tbuckley/cabot-search huggingface dataset:
TMOD-34. GENERATION OF BRAIN-VESSEL-GBM ASSEMBLOIDS USING PATIENT-DERIVED GLIOBLASTOMA TISSUE
Authors: Taehyeong ha, Kihwan Hwang, Kyung Mi Nam, So Young Ji, Ho Kang, Jung Ho Han, Chae-Yong Kim
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is the most common malignant brain tumor of the central nervous system and has a significantly low survival rate of approximately 15 months. Current preclinical GBM models are limited by the lack of a normal human microenvironment and the inability of many tumor cell lines to accurately reproduce GBM biology. To address these limitations, we describe a detailed procedure to generate brain-vessel- GBM assembloids, which are fusions of glioblastoma organoids (GBOs) from resected patient tumor tissue and cerebral and vessel organoids derived from human pluripotent stem cells. The proposed methodology will be used to detect and treat brain tumors, which will enable personalized treatment for brain tumor diseases. By universalizing the methodology we present, we aim to encourage other scientists to further develop existing models for studying these lethal tumors.
INNV-17. SAME-DAY DISCHARGE AFTER LASER INTERSTITIAL THERMAL THERAPY: A PROSPECTIVE COHORT PILOT STUDY WITH A MATCHED CONTROL GROUP
Authors: Chandler Berke, Adham Khalafallah, Maxon Knott, Nikola Susic, Muhammet Gurses, Victor Lu, Michael Ivan, Ricardo Komotar, Ashish shah
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Laser interstitial thermal therapy (LITT) has emerged as a minimally invasive treatment modality for intracranial pathologies, offering precision and control over tissue damage. With implementation of enhanced recovery after surgery (ERAS) protocols within neurosurgery, identifying patients amenable for same-day discharge (SDD) is an important step towards streamlining perioperative care following LITT, and correspondingly, we aim to summarize our initial experience. METHODS We conducted a prospective study at the University of Miami Hospital of 7 patients who underwent LITT for intracranial pathologies and were discharged on the same day of ablation (post-ablation day 0, PAD0). We then performed a retrospective case-control study against a historic matched PAD1 cohort comparing categorical and continuous variables for statistical significance. RESULTS The mean age of the PAD0 cohort was 55 years with 71% males. Preoperative neurological status and comorbidities did not differ significantly between the PAD0 and PAD1 cohorts for KPS (median [IQR]: 80 [80-90] vs. 90 [80-90], p=0.40), mFI-5 (median [IQR]: 1 [1.5] vs. 0 [1], p=0.54), and mFI-11 (median [IQR]: 1 [1.5] vs. 1 [1], p=0.52). PAD0 outcomes demonstrated no immediate complications, neurosurgical readmissions, or significant neurological deficits within 6 months post-procedure and were non-significantly different than PAD1 patients. No PAD0 patient experienced intracranial hemorrhage or vasogenic edema following LITT that necessitated further intervention. CONCLUSIONS Our study demonstrates the safety and feasibility of same-day discharge following LITT for intracranial pathologies in the appropriately selected patient. Through meticulous patient selection and optimized perioperative protocols, expedited recovery without compromising patient outcomes was achieved. This approach holds potential for substantial cost savings and resource optimization within healthcare systems. Further research and quality improvement initiatives are warranted to refine patient selection criteria and maximize the benefits of same-day discharge in LITT practice.
RTID-03. A MULTICENTER, RANDOMIZED, CONTROLLED TRIAL OF FOCUSED-ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER DISRUPTION PLUS SYSTEMIC PEMBROLIZUMAB FOR PATIENTS WITH NSCLC BRAIN METASTASES (LIMITLESS)
Authors: Manmeet Ahluwalia, Ahmad Ozair, K Singh Sahni, Nader Sanai, Arjun Sahgal, Michael McDermott, Kingsley Nwaogu, Lisa Dye, Graeme Woodworth, Nir Lipsman
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Systemic therapy for brain metastases (BM) is hindered by blood-brain barrier (BBB). Low-intensity focused ultrasound (LIFU), combined with IV microbubble oscillators, leads to non-invasive BBB disruption, which could enhance intracranial delivery of systemic immune checkpoint inhibitors. This randomized controlled trial (RCT) aims to evaluate safety and efficacy of LIFU-mediated BBB disruption plus systemic pembrolizumab for NSCLC BM. METHODS LIMITLESS (NCT05317858) is an ongoing, multicenter, parallel-arm, open-label RCT that randomizes NSCLC BM patients on standard-of-care pembrolizumab monotherapy to LIFU plus pembrolizumab (arm 1) or pembrolizumab alone (arm 2) in a 2:1 ratio. Included patients have age ≥18 years, normal organ function, KPS ≥70, EGFR- and ALK-negative primary tumor, and ≤3 BM with ≥1 BM meeting RANO-BM measurable disease criteria. All patients receive standard-of-care therapy, while those on arm 1 undergo LIFU before each pembrolizumab dose (200mg IV q3weeks). Patients undergo pre-treatment brain MRI, followed by IV microbubbles for enhanced sonication effects. MR-guided BBB disruption is performed using transcranial 220kHz LIFU device with real-time acoustic-feedback-based power control for maintaining effective microbubble activation. Pembrolizumab is infused immediately after sonication, and repeat MRI is done 24-48 hours later to assess treatment effects. Primary study outcome is overall objective response rate (ORR) at 6 months as assessed using RANO-BM. Using Bayesian design for power analysis, a superior ORR of 60% is assumed for LIFU arm versus 30% for control arm for total sample size of N=96 (64 participants in LIFU and 32 in control arm), for 80% power using two-sided chi-square test with alpha=0.05. For upper-bound estimate, ORR of 45% in LIFU arm and 30% in control arm, the study needs N=369 participants (246 in LIFU arm and 123 in control arm). Secondary outcomes are best ORR and median time-to-response. Exploratory outcomes are median progression-free survival (PFS), overall survival (OS), median intracranial PFS, median extracranial PFS, and quality of life. Patient enrollment commenced in 2022 and remains ongoing.
NCMP-11. FACTORS INFLUENCING MANAGEMENT STRATEGY AND CLINICAL OUTCOMES IN LOW-GRADE IDH-MUTANT ASTROCYTOMA: A 10-YEAR INSTITUTIONAL CASE SERIES
Authors: Danielle Golub, Harshal A Shah, Akash Mishra, Daniel G Lynch, Siddhi Modi, Shimon Garrel, Rebecca Ronnen, Prashin Unadkat, Sanjeev Sreenivasan, Anuj Goenka, Amir R Dehdashti, Daniel G Eichberg, Deborah Gruber, Jian Y Li, Yonah Ziemba, Michael Schulder, Samuel Singer
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Low-grade IDH-mutant astrocytomas are rare primary brain tumors that typically affect young adults and slowly progress to more aggressive lesions when untreated. Since lengthy follow-up is required to identify high-risk subgroups and useful therapeutic strategies, consensus recommendations after maximal safe resection are still based on low-level evidence and remain unclear. METHODS Retrospective chart review of all adult patients with a pathological diagnosis of low-grade (grade 2) IDH-mutant astrocytoma from 2013–2023 at a multi-site tertiary care center was performed. Cases without confirmatory IDH-mutation testing or at least 6-month follow-up imaging were excluded. RESULTS A total of 32 patients were included with a mean age of 35.6 years (range: 18–69) and 15 (46.9%) females. Mean follow-up was 40.3 months (range: 8.1–120.7). Preoperative average maximal tumor diameter was 4.1cm (range: 1.4–7cm) with 18 (56.3%) cases involving eloquent cortex. Gross total resection (GTR) was achieved in 12 (37.5%) cases. Observation was the most prevalent postoperative management strategy (n=21, 65.6%), followed by temozolomide-based chemoradiation (n=5, 15.6%), temozolomide alone (n=2, 6.3%), PCV (n=2, 6.3%), radiation alone (n=1, 3.1%), and carboplatin (n=1, 3.1%). Progression of disease (POD) was eventually seen in 17 (53.1%) cases with a median progression-free survival (PFS) of 41.9 months. While GTR was protective against POD (OR:0.14, p=0.019*), initial postoperative management with adjuvant chemotherapy and/or radiation was not (OR:1.09, p=0.907). Additionally, seizures during the follow-up period were significantly associated with POD and a reduced PFS (median 32.5 versus 71.7 months, HR:3.88, p=0.013*). There were no differences in EOR or tumor localization between patients who did and did not have seizures during follow-up. CONCLUSIONS Although limited by sample size, this 10-year series confirms the importance of maximizing EOR for low-grade IDH-mutant astrocytoma and suggests that seizures during follow-up can identify high-risk cases that may benefit from more aggressive treatment.
QOL-25. DIGITAL PHENOTYPING OF PERIOPERATIVE MOBILITY METRICS IN PATIENTS UNDERGOING SURGICAL RESECTION OF SKULL BASE TUMORS
Authors: Christopher Hong, Niels Gudde, David Magnusson, Jakob Gerstl, John Kilgallon, J P Onnela, Timothy Smith
Journal: Neuro-Oncology (2024)

Abstract Current methods to assess quality of life and recovery after surgery for skull base tumors are limited and often biased by subjective patient-reported assessments, while objective, in-situ assessments are lacking. Smartphone-based digital phenotyping has been increasingly studied across pathologies, utilizing built-in technologies to measure behavioral patterns pertaining to sleep, physical mobility, social interactions, and cognitive functioning, among others. Here, we report our initial experience with smartphone-based digital phenotyping in patients who underwent resection of skull base lesions. Patients seen at our multi-disciplinary skull base center were enrolled under an institutional board-approved protocol and installed the Beiwe application, which passively collected GPS data 20 days pre- and up to 140 days post-surgery. Variables measured included time spent at home, number of separate significant places visited outside home, daily walking time, and daily number of steps taken. 26 patients were enrolled, comprised of 14 pituitary adenomas, 8 meningiomas, and 4 vestibular schwannomas. All patients demonstrated increased time spent at home, fewer number of significant locations visited, decreased walking time, and decreased total steps in the immediate post-operative period. For pituitaries, mean return to baseline for these variables was 25.7, 24.3, 80.2, and 88.9 days, respectively. For meningiomas, return to baseline was 56.5, 214.4, 45.0, and 45.6 days, respectively. For vestibular schwannomas, return to baseline was 219, 39.9, 35.1, and 36.4 days, respectively. This study demonstrates initial efficacy of digital phenotyping for a cohort of patients undergoing surgical resection of skull base lesions, based on passively collected smartphone GPS data during the peri-operative period. This is part of a larger, ongoing study enrolling surgical patients as well as non-operative controls for comparison. Such peri-operative mobility metrics may potentially be refined to predict postoperative outcomes following surgery such as improvement of neurological symptoms, postoperative CSF leak, infection, dysnatremia, and hospital length of stay.
ANGI-09. GRAPH NETWORK ANALYSIS IDENTIFIES GENETIC COMMUNITIES OF CSF2RA AND RBFOX1 AS REGULATORS OF INVASIVE HIGH-GRADE GLIOMA BIOLOGY
Authors: Matthew Flick, Victoria Stevens, Christopher Sereduk, Christopher Plaisier, Ramon Barajas, Leland Hu, Kasthuri Kannan, Nhan Tran
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND High-grade glioma (HGG) is the most common and aggressive form of primary brain cancer. Standard of care surgery employs Magnetic Resonance Imaging to identify the contrast enhancing (CE) core for resection, leaving a non-enhancing (NE) invasive rim of tumor which contributes to recurrence. Recent multi-omics analyses identified predominant neuronal and immune signatures within NE tumor. Here, we apply a graph network to integrate regionally heterogeneous data from a unique dataset of spatially-localized CE and NE biopsies from a large cohort of patients with HGG. METHODS RNA-sequencing of 1159 differentially expressed genes across 159 IDH-wt biopsies (74 patients) from NE/CE regions were represented as nodes in a Neo4j network. Candidate genes for network random walks occurred exclusively within NE communities detected by modularity optimization and localized by cell-type using single-cell RNA-sequencing (scRNAseq). CSF2RA and RBFOX1 were selected as sources (walk length = 5; 10,000 walks/source node). Frequently occurring genes (one-tailed test) in walks were ranked by correlation with CSF2RA/RBFOX1 expression in NE samples and analyzed by gene set enrichment analysis for biological processes (clusterProfiler). Random walk genes were visualized (DoHeatmap) against composite NE/CE scRNAseq profiles. RESULTS CSF2RA and RBFOX1 were upregulated in NE samples (logFC = 0.789, 1.85). Upregulation of CSF2RA, an immune receptor, in the Glycolytic/Plurimetabolic and RBFOX1, a neurodevelopmental regulator, in the Neuronal glioma subtypes were observed in NE samples (ANOVA p &amp;lt; 0.05). CSF2RA walk genes (n=46) enriched metabolic/proliferative signatures, while RBFOX1 walk genes (n=201) showed neurodevelopmental upregulation. scRNAseq localized CSF2RA to monocytes/macrophages while RBFOX1 was expressed in distinct astrocyte/neuroepithelial populations. CONCLUSION CSF2RA and RBFOX1’s gene networks modulate immune and neurodevelopmental processes influencing glioma progression in NE tumor. Understanding the region-specific roles of these networks may offer strategies for targeting cells in the invasive glioma rim.
CSIG-12. YAP1-TEAD SIGNALING CONTRIBUTES TO LUNG CANCER COLONIZATION OF THE BRAIN
Authors: Consuelo Torrini, Naema Nayyar, Elizabeth Summers, Varun Sasisekharan, Hiroaki Wakimoto, Priscilla Brastianos
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Lung cancer is the most common primary tumor to metastasize to the brain. Poor understanding of the brain metastasis process limits therapeutic options. Despite emerging data on the role of YAP signaling pathway in the development of brain tumors, a gap in knowledge remains regarding its role in brain colonization. We hypothesize that YAP1 and the associated TEAD transcriptional factors are responsible for lung cancer progression and that intervention with YAP/TEAD-targeted therapy will prevent brain dissemination. METHODS Lung cancer cells at different stages of cancer progression (VMRC-LCD and NCI-H1975, lung cancer cell lines; NCI-H1915 and LN001, brain metastatic cancer cells) were genetically engineered to overexpress or silence/knockout YAP1 using lentiviral transduction of constructs expressing shRNA/sgRNA or YAP1. We tested several tumor cell capabilities using well-established in vitro assays, including invasion and migration assays, and an in vivo brain metastasis (BM) model to determine the biological effects of YAP1/TEAD suppression at different stages of lung cancer progression. Dose-response assays were performed to determine IC50 of the TEAD inhibitor, verteporfin. RESULTS YAP overexpression enhances the proliferative phenotype in metastatic and BM cell lines but not in non-metastatic cells. However, YAP overexpression only increases the migration ability of BM cell lines such as LN001 and NCI-H1915 compared to the metastatic NCI-H1975 and non-metastatic lung cancer cells. Moreover, we showed the efficacy of the YAP1/TEAD inhibitor in patient-derived lung BM cells. Finally, our in vivo preliminary data showed YAP1 involvement in lung cancer cell colonization of the brain but not in sustaining brain metastasis growth. CONCLUSIONS Our findings showed YAP1 involvement in lung cancer cell colonization of the brain, suggesting YAP1 inhibition is a clinically actionable target for preventing lung cancer dissemination and providing a strong rationale to further evaluate the benefit of a YAP1/TEAD-targeted therapy in in vivo models of BM.
SURG-25. PREOPERATIVE EMBOLIZATION IMPROVES LOCAL CONTROL AND REPROGRAMS GENE EXPRESSION IN ATYPICAL WHO GRADE 2 MENINGIOMAS
Authors: Alexander Haddad, Rithvik Ramesh, Naomi Zakimi, Daniel Quintana, Eugene Gil, Aymen Kabir, Youssef Sibih, Blanca Morales, Shuhbhang Bhalla, Ramin Morshed, Ethan Winkler, Manish Aghi, David Raleigh
Journal: Neuro-Oncology (2024)

Abstract Preoperative embolization is hypothesized to reduce blood loss and surgical time for meningioma resection, but the impact of embolization on long-term clinical outcomes and molecular profiling of meningiomas is incompletely understood. To address this, we evaluated the impact of embolization on outcomes and molecular features of WHO grade 2 meningiomas. A series of patients with grade 2 meningiomas who underwent resection at our institution from 1997 to 2021 were identified and reviewed. Available DNA methylation profiling and bulk RNA sequencing data were analyzed (n=200). Univariate and multivariate analyses, Cox proportional hazards modeling, and propensity matching (sex, age at surgery, previous surgery, extent of resection, postoperative radiation) were used. A total of 357 patients with WHO grade 2 meningiomas were included, 129 (36.1%) of which underwent preoperative embolization. Mean age at diagnosis was 53.5 years and 61.4% of patients were female. There was no significant difference in time to recurrence with or without embolization for cases with gross total resection (229/357), but embolization was independently associated with improved local control for cases with subtotal resection even after accounting for postoperative radiotherapy (HR 0.49, 95% CI 0.32-2.20 p=0.028). The average time to recurrence of atypical WHO grade 2 meningioma was 3.3 years after subtotal resection and 6.7 years after embolization and subtotal resection (p&amp;lt;0.001, propensity matched). The distribution of Merlin-intact vs Immune-enriched vs Hypermitotic meningioma DNA methylation groups was equivalent with versus without embolization, but differential gene expression analysis of RNA sequencing data revealed enrichment of hypoxia related pathways after embolization that were unique to each DNA methylation group. In summary, these data show that preoperative embolization improves local control and reprograms gene expression in atypical WHO grade 2 meningiomas. Additional investigation into the impact of embolization on clinical outcomes and gene expression for meningiomas, especially for higher-grade tumors, is warranted.
EPCO-41. THE NUCLEOSOME REMODELING AND DEACETYLASE COMPLEX UNDERLIES SELECTIVE DEPENDENCY IN H3 G34-MUTANT DIFFUSE HEMISPHERIC GLIOMA
Authors: Jordan Roach, Lawryn Kasper, Jared Andrews, Chen He, Laura Hover, Jennifer Ocasio Adorno, Robert Teis, Julie Laffy, Masashi Nomura, Frederick Boop, Paul Klimo, Jason Chiang, Brian Abraham, Itay Tirosh, Mario Suvà, Suzanne Baker
Journal: Neuro-Oncology (2024)

Abstract Pediatric-type diffuse high-grade gliomas are fatal central nervous system malignancies of childhood. Recurrent mutations in histone H3.3 at amino acid 34 (glycine to arginine/valine) are a defining molecular feature of diffuse hemispheric glioma, H3 G34-mutant (H3 G34-mutant DHG), which arises preferentially in adolescents and young adults. Single-nuclei sequencing of age and anatomically matched H3 wild-type and H3 G34-mutant primary patient tumors identified aberrant neuronal-like transcriptional programs enriched for signatures of cortical interneurons derived from the medial ganglionic eminence. The extent to which these molecular signatures reflect cancer dependencies in H3 G34-mutant DHG is poorly understood. To identify transcriptional vulnerabilities governing cellular state and underlying developmental lineage, we performed CRISPR screening targeting the DNA-binding domains of 1,427 proteins in H3 G34-mutant DHG (n=6) and H3 K27-altered diffuse midline glioma (DMG) (n=3). Through these efforts, we identified developmentally relevant transcription factor vulnerabilities corresponding to neuronal and oligodendrocyte precursor cell-like hierarchies comprising H3 G34-mutant DHG and H3 K27-altered DMG cellular states, respectively. Intriguingly, we also identified multiple members of the nucleosome remodeling and deacetylase (NuRD) complex as selective dependencies in H3 G34-DHG compared to H3 K27-altered DMG and 32 other cancer cell line models screened using the same DNA-binding domain library. Genetic perturbation of the holo-NuRD structural subunit MBD3 conferred an upregulation of genes involved in neuronal differentiation and synapse formation consistent with NuRD-mediated modulation of the aberrant neuronal-like cell hierarchy observed in H3 G34-mutant DHG. To therapeutically target NuRD-associated class I HDAC activity, patient-derived H3 G34-mutant DHG cell lines were treated with quisinostat, a highly potent class I and II HDAC inhibitor. Pharmacologic inhibition of HDAC activity was sufficient to impair cell growth in vitro. Ongoing experiments are evaluating dependencies in vivo. Our results may suggest a differential requirement for chromatin repressive complex dysregulation in the pathogenesis of oncohistone-mutant pediatric-type diffuse high-grade gliomas.
NCMP-18. A CASE OF METASTATIC GLIOBLASTOMA MULTIFORME
Authors: Catherine Boldig, Yolanda Pina, Arnold Etame
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma multiforme (GBM) is the most common primary brain tumor and rarely causes metastasis. We present a case of a 43-year-old female who developed tingling and heaviness in her right lower extremity in March 2023. This sensation progressed to involve her entire right hemi-body over the next two months. She presented to the emergency department where an MRI show a large left frontal parietal mass measuring 5.2x3.7x3.7cm with significant mass effect. She underwent surgical resection and surgical pathology showed IDH1-mutant R132H, retained ATRX, MGMT promoter mutation, and ki-67 of 80%. She received 6 weeks chemoradiation and then started maintenance temozolomide at 150mg/m2. Temozolomide was increased to 200mg/m2 for cycle 3 maintenance. In March 2024, she presented to the hospital with pain radiating down her legs and saddle anesthesia. MRI lumbar spine showed infiltrating osseous mass at S1 and S2 and bilateral sacral ala with anterior and posterior extraosseous invasion, invading the spinal canal resulting in moderate to severe spinal canal narrowing and compression of the sacral nerve roots. She underwent biopsy of the lesion which showed IDH wildtype metastatic GBM. She also underwent lumbar puncture and cerebrospinal fluid cytology was negative. She experienced pancytopenia limiting chemotherapy options. In April 2024, she underwent PET scan which showed hypermetabolic epidural soft tissue in spinal canal at L5-S1 level, widespread hypermetabolic skeletal lesions, tiny left cervical level 4 lymph node, small hypermetabolic right hilar, aortocaval, left retroperitoneal nodes and a tiny left common iliac node. The incidence of extracranial metastasis is 0.4-2.0% with less than 25 reported cases of bone marrow spread. This is thought to be rare due to the absence of lymphatics within the brain and the limited survival associated with GBM. This metastasis may occur through vascular invasion, perineural spread, lymphatics, direct invasion, or iatrogenic spread into soft tissues.