tbuckley/cabot-search huggingface dataset:
IMMU-15. PROTEOGENOMIC DISCOVERY OF NOVEL TUMOR PEPTIDES AS NEOANTIGENS FOR PERSONALIZED T CELL IMMUNOTHERAPY IN MEDULLOBLASTOMA
Authors: Samuel Rivero-Hinojosa, Melanie Grant, Aswini Panigrahi, Huizhen Zhang, Veronika Caisova, Catherine Bollard, Brian Rood
Journal: Neuro-Oncology (2020)

Abstract T cell immunotherapies are promising new tools to combat high-risk subgroups of medulloblastoma without increasing the late effects burden. The ideal target antigen of an effective antitumor T-cell response is abundantly expressed by tumor cells but not by normal tissues, in order to limit off-target effects. Tumors translate a host of highly novel transcripts that are the result of aberrations in tumor DNA and the unmasking of alternative or novel exons. We developed a novel proteogenomic approach to identify tumor-restricted peptides and used them to select and expand T cells capable of mounting a tumor-specific cytotoxic immune response. Using RNA-seq and WGS data, we created personalized custom searchable databases containing predicted novel proteins from somatic mutations, novel junctions and fusion transcripts from 56 medulloblastoma tumors. By searching these databases with raw mass spectrometry data from paired medulloblastoma tumors, we identified tens of neoantigen peptides arising from the translation of tumor-specific transcripts; novel isoforms being the predominant source. We tested these peptides for their ability to select and expand autologous polyclonal populations of T cells and tested the immunogenicity of each individual peptide. Flow cytometry revealed populations of CD4+ and CD8+ cells with an activation profile marked by IFN-γ and TNF-α. Immunosuppressive marker profiles were also characterized. Using cytotoxicity assays, we demonstrated that tumor specific T cells can eliminate neoantigen bearing tumor cells. Thus, proteogenomics can identify immunogenic tumor specific peptides that can be used to create a personalized, targeted T cell therapy for children with high risk medulloblastoma.
EPID-17. A SINGLE INSTITUTE EXPERIENCE IN THE REGISTRATION STUDY OF PEDIATRIC SOLID TUMOR IN JAPAN CHILDREN’S CANCER GROUP
Authors: Keiko Furukawa, Yohei Mineharu, Yoshiki Arakawa
Journal: Neuro-Oncology (2020)

Abstract A larger scale prospective registration study has been conducted nationwide in Japan since 2011, called as “registration study in pediatric solid tumor”, in Japan Children’s Cancer Group (JCCG). In this study, clinical data and surgical specimen are collected into the National Center for Child Health. Kyoto University Hospital has participated in this study since IRB approval in 2011. We reviewed our registered patients to the registration study and assessed the current status. 40 patients with pediatric brain tumors participated in this study from 2011 to 2020. There were 13 intracranial germ cell tumors, 9 medulloblastomas, 6 gliomas in 4 diffuse midline gliomas, 4 pilocytic astrocytoma, and 4 other types of tumor. The informed consent was obtained from 36 patients by pediatricians and 3 patients by neurosurgeons. Twenty-five surgical specimens were collected for central review. The reasons of no surgical specimens were nonsurgical management in 6 patients and no enough FFPE sample in 3 patients. There was no discrepancy between central review and institutional diagnosis. The status of clinical data entry was complete in 13 patients and uncomplete in 9 patients. These registration data including pathological diagnosis, molecular diagnosis, treatment, clinical information in patients with pediatric brain tumor are very important to realize current status. To conduct this study certainly, the collaboration among pediatrician, neurosurgeon, and supporting staff should be needed in collecting specimens and clinical data.
IMMU-01. SINGLE CELL SEQUENCING OF MELANOMA BRAIN METASTASES UNVEILS HETEROGENEITY OF THE TUMOR MICROENVIRONMENT IN RESPONSE TO IMMUNE CHECKPOINT BLOCKADE
Authors: Christopher Alvarez-Breckenridge, Samuel Markson, Jackson Stocking, Matt Lastrapes, Naema Nayyar, Mia Bertalan, Alexander Kaplan, Maria Martinez-Lage Alvarez, Benjamin Izar, Mario Suva, Ryan Sullivan, Daniel Cahill, Scott Carter, Priscilla Brastianos
Journal: Neuro-Oncology (2020)

Abstract Immune checkpoint inhibitors (ICI) have revolutionized oncologic treatment for metastatic melanoma. With improved systemic control, there has been increasing prevalence of patients with brain metastases. Recent evidence has demonstrated intracranial responses in a subset of these patients treated with ICI. We hypothesize that the response to ICI in melanoma brain metastases (MBM) is reflective of unique features within the tumor microenvironment of the brain. A cohort of 27 patients, encompassing 8 pre- and 19 post-immunotherapy MBM underwent single cell RNA sequencing (Smart-Seq2). The cohort includes patients with longitudinal cranial resections and simultaneously resected, spatially distinct tumors. Each tumor underwent unsupervised transcriptomic analysis, differential gene expression, inferred copy number variation, and T-cell receptor (TCR) clonotyping. Published extracranial melanoma single cell datasets were used to compare the tumor microenvironment of the brain and periphery in response to ICI. A total of 14,027 cells (6,189 malignant, 7,838 non-malignant) were sequenced. Brain metastases demonstrated a heterogeneous distribution of macrophage states. Intracranial macrophages were found to be more tumor-supportive than their extracranial counterparts. MBM also included a distribution of reactive neutrophils and astrocytes. Analysis across pre- and post-treatment MBM demonstrated an increase in clonally expanded T cells in patients responding to ICI. Across longitudinal brain metastases collected from the same patients, there was evidence of identical T cell clones across timepoints and locations. Single cell sequencing of MBM provides insights into the cellular composition of the tumor and microenvironment. Our data suggest the cellular heterogeneity within MBM is unique when compared to extracranial disease. Additionally, T cell clonal expansion is found following ICI and T cells of the same clonotype infiltrate spatially and temporally separated brain metastases. These findings raise potential therapeutic implications as we learn to target the differential features of the innate and adaptive immune system within brain metastases and their extracranial counterparts.
Prevalence of specific variant carotid geometric patterns and incidence of cardiovascular events in older persons: The cardiovascular health study (CHS E-131)11Dr. Scuteri is currently affiliated with UO Geriatria, INRCA, Rome, Italy.
Authors: Angelo Scuteri, Teri A. Manolio, Emily K. Marino, Alice M. Arnold, Edward G. Lakatta
Journal: Journal of the American College of Cardiology (2004)
NIMG-21. DIFFERENTIATING TUMOR TYPES BASED ON THE PERITUMORAL MICROENVIRONMENT USING CONVOLUTIONAL NEURAL NETWORKS
Authors: Zahra Riahi Samani, Drew Parker, Jacob Antony Alappatt, Steven Brem, Ragini Verma
Journal: Neuro-Oncology (2020)

Abstract PURPOSE The differential diagnosis of glioblastoma (GBM) versus single brain metastasis (Met) is clinically important, and is undertaken with a clinical reading of MR images and/or tumor biopsy. We investigate whether Mets and GBMs can be differentiated based on the microstructure of the FLAIR-hyperintense peritumoral region measured by diffusion tensor imaging (DTI). We hypothesize that the peritumoral microstructure differs in extracellular water content, based on whether it is vasogenic edema or infiltrative. We use deep learning trained on DTI-based free-water volume fraction maps to discriminate between the peritumoral regions of Met and GBM neoplasms. Our results are also compared with mean diffusivity (MD), the most commonly used DTI metric. METHOD dMRI data of 143 patients with brain tumors (89 glioblastomas and 54 metastases, ages 19-87 years, 77 females and 66 males) were included. Free-water volume fraction maps were computed for the peritumoral regions (demarcated automatically). We developed a 7-layer convolutional neural network (CNN) architecture to distinguish microstructural patterns of Met and GBM tumors using 32 x 32 mm patches placed at random in the peritumoral area. The CNN was trained on patches from a training set of 113 patients and tested on the remaining 30 patients, where majority voting was applied to predict the tumor type for each patient. Although MD has been previously used in both tumor and peritumoral area for discriminating tumor type, we replicated the same process with MD only in the peritumoral area to provide a stronger comparison. RESULT We predicted tumor type with 93% accuracy, outperforming MD with 84% accuracy. CONCLUSION Our results demonstrate that deep learning with CNN on DTI-based free-water volume fraction map can be a promising tool for automatic distinction of tumor types, and has potential as a tumor biomarker.
GCT-44. A CASE OF INTRACRANIAL GERMINOMA WHICH RECURRED IN THE SPINAL CORD 13 YEARS AFTER THE INITIAL TREATMENT
Authors: Yasuhiro Murota, Juri Kiyokawa, Mariko Ishikawa, Hiroto Yamaoka, Satoshi Kaneko, Masataka Yoshimura, Shin Hirota, Shinji Yamamoto
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Central nervous system germinoma occurs most often in early teens, accounting for 15% of childhood brain tumors. Here, we report a case of germinoma which recurred in the spinal cord 13 years after complete remission. CASE DESCRIPTION: A 15-year-old boy presented with diabetes insipidus (DI). MRI showed a pineal gland tumor and ventriculomegaly. Biopsy was performed and the histological examinations revealed PLAP and c-kit positive pure germinoma. Ki67 LI was 64.4%. Gamma knife radiosurgery and 3 courses of ICE chemotherapy brought disappearance of the tumor. However, it recurred in lateral ventricles. Forty-Gray whole brain radiation resulted in complete remission of the tumor. For the sake of DI treatment and MRI examinations, he kept periodical visit to our hospital. Thirteen years later, when he was 28y/o, he complained paresthesia in the right upper extremity. MRI demonstrated gadolinium-enhance mass lesion in the cervical spinal cord. Recurrence of the tumor and multiple sclerosis were the principal differential diagnosis. Pulse steroid therapy did not make any change, and radiation therapy to the cervical spinal cord led to tumor disappearance. Nevertheless, the tumor recurred on the dorsal medulla oblongata one and a half years later. Biopsy of the tumor clarified that the tumor was germinoma. ICE chemotherapy which was limited to three courses due to severe bone marrow suppression was carried out. MRI proved no enhanced mass lesion in the central nervous system. DISCUSSION Germinoma may recur even after long period of remission, demonstrating that long-term follow-up is indispensable.
Abstract P258: Factors Associated With Imaging Choice of Acute Ischemic Stroke Patients and the Related Health Outcomes
Authors: Jason J Wang, Artem Boltyenkov, Gabriela Martinez, Jeffrey M Katz, Angela Hoang, Pina C Sanelli
Journal: Circulation (2020)

Introduction: Acute ischemic stroke (AIS) presents an ongoing challenge for population health and availability of healthcare resources. Imaging plays a critical role in both diagnosis and treatment decisions in AIS, but optimal utilization regarding advanced imaging with angiography and perfusion using either CTAP or MRAP remain uncertain according to national guidelines. Consequently, wide variation in AIS imaging exists in clinical practice, mostly defaulted to physician preferences and institutional factors, without a clear understanding of the benefits and risks involved in stroke care. Although CTAP and MRAP each have unique benefits and risks in the AIS setting, the effect of this risk-benefit tradeoff on health outcomes and utilization of resources is unknown. This study analyses the factors associated with imaging preferences and the related health outcomes. Method: We performed a retrospective study on an AIS registry consisting of consecutive patients admitted to our institution from November 1, 2011, through October 1, 2018. Imaging and treatment selections and modified Rankin Score (mRS) at discharge were the main outcomes. Independent variables include age, gender, race-ethnicity, and NIH stroke score (NIHSS) at admission. Multivariable logistic regression models were performed. P&lt;0.05 was considered statistically significant. Results: 1884 patients with curated imaging data during hospitalization were included. Among them, 32% were ≥80 years old, 47.4% female, 15.53% black, 60.3% white, and 24.4% with NIHSS≥10 at admission. CTAP and MRAP were performed in 21.1% and 72.2% patients, respectively. 46.1% received thrombolytics (IV-tPA), 1.3% had endovascular therapy (EVT), and 52.7% were not treated. The two clinical outcomes were independent functionality at discharge (mRS0-2) at 48.4%, and patients expired in hospital at 7.1%. Adjusted by all the factors, regression models showed that patients with NIHSS≥10 were more likely to receive CTAP (p&lt;0.0001, OR=3.39) and less likely to receive MRAP (p&lt;0.0001, OR=0.48); whereas age ≥80 was less likely to receive CTAP (p&lt;0.0001, OR=0.37) or MRAP (p&lt;0.0001, OR=0.37). NIHSS≥10 (p&lt;0.0001, OR=0.15) and IV-tPA (p=0.0006, OR=0.69) were negatively related to independent functionality at discharge, and MRAP (p&lt;0.0001, OR=1.97) was positively related to it. NIHSS≥10 (p=0.0212, OR=1.69) were positively related to mortality, while utilization of MRAP showed a negative relationship (p&lt;0.0001, OR=0.26) with it. Conclusion: Higher NIHSS was positively associated with mortality and utilization of CTAP, while it is negatively associated with MRAP. MRAP was positively related to independent functionality at discharge. Older age was negatively associated with CTAP or MRAP utilization.
PATH-26. INTEGRATED MOLECULAR AND CLINICAL ANALYSIS OF BRAF-MUTATED GLIOMA IN ADULTS
Authors: Karisa Schreck, Pinky Langat, Taibo Li, Wenya Linda Bi
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION BRAF mutations in glioma have been recognized as a significant driver of disease in pediatric low-grade glioma, but the implications of BRAF alterations on disease trajectory and response to treatment are unknown in adult glioma. Here, we characterize a multi-institutional cohort of adults with BRAF-altered glioma. METHODS We identified patients aged ≥ 18 years with glioma containing BRAF alteration on sequencing in multi-institutional cohorts (Dana-Farber/Brigham Cancer Center, Johns Hopkins Hospital, GENIE, TCGA). BRAF mutations were grouped into three previously-defined classes: I (RAS-independent/dimerization-independent), II (RAS-independent/dimerization-dependent), III (RAS-dependent/dimerization-dependent). RESULTS We identified 198 adults with BRAF-altered glioma (median age 42 years, range 18-85 years), including 17 WHO grade I, 33 grade II, 26 grade III, 114 grade IV, and 8 others. Glioblastoma (n=115) predominated, followed by grade II-III astrocytoma (n=31), pleomorphic xanthoastrocytoma (n=18), pilocytic astrocytoma (n=12), oligodendroglioma (n=7), or other glioma (n=15). Class I mutations (BRAFV600E) comprised 49% (n=97), class II mutations 4.5% (n=9) and class III mutations 4.5% (n=9). Rearrangements occurred in 9.6% (n=19), of which canonical fusions comprised 4% (n=8), occurring primarily in pilocytic astrocytomas; copy number gains affected 13% (n=26), and other alterations 19% (n=38). All pleomorphic xanthoastrocytomas and 43.5% of glioblastoma harbored BRAFV600E. Mutation of NF1, an inhibitor of RAS/ERK signaling, was significantly associated with class II/III BRAF mutations (64.3%) and not observed in BRAFV600E-altered glioma (0%, n=62; p&amp;lt; 0.0001). BRAFV600E was the sole alteration in a subset of glioma with class I mutations, while others harbored multiple genomic alterations. Among 45 patients with glioblastoma and detailed clinicopathologic data, 7 received RAF-targeted therapy, with variable clinical response. Overall survival was 26 months with BRAFV600E, 21 months with class II/III mutation, and 33 months with other BRAF-alteration. CONCLUSIONS This large cohort of BRAF-altered adult glioma demonstrates a broad range of alterations, with implications for treatment sensitivity and patient survival.
T cell receptor repertoires within liver allografts are different to those in the peripheral blood
Authors: Young-Seon Mederacke, Mikalai Nienen, Michael Jarek, Robert Geffers, Katharina Hupa-Breier, Nina Babel, Petra Reinke, Ingmar Mederacke, Florian Wolfgang Rudolf Vondran, Danny Jonigk, Heiner Wedemeyer, Elmar Jaeckel
Journal: Journal of Hepatology (2020)
RADT-07. STEREOTACTIC RADIOSURGERY OF PATIENTS WITH BRAIN METASTASES AND POOR PROGNOSIS
Authors: Maciej Harat, Maciej Blok, Joanna Kowalewska, Iza Miechowicz
Journal: Neuro-Oncology (2020)

Abstract PURPOSE/OBJECTIVE(S) Stereotactic radiosurgery (SRS) in patients with risk factors other than the number of intracranial metastases remains controversial. Here we define factors related to early death after SRS alone and compared SRS alone with WBRT in high-risk patients. The aim of our study was to verify if optimal brain treatment may extend survival in patients with poor prognosis and select optimal candidates. MATERIALS AND METHODS In this prospectively collected data, 180 patients with brain metastases and adverse prognostic factors not previously treated with WBRT were analyzed. SRS patients were divided into training (n=82) and validation (n=48) cohorts and compared to retrospective data of WBRT patients (n=50). Overall survival (OS) and probability of 3-month survival in relation to risk factors were defined by univariable and multivariable analyses. RESULTS In multivariable analysis, GPA (OR 0.44, 95%CI 0.21-0.95; p=0.001), extensive extracranial disease (OR 0.13, 95%CI 0.02-0.66; p=0.013), and serious neurological deficits (OR 0.13, 95%CI 0.04-0.45; p=0.001) were associated with early death. If one factor was favorable, 73% (training) and 92% (validation) of patients survived 3 months. Patients with coexisting GPA&amp;lt; 2, serious neurological deficits, and extracranial extensive disease had the highest risk of death within 3 months (AUC 0.822 training; 0.932 validation). Median survival of the WBRT and SRS cohorts was 86 days (interquartile range (IQR): 38-172 days) and 201 days (IQR: 86-not reached), respectively (p&amp;lt; 0.0001). OS in very high-risk patients (GPA&amp;lt; 2) was significantly longer in the SRS vs. WBRT group (123 vs. 58 days; p=0.008). CONCLUSIONS Extracranial oligometastatic disease, intact neurological status, or GPA ≥2 should be present to justify SRS in patients with 1-10 brain metastases. SRS alone is a viable treatment option in comparison to WBRT and most importantly survival benefits may be expected even for high-risk patients (GPA&amp;lt; 2).
Abstract 2172: Pharmacological Inhibition of Epsilon PKC Prevents the Progression of Hypertension-induced Heart Failure
Authors: Koichi Inagaki, Tomoyoshi Koyanagi, Lily Wong, Olga V Petrauskene, Daria Mochly-Rosen
Journal: Circulation (2006)

Introduction: Genetically manipulated mice provided conflicting data on whether protein kinase C epsilon (ϵPKC) should be inhibited or activated to cause heart failure. Hypothesis: we hypothesized ...
Asialoerythropoietin to Protect the Failing Heart: Is it Possible to Run With the Hare and Hunt With the Hounds?**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Peter van der Meer, Erik Lipsic, Dirk J. van Veldhuisen
Journal: Journal of the American College of Cardiology (2010)
BIOM-12. CIRCULATING TUMOR DNA IN ADULTS WITH GLIOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS OF BIOMARKER SENSITIVITY
Authors: James McMahon, Matthew Studer, Bryan Ulrich, Gustavo Pradilla
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Circulating tumor DNA (ctDNA) has emerged as a promising non-invasive biomarker to capture tumor genetics in patients with primary brain tumors. Research into its clinical utility, however, has not been standardized, as performance statistics of ctDNA remain undefined and optimal ctDNA assay and biospecimen sources for its evaluation have not been conclusively identified. We sought to determine a pooled sensitivity of the detection ctDNA in both CSF in plasma when compared to detecting the same mutant DNA in tumor tissue of gliomas. We then sought to compare ctDNA sensitivity between these two reservoirs, as well as between individual WHO grades of glioma. METHODS Following PRISMA guidelines, systematic review and meta-analysis was performed using published studies that assessed circulating tumor DNA in either plasma or CSF among adult patients with histopathology-confirmed glioma. Weighting of individual studies was conducted to reach an overall pooled sensitivity of ctDNA detection in both CSF and plasma. Chi-squared tests of independence were performed to compare overall sensitivity of ctDNA in CSF versus plasma, as well as to estimate the sensitivity of ctDNA for each WHO grade of glioma. RESULTS The overall reported sensitivity of ctDNA in CSF was found to be 77.4%, significantly higher than the 38.8% sensitivity in plasma (p&amp;lt; 0.0001). Sensitivity was significantly higher for high grade (82.8%) than low grade (60.5%) tumors in CSF (p=0.0023), and sensitivity was found to sequentially increase with increasing WHO grade. Qualitative analysis revealed evidence of greater sensitivity among single-allele PCR or small targeted next generation sequencing (NGS) panels, and increased sensitivity among larger tumors and those in proximity to cisternal or ventricular CSF. CONCLUSION Circulating tumor DNA is potentially a highly sensitive non-invasive biomarker among adults with gliomas. To maximize its sensitivity, CSF should be studied with targeted genetic analysis platforms, particularly in suspected high-grade gliomas.