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In preclinical models of prostate cancer (PC), disulfiram (DSF) reduced tumor growth only when co-administered with copper (Cu), and Cu uptake in tumors is partially regulated by androgen-receptor signaling. However, prior trials of DSF in PC used DSF as monotherapy.To assess the safety and efficacy of concurrent administration of DSF with Cu, we conducted a phase 1b clinical trial of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving Cu with DSF.Patients with mCRPC were treated in two cohorts: mCRPC with nonliver/peritoneal metastases (A), and mCRPC with liver and/or peritoneal metastases (B). Baseline Cu avidity was measured byWe treated nine patients with mCRPC (six on cohort A and three on cohort B). Bone and nodal metastases showed differential and heterogeneous Cu uptake onOral DSF is not an effective treatment for mCRPC due to rapid metabolism into an inactive metabolite, Me-DDC. This trial has stopped enrollment and further work is needed to identify a stable DSF formulation for treatment of mCRPC.

The number of new cases and deaths from prostate cancer (PCa) is highest for Black men compared with other racial and ethnic groups, and Black PCa patients have a shorter average survival as well as a greater risk of tumor recurrence than men of other racial and ethnic groups. However, recent studies have shown that Black PCa patients have a better response to certain therapeutic regimens than White PCa patients. This study focuses on addressing the critical need to determine novel relationships between ancestry-related genetic variation and PCa aggressiveness and response to secondary hormonal therapy in metastatic castration-resistant PCa (mCRPC). We conducted correlative science in a DoD Prostate Cancer Clinical Trials Consortium (PCCTC) prospective multicenter study of secondary hormonal therapy in mCRPC stratified by race, Abi Race. This study enrolled 50 self-reported Black and 50 self-reported White mCRPC patients, and such patients received abiraterone and prednisone until disease progression or adverse event. We performed metabolic profiling using serum samples from fasting patients at baseline and after treatment. In addition, we performed genome-wide genotyping using genomic DNA from whole blood specimens from patients at baseline. We then identified race- and ancestry-related metabolite and SNP variations that associated with outcome using a penalized Cox model approach. In addition, we used Ingenuity Pathway Analysis (IPA) and Lasso Analysis to further study race-related metabolites and SNPs. From these analyses, we identified sphingolipids such as ceramide as race-related metabolites associated with outcome as well as SNPs in Sphingosine Kinase Type 1-Interacting Protein (SKIP) associated with outcome. In addition, our analyses suggest that sphingolipids such as ceramides and SKIP may regulate cancer-related biofunctions differently in Black and White mCRPC patients undergoing abiraterone treatment. Both sphingolipids and SKIP are components of the Sphingosine Rheostat, the regulatory component of sphingolipid cellular metabolism often exploited by various cancers, in which ceramides displays a pro-apoptotic role whereas sphingosine-1-phosphate (S1P) is associated with an anti-apoptotic role and is indirectly regulated by SKIP via regulating the activity of Sphingosine Kinase (SPK1). Evaluation of the function of these sphingolipids and SKIP in PCa cell drug response and aggressiveness are currently underway. These findings are furthering understanding of race- and ancestry-related biological factors that influence response to secondary hormonal therapy in mCRPC and have the potential to impact selection of patients for secondary hormonal therapy and to mitigate PCa disparity. Citation Format: Sean Alan Piwarski, Tyler Allen, Bonnie LaCroix, Lauren Howard, Morgan Paul, Nick Bachelder, Alex Sibley, Steve Patierno, Terry Hyslop, Kouros Owzar, Daniel George, Jennifer Freedman. Race- and ancestry-related metabolites and SNPs associated with response to secondary hormonal therapy in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 984.

85 Background: Patients with advanced prostate cancer (APC) experience high mortality and increasingly deteriorating quality of life due to the disease itself and the therapies they are treated with. Despite recent advances in the treatment landscape, disparities in outcomes have only worsened. There is an urgent need to identify disparities in treatment patterns and outcomes in advanced disease in diverse populations. The International Registry for Men with Advanced Prostate Cancer (IRONMAN) is uniquely equipped to address these needs. Methods: IRONMAN is a prospective registry initiated in 2017 with a planned accrual of 5000 patients with newly diagnosed metastatic hormone-sensitive (mHSPC) and castration-resistant (CRPC) prostate cancer. As of 10/11/2022, 2890 patients have enrolled from 14 countries at 113 sites, with 2 more countries pending activation. Sites were selected to create a diverse cohort across race/ethnicity, geography and socioeconomic factors. Patients are followed for survival, clinically significant adverse events, changes in cancer treatments, biomarkers, and Patient-Reported Outcome Measures (PROMs). This analysis includes patients with treatment data reported from Baseline through Month 3 as of October 2021 (n=1931, 9 countries). Results: Patients were recruited across the USA (N=799), Australia (146), Canada (282), Spain (238), England (205), and all other countries (261). 61% had mHSPC, and 39% had CRPC at enrollment with little variation in these proportions across countries. Based on self-report, 87% of patients were White, 9% Black, 4% reported other races/ethnicities, and 353 did not report race. In the US, 18% of patients were Black. Globally, 22% of respondents reported current or former military service. The most common first systemic therapy on study was androgen receptor signaling inhibitors (ARSI) +/- ADT in 1039 (54%), ranging between 12% and 66% of patients by country. 19% received chemotherapy +/- ADT and 18% received ADT alone. ARSI use varied by age, race, and metastatic disease site. Conclusions: Our preliminary results highlight our ability to successfully enroll and follow APC patients from 113 sites across 14 countries, with 2890 of 5000 planned patients enrolled. Accrual is greater in de novo mHSPC patients than anticipated. Differences in treatment patterns are already emerging, with more ARSI use in the mHSPC setting in North America than other regions. Our data demonstrates that IRONMAN participating sites are rapidly adopting new treatment recommendations into clinical practice of real-world patients.

Background: Domestic violence against women is a serious health and social issue, with victims found across the world. Utilizing the collective help of bystanders has become an increasingly important step toward mitigating abuse. Advertising campaigns have shed light on the seriousness of domestic violence, however, messages promoting bystander intervention are comparatively less. Focus: The primary focus of this exploratory study is to test the ability of public service announcements (PSAs) to inspire behavior change, i.e. to call a helpline. Emotional ad appeals have the potential to motivate apathetic bystanders to intervene, however, their effectiveness can depend on one’s self-view. Using self-construal and congruity theory, the current study examined the impact of self-focused emotional appeals, namely guilt (negative) and hope (positive), on varying levels of self-construals (independent vs. interdependent). Hypotheses: Three key hypotheses were tested: Self-focused emotional appeals using guilt and hope will be more persuasive on an independent self-construal than an interdependent self-construal (H1). Individuals with a low independent self-construal will find a guilt appeal to be more persuasive than a hope appeal (H2a). Individuals with a high independent self-construal will find a hope appeal to be more persuasive than a guilt appeal (H2b). Importance to the Social Marketing Field: Domestic violence in India is an ongoing issue and PSAs have the ability to motivate behavior change. From the perspective of social marketing and strategy, this exploratory study will shed light on which pairing of self-construal and emotions (guilt or hope) in messages can bring about desired pro-social intentions. Method: A single-factor experimental design was implemented with participants ( n = 72) recruited from major metros in India. Results: Findings from a regression analysis revealed that guilt and hope were persuasive only on the independent self-construal. The next step was to explore the impact of guilt and hope within the independent self-construal (low vs. high). A simple slope test revealed that hope (vs. guilt) significantly strengthened the intentions to call the advertised helpline for those with low independent self-construal, while both hope and guilt were found to be equally effective on the high independent self-construal. Recommendations for Research and Practice: The findings add to the growing literature on domestic violence prevention messages by emphasizing the importance of emotional persuasion through cultural congruence. By taking varying levels of independent self-construal into consideration, social marketers can accordingly utilize emotional ad appeals like guilt and hope to help bystanders develop positive intentions to intervene. Limitations: Despite the significant findings, this exploratory study focused on the impact of two emotional ad appeals (guilt and hope) on a small sample of participants from a single country, India.

Purpose A recent meta-analysis suggested a link between Metabolic Syndrome (MS) and high-grade prostate cancer (PC), though few black men were included. We tested the link between MS and PC risk in a population of black and white men undergoing prostate biopsy. We hypothesized MS would be linked with aggressive PC, regardless of race. Methods Among men undergoing prostate biopsy at the Durham Veterans Affairs Hospital, we abstracted history of or treatment for hypertension (≥130/85 mmHg), dyslipidemia (HDL0.25). Conclusion Regardless of race, MS was associated with aggressive PC, but not overall PC risk. If confirmed in other studies, our data suggest that prevention of MS may reduce the risk of developing aggressive PC in both black and non-black men.

BackgroundSystemic 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.MethodsTo 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.ResultsLCD 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.ConclusionThese 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.

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.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.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.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.

Acquired resistance to EGFR inhibitors in metastatic colorectal cancer (mCRC) remains a hurdle for effective treatment. MET amplification has been indicated as a driver of acquired resistance. Clinical activity has been demonstrated for the combination of EGFR and MET inhibitors in mCRC. But the impact of this regimen on angiogenesis and inflammation remains largely unknown.In this non-randomized, open-label phase Ib/II study, four patients were treated with cabozantinib alone and 25 patients received the combination of cabozantinib and panitumumab. MET amplification was detected in blood in all four patients treated with cabozantinib monotherapy and 5/25 patients treated with cabozantinib and panitumumab combination therapy. Plasma samples from 28 patients were available for biomarker analysis.A panel of circulating protein biomarkers was assessed in patient plasma at baseline and on-treatment. Baseline marker levels were analyzed for prognostic value for clinical outcomes, including MET amplification as a covariate. HGF and OPN were prognostic for both progression-free survival (PFS) and overall survival (OS), while six markers (IL-6, VCAM-1, VEGF-R1, TSP-2, TIMP-1, ICAM-1) were prognostic only for OS. In patients with MET amplification, baseline PDGF-AA, PDGF-BB, TGF-β1, and VEGF-C levels were significantly higher, whereas baseline TGFβ-R3 levels were significantly lower than MET non-amplified patients. On-treatment change of four markers (CD73, PlGF, PDGF-BB, VEGF) were significantly different between MET amplified and non-amplified subpopulations.This study identified circulating HGF and several inflammatory and angiogenic proteins as prognostic biomarkers. Furthermore, MET amplification status is associated with both baseline expression and on-treatment modulation of members of angiogenesis and TGF-β pathway proteins.ClinicalTrials.gov identifier: NCT02008383.

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).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.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.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.

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

447 Background: Mortality from bladder cancer (BC) increases exponentially once it invades the muscle. At the population level, accurate delineation of these patients is challenging. Methods: To develop and validate a natural language processing (NLP) model for automatically identifying muscle-invasive BC (MIBC) patients, aiding in population-based BC research. All patients with a CPT code for transurethral resection of bladder tumor (TURBT) (N = 76,060) were selected from the Department of Veterans Affairs (VA) Corporate Data Warehouse database. A sample of 600 patients (with 2,337 full-text notes) who had TURBT and confirmed pathology results were selected for NLP model development (500 patients) and validation (100 patients). Muscle-invasion (yes/no), unknown, or no cancer, were confirmed by detailed chart review of pathology notes. The NLP performance was assessed by calculating the sensitivity, positive predictive value (PPV), and overall accuracy at the individual note and patient levels. Results: In the validation cohort, the NLP model had overall accuracy of 88% and 92% at the note and patient levels. Specifically, PPV and specificity for predicting muscle-invasion on note level were 83% and 70%, respectively. The model classified non-muscle invasive BC (NMIBC) with 98% sensitivity at both the note and patient levels. Although the sensitivity for MIBC was 70% for note-level determination, the sensitivity was 86% when evaluated at the patient level. When applying the model to 71,200 patients VA-wide, the model classified 13,642 (19%) as having MIBC and 47,595 (66%) as NMIBC. The NLP model was able to identify invasion status for 96% TURBT patients at the population level. Inherent limitations include relatively small training set given the size of the VA population. Conclusions: This NLP model for identifying muscle-invasion at the population level had high accuracy. The NLP model may be a practical and accurate tool for efficiently identifying BC invasion status and may potentially aid in population-based BC research in the VA.

3rd International Conference of Energy Harvesting, Storage, and Transfer (EHST'19) Many military systems produce thermal energy as a by-product. Generally, this so-called waste heat is lost to the surroundings. Capturing the waste heat and putting it to beneficial use could increase the efficiency of military systems, while having the added benefit of reducing thermal signatures. This paper outlines the application of modeling and simulation to estimate the usable electric power produced by a thermoelectric generator (TEG) array on the exhaust muffler of a small fossil fuel generator. The simulation results informed design, construction, and testing of an initial prototype. Key prototype test variables were temperature difference, load resistance, and electric current. The results of the experiment were compared to and used to update the initial model. This small-scale effort provides initial insight into the efficacy of applying thermoelectric generators to military systems. Future work will explore larger arrays, as well as detailed investigation of the tradespace to identify promising equipment or applications, and inform capability and acquisitions requirements. NEPTUNE program funded and scoped this research

How much trust do citizens have in government administrators, and what explains the variation in their attitudes? As measured by responses in the General Social Survey, it is found that attitudes about the trustworthiness of administrators are more positive than what might be generally thought, and that substantial variation characterizes all trusting attitudes. Perceptions of trustworthiness are influenced by sociodemographic background and interpersonal trust, whereas competence is influenced by political party affiliation. External political efficacy and general assessments of government are significant correlates of both. Thus, perceptions of competence correlate with whether government is doing what citizens want, while perceptions of trustworthiness are influenced by experiences with bureaucrats. Efforts to reform the public bureaucracy with an eye toward increasing trust require strategies to increase the competence and trustworthiness of the public service.

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