bluuebunny/crossref_metadata_2025_split huggingface dataset:
CNSC-33. GROUP3 MEDULLOBLASTOMA WITH BONE MARROW AND ABDOMINAL CAVITY METASTASIS:A CASE REPORT
Authors: Li Shaoqun , Chen Lian , Kang Haojing , Ye Minting , Lai Mingyao , Cai Linbo 
Published: November 2024

Abstract
Medulloblastoma is an infratentorial primitive neuro-ectodermal tumour, which is commonly occurring in childhood. It often spreads through the cerebrospinal fluid pathways with a very low rate of systemic metastases. Extra-central nervous system metastases have a poor prognosis in medulloblastoma. Here, we reported a case of Group3 medulloblastoma with bone marrow and abdominal cavity metastasis. A 10-year-old girl complained of headache, dizziness, vomiting and nausea. Magnetic resonance imaging(MRI) of the brain showed a large mass in the fourth ventricle and obstructive hydrocephalus. The surgery was performed to remove the mass and ventriculoabdominnal shunt was performed for obstructive hydrocephalus. Histological verification was proven classic medulloblastoma and next-generation sequencing confirmed molecular group of Gruop3 with MYC amplication. Radiotherapy was subsequently performed one month after the surgery. During the radiotherapy, brain MRI showed metastasis on the surface of the brain, which confer a poor prognosis. After the radiotherapy According to the therapeutic schedule, She would accept chemotherapy one month after the radiotherapy. But She suffered severe bone marrow suppression manifested as anaemia and thrombocytopenia, which can not be improved by medication and blood transfusion. A bone marrow aspiration was subsequently performed, and bone marrow smear showed large numbers of tumor cells at high magnification and was lack of normal hematopoietic cells. The girl was deteriorating rapidly with jaundice, ascites, hepatosplenomegaly and pancreatitis after the bone marrow aspiration. We found a lot of tumor cells in the bleeding tendency ascites and finally confirmed bone marrow and abdominal cavity metastasis concurrently. Eventually, She died less than a month after the metastasis and the overall survival was only 6 months. This typical case demonstrated severe bone marrow suppression of unknown origin should caused alarm and be performed bone marrow aspiration as soon as possible. The prognosis of medulloblastoma with extra-central nervous system metastases is poor and people may die in months.
CNSC-44. TARGETING OF THE YAP/TAZ-TEAD AXIS DIMINISHES VIABILITY AND DIFFERENTIATION POTENTIAL IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Macias Jorge Luis Jimenez , Oh Se-Yeong , Hu Zhengang , Yin Kevin , Sele Nisan , Boon Nikki , Sing Anson , Sloan Steven A , Read Renee D 
Published: November 2024

Abstract
Pediatric high-grade gliomas (pHGGs) are invasive and fast-growing brain malignancies. They account for up to 40% of all brain tumor-related deaths in childhood. Genetic alterations that characterize these gliomas include H3 onco-histone mutations and genetic alterations in receptor-tyrosine kinases (RTKs), including amplification, mutation, and gene fusions in RTKs. However, direct targeting with tyrosine kinase inhibitors (TKIs) has shown at best partial responses in patients due to the molecular heterogeneity within these tumors and the lack of pharmaceutical penetration into the central nervous system (CNS). Thus, alternative therapeutic approaches to treat pHGGs are urgently needed. The YAP/TAZ transcription factors, which cooperate with TEAD co-factors to promote target gene expression, orchestrate stem-cell fate decisions and proliferation downstream of growth factor signaling pathways, such as RTKs. We observed that YAP expression is upregulated in RTK mutant and H3 mutant pHGGs. Depletion of YAP via RNAi methods decreased proliferation, inhibited pHGG stem cell self-renewal, and induced apoptosis of pHGG cells. Use of Verteporfin (VP), a FDA-approved YAP/TAZ small molecule inhibitor, mimicked the effects seen by YAP genetic depletion. Using an in vitro human cortical organoid-tumor model in which tumor cells are engrafted to human brain cortical organoids, we screened for responses in tumor cells and in non-tumor cells in the neural microenvironment upon VP treatment, using single-cell RNA-sequencing and immunofluorescence to visualize responses. These organoid models offer improved models for modeling how the neural CNS microenvironment shapes responses of tumor cells to YAP/TAZ inhibition and VP treatments. Results from our work showing that YAP/TAZ-TEAD inhibition is a promising therapeutic avenue for management of pHGGs will be presented. Further pre-clinical work will follow to correlate observation and understand the therapeutic efficacy of YAP/TAZ-TEAD inhibition for pHGG treatment.
CNSC-59. EPIGENETIC POTENTIATION OF ANTI-TUMOR IMMUNE RESPONSES USING VIRAL MIMICRY IN GLIOMAS
Authors: Chandar Jay , Seetharam Deepa , Desgraves Jelisah , Ramsoomair Christian , Castro Jesus , Hudson Anna , Govindarajan Vaidya , Zhang Yong , Sonabend Adam , Valdez Mynor Mendez , Maric Dragan , Govindarajan Vasundara , Rivas Sarah , Lu Victor , Alvarado Alexandra , Tiwari Ritika , Sharifi Nima , DeMarino Catherine , Johnson Kory , De La Fuente Macarena , Nasany Ruham Alsiekh , Noviello Teresa , Ivan Michael , Komotar Ricardo , Iavarone Antonio , Nath Avindra , Heiss John , Ceccarelli Michele , Chiappinelli Katherine , Figueroa Maria , Bayik Defne , Shah Ashish 
Published: November 2024

Abstract
Clinical trials using immune checkpoint inhibition(ICI) have traditionally failed in glioblastoma (GBM). Viral mimicry, which augments anti-tumor immune responses and sensitizes response to immunotherapy in other cancers, involves the epigenetic activation of endogenous retroelements (REs). REs are silenced via the HUSH complex and H3K9me3. This process is mediated by ZNF638. We aimed to elucidate the role of viral mimicry in enhancing ICI through epigenetic reprogramming of the HUSH complex. We demonstrated that RE expression among 48 superfamilies inversely correlated with ZNF638 expression in gliomas, based on data from 71 newly-diagnosed GBMs. Using transcriptional deconvolution, we showed ZNF638 negatively correlates with innate antiviral immune response signatures(TLR3)(RTLR3=-0.300,pTLR3=0.00006). We validated these in-silico results in pure glioma cell lines, patient-derived GBM neurospheres, and syngeneic murine models. ZNF638 knockdown induced intracellular RE-mediated dsRNA signaling cascades via RIG-I and TLR3. This knockdown significantly increased PD-L1 expression(p&lt;0.001), reduced H3K9 trimethylation, and enhanced cytoplasmic dsRNA accumulation in glioma cell lines. In patient-derived GBM neurospheres, ZNF638 knockdown upregulated immune and antiviral programs. Additionally, knockdown resulted in upregulation of several endogenous repeat elements (Alu, LTR). Single-cell RNA sequencing showed ZNF638 clustering in neural progenitor-like and oligodendrocyte-like cells, with increased retroelement expression in low ZNF638 cells. Tumors with lower ZNF638 expression showed increased CD8+ populations. Bulk RNA sequencing deconvolution revealed that ZNF638 is linked to reduced CD8 and DC infiltration in gliomas (RCD8=-0.202,RDC=-0.198;pCD8=8.79E-06,pDC=1.34E-05). In immunocompetent mice, ZNF638 KO and PD-L1 inhibition significantly improved survival (mOS &gt;50 days, p&lt;0.0001) and reduced tumor volume (p&lt;0.001). Analysis of cohorts from multiple cancer types treated with anti-PD1 therapy demonstrated that ZNF638 expression predicts therapeutic response and overall survival. Our findings suggest that epigenetic reprogramming through HUSH inhibition may potentiate immunotherapy for GBM.
CNSC-60. SYNERGISTIC IMMUNOMODULATION THROUGH DUAL ANTIBODY THERAPY TARGETING CD47 AND CD24 FOR ENHANCED ANTITUMOR IMMUNITY IN GLIOBLASTOMA
Authors: Ha JongHoon , Wang Yifan , Dong Shiyan , Kim Betty Y S , Jiang Wen 
Published: November 2024

Abstract
Tumor cell phagocytosis by antigen-presenting cells (APCs) plays a pivotal role in fostering antitumor immunity. However, glioblastoma, known for its evasive strategies, exploits key phagocytosis checkpoints, including CD47, CD24, and beta-2-microglobulin. While mono-treatment targeting CD47 blockade has shown some antitumor responses in glioma, prolonged tumor-suppressing ability and significant extension of survival remain elusive. In this study, we combine anti-CD47 and anti-CD24 antibody treatments, unveiling a synergistic effect in promoting tumor cell phagocytosis. This enhanced phagocytosis profile triggers the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway in APCs, thereby facilitating efficient T cell priming. This orchestrated interplay between innate and adaptive antitumor immunity not only attenuates glioblastoma growth and extends overall survival. These findings illuminate a promising avenue for harnessing phagocytosis modulation as a strategic approach to treat challenging tumors equipped with multiple immune checkpoints.
CNSC-62. DIFFERENTIAL SURVIVAL IMPACT OF TRASTUZUMAB DERUXTECAN IN HER2-POSITIVE VERSUS HER2-LOW BREAST CANCER PATIENTS WITH BRAIN METASTASES
Authors: Ranjan Tulika , Podder Vivek , Bardhan Mainak , McCracken Andrea , Hurmiz Charlie , Mahtani Reshma L , Ahluwalia Manmeet Singh 
Published: November 2024

Abstract

BACKGROUND
Brain metastases (BM) in breast cancer (BC) present significant treatment challenges, with varying outcomes based on HER2 expression. There is limited real-world evidence of outcomes with the use of trastuzumab deruxtecan (T-DXd) on survival in patients (pts) with HER2-low and HER2-positive (HER2+) MBC with BM.

METHODS
We conducted a retrospective cohort study using data from seven US-based health systems within the Guardian Research Network (GRN). We included pts treated with T-DXd from December 2019 to December 2023, classified as HER2-low (IHC 1+ or IHC 2+/HER2 FISH non-amplified) or HER2+ (IHC 3+ or HER2+ with FISH amplified). Survival analysis was performed using Kaplan-Meier curves and the log-rank test.

RESULTS
125 pts with BCBM treated with T-DXd were included in the final analysis, of which 70 (56%) were HER2+ and 55 (44%) were HER2-low. The median age at BM diagnosis was 60.5 years (range 21.6 to 87.1 years). HER2 low pts had a higher prevalence of ER+ disease than HER2+ pts (81.9% vs. 55.7%, p=0.01). Most of these pts (≥75%) had received multiple prior lines of therapy. HER2+ pts with BM had a median overall survival (mOS) of 9.3 months (95% CI: 6.79-11.88), significantly longer than 4.3 months (95% CI: 1.89-6.82) in HER2-low pts (p &lt; 0.001). At 6 months, OS for HER2+ pts with BM was 40% compared to 25% in HER2-low pts. At 12 months, OS for HER2+ pts was 20% compared to 10% in HER2-low pts.

CONCLUSIONS
This study represents the largest real-world evidence to date on the effectiveness of T-DXd in treating BM from breast cancer. HER2+ BCBM exhibited longer mOS and 12-month survival rates than pts with HER2-low disease, suggesting HER2 expression is crucial in determining T-DXd’s effectiveness. Future research should explore combination therapies and identify predictive biomarkers to optimize treatment strategies through clinical trials.
CNSC-63. THE COMPLEX RELATIONSHIP BETWEEN GENETIC ETIOLOGIES OF GLIOBLASTOMA AND PATIENT SURVIVAL: A RETROSPECTIVE ANALYSIS
Authors: Nashman Zarrar , Ullah Tasfiq , Hoffman Pauline 
Published: November 2024

Abstract
Data Analysis was done using the NIH GDC Data Portal with glioblastomas being the only selected primary diagnosis (n=1381). Kaplan Meier plots were generated for various genes and mutations and the survival data was compared between carriers and non-carriers. Median survival was 14 months post diagnosis when all patients are clustered together. Survival Plot of patients with IDH1 R132H mutation (n=35) vs without IDH1 R132H mutation (n=538) reveals that carriers have longer survival compared to non-carriers. The next seven cases with the highest number of specific mutations were a variation between TP53 and EGFR, both genes implicated in various cancers due to their roles in cancer suppression and proliferation respectively. The ten most frequent specific mutations observed were all missense mutations. Furthermore, patients without PTEN mutations (n=98) had better survival compared to patients who had PTEN mutations (n=623), particularly observed after one year. For specific mutations, IDH1 R132H was detected in 35 patients. All other specific mutation groups had less than 30 patients, therefore, a larger cohort would be beneficial in understanding the survival outcomes of various specific mutations. In terms of total number of mutations per gene, PTEN had the highest followed by TP53 and EGFR. In understanding the survival data, the best target for therapies can be narrowed, regardless of the increasingly evident polygenic pathology of glioblastoma.
CNSC-65. ELECTROPHYSIOLOGICAL AND SPATIAL TRANSCRIPTOMIC PROFILING OF GLIOMA-INFILTRATED CORTEX REVEAL LAYER SPECIFIC ALTERATIONS
Authors: Daniel Andy , Aabedi Alexander , Umbach Gray , Negussi Mikias , Herr Sanjeev , Gonzales Cesar Nava , Krishna Saritha , Kaur Jasleen , Fazzari Elisa , Nejo Takahide , Raleigh David , Bhaduri Aparna , Joseph Kevin , Ravi Vidhya , Brang David , Hervey-Jumper Shawn 
Published: November 2024

Abstract
Specialized neocortical circuits selectively organize neuronal signals and encode features of cognitive processing via local and long-range connections. Since glioma-infiltrated cortex is excitable and can participate in cognitive processing, the underlying laminar structure and functionality may still be preserved despite infiltration. Moreover, since glioma cells remodel existing neural circuits and microenvironmental factors drive invasion and proliferation, neuron-glioma interactions may demonstrate layer specificity. As glioma-infiltrated cortex remains poorly understood, we sought to characterize these regions using electrophysiological, structural, and genomic approaches. We assessed the power spectra of normal-appearing and glioma-infiltrated cortex using magnetoencephalography and subdural high-density electrode arrays. Immunohistochemistry of formalin-fixed paraffin-embedded (FFPE) samples of infiltrated cortex enabled protein-level neuronal and glioma identification to determine laminar preservation and spatial invasion patterns. Spatial transcriptomics of FFPE tissues and single-nucleus RNA-sequencing were used to identify cell populations, genomic alterations, and cell-cell communication within and across samples at testing and validation sites across the US and Europe. Increased delta range (1-4 Hz) power and decreased power in the beta range (12-20 Hz), activity thought to originate from deep layers, were identified as robust features of infiltrated cortex which were maintained across glioma subtypes (n = 139 patients) and preserved in a validation cohort (n = 8 patients). Immunohistochemistry revealed greater tumor burden within deep laminae regardless of glioma subtype (n = 20 samples). Tissue proteomics and spatial genomics analyses performed using glioma-infiltrated cortical samples (n = 10 samples; 29,011 spots) confirmed routine preservation of laminar organization, greater tumor burden in deep layers, as well as layer specific differences in glioma-related expression programs. Cell-cell communication analyses demonstrated increased interactions in glioma-infiltrated cortex across layers. These findings suggest that laminar structure may be preserved in glioma-infiltrated cortex while remodeling of neural circuits alters spatiotemporal activity in a predictable manner and support a deep to superficial invasion pattern. Thus, investigating glioma infiltration using layer-centric approaches may facilitate novel insights into neuron-glioma interactions.
CNSC-67. ANATOMICAL ORGANIZATION AND ELECTRICAL PROPERTIES OF GLIOMA-INNERVATING NEURONS
Authors: Hsieh Annie , Ganesh Sanika , Kula Tomasz , Irshad Madiha , Ferenczi Emily , Wang Wengang , Chen Yi-Ching , Hu Song-Hua , Li Zongyu , Joshi Shakchhi , Haigis Marcia , Sabatini Bernardo 
Published: November 2024

Abstract
Gliomas are the most common malignant primary brain tumors and are often associated with severe neurological deficits and mortality. Unlike many cancers, gliomas rarely metastasize outside the brain, indicating a possible dependency on the brain’s unique microenvironment. Recent discoveries have highlighted the existence of neuron-glioma synapses, suggesting that glioma cells depend on neuronal inputs and AMPA-receptor-mediated glutamate signaling for their proliferation. Yet, the specific locations and properties of the neurons that innervate gliomas remain elusive. In this study, we utilized transsynaptic tracing with a pseudotyped, glycoprotein-deleted rabies virus to specifically infect TVA and glycoprotein-expressing human glioblastoma cells in an orthotopic xenograft model. This approach allowed us to identify the presynaptic neuronal inputs to the glioma. Comprehensive whole-brain mapping and quantification revealed that these glioma-innervating neurons, predominantly glutamatergic, exhibit a consistent input pattern influenced by the tumor’s locations and engage selective neuromodulatory pathways. Notably, the electrophysiological properties of these neurons mirror those innervating the cortex in vivo. Our study introduces a novel method for investigating glioma-innervating neurons and reveals that these neurons are consistently integrated into the glioma network, displaying distinctive location-dependent neuromodulatory patterns. Our findings offer a promising scaffold for future interventions aimed at disrupting these critical neuronal inputs, potentially redefining therapeutic strategies against brain tumors.
CNSC-68. SEX DIFFERENCES IN GLYCINE BIOSYNTHESIS DRIVE RESPONSES TO COMBINED NUTRIENT DEPRIVATION AND PHARMACOLOGICAL INHIBITION IN PEDIATRIC HGG
Authors: Lu Jianyun , Marquez Camryn , Cho Kevin , Patti Gary , Rubin Joshua , Ippolito Joseph 
Published: November 2024

Abstract
In children and adults, high-grade gliomas (HGGs) are the most common and deadly primary brain malignancies. Generally, male HGGs occur at higher incidence and demonstrate more rapid proliferation, resulting in shorter overall male survival. Obscurity of molecular mechanisms driving this phenomenon prevents implementation of clinically effective treatments. Recently, a positive correlation between HGG cellular proliferation and metabolic reprogramming toward glycine biosynthesis was identified. By analyzing pediatric and adult HGG patient data, we discovered significantly worse outcomes unique to pediatric males bearing upregulation of serine and glycine biosynthesis transcripts. Previously, we have identified differential flux of glucose into serine and glycine biosynthesis drives sex differences in lung cancer. Therefore, we sought to confirm and target this paradigm in our NF1-/- DNp53 model of HGG. By performing metabolic tracing with [13C]-labeled glucose in male and female cells, we identified higher enrichment of [13C]-labeled serine and glycine in male cells relative to female cells. Through Western blotting, we identify male-specific upregulation of serine and glycine biosynthetic pathway enzymes in transformed cells, supporting our labelling results. Next, we sought to determine if inhibition of de-novo serine and glycine biosynthesis was similarly sex-biased. Utilizing serine-and-glycine-deprived media conditions, we identified a male-biased decrease in proliferation following pharmacological inhibition of de-novo serine and glycine biosynthesis. More precisely, in the absence of exogenous glycine, we discovered that inhibition of de-novo synthesis of glycine from serine drove male-specific decreases in proliferation. Additionally, we identified that transformed female cell robustness against inhibition of glycine biosynthesis is driven by the uptake of exogenous nucleotide precursors. These data confirm that sex differences in de-novo glycine biosynthesis drive sex differences in HGG cellular proliferation. As well, our work suggests that dietary restriction of serine and glycine, in-combination with pharmacological inhibition of de-novo glycine biosynthesis, represents a novel treatment paradigm.
STEM-01. SHARED ASTROCYTE-LIKE GLIOMA STEM CELLS DRIVE HETEROGENEITY AND IMMUNE DYNAMICS IN ADULT-TYPE DIFFUSE GLIOMAS
Authors: Zaman Ashraf , Muskovic Walter , Holton Emily , Pandya Madhavi , Zekanovic Rachael , Chin Venessa , Lam Eric , Moutinho Catia , Yeung Jacky , Teo Charlie , Sughrue Michael , Powell Joseph 
Published: November 2024

Abstract
Adult-type diffuse gliomas present significant treatment challenges due to their complex cellular composition and evolving nature. Understanding this heterogeneity is critical for the development of effective, targeted therapies. We conducted single-cell and single-nucleus RNA sequencing on a unique cohort of 66 tumours (single surgery) and 54 paired samples (two surgeries). This comprehensive dataset of approximately 900,000 cells allows us to dissect conserved cellular landscapes and dynamic evolution across diverse glioma subtypes. Using a novel phylogeny-based approach, we identified an astrocyte-like glioma stem cell (GSC) as the root of diverse glioma lineages. This discovery transforms our understanding of glioma development, pinpointing the GSC as a potential therapeutic target. The GSC’s similarity to healthy adult neural stem cells provides clues as to the origin of glioma heterogeneity and the shared basis of intratumoural diversity. Our analysis uncovered a shared cellular architecture across astrocytomas, oligodendrogliomas, and glioblastomas (GBMs). This architecture encompasses seven recurring malignant cell states: neuro-, oligo-, neuro-oligo-lineage, cycling (G1/S, G2/M), hypoxia-associated, and a quiescent astrocyte-like GSC. Importantly, these cell state proportions vary significantly between glioma subtypes. Additionally, we demonstrate that GBMs display substantially higher T-cell and myeloid cell infiltration than IDH-mutant gliomas. Counterintuitively, this correlates with a poorer prognosis, implying profound T-cell dysfunction and intricate myeloid cell-tumour interactions. Longitudinal analysis further highlights the dynamic nature of glioma cell populations and the immune landscape. Subtype-specific T-cell and myeloid gene expression profiles were identified, including potential targets such as PARD6G (GBM) and CXCL13 (IDH-mutant-astrocytoma), laying the groundwork for tailored immunotherapies and prognostic biomarkers. This study presents a comprehensive model of glioma heterogeneity and evolution. The model reveals a shared astrocyte-like GSC that fuels cellular diversity, coupled with distinct, dynamic immune landscapes in different glioma subtypes. These findings hold extraordinary potential for developing transformative treatment strategies. Future research functionally validating the GSC and its impact on tumour dynamics will be essential for translating these insights into improved patient outcomes.