tbuckley/cabot-search huggingface dataset:
P06.01.A TARGETING MRNA DECAPPING ENZYME SCAVENGER (DCPS) IS A PROMISING STRATEGY AGAINST GLIOBLASTOMA VIA THE DOWN-REGULATION OF STAT5B
Authors: H Duan, Y Xie, Y Yu, W Hu, W Ma, Y Mou
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Patients with glioblastoma (GBM) have poor prognosis and limited treatment options. The mRNA decapping enzyme scavenger (DCPS) is a cap-hydrolyzing enzyme. The inhibitor targeting DCPS exhibited excellent central nervous system bioavailability in vivo and was safe and well tolerated in healthy volunteers in a phase 1 clinical trial. In this study, we investigated the expression of DCPS in GBM and the anti-tumor activity of the DCPS inhibitor in various preclinical models of GBM. MATERIAL AND METHODS DCPS expression was examined in human GBM and paired peritumoral tissues. Its prognostic role was evaluated together with clinicopathological characteristics of patients. The anti-GBM effect of targeting DCPS was determined using GBM cell lines, patient-derived organoids,and orthotopic mouse models. The therapeutic mechanisms of DCPS inhibition were explored. RESULTS DCPS is overexpressed in GBMand associated with poor survival of patients with GBM. The DCPS inhibitor exhibited robust anti-GBM activities in GBM cell lines, patient-derived organoids and orthotopic mouse models, with drug exposure achievable in humans. Mechanistically, inhibition of DCPS downregulatedSTAT5Bexpression, thereby suppressing proliferation, survival and colony formation of GBM cells. CONCLUSION Inhibition of DCPS at doses achievable in humans downregulates STAT5B expression and reduces proliferation, survival and colony formation of GBM cells. Given the excellent anti-cancer activity and central nervous system bioavailability in vivo and good tolerance in humans, DCPS is a promising target for GBM.
P01.12.A PERSISTENT GENETIC AND EPIGENETIC CHANGES ARE INDUCED BY INVASION STIMULI IN GLIOBLASTOMA CELLS
Authors: T Müller, S Schreiner, C Cialini, U M Salcedo, M Mittelbronn, K H Plate, J Steinbach, A Hau
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND One key biological challenge in glioblastoma (GB) is the diffuse invasion of GB cells into the brain parenchyma beyond the margins of even supramaximal resection strategies. Various cell-intrinsic and extrinsic factors have been shown to regulate GB invasion, but it is unknown whether invasive GB cells acquire a persistent distinct genetic and epigenetic profile in response to environmental cues. MATERIAL AND METHODS Highly invasive isogenic subpopulations of GB cells (GBinv+ cells) were generated by serial invasion through matrix-coated transwell membranes. RNA sequencing and array-based DNA methylation profiling of control and GBinv+ cells were performed. Differentially expressed genes (DEGs) and differentially methylated probes (DMPs) were analysed using DESeq and RnBeads R package, respectively. Functional correlations of DEGs and DMPs were analysed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Candidate genes were validated using TCGA-LGG/GBM datasets and experimentally confirmed by genetic modulation of gene expression changes and applying classical in vitro invasion assays as well as the GLIoma Cerebral Organoid (GLICO) model for complex ex vivo tumor cell invasion analysis. RESULTS In classical in vitro invasion assays, the invasion potential of GBinv+ cells were more than 10-fold increased relative to the isogenic control cells baseline (p &amp;lt; 0.0001, students t-test). Increased invasion was also demonstrated using the GLICO model. GBinv+ cells were found to have unique transcriptomic and DNA-methylation profiles that persisted for &amp;gt;2 weeks after removal of the stimulus. Genetic deletion of candidate genes identified by profiling reduced invasive properties. CONCLUSION Our results indicate that the invasive sub-population of GB cells is characterized by a specific genetic and epigenetic profile and has enduring functional properties. The functional validation of the identified genes associated with invasion underscores their clinical relevance and suggests they may represent interesting new targets for experimental therapies.
OS08.6.A MACHINE LEARNING BASED PREDICTIVE RADIOMICS FOR EVALUATION OF CANCER IMMUNE SIGNATURE IN GLIOBLASTOMA: THE PRECISE-GBM STUDY
Authors: P Ghimire, M Modat, T Booth
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Immunotherapy is an effective personalized treatment for several cancers. Radiogenomics in glioblastoma patients may serve as pre-operative biomarkers of the tumor-host immune apparatus. Validated biomarkers would have the potential to stratify patients during immunotherapy clinical trials, and if trials are beneficial, facilitate personalized neo-adjuvant treatment. The aim of the study is to identify machine learning based radiological biomarkers that can predict immune status within the tumor microenvironment of IDH wildtype glioblastoma. MATERIAL AND METHODS This is a retrospective multicentre machine learning based study utilizing open access anonymized matched radiogenomic data of TCGA-GBM, CPTAC, Ivy GAP and REMBRANDT datasets. REMBRANDT data acted as a hold out dataset for validation. Imaging data consisted of pre-operative MRI based radiomics features extracted from deep learning based segmented tumours. Transcriptomic data-based overall immune scores and cell-specific (T cells and tumour associated macrophages-TAMS) scores were extracted using CIBERSORTx. Outliers were identified and filtered using principal component analysis. Combat and neuroCombat were utilized for data harmonization of genomic and imaging data respectively. Radiomic feature selection was performed using LASSO technique with cross validation. Support vector machine (SVM) was trained and tested with 80:20 radiomic data split, and binary labels based on (1) overall immune scores, and (2) immune cell-specific scores. Data query and analysis was performed using python. RESULTS One hundred and one patients with 15 in the hold out dataset were included in the study. Trained SVM models predicted the labels for immune score and cell-specific scores (T cells -CD4, CD8; TAMS - M0, M1, M2) with AUC of 0.93, 0.79, 0.86, 0.81, 0.95, 0.76; balanced accuracy of 0.72, 0.82, 0.93, 0.80, 0.86, 0.71 respectively. In the holdout set, the models predicted the labels with robust prediction sensitivity for overall immune scores (100%) and M2 (M2 pro-tumour subtype macrophages) scores (75%) and with robust prediction specificity for T cell scores (CD4: 100%, CD8: 90%) along with M0 (M0 precursor pro-tumour macrophages) (62.5%) and M1 (M1 anti-tumour subtype macrophages) (83%) scores. The radiomic signature employed for prediction models were a group of first order and second order radiomic features obtained after feature selection. CONCLUSION A radiogenomic SVM model non-invasively predicted immune status in wildtype glioblastoma microenvironment with good accuracy. This model has the potential to be utilized in a prospective glioblastoma clinical trial for immunotherapy.
JS02.7.A MAINTENANCE TEMOZOLOMIDE CHEMOTHERAPY FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA: DOES TIME OF ADMINISTRATION MATTER?
Authors: M Geurts, L Berchtold, F Koenig, B Naburs, D A Reardon, J C Tonn, R Stupp, T Gorlia, M Weller, M Preusser
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Chronotherapy, an innovative approach to improve survival or limit toxicity through timed administration of treatment, is of increasing in interest in cancer. In glioblastoma, preclinical models show that temozolomide activity depends on the time of the day it has been given. A retrospective study suggests improved outcomes for glioblastoma patients receiving temozolomide in the morning as compared to evening administration. METHODS We assessed toxicity and survival data in 755 patients enrolled in the CENTRIC EORTC 26071-22072 (n = 508) and CORE (n = 247) studies. Due to regulatory constraints, analyses had to be restricted to deceased patients only (n = 393 and n= 196 in CENTRIC and CORE respectively). We compared patients who were documented to have received temozolomide in the maintenance phase of the standard of care in the morning (&amp;lt;11.00AM) to those who received it in the evening (&amp;gt;6.00PM). Patients who received most of the maintenance temozolomide in the afternoon (between 11.AM and 6.00PM) were excluded. RESULTS A total of 260 (CENTRIC) and 154 (CORE) patients had at least one administration time available. In CENTRIC, n=102/260 (39%) received temozolomide in the morning and n=35/260 (13%) in the evening. In CORE, 50/154 (35%) patients received temozolomide in the morning and 34/154 (22%) in the evening. Patient- and disease characteristics were similar in both groups. There was no difference in general toxicity profiles between all groups (any AE, CENTRIC: morning 67/102 vs evening 24/35, p=0.8, CORE: morning 23/50 vs evening 14/34, p =0.7), but the morning group had a higher proportion of patients with bone marrow toxicity, compared to the evening group (CENTRIC: morning 34/102 vs evening 34/35, p=0.013, CORE: morning 12/50 vs evening 1/34, p&amp;lt;0.01). There was no difference in overall survival between the groups [CENTRIC median OS 20.1 months (95% CI: [14-33] months) morning vs 23.5 months (95% CI: [18-32] months) evening, p=0.5; CORE median OS, 10.9 months (95% CI: [10-13] months) morning vs 11.3 months (95% CI: [9.1-13] months) evening, p=0.8]. CONCLUSION In this large prospective dataset, there was no indication that time of administration of maintenance temozolomide matters for survival of patients with newly diagnosed glioblastoma. However, our data suggest that bone marrow toxicity might occur less frequently when temozolomide is administered in the evening compared to the morning. This observation warrants further investigation. Given the limitation to data from deceased patients only, this analysis might be significantly biased and does not yet exclude that timing of temozolomide matters in patients most likely to derive benefit.
P01.13.B SPATIALLY RESOLVED FUNCTIONAL PROFILING FOR GLIOBLASTOMA
Authors: A Buck, S Lee, R Wegmann, J Mena, F Vasella, J Friesen, L Regli, E Le Rhun, A Zeitlberger, M Neidert, N Tatari, G Hutter, M Weller, B Snijder, T Weiss
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma is the most common malignant primary brain tumor in adults with a poor survival and an unmet need for more effective therapies. Macroscopically, as observed through MR imaging and microscopy, these tumors are characterized by distinct tumor regions: a contrast-enhancing tumor core with a high cancer cell density and an infiltration zone that appears T2/FLAIR hyperintense without the uptake of contrast agent and consists of infiltrating tumor cells as well as non-malignant cells of the microenvironment. Previous genomic and transcriptomic studies revealed molecular differences between the tumor core and the infiltration zone. However, functional differences, such as drug sensitivity, between tumor regions are still largely unknown. MATERIAL AND METHODS To address this gap, we collected region-specific glioblastoma patient tissue samples from both the contrast-enhancing tumor core and the non-contrast-enhanced but 5-aminolevulinic acid (5-ALA) fluorescent infiltration zone directly from surgery. We utilized pharmacoscopy, a microscopy-based single-cell drug screening approach, to identify drug responses across regions and patients. RESULTS By profiling a library of 60 drugs across regions in a cohort of 23 patients, we identified region-specific drug responses and developed a complementarity score to pinpoint drug combinations capable of targeting both the tumor core and the infiltration zone. These combination treatments exhibited highly promising anti-tumor activity across regions and patients. CONCLUSION Given the high levels of functional spatial intra- and inter-tumor heterogeneity, relying on a single drug across patients may not be feasible for effective patient treatment. Thus, there is a strong rationale to administer drug combinations that not only consider regional heterogeneity but also account for patient-specific variations.
P10.08.A AUTOMATED LONGITUDINAL TREATMENT RESPONSE ASSESSMENT OF BRAIN TUMORS: A SYSTEMATIC REVIEW
Authors: T Shi, C Linares, T Vercauteren, T Booth
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Longitudinal assessment of tumor burden using imaging helps to determine whether there has been a response to treatment both in trial and real-world settings. From a clinical trial perspective, the time to develop disease progression (progression free survival) is an important endpoint. However, longitudinal response assessment is time-consuming and subject to interobserver variability. Automated response assessment techniques based on machine learning (ML) promise to enhance accuracy and reduce reliance on expert manual measurement. This systematic review evaluates the quality and performance accuracy of recently published studies. MATERIAL AND METHODS Following PRISMA guidelines and the CLAIM checklist, we searched PUBMED, EMBASE, and Web of Science for articles from January 2010 to November 2023. Our PROSPERO-registered study (CRD42024496126) focused on adult brain tumor treatment response assessment studies using ML methodologies. We determined the extent of development and validation of the automated tools and employed QUADAS-2 for study appraisal. RESULTS Eighteen studies, including fifteen retrospective and three prospective studies, were included. Data extracted from each study included information on the dataset, automated steps within the pipeline, automated models (referred to as index tests), and reference standards. Only limited conclusions are appropriate given the high bias risk and applicability concerns (particularly in relation to reference standards and patient selection), and the low level of evidence. CONCLUSION The study highlights ML’s potential in improving brain tumor longitudinal treatment response assessment. Interpretation is limited due to study bias and limited evidence of generalizability. Prospective studies with external datasets validating the latest neuro-oncology criteria are now required.
P07.03.B THE EFFECT OF SEX HORMONES ON THE COURSE OF MENINGIOMAS IN DIFFERENT HORMONAL PHASES IN THE FEMALE LIFE
Authors: A Taliansky, O Haisraely, N Atar, E Jan, D Modan-Moses
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The influence of gender on the incidence and the survival of patients with nervous system tumors (NST) is well known, but the mechanism is not fully understood yet. The effect of sex hormones on the course of NST in different hormonal phases in female life raises interest, but only the pregnancy condition has been discussed in detail, however, consensus has not been reached regarding clinical recommendations. Descriptions of the effect of fertility treatments (FT) on NST are in a few not recent reports. The importance of sex hormones replacement treatment (HRT) as a risk factor for radiation induced tumors in patients after radiotherapy for childhood NST has not been studied yet. MATERIAL AND METHODS We retrospectively evaluated the data of three cases of high-grade meningiomas in women of reproductive age treated in the Neuro-oncology unit at Sheba MC. RESULTS One case is a 41 years old woman, who received two cycles of FT in 2022 and was diagnosed with a Rt. Frontal WHO 2 meningioma on April 2023 that was treated by gross total resection (GTR). The second case is a 32 years old woman treated with radiotherapy and chemotherapy at age 10 years due to medulloblastoma, who on January 2023 was diagnosed and had GTR for a Lt. Frontal WHO 2 meningioma after 1 year of HRT. The last case is a 28 years old woman that had GTR for a Rt cerebellar WHO 2 meningioma in 2020. During 2023 the patient had FT for surrogate pregnancy and on February 2024 recurrent tumor was diagnosed and treated with radiosurgery. CONCLUSION There is not much information available regarding the effect of sex hormones on the course of meningiomas, possibly due to the low incidence of meningiomas during the reproductive years. In Israel, fertility treatments are included in the national healthcare and the number of treatment cycles is not limited. This allows the collection of information about the effect of fertility treatments on NST, especially meningiomas in women. This project initiated this year. A phenomenon of “ social” egg freezing that has been expanding in recent years caused an increase in the number of women applying for fertility treatments and the need for a large number of treatment cycles. Since the incidence of meningiomas increases with age, presumably, the use of fertility treatments at an older age may affect the incidence and the grade of meningiomas in women. We would like to raise the importance of this topic.
P10.07.B AN INNOVATIVE CELL TYPE-PAIRED SINGLE-CELL RNA SEQUENCING APPROACH DECIPHERING GLIOBLASTOMA HETEROGENEITY FOR THE IDENTIFICATION OF NOVEL SUBGROUPS WITH THERAPEUTIC POTENTIAL
Authors: A Grimaldi, C Esposito, V Ducret, M Lubrano, C Thiriez, C Maussion, L Fidon, C Hoffmann
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GB) is an aggressive brain cancer with poor prognosis and limited effective treatment. Many challenges hinder the success of anti-cancer therapies such as drug resistance, low surgical and pharmacological accessibility, and migration of cancer cell to nearing brain tissue. The origin of the tumoral population is often evasive due to a high tumoral cell heterogeneity, impeding drug discovery strategies. MATERIAL AND METHODS This study uses the public scRNAseq atlas ExtendedGBMap (Ruiz-Moreno et al., 2022). The processed dataset was filtered to only keep 48 patient samples that contributed both tumor and normal cells, and only 8 cell types were selected, consisting of 4 tumor/healthy pairs: Astrocyte-like/Astrocyte cells, (50335/201 cells), Mesenchymal-like/Mural cells (32795/2528 cells), Neuron Progenitor-like/Neuron cells (8580/1091 cells) and Oligodendritic Progenitor-like/Oligodendritic Progenitor cells (38684/933 cells). All other cells were excluded. Patient-wise differential expression analysis was performed comparing tumor versus healthy cells, independently of cell-type, using scanpy.tl.rank_genes_groups default t-test, and patient were clustered based on their statistical test scores for each gene in the matrix using the k-means algorithm. Genes were ranked based on their statistical score, and gene set enrichment analysis was carried out using the WikiPathways, GO:MolecularFunction, Reactome, and Hallmark databases. RESULTS This novel scRNAseq and paired tumor-healthy comparison based approach unraveled 3 main GB groups with distinct transcriptomic profiles. Group1 was enriched in DNA replication, glycolytic metabolism, amino-acid production, and Hypoxia. Group2 exhibited known activities of epithelial-to-mesenchymal transition, miRNA in cancer, and chondroitin/dermatan sulfate biosynthesis. Group3 was comprised of patients that did not seem to belong to any of the 2 groups, but that did not share any specific gene signature. CONCLUSION We present a new approach to GB patient subgroup identification with a potential for target discovery, exploiting bystander normal cells in high-throughput scRNAseq. This method partially overcomes inter-patient and intra-patient tumor heterogeneity and may support new therapeutic avenues for GB patients. We aim at validating and enriching this approach with paired scRNAseq and Spatial Transcriptomic data from the MOSAIC consortium.
OS02.4.A CAREGIVER PROGRAM IN NEURO-ONCOLOGY: UCSF EXPERIENCE CARING FOR MORE THAN 4,000 CAREGIVERS OVER THE LAST 10 YEARS
Authors: J W Taylor, M Page, E Rodriguez Almaraz, D Angelo, C Velasco, S M Chang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Caregivers of patients with primary brain tumors are at high risk for distress and as they navigate caring for their loved one with both a cancer diagnosis and neurologic disorder. The last decade has seen growth of caregiver research in the brain tumor community, with evidence that caregiver mastery may correlate with survival in patients with glioblastoma (GBM). The UCSF Gordon Murray Neuro-Oncology Program, the first of its kind, launched in 2014 with a mission to address their unique needs. Caregiver care is now fully integrated into the clinical care of patients with brain tumors at UCSF, providing personalized care across the disease trajectory and programming to address common challenges and foster resilience. The Program includes a nurse, administrator, and social worker. Referrals occur 1) at first clinic appointment; 2) from clinical staff; and 3) caregivers of patients with GBM receive proactive outreach over the first 6 months after diagnosis. Caregivers are also contacted for bereavement support. Dedicated programming provides educational materials focusing on common concerns and building community through monthly support groups, educational webinars, annual retreats and family camp. We report our practical experience of the Program serving over 4,000 caregivers since its inception. MATERIAL AND METHODS Total number of individual caregivers were included from 01/2014 - 12/2023. Detailed demographic information was extrapolated during clinical interviews from a subset. Information regarding caregiver concerns and interventions was extracted from the medical records between 01/2017 - 12/2023. RESULTS The UCSF Gordon Murray Caregiver serves an annual average of 400 caregivers and over 800 encounters. Demographic information obtained from a subset revealed 66% females; 77% between 41-64 years of age; 60% a spouse; 89% working full time; and 30% had children in the home. The most common concerns for caregivers were informational (42%), followed by emotional (25%), and practical (23%). Examples of informational concerns included desire for informational resources, understanding the treatment plan/side effects, and understanding patient behavioral changes. Emotionally, they feel overwhelmed, uncertain, and sad. Practical concerns included physically caring for patients and issues around medical insurance, disability, and finances. Caregivers also expressed frequent concerns around talking with children/family members and feelings of isolation. CONCLUSION Caregivers of patients with primary brain tumors are at high risk of distress and have unique needs based on the tumor location and symptoms from treatment. Our practical 10 year experience of a dedicated, fully integrated, caregiver program highlights real world concerns of caregivers and identifies opportunities to develop tailored interventions to address these needs.