tbuckley/cabot-search huggingface dataset:
P02.04.B CANCER-ASSOCIATED FIBROBLASTS IN LUNG CANCER BRAIN METASTASES: EFFECT ON CANCER CELL MIGRATION AND INVASION, AND MONOCYTE RECRUITMENT AND DIFFERENTIATION
Authors: B Vymolova, T Smetana, L Pfeiferova, J Sachova, M Kolar, N Ternerova, P Vymola, T Svablova, M Houdova Megova, P Busek, A Sedo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain metastases (BrM) are a frequent complication of lung cancer with dismal prognosis. The presence of cancer associated fibroblasts (CAF) was recently described in the BrM microenvironment, but their engagement in BrM biology is largely unknown. In this study, we evaluated the effect of CAF derived from lung cancer brain metastases (BrM-CAF) on cancer cells and the recruitment and differentiation of monocytes. MATERIAL AND METHODS Patient-derived BrM-CAF and cancer cells (BrM-CC) were isolated from lung cancer BrM. Normal fibroblasts were isolated from subgalear connective tissue. Monocytes were isolated from healthy donors’ peripheral blood. Patient-derived cell cultures were characterized using immunocytochemistry and RNA expression profiling. A transwell assay and a 3D spheroid-based assay were used to assess migration and invasion, respectively; cell growth was quantified using a kinetic label-free cell counting assay. Monocyte differentiation was evaluated by flow cytometry. RESULTS BrM-CAF expressed canonical fibroblast markers and their fibroblast-like phenotype was verified by RNA expression profiling. BrM-CC expressed epithelial markers. Conditioned media from BrM-CAF stimulated the migration of BrM-CC more than conditioned media from normal fibroblasts. In the invasion assay, the cancer cell invasive area was bigger in the presence of BrM-CAF; in addition, we observed a different pattern of invasion in BrM-CAF-containing spheroids, with more protrusions being formed. Direct co-culture with BrM-CAF diminished cancer cell proliferation. BrM-CAF conditioned media induced migration of monocytes. In direct co-culture with BrM-CAF, monocytes acquired a differentiated phenotype with both M1-like and M2-like features similar to that of tumor associated macrophages. CONCLUSION Using patient-derived cultures, we show that BrM-CAF promote cancer cell migration and invasion but decrease their proliferation. Moreover, BrM-CAF can contribute to the recruitment of peripheral monocytes and their differentiation into tumor-associated macrophages. Taken together, these results demonstrate the role of BrM-CAF in shaping the brain metastatic microenvironment. FUNDING This research was funded by the Charles University grant 342522; project NU22-03-00318 of Ministry of Health of the Czech Republic, Program Cooperatio, research area,,Oncology and Haematology“; Ministry of Education, Youth and Sports of the Czech Republic - LM2023053 of EATRIS-CZ and project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102) by the European Union - Next Generation EU.
P18.38.A ROLE OF CARBOHYDRATE-BINDING PROTEINS IN CONTROLLING GLIOBLASTOMA STEM CELL FATE AND TUMORIGENESIS
Authors: M Sliusar, L Chaillot, A Burban, A Sharanek, A Bikfalvi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Carbohydrate-binding proteins, galectins (GAL, LGALS), is a family of proteins that specifically bind β-galactoside sugars. Some members of the GAL family have been shown to be associated with tumor development, including glioblastoma (GB). However, their precise role is poorly investigated. MATERIAL AND METHODS Publicly available data sets were analyzed with SUMO software. scRNA-seq data analysis was conducted with the R toolkit Seurat and SingleR package. For in vitro experiments, patient-derived glioblastoma stem cells (GSCs) BTSC73 and BTSC12 were used as cellular models. Differentiation was induced by culturing GSCs on laminin-coated plates in media supplemented with 10% FBS. Hypoxia-response was studied at 1% O2. For depletion experiments siRNA silencing was used as well as CRISPR-Cas9. Proliferation was assessed by EDU staining. Cell death was assessed using Annexin/PI double staining assay. RESULTS We first conducted an in silico analysis for LGALS1, -3, -8, and -9 expression in GB. We found that specific combinations of these Galectins are associated with a poor prognosis. In GB patients. When scRNASeq data were analyzed, Galactins are distributed heterogeneously in different cell types in the tumor. For example, Gal3 is expressed in tumor cells, macrophages, and T-cells. We then conducted in vitro experiments to assess the role of Gal3 and Gal9. Depletion of LGALS3 in BTSC73 led to a decrease in cell number related to an effect on proliferation but not apoptosis. In addition, LGALS3 depletion in GSCs reduced stemness markers such as Sox2 and Nestin. We also investigated LGALS3 and LGALS9 expression during differentiation and found their expression increased which was also the case under hypoxia. CONCLUSION This indicates that Gals and especially Gal3 and Gal9 are involved in GB development including, proliferation stemness and differentiation.
KS03.4.A PATTERNS OF CARE AND CLINICAL OUTCOMES OF PATIENTS WITH GLIOBLASTOMA IN THE UNITED STATES FROM 2005-2020: A REAL-WORLD ANALYSIS
Authors: D Jayram, S Bellur, A Ozair, S Ahmad, L Hodgson, N Frias Perez, V Podder, M Ganiyani, M Ahluwalia
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Survival for glioblastoma (GBM) remains low, with disparities affecting outcomes. Standard of care (SoC) includes surgery and adjuvant chemoradiation. This study explores the demographics, treatment patterns, and outcomes of GBM pts in the United States (US). MATERIAL AND METHODS We conducted a retrospective study with the US National Cancer Database (NCDB), capturing more than 70% of newly diagnosed patients in US, for GBM pts diagnosed in 2005-2020 according to ESMO Guidance for Reporting Oncology Real-World (GROW). Trends were analyzed with descriptive statistics and X2-test between time periods: 2005-08, 2009-12, 2013-16, and 2017-20. Predictors of SoC receipt were analyzed with multivariate logistic regression. Kaplan-Meier method and log-rank test were used to estimate and compare median overall survival (mOS) for univariate association and Cox proportional-hazards analysis for multivariate modelling. Adjustment was made using demographic, socioeconomic, and clinical factors. Associations were reported as (Odds Ratio [OR]/Hazard Ratio [HR] 95% CI) per STROBE guidelines. RESULTS Of 104,697 GBM pts, 42.5% were female. 91.2% White, 5.7% Black, and 2.0% were Asian. 5.3% were Hispanic. Median age was 65 (IQR 57-73). Percentage of pts ≥ 65 years increased from 48.8% in 2005-08 to 54.0% in 2017-20. 56.5% of pts received SoC. SoC receipt rose over time: 2009-12 (OR 1.26, CI 1.21-1.31, P&amp;lt;0.001) vs 2013-16 (OR 1.36, CI 1.31-1.42, P&amp;lt;0.001) vs 2017-20 (1.51, CI 1.45-1.57, P&amp;lt;0.001). Older pts were less likely to receive SoC compared to pts aged &amp;lt;50: 50-64: (OR 0.81, CI 0.77-0.86, p&amp;lt;0.001), 65-74: (OR 0.59, CI 0.55-0.62, p&amp;lt;0.001) vs &amp;gt;74: (OR 0.23, CI 0.22-0.25, p&amp;lt;0.001). Females (OR 0.91, CI 0.89-0.93 P&amp;lt;0.001), Black (OR 0.81, CI 0.77-0.86, P&amp;lt;0.001), and Hispanics (OR 0.91, CI 0.86-0.97, P=0.004) were less likely to receive SoC than males, White, and non-Hispanics. Privately insured were more likely to receive SoC than with Medicare (OR 0.83, CI 0.80-0.87, P&amp;lt;0.001), Medicaid (OR 0.67, CI 0.64-0.71, P&amp;lt;0.001), and uninsured pts (OR 0.60, CI 0.55-0.64, P&amp;lt;0.001). SoC recipients had mOS of 14.6 months (CI 14.5-14.8) vs 4.8 (CI 4.7-4.9) for non-recipients (P&amp;lt;0.001). Compared to 2005-08, pts were more likely to survive in 2017-20 (HR 0.84, CI 0.82-0.85, P&amp;lt;0.001) followed by 2013-16 (HR 0.88, CI 0.86-0.89, P&amp;lt;0.001) and 2009-12 (HR: 0.93, CI 0.91-0.94, P&amp;lt;0.001). CONCLUSION Receipt of SoC has increased with significant improvement in OS. However, female, Black and Hispanic pts were less likely to receive SoC. Targeted efforts are warranted to mitigate disparities and increase receipt of SoC.
OS07.7.A DISSECTING SPATIAL DIVERSITY OF GLIOBLASTOMA GENOTYPES
Authors: J Zhang, T Joshi, D Hambardzumyan, D Heiland
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) remains an intractable cancer characterized by significant inter- and intra-patient heterogeneity. Recent research has established connections between key genetic drivers and distinct transcriptional profiles in GBM, yet the interactions between genetic changes and the transcriptional and spatial heterogeneity remain unclear. This study used genetically engineered mouse models, coupled with spatially resolved and single-cell RNA sequencing, to explore how specific genetic alterations influence the tumor microenvironment (TME) and cellular responses spatially. MATHODS We used nestin-Tva C57BL/6 mice and generated de novo GBM using overexpression of oncogenes in combinations with short hairpin RNAs (shRNAs) or deletion to various tumor suppressors, including Tp53, Cdkn2A, and Pten. We modeled key driver mutations for GBM: PDGFB, NF1, and EGFR. We conducted single-cell RNA sequencing, combined with spatially resolved transcriptomics and proteomics. Data integration techniques, including horizontal (mutual nearest neighbors) and vertical (weighted nearest neighbors) approaches, were used and analyzed with the SPATA2 software. Advanced computational methods, such as graph neural networks and single-cell deconvolution, were applied to examine GBM genotypes and the spatial variability within tumors and their TMEs. RESULTS Our findings revealed persistent cellular heterogeneity among tumor cells under various genetic conditions. However, specific genetic alterations influenced the cells toward dominant transcriptional states. NF1 and EGFR mutations resulted in shifts towards MES and AC-like states, respectively, unlike PDGFB, which promoted a NPC/OPC-like state. These transcriptional shifts were strongly associated with distinct microenvironmental changes, such as enhanced neuronal signaling in PDGFB-driven GBMs versus pronounced immune infiltration in NF1 and EGFR models. Utilizing weighted co-expression network analysis (WGCNA) and gene set enrichment analysis (GSEA) alongside spatial-niche deconvolution, we identified a mesenchymal transition leading to an immunosuppressive TME in NF1-driven GBMs and increased lymphocyte presence in EGFR-amplified GBMs, especially around blood vessels. Similar spatial patterns were observed in human spatially resolved transcriptomic data, highlighting the complexity and variability of genetic drivers in human GBMs. CONCLUSION Our genetically engineered mouse models provide a valuable platform for investigating GBM with defined driver mutations. By leveraging sophisticated analytical techniques and computational modeling, this study underscores the potential to elucidate the interactions between genetic drivers and the tumor microenvironment. Our approach paves the way for developing targeted therapies and precision medicine strategies in GBM.
OS04.6.A ONE STEP CLOSER TO THE END OF LIFE - A QUALITATIVE STUDY ABOUT THE EXPERIENCES OF PATIENTS AND THEIR FAMILIES IN RELATION TO THE RECURRENCE OF A HIGH-GRADE GLIOMA
Authors: H Sørensen von Essen, K Dahl Steffensen, F Rom Poulsen, K Piil
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND High-grade gliomas (HGG) are the most aggressive and infiltrative sub-type of primary brain tumors. Despite intensive treatment, the average survival time from diagnosis is less than two years, and all patients experience recurrence after the initial resection and oncological treatment. However, our understanding of patients’ and their families’ experiences related to the inevitable recurrence remains limited. This qualitative study aimed to explore how patients and their close family members cope with their fear of recurrence, and to understand their experiences when faced with the reality of recurrence. MATERIAL AND METHODS The present study is part of a larger study exploring the experiences of patients and their families related to the recurrence of an HGG. Semi-structured individual interviews were conducted. The interviews were audio recorded and transcribed verbatim. Following an inductive phenomenological hermeneutical approach, the interviews were coded, and the findings were divided into themes. RESULTS The study included 15 patients and 14 family members between the ages of 22 and 79. The analysis identified three overall themes. Theme I: Navigating the fear of recurrence. Theme II: Facing recurrence and preparing for death. Theme III: Redefining hope in the era of recurrence. The three themes were interrelated and provided an overall insight into the complex experiences related to the diagnosis of an HGG recurrence, which will be further elaborated on in the presentation. CONCLUSION During the disease trajectory of living with an HGG, patients and their family members tried their best to live life to the fullest and cope with their fear of the inevitable recurrence and death. They expressed an overall awareness about the prognosis, but their hopes and coping mechanisms left them off guard, causing the recurrence diagnosis to strike them as a shock. The recurrence was experienced as taking one step closer to the end of life, leading them to redefine their hopes and goals for the future. This new knowledge can be used to tailor advance-care-planning consultations, emphasizing patients’ and family members’ readiness to discuss end-of-life issues.
OS01.4.A MODELING EGFR REGULATION IN GLIOBLASTOMA REVEALS ASSOCIATIONS WITH ITS LIGANDS
Authors: S A Ghisai, N Barin, L van Hijfte, I de Heer, M J van den Bent, Y Hoogstrate, P J French
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Approximately half of the IDH-wildtype glioblastomas (GBM) exhibit EGFR amplification, with highly varying copy number levels. Additionally, extracellular mutations in EGFR occur, leading to either ligand hypersensitivity (R108K/A289V/G598V) or ligand-independence (EGFRvIII). Contrary to EGFR-mutated lung adenocarcinoma (LUAD), clinical trials with EGFR inhibitors have not yet improved survival outcome for GBM. Our research aimed to elucidate the molecular mechanisms of EGFR activation and regulation in GBM and make comparisons with LUAD. MATERIAL AND METHODS We devised Random Forest models to identify EGFR co-regulated genes and pathways in GBM by leveraging RNA-sequencing data from TCGA-GBM (n=142) and the Intellance-2/EORTC_1410 (n=211) trial. Additionally, we compared EGFR signaling patterns between GBM and LUAD, where LUAD RNA sequencing data (n=508) were collected from TCGA. Sources of expression signals were determined by screening both in-house and public single cell and single nucleus RNA sequencing (sc/snRNA-seq) data from GBM (n=28) and LUAD (n=45). Multiple primary and established GBM and LUAD cell lines were used for in vitro functional studies. RESULTS Among the significant EGFR predictor genes (TCGA-GBM: n=169, Intellance-II: n=166), we found two ligands (BTC and EREG). Expression of these ligands was inversely correlated with the EGFR amplification level and presence of ligand-sensitizing mutations. Samples with ligand-sensitive mutations showed a downregulation of genes involved in the RB and TP53 pathways (CDK4, MDM2, CDKN2A). Our analyses showed a tumor-type specific expression profile in GBM and LUAD when comparing tumors carrying activating mutations. Sc/snRNA-seq analysis showed that EGFR ligands were primarily expressed by non-malignant cells, but differed in their source of expression between tumor types: GBM (BTC: neurons, EREG: myeloid) and LUAD (BTC: cilia, EREG: myeloid). The level of expression of nearly all EGFR ligands was significantly higher in LUAD than in GBM, which may be related to the presence of ligand-sensitizing mutations in the latter. Functional analysis on primary cultured glioma- and established cell lines showed no overt differences between GBM and LUAD in EGFR internalization and ligand-induced transcriptional regulation. CONCLUSION EGFR ligands BTC and EREG showed a significant and negative association with EGFR expression in GBM. These findings emphasize the potential role of ligands in regulating EGFR, where EGFR activation seems to be triaged by the highly varying level of EGFR amplification, sensitivity of the receptor towards the different ligands and ligand expression levels. These findings provide a better understanding of EGFR regulation in GBM and might eventually be used for patient stratification.
PL02.1.A LOCOREGIONAL BI-SPECIFIC CAR-T CELLS TARGETING CD44 AND CD133 IN RECURRENT GLIOBLASTOMA: THE INTERIM RESULTS OF THE FIRST IN-HUMAN CLINICAL TRIAL
Authors: Y Zhai, G Li, W Zhang, T Jiang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Recurrent glioblastoma (rGBM) remains no standard of care exists, with a median overall survival of less than 1 year. Here, we report the pre-clinical data and the first four patients with rGBM in a phase I study of locoregionally administration of newly developed tandem CAR-T cell, targeting CD44 and CD133, armored with a truncated IL7Ra intracellular domain (Tris-CAR-T). MATERIAL AND METHODS The primary outcomes were safety and any adverse events associated with Tris-CAR-T administration. Secondary outcomes include the distribution and persistence of Tris-CAR-T cells, cytokine concentration, and the therapeutic effect according to immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria. At present, six patients of newly diagnosed rGBM underwent different doses of Tris-CAR-T administration via Ommaya reservoir of intratumoral or ventricular implantation. The first two patients had single or multi-doses of 107 Tris-CAR-T cells, the third and fourth patients had multiple doses of 108 Tris-CAR-T cells, and the last 2 patients had weekly doses of 0.5x108 Tris-CAR-T cells administration. Cytokine release syndrome and other side effects were assessed via cytokine quantification (serum and cerebrospinal fluid), K-CRP, and body temperature. Specimens of peripheral blood, cerebrospinal fluid, CAR-T products were collected for further bioinformatics analysis. RESULTS No neurotoxicity or adverse event greater than grade 1 was observed until now. Radiographic response and improvement in symptoms and signs were observed within days after the first infusion, and continued in the follow-up. Some patients underwent a remarkable tumor regression. CONCLUSION The newly constructed Tris-CAR-T cells are capable of GBM suppression with limited side effects. Long-term tumor control is considered to be related to dosage, product quality, and intervention frequency. A weekly or biweekly administration might be considered. The inspiring clinical response needs to be strengthened by follow-up and investigations in biological specimens (ClinicalTrials.gov identifier: NCT05577091)
P17.15.A PATTERNS OF CARE AND OUTCOMES IN BRAIN METASTASES FROM BILIARY TRACT CANCERS IN THE UNITED STATES: A REAL-WORLD ANALYSIS
Authors: D Jayram, A Ozair, S Ahmad, S Bellur, N Frias Perez, V Podder, M Ahluwalia
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Biliary tract cancers (BTC) are frequently diagnosed late in their disease course. Brain metastases (BM)s from BTC, while rare, lack contemporary literature. This study describes patient characteristics, patterns of care, and outcomes of BM from BTCs in the United States (US). MATERIAL AND METHODS This retrospective study was conducted following ESMO ‘Guidance for Reporting Real-World Oncology Evidence’ (GROW) guidelines using the National Cancer Database, a nationally representative US database capturing &amp;gt; 70% of oncology outcomes, for BTC BMs from 2010-2020. Patient attributes and patterns of care were analyzed with descriptive statistics. Kaplan-Meier estimation was used for median overall survival (mOS, 95% CI). RESULTS Of 88,274 BTC patients, 0.16% had BM (n=138). Median age was 65 years (IQR 58-74). Of patients with BMs, 50.7% were female. 78.26% were White, 13.04% Black, 1.45% Asian. 16.7% were Hispanic. Incidence proportion of patients with BMs increased from 5.8% (n=8) in 2010 to 12.32% (n=17) in 2020. 50.72% (n=70) had Medicare, 13.04% (n=18) Medicaid, 29.7% (n=41) were privately insured, and 4.4% (n=6) were uninsured. 46.4% (n=64) cases originated from the extrahepatic bile duct, 8.7% (n=12) in the ampulla of Vater, 2.9% (n=4) in the overlapping area of biliary tract, and 34.8% (n=58) were not specified. 41.3% (n=57) received no treatment. mOS for the whole cohort was 2.2 months (CI 0.1-16.9). mOS for treated patients was 4.0 months (CI 3.1-6.9). 41.3% (n=57) received chemotherapy, 23.9% (n=33) radiation to the brain, 14.5% (n=20) radiation to other sites, and 2.2% (n=3) surgery. Among chemotherapy recipients (n=57), 78.9% (n=45) received multiagent therapy, 15.8% (n=9) received single-agent therapy, and 5.3% (n=3) lacked specified agent numbers. Of the patients who underwent cranial radiation, 69.7% (n=23) received stereotactic radiosurgery and 30.3% (n=10) received whole brain radiation. 13.7% (n=19) received both cranial radiation and chemotherapy, and 0.7% (n=1) received cranial radiation, surgery, and chemotherapy. CONCLUSION Patients with BM from BTCs have a dismal prognosis. Clinical trials on efficacious therapies are urgently warranted for these patients.