Cognitive function in long-term testicular cancer survivors: Impact of modifiable factors.

No study has comprehensively examined associated factors (adverse health outcomes, health behaviors, and demographics) impacting cognitive function in long-term testicular cancer survivors (TC-survivors). TC-survivors given cisplatin-based chemotherapy completed comprehensive, validated surveys, including those which 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 (IQR: 38, 54); median time-since-chemotherapy: 10.9 years (IQR = 7.9, 15.9)], 13.7% reported cognitive dysfunction. Hearing loss (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 declines. 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.

5-α Reductase Inhibitors and Prostate Cancer Mortality.

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.

Testicular Germ Cell Tumors with Venous Tumor Thrombus: Prevalence, Presentation, and Management.

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.

Primary retroperitoneal lymph node dissection for metastatic non-seminomatous germ cell tumours: outcomes and adjuvant chemotherapy.

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.

MicroRNA for Prediction of Teratoma and Viable Germ Cell Tumor after Chemotherapy.

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.

Sterol-like drugs potentiate statin-triggered prostate cancer cell death by inhibiting SREBP2 nuclear translocation.

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.

Addressing controversial areas in the management of advanced prostate cancer in Canada Areas of consensus and controversy from the third Canadian consensus forum.

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 3rd 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.

Propensity-matched Analysis of Open Versus Robotic Primary Retroperitoneal Lymph Node Dissection for Clinical Stage II Testicular Cancer.

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.

Prognostic Factor Risk Groups for Clinical Stage I Seminoma: An Individual Patient Data Analysis by the European Association of Urology Testicular Cancer Guidelines Panel and Guidelines Office.

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.

Genetic testing practices among specialist physicians who treat prostate cancer A Canadian, cross-sectional survey.

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.

The Use of Salvage Chemotherapy for Patients with Relapsed Testicular Germ Cell Tumor (GCT) in Canada: A National Survey.

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.

Neoadjuvant Cabazitaxel plus Abiraterone/Leuprolide Acetate in Patients with High-Risk Prostate Cancer: ACDC-RP Phase II Trial.

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.

Guideline of guidelines: follow-up after orchidectomy for clinical stage 1 testicular cancer.

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.

Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry.

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 (PRS269). 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 PRS269. 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 PRS269 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 PRS269 developed from multi-ancestry GWASs and fine-mapping.

Evaluating Approaches for Constructing Polygenic Risk Scores for Prostate Cancer in Men of African and European Ancestry.

Genome-wide polygenic risk scores (GW-PRS) have been reported to have better predictive ability than PRS 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 GWAS and fine-mapping studies (PRS 269 ). GW-PRS models were trained using a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls 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 OR 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. However, 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 OR (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 data. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the multi-ancestry PRS 269 constructed with fine-mapping.

Development, multi-institutional external validation, and algorithmic audit of an artificial intelligence-based Side-specific Extra-Prostatic Extension Risk Assessment tool (SEPERA) for patients undergoing radical prostatectomy: a retrospective cohort study.

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.

The Burden of Uncontrolled Cardiovascular Risk Factors in Men With Prostate Cancer: A RADICAL-PC Analysis.

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.

The Importance of Repeat Imaging Prior to Treatment Decision-making in Testicular Cancer: Commentary From the Inaugural Global Society of Rare Genitourinary Tumors Summit.

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.

Low-volume grade group 2 prostate cancer candidates for active surveillance: a radical prostatectomy retrospective analysis.

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.