Low-grade Gliomas Research Articles

TGF-β Score based on Silico Analysis can Robustly Predict Prognosis and Immunological Characteristics in Lower-grade Glioma: The Evidence from Multicenter Studies.

Nowadays, mounting evidence shows that variations in TGF-β signaling pathway-related components influence tumor development. Current research has patents describing the use of anti-TGF-β antibodies and checkpoint inhibitors for the treatment of proliferative diseases. Importantly, TGF-β signaling pathway is significant for lower-grade glioma (LGG) to evade host immunity. Loss of particular tumor antigens and shutdown of professional antigenpresenting cell activity may render the anti-tumor response ineffective in LGG patients. However, the prognostic significance of TGF-β related genes in LGG is still unknown. We collected RNA-seq data from the GTEx database (normal cortical tissues), the Cancer Genome Atlas database (TCGA-LGG), and the Chinese Glioma Genome Atlas database (CGGA-693 and CGGA-325) for conducting our investigation. In addition, previous publications were explored for the 223 regulators of the TGF-β signaling pathway, and 30 regulators with abnormal expression in TCGA and GTEx database were identified. In order to identify hub prognostic regulators, least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analysis were used to screen from differentially expressed genes (DEGs). On the basis of 11 genes from LASSO-Cox regression analysis (NEDD8, CHRD, TGFBR1, TP53, BMP2, LRRC32, THBS2, ID1, NOG, TNF, and SERPINE1), TGF-β score was calculated. Multiple statistical approaches verified the predictive value of the TGF-β score for the training cohort and two external validation cohorts. Considering the importance of the TGF-β signaling pathway in immune regulation, we evaluated the prediction of the TGF-β score for immunological characteristics and the possible application of the immunotherapeutic response using six algorithms (TIMER, CIBERSORT, QUANTISEQ, MCP-counter, XCELL and EPIC) and three immunotherapy cohorts (GSE78820, Imvigor-210 and PRJEB23709). Notably, we compared our risk signature with the signature in ten publications in the meta-cohort (TCGA-LGG, CGGA-693 and CGGA-325), and the TGF-β score had the best predictive efficiency (C-index =0.812). In conclusion, our findings suggest that TGF-β signaling pathway-related signatures are prognostic biomarkers in LGG and provide a novel tool for tumor microenvironment (TME) assessment.

A Novel Prognostic Risk Score Model Based on RNA Editing Level in Lower-Grade Glioma

BackgroundLower-grade glioma (LGG) refers to WHO grade 2 and 3 gliomas. Surgery combined with radiotherapy and chemotherapy can significantly improve the prognosis of LGG patients, but tumor progression is still unavoidable. As a form of posttranscriptional regulation, RNA editing (RE) has been reported to be involved in tumorigenesis and progression and has been intensively studied recently. MethodsSurvival data and RE data were subjected to univariate and multivariate Cox regression analysis and lasso regression analysis to establish an RE risk score model. A nomogram combining the risk score and clinicopathological features was built to predict the 1-, 3-, and 5-year survival probability of patients. The relationship among ADAR1, SOD2 and SOAT1 was verified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) ResultsA risk model associated with RE was constructed and patients were divided into different risk groups based on risk scores. The model demonstrated strong prognostic capability, with the area under the ROC curve (AUC) values of 0.882, 0.938, and 0.947 for 1-, 3-, and 5-year survival predictions, respectively. Through receiver operating characteristic curve (ROC) curves and calibration curves, it was verified that the constructed nomogram had better performance than age, grade, and risk score in predicting patient survival probability. Apart from this functional analysis, the results of correlation analyses between risk differentially expressed genes (RDEGs) and RE help us to understand the underlying mechanism of RE in LGG. ADAR may regulate the expression of SOD2 and SOAT1 through gene editing. ConclusionIn conclusion, this study establishes a novel and accurate 17-RE model and a nomogram for predicting the survival probability of LGG patients. ADAR may affect the prognosis of glioma patients by influencing gene expression.

Phenotypic and epigenetic heterogeneity in FGFR2-fused glial and glioneuronal tumours.

FGFR-fused central nervous system (CNS) tumours are rare and are usually within the glioneuronal and neuronal tumours or the paediatric-type diffuse low-grade glioma spectrum. Among this spectrum, FGFR2 fusion has been documented in tumours classified by DNA-methylation profiling as polymorphous low-grade neuroepithelial tumours of the young (PLNTY), a recently described tumour type. However, FGFR2 fusions have also been reported in glioneuronal tumours, highlighting the overlapping diagnostic criteria and challenges. We investigated the FGFR2 fusion landscape in a French national series of tumours sent to the RENOCLIP-LOC network. We comprehensively analysed histology, radiology and molecular data including DNA-methylation profiling for 16 FGFR2-fused glioneuronal tumours. Most tumours were located in the temporal or parietal lobe with a median age at diagnosis of 7years [1-44]. Epilepsy was the most frequent symptom. Five patients had tumour progression or recurrence with a median progression-free survival of 22.6months. Histological phenotypes corresponding to PLNTY, GG, MVNT or unclassified tumours were recorded. Epigenetic profiling could not properly distinguish epigenetic clusters related to the GG and PLNTY methylation classes among FGFR2-fused glioneuronal tumours. However, a neuroradiological review identified strikingly distinct neuroradiological patterns. While delineating tumour types among the FGFR2-fused glioneuronal tumour spectrum, by histopathology or DNA-methylation profiling, remains challenging, neuroimaging data revealed two distinct patterns that could correlate to PLNTY and ganglioglioma. However, more series including extensive histo-radio-molecular data are needed to confirm this hypothesis.

Improving Deep Learning Models for Pediatric Low-Grade Glioma Tumours Molecular Subtype Identification Using MRI-based 3D Probability Distributions of Tumour Location.

Purpose: Pediatric low-grade gliomas (pLGG) are the most common brain tumour in children, and the molecular diagnosis of pLGG enables targeted treatment. We use MRI-based Convolutional Neural Networks (CNNs) for molecular subtype identification of pLGG and augment the models using tumour location probability maps. Materials and Methods: MRI FLAIR sequences of 214 patients (110 male, mean age of 8.54 years, 143 BRAF fused and 71 BRAF V600E mutated pLGG tumours) from January 2000 to December 2018 were included in this retrospective REB-approved study. Tumour segmentations (volumes of interest-VOIs) were provided by a pediatric neuroradiology fellow and verified by a pediatric neuroradiologist. Patients were randomly split into development and test sets with an 80/20 ratio. The 3D binary VOI masks for each class in the development set were combined to derive the probability density functions of tumour location. Three pipelines for molecular diagnosis of pLGG were developed: location-based, CNN-based, and hybrid. The experiment was repeated 100 times each with different model initializations and data splits, and the Areas Under the Receiver Operating Characteristic Curve (AUROC) was calculated, and Student's t-test was conducted. Results: The location-based classifier achieved an AUROC of 77.9, 95% confidence interval (CI) (76.8, 79.0). CNN-based classifiers achieved an AUROC of 86.1, 95% CI (85.0, 87.3), while the tumour-location-guided CNNs outperformed the other classifiers with an average AUROC of 88.64, 95% CI (87.6, 89.7), which was statistically significant (P-value .0018). Conclusion: Incorporating tumour location probability maps into CNN models led to significant improvements for molecular subtype identification of pLGG.

GLIOMA-RELATED EPILEPSY

Diffuse low-grade gliomas (LGGs), originating from glial tissue, have a propensity to progress to higher-grade tumors over time, presenting a complex challenge in clinical management. Glioma-associated epilepsy is a significant clinical indicator influencing both treatment strategies and prognostication. This study aims to assess the impact of glioma-related epilepsy on treatment outcomes and explore the current management guidelines. Material and Methods A retrospective analysis was conducted on 38 patients diagnosed with LGGs (WHO grades 2 and 3) treated in our neurosurgical department from 2013 to 2023. The focus was on glioma-related epileptic seizures, with outcomes evaluated using the Engel classification six months post-surgery. Additionally, anti-seizure medication (ASM) regimens were reviewed, and current National Institute for Health and Care Excellence (NICE) guidelines on low-grade gliomas were synthesized. Results Of the 38 patients, 30 had diffuse astrocytoma and 8 had oligodendroglioma. Among those with glioma-related epilepsy (n=25), management strategies included biopsy only (8%), gross total resection (GTR) (40%), subtotal resection (StR) (32%), and partial resection (PaR) (20%). No significant correlation was found between seizures and tumor volume, growth rate, or histological findings. However, a positive correlation between the extent of surgical resection and improved Engel outcomes was observed. Discussion Existing research suggests that early seizures may be a favorable prognostic indicator for malignant progression-free and overall survival. Epilepsy significantly impacts the quality of life for glioma patients. Exploring targeted epilepsy surgery for glioma-related seizures could potentially enhance patient outcomes and quality of life posttreatment. Conclusion Advancing approaches in epilepsy surgery for glioma-related seizures holds promise for improving patient quality of life and treatment efficacy. Further investigation into these strategies is warranted.

Analysis of Circulating Plasma MicroRNA Profile in Low-Grade and High-Grade Glioma – A Cross-Sectional Study

Background Glioma is the second most common type of brain tumor, accounting for 24% of all brain tumor cases. The current diagnostic procedure is through an invasive tissue sampling to obtain histopathological analysis, however, not all patients are able to undergo a high-risk procedure. Circulating microRNAs (miRNAs) are considered as promising biomarkers for glioma due to their sensitivity, specificity, and non-invasive properties. There is currently no defined miRNA profile that contributes to determining the grade of glioma. This study aims to find the answer for “Is there any significant miRNA that able to distinguish different grades of glioma?”. Methods This study was conducted to compare the expression of miRNAs between low-grade glioma (LGG) and high-grade glioma (HGG). Eighteen blood plasma samples from glioma patients and 6 healthy controls were analyzed for 798 human miRNA profiles using NanoString nCounter Human v3 miRNA Expression Assay. The differential expressions of miRNAs were then analyzed to identify the differences in miRNA expression between LGG and HGG. Results Analyses showed significant expressions in 12 miRNAs between LGG and HGG, where all of them were downregulated. Out of these significant miRNAs, miR-518b, miR-1271-3p, and miR-598-3p showed the highest potential for distinguishing HGG from LGG, with area under curve (AUC) values of 0.912, 0.889, and 0.991, respectively. Conclusion miR-518b, miR-1271-3p, and miR-598-3p demonstrate significant potentials in distinguishing LGG and HGG.

Abstract B071: Identifying the clinical utility of CSF as a source of liquid biopsy in pediatric brain tumors

Abstract Pediatric tumors of the central nervous system (CNS) are a leading cause of cancer-related childhood mortality. Along with imaging, it is essential to molecularly characterize tumor tissue for the diagnosis, treatment, and prognosis of these cancers. Biopsies of deeply-seeded lesions may not be possible or may carry significant risks. On the other hand, liquid biopsy, using cerebral spinal fluid (CSF), provides a minimally invasive alternative to identify and monitor tumor DNA at crucial time points, from diagnosis to follow-up. This allows for molecular diagnosis, identification of therapeutic targets, monitoring response to therapy, and early detection of recurrence or progression. The aim of our study was to assess the practicality and usefulness of liquid biopsies in a diverse group of CNS tumor patients. We used a combination of methods, including a targeted hybridization capture panel and low-pass whole genome sequencing (LP-WGS) based on the sample characteristics. We analyzed a total of 243 CSF samples from patients with CNS tumors including: low-grade glioma (LGG; N=57), high-grade glioma (HGG; N=53), medulloblastoma (MB; N=40), germinoma (CNS-GCT; N=29), and no prior biopsy (N=42). We found somatic mutations in 88% of CSF samples from HGG and 67% from LGG with known tumor DNA variants and sufficient sequencing quality. It's important to note that in LGG patients, samples collected from lumbar puncture were positive only in disseminated cases, while a higher positivity rate was found in cases where CSF was collected from ventricular spaces. Moreover, we observed positive copy number alterations (CNA) in CSF samples collected from HGG, embryonal tumors, and CNS-GCT patients at the time of diagnosis and follow-up with a sensitivity of 64%. Within our sample cohort that had an unknown or query tumor due to no prior biopsy, we were able to detect diagnostic, targetable mutations and/or a positive CNA profile in 30% of cases. This supports the utility of liquid biopsy as a diagnostic tool in in CNS lesions. This tool may also assist in monitoring for relapse in high-grade tumors. For example, in a case study, we were able to detect recurrent MB by indication of a positive CNA profile in keeping with the primary tumor CNV, six years post-surgical resection. In CNS- GCT patients, we found that LP-WGS was highly sensitive at diagnosis as we have observed similar CNV in both CSF and tumor DNA. In summary, the utility of our liquid biopsy platform in the context of CNS cancers is an impactful tool that can aid clinicians in diagnosis, treatment and monitoring disease in a minimally invasive manner. Citation Format: Liana Nobre, Mansuba Rana, Yoshiko Nakano, Ian Burns, Robert Siddaway, Richard Yuditskiy, Cyril Li, Andrew Bondoc, Anthony Liu, Uri Taboori, Cynthia Hawkins. Identifying the clinical utility of CSF as a source of liquid biopsy in pediatric brain tumors [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B071.

The Correlation Patterns of miRNA Expression with Targeted mRNA Transcripts in Glioma Patients with Wild-Type and Mutated Isocitrate Dehydrogenase (IDH) Genotypes.

Low-grade gliomas are divided into two main genetic phenotypes based on the presence or absence of mutations in the isocitrate dehydrogenase (IDH) genes. The mutated IDH phenotype (IDHmut), in contrast to the wild-type phenotype (IDHwt), is characterized by a more positive response to pharmacological intervention and a significantly longer survival time. In this study, we analyzed the differential co-expression of 225,000 microRNA-mRNA pairs at the level of correlations between microRNA levels and their potential mRNA targets. Analysis of the associative relationships of individual representatives of the selected pairs revealed that the level of mRNAs encoded by the ELN, ARL4C, C9orf64, PLAT, and FKBP9 genes associated with aggressive progression of glioma was increased in the IDHwt group. Meanwhile, the levels of miRNA-182, miRNA-455, and miRNA-891a associated with the negative prognosis in glioma were generally increased in the IDHmut group. Most (16/21) of the detected 21 microRNA-mRNA pairs with significant difference in regulation between IDHwt and IDHmut glioma samples had a weak or moderate positive correlation in IDHmut samples and a negative correlation in IDHwt samples. Therefore, our findings indicate that glioma samples from the IDHmut group with a positive prognosis potentially have a significantly less pronounced ability to microRNA-mediated regulation. We further suggest that such physiological disorders can lead to reduced tumor viability, resulting in an increased ability of the host to resist the spread of a malignant transformation of this genetic phenotype.

The prognostic impact of CDKN2A/B hemizygous deletions in IDH-mutant glioma.

Homozygous deletions of CDKN2A/B are known to predict poor prognosis in gliomas, but the impact of hemizygous deletions is less clear. This study aimed to evaluate the prognostic significance of hemizygous CDKN2A/B deletions in IDH-mutant low-grade astrocytomas and oligodendrogliomas. Tissue samples diagnosed as astrocytoma, IDH-mutant and oligodendroglioma, IDH-mutant, 1p/19q co-deleted CNS WHO grade 2 and 3 were collected from the archives of the Institute of Neuropathology in Heidelberg. DNA methylation analysis was performed on formalin-fixed paraffin-embedded (FFPE) samples. Evaluation of the CDKN2A/B locus was performed by visual inspection of copy-number plots derived from methylation-array data for each case. Hemizygous and homozygous losses were assessed in relation to whole chromosomal or larger segmental losses and gains in the chromosomal profile. Survival probabilities were assessed using the Kaplan-Meier method. A total of 334 low-grade glioma cases were identified, including 173 astrocytomas and 161 oligodendrogliomas. Hemizygous deletions in CDKN2A/B (37/173 in astrocytomas, 15/161 in oligodendrogliomas) did not confer significantly worse survival outcomes compared to CDKN2A/B wildtype cases in neither low grade astrocytoma (log-rank p= 0.2556; HR 2.29, 95% CI [0.76; 6.40], p= 0.135) nor oligodendroglioma (log-rank p= 0.2760; HR 0.17; 95% CI [0.01; 5.05]; p= 0.305), regardless of CNS WHO grade, which was further demonstrated on a subgroup of astrocytoma, IDH mutant CNS WHO 4 cases (log-rank p= 0.1680; HR 4.55, 95% CI [0.88; 24.51], p= 0.0689). Hemizygous CDKN2A/B deletions do not significantly worsen OS or PFS in IDH-mutant astrocytomas and oligodendrogliomas, CNS WHO grade 2 and 3.

SURG-33. INTRAOPERATIVE ULTRASSOUND X SODIUM FLUORESCEIN FOR GLIOMA SURGERY: WHICH IS BETTER?

Abstract BACKGROUND Improve quality of life with a maximum surgical resection is the main goal of neurosurgeons. A better delimitation of intrinsic brain tumors are required for achieving a maximum tumor removal. There are several technologies that may help. Considering two of them that have an easier access and are cheaper, we compared a high definition ultrasound (BK 3000) and sodium fluorescein (SF) during glioma surgeries. METHODS Adult patients with main radiological hypothesis of low or high grade glioma were included in a PhD study previously approved by ethics committee. 3-5mg/kg of SF was administered by intravenous infusion during anesthetic induction. An specific craniotomy transducer was used in all cases. All procedures were guided by the same neurosurgeon. RESULTS High definition ultrasound allows an excellent tumor delimitation in high and low grade tumors. However the gray scale and distinction of brain structures and residual lesion was difficult for surgeons who are not habituated to ultrasound use. SF did not help low grade glioma removal, and in these cases ultrasound were superior. Increased fluorescence is easily detected when compared to ultrasound information’s. For small residual tumor, SF helps more than US. For both technologies, when the surgical site had blood, the evaluation about grade of resection is not accurate because in ultrasound appears a posterior shadow and considering SF it seems that there are not further tumor because blood does not have increased fluorescence. CONCLUSIONS US showed superiority for low grade gliomas resection. Considering high grade, both technologies helps in different moments during the surgery and are complimentary. We used an specific probe for neurosurgery that has high quality and allowed detailed evaluations. These technologies helps surgeons take quick decision and optimized brain tumor removal. The neurosurgeon should be more familiar to US images because provide a real time evaluation with low cost. KEY WORDS: ultrasound; fluorescein; gliomas; brain tumors

TMOD-18. FUNCTIONAL DISSECTION OF RECURRENT COPY-NUMBER-ALTERATIONS INFORMS MECHANISMS OF LOW-GRADE-GLIOMA PROGRESSION

Abstract Low-grade gliomas (LGG) are slowly growing brain cancers that ultimately undergo a malignant progression to lethal secondary glioblastomas with a dismal prognosis. Despite intensive research, very little progress has been made in our understanding of this transformation. Hence, outside of known alternations in well-characterized driver genes CDKN2A, PTEN and PDGFRA, genetic drivers that underlie LGG transformation are largely unknown. Contrary to other types of cancer, LGGs exhibit very few driver mutations (30-40 mutations) as they progress. Interestingly, LGGs also exhibit a highly prevalent and heterogenous pattern of copy-number-alterations (CNAs) suggesting that they might be driven by changes in gene dosages that result from widespread chromosomal instability observed within these tumors. Through analysis of the human Mayo Clinic and TCGA LGG datasets (~1500 patients), we have identified eleven highly recurrent CNAs affecting LGG patients, many of which correlate with patient survival. We hypothesized that these CNAs contain driver genes that confer a growth advantage resulting in the highly recurrent CNA pattern and prognostic associations. To investigate the tumor suppressive potential of the ~1800 genes located in recurrently deleted regions and the oncogenic potential of the ~1200 genes located in recurrently amplified regions, our lab developed a novel in vivo ‘CRISPR-Knock Out and Activation Linked Assay’ (CRISPR-KOALA). Stereotaxic delivery of arm-level CNA lentiviral gRNA libraries targeting the mouse orthologs of genes in CNAs into the brain of our animal model (rs557mut;IDHmut;P53KO;AtrxKO;Cas9GFP: Yanchus et. al Science 2022) resulted in rapid formation of tumors compared to animals injected with control libraries. Deconvoluting the screen revealed enrichment of immune modulators such as Them6 as well as a modulator of NMDA receptors (Grina) implicating immune system and glutamate dysregulation in LGG malignant transformation. Taken together, our study provides insights into mechanisms underlying LGG progression which may serve to inform intervention strategies for this lethal disease.

EXTH-11. PEDIATRIC GLIOMA IMMUNE PROFILING IDENTIFIES TIM3 AS A THERAPEUTIC TARGET IN BRAF-FUSION PILOCYTIC ASTROCYTOMA

Abstract Despite being the leading cause of childhood mortality, pediatric gliomas have been relatively understudied. Repurposing of adult brain tumor immunotherapies in pediatric patients has not been successful, highlighting the need for pediatric-specific immunotherapies. Pilocytic astrocytomas (PA) are the most common pediatric glioma. While surgical resection of PA is the first-line treatment, the ten-year progression-free survival rate for patients with residual tumors is <50%. Notably, some PAs undergo spontaneous regression after partial resection, suggesting potential baseline tumor immunoreactivity. Whole transcriptome sequencing performed on a commercial platform of pediatric gliomas (n=250) showed that MAPK-driven gliomas have higher interferon signatures compared to other molecular subgroups. Single-cell sequencing identified a unique activated and cytotoxic microglia population designated MG-Act in BRAF-fused MAPK-activated PA (n=13; p < 0.05), but not in pediatric high-grade gliomas (n=5) or normal brain (n=3). TIM3 was expressed on the luminal side of endothelial cells and MG-Act, but not in the surrounding normal brain based on sequential multiplex imaging. Flow cytometry showed that TIM3 intensity is upregulated on immune cells in the PA tumor microenvironment (TME) relative to matched peripheral blood immune cells (n=6; p < 0.01). Anti-TIM3 reprogrammed fresh ex vivo immune cells from the TME of human PAs (n=3) to a pro-inflammatory cytotoxic phenotype. In a genetically engineered murine model of MAPK-driven low-grade gliomas, median survival (MS) was 252 days in mice treated with anti-TIM3 (n=21; p<0.01) relative to IgG control (MS: 110 days; n=20) or anti-PD-1 (MS: 134 days; n=20). The therapeutic activity of anti-TIM3 was abrogated in the CX3CR1 microglia knockout background. ScRNA sequencing data during the therapeutic window of anti-TIM3 in wild-type mice demonstrated enrichment of the MG-Act population within low-grade gliomas at two different longitudinal time points but not in IgG-treated controls. Together, these data indicate that anti-TIM3 should be considered for clinical trials in pediatric low-grade MAPK-driven gliomas.

IMMU-15. CD74/MIF SIGNALING AXIS DISRUPTION IN BONE MARROW-DERIVED MYELOID CELLS DELAYS MALIGNANT PROGRESSION IN A PRECLINICAL MODEL OF GLIOMA

Abstract INTRODUCTION CD74, a chaperone associated with the major histocompatibility complex class II (MHC-II), plays a crucial role in assembling and transporting MHC-II molecules on the cellular surface. Beyond its physiological function in antigen presentation, CD74 is a negative regulator of inflammation, and its dysregulation is associated with inflammatory disorders and cancer. Notably, tumor stem cells release macrophage migration inhibitory factor (MIF) to trigger CD74 immunosuppressive signaling in tumor-infiltrating immune cells, thereby abrogating CD8+ T cell activation and promoting angiogenesis. While CD74 expression is known in dendritic cells, macrophages and B cells, our recent findings reveal its upregulation in immunosuppressive macrophages within the low-grade glioma (LGG) tumor microenvironment, and its negative correlation with the survival of adolescent and young adult patients with LGG. HYPOTHESIS. We hypothesize that inhibiting CD74/MIF in immunosuppressive myeloid cells may affect tumor progression and prevent malignant transformation (MT) to high-grade glioma (HGG). METHODS To test our hypothesis, we isolated bone marrow cells from immunocompetent RCAS n/tv-a LGG bearing animals, differentiated them into bone marrow-derived myeloid cells (BMDMs), silenced CD74 expression, and co-cultured them with primary CD8+T cells. Moreover, we inhibited CD74/MIF signaling in vivo. RESULTS. Deconvolution analysis of tumor-infiltrating immune cells revealed upregulation of CD74 and its network in myeloid cells during LGG compared to HGG. Silencing CD74 in LGG BMDMs in vitro resulted in the downregulation of genes associated with migration, proliferation, and immunosuppression. The co-culture of LGG CD74KD-BMDMs with CD8+ T cells increased the expression of T cell activation genes. In vivo treatment of LGG mice with MIF inhibitors significantly decreased myeloid cell infiltration in the tumor microenvironment (TME) and prolonged survival. CONCLUSIONS These preclinical studies highlight a role for the CD74/MIF signaling axis in glioma and present a novel immunotherapeutic target to modulate the activity of immunosuppressive myeloid cells in order to delay MT.

NCOG-33. MTOR INHIBITORS AS ADJUVANT TARGETED THERAPY IN PEDIATRIC PATIENTS WITH PROGRESSIVE OR REFRACTORY LOW-GRADE GLIOMA: A SINGLE-CENTER RETROSPECTIVE STUDY

Abstract Low grade gliomas (LGG) represent about one-third of all pediatric central nervous system tumors, with about half having disease progression despite upfront surgery and adjuvant therapies. Current treatments for LGG progression either produce toxic side effects (i.e., radiation therapy) or do not generate durable responses. Targeted agents are an effective way of attacking tumors with identified genetic mutations, but in some cases, a complete response can be subverted by the heterogeneity of tumors. Additionally, most tumors do not carry any targetable mutations. Temsirolimus and everolimus are mTOR inhibitors that have previously been shown to be well-tolerated in early clinical studies in pediatric solid tumors. We performed a retrospective study to look at the toxicity profile of mTOR inhibitors when given in combination therapy and treatment response in patients with progressive or refractory LGG. We examined 20 patients with a diagnosis of LGG including mixed glioma and glioneuronal tumors who received treatment at our institution from 2016-2024 with targeted therapy, of which 8 patients also received temsirolimus or everolimus. Of these 8 patients, 2 had partial response, 2 had minor response, 3 had stable disease, and 1 had progressive disease. The average number of cycles received was 13.6 (range 3-24). Most observed side effects were grade 2 or less, including nausea, transaminitis, myelosuppression, diarrhea, and hyperlipidemia while grade 3/4 toxicities that required dose modification included mucositis, hyperglycemia, and hyperlipidemia. Overall, the addition of temsirolimus to treatment regimens of pediatric patients with heavily pretreated refractory LGG prolonged progression free survival by an average of 478 days with only one patient progressing while on therapy. These results demonstrate feasibility and preliminary efficacy of adding mTOR inhibitors as adjuvant therapy in this patient population. There is dire need of large prospective collaborative studies in the future.

QOL-29. PREVALENCE, MANAGEMENT, AND OUTCOMES OF PROCARBAZINE-ASSOCIATED HYPERSENSITIVITY REACTIONS IN PATIENTS RECEIVING PCV FOR LOW-GRADE GLIOMA

Abstract Procarbazine is an alkylating agent commonly used to treat low-grade gliomas as part of the PCV regimen. The use of procarbazine is frequently limited by the development of hypersensitivity reactions (HSRs), which often require dose reduction or cessation of procarbazine therapy prior to the completion of a planned treatment course. The prevalence, clinical characteristics, and potential predictors of these reactions are not well defined. We conducted a retrospective cohort study of patients with low-grade glioma who received PCV between January 2016 and January 2024 at a tertiary academic hospital. Data on patient demographics, tumor type, clinical characteristics, treatment course, and hypersensitivity reactions were collected and analyzed. 61 total patients were included. The overall prevalence of HSRs was 60.7% (95% CI: 48.4% - 72.9%). The median cycle during which HSRs occurred was cycle 3 (IQR: 2-4, Range: 1-5). All HSRs involved the development of rash, with 86.5% being pruritic and 21.6% involving the face. Treatments for HSRs included antihistamines (62.2%), topical corticosteroids (35.1%), and systemic corticosteroids (27.0%). Three patients with HSRs presented to the emergency department with concern for anaphylaxis, and one required treatment with epinephrine. Out of six patients rechallenged with procarbazine after experiencing HSRs, one patient redeveloped a diffuse, pruritic rash that resolved with systemic corticosteroids. A multiple logistic regression analysis was performed to assess the association between HSRs and gender, age at PCV C1D1, elevated liver enzymes, and concomitant anticonvulsant use, but no significant correlation was observed. In summary, our study provides a contemporary and comprehensive analysis of the prevalence and severity of HSRs to procarbazine in patients with low-grade glioma. The high rate of HSRs in this population, including a relatively high rate of suspected anaphylaxis, should be considered carefully by clinicians in choosing chemotherapy for low-grade glioma and warrants routine counseling and close monitoring.

NCOG-06. FACTORS ASSOCIATED WITH SOCIAL DISABILITY IN THE CHRONIC POSTOPERATIVE PERIOD IN PATIENTS WITH GLIOMAS

Abstract BACKGROUND Patients with low-grade gliomas may have no obvious problems during hospitalization or their initial return to social life; however, social life difficulties may gradually become more apparent long after the surgery. We investigated factors associated with social disabilities in patients with low-grade gliomas in the postoperative chronic phase. METHODS The study included 114 patients with WHO grade 2 or 3 gliomas who underwent surgery (mean age, 44.3±13.2 years). Seventy-six patients underwent an initial surgery and 38 underwent a second surgery. All patients underwent various brain functional assessments and interviews about their social lives over 1 year after the surgery (median, 23 months). Factors associated with social disabilities were determined using logistic multiple regression analysis and chi-square tests. Voxel-based lesion symptom mapping was used to examine the brain regions associated with social disabilities. RESULTS Social disabilities were observed in 12.3% of the patients. Factors associated with social disabilities were the number of surgeries (first vs. second, p=0.0052) and tumor location (left vs. right, p=0.0091). Patients with recurrence and right cerebral hemispheric lesions had a higher probability of social disability (42.1%, p<0.0001) than that of other patients. The reasons for social disability after right hemispheric recurrence were social behavior disorder (62.5%) and neuropsychological dysfunctions (37.5%). Social behavioral disorders include interpersonal problems, such as job switching owing to problems with others, poor interpersonal relationships, and sexually deviant behavior. No other apparent neuropsychological abnormalities were found in patients with social behavior disorders. Surgical resection of the deep part of the right prefrontal area is associated with social behavior disorders and right supplementary motor cortex resection is associated with neuropsychological disorders. CONCLUSION In lower grade glioma, patients with right hemispheric recurrence were more likely to develop social disabilities in the chronic phase, which was caused by social behavioral disorders and neuropsychological dysfunctions.

CNSC-41. DABRAFENIB AND TRAMETINIB AS A PROMISING TREATMENT OPTION FOR PEDIATRIC POPULATION WITH LOW-GRADE GLIOMAS THAT HAVE BRAF V600E MUTATION:A BREAKTHROUGH IN THE FIELD OF NEURO- ONCOLOGY

Abstract Two-thirds of all pediatric malignant central nervous tumors, including high-grade (glioblastoma, anaplastic astrocytoma) and low-grade (ganglioglioma, pilocytic astrocytoma) carcinomas, are gliomas. Low-grade glioma(LGG) exhibits genetic alterations caused by the BRAF kinase mutation, such as replacing glutamic acid (E) in place of valine (V) at the 600 positions, known as the V600E point mutation. Pediatric low-grade gliomas (PLGGs) also comprise around one-third of juvenile brain tumors and are the most frequent central nervous system tumors. Patients were randomized 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). Where possible, complete surgical removal is the mainstay of treatment for progressing or symptomatic PLGG.Radiation therapy has historically been used to treat PLGG in both up-front and salvage scenarios. To delay or avoid the necessity for radiation therapy in young children with advancing or incompletely resected PLGG, chemotherapy was created in 1980. On March 16, 2023, the Food and Drug Administration approved the use of trametinib (Mekinist, Novartis) with dabrafenib (Tafinlar, Novartis) in pediatric patients suffering from low-grade glioma (LGG) who require systemic therapy and are at least one year old. Nevertheless, early-stage clinical trials have produced encouraging results that may revolutionize the treatment of LGG in the near future.

PATH-38. INTRACRANIAL SARCOMA WITH DICER1 MUTATION IN A PATIENT WITH NEUROFIBROMATOSIS TYPE 1

Abstract A 16-year-old male with neurofibromatosis type 1 (NF1) and a history of low-grade gliomas presented for resection of a progressively enlarging, known low-grade glioma. On follow-up imaging for surgical planning of the low-grade glioma, a new area of concern was detected of a leptomeningeal-based lesion over the left frontal lobe. A biopsy of the frontal lobe lesion subsequently showed a primary intracranial sarcoma with DICER1 mutations, DICER1 p.Q1552 and p.D1709G. An important histology finding was that of prominent eosinophilic cytoplasmic globules, which are associated with intracranial sarcomas with DICER1 mutations. Additional molecular findings of this tumor included NF1 p.K1986fs and TP53 p.G279E mutations in the setting of this patient’s known history of NF1. A DICER mutation was not detected in the concurrent low-grade glioma at the time of his intracranial sarcoma diagnosis, thus thought not to be a germline-derived mutation. He went on to have a surgical resection with subsequent photon radiation therapy followed by consolidation chemotherapy. A Ewing sarcoma based regimen as per COG protocol AEWS1031 was selected for his therapy consisting of vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, etoposide (VDC-IE). This was chosen based on prior cases showing response to anthracycline-based regimens. This patient has overall shown improvement without signs of progression now 7 months out from his initial diagnosis. This case highlights the importance of recognizing the association of patients with NF1 being at an increased risk for the development of intracranial sarcomas with DICER1 mutations and correlation with histologic findings of eosinophilic cytoplasmic globules. It also points to the need for reporting these rare cases for optimization of therapy selection to provide a more standardized and evidence-based approach in the care for these patients.

NIMG-01. RADIOMIC DATA ANALYSIS WITH ENSEMBLE MACHINE LEARNING TECHNIQUES PREDICT GRADE, HISTOPATHOLOGIC SUBTYPE, AND 1P/19Q CO-DELETION STATUS IN PATIENTS WITH LOW-GRADE GLIOMAS

Abstract Low-grade gliomas (LGGs) are a diverse group of primary brain tumors characterized by their variable prognosis and treatment response. Traditionally, the management of LGGs has relied on histopathological analysis, which sometimes offers limited insight into tumor behavior and treatment outcomes. Recent advances in radiomics have enabled the extraction of detailed quantitative features from routine imaging, providing a non-invasive method to assess tumor characteristics. These radiomic features can capture underlying tumor heterogeneity more comprehensively than conventional methods. Integrating radiomic data with ensemble machine learning techniques offers a promising approach to enhance the prediction of tumor grade, histopathologic subtype, and genetic alterations such as 1p/19q co-deletion status in LGGs, potentially leading to more tailored therapeutic strategies. We combined radiomic-genomic data from 159 magnetic resonance imaging (MRI) scans from the updated LGG-1p19qDeletion dataset (Erickson 2020) and 114 MRI scans from the ReMIND dataset (Juvekar 2024). Expert radiologists performed segmentations. A total of 2446 extracted radiomic features were initially extracted. Feature selection was performed using wrapper- and filter-based techniques with cross-validation. Prediction models were built using machine learning techniques, including random forest and extreme gradient boosting. Using Random Forest, we achieved high accuracy in predicting histopathologic subtype (88.14%, AUC 96.68%) with precision of 87.86% and Dice score of 87.88%. For grade prediction (accuracy 76.19%, AUC 91.84%), precision was 73.91%, and the Dice score was 77.27%. For 1p/19q co-deletion status (accuracy 75.61%, AUC 82.74%), precision was 77.78%, and the Dice score was 73.68%. Our study establishes a robust radiomic workflow to predict tumor grade, histopathologic subtype, and 1p/19q co-deletion status in low-grade gliomas, enhancing diagnostic accuracy and treatment personalization. This methodology can be applied clinically to improve the stratification of treatment plans for low-grade gliomas, potentially leading to effective, personalized therapy options. Using multicentric data potentially improved external validity, something which past research lacked. Future research should focus on validating and deploying this model using observational multicentric study designs.

SURG-40. PEDIATRIC LOWER GRADE GLIOMA SURGERY IN THE ERA OF GENOMIC MEDICINE

Abstract INTRODUCTION In the 2021 WHO Brain Tumor Classification, pediatric-type gliomas are distinctly categorized from their adult counterparts. The continual evolution of cancer genomics has significantly broadened the spectrum of available treatment options. Here we would like to consider surgery for pediatric low-grade gliomas. METHODS We retrospectively analyzed 41 cases of low-grade gliomas or glioneuronal tumors in pediatric patients who underwent surgery at our institute from 2002 to 2023. We discussed surgical strategies based on molecular classification. RESULTS Among the cases, there were 34 gliomas and 7 glioneuronal tumors. According to the new WHO classification, they corresponded to 1) Adult-type diffuse gliomas, 2) Pediatric-type diffuse low-grade gliomas, 3) Circumscribed astrocytic tumors, or 4) Glioneuronal and neuronal tumors. Cases without molecular diagnosis were also considered in light of the new WHO classification. Among molecularly diagnosed astrocytomas involving the cerebral hemisphere, brain stem, spinal cord, there were no cases of 1), and 2) 3) were the main cases. It is important in surgical selection to note that these cases generally have a more favorable prognosis compared to the adult type and have usefulness in diagnosing MAPK pathway abnormalities leading to the selection of molecularly targeted drugs. 3) includes pilocytic astrocytoma, subependymal giant cell astrocytoma, and pleomorphic xanthoastrocytoma. Among these, in the treatment of pilocytic astrocytoma of the visual tract and hypothalamus, biopsy is essential for molecular diagnosis and therapeutic agent selection. 4) is mainly an epilepsy-related tumor. While their removal contributes to genetic diagnosis and epileptic seizure control, total removal may not always be deemed necessary. CONCLUSION Based on the new WHO classification, a reevaluation of treatment strategies for pediatric brain tumors is necessary.