tbuckley/cabot-search huggingface dataset:
INNV-22. CEREBELLOPONTINE EPIDERMOID CYST TO SQUAMOUS CELL CARCINOMA: MALIGNANT TRANSFORMATION, LEPTOMENINGEAL CARCINOMATOSIS, AND MANAGEMENT
Authors: Mirna Hennawy, Mostafa Fatehi, Stephen Yip, Justin Oh, Rebecca Harrison
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Intracranial epidermoid cysts (EDC) are rare, slow-growing, congenital tumors, that generally follow a benign course. EDCs have a rare potential for transformation to squamous cell carcinoma (SCC). We present a case of a malignant EDC transformation to SCC with leptomeningeal (LM) dissemination. METHODS Case report and review of literature. CASE PRESENTATION A 44-year-old female presented for evaluation of left-sided tinnitus and sensorineural hearing loss, which revealed a left cerebellopontine angle (CPA) tumor. She underwent a subtotal resection at age 47. One year later, she had rapid symptomatic recurrence of the cyst, as well as LM deposits of the right internal acoustic canal bundle, the left trigeminal nerve, and along the lumbar and sacral spine. She underwent repeat resection of the CPA lesion, with pathology now consistent with SCC, with CDKN2A loss. She received focal radiation therapy at the posterior fossa and the lumbar spine. SCC-directed chemotherapy with pembrolizumab and carboplatin followed by 5 cycles of pembrolizumab monotherapy was given as adjuvant therapy, prior to her developing symptomatic LM disease. CONCLUSION Malignant transformation of intracranial EDC is a rare occurrence in these typically benign tumours. Prognosis is especially poor when there is associated LM involvement, with median survival noted to be 10 months. Awareness of this phenomenon amongst clinicians is needed to ensure appropriate surveillance and aggressive treatment if it remains within patient wishes, though there is no consensus on recommendations for treatment. The patient presented has maintained disease stability with LM dissemination for over 10 months and ongoing, with a regimen of chemoradiotherapy informed by therapeutic approach to systemic SCC. To our knowledge, this is the first reported case of EDC to SCC transformation and LM dissemination stabilized with chemoradiotherapy using an immune-checkpoint inhibitor.
EXTH-63. FOCUSED ULTRASOUND HYPERTHERMIA MEDIATED CONTROL OF THERMAL RESPONSIVE CAR T CELL ACTIVITY IN BREAST CANCER BRAIN METASTASIS
Authors: Chulyong Kim, Ali Zamat, Zizhen Zha, Shwetha Sridhar, Gabe Kwong, Costas Arvanitis
Journal: Neuro-Oncology (2024)

Abstract HER2-targeted therapies are promising treatment options for metastatic breast cancer and have improved the median overall survival. However, breast cancer brain metastasis (BCBM), observed in up to 50% of HER2-positive breast cancer patients, remains a clinical challenge. While Chimeric Antigen Receptor (CAR) T cell therapy is promising therapeutic strategy to address the unmet need in treating BCBM, improving its effectiveness and safety is critical for clinical translation. We hypothesized that spatially and temporally controlled activity of CAR-T cells with a thermal gene switch (TS) under MRI-guided focused ultrasound (MRgFUS) would potentiate anti-tumor responses in difficult-to-treat BCBM. To test our hypothesis, we developed a closed-loop controlled MR-thermometry (MRTI) based FUS system (MRgFUS) and αHER2 CAR-T cells engineered with TS expressing the reporter gene firefly luciferase (TS.Fluc) or bi-specific engager on NKG2D ligands (TS.BTE) upon MRgFUS-hyperthermia (41.5°C). In vivo quantification of TS activity from intratumorally delivered TS.Fluc αHER2 CAR-T cells in HER2+ BCBM mice model (HER2+ MDA-MB-468 in NSG mice with primary human CAR-T cells) followed by pulsed MRgFUS-hyperthermia resulted in a ~10-fold increase in luminescent activity compared to unheated mice. To assess longitudinal activation, we quantified TS activity with a second sonication 4 days post the initial FUS treatment. Prior to the second sonication, TS.Fluc expression had returned to baseline levels, while following it robust TS.Fluc expression was observed again, demonstrating that MRgFUS can activate engineered T cells with TS in brain tumors with high spatiotemporal control. Subsequently we investigated the therapeutic efficacy of intratumorally delivered TS.BTE αHER2 CAR T cells in mixed tumor model of heterogeneous HER2 MDA-MB-468 (75% HER2+) and observed significant tumor regression of HER2- tumor cells in the treated group compared to controls, demonstrating the potential of the proposed strategy to noninvasively drive the local production of key transgenes and potentiate anti-tumor responses in difficult-to-treat BCBM.
BIOM-03. DABRAFENIB AND STEROIDS FOR THE TREATMENT OF ERDHEIM-CHESTER DISEASE WITH EXTENSIVE CENTRAL NERVOUS SYSTEM INVOLVEMENT
Authors: Carlen Yuen, Silin Bao, Mya Sandi Aung, Rhea Shishodia, Xiao-Tang Kong
Journal: Neuro-Oncology (2024)

Abstract Erdheim-Chester disease (ECD) is an exceedingly rare non–Langerhans cell CD68+ CD1a- S100- histiocytic multi-organ disease. Diagnosis of ECD is often delayed due to non-specific radiographic findings and heterogeneous lesional tissue. Increasingly, the role of genomic alterations is being recognized for both diagnosis and treatment of ECD. More than half of ECD patients harbor the BRAFV600E mutation. Evaluation for this mutation be can falsely negative on immunohistochemical staining and confirmation with molecular analyses is recommended. We present a case of the 44 year-old male with BRAFV600E-positive ECD treated successfully with steroids followed by single-agent dabrafenib.
BIOM-62. CIRCULATING TUMOR CELLS IN MEDULLOBLASTOMA: A NOVEL PERIPHERAL BIOMARKER FOR CNS DISEASE
Authors: Tevhide Ozkaya, Franklin Chien, Mert Boya, Rachel Gray, Robert Arthur, Henry Claussen, Jose Velazquez-Vega Velazquez Vega, Matthew Schneiderjan, Manoj Bhasin, Fatih Sarioglu, Tobey MacDonald
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma is an embryonal tumor of the cerebellum and the most common pediatric malignancy of the central nervous system (CNS). Diagnosis, staging, and disease monitoring require invasive neurosurgical biopsy or MRI. No blood or cerebrospinal fluid (CSF) biomarkers exist. We demonstrate the presence of circulating tumor cell clusters (CTCCs) in patients with medulloblastoma and use a transcriptomic approach to describe their gene expression. Design/Method: We enrolled 34 total patients in a longitudinal study: 24 with medulloblastoma and 10 without malignancy. CTCCs are captured from unprocessed whole blood using a physics-based label-free approach to CTCC isolation. RNA sequencing was performed on 21 samples at time of diagnostic resection from 6 patients with medulloblastoma. Sequencing reads were assessed for quality control, trimmed, and aligned to the human genome. Differential gene expression (DGE) was performed against whole blood from healthy controls. Reactome pathway database of curated, peer-reviewed gene sets are used for gene set enrichment analysis (GSEA). RESULTS The presence of peripherally CTCC patients with medulloblastoma is not previously known and was detected in all patients with medulloblastoma whereas none were observed from patients with non-malignant hematological conditions. RNA-sequencing demonstrate separation on principal component analysis and gene-expression heatmap against whole blood healthy control. DGE shows upregulation of genes indicating stem-like state. GSEA show enrichment of medulloblastoma molecular pathways and gene sets defining integrin, extracellular matrix remodeling, and cell adhesion pathways. Transient elevation of peripheral CTCC followed by return to baseline levels was associated with durable disease response to therapy, whereas persistence or elevation of CTCC in CSF correlated with disease recurrence. CONCLUSION The universal and specific finding of peripherally captured CTCC arising from parent tumor in the CNS within our patient cohort suggests a utility as a tumor biomarker. Future sequencing is planned comparing CTCC transcriptome against parent tumor.
BIOM-73. CYTOKINE DYNAMIC DURING RADIATION THERAPY PREDICTS SURVIVAL IN GLIOBLASTOMA
Authors: Sushant Puri, Lindsey Sloan, Peng Huang, Michele Doucet, Sudipto Ganguly, Lawrence Kleinberg
Journal: Neuro-Oncology (2024)

Abstract Radiation Therapy affects a wide range of circulating lymphocyte subpopulations that are integral to mounting a successful lymphocyte-mediated immune response. Lymphopenia is associated with inferior tumor control and could be addressed to improve outcomes in glioblastoma. RT is one significant and potentially actionable iatrogenic suppressor of immune response that may limit the success of therapy. We hypothesized that a comprehensive evaluation of serial cytokine measurements during concurrent radiation and chemotherapy in glioblastoma will provide information about systemic immune status during treatment. 16 patients were enrolled in a single-institution, observational, immune surveillance study between 2018 and 2019. Peripheral blood was collected prior to starting radiation, and then weekly for a total of 7 timepoints. Plasma was isolated from blood, and cytokine levels were measured with a Luminex 23-cytokine panel. Survival was defined at 2 years since diagnosis. Patients &amp;gt;2 years were called survivors and &amp;lt;2 years were called non-survivors. Cytokine levels were compared with a cohort of 4 healthy controls. All data are log2 transformed using formula log2(x+1). ANOVA was used to find cytokines that differ among 3 groups. Only for those cytokines with significant ANOVA results, pair-wise t-test was performed. We found a total of 12 cytokines that were increased in plasma in glioblastoma patients undergoing radiation compared to control. Top cytokines to show differences were IL-10, M-CSF, TGF-b3 and TIM-3 (p&amp;lt;0.05). The others to show a difference were IP-10, MCP-1, TGF-b2, IL-34, PD-L1, LAG-3, PD-1, and CTLA-4. These cytokines are known to be immunosuppressive, and our results demonstrate a soluble mechanism of immunosuppression in this patient population. This cytokine signature can predict early during treatment the overall survival in patients with glioblastoma.
PATH-17. MOLECULAR CLASSIFICATION OF H3K27-WILDTYPE SPINAL CORD GLIOMAS: IMPLICATIONS FOR PROGNOSIS AND THERAPEUTICS
Authors: Ruichao Chai, Huiyuan Chen, Qing Chang, Yongzhi Wang, Jiguang Wang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND H3K27-wildtype spinal cord gliomas (H3WT-SCGs) are rare and heterogeneous tumors that present significant challenges in pathological classification. Traditional histologic diagnoses often do not align well with the underlying molecular characteristics of these tumors. METHODS We characterized 55 cases of H3WT-SCGs using a comprehensive approach that included DNA methylation array, whole-exome sequencing, transcriptome sequencing, proteomics, and single-cell RNA sequencing. Unsupervised clustering analysis was performed to identify distinct molecular subtypes. RESULTS The analysis identified seven distinct spinal cord methylation (SCM) clusters: pilocytic astrocytomas (PA-SPINE), PA-immune enriched (PA-IME), diffuse leptomeningeal glioneuronal tumor (DLGNT), subependymoma (SUBEPN-SPINE), glioblastoma-like (GBM-like), and pleomorphic xanthoastrocytoma-like (PXA-like). There was a 61.8% discordance between SCM classes and traditional histologic diagnoses. The new molecular classification provided a better correlation with molecular features and patient prognosis. BRAF fusions were enriched in PA-SPINE and DLGNT (p = 0.04), and DLGNT showed significant chromosomal alterations, including 1p loss (p = 6.5e-08) and 1q gain (p = 3.6e-05). Notably, we identified two distinct classes of PA-SPINE: adult (older than 18 years) and pediatric. Adult PAs exhibited lower frequencies of BRAF fusions (p = 1.4e-03), shorter tumor lengths (p = 3.7e-04), and longer progression-free survival (p = 0.062). Adult PA neoplastic cells were less differentiated, with higher expression of EGFR and neuronal markers, and lower cytokine and chemokine expression compared to pediatric cases. Single-cell analysis revealed reduced infiltration of monocyte-derived macrophages and proliferative myeloid cells in adult cases. Both PA-IME and PA-pediatric clusters were characterized as immune-hot tumors with high immune cell enrichment. CONCLUSION This study defined clinically relevant molecular classes of H3WT-SCGs that better reflect patient prognosis and molecular characteristics compared to traditional histologic diagnoses. The findings suggest potential therapeutic implications, especially in immune-hot tumors like IME and PA-pediatric, which could benefit from targeted immunotherapies.
RBIO-10. RADIATION FRACTION SIZE DIFFERENTIALLY AFFECTS MYELOID-DERIVED SUPPRESSOR CELL (MDSC) SUBSETS IN WHO GRADE 1 MENINGIOMA
Authors: Kyra Boorsma Bergerud, Matthew Berkseth, Lydia Golden, Nicole Sando, Liam Chen, Andrew Venteicher, Lindsey Sloan
Journal: Neuro-Oncology (2024)

Abstract Meningiomas are often cured after focal therapy with surgical resection and/or radiotherapy (RT); however, a small proportion still recur. RT dose can be used to modulate anti-tumor immune responses, potentially through regulating immunosuppressive MDSCs. Here, we investigate the effect of a single fraction of RT (2Gy vs. 15Gy) on frequency and activation status of MDSC subsets in patients with WHO grade 1 meningioma. We hypothesize that 2Gy will promote immunosuppressive MDSC activity more than 15Gy. Fresh tumor cells from patients with a presumed diagnosis of meningioma were digested into primary cell cultures and treated with a single fraction of 2 or 15 Gy or were sham irradiated using a XRAD 320 Biological Irradiator. Cells were incubated for 18hrs prior to flow cytometric analysis. MDSC populations were identified as Live/Dead-CD11b+CD33+HLA-DR-. MDSC subsets were then divided into M-MDSC (CD14+CD15-) or G-MDSC (CD15+CD14-). Five WHO grade 1 meningiomas were analyzed. The total frequency of MDSCs in tumors increased from 3% with sham RT to 4% after irradiation with 2Gy (p=0.03). This was driven by a 2-fold increase in frequency of total M-MDSCs, as G-MDSCs decreased by half after 2Gy (p=0.03). After irradiation with 15Gy, M-MDSC frequency was nearly half that of 2Gy. The frequency of TGF-β+MDSCs increased after 15 Gy (p=0.02). The frequency of IL-10+G-MDSCs increased in response to 2Gy (p =0.03) but decreased 4-fold after 15Gy. 18hrs after 2Gy, IFN-γ+M-MDSCs increased compared to sham (p=0.01). In this small cohort of grade 1 meningiomas, a 2Gy fraction of RT appeared to support expansion of the M-MDSC subset. RT at both fraction sizes increased immunosuppressive cytokine producing-MDSCs: M-MDSC-IL-10; G-MDSC-TGF-β. These findings indicate the need for further studies to understand the subset-specific impact of RT on MDSC, a key immune cell type in brain cancers.
PATH-10. UTILIZATION OF TUMOR-DERIVED EXTRACELLULAR VESICLES FOR PATIENT STRATIFICATION AND BIOMARKER DISCOVERY
Authors: Katie Havranek, Claire Seibold, Tia Seibold, Margie Kinnersley, Kelley Van Vaerenberghe, Tre Blohm, Rachel Short-Miller, Sean Lodmell, Amanda Mast, Riley Kemp
Journal: Neuro-Oncology (2024)

Abstract Liquid biopsy is poised to play an increasingly important role in clinical decision making by enabling earlier cancer detection, diagnosis, patient stratification, and treatment monitoring. Most approaches rely on detection of cell-free circulating tumor DNA or circulating tumor cells in the peripheral blood of cancer patients. However, there are several limitations to these approaches, including miniscule abundance, unfavorable signal to noise ratios, and limited insight into mechanisms driving disease. Extracellular vesicles (EVs) are an alternative liquid biopsy analyte comprising lipid membrane encapsulated particles carrying diverse protein, nucleic acid, and metabolite cargos. Blood plasma of cancer patients contains EVs derived directly from tumor tissue that serve as rich sources of insight into tumor biology and disease pathology. We have developed a clinically applicable, multi-omic EV subpopulation interrogation pipeline that robustly profiles tumor-derived EVs in biofluids. We have demonstrated the ability of the platform to enrich cancer markers and detect activation of pathways driving oncogenesis across several different cancers, including brain cancer. There is a particularly compelling need for liquid biopsy-based solutions in neuro-oncology. We have applied our EV-omic (EVO) pipeline in combination with machine learning to distinguish adult high-grade gliomas from benign brain tumor and healthy patients, using blood-based EV proteomic and transcriptomic signatures. Marker profiles found to be most important for patient stratification combine markers known to be relevant in tumor tissue along with novel features. Furthermore, IDH status and MGMT methylation metadata derived from matched patient tissue for select cases was used to generate unique blood-based profiles for glioma subtypes. Lastly, we show preliminary longitudinal data demonstrating the utility of EVs to track tumor changes post-surgical resection and post-treatment. This work demonstrates that EV-omics can add significant value in the neuro-oncology space.
RBIO-07. IMMUNOMODULATORY PATHWAYS MEDIATE RADIOTHERAPY RESPONSE IN MALIGNANT PERIPHERAL NERVE SHEATH TUMORS
Authors: Iowis Zhu, Julian Chien, Kanish Mirchia, Kaeli Miller, Emily Payne, Joanna Pak, Varun Monga, Steve Braunstein, Line Jacques, Melike Pekmezci, John Liu, Harish Vasudevan
Journal: Neuro-Oncology (2024)

Abstract PURPOSE Malignant peripheral nerve sheath tumors (MPNSTs) are the most common cause of death in neurofibromatosis type 1 (NF-1) and are resistant to radiation therapy (RT), yet the mechanisms underlying RT response are poorly understood. Here, we elucidate mechanisms of RT response in NF-1 associated peripheral nerve sheath tumors through genome-wide CRISPRi screens, genomic analysis of mouse models, and molecular analysis of patient-derived tumor specimens. METHODS Patient derived NF1 mutant plexiform neurofibroma (pNF) cells (NF9511b, NF95.6), and MPNST cells (ST88-14; JH2-002) were used to measure RT responses by cell counts and flow cytometry. Genome-wide CRISPRi screens were used to identify functional modifiers of RT response in ST88-14 and JH2-002 MPNST cells. Nf1-/-; Tp53-/- mouse MPNSTs were subcutaneously implanted in immunocompetent C57/B6 mice, irradiated (2Gyx5), and dissociated for single-cell RNA sequencing (scRNA-seq) using 10x Genomics. Human MPNST tumor specimens (n=45) were analyzed with targeted DNA mutation sequencing and methylation arrays for cell type deconvolution. RESULTS Radiation single-dose response curves revealed MPNST cells (IC50 6.85Gy) were radioresistant compared to pNF cells (IC50 3.13Gy). Genome wide CRISPRi screens in ST88-14 and JH2-002 MPNST cells converged on cell cycle, DNA repair, and immunomodulatory gene sets mediating RT sensitivity. Irradiation of subcutaneous mouse Nf1-/-; Tp53-/- MPNSTs significantly decreased tumor growth (p=0.01, t-test). scRNA-seq of 32,763 cells from 4 irradiated and 3 unirradiated mouse Nf1-/-; Tp53-/- MPNSTs identified 8 tumor clusters and 7 non-tumor clusters. Irradiation demonstrated a pro-inflammatory effect with increased T-cell presence (5.8% versus 3.3%, p=0.04, t-test) and greater activation of immunostimulatory genes (Cxcl10, Stat1, Irf7) in T cells. In human MPNSTs, CDKN2A/B deletion (p=0.04, log-rank test) and decreased immune cell composition (p=0.03, log-rank test) were associated with significantly worse overall survival in response to RT. CONCLUSION MPNST RT responses may depend on immunomodulatory mechanisms that could be leveraged to improve clinical RT response.
NCMP-03. ASSOCIATION OF PROGESTERONE CONTRACEPTION WITH TUMOR-RELATED VISUAL IMPAIRMENT IN PREMENOPAUSAL WOMEN WITH MENINGIOMA REFERRED FOR RADIATION
Authors: Morgan Bailey, Chace Avery, Luke Pater, Timothy Struve, Ralph Vatner, Andrew Frankart, Sarah Sittenfeld, Kevin Shiue, Lalanthica Yogendran, Rekha Chaudhary, Jonathan Forbes, Norberto Andaluz, Matthew Hagen, Ady Kendler, Rocco Rossi, John Breneman, Kyle Wang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Meningiomas express ER/PR, but hormonal risk is poorly characterized and not always considered. We hypothesized that hormonal contraceptives lead to tumor-related visual deficits in premenopausal women referred for radiation. METHODS We conducted a retrospective case-control study with primary endpoint visual deficit prior to radiation for meningioma in women age ≤55. Key risk factors determined included age, grade, skull base location, hormonal supplementation / contraception, and neurofibromatosis / prior radiation (NF/priorRT). Univariate and multivariate (including factors with p&amp;lt;0.05 on univariate) logistic regression was performed to analyze associations with visual deficit. RESULTS 64 women (median age 46) receiving RT from 2012-2024 at a single academic institution were included. 45 (70%) had skull base tumors, 33 (52%) used estrogen or progesterone, and 23 (36%) used unopposed progesterone only, 15 specifically medroxyprogesterone acetate (Provera). Visual deficit was present in 35 patients (55%) and was independently associated with both skull base location (p=0.002, OR 11.5) and unopposed progesterone only use (p=0.008, OR 12) but not estrogen or progesterone use on multivariate analysis. Proportion with progesterone only use was 57% vs. 11% in patients with vs. without visual deficit (chi-sq p&amp;lt;0.001). In 5 with ER/PR testing, 3 were PR+ (all with visual deficits and history of medroxyprogesterone acetate) and 2 were PR- (neither with visual deficits nor hormone use). 13 women (20%) were actively using progesterone during RT. 17 women have been contacted at time of analysis, and 4 discontinued progesterone. CONCLUSIONS Progesterone increases risk for meningioma-related visual deficits in premenopausal women referred for radiotherapy, with a disproportionate number on Provera specifically. These data highlight the importance of age-appropriate counseling, consistent pathologic assessment of ER/PR status, and greater awareness of this issue amongst neurosurgeons and radiation oncologists.