tbuckley/cabot-search huggingface dataset:
Abstract 12872: Adherence to Guidelines for Heart Rate in Stable Ischemic Heart Disease in the Primary Care Setting
Authors: Justin Devera, Sonia Lin, Jennifer Marks, Preeti Singhal
Journal: Circulation (2021)

Per 2012 ACC/AHA Guidelines, patients with stable ischemic heart disease (IHD) should be treated with beta-blockers (BB) to target a resting heart rate (HR) of 55-60 bpm due to associations of higher HR with all-cause mortality. We sought to determine adherence to this in the resident primary care (PC) clinic at our institution. Two hundred twenty-nine patients with a medication list in the electronic medical record (EMR) that includes metoprolol succinate or tartrate or carvedilol who were seen in PC clinic in January 2020 were identified. Of these, 100 had a diagnosis of IHD, and their EMR were reviewed for vital signs; medication changes; and contraindications (CI) to BB titration such as hypotension, bradycardia, and max dosing; during their PC and cardiology visits. We found that 10% (10 of 100) had HR within goal during their PC visit, whereas 6 and 84 had HR below and above goal, respectively. Of the 90 whose HR was not at goal, 24 had some perceivable CI to BB titration. Of those without CI to titration, 9% (6 of 66) had their BB increased, 4.5% (3 of 66) had their BB switched to a different medication, and 85% (56 of 66) did not have their BB changed. Of those whose BB was unchanged, 79% (44 of 56) had no other antihypertensive changed. Moreover, 88% (74 of 84) of those with HR above goal had a HR also above goal at their last two PC visits. Sixty-eight of the 100 patients with IHD were also managed by cardiology, and in contrast, 18% (8 of 45) of those with HR not at goal and without CI to titration had their BB dose adjusted at their last cardiology visit. A chi-square test was performed to examine the relation between BB titration and clinic setting with no statistical significance, X 2 (1, N = 106) = 1.18, p = 0.28. In sum, adherence to guidelines for HR in stable IHD were poor and not significantly different in the PC and cardiology settings. Lack of provider initiative, perhaps due to trainee unfamiliarity with guidelines, may be one of many factors and warrants more investigation to improve quality of care.
CTNI-37. ISOEFFECTIVE HYPOFRACTIONATION FOR ELDERLY OR FRAIL PATIENTS WITH A NEWLY DIAGNOSED GLIOBLASTOMA: A POOLED INTERNATIONAL STUDY
Authors: Haley Perlow, Michael Yang, Brett Klamer, Jennifer Matsui, Livia Marrazzo, Beatrice Detti, Marta Scorrsetti, Elena Clerici, Andrea Arnett, Sasha Beyer, Mario Ammirati, Arnab Chakravarti, Raju Raval, Pierina Navarria, Silvia Scoccianti, John Grecula, Joshua Palmer
Journal: Neuro-Oncology (2021)

Abstract PURPOSE The standard of care (SOC) for elderly or frail glioblastoma (GBM) patients is 40 Gy in 15 fraction radiotherapy. However, this regimen has a lower BED compared to the Stupp regimen, 60 Gy in 30 fractions. We hypothesize that isoeffective hypofractionated radiation of 52.5 Gy in 15 fractions (BED equivalent to Stupp) will have superior survival compared to standard of care. METHODS Elderly GBM patients treated with 52.5 Gy in 15 fractions were pooled from 2 phase II studies, 1 phase 1 and a prospective observation study. Overall survival (OS) and progression free survival (PFS) were defined as the time elapsed between surgery/biopsy and death from any cause or progression. Univariate and multivariate analyses were performed. RESULTS 62 newly-diagnosed patients were eligible for this analysis. Median follow-up was 10 months. The median OS and PFS was 10.3 and 6.9 mos, respectively. Patients with KPS ≥ 70 and &amp;lt; 70 had a median OS of 15.3 and 9.5 mos. No survival difference was seen between unmethylated and methylated patients with a median OS of 10.2 and 10.3 months, respectively. Multivariable analysis demonstrated that concurrent chemotherapy was an independent prognostic factor for improved PFS and OS. Grade 3 neurologic toxicity was seen in 2 patients (3.2%). CONCLUSION This is the first pooled, prospective analysis of elderly/frail GBM patients treated with dose-escalated hypofractionated radiation. Treatment was well tolerated and demonstrated excellent OS and PFS, exceeding that from prior elderly trials (Roa; 6.5 mo [poor KPS]/Perry; 9.3mo [good KPS]). This treatment regimen gives the elderly population an alternative to Stupp that is not de-escalating therapy. Future prospective trials are needed to validate these results.
Abstract 12663: Impact of Increased Utilization of Expanded Criteria Donors at a High-Volume Heart Transplant Center: A Quasi-Experimental Analysis
Authors: Brian Wayda, Alexander T Sandhu, Erik J Henricksen, Jeffrey J Teuteberg, Kiran K Khush
Journal: Circulation (2021)

Introduction: Increased use of expanded criteria donors (ECDs) could alleviate the donor shortage in heart transplantation (HT), but whether ECDs confer acceptable outcomes remains unclear. We utilized a “natural experiment” to assess the impact of ECD utilization on outcomes. Methods: We evaluated outcomes before (2011-15; “pre-intervention”) and after (2016-18; “post-intervention”) the adoption of an aggressive ECD utilization strategy at our high-volume HT program. We compared pre- vs. post- intervention changes in outcomes at our program with those occurring concurrently at other programs in the United States. We defined an ECD as a donor with age &gt; 50 years, left ventricular ejection fraction &lt; 50%, and/or coronary artery disease. Results: ECD utilization at our program increased from 10.9% of all HTs pre-intervention to 28.0% post-intervention (p &lt; 0.0001), with a concurrent decrease in ECD utilization nationwide (12.5% to 11.7%; p = 0.08). There was no concurrent change at our program in recipient mix by priority status at listing, blood type, demographics, or comorbidities. Our program experienced significant decreases (pre- vs. post- intervention) in median wait times (67 to 42 days; p = 0.05) and the proportions with prolonged (&gt; 10 days) hospitalization (25.0% to 17.1%; p = 0.04) and any MCS or inotrope requirement (79.4% to 70.6%; p = 0.03) prior to transplant. Nationwide, median wait times were unchanged (p = 0.18) and prolonged pre-transplant hospitalization (p = 0.0009) and MCS/inotrope utilization (p &lt; 0.0001) were increasingly common. At our program, there was no significant change in a composite of death or graft failure at 30 days (2.8% to 1.9%; p = 0.32) or 1 year (6.9% to 8.1%; p = 0.21) post-HT. Concurrently, there were modest changes nationwide in this composite outcome at 30 days (4.3% to 3.7%; p = 0.05) and 1 year (9.9% to 8.6%; p = 0.003). Conclusions: A “natural experiment” employing increased ECD utilization at a high-volume HT program was associated with decreases in wait times, duration of hospitalization, and MCS or inotrope requirement prior to transplant, with no accompanying change in recipient mix or post-transplant outcomes. Broader ECD utilization is likely a safe and resource-saving strategy to alleviate the donor shortage in HT.
Abstract P325: The Role Of Runx1 In Cardiomyocyte Cell Cycle And Ploidy
Authors: Samantha K Swift, Michaela Patterson
Journal: Circulation Research (2021)

Adult mammalian cardiomyocytes (CMs) are thought to be post-mitotic and therefore unable to regenerate the myocardium after injury. In recent years various studies have shown that the adult mammalian CM is capable of a small amount of proliferation, potentially restricted to a subset of CMs. One such study demonstrated that having greater percentages of the rare mononuclear diploid cardiomyocyte (MNDCM) is associated with improved outcomes after myocardial infarction (MI). An accompanying genome-wide association analysis identified genetic loci associated with the frequency of the MNDCM population. One candidate to come out of this screen was Runx1. Concurrently, RUNX1 captured the attention of cardiac regeneration researchers due to its increased presence in disease states, with some suggesting it may be a marker for dedifferentiation (fetal gene induction). One recent study demonstrated improved calcium handling and decreased eccentric hypertrophy following RUNX1 ablation after injury, perhaps corroborating the idea that RUNX1 is involved with CM dedifferentiation. We hypothesize that Runx1 influences dedifferentiation in CMs, impacting ploidy, as well as CM cell cycle activity and post-MI outcomes. We found that CM-specific overexpression (OE) of Runx1 results in a doubling of the MNDCM population, thereby validating its influence on the population. Via multiple contexts including postnatal development and adult injury, knocking out Runx1 decreases DNA synthesis while Runx1 OE increases DNA synthesis. Furthermore, an initial analysis of RNAseq data demonstrates that RUNX1 OE in a neonatal mouse hearts demonstrated differential expression in genes related to cardiac conduction, contraction, heart development, regeneration, and regulation of cell differentiation . After MI in the adult mouse heart, the effects of Runx1 OE resulted in transient benefits which included increased cell cycle activity and preservation of function. These data suggest that Runx1 is not simply a marker of CM dedifferentiation, but also a regulator of the process including cell cycle activation. Ongoing work will tease apart this role in more detail and could establish RUNX1 as a prominent therapeutic target for mitigating effects of cardiac injury.
Abstract 12898: Eosinophilic Myocarditis Following Osimertinib Treatment for Epidermal Growth Factor Receptor Mutated Lung Adenocarcinoma
Authors: Charlotte Andersson, Kaitlin McCarter, Frederick Ruberg, Hans Meier-Ewert, Umit Tapan, Omar Siddiqi
Journal: Circulation (2021)

A 60-year-old man with oligometastatic adenocarcinoma of the lung presented with symptoms of heart failure 6 weeks after initiation of treatment with osimertinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. A transthoracic echocardiography (TTE) showed a moderately sized pericardial effusion, mildly increased left ventricular (LV) wall thickness, and mildly depressed LV ejection fraction (45-50%), without tamponade physiology. His TTE prior to treatment initiation was normal. He endorsed chest pain across the entire chest that had started on the second day after initiation of osimertinib and was worse when laying down. His serum troponin I concentration was elevated to 10.6 ng/mL upon admission and ECG showed sinus tachycardia. He was carefully diuresed with some improvement in symptoms. A peripheral eosinophilia was noted, which raised suspicion for eosinophilic myocarditis. A cardiac magnetic resonance imaging confirmed a mildly reduced LVEF of 51% and mildly increased LV wall thickness. There was diffuse late gadolinium enhancement throughout the entire myocardium, with increased T1 and T2 signals and the extracellular volume was increased to 40%, supporting a diagnosis of perimyocarditis. A left and a right heart catheterization were subsequently undertaken. His coronary arteries were normal and the right heart cathetherization showed unremarkable hemodynamics, including a right atrium pressure of 6 mm Hg, right ventricular pressure of 34/6 mm Hg, pulmonary artery pressure of 33/9 mm Hg, and a pulmonary capillary wedge pressure of 10 mm Hg. A right heart biopsy revealed a dense eosinophilic infiltration of the myocardium, consistent with an eosinophilic hypersensitivity reaction, manifesting as myocarditis. High dose prednisone was initiated and after 2 months of treatment, repeat TTE showed resolution of his pericardial effusion and normalization of the LV wall thickness and LVEF (65%). This case illustrates the value of multi-modality imaging and endomyocardial biopsy to diagnose rare complications of novel, targeted cancer therapeutics.
Food for thought: why is there more airway smooth muscle in asthma?
Authors: Brian G. Oliver
Journal: European Respiratory Journal (2021)

All definitions of asthma include reference to smooth muscle contraction, which manifests as either episodic wheeze, breathlessness, cough, bronchospasm and/or exacerbations. Furthermore, bronchodilators are one of most effective classes of therapeutic for the management of acute exacerbations and long-term treatment of asthma. It is therefore somewhat surprising that the smooth muscle cell is often under researched in comparison to inflammatory and epithelial cells in asthma. This likely relates to the difficulty of obtaining bronchoscopic samples and the expertise required to isolate and grow airway smooth cells in vitro . The in vitro growth of smooth muscle cells from bronchial biopsies was pioneered by the group led by J.L. Black [1]. The first publication from her group characterising airway smooth muscle cells in asthma was published 20 years ago, and described increased proliferation of smooth muscle cells ex vivo from people with asthma. It seems fitting that understanding the cause of this increased proliferation was elegantly investigated by Esteves et al. [2] in this issue of the European Respiratory Journal . Altered lipid metabolism in airway smooth muscle cells in asthma drives hyperplasia and may contribute to increased muscle bulk in vivo <https://bit.ly/3dypJMv>
Liquid biopsy identifies actionable dynamic predictors of resistance to Trastuzumab Emtansine (T-DM1) in advanced HER2-positive breast cancer
Authors: Matteo Allegretti, Alessandra Fabi, Elena Giordani, Cristiana Ercolani, Paolo Romania, Cecilia Nisticò, Simona Gasparro, Vittoria Barberi, Maria Ciolina, Edoardo Pescarmona, Diana Giannarelli, Gennaro Ciliberto, Francesco Cognetti, Patrizio Giacomini
Journal: Molecular Cancer (2021)
EXTH-30. HARNESSING CELLULAR STRESS FOR IMMUNE TARGETING OF DIPGS
Authors: Vidya Gopalakrishnan, Ajay Sharma, Sreepradha Sridharan, Donghang Cheng, Juan Bournat, Shavali Shaik, Arif Harmanci, Robert Siddaway, Tara Dobson, Jyothishmathi Swaminathan, Joshua Allen, Cynthia Hawkins, Soumen Khatua, Lin Xu, Wafik Zaky
Journal: Neuro-Oncology (2021)

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain tumor. An almost ubiquitous dominant negative mutation at lysine (K)-27 in genes encoding histone genes HIST1H3B and H3F3A found in patient tumors is a driver of DIPG development. ONC201, a small molecule DRD2 antagonist and ClpP agonist developed by Chimerix Inc, targets the unfolded protein response (UPR) and integrated stress response (ISR) signaling. It is under clinical investigation in patients with recurrent H3K27M DMGs. In adults, single agent studies have shown durable objective responses when administered orally. A multi-arm, non-randomized multi-institutional Phase I clinical trial (NCT03416530) for pediatric patients with H3K27M DMGs is open and accruing. Preliminary results suggest that the drug has a favorable safety profile and holds promise for patients with DIPGs and other midline gliomas. However, the mechanism of action of ONC201 against DIPGs warrants further study. Here, we show that ONC201 is cytotoxic to DIPGs in vitro and in vivo. RNA Seq analyses revealed cell context specific deployment of PERK-activated UPR and calcium signaling-associated RON tyrosine kinase-macrophage stimulating protein (MSP) signaling in DIPGs. Single cell proteomic assays revealed substantial heterogeneity in the sensitivity of DIPG cells to ONC201, and identified stem-like sub-populations of H3K27M DIPGs with intrinsic insensitivity to the drug. ONC201 treatment, which induces cellular stress, also sensitized DIPG cells to cytolytic activity by ex-vivo expanded and activated innate immune cells, in vitro. Ongoing in vivo experiments are expected to support a novel investigational study in patients with midline gliomas.
Abstract 13341: Enhanced External Counterpulsation Attenuates Coronary Microcirculation Dysfunction in Coronary Artery Disease With Diabetes: Primary Results of EECP-CMD Study
Authors: jianwen Liang, Wenbin Wei, Jian Shi, Hui Huang, Jiansheng Wu, Guifu Wu
Journal: Circulation (2021)

Introduction: Coronary microcirculation dysfunction (CMD) is recognized as a pivotal pathophysiological change of coronary artery disease (CAD) with diabetes, however, there is little evidence for CMD medication treatment. Though enhanced external counterpulsation (EECP), a non-invasive therapy to increase shear stress of coronary flow, has been proved to release angina and restore endothelial capacities, whether EECP could attenuate CMD remains unknown. Hypothesis: EECP could attenuate CMD in patients of CAD with diabetes. Methods: This is a single center, prospective, randomized, single blind, control clinical trial (ChiCTR1800019060). Forty-eight patients [age: (57.7±8.5) yrs, 30 males] diagnosed with CAD and diabetes were enrolled during March 2019 and October 2020 in the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China. The main exclusion criteria are as follows: type 1 diabetes or diabetes history≤3 years; ≥ 70 years old; acute coronary syndrome; chronic total occlusion lesions and contraindications for EECP. All accepted coronary angiography and index of microcirculation resistance (IMR) test with pressure wire, then were randomized to EECP (n=24) or control (n=24) group. All followed standard medication therapy as guidelines recommended, EECP group took 35 times of EECP (60 minutes per time, 5 times a week and 7 weeks for whole procedure) after IMR test. Another IMR test would be done at the end of 12-week follow-up, the occurrence of angina and the metabolic parameters, FMD, PWV, CPET and TTE would also be evaluated. Results: The baseline IMR displayed no significant difference in both groups [EECP: (26.56±3.70) vs. Control: (26.91±4.22), P =0.74], while IMR markedly decreased in the EECP group than control at the end of follow-up [(24.02±3.15) vs. (26.78±4.63), P =0.02]. After multivariate linear regression analysis, FMD and PWV were found to independently correlated with IMR change [FMD: (β=0.45, P =0.014); PWV: (β=-0.27, P =0.038)]. Apart from above, EECP reduced angina occurrence and improved exercise tolerance, early diastolic function of left ventricular. Conclusion: EECP attenuates CMD in CAD with diabetes through coronary microcirculation resistance decrease.
Abstract 13617: Trends and Outcomes of Endocarditis in Patients Undergoing Hemodialysis in Contemporary US Population From 2016-18
Authors: senada malik, Wilbert S Aronow
Journal: Circulation (2021)

Background: With increasing valvular interventions, the incidence of endocarditis in patients on chronic dialysis is significantly increasing. Therefore, we aimed to investigate and compare the contemporary outcomes and trends of endocarditis in patients receiving dialysis. Methods: All hospitalizations with a primary diagnosis of endocarditis between 2016 and 2018 identified in the Nationwide Inpatient Sample were categorized into those with or without chronic dialysis. The primary outcomes were inpatient mortality. Survey techniques were used to do comparative analyses using Stata. Results: Of 53,950 endocarditis hospitalizations that met inclusion criteria, 6,075(11.26%) had endocarditis with chronic dialysis. In-hospital mortality in endocarditis patients with and without chronic dialysis was 18.8% vs. 7.7%. Hospitalizations for endocarditis with chronic dialysis were associated with higher prevalence of diabetes (16.7% vs. 9.8%), hypertension (27.7% vs. 21.2%), coagulopathy (28.7% vs. 19.3%), sepsis (59.3% vs. 43.7%), liver disease (17.2% vs. 11.4%), congestive heart failure (54.5% vs. 39.6%) and renal failure (88.8% vs. 24.0%) as compared with endocarditis without chronic dialysis, all p-values &lt;0.05. Hospitalizations for endocarditis with chronic dialysis was seen less likely in patients with valvular disease (54.9% vs. 67.3%), solid tumor without metastasis (2.2% vs. 4.2%), and smoking (15.2% vs. 25.7%), all p-values &lt;0.05. In a multivariable logistic regression model, the patients with chronic dialysis were two times likely to die from endocarditis OR 1.97 (1.66-2.34; p-value &lt;0.001). Older age, liver disease, and higher elixhauser score were the independent predictors of in-hospital mortality in patients with chronic dialysis who had endocarditis. Conclusions: The prevalence of chronic dialysis has been increasing in patients with endocarditis and it contributes to significant complications including sepsis and mortality.
Abstract 11439: CD47 Functionalization of Bare Metal Stents Reduces In-Stent Restenosis in Hypercholesterolemic Rabbits
Authors: Vaishali Inamdar, Menekhem Zviman, George Bratinov, Emmett Fitzpatrick, Kristin Gardiner, Robert Levy, Stanley J Stachelek, Ilia Fishbein
Journal: Circulation (2021)

Background: Inflammatory mechanisms, which can be affected by altered metabolic profiles such as hypercholesterolemia (HC), contribute to the pathophysiology of in-stent restenosis (ISR). CD47 is a transmembrane protein that is known to inhibit immune cell and platelet activation. Previously in a rat model, we showed that immobilizing peptide sequences of CD47 (pepCD47) to stainless steel (SS) stent surfaces decreased platelet and leukocyte association, and significantly reduced ISR. In these current studies, we use HC rabbits to test the hypothesis that the pepCD47-modified stents will reduce ISR in a pro-atherogenic phenotype. Methods: PepCD47 was attached to SS using polybisphosphonate coordination chemistry and pyridyldithio/thiol conjugation. Bare metal (BM) and pepCD47 SS foils (n=6) were exposed to anticoagulated blood from normocholesterolemic (NC) or HC rabbits for 1 hr. The relative abundance of the surface-associated cells was determined fluorimetrically. Rabbits (n=4) were fed a HC diet for 4 weeks prior to placing BMS or pepCD47 stents bilaterally in the iliac locations. The diet was continued until sacrifice (4 weeks). After chemical dissolution of the stent struts, the segments were paraffin embedded, sectioned, stained and assessed morphometrically. The prevalence of peri-strut macrophages was determined by immunohistochemistry (IHC) as a percentage of a strut circumference infiltrated with macrophages. Results: An 8% decrease of platelet and leukocyte attachment to a pepCD47-derivatized SS compared to BM foils (p=NS) was observed with NC blood, while a significant 35% decrease of cell attachment (p&lt;0.002) was found between the pepCD47 and BM foils exposed to HC rabbit blood. Lumen area increased (25%) whereas the neointimal area, % stenosis and neointima to media ratio decreased (23%, 25%, and 25% p=0.04, respectively) in the arteries treated with pepCD47 stents compared to BMS controls. IHC showed a 34% reduction of macrophage infiltration in the peri-strut area (p=0.048). Conclusion: These results are the first to show the anti-restenotic properties of pepCD47 modified stents in a translational HC rabbit model. The anti-restenotic effects are likely due to CD47-mediated reduction of stent-triggered inflammation.