bluuebunny/crossref_metadata_2025_split huggingface dataset:
CCRG-04. RIBOCICLIB RESPONSIVE MENINGIOMA IN THE TREATMENT OF BREAST CANCER
Authors: Schipani Elke , Cathcart-Rake Elizabeth , Gilbertson Julie , Lanzino Giuseppe , Sener Ugur 
Published: November 2024

Abstract

BACKGROUND
Meningiomas are the most common primary intracranial tumors, typically managed with surgical resection and/or radiation therapy. Systemic therapy options are limited and reserved for cases refractory to conventional interventions. Cyclin dependent kinase (CDK) proteins are key cell cycle regulators. CDK inhibitors are clinically available, approved for treatment of breast cancer and in clinical trials for meningioma.

METHODS
We present a case where a patient with incidentally-discovered intracranial meningioma undergoing CDK inhibitor therapy with ribociclib for breast cancer experienced a radiographic response.

RESULTS
A 73-year-old female was diagnosed with estrogen receptor (ER) positive, progesterone receptor (PR) positive, HER2 negative metastatic invasive ductal carcinoma of the breast. She was treated with estrogen receptor antagonist fulvestrant and CDK 4/6 inhibitor ribociclib. MRI of the brain performed for disease staging demonstrated an extraaxial, dural-based, homogenously enhancing mass along the left posterior petrous ridge consistent with a meningioma. Two-month interval scan demonstrated a marginal decrease in size of the mass (15.6x18.3 mm to 15.4x17.5 mm). Systemic disease related to breast cancer concurrently improved. Two years later, with ongoing fulvestrant and ribociclib therapy, a repeat MRI brain demonstrated further decrease in size of the meningioma (13.4x16.8 mm).

CONCLUSIONS
Hormonally-directed therapies previously demonstrated limited benefit for meningiomas despite PR/ER positivity reported for these tumors. However, CDK 4/6 inhibitors abemaciclib and ribociclib have demonstrated activity in treatment of recurrent grade 2/3 meningiomas. The radiographic response noted in our case suggests there may be a role for systemic therapy even in treatment-naive cases that may not be amenable to surgical resection or radiation therapy.
CSIG-08. AGGRESSIVE HIGH-GRADE NF2 MUTANT MENINGIOMAS DOWNREGULATE ONCOGENIC YAP SIGNALING VIA THE UPREGULATION OF VGLL4 AND FAT3/4
Authors: Parrish Abigail , Arora Sonali , Thirimanne H Nayanga , Rudoy Dmytro , Schmid Sebastian , Sievers Philipp , Sahm Felix , Holland Eric , Szulzewsky Frank 
Published: November 2024

Abstract
Meningiomas are the most common primary brain tumors in adults. Although generally benign, a subset is of higher grade, shows aggressive growth behavior and recurs even after multiple surgeries. Around half of all meningiomas harbor inactivating mutations in NF2. While benign low-grade NF2 mutant meningiomas exhibit few genetic events in addition to NF2 inactivation, aggressive high-grade NF2 mutant meningiomas frequently harbor a highly aberrant genome. We and others have previously shown that NF2 inactivation leads to YAP1 activation and that YAP1 acts as the pivotal oncogenic driver in benign NF2 mutant meningiomas. Using bulk and single-cell RNA-Seq data from a large cohort of human meningiomas, we show that aggressive NF2 mutant meningiomas harbor decreased levels YAP1 activity compared to their benign counterparts. Furthermore, decreased expression levels of YAP target genes are significantly associated with an increased risk of recurrence. We then identify the increased expression of the YAP1 competitor VGLL4 as well as the YAP1 upstream regulators FAT3/4 as a potential mechanism for the downregulation of YAP activity in aggressive NF2 mutant meningiomas. High expression of these genes is significantly associated with an increased risk of recurrence. In vitro, overexpression of VGLL4 resulted in the downregulation of YAP activity in benign NF2 mutant meningioma cells, confirming the direct link between VGLL4 expression and decreased levels of YAP activity observed in aggressive NF2 mutant meningiomas. Our results shed new insight on the biology of benign and aggressive NF2 mutant meningiomas and may have important implications for the efficacy of therapies targeting oncogenic YAP1 in NF2 mutant meningiomas.
CSIG-10. DEFINING THE ROLE OF EZHIP ON CHROMOSOMAL INSTABILITY IN EPENDYMOMA
Authors: Faruck Lukmanul Hakkim 
Published: November 2024

Abstract
Diffuse Midline Gliomas (DMGs) are highly aggressive pediatric cancers with no effective treatments. Over 80% of DMGs harbor histone mutations, particularly H3.1 K27M, H3.3 K27M, and H3.3 G34R/V. These mutations impair the function of the Polycomb Repressive Complex 2 (PRC2), leading to reduced levels of H3K27me3. Overexpression of the EZHIP has been identified in ependymomas and DMGs. EZHIP overexpression is marked by widespread H3K27me3 loss and is mutually exclusive with histone mutations. EZHIP overexpression mimics the effects of the H3K27M mutation by reducing H3K27me3 levels. It is believed to inhibit the catalytic activity of EZH2 by binding to its SET domain, similar to the K27M mutant. Expression of EZHIP is tightly regulated and typically absent in most cell types. The transcriptional regulation of EZHIP is poorly understood; however, promoter hypermethylation is likely involved in regulating its expression. We investigate EZHIP’s role in DMG tumorigenesis, focusing on its regulation, impact on histone modifications, and chromosomal stability. Initial analyses have revealed transcription factor binding sites within the EZHIP promoter, including EGR2, SOX2, and ICP4, indicating that various transcription factors and viral infections might directly affect EZHIP expression. Utilizing RNA-Seq, we have identified both shared and unique transcriptomic alterations in DMG cells related to EZHIP expression and H3.3 K27M mutations. To study the role of EZHIP in tumorigenesis, we developed a mouse model expressing EZHIP-HA p2A PDFGB in RCAS-Nestin TVA mice. EZHIP expression induces high-grade tumors and significantly reduces survival. Our ongoing research suggests that EZHIP functions similarly to H3.3 K27M mutations in driving tumor growth, not only by reducing K27me3 but also through chromosomal missegregation. We aim to elucidate the full extent of EZHIP’s role in epigenetic control, histone post-translational modifications, chromosomal accessibility, and instability. Our findings will provide critical insights into the mechanisms underlying DMG tumorigenesis and potential therapeutic targets.
CSIG-15. ACROLEIN INDUCES THE MIR-30A-5P/NCAM AXIS VIA THE AKT/GSK3Β/Β-CATENIN PATHWAY, PROMOTING GLIOMA PROGRESSION
Authors: Chen Pin-Yuan , Liu Pei-Yu , Huang Chiungyin , Wang Hsiang-Tsui 
Published: November 2024

Abstract
Glioblastoma (GBM), the most aggressive brain tumor, exhibits resistance to treatment and thrives in low-oxygen (hypoxic) environments, leading to the accumulation of reactive oxygen species (ROS). Hypoxia activates the hypoxia-inducible factor (HIF)-1α pathway, enhancing tumor malignancy. Acrolein, a reactive aldehyde produced during lipid peroxidation in hypoxia, induces toxicity through DNA damage, inflammation, mitochondrial dysfunction, and oxidative stress. Our previous study found elevated acrolein levels in hypoxic glioma cells and linked acrolein-induced DNA damage (Acr-dG) with poor GBM prognosis. However, the role of acrolein in GBM progression remains unclear. This study aims to elucidate the impact of acrolein on GBM. In vitro experiments demonstrated acrolein production under hypoxia, which increased glioma cell migration and spheroid formation. RNA sequencing identified five affected pathways: cell adhesion molecules, PI3K-AKT signaling, ECM-receptor interaction, MAPK signaling, and neuroactive ligand-receptor interaction. Acrolein downregulated NCAM (neural cell adhesion molecule) via the miR-30a-5p-AKT-GSK3β/β-catenin axis in GBM cell lines and patient-derived cells. Overexpressing NCAM reduced cell migration and spheroid formation. Lower NCAM levels in GBM tissues correlated with poor patient survival. This study suggests the potential of NCAM as a therapeutic target for GBM and provides insights into early detection and treatment strategies for this malignancy.
CSIG-18. YAP/TAZ TARGET GENES MAY DETERMINE THE SELF-RENEWAL AND SURVIVAL OF GLIOBLASTOMA STEM CELLS
Authors: Ishan Mohamed , Oh Se-Yeong , Young Elizabeth , Hu Zhengang , Read Renee D 
Published: November 2024

Abstract
Glioblastoma, a neoplasm arising from neuro-glial stem/progenitor cells, is the most aggressive and lethal form of brain cancer, with a median survival of 14 months. Despite intensive treatments like surgery, radiation, and chemotherapy, recurrence is inevitable, underscoring the urgent need for new treatment strategies. Progress is limited by an incomplete understanding of the biological mechanisms that drive glioblastoma formation and progression, hindering the development of effective therapies. Key molecular pathways, particularly the receptor tyrosine kinases, such as EGFR, and their effector pathways play a critical role in the initiation and maintenance of glioblastoma. Our lab’s research using patient-derived glioblastoma neurospheres and mouse models has shown that the transcriptional co-activators YAP and TAZ are overexpressed downstream of EGFR activity in EGFR-amplified or mutant glioblastoma tumors. YAP/TAZ proteins interact with the TEAD family DNA-binding proteins to promote expression of transcriptional target genes, including SOX2, C-MYC, and EGFR itself in glioblastoma, creating a positive feedback loop that enhances tumor stem cell renewal, proliferation, and survival. Furthermore, our research has demonstrated that inhibiting YAP/TAZ activity with the drug Verteporfin induces apoptosis and promotes growth arrest in patient-derived EGFR-amplified/mutant glioblastoma models. Our findings highlight YAP/TAZ-TEAD as key mediators of glioblastoma stem cell (GSC) self-renewal and survival. Ongoing experiments aim to identify tumor cell-specific YAP/TAZ-TEAD transcriptional target genes predictive of response to YAP/TAZ inhibition in GSCs within EGFR-amplified glioblastomas. Our research seeks to uncover the epigenetic basis of YAP/TAZ dependencies and to determine which genes and cellular processes are critical for tumor stem cell survival, tumor progression, and sensitivity to YAP/TAZ inhibition. These target genes could serve as biomarkers for predicting therapeutic response to YAP/TAZ inhibitors in glioblastoma.
CSIG-24. BRAIN MICROENVIRONMENT-DEPENDENT NEURODEVELOPMENTAL LINEAGE PLASTICITY PROMOTES ADAPTATION TO ONCOGENE INHIBITION IN MALIGNANT GLIOMAS
Authors: Cadet Dimitri , Andrasz Cassidy , Bayley Nicholas , Fazzari Elisa , Fernandez Elizabeth , Okobi Quincy , Graeber Thomas , Bhaduri Aparna , Cloughesy Timothy , Nathanson David 
Published: November 2024

Abstract
Phenotypic plasticity drives non-genetic tumor adaptation in response to various microenvironmental and therapeutic pressures, consequently promoting tumor heterogeneity and progression. In malignant gliomas, the intrinsic and extrinsic mechanisms underlying phenotypic lineage plasticity and its contribution to drug resistance remain unclear. The epidermal growth factor receptor (EGFR) is frequently altered in glioma and serves as a critical regulator of normal radial glia (RG) cells – multipotent progenitors that give rise to cortical neurons and glia in the developing brain. Here, through interrogation of a large panel of diverse glioblastoma (GBM) patient-derived gliomaspheres and orthotopic xenografts, we find that enrichment of RG-like cells is significantly correlated with responses to pharmacological ablation of EGFR, highlighting EGFR as a crucial lineage survival factor for a population of malignant RG-like cells in GBM. Single-cell RNA sequencing and quantitative proteomics reveal that adaptation to EGFR inhibition is linked to a temporal contraction in RG-like cells and concomitant increase in lineage-restricted neuronal and oligodendrocyte progenitor (NPC/OPC)-like states exclusively in the orthotopic brain environment. This lineage transition is coupled to heightened RAS signaling gene expression programs and sustained activation of MAPK signaling, despite robust and durable inhibition of EGFR activation. Furthermore, constitutively active MEK – but not AKT – is sufficient to rescue tumor proliferation under EGFRi, suggesting that the brain microenvironment modulates RAS-MAPK oncogenic signaling to drive lineage transitions following EGFR blockade. Collectively, these results highlight a critical link between oncogenic signaling and neurodevelopmental lineage plasticity in malignant gliomas, presenting a compelling therapeutic opportunity to block tumor cell state transitions for more durable tumor responses in the native glioma tumor microenvironment.
CSIG-26. TARGETING EPIGENETIC DYSREGULATION AND ADAPTIVE RESISTANCE MECHANISMS IN DIPG/DMG
Authors: Xin Eric , Zhong Xiaowen , Huang Chris , Lu Richard 
Published: November 2024

Abstract
Diffuse intrinsic pontine gliomas (DIPG/DMG) are devastating pediatric brain tumors with very limited treatment options and a uniformly fatal prognosis. The recurrent histone H3K27M mutation in DIPG disrupts epigenetic regulation, leading to the hypothesis that this mutation-induced dysregulation creates a vulnerability to epigenetic targeting. We conducted a screening of compounds targeting epigenetic enzymes to identify potential inhibitors of patient-derived DIPG cell growth. High-throughput screening identified chaetocin, a fungal metabolite, as a potent inhibitor of DIPG cell growth. Chaetocin treatment selectively decreased proliferation and increased apoptosis in DIPG cells, significantly extending survival in DIPG xenograft models while restoring H3K27me3 levels. The loss of the H3K9 methyltransferase SUV39H1 also inhibited DIPG cell growth. Transcriptomic and epigenomic profiling showed that SUV39H1 loss or inhibition downregulated stemness and oncogenic networks, including growth factor receptor signaling. However, D2 dopamine receptor (DRD2) signaling adaptively upregulated, conferring resistance. Combining chaetocin with the DRD2 antagonist ONC201 or radiotherapy synergistically enhanced antitumor efficacy. This study reveals a therapeutic vulnerability in DIPG cells by targeting the SUV39H1-H3K9me3 pathway and compensatory signaling loops. Combining SUV39H1-targeting chaetocin with other agents, such as ONC201, may offer a new strategy for effective DIPG treatment. The findings suggest that chaetocin, by targeting and suppressing the H3K9me3 methyltransferase SUV39H1, inhibits DIPG tumor growth by downregulating stemness-related genes and growth factor signaling pathways. Overall, the study highlights a new therapeutic vulnerability in DIPG through the SUV39H1-H3K9me3 epigenetic pathway and compensatory signaling loops, suggesting an effective treatment strategy for DIPG.
CSIG-32. MODULATION OF HALLMARKS OF GLIOBLASTOMA MULTIFORME BY BIOACTIVE PHYTOCHEMICALS: A PRECLINICAL MECHANISTIC EVALUATION
Authors: Bobak Adam , Steves Michael , McMahon Emily , Spahiu Matea , Rahman Austin , Casarcia Nicolette , Bishayee Anupam 
Published: November 2024

Abstract
Glioblastoma multiforme (GBM) is an aggressive malignancy with extensive neovascularization, an immunosuppressive tumor microenvironment, and high recurrence rates. Bioactive plant secondary metabolites (phytochemicals), many from fruits and vegetables, have been extensively studied for GBM prevention and treatment. The objective of this study is to determine the effects of phytochemicals on GBM hallmarks and associated molecular mechanisms of action through evaluation of in vitro and in vivo studies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to collect articles using PubMed, ScienceDirect and Scopus. While 1,344 articles were screened, 115 in vitro and 36 in vivo studies met our inclusion criteria. The Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) review of bias tool assessed in vivo study bias. In vitro, 49 alkaloids, 10 phenolics, 2 sulfur- compounds, and 5 terpenoids modulated GBM hallmarks of cell growth, invasion, cell cycle progression, neovascularization, and apoptosis. The PI3K/Akt/mTOR pathway was suppressed by 13 phytochemicals. Apoptosis was induced by 15 phytochemicals activating caspase-3, whereas 11 compounds inhibited Bcl-2. Cell cycle modulation occurred through decreased cyclin-dependent kinases and increased p53, p21, and p27. In vivo, 17 alkaloids, 5 phenolics, 2 sulfur-compounds, and 2 terpenoids had effects on GBM hallmarks. Invasion and neovascularization were inhibited through MMP, HIF-1α, and VEGF modulation. Six phytochemicals induced apoptosis in vivo through caspases and Bcl-2. Utilizing the SYRCLE review of bias tool, the average score quality of animal studies is 10% with many indicators of bias unclear. Various phytochemicals show promise to prevent and treat GBM due to their effects on numerous GBM hallmarks. Study limitations include the inclusion of literature reporting effects of single agents and lack of clinical studies. Future research is warranted to fill gaps in our analysis before recommending phytochemicals for prevention and treatment of GBM, a perilous malignancy.
RADT-07. HYPOFRACTIONATED RADIOTHERAPY IN BRAINSTEM GLIOMAS- EXPERIENCE FROM A TERTIARY CARE CENTRE IN INDIA
Authors: Dagar Abhilash , Ghosh Adrija , Aashita Aashita , Vivekananda Abiramasundari , Amritt Adhar , Raj Jaswin , Hazarika Sangeeta , Sharma Aman , Sharma D N , Mallick Supriya 
Published: November 2024

Abstract
Brainstem Gliomas have limited therapeutic options and poor outcomes. Radiation forms the cornerstone of management but data is lacking. We performed an audit of brainstem glioma patients treated with hypofractionated radiation between July 2021 to May 2024. Diagnostic MRI was co-registered with planning CT to delineate GTV with an isotropic 5 mm margin for CTV and 3mm for PTV. Baseline clinical and imaging details, radiation details, acute toxicities, steroid usage, progression, and overall survival data were recorded. PFS and OS were defined from the date of diagnosis to progression and death respectively. This study included 31 Brainstem glioma patients. The median age at presentation was 14 years (2–80 years). Majority of patients were male (67.7%). The baseline performance status assessed by ECOG/Lansky was 0-2 in 83.9%. The most common presenting complaint was motor weakness in 51.6% followed by cerebellar symptoms in 29%. Baseline neurological deficit was seen in 90.3%. The most common epicenter of the disease was pons (67.7%). Biopsy was available in only 9.7% (2 patients: Diffuse Midline Glioma H3k27 altered,1: High-Grade Glioma). VP shunting was done in 29%. All patients were planned via VMAT technique. Median GTV volume 34.3cc (4.9-109.5cc). Median PTV volume was 95.1 cc (7.9-363.1 cc). Most frequently used regimen was 40Gy/15#/3 weeks in 74.3% of patients. Median PTV coverage D95% was 98.7% (90.5-99%). Only one patient received concurrent Temozolamide. Median Radiation treatment time was 22.5 days (-46 days). Steroid usage during radiation was seen in 41.9% of the patients. Naso-gastric tube was required in 12.9% patients. During radiation, aspiration and raised ICT were seen in in 12.9% each. At a median follow-up of 6.42 months, the median PFS was 6.42 months (3-9.83 months) and OS was 7.18 months (3-11.37 months). Hypofractionation seems a feasible approach in brainstem gliomas. International collaborative efforts are required.
RADT-12. DERIVING IMAGING BIOMARKERS FOR PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA USING DEEP LEARNING
Authors: Zhu Joshua , Hager Tommy , Chadha Saahil , Sritharan Durga , Weiss David , Hossain Sajid , Osenberg Klara , Moore Nicholas , Aneja Sanjay 
Published: November 2024

Abstract

PURPOSE
Primary central nervous system lymphoma (PCNSL) is typically treated with chemotherapy, steroids, and/or whole brain radiotherapy (WBRT). Determining which patients benefit from WBRT after chemotherapy and which are adequately treated with chemotherapy alone remains a clinical challenge. Although WBRT is associated with improved outcomes, it also carries a risk of neurocognitive side effects. This study aims to refine PCNSL patient phenotyping by leveraging deep learning (DL) extracted imaging biomarkers to enable personalized therapy.

METHODS
Our study included 71 patients treated between 2009-2021. The primary outcome of interest was overall survival (OS) assessed at one- and two-year cutoffs. The DL model leveraged an 8-layer 2D convolutional neural network analyzing individual slices of post-contrast T1-weighted pre-treatment MRI scans. Survival predictions utilized a weighted voting system related to tumor size. Model performance was assessed with accuracy, sensitivity, specificity, and F1 scores. Time-dependent AUCs were calculated and C-statistics were computed to summarize the results. Kaplan-Meier (KM) survival analysis assessed differences between low and high-risk groups and were evaluated using the log-rank test.

RESULTS
The cohort’s average age was 65.6 years with average OS of 2.80 years. For one-year OS, the model achieved an AUC of 0.73 (0.60-0.85), accuracy of 0.73 (0.61-0.82), sensitivity of 0.72 (0.54–0.85), and specificity of 0.73 (0.58–0.84). For two-year OS, the model achieved an AUC of 0.70 (0.58-0.82), accuracy of 0.70 (0.58-0.79), sensitivity of 0.68 (0.55–0.81), and specificity of 0.71 (0.55–0.84). Model performance is presented with respective 95% confidence intervals. KM curves showed the one and two-year models effectively discriminated between low- and high-risk group, reporting c-statistics of 0.73 (p&lt;.001) and 0.71 (p&lt;.001) respectively. A sub-analysis confirmed consistent model performance across different tumor volumes and focality.

CONCLUSION
DL classifiers of PCNSL MRIs can stratify patient phenotypes beyond traditional risk paradigms. Given dissensus surrounding PCNSL treatment, DL can augment risk stratification and treatment personalization, especially with regards to WBRT decision making.
RADT-13. REAL-WORLD DATA ON NEWLY DIAGNOSED WHO 4 GLIOMAS UNDERGOING TTFIELDS: SURVIVAL ANALYSIS AND RELAPSE PATTERNS FROM A SINGLE CENTER
Authors: Zhang Jing , Liu Yanwei , Qiu Xiaoguang , Zhang Wei 
Published: November 2024

Abstract

BACKGROUND
Tumor treating fields (TTFields) therapy is more and more widely used to treat patients with glioblastoma due to its effectiveness and low toxicity. In the 2023 V1 NCCN guidelines, TMZ combined with TTFields is the only preferred Class 1 recommended standard treatment for ndGBM patients aged ≤70 years.

METHOD
A total of 37 patients who were newly diagnosed as WHO 4 Gliomas in Tian Tan Hospital from 2020.8 to 2023.10 with TTFields were included in this retrospective analysis, and the median follow-up time was 449 days.

RESULT
The median age of the 37 patients was 50 years old, and 17 of them were male. Total resection was performed in 18 patients (48.6 %) and nearly total resection was performed in 14 patients (37.8%). The median time from diagnosis to first wearing of TTFields was 83 days(2.76 months). The median wearing time of TTFields was 9 months, and the median wearing compliance was 90%.The median PFS from diagnosis was 494 days (16.5 months). The 18 months OS rate was 86.7% from diagnosis to time of death after wearing TTFields. Among 37 patients receiving TTFields, 6 (16.2%) were found to have radiation damage. A total of 3 patients had non-radiological area and distal contralateral recurrence, and PFS were 7.2 months, 16.1 months, and 22.8 months, respectively.

CONCLUSION
PFS is associated with high total resection rate, early wearing of TTFields (median 2.76 months), and long wearing (median 9 months) with high compliance (median 90%). The recurrence pattern of patients with long-term wearing TTFields needs to be further explored. Currently, we are integrating clinical information and exploring the imaging characteristics of patients with distant metastases based on multimodality radiomics platform.