tbuckley/cabot-search huggingface dataset:
The Addition of Rituximab to CHOP Chemotherapy Improves Response Rate, Failure-Free Survival and Overall Survival for Follicular Grade 3 Lymphoma Compared to CHOP Alone
Authors: Michael J. Overman, Lei Feng, Barbara Pro, Peter McLaughlin, Mark Hess, Felipe Samaniego, Anas Younes, Jorge E. Romaguera, Frederick B. Hagemeister, Larry Kwak, Fernando Cabanillas, Maria A. Rodriguez, Luis E. Fayad
Journal: Blood (2007)
Progression of intervention-focused research for Gulf War illness
Authors: Jeremy E. Chester, Mazhgan Rowneki, William Van Doren, Drew A. Helmer
Journal: Military Medical Research (2019)

Abstract The Persian Gulf War of 1990 to 1991 involved the deployment of nearly 700,000 American troops to the Middle East. Deployment-related exposures to toxic substances such as pesticides, nerve agents, pyridostigmine bromide (PB), smoke from burning oil wells, and petrochemicals may have contributed to medical illness in as many as 250,000 of those American troops. The cluster of chronic symptoms, now referred to as Gulf War Illness (GWI), has been studied by many researchers over the past two decades. Although over $500 million has been spent on GWI research, to date, no cures or condition-specific treatments have been discovered, and the exact pathophysiology remains elusive. Using the 2007 National Institute of Health (NIH) Roadmap for Medical Research model as a reference framework, we reviewed studies of interventions involving GWI patients to assess the progress of treatment-related GWI research. All GWI clinical trial studies reviewed involved investigations of existing interventions that have shown efficacy in other diseases with analogous symptoms. After reviewing the published and ongoing registered clinical trials for cognitive-behavioral therapy, exercise therapy, acupuncture, coenzyme Q10, mifepristone, and carnosine in GWI patients, we identified only four treatments (cognitive-behavioral therapy, exercise therapy, CoQ10, and mifepristone) that have progressed beyond a phase II trial. We conclude that progress in the scientific study of therapies for GWI has not followed the NIH Roadmap for Medical Research model. Establishment of a standard case definition, prioritized GWI research funding for the characterization of the pathophysiology of the condition, and rapid replication and adaptation of early phase, single site clinical trials could substantially advance research progress and treatment discovery for this condition.
Feasibility and design of a cloud-based digital platform in patients with advanced cancer.
Authors: Olga Generalova, Mohana Roy, Evan Thomas Hall, Brianna Velazquez, Sumit Shah, Touran Fardeen, Kristen Cunanan, Melanie San Pedro-Salcedo, Heather A. Wakelee, Joel W. Neal, Sukhmani Kaur Padda, Millie Das, Alice C. Fan, Sandy Srinivas, George A. Fisher, Sigurdis Haraldsdottir, Tyler Paul Johnson, Gilbert Chu, Alex McMillan, Kavitha Ramchandran
Journal: Journal of Clinical Oncology (2019)

211 Background: Patient reported outcomes (PROs) allow for systematic and more continuous capture of the patient experience. PROs have been associated with improved symptom management and quality of life in patients with advanced cancer; however how to do this in a real world setting is not thoroughly described. We sought to provide a description of the implementation and feasibility of a digital PRO application in patients with advanced cancer at one academic center. Methods: This is an ongoing randomized trial, comparing digital PRO intervention vs standard of care, in advanced cancer patients from three oncology groups (thoracic, gastrointestinal, genitourinary). Prior to trial initiation, a lead in period to test workflows was conducted, as well as key stakeholder interviews to optimize engagement with the platform. Clinical team members (e.g. nurses, advanced practice providers) were critical to the workflows developed, thus operational leadership buy-in was required. We were unable to integrate our PRO platform with our digital EHR. Regular sponsor meetings addressed technical concerns and patient/provider feedback. Processes were tailored for each disease group to handle varying degrees of symptoms (mild, moderate and severe). Patient and clinician satisfaction and qualitative feedback was collected. We defined feasibility as &gt; 70% questionnaire completion on the platform. Results: There are 64 patients on the intervention arm and 64 on the control arm. Of eligible patients, 93% (128/138) enrolled in the study. During the study period, 447 digital symptom questionnaires were sent by the platform, of which 333 were completed (74%). The majority of clinicians (82%, n = 18) and patients (85%, n = 64) felt neutral or positive when asked if the tool was easy to use. Approximately half of clinicians (45%, n = 10) and patients (46%, n = 36) would probably or definitely recommend the platform. Conclusions: Web-based PRO reporting for patients with advanced cancer is feasible. Clinicians and patients found the platform both acceptable and easy to use. Future directions include integration with our EHR, expansion across disease groups and other centers, and creation of workflows that are integrated into routine clinical practice.
Health insurance literacy, status, and financial toxicity in women receiving treatment for metastatic breast cancer.
Authors: Courtney Williams, Stacey A. Ingram, Valerie Lawhon, Clara Wan, Kelly Kenzik, Andres Azuero, Maria Pisu, Jennifer Young Pierce, Janel Lowman, Jonathan Jones, Kendal Dekle, Stephen T. Mennemeyer, Ryan David Nipp, Gabrielle Betty Rocque
Journal: Journal of Clinical Oncology (2019)

96 Background: Though uninsurance rates declined after the Affordable Care Act, the number of underinsured, or individuals who spend &gt; 10% of their income on out-of-pocket (OOP) medical costs, continues to rise. In patients with metastatic breast cancer (MBC), underinsurance may lead to financial toxicity (FT), or patient-level financial burden and distress, since diagnosis and treatment is extremely costly. This study explores health insurance literacy and the association between FT and health insurance status in women receiving treatment for MBC. Methods: This cross-sectional study utilized survey data collected from 2017-2019 in women age ≥18 receiving treatment for MBC at two academic medical centers in Alabama. FT was measured by the Comprehensive Score for Financial Toxicity (COST) tool (11-item scale from 0-44, with lower scores indicating worse FT). Health insurance status and OOP costs were self-reported. Effect sizes were calculated using Cohen’s d or Cramer’s V. Mixed and generalized linear models clustered by site and treating medical oncologist estimated the association between FT and health insurance status. Results: In 81 women with MBC, median COST score was 24 (interquartile range [IQR] 17-30), 44% had private insurance, 40% Medicare, and 16% Medicaid. Though 25% and 33% of surveyed patients did not know their health insurance premium or deductible cost, respectively, privately insured patients more often knew the cost of their premiums (97%; V = 0.58) and deductibles (81%; V = 0.33) compared to publicly insured patients. In adjusted models, FT levels did not differ significantly based on health insurance type (private insurance COST 21, 95% confidence interval [CI] 18-25; Medicaid COST 23, 95% CI 17-29; Medicare COST 24, 95% CI 20-27). However, risk of severe FT (COST ≤13) was 147% higher for privately insured patients versus Medicare beneficiaries (risk ratio 2.47, 95% CI 1.44-4.21). Conclusions: Despite higher levels of health insurance literacy, privately insured patients receiving treatment for MBC may be at increased risk of severe FT. Further research is needed to understand causes of underinsurance in patients with MBC, which could lead to cancer-related FT.
Stop-Codon Mutation In The Extracellular Part Of G-CSFR Leading To G-CSF Unresponsiveness Due To Defects In Erk1/2 Phopsphorylation In a Patient With Severe Congenital Neutropenia
Authors: Olga Klimenkova, Cornelia Zeidler, Julia Skokowa, Karl Welte
Journal: Blood (2013)
Abstract 721: Human Neonatal Cardiac Progenitor Cells Derived Exosomes Induce Cardiomyocytes Proliferation
Authors: Sudhish Sharma, Lina Wang, Chetan Ambastha, Rachana Mishra, Sunjay Kaushal
Journal: Circulation Research (2019)

Background: Human neonatal cardiac progenitor cells (ckit+/CD45-/Lin-, CPCs) improve cardiac function and attenuate adverse left ventricular remodeling after myocardial infarction (MI) through their exosomes (nEXOs). Success of cell therapy to treat injured myocardium depends mainly on reactivation of endogenous quiescent cardiomyocytes to proliferate and recover the lost myocardium. Here, we investigated the mechanism of reactivating quiescent cardiomyocyte proliferation by exosomes. Hypothesis: RNAseq analysis of nEXOs identified miRs which may be responsible for modulation of Hippo signaling, thereby promoting cardiomyocytes proliferation. nEXOs effectively stimulate endogenous cardiomyocyte (CM) proliferation by targeting the Hippo pathway to restore cardiac function in an injured heart. Methods and Results: nCPCs were conditioned for 48 hours in serum free nutrition mix (Ham’sF12) and nEXOs were purified from supernatant using size exclusion chromatography (SEC; CL2B) coupled with ultracentrifugation. nEXOs were quantified by Nanosight (NS300) and characterized by transmission electron microscopy and flow cytometry for the presence of CD63 and CD9. Our results show recovery of cardiac function (ejection fraction = 63.4% vs 40.5%, n=10, p&lt;0.001)) and generation of myocardial mass in a rodent MI model following nEXOs’ intra-myocardial injection. We further show that nEXOs are preferentially acquired by CMs in the border zone of the infarction (m-cherry-Alix labeled EXOs). Our In vitro experiments show that miR-582-3p and miR-7641 (25nM) are the most effective miRs to induce proliferation of quiescent cardiomyocytes (40.1% and 48.8%, respectively, n=3). Increased miR-7641 expression led to a profound increase in quiescent CMs proliferation, in part through repression of the Hippo signal transduction pathway (increased YAP/pYAP ratio). By immunoblotting we show that LATs1/2 (a protein in the Hippo pathway) is directly targeted by miR-7641. nEXOs enriched with miR 7641 promote CM proliferation by 3 folds as compared to non-enriched nEXOs. Conclusion: Our data for the first time demonstrates the ability of nEXOs derived miRNA based therapeutic approaches to activate cardiomyocyte proliferation.
Microrna-Dependent Modulation Of Osteogenesis In a 3D In Vitro Bone Marrow Model System Of Multiple Myeloma
Authors: Michaela R Reagan, Yuji Mishima, Yong Zhang, Patricia Maiso, Salomon Manier, Yu-Tzu Tai, Priya Dhir, Zhi Ning Lu, Masoumeh Memarzadeh, Antonio Sacco, Yosra Aljawai, Susanna Santos, John Ready, David L. Kaplan, Aldo M Roccaro, Irene M. Ghobrial
Journal: Blood (2013)
Abstract 312: SGLT1 is Essential for Cardioprotection During Ischemia-Reperfusion Injury via Enhanced Glucose Utilization in Diet-induced Obese Mice
Authors: Akira Yoshii, Nagoshi Tomohisa, Yusuke Kashiwagi, Haruka Kimura, Yoshiro Tanaka, Yuhei Oi, Keiichi Ito, Takuya Yoshino, Toshikazu D Tanaka, MIchihiro Yoshimura
Journal: Circulation Research (2019)

Recent large clinical trials have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduced cardiovascular events in diabetic patients. However, the regulation and functional role of cardiac SGLTs (SGLT1 is the dominant isoform) compared with those of other glucose transporters (insulin-dependent GLUT4 is the major isoform) remain incompletely understood. Given that glucose is a preferential substrate for myocardial metabolism during ischemia-reperfusion injury (IRI), we hypothesized that SGLT1 contributes to cardioprotection during IRI via enhanced glucose transport, particularly in insulin-resistant phenotypes. The hearts from mice fed a high-fat diet (HFD) for 12 weeks or a normal-fat diet (NFD) were perfused with either non-selective SGLT-inhibitor phlorizin (to inhibit SGLT1) or selective SGLT2-inhibitors (tofogliflozin, ipragliflozin, canagliflozin) during IRI using Langendorff model. After ischemia-reperfusion, HFD impaired left ventricular developed pressure (LVDP) recovery compared with NFD. Although phlorizin-perfusion impaired LVDP recovery in NFD, a further impaired LVDP recovery and dramatically increased infarct size (indicated by CPK release into perfusate and TTC staining) were observed in HFD with phlorizin-perfusion. Meanwhile, none of the SGLT2-inhibitors significantly affected cardiac function or myocardial injury after ischemia-reperfusion under either diet condition. The plasma membrane expression of GLUT4 was significantly increased after IRI in NFD but was substantially attenuated in HFD, the latter of which was associated with a significant reduction in both myocardial glucose uptake and cardiac tissue ATP content. In contrast, regardless of the diet condition, SGLT1 expression remained constant during IRI, whereas SGLT2 was not detected. Of note, phlorizin considerably reduced myocardial glucose uptake and decreased cardiac tissue ATP content after IRI, particularly in HFD. In conclusion, cardiac SGLT1 but not SGLT2 plays a compensatory protective role and contributes to cardiac energy metabolism during acute phase of IRI via enhanced glucose utilization, particularly under insulin-resistant conditions, in which IRI-induced GLUT4 upregulation is compromised.
Prophylaxis Dose Adjustment in Hemophilia a Using a New Version of Population Pharmacokinetics Estimation Model Based on Bayesian Procedure
Authors: José María Sánchez-Raga, Maria Margalida Santandreu Estelrich, Bernat Galmés Sureda, Antonio Palomero Massanet, Guiomar Puget, Antonia Sampol, Mariana Canaro
Journal: Blood (2018)
Regression of Fibrosis Stage With Treatment Reduces Long-Term Risk of Liver Cancer in Patients With Hemochromatosis Caused by Mutation in HFE
Authors: Edouard Bardou-Jacquet, Emilie Morandeau, Gregory J. Anderson, Grant A. Ramm, Louise E. Ramm, Jeff Morcet, Guillaume Bouzille, Jeannette Dixon, Andrew D. Clouston, Fabrice Lainé, Bruno Turlin, Lawrie W. Powell, Yves M. Deugnier
Journal: Clinical Gastroenterology and Hepatology (2019)
Abstract 850: Metabolic Landscape of Human Heart Failure
Authors: Emily Flam, Cholsoon Jang, Kenneth Bedi, Kenneth Margulies, Zoltan Arany
Journal: Circulation Research (2019)

Heart failure is characterized by insufficient pumping to match the needs of the body. Heart failure is thought to be associated with dysfunctional mitochondria and metabolic alterations, but there is little to no direct evidence in humans. The heart metabolizes a variety of substrates for energy production, including fatty acids, glucose, ketones, and branch chain amino acids (BCAAs). In the healthy heart, fatty acids are the main fuel source, and oxidation is balanced with energy need. In heart failure, it is asserted that fatty acid oxidation is suppressed, and glucose utilization is increased, but this has not been directly measured in humans. If true, this metabolic switch toward glucose may contribute to mechanical insufficiency by disrupting the balance between metabolism and energetic need, thus representing a potential area for therapeutic intervention in heart failure. Prior studies were largely performed in animal models, and results are often inconsistent across models and species. Challenges have constrained the use of human myocardium, including costly and cumbersome techniques for in vivo assessment; limited availability of high-quality human myocardial tissue; and low yields and short durability of isolated human cardiomyocytes. We addressed these challenges by taking advantage of human explanted hearts available via the Penn Heart Transplant program to investigate the metabolic differences between failing and healthy human hearts. We performed metabolomics analysis using mass spectrometry on myocardium from 18 failing and 20 nonfailing human hearts. Of the 334 metabolites measured, 99 were significantly different between groups by Wilcoxon test and FDR correction. Metabolite set enrichment analysis revealed that the most enriched pathways included the glycerol phosphate shuttle, ammonia recycling, methylhistidine metabolism, and glutathione metabolism. The mitochondrial electron transport chain, BCAA catabolism, purine metabolism, the urea cycle, gluconeogenesis, glycolysis, ketone body metabolism, and the pentose phosphate pathway were also included in the top 50 most enriched pathways. These data will guide future targeted metabolic studies in human heart failure.
Novel clinical definitions for immune-related adverse events (irAEs): A QI intervention to improve accuracy in irAE diagnosis.
Authors: Amanda Brito, Shilpa Grover, Raja-Elie E Abdulnour, PRABHSIMRANJOT SINGH, Eric Yenulevich, Kenneth L. Kehl, Jian Ni, Nicole R. LeBoeuf, Joseph O. Jacobson, Osama E. Rahma
Journal: Journal of Clinical Oncology (2019)

290 Background: Use of immunotherapy has increased exponentially with survival benefit in many malignancies. As a result, suspected irAEs are commonly encountered, but lack of a gold standard for diagnosis puts patients at risk. We describe preliminary results of a QI project to improve accuracy of irAE diagnosis. Methods: Specialists at our institution created algorithms to define the likelihood of immune-related hepatitis, colitis, and pneumonitis based on clinical data, diagnostic results, and treatment response. Records of patients admitted from June-November 2018 with possible irAE were retrospectively reviewed by an oncology provider and an immunotoxicity specialist. A web-based tool automated irAE likelihood from clinical data based on the aglorithms. Reviewers could agree or disagree with the result and share their clinical impression. We evaluated concordance between providers and between provider and algorithm. Results: Of 65 patients, most had non-small-cell lung cancer (29%), melanoma (15%), or breast cancer (9%) and were treated with pembrolizumab (48%), nivolumab (23%), or ipilimumab/nivolumab (22%). There were 4 irAE-related deaths and 40 patients (71%) discontinued therapy for presumed toxicity. After 14 cases were excluded due to incomplete information, algorithms were applied to the remaining 51 cases (19 colitis, 8 hepatitis, 24 pneumonitis). The algorithm generated the likelihood of an irAE in 63% of reviews. Overall agreement with the algorithm was 86% (84-100% for individual algorithms), Kappa 0.8 (0.7-1.0). Overall concordance between reviewers was 76% (75-88%), Kappa of 0.7 (0.6- 0.8). Conclusions: While algorithm definitions and provider impressions were fairly consistent, cases lacking a generated likelihood suggest that some clinical scenarios are not addressed. Different interpretation of clinical information or varying experience with irAEs may explain inter-reviewer discordance, which underscores the importance of applying a standardized approach to irAE diagnosis across settings and experience levels. In the next improvement cycle, the algorithm will be refined to broaden algorithm scope, clarify criteria, and improve accuracy.
Medical record documentation of cancer patients after an integrated engagement plan.
Authors: Giovanni M. Bariani, Caroline Macedo, Mariana Da Silva, Karine Yamashita, Amanda Ruiz, Aline Pedroso, Carla Bernardes Ledo, Fabrícia de Santi Silva de Oliveira, Silvia de Lima Vieira, Camila Luciani, Artur Katz
Journal: Journal of Clinical Oncology (2019)

68 Background: Complete and accurate medical record (MR) documentation is essential to quality of cancer patient care, whose complex health and social needs should be addressed during medical consultation. We aimed to evaluate the MR compliance before and after an engagement plan (EP) and an education meeting (EM) for oncologists. Methods: An integrated EP was designed to improve medical notes in a Brazilian cancer center. Firstly, a pool of 160 selected MR of patients with prevalent neoplasms was reviewed to identify frequently missed components. Based on this result, a set of MR documentation standards was developed and presented in an EM for oncologists. To verify its effect, a cross-sectional analysis was performed using 25 standard elements collected from randomized MR before and after the EM such as pathology report, cancer stage, medical history, treatment plan, patient comprehension, and initial psychological assessment. It was given particular emphasis to psychological assessment during the EM as a low documentation of it was identified after the first MR review. The variation of the proportions pre- and post-EM was assessed using the chi-square test. Results: A total of 850 elements were collected from 34 patients’ MR two months pre-EM and 950 elements of 38 patients’ MR two weeks after. Of these patients, pre-EM 18 were under intravenous (IV) therapy and 16 under oral antineoplastic therapy and, post-EM, 14 and 24 patients were under IV and oral therapy, respectively. Pre-EM, MR compliance of patients under oral therapy was 68% and for patients under IV therapy 78% (P = 0.0013). Post-EM, the difference between MR compliance of patients under oral and IV therapy was 6% (82% vs. 88%, P = 0.0167). Overall MR compliance pre-EM was 73% and post-EM 84% (P &lt; 0.0001). Psychological assessment pre- and post-EM were 9% and 50% (P = 0.0002), respectively. Conclusions: Patients under IV therapy have a more accurate MR documentation than patients under oral therapy. Overall compliance of MR documentation was significantly improved after an EM, a part of an integrated EP. Psychological assessment documentation has not only improved, but it is expected that more attention has been given to this valuation by oncologists.
Abstract 586: VA-ECMO Increases Urinary Levels of the Biomarker Kidney Injury Marker-1 (KIM-1) in a Preclinical Model of Acute Myocardial Infarction
Authors: Xiaoying Qiao, Lija Swain, Lara Reyelt, Cody Machen, Andrew Jarrah, Aditya Chennjorwala, Paige Crowley, Shiva Annamalai, Sina Foroutanjazi, Allen Razavi, Navin Kapur
Journal: Circulation Research (2019)

Background: Acute kidney injury (AKI) is associated with increased morbidity and mortality in patients with acute myocardial infarction (AMI). Use of trans-valvular pumps and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for patients with AMI is growing. Trans-valvular pumps transfer rotational kinetic energy to blood and generate flow from the left ventricle into the ascending aorta. VA-ECMO drains blood from the venous system and returns oxygenated blood into the descending aorta, thereby increasing systemic perfusion. The impact of these support strategies on renal blood flow and function remains poorly understood. We hypothesized that compared to a trans-valvular pump, VA-ECMO is associated with increased renal injury in AMI. Methods and Results: Adult male swine were subjected to left anterior descending artery occlusion for 90 minutes followed by either immediate reperfusion (IRI), trans-valvular pumping (Impella CP) or VA-ECMO starting 30 minutes before reperfusion, or sham-operated controls (n=4/group). Compared to IRI, urinary levels of the biomarker kidney injury molecular 1 (KIM-1) were increased by VA-ECMO, not Impella. Inflammatory factors IL6 and IL1beta were increased by VA-ECMO, not Impella in both plasma and cortex tissue by ELISA analysis. KIM-1 protein expression for precursor KIM-1 and the extracellular domain (soluble) of KIM-1, as well as STAT3, HIF1alpha were analyzed by Western blot. Compared to sham, IRI and VA-ECMO reduced levels of soluble KIM-1 and increased levels of the KIM-1 protein precursor, pSTAT3 and HIF1a in the renal cortex. Impella had no impact on these protein levels. Conclusion: This is first study to identify that VA-ECMO, not Impella, increases urinary levels of KIM-1 , a highly sensitive biomarker of acute kidney injury. The shedding of KIM-1 extracellular domain from the renal cortex is associated with systemic inflammatory response. These findings may identity novel approaches to limit renal injury in AMI patients requiring mechanical circulatory support.