tbuckley/cabot-search huggingface dataset:
CTNI-17. A PHASE 1 WITH DOSE EXPANSION/PHASE 2 STUDY OF SELINEXOR IN COMBINATION WITH STANDARD OF CARE THERAPY FOR NEWLY DIAGNOSED OR RECURRENT GLIOBLASTOMA
Authors: Yazmin Odia, Patrick Wen, Minesh Mehta, Howard Colman, Erin Dunbar, Nicholas Butowski, Rebecca Harrison, Michael Schulder, John Boockvar, Frances Chow, Priya Kumthekar, Warren Mason, Vyshak Venur, Scott Plotkin, Andrew Lassman, Paul Duic, Sharon Tamir, Kai Li, Yang Liu, Gregory Mundy, Yasaman Damestani, Eric Sbar, Jatin Shah, Sharon Shacham, Samuel Goldlust
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive primary brain tumor with median overall survival of 15 months and 5-7 months for patients with newly diagnosed or recurrent disease (nGBM or rGBM), respectively. Selinexor is a first-in-class, oral, selective inhibitor of nuclear export which blocks exportin 1 (XPO1), forcing the nuclear retention and reactivation of tumor suppressor proteins, ultimately causing cancer cell death. Increased XPO1 expression in gliomas is associated with higher pathological grade and poorer prognosis. Consistent with these data, selinexor inhibited tumor growth and prolonged survival in an animal model of GBM. Importantly, selinexor showed encouraging intra-tumoral penetration and single-agent efficacy in rGBM (KING study). The current trial tests the hypothesis that adding selinexor to standard therapy will improve clinical outcomes for patients with nGBM or rGBM. METHODS To facilitate the successful development of new therapies, consensus recommendations are to use biomarker enrichment and flexible design that allows expansion of promising cohorts. Accordingly, this phase 1a dose finding study is followed by a phase 1b dose expansion (and ultimately by a 1:1 randomized phase 2 efficacy exploration trial) to independently evaluate: radiation + selinexor in nGBM with unmethylated MGMT promoter (Arm A), radiation + temozolomide + selinexor for nGBM with methylated MGMT promoter (Arm B), and lomustine + selinexor in rGBM (Arm C). Bevacizumab or TTField + selinexor in rGBM (Arms D &amp; E, respectively) are being considered. The Phase 1a primary endpoint is maximum tolerated dose/recommended phase 2 dose. The phase 1b primary endpoint is PFS at 3 months against historic controls. The phase 1b dose expansion is included to evaluate preliminary efficacy before launching into a randomized phase 2 trial. Patient quality of life during the trial will be objectively measured using digital devices (e.g. smartwatch/customized smartphone app). We are currently enrolling patients nationwide. Clinical Trial Registration number: NCT04421378.
STEM-08. ST6Gal1-MEDIATED SILALYLATION IS CRITICAL FOR GLIOBLASTOMA GROWTH
Authors: Sajina GC, Kaysaw Tuy, Lucas Rickenbacker, Brent Jones, Asmi Chakraborty, Ryan Miller, Xiaoguang Liu, James Mobley, Susan Bellis, Anita Hjelmeland
Journal: Neuro-Oncology (2021)

Abstract Although altered cell surface glycosylation was one of the earliest modifications observed in neoplastic progression, this facet of cancer cell biology has received meager attention, particularly in brain tumors. Among the various glycosyltransferases present in human cells, golgi sialyltransferase ST6Gal1 [beta-galactoside alpha-2,6-sialyltransferase 1] adds sialic acid residues in α2-6 linkage to membrane-bound and secreted N-glycans. ST6Gal1 is known to be pro-tumorigenic in epithelial cancers where it can promote epithelial to mesenchymal transformation, tumor-initiating cell (TIC) phenotypes, and survival of cells exposed to stressors such as chemo- and radiotherapy, hypoxia, or serum starvation. However, roles for this potent TIC regulator have not been well explored in GBM as experiments in standard cell lines suggested ST6Gal1 was epigenetically silenced. To explore our hypothesis that ST6Gal1-mediated α2,6 sialylation is elevated in Brain Tumor Initiating Cells (BTICs) and promotes GBM growth, we utilized GBM patient-derived xenografts (PDXs). ST6Gal1 is expressed in GBM PDX tissue sections and elevated in stem-like BTICs in comparison to differentiated GBM cells or astrocytes. Knockdown of ST6Gal1 in BTICs decreased growth and neurosphere formation capacity in vitro, suggesting that ST6Gal1 regulates BTIC maintenance. Similarly, cells isolated directly from PDXs that were sorted for high and low expression of α2,6 sialylation showed that α2,6 sialylationhigh GBM PDX have elevated neurosphere formation capacity and growth. Further, immunocompromised mice injected with sorted α2,6 sialylationhigh PDX cells had significantly lower survival compared to mice injected with α2,6 sialylationlow cells. Using proteomic analysis of ST6Gal1 KD vs NT PDX, we identified novel regulators of cancer stem cell biology directly modulated by ST6Gal1. As we identified a small subset of IDHwt GBMs with ST6Gal1 and SOX2 amplification, we are generating a novel gliomagenesis model with conditional ST6Gal1 overexpression. Together, our data strongly implicates ST6Gal1 as a regulator of GBM BTIC maintenance and GBM growth.
Evaluation of Hematopoietic Stem Cell Product As a New Site for Minimal Residual Disease By Next Generation Flow in Multiple Myeloma
Authors: Herbert Henrique de Melo Santos, Glaciano Ribeiro, Allan de souza Santos, Marcos Chaves, Joanna Leal, Juliana Andrade Santos, Alessandro de M. Almeida, Marco Aurelio Salvino, Mariane Melo Santos, Vania Hungria, Maria da Gloria B. Arruda, Edvan De Queiroz Crusoe
Journal: Blood (2021)
Tisagenlecleucel Vs Standard of Care As Second-Line Therapy of Primary Refractory or Relapsed Aggressive B-Cell Non-Hodgkin Lymphoma: Analysis of the Phase III Belinda Study
Authors: Michael R. Bishop, Michael Dickinson, Duncan Purtill, Pere Barba, Armando Santoro, Nada Hamad, Koji Kato, Anna Sureda, Richard Greil, Catherine Thieblemont, Franck Morschhauser, Martin Janz, Ian W. Flinn, Werner Rabitsch, Yok Lam Kwong, Marie José Kersten, Monique C. Minnema, Harald Holte, Esther Hian Li Chan, Joaquin Martinez-Lopez, Antonia MS Mueller, Richard T. Maziarz, Joseph P. McGuirk, Emmanuel Bachy, Steven Le Gouill, Martin Dreyling, Hideo Harigae, David A. Bond, Charalambos Andreadis, Peter A. McSweeney, Mohamed A. Kharfan-Dabaja, Simon Newsome, Evgeny Degtyarev, Chris Del Corral, Giovanna Andreola, Aisha Masood, Stephen J Schuster, Ulrich Jaeger, Peter Borchmann, Jason R. Westin
Journal: Blood (2021)
Children's sleep and fathers' health and wellbeing: A systematic review
Authors: Laetitia Coles, Karen Thorpe, Simon Smith, Belinda Hewitt, Leah Ruppanner, Olivia Bayliss, Martin O'Flaherty, Sally Staton
Journal: Sleep Medicine Reviews (2021)

Night-waking is typical across infancy and early childhood, inevitably disrupting family sleep. For some children, sleep problems develop and endure throughout childhood. This systematic review focused on fathers, and synthesised the evidence pertaining to the effects of children's sleep (from birth to 12 years) on fathers' health and wellbeing. A total of 29 studies were included. Key outcomes reported for fathers were: sleep and fatigue; mental and general health; and family functioning. An association between child sleep and father's sleep was observed when child's sleep was measured via actigraphy or paternal report, but not when measured via maternal report, suggesting that mothers may not always be aware of disruptions that awaken fathers. Findings showed poorer child sleep was associated with poorer general health and wellbeing among fathers, however, associations of poor child sleep with depression were fewer, and less frequent than those reported for mothers in the same households. Poor child sleep was negatively associated with the quality of family relationships, both within the couple and between parent and child. Future studies seeking to understand the interplay of child sleep and family wellbeing should apply objective measurement of sleep and integrate formal measures of family dynamics into the study design.
Abstract 11778: Comparison of Prenatal Diagnosis Rates and Cardiac Morphometry in Fetal Coarctation by Ultimate Surgical Repair Type
Authors: Mansi Gaitonde, YIJIN XIANG, Janet Figueroa, Subhadra Shashidharan, Erik Michelfelder
Journal: Circulation (2021)

Background: Fetal diagnosis of coarctation of aorta is challenging, with limited data examining prenatal detection rates in patients requiring simple vs. extensive arch reconstruction. This study aims to evaluate prenatal detection rate s and fetal cardiac morphometric differences in neonates requiring simple vs. complex coarctation repair. Methods: Pre- and postnatal records of neonates with isolated coarctation repair from the Society of Thoracic Surgeons database from Jan 2010 - Dec 2020 at our center were reviewed. Patients were classified as requiring discrete (Group 1) or extended arch repair (Group 2). Fetal echocardiograms were measured by a single observer blinded to repair type. Results: Of 228 neonates requiring repair, 67 (29%) had a prenatal diagnosis. The proportion with prenatal diagnosis was not different in group 1 (28%) vs. group 2 (32%) (χ2 = 0.45, p = 0.5). At the first fetal echo (median gestational age (GA) of 21.9 wks in group 1 vs 23.6 wks in group 2, p = 0.2), there were no differences between groups when comparing right ventricular (RV) and left ventricular (LV) dimensions, valvular dimensions, or aortic arch dimensions. At the final fetal echo (median GA of 33.7 wks in both groups, p = 0.6), there were statistical differences between group 1 and 2 in RV geometry with ratio of RV minor to major axis (0.72 vs 0.83, p = 0.03) and ratio of LV to RV minor axis (0.68 vs 0.59, p = 0.02), ascending aorta Z score (-2.6 vs -3.4, p = 0.03), distal arch Z score (-3.9 vs -4.6, p = 0.048), and ratio of isthmus to distal arch dimension (0.88 vs 1.02, p = 0.045) (Figure). Conclusion: The rate of prenatal diagnosis in fetuses requiring neonatal coarctation repair remains low, regardless of ultimate surgical repair type. Fetuses ultimately requiring extensive arch repair have smaller aortic sizes, and greater RV/LV size disproportion in the third trimester. This data may be useful in counseling families with regard to postnatal surgical management in fetuses with suspected coarctation.
Abstract 11611: The Wnt Inhibitor Secreted Frizzled-Related Protein 3 Protects Mitral Valve Endothelium from Mi-Induced Endothelial to Mesenchymal Transition
Authors: Zahra Alvandi
Journal: Circulation (2021)

Introduction: There are changes in the mitral valve (MV) leaflets seen within 2-6 months post-myocardial infarction (MI) that include endothelial to mesenchymal transition (EndMT) and fibrosis. Early modulation of EndMT and fibrosis in MV leaflets may limit ischemic mitral regurgitation and heart failure. The onset of EndMT and fibrosis in MV leaflets and the mechanism of their instigation are not known. Hypothesis: We hypothesized that circulating molecules present in plasma within days after MI incite EndMT and fibrotic processes in MV leaflets. Methods: Using flow cytometric analysis and immunofluorescence staining, we examined the onset of EndMT in 20 adult sheep: 8 sheep with IMI, 8 with sham surgery, and 4 naïve controls with immediate excision of hearts under general anesthesia. The effect of plasma on EndMT induction in primary MV endothelial cells (VECs) was assessed by qPCR, migration assays, and immunofluorescence staining. Plasma cytokine levels were assessed using a cytokine array. Immunoblotting, immunofluorescence staining, RNA sequencing and bioinformatic analysis were used to identify biochemical changes by post-MI plasma. Results: Ovine MVs harvested 8-10 days after inferior MI revealed an onset of EndMT, shown by increased CD31/α-SMA-positive cells in post-MI MV leaflets. In contract to sham plasma, post-MI plasma induced EndMT and pro-fibrotic markers and enhanced migration of primary mitral VECs. Analysis of sham versus post-MI plasma revealed a significant drop in the Wnt antagonist sFRP3 in post-MI plasma. Addition of recombinant sFRP3 to post-MI plasma reversed its EndMT-inducing effect on mitral VECs, measured by restored VE-cadherin, reduced α-SMA, and reduced TGFβ1-3 expression. RNA-seq analysis of mitral VECs exposed to post-MI showed upregulated FOXM1. Blocking FOXM1 with Siomycin A reduced EndMT and pro-fibrotic transcripts in mitral VECs treated with post-MI plasma. Finally, FOXM1 induced by post-MI plasma was downregulated by sFRP3. Conclusions: Reduced sFRP3 in post-MI plasma facilitates EndMT and fibrosis in mitral VECs by increasing the transcription factor FOXM1. Restoring sFRP3 levels and/or inhibiting FOXM1 may provide new strategies to minimize MI-induced maladaptive changes that occur in the MV.
Association of County-Level Poverty and Inequities With Firearm-Related Mortality in US Youth
Authors: Jefferson T. Barrett, Lois K. Lee, Michael C. Monuteaux, Caitlin A. Farrell, Jennifer A. Hoffmann, Eric W. Fleegler
Journal: JAMA Pediatrics (2021)

Youth firearm-related deaths are a public health crisis in the US. The association between county-level poverty and the risk of firearm-related deaths among youth is unknown, however.
Abstract 11942: Contemporary Management and Outcomes of Superior Vena Cava Syndrome in the United States: Insights From the Nationwide Readmissions Database
Authors: Matthew Zhao, Irfan Shafi, Abdul H Azizi, Vladimir Lakhter, Riyaz Bashir
Journal: Circulation (2021)

Introduction: The outcomes of superior vena cava (SVC) syndrome in contemporary clinical practice are not well known. We aimed to evaluate in-hospital mortality and unplanned readmission rates in these patients. Methods: We used the United States Nationwide Readmissions Database from January 2016 to December 2018 to identify patients hospitalized for SVC syndrome. We used ICD 10 codes to identify various treatments utilized in this cohort of patients. We assessed the in-hospital mortality and its independent predictors by using a multivariate logistic regression model. We also evaluated for 30-day unplanned readmission rates in these patients. Results: A total of 554 hospitalizations for SVC syndrome were identified. The most common treatment modalities included endovascular stenting (n=122; 22.0%), catheter-directed thrombolysis (n=54; 9.7%), and percutaneous thrombectomy (n=46; 8.3%). A total of 388 patients (70.0%) were managed non-invasively for their SVC syndrome. Hospitalized patients with SVC syndrome rarely received radiotherapy or open thrombectomy. In-hospital mortality was 3.6% (n=20), and its independent predictors included pulmonary embolism (OR 3.44; 95% CI 1.21-9.79; p=0.020), malignancy (OR 3.71; 95% CI 1.39-9.92; p=0.009), sepsis (OR 9.17; 95% CI 2.22-37.81; p=0.002), and pacemaker placement (OR 70.40; 95% CI 3.94-1257.17; p=0.004). Among patients who survived initial hospitalization and initial discharge (n=485; 87.5%), the unplanned 30-day readmission rate was 22.1% (n=107). Conclusions: In this nationwide observational study endovascular stenting was the most common treatment modality used to treat patients with SVC syndrome. These patients have high readmission rates as well as high in-hospital mortality. The major predictors of in-hospital mortality include pulmonary embolism, malignancy, sepsis, and pacemaker placement.
A Prediction Rule to Guide <i>JAK2</i> Testing in Patients with Suspected Polycythemia Vera
Authors: Benjamin Chin-Yee, Pratibha Bhai, Ian Cheong, Maxim Matyashin, Cyrus C. Hsia, Eri Kawata, Jenny Ho, Hanxin Lin, Ian Chin-Yee, Mike Kadour, Bekim Sadikovic, Alejandro Lazo-Langner
Journal: Blood (2021)
Memory Phenotype in Allogeneic Anti-BCMA CAR-T Cell Therapy (P-BCMA-ALLO1) Correlates with In Vivo Tumor Control
Authors: Hubert Tseng, Yan Zhang, Stacey A Cranert, Maximilian Richter, Karl Marquez, Jing Qiu, Benjamin Cho, Yening Tan, Min Tong, Christine Domingo, Leslie Weiss, Elvira Argus, Jessica Sparks, Eric M. Ostertag, Julia Coronella, Devon J Shedlock
Journal: Blood (2021)
Abstract 9946: Dapagliflozin versus Empagliflozin for Improving Outcomes of Type 2 Diabetes Mellitus Patients with Heart Failure and Reduced Ejection Fraction
Authors: Joseph Azuri, Enis Aboalhasan, Ariel Hammerman, Ronen Arbel
Journal: Circulation (2021)

Introduction: The co-morbidity of chronic heart failure and Type 2 diabetes mellitus (DM) is associated with a very high risk for CVmortality and HF-related hospitalizations (HHF). The Sodium-Glucose Transport protein 2 inhibitors (SGLT2i) dapagliflozin and empagliflozin improve the outcomes of this patient population. We aimed to compare their value for money for this indication. Hypothesis: Empagliflozin and dapagliflozin have comparable value for money for improving the HF outcomes of patients with HFrEF and DM. Methods: SGLT2i data was extracted from published results of empagliflozin and dapagliflozin in the subgroups of patients with co-morbidity of DM. The clinical outcome measure was HHF or CV mortality events. The economic measure was the cost needed to treat (CNT) to prevent one event, calculated by multiplying the one-year number needed to treat (NNT) to prevent one event by the annual cost of each therapy. Drug costs were based on the 2021 US National Average Drug Acquisition Cost prices. Secondary outcomes were the CNT to prevent one event of HHF and CV mortality as separate clinical outcomes. Sensitivity analysis was performed to mitigate differences between the trial’s populations Results: Treatment with empagliflozin in EMPEROR-REDUCED has resulted in an NNT of 17 (95% CI: 12-36) compared to 24 (95% CI: 16-60) with dapagliflozin in DAPA-HF. Accordingly the cost needed to treat to prevent one event of CVM or HHF was $81,550 (95% CI: $57,565-$172,694) and $108,563 (95% CI: $72,376-$271,408), respectively. The sensitivity analysis confirmed the primary results. The CNT to prevent CV mortality events is significantly lower with dapagliflozin and prevent HHF significantly lower with empagliflozin (Fig. 1). Conclusions: Empagliflozin and dapagliflozin have comparable value for money for improving HF outcomes of patients with HFrEF, with an advantage for dapagliflozin in CV mortality and for empagliflozin in preventing HHF.
Morally Injurious Experiences and Emotions of Health Care Professionals During the COVID-19 Pandemic Before Vaccine Availability
Authors: Ye Kyung Song, Sneha Mantri, Jennifer M. Lawson, Elizabeth J. Berger, Harold G. Koenig
Journal: JAMA Network Open (2021)

Moral injury in health care professionals (HPs) has worsened over the course of the COVID-19 pandemic. The trauma and burnout associated with moral injury has profound implications for the mental health of HPs.To explore the potential factors associated with moral injury for HPs who were involved in patient care during the COVID-19 pandemic in 2020, prior to the availability of vaccines.In this qualitative study, HPs were actively recruited to participate in a survey via snowball sampling via email and social media in 2 phases of 5 weeks each: April 24 to May 30, 2020 (phase 1), and October 24 to November 30, 2020 (phase 2). Overall, 1831 respondents answered demographic questions and assessments for moral injury, intrinsic religiosity, and burnout. Of those, 1344 responded to the open-ended questions. Responses to open-ended questions were coded iteratively and thematically analyzed within the framework of moral injury.Working in a patient care setting during the COVID-19 pandemic prior to the availability of vaccines.Inductive thematic analysis of open-response survey answers identified dominant emotions and common stressors associated with moral injury.There were 335 individuals (109 [32.6%] aged 35-44 years; 288 [86.0%] women; 294 [87.8%] White) in phase 1 and 1009 individuals (384 [38.1%] aged 35-44 years; 913 [90.5%] women; 945 [93.7%] White) in phase 2. In phase 1, the respondents were predominantly nurses (100 [29.9%]), physicians (78 [23.3%]), advanced practice practitioners (APPs) (70 [20.9%]), and chaplains (55 [16.4%]). In phase 2, the respondents were predominantly nurses (589 [58.4%]), physicians (114 [11.3%]), and APPs (104 [10.3%]). HPs faced numerous stressors, such as fear of contagion, stigmatization, short-staffing, and inadequate personal protective equipment. The emotions experienced were (1) fear in phase 1, then fatigue in phase 2; (2) isolation and alienation; and (3) betrayal.These findings suggest that HPs experienced moral injury during the COVID-19 pandemic. Moral injury was not only experienced after a single moral dilemma but also from working in morally injurious environments. These experiences can serve as potential starting points for organizations to engender and enhance organizational and individual recovery, team building, and trust. System-level solutions that address shortages in staffing and personal protective equipment are needed to promote HP well-being.
Abstract 13794: Prevalence, Treatment Patterns and Outcomes of Acute Myocardial Infarction in Hospitalizations With Acute Ischemic Stroke - A Nationwide Analysis
Authors: Aakash Sheth, Harsh P Patel, Udhayvir Grewal, Samarthkumar Thakkar, Terek Helmy, Paari Dominic
Journal: Circulation (2021)

Introduction: AHA/ASA guidelines recommend measuring troponin in patients with acute ischemic stroke (AIS) to monitor for acute myocardial infarction (AMI). However, large scale data on the prevalence and outcomes of AMI complicating AIS are lacking. Hypothesis: AMI in patients with AIS is associated with poorer outcomes. Methods: All patients with principal diagnosis of AIS with and without AMI were identified in the Nationwide Inpatient Sample from 2005 to 2018. Using Jonckheere-Terpstra test, propensity score matching, and univariate and multivariate logistic regression, trends of prevalence of STEMI and NSTEMI, in-hospital outcomes, and treatment patterns were obtained and compared between the AIS groups with and without AMI. Results: A total of 5,329,107 hospitalizations with AIS were identified, of which 117,955 hospitalizations had AMI (20,289 STEMI and 97,756 NSTEMI). The prevalence of STEMI decreased while that of NSTEMI increased significantly over time. After propensity score matching, the AIS group with AMI had higher all-cause in-hospital mortality (11.42% vs 3.51%; p&lt;0.0001), and a higher occurrence of adverse events (hemorrhagic transformation: 5.99% vs 4.31; p&lt;0.0001, craniotomy: 0.12% vs 0.06%; p&lt;0.0009) compared to the group without AMI. Among AIS patients, those with STEMI had higher all-cause in-hospital mortality (29.89% vs 15.57%; p&lt;0.0001). After adjusting for baseline characteristics, the AMI group that received cardiac catheterization and percutaneous coronary intervention had lower in-hospital mortality (7.49% vs 18.93%; p &lt; 0.0001) than the group that did not receive cardiac intervention. However, only 7.8% hospitalizations with AMI after AIS received cardiac interventions. Conclusions: Patients with AMI after AIS that underwent coronary angiography with or without intervention have improved survival. Large scale studies are needed to further prove the utility of cardiac intervention in these patients.