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Background: As a component of membrane lipids and the precursor of oxysterols and steroid hormones, reprogrammed cholesterol metabolism contributes to the initiation and progression of multiple cancers. Thus, we aim to further investigate the significances of cholesterol metabolism in lower-grade gliomas (LGGs)., Methods: The present study included 413 LGG samples from TCGA RNA-seq dataset (training cohort) and 172 LGG samples from CGGA RNA-seq dataset (validation cohort). The cholesterol metabolism-related signature was identified by the LASSO regression model. Bioinformatics analyses were performed to explore the functional roles of this signature in LGGs. Kaplan-Meier and Cox regression analyses were enrolled to estimate prognostic value of the risk signature., Results: Our findings suggested that cholesterol metabolism was tightly associated clinicopathologic features and genomic alterations of LGGs. Bioinformatics analyses revealed that cholesterol metabolism played a key role in immunosuppression of LGGs, mainly by promoting macrophages polarization and T cell exhaustion. Kaplan-Meier curve and Cox regression analysis showed that cholesterol metabolism was an independent prognostic indicator for LGG patients. To improve the clinical application value of the risk signature, we also constructed a nomogram model to predict the 1-, 3- and 5-year survival of LGG patients., Conclusion: The cholesterol metabolism was powerful prognostic indicator and could serve as a promising target to enhance personalized treatment of LGGs., (© 2023. The Author(s).)

Gliomas are the most common type of primary tumor in the central nervous system in adults. Isocitrate dehydrogenase (IDH) mutation status is an important molecular biomarker for adult diffuse gliomas. In this study, we were aiming to predict IDH mutation status based on terahertz time-domain spectroscopy technology. Ninety-two frozen sections of glioma tissue from nine patients were included, and terahertz spectroscopy data were obtained. Through Least Absolute Shrinkage and Selection Operator (LASSO), Principal component analysis (PCA), and Random forest (RF) algorithms, a predictive model for predicting IDH mutation status in gliomas was established based on the terahertz spectroscopy dataset with an AUC of 0.844. These results indicate that gliomas with different IDH mutation status have different terahertz spectral features, and the use of terahertz spectroscopy can establish a predictive model of IDH mutation status, providing a new way for glioma research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Gliomas are the most common type of primary tumor originating in the central nervous system of adults. Tumor histological type, pathological grade, and molecular pathology are significant prognosis and predictive factors. In this study, we were aiming to predict histological type and molecular pathological features based on terahertz time-domain spectroscopy technology. Nine gliomas with different grades, one meningioma, and one lymphoma were enrolled. There were significant differences in terahertz absorption coefficient between normal brain tissue, tumoral-periphery, and tumoral-center tissue in specific frequency bands (0.2-1.4 THz). Histological type, pathological grade, and glioma-specific biomarkers were closely related to the terahertz absorption coefficient in both tumoral-periphery and tumoral-center tissues. Interestingly, tumoral-periphery showed more obvious differences than tumoral-center tissues in almost all aspects. All the results show that the terahertz technology has potential application value in the intraoperative real-time glioma recognition and diagnosis of glioma histological and molecular pathological features., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: Tumour necrosis factor (TNF) superfamilies play important roles in cell proliferation, migration, differentiation, and apoptosis. We believe that TNF has a huge potential and might cast new insight into antitumour therapies. Therefore, we established this signature based on TNF superfamilies., Results: A six-gene signature derived from the TNF superfamilies was established. The Riskscore correlated significantly with the expression of immune checkpoint genes and infiltrating M2 macrophages in the tumour specimen. This signature was also associated with mutations in genes that regulate tumour cell proliferation. Univariate and multivariate regression analyses further confirmed the Riskscore, TNFRSF11b, and TNFRSF12a as independent risk factors in The Cancer Genome Atlas and Chinese Glioma Genome Atlas datasets., Conclusion: Our signature could accurately predict the prognosis of lower-grade gliomas (LGG). In addition, this six-gene signature could predict the immunosuppressive status of LGG and provide evidence that TNF superfamilies had correlations with some critical mutations that could be effectively targeted now., Competing Interests: None of the authors has any potential financial conflict of interest related to this manuscript., (Copyright © 2022 Rui Tao et al.)

Standard treatment regimen of gliomas has almost reached a bottleneck in terms of survival benefit. Immunotherapy has been explored and applied in glioma treatment. Immunosuppression, as a hallmark of glioma, could be alleviated by inhibiting certain abnormally expressed biomarkers. Here, transcriptome data of 325 whole grade gliomas were collected from the CGGA database. The TCGA RNA sequencing database was used for validation. Western blot was used to verify the expression level of VAT1 on cellular level. The results showed that the expression of VAT1 was positively correlated with the grades of glioma as classified by WHO. A higher expression level of VAT1 was observed in the mesenchymal subtype of gliomas. The area under the curve suggested that the expression level of VAT1 might be a potential prognostic marker of mesenchymal subtype. In survival analysis, we found that patients with high VAT1 expression level tended to have shorter overall survival, which indicated the prognostic value of VAT1 expression. The results of gene ontology analysis showed that most biological processes of VAT1-related genes were involved in immune and inflammatory responses. The results of GSEA analysis showed a negative correlation between VAT1 expression and immune cells. We also identified that the expression of immune checkpoints increased with VAT1 expression. Therefore, the high expression level of VAT1 in patients with glioma was a potential indicator of a lower survival rate for patients with gliomas. Remarkably, VAT1 contributed to glioma-induced immunosuppression and might be a novel target in glioma immunotherapy., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Background: Age is a powerful prognostic factor of high-grade glioma (HGG). However, the underlying genetic mechanisms of the discrepant prognosis among different age groups remain elusive., Methods: A total of 953 and 559 HGG patients from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) cohorts were enrolled and assigned as young, intermediate, elderly groups. The data of clinicopathological characteristics, mRNA, mutation, copy number alteration was analyzed., Results: Transcriptomic analysis revealed that diverse biological processes including immune response are altered between the young and elderly groups. Combined with the analysis of infiltrating immune cells and immune checkpoints, our results suggest an immune suppression status in the elderly group. Patients from different age groups exhibit different mutation and copy number alteration profiles., Conclusions: A multi-omics analysis is conducted to explore the biological basis of HGG patients of different age groups. This study suggests an immune-suppressive environment in elderly patients., (Copyright © 2021. Published by Elsevier Inc.)

Tumor-associated macrophages (TAMs) are regarded as the most abundantly infiltrating immune cells around the tumor microenvironment in gliomas, which plays an important role in tumorgenesis and immunosuppression. A total of 216 patients diagnosed with primary glioma were obtained from the Chinese Glioma Genome Atlas of which the RNA sequencing data was used as training set. RNA sequencing from the Cancer Genome Atlas was applicated for validation. We found that mesenchymal subtype showed strong positive correlation with macrophage-related genes (MRGs) expression. Survival analysis showed that high expression level of MRG predicted poor prognosis. A TAM-based nine-gene signature was constructed, which divided the samples into high- and low-risk of unfavorable outcome. The result of Cox regression analysis showed that the risk score was an independent prognostic factor in gliomas. Hence, the expression of TAMs was correlated with patient survival. The nine-TAM-related gene signature can predict patient survival efficiently., Competing Interests: Declaration of Competing Interest The authors of this manuscript have no conflict of interests to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To determine heterogeneity of high-grade glioma (HGG) and its surrounding area and explore quantitative analysis of invasion of HGG using diffusion tensor imaging., Methods: This study included 14 patients with HGG and preoperative magnetic resonance imaging and diffusion tensor imaging examinations. Three regions of interest were placed. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values of these regions of interest were measured, and specimens from the 3 regions of interest were obtained under navigation guidance. Postoperative examinations of specimens were carried out. Correlations between ADC and FA values and tumor cell density were evaluated., Results: Median survival was 36.7 months. As distance from the tumor increased, the number of tumor cells significantly decreased. Regarding levels of matrix metalloproteinase-9 and Ki-67, only the differences between tumor and distances of 1 cm and 2 cm away from the tumor were statistically significant. For analysis of the relationship between tumor cell density and ADC and FA values, the discriminant formulas were as follows: G1 = -13.678 + 14984.791 (X) + 14443.847 (Y) (tumor cell density ≥10%); G2 = -11.649 + 14443.847 (X) + 33.285 (Y) (tumor cell density <10%)., Conclusions: We verified the heterogeneity of HGG and its surrounding area and found that patients with extensive resection may have longer survival. We also found a few formulas using FA and ADC values to predict tumor cell density., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We investigated immune-related long non-coding RNAs (lncRNAs) that may be exploited as potential therapeutic targets in anaplastic gliomas. We obtained 572 lncRNAs and 317 immune genes from the Chinese Glioma Genome Atlas microarray and constructed immune-related lncRNAs co-expression networks to identify immune-related lncRNAs. Two additional datasets (GSE16011, REMBRANDT) were used for validation. Gene set enrichment analysis and principal component analysis were used for functional annotation. Immune-lncRNAs co-expression networks were constructed. Nine immune-related lncRNAs (SNHG8, PGM5-AS1, ST20-AS1, LINC00937, AGAP2-AS1, MIR155HG, TUG1, MAPKAPK5-AS1, and HCG18) signature was identified in patients with anaplastic gliomas. Patients in the low-risk group showed longer overall survival (OS) and progression-free survival than those in the high-risk group (P < 0.0001; P < 0.0001). Additionally, patients in the high-risk group displayed no-deletion of chromosomal arms 1p and/or 19q, isocitrate dehydrogenase wild-type, classical and mesenchymal TCGA subtype, G3 CGGA subtype, and lower Karnofsky performance score (KPS). Moreover, the signature was an independent factor and was significantly associated with the OS (P = 0.000, hazard ratio (HR) = 1.434). These findings were further validated in two additional datasets (GSE16011, REMBRANDT). Low-risk and high-risk groups displayed different immune status based on principal components analysis. Our results showed that the nine immune-related lncRNAs signature has prognostic value for anaplastic gliomas.

OBJECTIVE Insular glioma has a unique origin and biological behavior; however, the associations between its anatomical features and prognosis have not been well established. The object of this study was to propose a classification system of insular low-grade gliomas based on preoperative MRI findings and to assess the system's association with survival outcome. METHODS A total of 211 consecutively collected patients diagnosed with low-grade insular gliomas was analyzed. All patients were classified according to whether tumor involved the putamen on MR images. The prognostic role of this novel putaminal classification, as well as that of Yaşargil's classification, was examined using multivariate analyses. RESULTS Ninety-nine cases (46.9%) of insular gliomas involved the putamen. Those tumors involving the putamen, as compared with nonputaminal tumors, were larger (p < 0.001), less likely to be associated with a history of seizures (p = 0.04), more likely to have wild-type IDH1 (p = 0.003), and less likely to be totally removed (p = 0.02). Significant favorable predictors of overall survival on univariate analysis included a high preoperative Karnofsky Performance Scale score (p = 0.02), a history of seizures (p = 0.04), gross-total resection (p = 0.006), nonputaminal tumors (p < 0.001), and an IDH1 mutation (p < 0.001). On multivariate analysis, extent of resection (p = 0.035), putamen classification (p = 0.014), and IDH1 mutation (p = 0.026) were independent predictors of overall survival. No prognostic role was found for Yaşargil's classification. CONCLUSIONS The current study's findings suggest that the putamen classification is an independent predictor of survival outcome in patients with insular low-grade gliomas. This newly proposed classification allows preoperative survival prediction for patients with insular gliomas.

Anaplastic glioma is Grade III and the median overall survival is about 37.6 months. However, there are still other factors that affect the prognosis for anaplastic glioma patients due to variable overall survival. So we screened four-lncRNA signature (AGAP2-AS1, TPT1-AS1, LINC01198 and MIR155HG) from the lncRNA expression profile from the GSE16011, CGGA and REMBRANDT datasets. The patients in low risk group had longer overall survival than high risk group (median OS 2208.25 vs. 591.30 days; P < 0.0001). Moreover, patients in the low risk group showed similar overall survival to Grade II patients (P = 0.1669), while the high risk group showed significant different to Grade IV (P = 0.0005) with similar trend. So based on the four-lncRNA, the anaplastic gliomas could be divided into grade II-like and grade IV-like groups. On the multivariate analysis, it showed the signature was an independent prognostic factor (P = 0.000). The expression of four lncRNAs in different grades showed that AGAP2-AS1, LINC01198 and MIR155HG were increased with tumor grade, while TPT1-AS1 was decreased. Knockdown of AGAP2-AS1 can inhibit the cell proliferation, migration and invasion, while increase the apoptosis cell rates in vitro. In conclusion, our results showed that the four-lncRNA signature has prognostic value for anaplastic glioma. Moreover, clinicians should conduct corresponding therapies to achieve best treatment with less side effects for two groups patients.

Introduction: Contrast enhancement observable on magnetic resonance (MR) images reflects the destructive features of malignant gliomas. This study aimed to investigate the relationship between radiologic patterns of tumor enhancement, extent of resection, and prognosis in patients with anaplastic gliomas (AGs)., Methods: Clinical data from 268 patients with histologically confirmed AGs were retrospectively analyzed. Contrast enhancement patterns were classified based on preoperative T1-contrast MR images. Univariate and multivariate analyses were performed to evaluate the prognostic value of MR enhancement patterns on progression-free survival (PFS) and overall survival (OS)., Results: The pattern of tumor contrast enhancement was associated with the extent of surgical resection in AGs. A gross total resection was more likely to be achieved for AGs with focal enhancement than those with diffuse (p = 0.001) or ring-like (p = 0.024) enhancement. Additionally, patients with focal-enhanced AGs had a significantly longer PFS and OS than those with diffuse (log-rank, p = 0.025 and p = 0.031, respectively) or ring-like (log-rank, p = 0.008 and p = 0.011, respectively) enhanced AGs. Furthermore, multivariate analysis identified the pattern of tumor enhancement as a significant predictor of PFS (p = 0.016, hazard ratio [HR] = 1.485) and OS (p = 0.030, HR = 1.446)., Conclusion: Our results suggested that the contrast enhancement pattern on preoperative MR images was associated with the extent of resection and predictive of survival outcomes in AG patients.

Aldehyde dehydrogenases (ALDH) is a family of enzymes including 19 members. For now, ALDH activity had been wildly used as a marker of cancer stem cells (CSCs). But biological functions of relevant isoforms and their clinical applications are still controversial. Here, we investigate the clinical significance and potential function of ALDH1A3 in gliomas. By whole-genome transcriptome microarray and mRNA sequencing analysis, we compared the expression of ALDH1A3 in high- and low- grade gliomas as well as different molecular subtypes. Microarray analysis was performed to identify the correlated genes of ALDH1A3. We further used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis to explore the biological function of ALDH1A3. Finally, by mRNA knockdown we revealed the relationship between ALDH1A3 and the ability of tumor invasion. ALDH1A3 overexpression was significantly associated with high grade as well as the higher mortality of gliomas in survival analysis. ALDH1A3 was characteristically highly expressed in Mesenchymal (Mes) subtype gliomas. Moreover, we found that ALDH1A3 was most relevant to extracellular matrix organization and cell adhesion biological process, and the ability of tumor invasion was suppressed after ALDH1A3 knockdown in vitro. In conclusion, ALDH1A3 can serve as a novel marker of Mes phenotype in gliomas with potential clinical prognostic value. The expression of ALDH1A3 is associated with tumor cell invasion.

Contrast enhancement is a crucial radiologic feature of malignant brain tumors, which are associated with genetic changes of the tumor. The purpose of the current study was to investigate the potential relationship among tumor contrast enhancement with MR imaging, vascular endothelial growth factor (VEGF) expression, and survival outcome in anaplastic gliomas. MR images from 240 patients with histologically confirmed anaplastic gliomas were retrospectively analyzed. The volumes of T2 hyperintense, contrast enhanced regions and necrotic regions on postcontrast T1-weighted images were measured. The ratio of the enhanced volume to necrotic volume was compared between patients with high versus low levels of VEGF expression and was further used in the survival analysis. The volumetric ratio of enhancement to necrosis was significantly higher in patients with low VEGF expression than in those with high VEGF expression (Mann-Whitney, p = 0.009). In addition, the enhancement/necrosis ratio was identified as a significant predictor of progression-free survival (Cox regression model, p = 0.004) and overall survival (Cox regression model, p = 0.006) in the multivariate analysis. These results suggest that the volumetric ratio of enhancement to necrosis could serve as a noninvasive radiographic marker associated with VEGF expression and that this ratio is an independent predictor for progression-free survival and overall survival in patients with anaplastic gliomas.

The majority of patients with low-grade glioma (LGG) experience epileptic seizures as their initial symptom, while the underlying mechanisms of tumor-related seizures are still far from being fully understood. In addition to tumor type and location, genetic changes of LGGs are considered to be influential factors in causing epileptic seizures. Nevertheless, the molecular biomarkers associated with tumor-related epilepsy have rarely been identified. RNA sequence data from 80 patients with histologically confirmed LGG were collected from the Chinese glioma genome atlas database and significant differences in expression levels of 33 genes were found. One of the genes, Very large G-protein-coupled receptor-1 (VLGR1), had been previously associated with seizures. Therefore, we investigated the association between LGG-related epilepsy and VLGR1, which played a role in idiopathic epilepsy. The level of VLGR1 expression was compared between patients with epileptic seizures and those without using the reads per kilobase transcriptome per million method. To evaluate the prognostic role of VLGR1 gene expression, the progression-free survival was determined by the Kaplan-Meier method and a multivariate Cox model. We demonstrated that VLGR1 had a significantly lower expression level in patients with epileptic seizures compared to seizure-free patients (p = 0.003). Furthermore, VLGR1 was highly associated with the presence of seizures in a multivariate statistical model. However, VLGR1 could not serve as an independent prognostic factor to determine progression-free survival of LGG patients. Based on RNA sequence data analysis, our results suggest that low expression of VLGR1 is a significant risk factor of epileptic seizures in patients with LGG.

A comprehensive evaluation of cytokine levels in patients with gliomas could provide important information for the progression and host responses of gliomas. We studied a panel of 120 cytokines and growth factors and investigated their prognostic values for glioma. A protein antibody array was first performed to study the prognostic significance of 120 cytokines in the plasma samples of 45 glioblastoma patients prior to craniotomy or biopsy procedure. An independent set of plasma samples from 260 patients with astrocytomas (80 grade II, 80 grade III, 100 grade IV) with complete clinicopathologic data and follow-ups were used for validation. Ten cytokines were identified by significance analysis of microarray, in which four were associated with poor prognosis (IL-15, MCP-1, GDNF, IL-1R4/ST2), and six were associated with good prognosis (IGFBP-6, MIP-1δ, ICAM-3, IL-7, MIP-3β, and sgp130) of the glioblastoma patients. Moreover, a 4-cytokine panel composed of IL-7, IL1R4/ST2, sgp130 and MCP-1 showed significant correlation with overall survival of the glioblastoma patients (HR 2.068; 95 % CI 1.357-3.153; p = 0.001). In the validation set, the cytokine panel was significantly correlated with overall survival in the 260 glioma patients (HR 3.480, 95 % CI 1.890-6.422) in multivariate Cox regression analysis. It also showed strong correlation with survival in patients with malignant gliomas (grade III: HR 2.790, 95 % CI 1.597-3.984, p = 0.002; grade IV: HR 1.753; 95 % CI 1.502-2.255, p < 0.001). This panel of four cytokines: IL-7, IL1R4/ST2, sgp130, and MCP-1 can serve as a prognostic marker for patients with malignant gliomas.

The immune microenvironment is important for the development, progression, and prognosis of anaplastic glioma (AG). This complex milieu has not been fully elucidated, and a high-dimensional analysis is urgently required. Utilizing mass cytometry (CyTOF), we performed an analysis of immune cells from 5 patients with anaplastic astrocytoma, IDH-mutant (AAmut) and 10 patients with anaplastic oligodendroglioma, IDH-mutant and 1p/19q codeletion (AOD) and their paired peripheral blood mononuclear cells (PBMCs). Based on a panel of 33 biomarkers, we demonstrated the tumor-driven immune changes in the AG immune microenvironment. Our study confirmed that mononuclear phagocytes and T cells are the most abundant immunocytes in the AG immune microenvironment. Glioma-associated microglia/macrophages in both AAmut and AOD samples showed highly immunosuppressive characteristics. Compared to those in the PBMCs, the ratios of immune checkpoint-positive exhausted CD4+ T cells and CD8+ T cells were higher at the AG tumor sites. The AAmut immune milieu exhibits more immunosuppressive characteristics than that in AOD. [ABSTRACT FROM AUTHOR]