tbuckley/cabot-search huggingface dataset:
Thromboembolic incidents in prostate cancer patients: A nationwide propensity-matched study.
Authors: Vishal Devarkonda, Shafaqat Ali, Manoj Kumar, Faryal Farooq, Laxman Yashwant Byreddi, Muhammad Sultan, Muhammad Sohaib Afzal, Bilal Nasir, Sundeep Atluri
Journal: Journal of Clinical Oncology (2024)

e23082 Background: Venous thromboembolic events (VTE) are a major cause of morbidity and mortality in cancer patients. We aim to investigate the outcome and incidence of acute DVT and PE in prostate cancer compared to all other malignancies. Methods: The National Readmission Database (2016-2020) was utilized to identify all-cause admissions for patients with a history of prostate cancer. A Propensity Score Matching (PSM) model, matched such patients with subjects having any type of other malignancies. Pearson’s x2 test was applied to the PSM-2 matched cohorts to compare outcomes. Results: Among 3.2 million all-cause hospitalizations of prostate cancer patients, about 3.3% suffered a VTE. The majority had acute DVT (1.6%), followed by PE (1.1%) &amp; DVT with PE (0.6%). On a propensity-matched &amp; multivariate analysis, patients with prostate cancer have a lower incidence of acute PE (1.1% vs 1.9%, aOR: 0.57), DVT (1.9% vs 2.8%, aOR: 0.65) &amp; combined DVT with PE (0.6% vs 1%, aOR: 0.62) [p &lt; 0.001] as compared to other malignancies. Among different VTEs, the mortality was highest for Acute PE (aOR: 2.69), followed by DVT with PE (aOR: 1.68) &amp; DVT (aOR: 1.55) [p &lt; 0.001] in prostate cancer. Resource utilization is also higher in prostate cancer hospitalizations complicated by VTE, with patients suffering a DVT having the highest LOS (9 vs 3 days) &amp; total cost of hospitalization ($20,425 vs $14,452) [p &lt; 0.001] followed by DVT with PE and only PE [p &lt; 0.05]. Interestingly, patients with DVT have higher readmission rates as compared to PE at 30 days (16.6% vs 13.5%, p &lt; 0.001) and subsequently at 90-day intervals. Conclusions: The odds of venous thromboembolism were lower in prostate cancer when compared to all other patients with active cancer. The mortality was highest for PE in this cohort, while healthcare-related burden and readmission rates were higher for DVT. [Table: see text]
Peak study: A phase 3, randomized, open-label multi-center clinical study of bezuclastinib (CGT9486) and sunitinib combination versus sunitinib in patients with gastrointestinal stromal tumors (GIST).
Authors: William D. Tap, Neeta Somaiah, Yoon-Koo Kang, Albiruni Ryan Abdul Razak, Marcelo Garrido, Ingrid M.E. Desar, Antoine Italiano, Peter Reichardt, Breelyn A. Wilky, Michael C. Heinrich, Mihaela Druta, Arun S. Singh, Steven Attia, Sebastian Bauer, Cesar Serrano, Kevin Moynihan, Julia Lawrence, Andrew J. Wagner, Jonathan C. Trent
Journal: Journal of Clinical Oncology (2024)

TPS11588 Background: Imatinib is the worldwide standard for first-line therapy of advanced KIT-mutant GIST. However, secondary resistance mutations in the KIT ATP-binding domain (exons 13, 14), activation loop (exons 17, 18), or both develop and result in loss of imatinib-sensitivity. Bezuclastinib has a highly selective inhibition profile, leading to minimal off-target toxicities and allowing for combination with sunitinib. While no single tyrosine kinase inhibitor (TKI) inhibits all KIT mutations, the combination of bezuclastinib + sunitinib targets commonly occurring primary (exons 9, 11) and secondary (exons 13, 14, 17, and 18) KIT mutations and may provide more durable responses. The early signs of clinical activity, tolerability, and safety observed with the combination thus far in Peak Part 1 (Somaiah et al. [presentation] CTOS 2023. Paper 62) are consistent with the completed Phase 1/2 study (PLX121-01). Methods: Peak (NCT05208047) is a global, randomized, open-label, multi-part Phase 3 study evaluating the efficacy and safety of bezuclastinib + sunitinib versus sunitinib as second-line treatment in adult pts who were intolerant to imatinib or whose tumors had imatinib-resistance. Current Peak study sites are located in North America (3 countries), South America (3 countries), Europe (12 countries), and Asia-Pacific (4 countries). The lead-in portion to test a new formulation of bezuclastinib, (Part 1) completed enrollment in April 2023. Based upon PK and safety, a dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD was determined for Part 2 of the Peak study. Part 2 will enroll ~388 pts to be randomized (1:1) to bezuclastinib 600 mg QD + sunitinib 37.5 mg QD or sunitinib 37.5 mg QD alone. Key inclusion: &gt;1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1, Eastern Cooperative Oncology Group Performance Status 0-2, adequate organ function, and prior imatinib therapy (no other prior therapy). Key exclusion: known PDGFR mutations or succinate dehydrogenase deficiency, clinically significant cardiac disease, and use of strong CYP3A4 inhibitors or inducers. The primary endpoint is progression-free survival (PFS) confirmed by blinded independent central review per mRECIST v1.1. Additional efficacy (including overall survival and objective response rate) and safety endpoints will be evaluated and circulating tumor DNA (ctDNA) will be collected and assessed. Clinical trial information: NCT05208047 .
Evaluating hemoglobin thresholds for blood transfusions in oncology patients admitted in the intensive care unit.
Authors: Abijha Biju Boban, Andrew Strike, Dhaval Patel, Ania Rynarzewska
Journal: Journal of Clinical Oncology (2024)

e23319 Background: Current guidelines recommend transfusing at a hemoglobin (Hb) threshold of 7g/dl. There is a lack of evidence to support a specific threshold for transfusion in patients with active malignancy admitted to the Intensive Care Unit (ICU). This study attempts to determine an evidence-based threshold for blood transfusions in cancer. Methods: A retrospective study was done to study 561 patients with an active cancer diagnosis admitted to Northeast Georgia Medical Center ICU between 2017 and 2023 that received at least one unit of blood transfusion. Chi-Square test of association with Bonferoni correction was applied to the top five common cancers seen in ICU: Leukemia, Lymphoma, Brain tumors, Lung cancers, and GI cancers. It compared three thresholds of transfusion and looked for any change in mortality risk, readmissions, need for multiple transfusions, prevalence of new onset or recurrent heart failure, development of altered mental status, or cardiac arrest. The three thresholds for transfusions that were studied were &lt; 7g/dL, &lt; 8 g/dL, and &gt; 8 g/dL. The studied cancer types were further divided into either hematologic or solid tumors. Results: There was a decrease in overall cancer readmissions compared to expected over 30 days by 64%, 60 days by 44%, and 90 days by 47.5% when transfused for a Hb threshold of &lt;8 g/dL compared to an increase of 22.8%, 18.2%, and 18.8% in 30-, 60-, and 90-day readmissions when transfused for a Hb threshold of &lt;7 g/dL. When divided by cancer types, there was a significant decrease from expected by 30%, 47.5%, and 56% in 30-, 60-, and 90-day readmissions for patients with solid tumors for a Hb threshold of &lt; 8 g/dL. Mortality risk decreased by 50% and the need for multiple transfusions decreased by 21% when transfused for a Hb threshold of &lt; 8 g/dl. Of note, there was no significant association between transfusion levels and associated reactions. There was a decrease of 82% in altered mental status when transfused for threshold of Hb &lt;8 g/dL. Finally, significant association was not found with AKI, cardiac arrest, or heart failure and any Hb transfusion thresholds. Conclusions: Based on these results, there is a significant mortality benefit and decreased length of stay for cancer patients admitted to ICU when blood transfusion is undertaken at a hemoglobin threshold of &lt;8g/dL. These results should be further investigated in a randomized controlled trial.
Access to and equity in cancer clinical trials in Oregon.
Authors: Emmanuella Oyogoa, Michael Crespo, Trisha Marsh, David Castro, Kathleen Mayer, Eliana Turk, Jackilen Shannon, Eneida R. Nemecek
Journal: Journal of Clinical Oncology (2024)

e23100 Background: Approximately 20,000 people per year are diagnosed with cancer in Oregon. The OHSU Knight Cancer Institute is the only academic cancer center in the state, with the nearest center located almost 200 miles away. Clinical trials (CT) are essential for cancer care but only a small proportion of eligible people participate due to multiple factors. In this retrospective study, we identified the association between sociodemographic factors and cancer CT participation at OHSU. Methods: Adult patients referred to OHSU for evaluation and treatment of a new cancer 2019-2022 were included. Data collected included age, gender, race/ethnicity, zipcode, insurance, type of cancer and CT participation. Zip-codes were used to estimate poverty level as defined by the American Community Survey, rural vs. urban location and distance to the cancer center. Multivariate analysis was conducted to identify factors associated with CT participation. Results: A total of 14,261 patients with median age 65 (18-101) years were treated at OHSU from 2019-2022 (86% for solid tumors, 14% hematologic malignancies). Of these, 53% were &gt; 65yrs, 51% male and 8.5% self-identified as non-White (including Hispanic). These numbers are similar to those reported in the statewide cancer registry. About 61% of those &lt; 65 yrs were privately insured, 84% of those &gt; 65 yrs had Medicare, and 31% were from areas at or below the national poverty level. About 40% lived &gt; 30 miles from OHSU (29% &gt; 60 miles, 14% &gt; 120 miles) and 31.5% lived in rural areas. A total of 2134 patients (15%) participated in cancer CT (8% interventional, 6% interventional therapeutic and 10% noninterventional). Factors independently associated with decreased CT participation on multivariate analysis included age &gt; 65yrs regardless of type of insurance, &lt; 65yrs with public insurance, female, racial/ethnic minority, solid tumor diagnosis and cancer care at a community-based clinic (Table 1). Conclusions: Patient with cancer treated at OHSU are representative of the population in our catchment area and region. However, there is room to improve access and CT participation for older adults and persons from racial/ethnic minorities and disadvantaged backgrounds. Our study highlights the importance of understanding the catchment area and accounting for social determinants of health when implementing community outreach strategies for CT participation. [Table: see text]
Compliance with Centers for Medicare &amp; Medicaid Services (CMS) 2021 price transparency requirements among proton therapy centers.
Authors: Noah Maxwell Feder, Kasey Cargill, Tyler Wilhite, Heath Devin Skinner, Yvonne Marie Mowery, Christopher Wilke
Journal: Journal of Clinical Oncology (2024)

e23034 Background: Since 2019, the Centers for Medicare &amp; Medicaid Services (CMS) has required hospitals to publish gross charges for all goods and services provided. In 2021, CMS amended this requirement to include publishing standard charge files, which include cash and payer-negotiated prices for all goods and services provided. This was enacted in an attempt to reduce healthcare prices by reducing information asymmetry and generating competition among both insurers and hospitals. Since complex proton therapy is one of the most expensive modalities of cancer treatment, we aimed to determine proton therapy center compliance with CMS price transparency requirements. Methods: We searched for online standard charge files for the 44 proton therapy centers in the United States. To assess compliance with the nine CMS price transparency criteria, we obtained prices for proton therapy using keyword searches and billing code 77525, the CPT code for the per fraction technical charge billed for complex proton treatment delivery. Results: Out of 44 operating proton therapy centers, 5 (11.4%) are free-standing private practice centers that are not affiliated with a hospital system, and thus not required to publish standard charge files per CMS policy. Of the 39 centers required to publish, 39 (100%) published their standard charge files free of charge with appropriately named files, thus meeting Criteria 1-3. Twenty-seven (69.2%) centers met Criteria 4 by including data on complex proton therapy (CPT code 77525) and Criteria 5a by including the gross charge for the service. One (2.6%) center partially met Criteria 4. Seventeen (43.6%) centers included negotiated prices for commercial insurers, thus meeting Criteria 5b, while 3 (7.7%) partially met this criterion. Twenty-two (56.4%) centers met Criteria 5c and 5d by including the deidentified minimum and maximum negotiated commercial prices, respectively. Twenty-six (66.7%) centers met Criteria 5e by listing the cash price for complex proton therapy, which is typically paid out-of-pocket by patients. One (2.6%) center partially met Criteria 5c-e. In total, 17 (43.6%) out of 39 proton therapy centers were in complete compliance with the 2021 CMS price transparency requirements. Conclusions: In summary, 17 out of 39 eligible proton centers were fully compliant with the 2021 CMS price transparency requirements in regard to complex proton radiation therapy. This suggests that deficiencies exist among hospital compliance and the CMS review process used to identify non-compliance. Future directions are aimed at expanding this analysis to include evaluation of proton center compliance with other billing codes, such as simple and intermediate proton treatment delivery. [Table: see text]
Bioprinted Multi‐Composition Array Mimicking Tumor Microenvironments to Evaluate Drug Efficacy with Multivariable Analysis
Authors: Gihyun Lee, Soo Jee Kim, Je‐Kyun Park
Journal: Advanced Healthcare Materials (2024)

Abstract Current organ‐on‐a‐chip technologies confront limitations in effectively recapitulating the intricate in vivo microenvironments and accommodating diverse experimental conditions on a single device. Here, a novel approach for constructing a multi‐composition tumor array on a single microfluidic device, mimicking complex transport phenomena within tumor microenvironments (TMEs) and allowing for simultaneous evaluation of drug efficacy across 12 distinct conditions is presented. The TME array formed by bioprinting on a microfluidic substrate consists of 36 individual TME models, each characterized by one of three different compositions and tested under four varying drug concentrations. Notably, the TME model exhibits precise compartmentalization, fostering the development of self‐organized vascular endothelial barriers surrounding breast cancer spheroids affecting substance transport. Multivariable screening and analysis of diverse conditions, including model complexity, replicates, and drug concentrations, within a single microfluidic platform, highlight the synergistic potential of integrating bioprinting with microfluidics to evaluate drug responses across diverse TME conditions comprehensively.
The significant impact of experimental variables on the gut microbiome
Authors: Bhakti I Zakarauskas-Seth, Suphansa Sawamiphak
Journal: Cardiovascular Research (2024)

Journal Article Accepted manuscript The significant impact of experimental variables on the gut microbiome Get access Bhakti I Zakarauskas-Seth, Bhakti I Zakarauskas-Seth Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, GermanyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin https://orcid.org/0000-0003-0810-4173 Search for other works by this author on: Oxford Academic PubMed Google Scholar Suphansa Sawamiphak Suphansa Sawamiphak Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, GermanyDZHK (German Center for Cardiovascular Research), Partner Site Berlin Corresponding author: suphansa.sawamiphak@mdc-berlin.de https://orcid.org/0000-0003-2298-3565 Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, cvae119, https://doi.org/10.1093/cvr/cvae119 Published: 04 June 2024 Article history Received: 18 April 2024 Accepted: 18 April 2024 Published: 04 June 2024
Increased Positive Selection in Highly Recombining Genes Does not Necessarily Reflect an Evolutionary Advantage of Recombination
Authors: Julien Joseph
Journal: Molecular Biology and Evolution (2024)

Abstract It is commonly thought that the long-term advantage of meiotic recombination is to dissipate genetic linkage, allowing natural selection to act independently on different loci. It is thus theoretically expected that genes with higher recombination rates evolve under more effective selection. On the other hand, recombination is often associated with GC-biased gene conversion (gBGC), which theoretically interferes with selection by promoting the fixation of deleterious GC alleles. To test these predictions, several studies assessed whether selection was more effective in highly recombining genes (due to dissipation of genetic linkage) or less effective (due to gBGC), assuming a fixed distribution of fitness effects (DFE) for all genes. In this study, I directly derive the DFE from a gene’s evolutionary history (shaped by mutation, selection, drift, and gBGC) under empirical fitness landscapes. I show that genes that have experienced high levels of gBGC are less fit and thus have more opportunities for beneficial mutations. Only a small decrease in the genome-wide intensity of gBGC leads to the fixation of these beneficial mutations, particularly in highly recombining genes. This results in increased positive selection in highly recombining genes that is not caused by more effective selection. Additionally, I show that the death of a recombination hotspot can lead to a higher dN/dS than its birth, but with substitution patterns biased towards AT, and only at selected positions. This shows that controlling for a substitution bias towards GC is therefore not sufficient to rule out the contribution of gBGC to signatures of accelerated evolution. Finally, although gBGC does not affect the fixation probability of GC-conservative mutations, I show that by altering the DFE, gBGC can also significantly affect nonsynonymous GC-conservative substitution patterns.
The Tree Reconstruction Game: Phylogenetic Reconstruction Using Reinforcement Learning
Authors: Dana Azouri, Oz Granit, Michael Alburquerque, Yishay Mansour, Tal Pupko, Itay Mayrose
Journal: Molecular Biology and Evolution (2024)

Abstract The computational search for the maximum-likelihood phylogenetic tree is an NP-hard problem. As such, current tree search algorithms might result in a tree that is the local optima, not the global one. Here, we introduce a paradigm shift for predicting the maximum-likelihood tree, by approximating long-term gains of likelihood rather than maximizing likelihood gain at each step of the search. Our proposed approach harnesses the power of reinforcement learning to learn an optimal search strategy, aiming at the global optimum of the search space. We show that when analyzing empirical data containing dozens of sequences, the log-likelihood improvement from the starting tree obtained by the reinforcement learning–based agent was 0.969 or higher compared to that achieved by current state-of-the-art techniques. Notably, this performance is attained without the need to perform costly likelihood optimizations apart from the training process, thus potentially allowing for an exponential increase in runtime. We exemplify this for data sets containing 15 sequences of length 18,000 bp and demonstrate that the reinforcement learning–based method is roughly three times faster than the state-of-the-art software. This study illustrates the potential of reinforcement learning in addressing the challenges of phylogenetic tree reconstruction.
Clinical outcomes of patients receiving venetoclax and hypomethylating agents for AML in academic and academic-community partnerships.
Authors: Natalie Pham, Jeffrey Lantz, Caroline Jones, Debamita Kundu, Nicholas McCann, Firas El Chaer, Daniel Reed, Michael Kenneth Keng
Journal: Journal of Clinical Oncology (2024)

e23235 Background: Prior studies have reported improved outcomes for acute myeloid leukemia (AML) in academic over nonacademic settings potentially due to the availability of multidisciplinary teams, clinical trials and increased resources (1,2). Our institution has partnered with community practices to further evaluate this disparity. In this study, we analyzed treatment outcomes when nonacademic centers partnered with academic centers to treat AML using a regimen of venetoclax and a hypomethylating agent. Methods: We reviewed 92 patients with newly diagnosed AML treated with venetoclax and either decitabine or azacitidine at an academic center (n = 57) or community practice with academic center support (n = 35). When partnering with the community, patients received the first cycle of therapy at an academic center. Before discharge, our team completed financial screening, scheduled follow up appointments and provided prescriptions. The primary objective was to evaluate the overall response rate (ORR) with a secondary evaluation of differences in chemotherapy management and complications. Results: Patients in the academic setting tended to have more adverse risk disease (80.7% vs. 74.3%, p = 0.36) according to the European LeukemiaNet (ELN) (table). The overall survival (OS) of all patients was 10.7 months (95% CI 9.4-15.7) with no significant difference between the groups. The ORR was similar between the community and academic settings (40.0% vs. 36.8%, p = 0.46). The complete remission (CR) rate was 11.4% in the community versus 19.3% in the academic setting (p = 0.67), and the CR rates were improved in the academic group versus the community after cycle 2 (12.9% vs. 0%, p = 0.72) and cycle 3 (25.0% vs. 0%, p = 0.46). Adverse events were comparable, except for increased rates of fatigue (80.7 vs. 54.3%, p = 0.01) and diarrhea (33.3 vs. 11.4%, p = 0.04) in the academic setting. Conclusions: Contrary to prior studies, our evaluation and ongoing partnerships support the transition of AML treatment to a community setting with academic consultation. Although there were some differences in adverse events, the OS and ORR were similar. Furthermore, this study did not identify any significant safety concerns that could prevent patients from receiving this regimen in either setting. Our goal is to continue evaluating this partnership, as we design prospective studies to improve the care of this patient population. 1. Giri S et al. OS of AML Treated at Academic Center Vs Nonacademic Center. Blood 2015. 2. Halpern AB et al. Practice patterns &amp; outcomes for adults with AML. Hematol Am Soc 2020.[Table: see text]