Glioma

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The prognosis of patients with cerebral gliomas remains noticeably poor. Total surgical resection is almost unachievable due to considerable infiltrative ability of glial cells. Furthermore, adjuvant treatments are burdened by considerable limitations. Angiogenesis is the mechanism by which new blood vessels are formed from preexisting ones, thus supporting neoplasm progression. Gliomas are characterized by extensive microvascular proliferation. The extent of neovascularization in brain tumor correlates directly with the biological aggressiveness, degree of malignancy, and clinical recurrence of the tumor. Although a plethora of molecules can act as inducers of angiogenesis, the major growth factors include members of the vascular endothelium growth factor family. The new therapeutic approaches envisage the identification of specific biomarkers involved in this process and try to inhibit them, thus slowing down the neoplastic progression. Nanoparticles (NPs) show the ability to pass the blood–brain barrier, and moreover, when suitably modified, they can bind to specific overexpressed receptors in the glial cells. As carriers, they are able to protect the therapeutic agent and allow their sustained release. In this review, we describe some NP delivery systems which target specific biomarkers to intervene in the process of angiogenesis.

Background and Aim: Microvascular patterns (MVPs) and microvessel density (MVD) can influence the progression of glioblastomas. This study aims to study MVP and MVD using immunohistochemistry, and examine any correlation with the expression of matrix metalloproteinase-9 (MMP-9), p53, glial fibrillary acidic protein (GFAP), and Ki-67 labeling index (Ki-67 LI) in 24 cases of glioblastoma multiforme. Materials and Methods: MVPs and MVD were studied by a dual staining method using periodic acid–Schiff stain with CD34 (MVD_CD34), CD31 (MVD_CD31), von Willebrand factor (MVD_vWF), and factor VIII (MVD_FVIII). The expression of MMP-9, p53, GFAP, and Ki-67 LI was analyzed using immunohistochemistry. The Pearson coefficient of correlation and intraclass correlation were obtained using SPSS software. Results: Five distinct categories of MVP were found: Microvascular sprouting (MS)/simple vessels, vascular clusters (VCs), vascular garlands, glomeruloid tufts, and vasculogenic mimicry. Of the MVPs, MS was the most common pattern and was present in all cases. On calculating the Pearson's correlation coefficient, different MVPs gave varying results regarding their correlation with MMP-9, p53, GFAP, and Ki-67 LI. MS_{CD34, CD31, vWF} showed significant correlation with MMP-9 and Ki-67 LI, while MS_FVIII did not show any correlation with Ki-67 LI. Only VC_CD34 had a correlation with Ki-67 LI. No correlation between any of the MVPs and GFAP and p53 was appreciated. MVD ranged from: CD34 (9.2–41.9/hpf), FVIII (6.05–40.5/hpf), CD31 (5.1–40.7/hpf), and vWF (8.7–35.5/hpf). MVD_CD34 and MVD_CD31 correlated with MMP-9 and Ki-67, whereas, MVD_vWF and MVD _FVIII correlated with MMP-9. Interobserver agreement was seen only in the assessment of MVD and the MS type of MVP. Conclusion: MVD and MVPs had correlation with MMP-9, p53, GFAP, and Ki-67. These results could impact the development of strategies using antiangiogenic therapies.

High-grade glioma (HGG) is a devastating disease with very poor prognosis. Maximal resection of HGG improves survival and maximal visualization of the tumor, if reliable, improves the resection. Fluorescence is widely used as guidance mechanism and has demonstrated potential in maximizing the extent of HGG resection. Our goal is to summarize the current techniques using fluorescence during the resection of HGG and demonstrate how its use increases gross total resection rates, overall survival (OS), and progression-free survival (PFS). However, further prospective, multicenter, randomized controlled trials are still in need to prove the advantage of fluorescence-guided surgery on patients' OS/PFS.

Aim: This study aims to describe the immune infiltrations in low-grade glioma (LGG) with respect to their histological classification, isocitrate dehydrogenase 1 and 2 (IDH1/2) mutation status and survival. Materials and Methods: The IDH1/2 status (mutant or wild-type) of 66 World Health Organization Grade II and III gliomas were defined using next-generation sequencing or multiplex ligation-dependent probe amplification. The immune infiltrates of these tumors (46 mutant IDH, 20 wild-type IDH) were assessed immunohistochemically using a panel of antibodies (CD3, CD4, CD8, FOXP3, CD20, CD68, and CD163). Confirmatory analyses were performed on a cohort of lower grade gliomas from the Cancer Genome Atlas (TCGA). Statistical analyses were performed with Mann–Whitney U-tests and Kaplan–Meier survival estimates. Results: There was no relation between the amount of CD3+, CD4+, CD8+, or CD20+ lymphocyte infiltration and IDH mutation status in the tumors. FOXP3+ T regulatory cell infiltrates were rare, but more frequent in IDH1/2 wild-type tumors (P = 0.046). While the presence of these cells did not correlate with overall survival, FOXP3 messenger RNA expression was associated with survival in a distinct cohort of LGG from the TCGA (P < 0.05). CD4+ lymphocyte infiltrates, on the other hand, tended to prevail in astrocytic tumors as compared to oligodendrogliomas (P = 0.056). While CD68 (M1) microglial/monocytic cells were equally abundant in IDH mutant and wild-type tumors, the presence of round, activated M1 CD68+ microglia significantly associated with a mutant IDH status (P = 0.015). Conclusion: FOXP3+ expression and activated CD68+ M1 cells associated with IDH status in LGG, and might contribute to their differential evolution.

Background and Aim: The standard-of-care for patients with glioblastoma (GBM) is surgery followed by concurrent chemotherapy with temozolomide and radiotherapy. O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is commonly assessed in GBM as a predictive marker of response to temozolomide. Although MGMT methylation status has been shown to change between primary and recurrent GBM, no indication exists on retesting MGMT in recurrent GBM. In addition, what causes the change in MGMT methylation has yet to be identified. In this study, we aimed to investigate whether MGMT promoter methylation in recurrent GBM was influenced by intratumor heterogeneity in the initial GBM tumor. Materials and Methods: We investigated the status of MGMT promoter methylation in different samples taken from concentric layers of 24 GBMs and in 11-paired surgically resected recurrences. The neoplastic nature of samples submitted for methylation analysis was preliminary verified through histological examination; the fragments were accurately chosen to have adequate cellularity and minimal amount of nontumor contaminants. Results: About 27% (3 out of 11) of the recurrences had changed MGMT methylation status compared to the initial tumor. Initial tumor heterogeneity might play a role in this change, as all three cases had intratumor heterogeneity (with the central part of the tumor methylated and the peripheral part unmethylated) in the primary GBM. Conclusion: This study suggests that MGMT methylation variation in recurrent GBM may depend on intratumor heterogeneity in the initial tumor. Intratumor heterogeneity and possible changes in the recurrence should be taken into account when testing MGMT promoter methylation status as a predictive factor orienting therapeutic decisions in patients with GBM.

Online since 6^th Sep 2017.