tbuckley/cabot-search huggingface dataset:
Abstract 10782: Optimization of Preservation Solution and Temperature of Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Patch for Regenerative Therapy
Authors: Hiroko Iseoka, Shigeru Miyagawa, Takuji Kawamura, Ryohei Matsuura, Yoshiki Sawa
Journal: Circulation (2021)

Background: Regenerative therapy for heart failure is being practical as a new treatment. Since cell products contain living cells, it is important to apply the storage method according to the characteristics of the product in order to maintain its structure and function. A lot of studies have been done on suitable storage solutions for organs, and organ storage solutions may also be effective for cell product preservation, especially tissues with three-dimensional structures. In this study, we investigated the optimal storage conditions for human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) patches. Methods and Results: We evaluated the properties of iPSC-CM patches after storage in cell culture buffer solution (BS), intracellular fluid type organ preservation solution A (PSA), and extracellular fluid type organ preservation solution B (PSB) and under room temperature or 4°C. Although the patches maintained their sheet-like morphology up to 120hrs , the sarcomere structure was disrupted, and the viability decreased over time after 48hrs of storage in BS at room temperature. Myocardial contraction/relaxation velocity and cytokine production after reculture of the stored patches showed a significant decrease after 96hrs of storage in BS at room temperature. We tested whether PSA and PSB improve the preservation of the patches compared to the BS in 48hrs storage. As a result, contraction velocity after reculture was comparable for PSA (17.1±4.4 μm/sec), PSB (10.0±0.9 μm/sec) and BS (12.9±1.4μm/sec). However, cell viability after storage was significantly decreased in PSA (13.9±19.9%) and PSB (68.4±26.1%) compared to BS (90.6±4.1%). Although sarcomere structure was maintained in BS, it was disrupted in PSA and PSB. No improvement was observed in contraction velocity, cell viability and sarcomere structure in PSA at 4°C compared to BS at room temperature. Conclusions: The iPSC-CM patches maintained their structure and function for up to 48 hrs under storage conditions in BS at room temperature. The buffer solution, intracellular or extracellular fluid type organ preservation solution have different ionic balances, suggesting that the optimal storage conditions differ according to tissue structure and cell type.
Abstract 10185: Interaction Between Sex and Left Ventricular Reverse Remodeling and Its Association with Outcome After Transcatheter Aortic Valve Implantation
Authors: Jurrien H Kuneman, Steele Butcher, Jan Stassen, Gurpreet Singh, Stephan Milhorini Pio, Kensuke Hirasawa, Frank van der Kley, Nina A Ajmone Marsan, Juhani Knuuti, Jeroen J Bax, Victoria Delgado
Journal: Circulation (2021)

Introduction: Women with severe aortic valve stenosis (AS) have better long-term prognosis after transcatheter aortic valve implantation (TAVI) compared to men. Whether this is caused by sex-related differences in left ventricular (LV) reverse remodeling after TAVI is unknown. Purpose: To examine the interaction between sex and LV reverse remodeling with outcome after TAVI. Methods: Patients with severe AS who had undergone transfemoral TAVI between 2007 and 2018 were selected. LV dimensions, volumes and ejection fraction (LVEF) were assessed by transthoracic echocardiography at baseline before TAVI, and at 6 and 12 months after TAVI. LV reverse remodeling was defined as %LV mass index (LVMi) reduction from baseline. The primary outcome was all-cause mortality. Results: A total of 459 patients (80±8 years; 52% male) were included. Before TAVI, indexed LV end-diastolic and end-systolic volume as well as LVMi were smaller in women versus men. At 6 and 12 months follow-up, both sexes showed significant reductions in LV volumes and LVMi accompanied by improvement in LVEF, without significant differences between the sexes over time (p for interaction=0.51, p=0.43, p=0.44 and p=0.30, respectively). During a median follow-up of 2.8 [IQR 1.9-4.3] years, 181 (39%) patients died. Women showed better outcome compared to men (log-rank p=0.024). In addition, male sex was independently associated with all-cause mortality in multivariable Cox regression (HR 1.423, 95% CI: 1.039-1.951, p=0.028). No association was observed between the interaction of %LVMi reduction and sex with outcome (p=0.64). Conclusions: Patients with severe AS had significant improvement in LVEF, reduction in LV volumes and LVMi at 6 and 12 months after TAVI, without significant differences between sexes over time. Women showed better survival after TAVI as compared to men despite being treated at older age. The interaction between %LVMi reduction and sex was not associated with survival.
Abstract 12408: Fragmented QRS is Independently Predictive of Long-Term Adverse Clinical Outcomes in Asian Patients Hospitalized for Heart Failure: A Retrospective Cohort Study
Authors: Jeffrey Shi Kai Chan, Jiandong Zhou, Sharen Lee, Andrew Li, Martin Tan, Keith S Leung, Kamalan Jeevaratnam, Tong Liu, Qingpeng Zhang, Gary Tse
Journal: Circulation (2021)

Introduction: Fragmented QRS (fQRS) results from myocardial scarring and predicts cardiovascular mortality and ventricular arrhythmia (VA). We evaluated the prevalence and prognostic value of fQRS in Asian patients hospitalized for heart failure. Hypothesis: fQRS is predictive of adverse clinical outcomes. Methods: This was a retrospective cohort study of adult patients hospitalized for heart failure between 1st January 2000 and 31st December 2019 at a tertiary center in Hong Kong. The baseline ECG was analysed. QRS complexes (&lt;120 ms) with fragmented morphology in ≥2 contiguous leads were defined as fQRS. The primary outcome was a composite of cardiovascular mortality, VA, and sudden cardiac death (SCD). The secondary outcomes were the components of the primary outcome, myocardial infarction, and new-onset atrial fibrillation. Results: In total, 2192 patients were included, of whom 179 (8.20%) exhibited fQRS. The follow-up duration was 5.63±4.09 years. fQRS in any leads was associated with a higher risk of the primary outcome (adjusted hazard ratio (HR) 1.541 [1.185, 2.004], p=0.001; Figure A), but not myocardial infarction or new-onset atrial fibrillation. fQRS in &gt;2 contiguous leads was an independent predictor of the primary outcome (HR 1.841 [1.119, 3.029], p=0.016; Figure B), driven by a higher risk of SCD (adjusted HR 2.679 [1.252, 5.729], p=0.011). In patients without ischaemic heart disease (N=1396), fQRS in any leads remained predictive of VA and SCD (adjusted HR 3.336 [1.343, 8.282], p=0.009, and 1.928 [1.135, 3.278], p=0.015, respectively), but not cardiovascular mortality (adjusted HR 1.049 [0.662, 1.662], p=0.839). Conclusions: fQRS is an independent predictor of cardiovascular mortality, VA, and SCD. Higher fQRS burden increased SCD risk. The implications of fQRS in heart failure patients without ischaemic heart disease require further studies.
A Phase I/II Clinical Trial of <i>Piggybac</i>-Modified GMR CAR-T Cell Therapy for CD116 Positive Relapsed/Refractory Myeloid Malignancies
Authors: Shoji Saito, Miyuki Tanaka, Aiko Hasegawa, Yoichi Inada, Hirokazu Morokawa, Yoko Usami, Shunsuke Kojima, Ryu Yanagisawa, Chinatsu Miyazawa, Keiko Ito, Hitoshi Sakai, Hideyuki Nakazawa, Haruko Tashiro, Shigeki Yagyu, Yozo Nakazawa
Journal: Blood (2021)
Abstract 10623: Validation of Embolic and Bleeding Risk Scores in Patients with Atrial Fibrillation and Cancer
Authors: Maria Cespon-Fernandez, Sergio Raposeiras Roubin, Emad Abu-Assi, Tamara Fernandez-Sanz, Isabel Muñoz-Pousa, Maria Melendo Viu, Pilar Cabanas-Grandio, Andrés Íñiguez-Romo
Journal: Circulation (2021)

Introduction: Atrial fibrillation (AF) is common among cancer patients. Anticoagulation can reduce the risk of stroke and systemic embolism in AF patients. However, anticoagulation in patients with cancer can be difficult given unpredictable changes in thrombosis and bleeding risk. Although CHA 2 DS 2 -VASc and HAS-BLED are useful, their predictive performance in patients with cancer is unknown. Hypothesis: CHA 2 DS 2 -VASc and HAS-BLED scores in AF patients with cancer could lead to misclassification. Methods: Overall, 16,056 AF patients between 2014 and 2018 were followed during a median follow-up of 4.9 years, including 1,137 with cancer history. We used C statistic and Brier score for assessing the performance of both scores. Results: Discrimination, assessed with C statistics (assuming death as a competing risk), was similar between cancer and non-cancer anticoagulated patients. However, in non-anticoagulated patients, c-statistic of CHA 2 DS 2 -VASc was poor and significantly lower in non-cancer patients. The overall precision of the CHA 2 DS 2 -VASc score was good throughout the follow-up (Brier score &lt;0.1), both in patients with and without cancer history. Regarding to HAS-BLED score, calibration and discrimination were poor in cancer patients, although without significant differences in comparison with non-cancer patients. In non-anticoagulated cancer patients and in those with active cancer, the embolic risk of CHA 2 DS 2 -VASc score = 1 was similar to CHA 2 DS 2 -VASc score ≥ 2. Only AF patients with cancer and CHA 2 DS 2 -VASc score = 0 presented a truly low risk of embolic events (negative predictive value 100%). A HAS-BLED score &gt; 3 did not identify AF patients with cancer at higher bleeding risk. Conclusions: In AF patients with cancer, neither the CHA2DS2-VASC score nor the HASBLED score were useful for predicting embolic and hemorrhagic events, respectively. However, a CHA 2 DS 2 -VASc score 0 is useful to identify low embolic risk patients with AF and cancer.
IMMU-04. UNVEILING THE TUMOR-METABOLOME-IMMUNITY AXIS OF GLIOMA
Authors: Mirco Friedrich, Lukas Bunse, Roman Sankowski, Wolfgang Wick, Marco Prinz, Michael Platten
Journal: Neuro-Oncology (2021)

Abstract The glioma microenvironment orchestrates tumor evolution, progression, and resistance to therapy. In high-grade gliomas, microglia and monocyte-derived macrophages constitute up to 70% of the tumor mass. However, the dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define myeloid cellular states in gliomas by longitudinal single-cell profiling and demonstrate their strict control by the tumor genotype. We report the unexpected and clinically highly relevant finding that human as well as murine gliomas with Isocitrate Dehydrogenase (IDH)1-R132H, a key oncogenic driver mutation of glioma, subdue their innate immune microenvironment by prompting a multifaceted reprogramming of myeloid and T cell metabolism. We employed integrated single-cell transcriptomic, time-of-flight mass cytometry and proteomic analyses of human healthy cortex control and glioma samples to identify myeloid cell subsets with distinct fates in IDH-mutated glioma that diverge from canonical trajectories of antigen-presenting cells as a result of a monocyte-to-macrophage differentiation block. Moving beyond single time point assessments, we now longitudinally describe differential immune cell infiltration and phenotype dynamics during glioma progression that are orchestrated by a fluctuating network of resident microglial cells and educated recruited immune cells. IDH mutations in glioma induce a tolerogenic alignment of their immune microenvironment through increased tryptophan uptake via large neutral amino acid transporter (LAT1)-CD98 and subsequent activation of the aryl hydrocarbon receptor (AHR) in educated blood-borne macrophages. In experimental tumor models, this immunosuppressive phenotype was reverted by LAT1-CD98 and AHR inhibitors. Taken together with direct effects on T cell activation, our findings not only link this oncogenic metabolic pathway to distinct immunosuppressive pathways but also provide the rationale and novel molecular targets for the development of immunotherapeutic concepts addressing the disease-defining microenvironmental effects of IDH mutations.
Abstract 13405: Prevalence of Cardiac Disease in Duchenne Muscular Dystrophy Patients by Age: A Cardiac Magnetic Resonance Natural History Study
Authors: Kathleen Lao, William Hor, Kan N Hor
Journal: Circulation (2021)

Introduction: Duchenne muscular dystrophy (DMD) patients universally develop cardiomyopathy and considered a dilated cardiomyopathy. Cardiac magnetic resonance imaging (CMR) revealed LGE prior to ventricular dysfunction. Various novel trials including gene therapy are ongoing with growing interest on how it impacts the heart. There is paucity of CMR data at a given age. A major barrier is lack of age specific data. Hypothesis: We therefore, sought to determine the prevalence left ventricular (LV) dilation by endiastolic volume (LVEDV), ejection fraction (LVEF) and late gadolinium enhancement (LGE) status at a given age. Methods: Retrospective review of CMR studies in DMD. LV dilation is defined as LVEDVi z-score &gt; 2, abnormal LVEF (&lt;55%) and LGE (yes or no). Patients were group by age in one year interval (given smaller numbers patients &lt; 7 years were grouped together as were those ≥ 20 years). Results: 683 DMD patients were identified with average of 48.8±24 (range 19-94) patients per group divided into 14 age groups. Mean age was 12.3±4 (range 4-39 years). Table 1 summarizes the CMR data by age. LV dilation was uncommon even in older age patients (mean 1.9±2.6%, range 0-8.7%). LVEF is rarely abnormal before 10 years (&lt;5%) but increased with age (69.9% in the ≥ 20 year group). In all groups mean % LVEF &lt; 55% is 24.6±20.6% (range 2.5-69.9). LGE can be found as young as 6.5 years but uncommon before age 10 years (&lt;10%), increased to nearly 20% by age 10 years and incrementally increased to &gt;50% after 11 (4.3% &lt; 7 year group to &gt; 80% by 18 years). Conclusions: This is the first and largest CMR natural history study by individual age showing low prevalence of LV dilation in DMD population. LVEF abnormality and LGE is uncommon before 10 years but increased with age. Future longitudinal assessment is ongoing to determine rate of change at a given age, quantifying LGE and myocardial strain for earlier cardiac disease assessment and modeling for disease progression at different age.
Abstract 13221: The Biomarker-Based ABC-ACS (Age, Biomarkers, Clinical History) Score Can Predict Major Bleeding Better Than Other Contemporary Scores in Patients on Dual Antiplatelet Therapy After Coronary Revascularization: Results of a Large Derivation and Validation Study
Authors: Gorav Batra, Johan Lindback, Richard C Becker, Robert A Harrington, Claes Held, Stefan K James, Tibor Kempf, Bo Lagerqvist, Renato D Lopes, Pierluigi Tricoci, Kenneth W Mahaffey, Philippe Steg, Robert F Storey, Eva Swahn, Kai C Wollert, Agneta Siegbahn, Lars Wallentin
Journal: Circulation (2021)

Introduction: Intense and prolonged antithrombotic treatment after acute coronary syndrome (ACS) reduces ischemia but increases bleeding. Risk prediction tools might help individualize antithrombotic treatment. Hypothesis: We have previously developed the ABC (age, biomarkers, clinical history) score for major bleeding in patients with atrial fibrillation. We hypothesized that the ABC score might be adapted for prediction of major bleeding in patients after coronary revascularization for ACS. Methods: A risk score was developed in 9,845 patients with ACS undergoing coronary revascularization in the PLATelet inhibition and patient Outcomes (PLATO) trial. Model discrimination and calibration was assessed using Harrell’s c-index and calibrations plots. Validation was performed in two external trial cohorts: Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) and Fragmin and Fast Revascularisation during Instability in Coronary Artery Disease (FRISC II). In addition, the novel score was compared to the PRECISE-DAPT and PARIS bleeding scores. Results: The ABC-ACS bleeding score was developed from 7,216 person-years of follow-up and 370 episodes of major bleeding in PLATO. Predictors of major bleeding, in order of relative strength, were age, growth differentiation factor-15 (GDF-15) and hemoglobin concentrations, type of P2Y 12 inhibitor and history of bleeding. The score showed good calibration, yielding c-indices of 0.71 in PLATO, 0.65 in TRACER and 0.70 in FRISC II, and performing better than the PRECISE-DAPT and PARIS scores (figure). Conclusions: The ABC-ACS bleeding score was internally and externally validated in three cohorts of patients with ACS and showed good discrimination and calibration. The ABC-ACS bleeding score performed better than other contemporary bleeding scores and might improve the decision-making process about intensity and duration of antithrombotic treatment.
Abstract 13671: Return to Play After COVID-19 Infection in Collegiate Competitive Athletes
Authors: Willis Ko, Ngoda Manongi, Justin Classie, Jonathan W Weinsaft, Gregory Pontone, Yuvrajsinh Parmar
Journal: Circulation (2021)

Introduction: COVID-19 infection has placed significant healthcare and economic burdens on society. Recent studies of patients recovered from COVID-19 infection demonstrate highly variable rates of cardiac involvement. A German cohort reported 78% cardiac involvement as defined by abnormalities seen on cardiac magnetic resonance imaging (CMR) while more recent data suggests rates of cardiac involvement between 0.3% and 3%. Competitive athletes represent a unique population as they may pose greater risk for sudden cardiac death during competition due to myocarditis as a sequela of COVID-19 infection. Hypothesis: We hypothesize that among athletes with non-severe COVID-19 infection, a symptom driven clinical pathway would lead to a safe and cost-effective return to sports. Methods: A retrospective analysis was conducted in a cohort of collegiate athletes with non-severe COVID-19 infection returning to competitive sports. The primary outcomes were the prevalence of cardiac involvement based on symptoms and abnormalities with electrocardiograms (ECG), troponin, or transthoracic echocardiogram (TTE). CMR were performed for ongoing cardiopulmonary symptoms or abnormal cardiac test results. Evaluation for myocarditis using CMR was based on the updated Lake Louise criteria. Athletes without evidence of cardiac involvement were permitted to participate in a graduated protocol to return to play. Results: A sample size of 83 athletes (mean age 20 years; female athletes 34%) diagnosed with COVID-19 infection by PCR was analyzed. Abnormal findings suggestive of cardiac involvement were detected by symptoms [82%, Standard Error of Mean (SEM) 0.04], ECG (2.5%, SEM 0.04), troponin (0%, SEM 0), and TTE (0%, SEM 0). CMR was clinically indicated in 7 patients and there were no abnormal findings. No patients were hospitalized and during a clinical surveillance period (median follow up of 105 days), there were no adverse cardiac or non-cardiac events. Conclusions: There is a low prevalence of cardiac involvement among collegiate athletes with non-severe COVID-19 infection. In this cohort, safe progression to competitive athletics using a symptom driven clinical pathway was demonstrated in a cost-effective manner.
RADT-02. FACTORS ASSOCIATED WITH NEW-ONSET SEIZURES AFTER STEREOTACTIC RADIOSURGERY FOR NEWLY DIAGNOSED BRAIN METASTASES
Authors: Ethan Srinivasan, Emily Lerner, Ryan Edwards, Aden Haskell-Mendoza, David Huie, Eugene Vaios, Justus Adamson, Peter Fecci
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Stereotactic radiosurgery (SRS) is a highly effective therapy for newly diagnosed brain metastases. Risk factors for new-onset seizures after SRS have not been well established. In this study, we aimed to characterize the variables predictive of seizure risk. METHODS Patients treated with SRS for newly diagnosed brain metastases were retrospectively reviewed at a single institution. Data on baseline demographics, radiation parameters, and clinical courses were collected. RESULTS 120 patients without previous seizure history were identified. Median age was 65 years (56-70.8) and baseline KPS 90 (80-90). 16 (13%) patients developed new-onset seizures within 3 months of SRS. In analyses comparing patients with and without new-onset seizures, there was no association between new-onset seizures and baseline KPS(90:80, p=0.48), prior resection (31%:28%, p=0.76), prior WBRT (6%:10%, p=1), immunotherapy or chemotherapy within 1 month (31%:21%, p=0.52 and 56%:57%, p=1), primary tumor site (p=0.07), number of lesions (2.2:3, p=0.21), cerebellar (25%:37%, p=0.41) or brainstem involvement (19%:14%, p=0.71), irradiated maximum target diameter (2.8:2.0cm p=0.191), maximum target volume (7.6:2.9 cm3 p=0.133), total dose of radiation (25:20Gy, p = 0.12), or use of fractionation (56%:35%, p=0.11). However, there was a significant difference in the total irradiated target volume (11.6 vs. 3.8 cm3, p=0.019) and a trend toward increased post-treatment seizures among patients with a total irradiated volume greater than 10cm3 (20%:9%, p=0.11, OR 2.4 [0.85-6.4]). Patients with seizures were also more likely to have received steroids (69%:34%, p=0.012) and AEDs (28%:15%, p=0.021) prior to SRS. CONCLUSIONS Our data suggest that total treatment volume is associated with new-onset seizures within 3 months of SRS. The association between seizures and exposure to steroids or AEDs prior to SRS may be a surrogate for neurologic symptoms at presentation. Patients undergoing SRS to larger volumes and necessitating prophylactic steroids or AEDs may benefit from counseling or intensification of anti-seizure therapy.
Abstract 10649: Changes Over Time in Hemoglobin A1c (hba <sub>1c</sub> ) Levels Predict Long-Term Survival Following Acute Myocardial Infarction
Authors: Arthur Shiyovich, Harel Gilutz, Ygal Plakht
Journal: Circulation (2021)

Introduction: Frequent fluctuations in hemoglobin A1c (HbA 1C ) values are independent predictors of diabetic complications and patient outcomes. Objective: To evaluate the prognostic significance of HbA 1C levels and its changes among diabetic patients after non-fatal AMI. Methods: Patients with diabetes mellitus (DM) who were admitted to a tertiary medical center with AMI throughout 2002-2017 and survived &gt;1year thereafter were evaluated. All the results of HbA 1C values during the follow-up period (up to 10-years after discharge) were obtained and analyzed. The changes (Δ) of HbA 1C were calculated for all pairs of tests in each patient. The time interval of ΔHbA 1C values was classified as rapid (&lt;1 year) and slow (≥1 year) change. The outcome was all-cause mortality. Results: A total of 4,066 patients were analyzed, mean age 66.4±11.9 years, 36% females. A U-shaped association was observed between HbA1C and mortality: adjOR=1.887 and adjOR=1.302 for HbA 1C &lt;5.5% and ≥8.0% respectively, as compared with 5.5-6.5% (p&lt;0.001). A U-shaped independent association between ΔHbA 1C and long-term survival was found: adjOR=2.376 and adjOR=1.340 for the groups of &lt;-2.5% and ≥2.5% HbA 1C changes respectively (p&lt;0.001 for each), as compared to the group of minimal ΔHbA 1C (±0.5%). Rapid increase in HbA 1C (but not decrease) following AMI was associated with greater risk for mortality. Conclusions: HbA 1C values, its changes and their rate are significant independent prognostic markers for long-term all-cause mortality with a U-shaped association following non-fatal AMI among DM patients. Thus, ΔHbA 1C and its timing, in addition to absolute HbA 1C values should be monitored among these patients.