tbuckley/cabot-search huggingface dataset:
P08.05.A LIQUID BIOPSY FOR GLIOBLASTOMA: UTILIZING PLASMA EXTRACELLULAR VESICLES FOR TUMOR DIAGNOSIS AND MONITORING
Authors: M Del Bene, E Zaccheroni, D Osti, S Faletti, S Cavallo, E Costanzi, F DiMeco, G Pelicci
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM), the deadliest brain tumor in adults, is traditionally diagnosed and characterized using neuroimaging and brain biopsies. These methods, however, suffer from limited specificity and sensitivity. The surgical risks associated with tumor sampling further complicate the monitoring of GBM’s molecular progression. Consequently, the identification of circulating GBM biomarkers is crucial for non-invasive tracking of the disease from diagnosis to relapse. Extracellular vesicles (EVs) secreted by GBM cells, which cross the blood-brain barrier and carry tumor-derived molecules, present a promising avenue for the continuous evaluation of GBM presence and status. MATERIAL AND METHODS We isolated extracellular vesicles (EVs) using Size Exclusion Chromatography (SEC) from 2 mL of plasma and characterized them via immunoblotting, flow cytometry, and transmission electron microscopy. The concentration and size of EVs were measured using Tunable Resistive Pulse Sensing (TRPS). We compared EV levels in 50 glioblastoma (GBM) patients pre-surgery with those in non-GBM controls, which included 100 healthy individuals and 50 patients with brain malignancies that present similarly to GBM in neuroimaging studies. Longitudinal assessments of plasma EVs were performed in 44 GBM patients by comparing pre-operative and post-operative samples taken 72 hours after surgery. Additionally, we analyzed surface markers on GBM and non-GBM plasma EVs using MACSPlex and conducted proteomic analyses via mass spectrometry in 27 GBM patients and 38 healthy individuals. RESULTS We found higher concentrations and mean sizes of plasma EVs in GBM patients compared to controls, with a noticeable decrease post-operatively. Multiplex flow cytometry indicated universal expression of CD9, CD63, and CD81 across all samples, with significant enrichment of CD63 and CD81 in GBM plasma EVs. The expression profiles of the other 34 markers were similar across all samples, suggesting dilution of tumor-derived EVs among non-tumor EVs. However, T-cell markers CD8 and HLA-DRDPDQ were more prevalent on GBM-derived EVs. Proteomic analysis identified over 2,000 proteins in all samples, with 117 being upregulated in GBM samples, predominantly within the complement cascade pathways. CONCLUSION Our findings suggest that monitoring circulating EV levels provides a reliable, non-invasive method for the differential diagnosis and follow-up of GBM patients. The combined analysis of EV concentration, size, and proteome offers potential as promising biomarkers for longitudinal monitoring of GBM, supporting the implementation of liquid biopsy in GBM care.
P02.22.A REARRANGEMENTS OF PERITUMORAL TISSUE THAT OCCUR ALONG WITH GLIOMA PROGRESSION
Authors: E Mori, C Spalletti, M Scalera, S Haddad, D Cangi, V Pillai, E Parmigiani, M Mainardi, S Landi, M Caleo, E Vannini
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma Multiforme (GBM) is a high-grade glioma known to infiltrate the surrounding brain parenchyma inducing a direct neuronal damage. Indeed, GBM mass is not an isolated and self-sustained entity but rather participates and interacts with the surrounding neuronal tissue. Specifically, tumoral cells induce neuron hyper-excitability while peritumoral cells seem to regulate tumor proliferation and progression. GBM affects 3 in 100,000 people and has a median survival of 15 months; it remains poorly understood and lethal. Therefore, gaining a deeper understanding of the alterations occurring in peritumoral tissues during GBM progression is of paramount importance. MATERIAL AND METHODS We investigate the plastic rearrangements of motor cortical areas in two different glioma-bearing mouse models using optogenetic stimulation, two photon imaging and immunohistochemical analyses. Specifically, we took advantage of Thy1-ChR2 transgenic mice, injected with two syngeneic lines of murine glioma cells (i.e. GL261 and PDGF+ Trp53-/- cells) into the motor cortex. Mice were optogenetically stimulated in 120 points per session (covering the entire extent of forelimb motor representation) at 3 different time points: baseline (before glioma cells injection), 14 and 21 days after tumor implantation. RESULTS We show that both models of glioma-bearing mice underwent a strong remapping of forelimb motor territory. Namely, an increased threshold required for eliciting a forelimb movement was coupled with a decrease of forelimb specificity in the peritumoral area with respect to naïve mice. In addition, glioma-bearing mice showed a decrease in the number of dendritic spines, along with reduced density of perineuronal nets (PNNs) and inhibitory interneuron markers in the peritumoral cortex. CONCLUSION We provide important insight into the interaction between GBM and surrounding tissue that can be used for developing more effective treatments to improve patients’ quality of life and survival.
OS11.5.A MYELOID CELLS DRIVE IMMUNOSUPPRESSION OF CHIMERIC ANTIGEN RECEPTOR T CELLS IN THE NEURONAL MICROENVIRONMENT OF GLIOBLASTOMA
Authors: J Zhang, J v Ehr, T Look, J K Benotmane, N Neidert, J Kueckelhaus, T Weiss, D H Heiland, Y A Yabo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Chimeric antigen receptor (CAR)-T cell therapy has been successful in hematologic malignancies but demonstrated limited success in solid cancers including glioblastoma. The heterogeneous nature of central nervous system malignancies and immunosuppressive microenvironment are major impediments to the efficacy of CAR-T cell therapy in glioblastoma. Here, we aim to explore the transcriptional adaptation of CAR-T cells and cellular interactions that may explain the T cell dysfunction in the glioblastoma microenvironment. MATERIAL AND METHODS We performed physically interacting cells sequencing (PIC-seq) to explore the transcriptional diversity of NKG2D CAR-T cells and control T cells in the glioblastoma ecosystem leveraging a human neocortical slice model. We investigated cellular interactions and receptor-ligand interactions through CellChat and integration of spatially resolved T cell receptor sequencing. CellOracle was used to reconstruct gene regulatory networks and identify key transcription factors associated with CD8 CAR-T cell dysfunction. Further, we used in-silico perturbation to identify transcriptional drivers that have the potential to enhance cytotoxic response of CAR-Ts. RESULTS We inoculated primary patient-derived glioma cells into human neocortical slices from surgical access tissue specimens. After 3 days of tumor growth, slices were treated with NKG2D CAR-Ts or control T cells. We observed that after an initial phase (2 days) of anti-tumor T cell response in the CAR-T group, tumor growth did not differ between conditions. After 7 days of treatment, PIC-seq was used to profile CAR-Ts (tomato+) and tumor cells (GFP+) as well as cells which were physically connected (+/+). We identified a transcriptional shift towards T cell exhaustion in CAR-T cells compared to T cells lacking the NKG2D construct. This transcriptional phenotype was driven by CAR-T cell-myeloid cell interaction. Integrative analysis identified that tumor-associated macrophages with enhanced phagocytic function in proximity to mesenchymal-like tumor cells located within hypoxic niches are the main drivers of T cell dysfunction. Gene regulatory network analysis demonstrated that MAF and BACH2 are key transcriptional regulators of CAR-T cell function. CONCLUSION Both myeloid-tumor and myeloid-T cell interactions collectively promote an immunosuppressive microenvironment in glioblastoma. Our data has the potential to catalyze the re-engineering and optimization of CAR-T cell therapies with sustained cytotoxic effect against glioblastoma.
P18.47.A THE PROGNOSTIC IMPACT OF CDKN2A/B HETEROZYGOUS DELETIONS IN IDH-MUTANT GLIOMA
Authors: F M Ippen, T Hielscher, K Göbel, D Friedel, D Reuss, A von Deimling, W Wick, F Sahm, A Suwala
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Homozygous deletions of CDKN2A/B confer unfavorable prognosis in IDH-mutant gliomas and are a criterion for CNS WHO grade 4 in IDH-mutant astrocytomas, but the role of heterozygous CDKN2A/B deletions remains less well understood. The aim of this study was to assess the prognostic impact of CDKN2A/B heterozygous deletions in IDH-mutant low-grade astrocytoma and oligodendroglioma. MATERIAL AND METHODS Tissue samples diagnosed as astrocytoma, IDH-mutant and oligodendroglioma, IDH-mutant, 1p/19q co-deleted CNS WHO grade 2 and 3 were collected from the archive of the Institute of Neuropathology in Heidelberg. DNA methylation analysis was performed on formalin-fixed paraffin-embedded (FFPE) samples. Evaluation of the CDKN2A/B locus was performed by visual inspection of copy-number plots derived from methylation-array data for each case. Heterozygous and homozygous losses were assessed in relation to whole chromosomal or larger segmental losses and gains in the chromosomal profile. Survival was assessed using the Kaplan-Meier method. RESULTS A total of 334 low-grade glioma cases were identified. Those cases included 173 astrocytomas and 161 oligodendrogliomas. Heterozygous deletions in CDKN2A/B (37/173 in astrocytomas, 15/161 in oligodendrogliomas) did not confer worse survival outcomes compared to CDKN2A/B wildtype cases in neither low grade astrocytoma (p= 0.2458) nor oligodendroglioma (p= 0.2779), regardless of CNS WHO grade, which was further demonstrated on a subgroup of astrocytoma, IDH mutant CNS WHO 4 cases (p= 0.1143). CONCLUSION Our study suggests that heterozygous CDKN2A/B deletions do not confer worse survival rates with respect to OS and PFS in astrocytoma, IDH-mutant and oligodendroglioma, IDH-mutant, 1p/19q co-deleted CNS WHO grade 2 and 3.
P14.12.A IMMUNOTHERAPEUTIC ADVANCES IN GLIOMA MANAGEMENT: THE RISE OF VACCINE-BASED APPROACHES
Authors: M Shah, W Awuah, J Tan, S Ranganathan, K Darko, P Ohenewaa Tenkorang, B Adageba, A Ahluwalia, V Shet, M Kundu, N Aderinto, T Abdul-Rahman, O Atallah
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Gliomas, originating from glial cells in the central nervous system, present formidable therapeutic challenges, especially the aggressive glioblastoma multiforme (GBM). Traditional treatments often fall short due to tumour heterogeneity and the protective CNS microenvironment. Glioma vaccines have emerged as promising immunotherapeutic strategies to combat these challenges. This review critically assesses the scientific rationale and clinical outcomes of glioma vaccines, aiming to elucidate their evolving role in glioma therapy. MATERIAL AND METHODS A systematic review of papers published between 2000 and 2024 that met the inclusion criteria was undertaken using several databases, including PubMed, EMBASE, Google Scholar, the Cochrane Library, and Scopus. RESULTS Glioma vaccines, including peptide-based, DNA/RNA-based, whole-cell, and dendritic cell vaccines, have shown promising outcomes in clinical trials. For example, the IMA950 peptide vaccine resulted in progression-free survival rates of 74% at 6 months and 31% at 9 months in newly diagnosed GBM patients. Similarly, the SurVaxM peptide vaccine led to 95.2% of patients remaining progression-free at 6 months, with an average progression-free survival of 11.4 months and an overall survival of 25.9 months. DNA/RNA-based vaccines targeting tumour-specific mutations have also shown efficacy. Trials integrating personalised vaccinations targeting unmutated antigens and neoepitopes yielded sustained responses in patients with newly diagnosed GBM. Additionally, whole-cell vaccines, when combined with adjuvants like GM-CSF, induced delayed-type hypersensitivity responses in 89% of patients and resulted in radiological evidence of response in 42% of cases, with clinical improvement observed in 26% of patients. Dendritic cell vaccines, such as DCVax-L and α-type-1 DC vaccines, demonstrated improvements in overall survival in GBM patients, with long-term benefits observed in patients with a methylated MGMT promoter. However, some trials reported adverse events such as allergic reactions and transient hepatotoxicity. CONCLUSION Glioma vaccines show promise in stimulating immune responses against tumours, offering potential benefits alongside standard treatments. Challenges in assessing vaccine efficacy and addressing treatment-related adverse effects emphasise the need for further research and clinical trials. Challenges like tumour heterogeneity and immune evasion persist, but advances in genetic engineering and immunotherapy offer hope for enhancing vaccine efficacy. Collaboration across disciplines is essential for translating these advances into effective glioma treatments.
P12.05.B COMBINED ANTI-ANGIOGENIC TREATMENT TO INCREASE INTRATUMORAL PERSISTENCE OF CAR T CELLS IN LUNG CANCER BRAIN METASTASES
Authors: J Blobner, C Eberle, L Dengler, J J Herold, T Xu, K J Mueller, N Teske, P Karschnia, H Ishikawa-Ankerhold, M Subklewe, N Thon, J Tonn, L von Baumgarten
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Metastatic lung cancer shows a devastating prognosis. Immunotherapeutic approaches including CAR T-cells show promise in hematologic malignancies. However, the presence of immunosuppressive factors within the tumor microenvironment and physical barriers like elevated interstitial pressure due to dysfunctional tumor vessels are one of the main obstacles especially in solid tumors. Therefore, we investigate potential synergistic effects of a combined anti-angiogenic treatment and CAR T cells. METHODS Here, we set up an immunocompetent syngeneic orthotopic cerebral metastasis model in mice by combining a chronic cranial window with repetitive intracerebral two-photon laser scanning microscopy (TPLSM). This model allows in-vivo characterization of fluorescent tumor cells and CAR T-cells on a single cell level over time. Intraparenchymal injection of red fluorescent EpCAM-transduced Lewis Lung carcinoma cells (EpCAM/tdtLL/2 cells) followed by injection of EpCAM-directed or undirected CAR T-cells into the adjacent brain tissue was performed. Additionally, aVEGF-A combined with aVEGF-R2 and the respective isotype control were injected intraperitoneally. RESULTS Compared to undirected CAR T-cells, mice receiving EpCAM-directed CAR T-cells showed higher intratumoral CAR T-cell densities after intraparenchymal injection. This finding was accompanied with reduced tumor growth and eventually translates into a survival benefit. However, intratumoral CAR T-cell numbers diminish over time indicating insufficient persistence inside of the tumor microenvironment. Additional anti-VEGF-A/VEGF-R2 treatment results in reduced tumor growth after EpCAM/GFPCAR T cell and GFPT cell treatment, respectively. Interestingly, in vivo imaging reveals higher intratumoral CAR T cell numbers after anti-angiogenic treatment compared to isotype controls pointing towards enhanced CAR T cell persistence resulting in a survival benefit. CONCLUSION Collectively, our findings indicate that locally injected CAR T-cells may safely induce relevant anti-tumor effects in brain metastases from lung cancer. Additional anti-angiogenic treatment provides a mechanism to enhance intratumoral CAR T cell persistence and reduce tumor growth.
P10.20.B MODELING UNCERTAINTY IN INDIVIDUAL PREDICTIONS OF COGNITIVE FUNCTIONING FOR UNTREATED GLIOMA PATIENTS USING BAYESIAN REGRESSION AND CLINICAL VARIABLES
Authors: S M Boelders, B Nicenboim, E O Postma, L S Ong, K Gehring
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Cognitive functioning is increasingly considered when making treatment decisions for patients with a glioma in view of a personalized onco-functional balance (balancing survival against the preservation of function). Previous research using machine-learning models found that predicting pre-operative cognitive functioning based on clinical variables resulted in accurate predictions for some, but inaccurate predictions for other patients. Therefore, the current study sets out to use Bayesian models to improve predictions while also providing estimates of uncertainty for each individual prediction. MATERIAL AND METHODS Pre-operative cognitive functioning was predicted for 340 patients with a glioma across eight cognitive tests. This was done using six increasingly complex Bayesian regression models including hierarchical models conditioned on tumor grade. Models used a comprehensive set of predictors associated with cognitive functioning in the literature. Point-wise predictions were compared against one another and previous work using machine learning. The best-performing model (R2) was interpreted and examples of how Bayesian prediction models can be applied in clinical practice were provided. RESULTS Bayesian models outperformed the machine-learning models used in previous work. Predictions, however, remained uncertain. The best-performing model allowed coefficients and intercepts to differ across tumors with a different grade while pulling the estimates toward the population mean. Moreover, the best-performing model included regularizing priors, causing it to use most variables for prediction while not relying strongly on any variable. CONCLUSION Bayesian models resulted in better predictions than machine learning models while also providing estimates of uncertainty for individual predictions. For the best possible predictions, tumors with a different grade are best modeled as different, yet related. Moreover, a holistic view of patients’ cognitive functioning is necessary. The uncertainty in individual predictions exemplifies the importance of measures of uncertainty for clinical practice.
P10.19.A MACHINE LEARNING-BASED PREDICTION OF INPATIENT CARE COSTS FOR PATIENTS WITH BRAIN METASTASES: A REAL-WORLD ANALYSIS
Authors: A Ozair, D Mukherjee
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain metastases (BMs) represent a significant cause of cancer-related morbidity and mortality. While BM-related healthcare costs have been previously described, predictive analytics based on recent data, particularly for inpatient care, remain unavailable. This study sought to evaluate inpatient care costs (IPCCs) of patients with BMs and perform predictive modelling through supervised machine learning (sML) using a contemporary, commercial claims database. MATERIAL AND METHODS This retrospective study, reported following STROBE and TRIPOD+AI reporting guidelines, included adult patients (aged 18-65 years) in the United States (US) with BMs included in the MarketScan Commercial Claims and Encounters Database who received inpatient care during January 2016 to December 2021. Eligible patients were identified using ICD-10 codes. IPCC measures were adjusted using the Medical Care component of the 2023 Consumer Price Index. Primary study outcome was total IPCC, represented by adjusted gross total payments. After log-transformation performed due to data skew, sML was carried out using Random Forest algorithm with 1000 iterations with a 70:30 training-test data split, followed by residual analysis and evaluation of predictive performance using root-mean-squared error (RMSE), out-of-bag error (OOBE), and calibration curve. Multivariable linear regression (MLR) modelling was carried out for sensitivity analyses. RESULTS A total of 25117 unique admissions across 13477 BM patients were included, with median (IQR) age of 57 years (51-61). Gross median (IQR) CPI-medical-care-adjusted values per admission were: total payments $28,119.51 (16847.45-55111.67); hospital payments $24,678.74 (14601.66-47864.84); and payments to principal physician $884.80 (441.07-2434.15), being 3.6% (IQR 1.9-6.8) of total payment. Median inpatient length of stay was 4 days (IQR 2-8). The ML model had an OOBE of 0.61 and, using test data, an RMSE of 0.85, indicating robust performance. CONCLUSION Contemporary IPCCs for BM patients in the US are substantial but driven minimally by payments to principal physician for services rendered. sML may be utilized to successfully predict IPCC for patients with BMs.
P18.50.A TUMOR VOLUMES AND FEASIBILITY OF EXTENSIVE RESECTION IN NON-CONTRAST ENHANCING GLIOBLASTOMAS THAT LACK HIGH GRADE HISTOLOGICAL FEATURES: A SINGLE CENTER STUDY
Authors: S Lakerveld, M M J Wijnenga, S L N Maas, V van Dis, M Smits, M Tesileanu, H J Dubbink, P J French, A J P E Vincent, M J van den Bent
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The clinical course and management of non-contrast enhancing glioblastomas that also lack the classic high grade histological features (non-CE GBMs) is unclear. Data on survival, clinical management including surgical therapies are sparse and conflicting. In this study we therefore investigated tumor volumes, surgical and postsurgical therapies and survival outcome of a single center cohort from the Netherlands. MATERIAL AND METHODS We identified adult cases of non-CE GBM in the Brain Tumor Center at Erasmus MC Cancer Institute in Rotterdam, the Netherlands from 2003-2024. Cases with ring-like contrast enhancement and/or central necrosis at time of diagnosis were excluded. Patients were classified as glioblastoma using a glioma-tailored NGS panel. Pre-and postoperative tumor volumes were segmented manually using open source software ITK-SNAP. Pre- and postoperative volumes were set equal when only a biopsy was performed. Clinical information and postoperative therapies were retrospectively collected from patient records. Overall survival was calculated from time of diagnostic MR scan. RESULTS We identified 77 patients with available imaging data. Median age of patients was 59 years. The presenting symptom was an epileptic seizure in 66.2% of patients. Tumor localization in 60 out of 77 patients involved mainly the temporal lobe. As initial surgical strategy 59 patients underwent a biopsy (stereotactic or open), and only 18 patients a resection (of which 5 were awake). In most cases a clinically relevant resection was considered not feasible. Of the 18 resected patients, 4 patients underwent a second resection at progression. Of the 59 biopsied patients, 5 underwent a subsequent resection, and 5 a second biopsy as the first biopsy was inconclusive. Patients that underwent a resection had higher KPS scores (≥90 in 95.7% vs 55.6%, P= 0.003), and lower rates of gliomatosis cerebri (8.7% vs 53.7%, P &amp;lt;0.001). Median preoperative tumor volume was 65 cc. In only 3 of 18 resected patients the postoperative tumor volume was ≤5 cc. After diagnosis, 41 patients underwent radiotherapy with concurrent temozolomide, of which 12 with a hypofractionated scheme. 12 patients only received radiotherapy and 13 patients only chemotherapy. Median OS was 21.1 months, with no significant difference in OS observed between the resection and biopsy group. CONCLUSION In this series on non-CE GBMs with low grade histological features, a clinically relevant resection was not feasible in most cases because of pre-operative size of the lesion and location, only in 3 patients a small postoperative volume of ≤5cc was achieved. This may contribute to the poor outcome of these patients compared to other series.