bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPID-23. FACILITY VOLUME STATUS IS PREDICTIVE OF SURVIVAL AND TREATMENT RECOMMENDATIONS IN PATIENTS WITH INTRACRANIAL MENINGIOMA
Authors: Brown Nolan , Chakravarti Sachiv , Kuo Cathleen , Neil Zachery , Nguyen Oanh , Mehkri Yusuf , Gendreau Julian 
Published: November 2023

Abstract

INTRODUCTION
There is a growing body of evidence demonstrating improved survival outcomes for patients with CNS neoplasms who are treated at high volume facilities (HVFs) as compared to low volume facilities (LVFs).

METHODS
The National Cancer Database (NCDB) was queried for adult patients who sought treatment for intracranial meningioma between 2004 and 2019 at one of 1,500 Commission on Cancer-accredited facilities. Data reported included patient sociodemographic information, patient comorbidity status, and relevant tumor characteristics. After patients were stratified by facility volume, the Mann-Whitney U and Fisher exact tests were used for bivariate analysis of both continuous and categorical variables. Multivariate Cox proportional hazard model and log-rank test were used to determine whether there was any association between facility volume and overall survival.

RESULTS
In total, 336,115 patients diagnosed with meningioma were included; 23,207 (6.9%) patients were treated at an HVF and 312,908 (93.1%) patients were treated at an LVF. On bivariate analysis, patients covered by private insurance were more likely to have been treated at an HVF (50.9% vs 36.8%, p=0.0043). Furthermore, with respect to county-based geographic trends, patients treated at HVFs were more likely to reside in an urban area (14.5% vs 11.6%, p=0.027). With respect to clinical characteristics, these patients had relatively larger tumors (4.22±10.47 cm vs. 4.11±11.03 cm, p&lt; 0.001). On multivariate analysis, significant survival benefits were observed for patients treated at HVFs (HR = 0.977, 95% CI 0.973–0.982, p &lt; 0.001). Patients treated at LVFs were significantly less likely to receive radiotherapy (OR = 0.988, 95% CI 0.985-0.992, p &lt; 0.001) as compared to patients treated for intracranial meningioma at HVFs.

CONCLUSION
Our results indicate that – for patients who underwent treatment for intracranial meningioma during the 15-year study period – treatment recommendations differed and appeared to be associated with a survival disadvantage at LVFs.
EPID-25. SIX CONSECUTIVE CASES OF PRIMARY INTRACRANIAL SARCOMA IN CHILDREN IN TWO PRIVATE INSTITUTIONS FROM LIMA DURING COVID-19 PANDEMIC
Authors: Lovaton-Espadin Rolando , Alaba-Garcia Wesley 
Published: November 2023

Abstract

INTRODUCTION
Peruvian health system was severely impacted by COVID-19 pandemic. Public hospitals were saturated by patients with COVID-19 rapidly. Many patients had to seek medical attention for other health conditions in private institutions. This situation was also observed in pediatric patients with brain tumors. The objective of the present study was to describe clinical and neuroimaging characteristics from pediatric patients diagnosed with brain tumors in two private institutions fron Lima-Peru during COVID-19 pandemic.

METHODS
Descriptive study of cases of brain tumor in patients aged less than 18 years observed in two private institutions from Lima-Peru from March 2020 to December 2021.

RESULTS
Six consecutive cases of intracranial tumors were detected during a large part of COVID-19 pandemic's first year (October 2020 to March 2021), all of them with diagnosis of primary intracranial sarcoma . Before the pandemic, the last primary intracranial sarcoma in children operated occurred in June 2018, and was the only case that year.

CONCLUSION
The present study found an unusual frequency of primary intracranial sarcoma in children in two private institutions from Lima-Peru during COVID-19 pandemic.
EPID-27. LIVING NEAR OIL AND GAS WELLS AND MORTALITY IN CHILDREN WITH BRAIN TUMORS
Authors: Hoang Thanh , Rathod Rutu , Schraw Jeremy , Peckham-Gregory Erin , Lupo Philip , Hughes Amy , Scheurer Michael 
Published: November 2023

Abstract
METHODS: The heating profile of MIONPs was assessed in the test tube and mouse brain in vivo. Computed tomography scan and magnetic particle imaging were used to confirm intracranial MIONP localization after convection enhanced delivery. Cell viability assays were performed following treatment with MHT and/or radiation. MHT-induced alterations to the tumor microenvironment were assessed in a syngeneic murine glioma model, and a survival study was performed in a GBM patient-derived xenograft (PDX) model to investigate synergism between MHT and CRT.
EPID-31. BRAIN TUMORS IN UNITED STATES MILITARY VETERANS
Authors: Waite Kristin , Bihn John , Cioffi Gino , Neff Corey , Kruchko Carol , Ostrom Quinn , Swinnerton Kaitlin , Elbers Danne , Mooney Michael A , Rachlin Jacob , Stein Thor , Brophy Mary , Do Nhan , Priemer David , Perl Daniel , Ferguson Ryan , Hickman Richard , Nabors Burt , Rusiecki Jennifer , Barnholtz-Sloan Jill , Fillmore Nathanael 
Published: November 2023

Abstract
Veterans account for ~7% of the adult United States population, with half seeking care through the Veterans Health Administration (VHA). A comprehensive analysis of incidence and survival for brain tumors in the Veteran population has been lacking. Veteran data was obtained from VHA Medical Centers that diagnose and treat cancer via the VHA Corporate Data Warehouse. Brain tumor statistics on the overall US population were generated from the Central Brain Tumor Registry of the United States data. Cases were defined as individuals (≥18 years) with a primary brain tumor, diagnosed between 2004-2018, and identified using administrative criteria based on International Classification of Diseases for Oncology, Third Edition (ICD-O-3) topography and morphology codes. Annual age-adjusted incidence rates (AAIR) and 95% confidence intervals were estimated per 100,000 population. Kaplan-Meier survival curves were generated to evaluate overall survival outcomes among Veterans. The Veteran population was primarily white (78%), male (93%), and between 60-64 years old (18%). Individuals with a primary brain tumor in the general US population were mainly female (59%) and between 18-49 years old (28%). The overall AAIR of primary brain tumors from 2004-2018 within the VA cancer registry was 11.6. Non-malignant tumors were more common than malignant tumors (AAIR:7.19 vs 4.42). The most diagnosed tumors in Veterans were non-malignant pituitary tumors (AAIR:2.96), non-malignant meningioma (AAIR:2.62), and glioblastoma (AAIR:1.96). In general, in the Veteran population, survival outcomes became worse with age and were lowest among individuals diagnosed with glioblastoma. Differences between the Veteran and US population can be broadly attributed to the differences in the demographic composition of these groups. Prior to this study, there have been no reports on national level incidence rates and survival outcomes for Veterans. Statistics like these provide vital information that drive efforts to understand disease burden and improve outcomes for individuals with primary brain tumors.
EPCO-04. SPATIAL TRANSCRIPTOMIC ANALYSIS OF MALIGNANT PERIPHERAL NERVE SHEATH TUMORS REVEALS THERAPEUTICALLY TARGETABLE MOLECULAR SIGNATURES IN REGIONS UNDERGOING HISTOPATHOLOGIC TRANSFORMATION
Authors: Mirchia Kanish , Cho Soo-Jin , Reddy Alyssa T , Jacques Line , Pekmezci Melike , Perry Arie , Raleigh David , Vasudevan Harish 
Published: November 2023

Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) evolve from plexiform neurofibromas (pNF) in patients with neurofibromatosis type-1 (NF-1) yet the cellular and transcriptomic mechanisms underlying this transformation remain unclear. Here, we perform spatial gene expression profiling on fifteen MPNSTs to correlate histologic observations with transcriptomic programs and identify mechanisms underlying malignant transformation. METHODS: Fifteen MPNSTs, including tumors with a histopathologically defined transition zone between adjacent low-grade and high-grade areas (n=3), were retrospectively identified. Spatial transcriptomic profiling was performed using Visium followed by downstream processing with SpaceRanger, Seurat, Harmony, and monocle. RESULTS: 50,807 unique spatial transcriptomes were distributed across 17 unique clusters, of which 12 were enriched for tumor cells and 5 for non-tumor microenvironment cells based on histologic evaluation, unsupervised cell-type assignment, marker gene expression, and cell signature gene sets. Transcriptomic clusters in low-grade areas were enriched for genes regulating mononuclear cell migration and cell-cell adhesion, while high-grade regions were enriched for Ras/Raf/MEK/ERK target genes, anti-apoptotic programs, and extracellular matrix reorganization genes. Trajectory inference beginning in low grade regions revealed spatially organized molecular signatures of malignant transformation enriched for cell cycle progression within histopathologically homogeneous regions. Moreover, the intermediate transformation zone between low-grade neurofibromatous and high-grade MPNST histopathologic regions was marked by loss of cell differentiation genes and increased cell cycle progression. CONCLUSIONS: Spatial transcriptomic analysis elucidates the cellular and gene expression patterns underlying progression from pNF to MPNST. Distinct cell populations exist across low-grade, transformation zone, and high-grade regions in MPNSTs highlighted by alterations in Ras/Raf/MEK/ERK signaling, cell differentiation and cell cycle programs, shedding light on targets for combinatorial molecular therapy to decrease the risk of malignant transformation and serving as a biomarker of aggressive peripheral nerve tumors to complement conventional histopathology.
EPCO-05. SPATIOTEMPORAL MODELLING OF GLIOBLASTOMA FOR DRUG PREDICTION
Authors: Manoharan Varsha Thoppey , Abdelkareem Aly , Osz Katalin , Chan Jennifer , Morrissy Sorana 
Published: November 2023

Abstract
Glioblastoma (GBM) is a lethal primary brain malignancy characterized by inevitable relapse. Understanding intra-tumoral heterogeneity and the microenvironmental influence on tumor progression is key to developing effective therapies. We employ 10X Genomics’ Visium Spatial Transcriptomics platform to study murine xenograft models of multi-regional and longitudinally derived cell lines from 4 GBM patients. This resource enables the study of tumor growth at spatial resolution and allows robust species-specific distinction of tumor and its microenvironment (TME). Using a matrix factorization approach, we delineate spatial gene expression programs (GEP) specific to the tumor and TME. We observe unique niches including progenitor cell-states along the leading edge (LE) of the tumor, oligodendrocyte-like (OC) and astrocytic-like (AC) states at the tumor core along with tumor-associated endothelial states. At early time-points, the homing of brain-resident microglia (MG), macrophages (BMDM), reactive astrocytes to the tumor site are observed. The invasiveness of GBM is a major obstacle, as these cells are therapeutically resistant and seed recurrence. Targeting the LE of GBM could therefore improve patient outcomes. Interestingly in our models, the LE state exhibits higher patient diversity; upregulation of ligand/receptor genes in secreted phosphoprotein, fibronectin, macrophage migration pathways highlighting prospective targets. Further, we analyzed protein-protein interaction networks of the LE programs, which revealed that upregulation of “hub genes” within the network significantly reduces patient survival. Further investigation of such program-specific vulnerabilities will help inform on combinatorial therapeutic strategies to control disease progression and paves the way for future testing of treatment response in both xenografts and syngeneic models.
EPCO-06. THE EPIGENETIC CIRCUIT OF HOXDERNA LONG NON-CODING RNA (LNCRNA) ACTIVATES GLIOBLASTOMA-SPECIFIC TRANSCRIPTION PROGRAMS AND SUPER-ENHANCERS GENOME-WIDE, SHAPING GLIAL CELL FATE AND TRANSFORMATION
Authors: Deforzh Evgeny , Kharel Prakash , Ivanov Pavel , Karelin Anton , Uhlmann Erik , Krichevsky Anna 
Published: November 2023

Abstract
The origin and genesis of highly malignant and heterogeneous glioblastoma remain unknown. We have recently reported a unique enhancer-associated lncRNA (eRNA) LINC01116 (named here HOXDeRNA) that is silent in the normal brain but is commonly activated during gliomagenesis and controls gene expression in miR-10b/HOXD locus in cis by reshaping the locus topology. CRISPR activation experiments suggested that HOXDeRNA is sufficient to transform human astrocytes into glioma-like cells. Conversely, the knock-down of this lncRNA strongly impacts glioma viability. We now describe the global, genome-wide regulatory role of HOXDeRNA. Once expressed in normal cells of astroglial lineage, HOXDeRNA binds to histone methyltransferase EZH2 and removes Polycomb repression from hundreds of genes encoding glioma-specific transcription factors and other essential oncogenes across the entire genome (in trans). Among them are the core neurodevelopmental transcription factors SOX2, OLIG2, POU3F2, and SALL2. This results in the activation of glioma transcriptional programs and downstream super-enhancers enriched for binding sites of glioma master transcription factors SOX2 and OLIG2. Moreover, HOXDeRNA-induced astrocyte transformation is accompanied by the activation of multiple oncogenes, such as EGFR, PDGFR, and BRAF. We further identified a specific structure within the HOXDeRNA that mediates its genome-wide promoter binding and gene regulatory activity as a PRC2 decoy. These results have been obtained using the combination of ChIRP-Seq, ChIP-Seq, RNA-Seq, CLIP, CRISPR activation, and base editing, and intersect our analysis of normal and cancer cells with large public datasets. Thus, we describe the first lncRNA driving a cancer-specific transcriptional program globally, altering the epigenetic landscape across all 23 chromosome pairs, and resulting in the neoplastic transformation of normal cells to glioma. Overall, the results help reconstruct the sequence of events underlying the process of astrocyte transformation and suggest new RNA-targeting approaches for glioblastoma therapies.
EPCO-09. CHARACTERIZING THE GBM CELLULAR LANDSCAPE BY LARGE-SCALE SINGLE-NUCLEUS RNA-SEQUENCING
Authors: Spitzer Avishay , Nomura Masashi , Garofano Luciano , Johnson Kevin , Nehar-Belaid Djamel , Oh Young Taek , Anderson Kevin J , Najac Ryan D , Bussema Lillian , Varn Frederick , D’Angelo Fulvio , Chowdhury Tamrin , Migliozzi Simona , Park Jong Bae , Ermini Luca , Golebiewska Anna , Niclou Simone , Das Sunit , Paek Sun Ha , Moon Hyo-Eun , Mathon Bertrand , Stefano Anna-Luisa Di , Bielle Franck , Laurenge Alice , Sanson Marc , Tanaka Shota , Saito Nobuhito , Keir Steve , Ashley David , Huse Jason , Yung W K Alfred , Lasorella Anna , Verhaak Roel , Iavarone Antonio , Tirosh Itay , Suva Mario 
Published: November 2023

Abstract
Tumor heterogeneity is a well-known hallmark of glioblastoma (GBM). Single-cell RNA-sequencing (scRNA-seq) technologies significantly extended our understanding of GBM intra-tumor heterogeneity. While the landmark scRNA-seq studies were limited by scale, recent technological advances have enabled analyzing increasing numbers of cells. Here, leveraging a large-scale single-nucleus RNA-sequencing (snRNA-seq) dataset containing 457,442 cells (271,444 malignant and 185,995 non-malignant) from 121 IDH-wildtype GBM tumor samples and matching whole-exome/whole-genome sequencing data, we dissected the GBM malignant and tumor microenvironment (TME) compartments with unprecedented resolution and scale. We identified three novel malignant cellular states - Glial progenitor cell-like (GPC-like), Neuron-like and Cilia-like - in addition to the cellular states previously defined in GBM (NPC-like, OPC-like, AC-like and MES-like). Cross-referencing our dataset with published scRNA-seq datasets suggests that GBM states mirror the developmental hierarchy observed in the developing human brain. Functional enrichment analysis demonstrated the heterogeneous nature of pathway and metabolic activities across the spectrum of cellular states. Analysis of the matched DNA-sequencing data revealed novel associations between the occurrence of certain genetic events and the abundance of specific cellular states. Similarly, we dissected the TME and robustly defined cellular states for different TME cell types, underscoring the heterogeneity found also within the TME compartment. Leveraging the large number of samples in our dataset and controlling for intra-tumor cell state frequency exposed three baseline gene expression programs - neuronal activity, glial development and extra-cellular matrix remodeling - termed State-Controlled Profiles (SCPs), that reflect the inter-tumor heterogeneity and are not influenced by the intra-tumor cell state distribution. Integrated analysis of the intra- and inter-tumor heterogeneity components revealed striking associations between certain TME cell types and states, malignant cell states and SCPs, suggesting that an interplay between the TME and malignant cells shapes the frequency of malignant states and baseline expression profile in each tumor.
EPCO-10. AN ONCOGENIC NEURODEVELOPMENTAL PROGRAM IN H3.3 K27M DIFFUSE MIDLINE GLIOMA INVOKES ABERRANT ASCL1-SMARCA4 EPIGENOMIC ACTIVITY
Authors: Knoepfler Paul , Klein Rachel , Yee Jennifer , Lewis Nichole 
Published: November 2023

Abstract
The histone variant H3.3 K27M mutation is common in diffuse midline gliomas (DMG) and is associated with poor prognosis. While some insights into K27M epigenetic functions have emerged, much less is known about how K27M impacts chromatin structure and function, and the resulting transcriptomic consequences. Recently, we developed isogenic CRISPR-edited DMG cell lines that are wild-type for histone H3.3 that can be compared to their matched K27M lines. ATAC-seq analysis of the matched sets of isogenic WT and H3.3K27M glioma cells pointed to unique K27M-associated accessible chromatin at regions corresponding to specific neurogenesis, NOTCH, and neuronal development pathways. These domains corresponded to genes that are overexpressed in H3.3K27M compared to our isogenic wild-type cell lines. Uniquely accessible enhancers and super-enhancers corresponding to increased gene expression in H3.3K27M cells were also mapped to genes involved in neurogenesis and NOTCH signaling, suggesting that these pathways are important for tumorigenesis. Motif analysis implicates specific transcription factors as central to the neuro-oncogenic K27M signaling pathway including, in particular, ASCL1 and NEUROD1. CUT&RUN for ASCL1 defined novel target genes in DMG and BioID identified key epigenomic cofactors for ASCL1 including SMARCA4. Large-scale computational analysis of both our and other groups’ data including by chromHMM identified novel functional chromatin domains and potential looping events related to K27M as well. Overall, our findings indicate that H3.3K27M changes specific chromatin functions altering neurodevelopmental gene expression resulting in aberrant activity of an oncogenic epigenomic program. Encouragingly, this program appears at least partially reversible upon editing K27M back to wild-type, pointing to potential translational impact moving forward to targeting this pathway.
EPCO-12. IN VIVO PERTURB-SEQ DEFINES BIOLOGICAL DRIVERS AND THERAPEUTIC VULNERABILITIES UNDERLYING RADIOTHERAPY RESISTANCE IN GLIOBLASTOMA
Authors: Liu John , Pak Joanna , Zou Christopher , Pan Sixuan , Payne Emily , Foster Kyla , Lin Katie , Casey-Clyde Tim , Seo Kyounghee , O'Loughlin Thomas , Wu David , Lim Daniel , Vasudevan Harish , Diaz Aaron , Ozawa Tomoko , Berger Mitchel , de Groot John , Weiss William , Gilbert Luke , Raleigh David 
Published: November 2023

Abstract
Glioblastomas are comprised of dynamic malignant cell states and microenvironment cell types. Mechanistic and functional studies of glioblastoma resistance to therapy have been limited by a lack of in vivo approaches for multiplexed interrogation of single cells. Here we use genome-wide and targeted CRISPR interference (CRISPRi) to identify therapeutic vulnerabilities in glioblastomas in vivo by coupling convection enhanced delivery (CED) with functional genomics and single-cell transcriptomics (perturb-seq). Human (GBM43, LN18) or mouse (GL261, SB28) glioblastomas expressing CRISPRi machinery were established intracranially in mice, and unmodified mouse glioblastomas were established intracranially in immunocompetent mice expressing CRISPRi machinery in the tumor microenvironment. Perturb-seq gene prioritization was performed using genome-wide CRISPRi screens ± radiotherapy in cell cultures. Dual-sgRNA Perturb-seq lentivirus libraries were transduced in vivo using CED, and single-cell RNA sequencing with sgRNA capture was performed ± radiotherapy. RESULTS: were validated using RNA sequencing of 254,288 single nuclei from 43 pairs of primary and recurrent patient-matched human glioblastomas. Perturb-seq ± radiotherapy of 98 genes underlying glioblastoma radiotherapy responses was performed across 414,092 single cells in vivo. Genetic perturbations reprogrammed tumor and microenvironment cell states in response to radiotherapy, and high dimensional manifolds revealed genetic dependencies in metabolic and DNA damage response pathways. The DNA-dependent protein kinase (DNA-PK) component PRKDC was identified as a driver of glioblastoma radiotherapy resistance through regulation of malignant cell-intrinsic growth and stress pathways, and regulation of malignant cell-extrinsic interferon pathways that controlled cell-cell interactions with the tumor microenvironment. PRKDC inhibition with nedisertib sensitized glioblastomas to radiotherapy and extended survival in vivo, and single-cell RNA sequencing revealed hyperactivation of cell stress and cytokine signatures with combination treatment. In summary, we report in vivo perturb-seq as a platform for simultaneous discovery and functional interrogation of therapeutic vulnerabilities in glioblastoma, and show DNA-PK inhibition sensitizes glioblastomas to radiotherapy in vivo.