tbuckley/cabot-search huggingface dataset:
Abstract P494: Association of Lipid Components With Mortality,Myocardial Infarction, and Stroke in Statin-Naïve Young Adults: A Nationwide Cohort Study
Authors: Heesun Lee, Jun-bean Park, Hyo Eun Park, Su-yeon Choi, Kyungdo Han, Hyung-Kwan Kim
Journal: Circulation (2020)

Background: Dyslipidemia is a modifiable cardiovascular risk factor with prognostic implications. Current strategies for lipid management in young adults are largely based on expert recommendations. We sought to investigate the risk of death and cardiovascular disease in relation to lipid components to establish evidence for primary prevention in young adults. Methods: In a nationwide cohort using the National Health Insurance claims database, we analyzed 5,688,055 statin-naïve subjects, aged 20-39 years, undergoing health check-up between 2009 and 2014. The study endpoint was a composite of clinical events, including death, myocardial infarction (MI), and stroke. We compared the incidence and the risk of clinical events according to lipid variables, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides. Results: During follow-up (median 7.1 years), clinical events occurred in 30,330 subjects (0.53%); 16,262 deaths (0.29%), 8,578 MIs (0.15%), and 5,967 strokes (0.10%). The risk of clinical events gradually increased with increasing TC and triglycerides, and decreasing HDL-C, with a great contribution by MI. LDL-C had a J-shaped association with the study endpoint, showing the lowest risk in LDL-C of 84-101 mg/dL. Among lipid variables, triglycerides remained the sole independent predictor (adjusted HR 1.20, p &lt;0.001), after adjusting for conventional risk factors. Conclusions: In ‘statin-naïve’ young adults aged 20-39 years, the risk of clinical events was proportional to lipid levels; positively with TC and triglycerides, negatively with HDL-C, and J-shaped with LDL-C. Triglycerides had the strongest and independent association with clinical events. Screening and intervention of abnormal lipid levels, particularly triglycerides, from an early age might be required.
EPEN-30. C11ORF95-RELA FUSION PROTEIN ENGAGES NOVEL GENOMIC LOCI TO DRIVE MURINE EPENDYMOMA GROWTH
Authors: Amir Arabzade, Yanhua Zhao, Srinidhi Varadharajan, Hsiao-Chi Chen, Austin Stuckert, Bryan Rivas, Sameer Agnihotri, Courtney Hodges, Donald Parsons, Susan Blaney, Thomas Westbrook, Charles Lin, Joanna Yi, Benjamin Deneen, Kelsey Bertrand, Stephen Mack
Journal: Neuro-Oncology (2020)

Abstract RATIONALE Over 70% of supratentorial (ST) ependymoma are characterized by an oncogenic fusion between C11ORF95 and RELA. C11ORF95-RELA fusion is frequently the sole genetic driver detected in ST ependymoma, thus ranking this genomic event as a lead target for therapeutic investigation. RELA is a transcription factor (TF) central to mediating NF-kB pathway activation in processes such as inflammation, cellular metabolism, and chemotaxis. HYPOTHESIS: We posited that C11ORF95-RELA acts as an oncogenic TF that aberrantly shapes the tumor epigenome to drive aberrant transcription. Approach: To this end we developed an in utero electroporation (IUE) mouse model of ependymoma to express C11ORF95-RELA during embryonic development. Our IUE approach allowed us to develop C11ORF95-RELA driven tumor models and cell lines. We comprehensively characterized the epigenome and transcriptome of C11ORF95-RELA fusion driven mouse cells by H3K27ac ChIP-seq, ATAC-seq, and RNA-seq. RESULTS This data revealed that: 1) C11ORF95-RELA directly engages ‘open’ chromatin and is enriched at regions with known RELA TF binding sites as well as novel genomic loci/motifs, 2) C11ORF95-RELA preferentially binds to both H3K27ac (active) enhancers and promoters, and 3) Bound C11ORF95-RELA promoter loci are associated with increased transcription of genes shared with human ependymoma. CONCLUSION Our findings shed light on the transcriptional mechanisms of C11ORF95-RELA, and reveal downstream targets that may represent cancer dependency genes and molecular targets.
Autologous Stem Cell Transplantation in Newly Diagnosed Elderly Multiple Myeloma Patients: A Single Centre Experience
Authors: Tamara Berno, Marcello Riva, Lucia Ammirati, Luca Brugnaro, Carmela Gurrieri, Antonio Branca, Nabergoj Mitja, Andrea Visentin, Silvia Imbergamo, Francesco Piazza, Livio Trentin, Renato Zambello, Gianpietro Semenzato
Journal: Blood (2017)
Covid-19: Evidence is lacking to support vitamin D’s role in treatment and prevention
Authors: Jacqui Wise
Journal: BMJ (2020)

Covid-19: Evidence is lacking to support vitamin D's role in treatment and prevention Jacqui WiseThere is "insufficient evidence" to support taking vitamin D solely to prevent or treat covid-19, say leading health bodies. 1 1 NICE.Covid-19 rapid guideline: vitamin D. 17 December 2020.www.nice.org.
GCT-61. CORRELATION OF PATTERNS OF DISEASE RECURRENCE WITH RADIOTHERAPY TECHNIQUES AND DOSE IN INTRACRANIAL GERM CELL TUMOURS (icGCT): LESSONS FROM THE UK COHORT OF SIOP GCT96 STUDY
Authors: Thankamma Ajithkumar, Henry Mandeville, Fernando Carceller, Milind Ronghe, Tina Foord, Stephen Lowis, Michelle Kwok-Williams, Gabriele Calaminus, Matthew Murray, James Nicholson
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND There are global variations in radiotherapy approaches for icGCT. An understanding of patterns of disease recurrence correlated with radiation techniques and doses is important in standardising and improving the quality of radiotherapy using high-precision techniques. METHODS AND RESULTS Data from 20 patients with tumour recurrence after treatment within the SIOP GCT96 study in the UK were analysed. Seven (35%) patients had germinoma and 13 (65%) had non-germinoma. Twelve patients had local recurrence, 5 had metastatic and 3 had local and metastatic disease. Radiotherapy details were retrieved in only 8 patients (40%). Six patients had received focal radiotherapy and two craniospinal radiotherapy. Of the patients who received focal radiotherapy, 4 had recurrence within the radiation portal, one had periventricular recurrence and one had marker-positive recurrence with no radiological lesions. Both patients who received CSI recurred within the CSF space. The main reasons for poor retrieval of treatment details were difficulty in retrieving archived information and that the study was conducted during a period before PACS or electronic radiotherapy records. CONCLUSION This study highlights the importance prospective data collection and analysis to understand the patterns of recurrence in icGCT. Even within a prospective study, radiotherapy techniques varied between centres. There is therefore an urgent need for centralised radiological review and prospective radiotherapy quality assurance measures in future clinical trials.
CTNI-09. A PHASE I HEALTHY VOLUNTEER STUDY ON THE RELATIVE BIOAVAILABILITY AND FOOD EFFECT OF CAPSULE AND GRANULE FORMULATIONS OF SELUMETINIB
Authors: Sarit Cohen-Rabbie, Alexandra Mattinson, Karen So, Nan Wang, Eileen McBride, Karthick Vishwanathan, Ronald Goldwater
Journal: Neuro-Oncology (2020)

Abstract Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective allosteric MEK 1/2 inhibitor approved by the FDA as a capsule formulation for treatment of pediatric patients ≥ 2 years old with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas. A new granule formulation is being developed to support dose flexibility and for patients unable to swallow capsules. This Phase I, open-label, single-center, randomized crossover pharmacokinetics study (NCT03649165) investigated the new granule versus capsule formulation in both fasted and fed (low-fat) states. Twenty-four healthy adult male volunteers were randomized to receive single-dose selumetinib in one of four treatment sequences: 25 mg granule (fasted); 50 mg capsule (fasted); 25 mg granule (fed); and 50 mg capsule (fed). Primary endpoint: to compare pharmacokinetics of the formulations in fasted state. Secondary endpoints: pharmacokinetics of the formulations in fasted versus fed states, granule palatability, safety and tolerability. In fasted state, a slight delay in absorption of selumetinib by ~0.60 h, with geometric mean ratios (90% CI) of 0.65 (0.58, 0.74) for Cmax/dose and 0.87 (0.81, 0.92) for AUC/dose, was detected when administered as granule versus capsule. For granule in fed versus fasted states, geometric mean Cmax and AUC ratios (90% CI) were 0.61 (0.51, 0.72) and 0.97 (0.91, 1.02). For capsule in fed versus fasted states, geometric mean Cmax and AUC ratios (90% CI) were 0.40 (0.33, 0.48) and 0.62 (0.55, 0.70). Granule palatability was acceptable; volunteers indicated they would take it again. Selumetinib was well-tolerated; for both formulations, few adverse events of mild intensity were reported; dry eyes (fasted) versus dry eyes and rhinorrhea (fed) were most frequent. This was the first study to test the granule formulation in humans; results indicate the granule formulation has similar AUC to the capsule formulation and minimal food effect, supporting planned clinical trials in pediatric patients.
TAMI-39. AGE-DEPENDENT PHENOTYPIC CONVERSION FROM NEURONAL ACTIVITY TO NEURO-INFLAMMATION IN GLIOBLASTOMA PROGRESSION
Authors: Daisuke Yamashita, Victoria Flanary, Rachel Munk, Kazuhiro Sonomura, Saya Ozaki, Riki Kawaguchi, Satoshi Suehiro, Sadashib Ghosh, Zhihong Chen, Shinobu Yamaguchi, Svetlana Komarova, Soniya Bastola, Joshua Bernstock, Gwendalyn King, Dr Kunieda, Dolores Hambardzumyan, Toru Kondo, Harley Kornblum, David Crossman, James Hackney, Steve Horvath, Taka-aki Sato, Myriam Gorospe, Ichiro Nakano
Journal: Neuro-Oncology (2020)

Abstract The rise in population aging worldwide is causing an unparalleled increase in death from many cancers, including glioblastoma (GBM). Here, we have explored the impact of aging and rejuvenation on GBM tumorigenesis. Compared with neuro-inflammatory old GBM, young GBM displayed elevated neuronal/synaptic signaling via brain-derived neurotrophic factor (BDNF) and SLIT and NTRK like-family member 6 (SLITRK6), promoting favorable survival rates. These effects were attributed to the rise in nicotinamide adenine dinucleotide (NAD+) levels, as brain rejuvenation by parabiosis or administration of nicotinamide mononucleotide (NMN) in mice elicited a younger phenotype with activated neuronal/synaptic signaling and improved outcomes. Our data indicate that age-associated NAD+ loss contributes to the highly aggressive GBM by the shift from neuronal/synaptic activity to neuro-inflammation in the elderly brain. These findings have therapeutic and preventive implications in GBM and provide mechanistic insights into the exacerbation of GBM tumorigenesis by aging.
DIPG-58. HISTONE H3 WILD-TYPE DIPG/DMG OVEREXPRESSING EZHIP EXTEND THE SPECTRUM OF DIFFUSE MIDLINE GLIOMAS WITH PRC2 INHIBITION BEYOND H3-K27M MUTATION
Authors: David Castel, Thomas Kergrohen, Arnault Tauziède-Espariat, Alan Mackay, Samia Ghermaoui, Emmanuèle Lechapt, Stefan Pfister, Christof Kramm, Nathalie Boddaert, Thomas Blauwblomme, Stéphanie Puget, Kévin Beccaria, Chris Jones, David Jones, Pascale Varlet, Jacques Grill, Marie-Anne Debily
Journal: Neuro-Oncology (2020)

Abstract Diffuse midline gliomas (DMG) H3 K27M-mutant were introduced in the 2016 WHO Classification unifying diffuse intrinsic pontine gliomas (DIPG) and gliomas from the thalamus and spinal cord harboring a histone H3-K27M mutation leading to Polycomb Repressor Complex 2 (PRC2) inhibition. However, few cases of DMG tumors presenting a H3K27 trimethylation loss, but lacking an H3-K27M mutation were reported. To address this question, we combined a retrospective cohort of 10 patients biopsied for a DIPG at the Necker Hospital or included in the BIOMEDE trial (NCT02233049) and extended our analysis to H3-wildtype (WT) diffuse gliomas from other midline locations presenting either H3K27 trimethylation loss or ACVR1 mutation from Necker, ICR, the HERBY trial, the INFORM registry study and the St. Jude PCGP representing 9 additional cases. Genomic profiling identified alterations frequently found in DMG, but none could explain the observed loss of H3K27 trimethylation. Similar observations were previously made in the PF-A subgroup of ependymoma, where the H3K27me3 loss resulted from EZHIP/CXorf67 overexpression rather than H3-K27M mutations. We thus analyzed EZHIP expression and observed its overexpression in all but one H3-WT DMGs compared to H3-K27M mutated tumors (EZHIP negative). Strikingly, based on their DNA methylation profiles, all H3-WT DMG samples analyzed clustered close to H3-K27M DIPG, rather than EZHIP overexpressing PF-A ependymomas. To conclude, we described a new subgroup of DMG lacking H3-K27M mutation, defined by H3K27 trimethylation loss and EZHIP overexpression that can be detected by IHC. We propose that these EZHIP/H3-WT DMGs extend the spectrum of DMG with PRC2 inhibition beyond H3-K27M mutation.
RARE-50. TREATMENT RESPONSE OF CNS HIGH-GRADE NEUROEPITHELIAL TUMORS WITH MN1 ALTERATION
Authors: Lorena V Baroni, Carlos Rugilo, Fabiana Lubieniecki, Claudia Sampor, Candela Freytes, Liana Nobre, Jordan R Hansford, Vajiranee S Malalasekera, Michal Zapotocky, Andrew Dodgshun, Vijay Ramaswamy, Daniel Alderete
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1) are a rare entity recently described as a high-grade tumor containing a mixture of solid and pseudopapillary patterns with MN1 rearrangement. METHODS CNS HGNET-MN1 patients were identified using genome wide methylation arrays across 5 institutions (the Hospital JP Garrahan, Hospital for Sick Children, the University Hospital Motol, Royal Children`s Hospital and Christchurch Hospital) and was correlated with treatment and outcome. Central imaging review with radiological features analysis was performed. RESULTS We identified 9 patients harboring CNS HGNET-MN1 tumors through application of the Heidelberg brain tumor classifier. Seven tumors were T supratentorial and two in the spinal cord. Median age was 5 (range 3.6–14.6). All patients had surgery (6 GTR and 3 STR) as initial management followed by radiotherapy (focal 5/CSI 1) and systemic chemotherapy in 2 patients. Four of the 9 patients relapsed by 3 years post diagnosis, with 2 local and 2 metastatic failures despite complete surgical resections and radiotherapy. Three patients died due to tumor relapse after 24 months despite upfront radiotherapy. Seven of 9 patients had an initial diagnosis of ependymoma. CONCLUSION Treatment of CNS HGNET-MN1 remains a major challenge with multiple failures, despite aggressive surgical resections and upfront involved field radiotherapy. Further multicenter, international prospective studies are required to determine the optimal treatment strategy for this group of tumors.
CXCL12-mediated monocyte transmigration into brain perivascular space leads to neuroinflammation and memory deficit in neuropathic pain
Authors: Chun-Lin Mai, Zhi Tan, Ya-Nan Xu, Jing-Jun Zhang, Zhen-Hua Huang, Dong Wang, Hui Zhang, Wen-Shan Gui, Jun Zhang, Zhen-Jia Lin, Ying-Tong Meng, Xiao Wei, Ying-Tao Jie, Peter M Grace, Long-Jun Wu, Li-Jun Zhou, Xian-Guo Liu
Journal: Theranostics (2020)

Emerging clinical and experimental evidence demonstrates that neuroinflammation plays an important role in cognitive impairment associated with neuropathic pain. However, how peripheral nerve challenge induces remote inflammation in the brain remains largely unknown. Methods: The circulating leukocytes and plasma C-X-C motif chemokine 12 (CXCL12) and brain perivascular macrophages (PVMs) were analyzed by flow cytometry, Western blotting, ELISA, and immunostaining in spared nerve injury (SNI) mice. The memory function was evaluated with a novel object recognition test (NORT) in mice and with Montreal Cognitive Assessment (MoCA) in chronic pain patients. Results: The classical monocytes and CXCL12 in the blood, PVMs in the perivascular space, and gliosis in the brain, particularly in the hippocampus, were persistently increased following SNI in mice. Using the transgenic CCR2RFP/+ and CX3CR1GFP/+ mice, we discovered that at least some of the PVMs were recruited from circulating monocytes. The SNI-induced increase in hippocampal PVMs, gliosis, and memory decline were substantially prevented by either depleting circulating monocytes via intravenous injection of clodronate liposomes or blockade of CXCL12-CXCR4 signaling. On the contrary, intravenous injection of CXCL12 at a pathological concentration in naïve mice mimicked SNI effects. Significantly, we found that circulating monocytes and plasma CXCL12 were elevated in chronic pain patients, and both of them were closely correlated with memory decline. Conclusion: CXCL12-mediated monocyte recruitment into the perivascular space is critical for neuroinflammation and the resultant cognitive impairment in neuropathic pain.
RONC-17. STEREOTACTIC RADIOSURGERY FOR SPINE METASTASES IN PEDIATRIC MALIGNANCIES
Authors: Kristina Woodhouse, Victor Albornoz Alvarez, David Boyce, Jing Li, Debra Yeboa, David Grosshans, Tina Briere, Claudio Tatsui, Laurence Rhines, Amini Behrang, Susan McGovern, Arnold Paulino, Mary Frances McAleer, Amol Ghia
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Spine stereotactic radiosurgery (SSRS) is a non-invasive technique that delivers ablative radiotherapy for optimal control of bony disease. While SSRS is known to provide excellent local control (LC) and minimal toxicity in adults, the role of SSRS in pediatrics is less clear. PURPOSE To evaluate SSRS in pediatric patients with spinal metastases. METHODS A retrospective review of patients (&amp;lt;18 yrs) treated with SSRS at MDACC was performed after IRB approval. Descriptive statistics were utilized for analysis. RESULTS From 2011–2019, 12 metastatic osseous sites (3 cervical, 4 thoracic, 5 lumbar-sacral) in 9 patients were treated. Median follow-up was 9 months (range 2–41). Six males (67%) and 3 females (33%) all KPS ≥70, received radiation to ≤3 contiguous vertebral bodies. Median age was 16 yrs (range 8–18). No patients required sedation. Histologies included 7 osteosarcomas, one rhabdomyosarcoma and one Ewing’s sarcoma. Metastatic epidural spinal cord compression scores ranged from 0 (6), 1b (3) and 3 (3). No sites had surgery prior to SSRS and one site received prior conventional radiation. SSRS doses included 24 Gy in 1 fraction (7), 24–27 Gy in 3 fractions (4) and 50 Gy in 5 fractions (1). Six-month LC was 83% with one local failure following 27 Gy. OS at 6 and 12 mo were 55% and 23%. There was no grade ≥3 acute toxicity, no radiation myelopathy or vertebral compression fractures. CONCLUSION In this initial report, SSRS represents a promising modality that is well tolerated and provides excellent LC. However, further follow-up is warranted in the pediatric setting.
NIMG-59. EVALUATION OF GLCM FEATURES BASED CLASSIFIERS IN DIFFERENTIATING TUMOR GRADES ON MULTI-MODAL MR IMAGES
Authors: Sushmita Datta, Roy Riascos-Castaneda, Jay-Jiguang Zhu
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Accurate classification of tumor grade is necessary for understanding tumor development critical in patient management. Radiomic features are gaining popularity in classifying the tumors with the application of various classifiers. We evaluate five classifiers using gray-level co-occurrence matrix (GLCM) features to classify low-grade gliomas (LGG) and high-grade gliomas (HGG). METHODS We included high resolution multi-modal MR images from pre-operative BraTS 2019 database. The database contains a total of 335 multi-modal MR images (259 HGG and 76 LGG) with manually-corrected segmentations of tumor compartments. Sixty four three-dimensional (3D) voxel-by-voxel GLCM feature images on T2-wighted (T2), fluid attenuated inversion recovery (FLAIR), and T1-weighted (T1) pre- and post-contrast images are computed. A total of 192 features within regions of enhanced tumor (ET), edema (ED), and non-enhanced tumor (NET) are obtained by taking averages of the GLCM features within each region. For classification, we evaluated k-nearest neighbor (kNN), learning vector quantization (LVQ), random forest classifier (RF), classification and regression trees (CART), and support vector machine (SVM) classifiers for differentiating LGG from HGG. The dataset is randomly split into ratio of 80 to 20 for training and validation. The models are trained using repeated 5-fold cross-validation. Best 10 models for each of the classifiers are selected based on accuracy by applying multiple random split. RESULTS The average accuracies of 10 best models selected for each of kNN, LVQ, RF, CART, and SVM classifiers are 0.88, 0.92, 1.00, 0.890, and 0.95 on training set, and 0.89, 0.88, 0.88, 0.89, and 0.90 on validation set. The performance of five classifiers on validation set is similar. The accuracy of SVM classifier is slightly higher on validation set even though the RF appears to be the best classifier on training set. CONCLUSION Voxel-by-voxel GLCM features help differentiate LGG and HGG with 0.89 of accuracy irrespective of the classifier.
Spirometric Classifications of Chronic Obstructive Pulmonary Disease Severity as Predictive Markers for Clinical Outcomes: The HUNT Study
Authors: Laxmi Bhatta, Linda Leivseth, Xiao-Mei Mai, Anne Hildur Henriksen, David Carslake, Yue Chen, Pablo Martinez-Camblor, Arnulf Langhammer, Ben Michael Brumpton
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
MODL-29. EVALUATING TUMOR-IMMUNE INTERACTIONS IN MOUSE MODELS OF DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Robin Furnish, Heather Bear, Xin Wei, Timothy Phoenix
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND While adult gliomas show some level of immune cell infiltration, diffuse intrinsic pontine glioma (DIPG) is characterized as having an “immune cold” state. We have developed new immunocompetent mouse models of DIPG. These models faithfully recapitulate the pathological hallmarks of DIPG and provides a unique platform to investigate immune modulatory therapies and potential therapeutic benefits of check point inhibitor combination therapies. METHODS To evaluate the effects of CDK4/6 inhibition (CDK4/6i) on cell proliferation and immune interactions we performed a series of in vitro and in vivo studies using DIPG mouse models. In vitro assays included dose response curves, transcriptional profiling, and MHC1 expression. In vivo preclinical studies treated mouse models with CDK4/6i with or without immune check-point inhibitors (ICI). We also examined other candidate immune modulatory therapies in vitro. RESULTS CDK4/6i (Abemeciclib) reduced proliferation of DIPG cells derived from mouse models, and displayed a modest increase in immune activation by MHC1 expression and transcriptome. Pilot in vivo preclinical studies did not show any significant changes in DIPG proliferation or immune changes with CDK4/6i treatment, ICI treatment, or the combination of CDK4/6i + ICI. In vitro testing of other immune-modulatory drugs identified additional candidates that can be tested in vivo. CONCLUSION CDK4/6i displayed in vitro action, but lacked efficacy in DIPG mouse models in vivo. Further use of spontaneous DIPG mouse models will provide a rapid preclinical platform to evaluate in vivo tumor-immune interactions, drug efficacy, and mechanisms of resistance.