tbuckley/cabot-search huggingface dataset:
CTNI-22. DABRAFENIB (D) AND TRAMETINIB (T) EITHER IN COMBINATION OR AS MONOTHERAPY IN PEDIATRIC PATIENTS HARBORING<i>BRAF</i> ALTERATIONS IN GLIOMAS OR OTHER RARE TUMORS: FINDINGS FROM AN EARLY ACCESS PROGRAM (EAP)
Authors: Mark Russo, AnaRita Ferreira, Michael Roughton, Sviatlana Rizk, Manar Aoun
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND In 2022, dabrafenib and trametinib (D+T) combination received an accelerated US FDA approval for use in adult and pediatric patients with BRAF V600E–mutated unresectable or metastatic solid tumors with no viable alternative therapy. However, to provide global access to therapy in countries where the suitable formulations and/or indications are not yet approved, EAPs are established. We report on patient data from an EAP for pediatric patients with BRAF V600-mutated gliomas or other rare tumors with BRAF alterations such as BRAF fusions, seeking clinical benefit from therapy with dabrafenib and/or trametinib. METHODS We analyzed data from the global EAP, where pediatric patients with BRAF alterations in solid tumors including gliomas or other rare tumors received D+T combination or monotherapy. Key eligibility criteria included: age &amp;lt;18 years, absence of approved indications, presence of BRAF V600E/K mutation or other BRAF alterations, and exhaustion of standard therapies. Requests were processed through a global system from November 2016 to December 12, 2022 (cutoff date). Key data on patient characteristics and median treatment duration (mDoT) were collected and will be presented. RESULTS Overall, 482 patients with solid or hematological malignancies were included, of which 35.1%, 31.7%, and 33.2% received combination therapy and dabrafenib and trametinib monotherapies, respectively. Across the treatment cohorts, median age was 4.2-6.6 years, and 49.4%-52.9% were males. Most patients had low-grade (72%) or high-grade (4.6%) gliomas, followed by Langerhans cell histiocytosis (17.8%) and other tumors (5.6%). The estimated mDoT for liquid and solid formulations were, respectively, 14.6 months and 10.1 months in combination therapy, 16.5 months and 12.8 months in dabrafenib monotherapy, and 8.8 months and 7.4 months in trametinib monotherapy. CONCLUSIONS EAP data represent a valuable real-world resource in understanding patient characteristics in rare tumors (pediatric gliomas). A significant number of treatment requests indicate substantial unmet need, and significant mDoT across age categories was suggestive of benefit to pediatric patients on therapy.
INNV-31. THE USE OF IVOSIDENIB IN PATIENTS WITH ENHANCING IDH1 MUTANT GLIOMAS
Authors: Maria Minor, Michal Nisnboym Ziv, Mallika Patel, Margaret Johnson, Kristen Batich, Justin Low, Madison Shoaf, Mustafa Khasraw, Annick Desjardins, Henry Friedman, David Ashley, Katherine Peters
Journal: Neuro-Oncology (2024)

Abstract Ivosidenib offers a novel targeted therapy for non-enhancing IDH1 mutated gliomas following initial resection. Potential effects of IDH inhibitors on enhancing disease in clinical settings are not well established. This study characterizes a cohort of patients with IDH1 mutated gliomas with enhancing disease, who were initiated on monotherapy, off-label ivosidenib between October, 2020 to August, 2023. The cohort included 21 patients ages 29 to 73 years, 11 female and 10 male. Diagnoses represented were astrocytoma IDH1 mutant, grade 2-4 (N=9) and oligodendrogliomas IDH1 mutant, grade 2-3 (N=12). Prior treatment exposures included radiation therapy (N=11), temozolomide (N=15), bevacizumab (N=3), and treatment naïve (N=6). Time from diagnosis to ivosidenib initiation was 9.1±2.7 years. Although all patients had enhancing disease, ivosidenib was initiated due to non-enhancing disease progression (N=7), enhancing disease progression (N=13), and temozolomide intolerance (N=1). Size of enhancement by cross-section measured &amp;gt;1cm (N=15) and &amp;lt;1cm (N=6). Best radiographic responses per RANO criteria were partial response (N=3), stable disease (N=11), and progressive disease (N=7). At last contact, eleven patients were maintained on ivosidenib with no evidence of disease progression since initiation with an average treatment duration of 25.5±6.4 months and overall survival of 11.7±3.1 years. Ten patients had disease progression at median 5.2±3.1 months following ivosidenib initiation, three of whom died 16.7 (range 6.8-34.4) months after treatment initiation with an overall survival of 9.4 years (range 4.6-13.6). Adverse events from therapy included diarrhea (N=2), CK elevation (N=4), and QTc prolongation (N=2). No patients discontinued ivosidenib due to adverse events. No significant difference was detected between patients with and without disease progression due to size of enhancement (p=0.4) or prior treatment exposure (p=0.3). Future studies should include biopsies to understand the role of enhancing lesions in treatment response of IDH inhibitors.
CTNI-36. THE FEASIBILITY OF USING BORTEZOMIB WITH CHEMOTHERAPY IN ATYPICAL TERATOID/RHABDOID TUMORS
Authors: Wan-Ling Ho, Ming-Yun Hsieh, Yu-Mei Liao, Shyh-Shin Chiou, Her-Shyong Shiah, Chang-Hsu Chiang, Shiann-Tarng Jou, Hsu-Ju Yen, Yi-Yen Lee, Muh-Lii Liang, Ting-Chi Yeh, Yu-Cheng Chou, Fang-Liang Huang, Shu-Huey Chen, Hsin-Lun Lee, Chia-Chun Kuo, Shu-Mei Chen, Min-Lan Tsai, Hsi Chang, Kevin Li-Chun Hsieh, Chia-Lang Fang, Chia-Yau Chang, Jinn-Li Wang, Chu-Chin Chen, Joon-Khim Loh, Pei-Chin Lin, Tzu-Chin Lin, Shih-Chung Wang, Yi-Fang Tu, Chao-Neng Cheng, Ming-Jung Chuang, Huy Minh Tran, Shian-Ying Sung, Irving Lai, Kuo-Sheng Wu, James S Miser, Yen-Lin Liu, Tai-Tong Wong
Journal: Neuro-Oncology (2024)

Abstract Atypical teratoid/rhabdoid tumors (ATRTs) are highly aggressive pediatric brain tumors with sensitivity to proteasome inhibitors in preclinical models. We evaluated the feasibility of combining the proteasome inhibitor bortezomib with chemotherapy. Patients aged 0-20 years with newly diagnosed ATRT were enrolled from January 2022 through December 2023. A modified Medical University of Vienna (MUV)-ATRT regimen was used. They were treated with bortezomib of 1.3 mg/m2/dose given intravenously or subcutaneously twice a week for 2 weeks concurrently with 6 cycles of chemotherapy and 2 additional cycles after high-dose chemotherapy. Radiation therapy was given prior to or at the end of chemotherapy. A total of 36 chemotherapy cycles with bortezomib in 6 patients were evaluated. The primary endpoint was grade 3 or higher non-hematologic toxicities. Numbers of cycles with grade 3+ toxicities included: AST/ALT elevation (1), hypokalemia (2), peripheral neuropathy (1), subdural hemorrhage (2), vomiting (2), oral mucositis (3), lung infection (2), urinary tract infection (8), sepsis (3), febrile neutropenia (20). No grade 3+ toxicities were considered bortezomib-related. Three patients completed 8 cycles of bortezomib treatment; 2 patients discontinued the study due to progressive disease after 2 and 4 cycles respectively; 1 patient completed 6 cycles of bortezomib and died of septic shock in complete remission after high-dose chemotherapy. Two patients had a surgical complete resection. Three patients were evaluable for response after bortezomib: 1 partial response and 2 stable disease. Two patients had progression-free survival for 16+ and 22+ months after diagnosis, respectively. Among the 3 patients with progressive disease, 2 had metastatic relapse and 1 had primary and metastatic relapse. There were 4 deaths due to metastatic PD (n=2), septic shock after high-dose chemotherapy (n=1), and septic shock after 2nd line treatment for PD (n=1). We conclude that adding bortezomib to standard and high-dose chemotherapy of ATRT was feasible with the occurrence of grade 3/4 toxicities no more than what was expected with chemotherapy alone. Metastatic relapse remains the major challenge of ATRT treatment.
ANGI-10. NETWORK ANALYSIS ESTABLISHES CSF2RA’S REGIONAL INFLUENCE ON HYPOXIA RESPONSE IN THE INVASIVE RIM OF HIGH GRADE GLIOMA
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. The hypoxic tumor microenvironment is thought to drive invasion into healthy brain, and understanding cellular responses to hypoxia may provide insight into combatting recurrence. 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 to identify gene networks regulating hypoxia response and invasion. 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 graph network. Candidate genes for network random walks occurred exclusively within NE communities detected by modularity optimization and were localized by cell-type using single-cell RNA-sequencing (scRNAseq). CSF2RA was selected as source (walk length = 5; 10,000 walks/source node). Frequently occurring genes (one-tailed test) in walks were ranked by correlation with CSF2RA expression in NE samples and analyzed by gene set enrichment analysis for biological processes (clusterProfiler). CSF2RA and hypoxia gene expression were visualized with DoHeatmap in composite NE/CE scRNAseq profiles. RESULTS CSF2RA, an immune receptor, was upregulated (logFC = 0.789) in NE samples, scRNAseq myeloid populations, and Glycolytic/Plurimetabolic glioma subtype. CSF2RA random walk genes (n=46) enriched metabolic/proliferative signatures. CSF2RA expression correlated negatively with hypoxia genes globally and regionally (NE/CE), while NE/CE scRNAseq revealed distinct cellular expression patterns of CSF2RA and hypoxia response genes. CONCLUSION CSF2RA expression may prime NE glioma cells for invasion by altering hypoxia response. The genetic network bridging CSF2RA and hypoxia response may be a targetable mechanism of tumor recurrence.
INNV-34. APPLICATION OF 200 KHZ TUMOR TREATING FIELDS (TTFIELDS) IN PATIENTS WITH INFRATENTORIAL HIGH-GRADE GLIOMA: CASE SERIES
Authors: Carlos Kamiya-Matsuoka, Chirag Patel, James Battiste
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND 200 kHz Tumor Treating Fields (TTFields) therapy is FDA-approved for supratentorial newly-diagnosed and recurrent glioblastoma. However, reports of its application in patients with infratentorial high-grade glioma (HGG) are rare. Based on computational modeling, the therapeutic field strength (~1 V/cm peak-to-peak) is thought to be achievable for infratentorial HGG. METHODS Two patients with infratentorial HGG received off-label 200 kHz TTFields therapy with the Optune® device (Novocure, Ltd.). To reduce impaired range of motion of the neck, the electrode transducer arrays were “skeletonized” by cutting a portion of the adhesive material surrounding them. Application of the electrode arrays was performed with the neck in flexion, to further promote neck range of motion. Cloth tape was used for reinforcement as necessary. Electrode arrays were changed every 2-3 days. We report the results of patient survival and adverse events. RESULTS Patient 1: 22-year-old man with high-grade diffuse pontine glioma with recurrences and prior treatments (including radiation, temozolomide, lomustine, and dopamine receptor D2 [DRD2] antagonist), tolerated TTFields combined with systemic treatment (initially with a bi-functional DNA alkylating agent; subsequently with temozolomide and bevacizumab) for 5 months with stable disease for 4 months. He experienced grade 1 rash of the neck. Patient 2: 58-year-old woman with diffuse glioma of the brainstem (H3K27M-mutated) with multiple recurrences and prior treatments (including concurrent radiation and temozolomide, and DRD2 antagonist), tolerated TTFields combined with systemic treatment (lomustine and bevacizumab). The TTFields infratentorial layout was iteratively modified with respect to placement of the electrode transducer arrays, for improved tolerability. With the TTFields+systemic combination therapy, the patient was stable for 8 months with no local TTFields-related side effects. CONCLUSIONS We provide initial post-marketing evidence that off-label use of 200 kHz TTFields in infratentorial HGG is safe and feasible. Prospective studies are necessary to validate the efficacy of this approach.
RADT-03. CONTRAST-ENHANCING LESIONS INDUCED BY CNS-DIRECTED INTENSITY MODULATED PROTON THERAPY: DEMOGRAPHIC AND CARDIOVASCULAR RISK FACTORS ANALYSIS
Authors: Omer Gal, Jen Yu, Minesh P Mehta, Matthew D Hall, Robert H Press, Yazmin Odia, Michael W McDermott, Zachary Fellows, Andrew Wroe, Alonso N Gutierrez, Rupesh Kotecha
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Lesions exhibiting radiation-induced contrast enhancement (RICE) may develop following cranial intensity modulated proton therapy (IMPT). The mechanisms underlying their development may be shared or amplified by existing patient comorbidities. The objective of this study was to assess a potential relationship between individual or composite cardiovascular risk criteria and RICE development, independent of dosimetric considerations. METHODS Data were reviewed for patients treated at a single tertiary care institution between 2017-2023. Time to RICE development was assessed using Kaplan-Meier. Cox regression analysis was used to determine hazard ratios (HRs) with 95% confidence intervals (CIs). Host-related risk factors for RICE development were assessed in a univariable analysis (UVA). A binary logistic regression model was built to ascertain the effects of age and cardiovascular risk factors on the likelihood of developing RICE (expressed as QRISK3 relative risk). RESULTS The study cohort included 137 patients; the median age was 40 years (range: 1-85), 51% female, and 53% Hispanic. Cardiovascular risk factors included smoking (18% past, 6% current), diabetes (7%), hypertension (22%), dyslipidemia (15%) and high body mass index (BMI, 50% were obese with BMI&amp;gt;25). At a median follow-up of 3 years, RICE developed in 36 (26%) patients. On UVA, RICE development was only associated with age ≥18 compared to &amp;lt;18 (HR 3.3, 95% CI: 1.2-9.4, p=0.024). None of the other evaluated risk factors were significantly associated with RICE (p&amp;gt;0.05). Additionally, logistic regression analysis showed increasing age was associated with likelihood of developing RICE (χ2=6.95, p=0.031), while QRISK3 score was not. CONCLUSIONS In this contemporary series of patients treated with IMPT, age was the only host factor associated with RICE, while other cardiovascular risk factors, evaluated individually or using established composite risk scores (QRISK3) were not associated with RICE. Additional research is needed to identify potential patient characteristics associated with RICE.
INNV-30. TOXICITIES AND OUTCOME AFTER CD19-DIRECTED CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY FOR NEUROLYMPHOMATOSIS
Authors: Leon D Kaulen, Philipp Karschnia, Sofia Doubrovinskaia, Wolfgang Wick, Maria Martinez-Lage, Ganesh Shankar, Jeremy S Abramson, Matthew J Frigault, Jorg Dietrich
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Lymphomatous infiltration of the peripheral nervous system (PNS), termed neurolymphomatosis, represents a distinct extranodal non-Hodgkin lymphoma variant with dismal outcome. CD19-directed chimeric antigen receptor (CD19-CAR) T-cell therapy has emerged as a safe and effective treatment for B-cell lymphomas. We aimed to assess toxicity and efficacy of CD19-CAR T-cells in neurolymphomatosis. METHODS Neurolymphomatosis treated with CD19-CAR T-cells were retrospectively identified at Massachusetts General Hospital over a six-year period. Toxicities were graded according to the ASTCT classification. Management, and response rates were recorded. RESULTS Eleven neurolymphomatosis cases, who had received a median 2 prior PNS-directed treatments (range: 1-3) before CD19-CAR T-cell exposure, were identified. Neurolymphomatosis localized to the nerve roots (8/11, 73%), plexus (5/11, 45%), peripheral (4/11, 36%) and cranial nerves (5/11, 45%). Low grade cytokine release syndrome was detected in 8/11 (73%; grade 1: N = 7; grade 2: N =1) cases. Low- and high-grade immune cell-associated neurotoxicity syndrome were recorded in 5/11 (45%; grade 1: N = 4; grade 2: N = 1) and 1/11 (9%; grade 4) patients, respectively. Seven of eleven neurolymphomatosis patients (64%) responded to CD19-CAR T-cells. Complete remissions were achieved in three cases (27%), of which two are still sustained now 9 and 46 months after CD19-CAR T-cell infusion. All radiographic responses were associated with remission of neurological symptoms. CONCLUSIONS CD19-CAR T-cell treatment was well tolerated and yielded promising efficacy in recurrent neurolymphomatosis, a difficult to treat condition with unmet medical need. Findings suggest that CD19-CAR may sufficiently penetrate the blood-nerve barrier, and toxicity and outcomes were overall similar to CAR-T cell therapy in CNS lymphoma.
INNV-20. FLUORESCEIN GUIDED SURGERY FOR ATYPICAL BRAIN LESIONS: IS IT USEFULL? CASE SERIES USING A LOW-COST DEVICE
Authors: Aline Lariessy Campos Paiva, João Luiz Vitorino Araujo, Renan Maximillian Lovato, Jean Gonçalves de Oliveira, José Carlos Esteves Veiga
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Sodium Fluorescein (SF) enhances in areas in the brain with a disrupted Blood brain barrier (BBB). In neurosurgery, SF is extensive used for malignant brain tumors. Solitary brain abscesses (BA) are characterized by the pathognomonic finding of BBB disruption. Consequently, FL may have the potential to improve the intra-operative visualization of BA. Other infections also disrupt BBB and SF may guide these surgeries. CASE SERIES A 32-year old male patient, previously diagnosed with HIV presented with headache and during investigation MRI disclosure an extensive leptomeningeal commitment. Leptomeningeal biopsy guided by fluorescein and using Varioguide system was performed and the diagnosis was primary central nervous system lymphoma (Diffuse large B-cell). During surgery, it was observed increased fluorescence in arachnoid. A 72-year old woman presented with headache, impairment of mental status and epilepsy and a KPS of 60. Her initial hypothesis was metastasis but patient did not have a primary situs diagnosis. An open biopsy was performed through temporal posterior craniotomy. During surgery no visible well delimited tumor was found, even with ultrasound use. Fluorescein guided biopsy was performed. Histological evaluation showed an Epstein-Barr virus infection causing encephalitis. This is an extremely rare presentation of this type of infection and SF was extremely helpful to guide the procedure. CONCLUSION This paper reported atypical uses of SF for brain mass lesions surgeries. One of our cases is a unique presentation of a virus encephalitis which mimicked metastasis and other of increased fluorescence in Lymphoma. These atypical use of SF are relevant for further neurosurgical plannings Keywords: Fluorescein, Lymphoma, Biopsy
INNV-16. ONCOPATH: OPTIMIZED TREATMENT GUIDELINE CONCORDANT PATHWAY PRESENTED ON A VISUAL-INTERACTIVE DASHBOARD FOR CLINICAL DECISION SUPPORT COMPUTED BY OVERLAYING PATIENT LONGITUDINAL DATA ON A KNOWLEDGE GRAPH
Authors: James Snyder, Sharon Hensley Alford, Tarun Kumar, Kirit Pindolia, Laila Poisson, Shilpa Mahatma, Tom Mikkelsen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND OncoPath provides a visual analysis of a brain tumor patient’s longitudinal clinical data overlayed on disease specific pathways with the goal of reducing knowledge discordant care and insurance authorization burden. By ingesting, curating and visually presenting the patient experience on guidelines, OncoPath aims to streamline clinical decision making and related processes. Understanding the patient’s journey compared to treatment guidelines is of value in addressing health equity and guideline adoption in real world settings. METHODS Data from 44 glioma patients diagnosed and treated between 2016-2021 were uploaded to OncoPath using natural language processing and other tools to capture abstractable data elements. The data was overlayed on guidelines using recursive graph modeling. Using the knowledge graph of a patient’s history, the model also recommends treatment options in an interactive visual dashboard representing NCCN guidelines. The dashboard includes the guidelines in graphical format with associated references and notation. RESULTS 28 males and 16 females age 21-38 years at diagnosis were abstracted. Cases represented 4 oligodendrogliomas, 13 astrocytomas, and 27 glioblastomas. Data was available through second line therapy, discharge to hospice or death. Cases were matched to the NCCN 2021 guidelines which was used for treatment decisions until November 2022. The patient data matched OncoPath except in 3 cases where KPS was not available resulting in premature pathway truncation. For these cases we inferred KPS based on subsequent treatment received to optimize the historic data. CONCLUSION To our knowledge, this is a first-of-a-kind technology in neuro-oncology that may improve time to treatment, reduce health utilization resources and can serve as a benchmarking tool for care delivery. The feasibility of clinically implementing such tools for decision support was demonstrated. This type of tool could be particularly useful in low-resource areas where disease specific expertise may not be available or to illuminate care discrepancies.