Treatment Of Low-grade Gliomas Research Articles

Identification and clinical validation of diverse cell-death patterns-associated prognostic features among low-grade gliomas

Low-grade glioma (LGG) is heterogeneous at biological and transcriptomic levels, and it is still controversial for the definition and typing of LGG. Therefore, there is an urgent need for specific and practical molecular signatures for accurate diagnosis, individualized therapy, and prognostic evaluation of LGG. Cell death is essential for maintaining homeostasis, developing and preventing hyperproliferative malignancies. Based on diverse programmed cell death (PCD) related genes and prognostic characteristics of LGG, this study constructed a model to explore the mechanism and treatment strategies for LGG cell metastasis and invasion. We screened 1161 genes associated with PCD and divided 512 LGG samples into C1 and C2 subtypes by consistent cluster analysis. We analyzed the two subtypes' differentially expressed genes (DEGs) and performed functional enrichment analysis. Using R packages such as ESTIMATE, CIBERSOTR, and MCPcounter, we assessed immune cell scores for both subtypes. Compared with C1, the C2 subtype has a poor prognosis and a higher immune score, and patients in the C2 subtype are more strongly associated with tumor progression. LASSO and COX regression analysis screened four characteristic genes (CLU, FHL3, GIMAP2, and HVCN1). Using data sets from different platforms to validate the four-gene feature, we found that the expression and prognostic correlation of the four-gene feature had a high degree of stability, showing stable predictive effects. Besides, we found downregulation of CLU, FHL3, and GIMAP2 significantly impairs the growth, migration, and invasive potential of LGG cells. Take together, the four-gene feature constructed based on PCD-related genes provides valuable information for further study of the pathogenesis and clinical treatment of LGG.

Elucidating the impact of parthanatos-related microRNAs on the tumoral immune microenvironment and clinical outcome in low-grade gliomas

Parthanatos, a cell death mechanism triggered by PARP-1 activation, is implicated in oncogenic processes, yet their role in low-grade gliomas (LGG) remains poorly understood. This research investigates Parthanatos-related miRNAs' prognostic and immunomodulatory potential, alongside their influence on therapeutic outcomes in LGGs. Comprehensive miRNA and mRNA profiles of LGG patients were extracted from TCGA and CGGA databases, integrating clinical parameters to identify Parthanatos-associated miRNAs. IHC data validated the expression levels of Parthanatos-related genes in glioma versus normal brain tissues. Protein–protein interaction networks and Spearman correlation analysis facilitated the identification of key miRNAs. Parthanatos-related miRNA indices (PMI) were screened using Lasso and assessed for their accuracy in predicting prognosis, comparing their associated potential molecular functions and heterogeneity of the immune microenvironment. Drug sensitivity was assessed between different groups and optimal therapeutic agents were predicted. Validate the expression levels of key miRNAs by qPCR. Ninety-one miRNAs significantly associated with Parthanatos were screened, through which a PMI prognosis model of nine miRNAs was constructed. The PMI score was able to independently predict the prognosis of patients with LGG, and the nomogram constructed based on the PMI provided a practical tool for clinical prediction of patient prognosis. The proportion of immune response was lower in patients in the high-risk group, and there were significant differences in drug sensitivity between different risk classes, while drugs such as Fasudil were identified as the most promising therapeutic agents for patients in the high-risk group. Our findings highlight the critical role of Parthanatos-associated miRNAs in the progression and treatment of LGG, offering novel insights into their prognostic value and therapeutic potential.

Longitudinal brain volumetrics in glioma survivors.

Radiation therapy (RT) is used selectively for patients with low-grade glioma (LGG) given the concerns for potential cognitive effects in survivors, but prior cognitive outcome studies among LGG survivors have had inconsistent findings. Translational studies that characterize changes in brain anatomy and physiology after treatment of LGG may help to both contextualize cognitive findings and improve the overall understanding of radiation effects in normal brain tissue. This study aimed to investigate the hypothesis that patients with LGG who are treated with RT will experience greater brain volume loss than those who do not receive RT. This retrospective longitudinal study included all patients with WHO grade 2 glioma who received posttreatment surveillance MRI at the University of Alabama at Birmingham. Volumetric analysis of contralateral cortical white matter (WM), cortical gray matter (GM), and hippocampus was performed on all posttreatment T1-weighted MRI sequences using the SynthSeg script. The effect of clinical and treatment variables on brain volumes was assessed using two-level hierarchical linear models. The final study cohort consisted of 105 patients with 1974 time points analyzed. The median length of imaging follow-up was 4.6 years (range 0.36-18.9 years), and the median number of time points analyzed per patient was 12 (range 2-40). Resection was performed in 79 (75.2%) patients, RT was administered to 61 (58.1%) patients, and chemotherapy was administered to 66 (62.9%) patients. Age at diagnosis (β = -0.06, p < 0.001) and use of RT (β = -1.12, p = 0.002) were associated with the slope of the contralateral cortical GM volume model (i.e., change in GM over time). Age at diagnosis (β = -0.08, p < 0.001), midline involvement (β = 1.31, p = 0.006), and use of RT (β = -1.45, p = 0.001) were associated with slope of the contralateral cortical WM volume model. Age (β = -0.0027, p = 0.001), tumor resection (β = -0.069, p < 0.001), use of chemotherapy (β = -0.0597, p = 0.003), and use of RT (β = -0.0589, p < 0.001) were associated with the slope of the contralateral hippocampus volume model. This study demonstrated volume loss in contralateral brain structures among LGG survivors, and patients who received RT experienced greater volume loss than those who did not. The results of this study may help to provide context for cognitive outcome research in LGG survivors and inform the design of future strategies to preserve cognition.

A Promising Breakthrough: The Potential of VORASIDENIB in the Treatment of Low-grade Glioma.

Gliomas are common malignant brain tumors characterized by diffuse brain infiltration. World Health Organization grade II and grade III diffuse gliomas are considered lower-grade gliomas (LGGs) and have isocitrate dehydrogenase (IDH) mutations. LGGs are challenging due to their infiltrative nature, making them capable of progressing into higher-grade malignancies. Vorasidenib is a novel therapeutic agent targeting mutant IDH1/2, sparking interest in the field. Vorasidenib inhibits mutant IDH1/2 through a unique mechanism, reducing the production of the oncometabolite 2-hydroxyglutarate (2-HG). This alteration affects key enzymes and DNA methylation, impacting tumor growth and invasion. Preclinical Evidence: Preclinical studies show vorasidenib's efficacy in inhibiting mutant IDH1/2 and 2-HG production in glioma models. It suppresses tumor growth, making it a potential treatment option. Early clinical trials demonstrate vorasidenib's clinical activity in non-enhancing gliomas. It reduces 2-hydroxyglutarate levels and tumor cell proliferation, with an objective response rate and prolonged progression-free survival. The drug's safety profile is favorable. Challenges and Future Directions: Challenges include identifying predictive biomarkers and optimizing sequencing or combinations with existing therapies. Further research is needed to establish long-term effectiveness, evaluate side effects, and explore combinations with immunotherapy. orasidenib significantly advances LGG treatment, targeting a prevalent mutation and slowing tumor growth. Promising preclinical and clinical evidence and manageable side effects suggest its potential impact on LGG management. However, more research, including large trials, is needed to confirm its efficacy and role in treatment.

Development of an m6A-Related lncRNAs Signature Predicts Tumor Stemness and Prognosis for Low-Grade Glioma Patients.

Growing evidence has revealed that m6A modification of long noncoding RNAs (lncRNAs) dynamically controls tumor stemness and tumorigenesis-related processes. However, the prognostic significance of m6A-related lncRNAs and their associations with stemness in low-grade glioma (LGG) remain to be clarified. A multicenter transcriptome analysis of lncRNA expression in 1,247 LGG samples was performed in this study. The stemness landscape of LGG tumors was presented and associations with clinical features were revealed. The m6A-related lncRNAs were identified between stemness groups and were further prioritized via least absolute shrinkage and selection operator Cox regression analysis. A risk score model based on m6A-related lncRNAs was constructed and validated in external LGG datasets. Based on the expression of LINC02984, PFKP-DT, and CRNDE, a risk model and nomogram were constructed; they successfully predicted the survival of patients and were extended to external datasets. Significant correlations were observed between the risk score and tumor stemness. Moreover, patients in different risk groups exhibited distinct tumor immune microenvironments and immune signatures. We finally provided several potential compounds suitable for specific risk groups, which may aid in LGG treatment. This novel signature presents noteworthy value in the prediction of prognosis and stemness status for LGG patients and will foster future research on the development of clinical regimens.

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

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 16 March 2023, the Food and Drug Administration approved the use of trametinib (Mekinist, Novartis) with dabrafenib (Tafinlar, Novartis) in pediatric patients suffering from 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.

INNV-11. USE OF IVOSIDENIB IN THE TREATMENT OF LOW GRADE GLIOMAS

Abstract IDH 1 and IDH 2 are crucial metabolic enzymes which covert isocitrate to alpha-ketoglutarate. During this process, NADP is reduced to NADPH. Mutant IDH produces an oncometabolite, D-2 hydroxyglutarate (2-HG). Elevated 2-HG levels interfere with epigenetic regulation and cellular metabolism leading to oncogenesis and have been postulated to play a role in multiple malignancies. Mutations in IDH1 and IDH2 have been found in AML, cholangiocarcinoma, myeloproliferative, myelodysplastic syndromes, and low-grade gliomas. IDH inhibitors, although not FDA approved for treatment of glioma, have shown promise as a treatment for low-grade gliomas with IDH mutation in clinical trials. Ivosidenib is an orally available inhibitor of IDH1. We examined patients with oligodendroglioma treated off-label with ivosidenib. RANO criteria for low grade glioma was used to determine radiographic response following ivosidenib initiation. Patient ages 28 , 37 , and 37 females with oligodendroglioma, IDH1 mutated, 1p/19q co-deleted, WHO grade 2 were treated with ivosidenib. Treatment was initiated between August 2022 and March 2023. Two patients had two prior recurrences each while the third patient was treated in the neoadjuvant setting following subtotal resection. Two had stable disease as best response at follow-up of 7 and 17 months while the third is awaiting interval follow up. Duration of ivosidenib therapy was 9, 19, and 3 months respectively and is ongoing in all patients. Only grade 1 leukopenia was observed in one patient which resolved without intervention. No seizures since surgery were observed in two patients, while yearly focal seizures occurred in the third patient. Median progression free survival was not able to be determined, however preliminary data reveals stable disease as best response in all three patients without side effects or increased seizure frequency. IDH inhibitors continue to be an area of interest and ongoing research in the treatment of low-grade glioma.

TMIC-13. EXHAUSTED CD8+ T CELLS MAINTAIN LOW-GRADE GLIOMAS IN NF1-MUTANT MICE

Abstract T cells are minor cellular constituents of the brain tumor microenvironment, but have recently been shown to play critical roles in glioma pathobiology and treatment. Previous studies from our laboratory have shown that T cells are required for the formation and growth of low-grade gliomas (LGGs) in murine models of the Neurofibromatosis type 1 (NF1) tumor predisposition syndrome. To better characterize the immune landscape of these pediatric low-grade tumors, we leveraged single cell RNA sequencing of human pediatric pilocytic astrocytomas and genetically engineered mouse LGG (Nf1-optic glioma) models. First, we showed that both human and murine LGGs contain a CD8+ T cell population expressing PD-1 and TIGIT, similar to conventional exhausted T cell populations. Second, these PD-1+/TIGIT+ CD8+ T cells are actively recruited to the tumor site by Ccl2 where they dictate tumorigenesis through the elaboration of Ccl4, a cytokine necessary for microglia Ccl5-mediated support of Nf1-OPG growth. As such, Ccl4 expression was enriched in PD-1+/TIGIT+ CD8+ T cells relative to all other T cell populations within these tumors. Third, this “exhausted” CD8+ T cell population was exclusively present in the optic nerves, but not in the blood, dura, or deep cervical nodes of optic glioma-bearing mice. Fourth, targeting this PD1+/TIGIT+ exhausted CD8+ T cell population with immune checkpoint monoclonal antibody inhibitors reduced CD8+ T cell tumoral recruitment, Ccl4 production, and optic glioma growth. Collectively, these findings establish an obligate role for PD-1+/TIGIT+ CD8+ T cells in Nf1-optic glioma control and suggest that immune checkpoint modulation may be useful for the treatment of LGGs in children.

The Comprehensive Analysis of m6A-Associated Anoikis Genes in Low-Grade Gliomas.

The relationship between N6-methyladenosine (m6A) regulators and anoikis and their effects on low-grade glioma (LGG) is not clear yet. The TCGA-LGG cohort, mRNAseq 325 dataset, and GSE16011 validation set were separately obtained via the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Altas (CGGA), and Gene Expression Omnibus (GEO) databases. In total, 27 m6A-related genes (m6A-RGs) and 508 anoikis-related genes (ANRGs) were extracted from published articles individually. First, differentially expressed genes (DEGs) between LGG and normal samples were sifted out by differential expression analysis. DEGs were respectively intersected with m6A-RGs and ANRGs to acquire differentially expressed m6A-RGs (DE-m6A-RGs) and differentially expressed ANRGs (DE-ANRGs). A correlation analysis of DE-m6A-RGs and DE-ANRGs was performed to obtain DE-m6A-ANRGs. Next, univariate Cox and least absolute shrinkage and selection operator (LASSO) were performed on DE-m6A-ANRGs to sift out risk model genes, and a risk score was gained according to them. Then, gene set enrichment analysis (GSEA) was implemented based on risk model genes. After that, we constructed an independent prognostic model and performed immune infiltration analysis and drug sensitivity analysis. Finally, an mRNA-miRNA-lncRNA regulatory network was constructed. There were 6901 DEGs between LGG and normal samples. Six DE-m6A-RGs and 214 DE-ANRGs were gained through intersecting DEGs with m6A-RGs and ANRGs, respectively. A total of 149 DE-m6A-ANRGs were derived after correlation analysis. Four genes, namely ANXA5, KIF18A, BRCA1, and HOXA10, composed the risk model, and they were involved in apoptosis, fatty acid metabolism, and glycolysis. The age and risk scores were finally sifted out to construct an independent prognostic model. Activated CD4 T cells, gamma delta T cells, and natural killer T cells had the largest positive correlations with risk model genes, while activated B cells were significantly negatively correlated with KIF18A and BRCA1. AT.9283, EXEL.2280, Gilteritinib, and Pracinostat had the largest correlation (absolute value) with a risk score. Four risk model genes (mRNAs), 12 miRNAs, and 21 lncRNAs formed an mRNA-miRNA-lncRNA network, containing HOXA10-hsa-miR-129-5p-LINC00689 and KIF18A-hsa-miR-221-3p-DANCR. Through bioinformatics, we constructed a prognostic model of m6A-associated anoikis genes in LGG, providing new ideas for research related to the prognosis and treatment of LGG.

Comprehensive Analysis of Ferroptosis Regulators with Regard to PD-L1 and Immune Infiltration in Low-Grade Glioma.

The prognosis of low-grade glioma (LGG) is highly variable and requires more accurate predictors. Ferroptosis, a newly discovered programmed cell death, has been demonstrated to play a crucial role in some types of tumors. However, prognostic prediction based on ferroptosis-related genes (FRGs) and the influence on the tumor microenvironment (TME) in LGG remains elusive. We derived expression profiles for LGG from public databases. Based on the expression of 25 FRGs in LGG, two independent subtypes and a risk model were successfully constructed. Different methods were applied to assess the tumor heterogeneity, tumor microenvironment, and the prognostic value. In addition, a competing endogenous RNA (ceRNA) regulatory axis was constructed. The subtypes had independent tumor heterogeneity, tumor microenvironments, and prognoses. LPCAT3, SLC1A5, HSPA5, and NFE2L2 were identified as the potential prognostic FRGs. Based on these four FRGs, our risk model possesses excellent potential to predict prognosis and varied immune infiltration abundance. The ceRNA regulatory axis provides a potential therapeutic target for LGG. Our molecular subtypes, risk model, and ceRNA regulatory axis have strong immune prediction and prognostic prediction capabilities which could guide LGG treatment.

Low-grade glial tumors: The experience of an oncology hospital in Türkiye

Objective: Several factors are important in the prognosis of low grade gliomas, besides genetic changes. The present study aims to examine the effect of other factors on prognosis except for genetic changes in low grade gliomas (LGGs). Materials and Methods: Patients diagnosed with “brain malignant neoplasm” who were referred to Hacettepe University Oncology Hospital were screened. Among these patients, 148 patients with a supratentorial low grade gliomas whose data are completely available were included. Patients were followed for at least five years after diagnosis or death within this period. Results: Mean age of diagnosis was 36.2±10.7 years, and 52.7% of patients (n=78) were females, Most common subtype was oligodendroglioma (n=86, 58.1%). Sixty-two of patients relapsed (41.9%). The 5-year mortality rate was 35.1% (n=52). Kaplan-Meier analysis of the variables, the only difference was between histopathological subtypes (p=0.03). Astrocytoma histology was related to wporse prognosis. Cox regression analysis of factors affecting 5-year mortality, advancing age (HR: 1.03, 95% CI: 1.00-1.06, p=0.03), astrocytoma (HR: 2.59, 95% CI: 1.35-4.98, p=0.004) and oligoastrocytoma (HR: 2.13, 95% CI: 1.02-4.43, p=0.04) were identified to increase the mortality risk. Conclusion: The age of the patients and the histopathologic subtype of the tumor must be taken into consideration during the follow-up and treatment of low grade gliomas.

Deep learning-assisted radiomics facilitates multimodal prognostication for personalized treatment strategies in low-grade glioma

Determining the optimal course of treatment for low grade glioma (LGG) patients is challenging and frequently reliant on subjective judgment and limited scientific evidence. Our objective was to develop a comprehensive deep learning assisted radiomics model for assessing not only overall survival in LGG, but also the likelihood of future malignancy and glioma growth velocity. Thus, we retrospectively included 349 LGG patients to develop a prediction model using clinical, anatomical, and preoperative MRI data. Before performing radiomics analysis, a U2-model for glioma segmentation was utilized to prevent bias, yielding a mean whole tumor Dice score of 0.837. Overall survival and time to malignancy were estimated using Cox proportional hazard models. In a postoperative model, we derived a C-index of 0.82 (CI 0.79–0.86) for the training cohort over 10 years and 0.74 (Cl 0.64–0.84) for the test cohort. Preoperative models showed a C-index of 0.77 (Cl 0.73–0.82) for training and 0.67 (Cl 0.57–0.80) test sets. Our findings suggest that we can reliably predict the survival of a heterogeneous population of glioma patients in both preoperative and postoperative scenarios. Further, we demonstrate the utility of radiomics in predicting biological tumor activity, such as the time to malignancy and the LGG growth rate.

Pharmacophore-based Identification of Potential Mutant Isocitrate Dehydrogenases I/2 Inhibitors: An Explorative Avenue in Cancer Drug Design.

Heterozygous mutations in the cytoplasmic and mitochondrial isoforms of isocitrate dehydrogenase enzymes 1 and 2 subtypes have been extensively exploited as viable druggable targets, as they decrease the affinity of isocitrate and higher affinity of D-2-hydroxyglutarate, an oncometabolite. Vorasidenib (AG-881) has recently been reported as a promising dual inhibitor of mutant isocitrate dehydrogenase 1 and 2 with the ability to penetrate the blood-brain barrier towards the treatment of low-grade glioma. In order to combat drug resistance and toxicity levels, this compelled us to further investigate this substance as a basis for the creation of potential selective inhibitors of mutant isocitrate dehydrogenases 1 and 2. By employing a wide range of computational techniques, binding moieties of AG-881 that contributed towards its selective binding to isocitrate dehydrogenase enzymes 1 and 2 were identified and subsequently used to generate pharmacophore models for the screening of potential inhibitor drugs that were further assessed by their pharmacokinetics and physicochemical properties. AG-881 was identified as the most favorable candidate for isocitrate dehydrogenase enzyme 1, exhibiting a binding free energy of -28.69 kcal/mol. ZINC93978407 was the most favorable candidatefor isocitrate dehydrogenase enzyme 2, displaying a strong binding free energy of -27.10 kcal/mol. ZINC9449923 and ZINC93978407 towards isocitrate dehydrogenase enzyme 1 and 2 showed good protein structural stability with a low radius of gyration values relative to AG-881. We investigated that ZINC9449923 of isocitrate dehydrogenase enzyme 1 and ZINC 93978407 of isocitrate dehydrogenase enzyme 2 could serve as promising candidates for the treatment of lower-grade glioma as they cross the blood-brain barrier, and present with lower toxicity levels relative to AG-881.

In brief: Dabrafenib (Tafinlar) and trametinib (Mekinist) for glioma.

The oral kinase inhibitors dabrafenib (Tafinlar – GSK) and trametinib (Mekinist – Novartis) have been approved by the FDA for use together for a sixth indication: treatment of low-grade glioma (LGG) with a BRAF V600E mutation in patients ≥1 years old who require systemic therapy.

870 Association of MGMT Methylation With Response to Chemotherapy in WHO Grade 2 Low Grade Glioma

INTRODUCTION: The role of adjuvant chemotherapy (AC) in the treatment of low-grade glioma (LGG) has been an area of controversy. While of O6-methylgaunine-DNA-methyltransferase (MGMT) promoter methylation is a predictor of response to AC in high grade glioma, its relevance in LGG is uncertain. METHODS: Overall survival was evaluated using Kaplan-Meier estimates and multivariable Cox proportional hazards regression. Subgroup analyses were conducted in cohorts defined by tumor size, tumor location, histology, extent of resection, and receipt of radiation. RESULTS: Between 2004 and 2018, 1,139 participants were diagnosed with WHO grade 2 LGG (median [IQR] age, 40 years [31-53]; 578 were male [51%]; 614 were MGMT methylated (54%)). In multivariate analysis, among the 512 patients (45%) receiving AC, there was improved overall survival in methylated compared to unmethylated cohorts (hazard ratio [HR], 0.48; 95% CI, 0.32-0.72; p &lt; 0.001). This association was not demonstrated in patients without AC (HR, 1.01; 95% CI, 0.63-1.60; p=0.985). On subgroup analysis, MGMT methylation status was associated with an independent improved response to chemotherapy in subgroups of patients with no 1p/19q codeletion [astrocytoma], tumor diameter ≥50mml, tumor diameter &lt;50mm, frontal lobe tumors, radiotherapy, no radiotherapy, and subtotal resection MGMT methylation was not associated with improved response to chemotherapy in patients with 1p/19q codeletion [oligodendroglioma] or gross total resection. CONCLUSIONS: MGMT methylation status was associated with response to AC in adult astrocytic LGG, irrespective of treatment with radiation. This relationship was not present for oligodendroglioma. If replicated in contemporary trials, these findings will substantially guide treatment decisions for many LGG patients.

Molecular subtypes based on centrosome-related genes can predict prognosis and therapeutic responsiveness in patients with low-grade gliomas.

Abnormalities in centrosome regulatory genes can induce chromosome instability, cell differentiation errors, and tumorigenesis. However, a limited number of comprehensive analyses of centrosome-related genes have been performed in low-grade gliomas (LGG). LGG data were extracted from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. The ConsensusClusterPlus" R package was used for unsupervised clustering. We constructed a centrosome-related genes (CRGs) signature using a random forest model, lasso Cox model, and multivariate Cox model, and quantified the centrosome-related risk score (centS). The prognostic prediction efficacy of centS was evaluated using a Receiver Operating Characteristic (ROC) curve. Immune cell infiltration and genomic mutational landscapes were evaluated using the ESTIMATE algorithm, single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm, and "maftools" R package, respectively. Differences in clinical features, isocitrate dehydrogenase (IDH) mutation, 1p19q codeletion, O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation, and response to antitumor therapy between the high- and low-centS groups were explored. "pRRophetic" R packages were used for temozolomide (TMZ) sensitivity analysis. qRT-PCR verified the differential expression of the centrosomal gene team, the core of which is CEP135, between LGG cells and normal cells. Two distinct CRG-based clusters were identified using consensus unsupervised clustering analysis. The prognosis, biological characteristics, and immune cell infiltration of the two clusters differed significantly. A well-performing centS signature was developed to predict the prognosis of patients with LGG based on 12 potential CRGs. We found that patients in the high-centS group showed poorer prognosis and lower proportion of IDH mutation and 1p19q codeletion compared to those in the low-centS group. Furthermore, patients in the high-centS group showed higher sensitivity to TMZ, higher tumor mutation burden, and immune cell infiltration. Finally, we identified a centrosomal gene team whose core was CEP135, and verified their differential expression between LGG cells and normal glial cells. Our findings reveal a novel centrosome-related signature for predicting the prognosis and therapeutic responsiveness of patients with LGG. This may be helpful for the accurate clinical treatment of LGG.

Correlation between ITGB2 expression and clinical characterization of glioma and the prognostic significance of its methylation in low-grade glioma(LGG).

Glioma is the most common primary tumor in the brain.Integrin beta 2(ITGB2) is a member of the leukocyte integrin family (leukocyte integrin), participating in lymphocyte recycling and homing, cell adhesion, and cell surface-mediated signal transduction. However, few studies on ITGB2 in gliomas have been reported yet.This study first discussed the relationship between ITGB2 expression and clinical characterization of glioma and the prognostic significance of its methylation in low-grade glioma. We collected Clinical data and transcription of glioma patients from TCGA, CGGA, and Rembrant datasets to analyze the differential expression of ITGB2 mRNA in glioma tissues and normal tissues. The box polts to evaluated the expression patterns of ITGB2 in different molecular subtypes. Receiver operating characteristic curve (ROC) were used to evaluate and verify the reliability of the model. Kaplan-Meier survival curves to evaluated the relationship between the level of ITGB2 mRNA expression and overall survival (OS). Using cox regression analysis to verify the ability of ITGB2 as an independent predictor of OS in glioma patients. We use TIMER to analyze and visualize the association between immune infiltration levels and a range of variables. The methylation of GBMLGG patients were obtained from the TCGA database through the biological portal. ITGB2 can be a potential marker for mesenchymal molecular subtype gliomas. COX regression analysis shows that ITGB2 is an independent predictive marker of OS in malignant glioma patients. Biological processes show that ITGB2 has involved glioma immune-related activities, especially closely related to B cells, CD4+Tcells, macrophages, neutrophils, and dendritic cells. ITGB2 is negatively regulated by ITGB2 methylation, resulting in low expression in LGG tissues. Low expression of ITGB2 and high methylation indicate good OS in patients with LGG. The ITGB2 methylation risk score (ITMRS) obtained from the ITGB2 methylation CpG site can better predict the OS of LGG patients. We used univariate and multivariate cox regression analysis of methylationsites, used the R language predict function to obtain the risk score of these ITGB2 methylation sites(ITMRS). ITGB2 can be used as a potential marker of mesenchymal molecular subtypes of gliomas and as an independent predictive marker of OS in patients with malignant gliomas. The ITMRS we established can be used as an independent prognostic factor for LGG and provide a new idea for the diagnosis and treatment of LGG.

Serine hydroxymethyltransferase 1 promotes low-grade glioma progression by activating mTORC1 signaling

ABSTRACT Objectives This research aimed to explore the role and potential mechanism of serine hydroxymethyltransferase 1 (SHMT1) involvement in low-grade glioma (LGG). Methods GEPIA were employed to analyze the expression and the correlation of LGG patient survival with the levels of SHMT1 in LGG based on the The Cancer Genome Atlas (TCGA) database. qRT-PCR and western blot were used to detect the expression of SHMT1 in LGG cells. Clone formation, EdU staining, MTT, Transwell and wound healing assays were conducted to analyze the proliferation, cell activity, migration and invasion of LGG cells. KEEG analysis was performed for enrichment pathways of SHMT1 in LGG. Results SHMT1 was up-regulated in LGG tissues and cells, and SHMT1 level was negatively correlated with survival of patients with LGG. SHMT1 overexpression evidently promoted cell proliferation, migration and invasion, whereas SHMT1 silence obtained the opposite results. Next, KEEG analysis revealed that SHMT1 activated the mTORC1 pathway in LGG. SHMT1 overexpression significantly promoted the phosphorylation of downstream proteins (P70SK6 and S6) in LGG cells. Further, inhibition of the mTORC1 signaling pathway partially abolished the promotion of LGG progression by SHMT1 overexpression. Conclusion SHMT1 promoted proliferation, invasion and migration of LGG cells via activating mTORC1 signaling pathway. This provided a novel perspective for the treatment of LGG.

RADT-40. RADIATION-INDUCED CONTRAST ENHANCEMENT FOLLOWING PROTON RADIOTHERAPY FOR LOW-GRADE GLIOMA DEPENDS ON TUMOR CHARACTERISTICS AND IS RARER IN CHILDREN THAN ADULTS

Abstract Proton beam radiotherapy (PRT) is used in the treatment of low-grade glioma (LGG) to mitigate long-term sequelae. Following PRT, increased rates of radiation-induced contrast enhancements (RICE) are suspected but poorly understood. We analyzed consecutive 227 patients (42 children and 185 adults) treated with PRT (54Gy RBE) for LGG from 2010 to 2020 and followed with serial clinical exams and magnetic resonance imaging for in median 5.6 years. Tumors were graded WHO 1 in a minority (n = 22, 12%) of adults, but a majority of children (n = 29, 69%). In contrast, tumors were graded WHO 2 in the majority (n = 160, 87%) of adults and a minority of children (n = 10, 24%). Five-year overall survival following PRT was 81% in adults and 91% in children. The risk of RICE was 5-fold more frequent in adults (25%) versus children (5%) (p = 0.0043). Also, within the adult cohort, RICE risk increases with age (p = 0,00128). In children and adults, RICE were symptomatic in 50% and 55% (n = 1 and 26) of cases with CTCAE grade 0 in 47% (n = 23), grade 1 in 25% (n = 12), 0% grade 2 (n = 0) and 29% grade 3 (n = 14), respectively. In adults, RICE risk was associated to WHO grading (8% in WHO grade 1 vs. 24% in WHO grade 2, p = 0.026), independent of age (p = 0.44) and irradiation dose (p = 0.005), but not independent of IDH mutational status. These data demonstrate effectiveness of PRT for LGG in both children and adults. The RICE risk is lower in children which are a main target group for PRT and differs with WHO grading.

EXTH-97. BONE MARROW-DERIVED ENGINEERED MYELOID CELLS ENHANCE THE TRAFFICKING AND ACTIVATION OF CYTOTOXIC T CELLS IN THE GLIOMA MICROENVIRONMENT

Abstract INTRODUCTION Gliomas are the most prevalent type of brain tumors in the adolescent and young adult population (AYA) and one of the leading causes of cancer- related death. Two-third of glioma AYA patients are affected by low-grade gliomas (LGGs), but yet there are no specific treatments. Therefore, a significant percentage of LGG patients experience tumor recurrence and malignant progression to high-grade glioma (HGG) and the immune microenvironment plays a critical role in mediating mechanisms of tumor progression and treatment resistance. Specifically, tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) have been shown to restrict cytotoxic effector trafficking and activation. To that end, first-line immunotherapies have limited efficacy in improving outcomes for HGGs. HYPOTHESIS We investigated the preclinical efficacy of a novel immunotherapeutic approach for the treatment of LGGs in AYA mice to modulate and reprogram the immunosuppressive tumor microenvironment (TME) and enhance the trafficking of activated effector T cells. METHODS Immunocompetent RCAS n/tv-a LGG bearing animals were treated at day 28 with a single retroorbital dose of bone-marrow derived myeloid cells, engineered for the release of Interlekin-2 (GEMys-IL2). The treatment was well tolerated and no sign of toxicity was noted. RESULTS Our results demonstrated that GEMys-IL2 efficiently crossed the BBB, infiltrate the glioma microenvironment, and activate infiltrating immune cells while altering the TME underscored by an increased CD8+ T cell population. Of note, the RCAS/t-va immunocompetent LGG to HGG progression mouse model treated with a single dose of GEMys-IL2 demonstrated a transient arrest of tumor burden within 14 days post treatment, which was associated with a significant advantage in overall survival. CONCLUSIONS These results highlight the pre-clinical efficacy and anti-tumoral therapeutic activity of GEMYys-IL2 on CD8+ T cell trafficking and activation to the TME in low-grade glioma in vivo, thus supporting its potential as a novel cell-mediated innate immunotherapy.