Search

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.

Purpose: Asian, Black, and Hispanic men are underrepresented in prostate cancer (PCa) clinical trials. Few novel prostate cancer biomarkers have been validated in diverse cohorts. We aimed to determine if Stockholm3 can improve prostate cancer detection in a diverse cohort., Methods: An observational prospective multicentered (17 sites) clinical trial (2019-2023), supplemented by prospectively recruited participants (2008-2020) in a urology clinic setting included men with suspicion of PCa and underwent prostate biopsy. Before biopsy, sample was collected for measurement of the Stockholm3 risk score. Parameters include prostate-specific antigen (PSA), free PSA, KLK2, GDF15, PSP94, germline risk (single-nucleotide polymorphisms), age, family history, and previous negative biopsy. The primary endpoint was detection of International Society of Urological Pathology (ISUP) Grade ≥2 cancer (clinically significant PCa, csPC). The two primary aims were to (1) demonstrate noninferior sensitivity (0.8 lower bound 95% CI noninferiority margin) in detecting csPC using Stockholm3 compared with PSA (relative sensitivity) and (2) demonstrate superior specificity by reducing biopsies with benign results or low-grade cancers (relative specificity)., Results: A total of 2,129 biopsied participants were included: Asian (16%, 350), Black or African American (Black; 24%, 505), Hispanic or Latino and White (Hispanic; 14%, 305), and non-Hispanic or non-Latino and White (White; 46%, 969). Overall, Stockholm3 showed noninferior sensitivity compared with PSA ≥4 ng/mL (relative sensitivity: 0.95 [95% CI, 0.92 to 0.99]) and nearly three times higher specificity (relative specificity: 2.91 [95% CI, 2.63 to 3.22]). Results were consistent across racial and ethnic subgroups: noninferior sensitivity (0.91-0.98) and superior specificity (2.51-4.70). Compared with PSA, Stockholm3 could reduce benign and ISUP 1 biopsies by 45% overall and between 42% and 52% across racial and ethnic subgroups., Conclusion: In a substantially diverse population, Stockholm3 significantly reduces unnecessary prostate biopsies while maintaining a similar sensitivity to PSA in detecting csPC.

Vitamin D 3 is a steroid hormone that confers anti-tumorigenic properties in prostate cells. Serum vitamin D 3 deficiency has been associated with advanced prostate cancer (PCa), particularly affecting African American (AA) men. Therefore, elucidating the pleiotropic effects of vitamin D on signaling pathways, essential to maintaining non-malignancy, may provide additional drug targets to mitigate disparate outcomes for men with PCa, especially AA men. We conducted RNA sequencing on an AA non-malignant prostate cell line, RC-77N/E, comparing untreated cells to those treated with 10 nM of vitamin D 3 metabolite, 1α,25(OH) 2 D 3 , at 24 h. Differential gene expression analysis revealed 1601 significant genes affected by 1α,25(OH) 2 D 3 treatment. Pathway enrichment analysis predicted 1α,25(OH) 2 D 3- mediated repression of prostate cancer, cell proliferation, actin cytoskeletal, and actin-related signaling pathways ( p < 0.05). Prioritizing genes with vitamin D response elements and associating expression levels with overall survival (OS) in The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA PRAD) cohort, we identified ANLN (Anillin) and ECT2 (Epithelial Cell Transforming 2) as potential prognostic PCa biomarkers. Both genes were strongly correlated and significantly downregulated by 1α,25(OH) 2 D 3 treatment, where low expression was statistically associated with better overall survival outcomes in the TCGA PRAD public cohort. Increased ANLN and ECT2 mRNA gene expression was significantly associated with PCa, and Gleason scores using both the TCGA cohort ( p < 0.05) and an AA non-malignant/tumor-matched cohort. Our findings suggest 1α,25(OH) 2 D 3 regulation of these biomarkers may be significant for PCa prevention. In addition, 1α,25(OH) 2 D 3 could be used as an adjuvant treatment targeting actin cytoskeleton signaling and actin cytoskeleton-related signaling pathways, particularly among AA men.

Importance: Magnetic resonance imaging (MRI)-based risk calculators can replace or augment traditional prostate cancer (PCa) risk prediction tools. However, few data are available comparing performance of different MRI-based risk calculators in external cohorts across different countries or screening paradigms., Objective: To externally validate and compare MRI-based PCa risk calculators (Prospective Loyola University Multiparametric MRI [PLUM], UCLA [University of California, Los Angeles]-Cornell, Van Leeuwen, and Rotterdam Prostate Cancer Risk Calculator-MRI [RPCRC-MRI]) in cohorts from Europe and North America., Design, Setting, and Participants: This multi-institutional, external validation diagnostic study of 3 unique cohorts was performed from January 1, 2015, to December 31, 2022. Two cohorts from Europe and North America used MRI before biopsy, while a third cohort used an advanced serum biomarker, the Prostate Health Index (PHI), before MRI or biopsy. Participants included adult men without a PCa diagnosis receiving MRI before prostate biopsy., Interventions: Prostate MRI followed by prostate biopsy., Main Outcomes and Measures: The primary outcome was diagnosis of clinically significant PCa (grade group ≥2). Receiver operating characteristics for area under the curve (AUC) estimates, calibration plots, and decision curve analysis were evaluated., Results: A total of 2181 patients across the 3 cohorts were included, with a median age of 65 (IQR, 58-70) years and a median prostate-specific antigen level of 5.92 (IQR, 4.32-8.94) ng/mL. All models had good diagnostic discrimination in the European cohort, with AUCs of 0.90 for the PLUM (95% CI, 0.86-0.93), UCLA-Cornell (95% CI, 0.86-0.93), Van Leeuwen (95% CI, 0.87-0.93), and RPCRC-MRI (95% CI, 0.86-0.93) models. All models had good discrimination in the North American cohort, with an AUC of 0.85 (95% CI, 0.80-0.89) for PLUM and AUCs of 0.83 for the UCLA-Cornell (95% CI, 0.80-0.88), Van Leeuwen (95% CI, 0.79-0.88), and RPCRC-MRI (95% CI, 0.78-0.87) models, with somewhat better calibration for the RPCRC-MRI and PLUM models. In the PHI cohort, all models were prone to underestimate clinically significant PCa risk, with best calibration and discrimination for the UCLA-Cornell (AUC, 0.83 [95% CI, 0.81-0.85]) model, followed by the PLUM model (AUC, 0.82 [95% CI, 0.80-0.84]). The Van Leeuwen model was poorly calibrated in all 3 cohorts. On decision curve analysis, all models provided similar net benefit in the European cohort, with higher benefit for the PLUM and RPCRC-MRI models at a threshold greater than 22% in the North American cohort. The UCLA-Cornell model demonstrated highest net benefit in the PHI cohort., Conclusions and Relevance: In this external validation study of patients receiving MRI and prostate biopsy, the results support the use of the PLUM or RPCRC-MRI models in MRI-based screening pathways regardless of European or North American setting. However, tools specific to screening pathways incorporating advanced biomarkers as reflex tests are needed due to underprediction.

Purpose: We sought to develop and validate a prostate biopsy risk calculator for Black men and compare it with the Prostate Cancer Prevention Trial version 2.0, Prostate Biopsy Collaborative Group, and Kaiser Permanente Prostate Cancer Risk Calculators for the detection of Gleason Grade Group (GG) ≥ 2 prostate cancer (PCa)., Materials and Methods: We prospectively recruited 2 cohorts of men undergoing prostate biopsy from 5 facilities in Chicago. The first cohort was split into development (70%) and internal validation (30%) groups. The second was used for external validation. Iterative logistic regression was used to develop 3 models for predicting GG ≥ 2 PCa. Models were compared for discrimination using the C statistics, calibration curves, and net benefit curves. The frequency of unnecessary biopsies and missed PCas was compared at 10% and 30% risk thresholds., Results: The 2 cohorts included 393 and 292 Black men, respectively. Our first model, Mistry-Sun 1, used serum PSA and prior negative biopsy. Mistry-Sun 2 added abnormal digital rectal exam (DRE) and an interaction term with abnormal DRE and PSA to Mistry-Sun 1. Mistry-Sun 3 added prostate volume, abnormal DRE, and age to Mistry-Sun 1. The C statistics were 0.74, 0.74, and 0.78, respectively, and were similar to or higher than established calculators. At the 10% and 30% risk thresholds our models had the fewest unnecessary biopsies and an appropriate proportion of missed GG ≥ 2 PCas., Conclusions: Tailoring a risk calculator to detect clinically significant PCa in Black men may improve biopsy decision-making and outcomes compared to tools developed in non-Black populations.

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.)

Objective: Shared decision-making (SDM) is an approach to patient-centered care that is strongly recommended when counseling patients for screening and treatment of prostate cancer. However, providers report lack of comfort with SDM and particularly in disparate populations. We report our experience designing and piloting an online workshop to educate practicing urologists on SDM in diverse populations. Our objective was to create a valued interactive SDM workshop to help urologists learn to lead SDM discussions with men form underserved populations. Therefore, we tested the hypothesis that urologists would agree or strongly agree that we met our learning objectives on postcourse survey., Materials and Methods: With the support of the American Urologic Association, we developed a case-based workshop with interactive role-playing to demonstrate and teach integration of SDM into clinical care. Cases were centered around screening and treatment decisions for localized prostate cancer in diverse patients. Brief surveys were used to track success with learning objectives and urologists' satisfaction with the workshop., Results: The session included 14 participants from 6 countries. A postworkshop survey indicated that 100% of respondents (8 of 8) "strongly agreed" that the activity met learning objectives, and 100% rated the session as "good" (1), "very good" (1), or "excellent" (6). Participants' knowledge also improved on shared decision-making concepts and the knowledge was maintained one month after the workshop., Conclusion: We successfully created and piloted an interactive online workshop to improve urologists' comfort using shared decision-making in caring for diverse patient populations. The course met its objectives and participant feedback for the course was positive. Sharing this process and framework for development of this intervention may inform future workshops that can be applied to medical students, residents, and providers., Competing Interests: Declaration of Competing Interest I declare that the authors have no competing interests as defined by Urologic Oncology: Seminars and Original Investigations, or other interests that might be perceived to influence the results and/or discussion reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: The Oncotype Dx Genomic Prostate Score (GPS) is a 17-gene relative expression assay that predicts adverse pathology at prostatectomy. We conducted a novel randomized controlled trial to assess the impact of GPS on urologist's treatment preference for favorable risk prostate cancer (PCa): active surveillance versus active treatment (i.e., prostatectomy/radiation). This is a secondary endpoint from the ENACT trial which recruited from three Chicago hospitals from 2016 to 2019., Methods: Ten urologists along with men with very low to favorable-intermediate risk PCa were included in the study. Participants were randomly assigned to standardized counseling with or without GPS assay. The main outcome was urologists' preference for active treatment at Visit 2 by study arm (GPS versus Control). Multivariable best-fit binary logistic regressions were constructed to identify factors independently associated with urologists' treatment preference., Results: Two hundred men (70% Black) were randomly assigned to either the Control (96) or GPS arm (104). At Visit 2, urologists' preference for prostatectomy/radiation almost doubled in the GPS arm to 29.3% (29) compared to 14.1% (13) in the Control arm (p = 0.01). Randomization to the GPS arm, intermediate NCCN risk level, and lower patient health literacy were predictors for urologists' preference for active treatment., Discussion: Limitations included sample size and number of urologists. In this study, we found that GPS testing reduced urologists' likelihood to prefer active surveillance., Conclusions: These findings demonstrate how obtaining prognostic biomarkers that predict negative outcomes before treatment decision-making might influence urologists' preference for recommending aggressive therapy in men eligible for active surveillance., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: To assess urologists' attitudes toward treating lesbian, gay, bisexual, transgender, or queer (LGBT) patients and counseling practices during diagnosis and treatment of prostate cancer., Methods: A 35-question survey was sent to program directors of U.S. urology residency programs., Results: 154 responses met the inclusion criteria. Respondents were primarily male, heterosexual, in academia, representing a range of ages and geography. 54.2% of respondents don't assume patients are heterosexual. While 88% of providers feel comfortable discussing sexual health with LGBTQ patients, 42.9% disagree that knowing sexual orientation is necessary to providing optimal care. 57.8% of respondents don't provide intake forms to indicate sexual orientation and 60.4% don't inquire about sexual orientation during history-taking. A majority (32.7%) reported 1-5 hours of LGBTQ health training. 74.3% believe more training is needed. 74.5% agreed to being listed as an LGBTQ-Friendly Provider currently, 65.8% felt they needed additional training. 63.6% agreed the prostate is a source of sexual pleasure. 55.9% believed it important to assess sexual satisfaction in patients who engage in receptive anal intercourse after prostate cancer treatment. Responses were mixed regarding the timing of resuming receptive anal intercourse after treatment and whether patients are counseled to refrain from anal stimulation before PSA testing. Answers to knowledge questions regarding anal cancer and communication were primarily correct; answers to questions regarding anejaculation and differences in health concerns were mixed., Conclusion: Ongoing education is necessary on specific differences between heterosexual and lesbian, gay, bisexual, transgender, or queer (LGBTQ) patient concerns and how to apply this knowledge in order to address the needs of a rapidly aging LGBTQ population., Competing Interests: Declaration of Competing Interest The authors report no financial disclosures or conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Most radical prostatectomies are completed with robotic assistance. While studies have previously evaluated perioperative outcomes of robot-assisted radical prostatectomy (RARP), this study investigates disparities in access and clinical outcomes of RARP., Study Design: The National Cancer Database (NCDB) was used to identify patients who received radical prostatectomy for cancer between 2010 and 2017 with outcomes through 2018. RARP was compared to open radical prostatectomy (ORP). Odds of receiving RARP were evaluated while adjusting for covariates. Overall survival was evaluated using a propensity-score matched cohort., Results: Overall, 354 752 patients were included with 297 676 (83.9%) receiving RARP. Patients who were non-Hispanic Black (82.8%) or Hispanic (81.3%) had lower rates of RARP than non-Hispanic White (84.0%) or Asian patients (87.7%, p < 0.001). Medicaid or uninsured patients were less likely to receive RARP (75.5%) compared to patients with Medicare or private insurance (84.4%, p < 0.001). Medicaid or uninsured status was associated with decreased odds of RARP in adjusted multivariable analysis (OR 0.61, 95% CI 0.49-0.76). RARP was associated with decreased perioperative mortality and improved overall survival compared to ORP., Conclusion: Patients who were underinsured were less likely to receive RARP. Improved access to RARP may lead to decreased disparities in perioperative outcomes for prostate cancer., (© 2023 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

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: Genetic factors play an important role in prostate cancer (PCa) susceptibility., Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry., Design, Setting, and Participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry., Outcome Measurements and Statistical Analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness., Results and Limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10 -4 )., Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry., Patient Summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

This study aimed to clarify the effect of wire structure and alkaline elements in wire composition on metal transfer behavior in metal-cored arc welding (MCAW). A comparison of metal transfer in pure argon gas was carried out using a solid wire (wire 1), a metal-cored wire without an alkaline element (wire 2), and another metal-cored wire with 0.084 mass% of sodium (wire 3). The experiments were conducted under 280 and 320 A welding currents, observed by high-speed imaging techniques equipped with laser assistance and bandpass filters. At 280 A, wire 1 showed a streaming transfer mode, while the others showed a projected one. When the current was 320 A, the metal transfer of wire 2 changed to streaming, while wire 3 remained projected. As sodium has a lower ionization energy than iron, the mixing of sodium vapor into the iron plasma increases its electrical conductivity, raising the proportion of current flowing through metal vapor plasma. As a result, the current flows to the upper region of the molten metal on the wire tip, with the resulting electromagnetic force causing droplet detachment. Consequently, the metal transfer mode in wire 3 remained projected. Furthermore, weld bead formation is the best for wire 3.

Purpose: Vitamin D metabolites may be protective against prostate cancer (PCa). We conducted a cross-sectional analysis to evaluate associations between in vivo vitamin D status, genetic ancestry, and degree of apoptosis using prostatic epithelial terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining., Experimental Design: Benign and tumor epithelial punch biopsies of participants with clinically localized PCa underwent indirect TUNEL staining. Serum levels of 25 hydroxyvitamin D [25(OH)D] and 1,25 dihydroxyvitamin D were assessed immediately before radical prostatectomy; levels of prostatic 25(OH)D were obtained from the specimen once the prostate was extracted. Ancestry informative markers were used to estimate the percentage of genetic West African, Native American, and European ancestry., Results: One hundred twenty-one newly diagnosed men, age 40-79, were enrolled between 2013 and 2018. Serum 25(OH)D correlated positively with both tumor (ρ = 0.17, p = 0.03), and benign (ρ = 0.16, p = 0.04) prostatic epithelial TUNEL staining. Similarly, prostatic 25(OH)D correlated positively with both tumor (ρ = 0.31, p < 0.001) and benign (ρ = 0.20, p = 0.03) epithelial TUNEL staining. Only Native American ancestry was positively correlated with tumor (ρ = 0.22, p = 0.05) and benign (ρ = 0.27, p = 0.02) TUNEL staining. In multivariate regression models, increasing quartiles of prostatic 25(OH)D (β = 0.25, p = 0.04) and Native American ancestry (β = 0.327, p = 0.004) were independently associated with tumor TUNEL staining., Conclusions: Physiologic serum and prostatic 25(OH)D levels and Native American ancestry are positively associated with the degree of apoptosis in tumor and benign prostatic epithelium in clinically localized PCa. Vitamin D may have secondary chemoprevention benefits in preventing PCa progression in localized disease., (© 2022 Wiley Periodicals LLC.)

Context: Men of African ancestry have demonstrated markedly higher rates of prostate cancer mortality than men of other races and ethnicities around the world. In fact, the highest rates of prostate cancer mortality worldwide are found in the Caribbean and Sub-Saharan West Africa, and among men of African descent in the USA. Addressing this inequity in prostate cancer care and outcomes requires a focused research approach that creates durable solutions to address the structural, social, environmental, and health factors that create racial disparities in care and outcomes., Objective: To introduce a conceptual model for evaluating racial inequities in prostate cancer care to facilitate the development of translational research studies and interventions., Evidence Acquisition: A collaborative review of literature relevant to racial inequities in prostate cancer care and outcomes was performed. Existing literature was used to highlight various components of the conceptual model to inform future research and interventions toward equitable care and outcomes., Evidence Synthesis: Racial inequities in prostate cancer outcomes are driven by a series of structural and social determinants of health that impact exposures, mediators, and outcomes. Social determinants of equity, such as laws/policies, economic systems, and structural racism, affect the inequitable access to environmental and neighborhood exposures, in addition to health care access. Although the incidence disparity remains problematic, various studies have demonstrated parity in outcomes when social and health factors, such as access to equitable care, are normalized. Few studies have tested interventions to reduce inequities in prostate cancer among Black men., Conclusions: Worldwide, men of African ancestry demonstrate worse outcomes in prostate cancer, a phenomenon driven largely by social factors that inform biologic, environmental, and health care risks. A conceptual model was presented that organizes the many factors that influence prostate cancer incidence and mortality. Within that framework, we must understand the current state of inequities in clinical prostate cancer practice, the optimal state of what equitable practice would be, and how achieving equity in prostate cancer care balances costs, benefits, and harms. More robust characterization of the sources of prostate cancer inequities should inform testing of ambitious and innovative interventions as we work toward equity in care and outcomes., Patient Summary: Men of African ancestry demonstrate the highest rates of prostate cancer mortality, which may be reduced through social interventions. We present a framework for formalizing the identification of the drivers of prostate cancer inequities to facilitate the development of interventions and trials to eradicate them., (Published by Elsevier B.V.)

Introduction: The Prostate Imaging Reporting and Data System (PIRADS) has shown promise in improving the detection of Gleason grade group (GG) 2-5 prostate cancer (PCa) and reducing the detection of indolent GG1 PCa. However, data on the performance of PIRADS in Black and Hispanic men is sparse. We evaluated the accuracy of PIRADS scores in detecting GG2-5 PCa in White, Black, and Hispanic men., Methods: We performed a multicenter retrospective review of biopsy-naïve Black (n = 108), White (n = 108), and Hispanic (n = 64) men who underwent prostate biopsy (PB) following multiparametric MRI. Sensitivity and specificity of PIRADS for GG2-5 PCa were calculated. Race-stratified binary logistic regression models for GG2-5 PCa using standard clinical variables and PIRADS were used to calculate area under the receiver operating characteristics curves (AUC)., Results: Rates of GG2-5 PCa were statistically similar between Blacks, Whites, and Hispanics (52.8% vs 42.6% vs 37.5% respectively, p = 0.12). Sensitivity was lower in Hispanic men compared to White men (87.5% vs 97.8% respectively, p = 0.01). Specificity was similar in Black versus White men (21.6% vs 27.4%, p = 0.32) and White versus Hispanic men (27.4% vs 17.5%, p = 0.14). The AUCs of the PIRADS added to standard clinical data (age, PSA and suspicious prostate exam) were similar when comparing Black versus White men (0.75 vs 0.73, p = 0.79) and White versus Hispanic men (0.73 vs 0.59, p = 0.11). The AUCs for the Base model and PIRADS model alone were statistically similar when comparing Black versus White men and White versus Hispanic men., Conclusions: The accuracy of the PIRADS and clinical data for detecting GG2-5 PCa seems statistically similar across race. However, there is concern that PIRADS 2.0 has lower sensitivity in Hispanic men compared to White men. Prospective validation studies are needed., (© 2022. The Author(s).)

A rare African ancestry-specific germline deletion variant in HOXB13 (X285K, rs77179853) was recently reported in Martinican men with early-onset prostate cancer. Given the role of HOXB13 germline variation in prostate cancer, we investigated the association between HOXB13 X285K and prostate cancer risk in a large sample of 22 361 African ancestry men, including 11 688 prostate cancer cases. The risk allele was present only in men of West African ancestry, with an allele frequency in men that ranged from 0.40% in Ghana and 0.31% in Nigeria to 0% in Uganda and South Africa, with a range of frequencies in men with admixed African ancestry from North America and Europe (0-0.26%). HOXB13 X285K was associated with 2.4-fold increased odds of prostate cancer (95% confidence interval [CI] = 1.5-3.9, p = 2 × 10 -4 ), with greater risk observed for more aggressive and advanced disease (Gleason ≥8: odds ratio [OR] = 4.7, 95% CI = 2.3-9.5, p = 2 × 10 -5 ; stage T3/T4: OR = 4.5, 95% CI = 2.0-10.0, p = 2 × 10 -4 ; metastatic disease: OR = 5.1, 95% CI = 1.9-13.7, p = 0.001). We estimated that the allele arose in West Africa 1500-4600 yr ago. Further analysis is needed to understand how the HOXB13 X285K variant impacts the HOXB13 protein and function in the prostate. Understanding who carries this mutation may inform prostate cancer screening in men of West African ancestry. PATIENT SUMMARY: A rare African ancestry-specific germline deletion in HOXB13, found only in men of West African ancestry, was reported to be associated with an increased risk of overall and advanced prostate cancer. Understanding who carries this mutation may help inform screening for prostate cancer in men of West African ancestry., (Copyright © 2022. Published by Elsevier B.V.)

Objective: To provide commentary on the disparities in access to clinical trials and precision oncology specific to Black men with Prostate Cancer (PCa) in the United States and lend a general framework to aid in closing these gaps., Materials and Methods: The ideas, commentaries and data presented in this narrative review were synthesized by utilizing qualitative and quantitative studies, reviews, and randomized control trials performed between 2010 and 2021. We searched PubMed using the key words "Medicaid", "Medicare", "clinical trials", "African Americans", "Black", "underrepresentation", "access", "Prostate Cancer", "minority recruitment", "racial disparities", "disparity", "genomics", "biomarkers", "diagnostic" "prognostic", "validation", "precision medicine", and "precision oncology" to identify important themes, trends and data described in the current review. Keywords were used alone and combination with both "AND" and "OR" terms., Results: Black men with prostate cancer (PCa) in the United States have earlier onset of disease, present with more advanced stages, and worse prostate cancer-specific survival than their White counterparts. Potential causative factors vary from disparities in health care access to differences in tumor immunobiology and genomics along with disparate screening rates, management patterns and underrepresentation in clinical and translational research such as clinical trials and precision oncology., Conclusion: To avoid increasing the racial disparity in PCa outcomes for Black men, we must increase inclusion of Black men into precision oncology and clinical trials, using multilevel change. Underrepresentation in clinical and translational research may potentiate poorly validated risk calculators and biomarkers, leading to poor treatment decisions in high-risk populations. Relevant actions include funding to include minority-serving institutions as recruitment sites, and inclusion of evidence based recruitment methods in funded research to increase Black representation in clinical trials and translational research., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The metabolism of normal prostate relies on glycolysis, with prostate cancer having reduced glycolysis and increased aerobic metabolism. Advanced glycation end products (AGEs) accumulate in tissues as a result of age and glycolytic rate. Differential AGE levels were recently observed in prostate cancer tissues. Herein we sought to quantify AGEs in benign and cancer prostate tissue in a diverse cohort of patients., Methods: Levels of the AGE Nε-(carboxylethyl)lysine (CML) were quantified by immunohistochemistry (IHC) in a tissue microarray which consisted of 3 cores from tumor and 2 cores from benign areas from 118 patients (87 African American and 31 European American). Ancestry informative markers for African Ancestry were available for 79 patients. Epithelial and stromal areas were quantified separately using an E-cadherin mask. CML levels were compared with clinical grade group and ancestry by mixed linear effect models. Age, prostate-specific antigen (PSA) levels, body mass index (BMI), and hemoglobin A1C were included as covariates., Results: CML levels were lower in areas of the tumor, for both epithelium and surrounding stroma, compared with benign, but did not significantly change with tumor grade group. Age, PSA levels, BMI, and hemoglobin A1C did not associate with CML levels. CML levels were inversely associated with the percentage of African Ancestry in all tissues., Conclusions: The low CML levels in cancer may reflect the reduced glycolytic state of the tissue. The inverse relationship between African Ancestry and CML levels in both benign and cancer areas suggests a state of reduced glycolysis. It is yet to be determined whether altered glycolysis and CML levels are bystanders or drivers of carcinogenesis., (© 2021 Wiley Periodicals LLC.)

Background: Black men are more likely than Non-Hispanic White (NHW) men to be diagnosed with high-risk prostate cancer. We examined the extent to which social factors were associated with differences in prostate cancer risk profiles between Black men and NHW men [using a modification to the original D'Amico risk groups based on prostate specific antigen (PSA), Gleason score (GS), and TNM stage (stage)], based on individual and combined clinicopathologic characteristics., Methods: We conducted a cross-sectional population-based study of 23,555 Black men and 146,889 NHW men diagnosed with prostate cancer in the California Cancer Registry from 2004 to 2017. We conducted multivariable logistic regression to examine the association of year of diagnosis, block group-level neighborhood socioeconomic status (nSES), marital status, and insurance type on differences in prostate cancer risk profiles between Black and NHW men., Results: High PSA (>20 ng/mL), GS, stage, individually and combined prostate cancer risk profiles were more common among Black men versus NHW men. In fully adjusted models, relative to NHW men, we observed a persistent 67% increased odds of high PSA among Black men. nSES was the factor most strongly associated with racial disparity in high PSA, accounting for 25% of the difference. Marital status was the factor that was second most associated with a racial disparity., Conclusions: nSES was the factor most strongly associated with racial disparities in high PSA prostate cancer., Impact: The influence of nSES on racial disparities in PSA, GS, stage, and prostate cancer risk profiles warrants further consideration., (©2021 The Authors; Published by the American Association for Cancer Research.)

Objective: To compare Prostate Health Index (PHI) and prostate-specific antigen (PSA) density as secondary tests after multiparametric magnetic resonance imaging (mpMRI) in improving the detection accuracy of Gleason grade group (GG) 2-5 prostate cancer (PCa) and in decreasing unnecessary biopsies in a multiethnic biopsy-naïve population., Methods: From February 2017 to February 2020, we recruited consecutive biopsy-naïve men in participating urology clinics for elevated PSA levels. They all had a PHI score, mpMRI, and prostate biopsy. Experienced genitourinary radiologists read all mpMRI studies based on PIRADS version 2.0. Logistic regression models were used to generate receiver operating characteristic curves. Models were tested for effect modification between Race (Black vs White) and both PHI and PSA density, and Race and PIRADS to determine if race impacted their prediction accuracy. Sensitivity, specificity, and predictive values of PHI and PSA density thresholds were calculated by PIRADS scores. The primary outcome was GG2-5 PCa, that is, Gleason score ≥3 + 4., Results: The study included 143 men, of which 65 (45.5%) were self-reported Black. Median age was 62.0 years and 55 men (38.4%) had GG2-5 PCa. Overall, 18.1% had PIRADS 1-2, 32.9% had PIRADS 3, and 49.0% had PIRADS 4-5. For the binary logistic regressions, the interactions between PIRADS and Race ( P  = .08), Log (PHI) and Race ( P  = .17), and Log (PSA density) and Race ( P  = .42) were not statistically significant. Within PIRADS 3 lesions, a PHI ≥49 prevented unnecessary biopsies in 55% of men and missed no GG2-5 PCa, yielding a negative predictive value of 100%. There was no reliable PHI or PSA density threshold to avoid PCa biopsies in PIRADS 1-2 or 4-5., Conclusions: PHI and PSA density can be used after mpMRI to improve the detection of GG2-5 PCa in a biopsy-naïve cohort. PHI may be superior to PSA density in PIRADS 3 lesions by avoiding 55% of unnecessary biopsies. Using both PHI and PSA density in series may further increase specificity and lead to fewer unnecessary biopsies, but further larger studies are warranted to determine the optimal threshold of each biomarker., (© 2021 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Background and Objectives: Prostate cancer is the most commonly diagnosed cancer in Nigerian men despite the lack of PSA based screening. Current prevalence estimates in Nigeria are based on cancer registry data obtained primarily from hospital admissions and therefore not truly reflective of prostate cancer incidence. Prior autopsy series did not adhere to modern pathologic quality practices. The aim of this study was to explore the prevalence of asymptomatic prostate cancer among Nigerian men at the time of autopsy., Methods: Prostates were collected at autopsy at the Universities of Lagos and Calabar Teaching Hospitals from men aged more than 40 who died from causes other than prostate cancer. Thirty-nine prostates from Nigerian men autopsied in 2017 to 2018 were formalin-fixed, weighed, and sliced at 4 mm intervals. Haematoxylin and eosin-stained paraffin sections were prepared from these slices. Presence and Gleason grade of prostatic adenocarcinomas and presence of high-grade prostatic intraepithelial neoplasia (HGPIN) were recorded., Results: Mean age of cases was 55 ± 11 years and mean prostatic weight was 23.0 ± 10.9 g. The crude prevalence of HGPIN was 20.6%. Overall crude prevalence of prostate cancer was 8.8% (n = 34), increasing from 8.3% for men aged 40-59 (n = 23) to 10.0% for men ≥60 years old (n = 10). Two tumors were small and had Gleason Grade 3 + 3 or 3 + 4, and one large stage T3 tumor with Gleason Grade 4 + 3 disease and neuroendocrine appearance was found in a 54-year-old man., Conclusions: The 8.8% prevalence of subclinical prostate cancer at autopsy was similar to previously reported Nigerian studies with more limited tissue sampling (6.7%-10%), but considerably lower than estimates in other populations, including African Americans. Our findings suggest that latent, clinically asymptomatic prostate cancer is less frequent in Nigerians than in African Americans, despite shared genetic ancestry. Future studies with increased sample size are warranted to provide insight in the natural history and true prevalence of prostate cancer in West Africa., (© 2021 Wiley Periodicals LLC.)

Purpose: The Genomic Prostate Score (GPS), performed on biopsy tissue, predicts adverse outcome in prostate cancer (PCa) and has shown promise for improving patient selection for active surveillance (AS). However, its impact on treatment choice in high-risk populations of African Americans is largely unknown and, in general, the effect of the GPS on this difficult decision has not been evaluated in randomized trials., Methods: Two hundred men with National Comprehensive Cancer Network very low to low-intermediate PCa from three Chicago hospitals (70% Black, 16% college graduates) were randomly assigned at diagnosis to standard counseling with or without a 12-gene GPS assay. The primary end point was treatment choice at a second postdiagnosis visit. The proportion of patients choosing AS was compared, and multivariable modeling was used to estimate the effects of various factors on AS acceptance., Results: AS acceptance was high overall, although marginally lower in the intervention group (77% v 88%; P = .067), and lower still when men with inadequate specimens were excluded ( P = .029). Men with lower health literacy who received a GPS were seven-fold less likely to choose AS compared with controls, whereas no difference was seen in men with higher health literacy ( P interaction = .022). Among men with low-intermediate risk, 69% had GPS values consistent with unfavorable intermediate or high-risk cancer. AS choice was also independently associated with a family history of PCa and having health insurance., Conclusion: In contrast to other studies, the net effect of the GPS was to move patients away from AS, primarily among men with low health literacy. These findings have implications for our understanding of how prognostic molecular assays that generate probabilities of poor outcome can affect treatment decisions in diverse clinical populations., Competing Interests: Peter H. GannConsulting or Advisory Role: Bristol Myers SquibbResearch Funding: Bristol Myers Squibb Michael R. AbernTravel, Accommodations, Expenses: Intuitive SurgicalNo other potential conflicts of interest were reported.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations., (Copyright © 2021 American Society of Human Genetics. All rights reserved.)

Purpose: The Prostate Health Index is validated for prostate cancer detection but has not been well validated for Gleason grade group 2-5 prostate cancer detection in Black men. We hypothesize that the Prostate Health Index has greater accuracy than prostate specific antigen for detection of Gleason grade group 2-5 prostate cancer. We estimated probability of overall and Gleason grade group 2-5 prostate cancer across previously established Prostate Health Index ranges and identified Prostate Health Index cutoffs that maximize specificity for Gleason grade group 2-5 prostate cancer with sensitivity >90%., Materials and Methods: We recruited a "cancer-free" Black control cohort (135 patients) and a cohort of biopsy naïve Black men (158) biopsied for elevated prostate specific antigen. Descriptive statistics compared the prostate cancer cases and controls and the frequency of Gleason grade group 2-5 prostate cancer across Prostate Health Index scores. Receiver operating characteristics compared the discrimination of prostate specific antigen, Prostate Health Index and other prostate specific antigen related biomarkers. Sensitivity and specificity for Gleason grade group 2-5 prostate cancer detection were assessed at prostate specific antigen and Prostate Health Index thresholds alone and in series., Results: Of biopsied subjects 32.9% had Gleason grade group 2-5 prostate cancer. In Blacks with prostate specific antigen from 4.0-10.0 ng/ml, Prostate Health Index and prostate specific antigen had similar discrimination for Gleason grade group 2-5 prostate cancer (0.63 vs 0.57, p=0.27). In Blacks with prostate specific antigen ≤10.0, a threshold of prostate specific antigen ≥4.0 had 90.4% sensitivity for Gleason grade group 2-5 prostate cancer; a threshold of prostate specific antigen ≥4.0 with Prostate Health Index ≥35.0 in series avoided unnecessary biopsy in 33.0% of men but missed 17.3% of Gleason grade group 2-5 prostate cancer. Prostate specific antigen ≥4.0 with Prostate Health Index ≥28.0 in series spared biopsy in 17.9%, while maintaining 90.4% sensitivity of Gleason grade group 2-5 prostate cancer., Conclusions: The Prostate Health Index has moderate accuracy in detecting Gleason grade group 2-5 prostate cancer in Blacks, but Prostate Health Index ≥28.0 can be safely used to avoid some unnecessary biopsies in Blacks.

A recent genome-wide association study (GWAS) in African descent populations identified novel loci associated with skin pigmentation. However, how genomic variations affect skin pigmentation and how these skin pigmentation gene variants affect serum 25(OH) vitamin D variation has not been explored in African Americans (AAs). In order to further understand genetic factors that affect human skin pigmentation and serum 25(OH)D variation, we performed a GWAS for skin pigmentation with 395 AAs and a replication study with 681 AAs. Then, we tested if the identified variants are associated with serum 25(OH) D concentrations in a subset of AAs (n = 591). Skin pigmentation, Melanin Index (M-Index), was measured using a narrow-band reflectometer. Multiple regression analysis was performed to identify variants associated with M-Index and to assess their role in serum 25(OH)D variation adjusting for population stratification and relevant confounding variables. A variant near the SLC24A5 gene (rs2675345) showed the strongest signal of association with M-Index (P = 4.0 x 10-30 in the pooled dataset). Variants in SLC24A5, SLC45A2 and OCA2 together account for a large proportion of skin pigmentation variance (11%). The effects of these variants on M-Index was modified by sex (P for interaction = 0.009). However, West African Ancestry (WAA) also accounts for a large proportion of M-Index variance (23%). M-Index also varies among AAs with high WAA and high Genetic Score calculated from top variants associated with M-Index, suggesting that other unknown genomic factors related to WAA are likely contributing to skin pigmentation variation. M-Index was not associated with serum 25(OH)D concentrations, but the Genetic Score was significantly associated with vitamin D deficiency (serum 25(OH)D levels less than 12 ng/mL) (OR, 1.30; 95% CI, 1.04-1.64). The findings support the hypothesis suggesting that skin pigmentation evolved responding to increased demand for subcutaneous vitamin D synthesis in high latitude environments., Competing Interests: The authors have declared that no competing interests exist.

The microbiome-gut-brain-axis is a complex phenomenon spanning several dynamic systems in the body which can be parsed at a molecular, cellular, physiological and ecological level. A growing body of evidence indicates that this axis is particularly sensitive to the effects of stress and that it may be relevant to stress resilience and susceptibility. Although stress-induced changes in the composition of the microbiome have been reported, the degree of compositional change over time, which we define as volatility, has not been the subject of in-depth scrutiny. Using a chronic psychosocial stress paradigm in male mice, we report that the volatility of the microbiome significantly correlated with several readouts of the stress response, including behaviour and corticosterone response. We then validated these findings in a second independent group of stressed mice. Additionally, we assessed the relationship between volatility and stress parameters in a cohort of health volunteers who were undergoing academic exams and report similar observations. Finally, we found inter-species similarities in the microbiome stress response on a functional level. Our research highlights the effects of stress on the dynamic microbiome and underscores the informative value of volatility as a parameter that should be considered in all future analyses of the microbiome., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.