tbuckley/cabot-search huggingface dataset:
LGG-46. MEKI WITH MIRDAMETINIB: EXPLORING ADAPTIVE SIGNALING PATHWAY DYNAMICS AND IMMUNE MODULATION IN PEDIATRIC GLIOMAS
Authors: Juliana M Pensabene, Natalia Muñoz Perez, Rita M Yazejian, Kirsten Moziak, Allison M Martin
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Glial neoplasms are among the most common types of solid tumors in children. The mitogen-activated protein kinase (MAPK) pathway is implicated in glioma tumorigenesis. Drugs targeting this pathway hold promise as novel therapy for this disease. Vertical inhibition of the MAPK pathway has been linked to increased inflammation in several other cancers but similar exploration in pediatric brain tumors is limited. Within the MAPK pathway, MEK plays a significant role as a modulator of ERK phosphorylation. This study investigates the therapeutic potential of the MEK inhibitor, Mirdametinib, and evaluates the drugs’ capacity to induce tumor-intrinsic inflammation by characterizing changes in PD-L1 expression and proliferation in a panel of pediatric glial neoplasms. METHODS Three cell lines were included in the panel (Res186, Res259, SF188) and were treated with Mirdametinib for 3, 5, or 7 days. P-ERK expression, analyzed by western blot, verified successful inhibition of MEK by Mirdametinib. The CCK8 cytotoxic assay was utilized to determine the drug’s 50% inhibitory concentration as well as its direct effects on cell viability. Changes in Ki67 expression assessed by flow cytometry further characterized Mirdametinib’s effects on cell proliferation. Flow cytometry was also utilized to measure changes in PD-L1 expression following treatment. RESULTS Despite minimal effects on proliferation as measured by Ki67 and CCK8, expression of P-ERK verifies successful inhibition of MEK. Western blot data also reveals increased Pi3K/AKT pathway activity in SF188 groups treated with Mirdametinib. FACS data for SF188 also demonstrates increased PD-L1 expression in response to treatment. CONCLUSIONS Data suggests that, in response to MEKi, gliomas utilize compensatory growth mechanisms through Pi3K/AKT signaling. Findings also point to immune-modulatory effects of MEKi. Supporting results in ongoing experiments are expected to further our understanding of these mechanisms and may help inform effective combination treatment strategies for pediatric gliomas.
GCT-16. LONG-TERM OUTCOMES AND COMPLICATION MANAGEMENT IN CNS GERM CELL TUMORS: INSIGHTS FROM A PHASE II HISTOPATHOLOGY-STRATIFIED TREATMENT TRIAL
Authors: Hirokazu Takami, Ryo Nishikawa, Tomonari Suzuki, Kazuhiko Takabatake, Takamitsu Fujimaki, Michinari Okamoto, Shigeru Yamaguchi, Masayuki Kanamori, Kenichiro Matsuda, Yukihiko Sonoda, Manabu Natsumeda, Toshiya Ichinose, Mitsutoshi Nakada, Ai Muroi, Eiichi Ishikawa, Masamichi Takahashi, Yoshitaka Narita, Fumi Higuchi, Masahiro Shin, Yohei Mineharu, Yoshiki Arakawa, Naoki Kagawa, Shinji Kawabata, Masahiko Wanibuchi, Takeshi Takayasu, Fumiyuki Yamasaki, Kentaro Fujii, Joji Ishida, Isao Date, Keisuke Miyake, Yutaka Fujioka, Daisuke Kuga, Shinji Yamashita, Hideo Takeshima, Naoki Shinojima, Akitake Mukasa, Shota Tanaka, Akio Asai, Masao Matsutani
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND This detailed examination merges outcomes from a Phase II clinical trial targeting central nervous system (CNS) germ cell tumors (GCTs) conducted between 1995 and 2003. It evaluates the impact of histopathologically driven treatment modalities on survival, recurrence, and post-treatment life and social outcomes, aiming to delineate the long-term effects of such stratified treatment approaches. METHODS The cohort comprised 228 patients, stratified into three groups based on histology: germinoma (n=161), intermediate prognosis (n=38), and poor prognosis (n=28), each receiving customized chemotherapy and radiation treatments. With a median follow-up duration of 222 months, this longitudinal study scrutinized survival rates, recurrence patterns, and a spectrum of socio-economic and health-related outcomes. RESULTS For the germinoma group, the 10- and 20-year event-free survival (EFS) rates stood impressively at 82% and 73%, respectively, with overall survival (OS) rates reaching 97% and 92%. The intermediate prognosis group witnessed 10- and 20-year EFS rates of 76% and 66%, and OS rates of 87% and 70%. The poor prognosis group recorded EFS rates of 49% at both intervals, with OS diminishing to 61% and 53%. Notably, germinomas localized in the basal ganglia exhibited high relapse rates absent initial whole-brain radiation, yet were effectively managed upon subsequent interventions. The comprehensive follow-up illuminated striking disparities in socio-economic achievements: higher educational attainments, more stable employment, and improved health outcomes were predominantly observed among patients without recurrence. Non-recurrent germinoma patients, in particular, showcased enhanced educational and employment status, vividly illustrating the profound impact of disease progression and treatment on life quality. CONCLUSIONS The findings highlight the critical importance of customized initial treatments for improving survival and life quality in CNS GCT patients, stressing the need for detailed long-term follow-up to address relapses and complications effectively. The study advocates for personalized care that balances treatment intensity to optimize long-term outcomes, enhancing post-treatment care.
GCT-17. EXPLORING NEW THRESHOLDS FOR BETA-HCG IN CENTRAL NERVOUS SYSTEM GERMINOMA
Authors: Malgorzata A Krawczyk, Simge Acar, Jinli Wang, Ute Bartels, Mohamed S Abdelbaki
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Human chorionic gonadotropin (beta-HCG) levels in serum and cerebrospinal fluid (CSF) are critical in the management of patients with germinoma. The threshold for beta-HCG diagnosis is a topic of debate and differs in Europe, ≤50 IU/L, North America ≤100 IU/L, and ≤200 IU/L in Brazil/Japan. METHODS We conducted a meta-analysis of English-language publications (1990-2023) to assess how beta-HCG cut-off levels impact treatment outcomes. Standard descriptive statistics summarized all data. RESULTS Forty-nine patients with biopsied germinoma were identified. Eighteen had beta-HCG level of 50-100 IU/L (cohort 1), 21 had 100-200 IU/L (cohort 2), and 10 had &amp;gt;200 IU/L (cohort 3). In cohort 1, treatment with chemotherapy plus radiotherapy was administered to 9 patients. Eight of them received radiotherapy like germinoma treatment (≤30Gy), primarily employing whole ventricle irradiation (WVI). Nine patients received radiotherapy alone with total dose 30-59.6Gy. Fifteen patients in cohort 2 received chemotherapy plus radiotherapy. Eight of them received radiotherapy ≤30Gy for different fields [WVI – 4, whole brain (WB) – 3, cerebrospinal irradiation (CSI) – 1). In 7 patients the dose of radiotherapy exceeded 30Gy (local radiotherapy – 4, CSI – 3). Radiotherapy alone was used in 5 patients, chemotherapy alone – 1 patient. In cohort 3, radiotherapy only was primarily used. Six patients received CSI (50-54Gy), one – CSI+WB+local radiotherapy (12.8Gy+27.2Gy+50.6Gy). One patient received combined treatment and 2 patients received chemotherapy alone. Relapses occurred in each cohort. In cohort 1 – 2 metastatic relapses (1 after WVI 24Gy, 1 after radiotherapy &amp;gt;30Gy). Three children from cohort 2, who received chemotherapy plus radiotherapy were diagnosed with relapse (1 after WB 23.4Gy, 2 after radiotherapy &amp;gt;30Gy). In cohort 3 two metastatic relapses were diagnosed – only after chemotherapy. CONCLUSIONS Relapse rates across all beta-HCG level are similar. However, study groups are small and treatment regimens vary, warranting further investigation.
MDB-13. GERMLINE<i>ELP1</i> DEFICIENCY SENSITIZES CEREBELLAR GRANULE NEURON PROGENITORS TO SHH MEDULLOBLASTOMA
Authors: Shiekh Tanveer Ahmad, Jesus Garcia-Lopez, Yiran Li, Brian Gudenas, Jennifer Hadley, Leena Paul, Melissa Batts, Taha Soliman, Marija Kojic, Aaron Pitre, Frederik Manz, Frederique Zindy, Alun Jones, Anand Mayasundari, Brandon Bianski, Christopher Tinkle, Abbas Shirinifard, Laura Janke, Meifen Lu, Stefan M Pfister, Amar Gajjar, Suzanne J Baker, Martine F Roussel, Zoran Rankovic, Sebastian M Waszak, Giles W Robinson, Brent A Orr, Brandon Wainwright, Lena M Kutscher, Hong Lin, Paul A Northcott
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Germline loss-of-function (LOF) variants in Elongator complex protein 1 (ELP1) are the most prevalent predisposing genetic events observed in medulloblastoma (MB), accounting for 30% of the Sonic Hedgehog 3 subtype (SHH-3). Molecularly, ELP1-associated SHH-MBs acquire somatic PTCH1 mutations in &amp;gt;80% of cases, and universal loss-of-heterozygosity of the wild-type ELP1 and PTCH1 alleles through loss of chromosome-arm 9q, resulting in their biallelic inactivation. Notably, germline ELP1 LOF occurs mutually exclusive with somatic/germline TP53 mutations in the SHH-3 subtype, suggesting that genetic perturbation of either ELP1 or TP53 may promote similar tumorigenic consequences in cerebellar granule neuron progenitors (GNPs), the accepted cellular origin of SHH-MB. Despite these findings, the molecular, biochemical, and cellular mechanism(s) by which ELP1-deficiency provokes malignant pathogenesis remain unknown. In this study, we sought to close this knowledge gap and functionally determine why children harboring pathogenic ELP1 germline variants are at an increased risk of developing SHH-MB. METHODS Mice were genetically engineered to mimic heterozygous Elp1 LOF (Elp1HET). We studied the effect of Elp1 LOF in GNPs using a combination of molecular profiling, immunophenotyping, and cellular assays. RESULTS GNPs from Elp1HET mice exhibited a spectrum of molecular and biochemical hallmarks of malignant transformation including increased DNA replication stress, DNA damage, accelerated cell cycle progression, and stalled differentiation. Orthotopic transplantation of Elp1HET GNPs engineered to harbor somatic Ptch1 inactivation yielded SHH-MB-like tumors with compromised p53 signaling, providing an explanation for the specificity of ELP1-associated tumors in SHH-3, and their exclusivity with TP53-mutant tumors. Treatment of ELP1-mutant patient-derived xenografts with an FDA-approved MDM2 inhibitor reactivated p53-dependent apoptosis and extended survival. CONCLUSIONS Collectively, our findings functionally substantiate the role of ELP1 deficiency in predisposition to SHH-3 MB and nominate therapeutic strategies to overcome p53 inhibition as a rational treatment option.
NFS-25. CANCER PREDISPOSITION SYNDROMES IN THE PROSPECTIVE PEDIATRIC BRAIN TUMOR COHORT
Authors: Marie Kopecka, Lucie Slamova, David Sumerauer, Katerina Trkova, Lucie Landova, Josef Zamecnik, Ales Vicha, Michal Zapotocky
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The etiology of pediatric cancer remains largely unclear, with only a small proportion of patients (8-10%) harboring cancer predisposition syndromes (CPS). However, prospective studies evaluating CPS in pediatric neuro-oncology patients are scarce. We aimed to investigate the incidence and spectrum of CPS in this patient population. METHODS Newly diagnosed pediatric brain tumor patients from 2020 to 2023 were consented, and their germline DNA was sequenced using a DNA panel for next-generation sequencing (NGS) or whole-exome sequencing. Patients with previously known NF1, NF2, or TSC were excluded from the study. RESULTS A total of 164 consecutive patients from our center were enrolled over four years. Pathogenic germline variants (UV4 or UV5) were detected in 24 cases (14.6%). Half of these mutated genes are known to be associated with pediatric tumors. Examples include variants in TP53 (two patients with high-grade glioma), biallelic FANCD1 (medulloblastoma), SMARCE1 (meningioma), NF1 (high-grade glioma), NF2 (meningioma), MSH2 (medulloblastoma), and others. The second group of patients harbored pathogenic variants without confirmed associations with pediatric cancer, including heterozygous variants in MUTYH (n=3), FANC genes (n=2), NBN (n=2), PALB2, XPC, and pathogenic variants in WRN or CHEK2 (n=3). In addition to pathogenic variants in CHEK2, variants of uncertain significance, such as c.470T&amp;gt;C, were also identified (total n=8). The majority of patients with a CHEK2 variant were diagnosed with glial tumors. Notably, 8.3% of patients with pediatric low-grade gliomas (LGG) from our cohort harbored a CHEK2 germline variant. CONCLUSIONS The incidence of CPS in our cohort (14.6%) is higher than what is reported in studies evaluating all pediatric cancer patients. This percentage might be underestimated due to the exclusion of known phacomatoses. The role of some variants, including those in CHEK2, warrants further investigation. This study was supported by the Ministry of Health of the Czech Republic, grant number NU21-07-00419.
IMG-19. CLINICAL UTILITY OF NON-FDG PET-MRI IN CHILDREN WITH CNS NEOPLASMS: A TERRITORY-WIDE STUDY FROM HONG KONG
Authors: Anthony P Y Liu, Carol L S Yan, P W Cheng, S S M Lo, Terry T W Chow, Eric C H Fu, Jeffrey P W Yau, Vincent Lee, Godfrey C F Chan, Dennis T L Ku, Matthew M K Shing, Deyond Y W Siu
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Magnetic resonance imaging (MRI) is the gold-standard for neuroimaging, yet details from anatomical scans might be inconclusive in certain scenarios. This study aimed to investigate the utility of amino-acid tracer positron emission tomography-magnetic resonance imaging (PET-MRI) based on a territory-wide Pediatric Neuro-Oncology cohort from Hong Kong. METHODS We reviewed the PET-MRI scans of pediatric patients with suspected/confirmed CNS neoplasms co-managed by Hong Kong Children’s Hospital and St. Teresa’s Hospital, Hong Kong from 5/2022-1/2024. Tracers used included C11-MET (n=10, before 5/2023) and F18-FET (n=15, in/after 5/2023). Lesion-to-normal SUVmax ratios (LNRmax) were measured with reference to adjacent or contralateral normal brain structures. RESULTS Twenty-five patients were included (M:F=13:12) with a median age of 10 years (range: 1-17). Anatomical sites of interest were the pituitary (n=13), basal ganglia (n=3), cerebellum (n=3), brainstem (n=2), frontal lobe (n=2), cerebellopontine angle (n=1), and spine (n=1). PET-MRI was performed as part of initial diagnostics in 21, to assess post-operative residual in 2, and for possible relapse in 2. Among those evaluated upfront (n=21), median SUVmax and LNRmax were 1.53 (range: 0.87-2.6) and 0.87 (range: 0.45-1.92) respectively in patients with presumed/confirmed low-grade glioneuronal (n=5) or non-oncologic lesions (n=8), versus 4.75 (range: 2.58-9.6) and 3.26 (range: 1.78-4.9) in patients with histologically/biochemically confirmed high-grade lesions (germinoma=6, high-grade glioma=2). Availability of functional PET imaging was deemed useful for scan interpretation in all 25 patients. Specifically, the use of PET-MRI facilitated decision for radiographic surveillance without biopsy/resection in 12 patients, refined tumor grading in 2 patients with discrepant clinical-histologic features, and allowed response-adapted therapy after serial scans in 5 patients. CONCLUSIONS Our study demonstrates the potential benefits of PET-MRI in the management of children with CNS pathologies. PET-MRI contributes to the diagnosis, monitoring, and treatment guidance of these patients, providing crucial information for clinical decision-making.
IMG-17. CHANGES IN GRAY MATTER VOLUMES AND THEIR RELATION WITH NEUROPSYCHOLOGICAL DOMAIN SCORES IN SURVIVORS OF A CHILDHOOD POSTERIOR FOSSA TUMOR
Authors: Kristien Bullens, Jeroen Blommaert, Charlotte SLeurs, Jurgen Lemiere, Sandra Jacobs
Journal: Neuro-Oncology (2024)

Abstract Posterior fossa tumors (PFT) often need neurotoxic radiotherapy (RT). These may affect the brain and contribute to neurocognitive impairment later in life. Therefore, we investigated region-based gray matter volumes (GMV) and their relation to neurocognitive functioning (NF) in PFT survivors. T1-weighted MRI (MPRAGE, resolution=.98x.98x1.2mm) and NF composite scores based on a compressive neuropsychological test battery: total Intelligence, verbal comprehension, working memory, perceptual reasoning, processing speed, language, learning and memory, complex attention (CA), and cognitive flexibility (CF), were analyzed for 17 survivors of PFT (12males, 5females, mean age at diagnosis=8.5±4.5y) and 19 age- and sex-matched controls. Cortical- and subcortical GMV were analyzed with region-based morphometry (RBM, fastsurfer). GMV and NF-scores were compared between controls and survivors, and surgery-only versus RT. Post-hoc analyses correlated GMV with NF-scores and clinical parameters (radiotherapy-dose, time since treatment, and time since diagnosis). Comparing controls with survivors, lower GMV were found for overall subcortical GMV (pFDR=0.020) as well as for several subcortical subregions: bilateral thalamus and bilateral ventral diencephalon (pFDR&amp;lt;0.01). Larger GMV was observed in the left inferiotemporal region (pFDR=0.027). Survivors obtained lower NF-scores on all domains (pFDR&amp;lt;0.007) except for CA and CF. RT-survivors had lower GMV in bilateral thalamus (pFDR&amp;lt;0.05), right ventral diencephalon (pFDR=0.033), and central corpus callosum (pFDR=0.033) compared to surgery-only. Higher GMV were found in bilateral middle temporal regions (pFDR&amp;lt;0.05). NF-scores were lower in RT- survivors, but none reached statistical significance after multiple comparison correction. Significant, positive correlations between GMV of bilateral thalamus and right ventral diencephalon was found for the working memory. Differences in GMV and NF scores were observed in PFT survivors. In this limited group, RT-survivors showed more deviant GMV compared to surgery-only survivors and controls. These results also suggest a potential relationship between deviant GMV and worse NF. Notwithstanding, research in larger populations is needed to validate our findings.
OTHR-24. CLINICAL COURSE OF ISOLATED PITUITARY STALK THICKENING IN PEDIATRIC PATIENTS AND RISK FACTOR FOR NEOPLASTIC ETIOLOGY: A SINGLE INSTITUTIONAL EXPERIENCE
Authors: Hannah K Miller, Vikram P Rajan, Hamza S Gorsi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The incidence of pituitary stalk thickening (PST) has increased in recent years due to the increased utilization of diagnostic MRI of the brain. The etiology of PST includes germ cell tumors, Langerhans cell histiocytosis (LCH), and lymphocytic hypophysitis, among others. The clinical significance of PST, appropriate diagnostic workup, and clinical course for these patients is not well documented. We report our institutional experience with patients presenting with PST. METHODS After IRB approval, we reviewed lists of patients discussed in pediatric tumor boards from 2003-2023 to identify patients with PST. We excluded patients with other significant intracranial masses from our analysis. We followed the clinical course of these patients to collect applicable data. RESULTS A total of 20 patients were identified with PST, five patients were excluded due to additional MRI findings. The median age of diagnosis with PST was 14 years; 60% of cases were female. Seven patients had diabetes insipidus (DI), and five patients had other endocrinological abnormalities. Initial diagnostic workup included serum and CSF tumor markers (AFP, B-HCG), skeletal survey, CBC, and CMP. With this initial workup, no patients were diagnosed with neoplasm. All patients were followed with serial MRIs. Four patients (26.6%) displayed progression of PST, warranting biopsy. The median time from diagnosis to biopsy was seven months (range 4-26 months). Among four patients with biopsy, two had LCH, one had germinoma, and one inconclusive result. Among those diagnosed with neoplasm, 100% of them had DI. Three patients had complete resolution of PST during the follow-up period. Eight patients had stable PST during the median follow-up period of 19.5 months (Range 3-59 months). CONCLUSIONS Most isolated PST among pediatric patients remained stable during the follow-up period. The risk for neoplastic process was high among patients with increasing thickening of pituitary stalk and DI.
IMMU-12. STANDARD OF CARE PLUS INDIVIDUALIZED MULTIMODAL IMMUNOTHERAPY (IMI) TO TREAT H3.3G34 DIFFUSE MIDLINE GLIOMA
Authors: Stefaan W Van Gool, Jennifer Kosmal, Peter Van de Vliet, Wilfried Stuecker
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The prognosis of patients with H3.3G34 diffuse midline glioma is uniformly dismal. Since approval of IO-Vac® as advanced therapy medicinal product (27/05/2015), we treated two young patients with IMI in connection to the standard of care. METHODS BN (male 14y, diagnosis 01/2022) and JV (female 21y, diagnosis 12/2021) received partial resection resp. biopsy. Both underwent standard radiochemotherapy. RESULTS BN received 3/6 TMZ/Lomustin maintenance chemotherapy before start IMI. JV started with 1/12 TMZ courses together with IMI. Five-day immunogenic cell death (ICD) immunotherapy (Newcastle Disease Virus bolus injections and local modulated electrohyperthermia) were added to each maintenance chemotherapy block. After maintenance chemotherapy plus ICD immunotherapy, both received active-specific immunotherapy with two IO-Vac® vaccinations (autologous mature dendritic cells loaded with ICD-induced antigenic extracellular microvesicles). Both started with modulatory immunotherapy (4x ipilimumab/nivolumab q3w and further 6x nivolumab q4w) in combination with maintenance ICD immunotherapy. BN had a spinal relapse 19 months after initial diagnosis. He restarted with local radiotherapy and thereafter Lomustin plus Nivolumab, ultimately stopped due to arthritis. He died 24 months after diagnosis. Because of the observation of spreading disease, JV is now further treated with maintenance ICD immunotherapy using local modulated electrohyperthermia to the brain and to the upper and lower spine. She shows no evidence of progressive disease after &amp;gt;25 months. CONCLUSIONS The addition of IMI to standard of care for young patients with H3.3G34 diffuse midline glioma might give a glimpse of hope, and further anecdotal experiences should be collected. Additional treatment of the spinal axis with modulated electrohyperthermia might be required for patients with DMG.