tbuckley/cabot-search huggingface dataset:
Venoarterial Extracorporeal Membrane Oxygenation to Heart Transplant—An Inflamed Bridge?—Reply
Authors: Thomas C. Hanff, Lee R. Goldberg, Edo Y. Birati
Journal: JAMA Cardiology (2020)

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Authors: Heinz Joachim Büttner, Franz-Josef Neumann
Journal: Journal of the American College of Cardiology (2007)
RADT-44. STEREOTATIC RADIOSURGERY FOR RESIDUAL LESIONS OF PINEAL NON-GERMINOMATOUS GERM CELL TUMORS AFTER CONVENTIONAL RADIOTHERAPY: A RETROSPECTIVE STUDY
Authors: Mingyao Lai, Juan Li, Qingjun Hu, Jiangfen Zhou, Junjie Zhen, Lei Wen, Linbo Cai
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE To evaluate the safety and efficacy of stereotatic radiosurgery (SRS) in treating residual lesions of pineal non-germinomatous germ cell tumors (NGGCTs) after conventional radiotherapy. METHODS The patients admitted to Guangdong Sanjiu Brain Hospital from 1 January 2008 to 31 December 2018 who diagnosed with pineal NGGCTs pathologically or clinically were retrospectively analyzed. Among those, the patients received conventional radiotherapy with or without SRS were included. The residual lesions after radiotherapy were defined with a maximum diameter &amp;gt; 10mm. Prognosis related parameters such as local control rate, progress-free survival, overall survival and treatment-related toxicity were determined. RESULTS The median follow-up time was 34 months (range 8-142 months). The objective response rate and disease control rate were 71.4% and 95.2%, respectively. Three-year progression-free survival rate was 85.2% and 3-year total survival rate was 88.0%. The univariate analysis revealed that both age and concurrent chemotherapy were not correlated with the prognosis (P=0.286, 0.824). Partial tumor resection before radiotherapy and chemotherapy, AFP＞500ng/ml, and no more than 4 cycles of adjuvant chemotherapy were poor prognostic factors (P=0.037, 0.010, 0.006). Moreover, no acute radiation response was observed after treatment with SRS. Only 1 out of 27 patients (3.7%) had brain neurotoxicity related to a prolonged course of radiochemotherapy. CONCLUSION SRS for residual lesions of NGGCTs following conventional radiotherapy appears to be well tolerant and improved local control. However, the combination of conventional radiotherapy and SRS warrants further investigations in a large-scale randomized controlled clinical trials.
IMMU-38. PRECLINICAL VALIDATION AND MANUFACTURE OF IL-8 RECEPTOR-MODIFIED CD70 CAR T CELLS FOR CLINICAL TRIAL
Authors: Linchun Jin, Haipeng Tao, Meng Na, Aida Karachi, Hector Mendez-Gomez, Frances Weidert, Alicia Hou, Elias Sayour, Duane Mitchell, Jianping Huang
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Chimeric antigen receptor (CAR) modified T cell therapy is a promising treatment strategy for cancer therapy. We developed IL-8 receptor-linked CD70CAR (8R-70CAR), aiming to enhance T-cell intratumoral trafficking and persistence, guided by IL-8-secreting tumors. The preclinical results show that 8R-70CAR T cells induce complete tumor regression and long-lasting antitumor immunity, which necessitate further clinical development of this technology. OBJECTIVE To assess the toxicity of 8R-70CAR T cells, evaluate in vitro tumor recognition and expansion of the 8R-70CAR T cells, and develop clinically compliant SOPs for the CAR T cell manufacture. METHODS The m8R-70CAR (mouse), h8R-70CAR (human), and control CAR were constructed. Toxicology: C57BL/6J mice were intravenously injected with or without 2x106 m8R-70CAR T cells after total body irradiation (5Gy). The body weight, clinical signs, hematology, serum chemistry, serum cytokines, gross pathology, and histopathology of 12 vital organs were evaluated. Tumor recognition: T cells derived from GBM patients were transduced with h8R-70CAR and then co-cultured with CD70+ glioblastoma. INF-g production was measured. Ex vivo expansion: The G-Rex system was utilized for CAR T cell production, and the expansion of h8R-70CAR T cells was assessed by cell count. RESULTS No CAR T cell-related toxicity was observed in mouse study. In addition to a robust antitumor reactivity, the h8R-70CAR T cells present an auto-stimulative property that elicits greater ex vivo expansion compared to other CAR T cells tested. An approximately 1200-fold expansion was achieved during the 2 weeks CAR T cell production without additional stimulation, which allows production of the CAR T cells on a clinical trial scale using &amp;lt; 100mL of whole blood. CONCLUSION The 8R-70CAR T cells are effective, auto-stimulative, and safe. These properties are fundamental for successful clinical applications in cancer treatment. A phase I trial using the 8R-70CAR T cells in newly diagnosed GBM will be initiated soon.
INNV-21. EFFECTIVE REGIMEN OF HIGH-DOSE METHOTREXATE PLUS TEMOZOLOMIDE FOR PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: A SINGLE-CENTER RETROSPECTIVE STUDY
Authors: Jun-ping Zhang, Jing-jing Ge, Cheng Li, Shao-pei Qi, Feng-jun Xue, Zhi-meng Gao
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE To evaluate the efficacy and safety of high-dose methotrexate combined with temozolomide in the treatment of newly diagnosed primary central nervous system lymphoma. METHODS A retrospective study was performed to analyze the clinical data of patients with primary central nervous system lymphoma treated with high-dose methotrexate plus temozolomide in the Department of Neuro-oncology, Capital Medical University, Sanbo Brain Hospital from May 2010 to December 2018. RESULTS A total of 41 patients were identified. Median age was 57 years (range, 27–76 years). The maximal extent of surgery was total resection in 6, partial resection in 8, and biopsy in 27 patients. Of the 35 patients with evaluable lesions, 32 achieved complete response (CR) and 3 achieved partial response. CR rate was 91.4%. The median follow-up time was 36.5 months (range, 4.9–115.4 months). After treatment, the median progression-free survival (PFS) was 45.1 months. PFS rate at 1, 2, 5 years were 85.4%, 70.1% and 43.8%, respectively. The OS rate at 1, 2, 5 years were 92.7%, 82.4% and 66.5%, respectively. The median PFS of patients younger than 65 years was better than that of patients ≥65 years (98.8 months vs 27.9 months, p=0.039). There was no association between efficacy and extent of resection (p=0.836). After disease progression, 6 of the 21 patients received radiotherapy. There was no statistical difference in OS between the patients with or without radiotherapy (36.9 months vs 28.4 months). The main severe adverse events were myelosuppression (36.6%) and elevated transaminase (34.1%). Three patients were discontinued due to drug-related toxicities. CONCLUSIONS High-dose methotrexate combined with temozolomide is effective in the treatment of primary central nervous system lymphoma, with a low incidence of severe adverse reactions. This efficacy may be better than the historical control of methotrexate alone or methotrexate plus rituximab.
REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19
Authors: David M Weinreich, Sumathi Sivapalasingam, Thomas Norton, Shazia Ali, Haitao Gao, Rafia Bhore, Bret J Musser, Yuhwen Soo, Diana Rofail, Joseph Im, Christina Perry, Cynthia Pan, Romana Hosain, Adnan Mahmood, John D Davis, Kenneth C Turner, Andrea T Hooper, Jennifer D Hamilton, Alina Baum, Christos A Kyratsous, Yunji Kim, Amanda Cook, Wendy Kampman, Anita Kohli, Yessica Sachdeva, Ximena Graber, Bari Kowal, Thomas DiCioccio, Neil Stahl, Leah Lipsich, Ned Braunstein, Gary Herman, George D Yancopoulos
Journal: New England Journal of Medicine (2020)

BackgroundRecent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads.MethodsIn this ongoing, double-blind, phase 1–3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody–positive or serum antibody–negative). Key end points included the time-weighted average change in viral load from baseline (day 1) through day 7 and the percentage of patients with at least one Covid-19–related medically attended visit through day 29. Safety was assessed in all patients.ResultsData from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was −0.56 log10 copies per milliliter (95% confidence interval [CI], −1.02 to −0.11) among patients who were serum antibody–negative at baseline and −0.41 log10 copies per milliliter (95% CI, −0.71 to −0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody–negative at baseline, the corresponding percentages were 15% and 6% (difference, −9 percentage points; 95% CI, −29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group.ConclusionsIn this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.)
Development and Assessment of a Systematic Approach for Detecting Disparities in Surgical Access
Authors: Jan H. Wong, William D. Irish, Eric J. DeMaria, Nasreen A. Vohra, Walter J. Pories, Michelle R. Brownstein, Maria S. Altieri, Warqaa Akram, Carl E. Haisch, David B. Leeser, Janet E. Tuttle
Journal: JAMA Surgery (2020)

Although optimal access is accepted as the key to quality care, an accepted methodology to ascertain potential disparities in surgical access has not been defined.To develop a systematic approach to detect surgical access disparities.This cross-sectional study used publicly available data from the Health Cost and Utilization Project State Inpatient Database from 2016. Using the surgical rate observed in the 5 highest-ranked counties (HRCs), the expected surgical rate in the 5 lowest-ranked counties (LRCs) in North Carolina were calculated. Patients 18 years and older who underwent an inpatient general surgery procedure and patients who underwent emergency inpatient cholecystectomy, herniorrhaphy, or bariatric surgery in 2016 were included. Data were collected from January to December 2016, and data were analyzed from March to July 2020.Health outcome county rank as defined by the Robert Wood Johnson Foundation.The primary outcome was the proportional surgical ratio (PSR), which was the disparity in surgical access defined as the observed number of surgical procedures in the 5 LRCs relative to the expected number of procedures using the 5 HRCs as the standardized reference population.In 2016, approximately 1.9 million adults lived in the 5 HRCs, while approximately 246 854 lived in the 5 LRCs. A total of 28 924 inpatient general surgical procedures were performed, with 4521 being performed in those living in the 5 LRCs and 24 403 in those living in the 5 HRCs. The rate of general surgery in the 5 HRCs was 13.09 procedures per 1000 population. Using the 5 HRCs as the reference, the PSR for the 5 LRCs was 1.40 (95% CI, 1.35-1.44). For emergent/urgent cholecystectomy, the PSR for the 5 LRCs was 2.26 (95% CI, 2.02-2.51), and the PSR for emergent/urgent herniorrhaphy was 1.83 (95% CI, 1.33-2.45). Age-adjusted rate of obesity (body mass index [calculated as weight in kilograms divided by height in meters squared] greater than 30), on average, was 36.6% (SD, 3.4) in the 5 LRCs vs 25.4% (SD, 4.6) in the 5 HRCs (P = .002). The rate of bariatric surgery in the 5 HRCs was 33.07 per 10 000 population with obesity. For the 5 LRCs, the PSR was 0.60 (95% CI, 0.51-0.69).The PSR is a systematic approach to define potential disparities in surgical access and should be useful for identifying, investigating, and monitoring interventions intended to mitigate disparities in surgical access that effects the health of vulnerable populations.
Metabolic Landscape of the Mouse Liver by Quantitative 31P Nuclear Magnetic Resonance Analysis of the Phosphorome
Authors: Ganeko Bernardo‐Seisdedos, Jon Bilbao, David Fernández‐Ramos, Fernando Lopitz‐Otsoa, Virginia Gutierrez de Juan, Maider Bizkarguenaga, Borja Mateos, Marcos F. Fondevila, Jordi Abril‐Fornaguera, Tammo Diercks, Shelly C. Lu, Rubén Nogueiras, José M. Mato, Oscar Millet
Journal: Hepatology (2020)

Background and Aims The liver plays a central role in all metabolic processes in the body. However, precise characterization of liver metabolism is often obscured by its inherent complexity. Phosphorylated metabolites occupy a prominent position in all anabolic and catabolic pathways. Here, we develop a 31 P nuclear magnetic resonance (NMR)–based method to study the liver “phosphorome” through the simultaneous identification and quantification of multiple hydrophilic and hydrophobic phosphorylated metabolites. Approach and Results We applied this technique to define the metabolic landscape in livers from a mouse model of the rare disease disorder congenital erythropoietic porphyria (CEP) as well as two well‐known murine models of nonalcoholic steatohepatitis: one genetic, methionine adenosyltransferase 1A knockout mice, and the other dietary, mice fed a high‐fat choline‐deficient diet. We report alterations in the concentrations of phosphorylated metabolites that are readouts of the balance between glycolysis, gluconeogenesis, the pentose phosphate pathway, the tricarboxylic acid cycle, and oxidative phosphorylation and of phospholipid metabolism and apoptosis. Moreover, these changes correlate with the main histological features: steatosis, apoptosis, iron deposits, and fibrosis. Strikingly, treatment with the repurposed drug ciclopirox improves the phosphoromic profile of CEP mice, an effect that was mirrored by the normalization of liver histology. Conclusions In conclusion, these findings indicate that NMR‐based phosphoromics may be used to unravel metabolic phenotypes of liver injury and to identify the mechanism of drug action.
RTID-10. SURGEONS TRIAL OF PROPHYLAXIS FOR EPILEPSY IN SEIZURE NAÏVE PATIENTS WITH MENINGIOMA: A RANDOMIZED CONTROLLED TRIAL (STOP ‘EM)
Authors: Michael Jenkinson, Adel Helmy, Helen Huckey, Samantha Mills, Robin Grant, Dyfrig Hughes, Tony Marson, Rebecca Tangney, Helen Bulbeck, Usama Ali, Carrol Gamble
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Meningioma is the commonest primary brain tumour. 70% of patients are seizure-free at presentation, but approximately 12% will have seizures within 12 months of surgery. Seizures impact quality of life. Neurosurgeons administer prophylactic anti-epileptic drugs (AED) to prevent seizures despite a lack of evidence to support this. A meta-analysis of RCTs in brain tumours suggests that older AED may prevent seizures in the first week after surgery but not thereafter. There are no studies assessing newer AEDs in the prophylactic setting. RESEARCH QUESTION In patients with meningioma who have never had a seizure and are undergoing surgical resection, does prophylactic levetiracetam reduce the risk of developing seizures? DESIGN multi-centre, double-blind RCT in 20 UK centres. 1:1 randomisation of 14 days levetiracetam 500mg bd started one day before surgery compared to placebo. PRIMARY OBJECTIVE Determine whether 2 weeks prophylactic levetiracetam reduces the risk of developing seizures within 12 months of surgery compared to placebo. ECONOMIC OBJECTIVE Estimate cost-effectiveness of prophylactic levetiracetam. SECONDARY OBJECTIVES Determine effect of prophylaxis on time to first seizure and first convulsive seizure, whether prophylaxis affects quality of life and influences return to driving, safety of prophylaxis. POPULATION seizure-naïve meningioma undergoing surgery. SAMPLE SIZE seizure rate at 12 months is 12.3%. A 50% reduction is clinically beneficial. A two-group chi-squared test with 5% two-sided significance level will have 90% power to detect the difference between a Group 1 proportion of 0.12 and a Group 2 proportion of 0.06 when the sample size in each group is 477. Allowing for 5% dropout, 1004 patients will be recruited. FUNDING NIHR (£1.64M) award June 2020. Study opens March 2021. TRANSLATIONAL RESEARCH MRI, blood and tissue will be collected to explore risk factors for seizures. CONCLUSIONS study will provide class I evidence of the role of prophylactic levetiracetam in meningioma surgery.
TAMI-58. A NOVEL ROLE FOR REST IN THE CONTROL OF THE MEDULLOBLASTOMA MICROENVIRONMENT
Authors: Shavali Shaik, Shinji Maegawa, Ajay Sharma, Amanda Haltom, Tara Dobson, Yanwen Yang, Keri Schadler, Vidya Gopalakrishnan
Journal: Neuro-Oncology (2020)

Abstract The REI Silensing Transcription Factor (REST) is a transcriptional repressor and a canonical regulator of neurogenesis. Its expression is elevated in human sonic hedgehog (SHH) subgroup of medulloblastomas (MBs), where functional studies shown its elevated expression to promote proliferation and block neuronal specification. A role for REST in the control of the MB tumor microenvironment (TME) has not been described previously. Here, we demonstrate that REST also controls the MB-TME, and specifically vascular remodeling. Using our unique RESTTG mouse model, we show that conditional expression of human REST transgene in cerebellar granule neuron progenitors (CGNPs), the cell of origin of a subset of SHH MBs, promoted increased vascular growth. In the context of constitutive activation of SHH signaling, a key driver of SHH-MB development, REST elevation drove tumor progression by altering the tumor vasculature. These findings were validated in mouse orthotopic models of human MB cell lines and through analyses of publicly available transcriptomic database of human MB samples. A strong positive correlation between REST and that of endothelial genes CD31/VEGFR1/ETS1 was seen in samples from patients with SHH-MBs subtypes that are associated with the worst prognosis. Proteomic analyses identified increased secretion of a number of pro-angiogenic factors in the context of upregulated REST expression in MB cells. Unexpectedly, in vitro and in vivo studies showed that MB cells expressed these endothelial markers and co-localized with endothelial cells suggesting that REST elevation may have altered the fate of cells that were destined to become neurons. Finally, ETS1 knockdown in MB cell lines not only downregulated VEGFR1 levels in these cells, and blocked tube formation in vitro, but also caused a reduction in tumor cell co-localization with endothelial cells. Collectively, these data suggest that REST elevation remodels MB vasculature through cell-intrinsic and cell-extrinsic mechanisms.
Gefitinib Versus Vinorelbine Plus Cisplatin as Adjuvant Treatment for Stage II-IIIA (N1-N2) EGFR-Mutant NSCLC: Final Overall Survival Analysis of CTONG1104 Phase III Trial
Authors: Wen-Zhao Zhong, Qun Wang, Wei-Min Mao, Song-Tao Xu, Lin Wu, Yu-Cheng Wei, Yong-Yu Liu, Chun Chen, Ying Cheng, Rong Yin, Fan Yang, Sheng-Xiang Ren, Xiao-Fei Li, Jian Li, Cheng Huang, Zhi-Dong Liu, Shun Xu, Ke-Neng Chen, Shi-Dong Xu, Lun-Xu Liu, Ping Yu, Bu-Hai Wang, Hai-Tao Ma, Jin-Ji Yang, Hong-Hong Yan, Xue-Ning Yang, Si-Yang Liu, Qing Zhou, Yi-Long Wu
Journal: Journal of Clinical Oncology (2020)

PURPOSE ADJUVANT-CTONG1104 (ClinicalTrials.gov identifier: NCT01405079 ), a randomized phase III trial, showed that adjuvant gefitinib treatment significantly improved disease-free survival (DFS) versus vinorelbine plus cisplatin (VP) in patients with epidermal growth factor receptor ( EGFR) mutation-positive resected stage II-IIIA (N1-N2) non–small-cell lung cancer (NSCLC). Here, we report the final overall survival (OS) results. METHODS From September 2011 to April 2014, 222 patients from 27 sites were randomly assigned 1:1 to adjuvant gefitinib (n = 111) or VP (n = 111). Patients with resected stage II-IIIA (N1-N2) NSCLC and EGFR-activating mutation were enrolled, receiving gefitinib for 24 months or VP every 3 weeks for four cycles. The primary end point was DFS (intention-to-treat [ITT] population). Secondary end points included OS, 3-, 5-year (y) DFS rates, and 5-year OS rate. Post hoc analysis was conducted for subsequent therapy data. RESULTS Median follow-up was 80.0 months. Median OS (ITT) was 75.5 and 62.8 months with gefitinib and VP, respectively (hazard ratio [HR], 0.92; 95% CI, 0.62 to 1.36; P = .674); respective 5-year OS rates were 53.2% and 51.2% ( P = .784). Subsequent therapy was administered upon progression in 68.4% and 73.6% of patients receiving gefitinib and VP, respectively. Subsequent targeted therapy contributed most to OS (HR, 0.23; 95% CI, 0.14 to 0.38) compared with no subsequent therapy. Updated 3y DFS rates were 39.6% and 32. 5% with gefitinib and VP ( P = .316) and 5y DFS rates were 22. 6% and 23.2% ( P = .928), respectively. CONCLUSION Adjuvant therapy with gefitinib in patients with early-stage NSCLC and EGFR mutation demonstrated improved DFS over standard of care chemotherapy. Although this DFS advantage did not translate to a significant OS difference, OS with adjuvant gefitinib was one of the longest observed in this patient group compared with historic data.
Non-alcoholic fatty liver disease: Not time for an obituary just yet!
Authors: Shivaram Prasad Singh, Prajna Anirvan, K. Rajender Reddy, Hari S. Conjeevaram, Giulio Marchesini, Mary E. Rinella, Kaushal Madan, Maria Letizia Petroni, Mamun Al-Mahtab, Stephen H. Caldwell, Guruprasad P. Aithal, Saeed S. Hamid, Geoffrey C. Farrell, Sanjaya K. Satapathy, Ajay Duseja, Subrat Kumar Acharya, Anuradha Supun Dassanayake, Khean-Lee Goh
Journal: Journal of Hepatology (2020)