Glioma Malignancy Grade Research Articles

Emerging nanoplatforms towards microenvironment-responsive glioma therapy.

Gliomas are aggressive intracranial tumors of the central nervous system with a poor prognosis, high risk of recurrence, and low survival rates. Radiation, surgery, and chemotherapy are traditional cancer therapies. It is very challenging to accurately image and differentiate the malignancy grade of gliomas due to their heterogeneous and infiltrating nature and the obstruction of the blood-brain barrier. Imaging plays a crucial role in gliomas which significantly plays an important role in the accuracy of the diagnosis followed by any subsequent surgery or therapy. Other diagnostic methods (such as biopsies or surgery) are often very invasive. Preoperative imaging and intraoperative image-guided surgery perform the most significant safe resection. In recent years, the rapid growth of nanotechnology has opened up new avenues for glioma diagnosis and treatment. For better therapeutic efficacy, developing microenvironment-responsive nanoplatforms, including novel nanotherapeutic platforms of sonodynamic therapy, photodynamic therapy, and photothermal treatments, are employed for improved patient survival and better clinical control outcome. In this review recent advancement of multifunctional nanoplatforms leading toward treatment of glioma is discussed.

Radiographic growth rate as a predictor of aggressiveness of diffuse gliomas without 1p19q codeletion.

The 2021 WHO classification of CNS tumors has refined the definition of adult-type diffuse gliomas without 1p19q codeletion. Nevertheless, the aggressiveness of gliomas is based exclusively on histomolecular criteria performed on a limited sample of the tumor. The authors aimed to assess whether the spontaneous radiographic tumor growth rate is associated with tumor aggressiveness and allows preoperative identification of malignancy grade of adult-type diffuse gliomas without 1p19q codeletion. The authors retrospectively reviewed the records of adult patients harboring a newly diagnosed supratentorial diffuse glioma without 1p19q codeletion, with available preoperative MRI follow-up between January 2008 and April 2022. The spontaneous radiographic tumor growth rate was quantified by tumor volume segmentation and regression of the evolution of the mean tumor diameter over time and was compared with clinical, imaging, histomolecular, and survival data. Ninety-six patients were included. The spontaneous radiographic tumor growth rates (mean 17.8 ± 38.8 mm/year, range 0-243.5 mm/year) significantly varied according to IDH1/2 mutation (p < 0.001), grade of malignancy (p < 0.001), and presence of microvascular proliferation (p < 0.001). The spontaneous radiographic tumor growth rate allowed preoperative identification of high-grade cases: 100% of grade 3 and 4 IDH-mutant diffuse astrocytomas had a spontaneous radiographic tumor growth rate ≥ 8.0 mm/year, and 100% of IDH-wild-type glioblastomas had a spontaneous radiographic tumor growth rate ≥ 42.0 mm/year. A spontaneous radiographic growth rate ≥ 8.0 mm/year was an independent predictor of shorter progression-free (p = 0.014) and overall (p = 0.007) survival. A mitotic count threshold ≥ 4 mitoses was the optimal threshold for identifying aggressive IDH-mutant astrocytomas based on spontaneous radiographic tumor growth. The spontaneous radiographic tumor growth rates could be used as an additional tool to preoperatively screen tumor aggressiveness of adult-type diffuse gliomas without 1p19q codeletion.

Human glioma malignancy grade and migratory capacity depending on expression of GDNF isoforms in vitro

To assess the expression of mRNA splice variants of GDNF in glioma cell cultures with various malignancy grades (I-IV) and degrees of migration. In this study, αGDNF and βGDNF expression was analyzed in 15 human glioma cell cultures using Southern blot hybridization of GDNF cDNA and reverse transcription with PCR to amplify splice variants of GDNF mRNA. The highest expression of αGDNF and βGDNF isoforms was observed in cell cultures of human gliomas with extensive migratory activity. Low βGDNF expression without αGDNF expression is typical only for gliomas with low migratory activity. In addition, we found additional patterns of mRNA expression that have not been previously described. The relationship between GDNF and malignancy grade is unclear. Nevertheless, GDNF expression is higher in glioblastomas. Overall GDNF expression is increased in glioma cells with high migration activity. At the same time, αGDNF and βGDNF isoforms demonstrate higher expression in actively migrating cells that can indicate their participation in regulation of tumor migration properties. No αGDNF expression with simultaneous low βGDNF expression may be a prognostic sign of low migration activity of human glioma cells.

MUC17 mutations and methylation are associated with poor prognosis in adult-type diffuse glioma patients

Diffuse gliomas are tumors that arise from glial or glial progenitor cells. They are currently classified as astrocytoma isocitrate dehydrogenase (IDH)-mutant or oligodendroglioma IDH-mutant, and 1p/19q-codeleted, both slower-growing tumors, or glioblastoma (GBM), a more aggressive tumor. Despite advances in the diagnosis and treatment of gliomas, the median survival time after diagnosis of GBM remains low, approximately 15 months, with a 5-year overall survival rate of only 6.8%. Therefore, new biomarkers that could support the earlier diagnosis and prognosis of these tumors would be of great value. MUC17, a membrane-bound mucin, has been identified as a potential biomarker for several tumors. However, the role of this mucin in adult gliomas has not yet been explored. Here, we show for the first time, in a retrospective study and by in silico analysis that MUC17 is one of the relevant mutant genes in adult gliomas. Moreover, that an increase in MUC17 methylation correlates with an increase in glioma malignancy grade. Patients with MUC17 mutations had a poorer prognosis than their wild-type counterparts in both GBM and non-GBM glioma cohorts. We also analyzed mutational profiles that correlated strongly with poor survival. Therefore, in this study, we present a new potential biomarker for further investigation, especially for the prognosis of adult diffuse gliomas.

Identification of novel prognostic targets in glioblastoma using bioinformatics analysis

BackgroundGlioblastoma (GBM) is the most malignant grade of glioma. Highly aggressive characteristics of GBM and poor prognosis cause GBM-related deaths. The potential prognostic biomarkers remain to be demonstrated. This research builds up predictive gene targets of expression alterations in GBM utilizing bioinformatics analysis.Methods and resultsThe microarray datasets (GSE15824 and GSE16011) associated with GBM were obtained from Gene Expression Omnibus (GEO) database to identify the differentially expressed genes (DEGs) between GBM and non-tumor tissues. In total, 719 DEGs were obtained and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for function enrichment analysis. Furthermore, we constructed protein–protein Interaction (PPI) network among DEGs utilizing Search Tool for the Retrieval of Interacting Genes (STRING) online tool and Cytoscape software. The DEGs of degree > 10 was selected as hub genes, including 73 upregulated genes and 21 downregulated genes. Moreover, MCODE application in Cytoscape software was employed to identify three key modules involved in GBM development and prognosis. Additionally, we used the Gene expression profiling and interactive analyses (GEPIA) online tool to further confirm four genes involving in poor prognosis of GBM patients, including interferon-gamma-inducible protein 30 (IFI30), major histocompatibility complex class II-DM alpha (HLA-DMA), Prolyl 4-hydroxylase beta polypeptide (P4HB) and reticulocalbin-1 (RCN1). Furthermore, the correlation analysis indicated that the expression of IFI30, an acknowledged biomarker in glioma, was positively correlated with HLA-DMA, P4HB and RCN1. RCN1 expression was positively correlated with P4HB and HLA-DMA. Moreover, qRT-PCR and immunohistochemistry analysis further validated the upregulation of four prognostic markers in GBM tissues.ConclusionsAnalysis of multiple datasets combined with global network information and experimental verification presents a successful approach to uncover the risk hub genes and prognostic markers of GBM. Our study identified four risk- and prognostic-related gene signatures, including IFI30, HLA-DMA, P4HB and RCN1. This gene sets contribute a new perspective to improve the diagnostic, prognostic, and therapeutic outcomes of GBM.

Cerebrovascular Dysregulation in Patients with Glioma Assessed with Time-shifted BOLD fMRI.

Background Microscopic vascular events, such as neovascularization and neurovascular uncoupling, are common in cerebral glioma. Mapping the cerebrovascular network remodeling at the macroscopic level may provide an alternative approach to assess hemodynamic dysregulation in patients with glioma. Purpose To investigate cerebrovascular dynamics and their relevance to tumor aggressiveness by using time-shift analysis (TSA) of the systemic low-frequency oscillation (sLFO) of the resting-state blood oxygenation level-dependent signal and a decision tree model. Materials and Methods In this retrospective study, 96 patients with histologically confirmed cerebral glioma were consecutively included (March 2012 to February 2017). TSA was performed to quantify the temporal properties of sLFO signals. Alteration in the time-shift properties was assessed in the tumor region and the contralesional hemisphere relative to the brains of healthy controls by using the Mann-Whitney U test. A decision tree model based on time-shift features was developed to predict the World Health Organization (WHO) glioma grade. Results A total of 88 patients with glioma (WHO grade II, 45; grade III, 21; grade IV, 22; mean age, 42 years; age range, 20-73 years; 51 men) and 40 healthy individuals from the 1000 Functional Connectomes Project (mean age, 32 years; age range, 24-49 years; 19 men) were included. The sLFO of the brain tissues was characterized by increased time shift in the tumor region and enhanced correlation with the global reference signal in the contralesional hemisphere compared with healthy brains. The proportion of tumor voxels with negative correlation to the reference signal significantly increased with the glioma malignancy grade. The decision tree model achieved an accuracy of 91% (80 of 88 patients) in predicting the glioma malignancy grade at the individual level (P = .004) based on the time-shift features. Conclusion Gliomas induced grade-specific cerebrovascular dysregulation in the entire brain, with altered time-shift features of systemic low-frequency oscillation signals. © RSNA, 2022 Online supplemental material is available for this article.

Evaluation of the malignant potential of gliomas using diffusion-weighted and gadolinium-enhanced magnetic resonance imaging

Objective: This study aimed to determine whether the apparent diffusion coefficients (ADCs) determined by diffusion-weighted imaging (DWI) of magnetic resonance imaging (MRI) could facilitate the malignancy grading of various gliomas. Methods: Sixty patients with a primary cerebral glioma underwent diffusion-weighted and gadolinium-enhanced (Gd) T1-weighted MRI using a 1.5-T MRI scanner. Scoring was performed based on signal intensities on DWI and Gd images. The mean and minimum ADC values were calculated, and Ki-67 staining was performed for each histological sample to evaluate their tumor proliferative potential. Then, the DWI, Gd, and combined scores were analyzed and compared with the Ki-67 staining index and malignant grade. The relationships among the mean and minimum ADC values, Ki-67 staining index, and malignant grade were also evaluated. Results: The minimum ADC was inversely correlated with the Ki-67 staining index, with a low minimum ADC suggestive of tumor malignancy. The qualitative evaluation of the D score of water molecule diffusion on DWI accurately reflected the pathological grades of gliomas, with an effectiveness that was at least as good as the quantitative analysis using the minimum ADC. The diagnostic value of Gd images in determining glioma malignancy grades was inferior to that of DWI. Conclusion: Both DWI and gadolinium-enhanced images of MRI should be considered essential for the diagnosis of tumor malignancy.

Investigation of the Relationship Between the Degree of Peritumoral Brain Edema and Pathological Features of Glioma Before Surgery

Background: Gliomas are the most common malignant tumors of the central nervous system (CNS). Preoperative prediction of the malignancy grade of gliomas are of particular importance. These tumors are often accompanied by peritumoral brain edema (PTBE). Previous studies have suggested that the degree of PTBE is an independent indicator of the prognosis of gliomas. Objectives: This study aimed to investigate the relationships between the degree of PTBE and the grade of glioma, isocitrate dehydrogenase 1 (IDH1) mutation status, and Ki-67 expression level in gliomas. Patients and Methods: In this retrospective cross-sectional study, a total of 82 patients were enrolled, according to the 2016 World Health Organization (WHO) classification of CNS tumors. Overall, 29 tumors were pathologically confirmed as low-grade gliomas (LGGs , grade I-II), whereas the remaining 53 tumors were classified as high-grade gliomas (HGGs, grade III-IV). The IDH1 mutations, Ki-67 expression, and magnetic resonance imaging (MRI) findings were retrospectively analyzed. The tumor and tumor + PTBE volumes were also measured, and the tumor edema index (EI) was calculated for each patient. Edema was then graded and correlated with the pathological parameters. Results: The degree of EI was higher in the HGG group compared to the LGG group, and the difference was statistically significant (z = -7.018, P &lt; 0.05). Besides, the degree of EI was higher in the IDH1 wild-type compared with mutant groups (z = -4.116, P &lt; 0.05). The degree of EI significantly associated with Ki-67 expression and patient’s age (P &lt; 0.05), whereas there was no significant association between the degree of EI and gender (z = -0.497, P = 0.619). The Spearman’s correlation test revealed that the EI degree was positively correlated with the Ki-67 expression level and age, with correlation coefficients of 0.740 and 0.466, respectively. Moreover, the multivariate logistic regression analysis indicated that EI and IDH1 had significant effects on differentiating LGGs from HGGs (P &lt; 0.05 for both). The receiver operating characteristic (ROC) curve analysis showed that EI was an optimal index for differentiating LGGs from HGGs, with an area under curve (AUC) of 0.822 (cutoff value: 1.722, sensitivity: 95.8%, specificity: 70.0%, 95% CI: 0.718 - 0.899). Conclusion: The degree of PTBE was found to be a valuable index for the differential diagnosis of LGGs from HGGs. It has a significant difference between IDH1 wild and mutation status, furthermore, it was positively correlated with the age and Ki-67 level.

Correlation between amide proton transfer-related signal intensity and diffusion and perfusion magnetic resonance imaging parameters in high-grade glioma

Amide proton transfer (APT) imaging is a magnetic resonance (MR) molecular imaging technique that is sensitive to mobile proteins and peptides in living tissue. Studies have shown that APT-related signal intensity (APTSI) parallels with the malignancy grade of gliomas, allowing the preoperative assessment of tumor grades. An increased APTSI in malignant gliomas has been attributed to cytosolic proteins and peptides in proliferating tumor cells; however, the exact underlying mechanism is poorly understood. To get an insight into the mechanism of high APTSI in malignant gliomas, we investigated the correlations between APTSI and several MR imaging parameters including apparent diffusion coefficient (ADC), relative cerebral blood volume and pharmacokinetic parameters obtained in the same regions-of-interest in 22 high-grade gliomas. We found a significant positive correlation between APTSI and ADC (ρ = 0.625 and 0.490 for observers 1 and 2, respectively; p < 0.001 for both), which is known to be inversely correlated with cell density. Multiple regression analysis revealed that ADC was significantly associated with APTSI (p < 0.001 for both observers). Our results suggest possible roles of extracellular proteins and peptides in high APTSI in malignant gliomas.

Inhibition of Intermedin (Adrenomedullin 2) Suppresses the Growth of Glioblastoma and Increases the Antitumor Activity of Temozolomide

Glioblastoma multiforme (GBM; grade IV glioma) is the most malignant type of primary brain tumor and is characterized by rapid proliferation and invasive growth. Intermedin (IMD) is an endogenous peptide belonging to the calcitonin gene-related peptide family and has been reported to play an important role in cell survival and invasiveness in several types of cancers. In this study, we found that the expression level of IMD was positively related to the malignancy grade of gliomas. The highest expression of IMD was found in GBM, indicating that IMD may play an important role in glioma malignancy. IMD increased the invasive ability of glioma cells by promoting filopodia formation, which is dependent on ERK1/2 activation. IMD-induced ERK1/2 phosphorylation also promoted GBM cell proliferation. In addition, IMD enhanced mitochondrial function and hypoxia-induced responses in GBM cells. Treatment with anti-IMD monoclonal antibodies not only inhibited tumor growth in both ectopic and orthotopic models of GBM but also significantly enhanced the antitumor activity of temozolomide. Our study may provide novel insights into the mechanism of GBM cell invasion and proliferation and provide an effective strategy to improve the therapeutic effect of GBM treatments.

Hemisphere-Specific Functional Remodeling and Its Relevance to Tumor Malignancy of Cerebral Glioma Based on Resting-State Functional Network Analysis.

Background: Functional remodeling may vary with tumor aggressiveness of glioma. Investigation of the functional remodeling is expected to provide scientific relevance of tumor characterization and disease management of glioma. In this study, we aimed to investigate the functional remodeling of the contralesional hemisphere and its utility in predicting the malignant grade of glioma at the individual level with multivariate logistic regression (MLR) analysis. Subjects and Methods: One hundred and twenty-six right-handed subjects with histologically confirmed cerebral glioma were included with 80 tumors located in the left hemisphere (LH) and 46 tumors located in the right hemisphere (RH). Resting-state functional networks of the contralesional hemisphere were constructed using the human brainnetome atlas based on resting-state fMRI data. Functional connectivity and topological features of functional networks were quantified. The performance of functional features in predicting the glioma grade was evaluated using area under (AUC) the receiver operating characteristic curve (ROC). The dataset was divided into training and validation datasets. Features with high AUC values in malignancy classification in the training dataset were determined as predictive features. An MLR model was constructed based on predictive features and its classification performance was evaluated on the training and validation datasets with 10-fold cross validation. Results: Predictive functional features showed apparent hemispheric specifications. MLR classification models constructed with age and predictive functional connectivity features (AUC of 0.853 ± 0.079 and 1.000 ± 0.000 for LH and RH group, respectively) and topological features (AUC of 0.788 ± 0.150 and 0.897 ± 0.165 for LH and RH group, respectively) achieved efficient performance in predicting the malignant grade of gliomas. Conclusion: Functional remodeling of the contralesional hemisphere was hemisphere-specific and highly predictive of the malignant grade of glioma. Network approach provides a novel pathway that may innovate glioma characterization and management at the individual level.

Intraoperative fluorescence control with chlorin E6 in resection of glial brain tumors

To evaluate an effectiveness and feasibility of fluorescence navigation with chlorin E6 in surgery of brain gliomas. The study included 30 patients with glial brain tumors grade II-IV. All patients were operated at the Polenov Russian Neurosurgical Institute. We used surgical microscope (Leica OHS-1), D-Light AF System (Karl Storz, Germany), original fluorescence module (St. Petersburg LOMO, developed by G.V. Papayan) and special software RSS Cam - Endo 1.4.313 for visual analysis of fluorescence. Histological examination included hematoxylin-eosin staining of specimens and immunohistochemical studies. Fluorescence was weak in all patients with Grade II gliomas and strong in almost all patients with Grade III-IV gliomas. Sensitivity of fluorescence diagnosis with chlorin E6 was 72.2% for Grade II gliomas, 83.8% for Grade III gliomas and 87.7% for Grade IV. Specificity of this method was 60% for Grade II gliomas, 66.7% for Grade III gliomas and 85.2% for Grade IV. Certain method of fluorescence imaging ensured resection of glial brain tumors using chlorin E6. Intensity of tumor fluorescence correlated with glioma malignancy grade. These results indicate that chlorin E6 is an effective photosensitizer for intraoperative fluorescence diagnosis in surgery for glioma.

Immune-Related lncRNA Risk Signatures Predict Survival of IDH Wild-Type and MGMT Promoter Unmethylated Glioblastoma.

Introduction Glioblastoma is the most malignant grade of glioma, and it is also the most common primary tumor in the brain. Immunotherapy is a kind of precise tumor treatment. However, there are limited studies about immune-related lncRNA. This study is aimed at analyzing immune-related lncRNAs in glioblastoma and screening out prognostic factors, providing new potential targets for glioblastoma immunology research. Material and Methods. Gene expression data and clinical data of IDH wild-type with MGMT promoter unmethylated glioblastoma were acquired from the TCGA and CGGA databases. Immune-related lncRNAs were identified with the help of data from the InnateDB database. Immune prognostic factors were recognized by Cox regression analysis. GSEA analysis pursued their potential functions. Results We found 318 immune-related lncRNAs. Among them, there were 137 immune-related lncRNAs that were upregulated and 181 that were downregulated. 15 prognostic lncRNAs were identified by Cox regression, and a total of 6 molecules were included in the following risk scoring model. GSEA showed that these lncRNAs participated in functions such as protein digestion and absorption and the PPAR signaling pathway. Conclusion There are limited studies about immune regulation mechanisms of lncRNA in IDH wild-type with MGMT promoter unmethylated glioblastoma. The identified immune-related lncRNAs in glioblastoma might contribute new targets and research directions for immunological molecular studies of glioblastoma.

Large-Scale Analysis Reveals the Specific Clinical and Immune Features of DGCR5 in Glioma.

PurposeLong non-coding RNA DGCR5 plays different roles in different types of cancer. The purpose of this study was to investigate the clinicopathological features, potential biological functions and prognostic significance of DGCR5 in glioma in a large-scale study.Materials and MethodsA total of 697 RNA-seq data from The Cancer Genome Atlas (TCGA) and 301 mRNA microarray data from Chinese Glioma Genome Atlas (CGGA) were enrolled in this study. R language was used as the main tool for statistical analysis and graphical work.ResultsDGCR5 showed a negative correlation with the WHO grade of malignancy in glioma. Specifically, DGCR5 expression was significantly decreased in GBM and IDH wild-type glioma. Gene ontology analysis showed that DGCR5 was predominantly enriched in immune-related biological processes. Additionally, DGCR5 showed a significant correlation with stromal and immune cell populations, inflammatory activities and immune checkpoints. Clinically, patients with low-expression level of DGCR5 exhibited a worse overall survival.ConclusionDGCR5 expression is downregulated in glioma, and low DGCR5 independently predicts worse prognosis in glioma patients. Moreover, DGCR5 is significantly associated with immune response and immune infiltration. These findings suggest that DGCR5 is a promising immunotherapy target and a novel prognostic biomarker for glioma.

Serum Lactate Levels are Associated with Glioma Malignancy Grade.

Serum Lactate Levels are Associated with Glioma Malignancy Grade.

Serum lactate levels are associated with glioma malignancy grade

ObjectiveRecent studies have suggested that high grade gliomas are associated with elevated serum lactate concentrations. The aim of the present study is to assess these findings in a sample of patients. Patients and methodsWe reviewed the anesthetic charts of patients with low-grade and high-grade glioma who underwent resection surgery and collected serum lactate concentration before tumor resection, as well as other demographic and tumor-related data (age, gender, WHO grade, and size of the tumor). A statistical comparison between patients with normal (<2 mmol/L) and elevated (≥ 2 mmol/L) serum lactate was performed. ResultsWe included a total of 152 patients (mean age 49.07 years). 62.5% of patients (n = 95) had a high-grade glioma and 37.5% (n = 67) a low-grade glioma. The multivariate regression showed that high grade gliomas had significantly higher lactate concentration (p < 0.01). The OR for elevated pre-resection serum lactate increased from 4.94 to 14.33 after adjusting for age and pre-surgical corticosteroid use, and the AUC for the final regression model was 0.98. ConclusionThis study reinforces the role of serum lactate as a potential biomarker of brain tumors malignancy, and its results encourage further research on this subject, in order to improve the understanding of this phenomenon and to assess its potential as prognostic and therapeutic monitoring tool.

Total DNA Methylation Changes Reflect Random Oxidative DNA Damage in Gliomas.

DNA modifications can be used to monitor pathological processes. We have previously shown that estimating the amount of the main DNA epigenetic mark, 5-methylcytosine (m5C), is an efficient and reliable way to diagnose brain tumors, hypertension, and other diseases. Abnormal increases of reactive oxygen species (ROS) are a driving factor for mutations that lead to changes in m5C levels and cancer evolution. 8-oxo-deoxyguanosine (8-oxo-dG) is a specific marker of ROS-driven DNA-damage, and its accumulation makes m5C a hotspot for mutations. It is unknown how m5C and 8-oxo-dG correlate with the malignancy of gliomas. We analyzed the total contents of m5C and 8-oxo-dG in DNA from tumor tissue and peripheral blood samples from brain glioma patients. We found an opposite relationship in the amounts of m5C and 8-oxo-dG, which correlated with glioma grade in the way that low level of m5C and high level of 8-oxo-dG indicated increased glioma malignancy grade. Our results could be directly applied to patient monitoring and treatment protocols for gliomas, as well as bolster previous findings, suggesting that spontaneously generated ROS react with m5C. Because of the similar mechanisms of m5C and guanosine oxidation, we concluded that 8-oxo-dG could also predict glioma malignancy grade and global DNA demethylation in cancer cells.

P11.11 Circulating Pro-Angiogenic Cells and Proteins in Patients with Glioma and Acute Myocardial Infarction: Differences in Neovascularization between Neoplasia and Tissue Regeneration

Abstract BACKGROUND Although extensive angiogenesis takes place in glial tumors, anti-angiogenic therapies have remained without the expected success. In the peripheral circulation of glioma patients increased numbers of endothelial precursor cells (EPCs) are present, potentially offering targets for anti-angiogenic therapy (Zheng et al., Ann Neurol, 2007). However, for an anti-angiogenic therapy to be successful, the therapy should specifically target glioma-related EPC subsets and secreted factors. Here we compared the EPC subsets and plasma factors in the peripheral circulation of patients with gliomas to acute myocardial infarctions (representing fysiologic regeneration). MATERIAL AND METHODS We investigated the five most important EPC subsets and 21 angiogenesis-related plasma factors in peripheral blood samples of 29 patients with glioma, 14 patients with myocardial infarction and 20 healthy people as controls, by an advanced FACS protocol (Huizer et al., PlosOne 2018) and Luminex assay. RESULTS In GBM patients all EPC subsets were elevated as compared to healthy subjects. In addition, HPC and KDR+ cell fractions were higher than in MI, while CD133+ and KDR+CD133+ cell fractions were lower. There were differences in relative EPC fractions between the groups: KDR+ cells were the largest fraction in GBM while CD133+ cells were the largest fraction in MI. An increase in glioma malignancy grade coincided with an increase in the KDR+ fraction while the CD133+ cell fraction decreased relatively. Most plasma angiogenic factors were higher in GBM than MI patients. In both MI and GBM, the ratio of CD133+ HPCs correlated significantly with elevated levels of MMP9. In the GBM patients MMP9 correlated strongly with levels of all HPCs. CONCLUSION In conclusion, the data demonstrate that EPC traffic in patients with glioma is different from that in normal tissue regeneration. Therefore, the effects of glioma extent beyond the brain, and future therapies aimed at lowering KDR+ cells and HPCs may add to effective treatment.

Circulating Proangiogenic Cells and Proteins in Patients with Glioma and Acute Myocardial Infarction: Differences in Neovascularization between Neoplasia and Tissue Regeneration.

Although extensive angiogenesis takes place in glial tumors, antiangiogenic therapies have remained without the expected success. In the peripheral circulation of glioma patients, increased numbers of endothelial precursor cells (EPCs) are present, potentially offering targets for antiangiogenic therapy. However, for an antiangiogenic therapy to be successful, the therapy should specifically target glioma-related EPC subsets and secreted factors only. Here, we compared the EPC subsets and plasma factors in the peripheral circulation of patients with gliomas to acute myocardial infarctions. We investigated the five most important EPC subsets and 21 angiogenesis-related plasma factors in peripheral blood samples of 29 patients with glioma, 14 patients with myocardial infarction, and 20 healthy people as controls, by FACS and Luminex assay. In GBM patients, all EPC subsets were elevated as compared to healthy subjects. In addition, HPC and KDR+ cell fractions were higher than in MI, while CD133+ and KDR+CD133+ cell fractions were lower. There were differences in relative EPC fractions between the groups: KDR+ cells were the largest fraction in GBM, while CD133+ cells were the largest fraction in MI. An increase in glioma malignancy grade coincided with an increase in the KDR+ fraction, while the CD133+ cell fraction decreased relatively. Most plasma angiogenic factors were higher in GBM than in MI patients. In both MI and GBM, the ratio of CD133+ HPCs correlated significantly with elevated levels of MMP9. In the GBM patients, MMP9 correlated strongly with levels of all HPCs. In conclusion, the data demonstrate that EPC traffic in patients with glioma, representing neoplasia, is different from that in myocardial infarction, representing tissue regeneration. Glioma patients may benefit from therapies aimed at lowering KDR+ cells and HPCs.

Specific clinical and immune features of CD68 in glioma via 1,024 samples.

BackgroundThere is a growing recognition that tumor-associated macrophages (TAMs) are recruited to the glioma environment, facilitating tumor proliferation and migration by creating an immunosuppressive microenvironment. CD68 has been widely reported as a specific marker of TAMs in cancer.PurposeTo clarify the role of CD68 in glioma, we investigated its function at the transcriptome level and relationship with clinical practice.Patients and methodsIn total, 325 RNA-seq data from Chinese Glioma Genome Atlas (CGGA) and 697 RNA-seq data from The Cancer Genome Atlas (TCGA) network were enrolled in this study. CD68-specific findings were further analyzed with R language, and the prognostic impacts were validated through analyzing the overall survival (OS).ResultsCD68 showed a positive correlation with the WHO grade of malignancy in glioma. Meanwhile, CD68 was predominantly expressed in IDH wide type and mesenchymal subtype. Gene ontology (GO) analysis revealed that CD68-related genes were closely related to inflammatory response and immune response. Moreover, seven cultures of metagenes further confirmed that CD68 was a specific marker for macrophages in inflammatory response and played an important role in suppressing T-cell-mediated immunity. The Pearson correlation test suggested that CD68 showed robust correlation with other markers of macrophages and immune checkpoints, including PD-1 and TIM-3. Clinically, a high expression level of CD68 in tumors exhibited a poor survival in glioma patients.ConclusionOur results demonstrated that CD68 acted as an immune suppressor and contributed to glioma progression in the tumor microenvironment. These findings may expand our understanding of CD68-specific clinical and immune features in glioma.