tbuckley/cabot-search huggingface dataset:
CD123 Expression Is Associated With High-Risk Disease Characteristics in Childhood Acute Myeloid Leukemia: A Report From the Children's Oncology Group
Authors: Adam J. Lamble, Lisa Eidenschink Brodersen, Todd A. Alonzo, Jim Wang, Laura Pardo, Lillian Sung, Todd M. Cooper, E. Anders Kolb, Richard Aplenc, Sarah K. Tasian, Michael R. Loken, Soheil Meshinchi
Journal: Journal of Clinical Oncology (2021)

Increased CD123 surface expression has been associated with high-risk disease characteristics in adult acute myeloid leukemia (AML), but has not been well-characterized in childhood AML. In this study, we defined CD123 expression and associated clinical characteristics in a uniformly treated cohort of pediatric patients with newly diagnosed AML enrolled on the Children's Oncology Group AAML1031 phase III trial (NCT01371981).AML blasts within diagnostic bone marrow specimens (n = 1,040) were prospectively analyzed for CD123 protein expression by multidimensional flow cytometry immunophenotyping at a central clinical laboratory. Patients were stratified as low-risk or high-risk on the basis of (1) leukemia-associated cytogenetic and molecular alterations and (2) end-of-induction measurable residual disease levels.The study population was divided into CD123 expression-based quartiles (n = 260 each) for analysis. Those with highest CD123 expression (quartile 4 [Q4]) had higher prevalence of high-risk KMT2A rearrangements and FLT3-ITD mutations (P < .001 for both) and lower prevalence of low-risk t(8;21), inv(16), and CEBPA mutations (P < .001 for all). Patients in lower CD123 expression quartiles (Q1-3) had similar relapse risk, event-free survival, and overall survival. Conversely, Q4 patients had a significantly higher relapse risk (53% v 39%, P < .001), lower event-free survival (49% v 69%, P < .001), and lower overall survival (32% v 50%, P < .001) in comparison with Q1-3 patients. CD123 maintained independent significance for outcomes when all known contemporary high-risk cytogenetic and molecular markers were incorporated into multivariable Cox regression analysis.CD123 is strongly associated with disease-relevant cytogenetic and molecular alterations in childhood AML. CD123 is a critical biomarker and promising immunotherapeutic target for children with relapsed or refractory AML, given its prevalent expression and enrichment in patients with high-risk genetic alterations and inferior clinical outcomes with conventional therapy.
Abstract 11051: A Common Variant Near the Fibrinogen Gamma Chain Gene is an Independent Risk Factor for Thrombosis After Congenital Heart Surgery
Authors: Evan T Mercer, Jeffrey G Weiner, Sara Van Driest, Joseph Breeyear, Todd L Edwards, Prince J Kannankeril
Journal: Circulation (2021)

Introduction: Postoperative thrombosis is a common complication after congenital heart disease (CHD) surgery in children, and is associated with increased mortality and morbidity. Identification of risk factors may allow preventive therapy and improved outcomes. Hypothesis: We tested the hypothesis that genetic variants are associated with postoperative thrombosis after CHD surgery in children. Methods: Children with CHD were prospectively enrolled in an observational cohort study at the time of initial surgical repair/palliation. Clinically detected thrombosis within 30 days of surgery while in hospital was the primary outcome. Patients were genotyped on the Axiom Precision Medicine Research Array. Clinical and genetic (8 common variants in candidate genes) factors were assessed for association with the primary outcome with univariate and multivariate analysis. A two-tailed P-value of &lt; 0.05 was considered statistically significant. Results: A total of 2,398 unique patients (median age 6 months, median weight 6.7 kg) had complete clinical and genetic data for analysis. Postoperative thrombosis occurred in 242 (10.1%). Patients with thrombosis were younger (P&lt;0.001), with longer bypass time (P&lt;0.001) and higher initial postoperative lactate (P&lt;0.001). Thrombosis was also associated with longer hospital stay (50 ± 59 days vs 16 ± 31days, P&lt;0.001) and mortality (15.3% vs 2.9%, P&lt;0.001). One common variant near fibrinogen gamma ( FGG , rs7659024, NC_000004.12:g.154599778G&gt;A) was associated with postoperative thrombosis, with a gene-dose effect (thrombosis observed in 8.9% GG, n=1370, 11% AG, n=869, 15.1% AA, n=159, P=0.025). In multivariate analysis age (per year older OR 0.7, 95% CI 0.61-0.79), bypass time (per hour OR 1.24, 95% CI 1.09-1.39), lactate (per mmol/L OR 1.15, 95% CI 1.19-1.32) and FGG genotype (GG reference, AG OR 1.51, 95% CI 1.09-2.08; AA OR 2.35, 95% CI 1.39-3.97) were each independently associated with postoperative thrombosis. Conclusions: A common variant near FGG previously associated with fibrinogen γ′ levels is an independent risk factor for postoperative thrombosis after CHD surgery. Preoperative genotyping with thromboprophylaxis for patients at sufficient risk may be considered.
Abstract 10418: Complex Action Potential Regulation in Cardiomyocytes from Induced Pluripotent Stem Cells (iPSC-CMs) Reveals a Novel Arrhythmia Susceptibility Mechanism
Authors: Yuko Wada, Tao Yang, Lynn Hall, Joseph Solus, Matthew Oneill, Ayesha Muhammad, Andrew Glazer, Dan M Roden
Journal: Circulation (2021)

Background: While the cardiac sodium channel ( SCN5A ) variants S1103Y and R1193Q have been associated with LQT3 and drug-induced arrhythmia, they are too common to be highly arrhythmogenic: S1103Y allele frequency is 8.1% in Africans and R1193Q 6.1% in East Asians. We have previously reported that S1103Y had no effect on QT in a large biobank or on action potential duration (APD) in iPSC-CMs. Here, we identify a mechanism underlying control of normal baseline repolarization with these variants and study whether the mechanism is generalizable. Methods: Late sodium current (I Na-L ), I Kr , and sensitivity to the blockers dofetilide (I Kr ) and GS967 (I Na-L ) were measured in natural or genome-edited iPSC-CMs carrying S1103Y, R1193Q, or R518X, a common KCNQ1 nonsense variant in the Jervell Lange-Nielsen (JLN) syndrome and unaffected family members. Results: Although APD was unaffected by S1103Y, I Na-L was increased 2~16-fold in SY/YY compared to SS cells (p&lt;0.01) and GS967 shortened APDs only in SY/YY but not in SS cells (p&lt;0.001). Further, I Kr was increased in SY/YY ([SY] 1.2 pA/pF, n=17, p&lt;0.001, [YY] 1.2 pA/pF, n=11, p&lt;0.01) compared to SS cells (0.67 pA/pF, n=20) and challenge with dofetilide prolonged APD by 100 msec at much lower concentrations in SY/YY (median 4.1 nM [SY], 4.2 [YY], n=5-11) compared to SS cells (249 nM, n=14, p&lt;0.001); afterdepolarizations were seen more often in SY/YY (8/16) than in SS cells (1/14). R1193Q also displayed no difference in baseline APD but increased I Kr and I Na-L and increased dofetilide sensitivity. In R518X JLN iPSC-CMs, I Ks was absent as expected but I Kr was increased (1.9 pA/pF, n=5), and editing R518X to wild-type increased I Ks (1.3 pA/pF, n=10) and dramatically decreased I Kr (0.2 pA/pF, n=4). Conclusions: S1103Y and R1193Q increase I Na-L but unexpectedly do not affect baseline repolarization. We hypothesize that increased I Kr through as yet undetermined mechanisms maintains normal repolarization but at the cost of increased sensitivity to I Kr block. The findings with R518X suggest this may be a general mechanism. Our data show that preposition to genetically- or drug-mediated arrhythmias is determined by a complex interaction among multiple repolarizing currents that is not fully captured by heterologous expression systems.
Abstract 12555: Safety and Efficacy of Catheter Ablation for Atrial Fibrillation and Predictors of Arrhythmia Recurrence in Octogenarians
Authors: Tauseef Akhtar, Ryan Wallace, Usama A Daimee, Erica Hart, Joseph E Marine, Ronald D Berger, Hugh G Calkins, David D Spragg
Journal: Circulation (2021)

Introduction: Increasing numbers of elderly patients are undergoing catheter ablation (CA) of atrial fibrillation (AF). However, data regarding the experience with this procedure in the octogenarians are limited. Objective: To describe safety and efficacy of index CA of AF and predictors of arrhythmia recurrence in octogenarians. Methods: We conducted a retrospective analysis of patients &gt; 80 years old undergoing index AF ablation between 2012 and 2020 at a large academic medical center. Procedural complications and efficacy, defined as freedom from any atrial tachyarrhythmia (ATA) lasting ≥30 seconds, were assessed. All patients were followed for at least 1 year. Predictors of ATA recurrence were also evaluated. Results: A total of 69 patients were included in our analysis. The median age was 82 (81-85) years, 53.6% were men, and 36.2% had persistent AF (PsAF). The mean left atrial (LA) diameter was 4.3 + 0.8 cm, while the median CHA 2 DS 2 -VASc score was 4 (3-4.5). The majority (n=48, 69.6%) underwent radiofrequency ablation, and the remaining (n=21, 30.4%) patients underwent cryoballoon ablation. Pulmonary vein (PV) isolation was performed in all patients, and 31 (44.9%) patients underwent additional non-PV ablation. None of the patients developed any procedural complications. Acute procedural success with PV isolation was achieved in all the patients, and a total of 44 (63.8%) patients remained free of ATA at 1-year of follow-up. Among the patients with ATA recurrence, 24 (34.8%) were on antiarrhythmic drugs, and 12 (17.4%) patients underwent repeat ablation. Anticoagulation was continued in all the patients. In a multivariable model, only AF type (PsAF) was associated with ATA recurrence at 1-year follow-up (HR=3.42, CI: 1.17-9.94, p=0.02). Conclusion: CA of AF appears to be a safe and effective procedure in octogenarians. AF type (PsAF) is an independent predictor of ATA recurrence at 1-year follow-up.
Abstract 13360: Racial Differences in Hospitalization Rates of Patients Who Receive a Diagnosis of Acute Coronary Syndrome in the Emergency Department
Authors: Duygu Islek, Mohammed K. Ali, Amita Manatunga, Alvaro Alonso, Viola Vaccarino
Journal: Circulation (2021)

Introduction: Although there is literature on missed diagnoses of acute coronary syndrome (ACS) in the Emergency Department (ED), and on avoidable admissions to hospitals, no previous studies have examined racial disparities in hospitalization rates among patients who received a discharge code of ACS in the ED. Hypothesis: We hypothesized that Non-White patients are more likely to be discharged home with a diagnosis of ACS than White individuals, and that health insurance, as a mediator, drives racial disparities in these hospitalization rates. Methods: We examined 51,022,910 discharge records of ED visits in Florida, New York, and Utah in years 2008, 2011, 2014, 2016/7, using state-specific data from the Healthcare Cost and Utilization Project. We identified ED admissions for acute myocardial infarction (AMI) or unstable angina using the International Classification of Disease ninth or tenth revision diagnosis codes, excluding those with chronic coronary heart disease to examine incident events only. We used generalized estimating equation models to compare risks of being sent home across race/ethnic groups including White, Black, Hispanic, and Asian/Pacific Islander patients. We used inverse probability weighting to estimate the mediating role of health insurance status on the associations. Results: Among 235,936 patients who visited the ED and received a discharge code of ACS in the study period, the proportion discharged home was 12 % among Black patients, 6 % among White patients, 9 % among Hispanic patients, and 9 % among Asian or Pacific islander patients. In age and sex-adjusted models the incidence risk ratio (IRR) for being discharged home was 1.3 (95% CI, 1.2 - 1.3) in Black patients 1.2 (95 % CI, 1.1 - 1.3) in Hispanic patients and 1.1 (95% CI, 0.9 -1.3) in Asian or Pacific Islander patients compared with White patients. Health insurance status did not play any role as a mediator. In patients below 55 years of age, differences were magnified for all racial groups compared to White patients. Conclusions: Racial disparities exist in hospitalization of AMI at the ED, which are especially marked among younger patients. Health insurance does not explain these racial differences; other possible causes need to be investigated.
Abnormal Extracardiac Development in Fetuses With Congenital Heart Disease
Authors: Gregor O. Dovjak, Tim Zalewski, Elisabeth Seidl-Mlczoch, Patricia A. Ulm, Vanessa Berger-Kulemann, Michael Weber, Daniela Prayer, Gregor J. Kasprian, Barbara Ulm
Journal: Journal of the American College of Cardiology (2021)

Knowledge about extracardiac anomalies (ECA) in fetal congenital heart disease (CHD) can improve our understanding of the developmental origins of various outcomes in these infants. The prevalence and spectrum of ECA, including structural brain anomalies (SBA), on magnetic resonance imaging (MRI) in fetuses with different types of CHD and at different gestational ages, is unknown.The purpose of this study was to evaluate ECA rates and types on MRI in fetuses with different types of CHD and across gestation.A total of 429 consecutive fetuses with CHD and MRI between 17 and 38 gestational weeks were evaluated. ECA and SBA rates were assessed for each type of CHD and classified by gestational age (<25 or ≥25 weeks) at MRI.Of all 429 fetuses with CHD, 243 (56.6%) had ECA on MRI, and 109 (25.4%) had SBA. Among the 191 fetuses with normal genetic testing results, the ECA rate was 54.5% and the SBA rate 19.4%. Besides SBA, extrafetal (21.2%) and urogenital anomalies (10.7%) were the most prevalent ECA on MRI in all types of CHD. Predominant SBA were anomalies of hindbrain-midbrain (11.0% of all CHD), dorsal prosencephalon (10.0%) development, and abnormal cerebrospinal fluid spaces (10.5%). There was no difference in the prevalence or pattern of ECA between early (<25 weeks; 45.7%) and late (≥25 weeks; 54.3%) fetal MRI.ECA and SBA rates on fetal MRI are high across all types of CHD studied, and ECA as well as SBA are already present from midgestation onward.
DDRE-01. CDK PATHWAY INHIBITION WITH ABEMACICLIB IMPROVES INTRACRANIAL AND EXTRACRANIAL RESPONSE TO CHECKPOINT BLOCKADE IN PRE-CLINICAL MODELS OF MELANOMA BRAIN METASTASIS
Authors: Naema Nayyar, Mohini Singh, Magali de Sauvage, Ashish Dahal, Michael Brehm, Priscilla Brastianos
Journal: Neuro-Oncology (2021)

Abstract While immune checkpoint inhibitors (ICI) have revolutionized treatment of metastatic melanoma, few of the 75% of patients who develop brain metastases benefit from immunotherapy. Inhibition of CDK4/6 pathway – altered in ~90% of melanoma patients – can reportedly increase tumor inflammation and sensitize extracranial tumors to ICI. To determine whether intracranial melanoma can be similarly sensitized, we studied efficacy of combination CDK4/6 inhibitor Abemaciclib and ICI in immunocompetent mouse models of melanoma brain metastases bearing concurrent intracranial and extracranial tumors. 8-week-old female C57BL/6 mice received subcutaneous injections of 2x105 YUMM1.7 or B16-F10 melanoma cells 3 days prior to intracranial injections of 5x104 YUMM1.7 cells or 5x103 B16-F10 cells respectively. Mice were randomized into 6 treatment groups (n=5-7/group): Abemaciclib alone, anti-PD-1 monotherapy, anti-PD-1 and anti-CTLA4 combined (combination ICI), Abemaciclib and anti-PD-1, Abemaciclib combined with anti-PD-1 and anti-CTLA4 (triple therapy), and treatment with vehicle and isotype-matched antibodies as control. In mice bearing YUMM1.7 tumors, subcutaneous tumor growth was significantly reduced compared to control in mice treated with Abemaciclib alone (p&amp;lt; 0.05), combination ICI (p&amp;lt; 0.05) and triple therapy (p&amp;lt; 0.05). However, improvement in survival was only observed with triple therapy (p=0.039) compared to control group. In mice bearing B16-F10 tumors, we observed striking reduction in subcutaneous tumor growth in mice treated with Abemaciclib and anti-PD-1 compared to control-treated mice (p=0.0016) or to mice receiving anti-PD-1 monotherapy (p=0.000056). This further corresponded to a significant increase in survival of Abemaciclib and anti-PD-1 treated mice compared to control (p=0.02). Additionally, we observed improved survival in mice treated with combination ICI (p=0.006) or triple therapy (p=0.01). These results indicate CDK4/6 inhibition with Abemaciclib can improve both extracranial and intracranial responses to ICI and sensitize melanoma brain metastases to immunotherapy. Our pre-clinical findings warrant further investigation to determine whether this combination approach can improve patient outcomes.
Impact of poverty and family adversity on adolescent health: a multi-trajectory analysis using the UK Millennium Cohort Study
Authors: Nicholas Kofi Adjei, Daniela K Schlüter, Viviane S Straatmann, Gabriella Melis, Kate M Fleming, Ruth McGovern, Louise M Howard, Eileen Kaner, Ingrid Wolfe, David C Taylor-Robinson
Journal: The Lancet Regional Health - Europe (2021)

Children exposed to poverty and family adversities including domestic violence, parental mental ill health and parental alcohol misuse may experience poor outcomes across the life course. However, the complex interrelationships between these exposures in childhood are unclear. We therefore assessed the clustering of trajectories of household poverty and family adversities and their impacts on adolescent health outcomes.We used longitudinal data from the UK Millennium Cohort study on 11564 children followed to age 14 years. Family adversities included parent reported domestic violence and abuse, poor mental health and frequent alcohol use. We used a group-based multi-trajectory cluster model to identify trajectories of poverty and family adversity for children. We assessed associations of these trajectories with child physical, mental and behavioural outcomes at age 14 years using multivariable logistic regression, adjusting for confounders.Six trajectories were identified: low poverty and family adversity (43·2%), persistent parental alcohol use (7·7%), persistent domestic violence and abuse (3·4%), persistent poor parental mental health (11·9%), persistent poverty (22·6%) and persistent poverty and poor parental mental health (11·1%). Compared with children exposed to low poverty and adversity, children in the persistent adversity trajectory groups experienced worse outcomes; those exposed to persistent poor parental mental health and poverty were particularly at increased risk of socioemotional behavioural problems (adjusted odds ratio 6·4; 95% CI 5·0 - 8·3), cognitive disability (aOR 2·1; CI 1·5 - 2·8), drug experimentation (aOR 2·8; CI 1·8 - 4·2) and obesity (aOR 1·8; CI 1·3 - 2·5).In a contemporary UK cohort, persistent poverty and/or persistent poor parental mental health affects over four in ten children. The combination of both affects one in ten children and is strongly associated with adverse child outcomes, particularly poor child mental health.The National Institute for Health Research (NIHR) Policy Research Programme, NIHR Applied Research Collaboration South London (ARC South London) at King's College Hospital NHS Foundation Trust and the Medical Research Council (MRC).
Abstract 13982: Evaluation of Electrocardiographic and Intracardiac Electrogram Characteristics for Response to His-Purkinje Conduction System Pacing in Patients With Left Bundle Branch Block Corrected by His Bundle Pacing
Authors: Weijian Huang, Rujie Zheng, Shengjie Wu
Journal: Circulation (2021)

Introduction: His-Purkinje conduction system pacing (HPCSP), including His bundle pacing (HBP) and left bundle branch pacing has been proved to improve clinical outcomes in patients with left bundle branch block (LBBB) and heart failure. However, some patients still remain non-responsive to HPCSP. We aimed to evaluate the effect of electrocardiographic and intracardiac electrogram characteristics for response to HPCSP in patients with typical LBBB which could be corrected by HBP. Methods: Consecutively enrolled patients with typical LBBB and baseline LVEF ≤40% from January 2012 to June 2020 who were able to achieve LBBB correction during HBP and implanted HPCSP. Baseline QRS duration, paced QRS duration, ΔQRSd, H-QRSend and ΔQRSend/H-QRSend were measured during the implantation. A 1-year absolute increase in LVEF≥15% identified super-response to HPCSP. Results: A total of 123 patients were included in the study (mean age 68.2±10.6 years; male 52.0%). Baseline characteristics of patients with ΔLVEF≥15% (N=93) and ΔLVEF&lt;15% (N=30) were comparable except for larger ΔQRSend/H-QRSend (0.42±0.07 vs 0.35±0.08 ms, p&lt;0.001), smaller baseline QRS duration (161.9±15.5 vs 172.3±17.4 ms, p=0.002) and paced QRS duration (100.9±14.9 vs 110.5±13.4 ms, p=0.002) in patients with ΔLVEF≥15%. Receiver-operating characteristic curve analysis demonstrated that a cut-off value of 0.39 for ΔQRSend/H-QRSend presented a sensitivity of 77% and specificity of 76% (AUC=0.776) to predict super-response to HPCSP. At multivariate analysis, larger ΔQRSend/H-QRSend, smaller paced QRS duration and baseline QRS duration remained predictors of super-response after HPCSP. Conclusions: HPCSP delivers favorable echocardiographic response in typical LBBB corrected by HBP. A larger ΔQRSend/H-QRSend, smaller baseline QRS duration and paced QRS duration are associated with a better response after HPCSP. ΔQRSend/H-QRSend is a novel and important predictor of LVEF increase.
First Reported Case Series of Concomitant Ruxolitinib and Ibrutinib for Graft-Versus-Host Disease (GVHD)
Authors: Thomas A Gagliardi, Jordan Milner, Cassey Paula, Mehmet Ozkayank, Oya Levendoglu-Tugal, Jessica C. Hochberg, Jeremy Rosenblum, Aliza Gardenswartz, Mitchell S. Cairo, Amir Steinberg
Journal: Blood (2021)
Abstract 13604: Patient Centered Prescription Using Optimization Algorithms for Statin Users
Authors: Yue Liang, Tatiana Lenskaia, Matt Loth, Prajwal Pradhan, Pui Ying Yew, Jennifer G Robinson, Terrence Adam, Chih-lin Chi
Journal: Circulation (2021)

Introduction: Clinical decision support (CDS) that does not optimize individual variability with best practice and treatment outcomes, cannot support patient-centered care. For example, a statin treatment CDS focused on cholesterol reduction without accounting for patient comorbidities, at risk lifestyle, or genetics, may well suggest a treatment that increases adverse effects, has a high cost, and has a low potential for improved outcome. We present a novel patient-centered decision support (PCDS) system for statin initiation that accounts for best practice and patient variation and ranks treatment options by their predicted ability to improve cardiac outcomes and reduce adverse effects for individual patients. Method: A total of 30 M de-identified claim records from 1.4 M adults receiving statin treatment over 1990-2020 are available in the OptumLabs® Data Warehouse and were used to train our counterfactual prediction algorithm. For a new patient, the PCDS system predicts LDL reduction, cardiac events, and other outcomes at 1 and 5 years, for every potential statin treatment. The PCDS then integrates doctor and patient preferences into a multi-objective optimization algorithm to generate a ranked list of treatment options. Conclusion: Our novel patient-centered decision support (PCDS) adds sophisticated AI modeling and optimization to account for evidenced-based best practice, patient variability, and adverse effect risk to produce a clear ranking of treatment options that can be re-ranked upon input of patient preferences and provider’s lifestyle, socioeconomics, culture, experience and environment factors. This PCDS approach leverages traditional CDS adjusted to individual preferences to aligned with the patient-centered care model.