe pan-urethal stricture, definitive perineal urethrostomy may be the most suitable solution. Repeated circumcisions can cause severe penile skin shortening which require more complex reconstruction, usually using scrotal skin.

Painful erections in some cases of male genital lichen sclerosus may limit sexual function. Malignancies have been reported to occur in penile lesions (rare).

Common signs and symptoms of penile malignancy include nodule or tumor growth, ulceration, blistering, hematuria, erythema, pain, purulent discharge, bleeding, lymphadenopathy, and failure to Further indication for surgical intervention is meatal respond to treatment for presumptive inflammatory or or urethral involvement for symptoms or signs of stenosis. If disease is localized only at meatus, simple infectious balanitis (Figure 4). meatotomy with topical postoperative corticosteroids may be effective. Stricture of the more proximal part For this reason, close follow-up care is indicated to quickly diagnose any malignant changes. Philippou et of the urethra should be treated by augmented urethroplasty (Figure 6). Full-thickness skin grafts or On examination are visible pale, whitish papules that al showed that the presence of histologicallypenile skin flaps should be avoided due to possibility are flat and atrophic, which often join in plaques of confirmed of disease recurrence. synchronous LS in different size, and in some patients involve all praeputial and glanular skin (Figure 1).9 Prepuce can patients with pSCC be phymotic or paraphimotic, non-retractile and is relatively high but is not urethral meatus can be involved with consequent associated with urine flow obstruction. Sometimes the prepuce and increased rates of glans become so adherent with is impossible to adverse separate except surgically (Figure 2). histopathological features, including carcinoma in situ.

LS can develop in extragenital skin grafts, although its association with the Figure 4: Ulceration is a sign of penile malignancy long-term risk for Figure 3: Severe meatal stricture recurrent pSCC is caused by BXO not apparent in the Buccal mucosa appears to be a durable source of non-genital tissue for urethral replacement. Attention present study.19 to detail in terms of graft harvest, preparation, and fixation helps avoid major post-operative Medical treatment complications. Dubey et al23 report that in BXO-related No consistently effective treatment has been developed for penile lichen sclerosus (BXO); however, strictures with a viable urethral plate, one-stage Figure 1: Whitish papules in penile glans dorsal on-lay buccal mucosal urethroplasty achieves several therapies have varying degrees of reported superb medium-term results. In 2007, Levine et al24 success. Topical steroids, especially super-potent evaluated the impact of stricture location and lichen The frenulum, urethral meatus, fossa navicularis, topical steroids, are the mainstay of medical therapy. sclerosus on surgical outcome and found when lichen penile shaft, and perianal areas may become They can offer a reliable option only in the sclerosus affects the penis, complete excision of the involved. The urethral meatus may narrow to the management of mild BXO limited to the prepuce in diseased urethra with multi-stage repair decreases point of causing urinary retention and even with boys with minimal scar formation. Steroid-based the rate of stricture recurrence associated with a retrograde urinary damage up to the kidneys (Figure creams are ineffective in persons with already one-stage repair. Urethra can be approached by lower established scarring. Studies have shown that 3). A sclerotic white ring at the tip of the prepuce is diagnostic at this stage. Erosions, fissures, petechiae, applying a potent topical steroid improves BXO in the sagittal incision or after penile degloving. serous and hemorrhagic bullae, and telangiectasias histologically early and intermediate stages of disease Another option is two-stage buccal mucosa of the glans have been reported, albeit uncommonly. and may inhibit further worsening in the late stages. urethroplasty with or without excision of urethra In hypospadiac patients using the praeputial flap for Regarding topical steroids and skin stretching, Ghysel affected by BXO. In the first option urethra is opened urethral reconstruction may lead to late onset BXO by marsupialization and the urethral epithelium cut et al reported on successful therapy with topical with consequent stricture. longitudinally steroid application and skin stretching on prepubertal until the boys with un-retractable foreskin and phimosis.20 The most severe albuginea, spread Successful treatment of BXO with topical tacrolimus complications of and buccal has been reported; an interesting new report notes BXO are urethral mucosa graft the successful use of intralesional adalimumab, a stricture and quilted in the medication for psoriasis, among other things.21 penile cancer.10,11 middle (Figure 7a, Controversy b). The other existed about the Surgery option is to excise incidence of LS A variety of surgical techniques can be used to treat diseased urethra involving the penile lichen sclerosus, depending on involved entities and to replace it anterior urethra in and progression. Early circumcision in childhood may with buccal men, until the decrease the risk of developing male genital lichen mucosa.

1970s when many sclerosus; nearly all cases have been reported in Post-operatively, authors proved its uncircumcised patients; it is wise to excise as much as transplant should presence in possible praeputial skin since it is more prone to be treated with pendular and recurrence of disease. Foreskin preputioplasty Figure 2: Adherence of prepuce and bulbar urethra, combined with intralesional triamcinolone might be a Figure 5: Surgical separation of glans some moisturizing cream or ointment glans especially in tenable alternative as against circumcision to treat and skin Monday, 23 March 2015

Prognosis Male genital lichen sclerosus is chronic and often a progressive disease.

Regression or improvement of atrophic areas is unexpected.

Steroid creams have been shown to limit the progression of the disease but do Figure 7d: Completed suture of not offer a cure in tubularized neourethral plate the majority of cases.

Circumcision can be a curative procedure in early disease.

Although there is conflicting evidence for treatment of recurring urethral strictures, repeated urethrotomy or urethral dilatation has poor long-term outcome.

Urethral stricture may recur after surgery and require additional repair of definitive perineostomy.

Malignancies have been reported to arise in penile lichen sclerosus lesions (around 5%); most common cancers are squamous cell carcinoma (SCC),25 adenosquamous carcinoma, and verrucous carcinoma. Although the average time between diagnosis of lichen sclerosus and subsequent diagnosis of penile malignancy is pretty long (17 years26 ), close follow-up is necessary in all progressive cases.

Due to space constraints the reference list has been omitted. Interested readers can send a request for the complete list at EUT@uroweb.org.

Monday, 23 March 07.30-11.00: Functional urology Hot topics below the belt

EUT Congress News

19

Post-chemotherapy RPLND: In whom?

Post-chemotherapy RPLND: a key procedure in the multimodal management of germ-cell tumours Dr. Nicola Nicolai Urology Unit, Testis Surgery Unit Fondazione IRCCS Istituto Nazionale dei Tumori Milan (IT)

Co-Author: Francesco Cattaneo, Milan (IT) The management of testicular germ cell tumours (GCT) has come to represent a model for the successful multidisciplinary approach to solid neoplasms1. Due to the development of effective chemotherapy regimens, the identification of reliable serum tumour markers and the appropriate integration of systemic chemotherapy and surgery, the overall survival for patients with testicular cancer is greater than 90%1.

Surgery remains an integral part of the management of patients with GCTs. However, its role has changed in recent years. This article will review the role of retroperitoneal lymph-node dissection (RPLND) in the management of patients with advanced seminoma and its role in non-seminomatous GCT (NSGCT).

Post-chemotherapy RPLND in seminoma In patients with metastatic seminoma, postchemotherapy residual masses are present in 55%–80% of cases. Resection of these residuals mostly reveals necrotic tissue. In lesions greater than 3 cm, viable tumour is expected in 11%–37% of cases2.

The approach to the patient with pure seminoma and a residual mass after chemotherapy remains controversial. One reason is that unfavourable histology occurs in about 10% of cases, as teratoma is virtually impossible, although exception occurs.

Secondly, a complete RPLND is often very difficult to perform owing to obliteration of tissue planes due to the severe desmo-plastic tissue reaction after chemotherapy. Consequently, perioperative morbidity is potentially much higher than that for NSGCT1.

As the vast majority of cases do not contain vital disease, observation has become a standard of care, and prevailed over active treatment such as surgery or radiation therapy, which represented the usual treatment of persisting residuals up to a couple of decades ago.

Traditional criteria for treatment delivery were size and the shape of the residual mass. A residual mass smaller than 3 cm showed no viable disease in different series of post-chemotherapy surgery.

A well-defined nodular residual mass was considered at higher risk of containing viable tumour, and it has been considered for rescue surgical treatment3.

In recent years, fluoro-deoxy-glucose-positron emission tomography (FDG-PET) imaging has been shown to differentiate necrosis and vital seminoma.

A positive post-chemo FDG-PET was more predictive for the presence of viable tumour than the size criterion using CT. Only two of 44 patients (5%) with negative scan were ultimately found to have viable seminoma and both false-negative scans were in residual masses less than 3 cm. So far, FDG-PET is now a useful tool to characterize post-chemotherapy residual masses in seminoma, especially when performed at an adequate interval following chemotherapy (six weeks after the end of the last chemotherapy course). Observation is justified in patients with a negative FDG-PET scans after primary chemotherapy, particularly for those with residual masses less than 3 cm4. Patients with positive scans after chemotherapy could be considered for further treatment, including surgical resection, if technically feasible.

Post-chemotherapy RPLND in non-seminoma Following completion of first-line cisplatin-based chemotherapy (i.e. BEP for 3 to 4 courses according to prognostic allocation) and normalization of serum tumour markers, a residual retroperitoneal mass is present in about 60-70% of cases with metastatic non-seminoma. In these patients, post-chemo RPLND may reveal necrotic debris and fibrosis, teratoma elements or viable tumour in approximately 40–50%, 30–40% and 6–20% of patients, respectively5,6.

Ideally, surgery should be spared in patients with no teratoma or vital tumour in the residual mass.

20

EUT Congress News

Predicting the histology of the residual mass before resection would be helpful to determine whether resection should be performed or not7. RPLND in non-seminoma is indicated after primary chemotherapy if remission is incomplete8. For an individual, post-chemotherapy RPLND offers a staging benefit, because active tumours is discovered and further decision may be assumed accordingly (e.g. supplemental chemotherapy Vs observation only) and a therapeutic benefit, because chemo-insensitive tumours (e.g., teratoma, teratoma with malignant transformation) or potentially chemo-resistant tumour are radically removed.

Unfortunately, imaging like CT or Magnetic Resonance Imaging (MRI) do not accurately predict histology, while PET-FDG does not add accuracy to traditional staging performed with CT scans and serum tumour markers determination9.

A prediction model has been developed and validated

by Vergouwe et al. A “score chart” may predict presence of benign histology with a relatively high accuracy (0.80). Nonetheless, this model was not successful in the urologic community. Eventually, the identified parameters are of common empiric use in the clinical practice. Presence versus absence of teratoma in the primary, shrinkage of the masses and normalisation of serum tumour markers are commonly perceived as determinants for RPLND administration10.

On the other hand, according to Memorial Sloan Kettering experience, the risk of teratoma or viable tumor outside the template of a modified dissection is associated with the size of residual mass24.

Intensity of RPLND Post-chemotherapy surgery is technically demanding.

More frequently, the standard resection of nodes allows sparing the most important retroperitoneal organs. Nonetheless, it is not rare that, in order to achieve a complete and radical dissection, further demolition may involve the kidney, the gross vessels, the liver and the spine. Such interventions also require a reconstructive specialised phase. This “maximal” surgery needs a multidisciplinary approach involving different specialists in a planned and shared policy prior to the intervention. Patients treated within centres that have interdisciplinary facilities under the control of GCT expert clinicians, benefit from a significant reduction in perioperative mortality from 6% to 0.8%25. In addition, specialized urologic surgeons are capable in reducing the local recurrence rate from 16% to 3%26 with a higher rate of complete resections.

PC-RPLND following salvage chemotherapy Depending on their risk profile, from 35% to 70% of patients experiencing a relapse following first-line chemotherapy will achieve a complete response to second-line, ifosfamide/cisplatin-based regimens27.

Patients with disease amenable to surgery are candidates for retroperitoneal lymph node dissection While in the case of complete remission after first-line (RPLND) in addition to resection of any extraretroperitoneal disease. In one of the more recent chemotherapy RPLND is not indicated9,11, in patients with lesions < 10 mm there is still an increased risk of experiences, nearly 50% have either viable GCT or residual cancer or teratoma9,12. Patients with negative teratoma, but the proportion of those with viable GCT markers and a residual retroperitoneal mass < 10 mm dropped down to 13% (from about 36%), probably as a result of improved salvage taxane-based chemotherapy are routinely treated with PC-RPLND at certain institutions, benefitting from the removal of potential regimens. The 10-year disease-specific survival was favourable in 70% of cases. The current data support low-volume teratoma or viable residual cancer7.

RPLND in selected patients after salvage chemotherapy.

However, reports have suggested that surveillance Salvage RPLND may be an option in this situation. Following a median follow-up of 5.4 years, only 5% of a series of In the case of persisting elevated markers following completion of chemotherapy, treatment resection of 455 men undergoing surveillance following residual tumours should be considered if complete chemotherapy had a retroperitoneal relapse13. In another series including 141 patients who underwent resection of all tumour seems feasible. A therapeutic benefit of post-chemotherapy surgery in patients with surveillance with a median follow-up of 15.5 years, elevated serum tumour markers has been 12 (9%) relapsed and eight of them remained alive and disease-free following further treatment. Only six demonstrated29. In these patients, retroperitoneal pathology revealed germ cell cancer in 53.5% of relapses were in the retroperitoneum, and four of patients, teratoma in 34.2% of patients, and fibrosis them are currently alive and disease-free11. These in 12.2% of patients, associating each condition with findings were confirmed by a series on 161 patients, five-year survival rates of 31.4%, 77.5%, and 85.7%, but with a shorter follow-up14. These data may respectively (five-year overall survival rate in was support the policy of surveillance alone in patients 55%). Risk factors negatively associated with survival with very small retroperitoneal residual masses. included an increasing preoperative serum β-hCG, an On the other hand, it is not so easy to let the benefits elevated serum AFP, redo-RPLND and germ cell of omitting RPLND prevail over risks. The rationale for cancer in the surgical specimen. A special case is when further chemotherapeutic options are lacking, PC-RPLND in patients with small (<10 mm) residual masses is based on: 1) prevention of the middle-term but RPLND seems technically feasible (desperation surgery)9,29.

3%–5% relapse rate in the abdomen, thus avoiding salvage chemotherapy and preventing mortality; Open vs mini-invasive surgery 2) serial CT scans are expensive and may be toxic in Open RPLND is associated with considerable terms of risk of a second cancer; 3) the omission of morbidity, particularly in terms of hospital stay and PC-RPLND potentially exposes patients to the risk of time to full recovery. Additionally, it requires a large very late relapse with teratoma, a chemo-resistant incision that is unwelcome by these young patients. variant of GCT15.

To overcome this, the laparoscopic approach (L-RPLND) has evolved since 1992. On the other hand, In persistent larger volume retroperitoneal disease technical difficulty of L-RPLND after chemotherapy can (>10 mm), all areas of primary metastatic sites must be significant. As a consequence, literature be completely resected within four to six weeks of concerning post-chemotherapy L-RPLND is still very completion of chemotherapy9,11,12. In these patients limited, prospective randomized trials are largely with post-chemotherapy viable NSGCT, a complete resection of residual masses included within a precise unavailable, and intermediate and long-term template of dissection, should be rigorously pursued. oncologic data are sparse. There are some data in the literature suggesting improved QoL after the laparoscopic procedure compared to open surgery30,31.

Extent of RPLND It is essential that the oncologic efficacy of RPLND The anatomical extent of PC-RPLND has been must not be compromised by strategies aimed at discussed for years, and the standard practice has become to perform a full bilateral template dissection reducing its short- and long-term morbidity. Recent studies have shown equal functional and oncological since the 1980’s, when most patients presented with results of L-RPLND as compared with open series32. high-volume residual disease when undergoing 16 Both unilateral and bilateral dissections are possible retroperitoneal surgery . with the laparoscopic approach, and a low morbidity and a high oncologic efficacy were reported by This approach however, may be associated with experienced centres33,34. Regarding robotic-assisted significant ejaculatory morbidity, mainly influencing PC-RPLND there is not enough evidence in the the ejaculation. To address the problem of dry literature on morbidity and complications, and we ejaculation after primary RPLND, modified template only have indications of feasibility and promising dissections17,18 and/or nerve-sparing techniques have potentials in favour of this experimental approach35. been developed19,20.

Both European21,22 and American23 experience provided support for modified template dissections, which permitted a high rate of preservation of antegrade ejaculation without an excess of abdominal recurrences.

Timing of RPLND with respect to other sites of residual disease The RPLND is the more common required surgical procedure, with frequency between 25% and 86%, following completion of chemotherapy. Thoracic

surgery (thoracotomy or video-assisted thoracoscopy) is performed in about 10% of patients to resect residual pulmonary nodules, whereas resection of other sites (liver, neck, bone, and brain) is less frequent36,37,38. Resection of necrosis is considered to have no therapeutic benefit, in contrast to resection of mature teratoma or cancer39. Retroperitoneal lymph node histology may be predictive of residual thoracic pathology, and selected patients with necrosis at retroperitoneal lymph node dissection (RPLND) could undergo observation only for their residual chest masses. RPLND should generally be performed before a thoracotomy is considered, so that supradiaphragmatic resection can be omitted when histology from RPLND does not contain cancer or teratoma.

Conclusions Post-chemotherapy RPLND remains a fundamental device in the multimodal management of germ-cell tumours. Application of RPLND requires a modulation based on histology, size of residuals and setting.

These variables may favour omission of surgery, full bilateral vs modified template dissection, open vs mini-invasive approach and standard vs maximal surgery in each individual case. This decisional process needs to be shared within a multidisciplinary context where physicians must have matured experience in the field of gem-cell testicular tumours.

References 1. Stephenson AJ, Sheinfeld J. The role of retroperitoneal lymph node dissection in the management of testicular cancer. Urol Oncol. 2004 May-Jun; 22(3):225-33; discussion 234-5.

2. Bachner M, Loriot Y, et al. 2-18fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) for postchemotherapy seminoma residual lesions: a retrospective validation of the SEMPET trial. Ann Oncol.

2012 Jan; 23(1): 59-64.

3. Flechon A1, Bompas E, et al. Management of postchemotherapy residual masses in advanced seminoma.

J Urol. 2002 Nov; 168(5):1975-9.

4. De Santis M, Becherer A, et al. 2–18fluoro-deoxy-Dglucose positron emission tomography is a reliable predictor for viable tumor in postchemotherapy seminoma: an update of the prospective multicentric SEMPET trial. J Clin Oncol 2004; 22: 1034–9.

5. Fox EP, Weathers TD, et al. Outcome analysis for patients with persistent nonteratomatous germ cell tumor in postchemotherapy retroperitoneal lymph node dissections. J Clin Oncol 1993;11:1294–9.

6. Fossa SD, Aass N, Ous S, et al. Histology of tumor residuals following chemotherapy in patients with advanced non-seminomatous testicular cancer. J Urol 1989;142:1239–42.

7. Fossa SD, Qvist H, et al. Is postchemotherapy retroperitoneal surgery necessary in patients with nonseminomatous testicular cancer and minimal residual tumor masses? J Clin Oncol 1992;10: 569–73.

8. Debono DJ, Heilman DK, et al. Decision analysis for avoiding postchemotherapy surgery in patients with disseminated nonseminomatous germ cell tumors.

J Clin Oncol 1997;15: 1455–64.

9. P. Albers (chair), W. Albrecht, F. Algaba, C. Bokemeyer, G. Cohn-Cedermark, K. Fizazi, A. Horwich, M.P. Laguna, N. Nicolai, J. Oldenburg. EAU 2014 Guidelines on Testicular Cancer.

10. Vergouwe Y1, Steyerberg EW, et al. Predicting retroperitoneal histology in postchemotherapy testicular germ cell cancer: a model update and multicentre validation with more than 1000 patients. Eur Urol. 2007 Feb;51(2):424-32.

11. Ehrlich Y, Brames MJ, et al. Long-term follow-up of Cisplatin combination chemotherapy in patients with disseminated nonseminomatous germ cell tumors: is a postchemotherapy retroperitoneal lymph node dissection needed after complete remission? J Clin Oncol 2010 Feb;28(4):531-6.

12. Carver BS, Shayegan B, Serio A, et al. Long-term clinical outcome after postchemotherapy retroperitoneal lymph node dissection in men with residual teratoma. J Clin Oncol 2007 Mar;25(9):1033-7.

13. Ravi P, Gray KP, O’Donnell EK et al. A meta-analysis of patient outcomes with subcentimeter disease after chemotherapy for metastatic non-seminomatous germ cell tumors. Ann Oncol 2014: 25: 331–338.

The reference list has been shortened due to space constraints. Interested readers can request for the complete list at EUT@uroweb.org.

Monday, 23 March 10.30-12.00: Thematic Session 15, Testicular cancer State-of-the-art lecture

Monday, 23 March 2015

Twitter in urology: Benefits and caveats Twitter- a handy tool for updates but proper use is essential Dr. Stacy Loeb Assistant Professor Urology and Population Health New York University New York (USA) Twitter @LoebStacy

Twitter is a form of social media using short messages (<140 characters) called “tweets” that are grouped together using subject headings called “hashtags” (indicated with the # symbol). It has become increasingly popular in society, with approximately 284 million monthly active users and 500 million tweets per day.

Twitter’s use in medicine is also expanding with more than 75,000 healthcare professionals on Twitter, generating more than 150,000 tweets per day.

Twitter is an extremely useful tool for both academic and clinical urology practice. First, it is a convenient way to stay up to date on major news and research.

All of the major journals participate in twitter, including European Urology and BJU International, so it is a quick way to learn about important new publications. The EAU Guidelines Office has also recently started using twitter to disseminate key messages and updates from each guidelines panel throughout the year (using the hashtag “#EAUguidelines”).

Twitter is also used increasingly at urology conferences, and most meetings now have their own pre-specified hashtag (e.g., #eau15 for this meeting). From 2012 to 2014, the number of tweets at the annual EAU congress increased from 347 to 5904.1 This year’s conference is expected to surpass this mark as more members continue to join Twitter.

Not only can social media be used for discussion

among conference attendees, it can also be used to follow the proceedings remotely. In fact, we recently performed a survey of urology twitter users and 76% indicated that they had used it for remote conference participation (Borgmann et al, unpublished data).

Educational opportunities There are several other educational opportunities available on twitter, including a worldwide twitterbased urology journal club (using the hashtag #urojc).2 Each month, a new article is discussed on twitter by urologists and trainees from around the world during a 48-hour period. The best tweet is awarded a prize, such as free registration to a major urology conference or subscription to a journal. In the two years since the journal club started, the number of participants has steadily increased from 189 in Year 1 to 373 by the end of Year 2.3 The authors of the studies often participated in the discussion of their work, adding significant value to the experience.

Other educational activities such as quizzes are available through the BJU International (@BJUIjournal) and Urology Quiz (@UrologyQuiz) accounts.

Twitter can also be a valuable asset for clinical urology practice as a forum to disseminate updates to colleagues and prospective patients. For example, twitter has been used to publicize new clinical trials, course offerings, and community events like support groups. It can be used by individual urologists to solicit advice on difficult clinical questions to a wide group of colleagues.

Many politicians, professional societies, journalists and other stakeholders are also active on twitter, so it is an excellent platform for advocacy. Our group previously reported on the significant twitter response after the United States Preventive Services Task Force recommendation against prostate cancer screening.4 The rapid flow of information makes twitter a great forum to advocate for important causes to a vast audience.

Inappropriate tweets Despite the many beneficial uses for twitter in academic and clinical urology practice, it is important to remember that it is a public forum and professionalism is essential. There can be serious negative consequences and disciplinary action for inappropriate behavior on social media. The EAU, AUA and BJU International have all published recommendations for proper use of social media, which should be considered required reading for active and prospective users.5-7 2014;66(1):112-117.

All three emphasize that content should be considered 3. Thangasamy I, Leveridge, M., Davies, B., Stork, B., Loeb, permanent. Tweets should be respectful and avoid S., Woo, H. International Urology Journal Club on any disclosure of confidential patient information.

Twitter- A Growing Educational Forum Paper presented Users who are part of a hospital or other organization at: American Urological Association 2015 Annual should identify themselves, and include a disclaimer Meeting2015; New Orleans, Louisiana. in their profile that posts represent their own opinion. 4. Prabhu V, Lee T, Loeb S, et al. Twitter Response to the All of these safeguards will help to ensure productive United States Preventive Services Task Force use of Twitter and other forms of social media in Recommendations against Screening with Prostate accordance with professional standards.

Specific Antigen. BJU international. Mar 25 2014.

In summary, twitter presents an exciting new way to keep up with urology research, clinical practice guidelines, and conferences. The online journal club and quizzes have brought a unique and modern approach to continuing medical education. Finally, Twitter is an exceptional way to network with colleagues, and its applications in the field continue to grow rapidly over time.

5. Roupret M, Morgan TM, Bostrom PJ, et al. European Association of Urology (@Uroweb) recommendations on the appropriate use of social media. European urology.

Oct 2014;66(4):628-632.

6. American Urological Association Social Media Best Practices. http://www.auanet.org/press-media/ social-media-bp.cfm. Accessed August 23, 2014.

7. Murphy DG, Loeb S, Basto MY, et al. Engaging responsibly with social media: the BJUI guidelines. BJU international. Jul 2014;114(1):9-11.

References 1. Wilkinson SE, Basto MY, Perovic G, Lawrentschuk N, Murphy DG. The social media revolution is changing the conference experience: analytics and trends from eight international meetings. BJU international. Aug 18 2014.

2. Thangasamy IA, Leveridge M, Davies BJ, Finelli A, Stork B, Woo HH. International Urology Journal Club via Twitter: 12-month experience. European urology. Jul

Monday, 23 March 10.30-12.00: Thematic Session 19 Controversies in the management of bladder cancer Point-counterpoint session: Social media and urology

re!

TP 51 2.0 03/2015/A-E

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IMAGE1 SPIES™ 3D 3D in FULL HD

KARL STORZ GmbH & Co. KG, Mittelstraße 8, 78532 Tuttlingen/Germany, www.karlstorz.com

Monday, 23 March 2015

EUT Congress News

21

ADVERTORIAL

Improving therapeutic management of NMIBC En-bloc resection – The future standard of care?

To date transurethral resection of bladder tumours (TURBT) is the cornerstone of treatment for non-muscle invasive bladder carcinoma (NMIBC)1. However, there is evidence of a high rate of tumour recurrence after primary resection. About 50-70% of all patients will have a recurrence after their initial treatment2. Despite all technological advances, NMIBC therefore continues to represent a challenging pathology.

The comparably insufficient therapeutic management of NMIBC might be associated with the limitations of conventional TURBT techniques and with an inadequate accuracy of standard white light cystoscopy (WLC)3. It has been observed that almost 81% of the tumours recurred at the site of previous resection, which indirectly hypothesizes that the technique of resecting the tumour is not adequate4.

Studies suggest that “en-bloc” resection could end the poor oncological safety profile of the “incise and scatter” principle behind the transurethral resection. The question to address is whether this technique is feasible for all NMIBC patients. gastrointestinal surgery, the tumour is elevated from the bladder with a submucosal fluid cushion. By elevating the mucosa, the resection level is raised and the risk of perforation of the muscularis is reduced.

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

With this technique, already established in endoscopic

Currently available studies on en-bloc resection provide encouraging data on the reduction of the recurrence rate typical of non-muscle invasive bladder tumours. New techniques to achieve en-bloc resection like the water-jet HybridKnife® system are constantly studied in further trials15.

HAL-guided cystoscopy holds promise in assisting en-bloc resections by helping to visualize tumour margins and confirming complete clearance of lesions12. HAL- guided en-bloc resection of bladder

EUT Congress News

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

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

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

22

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

Do you think the concept of “incise and scatter” during standard TURB needs to be changed since it is against the basic principle of oncological surgery?

“If possible, yes. One limiting factor of the surgical ‘incise and scatter’ technique is that it might contribute to tumour recurrence. En-bloc resection of tumours would be far preferable and demands further development and evaluation.”

How can this approach influence the bladder cancer therapy?

“Still randomized controlled clinical trials dealing with en-bloc resection are missing. If it indeed lowers the recurrence rates (probably not progression rates) it should become the new standard in smaller tumours (let say a bit over 1 cm maximum).”

For which patient group en-bloc TURB is feasible and safe (according to guidelines)?

“The concept of en-bloc resection has appeal; however, its application is limited by the size of the tumour and to me this also is the central selection criterion. The higher the grade the less willing I would be to incise the tumour, so the better it should be if the resection is en-bloc. Moreover, we should clearly visualize a tumour in case of an en-bloc resection. For that, HAL guidance seems ideal.”

Is en-bloc transurethral resection better than conventional techniques in terms of recurrence and progression?

“Theoretically it would make sense that the resection results and the recurrence rates can be improved with en-bloc resection but this has not been comprehensively proven yet. However, en-bloc techniques allow for more accurate pathologic staging of initial tumour (>90%). This better possibility for pathological assessment is a clear advantage of this approach.”

About Innovators in BC® While the number of active participants is constantly growing and after a very fruitful first year the Innovators in BC® will again present the “Bladder Cancer Topic of the Year” at this year’s EAU meeting in Madrid. Urologists and oncologists from several countries once more voted for the bladder cancer topic they believe should be further discussed and high on the agenda in 2015.

Innovators in BC® (www.innovators-in-bc.com) aims to change the way doctors and healthcare professionals look at bladder cancer. The main objective of this website is to provide science based information in order to raise awareness of bladder cancer in general, and to share information, experience and material with in-depth educational background. Its content has been compiled by medical professionals and is updated regularly by providing news about bladder cancer, summaries of congresses, current studies and publications. The website shares educational material for doctors, such as slide kits and patient cases. Moreover, improving early detection and intervention cystoscopy and resection could reduce the risk of subsequent recurrence and progression, for the patients’ benefit. The potential of Innovators in BC® will increase with its number of

Does currently available data allow for any conclusion about en-bloc resection of urothelial cancer?

“The performance of TURBT is constantly evolving; various techniques using different kinds of loops and laser have been described and studied. The feasibility of en-bloc resection has been demonstrated as well.

However, en-bloc resection still cannot be applied to all tumours and is currently only preferable for selected patients. Therapy always should be tailored in accordance with the particularities of each case.”

users. As a “living tool” the website requires the active participation and engagement of urologists and oncologists who could edit new content and raise the interest of the audience. Innovators in BC® is a restricted area for medical practitioners only from Austria, Belgium, Czech Republic, France (www. innovators-in-bc.fr), Germany, the Netherlands, Spain and Switzerland, developed by Ipsen. Without any commercial purpose the platform aims to be neutral and independent.

References 1. Sureka et al., Indian J Urol. 2014; 30(2):144-149 2. Thomas et al., Eur Urol Suppl 2008; 7:524-528 3. Filbeck et al., J Urol. 2002; 168(1):67-71.

4. Grimm et al., J Urol. 2003; 170:433-437 5. Dutta et al., J Urol. 2001; 166(2):490-3.

6. Brausi et al., Eur Urol. 2002; 41:523-531 7. Burger et al., Eur Urol. 2013 Nov;64(5):846-54 8. Gakis et al., World J Urol 2015, article in press 9. Ukai et al., J Urol. 2000; 163(3):878-9 10. Nagele et al., World J Urol. 2011; 29(4):423-7 11. He et al., J Endourol. 2014; 28(8):975-9 12. Witjes et al., Eur Urol. 2014; 66:863-871 13. Babjuk et al., EAU 2014; April 2014.

14. Kramer et al., Min Inv Ther.2014; 23:206-213 15. Fritsche et al., J Endourol 2011;25: 1599-603

Monday, 23 March 2015

Global threat of antibiotic resistance: No time to lose To fight resistance, urological community must accept its share of responsibility in antibiotic stewardship Prof. Magnus Grabe University of Lund Lund (SE)

Yes, how many times can a man turn his head Pretending he just doesn’t see?

The answer my friend is blowin’ in the wind The answer is blowin’ in the wind Yes, how many deaths will it take till he knows That too many people have died?

The answer my friend … (refrain) Bob Dylan, 1963 “Blowin’ in the Wind” is one of Bob Dylan’s greatest hits and a symbol for the civil rights and anti-war movement.

What has Dylan’s lyrics to do with antibiotic resistance? Or shouldn’t we also be asking the following?

• How long can we turn our heads away and avoid seeing the misuse of antimicrobial agents?

• How many people must die of infections, caused by microorganisms resistant to available antibiotics, before we act?

history. And yet, we will soon be confronted with their ineffectuality due to the dramatic development of resistance by the very microorganisms we aim to kill.

These microorganisms have an astounding capacity to adapt, mutate, select and transfer genes among themselves to outwit our weapons.

alone, with many hundreds of thousands more dying in other areas of the world.”

Reliable estimates of the true burden are however scarce. But the undeniable fact is that an increasing number of people will die due to the lack of active antibiotics. Antibiotic use differs markedly in Europe Among the best “killers” – the Fluoroquinolones – the with a three-fold higher prescription in highresistance of Escherichia coli has increased from consuming countries compared to countries with almost zero to 10% to 25% in most European lower prescription, and even among countries with countries, and even up to or above 50% in south and similar health status in the population3. south-eastern Europe1. The same goes for Klebsiella species and other Enterobacteriaceae. ESBL (Extended Urologists use antibiotics on a daily basis in all its fields.

Many urological patients suffer from complex conditions spectrum beta-lactamase) -producing bacteria have increased by three to five times, or more, in recent with obstruction, tumours, stone disease, and agerelated concomitant diseases, with a hospital bacterial years all over Europe and worldwide. profile and subsequent resistance pattern4. However, the The dreadful threat of having no antibiotics left for majority of urology patients have common, simple treatment is the emergence of the carbapenemase infections or undergo routine diagnostic and surgical ESBL-producing strains that simply defeat any procedures. Moreover, antibiotic prophylaxis regimens antibiotic including the carbapenem group, still one vary immensely from country to country, without any of our most powerful agents. Sadly, we can add to scientific base, and therefore there is an absolute need this long list the growing threat from the for more effective and strict clinical protocols.

Fluoroquinolone- resistant Pseudomonas spp, the Vancomycin-resistant Enterococci and so forth1.

The answer shouldn’t be blowin’ in the wind any more. The weak and complacent attitude must end!

The urological community, sharing the concern “What is urgently needed is a regarding the growing resistance, must act!

behavioural change. If we continue to run around with protective blinkers, we will only hit the wall of disaster.”

For too long a time, scientists, healthcare managers and politicians have been running around with blinkers, avoiding the issue on how to effectively address the rampant use- and especially the misuse of antimicrobial drugs- we so desperately need to provide modern health care.

In a recent report commissioned by the British Government, the economist Jim O’Neill estimated the extra number of deaths due to antibiotic resistance to at least 10 million by 2050, which he considers as an enormous cost for the global economy2. The figure, of course, is speculative, but it shows the potential impact and a possible scenario. The report also states The history of antibiotics is just 90 years old- and 70 that “antimicrobial resistant infections claim at least years in clinical practices- a very short time in medical 50,000 lives each year across Europe and the US

The research and discovery of new groups of antibiotics is not the only solution since smart microorganisms will adapt again. The EU, the US and many governments want to boost research and invest more money in developing new antibiotics, which is commendable. But we also need to examine alternative approaches; innovative infection treatment methods and management research must be encouraged. Large studies, quality registry and stringent infection control in clinical practice are required. Above all, what is urgently needed is a behavioural change. If we continue to run around with protective blinkers, we will only hit the wall of disaster. The urological community must accept its share of responsibility in antibiotic stewardship.

Stringent infection control and judicious use of antimicrobial agents are required to fight antibiotic resistance

The EAU Guidelines on Urological Infections aims to provide the urologist and physicians from other medical specialities with evidence-based guidance regarding the treatment and prophylaxis of urinary tract infections (UTI) and male genital infections. The Guidelines are a tool to achieve a reasonable practice. Compliance with the treatment and prophylaxis regimens would markedly lower the costs and the amount of prescribed antibiotic doses, reduce the misuse and, thus, contribute to limiting resistance development.

Access to antimicrobial agents is a civil right in good health care. Antibiotics use must be managed with care and with an insightful attitude we will avoid to simply be ‘blowin’ in the wind.’

Due to space constraints the reference list has been excluded. Interested readers can email at EUT@uroweb.org for the complete list.

Monday, 23 March 07.30-11.00: Plenary Session 3 Functional urology: Hot topics below the belt EAU Guidelines snapshot

State-of-the-Art ESWL requires Dornier OptiCouple!

Pioneering ESWL in the 1980s, Dornier MedTech has revolutionised stone therapy.

This method of treatment continues to be the first-line therapy in most stone situations.

For maximum ESWL treatment efficacy, the quality of the coupling of the shockwave source to the patient is one of the most important factors in energy transfer and hence in the quality of the stone fragmentation.

Study results show that air bubbles, cushion folds and incomplete coupling have an adverse effect on the propagation of the shockwaves and decrease the fragmentation efficiency.

Dornier as the leading innovator in shockwave technology has introduced a smart and effective feature supporting easy and fast removal of air bubbles in the coupling area.

Dornier OptiCouple increases the efficiency of ESWL tremendously.

Learn more about Dornier OptiCouple and visit our booth at EAU 2015, No. G52.

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Monday, 23 March 2015

YEARS

W E ' R E

A L L

A B O U T

P E O P L E.

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European Urology to launch EU FOCUS New publication expands EU’s coverage to include original research, novel discoveries Prof. Shahrokh Shariat Associate Professor Director, Bladder Cancer Outcomes and Translational Research Weill Medical College of Cornell University New York (USA) Co-Author: Alberto Briganti, Milan (IT) European Urology has become the definitive journal for scientists, clinicians, and trainees in urology, worldwide. It is dedicated to provide physicians the best research and key information at the intersection of biomedical science and clinical practice, presenting them in an understandable, clinically useful format.

The main mission is to keep practicing physicians informed on developments that are important to patients and maintain their links to both clinical science and the values of being a good physician based on the practice of value-based, patientcentered and evidence-based medicine.

Indeed, European Urology has developed a unique reputation as the “platinum standard” for quality biomedical research and for the best practices in urology. We can say today that is likely the most widely read, cited, and influential periodical in urology.

The rapid expansion of urologic subspecialties and the changing needs of urologists in the 21st century require, more than ever, a deeper understanding of urologic pathogenesis and recent treatment advances.

To delivers this to our readers through original, innovative, and timely scientific and educational content, we are proud to announce the launch of EU FOCUS.

EU FOCUS is an international peer-reviewed journal providing innovative and clinically relevant research for practitioners in urology and urologic subspecialties. The editorial team of Jim Catto will strive to publish articles that are stimulating to read, educate and inform readers with the most up-to-date research that aim to bring about positive change in our health care systems and the way we deliver urologic care.

We believe that successful communication of new knowledge will ultimately translate to clinical benefit for people with urologic diseases through innovative formats and technologies with new features that enable faster delivery and access.

One of the priorities of EU FOCUS is to work closely with the European School of Urology to enhance and support the educational needs of urologists on behalf of the EAU Education Office.

EU FOCUS is committed to maintain the status and integrity of European Urology and its parent organization, the EAU. We will continue to employ a highly rigorous peer-review and editing process to evaluate manuscripts for scientific quality, novelty, and importance. We will follow the set policies of European Urology to ensure that authors disclose all relevant financial associations and that those financial associations do not influence published content.

We hope to serve those who are in the frontline of providing urologic care to patients worldwide.

EU FOCUS Vision: We are committed to publishing influential original research, opinions, and reviews that advance the science of urology and improve the clinical care of patients with urologic diseases.

EU FOCUS Mission: To effectively convey the findings of important clinical research, actionable discoveries, and state-of-the-art treatment pathways to the urology community

European Board of Urology introduces EBU-Medbook On-line Residency Curriculum system offers handy tools Prof. Dr. Stefan Müller President European Board of Urology Bonn (DE)

The European Urology Residency Curriculum by EBU, introduced in 2012, covers at least five years of specialty training and highlights the breadth of knowledge that is needed in managing urology patients with emergency and chronic conditions.

The curriculum also presents practical steps and how these may be accomplished by the residents. Aside from the core theoretical knowledge, the curriculum aims to build-up and enhance the resident’s skills which are necessary for them to become a trained general urologist. The curriculum lists 14 core

procedures and all European countries consented that competency in these procedures is essential for a urologist to practice independently.

With these goals in mind, we have designed the curriculum as a template against which European training schemes can be compared. It will help both trainers and residents to understand what they must achieve and focus on in their training. Moreover, this curriculum can serve as a European guide with the implicit objective that a part of it may be incorporated into training courses currently used across Europe.

The end goal, we believe, is for the curriculum to enable both teachers and residents to have a system that would augment and support the trajectory of their training.

The increasing interest from residents and national societies motivated us to introduce an online version of the European Residency Curriculum. Instead of developing our own online system, we saw the benefit of using an available, portfolio-based system such as Medbook, which has been in use now for some years.

Benefits of a portfolio A portfolio not only supports the process of continuing professional development and training, but also provides an organizing principle and tool which can clearly demonstrate the areas of achievement, training status and performance levels needed for periodic assessment. Throughout their urology training the residents will undergo regular appraisals and, as a specialist, may also need to go through a revalidation process. This requires a systematic collection and presentation of evidence through a portfolio.

Understanding the value of maintaining a portfolio, gathering and presenting evidence, and using reflective practice will be of benefit throughout one’s career. Ultimately, a portfolio showcases the proof of achievement, and underscores the competencies required for training.

Sturmberg and Farmer noted: “Teachers want students to focus on their learning to become capable doctors; yet students primarily want to focus on passing their exams.” They also stressed that “…a

well-structured capability portfolio, regularly presented and reviewed, will be a useful tool to guide the journey and should have the potential to help drive deep learning and allow the assessment of capabilities that are hard to assess using conventional approaches” (Sturmberg JP, Farmer L. Educating capable doctors—a portfolio approach.

Linking learning and assessment. Med Teacher 2009;31;85-9.).

Medbook for EBU Medbook is an online platform specifically developed for medical professionals. Serving as an excellent tool for maintaining a portfolio, it can be kept throughout one’s professional career. Urology residents in Belgium and the Netherlands already use this online tool, which is not only recognized as part of institutional requirements but has also proven to be successful. EBU-Medbook is more comprehensive than the current EBU Residency Curriculum and is unique in the sense that it features the Objective Structured Assessment of Technical Skills and Tool (OSATS) of the 14 EBU core procedures.

Moreover, EBU-Medbook offers interactive modules for residents and tutors. The approval process enables residents to have their tutor evaluate surgical procedures, and the feedback also enables users to monitor the progress.

EBU-Medbook is available at the special rate of € EUR 65,00 (excluding VAT) per user per year.

In addition to this unique offer, users can try it for three months, free of charge.

A resident who is trained in one of the UEMS/EBU member countries that holds the full member status can sign-up for free, thanks to a grant from Astellas.

Details at www.medbook.ebu.com For more information visit the EBU Booth A42 in the Exhibit Hall.

Residents Module

24

EUT Congress News

Tutors Module

Monday, 23 March 2015

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25

STEPS: Five years of fostering collaboration in onco-urology Education of young clinicians remains paramount

By Alba Leon Partnerships are key to the management of oncourological diseases: partnerships between urologists, medical oncologists and radiotherapists; between experienced and younger clinicians and patients, clinicians, professional bodies and the pharmaceutical industry.

All these stakeholders have an important role to play in ensuring that appropriate education, diagnosis and management is delivered in this vital area of care. In keeping with the need for strong partnerships, the EAU, the EAU Section of Oncological Urology (ESOU), and Ipsen have developed the STEPS programme.

STEPS, or Sessions To Evaluate ProgresS in the management of urological cancers, is specifically designed for recently specialised onco-urologists who want to learn directly from world-leading experts in bladder, prostate, renal and testicular cancer. The CME accredited programme is a fundamental part of the EAU/ESOU strategic partnership with Ipsen, and is founded in their shared commitment to the education of young urologists.

Supporting motivated clinicians Education is a life-long endeavour. In many ways specialising in onco-urology is really just the first step in a new journey; and like with most journeys, insider knowledge and expert guidance will help along the way. One of the key objectives of STEPS is to give access to that knowledge and guidance; to offer access to world-leading experts whose experience has been painstakingly built over many years of working in the field.

As Peter Hammerer (DE) said: “We all have a responsibility to get involved in teaching, discussing and motivating the next generation of young bright urologists.”

Since 2011, groups of between 15 and 20 younger clinicians have been enrolled into STEPS each year.

Organised as a closed session of the annual ESOU meeting, all those involved must apply in advance and are selected by the ESOU Board members based on age, experience and motivation. Each applicant is asked to submit a letter of support from their head of department to ensure their commitment to the field, and write a letter explaining their own personal motivation to be part of STEPS. Through this selection process STEPS aims to maximize the opportunities open to younger clinicians by providing the opportunity for direct interaction with the ESOU Board and high-level experts, strengthen existing ties and encourage projects between researchers that offer scientific authenticity and integrity, and support ESOU in its continued scientific ambitions and research-focused projects.

The programme also aims to offer a novel educational opportunity, expose younger clinicians to the activities of EAU/ESOU, and build, over time, a network of specialists.

For 2011 fellow Gianluca Giannarini (IT): “STEPS allows us to share our view on several areas of uro-oncology and modern multidisciplinarity, and to further improve our network of collaboration.”

In keeping with the theme of partnership, STEPS fellows are asked to review a case study in one of the core discussion areas – bladder, prostate, renal or testicular cancer. This case study then becomes the starting point for learning. Asked in advance how they would manage the case, their diagnosis and management strategies are then reviewed by the session chairman and used to pose additional questions, test suggestions and theories, and

Participants and mentors of the STEPS programme

interrogate the group on their understanding and application of guidelines.

In addition, each group of five STEPS fellows has the opportunity to raise their own questions, discuss their own cases, and demonstrate their own research to a senior clinician. For Arnulf Stenzl (DE), this programme “may help stimulate them to go into academics and develop their own projects; and us senior practitioners may be able to help them.”

A multinational, multidisciplinary affair Traditionally focused on onco-urologists, STEPS encourages applications from medical oncologists and radiotherapists to incorporate the perspectives of all those involved in the multidisciplinary management of patients with urological cancers. As Susanne Osanto (NL) explained: “There is added value in looking at a case together. Multiple therapeutic options and scenarios are weighed to reach the best solution, thanks to the different expertise involved.

This is often not the solution that first came to mind.”

The groups are not only multidisciplinary. To date, fellows from 22 different countries have participated in the sessions, which make it a great example of collaboration across borders. The exchange provides young clinicians with an opportunity to see how different health systems and practices work, and the different tools that each system employs for the benefit of the patient. As Dr. Roman Sosnowski (PL), 2015 fellow, said: “it gave me an opportunity to see what onco-urological treatment looks like in other countries, and how I could perhaps look at treatment in a different way in my own daily practice.”

This is one of the crucial aspects of the STEPS experience. Bringing together a multinational group of medical professionals across expertises, and with different experiences, allows the fellows to see different and new treatment possibilities. It can highlight the pitfalls, but also the solutions provided by diverse approaches. It opens the door to creating international ties among medical practitioners, and a networking opportunity that can prove invaluable for the careers of these young medical professionals. For the EAU, ESOU and Ipsen this exchange of knowledge across borders continues to be one of the main goals of the STEPS programme, and an important element of its growth.

Supported by the ESOU Board, to date 16 different internationally recognised experts have inspired 72 fellows from 22 countries – and the objective is to keep this programme rolling to help improve the management of all patients with urological cancers.

Experience meets drive Younger clinicians often face challenges when dealing with cases that fall outside of the most commonly recommended treatments and guidelines. The STEPS

programme is an opportunity for the participating fellows to learn about urological cancers and their treatment beyond the literature, with an analytical and strategic approach that is a result of experience.

Fellows of the programme benefit from the experience of opinion leaders who have years of recognised international practice in their respective field. For each case chosen by the expert who leads the discussion, fellows prepare for a discussion on the most current literature, and their treatment experiences.

According to Axel Heidenreich (DE), one of the STEPS mentors, it is logical that the trend for personalised medicine “should be paired with more personalised educational programmes.” This view further supports the small group rationale of STEPS; while the small group size and high level of interactivity encourages questions, it also allows the experts to push fellows to demonstrate their understanding of state-of-the-art technologies and techniques that are the future of their practice – discussions on the latest developments in molecular medicine or new imaging techniques that could be applied to the challenges at hand are commonplace.

The interaction between different specialities, countries and levels of experience serve to motivate medical practitioners to think about new areas and opportunities that may offer innovative solutions in the management of urological cancers. The overall intention is to use this mix to create better solutions that benefit the patient.

discuss the multidisciplinary approach in the treatment of urological cancers.

Titled ‘STEPS by STEP: 5 years and beyond’ the session was another opportunity for all fellows who have participated in STEPS since 2011 to continue their discussions in an interactive and informal environment. Featuring presentations and discussion on what constitutes optimal onco-urological care within a multidisciplinary environment, the session also incorporated an interactive quiz with fellows battling to demonstrate their knowledge and distinguish themselves from their peers – all in the name of fun!

On a more serious note, the session gave the participants and organisers an important opportunity to assess the achievements of the STEPS programme after five years and to map the way forward. As Maurizio Brausi (IT), Chairman of ESOU and of the STEPS programme commented: “We would like the fellows to work towards forming a strong network, to do research, and to take advantage of all the opportunities that they can have when they cross

Participants benefit from expert insights in clinical practice

Having an international opinion leader validating the solutions offered by younger practitioners can have a clear benefit on confidence. As Jakob Dobruch (PL) explained: “When I saw a case at my hospital that was very similar to the case we discussed in STEPS, I felt confident that I was using the right approach.”

borders.” The EAU, ESOU and Ipsen all consider the STEPS programme a key event for expanding networks, encouraging research, and finding ways for young practitioners with complementary interests and expertise to collaborate – partnerships that offer a collaborative way forward in onco-urology.

“This is a great learning opportunity, not only for the fellows themselves, but also for us as experts,” said Hendrik van Poppel (BE), EAU Adjunct Secretary General - Education and a regular contributor to the STEPS sessions as an expert mentor.

By providing opportunities to young specialists who are interested in the field of onco-urology, the STEPS programme is just one way in which IPSEN supports the educational goals of ESOU. All young clinicians, recently specialised, and with an interest in oncourological specialities are invited to apply for the 2016 session which will take place during the ESOU2016 meeting in Warsaw, Poland from January 15 to 17.

STEPS- the future To mark the 5th anniversary of the STEPS programme, a meeting was held yesterday during the congress here in Madrid. Specially organised for the STEPS fellows the meeting brought together leading specialists in urology, oncology and radiotherapy, to

For more information about the STEPS programme, please visit the Ipsen representatives at booth NB E08, located in Hall 9 of the Congress Centre.

STEPS offers young urologists and experts an opportunity to collaborate in research and other networkinig activities

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EUT Congress News

Monday, 23 March 2015

ESU Course 31 - Infectious diseases Sepsis and Fournier´s gangrene Prof. Dr. Florian M.E. Wagenlehner Clinic for Urology, Pediatric Urology and Andrology Justus-LiebigUniversity Giessen (DE)

This article is based on the ESU course which aims to provides a broad, up- to-date coverage of the most important and recent problems of infectious diseases in urology. It targets definitions and classifications of urogenital tract infections as well as topics such as diagnosis, treatment and prophylaxis.

All four strategies need to be started as early as possible.

The management of infections, in general, and of urogenital tract infections in particular has been severely compromised in the recent years by the rapid and continuous increase of antimicrobial resistance, which affects all entities of urogenital tract infections, but is extremely relevant in severe infections such as urosepsis. Antimicrobials are among the most important drugs in the management of patients with severe infections. Inappropriate use of antimicrobials may cause therapeutic failure in the individual patient and, additionally, may contribute towards promoting the emergence of resistant pathogens, which might also readily spread in the hospital setting.

gram-positive cocci, enterobacteria, and anaerobic bacteria.

The released toxins facilitate platelet aggregation and entrapment of complement, which, in conjunction with the release of heparinase by anaerobic bacteria, leads to small vessel thrombosis and tissue necrosis.

The destruction of tissue enhances the An adequate initial (e.g. in the first hour) antibiotic potential of acute renal therapy has been shown to correlate with improved failure. Fournier’s Urogenital tract infections range from benign outcome in septic shock and is therefore critical also gangrene is a rapidly infections, such as uncomplicated and recurrent in severe UTI. Inappropriate antimicrobial therapy in progressing infection cystitis to life threatening infections, such as urosepsis severe UTI is linked to a higher mortality rate as it has leading to septic shock, and Fournier gangrene. In approximately 30% of all been shown with other infections as well. Empirical if not treated in time. septic patients the infectious focus is localised in the antibiotic therapy therefore needs to follow certain Therapy consists of urogenital tract and arises from infections of the rules, which might be based upon the expected immediate, operative parenchymatous urogenital organs, e.g. kidneys, bacterial spectrum, the institutional specific resistance debridement, followed prostate or testicles. rates and the individual patient´s requirements. by subsequent Empirical initial treatment should provide broad operations, until the This may comprise obstructive diseases of the urinary antimicrobial coverage and should later be adapted infectious process has tract, such as ureteral stones, stenosis of the on the basis of culture results. been controlled. collecting system, tumour formations or anomalies of the urinary system. Urosepsis may also occur after Urologic specific treatment of complicating factors in A combination of operations in the urogenital tract. In patients with the urinary tract represents a cornerstone in the antibiotic therapy with nosocomial UTI treated in urology the prevalence of management of urosepsis and can be performed broad-spectrum urosepsis was on average about 12%. minimally invasive in most of the cases. beta-lactam antibiotics, Severe sepsis and septic shock are major causes of Additionally, the specific sepsis therapy is summarized fluoroquinolones, and Figure 1: A typical case of Fournier´s gangrene showing gangrenous alterations of the admission and death in intensive care units (ICUs) in the so called “surviving sepsis campaign clindamycin is scrotal skin resulting in an estimated 751,000 cases and 215,000 guidelines,” where the treatment recommendations recommended. deaths annually in the United States. Sepsis is more were organized in sepsis bundles, such as a common in men than in women, showing that resuscitation bundle (tasks to begin immediately and After initial recovery the gender-related differences play an important role. In to be accomplished within six hours) and a plastic reconstructive surgery may be challenging Monday, 23 March recent years, the incidence of sepsis has increased, management bundle (tasks to be completed within depending on the extent of surgical debridement 08.30-11.30: ESU Course 31, Infectious Diseases but the associated mortality has decreased suggesting 24 hours). necessary. improved management of patients.

Fournier’s gangrene Most severe sepsis cases transferred to the intensive Urosepsis is also characterized by specific diseases care units reported in the literature are related to entities. One of those is Fournier´s gangrene. pulmonary (45%) or abdominal infections (20-30%), Fournier’s gangrene is a necrotizing fasciitis of dartos with the urogenital tract accounting for 10% in Europe and Colles’ fascias, clinically presenting with scrotal EAU Education Online proudly presents: and 30% in USA. Data retrieved from the world wide gangrenous alterations (Figure 1). It is mainly seen in Global Prevalence on Infection in Urology (GPIU) Study men in the fourth to seventh decade but also occurs exhibited a steady increase on the prevalence of in women. urosepsis in hospitalized urological patients over the last 12 years, with a current rate of 25%.

Causes are operations or trauma in the genital or perineal region, including microlesions, or infectious Urosepsis is defined as sepsis caused by an infection processes from the rectal or urethral areas. Important in the urogenital tract (see Table 1). Sepsis is a predisposing factors are diabetes mellitus, liver systemic response to infection. The signs and insufficiency, chronic alcoholism, hematologic symptoms of SIRS (systemic inflammatory response diseases, or malnutrition. Fatality rates nowadays syndrome) which were initially considered to be were 7.5% in one large North American study. ‘mandatory’ for the diagnosis of sepsis, are now How well do you know the EAU Guidelines? Educate and test yourself considered to be alerting symptoms.

The use of a Fournier’s gangrene severity index has with this first in a series of EAU Guidelines E-courses. The online been shown to correlate well with the course of the Treating urosepsis disease. A Fournier’s gangrene severity index course features questions formulated by experts in the field, reviewed threshold value of nine was significantly associated by the EAU Guidelines Office and the Young Urologists Office.

Treatment of urosepsis comprises four basic strategies: with outcome: A score greater than nine showed a 75% probability of death, while a score of nine or less i) supportive therapy (stabilization and was associated with a 78% probability of survival. maintaining blood pressure); Prostate Cancer ii) antimicrobial therapy; The infectious process follows anatomically preLearning Objectives iii) control or elimination of the urological formed spaces and in contrast to gas gangrene, the • Review the most updated EAU guidelines on Prostate complicating factor; and fascial borders are respected in Fournier’s gangrene.

Cancer iv) specific sepsis therapy.

A mixed bacterial flora is seen, consisting of

The First EAU Guidelines E-Course:

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Table 1: Terminological definitions used in sepsis

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Systemic inflammatory response syndrome (SIRS): Response to a wide variety of clinical insults, which can be infectious, as in sepsis but may be non-infectious in aetiology (e.g. burns, pancreatitis). This systemic response is manifested by two or more of the following conditions: • • • •

Temperature > 38°C or < 36°C Heart rate > 90 beats min Respiratory rate > 20 breaths/min or PaCO2 < 32mmHg (< 4.3kPa) WBC > 12,000 cells/mm3 or < 4,000 cells/mm3 or ≥ 10% immature (band) forms

Sepsis: Activation of the inflammatory process due to infection Severe sepsis: Sepsis associated with organ dysfunction, hypoperfusion or hypotension.

Hypoperfusion and perfusion abnormalities may include but are not limited to lactic acidosis, oliguria or an acute alteration of mental status Septic shock: Sepsis with hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to lactic acidosis, oliguria, or an acute alteration in mental status. Patients who are on inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured.

Monday, 23 March 2015

uroweb.org/education Accreditation by EU-ACME has been requested

More info: educationonline@uroweb.org

EUT Congress News

27

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Low testosterone?

TESTIM restores testosterone levels, producing significant improvement in sexual function and mood as well as increased BMD and improved lean body mass1

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Abbreviated Prescribing Information Prescribing Information: Testim 50mg Gel. Testim is a clear to translucent gel. One tube of 5 g gel contains 50 mg testosterone. Indication: Testosterone replacement therapy for male hypogonadism when testosterone deficiency has been confirmed by clinical features and biochemical tests. Dosage and administration: Recommended starting dose: One tube of 5 g gel daily. If serum testosterone levels are below the normal range, the dose may be increased from 50 mg (one tube) to 100 mg (two tubes) once daily. Once opened apply the entire content of the tube immediately to clean dry intact skin of the shoulders and/or upper arms, preferably in the morning. Wash hands immediately after use. Do not apply to the genital area. Not for use in children. Not clinically evaluated in males less than 18 years of age. Contraindications: Androgens are contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate. Hypersensitivity to testosterone (synthesised from soy) or to any of the excipients. Pregnancy and lactation: Testim is not indicated for women and must not be used in pregnant or breastfeeding women. Pregnant women must avoid skin contact with Testim application sites. Warnings and precautions: Prior to therapy, the risk of prostate cancer must be excluded. Examine breast and prostate gland at least yearly and twice yearly in elderly or at risk patients (those with clinical or familial factors). Monitor serum calcium levels in patients with skeletal metastases at risk of hypercalcaemia/hypercalcuria. Testosterone may

32

EUT Congress News

Day 3 – MONDAY- TESTIM Ad (HUG) v2.indd 1

cause oedema with or without congestive cardiac failure in patients with severe cardiac, hepatic or renal insufficiency. In this case, stop treatment immediately. Use with caution in patients with hypertension, ischemic heart disease, epilepsy, and migraine. Possible increased risk of sleep apnoea in patients who are obese or with chronic respiratory disease. Improved insulin sensitivity may occur. Irritability, nervousness, weight gain, prolonged or frequent erections may indicate excessive androgen exposure requiring dosage adjustment. If severe application site reaction occurs, discontinue treatment if necessary. Periodically monitor testosterone concentrations, full blood count, lipid profile, and liver function. Testosterone may produce a positive reaction in an anti-doping test. Not for use in women. The gel may be transferred to others by skin to skin contact, which could lead to adverse reactions (inadvertent androgenisation) by repeated contact. Inform the patient about the transfer risk, which can be prevented by covering or washing the site before contact. Testim gel should not be prescribed for patients who may not comply with safety instructions (e.g. severe alcoholism, drug abuse, severe psychiatric disorders). The content of the tube is flammable. Testim contains propylene glycol which may cause skin irritation. Interactions: Interactions have been reported with oral anticoagulants, ACTH, corticosteroids and propranolol. Laboratory tests have shown that androgens may decrease levels of thyroxine-binding globulin. Undesirable effects: Common (1% to <10%): Application site reactions (rash, erythema, pruritus), increased PSA, hypertension worsened, acne, headache, increased haematocrit, increased red blood cell count and increased haemoglobin. Uncommon (0.1% to <1%): Hot flushes/flushing, pruritus and peripheral oedema.

Very rare (<0.01% to not known): Azoospermia. Gynaecomastia may uncommonly develop

and persist. Other known reactions to testosterone are: Prostate cancer, electrolyte changes, decreased libido, anxiety, emotional liability, generalized paresthesia, nausea, jaundice and liver function test abnormalities, hirsutism, alopecia, seborrhoea, muscle cramps, increased frequency of erections, priapism, prostate abnormalities, altered blood lipid levels (including reduction of HDL cholesterol), and weight gain. Please refer to the Summary of Product Characteristics for the full safety information. Overdose: Reports describing overdose have included doses up to 150 mg testosterone. No dose limiting toxicity has been reported from these spontaneous cases. Presentation: Testim is supplied as a Carton containing 30 x 5g tubes. Price: £32.00.

Legal classification: POM. PL Number: 03194/0105. Please refer to the Summary of Product Characteristics for full prescribing information. Company name and address: Ferring Pharmaceuticals Ltd., The Courtyard, Waterside Drive, Langley, Berks, SL3 6EZ. Date of Preparation: August 2009 Reference: 1. Dean J et al. Rev Urol 2004;6(Suppl 6):S22-29.

Prescribing information may differ in each country.

Testim is not approved in all European markets. Testim is a registered trademark of Auxilium Pharmaceuticals, Inc.

Date of preparation: December 2014 TM/1924/2014/ECOa Monday, 23 March 2015

29/01/2015 12:03