tbuckley/cabot-search huggingface dataset:
CTNI-07. LONG-TERM EFFICACY AND SAFETY OF LAROTRECTINIB IN PATIENTS WITH TRK FUSION PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS: AN UPDATED ANALYSIS
Authors: Sébastien Perreault, Jean-Philippine Spano, Anna Nilsson, Rebecca J Deyell, François Doz, Birgit Geoerger, Mahmut Gumus, Ulrik N Lassen, Karsten Nysom, Lorena Valero-Arrese, Ahmed Idbaih, Vadim Bernard-Gauthier, Natascha Neu, Nicoletta Brega, Alexander Drilon, Theodore W Laetsch, Cornelis M van Tilburg
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Larotrectinib is a highly selective TRK inhibitor approved for TRK fusion tumor-agnostic use. We report updated data on larotrectinib-treated patients with TRK fusion primary CNS tumors. METHODS Patients enrolled in 2 clinical trials (NCT02637687 [SCOUT], NCT02576431 [NAVIGATE]) were included. Responses were independent review committee (IRC)-assessed (RANO). Patients from SCOUT could stop larotrectinib in the absence of on-treatment progression (wait-and-see). Data cutoff: July 2023. RESULTS Fifty-five patients (38 aged &amp;lt;18 years at enrolment) were evaluated, including 16 with non-measurable disease at baseline. Tumor histologic groups included: high-grade glioma (HGG; n=32), low-grade glioma (LGG; n=15), and other (n=8). For all patients (n=55), ORR was 27% (95% CI 16-41): 3 CR, 12 PR, 24 SD (15 for &amp;gt;24 weeks), 12 PD, and 4 not evaluable. For pediatric patients (n=38), ORR was 37% (95% CI 22-54). ORR in patients with measurable disease only was 38% (95% CI 23-55) for all patients (n=39) and 52% (95% CI 32-71) for pediatric patients (n=27). The 24-week disease control rates were 55% (95% CI 41-68) and 74% (95% CI 57-87) for all patients and pediatric patients, respectively. Median time to response, DoR, PFS, and OS were 2, 12 (95% CI 6-not estimable [NE]), 12 (95% CI 7-20), and 38 months (95% CI 23-NE), respectively. Treatment duration ranged from 1 to 64+ months. At data cutoff, 1 pediatric patient with HGG and 4 with LGG entered wait-and-see; median duration of first wait-and-see period was 20 months (range 4-29). One pediatric patient with LGG resumed treatment following disease progression in wait-and-see. Treatment-related adverse events were predominantly Grade 1/2. CONCLUSION Larotrectinib demonstrated rapid, durable responses and manageable safety in patients with TRK fusion primary CNS tumors. This supports the adoption of NGS panels containing NTRK gene fusions when testing patients to identify those who might benefit from TRK inhibitor therapy.
RADT-41. RADIOSURGERY FOR GLOMUS TUMORS: IMPACT OF MRI-PET FUSION ON TREATMENT PLANNING AND OUTCOMES
Authors: Sanjeev Sreenivasan, Jessica Jung, Emel Calugaru, Michael Schulder, Anuj Goenka
Journal: Neuro-Oncology (2024)

Abstract Paragangliomas present a challenge for stereotactic radiosurgery (SRS) treatment planning, particularly regarding the delineation of tumor boundaries. We propose that integrating 68Ga-DOTATATE PET scans alongside MRI in SRS planning will facilitate superior target identification and tumor coverage compared to reliance on MRI alone. A retrospective analysis of 9 patients diagnosed with paraganglioma who underwent MRI and 68Ga-DOTATATE PET imaging over a 20-month period was conducted. Images were imported into GammaPlan treatment planning software, partitioned into separate sessions: one with MRI and another with MRI-PET fusion. A single evaluator contoured paragangliomas as gross tumor volume (GTV) initially using MRI alone and subsequently with PET/MRI fusion. The pre- and post-PET fusion GTV volumes were compared. The standard deviation of the percentage increases in volume was calculated to assess variability across the sample. Of included 9 patients, 7 were females and median age was 58.3 years. Four patients had prior surgery. Seven patients were treated with Gamma Knife, while 2 with LINAC. Two patients were treated with single fraction SRS while 7 with hypofractionated SRS. Across all treated patients (n=9), GTV volumes significantly increased with PET fusion, with an average volume increase of 26.02% (n=8). One patient reported dryness of throat after SRS. Significant PET avidity over structures like temporal bone, internal jugular vein, petrous internal carotid artery and sigmoid sinus-IJV junction were included in PET/MRI fusion GTVs, which were missed on isolated MRI contours. At median 6-month follow up, all patients had a stable radiological response. Integration of 68Ga-DOTATATE PET scans with MRI enhances the visualization of paragangliomas in patients undergoing SRS. Further extensive studies are warranted to validate this observation and to better understand the variability in treatment response observed across the patient population. Our practice has initiated routine utilization of DOTATATE-PET imaging in paraganglioma patients undergoing SRS planning.
PATH-09. CLINICAL CHARACTERISTICS AND MOLECULAR CHARACTERISTICS OF 244 MEDULLOBLASTOMAS IN JAPAN
Authors: Kohichi Go, Asako Katsuma, Yasuhide Makino, Etsuko Yamamoto, Ema Yoshioka, Tomoko Shofuda, Daisuke Kanematsu, Shigeki Takada, Noritaka Sano, Masahiro Tanji, Yohei Mineharu, Kohei Fukuoka, Yoshinori Kodama, Masayuki Mano, Koichi Ichimura, Atsushi Sasaki, Junko Hirato, Takeshi Inoue, Ryo Nishikawa, Isao Date, Masahiro Nonaka, Motoo Nagane, Yoshiki Arakawa, Yonehiro Kanemura
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastomas are at least classified into four core subgroups, including WNT-activated, SHH-activated, group 3 and group 4. These molecular subgroups have been introduced in the WHO classification, which has become fundamental and indispensable. The JPMNG is co-organized by the Japan Society for Neuro-Oncology and the Japanese Society for Pediatric Neurosurgery, and we have summarized clinical and molecular characteristics of Japanese MBs. METHODS We enrolled 267 cases of medulloblastoma from 44 centers participating in the JPMNG study. Central histopathological diagnosis was performed by three neuropathologists, and molecular genetic diagnosis was performed by NanoString nCounter system or DNA methylation array, and their single nucleotide mutations and copy number aberrations have been also examined. RESULTS A total of 244 cases were finally analyzed, and the 4-subgroup classification was WNT: 39 (16%), SHH: 61 (25%), group3: 42 (17%), and group4: 102 (41.8%), respectively. In cases of less than 3 years old, no WNT have been found and 62.2% cases were SHH. In cases of WNT-MB, the majority being children (6-18 years) (31/39: 79.5%), and 8 cases (8/39: 20.5%) in adults older than 18 years. In cases between 3 to 17 years old, Group 4 is the most (48.6%), and these trends is almost consistent with published. references. Metastatic or MYC gain Group 3 MBs were poor prognosis, while Group 4 MBs with loss of chromosome 11 or whole chromosomal aberration were good prognosis. CONCLUSIONS Clinical and molecular characteristics of Japanese WBT-MB were almost consistent with those reported in other countries, and the relationship between molecular properties and prognosis of group3/group4 MBs were also reproducible. These findings suggest importance of molecular properties of MBs are preserved beyond ethnic differences, and will contribute to develop new therapeutic strategies.
CNSC-15. DURATION AND TIMING ANALYSIS OF TUMOR TREATING FIELDS (TTFIELDS) THERAPY FOR NEWLY DIAGNOSED HIGH-GRADE GLIOMA PATIENTS: A REAL-WORLD RETROSPECTIVE STUDY IN TWO CENTERS
Authors: Chun Wang, Lingchao Chen, Jianxiong Ji, Junyan Zhang, Kun Song, Yanhong Pan, Nainai Ma, Huijuan Zheng, Yang Xiao, Gao Chen, Fuyi Liu, Zhiyong Qin
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND In the EF-14 phase 3 trial, tumor treating fields (TTFields) plus temozolomide improved progression-free and overall survival versus temozolomide alone in newly diagnosed glioblastoma. However, the optimal duration and timing of TTFields treatment have not been reported yet. In this study, we aimed to analyze the relationship between the timing of TTFields use, the total duration of therapy, and daily compliance with overall survival in high-grade glioma (HGG) and, therefore, provided detailed suggestions for clinical use of TTFields. METHODS A total of 343 patients were screened retrospectively after resection or biopsy at two centers and received TTFields treatment from April 2019 to April 2023. All the patients were re-evaluated based on the 2021 WHO CNS5 Classification. We collected clinical data, including basic clinical information, pathology, surgery, radiotherapy, and TTFields. Follow-up for survival was performed for all patients in December 2023, and another follow-up is planned for June 2024. RESULTS After excluding non-HGG or lacking critical diagnostic information, 308 patients were included. Of these, 264 were Glioblastoma, IDH-wildtype, 27 were Astrocytoma, IDH-mutant, 3 were Oligodendroglioma, IDH-mutant, and 1p/19q-codeleted, and 14 were Diffuse midline glioma, H3 K27-altered, or Diffuse hemispheric glioma, H3 G34-mutant. Baseline characteristics were listed below: median age was 53 years; 56.82% male; median baseline KPS was 90; 75.97% underwent gross total resection; 51.30% received chemoradiation with concurrent TTFields. Only 26.30% of patients were still using TTFields by December 31, 2023. The median time difference between TTFields and surgery was 55.5 days. The overall TTFields median duration was 334 days, with a median compliance rate of 85%. By December 31, 2023, 59.09% of the patients were still alive. CONCLUSION The study group will continue to follow up on patients’ survival. Further analysis of the correlation between treatment duration, compliance or timing and survival will be performed.
DDDR-14. IMPROVED ANTI-GLIOBLASTOMA EFFICACY BY BRG399, A NOVEL ORAL MICROTUBULE BINDING AGENT
Authors: Mustafa Tansel Kendirli, Maria-Dorothea Nastke, Juan Aristizabal-Henao, Abbas Khojasteh, Michael Kiebish, Dinesh Chimmanamada, Vivek Vishnudas, Lawrence Recht, Stephane Gesta
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is a highly malignant form of brain tumor with a poor prognosis despite advances in treatments. Therapeutic resistance/relapse remains a significant challenge necessitating the development of novel approaches. BRG399 is a brain permeant, non P-gp substrate, microtubule-targeting agent that displays anti-cancer activity in vitro and in vivo. BRG399 was well tolerated in rat and dog toxicology studies. Anti-cancer activity (IC50) of BRG399 in in vitro models of GBM was assessed to have potency ranging from 42nm to 89nM in the 3 cell lines tested. Here, in vivo tumor activity of BRG399 was assessed in Sprague Dawley rats implanted with 3x105 C6 rat glioma cells into the right entorhinal cortex/subiculum region. 14 days post successful implantation tumors were assessed by MRI, rats were randomized to receive vehicle (2% Labrasol) or BRG399 (5, 10, 20 mg/kg groups) twice daily by oral gavage for 16 days, and MRIs were performed on survivors on days 31 and 45 post implantation. BRG399 administration resulted in a marked improvement in survival (from 7.7 ± 2.6 days to 25.5 ± 15.6 days, log-rank test, p:0.007) compared to controls. Six animals receiving BRG399 remained alive beyond day 60 of post-treatment initiation. To assess biodistribution of BRG399 in the brain, rats were implanted with C6 cells and tumor establishment assessed 12 days later by MRI. Animals were treated with vehicle or BRG399 (10, 20, 25 mg/kg) and plasma and brains were collected for bioanalytical assessment. Tissue single cell biodistribution was performed using TIMSTOF FLEX spatial OMICS. These results demonstrate a therapeutic effect of BRG399 on intracranial glioma-bearing rats with survival of the BRG399 treatment groups of strong statistical significance over the control group. Analysis of drug levels in plasma and brain will serve as guidance for dose and scheduling decisions for further therapeutic development.
RADT-27. REPORT OF 9 CASES OF EMBRYONAL TUMORS OF THE CENTRAL NERVOUS SYSTEM WITH MULTILAYERED ROSETTES (ETMR)
Authors: Ruyu Ai, Juan Li, Mingyao Lai, Linbo Cai
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE Embryonal Tumors of the Central Nervous System with Multilayered Rosettes (ETMR) are rare, and there’s no standard treatment protocol. This article reports on the current treatment status and prognosis of ETMR in our hospital. METHODS We retrospectively collected patients with ETMR who received treatment in the Oncology Department of Guangdong sanjiu Brain Hospital from January 2017 to January 2021, analyzed their clinical data. RESULTS Among 31 cases of central nervous system embryonic tumors (excluding medulloblastoma and ATRT), 9 (29.03%) were ETMR. The median age at diagnosis was 3 years old (1-15), and the male to female ratio was 4:5. Among them, 5 cases were accompanied by C19MC gene variation. Tumor location:6 was in supratentorial, 1 in the pineal region, 1 in the pons, 1 in the cerebellopontine. Eight patients underwent surgical resection at the first diagnosis, with 6 cases of total resection, 1 case of partial resection, and 1 case of biopsy. One case was misdiagnosed as a germinoma in the pineal region at the initial. After recurrence, surgical resection was performed to confirm the pathology as ETMR. One case was misdiagnosed as glioblastoma during the first surgery. The initial treatment for 4 patients after surgery was radiotherapy combined with concurrent chemotherapy. Recurrence patterns: 2 cases were intracranial dissemination, 2 cases were local recurrence, 1 was spinal cord dissemination. One patient did not receive treatment after surgery and tumor recurrence 3 months later. Survival analysis: The median survival time was 20 months. The 1-year progression-free survival rate (PFS) and overall survival rate (OS) were 22% and 61%, and the 2-year overall survival rate (OS) was 31%. CONCLUSION ETMR has a low incidence and poor prognosis. It is easy to misdiagnose and NGS is necessary to assist diagnosis when needed. More effective treatment methods need to be explored.
CTIM-08. FIRST IN HUMAN STUDY OF THE MRNA-BASED CANCER VACCINE CVGBM IN PATIENTS (PTS) WITH NEWLY-DIAGNOSED AND SURGICALLY RESECTED MGMT-UNMETHYLATED GLIOBLASTOMA (GBM): FIRST RESULTS FROM THE DOSE ESCALATION PHASE
Authors: Ghazaleh Tabatabai, Pierre Freres, Martin Glas, Peter Hau, Louisa von Baumgarten, Martin van Den Bent, Michael C Burger, Clemens Seidel, Ulrich Herrlinger, Iris Mildenberger, Bart Neyns, Henning Schafer, Antje Wick, Martin Falk, Laura Leticia Freitas de Chama, Peter Kelemen, Frauke Schwenke, Sven D Koch, Paula Romer Roche, Ulrike Gnad-Vogt
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION CVGBM is an investigational therapeutic mRNA-based vaccine encoding 8 epitopes derived from tumor associated antigens with potential relevance in GBM. This is an ongoing, first-in-human study evaluating the safety of CVGBM in pts with newly-diagnosed MGMT-unmethylated GBM. METHODS HLA-A*02:01-positive pts with newly-diagnosed MGMT-unmethylated GBM (CNS WHO Grade [Gr] 4) who had a gross total or partial resection and completed radiotherapy ± concomitant temozolomide received CVGBM on Days 1, 8, 15, 29, 43, 57 and 71 + 6 optional doses at 6-week intervals. Primary endpoints are safety, tolerability and dose-limiting toxicities (DLTs). Immunogenicity is an exploratory endpoint. RESULTS As of 29/2/2024, 16 pts were enrolled in the dose-escalation part (Part A); 3 each in DL 1 (12 µg), DL 2 (25 µg), and DL 3 (50 µg), and 7 in DL 4 (100 µg). For all cohorts, mean time on study from 1st dose to last visit was 4.5 months (min: 1.5; max: 8). 109 doses were administered (mean: 6.8 doses per pt). All pts completed the 2-week DLT evaluation period without DLTs. Of 156 treatment-emergent adverse events (TEAEs), the majority (73%) were CTCAE Gr 1 (21% Gr 2, 6% Gr 3). The most common related TEAEs were chills (n=13), pyrexia (n=12), headache (n=12), fatigue (n=11) and malaise (n=5), mostly of mild to moderate severity. 7 pts had 9 ≥ Gr 3 AEs assessed as potentially related to CVGBM by the investigators outside the DLT period (cerebral edema [n=2], leukoencephalopathy, pseudoprogression with cerebral edema, structural epilepsy, ataxia, hypertension, malaise and fever [1 of each]), evenly distributed across cohorts. First immunogenicity data are planned to be presented. CONCLUSIONS CVGBM was generally well tolerated with an acceptable safety profile. The highest tolerated dose was not reached. Based on all available safety data, the selected dose for trial expansion was 100 µg. Previously presented at ESMO 2024, “FPN (Final Publication Number): 4400, Ghazaleh Tabatabai et al. - Reused with permission.
RADT-20. POSTOPERATIVE RADIOTHERAPY PROVIDES ADDITIVE PROGRESSION-FREE SURVIVAL BENEFIT IN ATYPICAL MENINGIOMAS REGARDLESS OF EXTENT OF RESECTION
Authors: Umberto Tosi, Marialaura Simonetto, Alexandra Giantini-Larsen, Rohan Ramakrishna, Philip Stieg, Theodore Schwartz
Journal: Neuro-Oncology (2024)

Abstract WHO Grade II meningiomas represent a minority of all meningiomas. The creation of treatment algorithms has remained challenging, with the need to add postoperative radiotherapy (RT) following satisfactory gross total resection being oftentimes debated. Thus, the goal of this study was to understand which factors, if any, predispose to recurrence of atypical meningiomas following resection. Therefore, we retrospectively review a 90-patient cohort of WHO grade II meningiomas who underwent surgical resection. Patients were clustered based on tumor location, (convexity or non-convexity) and whether they had received postoperative RT. Following extraction of biographic characteristics, the extent of tumor resection and tumor recurrence were measured. A detailed uni- and multivariate analysis was carried out to determine which factors, if any, predisposed to recurrence. The cohort consisted of 90 patients with a WHO Grade II meningiomas. A gross total resection was achieved in 66.7% of patients. Patients who had a gross total resection and received postoperative RT had longer progression-free survival (p = 0.031) than patients with subtotal resections (STR), regardless of radiation status, and patients with a GTR who did not receive radiation. On uni- and multivariate analysis, receiving postoperative RT was the only factor associated with no recurrence of disease (p = 0.023); no association was found for extent of resection (p = 0.63) or location (p = 0.18). In conclusion, the treatment of WHO grade II meningiomas remains challenging. In this study, we showed how the addition of radiotherapy remains beneficial even in cases of gross total resection, regardless of location. We postulate how microscopic disease not observed on MRI may be responsible for these findings.
CNSC-39. INTEGRATED CLINICAL GENETIC ANALYSIS REVEALS NEUROTRANSMITTER RECEPTOR DYSREGULATION IN MENINGIOMAS CAUSING SEIZURE
Authors: A Basit Khan, Malcolm McDonald, Akdes Harmanci, Collin English, Arif Harmanci, Tiemo Klisch, Akash Patel
Journal: Neuro-Oncology (2024)

Abstract Molecular correlates of seizures in meningioma remain unexplored. Previously, we identified MenG molecular grouping, wherein MenG C meningiomas recur more than MenG A or B. We therefore sought to identify molecular and clinical drivers of seizures in meningioma. We identified 144 primary supratentorial meningiomas, excluding those with pre-existing epilepsy. Whole exome sequencing assessed somatic mutation burden. Bulk RNA-sequencing identified differentially expressed genes and gene ontologies (GO). Immunohistochemistry confirmed protein levels. No differences in canonical gene mutation burden (NF2, TRAF7, AKT1, KLF4, SMO, SMARC) was found between seizure and non-seizure groups. MenG C tumors had higher seizure incidence compared to MenG A or B (p=0.03). Seizure causing meningiomas, though extra-axial, exhibited dysregulated neuronal signaling genes. GABAA receptor subunit genes GABRA3 and GABRG1 were downregulated in tumors causing seizure (Log2FC=-1.67, padj=0.014; Log2FC=-2.24, padj=0.009). Immunohistochemistry confirmed expression of GABRB2 subunit, the first documentation of GABA receptor expression in meningiomas. Neuropeptide Y Receptor Y1 (NPY1R) is downregulated in seizure causing meningiomas (Log2FC=-1.64, padj=0.002). NPY1R loss correlates is observed in mesial temporal lobe epilepsy and post-electroconvulsive shock mouse brains. In GO analysis, the terms “GABA signaling pathway,” “neuropeptide signaling,” “excitatory postsynaptic membrane potential,” and “ionotropic glutamate pathway,” were downregulated in meningiomas with seizure (padj&amp;lt;0.05). We assessed which alterations within MenG C tumors caused seizures by identifying genes associated with both seizure presentation and MenG C classification. Glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) is downregulated in MenG C tumors (Log2FC=-2.29, padj=6.02E-07) and seizure causing tumors (Log2FC=-1.75, padj=0.03). Clinically, patients experiencing pre-operative seizures more frequently had cerebral edema, non-homogenous enhancement, intratumoral calcification, higher MIB-1, atypical grade 1, reduced GCS, and ER presentation; they were less likely to have incidental or headache presentation (p&amp;lt;0.05 for all). MenG classification predicts seizure presentation whereas somatic mutation status does not. Meningiomas causing seizures show pathologic neurotransmitter receptor dysregulation.
DNAR-13. LONG TERM FOLLOW-UP OF A LYNCH SYNDROME-ASSOCIATED GLIOBLASTOMA RESISTANT TO STANDARD-OF-CARE CHEMORADIATION
Authors: Merve Hazal Ser, Duru Baykal, Jessica D White, William G Breen, Ian F Parney, Tobias Walbert, Peter Forsyth, Arnold Etame, Robert Macaulay, Yolanda Pina, Uğur Sener
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Lynch syndrome is caused by pathogenic germline variants in the DNA mismatch repair (MMR) genes, predisposing individuals to malignancies, including glioblastoma (GBM). MMR-deficient tumors are resistant to monofunctional alkylators such as temozolomide but not to bifunctional alkylators such as the nitrosourea lomustine. Anti-programmed cell death protein 1 (PD1) immune checkpoint inhibitor (ICI) pembrolizumab represents another treatment option, which is approved by the United States Food and Drug Administration (FDA) for the treatment of mismatch repair deficient cancers. METHODS We present a patient with multifocal GBM and Lynch syndrome who experienced rapid progression following standard-of-care chemoradiation, followed by durable responses to lomustine and then to pembrolizumab. RESULTS A 58-year-old man with Lynch syndrome (MSH2 mutation) and prior history of colon cancer presented with seizures. Magnetic resonance imaging (MRI) brain identified right frontal and left parietal masses. Right frontal tumor was resected; pathology was consistent with GBM, IDH wildtype, MGMT-unmethylated. Both lesions were treated with radiation therapy (60 Gy, 30 fractions) with concurrent and adjuvant temozolomide. After two cycles of adjuvant temozolomide, his left parietal tumor progressed and was subtotally resected, followed by four cycles of lomustine (stopped due to myelotoxicity). He remained progression-free for 15 months. Surveillance MRI identified new enhancement involving the left frontal lobe, left periventricular white matter, and right internal auditory canal, concerning for leptomeningeal dissemination. MRI spine identified no additional lesions. Cerebrospinal fluid cytology was negative for tumor cells on two occasions. Patient was treated with pembrolizumab. He remains on treatment with stable disease four months after ICI initiation and 31 months after GBM diagnosis. CONCLUSIONS Patients with MMR-deficient GBM resist standard chemoradiation. Alternatives such as nitrosourea or ICI therapy may achieve durable responses. While data is insufficient to administer these agents as upfront therapy in this specific setting, both should be considered as options for recurrent disease.