tbuckley/cabot-search huggingface dataset:
EPEN-23. A COMPUTATIONAL ANALYSIS OF THE TUMOUR IMMUNE MICROENVIRONMENT IN PAEDIATRIC EPENDYMOMA
Authors: Timothy Ritzmann, Anbarasu Lourdusamy, Andrew Jackson, Lisa Storer, Andrew Donson, Andrea Griesinger, Nicholas Foreman, Hazel Rogers, Richard Grundy
Journal: Neuro-Oncology (2020)

Abstract Ependymoma is the third commonest childhood brain tumour. Relapse is frequent, often fatal and current therapeutic strategies are inadequate. Previous ependymoma research describes an immunosuppressive environment with T-cell exhaustion, indicating a lack of response to T-cell directed immunotherapy. Understanding the immune microenvironment is therefore critical. We present a computational analysis of ependymoma, gene expression derived, immune profiles. Using 465 ependymoma samples from gene expression datasets (GSE64415, GSE50385, GSE100240) and two RNA-seq databases from UK ependymomas, we applied bulk tumour deconvolution methods (CIBERSORT and xCell) to infer immune cell populations. Additionally, we measured checkpoint blockade related mRNAs and used immunohistochemistry to investigate cell populations in ependymoma sections. CIBERSORT indicated high proportions of M2-like macrophages and smaller proportions of activated natural killer (NK) cells, T follicular helper cells, CD4+ memory T-cells and B-cells. xCell overlapped with the M2-like macrophage and CD4+ memory T-cell signatures seen in CIBERSORT. On immunohistochemistry, T and B cells were scarce, with small numbers of CD8+, CD4+ and CD20+ cells in the parenchyma but greater numbers in surrounding regions. CD68 was more highly expressed in the parenchyma. Analysis of nine checkpoint ligands and receptors demonstrated only the TIM3/GAL9 combination was reliably detectable. GAL9 is implicated in tumour interactions with T-cells and macrophages elsewhere, possibly contributing to poorer outcomes. Our study supports the presence of myeloid cells being leading contributors to the ependymoma immune microenvironment. Further work will delineate the extent of myeloid contribution to immunosuppression across molecular subtypes. Modulation of tumour immunity may contribute to better clinical outcomes.
LGG-02. A BRAIN TUMOR DIAGNOSED AFTER TRANSITION TO THE DEPARTMENT OF ADULT NEUROSURGERY FROM THE DEPARTMENT OF PEDIATRICS
Authors: Yasushi Shibata
Journal: Neuro-Oncology (2020)

Abstract The patient was a 17-year-old boy with a history of 4 non-febrile convulsions at 15 and 16 years of age. He visited the Department of Pediatrics at a pediatric hospital. An electroencephalogram showed right frontal spike discharge. MRI was performed and judged to show no abnormality. The pediatric doctor diagnosed him with epilepsy. At 17 years old, he was referred to our Department of Adult Neurosurgery for transition. Physical and neurological examinations showed no abnormalities. Brain MRI showed right frontal cortical small tumor, with T1 low, T2 high, diffusion-weighted imaging low, and partial contrast enhancement. We diagnosed him with a brain tumor and symptomatic epilepsy. We surgically removed a right frontal cortical tumor. A pathological examination finalized the diagnosis of dysembryoplastic neuroepithelial tumor. MRI confirmed the total removal of the tumor. Anticonvulsant was started before surgery. No epileptic seizure was observed, so the anticonvulsant medication was gradually tapered and stopped at two years after the surgery. No epilepsy nor recurrence has been observed thus far. The problem with the initial management of this case at the Department of Pediatrics in the pediatric hospital was that the brain tumor was missed despite an MRI examination. Had the transition not happened, this brain tumor might not have been diagnosed. A brain tumor is a rare disease, and epilepsy is a common disease. However, in cases of non-febrile convulsion, a brain tumor should be considered. Collaboration within a single department, hospital and local area should be established.
Brachial Plexopathy Following High-Dose Melphalan and Autologous Peripheral Blood Stem Cell Transplantation for AL Amyloidosis
Authors: Vina Nguyen, Dina Brauneis, John Mark Sloan, Shayna Sarosiek, Karen Quillen, Anthony C Shelton, Vaishali Sanchorawala
Journal: Blood (2017)
Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity
Authors: Shelley E. Ackerman, Cecelia I. Pearson, Joshua D. Gregorio, Joseph C. Gonzalez, Justin A. Kenkel, Felix J. Hartmann, Angela Luo, Po Y. Ho, Heidi LeBlanc, Lisa K. Blum, Samuel C. Kimmey, Andrew Luo, Murray L. Nguyen, Jason C. Paik, Lauren Y. Sheu, Benjamin Ackerman, Arthur Lee, Hai Li, Jennifer Melrose, Richard P. Laura, Vishnu C. Ramani, Karla A. Henning, David Y. Jackson, Brian S. Safina, Grant Yonehiro, Bruce H. Devens, Yaron Carmi, Steven J. Chapin, Sean C. Bendall, Marcin Kowanetz, David Dornan, Edgar G. Engleman, Michael N. Alonso
Journal: Nature Cancer (2020)
41P Cardiotoxicity of immune checkpoint inhibitors: A meta-analysis of randomized clinical trials
Authors: E. Agostinetto, D. Eiger, M. Lambertini, M. Ceppi, M. Bruzzone, N.F. Pondé, C. Plummer, A.H. Awada, M. Piccart, E. de Azambuja
Journal: Annals of Oncology (2020)
NIMG-23. COMPARISON OF A RADIO-PATHOMIC MODEL VERSUS A RADIOLOGY-ONLY TUMOR SEGMENTATION MODEL FOR THE DETECTION OF INFILTRATIVE TUMOR IN GLIOMA PATIENTS
Authors: Samuel Bobholz, Allison Lowman, Jennifer Connelly, Elizabeth Cochran, Wade Mueller, Sean McGarry, Michael Brehler, Cassandra Gliszinski, Anna Wilczynski, Peter LaViolette
Journal: Neuro-Oncology (2020)

Abstract This study used large format autopsy tissue samples to compare radio-pathomic maps of brain cancer to a current tumor segmentation algorithm. We hypothesized that an MRI-based machine learning model trained with actual histology rather than radiologist annotations cellularity would 1) improve delineation between tumor and treatment effect, and 2) detect abnormal pathology beyond the contrast-enhancing tumor region. Seventeen patients with pathologically confirmed glioma were included in this study. At autopsy, 43 tissue samples were collected from 17 subjects from whole brain slices sectioned to align with the last axial MRI prior to death. Cellularity was calculated using a color deconvolution on 40X digitized H&amp;E stained slides from the tissue samples. In-house custom software was used to align tissue samples and cellularity information to the FLAIR image using manually defined control points. The DeepMedic algorithm was trained to segment tumors using the BraTs 2017 dataset, and then applied to our patients in order to create automated tumor probability maps. An MRI-based ensemble algorithm using a 5x5 voxel searchlight (input: T1, T1C, FLAIR, ADC) was used to predict cellularity at each voxel, using tissue samples from 14 subjects as ground truth. Both models were applied to 3 withheld test subjects in order to compare tumor probability and cellularity predictions to the pathological ground truth. The mutual information between tumor probability and actual cellularity was 1X10-15, relatively low compared to the rad-path predicted cellularity (=0.16), despite the tumor prediction model accurately highlighting regions of contrast enhancement. Additionally, the radio-pathomic ensemble model correctly identify regions of hypercellularity beyond the tumor segmentation model as well as regions of within the segmented tumor area. This study demonstrates the utility of training machine learning models with pathological ground truth rather than radiologist annotations for predicting localized tumor information, particularly in the post-treatment stage.
INNV-24. THE EXPERIENCE OF FATIGUED BRAIN TUMOUR PATIENTS RECEIVING INNOVATIVE LIFESTYLE INTERVENTIONS: QUALITATIVE RESULTS FROM THE BT-LIFE RANDOMISED CONTROLLED TRIAL
Authors: Claire Torrens, Julie Emerson, William Hewins, Amie Walker, Lisa Withington, Mairi Mackinnon, Sara Robson, Jo Dunlop, Michelle Welsh, Catherine McBain, Anthony Chalmers, Robin Grant, Alasdair G Rooney, Mary Wells
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Most brain tumour patients report clinically significant fatigue. Here, we aimed to explore patients’ views of the experience, acceptability and usefulness of participating in a trial of novel lifestyle interventions for fatigue. METHODS Qualitative sub-study within the ‘BT-LIFE’ multi-centre phase II RCT (submitted separately). Fatigued adult primary brain tumour patients in receipt of one of the trial interventions (‘Health Coaching’: eight coaching sessions targeting lifestyle behaviours; plus or minus ‘Activation Coaching’: two additional interviews targeting motivation to change) took part in a semi-structured interview following completion of the interventions. A realist approach to the ‘framework’ method was used to analyse verbatim transcripts, with inductive and deductive codes assigned to the realist domains of Context-Mechanism-Outcome. RESULTS Twenty themes and 53 sub-themes were derived from the data. Patients’ (n= 21) understanding of and engagement with the interventions were influenced by their expectations, attitudes to life, and experience of living with a brain tumour. Behaviour change was supported by goal-setting, monitoring using a weekly diary, the motivational ‘push’ by coaches, and family/ social support where available. Barriers to engagement included technical diary difficulties, time limitations including work and holiday schedules, and interference from life events. Most patients described beneficial changes in health behaviours, self-efficacy, and general health and wellbeing. About half indicated actual improvement in fatigue levels; others reported no direct change but they could now cope better with fatigue. A minority experienced no change or worsening fatigue. CONCLUSION Most fatigued brain tumour patients were able to make positive changes after lifestyle coaching, despite physical and cognitive impairments. However, their experiences were varied. Those for whom the interventions were a good ‘fit’ with their pre-existing outlook, lifestyle, and physical and emotional capabilities, appeared to achieve most benefit. These qualitative findings will inform further work addressing the disabling symptom of brain tumour-related fatigue.
CTIM-10. PHASE II STUDY OF PEMBROLIZUMAB PLUS SurVaxM FOR GLIOBLASTOMA AT FIRST RECURRENCE
Authors: Manmeet Ahluwalia, David Peereboom, Yasmeen Rauf, Cathy Schilero, Marci Ciolfi, Michael Ciesielski, Robert Fenstermaker
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Pembrolizumab is a potent humanized immunoglobulin G4 monoclonal antibody with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its interaction with programmed cell death ligand 2 (PD-L2). Survivin is a 16.5 kDa intracellular protein that belongs to the inhibitor of apoptosis protein (IAP) family. It acts in concert with the mitotic spindle apparatus to regulate cell division and localizes to the spindle microtubule organizing center (MTOC) during the G2/M phase of cell cycle progression. Survivin has also been shown to modulate the function of a number of terminal effector cell death proteases (caspases) leading to an inhibition of apoptosis. METHODS This is a Phase II study of two arms in patients with recurrent glioblastoma. Arm A is patients with first recurrence of glioblastoma who have failed prior chemotherapy and radiation but have not received any immunotherapy. Arm B is an exploratory arm of 10 patients who have failed prior anti-PD1 therapy. The ongoing study is a phase II clinical study with a 10 patient, toxicity run-in. All patients will receive the study drug combination consisting of SurVaxM and pembrolizumab with no randomization, stratification or dose escalation. RESULTS So far ten patients have been enrolled on the study as safety run in. Primary endpoint is Progression free survival at 6 months. Safety and tolerability of Pembrolizumab and SurVaxM, Response rates of Pembrolizumab and SurVaxM determined using RANO criteria are secondary endpoints. Additional secondary endpoints include Overall survival and Progression Free survival Exploratory endpoints include Cellular and humoral immune responses during concurrent administration of Pembrolizumab and SurVaxM. CONCLUSION This is an ongoing clinical trial.
Permeability of the Endothelial Barrier: Identifying and Reconciling Controversies
Authors: Lena Claesson-Welsh, Elisabetta Dejana, Donald M. McDonald
Journal: Trends in Molecular Medicine (2020)

In the microcirculation, endothelial permeability varies from least in arterioles to greatest in venules and is regulated in an organ-specific manner to control the extravasation of fluid, solutes, and large molecules.Inflammatory factors increase vascular permeability by inducing the formation of focal endothelial gaps that can be transient in acute inflammation or sustained in chronic conditions.Gap formation requires changes in the organization of tight junctions and adherens junctions that join endothelial cells and create a barrier.Adherens junction opening requires phosphorylation, loss of homophilic interactions, and internalization of VE-cadherin accompanied by changes in the cortical cytoskeleton.Sustained hyperpermeability in pathologic conditions can lead to edema, reduced vascular perfusion, impaired drug delivery, and exaggerated disease severity. Leakage from blood vessels into tissues is governed by mechanisms that control endothelial barrier function to maintain homeostasis. Dysregulated endothelial permeability contributes to many conditions and can influence disease morbidity and treatment. Diverse approaches used to study endothelial permeability have yielded a wealth of valuable insights. Yet, ongoing questions, technical challenges, and unresolved controversies relating to the mechanisms and relative contributions of barrier regulation, transendothelial sieving, and transport of fluid, solutes, and particulates complicate interpretations in the context of vascular physiology and pathophysiology. Here, we describe recent in vivo findings and other advances in understanding endothelial barrier function with the goal of identifying and reconciling controversies over cellular and molecular processes that regulate the vascular barrier in health and disease. Leakage from blood vessels into tissues is governed by mechanisms that control endothelial barrier function to maintain homeostasis. Dysregulated endothelial permeability contributes to many conditions and can influence disease morbidity and treatment. Diverse approaches used to study endothelial permeability have yielded a wealth of valuable insights. Yet, ongoing questions, technical challenges, and unresolved controversies relating to the mechanisms and relative contributions of barrier regulation, transendothelial sieving, and transport of fluid, solutes, and particulates complicate interpretations in the context of vascular physiology and pathophysiology. Here, we describe recent in vivo findings and other advances in understanding endothelial barrier function with the goal of identifying and reconciling controversies over cellular and molecular processes that regulate the vascular barrier in health and disease.
NIMG-61. UNUSUAL PRESENTATION OF NEUROSARCOIDOSIS: A CASE SERIES
Authors: B K Kleinschmidt-Demasters, David Ormond, Evan Winograd
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Neurosarcoidosis is a rare diagnosis, and even with known systemic disease or history, often remains a diagnosis of exclusion. Typical imaging findings of neurosarcoidosis include white matter lesions coupled with meningeal enhancement, or “sugarcoating” near the skull base. Occasionally, imaging can be quite unusual and mimic other entities. Other diagnoses to rule out include neoplastic, autoimmune, or infectious pachymeningitis, neoplastic lesions, neurosyphilis or tuberculosis. METHODS Our neuropathology database was queried for neurosarcoidosis from January 2008 until December 2019. These cases were then reviewed for cases with unusual presentations for further review and discussion. RESULTS Here we present 16 cases of neurosarcoidosis with histories and/or imaging that did not conform to the typical appearance of neurosarcoidosis. Along with a rare radiographic presentation, these cases also lacked CSF, laboratory, or systemic findings to suggest a diagnosis of neurosarcoidosis. 15 of these cases presented intracranially while 1 case presented within the spinal cord. CONCLUSIONS Neurosarcoidosis presentations can vary greatly. A better understanding of some unique patient presentations can help improve noninvasive diagnosis, although biopsy often remains necessary for confirmation.
CTIM-28. PHASE 2 TRIAL OF CONTROLLED IL-12 IN COMBINATION WITH PD-1 INHIBITOR IN ADULT SUBJECTS WITH RECURRENT GLIOBLASTOMA (rGBM)
Authors: Rimas Lukas, E Antonio Chiocca, Nancy Ann Oberheim Bush, Joseph Landolfi, Robert Cavaliere, John Yu, Sylvia Kurz, Nathan Demars, Jill Buck, Nira Hadar, John Miao, John Loewy, Yunxia Wang, Arnold Gelb, Laurence Cooper
Journal: Neuro-Oncology (2020)

Abstract Ad-RTS-hIL-12 (Ad) is a gene therapy candidate for intratumoral (IT) delivery that conditionally expresses IL-12 (IL-12) under the transcriptional control of orally administered veledimex (V) acting via the RheoSwitch Therapeutic Systemâ gene switch. Increased PD-1 expression in samples of rGBM following Ad+V (ASCO 2020) supports combination immunotherapy with a PD-1 inhibitor. Phase 1 trials in rGBM of Ad+V as monotherapy and in combination with PD-1 inhibitor revealed encouraging safety and survival data. This phase 2 trial (NCT04006119) in adults with rGBM is evaluating safety and efficacy (overall survival) of Ad + V with pre/post-operative cemiplimab-rwlc (cemi) 350 mg IV, Days -7, 15, then Q3W; Ad single IT injection (2 x 1011 viral particles, day of resection (Day 0) /craniotomy); and V (20 mg PO, Days 0–14). Longitudinal sampling of serum assessed IL-12 and endogenous cytokines production. Anti-tumor effects were described upon preliminary review. Serial MRI evaluated tumor response. Follow-up described overall survival. Initial safety data (51 unique adverse reactions in 28 subjects) appeared similar to Ad+V and the cemi label, respectively, being manageable without synergistic toxicities and generally reversible. Of 35 SAEs reported in 18 subjects, 10 SAEs in 7 subjects were related to Ad+V. IL-12 and IFN-g levels increased after Ad+V administration peaking on Day 3 at 34 ± 11 pg/mL and 13 ± 5 pg/mL (mean ± SEM), respectively. Immune-mediated anti-tumor effects were noted, including a post-treatment biopsy to rule out progression which demonstrated an immune infiltrate consistent with pseudoprogression and loss of tumor cell heterogeneity suggesting immunoediting. Enrollment is anticipated to be completed in 2Q2020 with follow-up ongoing and initial survival data will be presented. V crossed the blood-brain barrier to produce functional IL-12. Controlled IL-12 therapy and cemi is a rational combination with initial data consistent with immune-mediated anti-tumor effects with a favorable safety profile.
PATH-22. COMPREHENSIVE ANALYSIS OF DIVERSE LOW-GRADE NEUROEPITHELIAL TUMORS WITH FGFR1 ALTERATIONS REVEALS A DISTINCT MOLECULAR SIGNATURE OF ROSETTE-FORMING GLIONEURONAL TUMOR
Authors: Calixto-Hope G Lucas, Rohit Gupta, Pamela Doo, Matthew Wood, Marjorie Grafe, Han Lee, B K Kleinschmidt-Demasters, Nancy Ann Oberheim Bush, Jennie Taylor, Jennifer Clarke, Nicholas Butowski, Cassie Kline, Alyssa Reddy, Anurhada Banerjee, Sabine Mueller, Shawn Hervey-Jumper, Manish Aghi, Edward Chang, Philip Theodosopoulos, Jarod Roland, Kurtis Auguste, Peter Sun, Corey Raffel, Nalin Gupta, Julieann Lee, Joanna Phillips, Melike Pekmezci, Andrew Bollen, Tarik Tihan, Susan Chang, Mitchel Berger, Arie Perry, David Solomon
Journal: Neuro-Oncology (2020)

Abstract The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma (PA), dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined, nor are the histopathologic features of pilocytic astrocytomas with FGFR1 alterations versus those harboring the more common BRAF mutations or fusions. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and PA are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis refines the classification and histopathologic spectrum of LGNET with FGFR1 alterations.