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TERT promoter mutations are one of the most common genetic alterations in adult-type diffuse gliomas and show specific patterns compared with other genetic alterations according to glioma subtypes. This mutation has variable impacts on patient outcomes in association with other genetic alterations, including IDH1/2 mutations or histological types. The purpose of this paper is to review the current knowledge on the values of TERT promoter mutations in the diagnosis and prognostication of adult-type diffuse gliomas. We also aimed to discuss the interaction between the prognostic impacts of TERT promoter mutations and other molecular alterations. Although its impact on prognosis is somewhat complicated and enigmatic, the mutational status of the TERT promoter provides highly useful information for predicting patients' outcomes in the conventional classification of gliomas defined by IDH1/2 and 1p/19q status. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most highly malignant brain tumor in the human central nerve system. In this paper, we review new and significant molecular findings on angiogenesis and possible resistance mechanisms. Expression of a number of genes and regulators has been shown to be upregulated in GBM microvessel cells, such as interleukin-8, signal transducer and activator of transcription 3, Tax-interacting protein-1, hypoxia induced factor-1 and anterior gradient protein 2. The regulator factors that may strongly promote angiogenesis by promoting endothelial cell metastasis, changing the microenvironment, enhancing the ability of resistance to anti-angiogenic therapy, and that inhibit angiogenesis are reviewed. Based on the current knowledge, several potential targets and strategies are proposed for better therapeutic outcomes, such as its mRNA interference of DII4-Notch signaling pathway and depletion of b1 integrin expression. We also discuss possible mechanisms underlying the resistance to anti-angiogenesis and future directions and challenges in developing new targeted therapy for GBM.

p27Kip1 (p27) expression was immunohistochemically investigated in 28 astrocytic tumors, and compared with the cell proliferation index (MIB-1 staining index). Normal rat brains and surgical specimens from human nonneoplastic brain lesions were used as controls. In the rat brains, the astrocytes were exclusively p27-positive. The reactive astrocytes in various disease processes sometimes lacked p27 expression. The distribution of p27-positive cells was uniform in low-grade astrocytomas and heterogeneous in high-grade tumors. Double staining of p27 and MIB-1 showed a reciprocal pattern in most cases. The frequency of p27 expression was inversely correlated with MIB-1 staining index and tumor grade. However, several malignant gliomas showed high p27 expression in spite of high MIB-1 staining indices. In such cases, MIB-1-positive cells were occasionally p27-positive. In this paper we discuss the etiology of the anomalous p27 expression in a subset of malignant gliomas. [ABSTRACT FROM AUTHOR]

Oncogenic gene fusions have been reported in diffuse gliomas and may serve as potential therapeutic targets. Here, using next-generation sequencing analysis (Illumina TruSight Tumor 170 panel), we analyzed a total of 356 diffuse gliomas collected from 2017 to 2019 to evaluate clinical, pathological, and genetic features of gene fusion. We found 53 cases of glioblastomas harboring the following oncogenic gene fusions: MET (n = 18), EGFR (n = 14), FGFR (n = 12), NTRK (n = 5), RET (n = 2), AKT3 (n = 1), and PDGFRA fusions (n = 1). Gene fusions were consistently observed in both IDH-wildtype and IDH-mutant glioblastomas (8.8% and 9.4%, p = 1.000). PTPRZ1–MET fusion was the only fusion that genetically resembled secondary glioblastomas (i.e., high frequency of IDH mutation, ATRX loss, TP53 mutation, and absence of EGFR amplification), whereas other gene fusion types were similar to primary glioblastomas (i.e., high frequency of IDH-wildtype, TERT mutation, EGFR amplification, and PTEN mutation). In IDH-wildtype glioblastoma patients, multivariable analysis revealed that the PTPRZ1–MET fusion was associated with poor progression-free survival (HR [95% CI]: 5.42 (1.72–17.05), p = 0.004). Additionally, we described two novel cases of CCDC6–RET fusion in glioma. Collectively, our findings indicate that targetable gene fusions are associated with aggressive biological behavior and can aid the clinical treatment strategy for glioma patients. [ABSTRACT FROM AUTHOR]

Primary diffuse leptomeningeal gliomatosis (PDLG) is a rare and fatal disease characterized by diffuse infiltration of the leptomeninges by neoplastic glial cells without evidence of tumor in the brain parenchyma or spinal cord. We report a 60-year-old man with PDLG. He suffered transient right hemiparesis and generalized seizures. MRI showed diffuse leptomeningeal thickening and enhancement throughout the brain and spinal cord without any intraaxial involvement. Biopsy resulted in a diagnosis of glioblastoma with methylated MGMT promoter and wild-type IDH1. He underwent craniospinal radiotherapy and temozolomide treatment but despite concomitant adjuvant therapy he died 8 months after initial presentation. [ABSTRACT FROM AUTHOR]

The present retrospective data analysis was performed to determine whether intraoperative pathological diagnosis (IOD) using frozen section (FS) could clearly distinguish high-grade glioma from WHO grade II gliomas. IOD was retrospectively compared to the pathological diagnosis using permanent paraffin sections (PS) of 205 glioma cases out of 356 brain tumor cases in the pre-Carmustine (BCNU) wafer era in Japan. The sensitivity and specificity of IOD regarding the whole glioma category were 96.1 and 98.0 %, respectively. The positive predictive value and the underestimation ratio of glioma grading by IOD were 51.5 and 43.5 % in all glioma cases. In addition, 54.5 % of grade II glioma cases determined with IOD (grade II) were actually grade III or IV according to the PS pathology (grade III or IV cases). Recurrent cases and older age (≥50 years old) were predictive factors that resulted in underestimated grade II group (grade II/III + IV). The grade II/III group tended to more frequently contain non-astrocytic tumors compared to the grade II/II + IV groups, although the difference was not statistically significant. In conclusion, the temporary WHO grade by IOD is underestimated in approximately half of glioma cases. We should pay attention to underestimation with IOD. [ABSTRACT FROM AUTHOR]

A 54-year-old woman with a past history of uterine cancer developed a tumor in her right cerebellum. Magnetic resonance imaging with contrast enhancement revealed a mass composed of two components, inside and outside, although both components resided in the same high-intensity area on T2-weighted imaging. Surgical resection removed the bulk of the tumor. Pathological examination revealed two distinct pathological features of the tumor-the inner major component had the features of glioblastoma whereas outer minor component had those of pilocytic astrocytoma (PA). These two components occurred with intercalating transitional areas. No genetic differences, including BRAF alteration or IDH mutations, were detected in either component. Activation of Akt, which is reported to be associated with clinically aggressive and anaplastic PA was found in the PA component of this tumor. The transitional area also stained positive, suggesting the continuity of both components. Consequently, the glioblastoma in this case was likely to have developed as a result of malignant transformation of PA. This case provides additional support for the concept of anaplastic transformation of PA. [ABSTRACT FROM AUTHOR]

There have been some recent reports about glioblastoma with oligodendroglial (OG) components and malignant glioma with primitive neuroectodermal tumor (PNET)-like components. We investigated whether the presence and extent of OG components and PNET-like components influenced the prognosis in patients with glioblastoma. Eighty-six patients with glioblastoma were divided into an OG group (28 %), which revealed areas with a honeycomb appearance, and a non-OG group (72 %) without a honeycomb appearance. Patients with glioblastoma were also divided into a PNET group (27 %), which revealed areas with PNET-like features defined as neoplastic cells with high N/C ratios and hyperchromatic oval-carrot-shaped nuclei, and lacked the typical honeycomb appearance, and a non-PNET group (73 %) without PNET features. There were no significant differences in overall survival among the OG, the non-OG, the PNET, and the non-PNET groups. Two patients who survived longer than 36 months had both OG and PNET components with 1p or 19q loss of heterozygosity. Perinuclear halo, which is a characteristic feature of oligodendrogliomas, is an artifact of tissue fixation. Therefore, we should not readily use the term glioblastoma with OG components. PNET-like components, which are considered rare in malignant gliomas, may be frequently identified in glioblastomas. [ABSTRACT FROM AUTHOR]