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Background and Objective: The feasibility and safety of a robotic approach for postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) in testicular cancer have been demonstrated, but data on long-term oncological outcomes of this procedure are limited. Our aim was to evaluate oncological outcomes following robotic PC-RPLND in this setting., Methods: This retrospective cohort study included consecutive patients with testicular cancer treated with robotic PC-RPLND at 11 academic centers worldwide between 2011 and 2023. Patient characteristics, clinicopathological findings, and oncological outcomes were recorded. Recurrence-free survival (RFS) was estimated via the Kaplan-Meier method., Key Findings and Limitations: A total of 173 patients were included, of whom 159 underwent pure robotic PC-RPLND; 14 cases were converted to open surgery. Among the pure robotic cases, 152 (96%) had nonseminoma, 122 (77%) had International Germ Cell Cancer Collaborative Group good risk, and 120 (76%) had a postchemotherapy mass size ≤5 cm. Salvage chemotherapy was received by ten patients (6%). Median estimated blood loss, operative time, and length of hospital stay were 100 ml, 300 min, and 2 d, respectively. Final pathology revealed necrosis/fibrosis in 64 cases (40%), teratoma in 78 (49%), and viable germ-cell tumor in 17 (11%). At median follow-up of 22 mo (interquartile range 7-50), eight patients had disease recurrence, which was in-field in three cases. One port-site recurrence was identified. The median time to recurrence was 7 mo. The 4-yr RFS rate was 93%. Two cancer-related deaths were recorded. Subgroup analysis revealed that patients with conversion to open surgery were more likely to have a larger preoperative mass and received salvage chemotherapy before RPLND. In addition, conversion to open surgery was associated with a higher rate of perioperative complications; however, oncological outcomes were statistically similar to those for pure robotic PC-RPLND. The main limitation of the study is its retrospective nature., Conclusions and Clinical Implications: Robotic PC-RPLND in testicular cancer is associated with acceptable intermediate-term oncological outcomes in appropriately selected patients., Patient Summary: In this large multicenter study, we investigated the outcomes of robotic surgery after chemotherapy for advanced testicular cancer. We found that robotic surgery yields acceptable cancer control results., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Historically, Asia had a lower prostate cancer (PCa) incidence and mortality compared with Western countries, but the gap is narrowing. Paradoxically, Asians have been reported to present with more advanced disease though more favorable outcomes. Despite PCa becoming an emerging health priority in East Asia, our knowledge remains limited. We compared the prevalence of high-grade PCa on biopsy and disease progression after radical prostatectomy (RP) in East Asian men from Asia and non-East Asian men from Western countries., Methods: This retrospective cohort study included men who underwent prostate biopsy and RP at academic centers in Shanghai, China, and Toronto, Canada (2014-2019). The expanded RP cohort included East Asian men from Singapore (n=282) and non-East Asians from Paris (n=192). Primary endpoints included the proportion of men with Gleason score (GS) ≥8 on biopsy and metastasis-free survival (MFS) after RP for GS ≥8. Multivariable logistic regression and Cox proportional hazard models were performed. Propensity score matching was used to reduce imbalances between cohorts., Results: PCa was found on biopsy in 2,343 of 4,905 (48%) East Asians and 2,317 of 3,482 (67%) non-East Asians (P<.001). Prostate-specific antigen (PSA) levels at presentation and the proportion of men with GS ≥8 were higher in East Asians than non-East Asians (12.4 vs 6.6 ng/mL and 15.0% vs 8.8%, respectively; both P<.001). On multivariable analysis, there was no difference in the proportion of men with GS ≥8 between matched cohorts with PSA <20 ng/mL (n=3,572; odds ratio, 1.05 [95% CI, 0.77-1.43]; P=.76). No difference in MFS was found after RP between matched cohorts (hazard ratio, 0.97 [95% CI, 0.55-1.70]; P=.92)., Conclusions: This contemporary study demonstrates that East Asian men are equally as likely to harbor aggressive PCa on biopsy as non-East Asian men at PSA levels observed in screening programs, with no difference in disease aggressiveness after RP. The assumption that unfavorable PCa at diagnosis is more common but less aggressive in East Asians should be revisited and viewed in the context of the expected increase in the PCa burden worldwide.

Introduction: While observational studies suggest favorable associations between statin use and prostate cancer (CaP) outcomes, data from randomized-controlled trials remain inconclusive. Our study explores the relationship between statin use and survival outcomes in the context of the phase III ARAMIS study, a trial of darolutamide in the treatment of nonmetastatic castration-resistant prostate cancer., Methods: We reviewed all 1,509 patients in the ARAMIS trial. Statin use was identified at baseline. Statin users were matched 1:2 with nonusers using a propensity score matching model. The primary endpoint was metastasis-free survival (MFS). Kaplan-Meier curves were plotted for MFS comparing statin users and nonusers across ARAMIS trial arms. A multivariate Cox proportional hazards model was fitted using the propensity-matched cohort and incorporating statin use and all covariates., Results: Of the 1,509 patients in ARAMIS, 334 (22.1%) were statin users. We matched 297 statin users to 550 nonusers. Characteristics appeared well balanced. Among nonusers, 331 (60.3%) and 219 (39.7%) were in the ARAMIS darolutamide and placebo arms, respectively. Among statin users, 179 (60.3%) and 118 (39.7%) were in the ARAMIS darolutamide and placebo arms, respectively. Overall, we found no significant difference in MFS between statin users and nonusers (HR 1.05, 95% CI 0.80-1.38 P = .72). However, we found significant interaction between statin use and ARAMIS trial arm. Specifically, statin use had a stronger association with MFS in the placebo arm (P = 0.024). However, this is likely coincidental and due to the statin-placebo patients having higher nodal positivity than the nonusers-placebo patients (14.3% vs. 5.5%). Statin use was similarly not associated with the secondary outcomes of PSA progression-free survival (P = 0.42), time-to-pain progression (P = 0.85), or overall survival (P = 0.15)., Conclusions: In our secondary analysis of the ARAMIS trial, statin users had similar MFS and secondary outcomes compared to nonusers. These results suggest pursuing further statin synergies with amide-based androgen receptor axis target agents may not be fruitful., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Nishant Sangole is an employee of Bayer Canada., (Copyright © 2024. Published by Elsevier Inc.)

Background and Objective: Studies in metastatic nonseminomatous germ-cell tumor (NSGCT) suggest that the presence of teratomatous elements in the primary tumor is a risk factor for poor survival. Many guidelines have extrapolated this observation and recommend adjuvant retroperitoneal lymph-node dissection (RPLND) even for clinical stage I (CSI) teratoma confined to the testicle. Our objective was to assess relapse-free survival (RFS), cancer-specific survival (CSS), overall survival (OS) among patients with CSI pure teratoma in comparison to CSI NSGCT., Methods: Patients with CSI NSGCT managed with surveillance between 1980 and 2023 were identified in the prospectively maintained Princess Margaret Cancer Centre database. We compared cases with pure teratoma with or without somatic transformation in the primary tumor to all other nonteratomatous NSGCTs., Key Findings and Limitations: A total of 774 patients with CSI NSGCT were identified, including 63 (8.1%) with pure teratoma and/or somatic transformation in the primary tumor. Median follow-up was 61 mo. The pure teratoma group had superior RFS at 6 yr (85.2% vs 67.9%; p = 0.008). There were no significant differences in 6-yr CSS (100% vs 99.1%; p = 0.92) or OS (97.4% vs 98.1%; p = 0.33). Limitations include the single-center setting and the limited follow-up (median 61 mo), hindering the ability to detect late relapses., Conclusions and Clinical Implications: CSI pure teratoma managed with surveillance is associated with a low risk of relapse overall and significantly lower risk of relapse in comparison to other CSI NSGCTs. No patients with CSI teratoma in the study population died of testicular cancer. Guidelines should be revised to include surveillance as a preferred approach for CSI teratoma., Patient Summary: We compared survival rates after testicle removal in clinical stage I testicular cancer for two different tumor types. We found that cancer-specific and overall survival rates were similar for pure teratoma tumors and nonseminoma tumors, and that the recurrence rate was lower for pure teratoma tumors. Our results support surveillance as a suitable option after surgery for patients with clinical stage I testicular teratoma., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: To compare the outcomes and treatment burden of primary retroperitoneal lymph node dissection (pRPLND) alone versus pRPLND + adjuvant chemotherapy (AC) in patients with pathological stage II (PSII) non-seminomatous germ cell tumours (NSGCT)., Patients and Methods: Retrospective review of the Princess Margaret Cancer Center eTestes cancer database identified patients with PSII NSGCT after pRPLND between 1995 and 2020. The primary outcome was relapse-free survival (RFS). Secondary outcomes included disease-specific survival (DSS), burden of relapse treatment, and factors associated with relapse., Results: A total of 109 PSII patients were included in the study. There were 96 patients treated with pRPLND alone and 13 treated with pRPLND + AC. The median follow-up was 61 months. The 5-year RFS was 72% for the pRPLND-only group vs 92% for the pRPLND + AC group (hazard ratio [HR] 4.372, 95% confidence interval [CI] 0.59-32.36; P = 0.11). Within the pRPLND-only group the 5-year RFS differed by pN stage (pN1 = 94% vs pN2/N3 = 67%, P = 0.03). Despite a higher relapse rate within the pRPLND-only group, the DSS was similar at 5 years (98% pRPLND only vs 100% pRPLND + AC, P = 0.48). Only 24 (25%) of the patients in the pRPLND-only group required any subsequent chemotherapy. Despite achieving similar survival, the cumulative post-RPLND treatment burden was less for the pRPLND-only group than the pRPLND+AC group overall (average 1.23 vs 2.46 cycles of chemotherapy per patient in group)., Conclusion: The majority of patients with PSII NSGCT treated with pRPLND alone do not experience a recurrence or require chemotherapy. Despite a lower relapse risk when AC is given, no difference in survival was seen but higher chemotherapy burden was entertained. AC may constitute overtreatment for most patients with PSII NSGCT treated with pRPLND., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Background: Open retroperitoneal lymph node dissection (O-RPLND) is the accepted standard surgical approach to treat retroperitoneal nodal disease in testis cancer. Increasingly, robotic RPLND (R-RPLND) is being performed due to the potential for lower blood loss, shorter length of stay, and accelerated recovery., Objective: We have performed a propensity score matching (PSM) analysis comparing the survival and perioperative outcomes of O- and R-RPLND., Design, Setting, and Participants: Analyzing the data from all patients who underwent primary RPLND at our center between 1990 and 2022, we used PSM to create a 2:1 (O-RPLND:R-RPLND) matched cohort., Intervention: Primary O-RPLND versus R-RPLND., Outcome Measurements and Statistical Analysis: The primary endpoint was time to relapse. The secondary endpoints included operating time, length of stay, estimated blood loss (EBL), and surgical complications. Relapse-free survival rates were calculated using the Kaplan-Meier method, and log-rank tests were used to compare perioperative outcomes of O-RPLND versus R-RPLND., Key Findings and Limitations: A total of 178 patients underwent primary RPLND: 137 O-RPLND and 41 R-RPLND. After PSM, 26 patients in the R-RPLND group were matched with 38 in the O-RPLND group. After matching, no significant baseline differences were noted. After a median follow-up of 23.5 mo (interquartile range 4.4-59.2), one (3.8%) relapse was noted in the R-RPLND group versus three (7.8%) in the O-RPLND group; however, this was not significant (hazard ratio 0.65, 95% confidence interval 0.07-6.31, p = 0.7097). No in-field relapses occurred in either cohort. R-RPLND was associated with a shorter length of stay (1 vs 5 d, p < 0.0001) and lower EBL (200 vs 300 ml, p = 0.032), but longer operative time (8.8 vs 4.3 h, p < 0.0001)., Conclusions: R-RPLND offers low morbidity and improved perioperative outcomes, while maintaining oncologic efficacy of the open approach., Patient Summary: To the best of our knowledge, this is the first study to compare open and robotic retroperitoneal lymph node dissection (R-RPLND) using a propensity score-matched system. We encourage the discussion and inclusion of primary R-RPLND into the standard of care algorithm for patients with de novo clinical stage (CS) II and relapsed CS I with CS II equivalent disease., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

No study has comprehensively examined associated factors (adverse health outcomes, health behaviors, and demographics) affecting cognitive function in long-term testicular cancer survivors (TC survivors). TC survivors given cisplatin-based chemotherapy completed comprehensive, validated surveys, including those that assessed cognition. Medical record abstraction provided cancer and treatment history. Multivariable logistic regression examined relationships between potential associated factors and cognitive impairment. Among 678 TC survivors (median age = 46; interquartile range [IQR] = 38-54); median time since chemotherapy = 10.9 years, IQR = 7.9-15.9), 13.7% reported cognitive dysfunction. Hearing loss (odds ratio [OR] = 2.02; P = .040), neuropathic pain (OR = 2.06; P = .028), fatigue (OR = 6.11; P < .001), and anxiety/depression (OR = 1.96; P = .029) were associated with cognitive impairment in multivariable analyses. Being on disability (OR = 9.57; P = .002) or retired (OR = 3.64; P = .029) were also associated with cognitive decline. Factors associated with impaired cognition identify TC survivors requiring closer monitoring, counseling, and focused interventions. Hearing loss, neuropathic pain, fatigue, and anxiety/depression constitute potential targets for prevention or reduction of cognitive impairment in long-term TC survivors., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction: Primary retroperitoneal lymph node dissection (pRPLND) is a treatment option for clinical stage (CS) II testicular germ cell tumors (TGCTs) and CS I with retroperitoneal relapse. Increasing raw lymph node yield during pRPLND has been associated a decreased relapse risk. However, this metric has limitations due to variations in surgical templates and specimen processing methods. We aimed to evaluate the lymph node density (LND), which is the ratio of positive lymph nodes to the total number of nodes removed, as a prognostic marker for relapse after pRPLND., Methods: We reviewed all patients who underwent pRPLND at the Princess Margaret Cancer Centre between 1990 and 2022. The primary endpoint was relapse-free survival (RFS). RFS was calculated using the Kaplan-Meier product-limit method. The log-rank test was used to assess the impact of LND, and recursive binary partitioning was used to determine the threshold LND that provides optimum separation in RFS., Results: In this study, 178 patients were treated with pRPLND. A total of 137 (77%) patients had pathological evidence of nodal metastasis, 96 were treated with open RPLND, and 41 with robotic RPLND. The median number of lymph nodes harvested was 32 (IQR 23-43) and median total positive nodes was 2 (IQR 1-36). This translated into a median LND of 3.1% (IQR 1.7-57.1). There was no significant difference in the LND between robotic and open approaches (P = 0.6664). After a median follow-up of 38.6 months, 11 patients (8.02%) had relapsed. LND was not significantly associated with relapse (HR 1.018, 95% CI, 0.977-1.061). The optimal threshold to dichotomize LND that provides optimum separation in RFS was ≥ 26.75%, however, it did not reach statistical significance (P = 0.0651)., Conclusion: In conclusion, the LND was not associated with RFS after pRPLND in patients with TGCTs. The unique characteristics of TGCTs and the presence of other established risk factors limit the utility of the LND alone in predicting relapse., Competing Interests: Declaration of competing interest The authors have no conflict of interest to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To evaluate for the first time, comparative serum and prostate tissue concentrations of lipophilic and hydrophilic statins., Methods: After reviewing all patients who underwent radical prostatectomy between 1993 and 2019, we selected 80 patients taking atorvastatin (lipophilic) or rosuvastatin (hydrophilic) for cholesterol control and with available banked fresh-frozen tissue from the prostatectomy. Primary endpoint was serum and prostate statin concentration measured by HPLC-mass spectrometry analysis. Serum/prostate statin concentrations were compared between patients on atorvastatin and rosuvastatin, and patients receiving high- and low-dose statin, using the Mann-Whitney U test., Results: In total, 39 patients were taking atorvastatin and 41 were taking rosuvastatin. Thirty-eight and 42 were taking high- and low-dose statin, respectively. Statin concentration was measurable in the prostatic tissue of 15 patients (38.4%) taking atorvastatin (33.3% high-dose vs 42.8% low-dose) compared to 22 (53.6%) taking rosuvastatin (55% high-dose vs 52.3% low-dose). Median tissue concentration of rosuvastatin was greater than atorvastatin (3.98 ng/g vs 0.96 ng/g, P <.001). Dose-dependency was observed: median prostate concentration was higher in those taking high-dose versus low-dose statin for both atorvastatin (1.22 ng/g vs 0.79 ng/g, P = .69) and rosuvastatin (5.21 ng/g vs 1.99 ng/g, P <.001)., Conclusion: We have shown, for the first time, that lipophilic and hydrophilic statins can be measured in the prostate of patients with prostate cancer and that the concentrations are dependent on dose. Moreover, rosuvastatin, a hydrophilic statin, achieves a 4-fold higher concentration in the prostate., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Treatment intensification beyond androgen deprivation therapy (ADT) has shown survival benefit in patients with metastatic castration-sensitive prostate cancer (mCSPC). There is a need to better understand how these novel treatments fit in real-world practice., Methods: Using electronic medical records and administrative data, a population-based, retrospective cohort study of patients newly diagnosed with de novo mCSPC between 2010 and 2020 in Alberta, Canada, and initiated ADT was conducted. Treatment intensification was defined as the receipt of apalutamide, abiraterone acetate, enzalutamide, or chemotherapy (e.g., docetaxel) within 180 days of ADT initiation., Results: A total of 2515 de novo mCSPC were identified, with 2098 (83%) patients initiating ADT post-diagnosis. Of those, 525 (25%) received intensification beyond ADT. The percentage of patients who were intensified was 3% in 2010-2013 and gradually increased to 67% in 2020. From 2014-2017, docetaxel was the most commonly used approach, although it was supplanted by abiraterone acetate, apalutamide and enzalutamide from 2018 onwards. In multivariable logistic regression analyses of patients diagnosed from 2014-2020, significant predictors of intensification were younger age at diagnosis, lower Charlson comorbidity index, greater number of metastatic sites, shorter time to ADT initiation, referral to a medical oncologist, transurethral resection of the prostate or radiation prior to ADT, and more recent year of diagnosis (all p<0.05). Intensification increased for patients living in rural areas and with higher disease burden in 2018+ compared to 2014-2017., Conclusions: There has been a considerable increase in the use of ADT intensification therapies that correspond with the timing of clinical trial data and approvals of novel agents.

Background and Objective: There are limited data on the prevalence and management of testicular germ cell tumor (TGCT) cases presenting with venous tumor thrombus (VTT). Our objectives were to describe the prevalence of TGCT with VTT, to identify a multicenter retrospective cohort, and to ascertain expert opinion regarding optimal management of this entity., Methods: Using the IBM Marketscan database, we identified men with testicular cancer who underwent retroperitoneal lymph node dissection (RPLND) with concurrent VTT or inferior vena cava (IVC) tumor thrombectomy to estimate the prevalence of VTT in TGCT. To identify a multicenter retrospective cohort of patients, we surveyed surgeons and described the presentation, management, and outcomes for the cohort., Key Findings and Limitations: The prevalence of TGCT with VTT in the IBM Marketscan database was 0.3% (n = 7/2517) when using stringent criteria and 3.1% (n = 79/2517) when using broad criteria. In response to our survey, 16 surgeons from ten centers contributed data for 34 patients. Most patients (n = 29, 85%) presented with nonseminomatous germ cell tumor. Surgical management was used for 93.9% (n = 31), including postchemotherapy tumor thrombectomy with primary cavorrhaphy in 63%. The Marketscan analysis was limited to insured individuals and did not include clinicopathological details, and use of billing codes may have included patients with stromal tumors. In addition, lack of responses to the anonymous survey limited data capture, and the RedCap survey did not address symptoms specific to IVC obstruction or allow central review of the imaging leading to VTT diagnosis., Conclusions and Clinical Implications: VTT among males with TGCT is rare and requires complex multidisciplinary management, including venous tumor thrombectomy at the time of postchemotherapy RPLND., Patient Summary: Using a medical database, we estimated that the frequency of testicular cancer cases in which the tumor extends into a blood vessel (called venous tumor thrombus, VTT) is just 0.3-3.1%. We carried out a survey of surgeons with experience of this condition. Our results indicate that although testicular cancers respond well to chemotherapy, VTT is less responsive and complex surgery is necessary for this rare condition., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

MicroRNAs (miRNAs) are emerging as highly sensitive and specific markers for testicular germ cell tumors (GCTs) across the spectrum of disease. However, their utility in specific clinical scenarios requires further study. Here, we review the current evidence for miRNAs as tumor markers for the evaluation of treatment response in patients undergoing chemotherapy for the treatment of advanced testicular GCT., Competing Interests: Disclosure No authors have any relevant disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

There is an urgent need to provide immediate and effective options for the treatment of prostate cancer (PCa) to prevent progression to lethal castration-resistant PCa (CRPC). The mevalonate (MVA) pathway is dysregulated in PCa, and statin drugs commonly prescribed for hypercholesterolemia, effectively target this pathway. Statins exhibit anti-PCa activity, however the resulting intracellular depletion of cholesterol triggers a feedback loop that restores MVA pathway activity, thus diminishing statin efficacy and contributing to resistance. To identify drugs that block this feedback response and enhance the pro-apoptotic activity of statins, we performed a high-content image-based screen of a 1508 drug library, enriched for FDA-approved compounds. Two of the validated hits, Galeterone (GAL) and Quinestrol, share the cholesterol-related tetracyclic structure, which is also evident in the FDA-approved CRPC drug Abiraterone (ABI). Molecular modeling revealed that GAL, Quinestrol and ABI not only share structural similarity with 25-hydroxy-cholesterol (25HC) but were also predicted to bind similarly to a known protein-binding site of 25HC. This suggested GAL, Quinestrol and ABI are sterol-mimetics and thereby inhibit the statin-induced feedback response. Cell-based assays demonstrated that these agents inhibit nuclear translocation of sterol-regulatory element binding protein 2 (SREBP2) and the transcription of MVA genes. Sensitivity was independent of androgen status and the Fluva-GAL combination significantly impeded CRPC tumor xenograft growth. By identifying cholesterol-mimetic drugs that inhibit SREBP2 activation upon statin treatment, we provide a potent "one-two punch" against CRPC progression and pave the way for innovative therapeutic strategies to combat additional diseases whose etiology is associated with SREBP2 dysregulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Importance: 5-alpha-reductase-inhibitors (5-ARIs) are approved for treating benign prostatic hyperplasia (BPH) and have been found to reduce prostate cancer (PCa) risk by 25%. However, trials also have shown 5-ARIs to be associated with high-grade PCa. Whether 5-ARIs increase mortality among those with a diagnosis of PCa remains unclear., Objective: To determine long-term outcomes of clinically localized PCa arising in individuals taking 5-ARIs compared with nonusers., Design, Setting, and Participants: This population-based cohort study was conducted between January 2003 and October 2017. Eligible participants were men aged 65 years or older in Ontario, Canada, who developed clinically localized PCa with complete pathological abstraction from the Ontario Health Administrative Databases. Data analysis occurred from November 2017 to November 2022., Exposure: 5-ARIs before PCa diagnosis., Main Outcomes and Measures: The primary outcomes were overall mortality and PCa-specific mortality. Cause-specific hazard models with inverse probability treatment weights (IPTW) were used to examine associations of 5-ARI use with mortality outcomes. Sensitivity analyses based on prediagnostic 5-ARI use, Gleason score, comorbidity, 5-ARI indication, prostate-specific antigen modeling, and statin use were also performed., Results: The cohort included 19 938 patients with PCa. Of these, 2112 (10.6%; median [IQR] age, 74 [70-79] years) were 5-ARI users and 17 826 (89.4%; median [IQR] age, 71 [68-76] years) were nonusers. During a median (IQR) follow-up of 8.96 (6.28-12.17) years, 6053 (30.4%) died, including 1047 (5.3%) from PCa. 5-ARI use appeared to be associated with increased overall and PCa specific mortality in crude analyses; however, after IPTW, 5-ARI use was not associated with overall mortality (hazard ratio, 0.98; 95% CI, 0.90-1.07; P = .77) or PCa-specific mortality (hazard ratio, 1.02; 95% CI, 0.83-1.25; P = .84)., Conclusions and Relevance: In this population-based cohort study of 5-ARI use prior to PCa diagnosis including long-term follow-up and clinicopathologic details, prediagnostic 5-ARI use was not associated with PCa-specific or all-cause mortality. This study offers reassuring safety data for patients using 5-ARIs before PCa diagnosis for both BPH and chemopreventive reasons.

Background: The relapse rate in patients with clinical stage I (CSI) seminomatous germ cell tumor of the testis (SGCTT) who were undergoing surveillance after radical orchidectomy is 4-30%, depending on tumor size and rete testis invasion (RTI). However, the level of evidence supporting the use of both risk factors in clinical decision-making is low., Objective: We aimed to identify the most important prognostic factors for relapse in CSI SGCTT patients., Design, Setting, and Participants: Individual patient data for 1016 CSI SGCTT patients diagnosed between 1994 and 2019 with normal postorchidectomy serum tumor marker levels and undergoing surveillance were collected from nine institutions., Outcome Measurements and Statistical Analysis: Multivariable Cox proportional hazard regression models were fit to identify the most important prognostic factors. The primary endpoint was the time to first relapse by imaging and/or markers. Relapse probabilities were estimated by the Kaplan-Meier method., Results and Limitations: After a median follow-up of 7.7 yr, 149 (14.7%) patients had relapsed. Categorical tumor size (≤2, >2-5, and >5 cm), presence of RTI, and lymphovascular invasion were used to form three risk groups: low (56.4%), intermediate (41.3%), and high (2.3%) risks with 5-yr cumulative relapse probabilities of 8%, 20%, and 44%, respectively. The model outperformed the currently used model with tumor size ≤4 versus >4 cm and presence of RTI (Harrell's C index 0.65 vs 0.61). The low- and intermediate-risk groups were validated successfully in an independent cohort of 285 patients., Conclusions: The risk of relapse after radical orchidectomy in CSI SGCTT patients under surveillance is low. We propose a new risk stratification model that outperformed the current model and identified a small subgroup with a high risk of relapse., Patient Summary: The risk of relapse after radical orchidectomy in patients with clinical stage I seminomatous germ cell tumor of the testis is low. We propose a new risk stratification model that outperformed the current model and identified a small subgroup with a high risk of relapse., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: The management of prostate cancer (PCa) is rapidly evolving. Treatment and diagnostic options grow annually, however, high-level evidence for the use of new therapeutics and diagnostics is lacking. In November 2022, the Genitourinary Research Consortium held its 3 rd Canadian Consensus Forum (CCF3) to provide guidance on key controversial areas for management of PCa., Methods: A steering committee of eight multidisciplinary physicians identified topics for discussion and adapted questions from the Advanced Prostate Cancer Consensus Conference 2022 for CCF3. Questions focused on management of metastatic castration-sensitive prostate cancer (mCSPC); use of novel imaging, germline testing, and genomic profiling; and areas of non-consensus from CCF2. Fifty-eight questions were voted on during a live forum, with threshold for "consensus agreement" set at 75%., Results: The voting panel consisted of 26 physicians: 13 urologists/uro-oncologists, nine medical oncologists, and four radiation oncologists. Consensus was reached for 32 of 58 questions (one ad-hoc). Consensus was seen in the use of local treatment, to not use metastasis-directed therapy for low-volume mCSPC, and to use triplet therapy for synchronous high-volume mCSPC (low prostate-specific antigen). Consensus was also reached on sufficiency of conventional imaging to manage disease, use of germline testing and genomic profiling for metastatic disease, and poly (ADP-ribose) polymerase (PARP) inhibitors for BRCA-positive prostate cancer., Conclusions: CCF3 identified consensus agreement and provides guidance on >30 practice scenarios related to management of PCa and nine areas of controversy, which represent opportunities for research and education to improve patient care. Consensus initiatives provide valuable guidance on areas of controversy as clinicians await high-level evidence.

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Several medical organisations have developed evidence-based guidelines for the diagnosis, management, and follow-up of testicular cancer. This article aimed to review, compare, and summarise the most updated international guidelines and surveillance protocols for clinical stage 1 (CS1) testicular cancer. We reviewed a total of 46 articles on proposed follow-up strategies for testicular cancer, and six clinical practice guidelines including four guidelines published by urological scientific associations and two guidelines published by medical oncology associations. Most of these guidelines have been developed by panels of experts with different backgrounds in clinical training, and geographic practise patterns, which explains the considerable variability between published schedules, and recommended follow-up intensity. We present you with a comprehensive review of the most important clinical practice guidelines and propose unifying recommendations based on the most up to date evidence to help standardise follow-up schedules based on patterns and risk of disease relapse., (© 2023 BJU International.)

Purpose: Early treatment intensification with neoadjuvant therapy may improve outcomes in patients with high-risk, localized prostate cancer treated with radical prostatectomy. Our objective was to compare pathologic, oncologic, and safety outcomes of neoadjuvant abiraterone acetate plus leuprolide acetate with or without cabazitaxel prior to radical prostatectomy in patients with localized, high-risk prostate cancer., Patients and Methods: This open-label, multicenter, phase II trial randomized men with clinically localized, D'Amico high-risk prostate cancer to neoadjuvant abiraterone acetate (1,000 mg/day) and leuprolide acetate (22.5 mg every 3 months) with or without cabazitaxel (25 mg/m2) prior to radical prostatectomy. The primary outcome was pathologic complete response (pCR) or minimal residual disease (MRD). Secondary outcomes included surgical margins, lymph node involvement, pathologic stage, 12-month biochemical relapse-free survival (BRFS) rates, and safety profile., Results: The per-protocol population consisted of 70 patients [cabazitaxel arm (Arm A): 37, no cabazitaxel arm (Arm B): 33]. Median patient age and prostate-specific antigen levels were 63.5 years [interquartile range (IQR), 58.0-68.0] and 21.9 ng/mL (IQR, 14.6-42.8), respectively. pCR/MRD occurred in 16 (43.2%) versus 15 patients (45.5%) in arms A and B, respectively (P = 0.85). pCR occurred in two (5.4%) versus three patients (9.1%) in arms A and B, respectively (P = 0.66). Patients with ≤ 25% total biopsy cores positive had increased odds of pCR/MRD (P = 0.04). Patients with pCR/MRD had superior 12-month BRFS rates (96.0% vs. 62.0%, P = 0.03). Grade 3+ adverse events occurred in 42.5% and 23.7% of patients in arms A and B, respectively (P = 0.078)., Conclusions: Neoadjuvant cabazitaxel addition to abiraterone acetate/leuprolide acetate prior to radical prostatectomy did not improve pCR/MRD in clinically localized, high-risk prostate cancer., (©2023 American Association for Cancer Research.)

Introduction: In patients with prostate cancer (PCa), the identification of an alteration in genes associated with homologous recombination repair (HRR) has implications for prognostication, optimization of therapy, and familial risk mitigation. The aim of this study was to assess the genomic testing landscape of PCa in Canada and to recommend an approach to offering germline and tumor testing for HRR-associated genes., Methods: The Canadian Genitourinary Research Consortium (GURC) administered a cross-sectional survey to a largely academic, multidisciplinary group of investigators across 22 GURC sites between January and June 2022., Results: Thirty-eight investigators from all 22 sites responded to the survey. Germline genetic testing was initiated by 34%, while 45% required a referral to a genetic specialist. Most investigators (82%) reported that both germline and tumor testing were needed, with 92% currently offering germline and 72% offering tissue testing to patients with advanced PCa. The most cited reasons for not offering testing were an access gap (50%), uncertainties around who to test and which genes to test, (33%) and interpreting results (17%). A majority reported that patients with advanced PCa (74-80%) should be tested, with few investigators testing patients with localized disease except when there is a family history of PCa (45-55%)., Conclusions: Canadian physicians with academic subspecialist backgrounds in genitourinary malignancies recognize the benefits of both germline and somatic testing in PCa; however, there are challenges in accessing testing across practices and specialties. An algorithm to reduce uncertainty for providers when ordering genetic testing for patients with PCa is proposed.

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS 269 ). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS 269 . Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS 269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS 269 developed from multi-ancestry GWASs and fine-mapping., Competing Interests: Declaration of interests The authors have no conflicts of interest to disclose., (Copyright © 2023 American Society of Human Genetics. All rights reserved.)

Background: Accurate prediction of side-specific extraprostatic extension (ssEPE) is essential for performing nerve-sparing surgery to mitigate treatment-related side-effects such as impotence and incontinence in patients with localised prostate cancer. Artificial intelligence (AI) might provide robust and personalised ssEPE predictions to better inform nerve-sparing strategy during radical prostatectomy. We aimed to develop, externally validate, and perform an algorithmic audit of an AI-based Side-specific Extra-Prostatic Extension Risk Assessment tool (SEPERA)., Methods: Each prostatic lobe was treated as an individual case such that each patient contributed two cases to the overall cohort. SEPERA was trained on 1022 cases from a community hospital network (Trillium Health Partners; Mississauga, ON, Canada) between 2010 and 2020. Subsequently, SEPERA was externally validated on 3914 cases across three academic centres: Princess Margaret Cancer Centre (Toronto, ON, Canada) from 2008 to 2020; L'Institut Mutualiste Montsouris (Paris, France) from 2010 to 2020; and Jules Bordet Institute (Brussels, Belgium) from 2015 to 2020. Model performance was characterised by area under the receiver operating characteristic curve (AUROC), area under the precision recall curve (AUPRC), calibration, and net benefit. SEPERA was compared against contemporary nomograms (ie, Sayyid nomogram, Soeterik nomogram [non-MRI and MRI]), as well as a separate logistic regression model using the same variables included in SEPERA. An algorithmic audit was performed to assess model bias and identify common patient characteristics among predictive errors., Findings: Overall, 2468 patients comprising 4936 cases (ie, prostatic lobes) were included in this study. SEPERA was well calibrated and had the best performance across all validation cohorts (pooled AUROC of 0·77 [95% CI 0·75-0·78] and pooled AUPRC of 0·61 [0·58-0·63]). In patients with pathological ssEPE despite benign ipsilateral biopsies, SEPERA correctly predicted ssEPE in 72 (68%) of 106 cases compared with the other models (47 [44%] in the logistic regression model, none in the Sayyid model, 13 [12%] in the Soeterik non-MRI model, and five [5%] in the Soeterik MRI model). SEPERA had higher net benefit than the other models to predict ssEPE, enabling more patients to safely undergo nerve-sparing. In the algorithmic audit, no evidence of model bias was observed, with no significant difference in AUROC when stratified by race, biopsy year, age, biopsy type (systematic only vs systematic and MRI-targeted biopsy), biopsy location (academic vs community), and D'Amico risk group. According to the audit, the most common errors were false positives, particularly for older patients with high-risk disease. No aggressive tumours (ie, grade >2 or high-risk disease) were found among false negatives., Interpretation: We demonstrated the accuracy, safety, and generalisability of using SEPERA to personalise nerve-sparing approaches during radical prostatectomy., Funding: None., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Although metastatic germ cell tumor (GCT) is highly curable with initial cisplatin-based chemotherapy (CT), 20-30% of patients relapse. Salvage CT options include conventional (CDCT) and high dose chemotherapy (HDCT), however definitive comparative data remain lacking. We aimed to characterize the contemporary practice patterns of salvage CT across Canada., Methods: We conducted a 30-question online survey for Canadian medical and hematological oncologists with experience in treating GCT, assessing treatment availability, patient selection, and management strategies used for relapsed GCT patients., Results: There were 30 respondents from 18 cancer centers across eight provinces. The most common CDCT regimens used were TIP (64%) and VIP (25%). HDCT was available in 13 centers (70%). The HDCT regimen used included carboplatin and etoposide for two cycles (76% in 7 centers), three cycles (6% in 2 centers), and the TICE protocol (11%, in 2 centers). "Bridging" CDCT was used by 65% of respondents. Post-HDCT treatments considered include surgical resection for residual disease (87.5%), maintenance etoposide (6.3%), and surveillance only (6.3%)., Conclusions: HDCT is the most commonly used GCT salvage strategy in Canada. Significant differences exist in the treatment availability, selection, and delivery of HDCT, highlighting the need for standardization of care for patients with relapsed testicular GCT.

Testicular cancer is a rare cancer that often affects young and otherwise healthy patients. Imaging plays a critical role in the staging and surveillance of patients with testicular cancer. Indeterminate findings on staging or surveillance imaging, can lead to challenging management decisions for clinicians and patients. In this article, we review the importance of short-interval, repeat imaging for several scenarios faced by patients with testicular cancer and their clinicians. The challenging scenarios and recommendations provided in this article summarize the discussion from the inaugural Global Society of Rare Genitourinary Tumors (GSRGT) Summit held on December 11-12, 2020., (Copyright © 2022. Published by Elsevier Inc.)

Despite excellent outcomes with modern multidisciplinary care, clinicians caring for patients with testicular germ cell tumour (TGCTs) face clinical dilemmas across the spectrum of disease. Wrong treatment choices can lead to undertreatment or overtreatment of these young men. Unfortunately the currently available biomarkers alpha-fetoprotein and human chorionic gonadotropin, lack sufficient sensitivity and specificity to reliably aid in these clinical dilemmas. Thus, a sensitive and specific biomarker is desperately needed. Serum or plasma miRNA, in particular, miR-371a-3p, has shown great promise in discriminating the presence of TGCT and may represent a breakthrough for this disease. In this review, we discuss the potential role of miRNA across clinical states of TGCTs. We review their discovery, methods of assay, limitations and future potential., (© 2022 American Society of Andrology and European Academy of Andrology.)

Background: Outcomes for patients with metastatic renal cell carcinoma (mRCC) and tumour thrombus remain poor. Recent data suggest limited role for cytoreductive nephrectomy (CN) and data on thrombus response to systemic therapy (ST) is scarce. Here, we describe response and survival of patients with de novo mRCC and thrombi treated with ST with or without CN., Methods: Demographics, disease characteristics and survival of patients with de novo mRCC were collected. Progression-free survival (PFS) and overall survival (OS) in months (m) was calculated using the Kaplan-Meier method (log-rank)., Results: Between 2002 and 2019, 226 patients with mRCC were identified, 64 (28.3%) had tumour thrombus out of which 18 (28.1%) received only ST. Among 12 evaluable patients, thrombus response, stability and progression were seen in 3 (25%), 6 (50%) and 3 (25%) patients, respectively. Median OS was similar for patients with and without tumour thrombus treated with systemic therapy alone [OS: 12.1 m (8.8-27.7) vs. 13.9 m (7.9-21.5), p = 0.87]. CN predicted for better OS in patients with tumour thrombus [OS: 29.4 m (17.4-48.9) vs. 12.1 m (8.8-27.7), p = 0.01]., Conclusion: In this retrospective series of patients with mRCC and tumour thrombus, addition of CN to ST improved outcomes. Validation of these findings with contemporary regimens is needed., (© 2023. The Author(s).)

Wide-field image correction in systems that look through the atmosphere generally requires a tomographic reconstruction of the turbulence volume to compensate for anisoplanatism. The reconstruction is conditioned by estimating the turbulence volume as a profile of thin homogeneous layers. We present the signal to noise ratio (SNR) of a layer, which quantifies how difficult a single layer of homogeneous turbulence is to detect with wavefront slope measurements. The signal is the sum of wavefront tip and tilt variances at the signal layer, and the noise is the sum of wavefront tip and tilt auto-correlations given the aperture shape and projected aperture separations at all non-signal layers. An analytic expression for layer SNR is found for Kolmogorov and von Kármán turbulence models, then verified with a Monte Carlo simulation. We show that the Kolmogorov layer SNR is a function of only layer Fried length, the spatio-angular sampling of the system, and normalized aperture separation at the layer. In addition to these parameters, the von Kármán layer SNR also depends on aperture size, and layer inner and outer scales. Due to the infinite outer scale, layers of Kolmogorov turbulence tend to have lower SNR than von Kármán layers. We conclude that the layer SNR is a statistically valid performance metric to be used when designing, simulating, operating, and quantifying the performance of any system that measures properties of layers of turbulence in the atmosphere from slope data.

Background: The adoption of docetaxel for systemic treatment of metastatic prostate cancer (PCa), in both castration-sensitive (mCSPC) and castration-resistant (mCRPC) settings, is poorly understood. This study examined the real-world utilization of docetaxel in these patients and their outcomes., Methods: A retrospective population-based study used administrative data from Ontario, Canada, to identify men aged ≥66 years who were diagnosed with de novo mCSPC or mCRPC between 2014 and 2019 and received docetaxel. The study assessed treatment tolerability and toxicity, and survival in both cohorts. Descriptive and comparative statistical analysis were conducted., Results: The study identified 11.2% (399/3556) and 13.2% (203/1534) patients diagnosed with de novo mCSPC and with mCRPC who received docetaxel respectively. The median age in both cohorts was 72 years (IQR: 68-76). Overall, 43.9% (n = 175) patients with de novo mCSPC and 52.1% (n = 85) with mCRPC completed ≥6 cycles of docetaxel. Over two-fifth also needed dose adjustments in both cohorts. Hospitalization or emergency department visit for febrile neutropenia were noted in 15.8% (n = 63) of de novo mCSPC patients and similarly in 19% (n = 31) of mCRPC cohort. The median survival of PCa patients who completed ≥6 cycles of docetaxel was significantly longer relative to those who completed <4 cycles: 32.7 vs. 23.5 months (p < 0.001) for mCSPC and 20.5 vs. 10.7 (p = 0.012) for mCRPC respectively., Conclusions: In this population-based study of elderly patients with metastatic PCa, treatment with docetaxel was associated with poor tolerability and higher toxicity compared with clinical trials. Receipt of limited cycles and reduced overall dose of docetaxel were associated with inferior overall survival., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Guidelines support considering selected men with ISUP grade group (GG) 2 prostate cancer for active surveillance (AS). We assessed the association of clinical variables with unfavorable pathology at radical prostatectomy in low-volume GG 2 prostate cancer on biopsy in a retrospective cohort., Materials and Methods: This was a retrospective analysis of 378 men with low-volume (≤ 2 cores) GG 2 localized prostate cancer who underwent prostatectomy at a single tertiary cancer center. Multivariable logistic regression of unfavorable pathology, upgrading to ≥ T3, or GG ≥ 3 was performed in relation to clinical factors, common variables used in AS in GG 1 and percentage Gleason 4 at biopsy. We compared the performance of potential variables with commonly used combined AS restrictions in GG 1 prostate cancer., Results: In total, 128/378 (34%) men had unfavorable pathology at radical prostatectomy. On multivariable analysis, > 5% Gleason pattern 4 was independently associated with an increased risk of GG ≥ 3. A maximum percentage core involvement > 50% was independently associated with an increased risk of pT-stage ≥ 3 and unfavorable pathology. Restriction to patients with ≤ 5% Gleason 4 decreased the upgrading of both unfavorable pathology (OR = 0.62, p  = 0.041) and GG ≥ 3 (OR = 0.17, p  = 0.0007) compared to the full cohort, while restriction to those with ≤ 50% of max core involvement did not., Conclusion: In low-volume GG 2, the percentage of Gleason 4 of ≤ 5% was the strongest predictor in reducing upgrading at final pathology. This easily available pathological descriptor could be used to guide urologists and patients when considering AS in this setting.

The COVID-19 public health emergency forced the conversion of in-person SUO fellowship interviews into virtual interviews. We sought to understand applicant perspectives and preferences related to virtual interviews and whether programs should consider virtual interviews in the future. We distributed a survey to 2020 SUO Fellowship interview participants at 4 SUO urologic oncology fellowship programs. Response items were on a Likert scale scored 1-5 with higher scores indicating greater agreement with the survey item construct. Survey responses were collated and thematic mapping used to describe open text responses. Descriptive statistics were used for analysis of survey and open text results. Fifty-eight SUO fellowship applicants completed the survey. Virtual interviews successfully promoted interaction with SUO fellowship program faculty (mean 4.6, SD 0.6), outlined program research opportunities (mean 4.5, SD 0.7), and proffered opportunities to ask questions about the fellowship (mean 4.7, SD 0.5). Applicants exhibited weakly positive orientation to the adequacy of the virtual format (mean 3.5, SD 1.1). 63% of applicants would prefer a virtual format in the future. Qualitative feedback noted the benefits of virtual interviews were lower cost and reduced time away from residency. SUO fellowship applicants exhibited mixed preferences for virtual and in-person interviews. Although virtual fellowship interviews have benefits such as cost savings and time efficiency, notable weaknesses included challenges observing the culture of the programs. Following the pandemic, SUO fellowship programs may consider virtual interviews but should consider incorporating opportunities for informal interactions between faculty, fellows, and fellow applicants., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Cardiovascular disease (CVD) incidence is higher in men with prostate cancer (PC) than without., Objectives: We describe the rate and correlates of poor cardiovascular risk factor control among men with PC., Methods: We prospectively characterized 2,811 consecutive men (mean age 68 ± 8 years) with PC from 24 sites in Canada, Israel, Brazil, and Australia. We defined poor overall risk factor control as ≥3 of the following: suboptimal low-density lipoprotein cholesterol (>2 mmol/L if Framingham Risk Score [FRS] ≥15 and ≥3.5 mmol/L if FRS <15), current smoker, physical inactivity (<600 MET min/wk), suboptimal blood pressure (BP) (≥140/90 mm Hg if no other risk factors, systolic BP ≥ 120 mm Hg if known CVD or FRS ≥15, and ≥130/80 mm Hg if diabetic), and waist:hip ratio >0.9., Results: Among participants (9% with metastatic PC and 23% with pre-existing CVD), 99% had ≥1 uncontrolled cardiovascular risk factor, and 51% had poor overall risk factor control. Not taking a statin (odds ratio [OR]: 2.55; 95% CI: 2.00-3.26), physical frailty (OR: 2.37; 95% CI: 1.51-3.71), need for BP drugs (OR: 2.36; 95% CI: 1.84-3.03), and age (OR per 10-year increase: 1.34; 95% CI: 1.14-1.59) were associated with poor overall risk factor control after adjustment for education, PC characteristics, androgen deprivation therapy, depression, and Eastern Cooperative Oncology Group functional status., Conclusions: Poor control of modifiable cardiovascular risk factors is common in men with PC, highlighting the large gap in care and the need for improved interventions to optimize cardiovascular risk management in this population., Competing Interests: RADICAL-PC is an investigator-initiated study that is funded by Prostate Cancer Canada (grant CT2015-01); the Movember Foundation, Hamilton Health Sciences (Research Strategic Initiative Program); and the Canadian Cancer Society (grant 706677). The funders of the study had no role in design of the study, analysis, interpretation, writing of the manuscript, and in the decision to publish the results. Dr Klimis is supported by an AFP Fellowship Award, Department of Cardiology, McMaster University. Dr Pinthus has served on advisory boards for Ferring Pharmaceuticals and Myovant Sciences; and has received research grant from Ferring Pharmaceuticals. Dr Duceppe has received investigator-initiated research grants from Roche Diagnostics and Abbott Laboratories; and has received lecture fees and honoraria for participation in advisory board meetings with Roche Diagnostics. Dr Siemens has been involved in clinical trials with Merck, Pfizer, Astellas, and Bayer. Dr Lavallee is on the advisory board for Sanofi, Astellas, Janssen, and Knight. Dr Gopaul has received personal fees outside the submitted manuscript from AstraZeneca, TerSera, Bayer, Ferring, and Abvie. Dr Hanna is on the advisory board for and has received honorarium and research support from Astellas, Bayer, Merck, Tolmar, Sanofi, and Abbvie. Dr Iakobishvili consults and lectures for Bayer, Pfizer, Boehringer Ingelheim, Novo Nordisk, Medtronic, Sanofi Adventist, and AstraZeneca. Dr Selvanayagam has received research grant support from Biotronik, Bayer, Sanofi, Actelion, and Novartis; is on the advisory board for Sanofi, Faraday, and Recardio; and is on the speaker bureau for AstraZeneca, Boehringer-Ingelheim, Novartis, Abbot, Bayer, Sanofi, Biotronik, Circle CVI, and Takeda. Dr Leong has served on advisory boards for Ferring Pharmaceuticals, Myovant Sciences, and Tolmar; reports speaker’s honoraria from Abbvie; and is supported by the Clive Kearon Career Award, Department of Medicine, McMaster University. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Purpose: Tumor markers alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase assume a key role in the management of testicular germ cell tumors. While alpha-fetoprotein and human chorionic gonadotropin have modest sensitivity and specificity for germ cell tumors, lactate dehydrogenase has weak sensitivity and specificity. We explored the utility of lactate dehydrogenase in identifying relapse among stage I seminomatous and nonseminomatous germ cell tumors on surveillance., Materials and Methods: Patients with a history of stage I testicular germ cell tumors were identified from a prospectively maintained database at the Princess Margaret Cancer Centre from December 1980 to May 2021 and surveyed according to established institutional algorithm guidelines. The utility of lactate dehydrogenase elevation to independently detect germ cell tumor relapse was examined., Results: Among 1,014 seminoma and 676 nonseminomatous germ cell tumor patients, 176 and 176 patients relapsed with a median time to relapse of 13.6 and 8.9 months, respectively. Imaging alone was the most common mode of relapse detection in 144 and 74 of seminoma and nonseminomatous germ cell tumor patients, respectively. Lactate dehydrogenase was elevated in 49 cases of seminoma and 38 cases of nonseminomatous germ cell tumors at relapse, but was never the sole relapse indicator. Among 350 seminoma and 311 nonseminomatous germ cell tumor patients who never relapsed, 210 and 233, respectively, had at least 1 elevated lactate dehydrogenase value., Conclusions: Lactate dehydrogenase alone did not independently contribute to early relapse detection in stage I seminoma or nonseminomatous germ cell tumor. Elevated lactate dehydrogenase values were documented in a high proportion of nonrelapsing seminoma and nonseminomatous germ cell tumor cases.

Purpose: This study was designed to demonstrate the safety and feasibility of episcleral brachytherapy (ESB) for the treatment of anti-vascular endothelial growth factor (anti-VEGF) resistant neovascular age-related macular degeneration (nAMD) in a 6-subject cohort adjunct to anti-VEGF therapy., Methods: Six eyes of six subjects with anti-VEGF resistant nAMD (persistent fluid or hemorrhage despite frequent anti-VEGF treatment) were treated with ESB between May 2018 and July 2018 as part of a larger early feasibility trial. Baseline and follow-up exams with multi-modal imaging were conducted., Results: In this analysis, six eyes were included. The mean age was 74.7 years; 33% were female; 67% had polypoidal choroidal vasculopathy. The mean number of lifetime anti-VEGF injections received prior to the study enrollment was 33.9 injections and 10 injections in the year prior to the study enrollment. In the first and second years following ESB, the mean number of injections was 8.5 and 8, respectively. No evidence of radiation-induced toxicity through 2 years following ESB was observed. The mean baseline VA was 55.3 letters. At 1 year, the mean VA increased by 3.2 letters and 1.7 letters at year 2. At 2 years, the mean change in vascular complex on ICGA was - 18%, - 43% on OCTA, and - 5% on FA. The subjects also experienced a mean decrease in CRT on OCT of 21% after 2 years., Conclusions: The results from this six-subject cohort with 2-year data support additional investigations of ESB for nAMD, specifically those with persistent disease activity and treatment resistant nAMD., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: Epidemiological evidence supports a role for statins in improving survival in advanced prostate cancer, particularly among men receiving androgen-ablative therapies., Objective: To study the association between statin use and survival among men with prostate cancer receiving androgen deprivation therapy (ADT) or androgen receptor axis-targeted therapies (ARATs)., Data Sources: This systemic review and meta-analysis used sources from MEDLINE, EMBASE, Epub Ahead of Print, Cochrane Clinical Trials, Cochrane Systematic Reviews, and Web of Science from inception to September 6, 2022., Study Selection: Observational studies reporting associations of concurrent statin use and survival outcomes (in hazard ratios [HRs])., Data Extraction and Synthesis: Two authors independently abstracted all data. Summary estimates pooled multivariable HRs with 95% CIs using the generic inverse variance method with random-effects modeling. A priori specified subgroup and sensitivity analyses were undertaken, and heterogeneity, study quality, and publication bias were evaluated. Confidence in the evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach., Main Outcomes and Measures: Overall mortality and prostate cancer-specific mortality (PCSM)., Results: Twenty-five cohorts of 119 878 men (65 488 statin users [55%]) with more than 74 416 deaths were included. Concurrent statin use was associated with a 27% reduction in the risk of overall mortality (HR, 0.73 [95% CI, 0.66-0.82]; I2 = 83%) and a 35% reduction in the risk of PCSM (HR, 0.65 [95% CI, 0.58-0.73]; I2 = 74%), with substantial heterogeneity in both estimates. Subgroup analyses identified a PCSM advantage associated with statins for men receiving ARATs compared with ADT alone (HR, 0.40 [95% CI, 0.30-0.55] vs 0.68 [95% CI, 0.60-0.76]; P = .002 for difference). Confidence in the evidence was rated low for both outcomes., Conclusions and Relevance: The findings of this meta-analysis show that concurrent statin use was associated with reduced overall mortality and PCSM among men receiving androgen-ablative therapies for advanced prostate cancer. These findings are limited by the observational nature of the data and residual unexplained interstudy heterogeneity. Randomized clinical trials are warranted to validate these results.

Brachytherapy is widely used for the treatment of choroidal melanoma and has recently been explored for the treatment of wet age-related macular degeneration. We propose the use of low dose radiation via episcleral brachytherapy in refractory cases of central serous chorioretinopathy (CSCR). The pathogenesis of CSCR involves dilatation and hyperpermeability of large choroidal vessels. Low dose radiation can induce intimal proliferation in large choroidal vessels and decrease their hyperpermeability. Concerns about the use of brachytherapy in CSCR include damage to the choriocapillaris or the retinal vessels. This can be addressed with the use of a specialized device through which a very precise and appropriate dose can be delivered. The dose of the radiation delivered decreases exponentially at a depth of approximately 0.5-1.5 mm from the devise-sclera interface. Considering an increased choroidal thickness in cases of CSCR, delivery of a safe dose can be assured., (© 2022. The Author(s).)

Background: Testicular germ cell tumors (TGCT), histologically classified as seminomas and nonseminomas, are believed to arise from primordial gonocytes, with the maturation process blocked when they are subjected to DNA methylation reprogramming. SNPs in DNA methylation machinery and folate-dependent one-carbon metabolism genes have been postulated to influence the proper establishment of DNA methylation., Methods: In this pathway-focused investigation, we evaluated the association between 273 selected tag SNPs from 28 DNA methylation-related genes and TGCT risk. We carried out association analysis at individual SNP and gene-based level using summary statistics from the Genome Wide Association Study meta-analysis recently conducted by the international Testicular Cancer Consortium on 10,156 TGCT cases and 179,683 controls., Results: In individual SNP analyses, seven SNPs, four mapping within MTHFR, were associated with TGCT risk after correction for multiple testing (q ≤ 0.05). Queries of public databases showed that three of these SNPs were associated with MTHFR changes in enzymatic activity (rs1801133) or expression level in testis tissue (rs12121543, rs1476413). Gene-based analyses revealed MTHFR (q = 8.4 × 10-4), methyl-CpG-binding protein 2 (MECP2; q = 2 × 10-3), and ZBTB4 (q = 0.03) as the top TGCT-associated genes. Stratifying by tumor histology, four MTHFR SNPs were associated with seminoma. In gene-based analysis MTHFR was associated with risk of seminoma (q = 2.8 × 10-4), but not with nonseminomatous tumors (q = 0.22)., Conclusions: Genetic variants within MTHFR, potentially having an impact on the DNA methylation pattern, are associated with TGCT risk., Impact: This finding suggests that TGCT pathogenesis could be associated with the folate cycle status, and this relation could be partly due to hereditary factors., (©2022 American Association for Cancer Research.)

Importance: Statins appear to lower serum prostate-specific antigen (PSA) and improve prostate cancer (PCa) outcomes through cholesterol-dependent and independent mechanisms. While dietary modifications have an established role in serum cholesterol reduction, whether diet-driven cholesterol reductions yield similar PCa benefits to that observed with statins is unclear. We aimed to study the effect of dietdriven cholesterol reduction on serum PSA and estimated-PCa risk., Methods: A total of 291 men from six published randomized controlled trials of dietary interventions were included. Men were aged ≥40 years, free of PCa, and had baseline PSA <10.0 ng/mL. Participants received one of four diets (high-fiber, low-glycemic index, low-glycemic load, or cholesterol-lowering) for 8-24 weeks. The primary outcome evaluated the association between change from baseline low-density lipoprotein cholesterol (LDL-C) and PSA. How cholesterol reduction modified PCa risk was estimated using the Prostate Cancer Prevention Trial (PCPT) risk calculator (limited to age ≥55 years, baseline PSA ≥1.0 ng/mL)., Results: Baseline PSA was 0.90 ng/mL (interquartile range [IQR] 0.55-1.60) and LDL-C was 90 mg/dL (IQR 69-125). In multivariate regression, PSA decreased 1.9% (95% confidence interval [CI] 0.55-3.2, p=0.005) per 10% reduction in LDL-C. This regression was greater in men with baseline PSA ≥2.0 ng/mL (-5.4%, 95% CI 2.2-8.6] per 10% LDL-C reduction, p-interaction=0.001). In men with estimable PCPT risk, statin-comparable LDL-C reductions (≥15%) reduced PSA by 12% (p<0.001) and estimated PCa risk by 6.5% (p=0.005)., Conclusions: This is the first study to show that serum cholesterol reduction through dietary interventions significantly lowered serum PSA and estimated PCa risk. Whether cholesterol-lowering diets improve PCa outcomes warrants investigation.

Purpose: To identify factors associated with stent changes and prognosis in patients with malignant ureteral obstruction (MUO) undergoing de novo retrograde ureteral stenting. Materials and Methods: A retrospective cohort study was conducted at a tertiary referral center for consecutive MUO patients referred and initially managed with a ureteral stent. Multivariable regression models evaluated factors associated with the following outcomes: number of stent changes, time to first stent change, and overall survival. Results: A total of 120 patients from May 2009 to December 2019 were included; mean age was 63 years, majority (76.7%) were women, median duration of follow-up was 6.1 months. Majority (75%) of patients did not require a stent change at 3 months follow-up. Patients with a history of pelvic radiation (subdistribution hazard rate [sHR] 2.12, 95% confidence interval [CI] 1.23-3.67, p  = 0.007) and with a history of bowel resection (sHR 2.06, 95% CI 1.05-4.03, p  = 0.036) were independently associated with earlier stent changes. Patients with gastrointestinal (GI) malignancy (hazard rate [HR] 14.1, 95% CI 2.66-74.19, p  = 0.0019) and proximal ureter obstruction (HR 2.49, 95% CI 1.21-5.14, p  = 0.0136) were associated with higher rate of all-cause mortality. Conclusions: The majority of patients did not require stent change at their first stent surveillance cystoscopy at 3 months follow-up. Patients with a history of pelvic radiation or bowel resection were more likely to require stent change during their stent surveillance visits. GI malignancy and proximal ureter obstruction were associated with higher rates of mortality.