Tailored immunotherapy approach with nivolumab with or without ipilimumab in patients with advanced transitional cell carcinoma after platinum-based chemotherapy (TITAN-TCC): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Nivolumab is used after platinum-based chemotherapy in patients with metastatic urothelial carcinoma. Studies suggest improved outcomes for dual checkpoint inhibition with high ipilimumab doses. We aimed to examine the safety and activity of nivolumab induction and high-dose ipilimumab as an immunotherapeutic boost as a second-line treatment for patients with metastatic urothelial carcinoma. METHODS: TITAN-TCC is a multicentre, single-arm, phase 2 trial done at 19 hospitals and cancer centres in Germany and Austria. Adults aged 18 years or older with histologically confirmed metastatic or surgically unresectable urothelial cancer of the bladder, urethra, ureter, or renal pelvis were eligible. Patients had to have progression during or after first-line platinum-based chemotherapy and up to one more second-line or third-line treatment, a Karnofsky Performance Score of 70 or higher, and measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1. After four doses of intravenous nivolumab 240 mg induction monotherapy every 2 weeks, patients with a partial or complete response at week 8 continued maintenance nivolumab, whereas those with stable or progressive disease (non-responders) at week 8 received a boost of two or four doses of intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks. Patients who subsequently had progressive disease during nivolumab maintenance also received a boost, using this schedule. The primary endpoint was the confirmed investigator-assessed objective response rate in the intention-to-treat population and had to exceed 20% for the null hypothesis to be rejected (based on the objective response rate with nivolumab monotherapy in the CheckMate-275 phase 2 trial). This study is registered with ClinicalTrials.gov, NCT03219775, and is ongoing. FINDINGS: Between April 8, 2019, and Feb 15, 2021, 83 patients with metastatic urothelial carcinoma were enrolled and all received nivolumab induction treatment (intention-to-treat population). The median age of enrolled patients was 68 years (IQR 61-76), and 57 (69%) were male and 26 (31%) were female. 50 (60%) patients received at least one boost dose. A confirmed investigator-assessed objective response was recorded in 27 (33%) of 83 patients in the intention-to-treat population, including six (7%) patients who had a complete response. This objective response rate was significantly higher than the prespecified threshold of 20% or less (33% [90% CI 24-42]; p=0·0049). The most common grade 3-4 treatment-related adverse events were immune-mediated enterocolitis (nine [11%] patients) and diarrhoea (five [6%] patients). Two (2%) treatment-related deaths were reported, both due to immune-mediated enterocolitis. INTERPRETATION: Treatment with nivolumab and nivolumab plus ipilimumab boosts in early non-responders and patients who progress late significantly improved objective response rate after previous platinum-based chemotherapy compared with the rate reported with nivolumab in the CheckMate-275 trial. Our study provides evidence for the added value of high-dose ipilimumab 3 mg/kg and suggests a potential role for the combination as a rescue strategy in platinum-pretreated patients with metastatic urothelial carcinoma. FUNDING: Bristol Myers Squibb.

On-treatment risk model for predicting treatment response in advanced renal cell carcinoma.

PURPOSE: The field of immunotherapy combinations for advanced renal cell carcinoma (aRCC) has been expanded in recent years. However, the treatment response varies widely among individual patients. It is still a challenge to predict oncological outcome in clinical practice. We assessed the impact of an activated immune system reflected by changes in C-reactive protein (CRP) levels and the early onset of treatment-related adverse events (TRAEs) on the treatment response. METHODS: In this retrospective analysis of 57 aRCC patients, CRP kinetics based on previous descriptions of CRP flare-response, CRP response or CRP non-response, and the TRAEs, which occurred within a month after therapy initiation, were obtained for this study. According to logistic regression analysis of both factors, we stratified the patients into risk groups: the presence of CRP flare-response/response and early onset of TRAE (low-risk group); the presence of a single factor (intermediate-risk group); and without both factors (high-risk group). RESULTS: Ten patients (17%) experienced primary disease progression. No progressive disease was observed in the low-risk group, while 60% (n = 6/10) of the high-risk group showed a primary disease progression. Significantly, an increased risk of disease progression was observed by patients without CRP response and TRAEs (p < 0.001). CONCLUSION: The present analysis displays the predictive value of the on-treatment risk model based on CRP kinetics and the early onset of TRAEs, which can be easy to implement in clinical practice to optimize the treatment monitoring.

Molecular margin status after radical prostatectomy using glutathione S-transferase P1 (GSTP1) promoter hypermethylation.

OBJECTIVE: To assess the potential for molecular staging in biopsies of the prostatic fossa after radical prostatectomy (RP) by searching for occult tumour cells through analysis of glutathione S-transferase P1 (GSTP1) methylation status. PATIENTS AND METHODS: We analysed 2446 biopsies: 2286 biopsies from a group of 254 patients with clinically organ-confined prostate cancer who underwent RP and 160 biopsies from a control group of 32 patients. After prostate gland excision, biopsies were obtained from defined areas of the prostatic fossa and bisected for histopathological and molecular genetics analyses. Results were related to clinicopathological data including tumour stage, lymph node status, resection status, tumour grading, initial PSA level, and biochemical recurrence. RESULTS: In total, 34 patients (13.4%) had at least one core positive for the GSTP1 promoter hypermethylation, six of whom (17.6%) were characterised as having a clinically localised tumour stage (pT2, pN0) and 28 (82.4%) as an advanced tumour stage (≥pT3 and/or pN1). GSTP1 promoter hypermethylation significantly correlated with tumour stage (P < 0.001), International Society of Urological Pathology grading (P = 0.001), lymph node status (P < 0.001), surgical margin status (P < 0.001), and biochemical recurrence (P = 0.001). Furthermore, in 46 patients (18.1%) further analysis led to a down- or upgrading of conventional surgical margin status. Classical R-status (margins of the specimen) is significantly superior to histological sampling from the fossa (P = 0.006) but not to GSTP1 analysis from the fossa (P = 0.227). CONCLUSION: For the detection of residual tumour in the fossa after RP in order to better predict recurrence, molecular GSTP1 promoter hypermethylation has some value; however, the classical R-status (margins of the specimen) is simpler and more widely applicable with similar results.

German S3 Evidence-Based Guidelines on Focal Therapy in Localized Prostate Cancer: The First Evidence-Based Guidelines on Focal Therapy.

BACKGROUND: Focal therapy (FT) is an option to treat localized prostate cancer (PCa) and preserve healthy prostate tissue in order to reduce known side effects from primary whole-gland treatment. The available FT modalities are manifold. Until now, national and international PCa guidelines have been cautious to propose recommendations regarding FT treatment since data from prospective controlled trials are lacking for most FT modalities. Moreover, none of the international guidelines provides a separate section on FT. In this purpose, we provide a synopsis of the consensus-based German S3 guidelines for a possible international use. SUMMARY: The recently published update of the German S3 guidelines, an evidence- and consensus-based guideline, provides a section on FT with recommendations for diagnostic work-up, indications, modalities, and follow-up. This section consists of 12 statements and recommendations for FT in the treatment of localized PCa. KEY MESSAGE: The German S3 guidelines on PCa are the first to incorporate recommendations for FT based on evidence and expert consensus including indication criteria for FT, pretreatment, and follow-up diagnostic pathways as well as an extended overview of FT techniques and the current supportive evidence.

Time pressure predicts decisional regret in men with localized prostate cancer: data from a longitudinal multicenter study.

PURPOSE: A substantial proportion of men with localized prostate cancer (lPCa) later regret their treatment decision. We aimed to identify factors contributing to decisional regret. METHODS: We conducted a longitudinal study, in which men with lPCa were surveyed at four measurement points: T0 (baseline) = prior to treatment; T1 = 6; T2 = 12; T3 = 18 months after baseline. χ2-tests and independent t-tests were used to compare men undergoing different treatments [Active Surveillance (AS) vs. local treatment]. Logistic regression models were fitted to investigate the associations between predictors (time pressure, information provided by the urologist, impairment of erectile functioning, satisfaction with sexual life) and the criterion decisional regret. RESULTS: At baseline, the sample included N = 176 men (AS: n = 100; local treatment: n = 76). At T2 and T3, men after local therapies reported higher regret than men under AS. Decisional regret at T3 was predicted by time pressure at baseline (OR 2.28; CI 1.04-4.99; p < 0.05), erectile dysfunction at T2 and T3 (OR 3.40; CI 1.56-7.42; p < 0.01), and satisfaction with sexual life at T1-T3 (OR 0.44; CI 0.20-0.96; p < 0.05). CONCLUSIONS: Time pressure, erectile dysfunction, and satisfaction with sexual life predict decisional regret in men with lPCa. Mitigating time pressure and realistic expectations concerning treatment side effects may help to prevent decisional regret in PCa survivors. TRIAL REGISTRATION NUMBER: DRKS00009510; date of registration: 2015/10/28.

Triggers and oncologic outcome of salvage radical prostatectomy, salvage radiotherapy and active surveillance after focal therapy of prostate cancer.

PURPOSE: Due to the tissue preserving approach of focal therapy (FT), local cancer relapse can occur. Uncertainty exists regarding triggers and outcome of salvage strategies. METHODS: Patients with biopsy-proven prostate cancer (PCa) after FT for localized PCa from 2011 to 2020 at eight tertiary referral hospitals in Germany that underwent salvage radical prostatectomy (S-RP), salvage radiotherapy (S-RT) or active surveillance (AS) were reported. Prostate specific antigen (PSA) changes, suspicious lesions on mpMRI and histopathological findings on biopsy were analyzed. A multivariable regression model was created for adverse pathological findings (APF) at S-RP specimen. Kaplan-Meier curves were generated to determine oncological outcomes. RESULTS: A total of 90 men were included. Cancer relapse after FT was detected at a median of 12 months (IQR 9-16). Of 50 men initially under AS 13 received S-RP or S-RT. In total, 44 men underwent S-RP and 13 S-RT. At cancer relapse 17 men (38.6%) in the S-RP group [S-RT n = 4 (30.8%); AS n = 3 (6%)] had ISUP > 2. APF (pT ≥ 3, ISUP ≥ 3, pN + or R1) were observed in 23 men (52.3%). A higher ISUP on biopsy was associated with APF [p = 0.006 (HR 2.32, 97.5% CI 1.35-4.59)] on univariable analysis. Progression-free survival was 80.4% after S-RP and 100% after S-RT at 3 years. Secondary therapy-free survival was 41.7% at 3 years in men undergoing AS. Metastasis-free survival was 80% at 5 years for the whole cohort. CONCLUSION: With early detection of cancer relapse after FT S-RP and S-RT provide sufficient oncologic control at short to intermediate follow-up. After AS, a high secondary-therapy rate was observed.

MRI targeted single fraction HDR Brachytherapy for localized Prostate Carcinoma: a feasibility study of focal radiation therapy (ProFocAL).

OBJECTIVES: The aim of the study was to establish the setup and workflow for delivering focal MRI-guided high-dose-rate (HDR) brachytherapy for prostate cancer (PCA) and to assess patient comfort and safety aspects of MRI-guided single-fraction HDR. METHODS: Patients with histologically proven focal low- to intermediate-risk PCA with a single PIRADS 4/5 lesion were treated with percutaneous interstitial HDR brachytherapy in a single fraction with a minimum dose for the gross tumor volume of 20 Gy while sparing the organ at risk (OAR). Using a 3T-MRI, brachytherapy catheters were placed transgluteal in freehand technique. No antibiotic therapy or general analgesics were administered. Patient data, procedure time, patient discomfort, and complications were recorded. Quarterly PSA controls, biannual follow-up imaging, and annual re-biopsy were planned. RESULTS: So far, 9 patients were successfully treated and followed for 6 months. Mean intervention time was 34 min. Using the VAS scale, the pain reported for the intervention ranged from 2 to 3. Short-term follow-up showed no acute genitourinary or gastrointestinal toxicity so far. None of the patients displayed signs of infection. PSA levels in all patients decreased significantly. On follow up no residual PCA was detected treated region so far. PSA levels in all patients decreased significantly. On follow-up, no residual PCA was detected so far. CONCLUSIONS: MR-guided single-fraction focal HDR brachytherapy for localized PCA is feasible as well as safe for the individual patient. Catheters can be placed accurately and maximum therapeutic dose distribution can be restricted to the tumor. Countersigning the minimally invasive character of the procedure, no general anesthesia or antibiosis is necessary. KEY POINTS: • MR-guided focal HDR brachytherapy allows an accurate placement of catheters with maximum therapeutic dose distribution restricted to the tumor. • No major anesthesia or antibiosis is necessary emphasizing the minimal invasive character of the procedure. • Patients with low- and intermediate-risk prostate carcinoma in particular may benefit to halt disease progression whereas treatment-related morbidity is reduced compared with radical therapy.

A Stent for Every Stone? Prestenting Habits and Outcomes from a German Multicenter Prospective Study on the Benchmarks of Ureteroroscopic Stone Treatment (BUSTER).

INTRODUCTION: Previous studies have shown that prestenting in ureterorenoscopic stone removal (URS) is carried out more frequently in Germany than in other countries. OBJECTIVE: This investigation evaluated the impact of high prestenting rates on outcomes as well as the influence of stone characteristics and treatment habits on prestenting. METHODS: The dataset from the BUSTER observational study was used. Patient and stone characteristics, as well as treatment outcomes, were analyzed for 307 cases from 14 urological clinics in Germany. RESULTS: The overall prestenting rate was 70.0%. Prestenting rates were significantly higher for renal stones than ureteric stones (84.6 vs. 60.6%, p < 0.0001). Compared to the unstented cases, prestenting for renal stones improved stone-free rates (73.2 vs. 11.1%, p < 0.0001) and increased the rate of completely lesion-free URS (45.4 vs. 16.7%, p = 0.034) while reducing the rate of poststenting (from 100 to 80.8%, p = 0.041). None of these effects could be demonstrated when prestenting for ureteric stones. Prestenting rates were less variable for renal stones (57-100%) than for ureteric stones (0-100%, p < 0.01). CONCLUSIONS: This study confirms the benefits of prestenting in URS for renal stones but not for ureteric stones. There were considerable differences in prestenting rates between the participating clinics.

Use of the Prostate Health Index and Density in 3 Outpatient Centers to Avoid Unnecessary Prostate Biopsies.

OBJECTIVES: We investigated the diagnostic efficacy of the prostate health index (PHI) and PHI density (PHID) to avoid unnecessary prostate biopsies in 3 urological practices. METHODS: In 122 patients, total prostate-specific antigen (PSA), free PSA (f-PSA), the quotient from total PSA and f-PSA (f-PSA%), and [-2]pro-PSA were measured in the serum; PHI, PHID, and PSA density (PSAD) were calculated prior to prostate biopsy. Tissue sampling via transrectal biopsy was indicated in case of suspicious PSA (progression and/or elevation of PSA) and/or suspicious digital rectal examination. PSAD, PHI, and PHID were not used for biopsy indication. The diagnostic efficacy was determined with receiver-operating characteristic (ROC)and decision curve analyses. RESULTS: Based on prostate biopsies, 38% (n = 46) of the cases had no prostate carcinoma (PCa), 21% (n = 26) no clinically significant (insignificant) PCa, and 41% (n = 50) had clinically significant PCa. ROC analyses of the PSA parameters showed higher diagnostic efficacy for PHI and PHID (AUC 0.722 and 0.739) than for f-PSA%, PSA, and PSAD (AUC 0.612, 0.595, and 0.698, respectively) regarding carcinoma diagnosis. With a combined use of PHI and PHID (cutoff >40 and >0.9, respectively), only 1 clinically significant PCa would have been missed (sensitivity 98%); in 24 (20%) patients, biopsy could have been avoided. CONCLUSION: The integration of PHI and PHID could improve the diagnostic efficacy of risk calculators to avoid unnecessary prostate biopsies. However, as a prerequisite, validation of cutoff values in prospective studies is urgently required.

A Phase 4 Study of Everolimus to Evaluate Efficacy and Safety in Patients with Metastatic Renal-Cell Carcinoma after Failure of First-Line Sunitinib or Pazopanib (SUNPAZ).

INTRODUCTION: Sunitinib and pazopanib are both standard first-line therapies for clear-cell metastatic renal-cell carcinoma (mRCC). Everolimus is a well-established second-line treatment. OBJECTIVE: To estimate the efficacy and safety of second-line everolimus following pazopanib or sunitinib. METHODS: SUNPAZ was an open-label, phase 4 clinical trial of everolimus in patients with clear-cell mRCC progressing after first-line sunitinib or pazopanib. The primary end point was the number of patients without progression 6 months after starting everolimus. Secondary end points included progression-free survival (PFS), overall survival (OS), and overall response rate. Enrollment was terminated early due to slow recruitment; all analyses are descriptive. RESULTS: Patients who received prior sunitinib (n = 16) or pazopanib (n = 13) were enrolled. One of 12 patients in the sunitinib group and 6/13 patients in the pazopanib group were progression-free by month 6 in the full analysis set. Median PFS in the sunitinib and pazopanib groups was 2.8 and 8.0 months, and median OS was 14.8 months and 20.4 months, respectively. Fifteen patients in the sunitinib group and 13 in the pazopanib group experienced adverse events. CONCLUSIONS: Safety and efficacy results confirm the second-line everolimus profile. However, baseline differences in patient populations should be taken into consideration.

Rogaratinib in patients with advanced cancers selected by FGFR mRNA expression: a phase 1 dose-escalation and dose-expansion study.

BACKGROUND: The clinical activity of fibroblast growth factor receptor (FGFR) inhibitors seems restricted to cancers harbouring rare FGFR genetic aberrations. In preclinical studies, high tumour FGFR mRNA expression predicted response to rogaratinib, an oral pan-FGFR inhibitor. We aimed to assess the safety, maximum tolerated dose, recommended phase 2 dose, pharmacokinetics, and preliminary clinical activity of rogaratinib. METHODS: We did a phase 1 dose-escalation and dose-expansion study of rogaratinib in adults with advanced cancers at 22 sites in Germany, Switzerland, South Korea, Singapore, Spain, and France. Eligible patients were aged 18 years or older, and were ineligible for standard therapy, with an Eastern Cooperative Oncology Group performance status of 0-2, a life expectancy of at least 3 months, and at least one measurable or evaluable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. During dose escalation, rogaratinib was administered orally twice daily at 50-800 mg in continuous 21-day cycles using a model-based dose-response analysis (continuous reassessment method). In the dose-expansion phase, all patients provided an archival formalin-fixed paraffin-embedded (FFPE) tumour biopsy or consented to a new biopsy at screening for the analysis of FGFR1-3 mRNA expression. In the dose-expansion phase, rogaratinib was given at the recommended dose for expansion to patients in four cohorts: urothelial carcinoma, head and neck squamous-cell cancer (HNSCC), non-small-cell lung cancer (NSCLC), and other solid tumour types. Primary endpoints were safety and tolerability, determination of maximum tolerated dose including dose-limiting toxicities and determination of recommended phase 2 dose, and pharmacokinetics of rogaratinib. Safety analyses were reported in all patients who received at least one dose of rogaratinib. Patients who completed cycle 1 or discontinued during cycle 1 due to an adverse event or dose-limiting toxicity were included in the evaluation of recommended phase 2 dose. Efficacy analyses were reported for all patients who received at least one dose of study drug and who had available post-baseline efficacy data. This ongoing study is registered with ClinicalTrials.gov, number NCT01976741, and is fully recruited. FINDINGS: Between Dec 30, 2013, and July 5, 2017, 866 patients were screened for FGFR mRNA expression, of whom 126 patients were treated (23 FGFR mRNA-unselected patients in the dose-escalation phase and 103 patients with FGFR mRNA-overexpressing tumours [52 patients with urothelial carcinoma, eight patients with HNSCC, 20 patients with NSCLC, and 23 patients with other tumour types] in the dose-expansion phase). No dose-limiting toxicities were reported and the maximum tolerated dose was not reached; 800 mg twice daily was established as the recommended phase 2 dose and was selected for the dose-expansion phase. The most common adverse events of any grade were hyperphosphataemia (in 77 [61%] of 126 patients), diarrhoea (in 65 [52%]), and decreased appetite (in 48 [38%]); and the most common grade 3-4 adverse events were fatigue (in 11 [9%] of 126 patients) and asymptomatic increased lipase (in 10 [8%]). Serious treatment-related adverse events were reported in five patients (decreased appetite and diarrhoea in one patient with urothelial carcinoma, and acute kidney injury [NSCLC], hypoglycaemia [other solid tumours], retinopathy [urothelial carcinoma], and vomiting [urothelial carcinoma] in one patient each); no treatment-related deaths occurred. Median follow-up after cessation of treatment was 32 days (IQR 25-36 days). In the expansion cohorts, 15 (15%; 95% CI 8·6-23·5) out of 100 evaluable patients achieved an objective response, with responses recorded in all four expansion cohorts (12 in the urothelial carcinoma cohort and one in each of the other three cohorts), and in ten (67%) of 15 FGFR mRNA-overexpressing tumours without apparent FGFR genetic aberration. INTERPRETATION: Rogaratinib was well tolerated and clinically active against several types of cancer. Selection by FGFR mRNA expression could be a useful additional biomarker to identify a broader patient population who could be eligible for FGFR inhibitor treatment. FUNDING: Bayer AG.

Hospital volume in ureterorenoscopic stone treatment: 99 operations per year could increase the chance of a better outcome-results of the German prospective multicentre BUSTER project.

BACKGROUND: Despite the high utilisation of ureterorenoscopy (URS) in interventional stone treatment, there is little evidence of any link between annual hospital volume and outcome. METHODS: From January to April 2015, data from 307 URS patients were prospectively recorded in the multicentre observational BUSTER-Trial (Benchmarks of ureterorenoscopic stone treatment-results in terms of complications, quality of life, and stone-free rates). The best threshold value for annual hospital volume with an independent effect on the outcome (measured on stone-free and complication rates) of our study group was established with logistic regression. RESULTS: In 38.4% of cases of renal and 61.6% of ureteral stones, median stone size was 6 mm with an interquartile range (IQR) of 4-8 mm. The annual URS rate in the 14 participating hospitals ranged from 77 to 333 (median 144; IQR 109-208). The binary endpoint as a combination of completely stone-free or residual fragments small enough to pass spontaneously and a maximum complication severity of Clavien-Dindo grade 1 was attained in 234/252 (92.9%) cases with a hospital volume of ≥ 99 URS compared with 43/55 (78.2%) in < 99 URS (p = 0.002). Adjusted for patient-, stone- and physician-related factors, an annual hospital URS volume of ≥ 99 increases the chance of an optimum outcome (OR = 3.92; 95% CI 1.46-10.51; p = 0.007). CONCLUSIONS: An independent effect of URS hospital volume on outcome quality in the 14 participating hospitals was demonstrated. Threshold values for annual case numbers should be scientifically established irrespective of the considered procedure.

Ureteroenteric strictures: a single center experience comparing Bricker versus Wallace ureteroileal anastomosis in patients after urinary diversion for bladder cancer.

BACKGROUND: To evaluate the outcome and complication rate in a single institution experience using the two most commonly used techniques of ureteroenteric anastomosis, the Bricker and Wallace anastomosis. METHODS: A total of 137 patients underwent ileal conduit for bladder cancer. Ureters were anastomosed by two experienced surgeons, one performing a Bricker and the other, a Wallace anastomosis. Stricture was identified during clinical follow-up. RESULTS: Seventy-five patients underwent a Bricker anastomotic, and 65 received a Wallace anastomosis. The average age was 70 in both groups, males were predominant (66% Bricker, 70% Wallace). Follow up period was 36.5 months in Bricker group and 17 months in Wallace group. In both groups, the body mass index (BMI) was similar (26.1 kg/m2 Bricker and 26.4 kg/m2 Wallace). We observed that the stricture rate after performing the Bricker anastomosis technique was 25.3% (19/75) as compared to 7.7% (5/65) after Wallace anastomosis technique, which was statistically significant (p = 0.001). In the Bricker group, patients with strictures had higher BMI (28.3 vs. 25.7 kg/m2, p = 0.05). On average it took 8.5 months in the Bricker group and three months in the Wallace group (p = 0.6) to develop stricture. CONCLUSIONS: The stricture rate was significantly higher when Bricker technique was applied. Although the BMI was not different in both groups, patients with a higher BMI were more likely to develop stricture. We believe that the approach of the separate and refluxing technique of Bricker anastomosis especially in obese patients poses a higher risk for anastomotic stricture formation.

The importance of sexuality, changes in erectile functioning and its association with self-esteem in men with localized prostate cancer: data from an observational study.

BACKGROUND: Treatment for localized prostate cancer (PCa) can cause long-term changes in erectile functioning. However, data on the importance of sexuality and possible consequences of altered erectile functioning on self-esteem in men with localized PCa are lacking. METHODS: Self-report questionnaires were completed by 292 men with PCa, initially managed with active surveillance (AS) or radical prostatectomy (RP). Independent t-tests were conducted to evaluate group differences. A sequential multiple regression model was fitted to analyze the associations between the importance of sexuality, changes in erectile functioning and impairment of self-esteem. Interaction effects were tested using simple slope analyses. RESULTS: Participants were 70 ± 7.2 years old and 66.5% rated sex as being "rather/very important". The two groups differed markedly in changes in erectile functioning, importance of sexuality and impairment of self-esteem (p < .001), with higher values in RP patients. Regression analysis showed that after adjustment for control variables and importance of sexuality, changes in erectile functioning were still associated with impairment of self-esteem (B = .668, SE = .069, p < .001). The interaction of changes in erectile functioning and importance of sexuality reached significance (B = .318, SE = .062, p < .001). CONCLUSIONS: RP patients report more changes in erectile functioning than AS patients. Moreover, in men with localized PCa, erectile functioning and self-esteem are closely related. Sexuality seems to be important for the majority of these men. Physicians should address the possibility of erectile dysfunction and its potential effects on psychological well-being before the treatment decision.

Risk Factors for Ureteral Damage in Ureteroscopic stone Treatment: Results of the German Prospective Multicentre Benchmarks of Ureterorenoscopic Stone Treatment-Results in Terms of Complications, Quality of Life, and Stone-Free Rates Project.

BACKGROUND: The Post-Ureteroscopic Lesion Scale (PULS) is a validated, standardised scale that classifies iatrogenic ureteral lesions during ureteroscopy (URS). OBJECTIVE: To determine risk factors for the various PULS-grades caused by URS. METHOD: We prospectively investigated the independent influence of various risk factors in correlation with PULS-Grade 1+ and 2+ on 307 patients with ureterorenoscopic stone treatment from 14 German urologic departments. RESULTS: The following are the outcomes of the study: 117 (38.4%) and 188 (61.6%) of the calculi (median stone size 6 mm) were found in the kidney or ureter; 70% and 82.4% underwent preoperative or postoperative ureteral stenting; 44.3 and 7.2% received laser or ballistic lithotripsy; 60% of the patients presented with PULS grade 1+ and 8% with PULS grade of 2+. Only intracorporal lithotripsy revealed a significant independent risk factor for PULS grade 1+ or 2+. Both laser and ballistic therapies raised the probability of PULS grade 1+ by the factors 3.6 (p < 0.001) and 3.9 (p = 0.021), respectively. The ORs in conjunction with PULS grade 2+ were 3.1 (p = 0.038) and 5.8 (p = 0.014) respectively. Neither endpoint exhibited a significant difference regarding the lithotripsic procedure (laser vs. ballistic). CONCLUSION: Intracorporal lithotripsy is associated with a significant increase in damage to the ureter; further research is needed to determine its long-term effects.

Prospective Multicenter Phase II Study on Focal Therapy (Hemiablation) of the Prostate with High Intensity Focused Ultrasound.

PURPOSE: We evaluated focal therapy with high intensity focused ultrasound hemiablation in a prospective trial. MATERIALS AND METHODS: We performed a prospective, multicenter, single arm study in patients with unilateral low/intermediate risk prostate cancer who were treated from April 2013 through March 2016 in Germany in AUO (Arbeitsgemeinschaft Urologische Onkologie) Study Protocol AP 68/11. Unilateral prostate cancer was assessed by transrectal ultrasound guided biopsy and multiparametric magnetic resonance imaging. Hemiablation was done using the Ablatherm® or the Focal One® device. The oncologic outcome was assessed by the salvage treatment rate, multiparametric magnetic resonance imaging and rebiopsy at 12 months. Functional outcome, quality of life, anxiety and depression were measured by validated questionnaires at baseline and every 3 months. RESULTS: Of the 54 recruited patients 51 completed 12-month or greater visits. Mean ± SD followup was 17.4 ± 4.5 months. Mean prostate specific antigen decreased from 6.2 ± 2.0 to 2.9 ± 1.9 ng/ml at 12 months (p <0.001). Biopsy at 12 months was positive for any prostate cancer and for clinically significant prostate cancer in 13 (26.5%) and 4 (8.2%) of the 49 patients, respectively. Posttreatment multiparametric magnetic resonance imaging had limited 25% sensitivity for clinically significant prostate cancer. Ten patients (19.6%) underwent salvage treatment. Potency was maintained in 21 of the 30 men who were potent preoperatively. There was no increase in incontinence. Quality of life, anxiety and depression did not change postoperatively. The study was limited by a short followup and the lack of a control arm. CONCLUSIONS: Focal therapy hemiablation is safe with little alteration of functional outcome. The oncologic outcome is acceptable on short-term followup. Followup multiparametric magnetic resonance imaging performed poorly and should not replace repeat biopsy. Focal therapy has no impact on posttreatment anxiety and depression.

RANKL/RANK/OPG cytokine receptor system: mRNA expression pattern in BPH, primary and metastatic prostate cancer disease.

BACKGROUND: The cytokine system RANKL (receptor activator of NF-κB ligand), its receptor RANK and the antagonist OPG (osteoprotegerin) play a critical role in bone turnover. Our investigation was conducted to describe the gene expression at primary tumour site in prostate cancer patients and correlate the results with Gleason Score and PSA level. METHODS: Seventy-one samples were obtained from prostate cancer patients at the time of radical prostatectomy and palliative prostate resection (n = 71). Patients with benign prostate hyperplasia served as controls (n = 60). We performed real-time RT-PCR after microdissection of the samples. RESULTS: The mRNA expression of RANK was highest in tumour tissue from patients with bone metastases (p < 0.001) as compared to BPH or locally confined tumours, also shown in clinical subgroups distinguished by Gleason Score (< 7 or ≥ 7, p = 0.028) or PSA level (< 10 or ≥ 10 µg/l, p = 0.004). RANKL and OPG mRNA expression was higher in tumour tissue from patients with metastatic compared to local disease. The RANKL/OPG ratio was low in normal prostate tissue and high tumours with bone metastases (p < 0.05). Expression of all three cytokines was high in BPH tissue but did not exceed as much as in the tumour tissue. CONCLUSION: We demonstrated that RANK, RANKL and OPG are directly expressed by prostate cancer cells at the primary tumour site and showed a clear correlation with Gleason Score, serum PSA level and advanced disease. In BPH, mRNA expression is also detectable, but RANK expression does not exceed as much as compared to tumour tissue.

Feasibility study of MR-guided transgluteal targeted in-bore biopsy for suspicious lesions of the prostate at 3 Tesla using a freehand approach.

OBJECTIVE: The aim of our study was (1) to establish an in-bore targeted biopsy of suspicious prostate lesions, avoiding bowel penetration using a transgluteal approach and (2) to assess operator setup, patient comfort and safety aspects in the clinical setting for freehand real-time MR-guidance established for percutaneous procedures in an open MR-scanner. MATERIAL AND METHODS: 30 patients with suspect prostate lesions were biopsied in a cylindrical 3T-MRI system using a transgluteal approach in freehand technique. One to three biopsies were sampled using continuous dynamic imaging. Size, location and visibility of the lesion, intervention time, needle artefact size, interventional complications and histopathological diagnosis were recorded. RESULTS: All biopsies were technically successful. Nineteen patients showed evidence of prostate carcinoma. Cancer detection rate was 50 % in patients with previously negative TRUS-biopsy. The average intervention time was 26 min including a learning curve as the time was 13 min by the end of the study. No antibiotic prophylaxis was performed as none of the patients showed signs of infection. CONCLUSIONS: MR-guided targeted freehand biopsies of prostate lesions using a transgluteal approach are both technically feasible and time efficient in a standard closed-bore 3T-MR scanner as well as safe for the individual patient. KEY POINTS: • Open-bore freehand interventional principles were adapted to closed-bore systems. • Prostate MR-guided freehand biopsies were feasible in a clinical setting. • A transgluteal approach provides a short and simplified work flow. • An inoculation of the prostate with bowel flora is avoided. • The intervention time is comparable to the stereotactic approach.

Small renal carcinoma: the "when" and "how" of operation, active surveillance, and ablation.

Small, locally restricted renal cell carcinoma less than 4 cm in size should ideally be removed operatively by nephron-sparing tumour enucleation (partial kidney resection). In an increasingly elderly population, there is a growing trend toward parallel incidence of renal cell carcinoma and chronic renal insufficiency, with the latter's associated general comorbidities. Thus, for some patients, the risks of the anaesthesia and operation increase, while the advantage in terms of survival decreases. Transcutaneous radio-frequency ablation under local anaesthesia, transcutaneous afterloading high-dose-rate brachytherapy under local anaesthesia, and percutaneous stereotactic ablative radiotherapy may offer a less invasive alternative therapy. Active surveillance is to be regarded as no more than a controlled bridging up to definitive treatment (operation or ablation), while watchful waiting, on account of the lack of prognostic relevance and the symptomatology of renal cell carcinoma, with its comorbidity-related, clearly reduced life expectancy, does not involve any further diagnostic or therapeutic measures.

Autoantibodies Directed Against the Endothelin A Receptor in Patients With Benign Prostatic Hyperplasia.

BACKGROUND: Over-stimulation of G-protein coupled receptors (GPCRs) such as α1-adrenergic, muscarinic, endothelin, and AT1 receptors is considered to drive benign prostatic hyperplasia (BHP) which is often associated with lower urinary tract syndrome (LUTS). However, in addition to physiologic GPCR ligands, there is a new class of autoantibodies called functional autoantibodies that target the same GPCRs (GPCR-AABs) for over-stimulation, thus, presenting pathogenic potency. We hypothesize that patients with BPH/LUTS could carry GPCR-AABs representing potential targets for treatment. METHODS: GPCR-AABs were identified, quantified, and characterized in the serum from 20 patients (aged 55-82 years, median 71 years) with BPH using the bioassay of spontaneously beating cultured neonatal rat cardiomyocytes. RESULTS: A sum of 60% of the patients were positive for agonistic autoantibodies directed against the endothelin A receptor (ETA-AABs). ETA-AABs were associated with the IgG 1 subclass, targeted an epitope located on the second extracellular receptor loop and their agonistic activity could be neutralized by the aptamer BC007. CONCLUSIONS: Agonistic ETA-AABs could-via uncontrolled over-boarding endothelin A receptor stimulation-contribute to the pathogenesis of BPH/LUTS. The in vitro demonstrated ETA-AAB neutralization by the aptamer BC007 could open the door for a new treatment strategy in patients with BPH/LUTS. Prostate 77:458-465, 2017. © 2016 Wiley Periodicals, Inc.