tbuckley/cabot-search huggingface dataset:
BIOM-20. TUMOR-INTRINSIC AND PERIPHERAL FEATURES ASSOCIATE WITH SURVIVAL AFTER POLIO VIROTHERAPY IN RECURRENT GBM
Authors: Michael Brown, Gao Zhang, Kevin Stevenson, Xiang Lin, Yeqing Chen, Zhi Wei, Nike Beaubier, Hai Yan, Yiping He, Annick Desjardins, James Herndon, Frederick Varn, Roel Verhaak, Junfei Zhao, Allan Friedman, Henry Friedman, Frances McSherry, Andrea Muscat, Eric Lipp, Mustafa Khasraw, Katherine Peters, Dina Randazzo, John Sampson, Roger McLendon, Darell Bigner, Matthias Gromeier, Smita Nair, David M Ashley
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND PVSRIPO is a live-attenuated recombinant rhino:poliovirus that mediates antitumor efficacy by engaging antitumor immunity. A subset (~20%) of patients with recurrent GBM (rGBM) survive &amp;gt;24 months after therapy. We previously reported that low tumor mutation burden (TMB) is associated with longer survival after PVSRIPO and immune checkpoint blockade therapy in rGBM, and that low TMB associates with higher inflammatory gene expression signatures in rGBM tumors. METHODS Clinical features were tested for association with survival after PVSRIPO therapy. Whole exome sequencing and RNA-sequencing of tumors were used to correlate mutational landscape, tumor mutation burden (TMB), and gene expression signatures of patient tumors with survival. An in vitro assay that measures inflammatory responses of patient PBMCs to PVSRIPO was performed. An independent cohort of paired primary and recurrent GBM tumors was used to assess longitudinal changes in TMB and gene expression signatures after standard of care treatment. RESULTS A short time to recurrence and low TMB associated with longer survival after PVSRIPO therapy; these features were not prognostic for longer survival in immunotherapy naïve rGBM cohorts. Unexpectedly, higher pre-treatment polio neutralizing antibody titers were also associated with longer survival after PVSRIPO therapy in two independent clinical cohorts. PBMCs from patients surviving longer after PVSRIPO therapy mounted higher TNF, but lower IFN-a responses after in vitro challenge with PVSRIPO. In analysis of paired primary vs recurrent GBM tumors, we discovered that patients with low TMB upon recurrence were more likely to experience increased tumor inflammation and suppression of overall TMB. Low TMB in rGBM tumors was also associated with neoantigen depletion. Collectively, these observations imply that patients with low TMB and/or shorter duration of standard of care therapy may have intact immune surveillance, and that pre-treatment immunological status may dictate survival response to polio virotherapy.
Abstract 9954: Determinants of Death in Patients with Infective Endocarditis: A Population Attributable Risk Analysis
Authors: Hang Long Li, Yi Kei Stephanie Tse, Si-Yeung Yu, Qingwen Ren, Meizhen Wu, Kwan Yu LI, Pui Fai Wong, Nicole Wing Lam Hon, Lok Yee Jane Lam, Shuk Yin Yu, Kai Hang Yiu
Journal: Circulation (2021)

Introduction: Despite improvements in guidelines, the prognosis of infective endocarditis (IE) remains poor. To guide future development of management strategies, we aim to fill the knowledge gap and identify the evolving factors contributing to mortality. Methods: All patients diagnosed with IE from 2002 to 2019 were included from a well-validated territory-wide database in Hong Kong. Information including demographics, comorbidities and Charlson Comorbidity Index (CCI), microbiological culture and sensitivity tests, and surgical interventions were retrieved. The primary outcome was 1-year all-cause mortality. Using population attributable fraction (PAF) analysis, we quantified the relative contribution of each factor to the risk of death. The temporal trends in risk attributable to each factor was also evaluated using linear regression. Results: Of a total of 5139 patients (mean age 60 years, 37% female), 1642 (32%) died in one year. Age ≥ 60 years and CCI ≥ 1 were the most detrimental contributors to death, with PAF of 19.2% (14.5 to 23.9) and 14.6% (10.6 to 18.5), respectively (Figure). Concurrently, a hospital-acquired nature and severe renal disease also increased the risk of death, with PAF of 1.8% (0.2 to 3.4) and 1.8% (0.5 to 3.2), respectively. Methicillin-resistant Staphylococcus Aureus (MRSA) endocarditis was the most important microbiological factor penalizing survival (PAF 3.4% [2.5 to 4.3]). Surgical intervention was protective, with PAF of -7.9% (-9.5 to -6.4), and the PAF of surgery significantly increased over time (P &lt; 0.001). Discussion: Age, comorbidities, impaired renal function, hospital-acquired IE and MRSA were the most detrimental contributors to adverse outcomes; the mounting coexistence represents a major challenge to diagnosis, treatment, and prognosis. Surgical intervention offered significant and increasing survival benefits, and a surgery-centered approach in management of endocarditis should be promoted.
Abstract 13324: One-Year Outcomes in Patients With Cardiogenic Shock: Insights From the Inova-Shock Registry
Authors: Shashank Sinha, Carolyn Rosner, Behnam N Tehrani, Aneel Maini, Alexander G Truesdell, PRAMITA BAGCHI, James Cameron, Abdulla Damluji, mehul desai, Shashank Desai, Kelly C Epps, Christopher Defilippi, Leonard Genovese, Hala Moukhachen, James Park, Mitchell Psotka, Anika Raja, Matthew W Sherwood, Ramesh Singh, Daniel Tang, Karl Young, Christopher M O'Connor, Wayne B Batchelor
Journal: Circulation (2021)

Introduction: Historically, studies have focused on short-term morbidity and mortality associated with cardiogenic shock (CS). Little is known about post discharge outcomes following acute myocardial infarction (AMI-CS) as compared to acute decompensated heart failure (ADHF-CS). Methods: We examined 520 (219 AMI-CS, 301 ADHF-CS) consecutive patients with CS (1/3/2017-12/31/2019) in a single center registry. Results: Median duration of post discharge follow up was 433 days (IQR, 199-699). Mean age was 61.5±13.5 years, 71% were male, and 64% had chronic kidney disease. The AMI-CS cohort was older (65.6 vs. 58.5, p &lt;0.001), had more cardiac arrest (35.2% vs. 16.0%, p &lt; 0.001), higher baseline lactates (2.7 vs. 2.2, p &lt; 0.01), and decreased pulmonary artery pulsatility indices (1.21 vs. 1.50, p &lt; 0.01). AMI-CS patients had higher in-hospital mortality (38.8% vs. 24.6%, p&lt; 0.001) and at 30 days (46.1% vs. 31.9%, p =0.01) as compared to ADHF-CS. However, this difference was no longer significant at 12 months (52.9% vs. 44.3%, p =0.07). Patients with low (0-3), intermediate (4-5), and high-risk (6-9) CardShock scores on admission had 12-month mortalities of 18.3%, 42.5%, and 82.0%, respectively. For the 361 (69.4%) patients who survived to discharged, 28.9% (n=98) experienced a Major Adverse Cardiovascular Events (MACE) at least once in the 12 months post discharge and 22.7% (n=82) were readmitted within 30 days. There was no significant difference in the occurrence of MACE between the two cohorts (AMI-CS= 27.2% vs ADHF-CS= 31.9%, p=0.57) but the 30-day readmission rate was lower in the AMI-CS cohort as compared to the ADHF-CS group (19.6% vs 24.8%, p&lt; 0.01). Conclusions: There is substantial one-year morbidity and mortality in patients with AMI-CS and ADHF-CS. The AMI-CS cohort had higher in-hospital mortality, which persisted post discharge, as compared to ADHF-CS patients. CardShock risk stratification may be useful for longer term prognostication in CS patients.
Abstract 12592: Acute Administration of N-Acytylcysteine Leads to Highly Specific Sub-Regional Changes in AF Electrogram Characteristics - A New Way to ‘Uncover’ Regions of High Oxidative Injury in the Fibrillating Atrium?
Authors: Markus Rottmann, Anna Pfenniger, Shin Yoo, David Johnson, Gail E Geist, Wenwei Zhang, Bassel Shanab, Suman Mandava, Amy Burrel, Andrew J Wasserstrom, Susan Kim, Bradley P Knight, Rod S Passman, Rishi Arora
Journal: Circulation (2021)

Introduction: It is currently not possible to measure and therapeutically target oxidative injury (OI) in the intact fibrillating atrium. Hypothesis: We postulated that measurement of AF electrogram characteristics after acute administration of a reactive oxygen species (ROS) scavenger can help ‘uncover’ regions of high OI in the fibrillating human atrium. Methods: We mapped in both atria pre/post NAC (intravenous, 100mg/kg) in 15 persistent AF dogs (3-14 weeks rapid atrial pacing) using a high-density epicardial mapping-plaque (6 atrial regions in both atria, 130 electrodes, electrode-distance 2.5mm) and in 4 patients using the HD-grid catheter. We quantified the OS-levels as ratio of oxidatively damaged nuclei ( Figure A ) against the total number in 8-OHdG staining (N=36) and the degree of dense fibro-fatty tissue in Masson’s trichrome stained tissue (N=24) using Qupath. We analyzed cycle length (CL) and dominant frequency (DF) in ‘hot spot’-sub-region sizes with &gt;10% change pre vs. post NAC. Results: Oxidative stress (OS) levels, highest in the left atrial free wall, lowest in the appendages increased with increasing degree of fibro-fatty tissue (R=0.6,P&lt;0.05) and with decreasing cycle length (R=0.5, P&lt;0.05) in all regions ( Figure C ). NAC selectively reduced AF characteristics in ‘hot spot’-sub-regions ( Figure D ). OS level correlated with delta CL, delta DF, and delta Organization Index in delta maps (NAC - baseline) (R=0.5, P&lt;0.05, all comparisons) ( Figure E) . In patients, NAC ( Figure G) reduced AF characteristics in subregions ( Figure H) and increased cycle length from 210±50ms to 252±18ms (P&lt;0.05) in the left atrium ( Figure I ). Conclusions: OS-level correlated with the degree of dense fibro-fatty tissue and with electrogram measures in both atria. Acute scavenging of ROS reduced AF characteristics in the left atrium in dogs and patients. We might have found a new way to target regions of high OS in the atrium in the individual patient.
Abstract 13663: Safety and Possible Effectiveness of Paclitaxel Associated to LDL-Like Nanoparticles (LDE) in the Treatment of Patients With Chronic Ischemic Heart Disease
Authors: LUCAS L MARINHO, Fabiana H Rached, Thauany Tavoni, Ana Paula T Cardoso, Roberto Vitor A Torres, Carlos V Serrano, Cesar H Nomura, Raul C Maranhao
Journal: Circulation (2021)

Introduction: Experimental studies have shown that anti-proliferative chemotherapeutic agents such as paclitaxel (PTX), associated to solid lipid nanoparticles (LDE), have marked anti-atherosclerotic effects. The combination with LDE nearly abolishes PTX toxicity. Hypothesis: Treatment with LDE-PTX in patients with chronic ischemic heart disease (CIHD) is tolerable and safe, and favorably changes plaque characteristics, as denoted by coronary computerized tomography angiography (CCTA). Methods: In this prospective, randomized, double-blind, placebo-controlled study, patients with multivessel CIHD received IV infusions of either LDE-PTX (n=20; PTX dose: 175 mg/m2 body surface) or LDE alone (n=20; placebo group). Infusions were administered every 3 weeks for 6 times. Analysis of cardiovascular risk and inflammatory biomarkers and CCTA data was performed at baseline and at the end of the study. Clinical and laboratorial safety evaluations were made before each infusion. Results: Overall, patients aged 65.6 ±8 yrs, 58% had diabetes, 50% had history of myocardial infarction and 91% were under statin and aspirin therapy. Baseline demographics, risk factors and laboratory data were similar between infusion groups. There was no statistical difference regarding the levels of hsCRP, IL-1β, IL-6, IL-8 and TNF-α from baseline to follow-up between groups, but there was a trend for decrease in IL-6 levels in the LDE-PTX group (-16%), not observed in the placebo group. Regarding the CCTA high-risk plaques, a tendency for reduction of the napking-ring signal after infusion was observed in the LDE-PTX group (figure 1) compared to placebo (p=0.098). No clinical or laboratorial toxicities were observed. Conclusions: This study shows that LDE-PTX was safe in CIHD patients and showed signs of benefits in reducing inflammatory biomarkers and modification of high-risk plaque characteristics.
Abstract 12645: National Trends, Predictors and Outcomes of Inpatient Palliative Care Use in Cardiac Arrest Complicating Acute Myocardial Infarction
Authors: Sri Patlolla, Ardaas Kanwar, Saraschandra Vallabhajosyula
Journal: Circulation (2021)

Introduction: Multi-disciplinary care with integration of the palliative care services (PCS) in acutely ill cardiac patients is known to improve resource utilization and overall patient care. However, there are limited data on the role of PCS in the care of acute myocardial infarction (AMI) patients with cardiac arrest (CA). Methods: We used the National Inpatient Sample (2000-2017) to identify adult AMI admissions with concomitant CA. We evaluated temporal trends and predictors of PCS use, and in-hospital mortality, length of stay, and discharge disposition in AMI-CA admissions with and without PCS use. A propensity matching analysis using 1:1 nearest neighbor matching was performed between cohorts with and without PCS use to derive a propensity-matched sample with standardized differences &lt;5% for all baseline characteristics. Results: During the study period, there were a total of 584,263 AMI-CA admissions, of which 26,919 (4.6%) received PCS. PCS use increased from &lt;1% in 2000 to 11.5% by 2017. AMI-CA admissions that received PCS were on an average older (70.1 ± 13.0 vs 66.7 ± 13.5), had greater comorbidity with higher rates of cardiogenic shock (44.5% vs 26.6%) and non-cardiac organ failure (80.6% vs 41.6%)(all p&lt;0.001). Admissions receiving PCS had lower rates of angiography (48.6% vs 63.3%) and percutaneous coronary intervention (37.4% vs 46.9%) use (p&lt;0.001). Older age, greater comorbidity, and acute organ failure were independently associated with PCS use. In-hospital mortality was higher in the PCS cohort (84.6% vs 42.9%, adjusted odds ratio 3.62 [95% CI 3.48-3.76]; p&lt;0.001). Similar findings were seen in the propensity-matched cohort with higher in-hospital mortality for AMI-CA admissions receiving PCS (84.7% vs 66.2%, p&lt;0.001) The PCS cohort had higher do-not-resuscitate status use (47.6% vs. 3.7%), shorter hospital stays (4 vs 5 days), and more frequent skilled nursing facility discharges (73.6% vs. 20.4%); p&lt;0.001. Conclusions: Despite an increase in PCS use in AMI-CA, it remains significantly underutilized, highlighting the need to further integrate PCS specialists into the care of high-risk conditions such as cardiac arrest to deliver holistic patient care.
Relapsed Refractory Acquired Thrombotic Thrombocytopenic Purpura (aTTP) Following COVID-19 Vaccination
Authors: Michael T. Francisco, Adrienne E. Kaufman, Donald Northfelt, Leslie Padrnos, Allison C. Rosenthal, Jennifer Andres, Jill Adamski, Theresa Kinard, John Camoriano
Journal: Blood (2021)
Abstract 14234: Stroke Center Volume, Not Accreditation Status, is Associated With Outcomes of Stroke Patients Treated by Mechanical Thrombectomy
Authors: Muhammad Waqas, Tatsat Rajendra R Patel, Justin Cappuzzo, Bennett R Levy, Jason M Davies, Kenneth V Snyder, Elad I Levy, Adnan H Siddiqui, Vincent M Tutino
Journal: Circulation (2021)

Introduction: In the USA, endovascular capable stroke centers (ECC) that perform mechanical thrombectomy (MT) for large vessel stroke can be accredited by a number of agencies. However, there remains little evidence on recommendations for minimum case volume required for centers to maintain competency. Hypothesis: Clinical outcomes (namely hospital mortality and home discharge disposition) of stroke patients treated by MT are associated with center volume but not accreditation status. Methods: We obtained nationwide MedPAR data from the Center for Medicare and Medicaid Services (CMS) for 2017 and 2018. Endovascular MT cases were identified using ICD 10 codes. A list of ECCs was obtained from the Joint Commission, HFAP, DNV, and State Health Departments and was cross-referenced with a list of accredited centers. Independent t-tests were used to compare the mean rates of mortality and home discharge between accredited and non-accredited centers. Pearson’s correlation was used to test the association of annual case volume (in 10 groups in logarithmic increments from minimum to maximum) with the rates of mortality and home discharge. Results: In 2017 and 2018, we identified 29,536 cases of MT that were performed at 847 centers (of which 354 were accredited) across the USA. There was no significant difference between accredited and non-accredited centers with regard to hospital mortality (14.8% vs. 14.5%, p-value=0.34) and home discharge disposition (12.1% vs. 12.0%, p-value=0.78). Hospital mortality was significantly negatively correlated with center volume (r=-0.83, 95%CI=-0.96 to -0.44, p-value=0.003), whereas home discharge disposition was significantly positively correlated with center volume (r=0.68, 95%CI=0.09 to 0.92, p-value=0.030). Conclusions: Accreditation showed no correlation to clinical outcomes. However, increasing volume of MT cases in ECCs correlated to increasing mortality and decreasing rate of home discharge.
Early Platelets Elevation after Complete Remission in Favorable- and Intermediate-Risk Acute Myeloid Leukemia Is an Independent Predictor of Favorable Outcomes:a Retrospective Study
Authors: Xiaoling Wen, Ruijuan Zhang, Ruoqi Li, Jiahong Zhai, Suxia Yang, Yaozi Wang, Xialin Zhang, Yanhong Tan, Linhua Yang
Journal: Blood (2021)
Abstract 12003: TN-C Promotes Cardiac Fibrosis and Endothelial Dysfunction in Duchenne Muscular Dystrophy
Authors: Petra Lujza L Szabo, Milat Inci, Janine Ebner, Karlheinz Hilber, Dietmar Abraham, Sandra Trojanek, Sarah Costantino, Francesco Paneni, Attila Kiss, Bruno Podesser
Journal: Circulation (2021)

Background: Cardiac fibrosis and heart failure are major contributors to mortality in Duchenne muscular dystrophy (DMD) patients. Recently, it has been found that Tenascin C (TN-C) plays a maladaptive role in adverse left ventricular (LV) remodelling and fibrosis. Aims: To 1) elucidate the vascular dysfunction and cardiac fibrosis in link to TN-C in a mouse model of DMD and 2) explore the effect of knocking out TN-C in dystrophic mice. Methods: Male wt, mdx and mdx TN-C KO mice were used. Echocardiography was performed, and fibrosis was assessed on cardiac tissue sections. To test the vascular reactivity wire myography was used and CD31+ endothelial cells (ECs) were isolated from mouse lung tissues and characterized for oxidative stress and inflammatory marker expression. To explore further the signalling pathways contributing to cardiac fibrosis, human cardiac fibroblasts (hCFs) were treated with TN-C or TGF-β, then fibrotic markers and epigenetic regulation of p65 were assessed. Results: Cardiac fibrosis was markedly enhanced in mdx mice compared to age-matched wt animals. This was accompanied by upregulation of TN-C in cardiac tissue and plasma. In addition, vascular endothelial function was impaired in mdx mice. In line with that, endothelial cells isolated from mdx mice also showed a marked upregulation of oxidative stress and inflammatory markers. Interestingly, mdx- TN-C KO mice showed preserved vascular function as well as reduced cardiac fibrosis compared to age-matched mdx mice. hCFs treated with TN-C or TGF-β showed increased collagen production and elevated α-SMA and matrix metalloproteinase 2, 3 and 9 (MMP-2, 3 and 9) expressions. TN-C siRNA reduced the expression of collagen and α-SMA, but not MMPs. In addition, both TN-C and TGF-β promote p65/ NF-κB promoter demethylation and subsequently stimulate pro-inflammatory and pro-fibrotic signalling. These effects were reversed by applying p38 MAPK inhibitor in hCFs. Conclusions: TN-C facilitates oxidative stress and inflammation in ECs and fibroblasts, contributing to severe endothelial dysfunction and cardiac fibrosis. In addition, activation of NF-κB p65 signalling pathway may play a role in TN-C induced fibrosis. Thus, TN-C may be a critical mediator and potential target for therapy in DMD.
Abstract 13296: Bivalirudin versus Unfractioned Heparin in Patients With Diabetes Mellitus Undergoing Elective Percutaneous Coronary Intervention: Results at One Year
Authors: Yulong Li, Jiawen Li, Yuejin Yang, Jinqing Yuan, Xueyan Zhao
Journal: Circulation (2021)

Introduction: Patients with Diabetes Mellitus (DM) and coronary heart disease have high risk in bleeding and thrombotic events. However, data on safety and effectiveness of bivalirudin in patients with DM undergoing elective percutaneous coronary intervention (PCI) are lacking which needs further scientific research. Methods: 1152 patients undergoing elective PCI anticoagulated with bivalirudin and 10250 patients anticoagulated with unfractioned heparin (UFH) were performed propensity score matching at 1:4 ratio. Finally, 376 (bivalirudin group) and 878 (UFH with or without glycoprotein IIb/IIIa inhibitors [GPI] group)patients with DM were enrolled respectively. The safe endpoints were according to the Bleeding Academic Research Consortium (BARC) 2, 3 or 5 bleeding and BARC 3 or 5 bleeding. The effective endpoint was major adverse cardiac and cerebrovascular events (MACCE), including death, MI, revascularization, stent thrombosis and stroke. Results: During one-year follow-up, multivariate Cox analysis showed there was no significant difference in the risk of BARC 2,3 or 5 bleeding (P=0.451) and BARC 3 or 5 bleeding (P=0.124) between bivalirudin group and UFH with or without GPI group. As for MACCE, there was no significant difference between bivalirudin group and UFH with or without GPI group (P=0.153). Moreover, there was a reduction in the risk of MI between bivalirudin group and UFH with or without GPI group (HR:0.199, 95%CI: 0.047-0.845, P=0.029) but no significant difference in the risk of death, revascularization, stent thrombosis or stroke (all P&gt;0.05). Conclusions: Although DM is considered a high risk factor for bleeding and thrombotic events, compared with UFH with or without GPI, bivalirudin reduced the risk of MI in patients with DM undergoing elective PCI and did not increase the risk of MACCE, while the risk of bleeding was similar in two groups.