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Context The European Association of Urology (EAU) has released an updated version of the guidelines on non–muscle-invasive bladder cancer (NMIBC). Objective To present the 2021 EAU guidelines on NMIBC. Evidence acquisition A broad and comprehensive scoping exercise covering all areas of the NMIBC guidelines since the 2020 version was performed. Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries. Previous guidelines were updated, and the level of evidence and grade of recommendation were assigned. Evidence synthesis Tumours staged as Ta, T1 and carcinoma in situ (CIS) are grouped under the heading of NMIBC. Diagnosis depends on cystoscopy and histological evaluation of tissue obtained via transurethral resection of the bladder (TURB) for papillary tumours or via multiple bladder biopsies for CIS. For papillary lesions, a complete TURB is essential for the patient’s prognosis and correct diagnosis. In cases for which the initial resection is incomplete, there is no muscle in the specimen, or a T1 tumour is detected, a second TURB should be performed within 2–6 wk. The risk of progression may be estimated for individual patients using the 2021 EAU scoring model. On the basis of their individual risk of progression, patients are stratified as having low, intermediate, high, or very high risk, which is pivotal to recommending adjuvant treatment. For patients with tumours presumed to be at low risk and for small papillary recurrences detected more than 1 yr after a previous TURB, one immediate chemotherapy instillation is recommended. Patients with an intermediate-risk tumour should receive 1 yr of full-dose intravesical bacillus Calmette-Guerin (BCG) immunotherapy or instillations of chemotherapy for a maximum of 1 yr. For patients with high-risk tumours, full-dose intravesical BCG for 1–3 yr is indicated. For patients at very high risk of tumour progression, immediate radical cystectomy should be considered. Cystectomy is also recommended for BCG-unresponsive tumours. The extended version of the guidelines is available on the EAU website at https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/ . Conclusions These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice. Patient summary The European Association of Urology has released updated guidelines on the classification, risk factors, diagnosis, prognostic factors, and treatment of non–muscle-invasive bladder cancer. The recommendations are based on the literature up to 2020, with emphasis on the highest level of evidence. Classification of patients as having low, intermediate, or and high risk is essential in deciding on suitable treatment. Surgical removal of the bladder should be considered for tumours that do not respond to bacillus Calmette-Guerin (BCG) treatment and tumours with the highest risk of progression.

Background Owing to the morbidity of established radical treatment options for prostate cancer, alternative whole-gland and focal treatment strategies have emerged. High-intensity focused ultrasound (HIFU) is one of the most studied sources for tissue ablation and has been used since the 1990s. Objective To provide 21-yr oncological long-term follow-up data of an unselected series of patients who underwent whole-gland HIFU for nonmetastatic prostate cancer. Design, setting, and participants A total of 674 patients were treated between November 1997 and November 2012 in one university center. Outcome measurements and statistical analysis The oncological outcome was assessed by biopsy failure–free survival (BFFS), salvage treatment–free survival (STFS), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS). Multivariable Cox proportional hazard regression analyses were performed to estimate the prognostic relevance of clinical variables. Results and limitations In total, 560 patients were included into the evaluation and the median follow-up was 15.1 yr, with a range up to 21.4 yr. At 15 yr, CSS rates for low-, intermediate-, and high-risk patients were 95%, 89%, and 65%, respectively; MFS, STFS-1 (salvage treatment other than HIFU), STFS-2 (salvage treatment including repeat HIFU), and BFFS rates were 91%, 85%, and 58%; 77%, 63%, and 29%; 67%, 52%, and 28%; and 82%, 73%, and 47%, respectively. Preoperative high-risk category was an independent predictor of inferior OS, CSS, MFS, STFS, and BFFS. Conclusions Although whole-gland HIFU achieved good long-term cancer control in low- and intermediate-risk patients, high-risk patients should not be treated routinely by HIFU. Intermediate-risk patients achieve high CSS and MFS rates, but a relevant salvage treatment rate has to be reckoned with. Long-term data after whole-gland therapy might help derive implications for focal treatment sources and patient selection. Patient summary Long-term data after whole-gland high-intensity focused ultrasound (HIFU) therapy are crucial to prove its oncological efficacy, and may help derive implications for focal treatment strategies and patient selection. In this context, whole-gland HIFU achieved good long-term cancer control up to 21 yr in low- and intermediate-risk prostate cancer (PCa) patients. Owing to considerably inferior long-term cancer control, it should not routinely be used in high-risk PCa patients.

Background Robotic-assisted laparoscopic prostatectomy (RALP) using a combination of capnoperitoneum and steep Trendelenburg positioning (STP) results in important pathophysiological pulmonary changes. The aim of the study was to evaluate if restrictive crystalloid administration and individual management of positive end-expiratory pressure (PEEP) improve peri- and postoperative pulmonary function in patients undergoing RALP in permanent 45 degree STP.Methods 98 patients undergoing RALP under standardized anesthesia were either allocated to a standard PEEP (5 mmHg) group or an individualized high PEEP group. Furthermore, each group was divided into a liberal vs restrictive crystalloid group (30 ml vs 15 ml per kg predicted body weight). Individualized PEEP levels were determined by means of preoperative PEEP titration in STP. In each of the four study groups following intraoperative parameters were analyzed: ventilation setting (PIP, driving pressure [Pdriv], lung compliance [LC], mechanical power [MP]), and postoperative pulmonary function (bed-side spirometry). The following spirometric parameters were measured pre- and postoperatively: the Tiffeneau index (FEV1/FVC ratio) and mean forced expiratory flow (FEF25 − 75). Data are shown as mean ± standard deviation (SD), and groups were compared with ANOVA. A P-value of Results The two individualized high PEEP groups (mean PEEP 15.5 [± 1.71 cmH2O]) showed significantly higher PIP and MP levels but significantly decreased Pdriv and increased LC. On the first and second postoperative day, patients with individualized higher PEEP levels had a significantly higher mean Tiffeneau index (day 1: 77.6% (± 6.6) vs 73.6% (± 8.8), P = 0.014; day 2: 76.5% (± 6.1) vs 72.7% (± 9.3), P = 0.021) and FEF25 − 75 (day 1: 2.41 liter/sec (± 0.9) vs 1.95 liter/sec (± 0.8), P = 0.009; day 2: 2.45 liter/sec (± 0.9) vs 2.07 liter/sec (± 0.8), P = 0.033). Perioperative oxygenation and postoperative spirometric parameters were not influenced by restrictive or liberal crystalloid infusion in either of the two PEEP groups.Conclusions Higher individualized PEEP levels during RALP improved blood oxygenation, lung-protective ventilation, and postoperative pulmonary function up to 48 hours after surgery. Restrictive crystalloid infusion during RALP seemed to have no effect on peri- and postoperative oxygenation and pulmonary function.

Purpose: Transcutaneous tibial nerve stimulation (TTNS) has proven to be a valuable treatment option for various lower urinary tract conditions, such as overactive bladder syndrome and neurogenic detrusor overactivity. The aim of this study was to investigate acute changes in urodynamic parameters due to bilateral TTNS.Methods: Fifty-one patients (18–87 years; 61% female) with various lower urinary tract symptoms were enrolled in this study. They were single-blinded and randomly assigned to receive simultaneous bilateral TTNS either during their first urodynamic examination, followed by a second round using a placebo stimulation technique, or vice versa.Results: For subjects without signs of anatomical pathologies, the filling volume at the first desire to void (FDV) increased significantly by 54 mL (interquartile range [IQR], 26–81 mL; P100 mL) increased by 76 mL compared to patients without urinary retention (IQR, 6–166 mL; P=0.03).Conclusions: Compared to placebo, simultaneous bilateral TTNS showed significant improvements in bladder functioning, such as delayed FDV, increased maximum cystometric capacity, and reduced urinary retention. Patients with signs of anatomical pathologies did not seem to benefit from TTNS. Further studies need to be conducted to compare the effectiveness of bilateral versus unilateral TTNS.

Aim [99mTc]Tc-PSMA-based radioguided surgery (TPRS) represents a curative approach for localized relapse of prostate cancer. For its simplified regulatory permission, the radiation protection authorities require a 99mTc- activity below the exemption limit of 10 MBq at the time of surgery. Our aim was to determine the optimal amount of radioactivity (OAR) to comply with that limit and to estimate the maximum number of TPRS procedures per year and surgeon without triggering the full monitoring obligations. Methods In this retrospective study, a dose rate meter was calibrated using measurements on phantoms and from recently injected (1 min p. i.) patients to determine the activity in the patient from measured dose rates. The effective half-life of 99mTc-PSMA-I&S in patients was determined from repeated dose rate measurements to estimate dose parameters of relevance for radiation protection. External exposures of the surgeons were measured with personal dosimeters calibrated in Hp(10). The surgeon’s finger dose Hp(0.07) is estimated from radioactivity measured in resected lymph nodes. Potenzial incorporations were estimated for an activity of 10 MBq. Results From the first 6 subsequent patients, an effective half-life of 4.15 h was observed. Assuming an operation time 24 h p. i., the OAR was 550 MBq. Operations lasting in average 2 h in a distance of 0.25 m to the patient imply a body dose for surgeons of 4.16 µSv per procedure. Based on these estimates, the surgeon’s Hp(10) is less than 1 mSv per year with up to 241 operations per year. Hp(0.07) and potential incorporation of activity do not lead to further limitations. Summary All radiation protection regulations are met with adherence to OAR recommended here without triggering the full monitoring obligations from radiation protection regulations.

PurposeTo date, over 4.2 million Germans and over 235 million people worldwide have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Uro-oncology (UO) patients are particularly vulnerable but in urgent need of life-saving systemic treatments. Our multicentric study examined the impact of the COVID-19 crisis on the medical care of UO patients in German university hospitals receiving ongoing systemic anti-cancer treatment and to detect the delay of medical care, defined as deferred medical treatment or deviation of the pre-defined follow-up assessment.MethodsData of 162 UO patients with metastatic disease undergoing systemic cancer treatment at five university hospitals in Germany were included in our analyses. The focus of interest was any delay or change in treatment between February 2020 and May 2020 (first wave of the COVID-19 crisis in Germany). Statistical analysis of contingency tables were performed using Pearson’s chi-squared and Fisher’s exact tests, respectively. Effect size was determined using Cramér’s V (V).ResultsTwenty-four of the 162 patients (14.8%) experienced a delay in systemic treatment of more than 2 weeks. Most of these received immuno-oncologic (IO) treatments (13/24, 54.2%,p = 0.746). Blood tests were delayed or canceled significantly more often in IO patients but with a small effect size (21.1%,p = 0.042,V = 0.230). Treatment of patients with renal cell carcinoma (12/73, 16.4%) and urothelial carcinoma (7/32, 21.9%) was affected the most.ConclusionsOur data show that the COVID-19 pandemic impacted the medical care of UO patients, but deferment remained modest. There was a tendency towards delays in IO and ADT treatments in particular.

Introduction: After implantation of an artificial urinary sphincter (AUS) due to stress urinary incontinence, in some cases revision procedures may be necessary. This is mostly due to device infection or cuff erosion in the long term. The aim of this study was to evaluate the impact of early revision procedures (prior to or immediately after AUS activation) on the long-term outcome. Methods: We retrospectively evaluated patients who underwent primary AUS implantation between 2006 and 2019. Patients with previous radiotherapy, urethroplasty, urethral stent placement, or repeat AUS implantation were excluded. Early revision was defined as prior to or immediately after AUS activation and comprised pump repositioning or cuff size adaptation due to difficulties in using the pump, persistent urinary incontinence, or urinary retention. Patients were compared with regard to complication rates, functional outcome, and patient satisfaction. Univariable and multivariable logistic regression analyses were performed to analyze risk factors for early AUS revision. Kaplan-Meier analysis evaluated explantation-free survival. Results: A total of 250 patients were included. Twenty patients (8%) required early revision (pump repositioning in 15 cases [75%], cuff downsizing in 3 cases [15%], and cuff upsizing in 2 cases [10%]). Mean follow-up was 78.6 months. 96.4% of all patients were objectively continent at the time of last follow-up without differences between both groups, and patient satisfaction was high in both groups. No differences with regard to mechanical implant failure, tissue atrophy, and AUS explantation due to cuff erosion or implant infection were observed. Explantation-free survival was comparable in both groups. On univariable logistic regression analysis, coronary artery disease and transcorporal cuff placement were associated with early AUS revision. Conclusion: Early revision after AUS implantation can be performed without negative impact on the long-term outcome.

To assess the true cumulative morbidity after RC by implementing the Comprehensive Complication Index (CCI) over a 90-day period, since recent evidence suggests underreporting of the cumulative morbidity after radical cystectomy (RC) with inconsistent complication rates when reported with conventional reporting systems.Medical records of 433 patients with bladder cancer who underwent RC were retrospectively reviewed over a 90-day period. Clinical variables were assessed and complications were graded by the Clavien-Dindo Classification (CDC). The resulting 30- and 90-day CCI-scores were calculated and compared for each patient. Multivariable regression models for developing at least one severe (≥CDC IIIb) complication were designed.Overall, 848 complications were recorded in 371 patients (85.7%). Severe complications occurred in 130 patients (30%) and the cumulative morbidity corresponded to the level of a severe complication in 159 patients (36.7%), meaning an upgrade in 6.7% of patients compared to the CDC. The 90-day CCI (24.2 (median, IQR 20.9-39.7)) was higher than the 30-day CCI (22.6 (median, IQR 8.7-39.7)), (p 0.001). Comorbidity indices (ASA, ACE 27), BMI, and incontinent urinary diversions were independent risk factors for suffering a severe complication within 90 days post-surgery.The cumulative morbidity (CCI) after RC seems to be higher than previously reported with CDC, especially over a 90-day period. The CCI is an appropriate assessment-tool with an upgrade in morbidity in a significant proportion of patients when compared to the CDC. BMI, several comorbidity indices, and incontinent urinary diversions are independent risk factors for suffering a severe complication after RC.

BACKGROUND: AQP proteins show a variety of functions in human cell metabolism. The role of different AQP subtypes in tumor metabolism and prognosis are subject of ongoing research. OBJECTIVE: To investigate the mRNA expression of Aquaporin (AQP) 3, 4, 7 and 9 in pT1 non-muscle-invasive bladder cancer (NMIBC) and its prognostic value in therapeutic decision making. METHODS: Formalin-fixed-paraffin-embedded (FFPE) tissues from transurethral resection of the bladder (TURB) from 112 patients with initial diagnosis of stage pT1 NMIBC were analyzed retrospectively together with clinical data and therapeutic approaches. mRNA expression of AQP3, 4, 7 and 9 was measured and quantified using RT-qPCR. RESULTS: Of the 112 patients (83.9%male, median age 72 years), 40 had a recurrence (35.7%), 16 a progression (14.3%) and 14 patients (12.5%) died tumor-related. mRNA expression for AQP3 was detected in 99.1%, AQP4 in 46.4%, AQP7 in 86.6%and AQP9 in 97.3%. Spearman analysis revealed statistically significant correlations between AQP3, AQP7 and AQP9 mRNA expression with adverse clinical and histopathological parameters (WHO1973 grade 3, concomitant Cis or multifocality). High AQP9 mRNA expression was associated with worse PFS in the total cohort (p = 0.034) and in Grade 3 tumors (p = 0.003) in Kaplan-Meier analysis. In patients with bladder sparing approach, high AQP3 mRNA expression was significantly associated with worse CSS in patients receiving BCG therapy (p = 0.029). CONCLUSIONS: mRNA expression of AQP3, 7 and 9 correlates with adverse clinical and pathological parameters. AQP3 and 9 may help to identify a subgroup of highest risk patients who may be considered for early cystectomy.

Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer (BC). FGFR3 mutations are common in noninvasive BC and associated with favorable BC prognosis. Overexpression was reported in up to 40% of FGFR3 wild-type muscle-invasive BC. We analyzed FGFR3 mutations, FGFR3, and p53 protein expression and assessed their prognostic value in a cohort of 1000 chemotherapy-naive radical cystectomy specimens. FGFR3 mutations were found in 11%, FGFR3 overexpression was found in 28%, and p53 overexpression was found in 69% of tumors. Among FGFR3 mutant tumors, 73% had FGFR3 overexpression versus 22% among FGFR3 wild-type tumors. FGFR3 mutations were significantly associated with lower pT stage, tumor grade, absence of carcinoma in situ, pN0, low-level p53, and longer disease-specific survival (DSS). FGFR3 overexpression was associated only with lower pT stage and tumor grade. Moreover, FGFR3 overexpression was not associated with DSS in patients with FGFR3 wild-type tumors. In conclusion, FGFR3 mutations identified patients with favorable BC at cystectomy. Our results suggest that FGFR3 mutations have a driver role and are functionally distinct from FGFR3 overexpression. Hence, patients with FGFR3 mutations would be more likely to benefit from anti-FGFR3 therapy. Ideally, further research is needed to test this hypothesis. Patient summary: Oncogenic fibroblast growth factor receptor 3 (FGFR3) mutations are very common in bladder cancer. In this report, we found that these FGFR3 mutations were associated with favorable features and prognosis of bladder cancer compared with patients with FGFR3 overexpressed tumors only. As a consequence, patients with FGFR3 mutant tumors would be more likely to benefit from anti-FGFR3 therapy than patients with FGFR3 protein overexpression only.

ZusammenfassungDas Hochrisiko-NMIBC ist eine Herausforderung, da es zwar noch nicht muskelinvasiv ist, aber eine hohe Progressionsneigung aufweist. Eine Erfassung der Prognosegruppe ist wichtig und über Nomogramme empfohlen. Neben einer gründlichen transurethralen Resektion empfiehlt sich eine adjuvante Therapie mit BCG, was momentan teils aber nur eingeschränkt verfügbar ist. Daneben ist eine hypertherme Chemotherapie untersucht, deren Datenbasis zum jetzigen Zeitpunkt aber keine breite Anwendung rechtfertigt. Neue Ansätze wie die Checkpoint-Blockade-Inhibition werden untersucht, bieten aber keine Möglichkeit zur breiten praktischen Anwendung bei uns. Eine radikale Zystektomie ist daher in Anbetracht der hohen Progressionsneigung bei ungünstiger Tumorkonstellation immer zu indizieren.

Purpose Inguinal lymphadenectomy in penile cancer is associated with a high rate of wound complications. The aim of this trial was to prospectively analyze the effect of an epidermal vacuum wound dressing on lymphorrhea, complications and reintervention in patients with inguinal lymphadenectomy for penile cancer. Patients and methods Prospective, multicenter, randomized, investigator-initiated study in two German university hospitals (2013–2017). Thirty-one patients with penile cancer and indication for bilateral inguinal lymph node dissection were included and randomized to conventional wound care on one side (CONV) versus epidermal vacuum wound dressing (VAC) on the other side. Results A smaller cumulative drainage fluid volume until day 14 (CDF) compared to contralateral side was observed in 15 patients (CONV) vs. 16 patients (VAC), with a median CDF 230 ml (CONV) vs. 415 ml (VAC) and a median maximum daily fluid volume (MDFV) of 80 ml (CONV) vs. 110 ml (VAC). Median time of indwelling drainage: 7 days (CONV) vs. 8 days (VAC). All grade surgery-related complications were seen in 74% patients (CONV) vs. 74% patients (VAC); grade 3 complications in 3 patients (CONV) vs. 6 patients (VAC). Prolonged hospital stay occurred in 32% patients (CONV) vs. 48% patients (VAC); median hospital stay was 11.5 days. Reintervention due to complications occurred in 45% patients (CONV) vs. 42% patients (VAC). Conclusions In this prospective, randomized trial we could not observe a significant difference between epidermal vacuum treatment and conventional wound care.

Background: Papillary urothelial neoplasm of low malignant potential (PUN-LMP) was introduced as a noninvasive, noncancerous lesion and a separate grade category in 1998. Subsequently, PUN-LMP was reconfirmed by World Health Organization (WHO) 2004 and WHO 2016 classifications for urothelial bladder tumors. Objectives: To analyze the proportion of PUN-LMP diagnosis over time and to determine its prognostic value compared to Ta-LG (low-grade) and Ta-HG (high-grade) carcinomas. To assess the intraobserver variability of an experienced uropathologist assigning (WHO) 2004/2016 grades at 2 time points. Materials and methods: Individual patient data of 3,311 primary Ta bladder tumors from 17 hospitals in Europe and Canada were available. Transurethral resection of the tumor was performed between 1990 and 2018. Time to recurrence and progression were analyzed with cumulative incidence functions, log-rank tests and multivariable Cox-regression stratified by institution. Intraobserver variability was assessed by examining the same 314 transurethral resection of the tumorslides twice, in 2004 and again in 2018. Results: PUN-LMP represented 3.8% (127/3,311) of Ta tumors. The same pathologist found 71/314 (22.6%) PUN-LMPs in 2004 and only 20/314 (6.4%) in 2018. Overall, the proportion of PUN-LMP diagnosis substantially decreased over time from 31.3% (1990-2000) to 3.2% (2000-2010) and to 1.1% (2010-2018). We found no difference in time to recurrence between the three WHO 2004/2016 Ta-grade categories (log-rank, P = 0.381), nor for LG vs. PUN-LMP (log-rank, P = 0.238). Time to progression was different for all grade categories (log-rank, P < 0.001), but not between LG and PUN-LMP (log-rank, P = 0.096). Multivariable analyses on recurrence and progression showed similar results for all 3 grade categories and for LG vs. PUN-LMP. Conclusions: The proportion of PUN-LMP has decreased to very low levels in the last decade. Contrary to its reconfirmation in the WHO 2016 classification, our results do not support the continued use of PUN-LMP as a separate grade category in Ta tumors because of the similar prognosis for PUN-LMP and Ta-LG carcinomas. (C) 2019 Elsevier Inc. All rights reserved.

Introduction: While holmium laser enucleation of the prostate (HoLEP) is accepted as safe and efficient, a long learning curve is considered the main reason for its slow adoption in clinical practice. So far, no standardized and easy-to-use parameter has been implemented to measure surgical experience or efficiency which could be useful for training and quality control purposes. The aim of the present study was to evaluate the learning curves of 2 HoLEP beginners and to identify applicable efficiency outcome measures as well as potentially complicating factors in performing HoLEP. Patients and Methods: A total of 594 patients treated by HoLEP between September 2016 and May 2019 were enrolled. The procedures were initially performed by 1 HoLEP expert (reference surgeon); over time, 2 further surgeons were trained. Baseline characteristics, enucleation weight, morcellation and enucleation time, laser energy usage, and postoperative results were recorded prospectively. The learning curves of the 2 novices were analyzed and compared to the reference surgeon. Logistic regression analyses were performed to identify predictors for postoperative grade ≥2 complications. Results: Median enucleation ratio and complication rates did not significantly alter along the learning curves. Median enucleation speed and laser energy application of the 2 novices significantly improved with growing experience. Combining these variables, we introduced the “HoLEP efficiency score” (HES) which demonstrated the most appropriate value to reflect the surgical experience and efficiency. The median HES for the reference surgeon was 82.8 min kJ/g. For the 2 novices, a drop from 130 and 124.4 min kJ/g by −57 and −30%, respectively, was observed. Among several tested clinical parameters, the presence of prostate cancer (p = 0.047) and the surgical caseload (p < 0.001) influenced the HES. On multivariable logistic regression, American Society of Anesthesiologists score and prostate cancer were independent predictors for grade ≥2 complications (p = 0.002, odds ratio [OR] 2.042 and p = 0.038, OR 1.940). Conclusion: We introduce the HES as an objective and measurable tool to quantify surgical efficiency. In clinical practice, the HES may find application in training and quality control purposes as well as in comparing surgical modifications and hardware. Patients with prostate cancer seem to be more challenging cases and have a higher risk for complications, and may preferably be treated by experienced surgeons.

Marker research, and in particular urine bladder cancer marker research throughout the past three decades, devours enormous scientific resources in terms of manpower (not to mention time spent on reviewing and editorial efforts) and financial resources, finally generating large numbers of manuscripts without affecting clinical decision making. This is mirrored by the fact that current guidelines do not recommend marker use due to missing level 1 evidence. Although we recognize the problems and obstacles, the authors of this commentary feel that the time has come to abandon the current procedures and move on to prospective trial designs implementing marker results into clinical decision making. Our thoughts and concerns are summarized in this comment.

Purpose: To evaluate the risk factors associated with positive surgical margins' (PSMs) location and their impact on disease-specific survival (DSS) in patients with bladder cancer (BCa) undergoing radical cystectomy (RC). Methods: We analyzed a large multi-institutional cohort of patients treated with upfront RC for non-metastatic (cT1-4aN0M0) BCa. Multivariable binomial logistic regression analyses were used to assess the risk of PSMs at RC for each location after adjusting for clinicopathological covariates. The Kaplan–Meier method was used to estimate DSS stratified by margins’ status and location. Log-rank statistics and Cox’ regression models were used to determine significance. Results: A total of 1058 patients were included and 108 (10.2%) patients had PSMs. PSMs were located at soft-tissue, ureter(s), and urethra in 57 (5.4%), 30 (2.8%) and 21 (2.0%) patients, respectively. At multivariable analysis, soft-tissue PSMs were independently associated with pathological stage T4 (pT4) (Odds ratio (OR) 6.20, p < 0.001) and lymph-node metastases (OR 1.86, p = 0.04). Concomitant carcinoma-in-situ (CIS) was an independent risk factor for ureteric PSMs (OR 6.31, p = 0.003). Finally, urethral PSMs were independently correlated with pT4-stage (OR 5.10, p = 0.01). The estimated 3-years DSS rates were 58.2%, 32.4%, 50.1%, and 40.3% for negative SMs, soft-tissue-, ureteric- and urethral PSMs, respectively (log-rank; p < 0.001). Conclusions: PSMs’ location represents distinct risk factors’ patterns. Concomitant CIS was associated with ureteric PSMs. Urethral and soft-tissue PSM showed worse DSS rates. Our results suggest that clinical decision-making paradigms on adjuvant treatment and surveillance might be adapted based on PSM and their location.

Genetic variation in the transmembrane channel-like (TMC)6/TMC8 region has been linked to β-type human papillomavirus (HPV) infection and squamous cell carcinoma (SCC) of the skin and the head and neck, α-type HPV persistence and progression to cervical cancer. The functional variant rs7208422 of the TMC8 gene was suggested to have a high impact on susceptibility to β-papillomaviruses and their oncogenic potential and to also have an influence on α-type HPV-related disease. The aim of the present study was to evaluate a possible influence of rs7208422 on penile cancer risk, a known α-type HPV-related malignancy. Therefore, the distribution of rs7208422 was determined by direct Sanger sequencing of 104 Caucasian penile SCC cases and compared to data of 3,810 controls taken from the literature. HPV detection was performed by usage of GP5+/6+ primers and subtype-specific PCR. It was observed that the distribution of rs7208422 followed the Hardy-Weinberg equilibrium in both cases and controls. HPV DNA was detected in 39% of the penile SCC cases. Overall, there was no significant difference in the distribution of rs7208422 neither between cases and controls (P=0.726) nor between HPV-positive and -negative penile SCC cases (P=0.747). There was also no association between rs7208422 genotypes and age of disease onset (P=0.740). In conclusion, the present data argue against a significant impact of rs7208422 on the risk for the development of penile SCC in Caucasians. Even in combination with the HPV status, the SNP appears not to influence the risk of penile SCC in HPV-positive cases.

There is increasing interest in the use of cell-free circulating tumor DNA (ctDNA) as a serum marker for therapy assessment in prostate cancer patients. Prostate cancer is characterized by relatively low numbers of mutations, and, in contrast to many other common epithelial cancers, commercially available single nucleotide mutation assays for quantification of ctDNA are insufficient for therapy assessment in this disease. However, prostate cancer shares some similarity with translocation-affected mesenchymal tumors (e.g., leukemia and Ewing sarcoma), which are common in pediatric oncology, where chromosomal translocations are used as biomarkers for quantification of the tumor burden. Approximately 50% of prostate cancers carry a chromosomal translocation resulting in generation of the TMPRSS2-ERG fusion gene, which is unique to the tumor cells of each individual patient because of variability in the fusion breakpoint sites. In the present study, we examined the structural preconditions for TMPRSS2-ERG fusion sites in comparison with mesenchymal tumors in pediatric patients to determine whether the sequence composition is suitable for the establishment of tumor-specific quantification assays in prostate cancer patients. Genomic repeat elements represent potential obstacles to establishment of quantification assays, and we found similar proportions of repeat elements at fusion sites in prostate cancer to those reported for mesenchymal tumors, where genomic fusion sequences are established as biomarkers. Our data support the development of the TMPRSS2-ERG fusion gene as a noninvasive tumor marker for therapy assessment, risk stratification, and relapse detection to improve personalized therapy strategies for patients with prostate cancer.

Zusammenfassung Hintergrund Gemäß einer aktuellen Metaanalyse zeigt in Europa jeder zweite Patient mit einem Peniskarzinom (PeK) eine Assoziation mit dem Humanen Papillomavirus (HPV). Es liegen keine Daten darüber vor, inwieweit UrologInnen die Häufigkeit dieser viralen Karzinogenese kennen. Methoden Es wurde ein 14-Items umfassender deutschsprachiger Survey erstellt und in Q3/2018 einmalig an UrologInnen von 45 Kliniken in Deutschland (n = 34), Österreich (n = 8), der Schweiz (n = 2) und Italien/Südtirol (n = 1) verschickt. Insgesamt waren nach vorher definiertem Qualitätsstandard 557 Fragebögen auswertbar (mediane Rücklaufquote 85,7 %). In dem Survey wurde u. a. nach der Häufigkeit HPV-assoziierter PeK in Europa gefragt und 4 Antwortmöglichkeiten vorgegeben: (A)-„ 50 – 75 %“, (D)-„kein Wissen über die Häufigkeit des Zusammenhangs“. Es wurde in der Auswertung eine Toleranz von 50 % akzeptiert, sodass B und C (25 – 75 %) als korrekte Antworten gewertet wurden. Mittels eines Bootstrap-korrigierten multivariaten logistischen Regressionsmodells wurden Kriterien identifiziert, die unabhängig eine richtige Antwort der Befragten vorhersagten. Ergebnisse Die Kategorien A – D wurden von 19,2 % (n = 107), 48,8 % (n = 272), 12,9 % (n = 72) bzw. 19 % (n = 106) als Antwort gewählt, sodass der Endpunkt von 61,8 % (n = 344) der UrologInnen erreicht wurde (B + C). Die selbstständige Durchführung der Chemotherapie durch die Urologische Klinik (OR 1,55; p[Bootstrap] = 0,036) und die Anzahl der urologischen Klinikbetten (OR 1,02; p[Bootstrap] = 0,025) waren die einzigen Studienkriterien, die signifikant das richtige Ergebnis prädizierten. Der Status einer Universitätsklinik (p = 0,143), eine leitende Position der UrologInnen (p = 0,375) bzw. die jährliche Anzahl behandelter PeK-Patienten (p = 0,571) blieben hingegen ohne signifikanten Einfluss auf den Endpunkt. Schlussfolgerung Unsere Studienergebnisse zeigen, dass sich deutschsprachige Klinik-UrologInnen der Häufigkeit einer gegenwärtigen HPV-Assoziation des PeK nur unzureichend bewusst sind.

Prostate cancer is the second most common cancer in men worldwide, and sedentary behavior is widespread, yet reviews and meta-analyses summarizing the role of sedentary behavior as a potential risk factor for prostate cancer are scarce. We searched PubMed, Web of Science, and Cochrane databases for relevant articles up to January 2019. We pooled maximally adjusted risk estimates in a random effects model and performed meta-regression meta-analysis, assessed heterogeneity and publication bias using I², funnel plots, and Egger and Begg tests, and conducted sensitivity analyses and influence diagnostics. Data from 12 prospective cohort studies including a total of 30,810 prostate cancer cases were analyzed. We found no statistically significant association between high versus low sedentary behavior and prostate cancer incidence [RR = 1.07; 95% confidence interval (CI), 0.99–1.16; P = 0.10]. We noted that adjustment for body mass index (BMI) modified the relation of sedentary behavior to prostate cancer, particularly aggressive cancer. Sedentary behavior was related to a statistically significant increased risk of aggressive prostate cancer in analyses not adjusted for BMI (RR = 1.21; 95% CI, 1.03–1.43), whereas no association was apparent in BMI-adjusted analyses (RR = 0.98; 95% CI, 0.90–1.07), and the difference between those summary risk estimates was statistically significant (Pdifference = 0.02). Sedentary behavior is not independently associated with prostate cancer. However, prolonged sedentary behavior may be related to increased risk of aggressive prostate cancer through a mechanism involving obesity. This finding represents a potentially important step toward considering sedentary behavior as a modifiable behavioral risk factor for aggressive prostate cancer.

Insbesondere in den letzten zehn Jahren gab es in der Urologie eine exponentielle Zunahme robotisch assistierter Operationen. Die Weiterentwicklung der minimalinvasiven Chirurgie fordert ein Uberdenken der etablierten Ausbildungsparadigmen aus dem Bereich der offenen Chirurgie. An einer gut strukturierten Klinik mit entsprechender Fallzahl sollte die robotische Ausbildung dabei niemals zulasten der Ergebnisqualitat gehen.

Context The oncological efficacy of routine lymphadenectomy (lymph node dissection [LND]) at the time of radical nephroureterectomy (RNU) remains controversial. Objective To systematically review the available literature assessing the impact of LND in upper tract urothelial carcinoma (UTUC) patients. Evidence acquisition Embase, Medline, and Cochrane databases were searched for all studies comparing outcomes of patients undergoing RNU without LND versus any form of LND. We identified nine retrospective studies eligible for inclusion in this systematic review. We took cancer-specific survival (CSS) as the primary end point, and performed a narrative review and risk of bias assessment. Evidence synthesis Six studies compared outcomes of no LND versus LND. Three studies compared complete LND versus incomplete LND versus no LND. The incidence of pN+ in patients with high-stage (≥pT2) tumours ranged from 14.3% to 40%. Pre- and postoperative characteristics differed among the study groups, potentially biasing the results, as demonstrated by the risk of bias assessment, potentially favouring the LND group. Oncological outcomes such as cancer-specific, overall, recurrence-free, and metastasis-free survival were reviewed, demonstrating a survival benefit with LND in high-stage disease of the renal pelvis. Conclusions Template-based and complete LND improves CSS in patients with high-stage (≥pT2) UTUC and reduces the risk of local recurrence. The impact of LND in ureteral tumours remains uncertain. Patient summary Studies comparing radical nephroureterectomy with or without the removal of nodes (lymph node dissection [LND]) were analysed. LND improves survival in patients with high-stage disease of the renal pelvis, if it is performed according to an anatomical template-based approach.

To compare the oncological long-term efficacy of whole gland high-intensity focused ultrasound (HIFU) therapy and radical prostatectomy (RP) in patients with clinically localized prostate cancer. 418 patients after open RP (1997–2004) were compared with 469 patients after whole gland HIFU (1997–2009) without preselection. Oncological follow-up focused on biochemical relapse, salvage treatment, life status and cause-specific mortality. The univariate log rank test was used to compare both treatment options regarding overall survival (OS), cancer-specific survival (CSS), biochemical failure-free survival (BFS) and salvage treatment-free survival (STS). To adjust the treatment effect for further prognostic baseline variables, a multivariable Cox proportional hazards regression model was calculated for each end point. Median follow-up was 13.3 years in the RP group and 6.5 years in the HIFU group. OS/CSS/BFS/STS rates at 10 years were 91/98/80/80% after RP and 76/94/70/71% after HIFU. HIFU therapy (reference RP) was a significant and independent predictor for an inferior OS, CSS and STS. In subgroup analysis, HIFU provided significantly reduced CSS for intermediate- (p = 0.010) and high-risk patients (p = 0.048); whereas no difference was observed in the low-risk group, intermediate-risk HIFU patients showed a significantly inferior STS (p = 0.040). While whole gland HIFU offers a comparable long-term efficacy for low-risk patients, sufficient cancer control for high-risk patients is more than doubtful. For the subgroup of intermediate-risk patients, CSS rates seem to be comparable up to 10 years suggesting that HIFU may be an alternative for older patients, although a higher risk of salvage treatment should be expected.

Papillary renal cell carcinoma (PRCC) is currently divided in 2 subtypes. We reviewed a large cohort of PRCC and correlated subtype, morphological features and diagnostic marker expression with overall survival (OS) to uncover differences between the 2 subtypes. Three hundred seventy-six renal tumors initially diagnosed as PRCC with clinical and survival data were collected from the participating centers. Two hundred forty-six tumors were classified as PRCC1 (65.4%) and 130 as PRCC2 (34.6%) and graded according to the 2016 World Health Organization/International Society of Urological Pathology grading system. Morphological features (abundant cytoplasm, necrosis, fibrous stroma, foamy macrophages and psammoma bodies) were noted. Immunohistochemical stains (MIB1, p53, Racemase, EMA, CK7, CK20, E-Cadherin) were performed using tissue microarrays. χ2-Tests, log-rank tests and uni- and multivariate Cox regression analysis were performed. Both subtypes displayed different morphological features and immunohistochemical profiles: abundant cytoplasm was more frequent in PRCC2, while foamy macrophages were more common in PRCC1. Abundant cytoplasm and presence of psammoma bodies were associated with poorer OS. PRCC1 showed more frequent CK7 expression, PRCC2 more frequent E-Cadherin, p53 and higher MIB1 expression (>15%). Expression of Racemase and CK7 was associated with better OS, while high MIB1 (>15%) was associated with poorer OS. In multivariate analysis, the only independent predictors of OS were proliferation (MIB1), tumor stage, metastasis and age at surgery. Subtype was not an independent prognostic factor. Therefore, PRCC subtype on its own is not suitable for estimating survival. More data focusing on PRCC tumor biology is needed to define prognostic subgroups, especially in PRCC2.

The role of the androgen receptor (AR) in non-muscle-invasive bladder cancer (NMIBC) remains controversial. We retrospectively analyzed the mRNA expression of AR using RT-qPCR in 95 patients with high-risk NMIBC treated with a bladder-sparing approach and correlated AR with clinical data and recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). The mRNA expression of AR and KRT5, i.e., the basal-like subtype, was strongly correlated (rs = 0.456, p &lt, 0.001). AR (p = 0.053) and KRT5 (p = 0.029) mRNA expression was negatively correlated with tumor grade. Kaplan–Meier analyses indicated significantly prolonged CSS (p = 0.020) and OS (p = 0.015) and a trend towards longer RFS (p = 0.051) in patients with high AR expression. High KRT5 expression was associated with significantly longer RFS (p = 0.033), CSS (p = 0.029) and OS (p = 0.030), while high KRT20 expression was associated with reduced RFS (p = 0.042). In multivariable analysis, none of the molecular markers was an independent prognostic factor. When performing a substratification with regard to molecular markers and clinicopathological parameters, high AR expression showed improved OS in patients with high KRT20 mRNA expression (p = 0.041). Women showed significantly longer OS in cases with high AR expression (p = 0.011). High AR was associated with significantly improved CSS in males (p = 0.044) and patients with instillation therapy (p = 0.040), while OS was improved regardless of instillation therapy. Younger patients with high AR expression had significantly improved RFS (p = 0.021), CSS (p = 0.014) and OS (p = 0.007). RFS was also improved in patients with high AR and low expression of either KRT5 (p = 0.003) or KRT20 (p = 0.014), but not in patients with high expression of KRT5 or KRT20. In conclusion, high AR mRNA expression is correlated with KRT5 mRNA expression and is associated with an improved outcome in high-risk NMIBC.

Background: Increasing life expectancy and demographic change result in a rising number of geriatric patients, but knowledge about geriatric treatment options and adapted diagnostic pathways is low. Simultaneously, urinary tract infections (UTIs) are common in older people and often difficult to treat. Methods: Patients with a UTI at a urological outpatient department between January 01, 2016, and December 31, 2017, were retrospectively identified in the data system. One thousand one hundred fifteen patients with “N30” and “N39” diagnosis were included in this study, 965 of which were under the age of 75 (group 1) and 150 of which 75 years or older (group 2). Results: Of 150 patients in group 2, 41.6% had nitrite-positive urine (vs. 20.9% in group 1, p < 0.05 in χ2 testing). Patients in group 2 often had indwelling devices (30.3 vs. 6.0%, p < 0.05) and presented a sterile urine culture in only 20.7% (vs. 40.1% in group 1). Regarding calculated antibiotic therapy, there were significant differences concerning prescription of ciprofloxacin (34.9 vs. 25%, p < 0.05) and fosfomycin (12.7 vs. 40.7%, p < 0.05). Conclusion: UTI in geriatric patients should be treated differently than in younger patients because antibiotic resistance is high. The group with indwelling devices is complex. Individual strategies for geriatric patients should be considered.

Tumor budding is defined as a single cell or a cluster of up to 5 tumor cells at the invasion front. Due to the difficulty of identifying patients at high risk for pT1 non-muscle-invasive bladder cancer (NMIBC) and the difficulties in T1 substaging, tumor budding was evaluated as a potential alternative and prognostic parameter in these patients. Tumor budding as well as growth pattern, invasion pattern and lamina propria infiltration were retrospectively evaluated in transurethral resection of the bladder (TURB) specimens from 92 patients with stage pT1 NMIBC. The presence of tumor budding correlated with multifocal tumors (p = 0.003), discontinuous invasion pattern (p = 0.039), discohesive growth pattern (p p p = 0.005), PFS (p = 0.017) and CSS (p = 0.002). In patients who received BCG instillation therapy (n = 65), the absence of tumor budding was associated with improved RFS (p = 0.012), PFS (p = 0.011) and CSS (p = 0.022), with none of the patients suffering from progression or dying from the disease. Tumor budding is associated with a more aggressive and invasive stage of pT1 NMIBC and a worse outcome. This easy-to-assess parameter could help stratify patients into BCG therapy or early cystectomy treatment groups.

Background: In the current European Association of Urology (EAU) non-muscle invasive bladder cancer (NMIBC) guideline, two classification systems for grade are advocated: WHO1973 and WHO2004/2016. Objective: To compare the prognostic value of these WHO systems. Design, setting, and participants: Individual patient data for 5145 primary Ta/T1 NMIBC patients from 17 centers were collected between 1990 and 2019. The median follow-up was 3.9 yr. Outcome measurements and statistical analysis: Univariate and multivariable analyses of WHO1973 and WHO2004/2016 stratified by center were performed for time to recurrence, progression (primary endpoint), cystectomy, and duration of survival, taking into account age, concomitant carcinoma in situ, gender, multiplicity, tumor size, initial treatment, and tumor stage. Harrell's concordance (C-index) was used for prognostic accuracy of classification systems. Results and limitations: The median age was 68 yr; 3292 (64%) patients had Ta tumors. Neither classification system was prognostic for recurrence. For a four-tier combination of both WHO systems, progression at 5-yr follow-up was 1.4% in lowgrade (LG)/G1, 3.8% in LG/G2, 7.7% in high grade (HG)/G2, and 18.8% in HG/G3 (log rank, p < 0.001). In multivariable analyses with WHO1973 and WHO2004/2016 as independent variables, WHO1973 was a significant prognosticator of progression (p < 0.001), whereas WHO2004/2016 was not anymore (p = 0.067). C-indices for WHO1973, WHO2004, and the WHO systems combined for progression were 0.71, 0.67, and 0.73, respectively. Prognostic analyses for cystectomy and survival showed results similar to those for progression. Conclusions: In this large prognostic factor study, both classification systems were prognostic for progression but not for recurrence. For progression, the prognostic value of WHO1973 was higher than that of WHO 2004/2016. The four-tier combination (LG/G1, LG/G2, HG/G2, and HG/G3) of both WHO systems proved to be superior, as it divides G2 patients into two subgroups (LG and HG) with different prognoses. Hence, the current EAU-NMIBC guideline recommendation to use both WHO classification systems remains correct. Patient summary: At present, two classification systems are used in parallel to grade non-muscle-invasive bladder tumors. Our data on a large number of patients showed that the older classification system (WHO1973) performed better in terms of assessing progression than the more recent (WHO2004/2016) one. Nevertheless, we conclude that the current guideline recommendation for the use of both classification systems remains correct, since this has the advantage of dividing the large group of WHO1973 G2 patients into two subgroups (low and high grade) with different prognoses. (c) 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Background: The European Association of Urology (EAU) prognostic factor risk groups for non–muscle-invasive bladder cancer (NMIBC) are used to provide recommendations for patient treatment after transurethral resection of bladder tumor (TURBT). They do not, however, take into account the widely used World Health Organization (WHO) 2004/2016 grading classification and are based on patients treated in the 1980s. Objective: To update EAU prognostic factor risk groups using the WHO 1973 and 2004/2016 grading classifications and identify patients with the lowest and highest probabilities of progression. Design, setting, and participants: Individual patient data for primary NMIBC patients were collected from the institutions of the members of the EAU NMIBC guidelines panel. Intervention: Patients underwent TURBT followed by intravesical instillations at the physician's discretion. Outcome measurements and statistical analysis: Multivariable Cox proportional-hazards regression models were fitted to the primary endpoint, the time to progression to muscle-invasive disease or distant metastases. Patients were divided into four risk groups: low-, intermediate-, high-, and a new, very high-risk group. The probabilities of progression were estimated using Kaplan-Meier curves. Results and limitations: A total of 3401 patients treated with TURBT ± intravesical chemotherapy were included. From the multivariable analyses, tumor stage, WHO 1973/2004–2016 grade, concomitant carcinoma in situ, number of tumors, tumor size, and age were used to form four risk groups for which the probability of progression at 5 yr varied from 40%. Limitations include the retrospective collection of data and the lack of central pathology review. Conclusions: This study provides updated EAU prognostic factor risk groups that can be used to inform patient treatment and follow-up. Incorporating the WHO 2004/2016 and 1973 grading classifications, a new, very high-risk group has been identified for which urologists should be prompt to assess and adapt their therapeutic strategy when necessary. Patient summary: The newly updated European Association of Urology prognostic factor risk groups for non–muscle-invasive bladder cancer provide an improved basis for recommending a patient's treatment and follow-up schedule. The updated European Association of Urology prognostic factor risk groups for patients with non–muscle-invasive bladder cancer provide urologists with information that they should take into account when choosing a patient's treatment and scheduling follow-up.

Introduction: Lymphocele (LC) formation is a common complication which may cause severe symptoms after robot-assisted radical prostatovesiculectomy (RARP) with concomitant pelvic lymph node dissection (PLND). Compared to open radical prostatectomy, the amount of data on potential risk factors for LC formation is still limited. The aim of the present study was to identify risk factors for symptomatic LC formation (sLC) after RARP with PLND. Methods: We used the data of a prospective multicentre series of 232 RARP patients which were treated between March 2017 and December 2017. The primary endpoint was the presence of sLC within 90 days. Asymptomatic LC (aLC) formation was also recorded. We evaluated clinical, perioperative, and histopathological criteria and compared their distribution in patients with and without post-operative sLC. Uni- and multivariable logistic regression analyses (MVAs) were performed to identify potential predictors for LC formation. Regarding the influence of patients’ BMI, 2 models were calculated: BMI continuously (model 1) and BMI dichotomized with cut-off 30 kg/m2 (WHO definition, model 2). Results: Post-operative sLC was present in 21 patients (9.1%), while aLC was detected in 49 patients (21.1%) 90 days after RARP with PLND. Patients with sLC showed higher median baseline PSA levels (9.8 vs. 8.1 ng/mL), higher prevalence of obesity (BMI >30; 42.9 vs. 19.9%), and longer median console time (180 vs. 165 min) compared to patients without sLC. On MVA higher BMI {model 1: OR 1.145 (confidence interval [CI] 1.025–1.278); model 2: OR 2.761 (1.045–7.296)}, longer console time (model 1: OR 1.013 [1.005–1.021]; model 2: OR 1.013 [1.005–1.020]) and an ISUP grade ≥3 (model 1: OR 3.247 [1.182–8.917]; model 2: OR 2.791 [1.050–7.423]) were identified as independent predictors for sLC development. Conclusion: Patients with aggressive tumours and higher BMI should be informed about a potentially increased risk for sLC formation. In case of a long console time, a close and regular follow-up should be considered to check for LC development.

BACKGROUND: Lymphoceles are a common postoperative complication after radical prostatectomy with pelvic lymphadenectomy. Therapeutic options include cannulation and drainage (CD), drainage and instillation (DI), or laparoscopic fenestration (LF). The aim of this study was to investigate the epidemiology of symptomatic lymphoceles (SLC) and evaluate the treatment options. METHODS: We retrospectively analysed all patients who underwent robot-assisted radical prostatectomy (RARP) at our clinic from January 1, 2014 to December 31, 2018. All documented lymphoceles of these patients were recorded and analysed with regard to symptoms, possible infection and the treatment option (or options) chosen. RESULTS: We were able to include all 1,029 patients who underwent RARP in the aforementioned period of time. Of these, 18.1% were diagnosed with a lymphocele either when discharged or when readmitted and 6.9% experienced an SLC requiring treatment. Thirteen-point-seven percent of patients readmitted with SLC showed an accompanying thrombosis. Due to recurring or bilateral SLCs receiving different treatment options for each side, there was a total of 115 SLCs treated. CD was carried out in 102 cases. Twenty-point-six percent of patients were sufficiently treated this way, the rest required further treatment or experienced recurrences not requiring further treatment. DI was carried out in 56 cases. Of those patients, 46.4% were sufficiently treated. LF was carried out in 54 cases (either after CD, or after DI, or primarily). Of those patients, 98.1% were treated sufficiently. LF had a statistically significant higher success rate compared to CD and DI (P

Objective To examine the disease-specific survival(DSS) after checkpoint inhibitor(CPI) therapy based on FGFR alterations and FGFR mRNA expression levels in patients with metastatic urothelial cancer(mUCa) within a multi-center cohort. Methods Within a cohort of 72 patients with mUCa from five academic centers in Germany FGFR alterations, as well as FGFR1-4 mRNA expression levels in tumor samples from the primary tumor or metastatic sites. Spearman rank correlations, logistic regression, as well as Kaplan-Meier survival analyses and univariate Cox proportional hazards regression models were employed to examine the impact of different FGFR patterns on the DSS after CPI treatment. Results FGFR3 mutations or gene fusions (gene alterations) were detected in 16.9% of all samples. Patients with or without FGFR3 gene alterations did not show different oncological outcomes undergoing CPI treatment. Low expression of FGFR2 mRNA alone, as well as the combination of either low FGFR2mRNA expression and FGFR3 gene alteration or high FGFR3mRNA expression (P = 0.027), identified a subgroup of patients with unfavorable outcomes, comprising 40% of the total cohort. This trend was also observed in univariate Cox proportional hazards regression analysis(FGFR3 gene alteration: Hazard ratio(HR) 5.33, 95%Confidence interval(CI)1.76-15.0, P = 0.004; FGFR3mRNA expression:HR 3.04, 95%CI 1.40-7.13, P = 0.005). Conclusion Assessment of FGFR mRNA expression identified a high-risk subgroup of patients with mUCa. These patients showing overexpression of FGFR3 mRNA were found to have unfavorable DSS after CPI treatment. Using this approach may be suitable for identifying a patient population with poor response to CPI treatment, which may benefit from early FGFR inhibition.

Background: Urine examination has relevance for treatment, and reliability of positive urine culture (UC) is of importance. The technique of urine sampling (US), storage, and transportation is important. The objective of this study was to investigate if detailed patient information for the technique of US and hygiene reduces rates of contaminated UC in screened male patients, as this group was not investigated yet. Methods: All patients independently of complaints were enrolled prospectively and consecutively in an outpatient setting in 2 groups – the first group did not receive detailed information and the second group did. We examined 372 consecutive patients in 2017, 190 not receiving (median age 69 years) and 182 receiving information (median age 70 years), with comparable numbers of patients and age. The result of UC and age was imposed. Results: In all,74.2% of preclarification UC showed a contamination (n = 95) and 75.5% after clarification (n = 83), without significant differences (p = 0.827). This study is limited by the fact that adherence could not be checked. Conclusions: Similar to studies with females, no difference occurred in rates of contaminated UC, so detailed information regarding the US technique does not decrease rates of contaminated UC and vice versa does not increase the quality of midstream-sampled UC in male patients.

BackgroundPenile cancer represents a rare malignant disease, whereby a small caseload is associated with the risk of inadequate treatment expertise. Thus, we hypothesized that strict guideline adherence might be considered a potential surrogate for treatment quality. This study investigated the influence of the annual hospital caseload on guideline adherence regarding treatment recommendations for penile cancer.MethodsIn a 2018 survey study, 681 urologists from 45 hospitals in four European countries were queried about six hypothetical case scenarios (CS): local treatment of the primary tumor pTis (CS1) and pT1b (CS2); lymph node surgery inguinal (CS3) and pelvic (CS4); and chemotherapy neoadjuvant (CS5) and adjuvant (CS6). Only the responses from 206 head and senior physicians, as decision makers, were evaluated. The answers were assessed based on the applicable European Association of Urology (EAU) guidelines regarding their correctness. The real hospital caseload was analyzed based on multivariate logistic regression models regarding its effect on guideline adherence.ResultsThe median annual hospital caseload was 6 (interquartile range (IQR) 3–9). Recommendations for CS1–6 were correct in 79%, 66%, 39%, 27%, 28%, and 28%, respectively. The probability of a guideline-adherent recommendation increased with each patient treated per year in a clinic for CS1, CS2, CS3, and CS6 by 16%, 7.8%, 7.2%, and 9.5%, respectively (each p < 0.05); CS4 and CS5 were not influenced by caseload. A caseload threshold with a higher guideline adherence for all endpoints could not be perceived. The type of hospital care (academic vs. non-academic) did not affect guideline adherence in any scenario.ConclusionsGuideline adherence for most treatment recommendations increases with growing annual penile cancer caseload. Thus, the results of our study call for a stronger centralization of diagnosis and treatment strategies regarding penile cancer.

Stage pT1 bladder cancer (BC) shows highly diverse outcomes. Predictive markers are required to stratify patients for personalized treatment. The present study aimed to validate immune response quantification as a prognostic marker. Patients with pT1 BC (n = 167) treated by transurethral resection of the bladder (TURB) were enrolled. Formaldehyde-fixed paraffin-embedded material was stained for CD3 and CD8. Corresponding T cells were counted in three regions with the highest immune response. Numbers of tertiary lymphoid structures (TLS) and lymphocyte aggregates (LA) were quantified. High CD3+ stroma T-cell infiltration was associated with improved survival (p = 0.045), especially in the G3 subgroup (p = 0.01). Cluster with higher immune response showed less recurrence (p = 0.034) and favorable overall survival (OS) (p = 0.019). In contrast, higher CD3+ and CD8+ tumor T-cell infiltration seemed to have a negative impact on prognosis. TLS and LA were more frequently observed in G3 tumors, indicating an increased anti-tumoral immune response. We proved the role of immune cell infiltration and showed that higher infiltration numbers of CD3+ (not CD8+) lymphocytes in the stroma are associated with favorable outcome. Immune cell quantification could be used as a marker to help stratify patients&rsquo, risk and therefore, to optimize patients&rsquo, management and follow-up examination as well as possible therapies.

BackgroundAssessment of the immune status of muscle-invasive bladder cancer (MIBC) has previously shown to be prognostically relevant after treatment with curative intent. We conducted this study to develop a clinically applicable immune gene expression assay to predict prognosis and adjuvant chemotherapy benefit.Patients and methodsGene expression ofCD3Z,CD8AandCXCL9, immune cell (IC) populations including stromal tumor infiltrating lymphocytes (sTILs), T-cells, natural killer cells (NK-cells), macrophages, Programmed cell death protein 1 positive (PD-1) IC and tumor subtypes (MD Anderson Cancer Center/MDACC-approach) were assessed in 187 MIBC patients (Comprehensive Cancer Center Erlangen-EMN/CCC-EMN-cohort). A gene expression signature was derived by hierarchical-clustering and validated in The Cancer Genome Atlas (TCGA)-cohort. IC populations in the TCGA cohort were assessed via CIBERSORT. Benefit of platinum-containing adjuvant chemotherapy was assessed in a pooled cohort of 125 patients. Outcome measurements were disease specific survival, disease-free survival and overall survival.ResultsThe gene expression signature ofCXCL9,CD3ZandCD8Acorrelates with quantitative amounts of specific IC populations and sTILs (CCC-EMN: ρ-range: 0.44–0.74; TCGA: ρ-range: 0.56–0.82) and allows stratification of three different inflammation levels (inflamed high, inflamed low, uninflamed). Highly inflamed tumors are preferentially basal subtype and show favorable 5-year survival rates of 67.3% (HR=0.27; CCC-EMN) and 55% (HR=0.41; TCGA). Uninflamed tumors are predominantly luminal subtypes and show low 5-year survival rates of 28% (CCC-EMN) and 36% (TCGA). Inflamed tumors exhibit higher levels of PD-1 and Programmed cell death 1 ligand 1 (PD-L1). Patients undergoing adjuvant platinum-based chemotherapy with ‘inflamed high’ tumors showed a favorable 5-year survival rate of 64% (HR=0.27; merged CCC-EMN and TCGA cohort).ConclusionThe gene expression signature ofCD3Z,CD8AandCXCL9can assess the immune status of MIBC and stratify the survival of MIBC patients undergoing surgery and adjuvant platinum-based chemotherapy. Furthermore, the assay can identify patients with immunological hot tumors with particular high expression of PD-L1 potentially suitable for immunotherapy.

Background Lymphocele is the most common complication arising after pelvic lymph node dissection (PLND) in the setting of robot-assisted radical prostatectomy (RARP). The only data available until now on the utility of a peritoneal flap to prevent lymphocele were retrospectively acquired. Methods A randomized, controlled, multi-center trial with blinded assessment of endpoints was carried out on 232 patients with prostate cancer who underwent RARP with PLND. The patients in the intervention group were given a peritoneal flap; in the control group, surgery was performed without this modification. The two joint primary endpoints were the rates of symptomatic lymphocele during the same hospitalization as the operative procedure (iT1) and within 90 days of surgery (iT2). The secondary endpoints were lymphocele volume, the need for treatment of lymphocele, complications requiring an intervention, and the degree of postoperative stress incontinence. German Clinical Trials Register number: DRKS00011115. Results The data were evaluated in an intention-to-treat analysis, which, in this trial, was identical to an as-treated analysis. 108 patients (46.6%) were allotted to the intervention group. There were no statistically significant intergroup differences with respect to any clinical or histopathological criteria. A median of 16 lymph nodes were removed (interquartile range, 11-21). A symptomatic lymphocele arose in 1.3% (iT1) and 9.1% (iT2) of the patients, without any statistically significant difference between the two trial groups (p = 0.599 and p = 0.820, respectively). Nor did the groups differ significantly with respect to lymphocele volume (p = 0.670 on hospital discharge [T1], p = 0.650 90 days after surgery [T2]) or the type and frequency of need for subsequent surgical intervention (p = 0.535; iT2). 81.5% of all patients (n = 189) had no complications at all in the first three months after surgery. Nor were there any intergroup differences at 90 days with respect to the degree of stress urinary incontinence (p = 0.306) or complications (p = 0.486). Conclusion A peritoneal flap after RARP was not found to influence the rate of postoperative lymphocele, whether asymptomatic or requiring treatment.

Context This review focuses on the most widely used risk stratification and prediction tools for non–muscle-invasive bladder cancer (NMIBC). Objective To assess the clinical use and relevance of risk stratification and prediction tools to enhance clinical decision making and counselling of patients with NMIBC. Evidence acquisition The most frequent, currently used risk stratification tools and prognostic models for NMIBC patients were identified by the members of the European Association of Urology (EAU) Guidelines Panel on NMIBC. Evidence synthesis The 2006 European Organization for Research and Treatment of Cancer (EORTC) risk tables are the most widely used and validated tools for risk stratification and prognosis prediction in NMIBC patients. The EAU risk categories constitute a simple alternative to the EORTC risk tables and can be used for comparable risk stratification. In the subgroup of NMIBC patients treated with a short maintenance schedule of bacillus Calmette-Guerin (BCG), the Club Urologico Espanol de Tratamiento Oncologico (CUETO) scoring model is more accurate than the EORTC risk tables. Both the EORTC risk tables and the CUETO scoring model overestimate the recurrence and progression risks in patients treated according to current guidelines. The new concept of conditional recurrence and progression estimates is very promising during follow-up but should be validated. Conclusions Risk stratification and prognostic models enable outcome comparisons and standardisation of treatment and follow-up. At present, none of the available risk stratification and prognostic models reflects current standards of treatment. The EORTC risk tables and CUETO scoring model should be updated with previously unavailable data and recalculated. Patient summary Non-muscle-invasive bladder cancer is a heterogeneous disease. A risk-based therapeutic approach is recommended. We present available risk stratification and prediction tools and the degree of their validation with the aim to increase their use in everyday clinical practice.

Introduction Current results concerning the effect of body mass index (BMI) on positive surgical margins (PSMs) after robot-assisted radical prostatectomy (RARP) in patients with localized prostate cancer are inconsistent. Therefore, the aim of this study was to further analyse the association between BMI and PSMs after RARP. Material and methods Between March 2017 and December 2017 a multicentre, prospective, randomised, single-blind series with a blinded outcome assessment of 232 RARP patients was performed. Multivariate logistical regression models were used to analyse the independent effect of obesity, with body-mass-index (BMI) dichotomised at 30 kg/m2 (model-1) and at 90th percentile (model-2), on PSMs. Results Median BMI was 27.2 kg/m2, PSMs were found in 15.5% (n = 36). In multivariate model-1, obesity did not have a significant effect on PSMs (OR 2.34, p = 0.061). However, if BMI was dichotomized at the 90th percentile (BMI ≥33.7 kg/m²), patients with a higher BMI showed PSMs four-times more frequently (OR 3.99, p = 0.013). In both models, preoperative prostate-specific antigen (PSA) levels and pathological tumour stage had a significant effect on PSMs. There was no significant correlation between BMI and the extent of PSMs, nor a significant difference between the BMI groups and the localisation of PSMs. There was a higher percentage of posteriolateral PSM localisation in obese patients compared to patients with a BMI of less than 30 kg/m2 (58.3% and 25.3% of the localisations were posterolateral in obese and non-obese patients, respectively), however this effect was not statistically significant (p = 0.175). Conclusions In addition to a longer operation time and about twice as many complications, patients with a BMI of ≥33.7 kg/m² had a higher PSM rate after RARP. Differences in localization of PSMs in relation to obesity should be evaluated in future research.

Although it is well-known that smoking can cause lung cancer, the relationship between smoking and urologic cancers seems not as obvious and awareness is not widespread in the general population. For the KRAUT (knowledge of the relation between smoking and urological tumors among patients with a urological tumor disease) study, 258 patients with the diagnosis of urological cancer were interviewed using a questionnaire. Most (72.1%) stated that they never had a conversation regarding this topic with any doctor. Educational work in this field should be intensified to reduce the development and progression of urologic cancer. Purpose: Our objective was to investigate whether patients with urologic tumors were aware of smoking as a risk factor for the development and progression of several urologic cancers and the extent of the medical education they had received. Another aim was to investigate whether gender or age influenced patients' willingness to change their smoking habits. Materials and Methods: Patients with histologically malignant urologic tumors were enrolled in our questionnaire-based study from September 2013 to December 2014 in 2 urology departments. Patients were asked about their smoking habits and their general understanding of the relationship between smoking and the onset of cancer (urologic cancer and lung cancer). Also, the extent of information they had acquired from a physician was assessed. The descriptive and oncologic data of the patients were recorded. Results: Of 258 enrolled patients, 186 (72.1%) had never had an informational discussion with a doctor about smoking and their urologic tumor disease. Of the 160 active and former smokers, only 45 (28.1%) were planning to stop or reduce smoking because of their tumor disease. The willingness to change smoking habits was greater for women, with a statistically significant difference (odds ratio, 5.59;P = .002). Younger patients aged

Zusammenfassung Hintergrund Bei etwa jedem dritten Patienten mit einem penilen Plattenepithelkarzinom (PSCC) gilt die Infektion mit Humanen Papillomaviren (HPV) als entscheidender Faktor der Karzinogenese. Erste Daten zur optimierten Risikostratifizierung und Therapie anhand des HPV-Status existieren; somit hat der Nachweis einer HPV-Genese möglicherweise mehr als lediglich eine epidemiologische Dimension. Referenz zur Detektion von HPV ist die aufwendige Polymerase-Kettenreaktion (PCR). Unklar ist, ob Alternativen wie die In-situ-Hybridisierung (ISH) oder verschiedene Surrogatmarker (immunhistochemischer Nachweis einer p16INK4a-Expression, histologischer Subtyp, Tumorinvasionsfront, Koilozytose), zur Bestimmung des HPV-Status ausreichend sind. Methoden In dieser unizentrischen Studie an 34 Patienten mit PSCC wurden eine Multiplex nested-PCR zur Festlegung des HPV-Status und Genotypisierung der HPV-DNA sowie eine ISH durchgeführt. Diverse histologische Kriterien und p16INK4a wurden durch zentralen Review bestimmt. Der Einfluss verschiedener Kriterien auf die karzinomspezifische Mortalität (CSM) wurde mit Cox-Regressionsmodellen geprüft (FU: 92 Mon.). Ferner erfolgte der Vergleich der diskriminativen Qualitäten verschiedener Tumorinvasionsmuster (u. a. TNM-Klassifikation 7. vs. 8. Auflage) hinsichtlich der CSM-Prädiktion. Ergebnisse Gemäß PCR-Analyse wiesen 26 % der Patienten HR-HPV auf (n = 9). ISH und die untersuchten histologischen Kriterien zeigten eine unzureichende Vorhersagegenauigkeit des HPV-Status (p > 0,3). p16INK4a erreichte in den Testkriterien Sensitivität, Spezifität, positiv-prädiktiver und negativ-prädiktiver Wert sowie Gesamtübereinstimmung 66,7 %, 84 %, 60 %, 87,5 % bzw. 79,4 % (AUC: 0,753; p = 0,026). Keines der Untersuchungskriterien (inkl. PCR) korrelierte signifikant mit der CSM. Im Vergleich zur 7. wies die 8. Auflage der pT-Klassifikation eine bessere CSM-Prädiktion auf (C-Indizes 70,2 % vs. 72,9 %). In Addition zur Schwellkörper-Invasion besaß die Urethra-Infiltration keinen eigenständigen prädiktiven Wert. Eine durch uns vorgeschlagene Neu-Gruppierung der Schwellkörper-Invasionsmuster erzielte eine Diskriminationssteigerung bzgl. der CSM (C-Index 77,9 %). Schlussfolgerung p16INK4a erlaubt – im Gegensatz zur ISH und den untersuchten histologischen Kriterien – eine akzeptable Vorhersage des HPV-Status. Der Nachweis von HPV-DNA inkl. seiner Surrogatmarker hatte keinen Einfluss auf die CSM. Die 8. Auflage der pT-Klassifikation scheint prognostisch sinnvoll, da die urethrale Tumorinvasion keinen eigenständigen Einfluss auf die CSM aufweist.

OBJECTIVE To investigate the role of forkhead box protein M1 (FOXM1) mRNA expression and its prognostic value in stage pT1 non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS Clinical data and formalin-fixed paraffin-embedded tissues from transurethral resection of the bladder from patients with stage pT1 NMIBC, treated with an organ-preserving approach, were analysed retrospectively. Total RNA was isolated using commercial RNA extraction kits, and mRNA expression of FOXM1, MKI67, KRT20 and KRT5 was measured by single-step quantitative RT-PCR using RNA-specific TaqMan Assays. Statistical analysis was performed using Spearman's Rho, Wilcoxon or Kruskal-Wallis tests, Kaplan-Meier estimates of recurrence-free (RFS), progression-free (PFS) and cancer-specific survival (CSS) and Cox regression analysis. RESULTS Data from 296 patients (79.4% men, median age 72 years) were available for the final evaluation. Spearman correlation analysis showed that mRNA expression of FOXM1 was significantly correlated with MKI67 (ρ: 0.6530, P < 0.001) and with the luminal subtype, reflected by the positive correlation with KRT20 (ρ: 0.2113, P < 0.001). Furthermore, there was also a strong correlation of FOXM1 expression with adverse clinical and pathological variables, such as concomitant carcinoma in situ (P = 0.05), multifocal tumours (P = 0.005) and World Health Organization 1973 grade 3 disease (P < 0.001). Kaplan-Meier analysis showed overexpression of FOMX1 to be associated with worse PFS (P = 0.028) and worse CSS (P = 0.015). FOXM1 overexpression was also shown to be a predictive risk factor for CSS (hazard ratio 1.61 [1.13-2.34], L-R chi-squared: 7.19, P = 0.007). FOXM1 overexpression identified a subgroup of patients within the luminal subtype with worse RFS (P = 0.017), PFS (P < 0.001) and CSS (P = 0.015). Patients with low FOXM1 expression had better outcomes, irrespective of instillation therapy, whereas patients with high FOXM1 expression benefitted from intravesical chemotherapy with mitomycin C. CONCLUSION High FOXM1 expression was associated with adverse clinical and pathological features and worse outcomes, and predicted response to intravesical instillation therapy in patients with stage pT1 NMIBC.

Advanced Peyronie's disease (PD) with severe penile curvature requires grafting following plaque incision or partial plaque excision. So far, the ideal graft material has not been identified although various grafts have been studied. In this first matched pair analysis we compared the outcome after grafting with small intestinal submucosa (SIS) and self-adhesive collagen fleece (CF). We retrospectively identified 43 patients after SIS grafting with complete follow-up data sets to be eligible for the present study. A total of 43 patients after CF grafting were matched case by case to the SIS group using the degree of preoperative penile curvature as the primary matching factor. Postoperative outcome was compared with the focus on penile straightening, penile length, potency, relapse rates and long-term complications. Median degree of curvature was 80° in each group. Mean follow-up periods were 31 months after SIS and 39 months after CF grafting. The CF grafting procedure was significantly faster than SIS grafting (80 vs. 104 min, p

Background Acute renal colic (ARC) is an emergency that can mostly be treated conservatively, but can be life threatening in combination with urinary tract infection (UTI). Assessment for infection includes white blood cell (WBC) count and C-reactive protein (CRP), but these parameters are often unspecifically elevated and might lead to antibiotic over-therapy. In times of increasing antibiotic resistance, however, unnecessary antibiotic therapy should be avoided. Objectives The goal of the study was to investigate the prevalence of UTI proven by urine culture (UC) in patients with ARC and to identify predictive factors in the emergency setting. Patients and Methods We prospectively enrolled 200 consecutive patients with ARC and evaluated blood test results, urinalysis, UC, symptoms suspicious for UTI, and time between symptom onset and admission, as well as body temperature. Logistic regression analyses were performed to identify predictive factors. Results There were 196 patients eligible for statistical analysis. UTI proven by positive UC was detected in 26 patients (13%). On multivariate logistic regression analysis, suspicious urinalysis (positive nitrite or bacteria > 20/high-power field [hpf] or WBC > 20/hpf), patient age ≥ 54 years and CRP ≥ 1.5 mg/dL (fivefold increase) were significant predictors for the presence of UTI. Neither elevated WBC count nor typical UTI symptoms were associated with UTI. Conclusions Based on our results, a routine antibiotic prophylaxis in patients with ARC does not seem to be appropriate. Patient age and CRP can help to decide if antibiotic treatment might be indicated, even in case of a not clearly suspicious urinalysis.