bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOM-52. PROTEOMIC PROFILE OF CEREBROSPINAL FLUID IN MEDULLOBLASTOMA AND THEIR RELATED EXTRACELLULAR VESICLE PROTEIN
Authors: Choi Seung Ah , Kim Joo Whan , Dan Kisoon , Ha Saehim , Phi Ji Hoon , Han Dohyun , Kim Seung-Ki 
Published: November 2023

Abstract
The development of a sensitive diagnostic method for medulloblastoma (MBL), a common malignant brain tumor in children, is still a challenge. Cerebral spinal fluid (CSF) contains various substances such as soluble proteins and extracellular vesicles (EVs) and may reflect pathological changes in the central nervous system. Especially, EVs within CSF have great potential in the dynamic monitoring and intervention strategies of MBL. This study attempted to determine whether the total CSF protein selected based on proteome information distinguished from the CSF in MBL is also considered in EVs cargo proteins. CSF samples from patients with MBL (N = 44) and hydrocephalus (HC, control, N = 18) were analyzed with LC-MS. A machine-learning approach was used to identify protein biomarkers discriminating MBL CSF. The biomarker potential of the selected proteins was verified through ELISA and ROC analysis. TEM, Nanosight, and Exoview systems were used to analyze the physiological and biological characteristics of proteins in EVs from MBL CSF. Proteomic analysis revealed four elevated soluble proteins (Transketolase (TKT), SPTBN1, HSP90AA1 and NME1-NME2) in MBL CSF. Verification of the selected proteins in whole CSF confirms that TKT was significantly elevated in MBL than in HC. Importantly, the AUC value of TKT was 0.94, which was recognized as an excellent diagnostic marker. In additional TKT analysis, when MBL was divided into subtypes, Group 4 was the most significant compared to HC, and when divided into metastasis group, metastasis was more significant than non-metastatic compared to HC. Consistently, TKT was more abundant in MBL CSF EVs compared to HC CSF EVs. Our results provide insights into the relevance of the proteins in CSF to the cargo proteins reflected in EVs, while also proposing TKT in CSF EVs as an MBL diagnostic marker.
BIOM-53. MENINGIOMA COPY NUMBER VARIANT THRESHOLDS REVEAL OPTIMAL SIZES FOR GAINS OR LOSSES THAT PREDICT LOCAL FREEDOM FROM RECURRENCE OR OVERALL SURVIVA
Authors: Nguyen Minh , Chen William , Choudhury Abrar , Magill Stephen , Raleigh David 
Published: November 2023

Abstract

INTRODUCTION
Meningiomas demonstrate heterogeneous rates of postoperative local freedom from recurrence (LFFR) and overall survival (OS). Risk-stratification models incorporating copy number variants (CNVs) improve outcome prediction, but optimal size thresholds for defining CNVs in meningiomas are unknown, and previous models have used thresholds ranging from 5-80% that are applied uniformly across all chromosome arms. Here we show that optimizing chromosome-specific CNV size thresholds improves meningioma risk-stratification.

METHODS
565 retrospective meningiomas with clinical data and DNA methylation profiles from 2 international institutions were included. CNVs were defined from DNA methylation profiles using iterative thresholds ranging from 5-95% for each chromosome arm. The area under the curve (AUC) for 5-year LFFR or OS was calculated using CNVs across iterative thresholds for each chromosome arm. LASSO and Elastic Net Cox regressions were used to generate multi-CNV models for LFFR or OS.

RESULTS
AUC for LFFR or OS peaked with CNV thresholds that were unique to each chromosome arm. Chromosome 1p deletion had optimal AUCs for LFFR and OS of 0.72 and 0.70 at thresholds of 40% and 30%, respectively. Chromosome 1q amplification had optimal AUCs for LFFR and OS of 0.58 and 0.60 at thresholds of 25% and 20%, respectively. Two previously published CNV-based risk-stratification models (integrated score and integrated grade, optimal LFFR thresholds of 5% and 20%, AUCs of 0.77 and 0.78, respectively) demonstrated heterogeneous sensitivity to CNV thresholds. LASSO and Elastic Net Cox regression identified size-dependent risk-stratification models incorporating loss of 1p, 3q, 4p, 5p/q, 6p/q, 9p, 10q, 11p, 12q, 13q, 14q, 17q, and 18p/q, and gain of 1q, 9q, 10p, and 17q. The optimal AUCs for LFFR and OS from multi-CNV models were 0.77 and 0.77 at thresholds of 25% and 35%, respectively.

CONCLUSIONS
Interrogating CNV thresholds reveals optimal chromosome-specific CNV sizes for predicting LFFR and OS.
BIOS-06. MACHINE LEARNING MADE EASY: DESIGN OF A PROPOSAL FOR A MEDICAL STUDENT EDUCATIONAL SESSION ON HIGH YIELD STRATEGIES FOR LEARNING AND APPLYING DATA SCIENCE
Authors: Brown Nolan , Kuo Cathleen , Neil Zachery , Gendreau Julian 
Published: November 2023

Abstract
Machine learning is a burgeoning field in data science that has many applications in medicine, and it is especially useful in neurosurgery due to the often-complex and potentially emergent nature of day-to-day cases. Machine learning models have the potential to deliver accurate patient prognostication while offering the benefit of providing real-time AI supported clinical decision-making with high data granularity. These models can utilize numerical inputs for more straightforward applications and, with practice, can enable clinicians and trainees to incorporate advanced imaging sequences as inputs to optimize the accuracy of patient prognostication. In the future, these models will become much more commonplace in the clinical setting for neurosurgeons. As medical school curricula do not typically incorporate these statistical techniques into biomedical statistics courses, symposia centered on machine learning could prove essential to medical students seeking to learn these skills. This session would include a brief overview of machine learning models and the procedures for using the programming language of RStudio for the development of novel internet-based prognostication calculators. The benefit of RStudio is that it is user friendly and pre-designed templates are available that can enable students to perform facile customization in tailoring the code to the needs of their clinical investigation. There will be a brief overview of accuracy verification involving discussion of receiver operating curves with the use of training and testing datasets - the heart of machine learning. We have designed and outlined a curriculum that will enable students to identify and classify different techniques (support vector machines, logistic regression, clustering, nearest neighbor classifiers), and recognize the utility of machine learning approaches to neurosurgical outcomes prognostication. Our hope is that students will leave this symposium well-equipped with a newfound confidence and the baseline conceptual framework needed to begin exploring the awesome world of machine learning throughout their training.
BIOS-08. A COMPREHENSIVE ANALYSIS OF METRICS AFFECTING GLIOBLASTOMA RANDOMIZED CONTROLLED TRIALS ROBUSTNESS
Authors: Hameed Farrukh , Sathyamurthi Sam , Sajjad Omar , Hassan Maadeha , Arikawa Kinji , Priyadarshini Mamindla , Wang Yan , Zinn Pascal 
Published: November 2023

Abstract

INTRODUCTION
Randomized controlled trials (RCTs) are the gold standard for evaluating the effectiveness of oncological interventions. RCTs are influenced by various factors, including trial design, outcome measures, sample size, recruitment, and retention. These factors can impact the robustness of a trial.

OBJECTIVE
We comprehensively evaluate the characteristics and robustness of RCTs supporting current GBM management by evaluating trial design, treatment effects, reporting strategies, primary outcome description, patients’ loss to follow-up as well as author and patient demographics.

METHODS
We conducted database searches and all GBM RCTs with significant outcomes published between 2010-2022 were included. Trial characteristics, survival times, the fragility index (FI-minimum number of patients needed to switch to nullify trial outcome) were assessed. Multivariable regression was performed to assess association of trial characteristics with robustness.

RESULTS
Of the 310 RCTs identified, 95 (30.6%) trials reported overall survival as primary end point, 92 (29.7%) progression free survival and 123 (39.7%) examined safety profiles of drugs. Of these, 178 (57.4%) were published from 2015-2022. The trials had a median power of 80.0% (interquartile range [IQR] 80.0-90.0). The median number of enrolled patients was 46 (IQR 24-108) with a median of 2 (IQR 1-5) loss to follow up. Of these trials, 68 were eligible for FI calculation. The median FI was 4.0 (IQR 2.0-11.50), with 38 trials (55.9%) having an FI &lt; 4 and a third of the trials had FI less than number of patients loss to follow up. After adjusting for co-variates, recently published trials, multiple centers trials and commercial sponsorship was associated with significantly higher FI (p&lt; 0.05).

CONCLUSION
Trials supporting current GBM management guidelines have alarmingly low robustness. While the robustness of trials has improved over time, future trials must consider additional metrics in their planning.
CNSC-05. LOCAL AND GLOBAL FUNCTIONAL CONNECTOME DISRUPTION IN PATIENTS WITH GLIOMAS
Authors: Sprugnoli Giulia , Rigolo Laura , Pandit Siddharta , Juvekar Parikshit , Faria Meghan , Tie Yanmei , Sverzellati Nicola , Rossi Simone , Golby Alexandra , Santarnecchi Emiliano 
Published: November 2023

Abstract
The aim of the study was to map the disruption of functional connectome in patients with gliomas using resting-state functional MRI (rs-fMRI) acquired before surgery (3T scanner). 54 patients with gliomas were included (M = 34, mean age = 50.8 y). Manual segmentation of lesions was performed on T1w and T2w MRI scans. Whole-brain measures of network centrality, modularity, integration and segregation were computed for a set of Regions of Interest (ROIs) including the Harvard Oxford anatomical atlas and tumor-related ROIs (i.e., edema, solid tumor, necrotic core). The analysis was performed on adjacency matrices obtained with a cost of 0.15, i.e. considering the 15% of the edges with the largest correlation coefficient values for each subject. A p&lt; 0.05, two-sided, FDR corrected threshold was used for statistical analysis. In newly diagnosed patients (n = 18), we found a decrease of Integration (Degree, Global Efficiency) and Centrality (Betweenness Centrality) and an increase of Segregation (Local Efficiency) in the tumor ROIs compared to healthy brain regions. A similar integration/segregation imbalance pattern was present across the edema, solid tumor and necrotic core, with the edema being the most similar to healthy grey matter and the necrosis being the more altered, possibly reflecting tumor cells’ density and neuronal disruption. In patients at recurrence (n = 36), the same pattern was found, though with a less clear separation among tissue classes, possibly due to the altered anatomical/functional environment caused by functional plastic rearrangement and the effects the treatment(s). Finally, a significant correlation with overall survival was found for local efficiency values of the edema (p&lt; 0.05, r 0,53=, R2 = 28%). We found significant alterations of functional connectome measures in brain regions affected by the tumor, with a decrease of network integration and an increase of network segregation measures characterizing different levels of tumor infiltration and potentially correlating with clinical outcomes.
CNSC-07. USING CRISPR-CAS9 SCREENING TO IDENTIFY BIOMARKERS FOR MMF SENSITIVITY IN GLIOBLASTOMA MULTIFORME
Authors: Buechler Killian , Shireman Jack , Ventarapragada Divya , McManus Graysen , Fares Jawad , Park Cheol , Kumthekar Priya , Ahmed Atique 
Published: November 2023

Abstract
Glioblastoma (GBM) the most common malignant brain tumor with a median survival of 21 months. Recurrent GBM remains resistant to available therapies. Our phase I clinical trial investigates combining mycophenolate mofetil (MMF) and temozolomide (TMZ) to target de novo purine biosynthesis in GBM. Previously, our lab revealed that GBM cells upregulate purine biosynthesis and inhibit purine salvage through the ARL13B-IMPDH2 axis during TMZ therapy. Targeting IMPDH2 with MMF/TMZ extended survival in GBM patient-derived xenograft models. In preparation for Phase II of our clinical trial, we aim to identify a predictive biomarker for MMF+ TMZ therapy. In a CRISPR-Cas9-mediated knockout screen, we identified ten genes, including SLC1A5, showing enrichment (differential β score mean values &gt; 60), indicating sensitivity to MMF/TMZ. SLC1A5 displays a wide distribution of expression in Glioviz patient datasets and encodes the glutamine transporter ASCT2, which is crucial for de novo purine biosynthesis. RNA-seq and protein expression analysis in six glioma cell lines confirmed that high SLC1A5 expression appears to correlate with sensitivity to MMF/TMZ (IC50 0.58-21.30 μM), while low expression led to resistance (IC50 73.43-1148 μM). Knockdown of SLC1A5 in a high-expression cell line demonstrated reduced sensitivity to MMF/TMZ (IC50 2.099 vs IC50 1007 μM). To further validate our findings, we plan to perform SLC1A5 overexpression in low-expression glioma cell lines. We hypothesize that GBM patients with higher SLC1A5 expression may respond favorably to MMF/TMZ therapy due to the reliance of their tumors on de novo purine biosynthesis. We aim to combine this data with analysis of our Phase I clinical samples to retrospectively establish SLC1A5 as a biomarker for MMF/TMZ sensitivity and investigate its role in tumorigenic purine metabolism. Identifying predictive markers will enhance personalized treatment strategies for GBM, offering hope for improved outcomes.
CNSC-11. SEIZURE PRESENTATION IN IDH WT GLIOMA IS RELATED TO UPREGULATED SYNAPTIC SIGNALING AND IONIC TRANSPORT GENES
Authors: McDonald Malcolm , Khan Abdul , Athukuri Prazwal , Lozzi Brittney , Deneen Benjamin , Mandel Jacob , Rao Ganesh 
Published: November 2023

Abstract
Isocitrate dehydrogenase wildtype (IDH WT) glioblastoma (GBM) is the most common malignant brain tumor in adults and is universally lethal. Seizures often occur as a presenting sign of tumor. Recent studies have implicated tumor-neuron communication facilitating synaptic remodeling and peritumoral circuit hyperactivity influencing tumor growth. We assessed the clinical and transcriptional effect of seizure presentation on GBM biology. 63 tumor samples were analyzed for clinical characteristics. Bulk RNA sequencing data was used to identify differentially expressed genes (DEGs), gene sets enrichment analysis (GSEA), and gene ontologies (GO). 24 IDH WT GBM patients presented with seizures compared to 39 patients presenting with other symptoms. There were no significant differences between age at presentation, sex, tumor lobe, tumor location, or grade of tumor. GSEA of gene ontologies revealed upregulated genes in the seizure cohort were largely related to synaptic signaling, ionic transport, and receptor signaling (p-val&lt; 0.05). Alternatively downregulated gene sets were related to extracellular matrix organization, and inflammatory and immune response (p-val&lt; 0.05). Focusing on significantly upregulated DEGs (padj&lt; 0.05,) biological processes related to glutamatergic synaptic transmission and cellular components related to synaptic structures were upregulated. Alternatively, significantly downregulated DEGs (padj&lt; 0.05) were related to biological processes of immunity and extracellular matrix organization and cellular components related to the extracellular matrix. Upregulated genes include IGFN1 and THBS4, both involved in synapse assembly, and SLC17A3, involved in presynaptic glutamate sorting (Log2FC &gt;1,padj &lt;0.05). The downregulated genes include numerous collagen related genes and immune related genes and KCNJ15, an inward rectifying potassium channel and GABRR1, a GABA-rho subunit. Using bulk RNA sequencing in a clinically similar set of IDH WT tumors, we found gene sets and gene ontologies related to synaptic signaling and glutamatergic signaling upregulated in patients with seizures while genes related to both extracellular matrix and immune inflammation were downregulated.
CNSC-12. PATHOLOGY SPECIFIC, PHARMACOLOGICALLY REVERSIBLE LOSS OF NEURONAL FUNCTION IN HUMAN GLIOMAS
Authors: Umbach Gray , Hervey-Jumper Shawn 
Published: November 2023

Abstract
Prior evidence has demonstrated that neuronal activity is preserved within glioma-infiltrated cortex and maintains the ability to engage in task specific computations albeit with information loss. These findings support a potential therapeutic target to rescue cognitive impairments seen in nearly all afflicted patients if neuronal activity can be recovered. We developed an in vivo human behavioral and electrophysiological model to assess neuronal population tuning responses within primary sensory cortex including the decodability of stimuli and task-related changes in population spiking in a cohort of 14 human patients undergoing awake resection. We placed high-density electrode arrays to record human local field potentials from gliomas projecting to the cortical surface. We next designed a static sensory detection threshold task, stimulating with a tachometer at two different face and hand sites totaling 11,200 trials while recording from macroelectrode cortical contacts over both tumor-infiltrated (50 electrodes) and normal appearing cortex (52 electrodes). In tumor-infiltrated cortex, the ability to decode the site of stimulation using the oscillatory power in both theta (4-8 Hz) and gamma (32-70 Hz) bands was reduced compared to normal appearing cortex. However, tumor-infiltrated cortex-maintained selectivity between hand and face stimulation. Targeted next-generation tumor sequencing uncovered novel molecular targets of glioma-neuronal integration. The degree of loss of selectivity correlated with WHO grade and pathology. WHO grade 4 tumors and oligodendrogliomas compared to astrocytomas demonstrating greater loss of selectivity. Gabaergic agonist has been postulated to restore neuronal selectivity in aging and neurodegenerative disease. Therefore, we next computed GABA agonist dose (estimated by time off Propofol and beginning of behavioral testing). Higher concentrations of GABA agonist correlated with improved theta band selectivity and decodability. These results suggest that loss of neuronal computations in glioma-infiltrated cortex is caused by loss of neuronal selectivity and is both tumor selective and pharmacologically reversible.
CNSC-14. T-TYPE CALCIUM CHANNELS REGULATE NEURON-GLIOBLASTOMA INTERACTIONS AND PROMOTE TUMOR GROWTH
Authors: Dube Collin , Zhang Ying , Saha Shekhar , Lai Michelle , Gibert Myron , Escalante Miguel , Hudson Kadie , Yener Ulas , Hanif Farina , Kefas Benjamin , Xu Esther , Sorot Aditya , Sontheimer Harald , Abounader Roger 
Published: November 2023

Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor with a dismal median survival of 15 months. Glioblastoma utilizes calcium signaling to regulate communication between tumor cells and the neuronal microenvironment. T-type calcium channels (TTCCs) are voltage gated calcium channels expressed in various types of neurons throughout the brain regulating glutamatergic synaptic transmission. We analyzed spatial transcriptomics of human GBM tumors and found that TTCCs are expressed in infiltrating tumor regions and enriched for neuronal development spatial patterns and exhibit neurodevelopmental signatures. Analysis of single cells transcriptomic of human GBM tumors demonstrated that TTCCs are enriched in neuronal subtypes. To complement publicly available data,we treated Glioblastoma Stem cells (GSCs) with an FDA-approved repurposed TTCC blocker, mibefradil, and found downregulation of genes associated with neuron processes such as synapse organization, postsynaptic density and glutamatergic synapses. Treatment of GSCs with mibefradil abrogated cell proliferation in the presence of glutamate. We examined the effects of neuronal Cav3.2 on GBM growth. Genetic Cav3.2 knockout (Cav3.2 KO) in the microenvironment of mice xenografted with syngeneic cell lines (GL261 and CT2A) exhibited significant tumor volume reduction as well as increased survival compared to WT mice in both cell lines. Cav3.2 KO tumors exhibited a decrease in proliferation (Ki67+) and neuronal connections (VGlut1) measured by immunofluorescence compared to WT mice. Cav3.2KO neuron-GBM co-cultures exhibited a significant decrease in proliferation compared to WT neuron-GBM co-cultures. Cav3.2KO neuron-GBM co-cultures exhibited a decrease in synaptic connections and a decrease in neuronal projections to GBM cells compared to WT neuron-GBM co-cultures. Transcriptomic analysis of tumors from Cav3.2KO tumors revealed deregulation of genes associated synaptic transmission, glutamatergic synapses and postsynaptic specialization. Altogether, our findings indicate a role of Cav3.2 in regulating tumors and neurons and promoting GBM progression.
CNSC-31. BESPOKE THREE- PHOTON MICROSCOPY AND ANALYSIS ENABLE DEEP INTRAVITAL BRAIN TUMOR IMAGING
Authors: Soyka Stella , Schubert Marc , Tamimi Amr , Maus Emanuel , Denninger Robert , Wißmann Niklas , Reyhan Ekin , Tetzlaff Svenja , Beretta Carlo , Drumm Michael , Schroers Julian , Steffens Alicia , Walshon Jordain , McCortney Katy , Heiland Sabine , Golebiewska Anna , Kurz Felix , Wick Wolfgang , Winkler Frank , Kreshuk Anna , Kuner Thomas , Horbinski Craig , Prevedel Robert , Venkataramani Varun 
Published: November 2023

Abstract
Glioblastoma is the most common primary brain tumor with a poor prognosis due to its aggressive invasiveness, inevitable recurrence, and therapy resistance. One hallmark of the disease is its whole brain dissemination via preexisting brain structures like blood vessels or white matter tracts. While intravital glioblastoma imaging has been limited to the superficial cortical layers, we developed a method of three photon microscopy allowing the investigation of glioblastoma invasion and colonization in the white matter up to a depth of 1.2 mm over extended time periods. Our method, combining adaptive optics 3P imaging, customized deep learning- based denoising and machine learning segmentation, enables longitudinal volumetric multicolor imaging, being able to distinguish GBM cell signal from myelin structures as well as blood vessel signal. Thus, GBM cells and their interactions with and influence on the microenvironment within the white matter can be investigated longitudinally. We found that compared to cortical invasion, a majority of GBM cells in the corpus callosum are aligned with myelinated axonal tracts, showing the influence of the tumor microenvironment on GBM cell directionality. Also, we found that most GBM cells enter the corpus callosum via a perivascular route. We identified two blood vessel-related mechanisms that allow invasion orthogonal to the myelinated axonal tract direction. We discovered that white matter tract directionality did not change significantly in the early stages of GBM colonization. This might explain limitations of modern clinical imaging to depict white matter glioma infiltration. However, we found that the shape of THG discontinuities differs between GBM cells and other resident cells, which could potentially serve as an imaging biomarker. To summarize, this tailored three-photon microscopy methodology allows unprecedented intravital investigation of GBM invasion in the gray and white matter, enabling the discovery of novel (sub-)cellular mechanisms in cancer and its microenvironment deep in the brain.