bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOM-47. SINGLE NUCLEOTIDE POLYMORPHISM IN SMARCB1 MUTATION FOR SCHWANNOMATOSIS
Authors: Lakhina Yuliya , Campbell Melissa , Henshey Brett , Yonk Marybeth , Haney Hurley , Tora Muhibullah , Du Yuhong , Koshkin Sergei , Lei Kecheng , Boulis Nicholas 
Published: November 2024

Abstract
Schwannomatosis, a form of neurofibromatosis, involves critical roles for the SMARCB1 gene. Clinical diagnosis guidelines recommend considering pathogenic variants or suspecting schwannomatosis to exclude splicing-related intron mutations. However, some patients may initially present with non-significant mutations and lack clinical signs of schwannoma, leading to misdiagnosis, missed annual assessments, malignancy awareness, and genetic consultation opportunities during pregnancy. Here, we reported a patient with a sporadic synonymous mutation in the SMARCB1 gene (SNP c.1032 C&gt;T (p.Gly344Gly(GGC&gt;GGT)) in exon 8), not previously associated with schwannomatosis. This patient, a 55-year-old female with an 8-year history of schwannomatosis, presented to the neurosurgical department for recurrent tumor removal. Initially, the clinical impact of the SMARCB1 mutation was undetermined, and other genes tested were wild-type. Both schwannomas exhibited a mosaic loss of nuclear SMARCB1 protein, ranging from 10% to 60%. Protein assays confirmed low levels of SMARCB1 protein, with a significant loss in the distal thigh schwannoma. It highlights the tumorigenic potential of single nucleotide polymorphism in the SMARCB1 gene and aids clinicians in making more accurate diagnoses in patients with pathologically confirmed schwannoma. It underscores the importance of long-term follow-up, increased awareness of recurrence and malignancy, and timely surgical planning in such patients.
BIOM-49. PATIENT-CENTRIC INTEGRATED GRAPH DATABASE REVEALS CRITICAL BIOMARKERS IN THE RECURRENCE OF IDH WILD-TYPE GLIOMA
Authors: Liu Yang , Kannan Kasthuri , Huse Jason 
Published: November 2024

Abstract

BACKGROUND
IDH wild-type glioblastoma (GBM) represents a formidable therapeutic challenge due to its consistent recurrence and progression despite standard treatments. Understanding the molecular and cellular mechanisms driving GBM recurrence through data integration is crucial. This study employs a novel graph database strategy to uncover insights into these tumors and identify functional biomarkers through graph algorithms-based pathway enrichment analysis.

METHOD
We developed a stand-alone graph database using Neo4j for primary-recurrent paired GBMs, integrating clinical and gene expression data from the Glioma Longitudinal AnalySiS (GLASS) Consortium and internal MD Anderson cohort. Based on log2 fold-change, we used hierarchical trees for differentially expressed genes to decompose the expression profile. Nodes in the database represent patients with considerable absolute log2 values determined by hierarchical trees, while shared patients define the edges. We applied graph algorithms such as degree centrality and community detection to identify potential biomarkers and supplemented these analyses with pathway identification to refine the biomarker list. Further, we divided the data set into 80% training and 20% testing sets. We evaluated the predictive performance of these biomarkers using machine learning models, including logistic regression, random forest, SVM, and neural networks.

RESULTS
DEG analysis revealed 33 down-regulated and 418 up-regulated genes in recurrent tumors. The top enriched pathways included neuroactive ligand-receptor interaction and GPCR ligand binding. Our database approach implicated 35 out of 451 genes as significant drivers of recurrence in IDH wild-type GBM. The prediction performance of these biomarkers was comparable to features selected through

methods
such as mRMR and logistic lasso and target identification

methods
like WGCNA.

CONCLUSION
Our innovative systems biology approach reveals that ligand-receptor interactions are crucial in driving recurrence in IDH wild-type GBM. This method also yielded promising mechanistic targets for recurrence, prompting focused and therapeutically relevant functional analyses. Moreover, this methodology is not limited to our study but can be applied in other multi-omics settings, offering a robust tool for biomarker discovery and validation.
BIOM-52. THE DYNAMIC GLIOMA CSF PROTEOME: IMPACT OF LOCATION AND RESECTION FOR DISEASE MONITORING
Authors: Riviere-Cazaux Cecile , Graser Christopher , Warrington Arthur , Hoplin Matthew , Andersen Katherine , Malik Noor , Carlstrom Lucas , Ghadimi Keyvan , Himes Benjamin , Jusue-Torres Ignacio , Sarkaria Jann , Meyer Fredric , Van Gompel Jamie , Kizilbash Sani , Sener Ugur , Michor Franziska , Campian Jian , Parney Ian , Burns Terry 
Published: November 2024

Abstract
While serial sampling of glioma tissue is rarely performed before recurrence, cerebrospinal fluid (CSF) can be acquired serially to evaluate candidate monitoring and pharmacodynamic biomarkers in patients with gliomas. However, the impact of key variables to consider in longitudinal CSF, including anatomical location and post-surgical changes, remains unknown. To that end, pre- versus post-resection intracranial CSF samples from patients with gliomas were obtained at early (1-16 days; n=20) or delayed (86-153 days; n=11) timepoints, as well as lumbar-versus-intracranial glioma CSF samples (n=14). Using aptamer-based proteomics, we identified significant differences in the glioma CSF proteome between lumbar, subarachnoid, and ventricular CSF. Indeed, intracranial CSF in paired lumbar/intracranial samples had nearly 1600 unique aptamers, regardless of which intracranial location was compared to the paired lumbar CSF, including in enrichment style analyses that evaluated the overlap between protein states. Importantly, resection had a significant, evolving longitudinal impact on the CSF proteome, with subsets of proteins associated with early versus delayed post-resection changes, many of which were enriched for inflammatory-related pathways. Interestingly, despite increased contamination from surgical debris, enrichment for plasma-associated proteins decreased with resection (FDR: 0.000), suggesting that a portion of the baseline glioma panel could be derived from plasma-originating analytes due to blood-brain barrier disruption. Despite these challenges, our data still revealed preliminary candidate monitoring biomarkers, such as brevican, that increased with progression (example patient: fold-change of 3.58x and 2.08x through lomustine and bevacizumab, respectively), but not pseudoprogression (Fold change less than 1.5). Serial intracranial CSF samples suggested the early potential for disease monitoring and evaluation of pharmacodynamic impact of targeted therapies, including bevacizumab and pembrolizumab. In conclusion, our available data to date suggest that the intracranial glioma CSF proteome provides an abundant and evolving source of candidate biomarkers to longitudinally discern the impact of resection and systemic treatments.
BIOM-53. LOW-PASS WHOLE GENOME SEQUENCING OF CEREBROSPINAL FLUID IDENTIFIES TUMOR AGNOSTIC TP53 ABERRATIONS IN LEPTOMENINGEAL METASTATIC DISEASE
Authors: Malani Rachna , Zhang Yingqi , Dean Charlie , Boatz Laura , Harrison Brion , Wei Mei , Akerley Wallace , Bronner Marry , Underhill Hunter 
Published: November 2024

Abstract
Leptomeningeal metastatic disease (LMD) is the spread of cancer cells into the cerebrospinal fluid (CSF)-filled spaces surrounding the central nervous system (CNS). Once LMD occurs, patients endure devastating neurologic symptoms and survive for only a few weeks to months. The clinical diagnosis of LMD has risen as patient survival from non-CNS metastatic disease improves. Unfortunately, detection of LMD even in symptomatic patients is &lt;50% using the current gold standard – CSF cytology. Therefore, a strong clinical need exists for the sensitive and early detection of LMD. Here, we sought to develop a minimally invasive liquid biopsy approach to diagnose LMD using next-generation sequencing. Because copy number variations (CNVs) are common in cancer and increase after chemoradiation, we hypothesized that CNV detection in CSF may offer a means to detect LMD since patients have already undergone treatment for the underlying disease. Specifically, we sought to develop low-pass whole genome sequencing (lpWGS) of cell-free DNA in CSF to detect CNVs associated with LMD. A novel lpWGS algorithm was developed using FASTQ files trimmed to 30 million total paired reads. The genome was partitioned into one million continuous base pair segments excluding problematic areas yielding 2,445 regions across 22 autosomes. Control samples were used to model the read depth for each region to establish the euploid state. Read depth across the genome for all samples was 0.6X. CSF samples from lung cancer, breast cancer, and melanoma patients with LMD demonstrated prominent evidence of monosomies and trisomies throughout the genome. Lung cancer exhibited frequent amplifications (&gt;4-fold). Notably, we observed 17p monosomy in CSF regardless of cancer type which indicates TP53 haploinsufficiency may support LMD progression, a conjecture supported by a codeletion of TP53 in one patient. lpWGS detects LMD in solid tumor cancers and may also identify novel mechanisms for LMD progression.
BIOM-55. SENSITIVITY OF IMMUNOHISTOCHEMISTRY WITH BRAF VE1 ANTIBODY FOR BRAF V600E IN PRIMARY CENTRAL NERVOUS SYSTEM TUMORS
Authors: Blaquier Juan , Egea Sophie , Gultekin Sakir , D’Angelo Fulvio , Iavarone Antonio , de la Fuente Macarena 
Published: November 2024

Abstract

BACKGROUND
BRAF gene encodes for a key protein of the RAS-RAF-MEK-ERK pathway. BRAF alterations are found in a variety of primary central nervous system (CNS) tumors ranging from 3% of glioblastomas to 60% of pleomorphic xanthoastrocytomas. BRAF V600E mutation is the most common BRAF alteration found in CNS malignancies, and it has been successfully targeted with BRAF/MEK inhibitors. Novel BRAF inhibitors, still in development, have shown promising antitumor activity. Next-generation sequencing (NGS) has become a standard test in the era of histo-molecular diagnosis, but it can be unavailable or inaccessible, and results usually take longer. Immunohistochemistry (ICH) with VE1 antibody for BRAF V600E protein has shown high discordant results with sequencing in other tumor types. We aimed to establish the concordance of BRAF VE1 and NGS sequencing in CNS tumors.

METHODS
Single-center retrospective analysis of patients with BRAF V600E mutant CNS tumors by NGS testing.

RESULTS
30 patients with BRAF V600E mutant primary CNS tumors by NGS were included, 18 were male. 15 were classified as IDH-wildtype gliomas, 4 low grade neuroepithelial gliomas, 8 pleomorphic xanthoastrocytoma, 2 pilocytic astrocytomas and 1 papillary craniopharyngioma. IHC testing with BRAF VE1 antibody was done at the initial pathological classification in 23 of the cases being positive in 15 and negative in 8 cases. In 7 cases IHC was not done but has been requested for retrospective analysis and results are pending. Sensitivity for BRAF VE1 IHC was 65%.

CONCLUSION
When compared to NGS testing, ICH with BRAF VE1 antibody for BRAF V600E in CNS tumors shows modest sensitivity, being a limited tool when results are needed promptly or NGS is inaccessible. Determining specificity of the test will be crucial to establish its reliability for patient selection. Sequencing should be obtained when possible and remains the more reliable method for detecting V600E.
BIOM-71. EXPANDING THE SPECTRUM OFTERT PROMOTER NON-CANONICAL SEQUENCE VARIANTS IN CNS TUMORS: A CASE SERIES
Authors: Cook David , Trejo-Lopez Jorge , Pitel Beth , Saha Neiladri , Koganti Tejaswi , Hardcastle Jayson , Smoley Stephanie , Isaacson Matthew , Gandham Mallika , Sivasankaran Gopinath , Dasari Surendra , Fung Kar-Ming , Powell Suzanne , Trivedi Darshan , Abdullaev Zied , Aldape Kenneth , Quezado Martha , Pratt Drew , Cimino P J , Edgar Mark , Vaubel Rachael , Raghunathan Aditya , Giannini Caterina , Jenkins Robert , Ida Cristiane 
Published: November 2024

Abstract
Most TERT promoter (TERTp) clinically relevant sequence variants in CNS tumors are the canonical C228T and C250T mutations. Non-canonical TERTp mutations have been reported mainly in non-CNS tumors. We describe 12 CNS tumors with non-canonical TERTp variants interpreted as clinically relevant. Using clinical targeted NGS panels (2020-2024), we detected c.-100_-79dup (n=2), c.-92_-91insGGCGGCCCCGCCCCTTCCTTTC (n=1), c.-118_-117insTCCCCGGCCCAGCCCCTTCCGGG (n=1), c.-123_-76dup (n=1), c.-110_-89dup (n=2), and c.-57A&gt;C (n=5). Most cases had chromosomal microarray (n=11) and/or methylation array data analyzed using the NCI/Bethesda v.2 classifier (n=9). All non-canonical TERTp variants occurred at a variant allele frequency suggestive of somatic clonal origin (mean, 34%; range, 18-46), and in adults (mean age, 60 years; range, 36-88). Except for the c.-57A&gt;C variant, all non-canonical TERTp variants occurred in tumors with histological and/or molecular diagnostic features of glioblastoma, IDH-wildtype (GBM), often epigenetically aligning to this tumor type. All five tested cases matched to superfamily glioblastoma (score ≥ 0.9), with three to class GBM_RTK_I (&gt;0.9 in 2, 0.86 in 1) and two to GBM_RTK_II (&gt;0.9). The size and sequence of such variants suggest that these may be functionally equivalent to canonical mutations or generate favorable TERTp activation motif conformations like previously reported activating duplications. The c.-57A&gt;C variant is a well-established oncogenic mutation observed in other cancer types but has not been reported in CNS tumors. We describe five cases with the c.-57A&gt;C variant: one GBM matching to methylation class GBM_MES_TYP (0.99); two oligodendroglioma, IDH-mutant and 1p/19q-codeleted, one of which had methylation data matching to class O_IDH (0.99); one diffuse glioma, IDH-mutant, which was partially 1p/19q-codeleted and matched to class O_IDH (0.99); and one anaplastic meningioma, aligning to superfamily meningioma (0.99)/MNG_MAL (0.79). Our findings show that non-canonical TERTp variants typically occur in tumor types that often harbor TERTp canonical mutations, expanding the spectrum of TERTp clinically relevant variants that are molecular biomarkers in CNS tumors.
BIOS-05. PEPTIDE-BASED VACCINES VERSUS DENDRITIC CELL-BASED VACCINE THERAPIES FOR PATIENTS WITH GLIOBLASTOMA: A NETWORK META-ANALYSIS OF CONTROLLED CLINICAL TRIALS
Authors: Suresh Vinay , Bardhan Mainak , Dey Debankur , Goel Archit , Mohammad Adeeb Ali , Panchawagh Suhrud , Podder Vivek , Odia Yazmin , Chen Zhijian 
Published: November 2024

Abstract

BACKGROUND
Glioblastoma (GBM) is the most prevalent primary CNS malignancy in adults, often with a bleak prognosis. Reports suggest the efficacy of dendritic cell vaccines (DCV) and peptide vaccines in extending overall survival (OS). We aimed to compare their efficacy using network meta-analysis (NMA).

METHODS
We systematically searched PubMed, Cochrane database, SCOPUS, and Clinicaltrials.gov up to February 2024 for controlled trials on DCV or peptide vaccines for GBM. NMA was conducted using the frequentist approach to obtain direct and indirect comparisons of each vaccine. Pairwise analyses were performed using the inverse variance method, comparing each vaccine’s efficacy. PEPvIII-KLH and Rindopepimut were merged into “Peptide-based vaccines” [PEP], and standard of care (SOC) and (Placebo + SOC) were merged. Primary outcome: hazard ratio (HR) of overall survival with 95% confidence intervals.

RESULTS
Analysis included 5 studies with 451 patients (vaccine arm) and 445 controls, with SOC/[Placebo + SOC] as reference. Common effects model showed DCV + SOC significantly reduced the HR to 0.3385 [0.1753; 0.6539], while the peptide-based vaccine + SOC reduced the HR to 0.8276 [0.6960; 0.9840]. In the random effects model, DCV + SOC had an HR of 0.3132 [0.0839; 1.1688], and the peptide-based vaccine + SOC had an HR of 0.3888 [0.1383; 1.0928]. Heterogeneity: tau^2 = 0.6473, tau = 0.8045, I^2 = 77.7% [39.5%; 91.8%]. In a pairwise meta-analysis comparing the DCV+SOC and SOC/[Placebo + SOC] consisting of 2 trials, the common and random effects models both estimated an HR of 0.3385 [0.1753; 0.6539, I^2 = 0.0%]. Comparing the PEP+SOC and SOC/[Placebo + SOC] based on 3 trials, the common effect model estimated an HR of 0.8276 [0.6960; 0.9840], while the random effects model estimated an HR of 0.3874 [0.1360; 1.1039, I^2 = 84.4%].

CONCLUSION
Based on current evidence, DCV vaccines perform better than peptide-based vaccines in reducing mortality in GBM patients. Further trials are required to validate their efficacies.
CNSC-04. UNDERSTANDING PEDIATRIC BRAIN TUMOR CHEMOTHERAPY INDUCED LONG-TERM DEFICITS IN HIGH-ORDER NEUROCOGNITIVE AND SENSORIMOTOR FUNCTION
Authors: Singh Anand , Harris Momo , Mahalingam Rajasekaran , Ban Kechen , Bertrand Renae , Zimbwa Shungu , Kasm Khalil Ali Ahmad , Pan Yuan 
Published: November 2024

Abstract
Because of major advancements in cancer treatment especially chemotherapy, 85% of children with cancer are predicted to survive for 5 years or more. However, chemotherapy can cause long-term health problems when childhood cancer survivors enter adulthood (known as late effects). The neurocognitive features of these late effects (chemobrain) include trouble in concentrating, memorizing, and decreased processing speed, and results in lower IQ and academic achievement, poor hand-eye coordination, and slower development over time. Despite such a negative impact on the quality of life of cancer-surviving children, the mechanism is poorly understood and there is no FDA-approved drug to prevent or cure these side effects. To gain a better understanding of the mechanism underlying chemotherapy-induced cognitive impairments, we developed a pre-clinical model using carboplatin in juvenile mice to study long-term neurological defects. Carboplatin is commonly used chemotherapy drug in pediatric brain tumor patients. We have tested the capacity of different doses of carboplatin and its long-term effect on cognitive and sensorimotor function and performed single nuclear RNA sequencing (snRNAseq) of the hippocampus. Our preliminary data demonstrated dose-dependent deficits in executive and sensorimotor function 7-9 weeks after carboplatin administration in the mice of both sexes. snRNAseq of the hippocampus showed changes in the glial cell number as well as genes associated with oxidative phosphorylation and neurodegeneration at early and late time points. Bioenergetics using Seahorse in the brain synaptosomes revealed mitochondrial dysfunction in the form of decreased maximum respiratory capacity long after carboplatin treatment. This study established a preclinical model that can be leveraged to mechanistically understand the long-term neurocognitive side effects of brain tumor chemotherapy during childhood. Future studies will aim to identify potential targets to prevent and/or treat the neurotoxic effects of cancer treatment in pediatric patients.
CNSC-12. IMMUNOLOGICALLY TARGETING U1 MUTANT SHH MEDULLOBLASTOMA
Authors: Kameda Michelle , Zheng Rong , Ahmed Nabil , Cheng Chonghui , Taylor Michael 
Published: November 2024

Abstract

OBJECTIVES
Medulloblastoma (MB) is the most common malignant pediatric brain tumor representing a significant burden of morbidity and mortality in the US. MB is comprised of four subgroups: Wnt, Shh, Group 3, and Group 4. Shh tumors represent 25% of cases and subdivides into Shh-beta and Shh-gamma, Shh-alpha, and Shh-delta. Half of Shh MB carry an identical somatic point mutation in a non-coding small nuclear RNA (snRNA) called U1 (r.3A&gt;G) which is found in 97% of Shh-d tumors, and in most Shh-alpha tumors with TP53 mutations. Current therapies for patients with TP53 and U1 mutant Shh-alpha MB observe rare survivors, and adult Shh-delta patients continue to experience significant morbidity and mortality calling for urgent prioritization of these tumors for targeted therapy.

METHODS
Cryptic exons were identified in both Shh-delta U1 snRNA mutant samples and Shh-delta U1 wildtype (WT) samples using CryEx pipeline. In-house scripts were utilized for selecting for cryptic exons that are uniquely expressed in Shh-delta U1 snRNA mutant compared to wildtype (WT) samples.

RESULTS
Analyzing 180 Shh MB RNA-seq samples, we identified 23% Shh-alpha, no Shh-beta, 97% of Shh-delta and 3% Shh-gamma harbored the U1 mutation. The splicing landscape was then interrogated comparing Shh-delta U1 snRNA mutant samples to WT samples. Expressed exons were filtered to exclude known exons to identify novel or cryptic exons. To select for Shh-delta U1 snRNA mutant induced cryptic exons, CryEx arising from introns, not identified in Shh-delta U1 WT and included &gt;10% of their inclusion rates measured by percent spliced in (PSI) in Shh-delta U1 snRNA mutant samples were filtered. Of the middle CryEx, we identified 43,188 that were U1 mutant induced. Further filtering for cell surface Middle CryEx, three of the 75 middle CryEx overlapped.

CONCLUSION
The PTCH1 neoantigen formed from the CryEx insertion translates a protein that is unique to the tumor cells (i.e., not in normal tissue) was identified as a juxtamembrane for therapeutic drug discovery.
CNSC-13. CROSSTALK BETWEEN SENSORY NEURONAL ACTIVITY AND TUMOR CELLS PROMOTES MALIGNANCY AND CANCER PAIN
Authors: Ahmad Kasm Khalil Ali , Ban Kechen , Irshad Khushboo , Cortez Ibdanelo , Shen Cheng-En , Singh Anand , Rasheed Sami Mohd , Willcox Kendal , Grace Peter M , Hirbe Angela , Shepherd Andrew J , Pan Yuan 
Published: November 2024

Abstract

BACKGROUND
Nerve infiltration of solid tumors is associated with poor prognosis in multiple cancer types. Understanding the role of neuronal activity in cancer progression offers innovative approaches for treating malignancies and cancer-associated neurological issues such as pain. Pain perception is mediated by the activity of peripheral sensory neurons. Many cancer types induce pain, and sensory innervation could support tumor growth, raising the interesting hypothesis that cancer pain-associated neuronal activity promotes malignancies. Our study aims to test the hypothesis using malignant peripheral nerve sheath tumor (MPNST) as the experimental platform.

METHODS
in vivo allograft models were established by implanting mouse MPNST cells into the sciatic nerves of male and female mice, followed by performing pain behavior assays (von Frey, Hargreaves, and conditioned place preference tests) and tumor growth measurements. Primary mouse dorsal root ganglion (DRG) sensory neuron cultures were prepared for calcium imaging and neuron-tumor co-culture experiments.

RESULTS
MPNST tumor-bearing mice exhibited hypersensitivity to noxious and non-noxious stimuli (evoked pain) and ongoing pain, compared to the sham controls. MPNST-conditioned media increased intracellular calcium concentration and ATF3 (indicator for nerve injury/stress) expression in primary sensory neuron culture, suggesting that MPNST tumor cell secretory factors may induce pain by triggering sensory neuron injury/stress responses that increase sensory neuron activity/sensitivity. Reciprocally, we found that stimulation of sensory neuron activity accelerates MPNST tumor growth. The conditioned media from stimulated sensory neurons increased tumor proliferation (EdU assay) in vitro, suggesting that sensory neuron activity-induced paracrine factors increase MPNST cell growth.

CONCLUSIONS
MPNST is a devastating cancer that grows within peripheral nerves which induce intractable pain. Our findings demonstrate a feedforward cycle where the cancer cells induce sensory neuron hypersensitivity/hyperactivity (pain) which in turn further accelerates tumor growth. Future studies will identify the molecular mechanisms underlying this crosstalk between MPNST and sensory neuron activity.