Characterization of the Biological Variability of the Angiome Biomarkers over Time in Healthy Subjects.

BACKGROUND: Biomarker analyses are an integral part of cancer research. Despite the intense efforts to identify and characterize biomarkers in cancer patients, little is known regarding the natural variation of biomarkers in healthy populations. Here we conducted a clinical study to evaluate the natural variability of biomarkers over time in healthy participants. METHODS: The angiome multiplex array, a panel of 25 circulating protein biomarkers, was assessed in 28 healthy participants across 8 timepoints over the span of 60 days. We utilized the intraclass correlation coefficient (ICC) to quantify the reliability of the biomarkers. Adjusted ICC values were calculated under the framework of a linear mixed-effects model, taking into consideration age, sex, body mass index (BMI), fasting status, and sampling factors. RESULTS: ICC was calculated to determine the reliability of each biomarker. HGF was the most stable marker (ICC=0.973), while PDGF-BB was the most variable marker (ICC=0.167). In total, ICC analyses revealed that 22 out of 25 measured biomarkers display good (≥0.4) to excellent (>0.75) ICC values. Three markers (PDGF-BB, TGF-1, PDGF-AA) had ICC values <0.4. Greater age was associated with higher IL-6 (p=0.0114). Higher BMI was associated with higher levels of IL-6 (p=0.0003) and VEGF-R3 (p=0.0045). CONCLUSIONS: Of the 25 protein biomarkers measured over this short time period, 22 markers were found to have good or excellent ICC values, providing additional validation for this biomarker assay. IMPACT: This data further supports the validation of the angiome biomarker assay and its application as an integrated biomarker in clinical trial testing.

Select black men are potential candidates for prostate hemi-ablation based on radical prostatectomy histopathology for intermediate-risk prostate cancer-a multicenter SEARCH cohort study.

IMPORTANCE AND OBJECTIVE: Partial gland ablation (PGA) is increasingly popular as a treatment for men with intermediate-risk prostate cancer (IR-PCa) to preserve functional outcomes while controlling their cancer. We aimed to determine the impact of race and clinical characteristics on the risk of upstaging (≥pT2c) and having adverse pathological outcomes including seminal vesicle invasion (SVI), extra prostatic extension (EPE) and lymph node invasion (LNI) at radical prostatectomy (RP) among men with IR disease eligible for PGA with hemi-ablation (HA). DESIGN: Retrospective analysis. SETTING: Multicenter. PARTICIPANTS AND MEASURES: We studied patients diagnosed with unilateral IR-PCa treated with RP between 1988 and 2020 at 9 different Veterans Affairs hospitals within the SEARCH cohort. We analyzed differences in clinicopathological characteristics and outcome variables (odds of ≥pT2c and SVI, EPE and LNI) by race using multivariable logistic regression after adjusting for covariates. RESULTS: Among 3127 patients, 33% were African American (AA) men with unilateral IR-PCa undergoing RP. Compared to non-AA men, AA individuals were younger (61 vs. 65 years, p < 0.001), presented with a higher prostate specific antigen (PSA) category (≥10 ng/ml; 34 vs. 26%, p < 0.001), and had a lower clinical stage (p < 0.001). Among the 2,798 (89.5%) with ≥pT2c stage, AA men exhibited higher ≥ pT2c rates (93 vs. 89%, p < 0.001), primarily due to increased pT2c staging (64 vs. 57%), where upstaging beyond pT2 was lower than non-AA men (29 vs. 32%). On multivariable analysis, AA men were found to have higher odds of ≥pT2c (odds ratio [OR]: 1.39 CI, 1.02-1.88, p = 0.04), lower odds of EPE (OR: 0.73 CI, 0.58-0.91, p < 0.01) and no statistically significant associations with LNI (OR: 0.79 CI, 0.42-1.46, p = 0.45) and SVI (OR: 1 CI, 0.74-1.35, p = 0.99) compared to non-AA men. On multivariable analysis, clinical features associated with higher odds of ≥pT2c were pre-operative PSA ≥ 15 (OR = 2.07, P = 0.01) and higher number of positive cores (HPC) on biopsy (OR = 1.36, P < 0.001). Similarly, PSA ≥ 15, Gleason grade ≥3 and HPC on biopsy were associated with higher odds of SVI, EPE and LNI, respectively. CONCLUSIONS: In men with IR-PCa undergoing RP, AA men demonstrated an overall higher likelihood of ≥pT2c with lower upstaging beyond pT2, lower likelihood of EPE and no significant difference in likelihood of SVI and LNI compared to non-AA men. These findings support select AA men to be potential candidates for PGA, such as HA. Clinical factors are predictive of higher pathological stage and adverse pathological outcomes at RP and could be considered when selecting candidates for PGA.

Primary Care Use and 90-Day Mortality Among Older Adults Undergoing Cancer Surgery.

Importance: Multimorbidity and postoperative clinical decompensation are common among older surgical patients with cancer, highlighting the importance of primary care to optimize survival. Little is known about the association between primary care use and survivorship among older adults (aged ≥65 years) undergoing cancer surgery. Objective: To examine primary care use among older surgical patients with cancer and its association with mortality. Design, Setting, and Participants: In this retrospective cohort study, data were abstracted from the electronic health record of a single health care system for older adults undergoing cancer surgery between January 1, 2017, and December 31, 2019. There were 3 tiers of stratification: (1) patients who had a primary care practitioner (PCP) (physician, nurse practitioner, or physician assistant) vs no PCP, (2) those who had a PCP and underwent surgery in the same health system (unfragmented care) vs not (fragmented care), and (3) those who had a primary care visit within 90 postoperative days vs not. Data were analyzed between August 2023 and January 2024. Exposure: Primary care use after surgery for colorectal, head and neck, prostate, ovarian, pancreatic, breast, liver, renal cell, non-small cell lung, endometrial, gastric, or esophageal cancer. Main Outcomes and Measures: Postoperative 90-day mortality was analyzed using inverse propensity weighted Kaplan-Meier curves, with log-rank tests adjusted for propensity scores. Results: The study included 2566 older adults (mean [SEM] age, 72.9 [0.1] years; 1321 men [51.5%]). Although 2404 patients (93.7%) had health insurance coverage, 743 (28.9%) had no PCP at the time of surgery. Compared with the PCP group, the no-PCP group had a higher 90-day postoperative mortality rate (2.0% vs 3.6%, respectively; adjusted P = .03). For the 823 patients with unfragmented care, 400 (48.6%) had a primary care visit within 90 postoperative days (median time to visit, 34 days; IQR, 20-57 days). Patients who had a postoperative primary care visit were more likely to be older, have a higher comorbidity burden, have an emergency department visit, and be readmitted. However, they had a significantly lower 90-day postoperative mortality rate than those who did not have a primary care visit (0.3% vs 3.3%, respectively; adjusted P = .001). Conclusions and Relevance: These findings suggest that follow-up with primary care within 90 days after cancer surgery is associated with improved survivorship among older adults.

Intensifying Salvage Therapy in Prostate-specific Antigen Recurrent Prostate Cancer After Radical Prostatectomy with Apalutamide, Salvage Radiation, and Docetaxel: The Phase 2 STARTAR Trial.

BACKGROUND AND OBJECTIVE: Androgen deprivation therapy (ADT) with salvage radiation therapy (RT) improves survival for patients with prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP) for prostate cancer (PC), but many patients suffer further relapse. This study aims to determine the benefit of the combination of ADT, apalutamide, salvage RT, and docetaxel for high-risk PSA recurrent PC. METHODS: STARTAR is a multicenter, investigator-initiated phase 2 trial of men with PSA recurrent PC after RP. The key inclusion criteria included M0 by computed tomography/bone scan, Gleason 7 with either T3/positive margin/N1 disease or Gleason 8-10 prostate adenocarcinoma, PSA relapse (0.2-4 ng/ml) <4 yr after RP, and fewer than four positive resected lymph nodes. Patients received ADT with apalutamide for 9 mo, RT starting week 8, and then six cycles of docetaxel. The primary endpoint was 36-mo progression-free survival (PFS) with testosterone recovery and compared against the prior STREAM trial. KEY FINDINGS AND LIMITATIONS: We enrolled 39 men, including those with Gleason 8-10 (46%), pN1 (23%); the median PSA was 0.58 ng/ml. The median follow-up was 37 mo. All patients achieved undetectable PSA nadir. At 24 and 36 mo, PFS rates were 84% and 71%, respectively, which improved significantly over 3-yr 47% historic PFS and 54% enzalutamide/ADT/RT (STREAM) PFS rates (p = 0.004 and p = 0.039, respectively). Common any-grade adverse events included 98% hot flashes, 88% fatigue, 77% alopecia, 53% rash (10% G3), and 5% febrile neutropenia. CONCLUSIONS AND CLINICAL IMPLICATIONS: In this phase 2 trial of ADT, apalutamide, salvage RT, and six cycles of docetaxel for high-risk PSA recurrence, the 3-yr PFS rate improved to 71%, indicating feasible and efficacious treatment intensification, with durable remissions beyond historic data. PATIENT SUMMARY: Prostate cancer recurrence after surgical removal of the tumor occurs often, and current treatment options to limit recurrence after surgery are only partially effective. In this study, we found that the addition of an androgen receptor inhibitor and docetaxel chemotherapy to standard postsurgery radiation therapy and androgen deprivation therapy significantly improved progression-free survival at 3 yr after treatment. These results suggest that intensification of treatment after surgery can provide long-term benefit to a subset of patients with high-risk prostate cancer.

Updated 5-year results for short course abiraterone acetate and LHRH agonist for unfavorable intermediate and favorable high-risk prostate cancer.

Combined androgen deprivation therapy (ADT) and radiotherapy (RT) improves outcomes for intermediate and high-risk prostate cancer. Treatment intensification with abiraterone acetate/prednisone (AAP) provides additional benefit for high-risk disease. We previously reported 3-year outcomes of a single-arm prospective multicenter trial (AbiRT trial) of 33 patients with unfavorable intermediate risk (UIR) and favorable high risk (FHR) prostate cancer undergoing short course, combination therapy with ADT, AAP, and RT. Here we report the final analysis demonstrating a high rate of testosterone recovery (97%) and excellent biochemical progression-free survival (97%) at 5 years. These data support comparative prospective studies of shorter, more potent ADT courses in favorable high-risk prostate cancer.

Pain and Its Association with Survival for Black and White Individuals with Advanced Prostate Cancer in the United States.

Bone pain is a well-known quality-of-life detriment for individuals with prostate cancer and is associated with survival. This study expands previous work into racial differences in multiple patient-reported dimensions of pain and the association between baseline and longitudinal pain and mortality. This is a prospective cohort study of individuals with newly diagnosed advanced prostate cancer enrolled in the International Registry for Men with Advanced Prostate Cancer (IRONMAN) from 2017 to 2023 at U.S. sites. Differences in four pain scores at study enrollment by race were investigated. Cox proportional hazards models and joint longitudinal survival models were fit for each of the scale scores to estimate HRs and 95% confidence intervals (CI) for the association with all-cause mortality. The cohort included 879 individuals (20% self-identifying as Black) enrolled at 38 U.S. sites. Black participants had worse pain at baseline compared with White participants, most notably a higher average pain rating (mean 3.1 vs. 2.2 on a 10-point scale). For each pain scale, higher pain was associated with higher mortality after adjusting for measures of disease burden, particularly for severe bone pain compared with no pain (HR, 2.47; 95% CI: 1.44-4.22). The association between pain and all-cause mortality was stronger for participants with castration-resistant prostate cancer compared with those with metastatic hormone-sensitive prostate cancer and was similar among Black and White participants. Overall, Black participants reported worse pain than White participants, and more severe pain was associated with higher mortality independent of clinical covariates for all pain scales. SIGNIFICANCE: Black participants with advanced prostate cancer reported worse pain than White participants, and more pain was associated with worse survival. More holistic clinical assessments of pain in this population are needed to determine the factors upon which to intervene to improve quality of life and survivorship, particularly for Black individuals.

Are higher follicle-stimulating hormone levels before androgen deprivation therapy for prostate cancer associated with oncological and cardiac outcomes and overall survival?-a population-level analysis.

Background: Androgen deprivation therapy (ADT), commonly delivered via a luteinizing hormone-releasing hormone (LHRH) agonist, is the standard treatment for advanced prostate cancer (PC). While quite effective, it has been associated with an increased risk of major adverse cardiovascular events (MACE). The exact mechanisms are not clear. However, it has been theorized that follicle-stimulating hormone (FSH), a pituitary hormone that is involved in controlling normal testosterone levels, which is decreased with LHRH-agonist therapy, may be the culprit. We performed a retrospective population-level study to test the link of FSH levels on the development of MACE, castrate-resistant PC (CRPC), and death among men starting ADT. Methods: All men (n=1,539) who had an FSH level between 1999 and 2018 within 2 years prior to starting ADT and complete data were identified within the Veterans Affairs (VA) Health System. FSH was dichotomized as low/normal (≤8 IU/mL) and high (>8 IU/mL), using established cut-points. The associations between FSH and time to MACE, death, and CRPC were tested using log-rank tests and multivariable Cox proportional hazards models. Results: Patients with high FSH were older (median 76 vs. 73 years, P<0.001), started ADT earlier (median 2007 vs. 2009, P=0.027), and had lower body mass index (BMI) (median 29.1 vs. 30.1 kg/m2, P=0.004) compared to those with low/normal FSH. On multivariable analysis, there was no association between FSH and time from ADT to MACE, CRPC, or death. Conclusions: In this population-level study of men receiving an FSH test prior to starting ADT, there was no association between FSH levels and time from ADT to MACE, CRPC, or death. Although further studies are needed, these results do not support a link between pre-ADT FSH and long-term oncological or cardiovascular outcomes.

Exposure to Agent Orange and Risk of Bladder Cancer Among US Veterans.

Importance: To date, limited data exist regarding the association between Agent Orange and bladder cancer, and the Institute of Medicine concluded that the association between exposure to Agent Orange and bladder cancer outcomes is an area of needed research. Objective: To examine the association between bladder cancer risk and exposure to Agent Orange among male Vietnam veterans. Design, Setting, and Participants: This nationwide Veterans Affairs (VA) retrospective cohort study assesses the association between exposure to Agent Orange and bladder cancer risk among 2 517 926 male Vietnam veterans treated in the VA Health System nationwide from January 1, 2001, to December 31, 2019. Statistical analysis was performed from December 14, 2021, to May 3, 2023. Exposure: Agent Orange. Main Outcomes and Measures: Veterans exposed to Agent Orange were matched in a 1:3 ratio to unexposed veterans on age, race and ethnicity, military branch, and year of service entry. Risk of bladder cancer was measured by incidence. Aggressiveness of bladder cancer was measured by muscle-invasion status using natural language processing. Results: Among the 2 517 926 male veterans (median age at VA entry, 60.0 years [IQR, 56.0-64.0 years]) who met inclusion criteria, there were 629 907 veterans (25.0%) with Agent Orange exposure and 1 888 019 matched veterans (75.0%) without Agent Orange exposure. Agent Orange exposure was associated with a significantly increased risk of bladder cancer, although the association was very slight (hazard ratio [HR], 1.04; 95% CI, 1.02-1.06). When stratified by median age at VA entry, Agent Orange was not associated with bladder cancer risk among veterans older than the median age but was associated with increased bladder cancer risk among veterans younger than the median age (HR, 1.07; 95% CI, 1.04-1.10). Among veterans with a diagnosis of bladder cancer, Agent Orange was associated with lower odds of muscle-invasive bladder cancer (odds ratio [OR], 0.91; 95% CI, 0.85-0.98). Conclusions and Relevance: In this cohort study among male Vietnam veterans, there was a modestly increased risk of bladder cancer-but not aggressiveness of bladder cancer-among those exposed to Agent Orange. These findings suggest an association between Agent Orange exposure and bladder cancer, although the clinical relevance of this was unclear.

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.

Validation of the prostate cancer comorbidity index in predicting cause-specific mortality in men undergoing radical prostatectomy.

PURPOSE: Accurate prediction of competing risks of mortality remains a key component of prostate cancer treatment decision-making. We sought to validate the Prostate Cancer Comorbidity Index (PCCI) score for predicting other-cause mortality (OCM) and cancer outcomes in men undergoing radical prostatectomy (RP). MATERIALS AND METHODS: We sampled 4857 men with prostate cancer treated with RP in the VA from 2000-2018. Risks of OCM, 90-day all-cause mortality (ACM), prostate cancer-specific mortality, metastasis, and biochemical recurrence by PCCI score were assessed using Cox proportional hazards and logistic regression. We compared prediction of 90-day ACM between PCCI and the American Society of Anesthesiology (ASA) score, a validated predictor of short-term mortality. RESULTS: Over median follow-up of 6.7 years (IQR 3.7-10.3), there was a stepwise increase in risk of OCM with higher PCCI score, with hazards (95%CI) of 1.53 (1.14-2.04), 2.11 (1.55-2.88), 2.36 (1.68-3.31), 3.61 (2.61-4.98), and 4.99 (3.58-6.96) for PCCI 1-2, 3-4, 5-6, 7-9, and 10 + (vs. 0), respectively. Projected 10-year cumulative incidence of OCM was 8%, 12%, 16%, 19%, 26%, and 32% for scores of 0, 1-2, 3-4, 5-6, 7-9, and 10+ , respectively. Men with PCCI 7+ had greater odds of 90-day ACM (OR 3.48, 95%CI 1.26-9.63) while men with higher ASA did not. Higher PCCI score was associated with worse cancer outcomes, with the highest categories driving the associations. CONCLUSIONS: The PCCI is a robust measure of short- and long-term OCM after RP, validated for use in clinical care and health services research focusing on surgical patient populations.

Is time to castration resistant prostate cancer a potential intermediate end-point for time to metastasis among men initiating androgen deprivation therapy for non-metastatic prostate cancer with rapid PSA doubling time (<9 months)?

PURPOSE: Metastasis-free survival (MFS) is a surrogate for overall survival (OS) in men with non-metastatic castration-resistant prostate cancer (CRPC), but this endpoint may take years to develop in men with non-metastatic castrate-sensitive disease. The study objective was to examine whether progression to CRPC is a potential intermediate endpoint for developing metastatic disease in patients with biochemical recurrence (BCR) after radical prostatectomy (RP). MATERIALS AND METHODS: Men with BCR following RP who had PSA doubling times (PSADT) < 9 months and no metastasis at the time of initiating androgen deprivation therapy (ADT) (n = 210) were included. The primary objective was to assess the correlation between CRPC-free survival (CRPC-FS) and MFS, and the secondary objective was to assess the correlation between time to metastasis and time to CRPC. Kendall's Tau was used to test the correlation for the primary and secondary outcomes. RESULTS: The median MFS was 104 months (95% CI: 83-114) and median CRPC-FS was 100 months (95% CI: 80-114). Based on the Kaplan-Meier curve, the greatest difference in time to MFS and CRPC-FS was around 70% free survival, which was reached at 61.2 months for MFS and 49.6 months for CRPC-FS. Kendall's Tau for the correlation between CRPC-FS and MFS and between time to CRPC and time to metastasis was 0.867 (95% CI: 0.765-0.968) and 0.764 (95% CI: 0.644-0.884), respectively. CONCLUSIONS: Given the high correlation between CRPC-FS and MFS, after validation, CRPC-FS may serve as a potential intermediate endpoint in trials for men with BCR initiating ADT following local therapy.

Identification of Patients With Metastatic Prostate Cancer With Natural Language Processing and Machine Learning.

PURPOSE: Understanding treatment patterns and effectiveness for patients with metastatic prostate cancer (mPCa) is dependent on accurate assessment of metastatic status. The objective was to develop a natural language processing (NLP) model for identifying patients with mPCa and evaluate the model's performance against chart-reviewed data and an International Classification of Diseases (ICD) 9/10 code-based method. METHODS: In total, 139,057 radiology reports on 6,211 unique patients from the Department of Veterans Affairs were used. The gold standard was metastases by detailed chart review of radiology reports. NLP performance was assessed by sensitivity, specificity, positive predictive value, negative predictive value, and date of metastases detection. Receiver operating characteristic curves was used to assess model performance. RESULTS: When compared with chart review, the NLP model had high sensitivity and specificity (85% and 96%, respectively). The NLP model was able to predict patient-level metastasis status with a sensitivity of 91% and specificity of 81%, whereas sensitivity and specificity using ICD9/10 billing codes were 73% and 86%, respectively. For the NLP model, date of metastases detection was exactly concordant and within < 1 week in 55% and 58% of patients, compared with 8% and 17%, respectively, using the ICD9/10 billing codes method. The area under the curve for the NLP model was 0.911. A limitation is the NLP model was developed on the basis of a subset of patients with mPCa and may not be generalizable to all patients with mPCa. CONCLUSION: This population-level NLP model for identifying patients with mPCa was more accurate than using ICD9/10 billing codes when compared with chart-reviewed data. Upon further validation, this model may allow for efficient population-level identification of patients with mPCa.

Are higher pre-diagnosis follicle stimulating hormone levels associated with long-term prostate cancer risk?

BACKGROUND: Follicle stimulating hormone (FSH) is a pituitary hormone that helps regulate testosterone homeostasis. Although it is generally accepted that FSH levels increase with LHRH-agonist therapy for prostate cancer (PC), the specific impact of FSH levels on risk of PC diagnosis is largely unknown. The objective of this study was to perform a population-level analysis to assess the association between FSH levels and PC diagnosis. METHODS: All men (n = 386,018) who had a pre-PC diagnosis FSH level and complete data were identified within the Veterans Affairs Health System between 1999 and 2018. The association between FSH level and time from FSH test to PC diagnosis was tested using stratified Cox proportional hazards models. Multivariable models were adjusted for age, year, race, body mass index, and Charlson comorbidity index. Due to nonproportional hazards over time, time to PC was modeled separately: ≤4 years after an FSH test and >4 years following an FSH test. RESULTS: Median age at first FSH level was 64 years (interquartile range [IQR]: 54-72), median year of FSH was 2010 (IQR: 2005-2014), and 70% of the cohort was white. Median follow-up was 76 months (IQR: 38-126) during which 17,519 men (4.5%) were diagnosed with PC. On multivariable analysis, in the first 4 years after FSH test, there was no association between FSH and time to PC diagnosis. Starting from 4 years after FSH test, on multivariable analysis, a higher FSH level was associated with lower risk of PC with continuous modeling, but found no association with log continuous and categorical modeling. CONCLUSIONS: In this population-level study among male veterans receiving an FSH test for an unknown clinical indication, associations between FSH levels and PC risk were inconsistent and likely driven by selection bias and confounding variables. Future studies should consider different study designs.

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.

Change in distress about police brutality and substance use among young people, 2017-2020.

BACKGROUND: It is unknown whether increasing attention to police brutality is a source of stress associated with substance use risk among young people. METHODS: A longitudinal racially/ethnically diverse cohort from Los Angeles, California (n = 1797) completed baseline (2017; mean age: 17.9) and follow-up (2020; mean age: 21.2) surveys assessing level of concern, worry, and stress about police brutality (range: 0 'not at all' - 4 'extremely') and past 30-day nicotine, cannabis, alcohol, other drug, and number of substances used (0-19). Regression models, adjusted for demographic characteristics and baseline substance use, evaluated whether changes in distress about police brutality from 2017 to 2020 were associated with substance use in 2020 overall and stratified by race/ethnicity. RESULTS: Distress about police brutality increased between 2017 (mean: 1.59) and 2020 (mean: 2.43) overall. Black/African American and Hispanic/Latino respondents consistently had the highest mean distress levels at both timepoints. In the full sample, each one-unit greater increase in distress about police brutality from 2017 to 2020 was associated with 11% higher odds of cannabis use, 13% higher odds of alcohol use, and 8% higher risk of using an additional substance for the number of substances used outcome. Race/ethnicity-stratified models indicated that greater increases in distress from 2017 to 2020 was associated with substance use among Black/African American, Hispanic, and multiracial respondents in 2020, but not Asian American/Pacific Islander and White respondents. CONCLUSIONS: Distress about police brutality may be associated with substance use, particularly among certain racial/ethnic minority young people. Further investigation of whether police brutality affects health in disparity populations is needed.

Weight loss via a low-carbohydrate diet improved the intestinal permeability marker, zonulin, in prostate cancer patients.

BACKGROUND: Accumulating evidence suggest that gut microbiota may impact urologic health including prostate cancer (PC), potentially via affecting intestinal permeability (IP). Studies have indicated that disrupted IP may be improved by healthy diets and weight loss. In the Carbohydrate and Prostate Study 2 (CAPS2) clinical trial, which showed that a low-carbohydrate diet (LCD) reduced weight significantly in men with PC and suggestively slowed PC disease progression, we explored the impact of LCD on an IP marker, zonulin and an inflammation marker, high sensitivity C-reactive protein (hsCRP). METHODS: CAPS2 was a 6-month randomized controlled trial testing a LCD intervention vs. control on PC progression using prostate-specific antigen doubling time (PSADT) as the marker. All 45 participants had prior primary PC treatment, PSADT >3 and <36 months, and body mass index (BMI) ≥24 kg/m2. RESULTS: At 6-month, zonulin decreased in the LCD arm (median -8.3%, IQR -16.6, 0.3%) while the control increased slightly (median 1.4%, IQR -3.0, 13.3%; p = .014). No changes were observed in hsCRP. Linear regression models showed that weight change was significantly associated with log(PSADT) such that the greater the weight loss, the longer the PSADT(p = .003). There was a similar inverse trend between change in zonulin and log(PSADT) (p = .050). Nevertheless, the mediation analysis showed that zonulin was not a significant intermediary mechanism of the effect of weight change on PSADT (p = .3). CONCLUSION: Future studies are merited to examine further the potential association of IP with inflammation and to clarify if improvement in IP is associated with decreased PC progression. Trial registration: NCT01763944. KEY MESSAGESGut microbiota may impact urologic health including prostate cancer, potentially via affecting intestinal permeability.Weight loss significantly improved intestinal permeability in prostate cancer patients.Improvement in intestinal permeability was associated with slowed prostate cancer progression as indicated by the PSA doubling time.

Serum metabolomic analysis of men on a low-carbohydrate diet for biochemically recurrent prostate cancer reveals the potential role of ketogenesis to slow tumor growth: a secondary analysis of the CAPS2 diet trial.

BACKGROUND: Systemic treatments for prostate cancer (PC) have significant side effects. Thus, newer alternatives with fewer side effects are urgently needed. Animal and human studies suggest the therapeutic potential of low carbohydrate diet (LCD) for PC. To test this possibility, Carbohydrate and Prostate Study 2 (CAPS2) trial was conducted in PC patients with biochemical recurrence (BCR) after local treatment to determine the effect of a 6-month LCD intervention vs. usual care control on PC growth as measured by PSA doubling time (PSADT). We previously reported the LCD intervention led to significant weight loss, higher HDL, and lower triglycerides and HbA1c with a suggested longer PSADT. However, the metabolic basis of these effects are unknown. METHODS: To identify the potential metabolic basis of effects of LCD on PSADT, serum metabolomic analysis was performed using baseline, month 3, and month 6 banked sera to identify the metabolites significantly altered by LCD and that correlated with varying PSADT. RESULTS: LCD increased the serum levels of ketone bodies, glycine and hydroxyisocaproic acid. Reciprocally, LCD reduced the serum levels of alanine, cytidine, asymmetric dimethylarginine (ADMA) and 2-oxobutanoate. As high ADMA level is shown to inhibit nitric oxide (NO) signaling and contribute to various cardiovascular diseases, the ADMA repression under LCD may contribute to the LCD-associated health benefit. Regression analysis of the PSADT revealed a correlation between longer PSADT with higher level of 2-hydroxybutyric acids, ketone bodies, citrate and malate. Longer PSADT was also associated with LCD reduced nicotinamide, fructose-1, 6-biphosphate (FBP) and 2-oxobutanoate. CONCLUSION: These results suggest a potential association of ketogenesis and TCA metabolites with slower PC growth and conversely glycolysis with faster PC growth. The link of high ketone bodies with longer PSADT supports future studies of ketogenic diets to slow PC growth.

Phase I Study of Lenvatinib and Capecitabine with External Radiation Therapy in Locally Advanced Rectal Adenocarcinoma.

BACKGROUND: Neoadjuvant chemoradiation with fluoropyrimidine followed by surgery and adjuvant chemotherapy has been the standard treatment of locally advanced stages II and III rectal cancer for many years. There is a high risk for disease recurrence; therefore, optimizing chemoradiation strategies remains an unmet need. Based on a few studies, there is evidence of the synergistic effect of VEGF/PDGFR blockade with radiation. METHODS: In this phase I, dose-escalation and dose-expansion study, we studied 3 different dose levels of lenvatinib in combination with capecitabine-based chemoradiation for locally advanced rectal cancer. RESULTS: A total of 20 patients were enrolled, and 19 were eligible for assessment of efficacy. The combination was well tolerated, with an MTD of 24 mg lenvatinib. The downstaging rate for the cohort and the pCR was 84.2% and 37.8%, respectively. Blood-based protein biomarkers TSP-2, VEGF-R3, and VEGF correlated with NAR score and were also differentially expressed between response categories. The NAR, or neoadjuvant rectal score, encompasses cT clinical tumor stage, pT pathological tumor stage, and pN pathological nodal stage and provides a continuous variable for evaluating clinical trial outcomes. CONCLUSION: The combination of lenvatinib with capecitabine and radiation in locally advanced rectal cancer was found to be safe and tolerable, and potential blood-based biomarkers were identified. CLINICAL TRIAL REGISTRATION: NCT02935309.

A phase 2 trial of avelumab in men with aggressive-variant or neuroendocrine prostate cancer.

BACKGROUND: Men with progressive neuroendocrine or aggressive-variant metastatic prostate cancer (NEPC/AVPC) have a poor prognosis and limited treatment options, and immunotherapy has not been tested in such patients. METHODS: We conducted an open label single center phase 2 trial (NCT03179410) of men with progressive NEPC/AVPC either defined by histology or AVPC criteria. Avelumab (10 mg/kg every 2 weeks) was administered until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Secondary endpoints included ORR, radiographic progression-free survival (rPFS), overall survival, and safety. Correlative studies included longitudinal peripheral blood immune phenotyping. The study was limited by the small number of patients enrolled and by the early termination due to COVID-19. RESULTS: A total of 15 men with AVPC/NEPC were enrolled. The median age was 71 (range 51-85 years), and men had received a median of two prior therapies (range 1-3). Median PSA was 54 ng/dl (range 0-393), and 73% of men had liver metastasis. The ORR with avelumab in this setting by iRECIST or RECIST 1.1 was 6.7%, including one patient (6.7%) with a complete remission (CR), 20% with stable disease, and 67% with progressive disease. The patient with the CR had an MSH2 somatic mutation and MSI-high NEPC with central nervous system metastases, and his CR remains durable off all therapy for 2 years. The median rPFS was 1.8 months (95% CI 1.6-3.6 months), and median overall survival was 7.4 months (85% CI 2.8-12.6 months). Safety was consistent with the known profile of avelumab. Phenotyping of peripheral immune subsets suggest enhanced CXCR2-dependent myeloid and T-cell responses in this extraordinary responder. CONCLUSIONS: While the study was terminated early due to slow enrollment at the onset of the COVID-19 pandemic and lower than anticipated objective response rate, PD-L1 inhibition with avelumab monotherapy showed poor efficacy in patients with microsatellite stable NEPC/AVPC. Immune profiling revealed enhanced CXCR2 positive immune cell activation in the one extraordinary responder, suggesting potential mechanisms for further immunotherapy development in this population.

Red Blood Cell Distribution Width Is Associated with All-cause Mortality but Not Adverse Cancer-specific Outcomes in Men with Clinically Localized Prostate Cancer Treated with Radical Prostatectomy: Findings Based on a Multicenter Shared Equal Access Regional Cancer Hospital Registry.

BACKGROUND: Recent reports with a small number of patients showed an association of red blood cell distribution width (RDW) with prostate cancer (PCa) progression. OBJECTIVE: To investigate whether preoperative RDW can serve as a prognostic marker in patients with PCa undergoing radical prostatectomy (RP) in a large, equal access, and diverse patient cohort. DESIGN SETTING AND PARTICIPANTS: Data were retrospectively collected on 4756 men treated with RP at eight Veteran Affairs medical centers within the Shared Equal Access Regional Cancer Hospital (SEARCH) database from 1999 through 2017. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical recurrence (BCR) was the primary outcome, while metastasis, all-cause mortality (ACM), and prostate cancer-specific mortality (PCSM) were secondary outcomes. RESULTS AND LIMITATIONS: The mean (standard deviation) age was 62 yr (6.1), and 1589 (33%) men were black. The median (interquartile range) follow-up was 82 mo (46-127). Preoperative RDW either as a continuous variable or when stratified by quartiles was not associated with BCR. Likewise, preoperative RDW was not associated with metastases or PCSM. However, higher RDW was significantly associated with higher ACM, both as a continuous variable (p < 0.001) and when stratified by quartiles in univariable and multivariable models (p < 0.001). RDW was found to be correlated with D'Amico risk classification of PCa. Study limitations include its retrospective nature and lack of data regarding advanced PCa. CONCLUSIONS: Preoperative RDW was not associated with PCa outcomes in men treated with RP but was associated with ACM. While RDW may be a biomarker of overall health, it is not a biomarker for PCa outcomes. These results emphasize the importance of diverse, larger sized studies in genitourinary cancer research. PATIENT SUMMARY: Prostate cancer includes a wide spectrum of diseases with different genetic, pathological, and oncological behaviors. Red blood cell distribution width is helpful in predicting the overall survival for a localized prostate cancer patient, and hence, it can help inform personalized treatment decisions and operative care.