Outcomes of robot-assisted laparoscopic extended pelvic lymph node dissection for prostate Cancer.

INTRODUCTION: Extended pelvic lymph node dissection (ePLND) in men undergoing robot-assisted laparoscopic radical prostatectomy (RARP) is a widely used procedure. However, little is known about anatomical site-specific yields and subsequent metastatic patterns in these patients. PATIENTS AND METHODS: Data on a consecutive series of 1107 patients undergoing RARP at our centre between 2004 and 2018 were analysed. In men undergoing LN dissection, the internal, external and obturator nodes were removed and sent in separately. We performed an analysis of LN yields in total and for each anatomical zone, patterns of LN metastases and complications. Oncological outcome in pN+ disease was assessed including postoperative PSA persistence and survival. RESULTS: A total of 823 ePLNDs were performed in the investigated cohort resulting in 98 men being diagnosed as pN+ (8.9%). The median (IQR) LN yield was 19 (14-25), 10 (7-13) on the right and 9 (6-12) on the left side (P < 0.001). A median of six (4-8) LNs were retrieved from the external, three (1-6) from the internal iliac artery, and eight (6-12) from the obturator fossa. More men had metastatic LNs on the right side compared to the left (41 vs. 19). Symptomatic lymphoceles occurred exclusively in the ePLND group (2.3% vs. 0%, p = 0.04). Postoperatively, 47 (47.9%) of men with pN+ reached a PSA of < 0.1µg/ml. There was no association between a certain pN+ region and postoperative PSA persistence or BCRFS. The estimated cancer specific survival rate at 5 years was 98.5% for pN+ disease. CONCLUSION: Robot-assisted laparoscopic ePLND with a high LN yield and low complication rate is feasible. However, we observed an imbalance in more removed and positive LNs on the right side compared to the left. A high rate of postoperative PSA persistence and early recurrence in pN+ patients might indicate a possibly limited therapeutical value of the procedure in already spread disease. Yet, these men demonstrated an excellent survival.

Therapy decisions after diagnosis of prostate cancer in men with negative prostate MRI.

BACKGROUND: To investigate the clinical implications of magnetic resonance imaging (MRI) negative prostate cancer (PCa) in a cohort of men undergoing transperineal prostate biopsy. METHODS: We included all men without prior diagnosis of PCa undergoing transperineal template saturation ± fusion-guided targeted biopsy of the prostate between November 2014 and March 2018. Before biopsy, all patients underwent MRI and biopsies were performed irrespective of imaging results. Baseline characteristics, imaging, biopsy results, and follow-up information were retrieved from the patient charts. Patients were classified as either MRI negative (Prostate Imaging Reporting and Data System [PIRADS] ≤ 2) or positive (PIRADS ≥ 3). ISUP grade group 1 was defined as clinically nonsignificant (nsPCa) and ≥2 as clinically significant PCa (csPCa). Primary outcome was the individual therapeutic decision after diagnosis of PCa stratified according to MRI visibility. Secondary outcomes were the sensitivity and specificity of MRI, and the urooncological outcomes after radical prostatectomy (RP). RESULTS: From 515 patients undergoing prostate biopsy, 171 (33.2%) patients had a negative and 344 (66.8%) a positive MRI. Pathology review stratified for MRI negative and positive cases revealed nsPCa in 27 (15.8%) and 32 (9.3%) and csPCa in 26 (15.2%) and 194 (56.4%) of the patients, respectively. The rate of active treatment in the MRI negative was lower compared with the MRI positive cohort (12.3% vs. 53.2%; odd ratio [OR] = 0.12; p < 0.001). While men with negative MRI were more likely to undergo active surveillance (AS) than MRI positive patients (18.1% vs. 10.8%; OR = 1.84; p = 0.027), they rarely underwent RP (6.4% vs. 40.7%, OR = 0.10; p < 0.001). Logistic regression revealed that a negative MRI was independently protective for active treatment (OR = 0.32, p = 0.014). The specificity, sensitivity, negative, and positive predictive value of MRI for detection of csPCa were 49.2%, 88.2%, 56.4%, and 84.8%, respectively. The rate of adverse clinicopathological outcome features (pT3/4, ISUP ≥4, or prostate-specific antigen [PSA]-persistence) following RP was 4.7% for men with MRI negative compared to 17.4% for men with MRI positive PCa (OR = 3.1, p = 0.19). CONCLUSION: Only few men with MRI negative PCa need active cancer treatment at the time of diagnosis, while the majority opts for AS. Omitting prostate biopsies and performing a follow-up MRI may be a safe alternative to reduce the number of unnecessary interventions.

The Role of Additional Epididymis Resection during Hydrocelectomy: Is It of Any Benefit in Comparison to Simple Hydrocelectomy?

INTRODUCTION: Open hydrocelectomy via scrotal incision is the standard approach for secondary hydroceles. Traditionally, the Swiss urologic community offer hydrocelectomy with additional resection of the epididymis in elderly men with completed family planning. It is believed that the additional resection of the epididymis reduces the postoperative recurrence rate of hydroceles. However, there is no evidence supporting this theory. Therefore, the aim of this study was to compare the recurrence and complication rates for patients with secondary hydroceles undergoing either pure hydrocelectomy (puH) or hydrocelectomy with additional resection of the epididymis (HRE). MATERIALS AND METHODS: We reviewed all male patients who underwent surgical therapy for secondary hydroceles between May 2003 and February 2019 at our institution. Patient's baseline and perioperative characteristics as well as postoperative characteristics including complications and recurrence rates were gathered and compared between different surgical techniques. RESULTS: A total of 234 patients were identified. puH was performed in 93 (40%) cases and HRE in 141 (60%) patients. Patients in the HRE group were older (median age: 62 vs. 38 years, p < 0.001), had a higher ASA-Score (p < 0.001), were more often on platelet aggregation inhibitors (19% vs. 7.5%, p = 0.01), and had a longer median operative time (75 vs. 64 min, p < 0.001). During a median follow-up of 46 months, a similar number of recurrent hydroceles were found for puH (7 [7.5%]) and HRE (6 [4.5%]) (p = 0.3). Complications were observed in 19 (20%) cases after puH compared to 25 (18%) cases after HRE (p = 0.6). Patients after puH experienced more often severe complications (Clavien-Dindo Grade 3b) compared to the HRE group (5 vs. 12%, p = 0.046). CONCLUSION: puH and HRE showed similar results in terms of overall low recurrence rates and also in terms of postoperative complications, even though patients who underwent puH experienced slightly higher severe complications. Both procedures are safe and effective, but it seems that HRE does not provide a relevant clinical benefit in comparison to puH for the management of men with secondary hydroceles.

Long-Term Oncological Efficacy of Retroperitoneoscopic Radical Nephrectomy of Localized Renal Cell Cancer pT1-3 (≤12 cm).

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Tumor Stent for Chronic Ureteral Obstruction: Which Are Predictors of Stent Failure?

Purpose: To identify predictors of UROSOFT® tumor stent failure. According to the manufacturer, this reinforced ureteral stent has a maximal dwell time of 6 months. Nonetheless, stent failure may reduce this maximal dwell time. Methods: All patients undergoing first-time UROSOFT tumor stent insertion in our institution between 2010 and 2018 were considered for this retrospective analysis. Primary endpoint was stent failure and defined as premature stent exchange or percutaneous nephrostomy insertion. The local ethics committee approved the study protocol (study ID: BASEC 2020-00175). Results: In total, 182 patients were available for analysis. Median age was 68 years. Causes for tumor stent placement were extrinsic ureteral obstruction in 144 patients (79%) and intrinsic obstruction in 38 patients (21%). Tumor stent failure-free survival estimates at 1, 2, 3, 4, and 5 months were 89%, 83%, 76%, 65%, and 52%, respectively. Patients with stent failure had significantly higher grade of hydronephrosis, higher urinary culture bacterial growth, higher serum white blood cell count, higher C-reactive protein, and lower estimated glomerular filtration rate at the time of reintervention, compared with patients who underwent regular stent exchange. Of all baseline and perioperative parameters, we found bilateral insertion, intrinsic ureteral obstruction, and urinary tract infection (UTI) at time of tumor stent insertion to be significant and independent predictors of stent failure (all p < 0.05). Conclusion: Despite a theoretical maximal dwell time of 6 months, ∼50% of all cases are subject to premature stent failure. Predictors of stent failure are bilateral insertion, intrinsic ureteral obstruction, and UTI at the time of tumor stent insertion. Preoperative antibiotic therapy may impact on stent failure rate.

Prostate cancer detection rate in men undergoing transperineal template-guided saturation and targeted prostate biopsy.

OBJECTIVES: To compare prostate cancer (PCa) detection rate of transperineal template-guided saturation prostate biopsy (SBx) and multiparametric magnetic resonance imaging (mpMRI)/transrectal ultrasound fusion guided targeted biopsy (TBx). MATERIALS AND METHODS: We prospectively enrolled 392 men who underwent SBx and TBx in case of suspicious lesions from November 2016 to October 2019. Triggers for a biopsy were an elevated prostate-specific antigen (PSA) and/or positive digital rectal examination and only treatment naïve patients without a previous diagnosis of PCa were included. Study inclusion occurred before biopsy and a prebiopsy mpMRI was available in all men. SBx were taken from 20 different locations according to the modified Barzell zones. The primary endpoint was the detection rate of clinically significant PCa (csPCa) and insignificant PCa (ciPCa) by SBx and/or TBx by comparing the two methods alone and in combination. Additional TBx were taken for any prostate imaging-reporting and data system (PI-RADS) lesion ≥3 seen on the mpMRI. csPCa was defined as any Gleason score ≥7 and ciPCa as Gleason score 6. RESULTS: A total of 392 men with a median age of 64 years (interquartile range [IQR]: 58-69), a median PSA of 7.0 ng/ml (IQR: 4.8-10.1) were enrolled. Overall, PCa was found in 200 (51%) of all biopsied men, with 158 (79%) being csPCa and 42 (21%) ciPCa. A total of 268 (68%) men with a suspicious mpMRI and underwent a combined TBx and SBx, of whom csPCa was found in 139 (52%). In this subgroup, 116/139 (83%) csPCa would have been detected by TBx alone, and an additional 23 (17%) were found by SBx. Men with a negative mpMRI (PI-RADS < 3, n = 124, 32%) were found to have csPCa in 19 (15%) cases. In patients with a negative mpMRI in combination with a PSA density <0.1 ng/ml2 , only 8% (3/36) had csPCa. If only TBx would have been performed and all men with a negative mpMRI would not have been biopsed, 42/158 (27%) of csPCa would have been missed, and 38/42 (90%) ciPCa would have not been detected. On multivariable analysis, significant predictors of csPCa were increasing PSA (odds ratio, OR: 1.07 [95% confidence interval, CI: 1.03-1.11]), increasing age (OR: 1.07 [95% CI: 1.03-1.11]), PI-RADS score ≥ 3 (OR: 6.49 [95% CI: 3.55-11.89]), and smaller prostate volume (OR: 0.96 [95% CI: 0.95 -0.97] (p < 0.05 for all parameters). CONCLUSION: In comparison to SBx, TBx alone detects csPCa in only ¾ of all men with a positive mpMRI lesion. Thus, systematic biopsies in addition to TBx have to be considered at least in some who undergo a prostate biopsy. In men with a negative mpMRI, SBx still detects 15% csPCa, but similarly overdetecting ciPCa. According to our results, low PSA density and negative mpMRI findings could be used to decide which men can safely avoid biopsy.

Effectiveness of Flexible Ureterorenoscopy Versus Extracorporeal Shock Wave Lithotripsy for Renal Calculi of 5-15 mm: Results of a Randomized Controlled Trial.

BACKGROUND: Primary flexible ureterorenoscopy (URS) and extracorporeal shock wave lithotripsy (SWL) are treatment options in patients with renal calculi of 5-15 mm. OBJECTIVE: To compare effectiveness, complication rates, and pain scores between primary URS and SWL. DESIGN SETTING AND PARTICIPANTS: Between 2011 and 2016, patients with renal calculi between 5 and 15 mm were randomized to undergo either primary URS or SWL. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Stone-free rate and size of residual fragments assessed by computed tomography after 3 mo, complications, and pain scores were evaluated. RESULTS AND LIMITATIONS: The study was prematurely closed after randomizing 44 patients due to poor accrual. The 3-mo stone-free rate and mean residual stone size were, respectively, 61% and 1.8 mm after URS and 48% and 2.4 mm after SWL. Early post-treatment pain scores were significantly higher after URS than after SWL on day 1 (3.3 vs 1.6, p = 0.02) and day 7 (5.2 vs 3.4, p = 0.04), but were no longer detectable after 3 wk and 3 mo, respectively. One Clavien-Dindo grade II complication was observed after URS (5%) and SWL (4%), while one (4%) grade IIIb complication was observed after SWL. CONCLUSIONS: URS appears to be associated with higher early post-treatment discomfort, which could be associated with routine postoperative stenting. Owing to premature closure of this trial, the power was insufficient to formally compare URS and SWL; however, the present data might be informative to counsel patients about treatment outcomes and allow future meta-analyses. PATIENT SUMMARY: This study was ended prematurely, but it contributes data about efficacy and side effects of different treatment options in patients with renal calculi.

[Dignity of Small Renal Masses: Implications for Diagnostics and Therapy]. / Dignität kleiner Nierentumoren: Implikationen zur Abklärung und Therapie.

Dignity of Small Renal Masses: Implications for Diagnostics and Therapy Abstract. The ubiquitous availability of radiological imaging has increased the diagnosis of renal incidentalomas with a diameter ≤4 cm. If malignancy is suspected, these are often treated surgically without prior biopsy. However, several studies demonstrate a relevant proportion of benign tumors, equating to a degree of overtreatment. There are no Swiss data available. Renal tumors resected in our center between 2006 and 2014 (n = 404) were retrospectively examined for size on cross-sectional imaging and their respective histology, identifying 221 (54.7 %) small renal masses with a diameter ≤4 cm. Of these, 62 (28 %) were benign and three (1.4 %) were of unclear or low malignant potential. Among the remaining 156 malignancies, 116 (74.4 %) were classified as prognostically favorable, allowing for active surveillance, if the patient's clinical context allows.

Impact of short-term Dutasteride treatment on prostate-specific membrane antigen expression in a mouse xenograft model.

BACKGROUND: Dutasteride has been shown to increase expression of the prostate-specific membrane antigen (PSMA) in prostate cancer cells in previous in vitro studies. This 5-alpha-reductase inhibitor is commonly used for the treatment of symptomatic benign prostatic enlargement. The modulation of PSMA expression might affect PSMA-based prostate cancer imaging and therapy. AIM: The purpose of this work was to further analyze concentration-dependent effects of Dutasteride on PSMA expression in a mouse xenograft model. METHODS AND RESULTS: Four groups of mice bearing LNCaP xenografts were treated for 14 days with daily intraperitoneal injections of either vehicle control or different concentrations of Dutasteride (0.1, 1, 10 mg/kg). Total expression of PSMA, androgen receptor (AR), and caspase-3 protein was analyzed using immunoblotting (WES). In addition, PSMA, cleaved caspase-3 and Ki-67 expression was assessed and quantified by immunohistochemistry. Tumor size was measured by caliper on day 7 and 14, tumor weight was assessed following tissue harvesting. The mean PSMA protein expression in mice increased significantly after treatment with 1 mg/kg (10-fold) or 10 mg/kg (sixfold) of Dutasteride compared to vehicle control. The mean fluorescence intensity significantly increased by daily injections of 0.1 mg/kg Dutasteride (1.6-fold) as well as 1 and 10 mg/kg Dutasteride (twofold). While the reduction in tumor volume following treatment with high concentrations of 10 mg/kg Dutasteride was nonsignificant, no changes in AR, caspase-3, cleaved caspase-3, and Ki-67 expression were observed. CONCLUSION: Short-term Dutasteride treatments with concentrations of 1 and 10 mg/kg significantly increase the total PSMA protein expression in a mouse LNCaP xenograft model. PSMA fluorescence intensity increases significantly even using lower daily concentrations of 0.1 mg/kg Dutasteride. Further investigations are needed to elucidate the impact of Dutasteride treatment on PSMA expression in patients.

Benefit of a more extended pelvic lymph node dissection among patients undergoing radical prostatectomy for localized prostate cancer: A causal mediation analysis.

BACKGROUND: The therapeutic role of extended (ePLND) versus nonextended pelvic lymph node dissection (nePLND) to remove occult micrometastases in men undergoing radical prostatectomy for localized prostate cancer (PC) is conflicting. Therefore, our aim was to quantify the direct effect of ePLND versus nePLND (removal of occult micrometastases), which is not mediated through the detection of nodal disease and potential adjuvant therapy (indirect effect). METHODS: Retrospective, bi-center cohort study of consecutive patients undergoing radical prostatectomy and PLND for PC (January 2006 and December 2016). Patients were followed until April 2018 for the occurrence of either biochemical recurrence or secondary therapy (composite outcome). ePLND was compared to nePLND by unweighted and weighted survival analysis (total effect) as well as by causal mediation analysis (direct and indirect effect). RESULTS: Positive nodal disease was detected in 71 (7%) out of 1008 patients undergoing radical prostatectomy and PLND for PC (ePLND: 368 [36.5%]; nePLND: 640 [63.5%]). Survival analysis demonstrated results in favor of ePLND (unweighted hazard ratio: 0.77 [95% confidence interval: 0.59-1.01], p = .056; weighted hazard ratio: 0.75 [0.56-0.99], p = .044). The causal mediation analysis confirmed the total effect of 0.77 (0.71-0.82). After disentangling this total effect into an indirect effect (via detection of nodal disease and potential adjuvant therapy) and a direct effect (via removal of occult micrometastases), we identified an even more protective direct effect of 0.69 (0.63-0.75). CONCLUSIONS: Our results not only indicate the utility of ePLND but also that its impact is not restricted to a staging benefit and probably involves a therapeutic benefit mediated through the removal of occult micrometastases.

Diagnostic accuracy of ultrasonography, computed tomography, cystoscopy and cytology to detect urinary tract malignancies in patients with asymptomatic hematuria.

PURPOSE: To report the incidence of urinary tract malignancies (UTM) and to compare the diagnostic accuracy of cytology with cystoscopy, renal ultrasound (US) and computed tomography (CT) in patients with hematuria. METHODS: A retrospective analysis was conducted of patients who underwent cystoscopy, cytology, US and CT for hematuria between 2011 and 2017. Age, gender, BMI, smoking status, and results of further diagnostic interventions including transurethral resection of the bladder (TURB), ureterorenoscopy (URS), renal biopsy and imaging were extracted from medical charts. Logistic regression to identify risk factors for UTM was performed. Discriminatory accuracy of US, CT and cytology was assessed by 2 × 2 tables. RESULTS: Of 847 patients, 432 (51%) presented with non-visible hematuria (NVH) and 415 (49%) with visible hematuria (VH). Of all patients with NVH, seven (1.6%) had bladder cancer (BCA), three (< 1%) had renal cell cancer (RCC) and no single patient had upper tract urothelial cancer (UTUC). Of the patients with VH, 62 (14.9%) were diagnosed with BCA, 7 (1.6%) with RCC and 4 (< 1%) with UTUC. In multivariable analysis VH, higher age, smoking and lower BMI were associated with an increased risk for UTM. The specificity/negative predictive value of US for the detection of RCC or UTUC in patients with NVH and VH were 96%/100% and 95%/99%, respectively. CONCLUSION: Due to the low incidence of UTM, the necessity of further diagnostics should be questioned in patients with NVH. In contrast, patients with VH are at considerable risk for BCA, and cystoscopy and upper tract imaging is justified.

Risk factors and treatment outcomes of 239 patients with testicular granulosa cell tumors: a systematic review of published case series data.

PURPOSE: Testicular granulosa cell tumors (tGrCT) are rare sex cord-stromal tumors. This review aims to synthesize the available evidence regarding the clinical presentation and clinicopathological characteristics, treatment and outcomes. METHODS: We conducted a systematic literature search using the most important research databases. Whenever feasible, we extracted the data on individual patient level. RESULTS: From 7863 identified records, we included 88 publications describing 239 patients with tGrCT. The majority of the cases were diagnosed with juvenile tGrCT (166/239, 69%), while 73/239 (31%) patients were diagnosed with adult tGrCT. Mean age at diagnosis was 1.5 years (± 5 SD) for juvenile tGrCT, and 42 years (± 19 SD) for adult tGrCT. Information on primary treatment was available in 231/239 (97%), of which 202/231 (87%) were treated with a radical orchiectomy and 20/231 (9%) received testis sparing surgery (TSS). Local recurrence after TSS was observed in 1/20 (5%) cases. Metastatic disease was never observed in men with juvenile tGrCT but in 7/73 (10%) men with adult tGrCT. In 5/7 men with metastatic tGrCT, metastases were diagnosed at initial staging, while 2/7 patients developed metastases after 72 and 121 months of follow-up, respectively. Primary site of metastasis is represented by the retroperitoneal lymph nodes, but other sites including lungs, liver, bone and inguinal lymph nodes can also be affected. In comparison with non-metastatic adult tGrCT, men with metastatic adult tGrCT had significantly larger primary tumors (70 vs 24 mm, p 0.001), and were more likely to present with angiolymphatic invasion (57% vs 4%, p 0.002) or gynecomastia (29% vs 3%, p 0.019). In five out of seven men with metastatic disease, resection of metastases or platinum-based chemotherapy led to complete remission. CONCLUSION: Juvenile tGrCT represent a benign entity whereas adult tGCTs have metastatic potential. Tumor size, presence of angiolymphatic invasion or gynecomastia represent risk factors for metastatic disease. The published literature supports the use of testis sparing surgery but there is only limited experience with adjuvant therapies. In the metastatic setting, the reviewed literature suggests that aggressive surgical and systemic treatment might cure patients.

Management of Active Surveillance-Eligible Prostate Cancer during Pretransplantation Workup of Patients with Kidney Failure: A Simulation Study.

BACKGROUND AND OBJECTIVES: The general rule that every active malignancy is an absolute contraindication for kidney transplantation is challenged by kidney failure patients diagnosed with active surveillance-eligible prostate cancer during pretransplantation workup. Interdisciplinary treatment teams therefore often face the challenge of balancing the benefits of early kidney transplantation and the risk of metastatic progression. Hence, we compared the quality-adjusted life expectancy of different management strategies in kidney failure patients diagnosed with active surveillance-eligible prostate cancer during pretransplantation workup. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A discrete event simulation model was developed on the basis of a systematic literature search, clinical guidelines, and expert opinion. After model validation and calibration, we simulated four management strategies in a hypothetical cohort of 100,000 patients: Definitive treatment (surgery or radiation therapy) and listing after a waiting period of 2 years, definitive treatment and immediate listing, active surveillance and listing after a waiting period of 2 years, and active surveillance and immediate listing. Individual patient results (quality-adjusted life years; QALYs) were aggregated into strategy-specific means (± SEs). RESULTS: Active surveillance and immediate listing yielded the highest amount of quality-adjusted life expectancy (6.97 ± 0.01 QALYs) followed by definitive treatment and immediate listing (6.75 ± 0.01 QALYs). These two strategies involving immediate listing not only outperformed those incorporating a waiting period of 2 years (definitive treatment: 6.32 ± 0.01 QALYs; active surveillance: 6.59 ± 0.01 QALYs) but also yielded a higher proportion of successfully performed transplantations (72% and 74% versus 56% and 59%), with less time on hemodialysis on average (4.02 and 3.81 years versus 4.80 and 4.65 years). CONCLUSIONS: Among kidney failure patients diagnosed with active surveillance-eligible prostate cancer during pretransplantation workup, the active surveillance and immediate listing strategy outperformed the alternative management strategies from a quality of life expectancy perspective, followed by definitive treatment and immediate listing.

Apalutamide in combination with autophagy inhibitors improves treatment effects in prostate cancer cells.

BACKGROUND: ARN-509 (Apalutamide) is a unique androgen receptor (AR) antagonist for the treatment of castration-resistant (CR) prostate cancer (PC). It inhibits AR nuclear translocation, DNA binding and transcription of AR gene targets. As dysregulation of autophagy has been detected in PC, the targeting of autophagy is a potential approach to overcome early therapeutic resistance. Therefore, we investigated the characteristics of autophagic response to ARN-509 treatment and evaluated the potential effect of a combination with autophagy inhibition. METHODS: Human prostate cancer cells (LNCaP) were cultivated in a steroid-free medium. Cells were treated with ARN-509 (50 µM) alone or in combination with the autophagy inhibitors 3-methyladenine (3MA, 5 mM) or chloroquine (Chl, 20 µM) or with ATG5 siRNA knock-down. Cell viability and apoptosis were measured by flow cytometry and fluorescence microscopy. Autophagy was monitored by immunohistochemistry, AUTOdot and immunoblotting (WES). RESULTS: Treatment with ARN-509 led to cell death of up to 37% with 50 µM and 60% with 100 µM by day 7. The combination of 50 µM ARN-509 with autophagy inhibitors produced a further increase in cell death by day 7. Immunostaining results showed that ARN-509 induced autophagy in LNCaP cells as evidenced by elevated levels of ATG5, Beclin 1 and LC3 punctuation and by an increase in the LC3-II band detected by WES. Autophagic flux was restored by the treatment of cells with Chl, intensifying the LC3-II band. These findings were further supported by an enhanced autophagosome punctuation observed by Autodot staining. CONCLUSIONS: These data demonstrate that treatment with ARN-509 leads to increased autophagy levels in LNCaP cells. Furthermore, in combination with autophagy inhibitors, ARN-509 provided a significantly elevated antitumor effect, thus providing a new therapeutic approach potentially translatable to patients.

Sertoli Cell Tumors of the Testes: Systematic Literature Review and Meta-Analysis of Outcomes in 435 Patients.

BACKGROUND: Sertoli cell tumors (SCTs) of the testes are rare, and the literature provides only weak evidence concerning their clinical course and management. The objective of this study was to summarize evidence on SCTs' clinical presentation, clinicopathological risk factors for malignancy, treatment options, and oncological outcomes. MATERIALS AND METHODS: Data sources included Medline, Embase, Scopus, the Cochrane Database of Systematic Reviews, and Web of Science. Published case reports, case series, and cohorts were included. Data on clinicopathological variables, treatment of local or metastatic disease, site of metastasis, or survival were extracted from each study considered in this paper, and associations between clinicopathological variables and metastatic disease were analyzed. Whenever feasible, data on individual patients were collected. RESULTS: Of the 435 patients included, only one (<1%) showed local recurrence after testis-sparing surgery (TSS). Three patients underwent adjuvant retroperitoneal lymphadenectomy. Fifty patients presented with metastases, located in the retroperitoneal lymph nodes (76%), lungs (36%), and bones (16%); median time to recurrence was 12 months. Risk factors for metastatic disease included age, tumor size, necrosis, tumor extension to the spermatic cord, angiolymphatic invasion, and mitotic index. Patients with metastases had a median life expectancy of 20 months. In six patients, metastasectomy resulted in complete remission. CONCLUSION: Our findings suggest that few local recurrences result after TSS, and no adjuvant therapy can be regarded as a standard of care. Several risk factors are predictive of metastatic disease. Surgery leads to remission in metastatic disease, whereas systemic treatment alone does not result in long-term remission. IMPLICATIONS FOR PRACTICE: Testicular Sertoli cell tumors usually present without metastatic disease and show low local recurrence rates after testis-sparing surgery; no adjuvant therapy option can be regarded as a standard of care. Patients with risk factors should undergo staging investigations. Those with metastatic disease have poor prognoses, and metastasectomy may be offered in selected cases.

Photoselective vaporization of the prostate: study outcomes as a function of risk of bias, conflicts of interest, and industrial sponsorship.

PURPOSE: To investigate the outcomes of comparative studies on photoselective vaporization of the prostate (PVP) as a function of risk of bias (RoB), conflicts of interest (COI), and industrial sponsorship (IS). METHODS: We performed a systematic literature search for comparative studies on PVP [randomized controlled trials (RCTs) and non-randomized comparative studies (NRCSs)]. Study selection as well as comprehensive assessment of RoB, COIs, and IS were performed in duplicate. The identified studies were further rated by two independent board-certified urologists as either PVP-favourable or PVP-unfavourable. Descriptive statistics were performed among all identified studies and among the subgroups of studies rated as favourable and unfavourable, respectively. RESULTS: Sixty-five studies qualified for inclusion (25 RTCs and 40 NRCSs) of which 56 (86%) were rated favourable and 9 (14%) unfavourable. A majority of all studies mentioned the absence/presence of potential COIs (78%). In contrast, a sponsorship statement was only found in 29% of the investigations. Studies rated favourable demonstrated a higher percentage of COIs (39% versus 22%). IS was exclusively found among favourable studies. Furthermore, a serious or critical RoB was more often found in favourably rated NRCSs. CONCLUSIONS: COIs and IS seem to be associated with favourable study outcomes in comparative studies on PVP. The transparency of the whole research process from study conception to the dissemination of the results has to be further improved to prevent a harmful effect of COIs and IS on the internal validity of studies.

Risk Factors and Treatment Outcomes of 1,375 Patients with Testicular Leydig Cell Tumors: Analysis of Published Case Series Data.

PURPOSE: Leydig cell tumors are rare but they are the most common nongerm cell testicular tumors. Only limited evidence exists for reliably differentiating between benign and malignant Leydig cell tumors and for optimally managing the different types and stages of this rare disease. In this review we synthesize the available evidence on the clinical presentation and clinicopathological characteristics associated with Leydig cell tumor malignancy and management. MATERIALS AND METHODS: We analyzed published case series data on Leydig cell tumors. The association between clinicopathological variables and the presence of metastatic disease was assessed using regression analyses. RESULTS: We included 357 reports, reviewing available data from 1,375 patients (median age 34 years). Testis sparing surgery was performed in 463 patients. Local recurrence after testis sparing surgery occurred in 8 of 121 (7%) patients with available followup information. Metastases were found in 101 patients and were most often located in the retroperitoneal lymph nodes (60%), lungs (38%) and/or liver (29%). The multivariable models with or without multiple imputation predicting metastatic disease included older age, larger tumor size, presence of any adverse factor (larger tumor diameter, necrosis, angiolymphatic invasion, pleomorphism, high mitotic index, atypia) and any protective factor (Reinke crystals, lipofuscin pigments, gynecomastia) with model AUCs of 0.93. Durable remission after resection of metastases or use of platinum based chemotherapy was rarely seen. CONCLUSIONS: Our risk tables using clinicopathological parameters can help identify patients with malignant tumors. These patients should undergo disease staging and be followed or receive further treatment. In some patients with metastatic disease surgical and systemic treatment might result in disease control.

Influence of regular aspirin intake on PSA values, prostate cancer incidence and overall survival in a prospective screening trial (ERSPC Aarau).

OBJECTIVES: To analyze the influence of aspirin (ASA) intake on PSA values and prostate cancer (PCa) development in a prospective screening study cohort. METHODS: 4314 men from the Swiss section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) were included. A transrectal prostate biopsy was performed in men with a PSA level ≥ 3 ng/ml. Mortality data were obtained through registry linkages. PCa incidence and grade, total PSA, free-to-total PSA and overall survival were compared between ASA users and non-users. RESULTS: Median follow-up time was 9.6 years. In 789 men (18.3%) using aspirin [ASA +], the overall PCa incidence was significantly lower (6.8% vs. 9.6%, p = 0.015), but the multivariate Cox regression analysis showed no significant decrease in risk of PCa diagnosis (HR 0.84, p = 0.297). Total PSA values were significantly lower in ASA users for both baseline (1.6 vs. 1.8 ng/ml, p = 0.007) and follow-up visits (1.75 vs. 2.1 ng/ml, p < 0.001). Multivariate Cox regression analysis predicted significantly higher overall mortality risk among ASA users (HR 1.46, p = 0.009). CONCLUSIONS: In our study population, PCa incidence was significantly reduced among patients on aspirin. While we did not observe a statistically significant PCa risk reduction during the follow-up period, we found lower PSA values among ASA users compared to non-users, with a more distinct difference after 4 years of ASA intake, suggesting a cumulative effect and a potential protective association between regular ASA intake and PCa development. As for clinical practice, lowering PSA cutoff values by 0.4 ng/ml could be considered in long-term ASA users to avoid a potential bias towards delayed PCa detection.

External Validation and Comparison of Prostate Cancer Risk Calculators Incorporating Multiparametric Magnetic Resonance Imaging for Prediction of Clinically Significant Prostate Cancer.

PURPOSE: We sought to externally validate recently published prostate cancer risk calculators incorporating multiparametric magnetic resonance imaging to predict clinically significant prostate cancer. We also compared the performance of these calculators to that of multiparametric magnetic resonance imaging naïve prostate cancer risk calculators. MATERIALS AND METHODS: We identified men without a previous prostate cancer diagnosis who underwent transperineal template saturation prostate biopsy with fusion guided targeted biopsy between November 2014 and March 2018 at our academic tertiary referral center. Any Gleason pattern 4 or greater was defined as clinically significant prostate cancer. Predictors, which were patient age, prostate specific antigen, digital rectal examination, prostate volume, family history, previous prostate biopsy and the highest region of interest according to the PI-RADS™ (Prostate Imaging Reporting and Data System), were retrospectively collected. Four multiparametric magnetic resonance imaging prostate cancer risk calculators and 2 multiparametric magnetic resonance imaging naïve prostate cancer risk calculators were evaluated for discrimination, calibration and the clinical net benefit using ROC analysis, calibration plots and decision curve analysis. RESULTS: Of the 468 men 193 (41%) were diagnosed with clinically significant prostate cancer. Three multiparametric magnetic resonance imaging prostate cancer risk calculators showed similar discrimination with a ROC AUC significantly higher than that of the other prostate cancer risk calculators (AUC 0.83-0.85 vs 0.69-0.74). Calibration in the large showed 2% deviation from the true amount of clinically significant prostate cancer for 2 multiparametric magnetic resonance imaging risk calculators while the other calculators showed worse calibration at 11% to 27%. A clinical net benefit was observed only for 3 multiparametric magnetic resonance imaging risk calculators at biopsy thresholds of 15% or greater. None of the 6 investigated prostate cancer risk calculators demonstrated clinical usefulness against a biopsy all strategy at thresholds less than 15%. CONCLUSIONS: The performance of multiparametric magnetic resonance imaging prostate cancer risk calculators varies but they generally outperform multiparametric magnetic resonance imaging naïve prostate cancer risk calculators in regard to discrimination, calibration and clinical usefulness. External validation in other biopsy settings is highly encouraged.