tbuckley/cabot-search huggingface dataset:
IMMU-51. NEUROLOGIC IMMUNE-RELATED ADVERSE EVENTS MIMICS, RISK FACTORS, AND MECHANISMS: CLIPPERS AND ASEPTIC MENINGITIS
Authors: Carlen Yuen, Kourosh Rezania, Deric Park, Anthony Reder
Journal: Neuro-Oncology (2020)

Abstract Neurological immune-related adverse events (irAEs) are rare toxicities that occur following immune checkpoint blockade. It is imperative to distinguish between irAEs and their mimics for successful treatment. We present the first case of CLIPPERS-like lesions in a patient with thymic cancer, thymoma, and a family history of neuromyelitis optica, following treatment with pembrolizumab. The brainstem lesion was in the anatomic location of the respiratory and cardiac centers. We also present a second case of aseptic meningitis irAE in a patient with prior graft-versus-host-disease following a single dose of nivolumab. These cases add to the growing evidence of CNS complications from immune checkpoint inhibitors. Risk factors for irAEs are not well established, and we explore potential risk factors and a possible mechanism from dysfunctional regulatory T cells.
The granting of emergency use designation to COVID-19 candidate vaccines: implications for COVID-19 vaccine trials
Authors: Jerome Amir Singh, Ross E G Upshur
Journal: The Lancet Infectious Diseases (2020)

An efficacious COVID-19 vaccine is currently the world's leading research priority. Several nations have indicated that if there is a compelling case for use of a vaccine before it is licensed, they would be prepared to authorise its emergency use or conditional approval on public health grounds. As of Dec 1, 2020, several developers of leading COVID-19 candidate vaccines have indicated that they have applied, or intend to apply, for emergency authorisation for their vaccines. Should candidate vaccines attain emergency use designation and be programmatically deployed before their phase 3 trials conclude, such a strategy could have far reaching consequences for COVID-19 vaccine research and the effective control of the COVID-19 pandemic. These issues merit careful consideration.
NIMG-40. RADIOGENOMIC SIGNATURES OF DRIVER GENES IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS BASED ON PRE-OPERATIVE MULTI-PARAMETRIC MRI
Authors: Anahita Fathi Kazerooni, Erik Toorens, Spyridon Bakas, Hamed Akbari, Chiharu Sako, Elizabeth Mamourian, Sung Min Ha, Nina Thakur, Jennifer-Marie Rosado, Stephen Bagley, Tapan Ganguly, Nasrallah MacLean, Christos Davatzikos
Journal: Neuro-Oncology (2020)

Abstract PURPOSE Non-invasive and quantitative biomarkers of somatic mutations derived from multi-parametric MRI (MP-MRI) could potentially help in predicting the response of patients to therapy, leading to development of targeted and personalized treatments. In this study, we developed radiogenomic signatures of multiple driver genes using artificial intelligence (AI) methods. METHODS In this study, 2740 radiomic features, including shape and volumetric measures computed for different tumorous regions, and characteristics derived from histograms and gray-level co-occurrence matrix (GLCM), were extracted from pre-operative MP-MRI (T1, T1Gd, T2, T2-FLAIR, DTI, and DSC-MRI) scans of 161 patients with newly diagnosed glioblastoma. The tumor samples, collected surgically from these patients, were sequenced using an in-house targeted next generation sequencing (NGS) panel of genes. We constructed quantitative imaging signatures of somatic mutations in several genes from 161 IDH-wildtype glioblastoma patients, including ATRX, FGFR2, EGFR, MET, NF1, PDGFRA, PIK3CA, PTEN, RB1, TP53, using cross-validated SVM classifiers. RESULTS The cross-validated classification performance for each signature was assessed by area under the receiver operating characteristic (ROC) curve (AUC), indicating the following results: PTEN (n = 69, AUC = 0.64), EGFR (n = 52, AUC = 0.72), TP53 (n = 51, AUC = 0.67), NF1 (n = 33, AUC = 0.74), ATRX (n = 22; AUC = 0.74), FGFR2 (n = 6, AUC = 0.82), MET (n = 26, AUC = 0.77), PDGFRA (n = 14, AUC = 0.82), PIK3CA (n = 14, AUC = 0.78), RB1 (n = 14, AUC = 0.81). CONCLUSION Using multi-parametric MRI, we developed quantitative non-invasive in vivo signatures with the potential for pre-operative assessment of a glioblastoma’s molecular characteristics. These non-invasive radiogenomic biomarkers may be useful for understanding the molecular composition of a glioblastoma prior to surgical resection, thus enabling earlier selection of patients for targeted therapy trials and possible neoadjuvant treatment.
CBIO-05. LIPID METABOLIC REPROGRAMMING SENSITIZES A MOLECULARLY-DEFINED SUBSET OF GLIOBLASTOMAS TO FERROPTOSIS
Authors: Danielle Morrow, David Nathanson, Timothy Cloughesy, Robert Prins, Nicholas Bayley, Linda Liau, Steven Bensinger, Kevin Williams
Journal: Neuro-Oncology (2020)

Abstract Cancers, including the universally lethal glioblastoma (GBM), have reprogrammed lipid metabolism to fuel tumor growth. However, the molecular alterations responsible for aberrant lipid metabolism, and the potential for identifying new therapeutic opportunities are not fully understood. To systematically investigate the GBM lipidome, we performed integrated transcriptomic, genomic and shotgun lipidomic analysis of an extensive library of molecularly diverse patient-derived GBM samples. Using this comprehensive approach, we discovered two GBM sub-groups defined by their combined molecular and lipidomic profile. Triacylglycerides (TAGs) enriched in polyunsaturated fatty acids (PUFAs) were among the most significantly altered lipids between the two groups of GBM tumors. TAGs are the main components of lipid droplets, which sequester PUFA-TAGs away from membrane phospholipids where their peroxidation can lead to ferroptosis – a regulated from of PUFA-peroxidation dependent cell death. Accordingly, the GBM subgroup with a depletion of PUFA TAGs showed heightened sensitivity to ferroptosis. Our findings suggest a novel association between specific molecular signatures of GBM, lipid metabolism and ferroptosis. This relationship may present a new therapeutic opportunity to target reprogrammed lipid metabolism in a molecularly-defined subset of GBMs.
CBIO-10. REDUCED IRON EXPORT FUNCTIONS IN A CELL INTRINSIC MANNER TO DRIVE GLIOBLASTOMA GROWTH
Authors: Katie Troike, Erin Mulkearns-Hubert, Daniel Silver, James Connor, Justin Lathia
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM), the most common primary malignant brain tumor in adults, is characterized by invasive growth and poor prognosis. Iron is a critical regulator of many cellular processes, and GBM tumor cells have been shown to modulate expression of iron-associated proteins to enhance iron uptake from the surrounding microenvironment, driving tumor initiation and growth. While iron uptake has been the central focus of previous investigations, additional mechanisms of iron regulation, such as compensatory iron efflux, have not been explored in the context of GBM. The hemochromatosis (HFE) gene encodes a transmembrane glycoprotein that aids in iron homeostasis by limiting cellular iron release, resulting in a sequestration phenotype. We find that HFE is upregulated in GBM tumors compared to non-tumor brain and that expression of HFE increases with tumor grade. Furthermore, HFE mRNA expression is associated with significantly reduced survival specifically in female patients with GBM. Based on these findings, we hypothesize that GBM tumor cells upregulate HFE expression to augment cellular iron loading and drive proliferation, ultimately leading to reduced survival of female patients. To test this hypothesis, we generated Hfe knockdown and overexpressing mouse glioma cell lines. We observed significant alterations in the expression of several iron handling genes with Hfe knockdown or overexpression, suggesting global disruption of iron homeostasis. Additionally, we show that knockdown of Hfe in these cells increases apoptosis and leads to a significant impairment of tumor growth in vivo. These findings support the hypothesis that Hfe is a critical regulator of cellular iron status and contributes to tumor aggression. Future work will include further exploration of the mechanisms that contribute to these phenotypes as well as interactions with the tumor microenvironment. Elucidating the mechanisms by which iron effulx contributes to GBM may inform the development of next-generation targeted therapies.
Antibacterial, proangiogenic, and osteopromotive nanoglass paste coordinates regenerative process following bacterial infection in hard tissue
Authors: Jung Ju Seo, Nandin Mandakhbayar, Min Sil Kang, Ji-Young Yoon, Na-Hyun Lee, Junyong Ahn, Hae-Hyoung Lee, Jung-Hwan Lee, Hae-Won Kim
Journal: Biomaterials (2020)
Abstract 15306: Annual Transplant Volume Does Not Affect Center Specific Mortality- A PHTS Database Study
Authors: Aecha M Ybarra, Matthew J O’Connor, Seth Hollander, Maria Bano, Michelle Ploutz, Gabrielle Vaughn, Andrea N Lambert, Michael Wallendorf, James K Kirklin, Charles E Canter
Journal: Circulation (2020)

Introduction: Recent studies have suggested a relationship between mortality and center volume in pediatric heart transplantation; however, these studies utilize databases that lack granularity to assess patient risk profiles. Hypothesis: Utilizing the Pediatric Heart Transplant Society (PHTS) database, we hypothesized that there would be a difference in outcomes among centers based on yearly transplant volume, and that the patient’s clinical profiles would differ by center volume. Methods: We performed a retrospective analysis of the PHTS dataset from all pediatric (≤ 18 years of age) cases from 2009-2018. Centers were stratified into 5 groups based on annual volume: ≤ 4, 4-6, 6-9, 9-14, and &gt; 14 transplants. We evaluated specific variables, including those identified as significant risk factors in previous PHTS studies including mechanical ventilation, PRA &gt; 10%, high BUN, gender, and Fontan completion, within each group. We used Kaplan Meier for survival, contingency tables with Pearson Chi-square test for association, and analysis-of-variance to compare means. P&lt; 0.05 was considered statistically significant. Results: There were 6800 cases among 55 centers. Table 1 demonstrates that there was no significant difference in one-year post transplant survival among the groups, and the patient variables showing statistically significant differences followed no specific pattern among the center volume groups. It also demonstrates that there is no clear association between cumulative risk factors within individual patients and center volume. Conclusions: One-year post transplant survival is similar within the PHTS for all centers regardless of case volume. These group differences were different for different variables and did not segregate consistently between lower volume and higher volume groups suggesting there exists a complicated relationship among risk factors and center volume.
Mesenchymal Stromal Cells for Refractory Acute Graft-Versus-Host Disease By Compassionate Use Provide Comparable Results to Those of Phase II Clinical Trials
Authors: Alvaro Veiga, Alba Redondo, Miriam López-Parra, Olga López-Villar, Eva Villarón, Maria Díez-Campelo, Daniel Rivera, Natalia Espinosa, Nerea Arratibel, Mónica Baile, Estefania Pérez-López, Mónica Cabrero, Ana A. Martín, Lourdes Vázquez, Lucía López Corral, Dolores Caballero, Consuelo Del Cañizo, Fermin Sanchez-Guijo
Journal: Blood (2017)
EPEN-06. CHEMOTHERAPY OF RECURRENT EPENDYMOMA: LONG-TERM RESPONSE ONLY IN FEW CASES
Authors: Jonas Adolph, Stephan Tippelt, Ruth Mikasch, Stefan Pfister, Kristian Pajtler, Hendrik Witt, Olaf Witt, Brigitte Bison, Monika Warmuth-Metz, Rolf-Dieter Kortmann, Stefan Dietzsch, Torsten Pietsch, Beate Timmermann, Gudrun Fleischhack
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION The efficacy of chemotherapy in recurrent ependymoma is unclear. We present results from the German HIT-REZ-studies. METHODS 137 patients were analyzed regarding the treatment with chemotherapy at first recurrence, the time from first relapse to progression (PFS) and to either time-point of death or last follow-up (OS). Tumor response evaluation was based on MRI and clinically; molecular data was available in 80. RESULTS In our cohort, 96 patients (20 supratentorial, 73 infratentorial, 3 spinal) received chemotherapy during first recurrence: 49 (51.0%) temozolomide (TMZ) monotherapy, 12 (12.5%) HIT-SKK regime, 9 (9.4%) carboplatin/etoposide (CE) and 26 (27.1%) other combinations. In 19.8% (26.5% in TMZ), chemotherapy was administered prior to surgery (neoadjuvant), which resulted in tumor progression in 78% (85% in TMZ). Gross-total resection was achieved in 86% without neoadjuvant chemotherapy and in 74% (69% in TMZ) with neoadjuvant treatment. Switching to trofosfamide/etoposide (TE) after surgery and unresponsiveness to TMZ showed further progression in all cases of tumor-residuum after surgery. Regarding 1-year-PFS, treatment with HIT-SKK (50.0%±14.4%) or CE (55.6%±16.6%) was advantageous over TMZ (30.2%±6.7%). However, 5-y-OS was lower in CE (19.0% ±16.8%) than in TMZ (39.8%±7.7%) and HIT-SKK (42.9%±8.7%). Long-term control was seen in individual cases of TMZ, HIT-SKK and CE, with TMZ providing longest response of 72 months. CONCLUSION Neoadjuvant TMZ has no significant advantage regarding PFS. However, in few cases chemotherapy prevented progression after incomplete resection. Difficulties in response evaluation and variability in therapies hinder conclusions. Supported by the German Children’s Cancer Foundation
TAMI-63. GLIOBLASTOMA ASSOCIATED MESENCHYMAL STEM LIKE CELLS (G-MSC) WHICH INFILTRATE TUMORS IN HUMAN AND MOUSE ARE STRONGLY ASSOCIATED WITH IMMUNOSUPPRESSION
Authors: Sanam Dharma, Sheila Figel, Tara Barone, Michael Ciesielski, Robert Fenstermaker
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is the most aggressive form of brain cancer with an overall survival (OS) less than 16 months. Glioblastoma associated mesenchymal stem like cells (G-MSC) were identified in human patient samples, and higher presence of these cells in patient samples co-relates with lower overall survival. Our lab and others have also identified these cells in orthotopic GL261 glioblastoma murine models. We hypothesize that infiltration of G-MSC plays a key role in creating the highly immunosuppressive environment seen in GBMs. In order to investigate this, we utilized data from the TCGA database to stratify patients into two groups, showing higher or lower expression of the G-MSC markers (CD73, CD90, CD105). Patients expressing higher levels of G-MSC markers showed higher expression of CD4+ cells, as compared to patients with lower G-MSC marker expression. Further, patients with higher G-MSC markers showed high levels of PTGS2, the gene encoding cyclooxygenase 2 (COX2), a known tumor growth promoting and immunosuppressive molecule. We further investigated CD4+ T cell infiltration using GL261 orthotopic implants and observed that CD4+ T cells positively corelated with levels of G-MSC in these tumors. Our studies indicate that levels of G-MSC co-relate with immune cell infiltration and the expression of immunosuppressive factors such as COX2, underlining the importance of these cells in immunosuppression-driven resistance to therapy. These studies will be later utilized to develop rationale combination therapies to improve the overall survival in GBM.
Free-breathing MRI for monitoring ventilation changes following antibiotic treatment of pulmonary exacerbations in paediatric cystic fibrosis
Authors: Samal Munidasa, Marcus J. Couch, Jonathan H. Rayment, Andreas Voskrebenzev, Ravi Seethamraju, Jens Vogel-Claussen, Felix Ratjen, Giles Santyr
Journal: European Respiratory Journal (2020)

Treatment response in Cystic Fibrosis (CF) is traditionally monitored using pulmonary function tests (PFTs), such as spirometry. However, PFTs can be insensitive to treatment, particularly in early CF lung disease [1]. Hyperpolarized (HP) 129Xe MRI (Xe-MRI) has been shown to be feasible in children [2], more sensitive to early CF lung disease compared to PFTs [3 and captures improvements in ventilation inhomogeneity in pediatric CF patients receiving intravenous antibiotic treatment for a PEx [4]. However, access to hyperpolarized 129Xe gas is not widely available and Xe-MRI requires subjects to perform an extended breath-hold (10–15 s), which is challenging for very sick children. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Munidasa reports grants from Cystic Fibrosis Centre, grants from Natural Sciences and Engineering Research Council of Canada, grants from Canadian Institutes of Health Research, during the conduct of the study. Conflict of interest: Dr. Couch reports that he was supported by a MITACS Elevate Postdoctoral Fellowship, which was funded in part by Siemens Healthcare Limited. Dr. Couch is currently an employee of Siemens Healthcare Limited. This employment began after the conclusion of the study. Conflict of interest: Dr. Rayment reports other from Polarean Inc, outside the submitted work. Conflict of interest: Dr. Voskrebenzev reports In addition, Dr. Voskrebenzev has a patent Method of quantitative magnetic resonance lung imaging Conflict of interest: Dr. Seethamraju reports personal fees from Siemens Medical Solutions, USA Inc., outside the submitted work. Conflict of interest: Dr. Vogel-Claussen reports grants from Siemens Healthineers, during the conduct of the study; grants and personal fees from Boehringer Ingelheim, grants from GSK, grants and personal fees from Astra Zeneca, outside the submitted work; In addition, Dr. Vogel-Claussen has a patent Voskrebenzev, Gutberlet, Vogel-Claussen "Method of quantitative magnetic resonance lung imaging"Nr. EP3107066, US-2016-0367200-A1 22.12.2016 licensed to Siemens Healthineers. Conflict of interest: Dr. Ratjen has nothing to disclose. Conflict of interest: Dr. Santyr reports grants and non-financial support from Siemens Healthineers, grants from Canadian Institutes of Health Research, during the conduct of the study; grants and non-financial support from Siemens Healthineers, outside the submitted work.
DDRE-10. IMMUNE PROFILES ASSOCIATE WITH OUTCOMES IN HLA-A*02:01+, H3.3K27M+ PATIENTS WITH DIFFUSE MIDLINE GLIOMAS TREATED WITH H3.3K27M PEPTIDE VACCINE COMBINED WITH POLY-ICLC: A PNOC REPORT
Authors: Sabine Mueller, Jared M Taitt, Javier Villanueva-Meyer, Erin R Bonner, Takahide Nejo, Rishi R Lulla, Stewart Goldman, Anurhada Banerjee, Susan Chi, Nicholas S Whipple, John R Crawford, Karen Gauvain, Kellie Nazemi, Payal Watchmaker, Neil D Almeida, Kaori Okada, Andres Salazar, Ryan Gilbert, Javad Nazarian, Annette Molinaro, Lisa H Butterfield, Michael Prados, Hideho Okada
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Patients with diffuse midline gliomas (DMG), including diffuse intrinsic pontine glioma (DIPG), have dismal outcomes. We previously described the H3.3K27M mutation as a shared neoantigen in HLA-A*02.01+ H3.3K27M+ DMGs. Within the Pacific Pediatric Neuro-Oncology Consortium, we assessed the safety and efficacy of an H3.3K27M-targeted peptide vaccine. PATIENTS AND METHODS Newly diagnosed patients aged 3–21 years with positive HLA-A*02.01+ and H3.3K27M+ status were enrolled into two strata after completion of radiation therapy: Stratum A for DIPG (n=19); Stratum B for non-pontine DMG (n=10). Vaccine was administered in combination with poly-ICLC every three weeks for eight cycles, followed by once every six weeks. Immunological responses were assessed in peripheral blood mononuclear cells using mass cytometry. RESULTS 19 patients enrolled in Stratum A (median age=11 years) and 10 in Stratum B (median age=13 years). There were no grade 4 treatment-related adverse events (TRAE). Injection site reaction was the most commonly reported TRAE. Overall survival (OS) at 12 months was 40% (95% CI, 22% to 73%) for Stratum A and 39% (95% CI, 16% to 93%) for Stratum B. The median OS was 16.1 months in patients exhibiting an expansion of H3.3K27M-reactive CD8+ T-cells compared to 9.8 months for their counterparts (p=0.05). DIPG patients with below-median baseline levels of myeloid-derived suppressor cells had prolonged OS compared to their counterparts (p&amp;lt; 0.1). Immediate pre-treatment dexamethasone administration inversely associated with H3.3K27M-reactive CD8+ T-cell responses. However, neither tumor size or bulk CD8+ T-cell status was significantly associated with OS. CONCLUSION Administration of the H3.3K27M-specific vaccine is well tolerated. Patients with H3.3K27M-specific CD8+ immunological responses demonstrated prolonged OS compared to non-responders.
40P Efficacy and safety of immune checkpoint inhibitors in previously treated metastatic non-small cell lung cancer
Authors: R. Cunha, M. Fernandes, S. Abreu, C. Oliveira, J. Dias, S. Alves, A. Rodrigues, J. Oliveira, M.I. Pousa, M. Soares, I. Azevedo
Journal: Annals of Oncology (2020)
EPEN-47. PEDS: PEDIATRIC EPENDYMOMA DISCOVERY STUDY
Authors: Amy Smith, Kristian Pajtler, Koichi Ichimura, Emily Owens Pickle, Gudrun Fleischhack, Stephan Tippelt, Ana Aguilar-Bonilla
Journal: Neuro-Oncology (2020)

Abstract The prognosis for pediatric ependymoma remains unaffected by recent discovery. Upfront therapy is maximal surgical resection followed by radiation and the utility of histologic diagnosis remains unreliable. Nine molecular subgroups and possible genetic drivers of ependymoma have been identified, but the implementation of these findings into targeted therapy and stratified clinical trials has not occurred. It is imperative that researchers work collaboratively to move discovery towards clinical testing. Heterogeneity of ependymoma requires that we collect a large amount of data; progress in the field is dependent on deep analysis of this information. As we further subclassify ependymoma, it will be important to have a large patient population for enrollment onto clinical trials, which will maximize data collection and the amount of materials available for experimentation and analysis. Researchers in the United States, Europe, and Japan propose an international ependymoma research collaborative which aims to synthesize research across sites, foster drug discovery, and prove strategies to integrate clinical and molecular diagnostics into biology-based therapy. Our goal is to maximize information and materials from existing bio and data repositories and not to ‘re-create the wheel’. We envision PEDS as an open science platform and present this concept at ISPNO to invite our colleagues to harmonize efforts towards pediatric ependymoma discovery.
Effect of internationally imported cases on internal spread of COVID-19: a mathematical modelling study
Authors: Timothy W Russell, Joseph T Wu, Sam Clifford, W John Edmunds, Adam J Kucharski, Mark Jit
Journal: The Lancet Public Health (2020)

Countries have restricted international arrivals to delay the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These measures carry a high economic and social cost, and might have little effect on COVID-19 epidemics if there are many more cases resulting from local transmission compared with imported cases. Our study aims to investigate the extent to which imported cases contribute to local transmission under different epidemic conditions.