tbuckley/cabot-search huggingface dataset:
CBIO-16. DOSE INTENSIFIED TEMOZOLOMIDE IMPROVES INFILTRATION OF CD70 CAR T CELLS INTO THE GBM TUMOR MICROENVIRONMENT
Authors: Aida Karachi, Jianping Huang, Haipeng Tao, Farhad Dastmalchi, Linchun Jin, Duane Mitchell, Maryam Rahman
Journal: Neuro-Oncology (2021)

Abstract CD70 CAR T cells developed by our group have anti-tumor efficacy in syngeneic murine GBM model and are currently being developed for first-in-human testing. The objective of this study was to evaluate the impact of temozolomide (TMZ) in various dosing strategies on the expansion, persistence and function of the CD70 CAR T cells after infusion. C57BL/6 mice underwent intracranial implantation of KR-158 overexpressing CD70 tumor cells. Tumor bearing animals were treated with standard dose (SD) (50 mg/kg x 5 days), metronomic dose (MD) (25mg/kg x 10 days), or dose intensified (DI) (75mg/kg x 5 days) of TMZ, followed by 10×106 CAR T cells infusion. Peripheral blood was collected to monitor the persistence of CAR T cells in the systemic blood circulation. Six weeks post treatments, spleens and tumors were collected and CAR T cells abundance and function were measured. TMZ preconditioning resulted in the expected lymphopenia in animals by generation of dose dependent lymphopenia. Circulating CD70 CAR T cells peaked in the systemic blood 2 weeks after infusion (3-fold, p&amp;lt; 0.0001). Markers of T cell exhaustion including PD-1 and TOX expression on CAR T cells were not different between the three TMZ treatment groups compared to control. Six weeks post treatment, CD70 CAR T cells were found to be highly infiltrated within the tumor microenvironment in the DI TMZ group compared to the other groups (4-fold,p &amp;lt; 0.0001). Tumor infiltrating CD70 CAR T cells in the DI TMZ group did not have an increase in PD-1 and TOX expression which was seen in the MD and SD TMZ groups. DI TMZ preconditioning results in greater CD70 CAR T cell trafficking to the tumor without T cell exhaustion compared to lower doses of TMZ. The affects of TMZ on the immune microenvironment to enhance CAR T cell regimens warrants further study.
Neuromodulation Strategies for the Treatment of Depression
Authors: Susan K. Conroy, Paul E. Holtzheimer
Journal: American Journal of Psychiatry (2021)

For many decades, psychiatric treatment has been primarily guided by two major paradigms of psychopathology: a neurochemical paradigm leading to the development of medications and a psychological paradigm resulting in the development of psychotherapies. A third paradigm positing that psychiatric dysfunction results from abnormal communication within a network of brain regions that regulate mood, thought, and behavior has gained increased attention over the past several years and underlies the development of multiple neuromodulation and neurostimulation therapies. This neural circuit paradigm is not new. In the late 19th and early 20th centuries, it was a common way of understanding psychiatric illness and led to several of our earliest somatic therapies. However, with the rise of effective medications and evidence-based psychotherapies, this paradigm went mostly dormant. Its recent reemergence resulted from a growing recognition that medications and psychotherapy leave many patients inadequately treated, along with technological advances that have revolutionized our ability to understand and modulate the neural circuitry involved in psychiatric disorders. In this overview, the authors review the history and current state of neuromodulation for psychiatric illness and specifically focus on these approaches as a treatment for depression, as this has been the primary indication for these interventions over time.
Abstract 13539: CT-Derived Fractional Flow Reserve in Patients With Non-ST Elevation Myocardial Infarction
Authors: Andres P Palomo, Thomas F O'Connell, Rehan Tariq, Michael J Gallagher, Robert D Safian, Kavitha M Chinnaiyan
Journal: Circulation (2021)

Introduction: In patients with non-ST Elevation Myocardial Infarction (NSTEMI), coronary CTA has high diagnostic accuracy to diagnose obstructive coronary artery disease (CAD). The value of CT-derived fractional flow reserve (FFRCT) in NSTEMI patients is unclear. Hypothesis: In acute chest pain (ACP) patients diagnosed with an NSTEMI, FFRCT is feasible, safe and adjudicates the need for immediate revascularization. Methods: In ACP patients with NSTEMI and no prior coronary artery disease, those undergoing coronary CTA with FFRCT were compared to those having CTA alone for the composite major adverse cardiac event (MACE) endpoint of death, nonfatal myocardial infarction, unplanned percutaneous (PCI) or surgical (CABG) revascularization over 2 years. NSTEMI was defined as peak troponin I levels ≥ 0.04 ng/mL. FFRCT ≤ 0.80 was considered positive for hemodynamically significant stenosis. Results: From September 2015 to July 2018, 276 ACP patients with NSTEMI (mean age 59 years, 45% female) underwent CTA of which 35 (13%) had FFRCT (14 negative, 21 positive). Of the total, 126 (45.6%) had normal coronaries and 11 (4.0%) were uninterpretable. FFRCT patients were older (p&lt;0.001) with no difference in diabetes (14.3% vs. 14.1%, p=1.0), hypertension (57.1% vs. 49.4%, p=0.391), hyperlipidemia (34.3% vs. 28.2%, p=0.460) and mean troponin I levels (0.49 ± 0.9 ng/mL vs. 1.10 ± 4.58 ng/mL, p = 0.061). All FFRCT patients had &gt;25% stenosis on CTA (100% vs. 42%, p&lt;0.001). Among patients with comparable stenosis on CTA, FFRCT and CTA had equivalent MACE (5.7% vs. 18.5%, p=0.137), with no difference between FFRCT negative and positive patients (Table 1). Conclusions: In this small study, FFRCT did not add incremental value to CTA in patients with NSTEMI across similar stenosis categories with respect to MACE. Larger prospective studies are needed to examine FFRCT in NSTEMI.
Abstract 10238: Quantification of Myocardial Ischemia and Subtended Myocardial Mass at Adenosine Stress Cardiac Computed Tomography. A Feasibility Study
Authors: Finn van Driest, Rob van der Geest, Alexander Broersen, Jouke Dijkstra, Mohammed El Mahdiui, J Wouter Jukema, Arthur Scholte
Journal: Circulation (2021)

Introduction: Combination of computed tomography angiography (CTA) and adenosine stress CT myocardial perfusion (CTP) allows for coronary artery lesion assessment as well as myocardial ischemia. Nowadays, ischemia on CTP is assessed semi-quantitatively by visual analysis. The aim of this study was to fully quantify myocardial ischemia and the subtended myocardial mass on CTP. Methods: We included 33 patients referred for a combined CTA and adenosine stress CTP with good or excellent imaging quality on CTP. Firstly, the coronary artery tree was automatically extracted from CTA and the relevant coronary artery lesions (≥ 50%) were manually defined (fig 1A). Secondly, epi- and endocardial contours along with CTP deficits were manually defined in short-axis images (fig 1D, 1E). Thirdly, a Voronoi-based algorithm was used to quantify the subtended myocardial mass (fig 1B). Fourthly, the perfusion defect and subtended myocardial mass were spatially registered to the CTA and measured in grams (fig 1F, 1C). Finally, this can be used to quantitatively correlate the perfusion defect to the subtended myocardial mass. To assess reproducibility, left ventricular epicardial and endocardial contours along with perfusion defects were re-drawn. Results: Voronoi-based segmentation was successful in all cases. We assessed a total of 64 relevant coronary artery lesions. Average values for left ventricular mass, total subtended mass and perfusion defect mass were 118, 69 and 7 grams respectively. In 19/33 patients (58%) the total perfusion defect mass could be distributed over the relevant coronary artery lesion(s). Results were highly reproducible (r≥0.822, p&lt;0.01). Conclusions: Quantification of myocardial ischemia and subtended myocardial mass using a Voronoi-based segmentation algorithm seem feasible at adenosine stress CTP and allows for quantitative correlation of coronary artery lesions to corresponding areas of myocardial hypoperfusion.
Expression of Paraoxonase-2 in Different Stages of Cutaneous T Cell Lymphoma: Is It a Potential Biomarker for Aggressiveness?
Authors: Erika Morsia, Serena Rupoli, Elisa Molinelli, Davide Sartini, Anna Maria Offidani, Monica Emanuelli, Eleonora Salvolini, Attilio Olivieri, Gaia Goteri
Journal: Blood (2021)
Abstract 14361: Time Restricted Feeding Modifies Day-Night Rhythms in Heart Rate and Cardiac Conduction
Authors: Makoto Ono, Don E Burgess, Tanya Seward, Claude S Elayi, Karyn A Esser, Elizabeth A Schroder, Brian P Delisle
Journal: Circulation (2021)

Background: Heart rate and cardiac conduction cycle with periodicity of 24-hours. The balance of circadian output from the autonomic nervous system and cardiomyocyte clock differentially regulates the sinoatrial (SA) and atrioventricular (AV) node, which could render the cardiac rate and conduction sensitive to internal misalignment and increase cardiac arrhythmogenicity. Hypothesis: The light-dark cycle entrains the circadian clock in the suprachiasmatic nucleus whereas the timing of feeding entrains circadian clocks in the peripheral organs. We determined whether time restricted feeding (TRF) to the light (inactive) cycle in mice caused misalignment in heart rate and conduction. Methods: Telemetry was used to record the electrocardiogram (ECG) in wild type (WT) mice housed in 12-hour light and 12-hour dark cycles. Day-night rhythms in ECG recordings were calculated by fitting data to a cosine function in ad libitum feeding conditions (ALF), 24 hours or 2-weeks after switching to TRF. Phase is reported as the peak rhythm relative to lights on (ZT = 0h). Results: During ALF, WT mice showed aligned 24-hour rhythms in the RR- and PQ-intervals that peaked at the beginning of the light cycle (ZT=4.4±0.5h and 4.6±0.3h, n=6). Switching to TRF for 24 hours caused a sudden and large phase shift in the peaks of 24-hour rhythms to the dark cycle (ZT=21.6±0.6h and 20.0±0.5h, p&lt;0.05 compared to ALF). After 2 weeks of TRF, the RR- and PQ-intervals still peaked together at ZT=19.5±0.2h and 20.5±0.2h (p&lt;0.05 compared to ALF). TRF also increased the 24-hour rhythm amplitude in the RR- and PQ-intervals by 161% and 118% after 24 hours of TRF, and by 109% and 80% after 2 weeks of TRF. That is due to significant increase peak of RR- (ALF 126.4 ± 2.6 ms, 24 hours after TRF 174.8 ± 7.3 ms, 2-weeks after TRF 167.2 ± 9.4 ms, p&lt;0.01) and PQ-intervals (37.0 ± 1.3 ms, 41.5 ± 1.8 ms, 40.0 ± 1.1 ms, p&lt;0.01) in dark cycle. Conclusion: TRF does not cause internal misalignment between the 24-hour rhythms of the RR- and PQ-intervals. TRF does cause a dramatic phase shift and increases the RR- and PQ-interval rhythm amplitudes along with their peak value. TRF could represent an underrecognized electrophysiological modifier in the day-night rhythms for heart rate and cardiac conduction.
Abstract 9717: Reduction in Arnt/hif1 Beta Mediates Vascular Dysfunction in Mice with Type 2 Diabetes Mellitus
Authors: Rongxue Wu, Tu Nguyen, Mei Zheng, Maura Knapp, Nikola Sladojevic, Albert Sitikov, James K Liao, Rongxue Wu
Journal: Circulation (2021)

Introduction: Endothelial dysfunction, especially at the microvasculature level, is one of the most deleterious events in diabetes. ARNT is a transcription factor that functions as a master regulator of glucose homeostasis, but its role in diabetic vascular complications is poorly understood Hypothesis: Aberrations in ARNT expression might contribute to the vascular deficiencies associated with diabetes Methods and Results: We found a reduction in ARNT expression in microvascular endothelial cells (MVECs) derived from type 2 diabetic mice (db/db). Thus, we generated an inducible, EC-specific ARNT-knockout mutation (ArntΔEC, ERT2) to address the hypothesis that aberrations in ARNT expression might contribute to the vascular deficiencies associated with diabetes. We show here that loss of ARNT in the endothelium mimics diabetic phenotypes, such as impairs blood flow recovery after hindlimb ischemia (n=8-12, p&lt;0.01 vs Control group), delays wound healing, and exacerbates infiltration of pro-inflammatory neutrophils after myocardial infarction. Interestedly, the degree of these impairments in the KO mice was more remarkable in diabetic animals induced with high-fat chow (n=10, P&lt;0.01vs Control) In addition, the siRNA-mediated knockdown of ARNT activity reduced tube formation and cell viability measurements in HUVECs cultured under high-glucose conditions. The ArntΔEC, ERT2 mutation also reduced measures of cell viability while increasing the production of reactive oxygen species (ROS) in MVECs isolated from mouse skeletal muscle, and the viability of ArntΔEC, ERT2 MVECs under high-glucose concentrations increased when the cells were treated with a ROS inhibitor. Conclusions: Collectively, these observations suggest that declines in endothelial ARNT expression contribute to the suppressed angiogenic phenotype in diabetic mice, and that the cytoprotective effect of ARNT expression in ECs is at least partially mediated by declines in ROS production. Endothelial ARNT might be a critical mediator of endothelial function and could serve as a therapeutic target for diabetic complications.
RADT-05. PROSPECTIVE LONG-TERM EVALUATION OF MRI- AND CLINICAL CHANGES FOLLOWING STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES – IS REPEAT SRS A CONSEQUENCE, OR ALSO A CAUSE OF LONG-TERM SURVIVAL?
Authors: Bente Skeie, Per Øyvind Enger, Geir Olve Skeie, Jan Ingemann Heggdal
Journal: Neuro-Oncology (2021)

Abstract The use of stereotactic radiosurgery (SRS) for brain metastases are increasing. Response assessment is challenging and the clinical significance of radiological response and retreatments are poorly defined. Ninety-seven patients with a total of 406 brain metastases were followed prospectively for 10 years or until death. Volume changes over time and clinical outcome in response to first time SRS and SRS retreatments were analyzed. Tumors grew significantly before (p = 0.004), but shrunk at 1 and 3 months (p = 0.001) following SRS. Four response-patterns of were observed; tumors either continuously reduced in size (A, 62%), pseudo-progressed (PP, B, 13%), temporarily reduced in size (C, 24%), or grew continuously (D, 2%); corresponding to 75% local control (LC) at initial SRS. Predictors for LC were primary cancer site (p = 0.001), tumor volume (p = 0.002) and target cover ratio (p = 0.005). Subsequent SRS for new lesions resulted in 94% LC (87% A) and repeat-SRS for local failures in 80% LC (57% B), predicted by higher prescribed dose, p = 0.001 and p = 0.042, respectively. Overall survival was only 4.5 months if A-response for all lesions, 13.3 months if at least one B-response, 17.1 months if retreated C- or D-response (p &amp;lt; 0.001), (7.5 and 4.7 months if untreated). Quality of life (p = 0.003), steroid use (p = 0.019) and prior whole brain radiotherapy (p = 0.026) were predictors for survival. There are 4 response patterns to SRS predicted by tumor size, primary cancer site, target cover ratio and prescribed dose. Long-term survivors experienced a higher incidence of PP and were more often retreated for new lesions and local failures. The immune response induced by PP seems beneficial but further studies are needed.
Abstract 10626: Use of Targeted Bedside Simulation in the Pediatric Cardiac Intensive Care Unit: Codes on the Go
Authors: Nadia E Hoekstra, Joseph A Zakhar, Kimberly DiMaria, Robert Bishop
Journal: Circulation (2021)

Introduction: Early recognition of clinical decompensation and rapid intervention are essential to prevention of cardiac arrest (CA). Simulation provides a safe, realistic environment to improve performance of low frequency, high risk skills and practical knowledge. Codes on the Go (COTG) uses mobile bedside simulation emulating the most frequent causes of CA to improve early recognition of clinical changes that may lead to CA and improve performance of crucial tasks. Methods: COTG scenarios are based on our cardiac intensive care unit CA data including trends in etiology and knowledge gaps identified in code debriefs. Each simulation lasts 10 minutes (pre-brief, clinical scenario, and educational debrief). For each simulation, completion and timing of pre-identified objectives were recorded and participant feedback was obtained. Results: We conducted 56 simulations using our pilot scenario “Agitation &amp; Bradycardia”. Of these, 11 involved staff participating for the second time. When comparing the 45 first-time participants to the 11 repeat participants, the tasks showing the largest increase in completion were identifying that dexmedetomidine (dex) can worsen bradycardia, stopping the dex infusion, and using the appropriate CPR ratio. The average time-to-task decreased for 5 of 6 tasks measured between the first-time participants and repeat participants (Figure 1). The vast majority (98%) of participants agreed that feedback was done in a constructive, non-punitive way and the simulation had no negative impact on patient care or staff workflow. Conclusions: COTG is a customizable and low-cost way to improve performance of critical skills and knowledge. Repeat participation in the same scenario improved both completion of objectives and time-to-task without impeding workflow or patient care. This pilot study demonstrated successful proof-of-concept and further implementation of arrest scenario simulations will be implemented to expand its benefit.
NCOG-02. SURVIVAL AND TREATMENT OUTCOMES OF NEOPLASTIC MENINGITIS (NM)
Authors: Taylor Perison, Kayla Wheat, Salim Gnabode, Lori Lyn Price, Suriya Jeyapalan
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION NM occurs in 5 - 15% of cancer patients and Overall Survival (OS) in treated patients ranges from 2-6 months. The purpose of this study was to analyze the effect of prognostic factors on OS and calculate a graded prognostic assessment (GPA) score based on tissue type, similar to the index score created for cancer patients with brain metastases (BM). METHODS We conducted a single center, retrospective analysis of 118 patients diagnosed between 2006 and 2018 at TMC. The prognostic factors analyzed were: Age (&amp;lt; = 50yo =1pt), Karnofsky Performance Status (KPS &amp;gt; =60 =1 pt), and no extracranial metastases (1pt). The GPA score was calculated from 0.0 - 3.0 by adding the points together. Kaplan Meier curves were used to estimate OS for primary tumors with 10 or more patients (breast, lung, leukemia, lymphoma). Cox regression analysis was used to evaluate the association of the GPA with OS. RESULTS The GPA analysis by tumor type included 76% of the patient population. The median OS was 5 months (breast), 2 months (lung), 7 months (leukemia), and 2 months (lymphoma). We found that leukemia (p =0.008, N = 20) and lung cancer (p =0.002, N = 20) patients showed distinct separation between GPA groups on their Kaplan Meier curves. Higher KPS was associated with increased OS (p &amp;lt; 0.0001) using Cox regression. DISCUSSION: The GPA algorithm was only partially successful in our NM population, which may reflect the smaller number of patients in our study compared to the studies used to create the BM GPA. TMC is a contributing institution to a large, multi-institutional, multi-national registry of patients with NM disease (Neoplastic Meningitis Registry - NeMeRe). We plan to use this larger dataset to validate our GPA score as a useful tool for predicting OS in NM patients.
Abstract 12016: Surgical Mitral Valve Repair for Degenerative Mitral Regurgitation: Defining the Benchmark for Trans-Catheter Options
Authors: Benedetto Del Forno, Mariangela D’Ovidio, Davide Carino, Elisabetta Lapenna, Alessandro Verzini, Guido Ascione, Luigi Pinnarelli, Marina Davoli, Alessandro Castiglioni, Francesco Maisano, Ottavio Alfieri, Michele De Bonis
Journal: Circulation (2021)

Introduction: With the increasing trend of percutaneous treatment of mitral regurgitation (MR), defining the standard of care becomes crucial. The optimal treatment of degenerative MR has to provide excellent immediate and long-term outcomes. With this study we aim to present our results of surgical repair of degenerative MR. Methods: From January 2006 to December 2017, 4195 patients (median age 57 years [IQR 46;67], 68.9% men) underwent mitral valve repair (MVr) for degenerative MR at our Institution. The outcomes were retrieved using a deterministic record linkage with the National Health System, the National Tax Register and the clinical database. The follow-up was 100% complete. A Cox regression model was used to identify factors influencing outcomes. Kaplan-Meier estimates were used to assess survival. Competing risk analysis (CIF) with death as competing risk was used to assess the incidence of major adverse cardiovascular events and mitral valve (MV) reoperation. Results: The median EF was 60% [IQR 60;65], 17.8% of patients were in atrial fibrillation and 11.6% were in NYHA ≥3. Prolapse was posterior in 70.7%, bileaflet in 20.7%, and anterior in 8.5%. A resection technique was the most used approach (60.3%), followed by edge-to-edge (26.8%) and chordal implantation (9.2%). Thirty-day mortality was 0.5% (0.24% in isolated MVr cohort). At 13 years, overall survival was 86±13% (isolated MVr 90±10% vs non-isolated MVr 78±22% p &lt;0.0001). At multivariate analysis male sex, age, cancer, previous admission for CHF, NYHA class ≥3, complex surgery, CPB time, MR &gt;1+ at discharge and in-hospital stay were predictors of long-term mortality. At 13 years, CIF of rehospitalization for heart failure was 5.7±0.35% and CIF of MV reoperation was 1.9±0.2%. At multivariate analysis age, prolapse of the anterior leaflet and need of second pump run independently predicted reoperation. Conclusions: Surgical MVr can be performed with very low in-hospital mortality and excellent long-term survival in high-volume centers. At 13-years, in our series the rate of rehospitalization for heart failure was very low and MV reoperation was rare. These results can be used as surgical benchmark for percutaneous treatment of degenerative MR.