tbuckley/cabot-search huggingface dataset:
Entinostat plus Pembrolizumab in Patients with Metastatic NSCLC Previously Treated with Anti–PD-(L)1 Therapy
Authors: Matthew D. Hellmann, Pasi A. Jänne, Mateusz Opyrchal, Navid Hafez, Luis E. Raez, Dmitry I. Gabrilovich, Fang Wang, Jane B. Trepel, Min-Jung Lee, Akira Yuno, Sunmin Lee, Susan Brouwer, Serap Sankoh, Lei Wang, David Tamang, Emmett V. Schmidt, Michael L. Meyers, Suresh S. Ramalingam, Elaine Shum, Peter Ordentlich
Journal: Clinical Cancer Research (2020)

New therapies are needed to treat immune checkpoint inhibitor-resistant non-small cell lung cancer (NSCLC) and identify biomarkers to personalize treatment. Epigenetic therapies, including histone deacetylase inhibitors, may synergize with programmed cell death-1 (PD-1) blockade to overcome resistance. We report outcomes in patients with anti-programmed cell death ligand-1 [PD-(L)1]-resistant/refractory NSCLC treated with pembrolizumab plus entinostat in ENCORE 601.The expansion cohort of ENCORE 601 included patients with NSCLC who previously experienced disease progression with immune checkpoint inhibitors. The primary endpoint for the phase II expansion cohort is overall response rate (ORR); safety, tolerability, and exploratory endpoints are described.Of 76 treated patients, 71 were evaluable for efficacy. immune-regulated RECIST-assessed ORR was 9.2% [95% confidence interval (CI): 3.8-18.1], which did not meet the prespecified threshold for positivity. Median duration of response was 10.1 months (95% CI: 3.9-not estimable), progression-free survival (PFS) at 6 months was 22%, median PFS was 2.8 months (95% CI: 1.5-4.1), and median overall survival was 11.7 months (95% CI: 7.6-13.4). Benefit was enriched among patients with high levels of circulating classical monocytes at baseline. Baseline tumor PD-L1 expression and IFNγ gene expression were not associated with benefit. Treatment-related grade ≥3 adverse events occurred in 41% of patients.In anti-PD-(L)1-experienced patients with NSCLC, entinostat plus pembrolizumab did not achieve the primary response rate endpoint but provided a clinically meaningful benefit, with objective response in 9% of patients. No new toxicities, including immune-related adverse events, were seen for either drug. Future studies will continue to evaluate the association of monocyte levels and response.
Attention-Based Deep Neural Networks for Detection of Cancerous and Precancerous Esophagus Tissue on Histopathological Slides
Authors: Naofumi Tomita, Behnaz Abdollahi, Jason Wei, Bing Ren, Arief Suriawinata, Saeed Hassanpour
Journal: JAMA Network Open (2019)

Deep learning-based methods, such as the sliding window approach for cropped-image classification and heuristic aggregation for whole-slide inference, for analyzing histological patterns in high-resolution microscopy images have shown promising results. These approaches, however, require a laborious annotation process and are fragmented. This diagnostic study collected deidentified high-resolution histological images (N = 379) for training a new model composed of a convolutional neural network and a grid-based attention network, trainable without region-of-interest annotations. Histological images of patients who underwent endoscopic esophagus and gastroesophageal junction mucosal biopsy between January 1, 2016, and December 31, 2018, at Dartmouth-Hitchcock Medical Center (Lebanon, New Hampshire) were collected. The method achieved a mean accuracy of 0.83 in classifying 123 test images. These results were comparable with or better than the performance from the current state-of-the-art sliding window approach, which was trained with regions of interest. Results of this study suggest that the proposed attention-based deep neural network framework for Barrett esophagus and esophageal adenocarcinoma detection is important because it is based solely on tissue-level annotations, unlike existing methods that are based on regions of interest. This new model is expected to open avenues for applying deep learning to digital pathology.
Epicardial adipose tissue is associated with extent of pneumonia and adverse outcomes in patients with COVID-19
Authors: Kajetan Grodecki, Andrew Lin, Aryabod Razipour, Sebastien Cadet, Priscilla A. McElhinney, Cato Chan, Barry D. Pressman, Peter Julien, Pal Maurovich-Horvat, Nicola Gaibazzi, Udit Thakur, Elisabetta Mancini, Cecilia Agalbato, Robert Menè, Gianfranco Parati, Franco Cernigliaro, Nitesh Nerlekar, Camilla Torlasco, Gianluca Pontone, Piotr J. Slomka, Damini Dey
Journal: Metabolism (2020)

We sought to examine the association of epicardial adipose tissue (EAT) quantified on chest computed tomography (CT) with the extent of pneumonia and adverse outcomes in patients with coronavirus disease 2019 (COVID-19).
Abstract 15463: Pre-procedural Inr, Bleeding, and Mortality in the Catheterization Lab: Does INR Still Matter in the Radial First Era?
Authors: Shantum Misra, Bruce W Andrus, James T Devries
Journal: Circulation (2020)

Background: Warfarin anticoagulation presents a common barrier to undergoing cardiac catheterization procedures. Using radial access and other bleeding mitigation strategies, it is not known if elevated INR truly portends an increased risk of adverse events. We sought to understand the relationship between in hospital mortality and bleeding with INR in patients undergoing coronary interventional catheterization procedures. Methods: The prospectively-collected Dartmouth Dynamic Registry was queried for all patients who underwent catheterization with coronary intervention from 2014 to 2018. Of the 5015 patients identified, 2120 patients had a recorded INR value within 24 hours of the procedure. Demographics, procedural variables, and in hospital outcomes were collected. Patients were divided into two groups: INR &amp;lt1.8 and INR &amp;gt1.8. Incidence of bleeding (access site hematoma &amp;gt5cm, post procedure blood transfusion) as well as in-hospital mortality were queried for each group. Stata was used to determine statistical significance, using chi-square analysis for categorical variables and standard t-test for continuous variables. Results: Of the 2120 patients with INR values, 1968 patients were identified with INR &amp;lt1.8 (median INR 1.1; range 0.7-1.7) and 152 patients with INR &amp;gt1.8 (median INR 2.2; range 1.8-11.1). Patients with elevated INRs had higher acuity (urgent or emergent cases) and were older. Other baseline and procedural characteristics were similar. Outcomes between those with elevated INR and those with lower INR values were similar, including access site injury, hematoma, and need for transfusion (Table I). Overall mortality did not differ between the two groups. Conclusion: When compared to patients with INR &amp;lt1.8, patients with INR &amp;gt1.8 are more likely to undergo coronary intervention on an urgent or emergent basis. Despite this, there is no difference in bleeding, need for transfusion, or overall in-hospital mortality.
Abstract 12928: Vascular Complications in Covid-19 and Role of Zinc in Viral Inhibition
Authors: Donghui Zhu, Zhen Zhao
Journal: Circulation (2020)

Although COVID-19 is associated with severe respiratory dysfunctions, conspicuous vascular complications and neurological manifestations have been reported worldwide. Of note, two distinctive features have been noticed in severe patients, progressive increase of inflammation and an unusual trend of hypercoagulation. Interestingly, evidence is mounting that healthy blood vessels protect children from serious effects of COVID-19, such as stroke. These findings suggest vascular complications play a key role in the progress of COVID-19, warranting an investigation to its pathophysiology and treatment strategy related to vascular cells. Cell entry of this SARS-CoV-2 virus depends on binding of the viral spike (S) proteins to cellular receptor ACE2, which could be a key target for blocking the viral entry into host cells. ACE2 is a zinc (Zn) binding metallopeptidase while Zn possesses distinct antiviral properties against many human viruses including coronaviruses. Although the mechanistic studies are lacking, Zn appears to inhibit viral protease and polymerase enzymatic processes, and physical processes such as virus attachment, cell entry, and uncoating. In fact, our data showed that ACE2 has multiple affinity binding sites for Zn. Excess bindings of ionic Zn to ACE2 led to its conformational or functional change, therefore, interfering with its ability to metabolize its substrate as well as inhibiting its binding to S protein. Computational modeling also revealed that one critical Zn binding motif is located in ACE2’s binding domain to S protein, and docking affinity of S protein to ACE2 was significantly reduced after Zn binding to this specific site. Moreover, cell and animal studies using pseudo-virus bearing CoV-2-S protein validated that significantly lower infection of vascular cells in the presence of Zn was observed. Thus, targeting vascular complications in COVID-19 may offer strong benefits including the potential therapeutic role of Zn.
Abstract 14469: The Automatically Assessed P-wave Notch Associated With Not Only Left Atrial Enlargement but Also Cardio-ankle Vascular Index in Patients With Cardiovascular Risks: The Coupling Study
Authors: Tomoyuki Kabutoya, Satoshi Hoshide, Kazuomi Kario
Journal: Circulation (2020)

Background: The notched P-wave characteristics is associated with atrial remodeling. However, the relationship between notched P-wave characteristics and atherosclerosis remains unclear. Hypothesis: We hypothesized that notched P-wave would associated with measurements of atherosclerosis in patients with cardiovascular risk factors. Methods: We enrolled 4,877 subjects from the coupling Study who had ≥1 of cardiovascular risk factors. Twelve-lead electrocardiography was conducted, and the peak-to-peak distance in the M-shape was calculated automatically using a 12-lead ECG Analysis system (Fukuda Denshi, Tokyo). P waves were defined as "notched" if the peak-to-peak distance in the M-shape was ≥40 msec in lead II. We measured cardio-ankle vascular (CAVI), NT-proBNP, and Troponin T. We also assessed the left atrial diameter and left ventricular mass index (LVMI) by echocardiography in 501 patients. Results: The CAVI with notched P wave were significantly higher than those in the patients without notched P wave (9.75±1.56 vs. 8.86±1.37, p&lt;0.001). The LA diameter, LVMI, and BNP in the patients with notched P wave were significantly higher than those in the patients without notched P wave (LA dia.: 40.2±7.0 vs. 37.0±5.0 mm, p=0.008; LVMI: 105.7±25.7 vs. 96.9±25.2 g/m 2 , p&lt;0.001; median BNP: 41.6 vs. 16.5 pg/dL, p&lt;0.001). A multivariate regression analysis including age, gender, smoking, history of hypertension, dyslipidemia, diabetes revealed that notched P wave was independently associated with an increase of CAVI (odds ratio 2.14, 95%CI 1.40-3.27, p&lt;0.001). Conclusions: The automatically assessed P-wave notch associated with not only left atrial enlargement but also CAVI in patients with cardiovascular risks.
Immunosenescence: a key player in cancer development
Authors: Jingyao Lian, Ying Yue, Weina Yu, Yi Zhang
Journal: Journal of Hematology & Oncology (2020)

Immunosenescence is a process of immune dysfunction that occurs with age and includes remodeling of lymphoid organs, leading to changes in the immune function of the elderly, which is closely related to the development of infections, autoimmune diseases, and malignant tumors. T cell-output decline is an important feature of immunosenescence as well as the production of senescence-associated secretory phenotype, increased glycolysis, and reactive oxygen species. Senescent T cells exhibit abnormal phenotypes, including downregulation of CD27, CD28, and upregulation of CD57, killer cell lectin-like receptor subfamily G, Tim-3, Tight, and cytotoxic T-lymphocyte-associated protein 4, which are tightly related to malignant tumors. The role of immunosenescence in tumors is sophisticated: the many factors involved include cAMP, glucose competition, and oncogenic stress in the tumor microenvironment, which can induce the senescence of T cells, macrophages, natural killer cells, and dendritic cells. Accordingly, these senescent immune cells could also affect tumor progression. In addition, the effect of immunosenescence on the response to immune checkpoint blocking antibody therapy so far is ambiguous due to the low participation of elderly cancer patients in clinical trials. Furthermore, many other senescence-related interventions could be possible with genetic and pharmacological methods, including mTOR inhibition, interleukin-7 recombination, and NAD+ activation. Overall, this review aims to highlight the characteristics of immunosenescence and its impact on malignant tumors and immunotherapy, especially the future directions of tumor treatment through senescence-focused strategies.
Abstract 17002: Assessment of Exercise Function in Children With Hypertrophic Cardiomyopathy
Authors: Robert Przybylski, Mark E Alexander, Steven D Colan, Christa Miliaresis, Jonathan Rhodes
Journal: Circulation (2020)

Introduction: Hypertrophic cardiomyopathy (HCM) accounts for nearly half of pediatric cardiomyopathies. While impaired exercise function has been described in adults with HCM, little is known about exercise function in children with HCM. Hypothesis: Children with HCM have impaired exercise function. Methods: A retrospective cohort study was performed. Pts &lt;21 years with a diagnosis of HCM with a cardiopulmonary exercise test (CPET) between November 1, 2002 and May 31, 2019 were included. Pts with syndromic HCM were excluded. CPETs with respiratory exchange ratio &lt;1.09 were excluded. We compared indices of exercise performance to established population normal values using one-sample T-tests. In pts with multiple CPETs, we compared indices of exercise performance from the first to last CPET using paired T-tests. Results: We identified 124 pts with 240 CPETs. The average age at time of CPET was 14.8 ± 3.0 years. Average %predicted peak VO2 (78 ± 20%) was significantly less than the population average (p &lt;0.01), though there was wide variability (range 35-152% predicted). Peak VO2 was &lt;85% predicted in 67%, &lt;50% predicted in 7%, and absolute peak VO2 was &lt;25 cc/kg/min in 30% of tests. However, %predicted peak VO2 was &gt;100% in 13% of tests. The %predicted peak O2 pulse (88 ± 21%; p &lt;0.01; a surrogate for the forward stroke volume at peak exercise) and the %predicted peak heart rate (88.0 ± 12%; p &lt;0.01) were significantly lower than established population normal values. In 63 pts with multiple CPETs, significant declines in %predicted peak VO2 (83 ± 20% v. 75 ± 19%; p &lt;0.01) and O2 pulse (92 ± 22% v. 86 ± 21%; p &lt;0.01) were observed at an average interval of 4.5 years. We found no statistically significant association between %predicted peak VO2 and interventricular septal thickness, resting left ventricular outflow tract gradient or echocardiographic indices of diastolic left ventricular function. Conclusions: Exercise function is at least moderately impaired in a substantial portion of children with HCM and this impairment tends to worsen over time. However, there is a significant subset of patient with remarkably well-preserved exercise function. Echocardiographic measurements did not correlate with exercise function in our cohort.
Modern Treatment Methods of Heart Failure
Authors: UA Eyubova
Journal: Clinical Cardiology and Cardiovascular Interventions (2020)

Modern methods of treatment of heart include, first of all, pathogenetic therapy and modern methods of treatment. Complete pathogenetic treatment has been achieved after the use of sacubitril / valsartan which is neprilysin inhibitor, whose use has been initiated in recent years. According to data provided in 2017, 26 million people worldwide suffer from heart failure.
Abstract 163: Association of Diabetes With Coronary Artery Calcium in South Asians, African Americans, Caucasians, Chinese, and Hispanics: The Multi-Ethnic Study of Atherosclerosis (MESA) and the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study
Authors: Ned Premyodhin, Wenjun Fan, Millie Arora, Masood Younus, Matthew J Budoff, Alka M Kanaya, Namratha Kandula, Latha Palaniappan, Jamal S Rana, Nathan D Wong
Journal: Circulation (2020)

Introduction: South Asians (SA) have increased atherosclerotic cardiovascular disease (ASCVD) risk and SA ethnicity is considered a “risk-enhancing factor” in the latest prevention guidelines. Diabetes mellitus (DM) is common in SA, but it is not known how pre-DM or DM may contribute to subclinical atherosclerosis in SA compared to other ethnic groups. We examined the association of pre-DM and DM to coronary artery calcium (CAC) in SA compared to 4 other ethnic groups. Methods: We studied data from SA, African Americans (AA), non-Hispanic whites (NHW), Chinese (CH), and Hispanics (HS) aged 45-84 without known ASCVD. SA were taken exclusively from MASALA and other groups from MESA. The prevalence of CAC 0, 1-99, 100-399, and 400+ were examined among those who were normoglycemic, pre-DM and DM. Multiple logistic regression adjusted for age, sex, smoking, cholesterol, and blood pressure identified the associations of pre-DM and DM (compared to normal glucose) on the odds of any CAC &gt; 0 and significant CAC ≥ 100 by ethnicity. Results: Of the 7587 included individuals, mean age was 62±10 years, with 48% men, 10% SA, 25% AA, 34% NHW, 11% CH and 20% HS. The prevalence of pre-DM and DM varied significantly (p &lt; 0.01) across ethnic groups: SA (25% and 21%), AA (15% and 18%), NHW (11% and 6%), CH (17% and 13%) and HS (15% and 17%). The prevalence of any CAC and CAC ≥ 100 in those with DM were highest in NHW (80% and 48%) and SA (72% and 41%). Pre-DM was only associated with CAC ≥ 100 in NHW (OR = 1.5, p &lt; 0.01). Compared to other groups, SA with DM (compared to those normoglycemic) had the highest odds ratios (ORs) for CAC &gt; 0 (OR = 3.35, p &lt; 0.01) and CAC ≥ 100 (OR = 3.10, p &lt; 0.01) (p = 0.01 and 0.07 for ethnicity interactions, respectively) (Table). Conclusions: Diabetes was associated with higher odds of any or significant CAC among SA compared to other ethnic groups. Ongoing longitudinal follow-up of the MASALA study cohort might help explain if DM contributes to the often premature ASCVD outcomes in SA.
Evaluation of Adjuvant Treatments for T1 N0 M0 Triple-Negative Breast Cancer
Authors: Zhen Zhai, Yi Zheng, Jia Yao, Yu Liu, Jian Ruan, Yujiao Deng, Linghui Zhou, Peng Zhao, Si Yang, Jingjing Hu, Bajin We, Ying Wu, Dai Zhang, Huafeng Kang, Zhijun Dai
Journal: JAMA Network Open (2020)

Adjuvant chemotherapy remains the only recommended treatment for patients with triple-negative breast cancer (TNBC). However, the existing evidence is not enough to recommend adjuvant therapies to patients with T1 N0 M0 TNBC.To evaluate the association of different adjuvant therapies with survival outcome in patients with T1 N0 M0 TNBC stratified by cancer stage and age.Postoperative patients diagnosed as having T1 N0 M0 TNBC between 2010 and 2015 who were enrolled in the Surveillance, Epidemiology, and End Results cancer registry program were included in this population-based cohort study. Data analysis was performed from March 27, 2019, to August 10, 2020.Chemotherapy and radiotherapy.Kaplan-Meier curve and univariate and multivariable Cox proportional hazards regression analyses were performed to compare overall survival (OS) and breast cancer-specific survival (BCSS) between the different treatments.A cohort of 7739 eligible patients (mean [SD] age, 59.5 [12.4] years; all female) were included in the present study. The 5-year OS of the total patients was 91.7% (95% CI, 90.9%-92.5%), and median follow-up was 45 months (95% CI, 44-46 months). Patients aged 70 years and older or with T1a TNBC were more likely to receive adjuvant radiotherapy than chemotherapy. Although any adjuvant therapy could improve OS in T1 N0 M0 TNBC, only chemotherapy was associated with significantly better breast cancer-specific survival (BCSS adjusted hazard ratio: 0.657; 95% CI, 0.460-0.939; P = .02). Adjuvant radiotherapy after breast-conserving surgery was associated with better OS and BCSS in patients aged 70 years and older but not in those younger than 70 years. For patients with T1c BC, chemotherapy after breast-conserving surgery or other surgery was associated with improved OS, whereas only chemotherapy after other surgery was associated with better BCSS.The findings of this cohort study suggest that adjuvant therapies could improve OS in patients with T1 N0 M0 TNBC, whereas only chemotherapy was associated with better BCSS. Older patients with early-stage TNBC may benefit from adjuvant radiotherapy. Administration of adjuvant therapies to patients with different ages and cancer stages should be discussed carefully, which necessitates guidance from updated guidelines.
Abstract 13701: Change in Caregiver Burden From Before to 1 Year After Surgery: Findings From the Sustaining Quality of Life of the Aged: Transplant or Mechanical Support ( <i>Sustain-IT</i> ) Study
Authors: Ike Okwuosa, Adin-cristian Andrei, Menghan Liu, Michael G PETTY, Eileen M Hsich, Mary Amanda Dew, christopher sciortino, Duc T Pham, Clyde W Yancy, Anna Warzecha, Justin HARTUPEE, William Cotts, Salpy Pamboukian, Francis D Pagani, Brent Lampert, Maryl R Johnson, Margaret Murray, Koji Takeda, melana yuzefpolskaya, Scott C Silvestry, John A Spertus, James K Kirklin, Craig Collum, Kathleen L Grady
Journal: Circulation (2020)

Purpose: Caregivers (CGs) for patients with advanced heart failure (HF) assist in HF-specific disease management. In the SUSTAIN-IT study, we reported CG perception of difficulty and time needed to perform tasks for patients awaiting surgery in 3 groups: HF patients awaiting heart transplant (HT) without mechanical support (HT-non-MCS), HF patients awaiting HT bridged with mechanical support (HT-MCS), and HF patient awaiting left ventricular device implantation as destination therapy (DT-MCS). In this report, we compare CG perceived burden from baseline to 1 year after surgery. Methods: We enrolled 301 CGs of HF patients between 10/1/15-12/31/18 from 12 U.S. hospitals: 193 awaiting HT (92 with and 101 without MCS), and 108 scheduled for DT-MCS. Prior to surgery and 3, 6, and 12 months after surgery, CGs completed the Oberst Caregiver Burden Scale (OCBS) which has 15 items with 2 subscales: (1) time and (2) difficulty: range=1-5, higher score=more time required for tasks and more task difficulty. Analyses included t-tests, chi-square tests, and baseline-adjusted linear regression models. Results: CGs were age 61.0±10.3 years, the majority were spouses (85%), female (86%), and white (86%). Average time spent on caregiving was moderate and decreased significantly from baseline to 12 months after surgery for all groups (Figure). DT-MCS CGs spent significantly more time than HT CGs on tasks 12 months after surgery. There were no significant differences in perceived difficulty (which was low) in performing CG tasks in all groups from baseline to 12 months. DT-MCS CGs did perceive tasks to be more difficult than HT CGs at 12 months. Conclusion: CGs of advanced HF patients adapted well to assisting with care, without increased burden, 1 year after HT and DT-MCS surgery. CGs of DT-MCS patients required more time and reported CG tasks to be more difficult than HT CGs. Understanding differences in CG burden will aid in pre surgical risk discussions and post-surgical follow-up.
Clinical Features and Outcomes of Peripartum Cardiomyopathy in Nigeria
Authors: Kamilu M. Karaye, Hadiza Sa’idu, Sulaiman A. Balarabe, Naser A. Ishaq, Umar G. Adamu, Idris Y. Mohammed, Isa Oboirien, Ejiroghene M. Umuerri, Abaram C. Mankwe, Vincent Y. Shidali, Paschal Njoku, Sotonye Dodiyi-Manuel, Taiwo Olunuga, Veronica Josephs, Amam C. Mbakwem, Henry Okolie, Mohammed A. Talle, Muhammad S. Isa, Okechukwu S. Ogah, Simon Stewart
Journal: Journal of the American College of Cardiology (2020)