tbuckley/cabot-search huggingface dataset:
TMIC-51. NEUROIMMUNE-COMPETENT ORGANOID MODELING OF MICROGLIA/TUMOR INTERACTIONS AND DRUG RESPONSIVENESS
Authors: Katharina Sarnow, Emma Majercak, Qurbonali Qurbonov, Gustavo Alencastro Veiga Cruzeiro, Andrezza Do Nascimento Silva, Ishraq Haque, Daeun Jeong, Lissa Baird, Mariella Filbin, Xin Tang
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Due to its highly aggressive and infiltrative nature, lack of effective treatment options and localization in the skull base, diffuse intrinsic pontine glioma (DIPG) is universally fatal with less than a year median survival time. Studying how DIPG cells interact with brain cells in its microenvironment, including microglia which is the primary brain immune cell type, may lead to new therapeutic strategies to halt the invasion of DIPG into brain tissue. We developed a clinically relevant human immunocompetent brain organoid-DIPG fusion model for investigating the tumor invasion process at the cellular and molecular levels. METHODS Neuronal progenitor and GFP-labeled myeloid precursor cells were derived from human embryonic stem cells and combined to self-assemble and co-develop over two months into microglia-containing brain organoids (MiCBOs). The development of the MiCBOs as well as the distribution and motility of the microglia within the brain organoid was characterized by confocal and multiphoton microscopy, immunofluorescence staining and Western Blots. Confocal live-cell imaging was used to investigate the invasion of TdTomato-labeled tumor cells into MiCBO. We further performed single-cell RNA-Sequencing (scRNA-Seq) analysis to gain insight into the cell-specific gene expression changes after the confrontation of the MiCBOs with tumor spheroids. RESULTS MiCBOs contain viable, widely distributed and highly motile microglia as well as functionally mature neurons, highly resembling those in the human brain. scRNA-Seq showed distinct gene expression patterns in both microglia and tumor cells after confronting MiCBOs with DIPG spheroids, suggesting candidate signaling pathways between those two cell types. CONCLUSION Our novel MiCBO-DIPG fusion model provides a pathophysiologically-relevant system to elucidate molecular mechanisms underlying cell-cell interactions during tumor invasion in a human brain tissue context. This scalable model can be adapted to drug screening applications to identify therapeutics that modulate neuroimmune/tumor interactions and to establish the therapeutic index for anti-cancer medications.
EXTH-18. ADAPTER CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY TARGETING SSTR2 IN MENINGIOMA
Authors: Jiawei Chen, Christian Pellegrino, Maximilian Mastall, Frank Szulzewsky, Mitchell Bijnen, Hannah Van Hove, Nicholas Favalli, Gabriele Bassi, Vlad Moisoiu, Flavio Vasella, Luis Padevit, Marian Neidert, Patrick Cimino, Regina Reimann, Patrick Roth, Markus Manz, Melanie Greter, Eric Holland, Dario Neri, Michael Weller, Hans-Georg Wirsching
Journal: Neuro-Oncology (2024)

Abstract Effective treatment options for meningioma patients beyond surgical resection and radiotherapy are limited. This study presents preclinical and translational evidence supporting the efficacy of an adaptor CAR-T cell system targeting Somatostatin Receptor (SSTR) 2 in otherwise untreatable meningiomas. Tissue microarray analysis revealed that SSTR2 expression was generally heterogeneous but high or intermediate in most World Health Organization (WHO) grade 2 (87.8%) and grade 3 (87.5%) meningiomas. The fluorescein-linked, SSTR2 antagonist peptide octofluo was used in conjunction with adaptor FITC (AdFITC) CAR-T cells to treat experimental meningiomas. In vitro, 10 nM octofluo induced tumor cell killing within 72 hours at effector-target cell ratios (E:T) as low as 1:100. This was observed in two human meningioma cell lines, Ben-Men-1 (CAR-T cells vs. untransduced T-cells [UTT]: 47.9% vs. 4.7%, P &amp;lt; 0.001) and IOMM-Lee (CAR-T cells vs. UTT: 40.2% vs. 4.9%, P &amp;lt; 0.001). In vivo, the AdFITC CAR-T cell system inhibited meningioma growth (P = 0.002) and prolonged survival (P = 0.003) in the IOMM-Lee orthotopic model compared to PBS. In a genetically engineered murine meningioma model, the AdFITC CAR-T cell system not only restricted tumor growth (P = 0.0018) and improved survival (P &amp;lt; 0.0001), but cured a substantial proportion of meningioma bearing mice. This treatment also induced the expansion of both CD8+ CAR-T cells (P = 0.0041) and a host T-cell response. Preliminary ex vivo killing assays, involving co-culture of the AdFITC CAR-T cell system with patient-derived meningioma tissue, showed specific lysis rates of 15-20% (ET 1:1) within 12 hours. Targeting SSTR2 with the AdFITC CAR-T cell system emerges as a promising therapeutic approach for meningioma, an early phase clinical trial is warranted.
BIOM-53. LOW-PASS WHOLE GENOME SEQUENCING OF CEREBROSPINAL FLUID IDENTIFIES TUMOR AGNOSTIC TP53 ABERRATIONS IN LEPTOMENINGEAL METASTATIC DISEASE
Authors: Rachna Malani, Yingqi Zhang, Charlie Dean, Laura Boatz, Brion Harrison, Mei Wei, Wallace Akerley, Marry Bronner, Hunter Underhill
Journal: Neuro-Oncology (2024)

Abstract Leptomeningeal metastatic disease (LMD) is the spread of cancer cells into the cerebrospinal fluid (CSF)-filled spaces surrounding the central nervous system (CNS). Once LMD occurs, patients endure devastating neurologic symptoms and survive for only a few weeks to months. The clinical diagnosis of LMD has risen as patient survival from non-CNS metastatic disease improves. Unfortunately, detection of LMD even in symptomatic patients is &amp;lt;50% using the current gold standard – CSF cytology. Therefore, a strong clinical need exists for the sensitive and early detection of LMD. Here, we sought to develop a minimally invasive liquid biopsy approach to diagnose LMD using next-generation sequencing. Because copy number variations (CNVs) are common in cancer and increase after chemoradiation, we hypothesized that CNV detection in CSF may offer a means to detect LMD since patients have already undergone treatment for the underlying disease. Specifically, we sought to develop low-pass whole genome sequencing (lpWGS) of cell-free DNA in CSF to detect CNVs associated with LMD. A novel lpWGS algorithm was developed using FASTQ files trimmed to 30 million total paired reads. The genome was partitioned into one million continuous base pair segments excluding problematic areas yielding 2,445 regions across 22 autosomes. Control samples were used to model the read depth for each region to establish the euploid state. Read depth across the genome for all samples was 0.6X. CSF samples from lung cancer, breast cancer, and melanoma patients with LMD demonstrated prominent evidence of monosomies and trisomies throughout the genome. Lung cancer exhibited frequent amplifications (&amp;gt;4-fold). Notably, we observed 17p monosomy in CSF regardless of cancer type which indicates TP53 haploinsufficiency may support LMD progression, a conjecture supported by a codeletion of TP53 in one patient. lpWGS detects LMD in solid tumor cancers and may also identify novel mechanisms for LMD progression.
QOL-13. FROM SURVIVING TO THRIVING WITH A BRAIN TUMOR: THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO NEUROONCOLOGY MODEL FOR AN EMPOWERED AND ENGAGED PEER VOLUNTEER SUPPORT COMMUNITY
Authors: Naomi Hoffer, Eduardo Rodriguez-Almaraz, Mary Lacy Fetting, Elizabeth Choi, Mary Destri, Jennie Taylor, Susan Chang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain tumor patients often experience feelings of isolation, identity loss, and existential distress, and peer support can have a positive impact in these areas. Providing peer support, however, can be emotionally demanding and presents unique challenges for neuro-oncology patient volunteers, with little guidance available to address these issues. We describe an innovative program that supports volunteers and provides a roadmap for implementing peer volunteer programs in clinical neuro-oncology practices. METHODS In 2020, the UCSF Sheri Sobrato Brain Cancer Survivorship Program established an initiative to match brain tumor patients seeking support with trained patient volunteers. To address potential challenges, an optional, ongoing support community for volunteers was created by a health coach educator, with co-facilitation from a rehabilitation neuropsychologist and a social worker. The weekly meetings included supplemental training, personal check-ins, and group discussions. Volunteer feedback was collected through direct volunteer communication with the facilitator and an annual online survey. RESULTS From August 2020 through October 2023, 46 peer volunteers were trained in six cohorts. There were 116 patients requesting peer support. In total 132 volunteer-patient matches were made for an average of 2.87 matches per volunteer. Seventy percent of volunteers attended 11 or more meetings/year. Average attendance was 12 volunteers per meeting. All respondents to the annual online survey (n=31) reported a high level of satisfaction with the program. Volunteers highlighted benefits such as mutual support, impactful contributions, and personal growth and empowerment. Volunteers who reported higher levels of preparedness attended &amp;gt;11 meetings per year. DISCUSSION In our experience, patient peer volunteer programs show promise in reducing isolation and restoring purpose. This unique 3-year pilot suggests that ongoing group support and training is a plausible and effective way to enhance a peer volunteer program. Future efforts will focus on developing a structured curriculum for neuro-oncology patient peer volunteers.
EPCO-51. A MULTI-OMIC ANALYSIS OF REGIONAL HETEROGENEITY IN GLIOBLASTOMA
Authors: Yosef Ellenbogen, Alexander Landry, Jeff Liu, Yiyan Wu, Federico Gaiti, Gelareh Zadeh
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is the most common malignant brain tumor in adults. A hallmark of GBM is its intratumoral heterogeneity as well as infiltration into the surrounding brain. The growing understanding of the cellular diversity and cellular state diversity within GBM necessitates a need for a more granular evaluation of the molecular landscape of this disease. This study aimed to investigate this using single cell RNA sequencing combined with single-cell ATAC sequencing and spatial transcriptomics in order to delineate cellular states and enriched pathways between malignant cells in different regions of GBM. The study cohort consisted of 15 patients with primary GBM. Tumor samples were taken at the time of surgical resection using intraoperative stereotactic navigation from three anatomically distinct locations: periphery – the cortex or white matter in the peri-tumoral region that is beyond contrast-enhancing tumor, border – the contrast-enhancing border of the tumor on T1-weighted MRI, and core - the hypointense core region on T1-weighted MRI. Samples underwent combined snRNA and ATAC sequencing (10x Multiome) as well as spatial transcriptomics (10x Visium). Single-nucleus RNA + ATAC sequencing captured a total of 37,547 neoplastic cells and 18,498 non-neoplastic cells within the tumor microenvironment. The majority of non-neoplastic cells were identified within the periphery alongside a distinct group of neoplastic cells that exhibited unique a unique distribution of malignant cellular state and differentially regulated genetic pathways compared to malignant cells within the tumor border and core. Gene regulatory analysis of the malignant cells in the periphery identified a previously undefined set of enriched transcription factors that are periphery-specific regulon drivers. Overall, this analysis sheds light on the genetic and epigenetic differences between malignant GBM cells based on their location and warrant further investigation into the biology and targetable aspects of the malignant cells that exist beyond the contrast-enhancing border of the tumor.
INNV-38. 3 DAYS-ON-1 DAY-OFF FRACTIONATED USE PROTOCOL FOR IMPROVED COMPLIANCE AND PREVENTATIVE SKIN SAFETY FOR USE OF TUMOR TREATING FIELDS: PRACTICE IMPROVEMENT STRATEGY IN NEURO-ONCOLOGY
Authors: Na Tosha Gatson, Erika Leese, Sara Ornelas, Ramya Tadipatri, Jesse Manikowski, Chirag Patel, Yazmin Odia
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Compassionate care delivery requires that providers understand patient values and adopt practices aimed to improve the quality of extended survival. Many brain tumor clinical trials measure survival outcomes based on therapeutic interventions, but often fail to anticipate patient noncompliance and the provider’s ability to communicate the plan. Tumor Treating Fields (TTFields) is an FDA-approved locoregional, noninvasive therapy worn on the scalp to treat glioblastoma (GBM). When worn, TTFields therapy disrupts cancer cell viability and delays tumor progression but is complicated by mild-moderate skin irritation and real-world inconvenience of the unclear recommendation to wear the device an average of “≥18 hours/day or 75% of the time”. We simplified the physician instructions to encourage patient compliance and skin safety on TTFields. METHODS Adults with GBM were provided an easy-to-follow flow chart and advised across multiple centers to follow the 3-days-on (72 hours) and 1-day-off (16–24 hours) TTFields therapy use schedule and given skin-specific wound prevention guidance (cleansing selenium-based shampoo and reparative skin-barrier moisturizing) during the ‘off day’. We evaluated the ease to explain the 3-on-1-off schedule, patient adherence, and the presence and severity of skin AEs during follow-up visits. REAL-WORLD PRACTICE OUTCOMES Seventy-six patients received TTFields therapy using the 3-on-1-off protocol between 2015 and 2021 at two US healthcare centers. The median age was 57 years (range 25–81). The mean time on TTFields therapy was 73 weeks. Skin AEs occurred in 5% of patients on the 3-on-1-off protocol, as compared to 16% and 52% reported on EF-11 (NCT00379470) and EF-14 (NCT00916409) GBM studies, respectively. Majority of AEs were mild, and no patients discontinued TTFields therapy or modified electrode placement due to skin AEs while on the 3-on-1-off protocol. CONCLUSION We report real-world data confirming a practice improvement for patient compliance using a novel 3-on-1-off protocol which minimizes skin AEs and treatment interruptions to improves patient outcomes. An ounce of prevention is worth a pound of cure.
PATH-06. TRANSLATION INTO CLINICAL PRACTICE OF THE G1-G7 MOLECULAR SUBGROUP CLASSIFICATION OF GLIOBLASTOMA
Authors: Maria-Magdalena Georgescu
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma is the most frequent and malignant primary brain neoplasm. Glioblastoma growth is promoted by alterations in mediators from five major pathways: MAPK and PI3K canonical growth pathways, telomere elongation/TERT, cell cycle G1-phase and the p53 pathway. In a recent breakthrough study on a prospective Discovery cohort, I proposed the first all-inclusive molecular classification of glioblastoma into seven subgroups, G1-G7, based on MAPK pathway activation. New data from a subsequent, prospective Validation cohort validated the G1-G7 molecular subgroup classification, showing significant demographic and molecular differences between subgroups. Beside the initial histologic diagnosis, the G1-G7 classification requires next generation sequencing (NGS) of formalin-fixed paraffin-embeded (FFPE) samples and genomic-transcriptomic correlations between DNA mutations, copy number variations (CNVs) and RNA expression. Thus, in the Combined cohort containing tumors from over 220 glioblastoma patients, aproximately 75% of cases fell into three major subgroups, G1/EGFR, G3/NF1 and G7/Other, whereas the rest of 25% cases made up the four minor subgroups, G2/FGFR3, G4/RAF, G5/PDGFRA and G6/Multi-RTK. The name of the mutated most upstream, non-redundant, MAPK pathway effector corresponds to each subgroup, except for the G7/Other subgroup in which MAPK activation is minimal and PI3K pathway activation is dominant. The effectors of the other four pathways may be redundant; however, genomic-transcriptomic correlations showed subgroup specificity, with opposing trends for the G1/EGFR and G7/Other molecular subgroups. This first, all-inclusive, molecular subgroup classification of glioblastoma in a large prospective patient cohort allowed integrated pathway analysis, risk stratification and demographic comparison between Caucasian/White and African-American/Black patients. Most importantly, its implementation into clinical practice opened the avenue to controlled therapeutic approaches.
EPCO-29. PATHOMICS ANALYSIS IDENTIFIES POTENTIAL SUBTYPES OF DIFFUSE GLIOMAS IN H&amp;E-STAINED WHOLE-SLIDE IMAGES
Authors: Aline Becker, Jany Chan, Jason Weible, Raghu Machiraju, Arnab Chakravarti
Journal: Neuro-Oncology (2024)

Abstract IDH status is the first criteria of diagnostic definition for diffuse gliomas in the 2021 WHO classification. While sufficient number of molecular tools are available to identify IDH1 and/or IDH2 mutations, they impose a time and cost burden on patients. We previously trained deep learning models visually differentiate IDH wild-type (IDHwt) and IDH mutant (IDHmut) gliomas in a small set of H&amp;E-stained whole image slides (WSIs) from TCGA using an Uncertainty-Aware Convolutional Neural Network (CNN) at 10x magnification. In this follow-up study, we aimed to improve our models by expanding our annotations of a more representative subset of the TCGA public data, increasing the sampling magnification to 20x, redesigning the preprocessing filters, adjusting the training pipeline to reduce overfitting, and assessing the confidence in model prediction via uncertainty metrics. METHODS By modifying the pre-processing methods from our pilot study, we increased the number of expert-annotated WSIs. Using a 2:1:2 train/validation/test split, we fine-tuned a ResNet18 deep learning model with a pre-trained feature extractor and Monte Carlo dropouts. To identify image features critical for separating by IDH status, we extracted the learned embeddings and performed post-hoc analyses (PCA, t-SNE, and UMAP). RESULTS The new set of annotations resulted in ~15-fold increase in the number of WSIs (i.e.,&amp;gt;2.5 million tiles), without any data augmentation. Our prototype model demonstrated clear separation of cases according to IDH status (sensitivity = 0.63, specificity = 0.91, weighted F1 = 0.81). CONCLUSION We successfully improved the prediction of IDH status in H&amp;E-stained WSIs and identified potential subtypes of IDHwt and IDHmut diffuse gliomas after significantly increasing the dataset size with appropriate expert annotations. We are currently addressing the data imbalance by annotating additional IDHmut glioma WSIs. Furthermore, we will integrate other biomarkers (1p19q, EGFR etc.) to increase the robustness of histo-pathomics as a surrogate for molecular tests.
ANGI-03. GLIOMA STEM CELLS INDUCE VASECTASIA – A NON-ANGIOGENIC BRAIN TUMOUR NEOVASCULARIZATION PROCESS DRIVEN BY INTERCELLULAR EGFR TRANSFER THROUGH EXTRACELLULAR VESICLES
Authors: Janusz Rak, Cristiana Spinelli, Lata Adnani, Fang Cheng Wong, Brian Meehan, Laura Montermini, Sidong Huang, Minjun Kim, Tamiko Nishimura, Sidney Croul, Ichiro Nakano, Yasser Riazalhosseini
Journal: Neuro-Oncology (2024)

Abstract Tumour neovascularization in glioblastoma (GBM) is abundant, abnormal and poorly understood, and it likely involves multiple co-existing mechnanisms with distinct modes of regulation. Since glioma stem cells (GSCs) engage in bidirectional interactions with the vasculature we dissected the resulting vascular responses elicited by either proneural (PN), or mesenchymal (MES) GSC subtypes established from patients isolates and able to drive progression of orthotopic intracranial xenografts in mice. We report here that while PN-GSCs elicited mostly angiogenesis-type vascular capillary growth processes, their MES-GSC counterparts elicited non-angiogenic growth of enlarged vessels (vasectesia), paradoxically associated with reduced blood vessel density. Vasectasia was dependent on the expression of oncogenic EGFR/EGFRvIII by MES-GSCs, and on the related kinase/signalling activity, as EGFR/EGFRvIII gene disruption and Dacomitinib treatment suppressed formation of large blood vessels in vivo and resulted in a preponderance of a small calliber (angiogenic) vasculature throughout xenografts. Notably, the analysis of spatial transcriptomes and single cell RNA sequencing revealed distinct molecular traits of endothelial cells asociated with vasectasia and angiogesis, the former enriched in Birc5, but depleted for angiogenic tip cell markers (Vegfr2, Apln). Mechnaistically, vasectasia was linked to the intercellular transfer of EGFR from MES-GSCs to endothelial cells resulting in ectopic activation of EGFR signalling in the endothelial cell bacground, both in vitro and in a model of in vivo blood vessel recruitment into implanted matrigel pellets. Simultaneous pharmacological blockade of both, angiogenesis (anti-VEGR2) and vasectasia (Dacomitinib) lead to a marked increase in survival of mice with aggressive GBM lesions initiated by MES-GSCs. We suggest that, vasectasia driven by intercellular transfer of oncogenic EGFR may represent a new, subtype-specific mechanism of GBM neovascularization, and a plausible target for agents aiming to modify vascular tumour microenvironment.
NCOG-30. FACTORS ASSOCIATED WITH COGNITIVE IMPAIRMENT IN LONG-TERM IDH-MUTANT GLIOMA SURVIVORS
Authors: Tyler Lanman, Hana Gross, Caylin M Faria, Julie Miller, Daniel P Cahill, Helen Shih, Giuliana Zarella, Jorg Dietrich, Michael Parsons
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Cognitive deficits are less frequent in patients with IDH mutant (IDHm) than wild-type glioma at time of diagnosis, but less is known about factors that influence cognition for long-term survivors. We evaluated long-term neuropsychological outcomes of patients with IDHm glioma. METHODS Patients with IDHm glioma who underwent clinical neuropsychological assessment at Massachusetts General Hospital 3+ years after diagnosis were included and compared to a previously published cohort of IDHm patients tested prior to surgery/diagnosis (Wefel et al., 2016). RESULTS Sixty-three patients were included for analysis (54% male; median age 45 [range 21-75], 16 years of education, and 7 years from diagnosis [range 3-28]). Thirty-eight patients (60%) had astrocytoma and 24 (40%) had oligodendroglioma; 28 (44%) were grade 2, 31 (49%) grade 3, and 4 (6%) grade 4. Fifty-five patients (87%) received radiation and 51 (81%) received chemotherapy. Cognitive impairment (defined as Z score ≤-1.5 on at least two tests) was present in 30 patients (48%) and was associated with lower scores in neurologic aspects of quality of life (QoL; p&amp;lt;0.01), grade 3/4 relative to grade 2 (p=0.01), older age (p=0.03), left-sided lateralization (p=0.02), and less education (p=0.01). Prior radiation (p=0.07) and photon relative to proton radiation (p=0.06) trended toward poorer function. Tumor type, disease duration, and extent of resection were not significant factors (p&amp;gt;0.05). Compared to the pre-diagnosis IDHm cohort, impairment was significantly more common on tests of processing speed and language. Learning/memory, executive, and visuospatial function trended toward more frequent impairment but were not significant. Attention had comparable frequency of impairment. CONCLUSIONS In this cohort of IDHm glioma survivors, neurocognitive deficits were common, related to QoL, and associated with some expected clinical factors, but not length of survival. These findings emphasize the need for future research on interventions aimed at supporting patients’ neurocognitive abilities and QoL.