Clinical prognostic value of the isocitrate dehydrogenase 1 single-nucleotide polymorphism rs11554137 in glioblastoma.

The presence of the single-nucleotide polymorphism (SNP) rs11554137:C>T in the IDH1 gene is associated with a significantly lower survival in acute myeloid leukemia patients. The impact of its presence in glioblastoma on patient survival is unclear. We retrospectively reviewed 171 adult (> 18 years of age) patients treated at a single, tertiary academic center for supratentorial glioblastoma (WHO grade IV) between 2013 and 2017. We conducted Kaplan-Meier overall and progression free survival analyses based on the IDH1 and IDH2 gene status of patients' glioblastoma (IDH wild type, mutant, and IDH1 rs11554137:C>T SNP). Multivariate Cox survival analyses were conducted accounting for age at diagnosis, preoperative Karnofsky performance status score, treatment (extent of resection, postoperative radiotherapy, and temozolomide), IDH gene variant, and MGMT promoter methylation status. Presence of rs11554137:C>T SNP in glioblastoma samples did not correlate with presence of IDH1 mutation. Patients with rs11554137:C>T SNP did not have histories of prior lower-grade gliomas. Patients with IDH mutant glioblastoma had a distinctly higher survival profile than both rs11554137:C>T SNP and IDH wild type glioblastomas. No survival difference was noted between patients with glioblastoma harboring the SNP and patients with IDH wild type glioblastoma. In this study, clinical prognostication in glioblastoma patients was largely dependent on the classification of IDH mutant and wild type glioblastoma, and not on the presence of IDH1 rs11554137:C>T SNP in the tumor.

The tumour-associated carbonic anhydrases CA II, CA IX and CA XII in a group of medulloblastomas and supratentorial primitive neuroectodermal tumours: an association of CA IX with poor prognosis.

BACKGROUND: Medulloblastomas (MBs) and supratentorial primitive neuroectodermal tumours (PNETs) are the most common highly aggressive paediatric brain tumours. In spite of extensive research on these tumours, there are only few known biomarkers or therapeutic target proteins, and the prognosis of patients with these tumours remains poor. Our aim was to investigate whether carbonic anhydrases (CAs), enzymes commonly overexpressed in various tumours including glioblastomas and oligodendrogliomas, are present in MBs and PNETs, and whether their expression can be correlated with patient prognosis. METHODS: We determined the expression of the tumour-associated carbonic anhydrases CA II, CA IX and CA XII in a series of MB/PNET specimens (n = 39) using immunohistochemistry. RESULTS: Endothelial CA II, cytoplasmic CA II, CA IX and CA XII were expressed in 49%, 73%, 23% and 11% of the tumours, respectively. CA II was detected in the neovessel endothelium and the tumour cell cytoplasm. CA IX was mainly expressed in the tumour cells located in perinecrotic areas. CA XII showed the most homogenous distribution within the tumours. Importantly, CA IX expression predicted poor prognosis in both univariate (p = 0.041) and multivariate analyses (p = 0.016). CONCLUSIONS: We suggest that CA IX should be considered a potential prognostic and therapeutic target in MBs and PNETs.

Neuronal nitric oxide synthase expression in glial tumors: correlation with malignancy and tumor proliferation.

INTRODUCTION: Increased vascular permeability, vasodilatation, neovascularization and free radical injury in malignant tumors and adjacent normal tissues are believed to be mediated by nitric oxide (NO). High levels of neuronal nitric oxide synthase (nNOS) have been demonstrated in cultured and intracerebral cells. Our aim was to investigate nNOS expression in human glial tumors and to assess its correlation with the histologic grade and proliferative potential. METHODS: Tissue specimens were obtained from 29 patients with supratentorial astrocytomas [15 glioblastoma multiforme (GBM), six anaplastic astrocytomas (AA) and eight low grade astrocytomas (LGA)] diagnosed and classified according to the current WHO classification of nervous system tumors. Immunohistochemical staining was performed in paraffin embedded specimens with polyclonal anti-nNOS antibody, and the levels of nNOS expression was evaluated as slight, moderate or dense on the basis of intensity and the extent of distribution of nNOS immunoreactivity. Proliferative potential was evaluated with immunostaining for Ki-67. RESULTS: There was a significant positive correlation between the histologic grade and nNOS expression in terms of intensity and the extent of distribution of nNOS immunoreactivity (p<0.05). Greater values of Ki-67 indices were demonstrated in tumors with higher nNOS expression, indicating a positive correlation between proliferative potentials and expression of nNOS immunoreactivity. CONCLUSION: Our study suggests that nNOS expression is increased in glial tumors, which was significantly correlated with histologic grade and proliferative potential. NO overproduction due to overexpression of nNOS activity, seems to have significant correlation with malignancy in glial tumors, and may provide another target for anti-proliferative therapy in the future.

Stem cell marker nestin and c-Jun NH2-terminal kinases in tumor and peritumor areas of glioblastoma multiforme: possible prognostic implications.

PURPOSE: It has been hypothesized that brain tumors are derived from stem cell or transiently dividing precursor transformation. Furthermore, c-Jun NH(2)-terminal kinases (JNKs) have been involved in gliomagenesis. This study analyzes stem cell marker nestin and JNK expression in glioblastoma multiforme (GBM) and peritumor tissue and assesses their possible prognostic implications. EXPERIMENTAL DESIGN: Nestin and both total JNK (tJNK) and phosphorylated JNK (pJNK) expression was investigated by immunohistochemistry in 20 GBMs. Samples were derived from tumors (first area), from tissues at a distance <1 cm (second area), and between 1 and 3.5 cm (third area) from the macroscopic tumor border. The relationships between patients' age, Karnofsky performance status, gender, protein expression, and survival were analyzed. RESULTS: Nestin cytoplasmic immunoreactivity was observed in the majority of cells in tumor but infrequently in peritumor areas. tJNK, observed in the nucleus and cytoplasm, was widely expressed in the three areas; pJNK, mostly located in the nuclei, was found in a variable percentage of cells in the tumor and peritumor tissue. Nestin and JNK expression in peritumor areas was independent of the presence of neoplastic cells. Univariate analysis indicated that survival was longer (19 versus 12 months; P = 0.01) for patients whose pJNK/nestin and (pJNK/tJNK)/nestin ratios in the second area were > or =2.619 and > or =0.026, respectively. The same variables showed an independent prognostic value in multivariate analysis. CONCLUSIONS: Nestin and JNK expression indicates that peritumor tissue, independently of the presence of neoplastic cells, may present signs of transformation. Moreover, pJNK/nestin and (pJNK/tJNK)/nestin ratios in that tissue seem to have some prognostic implications in GBM patients.

Histone deacetylase inhibitors induce cell death in supratentorial primitive neuroectodermal tumor cells.

Histone deacetylase inhibitors (HDIs) are a promising new class of antineoplastic agents with the capacity to induce differentiation and/or apoptosis of cancer cells. The objective of this study was to evaluate the activity of HDIs against supratentorial primitive neuroectodermal tumor (sPNET) cells. We show that the HDIs, suberoylanilide hydroxamic acid, sodium butyrate, and trichostatin A, induced cell death, and activated caspase-3 and -9 in a sPNET cell line, PFSK. The poly-caspase inhibitor z-VAD-fmk partially prevented the action of HDIs, as judged by determining the mitochondrial membrane potential and by quantifying internucleosomal DNA fragmentation. In conclusion, the HDIs explored possess potent activity against sPNET cells, suggesting that HDIs may be effective in the treatment of sPNET.

Expression of cathepsin B and microvascular density increases with higher grade of astrocytomas.

Samples were taken from supratentorial gliomas border and normal brain autopsy which were divided into four groups, these including eight cases normal brain tissues, 30 cases of astrocytomas, 25 cases of anaplastic astrocytomas and 22 cases of glioblastomas. Cathepin B (CB) expression and microvessel density (MVD) were determined with immunohistochemical studies. Staining results of CB was scored according to the percentage of positive cells, graded as negative (-), weak (+), moderate (++), and strong (+ + +). MVD was analyzed by Weidner's revised technique. CB positive staining was negative in eight cases of normal brain tissue. Only 9 out of 30 cases of astrocytomas showed a low percentage of positive cells that were stained in a light, diffuse cytoplasmic pattern (score +). Twenty-two out of 35 cases of anaplastic astrocytomas showed positive light, granular staining pattern, it including five samples (score +), and 17 samples (score + +). In contrast, all 22 cases of glioblastomas were stained all, and it was present in a course, granular staining pattern with an intensity of score (+ +) of two sample, and score (+ + +) of 20 samples. Positive staining tumor cells were found in extracellular matrix (ECM), basement membrane (BM), and the endothelial cells of blood vessels were also positive stained. Along with elevating glioma grade, CB expression and MVD value were both increased. Therefore, it showed MVD value was positive correlated with expression of CB. It highly suggested that CB and angiogenesis plays an important role in glioma progression.

Mononuclear leukocyte ADP-ribosylation as an indicator of immune function in malignant-glioma patients treated with betamethasone for cerebral edema.

Glioma patients receiving corticosteroids (16 mg/day betamethasone) were examined for evidence of immune cell dysfunction by using quantitative estimates of adenosine diphosphate (ADP)-ribosylation in peripheral mononuclear leukocytes as the physiological indicator. The duration of daily treatment with corticosteroids varied from 0 to 35 days at the time of collection of the blood samples. Even after adjustment for covariate factors such as age, sex, smoking habits, alcohol use, antiepileptic medications, and tumor grade, there still remained a highly significant dose-dependent inverse relationship between constitutive and hydrogen peroxide-induced mononuclear leukocyte ADP-ribosylation levels and the duration of corticosteroid treatment (beta coefficients -0.40 and -0.29, respectively; p less than 0.03). No other variable under consideration significantly influenced ADP-ribosylation levels after statistical adjustment. These data support a mutual interdependence of mononuclear leukocyte ADP-ribosylation and corticosteroid-induced immune cell dysfunction in vivo.