tbuckley/cabot-search huggingface dataset:
Defects in <i>LC3B2</i> and <i>ATG4A</i> underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans
Authors: Alon Schneider Hait, David Olagnier, Vanessa Sancho-Shimizu, Kristian Alsbjerg Skipper, Marie Helleberg, Simon Muller Larsen, Chiranjeevi Bodda, Liviu Ionut Moldovan, Fanghui Ren, Nanna-Sophie Brinck Andersen, Michelle M. Thomsen, Mette Ratzer Freytag, Sathya Darmalinggam, Isobel Parkes, Darshana D. Kadekar, Stine Hess Rahbek, Demi van der Horst, Lasse Sommer Kristensen, Kristina Eriksson, Jørgen Kjems, Serge Mostowy, Mette Christiansen, Jacob Giehm Mikkelsen, Christian Thomas Brandt, Søren R. Paludan, Trine H. Mogensen
Journal: Science Immunology (2020)

Autophagy defects predispose to recurrent HSV2 meningitis and reveal an important role for autophagy in antiviral immunity.
BIOM-03. INVASIVE HISTOPATHOLOGY DRIVES POOR OUTCOMES IN SURGICALLY RESECTED BRAIN METASTASES
Authors: Matthew Dankner, Maxime Caron, Tariq Al-Saadi, WenQing Yu, Veronique Ouellet, Rima Ezzeddine, Matthew G Annis, Phuong Uyen Le, Javad Nadaf, Noah S Neubarth, Paul Savage, Dongmei Zuo, Charles P Couturier, Jean Monlong, Haig Djambazian, Huda Altoukhi, Guillaume Bourque, Jiannis Ragoussis, Roberto J Diaz, Morag Park, Marie-Christine Guiot, Stephanie Lam, Kevin Petrecca, Peter M Siegel
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Surgery as a single modality for the treatment of brain metastases (BrM) results in local recurrence (LR) in 60% of patients. These failure rates are reduced by half with post-operative radiotherapy. The non-invasive nature of BrM has led to the assumption that local recurrence is caused by spillage of cancer cells into the surgical cavity at the time of surgery. We present evidence suggesting that invasion of metastatic cancer cells into the adjacent brain is present in the majority of BrM and is associated with LR, leptomeningeal metastasis (LM), and overall survival (OS). METHODS We assessed the histopathological growth pattern (HGP) of 164 surgically resected BrM. HGP was correlated with LR, LM and OS. Single-cell transcriptomics (scRNAseq) was performed on 15,615 cells from metastasis center (MC) and surrounding brain (SB) adjacent to the tumor. N=30 orthotopic patient-derived xenograft models (OPDX) were established from BrM. RESULTS 56/164 (34%) BrM specimens showed a minimally invasive (MI) HGP between the tumor and adjacent brain while 108/164 (66%) showed significant invasion of tumor lobules or single-cells into the brain (HI-HGP). HI-HGP was associated with LR, LM and shortened OS in BrM patients. scRNAseq identified abundant cancer cells in SB that overexpressed pathways and genes involved in cell survival and stress adaptation compared to matched cancer cells in MC. Validation of these targets with immunohistochemistry in patient and OPDX tissues revealed cold-inducible RNA binding protein (CIRBP) overexpression in HI-HGP patient and OPDX BrM. Modulation of CIRBP expression in OPDX and cell line models of HI-HGP BrM delayed BrM progression and extended OS. CONCLUSION HI-HGP is a poor prognostic indicator in patients with surgically resected BrM, establishing HGP as an important prognostic factor that should be considered by clinicians treating BrM patients. We identify CIRBP as a functional mediator of this process.
QOL-07. CORTICAL VOLUME AND THICKNESS IN ADULT SURVIVORS OF CHILDHOOD POSTERIOR FOSSA TUMORS
Authors: Charlotte Sleurs, Jurgen Lemiere, Jeroen Blommaert, Sabine Deprez, Karen Van Beek, Anne Uyttebroeck, Sandra Jacobs
Journal: Neuro-Oncology (2020)

Abstract PURPOSE A brain tumor treatment including cranial radiotherapy has previously been associated with long-term neurocognitive sequelae. Since underlying neurological mechanisms remain inconclusive, we investigated cortical features in childhood posterior fossa tumor survivors. METHODS T1-weighted MRI (MPRAGE, resolution=.98x.98x1.2mm) was acquired to investigate the cortical structure in adult survivors of childhood infratentorial tumors (n=19, 15males) (16.4–34.8 years old, &amp;gt;2years after treatment). These scans were compared to age- and gender- matched controls. Supratentorial cortical volume and thickness were investigated using voxel-based morphometry (VBM) and surface-based morphometry (SBM), respectively. We compared patients and controls, irradiated (n=13) versus non-irradiated patients, and investigated the age at radiotherapy (peak level: p&amp;lt;.001). RESULTS Lower GM volumes were encountered in multiple brain areas of patients compared to controls, with the largest clusters in the right and left occipital fusiform gyri. Irradiated patients showed lower GM volumes then non-irradiated patients in the superior and middle frontal gyri, the right supramarginal gyrus and precuneus. Age at radiotherapy was associated with GM volume in the inferior frontal gyrus. SBM yielded larger cortical thickness in patients in the left precuneus, inferior temporal and fusiform gyrus. The opposite effect was only marginally significant, in the left temporal lingual gyrus. Age at radiotherapy was not associated with cortical thickness, but radiotherapy was associated with lower thickness of the left pars opercularis. CONCLUSION Widespread differences in cortical volumes and thickness were observed in posterior fossa tumor survivors. Both radiotherapy and age at radiotherapy could be suggested as risk factors for long-term cortical development.
C-Terminal BRE Overexpression in 11q23-Rearranged and t(8;16) Acute Myeloid Leukemia Is Caused By Intragenic Transcription Initiation
Authors: Anna E. Marneth, Koen Prange, Adil S.A. Al Hinai, Saskia M. Bergevoet, Niccolo Tesi, Eva Janssen-Megens, Bowon Kim, Nilofar Sharifi, Marie-Laure Yaspo, Mathijs A. Sanders, Elodie C.G. Stoetman, Jeroen Knijnenburg, Susan T.C.J.M. Peters, C. Michel Zwaan, Hendrik G. Stunnenberg, Marry M. van den Heuvel-Eibrink, Torsten Haferlach, Maarten Fornerod, Joop H. Jansen, Peter J.M. Valk, Bert A. Van der Reijden, Joost H.A. Martens
Journal: Blood (2017)
MODL-08. OPTIMIZATION OF A NOVEL LOCAL DELIVERY SYSTEM FOR THE TREATMENTS OF SUPRATENTORIAL EPENDYMOMA
Authors: Lisa Ruff, Chris Parkins, Sabrina Terranova, Erica Nathan, Paraskevi Kasapidou, Renata Lang, Oren Scherman, Richard J Gilbertson
Journal: Neuro-Oncology (2020)

Abstract Ependymomas are the third most common paediatric brain tumour, incurable in up to 40% of cases. Until recently, ependymomas were regarded as a single disease group with all patients receiving combinations of maximal surgical resection and radiotherapy. Use of chemotherapy has been limited by the resistant nature of the tumour and poor access to tumours behind the blood brain barrier (BBB). It is now known that ependymoma comprises up to nine different molecular subgroups. One subgroup is characterized by a novel fusion protein, C11orf95-RELA, which acts as a potent driver of oncogenesis resulting in a poor prognosis. Here, we present the optimization of a novel drug delivery system that uses biodegradable hydrogels to deliver drugs with potent anti-ependymoma properties into post-resection cavity of supratentorial ependymoma. Our previous high-throughput in-vivo drug screens identified candidate ependymoma therapies with poor BBB penetrance properties. Using in-vitro delivery assays, we have confirmed and monitored the release of these compounds from the hydrogel. Additionally, we have implemented this delivery system in our preclinical mouse hospital in which mice receive standard-of-care surgery and radiotherapy. The efficacy of hydrogel-based delivery of these compounds is now being tested preclinically, in combination with radiotherapy. Treatment for ependymoma patients have not changed in the last 30 years and therefore an effective chemotherapy could add a great survival benefit to in the clinic.
EPCT-11. PHASE 1 STUDY OF FLUVASTATIN-CELECOXIB COMBINATION IN CHILDREN WITH RELAPSING/REFRACTORY OPTICO-CHIASMATIC LOW-GRADE GLIOMA OR HIGH-GRADE GLIOMAS (FLUVABREX): FINAL RESULTS
Authors: Nicolas Andrew, Arthur Sterin, Caroline Solas, Marie-Cécile Le Deley, Alicia Probst, Isabelle Aerts, Cécile Faure-Conter, Anne-Isabelle Bertozzi, Pascal Chastagner, Natacha Entz-Werle, Emilie De Carli, Philippe Dory-Lautrec, Gauthier Bouche, Pierre Leblond
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Preclinical data support the activity of celecoxib and fluvastatin in high grade (HGG) and low grade gliomas (LGG). A Phase I study was designed to evaluate this combination in children with refractory/relapsed glioma. AIM: To assess the safety, pharmacokinetics (PK), maximum tolerated dose, Recommended Dose for Phase II (RDP2). METHOD: Multicenter phase I trial, including patients aged 6 to 21 year old. Fluvastatin starting dose was 2 mg/kg/day, 14/28 days, with fixed dose of celecoxib (200–800 mg /day). Four dose levels of fluvastatin (2, 4, 6, 8 mg/kg/day) were evaluated. A Continual Reassessment Method was used for dose escalation. Dose-limiting toxicities (DLT) were determined on the 1st cycle. PK samples were obtained at D1 and D14 of cycle 1, pre-dose of cycle 2. RESULTS 20 patients were enrolled with a median age of 12 years (5.9–19). They previously received a median of 3 (1–7) lines of treatment. Ten patients were treated for LGG and 10 for HGG, receiving a median of 3.5 cycles (1–21). Patients with LGG received a median of 9 cycles (1–21). Among the 17 patients evaluable for DLT, 2 DLTs were reported: 1 grade 3 maculo-papular rash (4 mg/kg), and 1 grade 4 increase of CPK (6 mg/kg). The RP2D of fluvastatin is 6 mg/kg/day. CONCLUSION In children with refractory/relapsed glioma, the RDP2 of fluvastatin associated with celecoxib is 6 mg/kg/day. This combination is well tolerated encouraging a phase 2 study in LGG.
Impact of Plaque Burden Versus Stenosis on Ischemic Events in Patients With Coronary Atherosclerosis
Authors: Martin Bødtker Mortensen, Omar Dzaye, Flemming Hald Steffensen, Hans Erik Bøtker, Jesper Møller Jensen, Niels Peter Rønnow Sand, Kristian Hay Kragholm, Henrik Toft Sørensen, Jonathon Leipsic, Michael Mæng, Michael J. Blaha, Bjarne Linde Nørgaard
Journal: Journal of the American College of Cardiology (2020)
Inorganic Nitrate Therapy Improves Doxorubicin-Induced Cardiomyopathy: A New Window for an Affordable Cardiovascular Therapy for Everyone?⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Andreas Daiber, Tommaso Gori, Thomas Münzel
Journal: Journal of the American College of Cardiology (2011)
MBCL-51. POST-AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION (AuHCT) PRACTICES FOR YOUNG CHILDREN WITH MALIGNANT BRAIN TUMORS
Authors: Mahvish Rahim, Jeffrey Auletta, Girish Dhall, Jonathan Finlay, Scott Coven
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND “Head Start” protocols have used autologous hematopoietic stem cell transplant (AuHSCT) for infants and young children with malignant brain tumors in order to avoid cranial irradiation. The post-AuHSCT practice for children with a brain tumor diagnosis varies greatly. The goal of this research study is to explore practices and attitudes about post-AuHSCT care for children with brain tumors. DESIGN: An anonymous REDCap survey link was provided to all site primary investigators and additional support personnel at “Head Start” institutions. The survey questions defined the role of the medical provider completing the form and explored the various practices relating to transition, management, communication and overall satisfaction. RESULTS Twenty-one individual replies have been received so far. The majority report that prophylactic medicines were discontinued upon WBC recovery; however, management of discontinuation was split evenly between the neuro-oncology and stem-cell transplant teams. Nearly half of responders follow T-cell recovery following transplant without immunology guidance. Post-AuHCT vaccination practices are highly variable, with no clear consensus. Lastly, most responders reported adequate ease of transition and communication between the neuro-oncology and transplant teams. CONCLUSIONS This work underscores the need for both multidisciplinary communication for children with brain tumors in the post-AuHCT period and for the development of standardized vaccination and other prophylaxis practices.
INNV-17. NEXT GENERATION SEQUENCING IMPACTS OUTCOMES IN RECURRENT PRIMARY GLIOBLASTOMA: A SINGLE-CENTER RETROSPECTIVE ANALYSIS
Authors: Daniel Zeitouni, Michael Catalino, Jordan Wise, Kathryn Pietrosimone, Sean McCabe, Naim Rashid, Simon Khagi
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND GBM is driven by various genomic alterations. Next generation sequencing (NGS) may reveal targetable alterations. The goal of this study was to describe how NGS can inform targeted therapy (TT) selection. METHODS The medical records of patients (pts) with GBM from 2017–2019 were reviewed. Pts with actionable mutations were included in the analysis. At first progression (PD1), two cohorts of pts were defined: cohort A received TT, while cohort B received physician’s choice chemotherapy (PCC). Regression analyses were used to determine OS and PFS between cohorts. A stratified cox model was utilized to assess the effect of TT, where KPS level (low vs high) was utilized as a stratification factor. A heat map was generated describing the landscape of mutations. Disease response in cohort A was graded per RANO criteria. RESULTS There were 38 GBM pts with actionable alterations. Cohort A had 15 (39%) pts and cohort B had 23 (61%) pts. Of the 26 common alterations, 11 (42%) were deemed actionable. Pts with higher KPS were more likely to receive TT. Pts with a KPS ≥ 70 had a longer PFS while on TT. Although not well powered, pts in cohort A had a longer median OS relative to cohort B (HR 0.37 CI 0.10–1.38). The objective response rate (ORR) was 93%, with afatinib and cabozantinib resulting in complete response, one pt had progressive disease while on TT. CONCLUSION NGS for recurrent GBM yields a high rate of actionable alterations. Pts that go on TT are often younger and with higher KPS. This likely plays into their improved survival; however, it is notable that the high ORR reflects the value of NGS in deciding on TT to match alterations that are likely to respond. In conclusion, patient selection and availability of NGS impacts outcomes in recurrent GBM.
RARE-38. CLINICAL PRESENTATION OF MGA-NUTM1 FUSION TRANSCRIPT SARCOMA
Authors: Pongpak Pongphitcha, Nongnuch Sirachainan, Artit Jinawat, Atthaporn Boonkird, Putipun Puataweepong, Chaiyos KhongKhatithum, Samart Pakakasama, Usanarat Anurathapan, Duantida Songdej, Eric Bouffet, Suradej Hongeng
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND MGA-NUTM1 fusion gene tumor are recently described as new subtype of NUTM1-rearranged tumors. Regarding its rarity, standard treatment has not been reported. Here we described clinical presentation, radiologic finding, immunohistological profile, and treatment of a boy with MGA-NUTM1 fusion gene tumor. CASE REPORT: A 13-year-old boy with 2-month history of progressive right hemiparesis and headache. Magnetic resonance imaging (MRI) revealed 7.8 x10.6 x 8.0 cm well defined heterogeneous enhancing mass at left fronto-parietal lobe. CT chest and abdomen, bone scan, MRI spine, and CSF studies were unremarkable. He underwent craniotomy with total tumor removal. Pathology demonstrated high grade spindle cell sarcoma. The immunohistological profile was positive for BCOR, NUT1, and TEL1, but negative for CD34, STAT6, desmin, SMA, actin sarcomeric, EMA, PR, S100, SOX10, BCL 6, and SABT2. The INI-1 showed nuclear expression and Ki-67 was positive in 50% of tumor nuclei. Molecular test for MGA-NUTM1 fusion transcript was positive, while SYT-SSX1, SYT-SSX2, and SYT-SSX4 fusion transcripts were negative. Four months after operation, MRI showed newly-seen two small enhancing foci at lateral and inferior aspects of the surgical cavity. He underwent re-surgery. Then focal radiation (54Gy and boost up to 60Gy at recurrent area) to the resection cavity was decided. Post-radiation chemotherapy including ifosfamide 3 g/m2 and etoposide 150 mg/m2 on Day 1–2, and carboplatin 500 mg/m2 on Day 3, every 21–28 days was started. He has completed the first course of chemotherapy without any complication. CONCLUSION MGA-NUTM1 fusion CNS sarcoma is rare. Treatment may require surgery, radiation and chemotherapy.
PDE inhibition in distinct cell types to reclaim the balance of synaptic plasticity
Authors: Ben Rombaut, Sofie Kessels, Melissa Schepers, Assia Tiane, Dean Paes, Yevgeniya Solomina, Elisabeth Piccart, Daniel van den Hove, Bert Brône, Jos Prickaerts, Tim Vanmierlo
Journal: Theranostics (2020)

Synapses are the functional units of the brain.They form specific contact points that drive neuronal communication and are highly plastic in their strength, density, and shape.A carefully orchestrated balance between synaptogenesis and synaptic pruning, i.e., the elimination of weak or redundant synapses, ensures adequate synaptic density.An imbalance between these two processes lies at the basis of multiple neuropathologies.Recent evidence has highlighted the importance of glia-neuron interactions in the synaptic unit, emphasized by glial phagocytosis of synapses and local excretion of inflammatory mediators.These findings warrant a closer look into the molecular basis of cell-signaling pathways in the different brain cells that are related to synaptic plasticity.In neurons, intracellular second messengers, such as cyclic guanosine or adenosine monophosphate (cGMP and cAMP, respectively), are known mediators of synaptic homeostasis and plasticity.Increased levels of these second messengers in glial cells slow down inflammation and neurodegenerative processes.These multi-faceted effects provide the opportunity to counteract excessive synapse loss by targeting cGMP and cAMP pathways in multiple cell types.Phosphodiesterases (PDEs) are specialized degraders of these second messengers, rendering them attractive targets to combat the detrimental effects of neurological disorders.Cellular and subcellular compartmentalization of the specific isoforms of PDEs leads to divergent downstream effects for these enzymes in the various central nervous system resident cell types.This review provides a detailed overview on the role of PDEs and their inhibition in the context of glia-neuron interactions in different neuropathologies characterized by synapse loss.In doing so, it provides a framework to support future research towards finding combinational therapy for specific neuropathologies.
HGG-50. TWO CASES OF H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA OF CERVICAL SPINAL CORD
Authors: Masae Kuroha, Kaoru Tamura, Motoki Inaji, Satoka Hashimoto, Daisuke Kobayashi, Yoji Tanaka, Tadashi Nariai, Taketoshi Maehara
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND “Diffuse midline glioma, H3 K27M-mutant’ was newly categorized as a separate pathological entity in the 2016 WHO classification, based on recently discovered mutation. Spinal cord glioma with H3 K27M-mutant is rare, so we reported the clinical course of two cases. CASE 1: A 17-year-old male presented with posterior headache and right limbs paralysis. MRI showed cervical spinal cord with expansion, T2-weighted high intensity and a part of enhancement. The biopsy revealed a diffuse midline glioma, H3 K27M-mutant. He received bevacizumab plus radiotherapy-temozolomide. In a few months, he had quadriplegia and cranial nerve paralysis and needed respirator. There was not expansion of mass, but intracranial dissemination. CASE 2: A 16-year-old male presented with posterior neck pain and right limbs paralysis. On brain stem and cervical spine, MRI findings were same to case 1. The biopsy was undergone and revealed H3 K27M mutation. He received bevacizumab in addition to radiotherapy-temozolomide. Although he also had quadriplegia, the progression of tumor has stopped. He has received chemotherapy with respirator at home. DISCUSSION It was previously reported that the prognostic factors for diffuse midline glioma were tumor location, H3 K27M-mutation and age, but there are few relevant studies. The consensus on the treatment is also not clearly determined. Because the cervical spinal cord gliomas are rapidly advanced miserably, we added bevacizumab to standard radiotherapy-temozolomide for initial treatment. In addition, whole brain and spine radiation may be considered to avoid dissemination. Multicenter study is important to collect information and improve treatment of H3 K27M-mutant glioma.
NFB-06. TREATMENT CHALLENGES IN PEDIATRIC GLIOBLASTOMA MULTIFORME WITH CONCURRENT SOMATIC AND GERMLINE NF1 MUTATIONS WITH GERMLINE MISMATCH REPAIR MUTATIONS: TWO UNIQUE CASES
Authors: Muhammed Baig, Maureen Mork, Soumen Khatua, John Slopis, Wafik Zaky, Racheal Bingham, Sumit Gupta, Greg Fuller, Zsila Sadighi
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION We report the first known cases of pediatric glioblastoma (GBM) with prior clinical NF1 diagnoses, one with concurrent germline Lynch syndrome (LS) and NF1, and the other with somatic NF1 mutation and germline constitutional mismatch repair deficiency (CMMRD). METHODS Two pediatric GBM cases with prior NF1 clinical diagnoses based on neurocutaneous criteria were reviewed. Next generation sequencing and immunohistochemical staining were used for somatic and germline NF1 and MMR gene mutation detection, and for MMR protein expression, respectively. RESULTS Sixteen year old male with prior NF1 clinical diagnosis had resection of right frontal GBM revealing somatic mutations of POLE and PMS2, but not NF1. His father had confirmed LS with MSH2 mutation and no neurocutaneous stigmata. Patient’s germline testing revealed both pathogenic MSH2 plus NF1 mutations confirming LS and NF1. Treatment consisted of chemoradiation with temozolomide followed by adjuvant temozolomide with stable disease at 8 cycles. Nineteen year old male with former NF1 clinical diagnosis had 2 GBMs, first in left midbrain biopsied revealing somatic PMS2 and NF1 mutations underwent radiation then 7 cycles of temozolomide, then new left frontal GBM underwent resection followed by radiation and 5 cycles of pembrolizumab stable at 5th cycle. CONCLUSION Children with NF1 stigmata and GBM can have concurrent NF1 and LS, or CMMRD with NF1 somatic mutations. Our patients tolerated alkylating agents, despite risk for secondary malignancies as upfront therapy and at recurrence checkpoint inhibitors. Upfront therapy in GBM with mismatch repair syndrome with checkpoint inhibitors should be studied.