Maternal adverse childhood experiences (ACEs) and offspring imprinted gene DMR methylation at birth.

Adverse childhood experiences (ACEs) contribute to numerous negative health outcomes across the life course and across generations. Here, we extend prior work by examining the association of maternal ACEs, and their interaction with financial stress and discrimination, with methylation status within eight differentially methylated regions (DMRs) in imprinted domains in newborns. ACEs, financial stress during pregnancy, and experience of discrimination were self-reported among 232 pregnant women. DNA methylation was assessed at PEG10/SGCE, NNAT, IGF2, H19, PLAGL1, PEG3, MEG3-IG, and DLK1/MEG3 regulatory sequences using pyrosequencing. Using multivariable linear regression models, we found evidence to suggest that financial stress was associated with hypermethylation of MEG3-IG in non-Hispanic White newborns; discrimination was associated with hypermethylation of IGF2 and NNAT in Hispanic newborns, and with hypomethylation of PEG3 in non-Hispanic Black newborns. We also found evidence that maternal ACEs interacted with discrimination to predict offspring PLAGL1 altered DMR methylation, in addition to interactions between maternal ACEs score and discrimination predicting H19 and SGCE/PEG10 altered methylation in non-Hispanic White newborns. However, these interactions were not statistically significant after multiple testing corrections. Findings from this study suggest that maternal ACEs, discrimination, and financial stress are associated with newborn aberrant methylation in imprinted gene regions.

AHRR Hypomethylation mediates the association between maternal smoking and metabolic profiles in children.

BACKGROUND: Tobacco smoking during pregnancy is associated with metabolic dysfunction in children, but mechanistic insights remain limited. Hypomethylation of cg05575921 in the aryl hydrocarbon receptor repressor (AHRR) gene is associated with in utero tobacco smoke exposure. In this study, we evaluated whether AHRR hypomethylation mediates the association between maternal smoking and metabolic dysfunction in children. METHODS: We assessed metabolic dysfunction using liver fat content (LFC), serum, and clinical data in children aged 7-12 years (n=78) followed since birth. Maternal smoking was self-reported at 12 weeks gestation. Methylation was measured by means of pyrosequencing at 3 sequential CpG sites, including cg05575921, at birth and at ages 7-12. Regression models were used to evaluate whether AHRR methylation mediated the association between maternal smoking and child metabolic dysfunction. RESULTS: Average AHRR methylation at birth was significantly higher among children of nonsmoking mothers compared with children of mothers who smoked (69.8% ± 4.4% vs. 63.5% ± 5.5, p=0.0006). AHRR hypomethylation at birth was associated with higher liver fat content (p=0.01), triglycerides (p=0.01), and alanine aminotransferase levels (p=0.03), and lower HDL cholesterol (p=0.01) in childhood. AHRR hypomethylation significantly mediated associations between maternal smoking and liver fat content (indirect effect=0.213, p=0.018), triglycerides (indirect effect=0.297, p=0.044), and HDL cholesterol (indirect effect = -0.413, p=0.007). AHRR methylation in childhood (n=78) was no longer significantly associated with prenatal smoke exposure or child metabolic parameters (p>0.05). CONCLUSIONS: AHRR hypomethylation significantly mediates the association between prenatal tobacco smoke exposure and features of childhood metabolic dysfunction, despite the lack of persistent hypomethylation of AHRR into childhood. Further studies are needed to replicate these findings and to explore their causal and long-term significance.

Are associations between obesity and prostate cancer outcomes following radical prostatectomy the same in smokers and non-smokers? Results from the SEARCH Cohort.

PURPOSE: Obesity and smoking have been associated with poor prostate cancer (PC) outcomes. We investigated associations between obesity and biochemical recurrence (BCR), metastasis, castrate resistant-PC (CRPC), PC-specific mortality (PCSM), and all-cause mortality (ACM) and examined if smoking modified these associations. METHODS: We analyzed SEARCH Cohort data from men undergoing RP between 1990 and 2020. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between body mass index (BMI) as a continuous variable and weight status classifications (normal: 18.5 ≤ 25 kg/m2; overweight: 25-29.9 kg/m2; obese: ≥ 30 kg/m2) and PC outcomes. RESULTS: Among 6,241 men, 1,326 (21%) were normal weight, 2,756 (44%) overweight and 2159 (35%) obese; 1,841 (30%) were never-smokers, 2,768 (44%) former and 1,632 (26%) current-smokers. Among all men, obesity was associated with non-significant increased risk of PCSM, adj-HR = 1.71; 0.98-2.98, P = 0.057, while overweight and obesity were inversely associated with ACM, adj-HR = 0.75; 0.66-0.84, P < 0.001 and adj-HR = 0.86; 0.75-0.99, P = 0.033, respectively. Other associations were null. BCR and ACM were stratified for smoking status given evidence for interactions (P = 0.048 and P = 0.054, respectively). Among current-smokers, overweight was associated with an increase in BCR (adj-HR = 1.30; 1.07-1.60, P = 0.011) and a decrease in ACM (adj-HR = 0.70; 0.58-0.84, P < 0.001). Among never-smokers, BMI (continuous) was associated with an increase in ACM (adj-HR = 1.03; 1.00-1.06, P = 0.033). CONCLUSIONS: While our results are consistent with obesity as a risk factor for PCSM, we present evidence of effect modification by smoking for BCR and ACM highlighting the importance of stratifying by smoking status to better understand associations with body weight.

Time from biopsy to radical prostatectomy by race in an equal-access healthcare system: Results from the SEARCH cohort.

BACKGROUND: We previously showed that within an equal-access health system, race was not associated with the time between prostate cancer (PC) diagnosis and radical prostatectomy (RP). However, in the more recent time-period of the study (2003-2007), Black men had significantly longer times to RP. We sought to revisit the question in a larger study population with more contemporary patients. We hypothesized that time from diagnosis to treatment would not differ by race, even after accounting for active surveillance (AS) and the exclusion of men at very low to low risk of PC progression. METHODS: We analyzed data from 5885 men undergoing RP from 1988 to 2017 at eight Veterans Affairs Hospitals from SEARCH. Multiple linear regression was used to compare time from biopsy to RP and to examine the risk of delays (>90 and >180 days) between races. In sensitivity analyses we excluded men deemed to have initially chosen AS based on having >365 days from biopsy to RP and men at very low to low PC risk for progression according to National Comprehensive Cancer Network Clinical Practice Guidelines. RESULTS: At biopsy, Black men (n = 1959) were younger, had lower body mass index, and higher prostate specific antigen levels, (all p < 0.02), compared to White men (n = 3926). Time from biopsy to RP was longer in Black men (mean days: 98 vs. 92; adjusted ratio of mean number of days, 1.07 [95% confidence interval: 1.03-1.11], p < 0.001); however, there were no differences in delays >90 or >180 days after adjusting for confounders (all p ≥ 0.286). Results were similar following the exclusion of men potentially under on AS and at very low and low risk. CONCLUSIONS: In an equal-access healthcare system, we did not find evidence of clinically relevant differences in time from biopsy to RP in Black versus White men.

Prostate-Specific Antigen Screening in Transgender Patients.

CONTEXT: Approximately 0.4-1.3% of the worldwide population is transgender. Although the exact prevalence is unknown, there is an increase in open identification as transgender. Among transgender women (TW), the prostate is retained even after gender-affirmation surgery, thus necessitating ongoing screening for prostate cancer (CaP). However, little is known about CaP screening in this population. OBJECTIVE: To assess our current understanding of CaP incidence and prostate-specific antigen (PSA) screening in TW. EVIDENCE ACQUISITION: We performed a nonsystematic narrative review of all PubMed publications through June 2022 according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. Given the limited primary research on this subject, case reports were also included. Studies were reviewed to understand PSA screening practices and reports of CaP in this population, as applicable. EVIDENCE SYNTHESIS: There is no consensus regarding PSA screening in TW from any of the major societies, and TW are largely absent from guidelines. Case report data suggest that TW with CaP may have more aggressive disease, and these cancers may have been pre-existing prior to present before gender-affirming hormone therapy (GAHT) or be castrate-resistant. CONCLUSIONS: We are in the infancy of our understanding of PSA screening in TW. Important avenues for future research include understanding the risks/benefits of PSA screening in TW, how best to mitigate potential negative psychological effects of PSA screening in TW, establishing baseline PSA values for those on GAHT (and determining what values should be considered "elevated"), establishing when to initiate PSA screening for those on GAHT, and establishing the accuracy of biomarkers for those undergoing GAHT. PATIENT SUMMARY: We examined patterns of prostate cancer screening for transgender women. Little is known about prostate cancer incidence or screening in this population. Additional research is needed to establish guidelines for screening in this population.

Metabolic syndrome is associated with aggressive prostate cancer regardless of race.

PURPOSE: Recent meta-analyses suggest the Metabolic Syndrome (MS) increases high-grade prostate cancer (PC), although studies are inconsistent and few black men were included. We investigated MS and PC diagnosis in black and white men undergoing prostate biopsy in an equal access healthcare system. We hypothesized MS would be linked with aggressive PC, regardless of race. METHODS: Among men undergoing prostate biopsy at the Durham Veterans Affairs Hospital, medical record data abstraction of diagnosis or treatment for hypertension (≥ 130/85 mmHg), dyslipidemia (HDL < 40 mg/dL), hypertriglyceridemia (≥ 150 mg/dL), diabetes, hyperglycemia (fasting glucose ≥ 100 ml/dL), and central obesity (waist circumference ≥ 40 inches) were done. Biopsy grade group (GG) was categorized as low (GG1) or high (GG2-5). Multinomial logistic regression was used to examine MS (3-5 components) vs. no MS (0-2 components) and diagnosis of high grade and low grade vs. no PC, adjusting for potential confounders. Interactions between race and MS were also tested. RESULTS: Of 1,051 men (57% black), 532 (51%) had MS. Men with MS were older, more likely to be non-black, and had a larger prostate volume (all p ≤ 0.011). On multivariable analysis, MS was associated with high-grade PC (OR = 1.73, 95% CI 1.21-2.48, p = 0.003), but not overall PC (OR = 1.17, 95% CI 0.88-1.57, p = 0.29) or low grade (OR = 0.87, 95% CI 0.62-1.21, p = 0.39). Results were similar in black and non-black men (all p-interactions > 0.25). CONCLUSION: Our data suggest that metabolic dysregulation advances an aggressive PC diagnosis in both black and non-black men. If confirmed, prevention of MS could reduce the risk of developing aggressive PC, including black men at higher risk of PC mortality.

Racial disparities in liver cancer: Evidence for a role of environmental contaminants and the epigenome.

Liver cancer incidence has tripled since the early 1980s, making this disease one of the fastest rising types of cancer and the third leading cause of cancer-related deaths worldwide. In the US, incidence varies by geographic location and race, with the highest incidence in the southwestern and southeastern states and among racial minorities such as Hispanic and Black individuals. Prognosis is also poorer among these populations. The observed ethnic disparities do not fully reflect differences in the prevalence of risk factors, e.g., for cirrhosis that may progress to liver cancer or from genetic predisposition. Likely substantial contributors to risk are environmental factors, including chemical and non-chemical stressors; yet, the paucity of mechanistic insights impedes prevention efforts. Here, we review the current literature and evaluate challenges to reducing liver cancer disparities. We also discuss the hypothesis that epigenetic mediators may provide biomarkers for early detection to support interventions that reduce disparities.

Racial differences in circulating mitochondria-derived peptides may contribute to prostate cancer health disparities.

INTRODUCTION: The mitochondrial genome has small open reading frames (sORF) which produce measurable mitochondrial-derived peptides (MDPs), including humanin, SHLP2, and MOTS-c. Previously, among men undergoing prostate biopsy, we found higher serum SHLP2 was linked with lower prostate cancer (PC) risk in European American men (EAM), while null associations were found in African American men (AAM). Here, in different patients undergoing prostate biopsy, we tested the link between SHLP2, humanin and MOTS-c and PC risk by race. METHODS: Plasma SHLP2, humanin, and MOTS-c were measured in 198 men (50/49 EAM/AAM cases; 50/49 EAM/AAM controls) undergoing biopsy. Logistic and multinomial regression models tested associations between each MDP and PC diagnosis, low-grade (grade group, GG1) and high-grade (GG2-5). Models were adjusted for age, body mass index, digital rectal examination, and prostate specific antigen (PSA). We tested interactions between MDPs and race. RESULTS: Among controls, humanin was similar by race (p = 0.60), but both SHLP2 (p = 0.007) and MOTS-c (p = 0.026) were lower in AAM controls versus EAM controls. Among EAM, higher MDP values were associated with lower PC risk (all p ≤ 0.001), with null associations in AAM (all p-interactions ≤ 0.01). Similarly, higher MDP expression was associated with decreased risk of low- and high-grade PC in EAM (all p ≤ 0.005) with null associations in AAM. CONCLUSIONS: Higher MDP levels were associated with lower PC risk in EAM but not AAM. Generally, AAM controls had lower MDP levels. These data support MDPs and mitochondrial dysfunction in PC, suggesting greater dysfunction in AAM may contribute to excess PC risk. Future larger studies are needed to confirm these results.

Extended Human Papillomavirus Genotyping to Predict Progression to High-Grade Cervical Precancer: A Prospective Cohort Study in the Southeastern United States.

BACKGROUND: High-risk human papillomavirus (hrHPV) testing is utilized in primary cervical cancer screening, generally along with cytology, to triage abnormalities to colposcopy. Most screening-based hrHPV testing involves pooled detection of any hrHPV or of HPV16/18. Cervical neoplasia progression risks based on extended hrHPV genotyping-particularly non-16/18 hrHPV types-are not well characterized. HPV genotype-specific incidence of high-grade cervical intraepithelial neoplasia or more severe (CIN2+) following an abnormal screening result was examined. METHODS: We assessed a US-based prospective, multiracial, clinical cohort of 343 colposcopy patients with normal histology (n = 226) or CIN1 (n = 117). Baseline cervical samples underwent HPV DNA genotyping, and participants were followed up to 5 years. Genotype-specific CIN2+ incidence rates (IR) were estimated with accelerated failure time models. Five-year CIN2+ risks were estimated nonparametrically for hierarchical hrHPV risk groups (HPV16; else HPV18/45; else HPV31/33/35/52/58; else HPV39/51/56/59/68). RESULTS: At enrollment, median participant age was 30.1 years; most (63%) were hrHPV-positive. Over follow-up, 24 participants progressed to CIN2+ (7.0%). CIN2+ IR among hrHPV-positive participants was 3.4/1,000 person-months. CIN2+ IRs were highest for HPV16 (8.3), HPV33 (7.8), and HPV58 (4.9). Five-year CIN2+ risk was higher for HPV16 (0.34) compared with HPV18/45 (0.12), HPV31/33/35/52/58 (0.12), and HPV39/51/56/59/68 (0.16) (P = 0.05). CONCLUSIONS: Non-16/18 hrHPV types are associated with differential CIN2+ progression rates. HPV16, 33, and 58 exhibited the highest rates over 5 years. HPV risk groups warrant further investigation in diverse US populations. IMPACT: These novel data assessing extended HPV genotyping in a diverse clinical cohort can inform future directions to improve screening practices in the general population.

Radium-223 Utilization Patterns and Outcomes in Clinical Practice.

INTRODUCTION: Radium-223 was approved for metastatic castration-resistant prostate cancer based on the ALSYMPCA trial. We characterize radium-223 treatment patterns and overall survival (OS) in a large equal access health system. METHODS: We identified all men within the Veterans Affairs (VA) Healthcare System who received radium-223 between January 2013 and September 2017. Patients were followed until death or last followup. We abstracted all treatments received prior to radium; no treatments after radium were abstracted. Our primary aim was understanding practice patterns, and secondary outcome was the association between treatment pattern and OS measured using Cox models. RESULTS: We identified 318 bone metastatic castration-resistant prostate cancer patients who received radium-223 within the VA Healthcare System. Of these patients 277 (87%) died during followup. The 5 predominant treatment patterns that encompassed 88% of patients (279/318) were 1) androgen receptor-targeted agent (ARTA)-radium, 2) docetaxel-ARTA-radium, 3) ARTA-docetaxel-radium, 4) docetaxel-ARTA-cabazitaxel-radium and 5) radium alone. Median OS was 11 months (95% CI 9.7-12.5). Men who received ARTA-docetaxel-radium had the worst survival. All other treatments had similar outcomes. Only 42% of patients completed the full 6 injections; 25% received only 1 or 2 injections. CONCLUSIONS: We identified the most common radium-223 treatment patterns and their association with OS within the VA population. The better survival in ALSYMPCA (14.9 months) vs our study (11 months) along with 58% of patients not receiving the full radium-223 course suggests radium is being used later in the disease course in the real world in a more heterogeneous population.

Association between PEG3 DNA methylation and high-grade cervical intraepithelial neoplasia.

BACKGROUND: Epigenetic mechanisms are hypothesized to contribute substantially to the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer, although empirical data are limited. METHODS: Women (n = 419) were enrolled at colposcopic evaluation at Duke Medical Center in Durham, North Carolina. Human papillomavirus (HPV) was genotyped by HPV linear array and CIN grade was ascertained by biopsy pathologic review. DNA methylation was measured at differentially methylated regions (DMRs) regulating genomic imprinting of the IGF2/H19, IGF2AS, MESTIT1/MEST, MEG3, PLAGL1/HYMAI, KvDMR and PEG10, PEG3 imprinted domains, using Sequenom-EpiTYPER assays. Logistic regression models were used to evaluate the associations between HPV infection, DMR methylation and CIN risk overall and by race. RESULTS: Of the 419 participants, 20 had CIN3+, 52 had CIN2, and 347 had ≤ CIN1 (CIN1 and negative histology). The median participant age was 28.6 (IQR:11.6) and 40% were African American. Overall, we found no statistically significant association between altered methylation in selected DMRs and CIN2+ compared to ≤CIN1. Similarly, there was no significant association between DMR methylation and CIN3+ compared to ≤CIN2. Restricting the outcome to CIN2+ cases that were HR-HPV positive and p16 staining positive, we found a significant association with PEG3 DMR methylation (OR: 1.56 95% CI: 1.03-2.36). CONCLUSIONS: While the small number of high-grade CIN cases limit inferences, our findings suggest an association between altered DNA methylation at regulatory regions of PEG3 and high grade CIN in high-risk HPV positive cases.

Safety of concomitant therapy with radium-223 and abiraterone or enzalutamide in a real-world population.

BACKGROUND: Real-world utilization and outcomes of combination therapy for men with metastatic castrate-resistant prostate cancer (mCRPC) are largely unknown. We evaluated the overall survival (OS) and skeletal-related events (SREs) among men who received radium-223 with or without concomitant abiraterone or enzalutamide in the Veterans Affairs (VA) Health System. METHODS: We reviewed charts of all mCRPC patients who received radium-223 in the VA from January 2013 to September 2017. We used Cox models to test the association between concomitant therapy versus radium-223 alone on OS and SRE. Sensitivity analyses were performed for concomitant use of denosumab/bisphosphonates. RESULTS: Three hundred and eighteen patients treated with radium-223 were identified; 116/318 (37%) received concomitant abiraterone/enzalutamide. Two hundred and seventy-seven (87%) patients died during follow-up. Patients who received concomitant therapy were younger at radium-223 initiation (median age 68 vs. 70, p = .027) and had a longer follow-up (median 29.5 vs. 17.9 months, p = .030). There was no OS benefit for those on concomitant therapy (hazard ratio [HR]: 0.87, 95% confidence interval [CI]: 0.67-1.12, p = .28). There was a trend for an increased SRE risk for patients on concomitant therapy (HR: 1.87, 95% CI: 0.96-3.61, p = .066), but this was not significant. When analyses were limited to men using bone heath agents, similar results were seen for OS (HR: 0.86, 95% CI 0.64-1.15, p = .30) and SRE (HR: 2.36, 95% CI: 0.94-5.94, p = .068). CONCLUSIONS: Despite the common use of concomitant therapy in this real-world study, there was no difference in OS among mCRPC patients. A nonsignificant increased SRE risk was observed. Further work needs to evaluate the optimal sequence, timing, and safety of combination therapies.

Monocyte counts and prostate cancer outcomes in white and black men: results from the SEARCH database.

PURPOSE: Circulating inflammatory markers may predict prostate cancer (PC) outcomes. For example, a recent study showed that higher peripheral blood monocyte counts were associated with aggressive PC in Asian men undergoing radical prostatectomy (RP). Herein, we investigated whether peripheral monocyte count can predict long-term PC outcomes after RP in black and white men. METHODS: We retrospectively reviewed data on 2345 men undergoing RP from 2000 to 2017 at eight Veterans Affairs hospitals. Data on monocyte count within 6 and 12 months prior to surgery were collected. The study outcomes were biochemical recurrence (BCR), castration-resistant PC (CRPC), metastasis, all-cause mortality (ACM), and PC-specific morality (PCSM). Cox-proportional hazard models were used to assess the associations between pre-operative monocyte count and the above-mentioned outcomes accounting for confounders. RESULTS: Of 2345 RP patients, 972 (41%) were black and 1373 (59%) were white men. In multivariable analyses, we found no associations between monocyte count and BCR among all men (HR: 1.36, 95%CI 0.90-2.07) or when analyses were stratified by race (HR: 1.30, 95%CI 0.69-2.46, in black men; HR:1.33, 95%CI 0.76-02.33, in white men). Likewise, no overall or race-specific associations were found between monocyte count and CRPC, metastases, ACM, and PCSM, all p ≥ 0.15. Results were similar for monocyte count measured at 12 months prior to RP. CONCLUSION: In black and white PC patients undergoing RP, peripheral monocyte count was not associated with long-term PC outcomes. Contrary to what was found in Asian populations, monocyte count was not associated with PC outcomes in this study.

Asian Race and Risk of Prostate Cancer: Results from the REDUCE Study.

BACKGROUND: Global prostate cancer incidence rates are lower in Asian men than Caucasian men. Whether this is the result of less screening in Asian men remains to be determined. We examined whether Asian race was associated with prostate cancer diagnosis in the Reduction by Dutasteride of Cancer Events (REDUCE) study. METHODS: REDUCE was a 4-year, multicenter, randomized trial of dutasteride versus placebo for prostate cancer prevention among men who underwent prostate-specific antigen (PSA)-independent biopsies at 2 and 4 years. Eligible men were ages 50 to 75 years, had PSA between 2.5 and 10 ng/mL, and a negative prestudy prostate biopsy. We tested the association between Asian and Caucasian race and prostate cancer diagnosis using logistic regression. RESULTS: Of 8,122 men in REDUCE, 5,755 (71%) were Caucasian and 105 (1.8%) were Asian. Asians had lower body mass index (24.8 vs. 26.9 kg/m2, P < 0.001), had smaller prostate volume (35.0 vs. 43.5 cc, P < 0.001), and were less likely to have abnormal digital rectal exams (P = 0.048), but were similar in baseline age, PSA, family history of prostate cancer, and smoking status compared with Caucasian men (all P ≥ 0.164). Asian men were equally likely to receive any on-study biopsy compared with Caucasian men (P = 0.634). After adjusting for potential confounders, Asian men were less likely to be diagnosed with prostate cancer during the 4-year study (OR = 0.49; 95% confidence interval, 0.28-0.88; P = 0.016), compared with Caucasian men. CONCLUSIONS: In REDUCE, where all men underwent biopsies largely independent of PSA, Asian race was associated with lower prostate cancer diagnosis. IMPACT: These findings suggest that lower prostate cancer risk in Asian men may be due to biological, genetic, and/or lifestyle factors.

Obesity, race, and long-term prostate cancer outcomes.

BACKGROUND: The authors previously found that obesity was linked with prostate cancer (PC)-specific mortality (PCSM) among men who underwent radical prostatectomy (RP). Herein, in a larger RP cohort, the authors investigated whether the association between obesity and long-term PC outcomes, including PCSM, differed by race. METHODS: Data from 5929 patients who underwent RP and were in the Shared Equal Access Regional Cancer Hospital (SEARCH) database were analyzed. Prior to RP, body mass index (BMI) was measured and recorded in the medical records. BMI was categorized as normal weight (<25 kg/m2 ), overweight (25-29.9 kg/m2 ), and obese (≥30 kg/m2 ). The authors assessed the association between BMI and biochemical disease recurrence (BCR), castration-resistant prostate cancer (CRPC), metastasis, and PCSM, accounting for confounders. RESULTS: Of the 5929 patients, 1983 (33%) were black, 1321 (22%) were of normal weight, 2605 (44%) were overweight, and 2003 (34%) were obese. Compared with white men, black men were younger; had higher prostate-specific antigen levels; and were more likely to have a BMI ≥30 kg/m2 , seminal vesicle invasion, and positive surgical margins (all P ≤ .032). During a median follow-up of 7.4 years, a total of 1891 patients (32%) developed BCR, 181 patients (3%) developed CRPC, 259 patients (4%) had metastasis, and 135 patients (2%) had died of PC. On multivariable analysis, obesity was found to be associated with an increased risk of PCSM (hazard ratio, 1.78; 95% confidence interval, 1.04-3.04 [P = .035]). No interaction was found between BMI and race in predicting PCSM (P ≥ .88), BCR (P ≥ .81), CRPC (P ≥ .88), or metastasis (P ≥ .60). Neither overweight nor obesity was associated with risk of BCR, CRPC, or metastasis (all P ≥ .18). CONCLUSIONS: Obese men undergoing RP at several Veterans Affairs hospitals were found to be at an increased risk of PCSM, regardless of race.

Soluble Endoglin (sCD105) as a Novel Biomarker for Detecting Aggressive Prostate Cancer.

BACKGROUND/AIM: We have previously found elevated levels of endoglin (CD105) in the prostate cancer (PC) tissue of men with poor prognosis, compared to men with indolent disease. Herein, we examined whether plasma levels of the soluble form of CD105 (sCD105) differ according to the PC grade at diagnosis. PATIENTS AND METHODS: We measured sCD105 in 73 subjects with biopsy-confirmed PC at the Durham, North Carolina, Veteran Affairs Health System. The association between sCD105 and intermediate/high-grade PC risk [Gleason Group (GG) 2-5 vs. 1] was examined using regression models. RESULTS: Of 73 men, 27 had low-grade PC and 46 high-grade PC. Higher GG was linked to lower sCD105 (GG1: 6938 pg/ml, GG2-3: 6150 pg/ml, GG4-5: 5554 pg/ml; p=0.012). On multivariable analysis, lower sCD105 was associated with increased high-grade PC risk (ORper 1000 units=1.33, p=0.028). CONCLUSION: Lower sCD105 levels were associated with intermediate and high-risk PC. Further investigation is warranted in a larger PC cohort.

Validation of a genomic classifier for prediction of metastasis and prostate cancer-specific mortality in African-American men following radical prostatectomy in an equal access healthcare setting.

BACKGROUND: The Decipher 22-gene genomic classifier (GC) may help in post-radical prostatectomy (RP) decision making given its superior prognostic performance over clinicopathologic variables alone. However, most studies evaluating the GC have had a modest representation of African-American men (AAM). We evaluated the GC within a large Veteran Affairs cohort and compared its performance to CAPRA-S for predicting outcomes in AAM and non-AAM after RP. METHODS: GC scores were generated for 548 prostate cancer (PC) patients, who underwent RP at the Durham Veteran Affairs Medical Center between 1989 and 2016. This was a clinically high-risk cohort and was selected to have either pT3a, positive margins, seminal vesicle invasion, or received post-RP radiotherapy. Multivariable Cox models and survival C-indices were used to compare the performance of GC and CAPRA-S for predicting the risk of metastasis and PC-specific mortality (PCSM). RESULTS: Median follow-up was 9 years, during which 37 developed metastasis and 20 died from PC. Overall, 55% (n = 301) of patients were AAM. In multivariable analyses, GC (high vs. intermediate and intermediate vs. low) was a significant predictor of metastasis in all men (all p < 0.001). Consistent with prior studies, relative to CAPRA-S, GC had a higher C-index for 5-year metastasis (0.78 vs. 0.72) and 10-year PCSM (0.85 vs. 0.81). There was a suggestion GC was a stronger predictor in AAM than non-AAM. Specifically, the 5-year metastasis risk C-index was 0.86 in AAM vs. 0.69 in non-AAM and the 10-year PCSM risk C-index was 0.91 in AAM vs. 0.78 in non-AAM. However, the test for interaction of race and the performance of the GC in the Cox model was not significant for either metastasis or PCSM (both p ≥ 0.3). CONCLUSIONS: GC was a very strong predictor of poor outcome and performed well in both AAM and non-AAM. Our data support the use of GC for risk stratification in AAM post-RP. While our data suggest that GC may actually work better in AAM, given the limited number of events, further validation is needed.

Racial Discrepancies in Overall Survival among Men Treated with 223Radium.

PURPOSE: Several recent studies on metastatic castration resistant prostate cancer demonstrated improved overall survival in black vs white men. 223Radium is Food and Drug Administration approved for metastatic castration resistant prostate cancer based on a survival benefit in the ALSYMPCA (A Phase III Study of Radium-223 Dichloride in Patients with Symptomatic Hormone Refractory Prostate Cancer with Skeletal Metastases) trial, in which 94% of participants were white. We identified a real world population of patients with metastatic castration resistant prostate cancer who received 223radium to compare differences in baseline characteristics and outcomes in black vs nonblack men. MATERIALS AND METHODS: We reviewed the charts of all men who received 223radium in the entire Veterans Affairs system. We compared treatment patterns and baseline characteristics between black and nonblack men. We used Cox models to analyze predictors of time from 223radium start to overall survival and time to skeletal related events. RESULTS: We identified 318 patients treated with 223radium, including 87 (27%) who were black. Median followup after 223radium initiation was 25.3 months (IQR 13.8-37.1). Black men were younger than nonblack men when starting 223radium (median age 67 vs 70 years, p <0.001) and they had higher prostate specific antigen (median 159.9 vs 90.2 ng/ml, p=0.014) and alkaline phosphatase (median 163 vs 135 IU/l, p=0.017). A greater proportion of black men received docetaxel prior to 223radium (77% vs 55%, p <0.001). On multivariable analysis black race was associated with a decreased risk of mortality from the time of 223radium initiation (HR 0.75, 95% CI 0.57-0.99, p=0.045). CONCLUSIONS: Black men had longer overall survival than nonblack men, although they appeared to receive radium later in the disease course. Further studies are required to verify our findings and explore biological differences between black and nonblack men with metastatic castration resistant prostate cancer.

Natural killer cell activity and prostate cancer risk in veteran men undergoing prostate biopsy.

BACKGROUND: A previous pilot study found that men with a positive prostate biopsy had low numbers of circulating natural killer (NK) cells, compared to biopsy negative men. METHODS: To confirm these data, we analyzed differences in NK cells from 94 men undergoing prostate biopsy to determine whether NK cells could predict for a positive biopsy. NK cells activity (NKA) was measured by an in vitro diagnostic system, with a pre-defined cut-off value for NKA at 200 pg/mL. Logistic regression and receiver operator characteristics (Area Under the Curve (AUC)) analyses were used to test the diagnostic value of NKA. RESULTS: The NKA test performance showed specificity of 88%, positive predictive value of 84%, sensitivity of 34%, and a negative predictive value of 41%. Among the 94 men analyzed, NKA was not significantly linked with age, race, digital rectal examination (DRE), prostate volume, PSA or biopsy grade group (all P ≥ 0.14). In multivariable logistic regression analysis, the odds ratio (OR) of low NKA (<200 pg/mL) for the detection of PC was 4.89, 95%CI 1.34-17.8, with a ROC area under the curve of 0.79 in all participants and increasing to 0.83 and 0.85 for the detection of PC and high-grade PC, respectively, among men with a normal DRE. CONCLUSIONS: Men with a low NKA value had five-times higher odds of PC at biopsy. The implementation of this NKA assay in the clinic together with PSA may help to advise patients with the highest risk of PC whether, or not, to undergo a prostate biopsy.