Combination of MRI-based prediction and CRISPR/Cas12a-based detection for IDH genotyping in glioma.

Early identification of IDH mutation status is of great significance in clinical therapeutic decision-making in the treatment of glioma. We demonstrate a technological solution to improve the accuracy and reliability of IDH mutation detection by combining MRI-based prediction and a CRISPR-based automatic integrated gene detection system (AIGS). A model was constructed to predict the IDH mutation status using whole slices in MRI scans with a Transformer neural network, and the predictive model achieved accuracies of 0.93, 0.87, and 0.84 using the internal and two external test sets, respectively. Additionally, CRISPR/Cas12a-based AIGS was constructed, and AIGS achieved 100% diagnostic accuracy in terms of IDH detection using both frozen tissue and FFPE samples in one hour. Moreover, the feature attribution of our predictive model was assessed using GradCAM, and the highest correlations with tumor cell percentages in enhancing and IDH-wildtype gliomas were found to have GradCAM importance (0.65 and 0.5, respectively). This MRI-based predictive model could, therefore, guide biopsy for tumor-enriched, which would ensure the veracity and stability of the rapid detection results. The combination of our predictive model and AIGS improved the early determination of IDH mutation status in glioma patients. This combined system of MRI-based prediction and CRISPR/Cas12a-based detection can be used to guide biopsy, resection, and radiation for glioma patients to improve patient outcomes.

Anti-tumor effects of telmisartan in glioma-astrocyte non-contact co-cultures: A critical role of astrocytic IL-6-mediated paracrine growth promotion.

Telmisartan, an angiotensin II type 1 receptor (AT1R) blocker, exhibits broad anti-tumor activity. However, in vitro, anti-proliferative effects are shown at doses far beyond the therapeutic plasma concentration. Considering the role of tumor microenvironment in glioma progression, glioma-astrocyte co-cultures were employed to test the anti-tumor potential of low-dose telmisartan. When a high dose was required for a direct anti-proliferative effect on glioma cell lines, a low dose significantly inhibited glioma cell proliferation and migration in the co-culture system. Under co-culture conditions, upregulated IL-6 expression in astrocytes played a critical role in glioma progression. Silencing IL-6 in astrocytes or IL-6R in glioma cells reduced proliferation and migration. Telmisartan (5 µM) inhibited astrocytic IL-6 expression, and its anti-tumor effects were reversed by silencing IL-6 or IL-6R and inhibiting signal transducer and activator of transcription 3 (STAT3) activity in glioma cells. Moreover, the telmisartan-driven IL-6 downregulation was not imitated by losartan, an AT1R blocker with little capacity of peroxisome proliferator-activated receptor-gamma (PPARγ) activation, but was eliminated by a PPARγ antagonist, indicating that the anti-glioma effects of telmisartan rely on its PPARγ agonistic activity rather than AT1R blockade. This study highlights the importance of astrocytic IL-6-mediated paracrine signaling in glioma growth and the potential of telmisartan as an adjuvant therapy for patients with glioma, especially those with hypertension.

Serum beta2-microglobulin acts as a biomarker for severity and prognosis in glioma patients: a preliminary clinical study.

BACKGROUND: Gliomas are the deadliest malignant tumors of the adult central nervous system. We previously discovered that beta2-microglobulin (B2M) is abnormally upregulated in glioma tissues and that it exerts a range of oncogenic effects. Besides its tissue presence, serum B2M levels serve as biomarkers for various diseases. This study aimed to explore whether serum B2M levels can be used in the diagnosis and prognosis of gliomas. METHODS: Medical records from 246 glioma patients were retrospectively analyzed. The relationship between preoperative serum B2M levels and clinicopathological features was examined. Kaplan-Meier analysis, alongside uni- and multivariate Cox regression, assessed the association between B2M levels, systemic inflammatory markers, and glioma patient prognosis. Receiver operating characteristic (ROC) curve analysis evaluated the diagnostic significance of these biomarkers specifically for glioblastoma (GBM). RESULTS: Patients with malignant gliomas exhibited elevated preoperative serum B2M levels. Glioma patients with high serum B2M levels experienced shorter survival times. Multivariate Cox analysis determined the relationship between B2M levels (hazard ratio = 1.92, 95% confidence interval: 1.05-3.50, P = 0.034) and the overall survival of glioma patients. B2M demonstrated superior discriminatory power in distinguishing between GBM and non-GBM compared to inflammation indicators. Moreover, postoperative serum B2M levels were lower than preoperative levels in the majority of glioma patients. CONCLUSIONS: High preoperative serum B2M levels correlated with malignant glioma and a poor prognosis. Serum B2M shows promise as a novel biomarker for predicting patient prognosis and reflecting the therapeutic response.

Unveiling novel cell clusters and biomarkers in glioblastoma and its peritumoral microenvironment at the single-cell perspective.

BACKGROUND: Glioblastoma (GBM) is a highly heterogeneous, recurrent and aggressively invasive primary malignant brain tumor. The heterogeneity of GBM results in poor targeted therapy. Therefore, the aim of this study is to depict the cellular landscape of GBM and its peritumor from a single-cell perspective. Discovering new cell subtypes and biomarkers, and providing a theoretical basis for precision therapy. METHODS: We collected 8 tissue samples from 4 GBM patients to perform 10 × single-cell transcriptome sequencing. Quality control and filtering of data by Seurat package for clustering. Inferring copy number variations to identify malignant cells via the infercnv package. Functional enrichment analysis was performed by GSVA and clusterProfiler packages. STRING database and Cytoscape software were used to construct protein interaction networks. Inferring transcription factors by pySCENIC. Building cell differentiation trajectories via the monocle package. To infer intercellular communication networks by CellPhoneDB software. RESULTS: We observed that the tumor microenvironment (TME) varies among different locations and different GBM patients. We identified a proliferative cluster of oligodendrocytes with high expression of mitochondrial genes. We also identified two clusters of myeloid cells, one primarily located in the peritumor exhibiting an M1 phenotype with elevated TNFAIP8L3 expression, and another in the tumor and peritumor showing a proliferative tendency towards an M2 phenotype with increased DTL expression. We identified XIST, KCNH7, SYT1 and DIAPH3 as potential factors associated with the proliferation of malignant cells in GBM. CONCLUSIONS: These biomarkers and cell clusters we discovered may serve as targets for treatment. Targeted drugs developed against these biomarkers and cell clusters may enhance treatment efficacy, optimize immune therapy strategies, and improve the response rates of GBM patients to immunotherapy. Our findings provide a theoretical basis for the development of individualized treatment and precision medicine for GBM, which may be used to improve the survival of GBM patients.

The Role of Beta2-Microglobulin in Central Nervous System Disease.

Central nervous system (CNS) disorders represent the leading cause of disability and the second leading cause of death worldwide, and impose a substantial economic burden on society. In recent years, emerging evidence has found that beta2 -microglobulin (B2M), a subunit of major histocompatibility complex class I (MHC-I) molecules, plays a crucial role in the development and progression in certain CNS diseases. On the one hand, intracellular B2M was abnormally upregulated in brain tumors and regulated tumor microenvironments and progression. On the other hand, soluble B2M was also elevated and involved in pathological stages in CNS diseases. Targeted B2M therapy has shown promising outcomes in specific CNS diseases. In this review, we provide a comprehensive summary and discussion of recent advances in understanding the pathological processes involving B2M in CNS diseases (e.g., Alzheimer's disease, aging, stroke, HIV-related dementia, glioma, and primary central nervous system lymphoma).

TERT mutations-associated alterations in clinical characteristics, immune environment and therapy response in glioblastomas.

OBJECTIVE TERT: is the most frequently mutated gene in adult glioblastomas (GBMs) defined by the 2021 World Health Organization classification system. The present study aims to explore differences in clinical characteristics and immune microenvironment between TERT mutant and wild-type GBM. METHODS: Three GBM-related cohorts consisting of 205 GBM patients in our cohort, 463 GBM patients without immune checkpoint inhibitor(ICI) therapy and 1465 tumour patients (including 92 GBM cases) receiving ICI treatment in the MSK cohort were included. Retrospective analysis and immunohistochemistry assay were used for investigating the local (including tumour cells, local immune cells, and seizures) and systemic (including circulating immune cells, coagulation-related functions, and prognosis) effects of TERT mutations. Besides, differences in genetic alterations and immunotherapy responses between TERT mutant and wild-type GBMs were also explored. RESULTS: We found that TERT mutant and wild-type GBMs possessed similar initial clinic symptoms, circulating immune microenvironment and immunotherapy response. With respect to that in TERT wild-type GBMs, mutations in TERT resulted in higher levels of tumour-infiltrating neutrophils, prolonged coagulation time, worse chemotherapy response and poorer overall survival. CONCLUSION: Mutations in TERT alter the local immune environment and decrease the sensitivity of GBM to chemotherapy.

Telmisartan inhibits microglia-induced neurotoxic A1 astrocyte conversion via PPARγ-mediated NF-κB/p65 degradation.

Astrocytes are crucially involved in neuroinflammation. Activated astrocytes exhibit at least two phenotypes, A1 (neurotoxic) and A2 (neuroprotective). The A1 phenotype is the major reactive astrocyte phenotype involved in aging and neurodegenerative diseases. Telmisartan, which is an antihypertensive agent, is a promising neuroprotective agent. This study aimed to investigate the effects of telmisartan on the phenotype of reactive astrocytes. Astrocytes were activated by culturing with the conditioned medium derived from lipopolysaccharide-stimulated microglia. This conditioned medium induced early, transient A2 astrocyte conversion (within 24 h) and late, sustained A1 conversion (beginning at 24 h and lasting up to 7 days), with a concomitant increase in the production of pro-inflammatory cytokines (interleukin [IL]-1ß, tumor necrosis factor [TNF]α, and IL-6) and phosphorylation of nuclear factor-κB (NF-κB)/p65. Telmisartan treatment promoted and inhibited A2 and A1 conversion, respectively. Telmisartan reduced total and phosphorylated p65 protein levels. Losartan, a specific angiotensin II type-1 receptor (AT1R) blocker, did not influence the reactive state of astrocytes. Additionally, AT1R activation by angiotensin II did not induce the expression of pro-inflammatory cytokines and A1/A2 markers, indicating that the AT1R signaling pathway is not involved in the astrocyte-mediated inflammatory response. A peroxisome proliferator-activated receptor γ (PPARγ) antagonist reversed the effects of telmisartan. Moreover, telmisartan-induced p65 downregulation was reversed by the proteasome inhibitor MG132. These results indicate that telmisartan suppresses activated microglia-induced neurotoxic A1 astrocyte conversion through p65 degradation. Our findings contribute towards the elucidation of the anti-inflammatory activity of telmisartan in brain disorders.

ZDHHC15 promotes glioma malignancy and acts as a novel prognostic biomarker for patients with glioma.

BACKGROUND: Glioma is the most common and aggressive tumor in the adult brain. Recent studies have indicated that Zinc finger DHHC-type palmitoyltransferases (ZDHHCs) play vital roles in regulating the progression of glioma. ZDHHC15, a member of the ZDHHCs family, participates in various physiological activities in the brain. However, the biological functions and related mechanisms of ZDHHC15 in glioma remain poorly understood. METHODS: Data from multiple glioma-associated datasets were used to investigate the expression profiles and potential biological functions of ZDHHC15 in glioma. Expression of ZDHHC15 and its association with clinicopathological characteristics in glioma were validated by quantitative reverse transcription PCR (RT-qPCR) and immunohistochemical experiments. GO enrichment analysis, KEGG analysis, GSEA analysis, CCK-8, EdU, transwell, and western blotting assays were performed to confirm the functions and mechanism of ZDHHC15 in glioma. Moreover, we performed Kaplan-Meier analysis and Cox progression analysis to explore the prognostic significance of ZDHHC15 in glioma patients. RESULTS: ZDHHC15 expression was significantly up-regulated in glioma and positively associated with malignant phenotypes. Results from the GO and KEGG enrichment analysis revealed that ZDHHC15 was involved in regulating cell cycle and migration. Knockdown of ZDHHC15 inhibited glioma cell proliferation and migration, while overexpression of ZDHHC15 presented opposite effects on glioma cells. Besides, results from GSEA analysis suggested that ZDHHC15 was enriched in STAT3 signaling pathway. Knockdown or overexpression of ZDHHC15 indeed affected the activation of STAT3 signaling pathway. Additionally, we identified ZDHHC15 as an independent prognostic biomarker in glioma, and higher expression of ZDHHC15 predicted a poorer prognosis in glioma patients. CONCLUSION: Our findings suggest that ZDHHC15 promotes glioma malignancy and can serve as a novel prognostic biomarker for glioma patients. Targeting ZDHHC15 may be a promising therapeutic strategy for glioma.

In situ embedding of glucose oxidase in amorphous ZIF-7 with high catalytic activity and stability and mechanism investigation.

Glucose oxidase (GOx) has a great application potential in the determination of glucose concentration. However, its sensitivity to the environment and poor recyclability limited its broader application. Herein, with the assistance of DA-PEG-DA, a novel immobilized GOx based on amorphous Zn-MOFs (DA-PEG-DA/GOx@aZIF-7/PDA) was developed to impart excellent properties to the enzyme. SEM, TEM, XRD, and BET analyses confirmed that GOx was embedded in amorphous ZIF-7 with ∼5 wt% loading. Compared with free GOx, DA-PEG-DA/GOx@aZIF-7/PDA exhibited enhanced stability, excellent reusability, and promising potential for glucose detection. After 10 repetitions, the catalytic activity of DA-PEG-DA/GOx@aZIF-7/PDA can maintain 95.53 % ± 3.16 %. In understanding the in situ embedding of GOx in ZIF-7, the interaction of zinc ion and benzimidazole with GOx was studied by using molecular docking and multi-spectral methods. Results showed that zinc ions and benzimidazole had multiple binding sites on the enzyme, which induced the accelerated synthesis of ZIF-7 around the enzyme. During binding, the structure of the enzyme changes, but such changes hardly affect the activity of the enzyme. This study provides not only a preparation strategy of immobilized enzyme with high activity, high stability, and low enzyme leakage rate for glucose detection, but also a more comprehensive understanding of the formation of immobilized enzymes using the in situ embedding strategy.

Local and systemic effects of IDH mutations on primary glioma patients.

Adult gliomas are divided into isocitrate dehydrogenase (IDH) wild-type and IDH mutant subtypes according to the new 2021 World Health Organization classification system. However, the local and systemic effects of IDH mutations on primary glioma patients are not well illustrated. Retrospective analysis, immune-cell infiltration analysis, meta-analysis, and immunohistochemistry assay were applied in the present study. The results from our cohort showed that IDH mutant gliomas own a lower proliferating rate compared to that in wild-type gliomas. Patients with mutant IDH exhibited a higher frequency of seizures in both our cohort and the cohort from the meta-analysis. Mutations in IDH result in lower levels of intra-tumour but higher levels of circulating CD4+ and CD8+ T lymphocytes. Levels of neutrophils in both intra-tumour and circulating blood were lower in IDH mutant gliomas. Moreover, IDH mutant glioma patients receiving radiotherapy in combination with chemotherapy exhibited better overall survival with respect to radiotherapy alone. Mutations in IDH alters the local and circulating immune microenvironment, and increases the sensitivity of tumour cell to chemotherapy.

Anchoring of Polymer Loops on Enzyme-Immobilized Mesoporous ZIF-8 Enhances the Recognition Selectivity of Angiotensin-Converting Enzyme Inhibitory Peptides.

Immobilized angiotensin-converting enzyme (ACE) is a promising material for the rapid screening of antihypertensive drugs, but the nonspecific adsorption is a serious problem in separation processes involving complex biological products. In this study, triblock copolymers with dopamine (DA) block as anchors and PEG block as the main body (DA-PEGx-DA) were attached to an immobilized ACE (ACE@mZIF-8/PDA, AmZP) surface via the "grafting to" strategy which endowed them with anti-nonspecific adsorption. The influence of DA-PEGx-DA chain length on nonspecific adsorption was confirmed. The excellent specificity and reusability of the obtained ACE@mZIF-8/PDA/DA-PEG5000-DA (AmZPP5000) was validated by screening two known ACE inhibitory peptides Val-Pro-Pro (VPP, competitive inhibitory peptides of ACE) and Gly-Met-Lys-Cys-Ala-Phe (GF-6, noncompetitive inhibitory peptides of ACE) from a mixture containing active and inactive compounds. These results demonstrate that anchored polymer loops are effective for high-recognition selectivity and AmZPP5000 is a promising compound for the efficient separation of ACE inhibitors in biological samples.

Anti-Vascular Endothelial Growth Factor Therapy Abolishes Glioma-Associated Endothelial Cell-Induced Tumor Invasion.

Tumor-remodeled endothelial cells not only facilitate the formation of tumor angiogenesis but also promote tumorigenesis. In this study, we aimed to explore the interaction between glioma-associated endothelial cells (GAEs) and glioma cells. We found that different subtypes of glioma owned distinct GAE abundance. Glioma patients with high GAE abundance exhibited poor prognosis. Both the results of the bioinformatics analysis and the in vitro co-culture system assay revealed that GAE promoted glioma cell invasion. Besides, anti-vascular endothelial growth factor (VEGF) therapy partially abolished the effects of GAE on gliomas. Moreover, anti-VEGF therapy upregulated IL-2 expression in GAE, and exogenous IL-2 administration inhibits GAE-induced glioma cell invasion. Collectively, our present study provides a novel outstanding of the interaction between GAE and glioma cells.

Earlier cranioplasty following posttraumatic craniectomy is associated with better neurological outcomes at one-year follow-up: a two-centre retrospective cohort study.

PURPOSE: Cranioplasty (CP) after decompressive craniectomy (DC) is routinely performed for reconstructive purposes and improves rehabilitation. However, the optimal timing of CP remains controversial. This study aimed to assess differences in clinical outcomes following different timings of CP in patients with traumatic brain injury. MATERIALS AND METHODS: Patients with traumatic brain injury who underwent CP after DC in Zhongnan Hospital of Wuhan University from 1 January 2010 to 1 May 2017, and in Affiliated Hospital of Guizhou Medical University from 1 January 2015, to 1 May 2017, were retrospectively reviewed. According to the timing of CP, patients were divided into an 'early group' (3-6 months) and a 'late group' (6-12 months). The clinical characteristics of patients and postoperative complications occurred within 1-year follow-up were analysed. The neurological function was assessed with Barthel Index (BI). RESULTS: A total of 100 patients (58 cases in early group and 42 cases in late group) were included. The median interval between DC and CP was 135 days and 225 days in the early and late CP groups, respectively. The overall complication rate after CP was 16%, and no significant difference in complication rate was observed between the early and late CP groups (17.2% vs.14.3%, p = 0.69). The neurological function was improved in early CP group (pre-CP 85.77 ± 11.61 vs. post-CP 95.34 ± 9.02, p < 0.001, but not in late CP group (pre-CP 82.74 ± 22.82 vs. post-CP 88.93 ± 22.86, p = 0.22). In addition, a significantly higher proportion of patients in the early CP group showed neurological functional improvement in comparison with the late CP group (early vs. late: 74.1% vs. 57.1%, p = 0.04). Multivariate analysis further demonstrated that the timing of CP is an independent predictor for neurological outcomes (OR = 0.32, 95% CI 0.13-0.82, p = 0.02). CONCLUSION: Early CP (3-6 months) following posttraumatic DC was associated with better neurological outcomes than late CP (>6 months).

Prognostic Value of Systemic Immune-Inflammation Index (SII) in Patients with Glioblastoma: A Comprehensive Study Based on Meta-Analysis and Retrospective Single-Center Analysis.

Inflammation is related to cancer. The systemic immune-inflammation index (SII) has been linked to the prognosis of many types of cancer. The present study aimed to determine the prognostic value of the SII in glioblastoma (GBM) patients based on meta-analysis and single-center retrospective analysis. Relevant publications published before 1 October 2022 were identified by searching PubMed, EMBASE, Cochrane Library databases, and Web of Science. Moreover, 208 GBM patients from Zhongnan Hospital were incorporated. Kaplan−Meier and Cox regression analyses determined the prognostic significance of inflammatory markers. By combining these indicators, we developed scoring systems. Nomograms were also built by incorporating independent variables. The accuracies of nomograms were evaluated by Harrell's concordance index (c-index) and the calibration curve. According to meta-analysis, an elevated SII predicted the worst overall survival (OS) (Hazard ratio [HR] = 1.87, p < 0.001). Furthermore, a higher SII (>510.8) (HR = 1.782, p = 0.007) also predicted a poorer outcome in a retrospective cohort. The scoring systems of SII-NLR (neutrophil-to-lymphocyte ratio) showed the best predictive power for OS. The nomogram without MGMT (c-index = 0.843) exhibited a similar accuracy to that with MGMT (c-index = 0.848). A pre-treatment SII is independently associated with OS in GBM. A nomogram integrating the SII-NLR score may facilitate a comprehensive survival evaluation independent of molecular tests in GBM.

A narrative review on the management of glioblastoma in China.

BACKGROUND AND OBJECTIVE: Glioma is the most common intracranial primary malignant tumor, and half of it is glioblastoma. Despite receiving the standard treatment, the prognosis of glioblastoma is still poor and its 5-year survival rate in China is only 9%. In addition, new targeted and immunotherapy therapy and tumor treating fields also have certain curative effects on glioblastoma. To help clinicians and patients make appropriate treatment based on current evidences, we summarize the Chinese guidelines on the management of glioma and review the recent management of glioblastoma. METHODS: We systematically searched PubMed, China National Knowledge Infrastructure (CNKI) and Wanfang databases to retrieve guidelines on glioma in China published from the establishment of the database to 24 January 2022. We performed a narrative review of current clinical study related to the management of glioblastoma, especially in the surgical, targeted and immunotherapy therapy and tumor treating fields. KEY CONTENT AND FINDINGS: In this review, 19 guidelines were included, including 8 subclassified as the guideline, 8 subclassified as the consensus and 3 subclassified as the standard. Two guidelines reported the contents of the system search, 4 guidelines are updated, and 9 guidelines reported the source of funding. At present, most clinical trials on the immune and targeted therapy of glioblastoma are ongoing in China. CONCLUSIONS: China's guidelines still need to be improved in terms of preciseness, applicability and editorial independence. In addition, the cooperation in clinical research of glioblastoma in multiple centers needs to be strengthened in China.

Current knowledge of protein palmitoylation in gliomas.

Malignant tumor cells can obtain proliferative benefits from deviant metabolic networks. Emerging evidence suggests that lipid metabolism are dramatically altered in gliomas and excessive fatty acd accumulation is detrimentally correlated with the prognosis of glioma patients. Glioma cells possess remarkably high levels of free fatty acids, which, in turn, enhance post-translational modifications (e.g. palmitoylation). Our and other groups found that palmitoylational modification is essential for remaining intracellular homeostasis and cell survival. Disrupting the balance between palmitoylation and depalmitoylation affects glioma cell viability, apoptosis, invasion, self-renew and pyroptosis. In this review, we focused on summarizing roles and relevant mechanisms of protein palmitoylational modification in gliomas.

Palmitoyl transferases act as potential regulators of tumor-infiltrating immune cells and glioma progression.

High immune-cell infiltration in glioblastomas (GBMs) leads to immunotherapy resistance. Emerging evidence has shown that zinc finger Asp-His-His-Cyc-type (ZDHHC) palmitoyl transferases participate in regulating tumor progression and the immune microenvironment. In the present study, a large cohort of patients with gliomas from The Cancer Genome Atlas (TCGA) and Rembrandt databases was included to perform omics analysis of ZDHHCs in gliomas. CCK-8, flow cytometry, quantitative real-time PCR, western blotting, and transwell assays were performed to determine the effects of ZDHHC inhibition on glioma cells and microglia. We found that five (ZDHHC11, ZDHHC12, ZDHHC15, ZDHHC22, and ZDHHC23) out of 23 ZDHHCs were aberrantly expressed in gliomas and might play their roles through the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. Further results indicated that inhibition of ZDHHCs with 2-bromopalmitate (2-BP) suppressed glioma-cell viability and autophagy, as well as promoted apoptosis. Targeting ZDHHCs also promoted the sensitivity of glioma cells to temozolomide (TMZ) chemotherapy. In addition, the inhibition of ZDHHCs weakened the migratory ability of microglia induced by glioma cells in vitro and in vivo. Taken together, our findings suggest that the inhibition of ZDHHCs suppresses glioma-cell viability and microglial infiltration. Targeting ZDHHCs may be promising for glioma treatments.

Advances in the Immunotherapeutic Potential of Isocitrate Dehydrogenase Mutations in Glioma.

Isocitrate dehydrogenase (IDH) is an essential metabolic enzyme in the tricarboxylic acid cycle (TAC). The high mutation frequency of the IDH gene plays a complicated role in gliomas. In addition to affecting gliomas directly, mutations in IDH can also alter their immune microenvironment and can change immune-cell function in direct and indirect ways. IDH mutations mediate immune-cell infiltration and function by modulating immune-checkpoint gene expression and chemokine secretion. In addition, IDH mutation-derived D2-hydroxyglutarate can be absorbed by surrounding immune cells, also affecting their functioning. In this review, we summarize current knowledge about the effects of IDH mutations as well as other gene mutations on the immune microenvironment of gliomas. We also describe recent preclinical and clinical data related to IDH-mutant inhibitors for the treatment of gliomas. Finally, we discuss different types of immunotherapy and the immunotherapeutic potential of IDH mutations in gliomas.

Cumulative Scoring Systems and Nomograms for Predicating Survival in Patients With Glioblastomas: A Study Based on Peripheral Inflammatory Markers.

Inflammation is a hallmark of cancers. The purpose of the present study was to evaluate the prognostic potential of hematological inflammatory markers in glioblastoma multiforme (GBM) patients. The clinical data of 99 patients with lower-grade gliomas and 88 patients with GBMs were retrospectively analyzed. The optimal cutoff values for peripheral markers were determined by X-tile. Kaplan-Meier and Cox proportional hazard regression analyses were performed to identify markers with prognostic significance. Several scoring systems were constructed by combining these prognostic markers. The predictive accuracies of nomograms incorporating these scoring systems were evaluated by Harrell's concordance index and receiver operating characteristic curve analysis. GBM patients exhibited higher neutrophil counts (p=0.001), neutrophil-to-lymphocyte ratio (NLR) (p<0.001), and platelet-to-lymphocyte ratio (PLR) (p=0.001), as well as lower lymphocyte counts (p=0.023), lymphocyte-to-monocyte ratio (LMR) (p=0.015), and albumin-to-globulin ratio (AGR) (p=0.003) than those with lower-grade gliomas. Multivariate analysis indicated that a high NLR (> 2.0) (Hazard ratio[HR]=2.519, 95% confidence interval (CI): 1.220-5.204, p=0.013), low LMR (< 2.3) (HR=2.268, 95%CI: 1.172-4.386, p=0.015), or low AGR (< 1.7) (HR=2.924, 95%CI: 1.389-6.135, p=0.005) were associated with poor overall survival in GBM patients. The scoring systems of AGR-NLR, AGR-LMR, and LMR-NLR were associated with GBM survival. The nomogram integrating AGR-NLR score had the best efficacy in predicting GBM survival (c-index=0.874). Pretreatment scores of AGR-NLR, AGR-LMR, and LMR-NLR may serve as prognostic factors for GBM patients, and a nomogram integrating AGR-NLR may provide a reliable tool to facilitate personalized preoperative evaluations.