tbuckley/cabot-search huggingface dataset:
Nomogram for prediction of fatal outcome in patients with severe COVID-19: a multicenter study
Authors: Yun Yang, Xiao-Fei Zhu, Jian Huang, Cui Chen, Yang Zheng, Wei He, Ling-Hao Zhao, Qian Gao, Xuan-Xuan Huang, Li-Juan Fu, Yu Zhang, Yan-Qin Chang, Huo-Jun Zhang, Zhi-Jie Lu
Journal: Military Medical Research (2021)

Abstract Background To develop an effective model of predicting fatal outcomes in the severe coronavirus disease 2019 (COVID-19) patients. Methods Between February 20, 2020 and April 4, 2020, consecutive confirmed 2541 COVID-19 patients from three designated hospitals were enrolled in this study. All patients received chest computed tomography (CT) and serological examinations at admission. Laboratory tests included routine blood tests, liver function, renal function, coagulation profile, C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), and arterial blood gas. The SaO 2 was measured using pulse oxygen saturation in room air at resting status. Independent high-risk factors associated with death were analyzed using Cox proportional hazard model. A prognostic nomogram was constructed to predict the survival of severe COVID-19 patients. Results There were 124 severe patients in the training cohort, and there were 71 and 76 severe patients in the two independent validation cohorts, respectively. Multivariate Cox analysis indicated that age ≥ 70 years ( HR = 1.184, 95% CI 1.061–1.321), panting (breathing rate ≥ 30/min) ( HR = 3.300, 95% CI 2.509–6.286), lymphocyte count &lt; 1.0 × 10 9 /L ( HR = 2.283, 95% CI 1.779–3.267), and interleukin-6 (IL-6) &gt; 10 pg/ml ( HR = 3.029, 95% CI 1.567–7.116) were independent high-risk factors associated with fatal outcome. We developed the nomogram for identifying survival of severe COVID-19 patients in the training cohort (AUC = 0.900, 95% CI 0.841–0.960, sensitivity 95.5%, specificity 77.5%); in validation cohort 1 (AUC = 0.811, 95% CI 0.763–0.961, sensitivity 77.3%, specificity 73.5%); in validation cohort 2 (AUC = 0.862, 95% CI 0.698–0.924, sensitivity 92.9%, specificity 64.5%). The calibration curve for probability of death indicated a good consistence between prediction by the nomogram and the actual observation. The prognosis of severe COVID-19 patients with high levels of IL-6 receiving tocilizumab were better than that of those patients without tocilizumab both in the training and validation cohorts, but without difference ( P = 0.105 for training cohort, P = 0.133 for validation cohort 1, and P = 0.210 for validation cohort 2). Conclusions This nomogram could help clinicians to identify severe patients who have high risk of death, and to develop more appropriate treatment strategies to reduce the mortality of severe patients. Tocilizumab may improve the prognosis of severe COVID-19 patients with high levels of IL-6.
IMMU-28. IMMUNOGENOMIC ANALYSIS REVEALS LGALS1 CONTRIBUTES TO THE IMMUNE HETEROGENEITY AND IMMUNOSUPPRESSION IN GLIOMA
Authors: Qun Chen, Jinquan Cai, Bo Han, Xiangqi Meng
Journal: Neuro-Oncology (2020)

Abstract Mutualistic and dynamic communication between tumour cells and the surrounding microenvironment accelerates the initiation, progression, chemoresistance and immune evasion of glioblastoma (GBM). However, the immunosuppressive mechanisms of GBM has not been thoroughly elucidated to date. We enrolled six microenvironmental signatures to identify glioma microenvironmental genes. The functional enrichment analysis such as ssGSEA, ESTIMATE algorithm, Gene Ontology, Pathway analysis is conducted to discover the potential function of microenvironmental genes. In vivo and in vitro experiments are used to verify the immunologic function of LGALS1 in GBM. We screen eight glioma microenvironmental genes from glioma databases, and discover a key immunosuppressive gene (LGALS1 encoding Galectin-1) exhibiting obviously prognostic significance among glioma microenvironmental genes. Gliomas with different LGALS1 expression have specific genomic variation spectrums. Immunosuppression is a predominate characteristic in GBMs with high expression of LGALS1. Knockdown of LGALS1 remodels the GBM immunosuppressive microenvironment by down regulating M2 macrophages and myeloid-derived suppressor cells (MDSCs), and inhibiting immunosuppressive cytokines. Our results thus implied an important role of microenvironmental regulation in glioma malignancy and provided evidences of LGALS1 contributing to immunosuppressive environment in glioma and that targeting LGALS1 could remodel immunosuppressive microenvironment of glioma.
Acute Adverse Reactions to Gadolinium in CMR: “Gadol” News!⁎⁎Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Authors: Natalie Bello, Warren J. Manning
Journal: JACC. Cardiovascular imaging (2011)
STEM-02. IN VIVO PHAGE DISPLAY IDENTIFIES PEPTIDE TARGETING N-CADHERIN ON GLIOMA STEM CELLS
Authors: Marine Potez, Jongmyung Kim, Chunhua She, Neelkamal Chaudhary, James Liu
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor with high mortality rates and resistance to conventional therapy. Glioma stem cells (GSCs) comprise a sub-population of glioma tumor cells with the ability of self-renewal and tumor recapitulation, and may be responsible for GBM’s treatment resistant properties. Identification of surface receptors that are novel and specific to GSCs may be the key to the development of effective therapeutic strategies. We have selected a GSC specific targeting peptide isolated through in vitro and in vivo phage display biopanning. This screening technique allowed us to determine a peptide (GBM-IC2) which binds specifically to GSCs in vitro, and to GBM tissue in vivo. Although this screening process allows for isolation of cell specific targeting peptides, it does so without identification of the cellular binding partner. Given the specificity of the peptide, identification of the cellular receptor may allow for discovery of novel markers to identify GSCs. To identify the peptide binding partner of GBM-IC2, the biotinylated peptide was incubated with GSC protein lysate. The peptide, along with its binding partner, was isolated using streptavidin agarose resin. The binding partner protein was then identified using mass spectroscopy. This revealed N-cadherin (CDH2) as a potential binding partner for the GBM-IC2 peptide. GBM-IC2 demonstrated specificity for targeting CDH2 compared to control peptide using ELISA. Lentiviral induced overexpression of CDH2 in HEK293 cells allowed for GBM-IC2 peptide binding. Competition assay was performed by applying anti-CDH2 antibody to GBM-IC2 peptide and GSCs in culture. Application of anti-CDH2 antibody decreased peptide binding to GSCs, confirming CDH2 as the binding partner for GBM-IC2. These results demonstrate that cell specific targeting peptides isolated through phage display may lead to the isolation of novel cell specific proteins through immunoprecipitation isolation and mass spectroscopy analysis.
EXTH-36. PHARMACEUTICAL INHIBITION OF CYCLIN DEPENDENT KINASE 4/6 (CDK4/6) IN GLIOBLASTOMA
Authors: Oluwademilade Nuga, Yuling Meng, Artem Berezovsky, Kevin Nelson, Ana de Carvalho
Journal: Neuro-Oncology (2020)

Abstract Potent and selective CDK4/6 inhibitors (CDK4/6i) have potential for treating glioblastoma. Although genomic abnormalities affecting CDK4/6-RB1 signaling axis, such as CDK4 or CDK6 amplification and CDKN2A deletion, which are frequent in GBM, have been proposed to predict response of RB1-wildtype GBM to CDK4/6i, there is not enough data validating these biomarkers as sufficient for patient selection. Here we employ a panel of GBM patient derived cancer stem cells (CSC) representing the most frequent somatic genomic alterations in GBM to test their response to CDK4/6i. Twelve CSC lines were treated in quintuplicate for 4–7 days with 0–10 mM Abemaciclib, Ribociclib or vehicle control. Cell viability was measured using CellTiterGlo and dose response curves were analyzed using GRmetrics in R to determine Area Above the Curve (AAC) and IC50, factoring variable growth rates among cell lines. Experiments were repeated 2–4 times. Abemaciclib was more potent in reducing cell viability, based on the RB1-null CSC line measured resistance (mean AAC = 0.3 +/- 0.06), ribociclib was more specific (mean AAC = 0.05 +/-0.01). 4/7 CSCs with CDKN2A homozygous deletion were sensitive (mean AAC &amp;gt; 0.7) while 3/7 were resistant (mean AAC &amp;lt; 0.33) to 4 and 7-day treatments of abemaciclib. One CSC from a newly diagnosed GBM bearing CDK4, MYC and EGFR amplifications was sensitive to both inhibitors (mean AAC = 0.5 abemaciclib and ribociclib), while CSC from the matched recurrent tumor presenting the same driver genomic alterations was significantly more resistant (mean AAC = 0.2 for abemaciclib and ribociclib) (p &amp;lt; 0.05, t-test). Additionally, we exposed a sensitive cell line to conditioned media from a resistant cohort, resulting in significantly reduced proliferation and increased resistance to CDK4/6i (p&amp;lt; 0.05, Dunn). These findings underscore the importance of a utilizing a robust molecular profiling approach in evaluating which patients will benefit from CDK4/6i therapy.
Cell-autonomous role of Presenilin in age-dependent survival of cortical interneurons
Authors: Jongkyun Kang, Jie Shen
Journal: Molecular Neurodegeneration (2020)

Mutations in the PSEN1 and PSEN2 genes are the major cause of familial Alzheimer's disease. Previous studies demonstrated that Presenilin (PS), the catalytic subunit of γ-secretase, is required for survival of excitatory neurons in the cerebral cortex during aging. However, the role of PS in inhibitory interneurons had not been explored.
Effect of Prehospital Crushed Prasugrel Tablets in Patients With ST-Segment–Elevation Myocardial Infarction Planned for Primary Percutaneous Coronary Intervention
Authors: Georgios J. Vlachojannis, Jeroen M. Wilschut, Rosanne F. Vogel, Miguel E. Lemmert, Ronak Delewi, Roberto Diletti, Nancy W.P.L. van der Waarden, Rutger-Jan Nuis, Valeria Paradies, Dimitrios Alexopoulos, Felix Zijlstra, Gilles Montalescot, Dominick J. Angiolillo, Mitchell W. Krucoff, Nicolas M. Van Mieghem, Pieter C. Smits
Journal: Circulation (2020)

Early treatment with a potent oral platelet P2Y12 inhibitor is recommended in patients presenting with ST-segment-elevation myocardial infarction scheduled to undergo primary percutaneous coronary intervention (pPCI). The impact on coronary reperfusion of crushed P2Y12 inhibitor tablets, which lead to more prompt and potent platelet inhibition, is unknown. We conducted a randomized controlled, multicenter trial in the Netherlands, enrolling patients with ST-segment-elevation myocardial infarction scheduled to undergo pPCI. Patients were randomly allocated to receive in the ambulance, before transfer, a 60-mg loading dose of prasugrel either as crushed or integral tablets. The independent primary end points were thrombolysis in myocardial infarction (TIMI) 3 flow in the infarct-related artery at initial coronary angiography, and complete (≥70%) ST-segment resolution 1 hour after pPCI. The safety end points were TIMI major and Bleeding Academic Research Consortium ≥3 bleedings. Secondary end points included platelet reactivity and ischemic outcomes. A total of 727 patients were assigned to either crushed or integral tablets of prasugrel loading dose. The median time from study treatment to wire-crossing during pPCI was 57 (47-70) minutes. The primary end point TIMI 3 flow in the infarct-related artery before pPCI occurred in 31.0% in the crushed group versus 32.7% in the integral group (odds ratio, 0.92 [95% CI, 0.65-1.30], P=0.64). Complete ST-segment resolution 1 hour after pPCI was present in 59.9% in the crushed group versus 57.3% in the integral group (odds ratio, 1.11 [95% CI, 0.78-1.58], P=0.55). Platelet reactivity at the beginning of pPCI, measured as P2Y12 reactivity unit, differed significantly between groups (crushed, 192 [132-245] versus integral, 227 [184-254], P≤0.01). TIMI major and Bleeding Academic Research Consortium ≥3 bleeding occurred in 0% in the crushed group versus 0.8% in the integral group, and in 0.3% in the crushed group versus 1.1% in the integral group, respectively. There were no differences observed between groups regarding ischemic events at 30 days. Prehospital administration of crushed prasugrel tablets does not improve TIMI 3 flow in the infarct-related artery before pPCI or complete ST-segment resolution 1 h after pPCI in patients presenting with ST-segment-elevation myocardial infarction scheduled for pPCI. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03296540.
NCMP-17. MISMATCH REPAIR MUTATIONS AND THE CENTRAL NERVOUS SYSTEM: A CASE SERIES OF GERMLINE MUTATIONS AND CNS MALIGNANCY
Authors: Amber Ruiz, Jerome Graber
Journal: Neuro-Oncology (2020)

Abstract Our understanding of genetic predispositions for malignancy is continually evolving. One family of germline mutations well described in the literature is that of the DNA mismatch repair mechanism (MMR). Lynch syndrome (LS) is due to a loss of function mutation of several MMR genes- MSH2, MLH1, MSH6, and PMS2. Germline MMR mutations lead to microsatellite instability and loss of genomic integrity resulting in an increased risk for various cancers (colorectal, genitourinary, etc). LS may be as common as 1 in 400 people and some MMR mutations have been associated with gliomas. There is a paucity of information regarding frequency of glioma subtypes as well as tumor genetic and molecular characteristics which have important clinical implications. We describe a case series of 6 individuals with germline MMR mutations and brain tumors. Those with MSH2 and PMS2 mutations (n=3) developed glioblastomas at a mean age at diagnosis of 48 years. These tumors expressed MGMT hyper-methylation and high tumor mutational burden. Only one had IDH-1 mutation. Those with MLH1 mutations (n=3), did not develop gliomas. This raises the question of differential glioma subtype development based on MMR gene. It also highlights the possibility of Lynch-associated gliomas having more favorable treatment response due to MGMT methylation and potential response to immunotherapy based on high tumor mutational burden. Though the sample size is small, there appears to be a preponderance of women compared to men (5:1 respectively). Larger studies are needed to verify CNS involvement in germline MMR mutations. In doing so, we hope to identify factors that may influence clinical management and lead to a better understanding of treatment response and disease prognosis.
EXTH-71. CYTOSTATIC HYPOTHERMIA FOR GLIOBLASTOMA
Authors: Syed Faaiz Enam, Jianxi Huang, Cem Kilic, Connor Tribble, Martha Betancur, Stephanie Blocker, Steven Owen, Ravi Bellamkonda
Journal: Neuro-Oncology (2020)

Abstract As a cancer therapy, hypothermia has been used at sub-zero temperatures to cryosurgically ablate tumors. However, these temperatures can indiscriminately damage both tumorous and healthy cells. Additionally, strategies designed to kill tumor typically accelerate their evolution and recurrence can be inevitable in cancers such as glioblastoma (GBM). To bypass these limitations, here we studied the use of hypothermia as a cytostatic tool against cancer and deployed it against an aggressive rodent model of GBM. To identify the minimal dosage of ‘cytostatic hypothermia’, we cultured at least 4 GBM lines at 4 continuous or intermittent degrees of hypothermia and evaluated their growth rates through a custom imaging-based assay. This revealed cell-specific sensitivities to hypothermia. Subsequently, we examined the effects of cytostatic hypothermia on these cells by a cursory study of their cell-cycle, energy metabolism, and protein synthesis. Next, we investigated the use of cytostatic hypothermia as an adjuvant to chemotherapy and CAR T immunotherapy. Our studies demonstrated that cytostatic hypothermia did not interfere with Temozolomide in vitro and may have been synergistic against at least 1 GBM line. Interestingly, we also demonstrated that CAR T immunotherapy can function under cytostatic hypothermia. To assess the efficacy of hypothermia in vivo, we report the design of an implantable device to focally administer cytostatic hypothermia in an aggressive rodent model of F98 GBM. Cytostatic hypothermia significantly doubled the median survival of tumor-bearing rats with no obvious signs of distress. The absence of gross behavioral alterations is in concurrence with literature suggesting the brain is naturally resilient to focal hypothermia. Based on these findings, we anticipate that focally administered cytostatic hypothermia alone has the potential to delay tumor recurrence or increase progression-free survival in patients. Additionally, it could also provide more time to evaluate concomitant, curative cytotoxic treatments.
QOL-20. IMPACT OF RADIATION DOSE AND VOLUME ON MEMORY FUNCTIONING IN CHILDREN WITH MEDULLOBLASTOMA: A REPORT FROM CHILDREN’S ONCOLOGY GROUP (COG) ACNS0331
Authors: Leanne Embry, Paul Colte, Patsy Cullen, Jeff Michalski, Yimei Li, Yuanyuan Han, Kristina Hardy
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND/OBJECTIVES We examined longitudinal verbal and visual memory functioning in children treated for medulloblastoma on COG protocol ACNS0331. METHODS Children with medulloblastoma participated in neuropsychological testing at three timepoints over a 6-year period. Children aged 3–7 years were randomized to receive craniospinal irradiation (CSI) of either 23.4Gy (standard dose; SDCSI) or 18Gy (lower dose; LDCSI). Children aged 8+ received SDCSI. All children were also randomized to receive either a reduced radiation boost to the involved field (IFRT) or a standard boost to the whole posterior fossa (PFRT). Memory functioning was evaluated an average of 0.67(T1), 2.95(T2), and 4.90(T3) years post-diagnosis. RESULTS Of 464 eligible patients enrolled on ACNS0331, 354 (76%; 65.3% male, 83.1% white) completed some neuropsychological testing. Mean age at diagnosis was 9.1 years (range=3–19). Verbal and visual short-term memory and learning were broadly within the average range for the overall sample at all three timepoints. However, a large percentage of children exhibited scores ≥1SD below the mean on tasks of verbal learning both immediately (43.4%) and after a delay (40.7%) at T3. In addition, 58.6% of children randomized to SDCSI exhibited impairment in verbal learning after a delay compared to 34.8% of children randomized to LDSCI, and 35.0% of those aged ≥8 at diagnosis receiving SDCSI. CONCLUSIONS Younger children receiving SDCSI have particularly high rates of memory impairment five years after diagnosis of medulloblastoma. Limiting CSI dose and/or volume in young children treated for this diagnosis may improve outcomes for memory functioning.
EPID-10. EPIDEMIOLOGY STUDY OF UNCOMMON CHILDHOOD BRAIN TUMOURS IN ASIAN CHILDREN
Authors: Godfrey Chi-Fung Chan, Anthony Pak-Yin Liu, Matthew Ming-Kong Shing, Dennis Tak-Noi Ku
Journal: Neuro-Oncology (2020)

Abstract Our local registry identified 656 brain tumours from Jan 1999 to Dec 2018, (incidence: 29.8/yr/million). Other from Glioma, Medulloblastoma/PNET, Germ Cell tumours, Ependymoma, the remaining rarer tumours accounted for 18% (n=118). The 7 more common groups are: craniopharyngioma(n=28); ATRT(n=18); choroid plexus papilloma/CA(n=12); Ganglioglioma(n=11); ETMR(n=7); DNET(n=7); meningioma(n=6). Their respective incidences are 1.27; 0.81; 0.55; 0.5; 0.32; 0.32 0.27/yr/million. For craniopharyngioma, M:F=15:13 and median age was 7.4yrs (2mons-16.5yrs). 12/28 children had surgery alone and 13/28 had focal RT post-surgery with better outcome. 3 underwent intra-cystic interferon-beta also stable. For ATRT, M:F=7:8 and median age was 2.3yrs (4mos-14.2yrs). 2 had metastatic disease and 7/18 patients remained alive. For choroid plexus tumours, there were 7 papilloma, 2 atypia and 3 carcinoma. M:F=5:6 and median age was 1.5yrs (4mos-14yrs). All papilloma, 1/2 atypia and 1/3 carcinoma survived. For ganglioglioma, M:F=7:4 with median age of 5.5yrs (5mos-13.2yrs). They commonly presented with seizure and only one died (brainstem primary). The ETMR includes ependymoblastoma and medulloepithelioma, they had quite different clinical characteristics and outcome. 6/7 DNET had convulsion and M:F=6:1. Median age was 11.5yrs (2.66-14yrs). They all survived even if incompletely resected. For meningioma, 1/6 had germline mutation of NF-2 gene. M:F=3:3 and onset was &amp;gt;8yrs except the NF-2 patient. All survived but the NF-2 had multiple recurrences. 4 patients developed secondary meningioma due to irradiation but they were &amp;gt;18yrs so excluded. In summary, rarer forms of childhood brain tumours only accounted for &amp;lt;20% of all brain tumours and they had diverse presenting features and outcome.
COVD-04. REAL-WORLD PERSPECTIVES: TUMOR TREATING FIELDS (TTFIELDS) UTILITY TO OPTIMIZE TREATMENT OF PATIENTS WITH GLIOBLASTOMA (GBM) AMIDST COVID-19 PANDEMIC
Authors: Peggy Frongillo, Melissa Shackelford, Lindsay Rain
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Due to the unprecedented, COVID-19 pandemic and resulting health/safety guidelines, rapid-adjustments to treatment plans for patients battling glioblastoma (GBM; debilitating, aggressive cancer) were critical. Tumor Treating Fields (TTFields; FDA-approved for GBM; antimitotic device) are alternating electric fields (200 kHz) delivered through scalp-placed transducer arrays to target rapidly dividing GBM cells. Visitor restrictions at cancer-centers and often overburdened healthcare teams provided obstacles to cancer therapy. Health and safety of patients/caregivers, healthcare providers (HCPs), and patient Device Support Specialists (DSS) were prioritized. We evaluated the impact of Novocure® (device manufacturer) implemented strategies on overcoming limitations/restrictions to treatment-access during COVID-19. TREATMENT/PROTOCOL TTFields (Optune) offers a viable noninvasive, built-in-care system for convenient at-home use. TTFields provides survival benefit with continuous, portable-usage and is tolerable (no-related systemic effects) without overall impact on quality-of-life (except itchy skin). Novocure adopted/amended protocols to meet health guidance/regulation (ie, World Health Organization, Centers for Disease Control and Prevention, local, hospital/clinic directives). PERSPECTIVES COVID-19 forced a change in treatment patterns imposed by quarantine limitations. This, coupled with the vulnerabilities of immunocompromised patients with GBM, necessitated new-access to TTFields. A COVID-19 task force was created to monitor developments, providing directives to minimize risks to patients/caregivers and employees. Hygiene-practices/full-personal protective equipment were applied for live patient-appointments with DSS. Virtual education appointments were executed to guide patients/caregivers through treatment-initiation. New, no-contact, monthly-usage data downloads were employed. Communication measures were implemented, informing HCPs of process changes impacting patients. To date, no observed differences were noted for virtual to non-virtual patient starts, demographics, time-to-start (42-days), treatment discontinuations, percentage continuing therapy (90%), and overall complaints. No new safety signals were observed utilizing new approaches. CONCLUSIONS TTFields care-delivery has been transformed during COVID-19 and preemptively in regards to other future access-limiting events, with adoption of virtual-platforms/protocols, resulting in enhanced access and education for patients/caregivers and healthcare teams.