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Summary: Background: We aimed to assess real-world efficacy of the PARP inhibitor, olaparib, in US Veterans with metastatic prostate cancer (mPC) by leveraging the national data repository and evaluate a novel approach to assess treatment efficacy in tumors considered rare or harboring rare mutations. Methods: Included Veterans had 1) mPC with somatic or germline alterations/mutations in genes involved in homologous recombination repair (HRR), 2) received olaparib monotherapy as well as a novel hormonal therapy/androgen receptor pathway inhibitors (NHT/ARPI), and/or chemotherapy, and 3) estimable rates of tumor growth (g-rate) using PSA values obtained while receiving treatment. Previous work has shown an excellent inverse correlation of g-rate with survival. Using g-rate, we determined tumor doubling time (DT) and DT ratios (DT on olaparib/DT on prior medication). We postulated that a DT ratio ≥ 1 was associated with benefit. Findings: We identified 139 Veterans, including 42 Black males with tumors harboring mutations/alterations in HRR genes who received olaparib: BRCA2 (50), ATM (32), BRCA1 (10), other mutations (47). 62/139 (45%) of all and 21/42 (50%) of Black Veterans had DT ratios ≥1, including 31, 10, 2, and 19 with BRCA2, ATM, BRCA1, and other mutations, respectively (p = 0.006). Median survival with DT ratios ≥1 was superior, being 24.5 vs. 11.4 months for DT ratio

Background: We aimed to assess real-world efficacy of the PARP inhibitor, olaparib, in US Veterans with metastatic prostate cancer (mPC) by leveraging the national data repository and evaluate a novel approach to assess treatment efficacy in tumors considered rare or harboring rare mutations., Methods: Included Veterans had 1) mPC with somatic or germline alterations/mutations in genes involved in homologous recombination repair (HRR), 2) received olaparib monotherapy as well as a novel hormonal therapy/androgen receptor pathway inhibitors (NHT/ARPI), and/or chemotherapy, and 3) estimable rates of tumor growth (g-rate) using PSA values obtained while receiving treatment. Previous work has shown an excellent inverse correlation of g-rate with survival. Using g-rate, we determined tumor doubling time (DT) and DT ratios (DT on olaparib/DT on prior medication). We postulated that a DT ratio≥ 1 was associated with benefit., Findings: We identified 139 Veterans, including 42 Black males with tumors harboring mutations/alterations in HRR genes who received olaparib: BRCA2 (50), ATM (32), BRCA1 (10), other mutations (47). 62/139 (45%) of all and 21/42 (50%) of Black Veterans had DT ratios ≥1, including 31, 10, 2, and 19 with BRCA2, ATM, BRCA1, and other mutations, respectively (p = 0.006). Median survival with DT ratios ≥1 was superior, being 24.5 vs. 11.4 months for DT ratio <1 (p = 0.01, HR 0.50, 95% CI 0.29-0.85). Benefit from olaparib, defined as DT ratio ≥1, was not observed for germline status, starting PSA value, number of prior therapies, or immediate prior therapy. Compared to matched cohorts, tumors in the olaparib cohort had shorter DTs with enzalutamide in first line (367 vs. 884 days; p = 0.0043)., Interpretation: Using equations indifferent to timing of assessments ideal for real-world efficacy analyses, we showed DT ratio ≥1 representing slower tumor growth on olaparib relative to the prior therapy correlates with improved survival. Olaparib efficacy in Veterans with mPC harboring mutations/alterations in HRR genes emulates clinical trial results. Black men had comparable results. Compared to matched cohorts, in first line, enzalutamide was less efficacious in tumors harboring mutations/alterations in HRR genes., Funding: American Society of Clinical Oncology Conquer Cancer Foundation (ASCO CCF), the Blavatnik Family Foundation and the Prostate Cancer Foundation (PCF)., Competing Interests: Declaration of interests All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Leptospirosis is a re-emerging zoonotic infectious disease caused by pathogenic bacteria of the genus Leptospira. Regional differences in the disease manifestation and the role of ecological factors, specifically in regions with a subarctic and arctic climate, remain poorly understood. We here explored environmental and socio-economic features associated with leptospirosis cases in livestock animals in the Russian Arctic during 2000–2019. Spatial analysis suggested that the locations of the majority of 808 cases were in “boreal” or “polar” climate regions, with “cropland,” “forest,” “shrubland,” or “settlements” land-cover type, with a predominance of “Polar Moist Cropland on Plain” ecosystem. The cases demonstrated seasonality, with peaks in March, June, and August, corresponding to the livestock pasturing practices. We applied the Forest-based Classification and Regression algorithm to explore the relationships between the cumulative leptospirosis incidence per unit area by municipal districts (G-rate) and a number of socio-economic, landscape, and climatic factors. The model demonstrated satisfactory performance in explaining the observed disease distribution (R2 = 0.82, p < 0.01), with human population density, livestock units density, the proportion of crop area, and budgetary investments into agriculture per unit area being the most influential socio-economic variables. Climatic factors demonstrated a significantly weaker influence, with nearly similar contributions of mean yearly precipitation and air temperature and number of days with above-zero temperatures. Using a projected climate by 2100 according to the RCP8.5 scenario, we predict a climate-related rise of expected disease incidence across most of the study area, with an up to 4.4-fold increase in the G-rate. These results demonstrated the predominant influence of the population and agricultural production factors on the observed increase in leptospirosis cases in livestock animals in the Russian Arctic. These findings may contribute to improvement in the regional system of anti-leptospirosis measures and may be used for further studies of livestock leptospirosis epidemiology at a finer scale.

We examined data from US Veterans with prostate cancer (PC) to assess disease response to immune checkpoint inhibitors (ICI) as monotherapy or combined with abiraterone or enzalutamide to assess ICI efficacy in the real-world. We queried the VA corporate data warehouse (CDW) to identify Veterans with a diagnosis of PC who received ICI for any malignancy and had ≥1 PSA measurement while receiving ICI. To evaluate ICI monotherapy, we restricted analysis to Veterans who had not received LHRH agonists/antagonists, PC-directed medical therapy, or radiation/extirpative surgery of the bladder/prostate within and preceding the duration of ICI administration. For ICI combination analysis, we identified Veterans who received abiraterone or enzalutamide for PC while on ICI. We calculated rates of tumor (PSA) growth (g-rates), comparing them to a 1:2 matched reference cohort. We identified 787 Veterans with PC and ≥1 PSA measurement while receiving an ICI. Median duration of ICI therapy was 155 days. 223 Veterans received ICI monotherapy, with only 17(8%) having a reduction in PSA (median decline = 43%). 12 (5%) had PSA declines >30% (PSA30) which included 6 (3%) who had PSA reductions greater than 50% (PSA50). Median g-rates for ICI plus abiraterone (n = 20) or enzalutamide (n = 31) were 0.000689/d -1 and 0.002819/d -1 , respectively, and were statistically insignificant compared to g-rates of matched cohorts receiving abiraterone (g = 0.000925/d -1 , P = 0.73) or enzalutamide (g = 0.001929/d -1 , P = 0.58) alone. Our data align with clinical trial data in PC, demonstrating limited benefit from ICI monotherapy and predicting no survival benefit from simultaneous abiraterone or enzalutamide with an ICI using g-rate., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Harshraj Leuva reports financial support was provided by Conquer Cancer Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Leptospirosis is a re-emerging zoonotic infectious disease caused by pathogenic bacteria of the genus Leptospira . Regional differences in the disease manifestation and the role of ecological factors, specifically in regions with a subarctic and arctic climate, remain poorly understood. We here explored environmental and socio-economic features associated with leptospirosis cases in livestock animals in the Russian Arctic during 2000-2019. Spatial analysis suggested that the locations of the majority of 808 cases were in "boreal" or "polar" climate regions, with "cropland," "forest," "shrubland," or "settlements" land-cover type, with a predominance of "Polar Moist Cropland on Plain" ecosystem. The cases demonstrated seasonality, with peaks in March, June, and August, corresponding to the livestock pasturing practices. We applied the Forest-based Classification and Regression algorithm to explore the relationships between the cumulative leptospirosis incidence per unit area by municipal districts (G-rate) and a number of socio-economic, landscape, and climatic factors. The model demonstrated satisfactory performance in explaining the observed disease distribution ( R 2 < 0.01), with human population density, livestock units density, the proportion of crop area, and budgetary investments into agriculture per unit area being the most influential socio-economic variables. Climatic factors demonstrated a significantly weaker influence, with nearly similar contributions of mean yearly precipitation and air temperature and number of days with above-zero temperatures. Using a projected climate by 2100 according to the RCP8.5 scenario, we predict a climate-related rise of expected disease incidence across most of the study area, with an up to 4.4-fold increase in the G-rate. These results demonstrated the predominant influence of the population and agricultural production factors on the observed increase in leptospirosis cases in livestock animals in the Russian Arctic. These findings may contribute to improvement in the regional system of anti-leptospirosis measures and may be used for further studies of livestock leptospirosis epidemiology at a finer scale.p < 0.01), with human population density, livestock units density, the proportion of crop area, and budgetary investments into agriculture per unit area being the most influential socio-economic variables. Climatic factors demonstrated a significantly weaker influence, with nearly similar contributions of mean yearly precipitation and air temperature and number of days with above-zero temperatures. Using a projected climate by 2100 according to the RCP8.5 scenario, we predict a climate-related rise of expected disease incidence across most of the study area, with an up to 4.4-fold increase in the G-rate. These results demonstrated the predominant influence of the population and agricultural production factors on the observed increase in leptospirosis cases in livestock animals in the Russian Arctic. These findings may contribute to improvement in the regional system of anti-leptospirosis measures and may be used for further studies of livestock leptospirosis epidemiology at a finer scale., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zakharova, Korennoy, Iashin, Toropova, Gogin, Kolbasov, Surkova, Malkhazova and Blokhin.)