tbuckley/cabot-search huggingface dataset:
BIOM-21. SMALL EXTRACELLULAR VESICLES AS A NOVEL LIQUID BIOPSY APPROACH FOR GLIOBLASTOMA
Authors: Yangen He, Ashish Kumar, Sangeeta Singh, Susy Kim, Yixin Su, Denise Herpai, Ashley Fansler, Christopher Whitlow, Roy Strowd, Waldemar Debinski, Glenn Lesser, Gagan Deep
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) remains the most common and aggressive primary malignant brain tumor, with limited treatment options and poor overall survival. Diagnosis, prognosis, and assessment of treatment effectiveness are hampered by the lack of sensitive, tumor-specific, non-invasive blood-based assays which could be followed serially. Small extracellular vesicles (sEV) are nano-sized (≤200 nm) membrane-bound bodies secreted by all cells, encapsulating cargo reflective of their parent cells. sEVs have emerged as promising molecular disease indicators. Here, we report the feasibility of isolating glioma-specific sEV (sEVglioma) from plasma and characterizing them for GBM-specific molecular biomarkers. Plasma samples were collected from 31 glioma patients (grades 3 and 4 GBM, grades 2 and 3 astrocytoma) and 9 healthy individuals. Total sEVs (TE) were isolated from plasma by a modified precipitation (ExoQuick™) method, followed by immunoprecipitation to isolate sEVglioma employing surface markers targeting the cellular origin of gliomas, including astrocyte (GLAST and EAAT2), oligodendrocyte precursor cell (OSP and MOG), and neural stem cell (CD133). The average size of sEVglioma was less than 200 nm. Importantly, compared to TE, sEVglioma showed significant enrichment for glioma-specific biomarkers such as ephrin type-A receptor 2 (14.7-fold), tenascin-C (22.7-fold), and glial fibrillary acidic protein (8.4-fold). Similarly, sEVglioma demonstrated higher expression of the GBM biomarker EGFRvIII (3.6-fold). These results were confirmed by confocal microscopy. Interestingly, the expression of specific miRNAs (miR-9a-5p, miR-16-5p, miR-21-5p) in sEVglioma was higher in glioma patients with shorter survival (&amp;lt;12 months) compared to longer survival (&amp;gt;20 months). Lastly, we successfully detected the existence of wild-type IDH1 and absence of mutated IDH1 R132H in sEVglioma from GBM patients, validated with cell line experiments. In conclusion, we present a novel liquid biopsy approach for isolating sEVglioma from blood, providing valuable molecular and genetic information. This approach promises early detection, potential to distinguish pseudo-progression, and assessment of treatment effectiveness with remarkable precision.
DDEL-15. PHARMACOKINETIC ANALYSIS OF CARBOPLATIN AND FLUORESCEIN BRAIN PENETRATION AND PERMANENCE FOLLOWING ULTRASOUND-BASED BLOOD-BRAIN BARRIER OPENING ON GLIOBLASTOMA CLINICAL TRIAL
Authors: Karl J Habashy, Tim Synold, Ye Feng, Kwang-Soo Kim, Cristal Gomez, Christina Amidei, Rachel Ward, Sarah VanderMolen, Ashkan Zarrieneh, Victor A Arrieta, Jawad Fares, Kirsten B Burdett, Hui Zhang, Crismita Dmello, Li Chen, John F Bebawy, Michael Canney, Roger Stupp, Jana Portnow, Adam M Sonabend
Journal: Neuro-Oncology (2024)

Abstract The blood-brain barrier (BBB) impedes the passage of most circulating drugs into the brain. Low-intensity pulsed ultrasound with microbubbles (LIPU/MB) transiently opens the BBB, improving drug delivery to the brain. The implication of this transient BBB opening on parenchymal drug permanence is unknown. We compared the parenchymal levels and permanence/retention of temozolomide, carboplatin, and fluorescein, and investigated in a clinical trial (NCT04528680) the effect of LIPU/MB on the permanence of carboplatin and fluorescein in the human brain. Four patients underwent intraoperative LIPU/MB (SonoCloud-9, Carthera) with intravenous carboplatin and fluorescein infusion. Microdialysis catheters were implanted into sonicated and non-sonicated brain for continuous drug measurement over 24 hours. Published data from a microdialysis study of temozolomide were used for comparison. Temozolomide and carboplatin exhibited similar brain-to-plasma AUC ratios (17.8 ± 13.3%; 16.3 ± 8.2%, respectively) which were higher than that of fluorescein (10.4 ± 6.9%). Parenchymal half-life was the longest for fluorescein (13.6 ± 11.0 hours), followed by carboplatin (5.1 ± 1.9 hours) and temozolomide (2.9 ± 1.6 hours). LIPU/MB led to sustained elevated parenchymal drug concentrations, achieving a 3.1-fold increase in AUC for both carboplatin (P = 0.02), and fluorescein (P = 0.04), and higher parenchymal than systemic drug levels starting at 21 hours and 7 hours for these drugs respectively (P &amp;lt; 0.05), timepoints where these drugs had mostly cleared from the plasma. Fluorescein exhibits prolonged permanence in the brain parenchyma and may be “trapped” by the BBB. In the context of transient BBB opening by LIPU/MB, parenchymal carboplatin and fluorescein concentrations remain elevated over time, supporting the notion that the BBB exhibits a bi-directional restriction of drug passage. Future studies are warranted to explore the efficacy of drug trapping to achieve prolonged/sustained exposure of cytotoxic drugs for brain tumor therapy.
NIMG-63. LEVERAGING LLMS FOR ACCURATE DIFFERENTIATION OF RADIATION NECROSIS AND TUMOR PROGRESSION IN BRAIN MRI REPORTS: A STUDY ON AUTOMATED SCORING AND CLINICAL IMPLICATIONS
Authors: Eulanca Liu, Shir Goldfinger, William Delery, Erika Jank, James Lamb, Stephen Tenn, John Hegde, Tania Kaprealian, Michael Steinberg, Ricky Savjani
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Accurate differentiation between radiation necrosis and tumor progression or recurrence in patients treated with stereotactic radiosurgery for brain metastases is critical for guiding clinical management. This study leverages the advanced natural language processing capabilities of Meta Llama3, an artificial intelligence (AI) large language model (LLM), combined with prompt engineering, to rapidly categorize brain magnetic resonance imaging (MRI) radiology reports. Our objective was to develop an automated scoring system to classify concern for radiation necrosis, tumor progression, equivocal findings, or stable exams. METHODS Using a comprehensive dataset of reports annotated by expert radiologists, we ran inference on a 70-billion parameter Llama3 model (temperature 0.2, top_p 0.9) with specific prompts designed to capture the nuanced language and diagnostic criteria related to radiation necrosis or tumor progression. RESULTS The first pass was performed on a training dataset of 107 reports and did not predefine the clinical conditions. This demonstrated 43.4% accuracy in scoring when compared to a human user’s classification of each report. Agreement between the human reader and Llama3 was assessed using the Gwet agreement coefficient, AC1=0.411 (99%CI 0.396-0.426). Multiple iterations of targeted prompt engineering were then employed to narrow the definition of radiation necrosis and tumor progression, with specific examples and nuanced language used to achieve a higher degree of accuracy at 72.0%, AC1=0.719 (99%CI 0.717-0.722). DISCUSSION/FUTURE DIRECTIONS This surpasses recent demonstration of lower human-LLM agreement in radiographic score assignment, with further room for calibration on a dataset of several thousand reports. Next, we will correlate automated interpretations with actual clinical management decisions for radiation necrosis (e.g., initiation of steroids, bevacizumab, Laser Interstitial Thermal Therapy, and/or repeat imaging). This automated scoring system holds significant potential for LLMs in clinical applications. Future work will focus on integrating this model into clinical workflows and expanding its capabilities to include longitudinal monitoring of patient outcomes.
INNV-07. IVOSIDENIB AND BEVACIZUMAB IN HEAVILY PRETREATED PATIENTS WITH IDH1 MUTANT GLIOMAS
Authors: Mallika P Patel, Michal Nisnboym Ziv, Maria Minor, Margaret O Johnson, Kristen Batich, Justin Low, Madison L Shoaf, Mustafa Khasraw, Henry S Friedman, David M Ashley, Annick Desjardins, Katherine B Peters
Journal: Neuro-Oncology (2024)

Abstract Isocitrate dehydrogenase 1 (IDH1) inhibitors are transforming the treatment of patients with non-enhancing IDH1 mutant gliomas that have only undergone surgical resection. Questions remain on the utility of IDH1 inhibitors in patients that have received prior therapies such as radiation therapy (RT) and chemotherapy (e.g. temozolomide (TMZ)) and have progressive disease. We evaluated the safety and efficacy of ivosidenib, an oral IDH1 inhibitor, in combination with bevacizumab (BEV), a monoclonal antibody targeting VEGF-A, in IDH1 mutant glioma patients that were heavily pretreated. Fourteen patients received combination ivosidenib and bevacizumab starting between February 2021 to July 2023. In our small cohort, patient age range was 26 to 73 years with seven female patients and seven male patients. Diagnoses represented were astrocytoma, IDH1 mutant (n=10) and oligodendroglioma, IDH1 mutant (n=4). At the time of IDH1 therapy initiation, the majority of patients (n=10) had a grade 3 tumor. All patients (n=14) had canonical IDH1 mutation (p.Arg132His) and had enhancing disease. Therapies initiated prior to ivosidenib therapy included: prior RT (n=12), prior TMZ (n=14) and prior BEV (n=10). The median number of progressions prior to initiation of ivosidenib combination therapy was 3 (range 2 to 6). All patients received ivosidenib dosed at 500 mg daily with bevacizumab doses varying from 5 to 15 mg/kg IV dosed every 2 to 3 weeks. Combination therapy was well tolerated with minimal patients experiencing toxicities requiring dose interruptions; diarrhea (n=2), creatine phosphokinase elevations (n=1), QTc prolongation (n=1), and thrombocytopenia (n=1). The median treatment duration on ivosidenib combination therapy was 4.42 months (range 0.69 to 11.4 months). In this cohort, the combination of ivosidenib and bevacizumab was well tolerated. More information is needed on the benefit of ivosidenib in combination with other therapies and in heavily pretreated patients with IDH1 mutant gliomas.
CCRG-01. MYT1 BLOCKADE AS A NOVEL GLIOMA THERAPEUTICS THROUGH ABROGATIING OF THE G2/M CELL CYCLE CHECKPOINT
Authors: Fengchao Lang, James Cornwell, Wei Zhang, Meili Zhang, Hua Song, Mirit Aladjem, Michael Aregger, Steven Cappell, Chunzhang Yang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The cell cycle is tightly regulated by checkpoints, which play a vital role in controlling its progression and timing. Cancer cells exploit the G2/M checkpoint, which serves as a resistance mechanism against genotoxic anticancer treatments, allowing for DNA repair prior to cell division. Manipulating cell cycle timing has emerged as a potential strategy to augment the effectiveness of DNA damage-based therapies. METHODS In this study, we conducted a forward genome-wide CRISPR/Cas9 screening with repeated exposure to the alkylating agent temozolomide (TMZ) to investigate the mechanisms underlying tumor cell survival under genotoxic stress. The screening hits were validated through in patient derived glioma cells and xenografts. RESULTS Our findings revealed that canonical DNA repair pathways, including the Ataxia–telangiectasia mutated (ATM)/Fanconi and mismatch repair, determine cell fate under genotoxic stress. Notably, we identified the critical role of PKMYT1, in ensuring cell survival. Depletion of PKMYT1 led to overwhelming TMZ-induced cytotoxicity in cancer cells. Isobologram analysis demonstrated potent drug synergy between alkylating agents and a Myt1 kinase inhibitor, RP-6306. Mechanistically, inhibiting Myt1 forced G2/M-arrested cells into an unscheduled transition to the mitotic phase without complete resolution of DNA damage. This forced entry into mitosis, along with persistent DNA damage, resulted in severe mitotic abnormalities. Ultimately, these aberrations led to mitotic exit with substantial apoptosis. Preclinical animal studies demonstrated that the combination regimen involving TMZ and RP-6306 prolonged the overall survival of glioma-bearing mice.
EPCO-20. MUTANT IDH INHIBITORS INDUCE LINEAGE DIFFERENTIATION IN IDH-MUTANT OLIGODENDROGLIOMA
Authors: Avishay Spitzer, Simon Gritsch, Masashi Nomura, Alexander Jucht, Jerome Fortin, Ramya Raviram, Hannah R Weisman, L Nicolas Gonzalez Castro, Nicholas Druck, Rony Chanoch-Myers, John J Y Lee, Ravindra Mylvaganam, Rachel Lee Servis, Jeremy Man Fung, Christine K Lee, Hiroaki Nagashima, Julie J Miller, Isabel Arrillaga-Romany, David N Louis, Hiroaki Wakimoto, Will Pisano, Patrick Y Wen, Tak W Mak, Marc Sanson, Mehdi Touat, Dan A Landau, Keith L Ligon, Daniel P Cahill, Mario L Suvà, Itay Tirosh
Journal: Neuro-Oncology (2024)

Abstract IDH-mutant gliomas exhibit variable responses to mutant-IDH inhibitor (IDHi) therapy; yet, the molecular mechanisms underlying these responses remain poorly understood. Here, we investigate the cellular underpinnings of response by leveraging single cell/nuclei RNA-sequencing of on-treatment IDH-mutant oligodendroglioma tumor samples resected from three patients who benefited clinically from treatment. We integrate these findings with single cell and bulk RNA-seq data from independent cohorts and experimental models. We find that IDHi treatment promotes robust differentiation towards the astrocytic lineage, accompanied by stem-like cell depletion and reduced proliferation. Notably, NOTCH1 mutations are associated with impaired astrocytic differentiation, potentially negatively impacting response to IDHi. This study unveils the differentiating effects of IDHi on oligodendroglioma cellular hierarchies and identifies a potential genetic marker for optimizing patient selection. Paper was recently published in Cancer Cell (10.1016/j.ccell.2024.03.008).
CTNI-40. PSYCHOLOGICAL DOMAINS CORRELATE WITH ADHERENCE IN TTFIELDS TREATMENT OF GLIOBLASTOMA
Authors: Martin Proescholdt, Amer Haj, Melissa Schmidmeier, Andreas Muehlberger, Nils-Ole Schmidt
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Adherence is critical to the success of the treatment with Tumor Treating Fields (TTFields) for Glioblastoma Multiforme (GBM). Previously found factors influencing treatment adherence in general are social support, belief in the efficacy of treatment, communication with physicians, anxiety, and depression. We propose those five factors predict adherence to TTFields treatment since, to our knowledge, no systematic data exists for this treatment. METHODS We conducted a longitudinal study and included 25 patients with newly diagnosed GBM who received treatment with TTFields. Participants were invited to take part in six structured interviews, each four weeks apart, during their treatment with TTFields, assessing the five factors expected to influence treatment adherence over time. RESULTS We found a significant impact of communication, anxiety, and depression on treatment adherence with TTFields. Furthermore, also the time point during treatment (days of treatment) was significantly related to adherence. Better physician communication and a higher level of anxiety were associated with higher adherence and higher depression with less adherence. A higher belief in efficacy showed a trend toward significantly improving treatment adherence. When results were separately compared for early, middle, and later 90-day treatment phases, factors seemed to be differentially influential, with belief in efficacy being significantly relevant in the first, efficacy, communication, and anxiety in the second, and depression in the third phase of treatment with TTFields. CONCLUSIONS Our findings not only confirm the predictive role of psychosocial factors in treatment adherence but also provide specific targets for psychological interventions. This suggests that by addressing these factors, healthcare providers can potentially increase treatment adherence among GBM patients. Moreover, our results indicate that these interventions may be most effective when tailored to the specific phase of treatment, offering a practical approach for healthcare providers.
EPCO-25. TRANSPOSABLE ELEMENTS INDUCE ONCO-EXAPTATION EVENTS IN MALIGNANT ATRX-DEFICIENT GLIOMAS
Authors: Prit Benny Malgulwar, William E Johnson, Sharvari Dharmaiah, Annette A Machado, Bhargavi Brahmendra Barathi, Lina Lu, Anand Singh, Ajay Saw, Carla Danussi, David Irwin, Kunal Rai, Ruli Gao, Jason T Huse
Journal: Neuro-Oncology (2024)

Abstract Deficiency of ATRX (Alpha Thalassemia/Mental Retardation Syndrome X-linked), a core member of SWI/SNF family chromatin regulator is altered in diffuse gliomas and coexist with IDH1/2 mutations in adults and histone G34R/V alterations in pediatric populations. Loss of ATRX has been associated with global alterations in chromatin accessibility and epigenomics landscape, however, the detail mechanism behind the oncogenic transformation remains elusive. Integrating transcriptomics and in-depth positional epigenome analysis over repetitive DNA sequences in progenitor and tumors models of murine and human gliomas, we describe ATRX-deficient gliomas is fundamentally a disease of altered Transposable Elements (TE’s) and regulates neuronal differentiation and cell motility in gliomas, as validated pharmacologically and genetically. Epigenome assessment reported de-repression of LINE-1 (Long interspersed nuclear elements-1), specifically at Lamina-Associated Domains (LADs) with gain of enhancer histone marks, with association in chromatin loops/topology in ATRX-deficient glioma cells. Moreover, our single cell-RNA seq analysis focusing on TE’s and molecular docking studies in human glioma stem cells demonstrated LINE-1 regulates oncogenic alternative splicing events and neuro-developmental signatures. Expanding the analysis, we identified a subset of evolutionary young regulatory TE’s to play critical role in ATRX-deficient gliomas involved in neuronal differentiation phenotype. To summarize, our cross-species analysis establishes tangible links between ATRX deficiency and multiscale dysregulated 3D-epigenomic architecture that hijack regulates onco-exaptation programs in gliomas. We further discover that enhancer-like TE’s fine-tune the transcriptional program with important clinical implications, that could help in developing treatment options in malignant gliomas.
TMIC-02. SINGLE-CELL HIGH-DIMENSIONAL MASS CYTOMETRY (CYTOF) REVEALS IMMUNE LANDSCAPE OF PITUITARY NEUROENDOCRINE TUMORS
Authors: Xiaopeng Guo, Mengqi Chang, Yongsheng Huang, Fan Zhang, Yuanli Zhao, Bing Xing
Journal: Neuro-Oncology (2024)

Abstract Pituitary neuroendocrine tumors (pitNETs) are a group of neoplasms in the sellar region, ranking as the second most common primary brain tumors, with some exhibiting aggressive behaviors. While immunohistochemical staining has been utilized to characterize the tumor immune microenvironment (TIME) of pitNETs, single-cell analysis remains underexplored. High-dimensional mass cytometry (CyTOF) offers a valuable approach for precise quantification of intratumoral leukocytes and potential therapeutic insights. We prospectively enrolled 56 patients with pitNETs of varying endocrine function, histology, and lineage. CyTOF, employing heavy metal-tagged antibodies, was employed to simultaneously measure 37 cellular parameters at single-cell resolution. Analysis revealed a total of 71,049 CD45+ immune cells. Macrophages (mean, 50.7%) and T cells (mean, 28.7%) were the predominant leukocytes, followed by NK cells, dendritic cells, B cells, and neutrophils. The immune cell composition within the TIME exhibited heterogeneity, with distinct patterns observed between functioning and non-functioning pitNETs. Functioning pitNETs displayed fewer macrophages (28.9% vs. 62.9%) and more T cells (44.9% vs. 19.6%) compared to non-functioning pitNETs. Subgroups within functioning (somatotroph, mammosomatotroph, lactotroph) and those within non-functioning pitNETs (null-cell, gonadotroph, corticotroph) shared similar immune profiles, respectively. PIT-1 lineage pitNETs demonstrated a T cell-dominated pattern, while SF-1, T-PIT, and null-cell lineage pitNETs exhibited macrophage predominance. In functioning pitNETs, macrophage abundance negatively correlated with invasiveness, Ki-67 index, and recurrence, while CD4 T cells showed positive correlations. Further unsupervised clustering identified 27 subpopulations of intratumoral immune cells, with some serving as critical predictors of tumor behavior. Our study provides a comprehensive single-cell immune profile of pitNETs, revealing distinct features across subtypes and targeted therapeutic implications.
TMET-26. TARGETING TRANSSULFURATION VIA SUPPRESSION OF THYROID HORMONE SIGNALING: A WINDOW OF OPPORTUNITY TRIAL OF METHIMAZOLE IN PATIENTS WITH PROGRESSIVE WHO GRADE 4 GLIOMAS (NCT05607407)
Authors: David Peereboom, Justin Lathia, Lilyana Angelov, G H Barnett, Christine Cordova, Andrew Dhawan, Lea El Hage, Matthew Grabowsky, Rachel Hufsey, Mina Lobbous, Mark Malkin, Alireza Mohammadi, Andras Ponti, D J Silver, Pranay Soni, Glen Stevens, Alejandro Torres-Trejo, Kailin Yang, Christopher Hine
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Gaseous hydrogen sulfide (H2S), a by-product of cysteine metabolism, inhibits cancer cell behavior and growth in glioblastoma (GBM) models. H2S production capacity (HPC) is decreased in human GBM specimens compared to non-tumor controls. Thus, boosting HPC is a novel strategy for GBM treatment. Suppression of thyroid hormone signaling increases endogenous production of H2S. Hypothesis: hypothyroidism induced by methimazole will enhance the efficacy of chemotherapy in WHO grade 4 gliomas by increasing HPC within the tumor. Goal: proof of concept that methimazole, by reducing thyroid hormone signaling, can increase HPC in patients with WHO grade 4 gliomas (G4G). METHODS This window of opportunity trial evaluates safety, HPC in plasma and tumor, and efficacy of methimazole + chemotherapy in patients with progressive G4G. MAIN OBJECTIVE 10% increase in HPC and a 1.5-fold increase in peripheral blood sulfhydration signaling. Patients planned for a clinically-indicated resection receive pre-op (5-7 days) and post-op methimazole with the addition of investigator’s choice of chemotherapy 1 month after starting post op methimazole. Patients receive methimazole + chemotherapy until progression. Pre- and post-op plasma and resected tumor tissue are assayed for HPC and proteins relevant to H2S production. Key eligibility: progressive G4G for whom a clinically-indicated resection is planned; normal thyroid function with no history of thyroid dysfunction. Patients may have received unlimited prior regimens including bevacizumab. RESULTS To date 12 patients (8 male) median age 56 years enrolled, 3 of whom are in pre-op phase. Relative to age/sex matched control, post-methimazole plasma at all time points tested but not tumor HPC increased (minimum increase 56%, p 0.041). No grade 3-5 toxicities or significant changes in thyroid function tests. PFS6 0 for first 6 patients. CONCLUSIONS Induction of subclinical hypothyroidism is feasible and safe in recurrent GBM with significant increases in plasma but not tumor HPC. The protocol is being modified to increase methimazole doses and allow earlier addition (10 days) of post-op chemotherapy.