bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOM-47. CLINICAL AND MOLECULAR FEATURES OF PATIENTS WITH LI-FRAUMENI SYNDROME AND GLIOMA: AN MD ANDERSON CANCER CENTER EXPERIENCE
Authors: Lam Keng , Kamiya-Matsuoka Carlos 
Published: November 2023

Abstract

BACKGROUND
Li-Fraumeni Syndrome (LFS) predisposes patients for cancer, including gliomas, due to pathogenic TP53 germline variants. Little is known about their treatment course, molecular markers, and prognosis.

METHODS
This is a retrospective study of patients with diagnosis of LFS and glioma at MD Anderson Cancer Center from 2013 to 2023. Data collected includes next generation sequencing and treatment history. We analyzed descriptive statistics and Kaplan-Meier method to report their clinical characteristics and median progression-free survival (mPFS), defined as the time from initial diagnosis to first recurrence.

RESULTS
14 patients with LFS had diagnosis of glioma, with half of them as the first manifestation of cancer. There were 8 IDH-mutant gliomas (all WHO grade 2 astrocytoma), 4 IDH-wildtype WHO grade 4 glioblastoma, and 2 gliomas with no molecular markers (WHO grade 3 astroblastoma and astrocytoma). Only IDH1 mutations were identified: R132H (n = 4), R132S (n = 2), and R132L (n = 2). ATRX status was tested in 12 gliomas, 8 with retained protein expression. ATRX co-mutation in IDH-mutant astrocytoma occurred in 38% of cases. TP53 status was tested in 12 gliomas, with 6 having positive expression on immunostaining. MGMT methylation status (n = 8) was detected in 2 IDH-mutant gliomas whereas all glioblastomas were unmethylated. For treatment, 7 patients with low-grade glioma opted for observation after initial diagnosis despite 5 being considered high-risk for recurrence (subtotal resection/ &gt; 40 years of age). The mPFS for low-risk and high-risk low-grade astrocytoma on observation was 29.1 months and 28.5 months respectively. Based on IDH status, the mPFS for glioblastoma and IDH-mutant grade 2 astrocytoma was 6.4 months and 25.5 months respectively.

CONCLUSIONS
LFS patients may have glioma with higher incidence of non-canonical IDH1 mutations, lower likelihood of ATRX and IDH1 co-mutations, and less likely to be treated upfront after initial diagnosis despite having high risk profile for low grade glioma.
BIOM-49. FGFR ALTERATIONS IN GLIOMAS; CLINICAL, RADIOGRAPHIC AND MOLECULAR CHARACTERIZATION
Authors: Hill Colin , Iavarone Antonio , Tajera Dalissa , de la Fuente Macarena 
Published: November 2023

Abstract

BACKGROUND
FGFR-TACC is the most prevalent type of gene fusion in adult gliomas. It is present in 3-6% of IDH WT (wild-type) gliomas. Due to their histopathological and molecular features, it has been suggested that FGFR3-TACC3 fusions (F3T3) gliomas represent a unique entity among IDH WT gliomas. F3T3 are potent oncogenes that confer sensitivity to FGFR inhibitors. Preliminary data showed promising results of these alterations as actionable targets by FGFR inhibitors.

METHODS
We retrospectively analyzed molecular data on 912 glioma patients treated at our institution from 2014 to 2023.

RESULTS
We identified 22 gliomas (2.5%) with FGFR alterations. Median age was 60 years, 14 were female. 14 patients (64%) self-identified as Hispanic. 18 had a diagnosis of glioblastoma, 3 had other gliomas, and one had a low-grade neuroepithelial neoplasm. Ten patients had tumor location in the temporal lobe, 6 frontal, 5 parietal, 3 occipital, 1 multifocal, and 1 basal ganglia. 19 patients had enhancing tumors, while three were non-enhancing. The most common FGFR alteration was FGFR3-TACC3 fusion in 14/22 patients, 6 had FGFR mutations (either single base or amino acid substitutions), one had FGFR-LMNB2 fusion, and one had FGFR3 amplification. 86.4% of our patient cohort (19/22) had a confirmed TERT promoter mutation, while 100% of GBM patients with known TERT promoter status had an associated TERT promoter mutation. 10/22 had CDKN2A/B alterations. One patient had pathology-proven systemic metastases.

CONCLUSIONS
FGFR3-TACC3 fusions (F3T3) gliomas represent a unique entity among IDH WT gliomas. In our cohort, 100% of the patients with F3T3-positive glioblastomas also had an associated TERT promoter mutation. To our knowledge, this is one of the larger cohorts showing the association between FGFR3 and TERT promoter alterations in glioblastomas.

RESULTS
will be validated through the upcoming clinical trial ETCTN 10559, including tumor evolution and mechanisms of resistance.
BIOM-58. ZERO-WASTE MOLECULAR DIAGNOSTICS FROM BIOPSY NEEDLE WASHES
Authors: Wadden Jack , John Vishal , Niculcea Michael , Kong Seongbae , Aittaleb Rayan , Cartaxo Rodrigo , Verbal Kait , Bruzek Amy , Magge Suresh , Yadavilli Sridevi , Erez Nir , Furth Noa , Shema Efrat , Marapudi Neena , Heth Jason , Al-holou Wajd , Garton Hugh , Nazarian Javad , Koschmann Carl 
Published: November 2023

Abstract

BACKGROUND
Brain tumor classification has increasingly integrated molecular diagnostics into official criteria. However, biopsy tissue is limited due to the small quantity acquired in eloquent areas of the brain and is, therefore, usually earmarked for histology. We have identified that the fluid used to wash biopsy needles contains excess tumor material that can be diagnostically useful. Characterization of this non-zero-sum waste material provides an opportunity for improvement in the diagnosis and treatment for brain tumor patients.

METHODS
For suspected or established high grade brain tumor biopsies (n = 37 across a multi-institutional cohort at submission), neurosurgeons were instructed to save fluid used to wash biopsy needles. Samples were processed and characterized in a variety of methods to establish diagnostic utility including (1) cell-free DNA isolation and targeted panel sequencing (n = 13), (2) isothermal amplification of cell-free DNA from raw wash water for rapid diagnostics (n = 2), (3) cell-line generation (n = 24) and, (4) cell-free mutant protein capture and quantification (n = 9).

RESULTS
(1) 13 wash samples were considered for cf-tDNA extraction and Illumina TruSight Oncology 500 panel sequencing (with extracted DNA ranging from 20ng-40ug). In 2 returned cases (11 pending), concordance was 100% with clinical targeted panel sequencing where panels overlapped. (2) One case suspected of harboring H3K27M was subjected to targeted, loop-mediated isothermal amplification and Oxford Nanopore real-time sequencing, confirming an H3.3K27M diagnosis (11.8% allele fraction) within 1hr35min of receipt of sample from the operating room. (3) 5 cases resulted in primary cell culture generation (4) A novel single-molecule mutant protein quantification technique was performed on 9 cases.

RESULTS
from all analyses and concordance with outstanding sequencing will be presented.

CONCLUSION
We demonstrate that biopsy byproducts contain enough high-quality tumor-derived material to perform a variety of useful diagnostics with the potential to have immediate translational impact on standard of care.
BIOM-60. CONCATEMERIC CONSENSUS ERROR CORRECTED SEQUENCING (CCEC-SEQ) APPROACH FOR PLASMA CELL-FREE TUMOR DNA-BASED TREATMENT RESPONSE MONITORING IN PATIENTS WITH BRAIN TUMORS
Authors: Wadden Jack , John Vishal , Aittaleb Rayan , Koschmann Carl 
Published: November 2023

Abstract

BACKGROUND
Diffuse midline gliomas (DMG) are aggressive and universally fatal with a median survival rate of only 9-12 months. MRIs can be difficult to interpret due to diffuse disease and radiation-induced swelling. Recent work has shown that liquid biopsy of cell-free tumor DNA (cf-tDNA) in patient plasma using digital droplet PCR (ddPCR) might help supplement radiographic monitoring, and enable more quantitative, low-cost, rapid tests. Nanopore sequencing has been employed to quickly and affordably measure and track treatment response in DMG patient cerebrospinal fluid (CSF) where cf-tDNA variant allele fractions are high ( &gt;1%). However, plasma cf-tDNA signal is much lower than CSF (typically &lt; 0.5%), and no platforms have demonstrated the feasibility of quickly (&lt; 1day) sequencing brain tumor cf-tDNA in plasma samples to our knowledge.

METHODS
To solve these problems, we have developed a same-day, multiplexed, concatemeric consensus error corrected (CCEC-Seq) assay approach for Nanopore sequencing. We combine multiplex PCR and loop-mediated isothermal amplification (LAMP) to capture short cf-tDNA fragments and concatemerize them. Sequenced concatemer segments should agree, and allow informatic consensus error correction, reducing Nanopore error rates.

RESULTS
We generated a multiplex (n = 8) DMG hotspot loci panel, which was able to reduce sequencing false positive call rates by 3.1x-10.8x. We were able to employ the CCEC-Seq technique on serial plasma samples from a patient with DMG with H3.3K27M mutation undergoing treatment with ONC201 with results comparable to a previously validated ddPCR assay. Ongoing work will apply this multiplex CCEC-Seq panel to a larger cohort of serial DMG plasma samples.

CONCLUSION
To our knowledge, this is the first demonstration of same-day, sequencing-based, liquid biopsy protocol for a plasma sample from a brain tumor patient. This approach has the potential to greatly reduce resource requirements, and ease of operation for liquid biopsy for DMG and other brain tumor disease monitoring.
BIOM-61. EXPLORING HOMOLOGOUS RECOMBINATION DEFICIENCY IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Xu Ke , Savage Evan , Myers Jason , Rampersaud Evadnie , Hui Yawei , Chang Ti-Cheng , Wu Gang , Tinkle Christopher , Shelat Anang 
Published: November 2023

Abstract
Homologous recombination deficiency (HRD) has been extensively studied in breast cancer and ovarian cancer given its correlation with sensitivity to Poly (ADP-ribose) polymerases (PARP) inhibitors. In these cancers, HRD is most frequently caused by biallelic inactivation of BRCA1/2 and tumors often exhibit ‘genomic scars’ such as elevated HRD.sum score and specific mutational signatures, including specific single nucleotide variant (SNV), small insertion/deletion (Indel), and structural variant (SV) signatures. Despite its clinical relevance, HRD has not been systematically studied in pediatric cancers and its therapeutic predictive value is unknown. Here, we evaluated HRD in 255 tumor-normal paired whole-genome-sequenced (WGS) samples of pediatric high-grade glioma (pHGG) and 23 tumor-normal paired WGS samples of breast cancer (BC) as comparison. We found that 9% of the pHGG samples have HRD.sum score greater than 40, an indicator of HRD in several adult cancers. However, while we identified HRD-related SNV signature SBS3 and SV signature RS5 in some of the pHGG samples, HRD-related Indel signature ID6 was not identified. We also evaluated two composite scores, namely, HRDetect and CHORD, on our samples. While virtually all BC samples with BRCA1/2 loss were predicted to be HRD by both scores, none of the pHGG samples was predicted to be HRD by either score. We profiled somatic and germline variants from over 500 DNA damage response genes in the pHGG samples and identified TP53 as the most frequently mutated genes with biallelic loss, whereas biallelic loss of BRCA1/2 was not found. Overall, our study suggests that HRD exists in a fraction of pHGG samples, but is driven by inactivation of genes other than BRCA1/2, resulting in a different set of genomic scars compared to those in BCs. Functional analysis of sensitivity to PARP inhibitor and related DNA damage inhibitors is ongoing to evaluate potential therapeutic relevance of these genomic scars.
BIOM-65. NEW BIOMARKERS FOR THE DIAGNOSIS OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA IN CEREBROSPINAL FLUID: AN EXPLORATORY MULTICENTER RETROSPECTIVE COHORT STUDY
Authors: van Rooij Josephus , Wessels Peter , Delemarre Eveline , Meek Bob , Ruven Henk , Seute Tatjana , Minnema Monique , Nierkens Stefan , Snijders Tom 
Published: November 2023

Abstract

BACKGROUND
Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma which may be treated with curative intent. Diagnosis often requires a brain biopsy, which is associated with complications and delay of diagnosis. Cerebrospinal fluid (CSF) analysis can currently provide a diagnosis (without the need for a biopsy) in only a minority of PCNSL patients. The aim of this study is to identify new potential biomarkers in CSF for patients with clinical suspicion of PCNSL, to improve the diagnostic yield of CSF analysis.

METHODS
CSF samples were analyzed from a retrospective cohort that included patients with clinical suspicion of PCNSL at two Dutch hospitals between August 2020 and October 2021. First-step analysis consisted of targeted multiplex biomarker analysis using a proximity extension assay (Olink), allowing the simultaneous analysis (relative expression levels) of 184 protein markers in a small CSF volume. To validate the discovered biomarkers in a quantitative manner, a second analysis was performed in a subgroup of patients with a bead-based multiplex immune-assay (Luminex).

RESULTS
A total of 76 patients were included, of whom 11 patients (14%) were diagnosed with PCNSL. The mean age was 62 years (range 22-83 years), and 62% of the patients were male. In the primary analysis, 31 markers showed significant differences (p&lt; 0.05) between PCNSL patients and controls. After correction for multiple testing, 6 markers remained significant, including the known chemokine marker CXCL13, as well as new markers. The quantitative analysis confirmed significant differences (p&lt; 0.05) for 3 markers: CXCL10, programmed cell death protein 1 (PDCD1) and FAS natural ligand (FASLG).

CONCLUSION
We identified a novel panel of potential diagnostic markers in CSF for the diagnosis of PCNSL. The diagnostic value of these markers will be validated in an ongoing multicenter prospective study.
BIOS-02. RECAPITULATE TUMOR DIVERSION AND SPATIAL PATTERNING IN GLIOBLASTOMA BACKGROUND
Authors: Lo Wei-Lun , Khoa Hoang Dang Ta , Chuang Jian-Ying 
Published: November 2023

Abstract

BACKGROUND
Intra-tumoral heterogeneity of glioblastoma multiforme (GBM) drives aggressive behavior and intrinsic therapeutic resistance. To investigate heterogeneity, high-resolution sequencing techniques provided us to feature tumor molecular subtyping and simulate differentiation. In our study, we proposed to dissect tumor heterogeneity in different anatomical regions by single cell transcriptome analysis. Material and Method We performed single-cell RNA sequencing on 10675 adult IDH-wild type GBM cells from six pairs of tumor core (central necrotic part of tumor) and tumor margin (junction between tumor and brain). Subtyping following RNA velocity was performed to investigate tumor diversity. Result Four subgroups of tumor cells (OPC-like (oligoprogenitor cell), NPC-like (neuroprogenitor cell), AC-like (astrocyte), and MES-like (mesenchymal) )were identified. The higher cell population of OPC/NPC at tumor margin and AC/MES at tumor core was found. The RNA velocity analysis showed the major diversity order was OPC at margin, OPC at core, NPC at margin, and AC with MES at core.

CONCLUSION
We explore the spatial pattern of tumorigenesis of GBM that OPC at margin part could be the tumor initiating cell. Further investigation of biological characteristics of OPC could be the strategies to block tumor differentiation and progression.
CNSC-01. THE ROLE OF SEROTONERGIC RECEPTOR, HTR2B, ON MYELOID DERIVED SUPPRESSOR CELLS IN THE BRAIN METASTATIC ENVIRONMENT
Authors: Iyer Mukund , Das Diganta , Nakamura Brooke , Sedighi Saman , Reed Max , Pakravan Alexa , Shah Priya , Jang Julie , Baugh Aaron , Gonzalez Edgar , Torres Evanthia Roussos , Neman Josh 
Published: November 2023

Abstract
In the United States, greater than 12% of cancer patients develop brain metastases (br-mets) and median survival remains an abysmal 4-6 months. Throughout the metastatic cascade, tumor cells attract and reprogram stromal cells, such as myeloid derived suppressor cells (MDSCs), which support cancer growth by promoting tissue remodeling, EMT, invasion, immunosuppression, angiogenesis. Once tumor cells have breached the brain’s CNS defenses, infiltrating immune cells can penetrate the glia limitans and enter the CNS parenchyma to help establish the brain metastatic niche. However, there is scant understanding of MDSC’s contribution to the brain metastatic microenvironment. The brain metastatic environment is particularly unique because CNS-resident cells such as microglia, astrocytes, choroid plexus, and neurons function as local mediators to alter invading immune cell plasticity and differentiation. We have demonstrated that MDSCs in the brain microenvironment respond to the neurotransmitter serotonin, upregulate the serotonergic receptor, HTR2B, resulting in increase pNF-κB and its associated signaling genes (IL-6, IL-1B, COX2, CXCL2, NOS2). Furthermore, HTR2B knockdown in MDSCs alters downregulates expression of pNF-κB signaling genes. Additionally, MDSCs in this environment support tumor cell proliferation while hindering their acquisition of neuronal traits. A better understanding of the role of HTR2B in brain metastasis may allow us to develop new treatment strategies for patients of this devastating disease.
CNSC-06. REDIRECTING IMMUNOSUPPRESSIVE GLIOMA MICROENVIRONMENT THROUGH PHARMACOLOGICAL INTERVENTION TARGETING NEURONAL ACTIVITY
Authors: Nejo Takahide , Krishna Saritha , Yamamichi Akane , Jimenez Christian , Lakshmanachetty Senthilnath , Young Jacob , Phyu Su , Watchmaker Payal , Hervey-Jumper Shawn , Okada Hideho 
Published: November 2023

Abstract
Recent single-cell RNA-sequencing analyses have revealed a strong association between glioma-neuronal circuit remodeling and regional immunosuppression. Subsequent preclinical investigations using syngeneic tumor models demonstrated that genetic disruption of circuit assembly genes, including Thrombospondin-1 (TSP-1/Thbs1) in GBM cells suppressed synaptogenesis, excitatory neurotransmitter ligand and receptor density in addition to neuronal activities while simultaneously restoring inflammatory responses, indicating glioma-neuron-immune cross talk. However, the underlying mechanisms and directions of causality remain unclear. Here we test the hypothesis that tumor-derived synaptogenic factors directly reprogram the tumor immune microenvironment (“model 1”). Alternatively, tumor intrinsic neuronal activity may indirectly regulate adaptive immunity (“model 2”). In this study, we performed in-vitro bone-marrow-derived macrophage (BMDM) reprogramming assays evaluating various stimulation conditions and in-vivo experiments evaluating the effect of neuronal activity-oriented therapy on the tumor-associated macrophages (TAMs). Our in-vitro assays demonstrated that, secreted factors from mouse neonatal cortical neurons (not tumor-derived synaptogenic factors) induced an anti-inflammatory, M2-like phenotype of BMDMs, corroborating the proposed model 2. This M2-inducing effect was inhibited when the neuronal activities were suppressed pharmacologically, using perampanel (PER), a noncompetitive inhibitor of neuronal AMPA-type glutamate receptors. Direct treatment of BMDMs with PER did not affect the polarization patterns, further supporting the M2-inducing effect of glutamatergic excitatory neuronal signals. In in-vivo syngeneic orthotopic tumor models, treatment with PER significantly prolonged survival compared to the non-treated group (27.5 [PER] vs. 23 days [control], p = 0.01). Flow cytometric analysis of brain-infiltrating leukocytes showed that TAMs isolated from PER-treated mice exhibited a more proinflammatory M1-like polarization compared to the control group (median M1/M2 ratio, 1.2 [PER] vs. 0.7 [control], p = 0.004), which explained the improved prognosis. Collectively, these findings unveil novel immunosuppression mechanisms induced by glioma-neuronal circuit remodeling and the resulting excitatory neuronal signals, and potential therapeutic vulnerabilities that could be targeted in combination with cancer immunotherapy.
CNSC-08. PROTEOGENOMIC ANALYSIS OF LONGITUDINAL TRAJECTORY OF GLIOBLASTOMA EVOLUTION
Authors: Park Jong Bae , Iavarone Antonio 
Published: November 2023

Abstract
The evolutionary trajectory of glioblastoma after therapy is a multifaceted biological process that extends beyond discrete genetic alterations alone. Here, we performed a proteogenomic analysis of 123 longitudinal glioblastoma pairs, temporally separated by standard-of-care treatment. Integrative analyses identified a prevalence of a highly proliferative cellular state at diagnosis and its replacement by recurrent tumors sharing activation of neuronal differentiation and synaptogenicpathways. Proteomic and phosphoproteomic analyses revealed that the molecular transition from the proliferative to the neuronal state at recurrence is marked by coherent post-translational activation of the WNT/PCP signaling pathway and the BRAF protein kinase. Multi-omic analysis of the Patient-Derived Xenograft (PDX) model demonstrated similar patterns of evolutionary trajectory, marked by activation of neuronal signaling programs that were consistently observed in longitudinal patients. Inhibition of the BRAF kinase with small molecule inhibitors impaired both neuronal differentiation and migration capability of recurrent glioblastoma cells, which are the phenotypic hallmarks of glioblastoma progression after therapy. This work provides comprehensive insights into the biological mechanisms of glioblastoma evolution and treatment resistance and highlights new therapeutic opportunities to effectively counter them in the clinic.
CNSC-09. CHI3L1 IS A MOLECULAR MARKER FOR GLIOBLASTOMA NETWORK CONNECTIVITY AND FUNCTIONALLY ORCHESTRATES TUMOR MICROTUBE FORMATION
Authors: Hoffmann Dirk , Hai Ling , Wagener Robin , Hausmann David , Azorín Daniel Domínguez , Xie Ruifan , Huppertz Magnus-Carsten , Hiblot Julien , Sievers Philipp , Ito Jakob , Weil Sophie , Cebulla Gina , Mandelbaum Henriette , Jung Erik , Kourtesakis Alexandros , Ernst Kati , Reibold Denise , Warnken Uwe , Venkataramani Varun , Will Rainer , Suva Mario , Herold-Mende Christel , Sahm Felix , Winkler Frank , Schlesner Matthias , Wick Wolfgang , Kessler Tobias 
Published: November 2023

Abstract
Chitinase 3-like 1 (CHI3L1) is a secreted glycoprotein and its RNA expression elevated in glioblastoma (GB) compared to other tumor types and related normal tissues. Furthermore, transcript levels in GB dictate aggressiveness through modulating stemness, proliferation and tumor microenvironment. This ultimately influences patient survival. We here provide evidence that the pathogenic relevance of CHI3L1 expression is associated with the extent of tumor microtubes (TMs) - ultralong membrane tubes that connect GB cells (GBCs) to a network with considerable relevance for tumor progression and therapy resistance. Single cell RNA profiling of xenografted GBCs with different degrees of morphological and functional TMs identified CHI3L1 as a prognostic marker for TM network extent. We demonstrate that both RNA and protein expression levels are suitable markers in preclinical in vitro systems modeling TM connectivity as well as in clinical specimens. Genetic perturbation of CHI3L1 influenced GBC network integration, caused a shift of the dominant cell state and altered the phosphorylation status of the TM-driver GAP43. Pharmacological blocking of CHI3L1 with an antibody reduced TM networks, thus providing a handle for future clinical translation. Together, these data identify a functional and upstream role of CHI3L1 in governing tumor cell connectivity, CHI3L1 RNA and protein expression as a novel way to determine overall GBC connectivity for future trials, and finally a new therapeutic target for tumor network-disrupting strategies.