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Objectives: To determine the impact of prior pelvic radiation therapy (XRT) on outcomes following radical cystectomy (RC) for bladder cancer., Materials and Methods: We performed a retrospective review comparing patients with bladder cancer requiring RC and prior history of XRT for prostate cancer to those undergoing RC without XRT history at our institution from 2011-2018. Propensity score matching was performed with the following variables: age, chronic kidney disease, nutritional deficiency, neoadjuvant chemotherapy use, Charlson comorbidity index, surgical approach, urinary diversion type, and pathologic T-stage. Perioperative, pathologic and oncologic outcomes were analyzed., Outcome Measurements and Statistical Analysis: Categorical variables were assessed utilizing the Pearson Chi Square Test, and continuous variables with the Wilcoxon rank-sum test. The Kaplan-Meier method with stratified-log rank was used to compare survival outcomes. Multivariable Cox proportional hazards models were utilized to identify predictors of overall and recurrence free survival., Results: 227 patients were included, of which 47 had radiotherapy for prostate cancer. 47% of patients in the radiation cohort received external beam radiation therapy, 47% received brachytherapy and 7% received both. There were no differences in recurrence-free survival (P = 0.82) or overall survival (P = 0.25). Statistically significant differences in perioperative or postoperative outcomes such as 90-day complication, readmission, mortality rates, or ureteroenteric anastomotic stricture rates were not found. Rates of node-positive disease, median lymph node yield, positive surgical margin rates, lymphovascular invasion, or variant histology were not significantly different between cohorts., Conclusions: After matching for T-stage and other clinical variables, history of pelvic XRT for prostate cancer in patients who later required RC for bladder cancer, was not associated with an increased rate of perioperative complications or an independent predictor of RFS or OS., Competing Interests: Conflict of Interest None of the authors have any relevant disclosures or conflicts of interest to report., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Inherited mutations in DNA-repair genes such as BRCA2 are associated with increased risks of lethal prostate cancer. Although the prevalence of germline mutations in DNA-repair genes among men with localized prostate cancer who are unselected for family predisposition is insufficient to warrant routine testing, the frequency of such mutations in patients with metastatic prostate cancer has not been established., Methods: We recruited 692 men with documented metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis. We isolated germline DNA and used multiplex sequencing assays to assess mutations in 20 DNA-repair genes associated with autosomal dominant cancer-predisposition syndromes., Results: A total of 84 germline DNA-repair gene mutations that were presumed to be deleterious were identified in 82 men (11.8%); mutations were found in 16 genes, including BRCA2 (37 men [5.3%]), ATM (11 [1.6%]), CHEK2 (10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 [0.4%]), and PALB2 (3 [0.4%]). Mutation frequencies did not differ according to whether a family history of prostate cancer was present or according to age at diagnosis. Overall, the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer (P<0.001), including men with high-risk disease, and the prevalence of 2.7% in the Exome Aggregation Consortium, which includes 53,105 persons without a known cancer diagnosis (P<0.001)., Conclusions: In our multicenter study, the incidence of germline mutations in genes mediating DNA-repair processes among men with metastatic prostate cancer was 11.8%, which was significantly higher than the incidence among men with localized prostate cancer. The frequencies of germline mutations in DNA-repair genes among men with metastatic disease did not differ significantly according to age at diagnosis or family history of prostate cancer. (Funded by Stand Up To Cancer and others.)., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is metabolized in patients to Δ(4)-abiraterone (D4A), which has even greater antitumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least three 5α-reduced and three 5β-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumor-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A critical need in understanding the biology of prostate cancer is characterizing the molecular differences between indolent and aggressive cases. Because DNA methylation can capture the regulatory state of tumors, we analyzed differential methylation patterns genome-wide among benign prostatic tissue and low-grade and high-grade prostate cancer and found extensive, focal hypermethylation regions unique to high-grade disease. These hypermethylation regions occurred not only in the promoters of genes but also in gene bodies and at intergenic regions that are enriched for DNA-protein binding sites. Integration with existing RNA-sequencing (RNA-seq) and survival data revealed regions where DNA methylation correlates with reduced gene expression associated with poor outcome. Regions specific to aggressive disease are proximal to genes with distinct functions from regions shared by indolent and aggressive disease. Our compendium of methylation changes reveals crucial molecular distinctions between indolent and aggressive prostate cancer., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Due to the protracted natural history of the clinical progression of prostate cancer, biochemical recurrence (BCR) is often used to compare treatment modalities. However, BCR definitions and posttreatment prostate-specific antigen kinetics vary considerably among treatments, calling into the question the validity of such comparisons., Objective: To analyze prostate cancer-specific mortality (PCSM) according to treatment-specific nomogram-predicted risk of BCR for men treated by radical prostatectomy (RP), external-beam radiation therapy (EBRT), and brachytherapy., Design, Setting, and Participants: A total of 13 803 men who underwent RP, EBRT, or brachytherapy at two US high-volume hospitals between 1995 and 2008., Intervention: RP, EBRT, and brachytherapy., Outcome Measurements and Statistical Analysis: The 5-yr progression-free probability (5Y-PFP) was calculated for each patient based on the treatment received using a validated treatment-specific nomogram. Fine and Gray competing risk analysis was then used to estimate PCSM by a patient's predicted 5Y-PFP. Multivariable competing risk regression analysis was used to determine the association of treatment with PCSM after adjusting for nomogram-predicted 5Y-PFP., Results and Limitations: Men receiving EBRT had higher 10-yr PCSM compared with those treated by RP across the range of nomogram-predicted risks of BCR: 5Y-PFP >75%, 3% versus 0.9%; 5Y-PFP 51-75%, 6.8% versus 5.9%; 5Y-PFP 26-50%, 12.2% versus 10.6%; and 5Y-PFP ≤25%, 26.6% versus 21.2%. After adjusting for nomogram-predicted 5Y-PFP, EBRT was associated with a significantly increased PCSM risk compared with RP (hazard ratio: 1.5; 95% confidence interval, 1.1-2.0; p=0.006). No statistically significant difference in PCSM was observed between patients treated by brachytherapy and RP, although patient selection factors and lack of statistical power limited this analysis., Conclusions: EBRT patients with similar nomogram-predicted 5Y-PFP appear to have a significantly increased risk of PCSM compared with those treated by RP. Comparison of treatments using nomogram-predicted BCR end points may not be valid., Patient Summary: Biochemical recurrence (BCR) outcomes after external-beam radiation therapy and radical prostatectomy are associated with different risks of subsequent prostate cancer-specific mortality. Physicians and patients should cautiously interpret BCR end points when comparing treatments to make treatment decisions., (Copyright © 2014. Published by Elsevier B.V.)

Recent epidemiologic data show that low serum cholesterol level as well as statin use is associated with a decreased risk of developing aggressive or advanced prostate cancer, suggesting a role for cholesterol in aggressive prostate cancer development. Intracellular cholesterol promotes prostate cancer progression as a substrate for de novo androgen synthesis and through regulation of AKT signaling. By conducting next-generation sequencing-based DNA methylome analysis, we have discovered marked hypermethylation at the promoter of the major cellular cholesterol efflux transporter, ABCA1, in LNCaP prostate cancer cells. ABCA1 promoter hypermethylation renders the promoter unresponsive to transactivation and leads to elevated cholesterol levels in LNCaP. ABCA1 promoter hypermethylation is enriched in intermediate- to high-grade prostate cancers and not detectable in benign prostate. Remarkably, ABCA1 downregulation is evident in all prostate cancers examined, and expression levels are inversely correlated with Gleason grade. Our results suggest that cancer-specific ABCA1 hypermethylation and loss of protein expression direct high intracellular cholesterol levels and hence contribute to an environment conducive to tumor progression.

Objective: To describe a novel robotic transrectal ultrasound platform for real-time navigation during robot-assisted laparoscopic radical prostatectomy (RALP) and to report its early clinical application., Methods: Five men undergoing RALPs at our Institution agreed to participate in this Institutional Review Board-approved pilot study. All of them were eligible for a bilateral nerve sparing procedure. Before docking the da Vinci robot, a transrectal ultrasound tri-plane side-fire probe was placed. A modified ViKY Endoscope Holder was used during RALPs to move the probe thanks to a remote control placed under the console surgeon's control during RALPs. During each procedure, attempt was made to estimate prostate volume, define 12 reference points, and to precisely identify location of the neurovascular bundles using Doppler ultrasound. The TilePro was used during the procedures to allow real-time ultrasound imaging to guide robotic instruments during dissection., Results: Median robotic transrectal ultrasound probe holder (R-TRUS) setup time was 11 minutes (interquartile range [IQR], 10-14). Prostate volume calculation, reference point definition, neurovascular bundle identification, and instrument tip visualization were successful in all men. In 1 patient with a large prostate (120 mL), R-TRUS was withdrawn during recto-prostatic dissection. There were no rectal injuries., Conclusion: R-TRUS during RALPs is feasible and safe. It allows real-time TRUS navigation and guidance. Further studies are needed to evaluate its impact on oncological and functional outcomes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: To assess the utility of the percent free prostate-specific antigen (%fPSA) for the prediction of prostate cancer in men undergoing repeat biopsy., Methods: A retrospective review was performed of 1037 patients in an institutional review board-approved repeat prostate biopsy database. A total of 617 patients who underwent 683 biopsies had all their data available for analysis. The patients were categorized as having undergone 1 repeat biopsy or >1 repeat biopsy., Results: The overall cancer detection rate was 27% and 22% in men who underwent 1 and >1 repeat biopsy, respectively. The area under the receiver operating characteristic curve for the %fPSA was 0.65 for men who underwent 1 repeat biopsy. Multivariate analysis demonstrated that a positive family history, decreasing %fPSA, and presence of high-grade intraepithelial neoplasia and/or atypical small acinar proliferation predicted for cancer. The univariate odds ratio for every 5% decrease in the %fPSA was 1.5 (95% confidence interval 1.2-1.7). The performance of %fPSA was further improved in men who underwent >1 repeat biopsy, with an area under the curve of 0.72. In men who underwent >1 repeat biopsy, multivariate analysis showed that a decreasing %fPSA, >20 cores removed, and high-grade intraepithelial neoplasia predicted for cancer. The univariate odds ratio for every 5% decrease in the %fPSA was 1.8 (95% confidence interval 1.4-2.3). A %fPSA cutoff of 10% achieved 90% and 91% specificity in the 1 repeat biopsy and >1 repeat biopsy groups, respectively., Conclusions: %fPSA is useful in predicting for prostate cancer in the repeat biopsy population, particularly for those who have undergone multiple repeat biopsies. A persistently low %fPSA should prompt additional investigation in these men., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: To validate the performance of percentage of free prostate-specific antigen (%fPSA) in men undergoing extended scheme biopsy. The current cutoff values for %fPSA were chosen using data from sextant biopsies, which have been known to miss a significant number of prostate cancer cases. Additionally, we sought to validate the use of %fPSA in men with a total PSA < 4.0 ng/mL or > 10.0 ng/mL., Methods: We evaluated %fPSA performance in 1077 men who had undergone initial extended prostate biopsy. The men were categorized according to their PSA level into 2 groups (>4.0 and ≤4.0) ng/mL., Results: The overall cancer detection rate was 42.1%. The mean PSA level was 7.6 ng/mL, and the mean %fPSA was 18.0%. The area under the curve for %fPSA was 0.59 (95% confidence interval 0.57-0.61) for all PSA levels, comparable to previous reports from sextant biopsy series. The performance of %fPSA in predicting prostate cancer on initial extended biopsy was improved with a PSA level of ≤4.0 ng/mL (area under the curve 0.66, 95% confidence interval 0.62-0.70) compared with a PSA level >4.0 ng/mL (area under the curve 0.57, 95% confidence interval 0.55-0.59; P < .001). A specificity of 85% was achieved for a %fPSA cutoff of 11% for the ≤4.0-ng/mL group and 10% for the >4.0-ng/mL group., Conclusions: The performance of %fPSA in predicting the presence of prostate cancer was not altered when an extended biopsy scheme was used. Although a %fPSA level greater than our cutoffs would not rule out prostate cancer, a low %fPSA would be particularly useful in predicting prostate cancer, especially in men with normal digital rectal examination findings and a PSA level <4 ng/mL., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The clinical success of the nucleoside analogs 5-aza-cytidine (5-azaC) and 5-aza-2'deoxycytidine (5-aza-dC) as DNA methyltransferase (DNMT) inhibitors has spurred interest in the development of non-nucleoside inhibitors with improved pharmacologic and safety profiles. Because DNMT catalysis features attack of cytosine bases by an enzyme thiol group, we tested whether disulfiram (DSF), a thiol-reactive compound with known clinical safety, demonstrated DNMT inhibitory activity., Methods: Inhibition of DNMT1 activity by DSF was assessed using methyltransferase activity assays with recombinant DNMT1. Next, prostate cancer cell lines were exposed to DSF and assessed for: i) reduction of global 5-methyl cytosine ((5me)C) content using liquid chromatography/tandem mass spectrometry (LC-MS/MS); ii) gene-specific promoter demethylation by methylation-specific PCR (MSP); and iii) gene-reactivation by real-time RT-PCR. DSF was also tested for growth inhibition using prostate cancer cell lines propagated in vitro in cell culture and in vivo as xenografts in nude mice., Results: Disulfiram showed a dose-dependent inhibition of DNMT1 activity on a hemimethylated DNA substrate. In prostate cancer cells in culture, DSF exposure led to reduction of global genomic (5me)C content, increase in unmethylated APC and RARB gene promoters, and associated re-expression of these genes, but did not significantly alter prostate-specific antigen (PSA) expression. DSF significantly inhibited growth and clonogenic survival of prostate cancer cell lines in culture and showed a trend for reduced growth of prostate cancer xenografts., Conclusions: Disulfiram is a non-nucleoside DNMT1 inhibitor that can reduce global (5me)C content, reactivate epigenetically silenced genes, and significantly inhibit growth in prostate cancer cell lines., (Copyright © 2010 Wiley-Liss, Inc.)

Human prostatic carcinogenesis is characterized by the accumulation of both genetic and epigenetic alterations. The epigenetic changes appear earlier and more consistently, and because the DNA sequence remains intact, may be therapeutically reversible. The mechanism(s) by which epigenetic changes appear during the pathogenesis of prostate cancer have not been established. Nonetheless, new methods for the detection of abnormal DNA methylation, a molecular biomarker of epigenetic alterations, are poised to provide clinical tests potentially useful for prostate cancer detection and diagnosis. In addition, new drugs targeting DNA methyltransferases and other enzymes involved in the maintenance of chromatic structure have been introduced into clinical trials for the treatment of advanced prostate cancers. If sufficiently safe strategies for chromatin modulation can be discovered and developed, epigenetic alterations may become rational targets for both prostate cancer prevention and prostate cancer treatment.