tbuckley/cabot-search huggingface dataset:
CTIM-16. PHASE 2 STUDY OF PEMBROLIZUMAB PLUS TTFields PLUS TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED glioblastoma (2-THE-TOP)
Authors: David Tran, Ashley Ghinaseddin, Dongjiang Chen, Maryam Rahman
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Emerging data indicate that TTFields, the new anti-mitotic treatment for GBM, stimulate immunity via the type-1 interferon (T1IFN) pathway of STING and AIM2 inflammasomes. Thus, we hypothesize that TTFields synergize with immune checkpoint inhibitors to induce anti-tumor immunity in GBM. METHODS We conduct a phase 2 study combining pembrolizumab, TTFields and maintenance TMZ in 25 patients with newly diagnosed GBM (ndGBM). To distinguish immune effects of TTFields from pembrolizumab, TTFields is started at cycle 1 of TMZ and pembrolizumab (200mg Q3Wks) at cycle 2. The primary endpoint is PFS vs. the historical control of TTFields plus TMZ (JAMA/318:2306-2316). Secondary endpoints include toxicity, immune signature of TTFields vs. pembrolizumab by single-cell RNAseq of PBMCs, and OS. RESULTS As of 05/24/2021, 25 patients with a median age of 61 years were enrolled. Eight (32%) and 4 (16%) had biopsy only and partial resection, respectively. Eighteen (72%) had unmethylated MGMT and 3 (12%) had an IDH mutation. The median follow-up was 14.7 months. Twelve (48%) were progression-free, and 15 (60%) were alive. Of 19 patients with follow-up &amp;gt;=9 months, the median PFS was &amp;gt;=11.2 months vs. 6.7 months in the control. Six (24%) patients with measureable tumors achieved partial to complete response. The most common serious adverse events were thrombosis, seizure, and metabolic disturbances in 4 (16%), 3 (12%), and 2 (8%) patients, respectively. We sequenced 193,760 PBMCs in 12 patients before pembrolizumab and detected robust post-TTFields T cell activation in 11 of 12 patients via the T1IFN trajectory with a strong correlation with the TCRab clonal expansion Simpson index (Spearman coefficient r=-0.8, P=0.014). Importantly, we defined a T cell-based gene signature of TTFields effects on TCRab clonal expansion. CONCLUSION The triple combination is well tolerated and shows early evidence of efficacy in ndGBM patients. Survival and molecular data will be updated.
Abstract 13039: Putative Protective Effects Of Caffeine And Its Metabolites On Coronary Heart Disease In The Middle East
Authors: Ehsan Ullah, Khalid Kunji, Ayman El-Menyar, Reem Elsousy, Maryam Al-Nesf, Alka Beotra, Mohammed Al-Maadheed, Vidya Mohamed-Ali, Mohamad Saad, Jassim Al Suwaidi
Journal: Circulation (2021)

Introduction: Protective association between coronary heart disease (CHD) and caffeine intake and its metabolism has been reported. Some of the caffeine’s beneficial actions may be attributed to its direct effect on the endothelial cell, stimulating the production of nitric oxide (NO), as well as its role as an adenosine receptor antagonist. In the Middle East and Gulf region CHD is rampant, and caffeine consumption is also relatively high. The interaction of the two is of interest and will be investigated in this study. Hypothesis: Caffeine is a protective factor for CHD in the Middle East. Methods: The Qatar Cardiovascular Biorepository provided 1,001 CHD patients and the Qatar Biobank provided 2,999 control subjects. Metabolites in the caffeine pathway (KEGG, hsa00232) were quantified and curated via liquid chromatography-mass spectrometry by Metabolon Inc. We then subjected data to standard quality control procedures. Association between metabolite levels and CHD was tested by logistic univariate regression, controlling for age, BMI, and sex. Results: The caffeine KEGG pathway contains 22 compounds. Eleven were present in our cleaned metabolomics panel, and all of them were reduced in CHD patients (Figure 1). Five were significant at P &lt;0.05: caffeine ( P =5.26x10 -3 ), 1,7-dimethyluric acid ( P =2.96x10 -4 ), paraxanthine ( P =8.67x10 -3 ), theobromine ( P =2.33x10 -5 ), and 1-methylxanthine ( P =1.17x10 -2 ). Through pathway enrichment analysis, caffeine metabolism pathway was found to be significantly enriched with an FDR P =4.59x10 -34 and an enrichment ratio of 44.23. Conclusions: The finding of lower levels of caffeine and several of its metabolites in CHD patients in this study suggests a potential protective effect for this stimulant. However, this is a cross-sectional cohort study, so we are observing only association at a slice in time.
Australia, a laggard in responding to climate change, produces an impressive report on climate change and health
Authors: Richard Smith
Journal: BMJ (2021)

<h3></h3> Bickerstaff's Brainstem Encephalitis (BBE) is a condition causing impairment of sensorium in association with ophthalmoplegia and ataxia. Here we present a case of BBE presenting with bilateral vocal cord paralysis. A 35-year-old female presented with a sore throat and shortness of breath in the context of a fall and ankle injury the previous day. She became confused and agitated in hospital. Several hours after pres- entation she was found cyanosed with stridulous breathing (with normal saturations). Fibre-optic nasola- ryngoscopy revealed bilateral vocal cord palsy. She was intubated and transferred to ICU. Investigations including a full infection screen, CSF analysis and MRI were normal and non-diagnostic. Examination during a sedation hold revealed a unilateral third, fourth, and bilateral sixth and seventh cranial nerve palsies. She had flaccid quadriparesis and was globally areflexic. Nerve conduction studies showed a motor predominant polyneuropathy. A diagnosis of BBE was made based on the clinical findings with acute confusion. She was treated with plasma exchange and immunoglobulins and was discharged with almost complete recovery. There are no previous case reports of vocal cord paralysis being the presenting feature of BBE. Neurologi- cal disease accounts for only 12% of cases of bilateral cord palsy. These causes may be systemic such as myasthenia gravis or diphtheria, or focal affecting the nucleus ambiguus in the medulla. However, clini- cians must recognise these cases promptly to ensure adequate investigation and treatment.
Abstract 237: Cerebral and Somatic rSo2 Monitoring During Pediatric Cardiopulmonary Resuscitation
Authors: Thomas J Abramo, Mark Meredith, Mathew Locklear, Cristina E Estrada
Journal: Circulation (2012)

Pediatric resuscitation/arrest has no assessment for tissue resuscitative efforts. Patients have inadequate tissue perfusion despite adequate systemic perfusion during resuscitation. Traditional methods for effective resuscitation have inherent flaws and don’t assess tissue resuscitation. Resuscitated patients by global methods, have significant tissue hypoxia. Refinement in goal directed therapy is to detect tissue resuscitation effects. During resuscitation, better endpoints are needed to guide resuscitation and endpoints. Near-infrared spectroscopy (NIRS) permits noninvasive readings of cerebral and somatic rSO2 tissue saturation. NIRS in adult resuscitations is predictor for survival and neurological outcome. A 15% rSO2 means no detectable tissue O2Hgb. A 95% rSO2 is interpreted as increased perfusion with no tissue O2 extraction. Purpose: Retrospective analysis of Pediatric ED (PED) Resuscitation/CPR cases with cerebral &amp; somatic rSO2 monitoring. Methods: 1/09- 2/12 PED patients with resuscitation/CPR had noninvasive monitoring with cerebral &amp; somatic rSO2 monitoring. Probes were placed on left &amp; right forehead &amp; right deltoid. Recordings were every 30 seconds. Medical records and autopsy were reviewed. Results: Twenty nine patients were monitored Age 9 wks -16 yrs with 75% males. All patients expired. Patient’s etiology were Trauma or Medical: Sepsis, SUID, Drowning, Ingestion. Conclusion: Preliminary data shows unique Cerebral &amp; Somatic rSO2 monitoring in pediatric resuscitation and CPR. As in adult studies, cerebral and somatic rSO2 for our patients showed similar rSO2 of 95% and 15%. Small sample size precludes definitive conclusions. Our observations shows cerebral and somatic rSO2 gives real-time information on tissue oxygenation during pediatric resuscitations. A large validation study using cerebral and somatic rSO2 with global monitoring is warranted.
Comparison of Efficacy and Safety Profile of Allogeneic Versus Autologous CD19 Chimeric Antigen Receptor T Cell Therapy in Hematological Malignancies: A Systematic Review and Meta-Analysis
Authors: Moazzam Shahzad, Ali Hussain, Raheel S Siddiqui, Amna Y Shah, Muhammad Salman Faisal, Iqra Anwar, Aung M Tun, Marc Hoffmann, Rajat Bansal, Leyla Shune, Ghulam Rehman Mohyuddin, Muhammad Umair Mushtaq, Joseph P. McGuirk, Nausheen Ahmed
Journal: Blood (2021)
Abstract 10168: Association Between the Grade of Cytokine Release Syndrome and Cardiac Dysfunction After Chimeric Antigen Receptor T Cell Therapy for Diffuse Large B Cell Lymphoma Patients
Authors: Isamu Sunayama, Yoshiyuki Orihara, Kyung-duk Min, Satoshi Yoshihara, Kyoko Yoshihara, Yuki Matsumoto, Koichi Nishimura, Tetsuo Horimatsu, Yoshiro Naito, Akiko Goda, Hiroya Tamaki, Satoshi Higasa, Masanori Asakura, Masaharu Ishihara
Journal: Circulation (2021)

Introduction: As Chimeric Antigen Receptor T cell (CAR-T) therapy gains its clinical advantage in the management of diffuse large B cell lymphoma (DLBCL), accumulating evidence shows that it often accompanies cardiac dysfunction. Previous retrospective studies indicated the involvement of cytokine release syndrome (CRS) in cardiac dysfunction after CAR-T therapy, but their association is not fully investigated. Therefore, we designed a prospective study to clarify the association between the grade of CRS and cardiac dysfunction in the DLBCL patients after CAR-T therapy. Methods: In this prospective study, 14 DLBCL patients who underwent CAR-T therapy from July 2020 to May 2021 were enrolled. Before and after CAR-T therapy, we collected the levels of troponin T (TnT) as a marker for myocardial damage, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) as markers for systolic function, and E/e’ and left atrial volume index (LAVI) as markers for diastolic function. We classified all patients into two groups according to the severity of CRS after CAR-T therapy, namely the low-CRS Group (CRS&lt;3) and the high-CRS Group (CRS≧3). The markers for cardiac injury and dysfunction were further analyzed in both groups. Results: Average age was 56.4 years and 7 patients (50%) were female. The number of patients in the low-CRS and high-CRS Group were 11 and 3, respectively. Before CAR-T therapy, there were no differences in cardiac function between the two groups. From the hyper-early phase of CAR-T therapy, the increase of TnT, E/e’ and LAVI from the baseline were significantly larger in the high-CRS Group compared to the low-CRS Group (P=0.023, 0.039, and 0.024, respectively). Subsequently, the decrease of GLS from the baseline became significantly larger in the high-CRS Group compared to the low-CRS Group (P=0.049). These results indicated that cardiac dysfunction after CAR-T therapy occurred in the order of myocardial damage, diastolic dysfunction, and systolic dysfunction. Conclusion: We for the first time demonstrated the association between high-grade CRS and cardiac dysfunction after CAR-T therapy through a prospective study.
Abstract 14112: Outcomes of Subcutaneous Implantable Cardioverter-Defibrillator Procedures in Obese versus Non-Obese Patients: A Retrospective Cohort Study
Authors: Clay Hoster, Henry Huang, Timothy Larsen, Kousik Krishnan, Richard Trohman, Graham Peigh, Nishant Verma, Parikshit Sharma, Jeremiah Wasserlauf
Journal: Circulation (2021)

Introduction: Obesity has been proposed as a risk factor for failed subcutaneous implantable cardioverter-defibrillator (S-ICD) shocks due to increased impedance associated with subcutaneous fat. Optimal implant technique, consisting of limiting subcutaneous fat underneath the coil and generator as well as posterior positioning of the generator, may overcome this barrier to successful conversion of ventricular fibrillation (VF) in obese patients. Hypothesis: Optimal S-ICD implant technique can result in successful defibrillation testing regardless of body mass index (BMI). Methods: Consecutive patients who underwent S-ICD placement and defibrillation testing at Rush University Medical Center between 2015-2021 were included. Defibrillation testing consisted of a 65 J shock after closure of the deep layer of the incision. Baseline demographics, procedural data, and chest radiographs were examined. A PRAETORIAN score was calculated based on distance between the coil and sternum, pulse generator to ribs, and posterior generator position. A PRAETORIAN &lt; 90 has been associated with low risk of conversion failure in prior studies. The primary endpoint was the rate of successful first conversion of VF in obese versus non-obese patients. Results: The study included 35 patients. Mean age was 44 ± 13 years, 60% were male, and 51.4% were obese (BMI ≥ 30). Mean PRAETORIAN scores for obese and non-obese patients were 84.7 ± 65.8 and 49.3 ± 31.3, respectively (p=0.067). There were 7 obese and 1 non-obese patients with a score ≥ 90 (p=0.041). Mean shock impedance was 69.3 ± 22.2 Ω and 60.9 ± 20.7 Ω, respectively (p=0.259). There were 3 (16.7%) failed initial shocks in obese patients, and 0 failed initial shocks in non-obese patients (p=0.23). All three obese patients with failed initial shocks had scores ≥ 90 (90, 150, 225). A second 65 J defibrillation test was successful in each of these cases with shock polarity reversal. Conclusions: In this single center study, a PRAETORIAN score &lt; 90 was associated with successful initial conversion from ventricular fibrillation in all obese and non-obese patients. The findings suggest that using optimal technique, a successful implant can be achieved regardless of BMI. Additional multi-center data collection is ongoing.
Abstract 12557: Echo-Guided vs. Device-Based Strategies for Optimization of Cardiac Resynchronization Therapy and Long-Term Clinical Outcomes: A Meta-Analysis
Authors: Fatima Ali-ahmed, Daniel Friedman, Nancy Allen Lapointe, Frederik Dalgaard, Andrzej S Kosinski, Siva K Mulpuru, Kevin P Jackson, Gillian Sanders, Sana M Al-Khatib
Journal: Circulation (2021)

Introduction: CRT optimizations has the potential to improve the 30% non-response rate. Randomized trials (RCTs) comparing device and echo-guided CRT optimization have been overall small and results have been conflicting. Methods: We searched the EMBASE and MEDLINE databases from January 2008 through September 2020 for RCTs and prospective observational studies that randomized patients to either echo-guided or device-based CRT optimization. Included studies had to report on at least one of the following outcomes of interest: all-cause mortality, heart failure hospitalization (HFH), NYHA class improvement, mean EF at follow up, LVEDD, 6MWD, and QoL. A meta-analyses on the outcomes of interest was performed using random effects models. Results: We included seven RCTs representing a total of 2,730 patients. Of those, 1,113 patients were randomized to echo-guided optimization, and 1,617 were randomized to device-based optimization. The mean age of patients was 64.5 years, and they were predominantly men (60%). In the device-based optimization group, there was 93 deaths (5.7%) and 142 HFH (5.1%). In the echo-guided optimization group, there was 57 deaths (10.2%) and 112 HFH (12.4%). On random effects meta-analysis, the device-based optimization group had a lower rate of HFH compared with the echo-guided optimization group (OR 0.81, 95% CL 0.70-0.95, Figure). However, differences in the following outcomes between the two groups were not statistically significant: all-cause mortality, mean follow up EF, LVEDD, NYHA class improvement, 6MWD improvement range or QoL. Conclusions: This meta-analysis suggests that echo-guided optimization of CRT is equivalent to device-based optimization in relation to the clinical outcomes of death, EF, LVEDD, NYHA and 6MWD but suggests that device-related optimization could reduce HFH. The latter merits further investigation in relation to different device-base optimization algorithms.
Abstract 13708: Left Ventricular Thrombus in Patients With Takotsubo Cardiomyopathy in the US Veteran Affairs Healthcare System
Authors: Bilal Alqam, Fuad Habash, Zaid Gheith, Srikanth Vallurupalli, Waddah Maskoun
Journal: Circulation (2021)

Introduction: Takotsubo cardiomyopathy is characterized by significant transient left ventricular (LV) dysfunction that is not due to obstructive coronary artery disease. LV thrombus is a known complication of Takotsubo cardiomyopathy, but the outcomes of these patients are not well described in the literature. The aim of our study was to investigate the rates and outcomes of patients diagnosed with Takotsubo cardiomyopathy with LV thrombus in the Veteran Affairs (VA) system. Methods: We performed a retrospective study using chart review for patients diagnosed with Takotsubo cardiomyopathy between 2005 and 2018 in the VA national database. We included patients who met the Mayo Clinic diagnostic criteria for Takotsubo cardiomyopathy. We collected data for demographics, clinical course, and outcomes. Results: 320 patients (69% males) were included. Median age was 64 years, 20.3% were known to have coronary artery disease, 34.7% had Diabetes and 61.3% had hypertension. 96.8% of patients had Apical variant of Takotsubo cardiomyopathy. LV thrombus was diagnosed in 8.8% of patients, all of those patients had apical variant of Takotsubo cardiomyopathy. There were no significant differences in the mortality rates in the hospital (14.3% vs 7.4%, p=0.15) and at 30-day follow up (4.2% vs 1.9%, p=0.45) in patients who developed LV thrombus compared to patients who did not. For patients who developed LV thrombus, only 1 patient developed a stroke on 30-day follow up; that patient was on therapeutic doses of warfarin for anticoagulation at the time of the stroke. Conclusions: In patients diagnosed with Takotsubo cardiomyopathy with LV thrombus, there was no significant difference in mortality rates in the hospital or at 30 day follow up when compared to patients with no LV thrombus. Only one of those patients developed a stroke during follow up, suggesting that the embolic risk is low with appropriate treatment.
IMMU-40. IMMUNE PROFILING OF MATCHED PRIMARY AND RECURRENT GLIOBLASTOMA TUMORS IDENTIFIED CD64 AS A NEGATIVE PREDICTOR FOR SURVIVAL
Authors: Tala Shekarian, Marie-Françoise Ritz, Tomàs Martins, Philip Schmassmann, Gregor Hutter
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND To target tumor-induced immune evasion mechanisms of glioblastoma for clinical research, we aimed at characterizing the immunological changes in patient-matched treatment-naïve and recurrent GBM samples. MATERIAL AND METHODS Proteins and total RNA were extracted from 15 patient-matched treatment-naïve (primary) and recurrent GBM fresh frozen tumor samples. The expression of genes involved in brain immune responses were compared using Nanostring panels encompassing Cancer and Neuroinflammation genes. Correlation analysis using log2-transformed patient-matched recurrent/primary expression ratio (log2(P/R)) and clinical outcome data (time to relapse and overall survival (OS)) was conducted. Proteomic was conducted to compare total protein expressions. Moreover, immunostaining was performed on a tissue microarray of matched tumor samples to visualize CD64+ cells, CD47+ tumor cells and microglia in order to assess quantitative transcriptome of these specific cell types using GeoMX technology. Functional assays are designed for deciphering phagocytosis induction by factors produced by primary and recurrent tumors. RESULTS Genes significantly differentially expressed between primary and recurrent tumors revealed “Antigen presentation” and “Microglia Pathogen Phagocytosis” as the most significant pathways enriched in recurrent tumors. Considering individual genes, a strong negative correlation (R2&amp;gt;0.4) between log2(R/P) and time to relapse and OS was found for 2 genes, FCGR1A (CD64) and CD47. We observed that only CD64 expression levels in recurrent samples also negatively correlated with OS. CD64 and CD47 proteins were quantified by proteomic analysis and log2 (R/P) of their levels also negatively correlated with time to relapse. Immunostaining revealed numerous CD64-positive cells in tumor biopsies resembling bushy or amoeboid microglia. CONCLUSION Upregulation of CD64 and CD47 expressions in recurrent GBM was identified as a negative predictor for time to relapse and OS. This suggests an important role of CD64 and CD47 and related inflammation dysregulation in tumor resistance and regrowth. Interfering with CD64-induced functions may represent a novel therapeutic option for GBM.
Abstract 10526: Surface Located Adiponectin On Adipocytes-derived Exosomes Mediates Adipocytes/cardiomyocytes Communication And Contributes To Cardioprotection
Authors: Zhen Zhang, Di Zhu, Zhijun Meng, Jianli Zhao, Peng Yao, jumpei tsukuda, Jonathan Koa, Demin Liu, Lu Gan, Wayne Bond LAU, Dina Xie, Bernard L Lopez, Theodore Christopher, Erhe Gao, Walter J Koch, Xinliang Ma, Yajing Wang
Journal: Circulation (2021)

Introduction and Hypothesis: Increasing evidence emphasizes the roles of adipocyte-cardiomyocyte (ADp-CM) communication plays in health and diabetes. We recently reported that diabetes switched ADp-derived Exosomes (ADp-Exo) from carrying cardioprotective molecules to delivering cardiotoxic molecules to CM. However, the molecular mechanisms mediating ADp-Exo cardioprotection and its alteration by diabetes remain unknown. Methods and Results: ADp-Exo was isolated from epididymal white adipocytes of WT mice. Western Blot demonstrated high level of adiponectin (APN), a potent cardioprotective adipokine, present in ADp-Exo. More interestingly, APN was detected on the surface of ADp-Exo by flow cytometry using Exo-flow kit (System Biosciences). To determine whether surface-located APN on ADp-Exo protect heart, WT ADp-Exo were intramyocardially injected. Mice were subjected to 90 minutes coronary occlusion, followed by 4 weeks of reperfusion. Cardiac function was evaluated by echocardiograph weekly. WT ADp-Exo significantly reduced MI/R injury in vivo , as evidenced by improved LVEF, radial and longitudinal myocardial Strain and SR (vs vehicle group, p&lt;0.05). Importantly, pre-incubation of ADp-Exo with an APN neutralization antibody blocked ADp-Exo cardioprotection. To determine the role of CM AdipoR1, ex vivo and in vitro experiments were performed. WT ADp-Exo activated AdipoR1 pathway (increased phosphorylation of ACC, ERK and AMPK) in CM and protected against cell injury and death (MTT and LDH assay). However, surface APN blocked WT ADp-Exo or APN -/- ADp-Exo failed to active this signaling and protection. WT ADp-Exo failed to activate cell salvage kinases in AdipoR1 -/- CM. Finally, overexpression of GRK2, a pathogenic molecule that we reported to cause AdipoR1 S205 phosphorylation, blocked WT ADp-Exo cardioprotection. AAV9-mediated overexpression of a phosphorylation resistant AdipoR1 (AdipoR1 S205A ) restored ADp-Exo protective action. Conclusions: We demonstrate for the first time that ADp-Exo surface located APN mediates ADp-CM communication via CM AdipoR1 pathway, promoting cardioprotection. This protective system is blocked by GRK2-induced AdipoR1 phosphorylation in diabetic heart, promoting MI/R injury.