bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOM-50. SERIAL INTRACRANIAL CEREBROSPINAL CELL-FREE DNA FOR DISEASE MONITORING IN PATIENTS WITH GLIOMAS
Authors: Riviere-Cazaux Cecile , Dong Xiaoxi , Wei Mo , Kumar Rahul , Carlstrom Lucas , Nesvick Cody , Andersen Katherine , Hoplin Matthew , Jusue-Torres Ignacio , Malik Noor , Sener Ugur , Ruff Michael , Uhm Joon , Campian Jian , Eckel-Passow Jeanette , Kaufmann Timothy , Routman David , Kizilbash Sani , Jia Shidong , Du Pan , Warrington Arthur , Burns Terry 
Published: November 2024

Abstract
Improved response assessment methods are needed for patients with gliomas. Intracranial cerebrospinal fluid (CSF) is longitudinally accessible and provides an abundance source of candidate biomarkers, such as cell-free DNA (cfDNA), for disease monitoring. To evaluate the clinical feasibility of molecular profiling from longitudinal intracranial CSF, CSF was acquired from patients with CSF access devices, including Ommaya reservoirs and ventriculoperitoneal shunts. cfDNA was extracted and analyzed via PredicineCARE (Next Generation sequencing) or PredicineSCORE (low pass whole genome sequencing). Five patients (2 females, 3 males; median age: 40 years, range 32-64 years) underwent longitudinal intracranial CSF collection via Ommaya reservoirs (n=4) or VP shunt (n=1). In total, forty-eight CSF samples were obtained (median volume: 4.00 mL; 0.5-5 mL), with 39 samples (81.3%) yielding sufficient cfDNA for variant profiling. Our initial findings suggest that tumor fraction increased by 6.28x, 2.87x, and 8.31x with radiographic progression in three patients. Tumor fraction decreased by 0.08x and 0.04x in two patients with paired immediate pre-versus-post chemoradiation samples. Despite ongoing pseudoprogression in one patient, tumor fraction decreased to unmeasurable levels from a post-resection baseline of 0.26. Patient-specific tumor-associated variant allelic frequencies (VAFs), including TP53, PTEN, TERT, and CDKN2A/B, decreased within individual patients after resection and chemoradiation. In two patients with isocitrate dehydrogenase (IDH) mutant gliomas, decreasing IDH1 VAF after resection and chemoradiation correlated with decreased CSF D-2-hydroxyglutarate (D-2-HG) levels (0.64x and 0.62x, respectively, for the first patient, and 0.01x and 0.07x for the other patient). Both CSF IDH1 VAF and CSF D-2-HG increased a patient who had radiographic progression (2.56x and 9.21x, respectively). Moreover, CNB decreased below the limit of quantification during treatment and increased above the limit at progression. In conclusion, longitudinal CSF cfDNA can feasibly be obtained via CSF access devices in patients with gliomas during their disease course toward evaluating candidate monitoring biomarkers.
BIOM-51. MOLECULAR SUBTYPES, CLINICAL CHARACTERISTICS, AND THERAPEUTIC IMPLICATIONS FOR CNS TUMORS WITHBCOR/BCORL1 FUSION/INTERNAL TANDEM DUPLICATION
Authors: Gojo Johannes , Federico Aniello , Geisemeyer Neal , Schmitt-Hoffner Felix , Mauermann Monika , Sill Martin , Bruckner Katharina , Korshunov Andrey , Stichel Damian , Capper David , Tauziede-Espariat Arnault , Varlet Pascale , Aldape Kenneth , Abdullaev Zied , Donson Andrew M , Pahnke Jens , Schüller Ulrich , Galbraith Kristyn , Snuderl Matija , Alexandrescu Sanda , Filbin Mariella , Gramatzki Dorothee , Urbanic-Purkart Tadeja , Ziad Fouzia , Toledano Helen , Kerl Kornelius , Hasselblatt Martin , Papusha Ludmila , Brandner Sebastian , Łastowska Maria , Miele Evelina , Lugt Jasper v d , Bunt Jens , Kramm Christof , André Nicolas , Appay Romain , Bouchoucha Yassine , Hansford Jordan , Zapotocky Michal , Kranendonk Mariette E , Nobusawa Sumihito , Solomon David , Haberler Christine , Jones Barbara , Sturm Dominik , Sahm Felix , Jäger Natalie , Pfister Stefan M , Hoff Katja v , Kool Marcel 
Published: November 2024

Abstract
Central nervous system (CNS) tumors with either BCOR internal tandem duplication (BCOR ITD) or gene fusions involving BCOR/BCORL1 (BCOR FUS) are recognized as tumor types with characteristic molecular and clinical features but lacking clear therapeutic guidance. In an extensive international effort, we compiled a retrospective cohort of 229 (148 BCOR ITD, 81 BCOR FUS) unique cases via molecular profiling of CNS tumors. By analyzing DNA methylation patterns of 220 tumors we confirmed distinct epigenetic profiles of BCOR ITD versus BCOR FUS. The majority (91 percent) of BCOR FUS primary tumors was localized in the supratentorial region whereas BCOR ITD were localized across all anatomical CNS compartments. Median patient age at diagnosis was 20 years for BCOR FUS and 4 years for BCOR ITD. Metastatic disease was rare in BCOR FUS patients but more common in BCOR ITD tumors where 10 percent presented with metastatic disease and one third showed CNS or (rarely) extra-CNS metastasis in the course of disease. This was also reflected in clinical outcome as 5-year overall survival (OS) was 89 percent in BCOR FUS but 61 percent in BCOR ITD. In contrast, 5-year progression-free survival (PFS) was comparable reaching 27 percent in BCOR FUS and 30 percent in BCOR ITD. Integrating treatment details we found a trend towards benefit of gross-total resection on OS (BCOR FUS, n=18, p&lt;0.08; BCOR ITD, n=67, p&lt;0.12) but not for PFS (BCOR FUS, n=16, p&lt;0.33; BCOR ITD, n=64, p&lt;0.59). Radiotherapy was associated with improved PFS (BCOR FUS, n=18, p&lt;0.01; BCOR ITD, n=70, p&lt;0.001) and OS (BCOR FUS, n=20, p&lt;0.01; BCOR ITD, n=73, p&lt;0.001). Further in-depth analyses of clinical outcome parameters (primary metastatic disease, radiotherapy approach, chemotherapy type, patient age) are currently ongoing. In summary, we provide first robust annotation of CNS BCOR tumor types, clinical outcomes and therapy.
BIOM-57. PERITUMORAL EDEMA AS A PREDICTOR OF PD-1 EXPRESSION IN BRAIN METASTASES
Authors: Elengickal Anthony , Wallace Gerald , Bansal Juhi , Reddy Ambur , Raval Girindra 
Published: November 2024

Abstract
Brain metastases represent a significant problem in oncology with associated high morbidity and mortality. They have been associated with increased peritumoral edema which can worsen neurological symptoms and patient outcomes. Peritumoral cerebral edema may be an important metric of interest as some MRI studies have suggested an association between molecular factors and peritumoral edema. We hypothesized that an association exists between PD-1 expression in brain mets from NSCLC and the radiographic peritumoral edema to enhancing tumor ratio (ETR). A retrospective analysis of tumor characteristics was conducted to identify patients with brain metastases from non-small cell lung cancer. Patients were stratified into three groups based on their tumor PD-1 expression levels: 0%, 1-49%, and 50% or higher. Tumor and edema volumes were measured in these patients using MRIs at the time of diagnosis and converted into edema to tumor ratios. Radiographic analysis has been completed for 19 patients with 9 having no PD-1 expression, 5 having low PD-1 expression, and 5 having high PD-1 expression. The no expression group had an average ETR of 3.02 while the low expression group had an average of 15.85 and the high expression group had an average of 9.12. These initial results show increased peritumoral edema in tumors with PD-1 expression when compared to tumors with no PD-1 expression, with a non-significant trend in favor of increased edema to tumor ratio (p = 0.055). The current project is ongoing with plans to expand patient cohorts to affirm or rule out significant ETR association by MRI.
BIOM-66. GENOME-WIDE DNA METHYLATION PATTERNS IN PERIPHERAL BLOOD OF PATIENTS WITH GLIOBLASTOMA ENROLLED ON THE PHASE II VERTU TRIAL
Authors: Vaios Eugene , Wimberly Courtney , Sim Hao-Wen , Barnes Liz , Koh Eng-Siew , Yip Sonia , Hall Merryn , Ashley David , Sulman Erik , Reitman Zachary , Walsh Kyle , Khasraw Mustafa 
Published: November 2024

Abstract

BACKGROUND
For patients with glioblastoma, the identification of a non-invasive biomarker for longitudinal molecular profiling could improve risk stratification, clinical trial design, and surveillance. In a secondary analysis of the phase II randomized VERTU trial (ACTRN12615000407594) of adult patients with newly diagnosed MGMT-unmethylated glioblastoma, we assessed the feasibility of characterizing peripheral blood genome-wide DNA methylation patterns.

METHODS
DNA was extracted from whole blood and serum samples at baseline and end-of-treatment (EOT) from patients enrolled on VERTU, which evaluated the PARP inhibitor veliparib combined with radiotherapy and temozolomide. Infinium FFPE QC qPCR and DNA Restoration Kits were used to restore and concentrate fragmented serum DNA. Genomic DNA was plated, bisulfite converted, and profiled for methylation patterns at &gt;935,000 CpG sites using the Infinium MethylationEPIC microarray V2.0. Quality control, pre-processing, leukocyte deconvolution, and calling of MGMT status were completed in R Studio.

RESULTS
Peripheral blood methylation data were generated and passed quality control for 104/104 baseline and 24/34 EOT samples available for analysis. The median concentration of genomic DNA at baseline and EOT was 104.50 ng/μl (range:1.97-550) and 0.98 ng/μl (range:0.11-19.8). The deconvoluted median leukocyte proportions differed significantly between baseline and EOT for neutrophils (0.64vs0.90,p&lt;0.01), CD4 memory (0.09vs0.00,p&lt;0.01), CD4 naive (0.03vs0.01,p=0.02), CD8 memory (0.04vs0.00,p&lt;0.01), monocyte (0.07vs0.03,p&lt;0.01), natural killer (0.05vs0.00,p&lt;0.01), and T regulatory (0.000vs0.001,p=0.01) cells. There were no differences in baseline leukocyte proportions between patients with (n=6) and without (n=98) biopsy-proven pseudoprogression. 2/104 samples were determined to be MGMT-methylated based on peripheral blood methylation analysis. Unsupervised hierarchical clustering based on the 1,000 most differentially methylated CpG sites generated two patient clusters (n=64, n=40).

CONCLUSIONS
To our knowledge, this is the first study to demonstrate the feasibility of analyzing peripheral blood methylation patterns from patients with glioblastoma receiving chemoradiation on a randomized clinical trial. Efforts are underway to correlate these blood methylation patterns with previously published tumor tissue methylation patterns and clinical outcomes.
BIOM-73. CYTOKINE DYNAMIC DURING RADIATION THERAPY PREDICTS SURVIVAL IN GLIOBLASTOMA
Authors: Puri Sushant , Sloan Lindsey , Huang Peng , Doucet Michele , Ganguly Sudipto , Kleinberg Lawrence 
Published: November 2024

Abstract
Radiation Therapy affects a wide range of circulating lymphocyte subpopulations that are integral to mounting a successful lymphocyte-mediated immune response. Lymphopenia is associated with inferior tumor control and could be addressed to improve outcomes in glioblastoma. RT is one significant and potentially actionable iatrogenic suppressor of immune response that may limit the success of therapy. We hypothesized that a comprehensive evaluation of serial cytokine measurements during concurrent radiation and chemotherapy in glioblastoma will provide information about systemic immune status during treatment. 16 patients were enrolled in a single-institution, observational, immune surveillance study between 2018 and 2019. Peripheral blood was collected prior to starting radiation, and then weekly for a total of 7 timepoints. Plasma was isolated from blood, and cytokine levels were measured with a Luminex 23-cytokine panel. Survival was defined at 2 years since diagnosis. Patients &gt;2 years were called survivors and &lt;2 years were called non-survivors. Cytokine levels were compared with a cohort of 4 healthy controls. All data are log2 transformed using formula log2(x+1). ANOVA was used to find cytokines that differ among 3 groups. Only for those cytokines with significant ANOVA results, pair-wise t-test was performed. We found a total of 12 cytokines that were increased in plasma in glioblastoma patients undergoing radiation compared to control. Top cytokines to show differences were IL-10, M-CSF, TGF-b3 and TIM-3 (p&lt;0.05). The others to show a difference were IP-10, MCP-1, TGF-b2, IL-34, PD-L1, LAG-3, PD-1, and CTLA-4. These cytokines are known to be immunosuppressive, and our results demonstrate a soluble mechanism of immunosuppression in this patient population. This cytokine signature can predict early during treatment the overall survival in patients with glioblastoma.
BIOM-76. EXPLORING CSF MICRORNA SIGNATURES AS DIAGNOSTIC BIOMARKERS IN IDH-WILDTYPE DIFFUSE GLIOMAS
Authors: Pirhoushiaran Maryam , Walker-Charles Kamilah , Putluri Satwik , Patel Nehal , Wang Daniel H , Arjuna Srividya , Dono Antonio , Nguyen Sophia , Huse Jason T , Kerrigan Brittany C Parker , Esquenazi Yoshua , Patel Chirag B , Lang Frederick F , Ballester Leomar Y 
Published: November 2024

Abstract
The most prevalent malignant tumors of the central nervous system are adult-type diffuse gliomas. Isocitrate dehydrogenase (IDH) mutations are identified in a subset of diffuse gliomas, leading to two distinct subtypes of gliomas: IDH-wildtype and IDH-mutant. In comparison to IDH-mutant gliomas, IDH-wildtype gliomas tend to be associated with a more rapid progression and lower overall survival rates. The analysis of differentially expressed microRNAs (DE-miRNAs) in cerebrospinal fluid (CSF) of IDH-wildtype diffuse gliomas could provide an effective and non-invasive approach to assist in the early diagnosis, classification, and management of the disease. Extracellular vesicle (EV)-derived miRNAs obtained from the CSF of 11 patients with IDH-wildtype diffuse gliomas and 8 controls were analyzed by microRNA sequencing (miRNA-seq). DE-miRNAs were defined using p-value≤0.05 and absolute log2 fold change (log2FC) ≥1. Candidate DE-miRNAs were validated by qRT-PCR in 24 samples (15 IDH-wildtype vs. 9 control) using the 2-ΔΔCT method, followed by receiver operating characteristic (ROC) curve analysis. Hsa-miR-24-3p was used as the internal control. miRNA-seq analysis identified hsa-miR-484, hsa-miR-223-3p, hsa-miR-1246, hsa-miR-323a-3p, hsa-miR-106b-3p, hsa-miR-21-5p, hsa-miR-15a-5p, has-miR-15b-5p, and hsa-miR-92a-3p among the top 20 upregulated miRNAs in the CSF of patients with IDH-wildtype diffuse gliomas. Further analysis by qPCR showed that patients with IDH-wildtype diffuse gliomas had significantly higher levels of has-miR-21-5p (2.28 ± 2.33) compared to control subjects (-2.22e-007 ± 1.08, p=0.012). The ROC curve analysis revealed an area under the curve (AUC) of 0.84 (95% CI, 0.68-1.0) for has-miR-21-5p CSF levels in distinguishing IDH-wildtype diffuse gliomas from control subjects. EV-derived miRNAs in CSF, including has-miR-21-5p, have the potential to distinguish IDH-wildtype diffuse gliomas from control individuals in a minimally-invasive manner and serve as diagnostic biomarkers.
BIOS-01. MACHINE LEARNING-BASED PREDICTION OF INPATIENT CARE COSTS FOR PATIENTS WITH BRAIN METASTASES: A REAL-WORLD ANALYSIS
Authors: Ozair Ahmad , Chen Chixiang , Woodworth Graeme , Mukherjee Debraj 
Published: November 2024

Abstract

INTRODUCTION
Brain metastases (BMs) are increasingly a cause of significant cancer-related morbidity, mortality, and economic burden. While BM-related healthcare costs have been previously described, predictive analytics based on contemporary cohorts, particularly for inpatient care, remain unavailable. This study sought to evaluate inpatient care costs (IPCC) and associated reimbursements for patients with BMs and perform predictive modeling through supervised machine learning (sML) using a contemporary, commercial US claims database.

METHODS
This retrospective study, reported following STROBE and TRIPOD+AI reporting guidelines, included adult patients (aged 18-65 years) in the United States (US) with BMs included in the MarketScan Commercial Claims and Encounters Database who received inpatient care during January 2016 to December 2021. Eligible patients were identified using ICD-10 codes. IPCC measures were adjusted using the Medical Care component of the 2023 Consumer Price Index. The primary study outcome was total IPCC, represented by adjusted gross total payments. After log-transformation performed due to data skew, sML was carried out using Random Forest algorithm with 1000 iterations with a 70:30 training-test data split, followed by residual analysis and evaluation of predictive performance using root-mean-squared error (RMSE), out-of-bag error (OOBE), and calibration curve. Multivariable linear regression was carried out for sensitivity analyses.

RESULTS
A total of 25117 unique inpatient admissions across 13477 BM patients were included, with median (IQR) age of 57 years (51-61). Gross median (IQR) CPI-medical-care-adjusted values per admission were: total payments $28,119.51 (16847.45-55111.67); hospital payments $24,678.74 (14601.66-47864.84); and payments to principal physician $884.80 (441.07-2434.15), being 3.6% (IQR 1.9-6.8) of total payment. Median inpatient length of stay was 4 days (IQR 2-8). ML model had an OOBE of 0.61 and, using test data, RMSE of 0.85, indicating robust performance. No major deviations were found on residual analysis.

CONCLUSIONS
Contemporary IPCCs for BM patients in US are substantial but driven minimally by payments to principal physician. sML may be utilized to successfully predict IPCC for BM patients.
CNSC-03. HIGH EXPRESSION OF PICCOLO AND SYNTAXIN-1A IN PAEDIATRIC MEDULLOBLASTOMA DUE TO BOTH: HIGH NEURONAL FRACTION AND ENDOGENOUS EXPRESSION
Authors: Timmer Marco , Kuhl Saskia , Goldbrunner Roland 
Published: November 2024

Abstract
Emerging evidence indicates that the “healthy” nervous system contributes to the pathogenesis of cancer. Tumor cells were found to form ultra-long protrusions with distinct synapses, mainly in the infiltrative zone, resulting in a neuron-to-brain tumor synaptic communication. Located at the presynapse, proteins of the cytomatrix of the active zone have been identified to maintain highly specialized functions in neurons. Further, the proteins were shown to be involved in progression in various tumors, but little is known about their role in brain tumors. This study examined the expression of CAZ proteins in glioma and medulloblastoma. Tumor samples of Astrocytoma, glioblastoma, pilocytic astrocytoma and medulloblastoma were obtained during neurosurgical resection. Transcription rate of following CAZ proteins was measured via qPCR: SNAP25, VAMP1, VAMP2, SYT1, PCLO, BSN, STX1A. To examine amount of neuronal tissue TUBB3 and for glial fraction GFAP were quantified. A medulloblastoma cell line (DAOY) was furthermore analyzed to evaluate origin of high expressed proteins. Medulloblastoma showed high expression of PCLO (pilocytic astrocytoma vs. medulloblastoma p=0.0126) and STX1A (pilocytic astrocytoma vs. medulloblastoma p=0.0006) compared to. Likewise a high transcriptional level of TUBB3 could be seen with significance to pilocytic astrocytoma (2.2 ± 1.4 vs. 0.2 ± 0.17; p = 0.0018), which could indicate a high amount of neuronal tissue in given medulloblastoma samples. To rule out a causal link between high proportion of neuronal tissue and high CAZ expression, a paediatric medulloblastoma cell line was analysed. High expression of PCLO and STX1A in absence of TUBB3 was shown (3.8 and 2.01 vs. 0.059), indicating endogenous expression of CAZ proteins in medulloblastoma.
CNSC-11. INVESTIGATION OF GLIOBLASTOMA NEURON-TUMOR NETWORKS WITH RABIES-BASED RETROGRADE TRACING
Authors: Tetzlaff Svenja K , Reyhan Ekin , Bengtson C Peter , Schroers Julian , Wagner Julia , Schubert Marc C , Layer Nikolas , Puschhof Maria C , Faymonville Anton J , Drewa Nina , Pramatarov Rangel L , Wissmann Niklas , Alhalabi Obada , Heuer Alina , Sivapalan Nirosan , Campos Joaquín , Boztepe Berin , Scheck Jonas G , Villa Giulia , Schröter Manuel , Sahm Felix , Forsberg-Nilsson Karin , Breckwoldt Michael O , Acuna Claudio , Suchorska Bogdana , Heiland Dieter Henrik , Saez-Rodriguez Julio , Venkataramani Varun 
Published: November 2024

Abstract
Glioblastomas are primary brain tumors known for their whole-brain invasion and high therapeutic resistance. In previous studies, neuron-to-glioma synapses have been shown to promote glioblastoma progression. A deep characterization of this communication and of tumor-connected neurons has not been possible due to technological limitations. We adapted a rabies virus-based retrograde tracing approach to investigate and manipulate neuron-tumor networks. Interestingly, we found that glioblastoma cells rapidly integrated into neural circuits across the brain, engaging with distal neurons of diverse subtypes in very early stages of tumor development. Beyond glutamatergic neurons, we identified cholinergic neurons as drivers of glioblastoma cell invasion. We revealed patient- and tumor cell state-dependent differences in the expression of synaptogenic genes which also correlated with neuron-tumor connectivity and tumor cell invasivity. Notably, radiotherapy led to increased neuron-tumor connectivity mediated via neuronal hyperexcitability. The anti-epileptic drug perampanel alongside radiotherapy mitigated this effect and enhanced treatment efficacy by simultaneous neuronal activity inhibition. Utilizing our rabies-based approach, we genetically ablated tumor-connected neurons leading to a significantly decreased tumor progression offering a potential novel therapeutic avenue. Taken together, we developed a framework for dedicated analysis of multicellular neuron-tumor networks and propose our methodology as a versatile and adaptable approach to tackle glioblastoma.
CNSC-19. ISCHEMIC STROKE DRIVES GLIOMA PROGRESSION BY REMODELING TUMOR-ASSOCIATED ASTROCYTES
Authors: Ye Qi , Madamba Christine , Choy Tiffany , Spjut Catalina , Harmanci Akdes Serin , Khatri Latha , Yalamanchili Hari Krishna , Rao Ganesh , Deneen Benjamin , Lee Hyun Kyoung 
Published: November 2024

Abstract
Ischemic stroke and glioma are two deadly neurological disorders worldwide. Recent epidemiological studies reveal an increased risk of brain tumors, notably glioma, in patients with a history of stroke, resulting in a 10% co-occurrence. Comparative transcriptome analyses of brain samples collected from patients with common neurological disorders show that glioma is particularly enriched with stroke-associated gene signatures, especially in pathways related to their shared pathological features. These findings suggest a stroke-glioma interrelationship; however, it remains unknown how stroke alters the brain microenvironment to drive tumor progression. Here, we induced photothrombotic stroke in three mouse glioma models recapitulating multiple aspects of human glioma. Across all glioma models, we consistently observed that stroke increases tumor proliferation and infiltration towards stroke-affected regions, accompanied by reduced survival compared to sham control groups. Further analyses using single-cell RNA sequencing and spatial transcriptomic profiling in our stroke-glioma models reveal pronounced stroke-induced glioma microenvironment changes, among which tumor-associated astrocytes (TAAs) are most dramatically remodeled. Remarkably, we identified a unique stroke-induced astrocyte (SAA) at the tumor leading edge of the stroke-glioma group, characterized by diminished physiological astrocyte signatures and increased chromosomal and metabolic reprogramming. Among the top differentially expressed genes in SAA compared with TAA, the sodium-bicarbonate cotransporter Slc4a4 is interesting due to its enriched expression in TAA in both human and mouse gliomas, and it is significantly down-regulated at the infiltrating tumor edge. Consequently, we examine whether restoring astrocytic Slc4a4 expression rescues stroke-induced glioma progression. We found that astrocytic Slc4a4 overexpression reduces glioma growth and infiltration, accompanied by extended astroglial scar formation. Collectively, our study demonstrates that a subset of TAAs induced by stroke exacerbates glioma pathology, highlighting an indispensable astrocytic contribution to the stroke-glioma interaction.