tbuckley/cabot-search huggingface dataset:
Abstract 11374: Characterization and Prevalence of Ventricular Aneurysms in Patients with Chagas Disease by CMR
Authors: Ramon Medina, Frida T Manrique, Julian F. Forero, Diana Vargas Vergara, González Russi Lorena, Fajardo Jorge, Juan José Diaztagle, Josep Brugada, Alejandro Olaya, Andrés Diaz, Hector M. Medina
Journal: Circulation (2021)

Introduction: Ventricular aneurysms (VA′s) are common in patients with Chagas disease (CD). However, its prevalence in this population is not well defined. We aim to determine the prevalence and characteristics of VA′s in CD patients using cardiac magnetic resonance (CMR). Methods: We performed CMR in a cohort of CD patients and no history of CAD. We included patients older than 18 years with positive CD serology and analyzed their clinical and CMR variables. VA′s were classified according to their location and the apical ones were subclassified as follows: Microaneurysms (limited to the segment AHA-17), macroaneurysms (with extension to apical segments) and giant aneurysms (with extension to midventricular segments). These findings were noticed during cine and late gadolinium enhancement (LGE) sequences (figure 1). Results: A total of 113 patients were included, of whom 57% were women, with a median age of 60 years. VA′s were more common in the apex (96%) vs the infer-lateral wall (4%) with a total prevalence of 23%. Among the 3 VA′s subtypes, macroaneurysm was the most common (48%) followed by microaneurysm (36%) and giant aneurysm (16%). Patients with VA′s had lower LVEF and higher ventricular volumes compared to those without VA′s. LGE was more frequent and had a larger extension in patients with VA′s (Table 1). Ventricular thrombi were identified in 15% of the patients with VA′s. Conclusions: In our cohort of CD patients, almost a quarter of the population presented with VA′s during CMR and most of them were located in the apical segments. Of these, macroaneurysm was the most frequent subtype followed by microaneurysm. VA’s are associated with ventricular thrombi in this population.
Abstract 10478: Comprehensive Mechanical Modelling of Thoracic Endovascular Aortic Repair in Type A Aortic Dissection
Authors: Xiaoxin Kan, Xun Yuan, M Yousuf Salmasi, James Moore, Sumesh Sasidharan, athanasios athanasiou, Xiao Y Xu, Christoph A Nienaber
Journal: Circulation (2021)

Background: Thoracic endovascular aortic repair (TEVAR) in selected proximal (Stanford type A) aortic dissection (TAAD) cases has been reported, however, the limitation and criteria for TEVAR applied in TAAD remain controversial. Virtual stent-graft (SG) deployment simulation based on the finite element method is an emerging tool that allows TEVAR to be reproduced for detailed analysis of biomechanical interaction between native vessel wall and SG device. Methods: A TAAD patient underwent an unsuccessful TEVAR followed by salvage open surgical repair. Pre-TEVAR CT angiogram was used to establish the 3D geometry of the dissected aorta for later analysis. Perioperative DSA was used to measure the aortic root motion and determine SG position in the simulation model. Specimen of the harvested aortic tissue was used for histological analysis and tensile test to define isotropic hyperelastic properties of the aortic wall. Results: Aortic root motion was decomposed into a component normal to the sinotubular junction (STJ) and a component parallel to the STJ. The largest motion was 4.14 mm in normal direction and 3.5 mm in parallel direction. The continuous motion was used to define the displacement boundary condition at the aortic root in a finite element model. The histology revealed preserved both elastic fibres and collagen at the proximal landing zone. A small area of inflammatory infiltration was noted at the tunica externa which may related to the dissected lamella. Tensile testing showed that the aortic wall ruptured at the stress of 250-1250 kPa while the lamella ruptured at 80-160 kPa. Simulation precisely reproduced the SG configuration after TEVAR procedure. Maximum principal stress at 301 kPa was found on the lamella during simulation, which is significantly higher than stress tolerance of the lamella. Conclusion: Microstructure of the lamella and aortic wall components determine the capacity in resisting SG induced focal stress. During the deployment, the proximal end of SG landed directly onto the lamella where the maximum stress exceeded the tolerance of the lamella thus causing rupture and allowing the SG to penetrate into the false lumen.
Abstract 10598: The Impact of Covid-19 on Excess Deaths Among Patients with Heart Failure
Authors: Lauren Gilstrap, Weiping Zhou, Jonathan Skinner
Journal: Circulation (2021)

Introduction: During the COVID-19 pandemic in 2020, patients with heart failure (HF) accounted for a large fraction of COVID-19 mortality. In addition, studies suggested that lockdowns and other restrictions may have increased mortality in this population, even among those without COVID-19. The purpose of this study is to provide an overarching measure of excess mortality for HF patients during 2020 in contrast to other Medicare enrollees age 65+ without HF, including those living in the community and in nursing homes. Methods: We used 100% fee-for-service Medicare Parts A and B between January 1, 2019 and December 31, 2020. Using International Classification of Diseases (ICD) 10 codes in the preceding year, we created 4 cohorts: 1) HF; 2) non-HF, 3) HF living in the community; 4) HF living in the nursing homes. We calculated excess deaths in 2020 by comparing 2020 observed mortality to corresponding rates in 2019 for each of the four groups; adjusted for age, sex and region. Results: In 2020, excess mortality was lower for patients with HF (1.13), compared to patients without HF (1.21; difference -0.08 for HF, p &lt;0.001). Among Black, Hispanic and Asian patients, excess mortality was higher overall, but still lower for with HF compared to those without HF (Figure 1). Patients with HF living in nursing homes also experienced overall higher excess mortality, but nursing home residents with HF also experienced less excess mortality (1.24) than nursing home residents without HF (1.39, p &lt;0.001). Conclusions: Mortality rates rose for all elderly groups during 2020, but HF patients’ excess mortality rose by less than those without HF, including among populations with known high burdens of COVID-19. Additional work is needed to understand the mechanism driving this, but restricted dietary options and improved medication compliance during lockdown may be playing a role.
EPCO-31. GERMLINE AND SOMATIC MUTATIONS IN PEDIATRIC GERM CELL TUMORS
Authors: Dong Song, Yang Zhao, Quanhua Mu, Zhuangzhuang Liang, Jiajia Wang, Liangliang Cao, Luonan Chen, jie ma, Jiguang Wang
Journal: Neuro-Oncology (2021)

Abstract Pediatric germ cell tumors (pGCTs), a group of germ-cell-originated neoplasms, currently lack sufficient study. Although somatic activation of KIT/AKT and RAS/MAPK pathways have been revealed, no driver mutations have been detected in most of GCT cases. To extensively explore germline and somatic mutations, we analyzed genomic and/or transcriptomic sequencing data of 236 pGCTs, including data from not only public datasets but also newly collected whole-genome-sequencing data of tumor samples together with case-unaffected-parents trios collected in Shanghai Xinhua Hospital. A new computational pipeline was developed and carried out to identify functional germline and somatic variants. Overall, &amp;gt; 30,000 germline and &amp;gt; 100,000 somatic mutations were detected and prioritized. Particularly, we found germline trisomy 21 in three cases, germline XXY in five cases, and one germline XO, demonstrating the enrichment of germline chromosomal abnormality in pGCTs (p-value &amp;lt; 0.0001). We identified 196 loss-of-function-like inherited germline mutations involving CBL (4/212), PTEN (3/212), TEX11 (2/212), and ATM (1/212). In addition, we detected 2,160 de novo germline mutations (DNMs), and showed an average of 69.7 DNMs per proband, which is compatible to the previously reported incidence. Moreover, we discovered recurrent somatic mutations in known driver genes such as KIT (27/110), KRAS (10/110), NRAS (4/110), MTOR (5/110), PTEN (3/110), and CBL (2/110). Interestingly, somatic hotspot RRAS2 mutations were detected in seven of 110 cases. Subsequent clinical association analysis showed that patients who harbored RRAS2 mutations were younger than those harboring KRAS mutations (p-value &amp;lt; 0.05). Somatic copy number changes were frequently observed, including chr12p+ (47/110), chr21q+ (47/110), chrX+ (34/110), chr13q- (27/110), and chr20q+ (26/110). Furthermore, we identified chromoplexy in nine out of 62 cases, and this alteration is significantly enriched in yolk sac tumors with the occurrence 7/11. Collectively, portraying the mutational landscape of pGCTs, we revealed its disease etiology and potential new drug targets.
IMMU-08. NOVEL NANOPARTICLE-BASED DELIVERY OF H3.3K27M PEPTIDE TO TUMOR-ASSOCIATED MACROPHAGES ENHANCES THE TUMOR HOMING OF H3.3K27M-TCR TRANSDUCED T-CELLS IN HLA-A2/DR1 TRANSGENIC MICE WITH H3.3K27M+
Authors: Akane Yamamichi, Polly Chuntova, Bunta Kakihara, Tiffany Chen, David Diebold, Naozumi Harada, Kazunari Akiyoshi, Hiroshi Shiku, Hideho Okada
Journal: Neuro-Oncology (2021)

Abstract We have identified a novel HLA-A*02:01-restricted CD8 T-cell epitope encompassing the H3.3K27M mutation and a corresponding high-affinity T-cell receptor (TCR) that recognizes the epitope. While the development of adoptive cell transfer therapy using TCR-transduced T-cells holds a promise, we still need to overcome multiple challenges, such as suboptimal T-cell trafficking and the immunosuppressive environment of malignant glioma. For example, tumor-associated macrophages (TAMs) mediate immunosuppression but do not function as effective antigen-presenting cells. We have developed a novel cholesteryl pullulan (CHP) nanogel as a highly biocompatible and efficient vaccine delivery system targeting TAMs. In this study, we investigated whether the CHP nanogel loaded with the H3.3K27M peptide would deliver the peptide to TAMs and convert TAMs to better antigen-presenting cells that enhance the anti- H3.3K27M+ glioma activity of the TCR-transduced T-cells. As a clinically relevant mouse model, we used HLA-A2/HLA-DR1-transgenic mice and generated a syngeneic glioma cell line that expresses H3.3K27M from their astrocytes. We also generated a retroviral vector encoding the H3.3K27M-specific TCR for transduction of mouse T cells. HLA-A2/HLA-DR1-transgenic mice bearing day 16 intracerebral H3.3K27M+ glioma received an intravenous administration of the CHP nanogel along with poly-ICLC, a Toll-like receptor 3 agonist. The mice then received an intravenous infusion of TCR-transduced or control, non-transduced T-cells on the following day. The triple combination regimen with the CHP, poly-ICLC and TCR-transduced T-cells significantly suppressed the tumor growth, associated with increased levels of T-cell infiltration into the tumors compared with the dual-therapy with poly-ICLC and TCR-T-cells without the CHP. Furthermore, TAMs isolated from CHP-treated mice showed evidence of CHP-uptake, abilities to stimulate proliferation of TCR-transduced T-cells, and higher levels of HLA.A2 expression. These results suggest that the antigen-loaded CHP nanogel can promote the local antigen-presentation to T-cells and represent a promising approach for improving the efficacy of adoptive T-cell therapy for gliomas.
80. Depletion of High-Content CD14+ Cells from Apheresis Products is Critical for the Successful Transduction and Expansion of CAR T Cells During Large-Scale cGMP Manufacturing
Authors: Xiuyan Wang, Jinrong Qu, Jolanta Stefanski, Fang Du, Oriana Borquez-Ojeda, Annisha Hack, Isabelle Riviere
Journal: Molecular Therapy (2015)

Adoptive transfer of chimeric antigen receptor (CAR) engineered T cells holds great promise as a novel strategy to treat patients with cancer. Apheresis products are a major source of starting material for large-scale T cell selection using CD3/28 magnetic beads. At the time of collection, the composition in various cell lineages is highly variable. We have successfully manufactured CAR T cell products starting from apheresis products containing as few as 0.5% to 3% of CD3+ cells. However, we have experienced manufacturing challenges with apheresis products containing a high fraction of CD14+ cells. We conducted a study with an apheresis product derived from a patient with acute lymphoblastic leukemia containing 70% CD14+ cells. 350 × 106 CD3+ cells were selected from the cryopreserved apheresis product using CD3/28 magnetic beads either with or without a prior 1.5 hr monocyte/granulocyte adherence step. This short adherence procedure decreased the CD14+ cell composition from 70% to 45%. A second overnight depletion by adherence in T-flasks and re-stimulation with CD3/28 magnetic beads on day 1 were also performed in the depleted group to ensure the proper activation of CD3+ cells. On day 3, 350×106 vs 20 x106 total cells were recovered from each group without and with the depletion step, respectively. Selected cells from both groups were transduced using the same dilution of vector stocks at a cell concentration of either 0.4×106/mL or 0.2×106/mL in tissue culture bags. On day 7, we observed a drastic difference in transduction efficiency between the group without depletion (4.5%) and the group in which the CD14+ cells were depleted (38%). Moreover, starting with 108 × 106 selected cells on day 3, a mere total of 12.3 × 106 (14.8% CD3+) were recovered on day 11 in the group without depletion. By contrast, cells from the depleted group expanded 350 fold from day 3 to day 10 (100% CD3+). Our results suggest that high CD14+ cell content poses a manufacturing challenge when the selection of the CD3+ cells in the apheresis product is performed with CD3/CD28 magnetic beads. The CD14+ cell threshold for successful manufacturing without depletion remains to be determined. However, monitoring the CD14 cell content and depleting these cells from starting apheresis products with high CD14 content prior to CD3/CD28 magnetic bead selection are critical to ensure success of the CAR T cell manufacturing process.
Abstract 10807: Pace-Capture versus No Pace-Capture Guided Ablation for Atrial Fibrillation: Systematic Review and Meta-Analysis
Authors: Kuldeep Shah, Siddharth Shah, Mohit K Turagam, Rahul Bhardwaj, Tahmeed Contractor, Ravi Mandapati, Andrea Natale, Dhanunjaya Lakkireddy, Jalaj Garg
Journal: Circulation (2021)

Introduction: Radiofrequency catheter ablation through circumferential lesions around pulmonary veins (PVs) ostia has been shown to be effective for treating atrial fibrillation. Arrhythmia recurrence has largely been due to recovery of conduction between PVs and left atrium. Hypothesis: To determine the efficacy of unexcitability to pacing along the ablation line as an endpoint of the PV isolation procedure. Methods: Electronic searches on PubMed, The Cochrane Library, EMBASE, EBSCO, Web of Science, and CINAHL databases from the inception through June 7, 2021was performed. Statistical analysis was performed using meta-package for R version 4.0 and Rstudio version 1.2. The primary outcome was recurrent atrial arrhythmias. Secondary outcomes were procedure time (minutes), fluoroscopic time (minutes), and procedural complications. Results: Three eligible studies consisting of 338 patients (Pace-capture group - 168 and No Pace-capture group - 170) were included in the meta-analysis. There was a statistically significant reduction of recurrent atrial arrhythmias in the Pace-capture group vs. No Pace-capture (21% versus 31%, RR 0.68; 95% CI 0.47 - 0.98; p = 0.04). Procedure duration was significantly longer in the pace group {mean difference (MD) 16, 95% CI 6.96-25.05, p&lt;0.001}; however, fluoroscopy times were not different (MD 2.24, 95% CI -0.27-4.75, p=0.08). No difference in procedural-related complications was noted between the two groups (RR 0.33, 95% CI 0.05-2.10; P=0.24). Conclusions: The endpoint of unexcitability along the ablation line was associated with a reduction in recurrent atrial arrhythmia after PV isolation, but as expected, it did prolong procedure time by ~16 min
Abstract 9786: Myocardial Contractile Dysfunction and Anti-Troponin I Immunoreactivity in a Mouse Model of Combination Immune Checkpoint Inhibitors
Authors: Shirley Xu, Badri Karthikeyan, Peninah Pechenik, Sharma Kattel, Joseph Spernyak, Steven Turowski, Swati D Sonkawade, Sarmila Nepali, Umesh C Sharma, Saraswati Pokharel
Journal: Circulation (2021)

Introduction: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many incurable cancers. However, serious cardiotoxic side effects, such as fatal myocarditis, have been reported. Autoimmunity against cardiac proteins has been suspected but the underlying mechanism is not known. Hypothesis: Combination ICIs are more cardiotoxic than monotherapy alone and can induce both T- and B-cell mediated responses against cardiac proteins. Methods: We intraperitoneally administered either 200μg of programmed cell death-1 (PD-1) antibody (Ab), 100μg of cytotoxic T-lymphocyte associated protein-4 (CTLA-4) Ab, both treatment Abs, or IgG control every 3 days for a total of 17 doses in mice. Cardiac function was monitored by MRI and myocardial inflammatory cells were characterized by immunohistochemistry. After identifying specific cardiac troponin I (cTnI) antigenic sequences by bioinformatic analyses, biotinylated peptides were synthesized and immobilized to streptavidin-coated plates for enzyme-linked immunosorbent assays (ELISA) to detect self-reactive anti-troponin Abs. Results: PD-1 Ab, CTLA-4 Ab, and the combination significantly decreased cardiac contractile velocities compared to IgG (peak systolic velocity cm/s: IgG -1.27 ± 0.131, PD-1 Ab -1.14 ± 0.0531, p=0.02 vs. IgG, CTLA-4 Ab -1.07 ± 0.0359, p&lt;0.01 vs. IgG, PD-1+CTLA-4 Ab -1.04 ± 0.0872, p&lt;0.001 vs. IgG). However, ejection fraction (EF) was only reduced with combination treatment (EF%: IgG 60.1 ± 2.80, PD-1+CTLA-4 Ab 56.6 ± 3.17, p=0.03). There were also significantly more myocardial CD8 + cells with combination treatment (cells/mm 2 : IgG 3.03 ± 1.34, PD-1+CTLA-4 Ab 7.93 ± 2.41, p=0.004). Serum ELISA showed cross-reactivity against cTnI, suggesting the formation of auto-antibodies and significantly high titers were detected with combination treatment (450 nm absorbance: IgG 0.162 ± 0.0859, PD-1+CTLA-4 Ab 0.397 ± 0.121, p=0.002). Conclusions: Our study showed that ICI-therapy induced myocardial inflammation (including CD8 + T-cell infiltration), contractile dysfunction, and immune-reactive antibodies directed against immunogenic targets of cTnI. These data suggest a novel mechanism of ICI-induced cardiotoxicity, which warrants further investigation.
Abstract 8887: Impact of Event Rate Assumptions on the Conclusions of Non-Inferiority Coronary Stent Trials
Authors: Matheus Simonato Dos Santos, Ori Ben-Yehuda, Flavien Vincent, Zixuan Zhang, Bjorn Redfors
Journal: Circulation (2021)

Background: Non-inferiority trials are increasingly common in assessing novel therapies. The outcome and interpretation of non-inferiority trials depends on the magnitude of the non-inferiority margin, whether a relative or absolute non-inferiority margin is used, and may be affected by imprecision in event rate estimation. Methods: We performed a systematic review of randomized non-inferiority coronary stent trials published within the past 5 years as a case study. For non-inferiority endpoints with absolute margins, the assumed corresponding relative margin was defined as the ratio of the absolute margin and the assumed event rate, and the observed corresponding relative margin as the ratio between the absolute margin and the observed event rate in the control arm. Results: A total of 58 trials, encompassing 106,989 patients, were identified and analyzed. The event rate in the control arms were overestimated by a median of 28% [2%-74%]. The majority of non-inferiority trials used absolute rather than relative margins (55/58; 94.8%). Due to overestimation, absolute non-inferiority margins became more permissive than originally assumed (observed relative non-inferiority margin 1.62 [1.50-1.80] versus assumed relative non-inferiority margin 1.47 [1.39-1.55], p&lt;0.001). Among trial comparisons that met non-inferiority with an absolute non-inferiority margin, 17/50 (34%) would not have met non-inferiority with a corresponding assumed relative non-inferiority margin. Conclusions: Assumed event rates are often overestimated in non-inferiority coronary stent trials. Because most of these trials use absolute margins to define non-inferiority, such overestimation results in excessively permissive non-inferiority margins.
Abstract 9743: Experiences of and Factors Associated with Dietary Sodium Adherence in Heart Failure From Patients’ and Their Caregivers’ Perspectives: A Qualitative Study
Authors: Seongkum Heo, JinShil Kim, Jae Lan Shim, Tammy Barbe, Vicki Black, Mee Ok Lee
Journal: Circulation (2021)

Introduction: The majority of patients with heart failure (HF) experience high prevalence of HF symptoms, which cause poor health-related quality of life and high rates of hospitalization. Poor dietary sodium adherence is prevalent and adversely affects HF symptoms and hospitalization rates. Support or lack of support from caregivers can affect patients’ dietary sodium adherence. However, experiences in dietary sodium adherence from both patients’ and caregivers’ perspectives have not been fully examined in patients with HF. Purpose: The purpose of this study was to explore HF patients’ and their caregivers’ experiences of dietary sodium adherence, including the status and factors associated with it. Methods: Qualitative data were collected from 22 patients with HF (67 years old, 72.7% female) and 18 their caregivers (52.2 years old, 33.3% female) using an interview guide with semi-structured questions and were analyzed based on conventional content analysis method. Results: Four themes were revealed: 1) lack of adherence to a low sodium diet, 2) barriers to dietary sodium adherence, 3) facilitators of dietary sodium adherence, and 4) distorted perceptions of dietary education from healthcare providers. The majority of patients did not adhere to a low sodium diet for most of the time. There were several barriers to dietary sodium adherence, including distorted perceptions, insufficient knowledge, disadvantages of dietary sodium adherence, and lack of family support. There were a few facilitators of dietary sodium adherence, including family support. The majority of patients received dietary education from their healthcare providers, but they did not recognize it and/or the detailed content. Conclusions: More effective interventions reflecting patients’ and caregivers’ knowledge about a low sodium diet and factors affecting patients’ eating habits need to be developed and delivered to patients with HF to improve their dietary sodium adherence. In particular, clinicians and healthcare providers need to provide clear explanations about the purpose and content of dietary recommendations with ways to follow the recommendations to patients and their caregivers to improve dietary sodium adherence more effectively.