Caffeinated energy shots significantly increased SBP and DBP over a 3-hour period compared with decaffeinated energy shots in healthy, nonhypertensive individuals.

219 Background: Notch signaling is a key determinant of cell fate. RO492 is a selective γ-secretase inhibitor blocking cleavage of Notch. We hypothesize that anti-androgen therapy will lead to an enriched population of basal prostate cancer stem cells. Targeting Notch following anti-androgen treatment will lead to delay in re-growth of mature luminal PC cells. We are using a novel double blind, placebo controlled randomized discontinuation design to treat men with rising PSA. A non-castrating anti-androgen (BIC) was used to induce initial tumor regression Methods: Pts with rising PSA after primary therapy for PC, and no radiographic evidence of disease were enrolled in this ongoing study. All pts received BIC 50mg/day for 16 weeks (induction phase). Pts achieving a >50% (modified from 80% decrease after the first 8 pts) decrease in PSA were randomized to placebo or RO492 20mg orally 3 days on/ 4 days off per week (randomization phase). Primary endpoint is PSA progression (increase in PSA by 50% over nadir with minimum PSA rise of 2ng/mL) during randomization phase. Pts meeting primary endpoint could receive 12 months of RO492 and BIC (combination phase). Serum is collected for evaluation of soluble markers of gamma secretase inhibition. 29 pts/arm in randomization phase gives 90% power to detect a decrease in1 yr PFS from 80% to 45% with 5% alpha. Results: We report on the first 16 patients that have enrolled. Median pretreatment PSA was 6.3ng/ml (0.35 to 34). 9 of 16 pts on the induction phase came off study due to PSA progression, although 5 of 9 pts would have been randomized using the 50% PSA response criteria. 6 pts have been randomized to RO492 or placebo (1 pt not yet randomized) and 2 pts have proceeded to combination phase. Median PSA decrease during induction phase in 6 pts who went on to randomization was 86% (69–97). Overall decline in PSA in induction phase was 67% (7.3-99%). Placebo/RO492 has been well tolerated with 1 pt experiencing g1 fatigue, and 1 pt experiencing g1 nausea in the combination phase. 8/16 pts had g1 breast tenderness with BIC. Conclusions: In this ongoing randomized phase II trial, BIC decreased PSA by >50% in 12/16 pts. Placebo/RO492 is well tolerated. Enrollment continues with analysis of plasma correlates to be compared to clinical results.

89 Background: Single agent atorvastatin and celecoxib have been associated with reductions in the risk of PC. Our laboratories have demonstrated that low doses of the drug combination have synergistic effects inhibiting the progression of LNCaP tumors to androgen independence. We therefore sought to determine the effects of the combination in androgen-dependent PC on PSA kinetics and the plasma correlates of IL-6, C-reactive protein (CRP), PGE-2, and the pharmacokinetics of the drug combination to validate preclinical biomarker findings. Methods: Patients with rising PSA after primary therapy for PC were enrolled. Patient must have three rising PSA values, each obtained at least 1 month apart. No prior hormone-ablative therapy was allowed, except in the neoadjuvant setting or in the setting of salvage XRT completed 3 months prior to enrollment. Patients with any history of coronary artery disease or a previous myocardial infarction in the past 6 months were excluded. All patients were treated with atorvastatin 20 mg daily and celecoxib 200 mg twice a day for 6 months. Paired pre-treatment and on treatment PSA kinetics were compared using the Wilcoxon Signed Rank test. Results: We report on 14 patients that have completed therapy. Median pretreatment PSA slope was 0.14 log PSA/mo (median PSADT 4.98 mos), in contrast to the median on treatment slope of 0.09 log PSA/mo (median PSADT 7.37 mos); p=0.11. Eleven of the fourteen patients completed the 6 months of therapy, 1 patient withdrew and 2 patients therapy was stopped early due to lack of response. A declining PSA was observed in one patient. The combination was well tolerated, with no clinically significant therapy related toxicities ( > grade 1) reported in 76 months of therapy. Conclusions: In this ongoing phase II trial, the combination of low dose atorvastatin and celecoxib has been well tolerated and demonstrates a tendency of increasing PSA doubling time. Enrollment continues with analysis of IL-6, CRP, and PGE-2 to be correlated to individual clinical results.

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Background: COVID-19 mortality rates vary widely across regions and sex/gender. Understanding the reasons behind such variation could help in developing suitable management strategies. Methods: This paper presents a comprehensive analysis of incidence and mortality rates on 2,331,363 cases and 46,239 deaths over a cumulative period of approximately 6.5 months from February to August 2020 across 411 districts of India in the age group 15-49. Together with health data from government surveys, we identify risk and protective factors across regions, socio-economic status, literacy, and sex. To obtain common indicators, we apply both machine learning techniques and statistical tests on different health factors. We also identify positive and negative correlates at multiple population scales by dividing the cohort into sub-cohorts formed from two Indian states that were further segregated by sex. Results: We show that males and females differ in their risk factors for mortality. While obesity (lasso regression coefficient: KA=0.5083, TN=0.318) is the highest risk factor for males, anemia (KA=0.3048, TN=0.046) is the highest risk factor for females. Further, anemia (KA=-0.0958, TN=-0.2104) is a protective factor for males, while obesity (KA=-0.0223, TN=-0.3081) is a protective factor for females. Conclusion: Districts with a high prevalence of obesity pose a significantly greater risk of severe COVID-19 outcomes in males. On the other hand, in females, the prevalence of anemia in districts is notably associated with a higher risk of severe COVID-19 outcomes. It is important to consider sex-wise heterogeneity in health factors for better management of health resources.

Incidence and mortality rates due to COVID-19 have varied widely in different parts of the world and placed a huge strain on hospital resources. Understanding the underlying reasons behind such variation is crucial to developing population-specific or even individual-specific management strategies. This paper presents a comprehensive analysis of incidence and mortality rates from data collected over a cumulative period of approximately 6.5 months from February to August 2020 across 411 districts of India, totalling over 2 million individuals. We identify the health factors which have both positive as well as negative correlates with high mortality rates, using data obtained from district-wise aggregated COVID-19 incidence and mortality rates and health data obtained from National Family Health Survey (NFHS). To obtain robust indicators, we apply both machine learning techniques as well as classical statistical methods and show that the same factors are identified by both methods. We also identify positive and negative correlates at multiple population scales by dividing the cohort into sub-cohorts formed from two Indian states which were further segregated by gender. We show that there is a disparity of risk factors among males and females. While obesity is the highest risk factor for men, anaemia is the highest risk factor for women. Hence, to better manage the health of a specific group of people, it is important to consider gender-wise heterogeneity in health risk factors which could contribute to differing vulnerabilities

464 Background: Treatment of patients with RCC using IAL from a haploidentical donor (sibling/parent), without prior conditioning of the recipient, induced tumor regressions in 3/13 patients with minimal toxicity (Strair J Clin Onc 2003:3785). Responses were not detected until after 2-3 courses, consistent with an immunologic mechanism. We hypothesize that combining the angiogenesis inhibitor SU with IAL will improve outcomes given the potential immune stimulatory benefit of VEGF inhibition and the benefit from preventing clinical progression prior to the development of an immune response in patients with rapid disease progression. Single agent SU has a median PFS of 11mos and response rate of 31%. Methods: Eligible pts with measurable metastatic clear cell RCC, no prior systemic therapy, adequate organ function, no CNS met, and a suitable donor (≥2/6 HLA A, B, DR match, CMV-, HIV-, HepB/C-) received SU 50mg/day in a 4 wk on/2wk off schedule with IAL administration commencing at the start of cycle number 2 of SU. IAL was given once every 8-16 weeks. The primary objective of the study is to determine the PFS of the combination of SU and IAL in 35 patients for 80% power to detect an increase in median PFS from 11 to 18 months. Results: A pre-planned futility analysis was performed. To date 9 pts (7M/2F), median age 63 (range 49-74) have been treated with 29 cycles of DLI. Median number of DLI/pt 2(1-7). 5 pts discontinued DLI due to disease progression, 4 due to loss of donor availability. Median time to disease progression was 41 weeks (range 12-180 weeks), with 4 pts on study for >80 weeks. Response rate (CR+PR): 44% (1/9 CR, 3/9 PR, 2/9 SD, 3/9 PD). DLI was well tolerated with G2 fever in 1pt and G1 fever in 5 pts as the only DLI related AEs. SU related AE lead to SU dose reduction in 8/9 pts. Conclusions: Co-administration of SU and IAL is feasible and safe with no significant IAL related toxicity. Further study accrual is required to determine if SU plus IAL is superior to single agent SU. Clinical trial information: NCT00853125.