bluuebunny/crossref_metadata_2025_split huggingface dataset:
CNSC-16. ASSOCIATION BETWEEN RESTING-STATE-NETWORK FUNCTIONAL CONNECTIVITY AND SURVIVAL IN RECURRENT GLIOMAS DIAGNOSED USING FET PET
Authors: Friedrich Michel , Werner Jan-Michael , Steinbach Joachim P , Sabel Michael , Herrlinger Ulrich , Piroth Marc , Stoffels Gabriele , Filss Christian P , Lohmann Philipp , Shah Nadim J , Ruge Maximilian I , Mottaghy Felix M , Goldbrunner Roland , Langen Karl-Josef , Fink Gereon R , Kocher Martin , Galldiks Norbert 
Published: November 2024

Abstract

BACKGROUND
Functional connectivity between glioma-infiltrated brain tissue and remote cortical regions has been linked to overall survival (OS) in patients with newly diagnosed glioblastoma. We studied the association of functional connectivity between tumor and resting-state networks and OS in patients with recurrent gliomas.

PATIENTS AND METHODS
The study included 82 patients (26-81 years; median ECOG performance score, 0) with recurrent gliomas (grade 4 glioblastoma, n=57; grade 3 and 4 astrocytoma, n=12; grade 2 and 3 oligodendroglioma, n=13) who had undergone first-line therapy. Diagnosis of recurrence was confirmed by amino acid PET using the tracer O-(2-[18F]-fluoroethyl)-L-tyrosine (FET). FET PET and resting-state functional MRI were simultaneously acquired on a 3T hybrid PET/MR scanner. We performed a seed-based dual regression analysis to determine the functional connectivity between metabolically active tumors and seven canonical resting state networks.

RESULTS
Average functional connectivity was highest in oligodendrogliomas (z-score, 6.9±1.9) and was inversely related to the tumor grade (p=0.031). Univariate Cox regression analysis revealed a significant (p&lt;0.05) positive association between OS and tumor connectivity with the visual, somatomotor, and dorsal attention networks. Subsequent stepwise multivariate Cox regression analysis refined this association to the dorsal attention network alone (HR, 0.88; 95% CI, 0.80-0.97; p=0.007). Patients with the highest functional connectivity (z-score&gt;8.3, n=21) had a median OS of 31.4 months, while those with the lowest functional connectivity (z-score&lt;4.3, n=21) had 10.6 months. Functional connectivity between tumors and the dorsal attention network showed an independent association with OS (HR, 0.90; 95% CI, 0.81-0.99; p=0.033) in a multivariate model, including various prognostic factors.

CONCLUSION
Recurrent gliomas exhibit significant functional connectivity to most of the major known resting-state networks, highest in oligodendrogliomas. The data suggest that high functional connectivity between the tumor and the dorsal attention network is an independent prognostic factor for improved OS.
CNSC-25. CONCURRENT IMMUNE CHECKPOINT BLOCKADE ENHANCES THE SURVIVAL BENEFIT OF CLINICALLY RELEVANT MAPK PATHWAY INHIBITORS IN A T CELL-DEPENDENT MANNER
Authors: Xing Yao Lulu , Park Jong-Whi , Grossauer Stefan , Panovska Dena , Bui Brandon , Morales Daniella , Nirschl Jeffrey , Feng Zhi-Ping , Anderson Wes , Levy Jean Mulcahy , Schreck Karisa , Prolo Laura , Hambardzymyan Dolores , Petritsch Claudia 
Published: November 2024

Abstract

BACKGROUND
Despite the availability of targeted therapies, gliomas carrying the BRAFV600E mutation remain challenging to treat. Combined pharmacologic BRAFV600E and MEK inhibition is clinically used in patients with BRAFV600E mutant gliomas, but primary and acquired resistance is reported in ~70% of high-grade glioma patients.

OBJECTIVES
To gain mechanistic insights into therapy adaptation and escape for developing combination therapies that enhance clinical effects of combined BRAFV600E inhibition with Dabrafenib and MEK inhibition with Trametinib (BRAFi+MEKi) in high-grade gliomas.

APPROACH
Patients’ pre- and post-treatment glioma tissues, patient-derived and mouse cell lines, and two novel immunocompetent mouse models for BRAFV600E mutant high-grade gliomas were analyzed for the effect of BRAFi+MEKi using a range of techniques including bulk and single-cell RNA sequencing, immunofluorescence staining, flow cytometry, and mass cytometry.

RESULTS
We present new data showing that the BRAFi+MEKi combination significantly reduced glioma cell viability while inducing glial differentiation programs, potentially associated with programmed death receptor (PD-1) signaling. This suggests a profound shift in the glioma cell differentiation state that is linked to an inclination toward T cell inhibition. This prompted us to combine BRAFi+MEKi with immune checkpoint inhibitors targeting PD-L1 and CTLA-4, which significantly decreased T cell inhibition. Furthermore, from mouse studies, this combination therapy conferred a survival benefit over single BRAFi+MEKi combination therapy alone. Additionally, BRAFi+MEKi treatment triggered an interferon-gamma response, indicative of cytotoxicity, and enhanced the expression of MHC molecules associated with antigen presentation, only in drug-sensitive but not drug-resistant gliomas. The lack of improved therapeutic efficacy of immune checkpoint blockade in athymic mice, which lack T cells, emphasized the critical role of T cell activity in driving the success of the combination treatment.

CLINICAL IMPACT
Our preclinical findings highlight the potential of concurrent BRAFi+MEKi treatment and immune checkpoint blockade for overcoming therapy resistance in BRAF mutant high-grade glioma patients.
CNSC-27. INTRATUMORAL CANCER CELL NETWORKS IN BRAIN METASTASES
Authors: Olshausen Niels , Hebach Nils R , Schlag Joana S , Thommek Calvin , Yang Yvonne , Hoffmann Dirk C , Mayer Chanté , Westphal Dana , Breckwoldt Michael O , Wick Wolfgang , Winkler Frank , Karreman Matthia A 
Published: November 2024

Abstract
Recently, we have shown that primary brain tumors form highly organized, small-world scale-free networks, reminiscent of early networks in neurodevelopment and highly resistant to therapy. Such putative cancer-cell intrinsic neural mechanisms are becoming an increasing focus in the field of Cancer Neuroscience, but it has not yet been shown whether tumors of non-CNS origin also have the ability to form multicellular networks which sustain proliferative signaling and increase resistance to therapy. We observed synchronized calcium activity using longitudinal microscopy both in vivo and in vitro that were reminiscent of gap junction coupled networks. Indeed, dye transfer experiments verified functional coupling of brain metastases cells in vitro. Similarly, inhibition of gap junctions with different pharmacological agents significantly reduced calcium oscillations and tumour proliferation in vitro. Furthermore, gap junctions are significantly upregulated in brain-tropic sublines compared to parental cells. To understand the functional relevance of these gap-junction coupled tumor cell networks, we performed bulk RNA-Sequencing of two melanoma metastasis models in monoculture under gap junction inhibition and control: We observed reduced calcium communication and a concordant downregulation of neurodevelopmental and synaptic pathways within the tumor cells upon network disconnection, highlighting a potential recapitulation of neural-like features in metastases to the brain. To investigate the therapeutic potential of targeting these networks, we treated mice with brain metastases with two brain-penetrant gap junction blockers and observed significantly reduced tumor burden. Finally, we investigated the presence of heterotypic networks between brain metastases cells and the brain microenvironment with our SR101 dye transfer pipeline. Contrary to our findings in primary brain tumors, no gap junction connections to cells of the brain microenvironment in those models with reduced tumor growth upon network inhibition could be detected, supporting a cancer cell intrinsic gap junction mediated network and highlighting a selectivity of these homogenous tumor networks and potential therapeutic vulnerability.
CNSC-32. CHARACTERISTIC ANALYSIS OF SPREAD AND METASTASIS OF HIGH-GRADE GLIOMA
Authors: Li Shaoqun , Lai Mingya , Wang Lichao , Zhang Yangqiong , Ye Minting , Li Juan , Ai Ruyu , Cai Linbo 
Published: November 2024

Abstract

OBJECT
Exploring the clinical characteristics of spread and metastasis of high-grade glioma is helpful for clinicians to further understand high-grade glioma, optimize clinical decision-making, and make treatment plans.

METHOD
Clinical data of patients diagnosed with WHO Grade 4 glioma with spread and metastasis in the course of disease in Guangdong Sanjiu Brain Hospital from January 1, 2017 to December 31, 2020 were collected and analyzed.

RESULTS
93 patients were included in the analysis, 59 males and 34 females, median age of 42 years (3-71 years). Tumors were located supratentorial in 78 patients (83.9%). Most patients (70, 75.3%) had tumors adjacent to the ventricular system. 28 patients (30.1%) had tumor spread at first diagnosis. All patients received surgical at first diagnosis, including total resection in 36 cases (38.7%), partial resection in 42 cases (45.2%), and biopsy in 15 cases (16.1%). In 48 patients (51.6%), ventricles were opened during operation. 69 cases (74.2%) were pathologically diagnosed with glioblastoma, 81 cases (92.0%) were IDH wild-type. MRI findings of dissemination were linear in 50.0% (46 cases), nodular type in 25.0% (23 cases), mixed type in 25.0% (23 cases), and the remaining 1 case was undetermined. Cerebrospinal fluid examination was performed in 37 cases, which 11 cases were cytological positive (29.7%). Median OS for patients with initial dissemination was 338 days. Of the 68 patients developed transmission after treatment, median OS fro initial diagnosis to transmission was 254 days, the overall median OS was 409 days. The overall median OS for all patients was 403 days. The median OS of newly diagnosed patients with tumor spread was lower than that of patients with tumor spread after treatment, but there was no statistical difference (p=0.05).

CONCLUSION
Most high-grade glioma patients develop tumor spread within 1 year, and these patients have unique clinical characteristics. The positive rate of cerebrospinal fluid tumor cells is low, MRI imaging is still the main diagnostic option.
CNSC-41. DABRAFENIB AND TRAMETINIB AS A PROMISING TREATMENT OPTION FOR PEDIATRIC POPULATION WITH LOW-GRADE GLIOMAS THAT HAVE BRAF V600E MUTATION:A BREAKTHROUGH IN THE FIELD OF NEURO- ONCOLOGY
Authors: Mughal Zaib Un Nisa , Ahmad Tagwa Kalool Fadlalla , Haseeb Abdul , Shafique Muhammad Ashir , Ahmdon Ola Elhadi Abbas , Mahgoub Abdulhadi Mohamed Ahmed 
Published: November 2024

Abstract
Two-thirds of all pediatric malignant central nervous tumors, including high-grade (glioblastoma, anaplastic astrocytoma) and low-grade (ganglioglioma, pilocytic astrocytoma) carcinomas, are gliomas. Low-grade glioma(LGG) exhibits genetic alterations caused by the BRAF kinase mutation, such as replacing glutamic acid (E) in place of valine (V) at the 600 positions, known as the V600E point mutation. Pediatric low-grade gliomas (PLGGs) also comprise around one-third of juvenile brain tumors and are the most frequent central nervous system tumors. Patients were randomized 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). Where possible, complete surgical removal is the mainstay of treatment for progressing or symptomatic PLGG.Radiation therapy has historically been used to treat PLGG in both up-front and salvage scenarios. To delay or avoid the necessity for radiation therapy in young children with advancing or incompletely resected PLGG, chemotherapy was created in 1980. On March 16, 2023, the Food and Drug Administration approved the use of trametinib (Mekinist, Novartis) with dabrafenib (Tafinlar, Novartis) in pediatric patients suffering from low-grade glioma (LGG) who require systemic therapy and are at least one year old. Nevertheless, early-stage clinical trials have produced encouraging results that may revolutionize the treatment of LGG in the near future.
CNSC-43. NEUROTRANSMITTER DEPENDENCY UNDERLIES TUMOR GROWTH IN HUMANIZED PEDIATRIC LOW-GRADE GLIOMA MODELS
Authors: Anastasaki Corina , Barakat Rasha , Mu Rui , Koleske Joshua P , Kernan Chloe M , Gao Yunqing , Cobb Olivia M , Gardner Corrine , Shu Hongjin , Nair Lakshmi Ramachandran , Dahiya Sonika , Eberhart Charles G , Phillips Joanna J , Mennerick Steven J , Strahle Jennifer M , Rodriguez Fausto J , Gutmann David H 
Published: November 2024

Abstract
Brain tumors arise in close association with neurons, suggesting that these non-neoplastic cells may be critical stromal drivers of brain tumor initiation and growth. Previously, we have shown that murine low-grade optic glioma formation and progression in the setting of Neurofibromatosis type 1 (NF1) is dictated by neurons and neuronal activity. In these studies, these neuronal dependencies reflected neuronal activity-driven enzymatic cleavage of a growth factor (neuroligin-3) from oligodendrocyte precursors cells (tumor initiation) or neuronal production of a paracrine factor to stimulate T cell support of optic glioma growth (tumor progression). Since neurons typically communicate with other neurons through neurotransmitters, we sought to explore the possibility that neurotransmitters operate to modulate low-grade glioma growth using humanized mouse models of pilocytic astrocytoma (PA). Leveraging single cell RNA sequencing of three independent sets of pediatric PAs, we identified neurotransmitter pathway enrichment in the tumor cells. This neurotransmitter pathway enrichment reflected aberrant expression of specific neurotransmitter receptors, which we confirmed in three independently generated PA tissue microarrays and in five distinct primary PA cell lines grown in vitro. Moreover, this aberrant neurotransmitter receptor expression established differential neurotransmitter PA growth dependencies in vitro. Importantly, interruption of neurotransmitter signaling in human PA xenografts attenuated tumor growth and ERK activation in Rag1-/- mice in vivo. Finally, we discovered crosstalk between neurotransmitter receptor and receptor tyrosine kinase signaling that revealed another target for therapeutic inhibition. Taken together, these findings elucidate a previously unknown neurotransmitter PA growth dependency amenable to therapeutic targeting.
CNSC-46. GLIOBLASTOMA INITIATION, MIGRATION, AND CELL TYPES ARE REGULATED BY CORE BHLH TRANSCRIPTION FACTORS ASCL1 AND OLIG2
Authors: Myers Bianca , Brayer Kathryn , Paez-Beltran Luis , Keith Matthew , Suzuki Hideaki , New Jessie , Anderson Rebekka , Lo Yunee , Mertz Conner , Kollipara Rahul , Borromeo Mark , Lu Richard , Bachoo Robert , Johnson Jane , Vue Tou Yia 
Published: November 2024

Abstract
Glioblastomas (GBMs) are highly aggressive, infiltrative, and heterogeneous brain tumors driven by complex genetic alterations. The neurodevelopmental transcription factors ASCL1 and OLIG2 are highly co-expressed in GBMs. However, their combinatorial roles in regulating the hierarchy and heterogeneity of GBM cells are unknown. Here, we show that induction of somatic mutations in neural progenitor cells lead to the dysregulation of ASCL1 and OLIG2, which then function redundantly and are required for brain tumor formation in a mouse model of GBM. Subsequently, the binding of ASCL1 and OLIG2 to each other’s loci and to downstream target genes then determine the cell types and degree of migration of tumor cells. Notably, single-cell RNA sequencing (scRNA-seq) reveals that a high level of ASCL1 is key in promoting neural stem cell (NSC)/astrocyte-like tumor cell types, which are highly proliferative, migratory, and are marked by upregulation of ribosomal protein, oxidative phosphorylation, cancer metastasis, and therapeutic resistance genes.
CNSC-49. ELUCIDATING THERAPEUTIC POTENTIAL OF USP1 INHIBITION IN DIFFUSE MIDLINE GLIOMAS
Authors: Yadav Monika , Klinestiver Adora , Gibson Garrett , Faisal Syed M , Messinger Dana , Koschmann Carl , Yadav Viveka Nand 
Published: November 2024

Abstract
Diffuse midline gliomas (DMGs) are aggressive childhood brain tumors with the H3K27M mutation in the H3F3A or H3C2 gene. Despite treatment advances, radiotherapy is the only viable option, but 99% of patients die within 1.5-2 years. Therefore, there is an urgent need to identify potential novel therapeutic targets for the treatment of DMGs. Ubiquitin-specific protease 1 (USP1) is a key deubiquitinating enzyme involved in genome integrity, cell cycle regulation, and cell homeostasis. USP1 is overexpressed in various cancers, including gliomas, is linked to poor prognosis. It promotes glioma stem cell (GSC) self-renewal and radio-resistance by regulating ID1 and CHEK1. Our recent findings show that ID1 is crucial for DMG invasion and migration. Inhibiting USP1 suppresses malignant growth, enhances radiation sensitivity, and improves chemotherapy response, highlighting its potential for combined therapies. However, USP1’s role in DMGs and its feasibility as a therapeutic target remain poorly understood. In this study, we investigated USP1 in DMGs for the first time. RNA sequencing revealed high USP1 expression in DMG patient samples and cell lines, directly linked to the H3K27M mutation. Correcting this mutation reduced USP1 expression in DMG cell lines. Pharmacologic inhibition of USP1 with the specific inhibitor SJB3-019A significantly reduced DMG cell proliferation, triggered apoptosis, and altered cell cycle profile. SJB3-019A-mediated USP1 inhibition decreases migration and invasion in multiple patient-derived DMG cell lines. Additional in vitro experiments revealed that USP1 inhibition leads to a significant decrease in the expression of ID1 and pAKT, suggesting the ID1/AKT pathway as a potential mechanism underlying the observed effects. H3K27M-mediated activation of USP1 in DMG is a promising therapeutic target, with inhibition by SJB3-019A reducing tumor aggressiveness by inhibiting invasion and migration. We will next assess SJB3-019A’s efficacy in vivo using genetically engineered isogenic mouse models (GEMM) with DNp53/PDGFRA/H3.3K27M (PPK) alterations and evaluate USP1 inhibition combined with radiation therapy as a potential radiosensitizer in DMGs.
CNSC-58. BIOPROCESSING OF VIABLE SURGICAL PEDIATRIC BRAIN TUMOR SPECIMENS FOR GENOME-GUIDED PERSONALIZED DRUG TESTING
Authors: Nasajpour Emon , Tran Caitlynn , Garcia Cesar , Xing Lulu , Lyle Geoff , Guinle Maria Isabel Barros , Bagley Bryce , Mahaney Kelly , Vogel Hannes , Learned Katrina , Vaske Olena , Grant Gerald , Prolo Laura , Maher Cormac , Petritsch Claudia 
Published: November 2024

Abstract
Novel treatment approaches are urgently needed for pediatric central nervous system (CNS) tumors as they are the leading cause of cancer-related deaths in children. A lack of research materials impedes progress towards developing such therapies. Although various brain cancer biobanks exist, these rarely store viable patient-derived tissue and cells for live cell analyses, including cell fate assays and testing for drug sensitivities. We propose that a biorepository of viable cell dissociates and tissue broadly representing CNS tumor entities overcomes these limitations. From a combination of molecular diagnoses and histopathologic assessment of over 120 samples collected, we generated a biorepository of roughly 35 distinct entities of pediatric CNS tumors in our Stanford neuro-bioprocessing cohort. Based on the Central Brain Tumor Registry of the United States, the proportion of subtypes represented in our cohort match that of the general population with exceptions. We established a standardized bioprocessing pipeline that can be used as a template for tissue collection and model development in the broader disease context and for multiple downstream applications. Our emphasis on cryostorage of viable cells and tissue facilitates ad hoc live cell analyses. In addition to gaining a better understanding of tumor pathophysiology, we attempted a rapid bed-to-bench-to-bedside approach using comparative RNA expression profile analyses in an individual patient’s pilocytic astrocytoma. Novel drug targets were identified by analyzing RNA transcripts that are highly expressed (outliers) compared with a compendium of 12,747 brain and non-brain tumor samples. We validated outliers as drug targets using acute cell isolates, and identified a novel target in recurrent low-grade glioma. These studies illustrate that biobanking of viable patient-derived material enables developing personalized therapies with the goal of improving patient outcomes. As demonstrated here, patient-derived acute cell isolates facilitate identifying drug vulnerability, creating an opportunity for more personalized treatment of patients with CNS tumors.
CNSC-70. THE ROLE OF MAP4K4 IN TUMOR CELL INVASION OBSERVED IN A 3D IN VITRO MODEL OF PEDIATRIC GLIOBLASTOMA
Authors: Garcia Cesar , Nettnin Ella , Arana Sophia , Nguyen Thien , Guinle Maria Isabel Barros , Wilson Christy , Petritsch Claudia K , Bassik Michael C , Prolo Laura M 
Published: November 2024

Abstract
Several CNS tumors such as pediatric glioblastoma (pGBM), diffuse midline glioma (DMG), and medulloblastoma (MB) are characterized by local invasive spread and dissemination of tumor cells into surrounding brain tissue. As identified by our group in a genome-wide CRISPR screen and several others, MAP4K4 is a mediator of cell invasion in several cancers, including glioblastoma and medulloblastoma. Recently, we validated the pro-invasive role of MAP4K4 in a panel of pGBM cell lines. To further validate this finding in the context of pGBM cellular invasion, we performed 3D Matrigel timelapse invasion assays. We performed single- and multi-spheroid encapsulation to track spheroid invasion and cell-to-cell interactions between multiple spheroids. Tumor spheroids were cultured in a round-bottom, non-adherent well plate encapsulated in a Matrigel matrix and treated with a MAP4K4 small molecule inhibitor (PF06260933 dihydrochloride) or had a MAP4K4 knockout performed with Cas9 editing. Cell invasion was recorded over 72 hours and three-dimensional structures were stained for actin and imaged 10 days post-initial seeding. We show that MAP4K4 KO (p ~ 0.00033), small-molecule inhibition in the presence of a TGFB receptor agonist (SRI-011381), (p ~ 0.001) and with drug alone (p ~ 0.013) decreased spheroid invasion and prevented single-cell invasion of pGBM cells (SF188) into the matrix. More surprisingly, abrogation of MAP4K4 prevented individual spheroids in a multi-spheroid co-culture, from forming integrated glioma networks through the formation of tube-like structures in the matrix. Based on our initial findings, it appears that MAP4K4 is necessary for single-cell invasion into a three-dimensional matrix. It also appears that MAP4K4 is required for cell-to-cell connections to form between spheroids in the 3D environment to allow for the formation of higher-ordered and spatially organized structures. Future directions include studying how MAP4K4 allows for the formation of glioma tumor networks in pediatric GBM.