Trusted Information Sources About the COVID-19 Vaccine Vary in Underserved Communities.

The COVID-19 pandemic was one of the deadliest global public health events. In the United States, over 1.1 million individuals have died, and now COVID-19 is the third leading cause of death (CDC, 2023). Vaccine uptake has stalled among different demographics. Vaccine hesitancy, a delay in accepting or refusing vaccines, poses a significant challenge regardless of the availability of safe and effective COVID-19 vaccines. This study aimed to identify disparate COVID-19 vaccine uptake among individuals in Western New York. The primary objective was to identify the factors contributing to lower rates of COVID-19 vaccination within this population.Data were collected from 585 adults recruited from 20 Niagara and Erie Counties sites using a self-administered survey on vaccine hesitancy, vaccination status, and COVID-19-related characteristics. The survey included the adult Vaccine Hesitancy Scale (aVHS) and acquired information on demographic characteristics and COVID-19 impact, knowledge, and information sources. Data were analyzed using descriptive statistics, a chi-squared test, a Wilcoxon rank-sum test, and a logistic regression model.Findings suggest that unvaccinated participants (n = 35) were concerned about vaccine side effects (48.6%). For vaccinated/unboosted participants (n = 52), they (40.0%) reported clinical concerns. After adjusting for gender and age, healthcare provider guidance and family guidance remained significant predictors of vaccination status, while clinical research studies were significant predictors of booster status. Findings from this study suggest public health interventions that target vaccine education and facilitate well-informed decisions about COVID-19 vaccines lead to less vaccine hesitancy.

Development of performance and learning rate evaluation models in robot-assisted surgery using electroencephalography and eye-tracking.

The existing performance evaluation methods in robot-assisted surgery (RAS) are mainly subjective, costly, and affected by shortcomings such as the inconsistency of results and dependency on the raters' opinions. The aim of this study was to develop models for an objective evaluation of performance and rate of learning RAS skills while practicing surgical simulator tasks. The electroencephalogram (EEG) and eye-tracking data were recorded from 26 subjects while performing Tubes, Suture Sponge, and Dots and Needles tasks. Performance scores were generated by the simulator program. The functional brain networks were extracted using EEG data and coherence analysis. Then these networks, along with community detection analysis, facilitated the extraction of average search information and average temporal flexibility features at 21 Brodmann areas (BA) and four band frequencies. Twelve eye-tracking features were extracted and used to develop linear random intercept models for performance evaluation and multivariate linear regression models for the evaluation of the learning rate. Results showed that subject-wise standardization of features improved the R2 of the models. Average pupil diameter and rate of saccade were associated with performance in the Tubes task (multivariate analysis; p-value = 0.01 and p-value = 0.04, respectively). Entropy of pupil diameter was associated with performance in Dots and Needles task (multivariate analysis; p-value = 0.01). Average temporal flexibility and search information in several BAs and band frequencies were associated with performance and rate of learning. The models may be used to objectify performance and learning rate evaluation in RAS once validated with a broader sample size and tasks.

Transcriptomic analysis of benign prostatic hyperplasia identifies critical pathways in prostatic overgrowth and 5-alpha reductase inhibitor resistance.

BACKGROUND: The medical therapy of prostatic symptoms (MTOPS) trial randomized men with symptoms of benign prostatic hyperplasia (BPH) and followed response of treatment with a 5α-reductase inhibitor (5ARI), an alpha-adrenergic receptor antagonist (α-blocker), the combination of 5ARI and α-blocker or no medical therapy (none). Medical therapy reduced risk of clinical progression by 66% but the reasons for nonresponse or loss of therapeutic response in some patients remains unresolved. Our previous work showed that prostatic glucocorticoid levels are increased in 5ARI-treated patients and that glucocorticoids can increased branching of prostate epithelia in vitro. To understand the transcriptomic changes associated with 5ARI treatment, we performed bulk RNA sequencing of BPH and control samples from patients who received 5ARI versus those that did not. Deconvolution analysis was performed to estimate cellular composition. Bulk RNA sequencing was also performed on control versus glucocorticoid-treated prostate epithelia in 3D culture to determine underlying transcriptomic changes associated with branching morphogenesis. METHOD: Surgical BPH (S-BPH) tissue was defined as benign prostatic tissue collected from the transition zone (TZ) of patients who failed medical therapy while control tissue termed Incidental BPH (I-BPH) was obtained from the TZ of men undergoing radical prostatectomy for low-volume/grade prostatic adenocarcinoma confined to the peripheral zone. S-BPH patients were divided into four subgroups: men on no medical therapy (none: n = 7), α-blocker alone (n = 10), 5ARI alone (n = 6) or combination therapy (α-blocker and 5ARI: n = 7). Control I-BPH tissue was from men on no medical therapy (none: n = 8) or on α-blocker (n = 6). A human prostatic cell line in 3D culture that buds and branches was used to identify genes involved in early prostatic growth. Snap-frozen prostatic tissue taken at the time of surgery and 3D organoids were used for RNA-seq analysis. Bulk RNAseq data were deconvoluted using CIBERSORTx. Differentially expressed genes (DEG) that were statistically significant among S-BPH, I-BPH, and during budding and branching of organoids were used for pathway analysis. RESULTS: Transcriptomic analysis between S-BPH (n = 30) and I-BPH (n = 14) using a twofold cutoff (p < 0.05) identified 377 DEG (termed BPH377) and a cutoff < 0.05 identified 3377 DEG (termed BPH3377). Within the S-BPH, the subgroups none and α-blocker were compared to patients on 5ARI to reveal 361 DEG (termed 5ARI361) that were significantly changed. Deconvolution analysis of bulk RNA seq data with a human prostate single cell data set demonstrated increased levels of mast cells, NK cells, interstitial fibroblasts, and prostate luminal cells in S-BPH versus I-BPH. Glucocorticoid (GC)-induced budding and branching of benign prostatic cells in 3D culture was compared to control organoids to identify early events in prostatic morphogenesis. GC induced 369 DEG (termed GC359) in 3D culture. STRING analysis divided the large datasets into 20-80 genes centered around a hub. In general, biological processes induced in BPH supported growth and differentiation such as chromatin modification and DNA repair, transcription, cytoskeleton, mitochondrial electron transport, ubiquitination, protein folding, and cholesterol synthesis. Identified signaling pathways were pooled to create a list of DEG that fell into seven hubs/clusters. The hub gene centrality was used to name the network including AP-1, interleukin (IL)-6, NOTCH1 and NOTCH3, NEO1, IL-13, and HDAC/KDM. All hubs showed connections to inflammation, chromatin structure, and development. The same approach was applied to 5ARI361 giving multiple networks, but the EGF and sonic hedgehog (SHH) hub was of particular interest as a developmental pathway. The BPH3377, 5ARI363, and GC359 lists were compared and 67 significantly changed DEG were identified. Common genes to the 3D culture included an IL-6 hub that connected to genes identified in BPH hubs that defined AP1, IL-6, NOTCH, NEO1, IL-13, and HDAC/KDM. CONCLUSIONS: Reduction analysis of BPH and 3D organoid culture uncovered networks previously identified in prostatic development as being reinitiated in BPH. Identification of these pathways provides insight into the failure of medical therapy for BPH and new therapeutic targets for BPH/LUTS.

The impact of marital status on tumor aggressiveness, treatment, and screening among black and white men diagnosed with prostate cancer.

PURPOSE: To examine the association of marital status with prostate cancer outcomes in a racially-diverse cohort. METHODS: The study population consisted of men (1010 Black; 1070 White) with incident prostate cancer from the baseline North Carolina-Louisiana Prostate Cancer (PCaP) cohort. Marital status at time of diagnosis and screening history were determined by self-report. The binary measure of marital status was defined as married (including living as married) vs. not married (never married, divorced/separated, or widowed). High-aggressive tumors were defined using a composite measure of PSA, Gleason Score, and stage. Definitive treatment was defined as receipt of radical prostatectomy or radiation. Multivariable logistic regression was used to examine the association of marital status with (1) high-aggressive tumors, (2) receipt of definitive treatment, and (3) screening history among Black and White men with prostate cancer. RESULTS: Black men were less likely to be married than White men (68.1% vs. 83.6%). Not being married (vs. married) was associated with increased odds of high-aggressive tumors in the overall study population (adjusted Odds Ratio (aOR): 1.56; 95% Confidence Interval (CI): 1.20-2.02) and both Black and White men in race-stratified analyses. Unmarried men were less likely to receive definitive treatment in the overall study population (aOR: 0.68; 95% CI: 0.54-0.85). In race-stratified analyses, unmarried Black men were less likely to receive definitive treatment. Both unmarried Black and White men were less likely to have a history of prostate cancer screening than married men. CONCLUSION: Lower rates of marriage among Black men might signal decreased support for treatment decision-making, symptom management, and caregiver support which could potentially contribute to prostate cancer disparities.

Surgical skill level classification model development using EEG and eye-gaze data and machine learning algorithms.

The aim of this study was to develop machine learning classification models using electroencephalogram (EEG) and eye-gaze features to predict the level of surgical expertise in robot-assisted surgery (RAS). EEG and eye-gaze data were recorded from 11 participants who performed cystectomy, hysterectomy, and nephrectomy using the da Vinci robot. Skill level was evaluated by an expert RAS surgeon using the modified Global Evaluative Assessment of Robotic Skills (GEARS) tool, and data from three subtasks were extracted to classify skill levels using three classification models-multinomial logistic regression (MLR), random forest (RF), and gradient boosting (GB). The GB algorithm was used with a combination of EEG and eye-gaze data to classify skill levels, and differences between the models were tested using two-sample t tests. The GB model using EEG features showed the best performance for blunt dissection (83% accuracy), retraction (85% accuracy), and burn dissection (81% accuracy). The combination of EEG and eye-gaze features using the GB algorithm improved the accuracy of skill level classification to 88% for blunt dissection, 93% for retraction, and 86% for burn dissection. The implementation of objective skill classification models in clinical settings may enhance the RAS surgical training process by providing objective feedback about performance to surgeons and their teachers.

Developing surgical skill level classification model using visual metrics and a gradient boosting algorithm.

Objective: Assessment of surgical skills is crucial for improving training standards and ensuring the quality of primary care. This study aimed to develop a gradient boosting classification model (GBM) to classify surgical expertise into inexperienced, competent, and experienced levels in robot-assisted surgery (RAS) using visual metrics. Methods: Eye gaze data were recorded from 11 participants performing four subtasks; blunt dissection, retraction, cold dissection, and hot dissection using live pigs and the da Vinci robot. Eye gaze data were used to extract the visual metrics. One expert RAS surgeon evaluated each participant's performance and expertise level using the modified Global Evaluative Assessment of Robotic Skills (GEARS) assessment tool. The extracted visual metrics were used to classify surgical skill levels and to evaluate individual GEARS metrics. Analysis of Variance (ANOVA) was used to test the differences for each feature across skill levels. Results: Classification accuracies for blunt dissection, retraction, cold dissection, and burn dissection were 95%, 96%, 96%, and 96%, respectively. The time to complete only the retraction was significantly different among the 3 skill levels (p-value = 0.04). Performance was significantly different for 3 categories of surgical skill level for all subtasks (p-values<0.01). The extracted visual metrics were strongly associated with GEARS metrics (R2>0.7 for GEARS metrics evaluation models). Conclusions: Machine learning (ML) algorithms trained by visual metrics of RAS surgeons can classify surgical skill levels and evaluate GEARS measures. The time to complete a surgical subtask may not be considered a stand-alone factor for skill level assessment.

Impact of an NCCN-Compliant Multidisciplinary Conference on Treatment Decisions for Localized Prostate Cancer.

BACKGROUND: We sought to investigate the impact of an NCCN-compliant multidisciplinary conference on treatment decisions of patients with localized prostate cancer. METHODS: A retrospective review of our quality assurance localized prostate cancer database was performed. All patients with localized prostate cancer who sought a second opinion at Roswell Park Comprehensive Cancer Center between 2009 and 2019 were presented to the multidisciplinary Localized Prostate Cancer Conference (LPCC) that includes urologists, radiation oncologists, pathologists, and patient advocates. Multivariable regression models were fit to evaluate variables associated with concordance between community recommendations, LPCC recommendations, and treatment received by patients. RESULTS: A total of 1,164 patients were identified, of whom 26% had NCCN very low-/low-risk, 27% had favorable intermediate-risk, 25% had unfavorable intermediate-risk, and 22% had high-/very high-risk prostate cancer. Pathology changed in 11% of patients after genitourinary pathologist review, which caused disease reclassification in 9%. Concordance between community and LPCC recommendations occurred in 78%, with lowest concordance for androgen deprivation therapy (21%) and radiotherapy (53%). Concordance between community recommendations and treatment received occurred in 65%, with lowest concordance for androgen deprivation therapy and radiotherapy; among those who were recommended radiotherapy as the only option by their community urologist, only 26% received it. Concordance between LPCC recommendations and treatment received occurred in 92%. CONCLUSIONS: Community recommendations differed from the multidisciplinary NCCN-compliant recommendations in 22% of patients, primarily for radiotherapy. Multidisciplinary recommendations matched the treatment received in 92% of patients compared with 65% for community recommendations.

Interactions of SNPs in Folate Metabolism Related Genes on Prostate Cancer Aggressiveness in European Americans and African Americans.

BACKGROUND: Studies showed that folate and related single nucleotide polymorphisms (SNPs) could predict prostate cancer (PCa) risk. However, little is known about the interactions of folate-related SNPs associated with PCa aggressiveness. The study's objective is to evaluate SNP-SNP interactions among the DHFR 19-bp polymorphism and 10 SNPs in folate metabolism and the one-carbon metabolism pathway associated with PCa aggressiveness. METHODS: We evaluated 1294 PCa patients, including 690 European Americans (EAs) and 604 African Americans (AAs). Both individual SNP effects and pairwise SNP-SNP interactions were analyzed. RESULTS: None of the 11 individual polymorphisms were significant for EAs and AAs. Three SNP-SNP interaction pairs can predict PCa aggressiveness with a medium to large effect size. For the EA PCa patients, the interaction between rs1801133 (MTHFR) and rs2236225 (MTHFD1), and rs1801131 (MTHFR) and rs7587117 (SLC4A5) were significantly associated with aggressive PCa. For the AA PCa patients, the interaction of DHFR-19bp polymorphism and rs4652 (LGALS3) was significantly associated with aggressive PCa. CONCLUSIONS: These SNP-SNP interactions in the folate metabolism-related genes have a larger impact than SNP individual effects on tumor aggressiveness for EA and AA PCa patients. These findings can provide valuable information for potential biological mechanisms of PCa aggressiveness.

Prostate cancer aggressiveness and financial toxicity among prostate cancer patients.

INTRODUCTION: Financial toxicity (FT) is a growing concern among cancer survivors that adversely affects the quality of life and survival. Individuals diagnosed with aggressive cancers are often at a greater risk of experiencing FT. The objectives of this study were to estimate FT among prostate cancer (PCa) survivors after 10-15 years of diagnosis, assess the relationship between PCa aggressiveness at diagnosis and FT, and examine whether current cancer treatment status mediates the relationship between PCa aggressiveness and FT. METHODS: PCa patients enrolled in the North Carolina-Louisiana Prostate Cancer Project (PCaP) were recontacted for long-term follow-up. The prevalence of FT in the PCaP cohort was estimated. FT was estimated using the COmprehensive Score for Financial Toxicity, a validated measure of FT. The direct effect of PCa aggressiveness and an indirect effect through current cancer treatment on FT was examined using causal mediation analysis. RESULTS: More than one-third of PCa patients reported experiencing FT. PCa aggressiveness was significantly independently associated with high FT; high aggressive PCa at diagnosis had more than twice the risk of experiencing FT than those with low or intermediate aggressive PCa (adjusted odds ratio [aOR] = 2.13, 95% CI = 1.14-3.96). The proportion of the effect of PCa aggressiveness on FT, mediated by treatment status, was 10%, however, the adjusted odds ratio did not indicate significant evidence of mediation by treatment status (aOR = 1.05, 95% CI = 0.95-1.20). CONCLUSIONS: Aggressive PCa was associated with high FT. Future studies should collect more information about the characteristics of men with high FT and identify additional risk factors of FT.

Active Surveillance in Prostate Cancer: Current and Potentially Emerging Biomarkers for Patient Selection Criteria.

BACKGROUND: Prostate cancer (PCa) represents one of the most frequent malignancies and the fifth leading cause of cancer death in adult men worldwide. PCa mortality rates have been declining in several Western countries; one of the possible reasons may be related to the application of prostate-specific antigen early detection policies. These early detection protocols increase PCa-specific patient survival; however, a high percentage of these cases corresponds to low-risk PCa that grows very slowly and is unlikely to metastasize to threaten survival. Many low-risk PCa patients receive aggressive therapies, such as radical prostatectomy and radiotherapy, that are costly for patients and/or health systems and generate side effects that affect the quality of life. An alternative to surgery and radiotherapy treatments for low-risk PCa is active surveillance (AS), a strategy based on close disease monitoring and intervention only if the disease progresses. However, proper identification of low-risk PCa patients at the time of diagnosis is essential for the effectiveness AS. The selection of AS candidates remains challenging; thus, effective prognostic biomarkers are needed. SUMMARY: This review article addresses the characteristics of the current and emerging PCa prognostic biomarkers, including tests available for tissue, blood, and urine analyses, for the appropriate selection of PCa patients for AS. In addition, and based on published literature, we performed a selection of potential new biomarkers that can distinguish low-risk PCa. KEY MESSAGES: The literature search yielded four tissue-based tests, two blood-based tests, and six urine-based tests that can be used to determine PCa risk classification. However, most available tests are expensive; thus, cost-effective analyses are needed in order to obtain the approval of government agencies and to be financed by the health systems. Available prognostic urine tests have shown great progress over the last years, and they have the advantage of being minimally invasive; therefore, they may become a routine disease progression test for patients under AS. In addition, new research conducted in the last decade has shown promising biomarkers, including mRNA, miRNA, long noncoding RNA, and metabolites, that could improve existing tests or allow the development of new tools for AS patient selection.

Using health insurance claims data to assess long-term disease progression in a prostate cancer cohort.

BACKGROUND: Long-term population-based cohort studies of men diagnosed with prostate cancer are limited. However, adverse outcomes can occur many years after treatment. Herein, we aim to assess the utility of using claims data to identify prostate cancer progression 10-15 years after diagnosis. METHODS: The study population was derived from the North Carolina-Louisiana Prostate Cancer Project (PCaP). PCaP-North Carolina (NC) included 1031 men diagnosed with prostate cancer from 2004 to 2009. An initial follow-up with a survey and manual medical record abstraction occurred from 2008 to 2011 (Follow-up 1). Herein, we extended this follow-up with linkage to healthcare claims data from North Carolina (2011-2017) and a second, supplementary 10-year follow-up survey (2018-2020) (Follow-up 2). Vital statistics data also were utilized. Long-term oncological progression was determined using these data sources in combination with expert clinical input. RESULTS: Among the 1031 baseline PCaP-NC participants, 652 were linked to medical claims. Forty-two percent of the men had insurance coverage for the entire 72 months of follow-up. In addition, 275 baseline participants completed the supplementary 10-year follow-up survey. Using all sources of follow-up data, we identified a progression event in 259 of 1031 (25%) men with more than 10 years of follow-up data after diagnosis. CONCLUSIONS: Understanding long-term clinical outcomes is essential for improving the lives of prostate cancer survivors. However, access and utility of long-term clinical outcomes with claims alone remain a challenge due to individualized agreements required with each insurer for data access, lack of detailed clinical information, and gaps in insurance coverage. We were able to utilize claims data to determine long-term progression due to several unique advantages that included the availability of detailed baseline clinical characteristics and treatments, detailed manually abstracted clinical data at 5 years of follow-up, vital statistics data, and a supplementary 10-year follow-up survey.

Glucocorticoids are induced while dihydrotestosterone levels are suppressed in 5-alpha reductase inhibitor treated human benign prostate hyperplasia patients.

BACKGROUND: The development of benign prostatic hyperplasia (BPH) and medication-refractory lower urinary tract symptoms (LUTS) remain poorly understood. This study attempted to characterize the pathways associated with failure of medical therapy for BPH/LUTS. METHODS: Transitional zone tissue levels of cholesterol and steroids were measured in patients who failed medical therapy for BPH/LUTS and controls. Prostatic gene expression was measured using qPCR and BPH cells were used in organoid culture to study prostatic branching. RESULTS: BPH patients on 5-α-reductase inhibitor (5ARI) showed low levels of tissue dihydrotestosterone (DHT), increased levels of steroid 5-α-reductase type II (SRD5A2), and diminished levels of androgen receptor (AR) target genes, prostate-specific antigen (PSA), and transmembrane serine protease 2 (TMPRSS2). 5ARI raised prostatic tissue levels of glucocorticoids (GC), whereas alpha-adrenergic receptor antagonists (α-blockers) did not. Nuclear localization of GR in prostatic epithelium and stroma appeared in all patient samples. Treatment of four BPH organoid cell lines with dexamethasone, a synthetic GC, resulted in budding and branching. CONCLUSIONS: After failure of medical therapy for BPH/LUTS, 5ARI therapy continued to inhibit androgenesis but a 5ARI-induced pathway increased tissue levels of GC not seen in patients on α-blockers. GC stimulation of organoids indicated that the GC receptors are a trigger for controlling growth of prostate glands. A 5ARI-induced pathway revealed GC activation can serve as a master regulator of prostatic branching and growth.

Diet and Health-related Quality of Life Among Men on Active Surveillance for Early-stage Prostate Cancer: The Men's Eating and Living Study (Cancer and Leukemia Group 70807 [Alliance]).

BACKGROUND: Health-related quality of life (HRQoL) among patients with localized prostate cancer (PC) on active surveillance (AS) and whether it may be improved through lifestyle-focused interventions remain underdefined. OBJECTIVE: To assess longitudinal changes in HRQoL in patients who received and those who did not receive a behavioral intervention that increased vegetable intake. DESIGN, SETTING, AND PARTICIPANTS: A secondary analysis of participants in the Men's Eating and Living (MEAL) study (Cancer and Leukemia Group 70807 [Alliance]), a randomized trial of vegetable consumption in patients on AS, was conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patient-reported outcomes (PROs) included the Memorial Anxiety Scale for Prostate Cancer (MAX-PC), the Expanded Prostate Cancer Index Composite 26 (EPIC-26), and the Functional Assessment of Cancer Therapy Scale-Prostate (FACT-P). Areas under the curves (AUCs) were used to summarize serial HRQoL. RESULTS AND LIMITATIONS: PROs were completed in 87% (n = 387) of the intention-to-collect population. Baseline characteristics of patients completing HRQoL measures did not differ significantly from the entire study population or between groups. Baseline scores were high for all PROs and remained stable over 24 mo, with no significant differences from baseline at any time point. In adjusted analyses, there were no significant differences in summary AUC measures comparing control with intervention for the total MAX-PC score (p = 0.173); EPIC-26 domains of urinary incontinence (p = 0.210), urinary obstruction (p = 0.062), bowel health (p = 0.607), sexual health (p = 0.398), and vitality (p = 0.363); and total FACT-P scores (p = 0.471). CONCLUSIONS: Among men with localized PC on AS enrolled in a randomized trial, HRQoL was high across multiple domains at baseline, remained high during follow-up, and did not change in response to a behavioral intervention that increased vegetable intake. PATIENT SUMMARY: Patients with localized prostate cancer enrolled on active surveillance experience minimal cancer-associated anxiety, suffer low levels of cancer-associated symptoms, and perceive high physical and emotional well-being.

Prediction of Incontinence after Robot-Assisted Radical Prostatectomy: Development and Validation of a 24-Month Incontinence Nomogram.

Incontinence after robot-assisted radical prostatectomy (RARP) is feared by most patients with prostate cancer. Many risk factors for incontinence after RARP are known, but a paucity of data integrates them. Prospectively acquired data from 680 men who underwent RARP January 2008-December 2015 and met inclusion/exclusion criteria were queried retrospectively and then divided into model development (80%) and validation (20%) cohorts. The UCLA-PCI-Short Form-v2 Urinary Function questionnaire was used to categorize perfect continence (0 pads), social continence (1-2 pads), or incontinence (≥3 pads). The observed incontinence rates were 26% at 6 months, 7% at 12 months, and 3% at 24 months. Logistic regression was used for model development, with variables identified using a backward selection process. Variables found predictive included age, race, body mass index, and preoperative erectile function. Internal validation and calibration were performed using standard bootstrap methodology. Calibration plots and receiver operating curves were used to evaluate model performance. The initial model had 6-, 12-, and 24-month areas under the curves (AUCs) of 0.64, 0.66, and 0.80, respectively. The recalibrated model had 6-, 12-, and 24-month AUCs of 0.52, 0.52, and 0.76, respectively. The final model was superior to any single clinical variable for predicting the risk of incontinence after RARP.

Deconstructing, Addressing, and Eliminating Racial and Ethnic Inequities in Prostate Cancer Care.

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.

Recreational and occupational physical activity in relation to prostate cancer aggressiveness: the North Carolina-Louisiana Prostate Cancer Project (PCaP).

PURPOSE: To examine associations between recreational and occupational physical activity and prostate cancer aggressiveness in a population-based, case-only, incident prostate cancer study. METHODS: Data were analyzed from the cross-sectional North Carolina-Louisiana Prostate Cancer Project of African-American (n = 1,023) and European-American (n = 1,079) men newly diagnosed with prostate cancer (CaP). High-aggressive CaP was defined as Gleason sum ≥ 8, or prostate-specific antigen > 20 ng/ml, or Gleason sum ≥ 7 and clinical stage T3-T4. Metabolic equivalent tasks (MET) were estimated from self-reported recreational physical activity in the year prior to diagnosis assessed retrospectively via a validated questionnaire and from occupational physical activity based on job titles. Associations between physical activity variables and high-aggressive prostate cancer were estimated using logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for multiple confounders. RESULTS: There was suggestive evidence that walking for 75-150 min/week for exercise is associated with lower odds of high-aggressive prostate cancer compared to no walking (OR = 0.69, 95% CI 0.47-1.01). Physical activity at the current job was associated with 24% lower odds of high-aggressive prostate cancer (highest vs. lowest tertile OR = 0.76, 95% CI 0.56-1.04). However, total MET-h/week of recreational physical activity and accumulation of high-level physical activity at the longest-held job were not associated with high-aggressive prostate cancer. Results did not vary by race. CONCLUSIONS: The odds of high-aggressive prostate cancer were lower among men who walk for exercise and those engaged in occupations with high activity levels.

Neighborhood deprivation and risk of mortality among men with prostate cancer: Findings from a long-term follow-up study.

BACKGROUND: The overall survival rate of prostate cancer (PCa) has improved over the past decades. However, huge socioeconomic and racial disparities in overall and prostate cancer-specific mortality exist. The neighborhood-level factors including socioeconomic disadvantage and lack of access to care may contribute to disparities in cancer mortality. This study examines the impact of neighborhood deprivation on mortality among PCa survivors. METHODS: North Carolina-Louisiana Prostate Cancer Project (PCaP) data were used. A total of 2113 men, 1046 AA and 1067 EA, with PCa were included in the analysis. Neighborhood deprivation was measured by the Area Deprivation Index (ADI) at the census block group level using data from the US Census Bureau. Quintiles of ADI were created. Cox proportional hazards and competing risk models with mixed effects were performed to estimate the effect of neighborhood deprivation on all-cause and PCa-specific mortality adjusted for age, race, study site, insurance status, and comorbidities. RESULTS: Participants living in the most deprived neighborhoods had an increased risk for all-cause mortality (quintiles 4 + 5: adjusted hazard ratio [aHR] = 1.51, 95% confidence interval [CI] = 1.16-1.96) compared to those in the least deprived (quintile 1) neighborhoods. The risk of prostate cancer-specific mortality was also higher among those living in the deprived neighborhoods (quintiles 4 + 5: aHR = 1.90, 95% CI = 1.10-3.50) than those in the least deprived neighborhood. CONCLUSIONS: The findings suggest neighborhood-level resources or health interventions are essential to improve survival among men with PCa. Additional research should focus on the mechanisms of how the neighborhood environment affects mortality.

5-Alpha reductase inhibitors induce a prostate luminal to club cell transition in human benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a progressive expansion of peri-urethral prostate tissue common in aging men. Patients with enlarged prostates are treated with 5-alpha reductase inhibitors (5ARIs) to shrink prostate volume by blocking the conversion of testosterone to dihydrotestosterone (DHT). A reduction in DHT levels can elicit atrophy and apoptosis of prostate secretory luminal cells, which results in a favorable clinical response characterized by improved lower urinary tract symptoms. However, the histologic response to 5ARI treatment is often heterogeneous across prostate acini and lower urinary tract symptoms can persist to require surgical intervention. We used two spatial profiling approaches to characterize gene expression changes across histologically normal and atrophied regions in prostates from 5ARI-treated men. Objective transcriptomic profiling using the Visium spatial gene expression platform showed that 5ARI-induced atrophy of prostate luminal cells correlated with reduced androgen receptor signaling and increased expression of urethral club cell genes including LTF, PIGR, OLFM4, SCGB1A1, and SCGB3A1. Prostate luminal cells within atrophied acini adapted to decreased DHT conditions by increasing NF-κB signaling and anti-apoptotic BCL2 expression, which may explain their survival. Using GeoMx digital spatial profiling with a probe set to assess ~18 000 RNA targets, we confirmed that atrophied acini expressing SCGB3A1 displayed higher levels of club cell markers compared with histologically normal acini with NKX3-1 expression. In addition, club-like cells within regions of 5ARI-induced atrophy closely resembled true club cells from the prostatic urethra. A comparison of histologically normal regions from 5ARI-treated men and histologically normal regions from untreated men revealed few transcriptional differences. Taken together, our results describe a heterogeneous response to 5ARI treatment where cells in atrophied acini undergo an adaptation from a prostate secretory luminal to a club cell-like state in response to 5ARI treatment. © 2021 The Pathological Society of Great Britain and Ireland.

Cholesterol-Lowering Intervention Decreases mTOR Complex 2 Signaling and Enhances Antitumor Immunity.

PURPOSE: There is a need for strategies to prevent prostate cancer. Cholesterol-lowering interventions are employed widely and safely to reduce risk of cardiovascular disease and has been proposed for chemoprevention. Using preclinical models and a window-of-opportunity clinical trial, we describe an adaptive antitumor immunity resulting from cholesterol lowering. EXPERIMENTAL DESIGN: Statins do not reliably lower serum cholesterol in mice. Therefore, oral ezetimibe was administered to mice to lower serum cholesterol to clinically relevant levels and evaluated the final adaptive immune response. T-lymphocytes-specific mTORC2 knockout mice were used to evaluate mTOR signaling and antitumor immunity. Pretreatment and posttreatment prostate tumors and lymphocytes were examined from a window-of-opportunity clinical trial where men with prostate cancer were treated with 2 to 6 weeks of aggressive cholesterol-lowering intervention prior to radical prostatectomy. RESULTS: Mice treated with oral ezetimibe exhibited enhanced antitumor immunity against syngeneic cancers in a CD8+ lymphocyte-dependent manner, produced immunity that was transferrable through lymphocytes, and had enhanced central CD8+ T-cell memory. In mice and in patients undergoing prostatectomy, lowering serum cholesterol inhibited mTORC2 signaling in lymphocytes and increased infiltration of CD8+ lymphocytes into prostate tumors. T-lymphocyte-specific mTORC2 knockout mice demonstrated enhanced CD8+ lymphocyte function and antitumor capacity. In patients, cholesterol-lowering intervention prior to prostatectomy decreased the proliferation of normal prostate and low-grade adenocarcinomas. CONCLUSIONS: Lowering serum cholesterol decreased signaling through mTORC2 and enhanced antitumor CD8+ T-cell memory. We provide a rationale for large-scale clinical testing of cholesterol lowering strategies for prostate cancer chemoprevention.

Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24.

BACKGROUND: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. MATERIALS AND METHODS: Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. RESULTS: CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings. CONCLUSION: We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.