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1.
J Neurosurg ; 118(1): 121-30, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23039152

ABSTRACT

OBJECT: Cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) is a major cause of subsequent morbidity and mortality. Cilostazol, a selective inhibitor of phosphodiesterase 3, may attenuate cerebral vasospasm because of its antiplatelet and vasodilatory effects. A multicenter prospective randomized trial was conducted to investigate the effect of cilostazol on cerebral vasospasm. METHODS: Patients admitted with SAH caused by a ruptured anterior circulation aneurysm who were in Hunt and Kosnik Grades I to IV and were treated by clipping within 72 hours of SAH onset were enrolled at 7 neurosurgical sites in Japan. These patients were assigned to one of 2 groups: the usual therapy group (control group) or the add-on 100 mg cilostazol twice daily group (cilostazol group). The group assignments were done by a computer-generated randomization sequence. The primary study end point was the onset of symptomatic vasospasm. Secondary end points were the onset of angiographic vasospasm and new cerebral infarctions related to cerebral vasospasm, clinical outcome as assessed by the modified Rankin scale, and length of hospitalization. All end points were assessed for the intention-to-treat population. RESULTS: Between November 2009 and December 2010, 114 patients with SAH were treated by clipping within 72 hours from the onset of SAH and were screened. Five patients were excluded because no consent was given. Thus, 109 patients were randomly assigned to the cilostazol group (n = 54) or the control group (n = 55). Symptomatic vasospasm occurred in 13% (n = 7) of the cilostazol group and in 40% (n = 22) of the control group (p = 0.0021, Fisher exact test). The incidence of angiographic vasospasm was significantly lower in the cilostazol group than in the control group (50% vs 77%; p = 0.0055, Fisher exact test). Multiple logistic analyses demonstrated that nonuse of cilostazol is an independent factor for symptomatic and angiographic vasospasm. The incidence of new cerebral infarctions was also significantly lower in the cilostazol group than in the control group (11% vs 29%; p = 0.0304, Fisher exact test). Clinical outcomes at 1, 3, and 6 months after SAH in the cilostazol group were better than those in the control group, although a significant difference was not shown. There was also no significant difference in the length of hospitalization between the groups. No severe adverse event occurred during the study period. CONCLUSIONS: Oral administration of cilostazol is effective in preventing cerebral vasospasm with a low risk of severe adverse events. Clinical trial registration no. UMIN000004347, University Hospital Medical Information Network Clinical Trials Registry.


Subject(s)
Phosphodiesterase 3 Inhibitors/therapeutic use , Subarachnoid Hemorrhage/complications , Tetrazoles/therapeutic use , Vasodilator Agents/therapeutic use , Vasospasm, Intracranial/prevention & control , Aged , Cilostazol , Female , Humans , Male , Middle Aged , Prospective Studies , Treatment Outcome , Vasospasm, Intracranial/drug therapy , Vasospasm, Intracranial/etiology
2.
J Neurooncol ; 77(1): 25-32, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16132527

ABSTRACT

Invasion of tumor cells into the surrounding normal brain tissues is a prominent feature of malignant gliomas. Malignant glioma cells secrete thrombospondin-1 which participates in the motility of glioma cells and binds cell surface heparan sulfate proteoglycan. To clarify the invasion mechanism of tumor cells, expression of the syndecans (syndecan-1, -2, -3, and -4), a major cell surface heparan sulfate proteoglycan family, was analyzed in malignant gliomas. Involvement of nuclear factor-kappaB (NF-kappaB) on syndecan-1 expression was also investigated. Using reverse transcription-PCR, the authors analyzed the expression of syndecan-1, -2, -3, and -4 in 10 malignant glioma cell lines, 2 glioblastoma specimens, and 2 normal brain specimens. All malignant glioma cell lines and glioblastoma specimens expressed all types of syndecan mRNA, except in one glioma cell line that lacked syndecan-3 expression. On the other hand, normal brain specimens expressed syndecan-2, -3, and -4 mRNA, but did not syndecan-1 mRNA. Syndecan-1 protein was localized in the cell surface of all malignant glioma cell lines by flow cytometry. Various levels of active nuclear factor-kappa B (NF-kappaB) was detected in all malignant glioma cell lines using immunoblotting. The expression of active NF-kappaB and syndecan-1 increased in U251 glioma cells after tumor necrosis factor-alpha or interleukin-1beta treatment, which can activate NF-kappaB. The amplification of active NF-kappaB and syndecan-1 by tumor necrosis factor-alpha or interleukin-1beta was suppressed by an inhibitor of NF-kappaB activation (emodin). Emodin also downregulated the expression of syndecan-1 mRNA in U251 cells. These results indicate that malignant glioma cells express all types of syndecans and suggest that NF-kappaB participates in the upregulation of the syndecan-1 expression at the transcriptional level, and increased expression of syndecan-1 could associate with extracellular matrices including thrombospondin-1.


Subject(s)
Brain Neoplasms/metabolism , Glioma/metabolism , Heparan Sulfate Proteoglycans/metabolism , Membrane Glycoproteins/metabolism , NF-kappa B/metabolism , Brain Neoplasms/genetics , Cell Line, Tumor , Cerebral Cortex/metabolism , Extracellular Matrix Proteins/genetics , Extracellular Matrix Proteins/metabolism , Fibroblast Growth Factor 2/physiology , Gene Expression Regulation, Neoplastic , Glioma/genetics , Heparan Sulfate Proteoglycans/classification , Heparan Sulfate Proteoglycans/genetics , Humans , Lymphotoxin-alpha/physiology , Membrane Glycoproteins/classification , Membrane Glycoproteins/genetics , Proteoglycans/classification , Proteoglycans/genetics , Proteoglycans/metabolism , RNA, Messenger/analysis , Syndecan-1 , Syndecan-2 , Syndecan-3 , Syndecan-4 , Syndecans , Thrombospondin 1/metabolism
3.
Neuropathology ; 25(2): 136-43, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15875906

ABSTRACT

Five malignant glioma cell lines (YMG1, 2, 3, 4, and 5) were established from surgical specimens obtained from patients with glioblastoma or anaplastic astrocytoma, and these lines were partially characterized. Three glioma cell lines (YMG1, 3, and 5) were weakly positive for GFAP by Western blot analysis and two cell lines were negative. S-100 protein was positive in all glioma cell lines. The expression of p53, p16, p15, cyclin-dependent kinase 4 (CDK4), and EGF receptor (EGFR) proteins was examined by Western blotting. YMG1 and 2 cell lines showed accumulation of p53 protein and loss of p16 and p15 expression. YMG3 and 4 showed accumulation of p53 protein and expression of p16 and p15 proteins. YMG5 revealed weak expression of p53 protein, suggesting wild-type p53, and loss of p16 and p15 expression. All cell lines expressed various levels of CDK4 protein. YMG1, 2, and 3 showed higher EGFR protein expression and YMG4 and 5 showed lower EGFR expression compared to U251 glioblastoma cells, which express high levels of EGFR. Fluorescence in situ hybridization analysis for EGFR gene expression did not show any amplification in the glioma cell lines. Immunohistochemical studies revealed that the patterns of p53 and EGFR expressions in the original tumor tissues were mostly correlated with those in the malignant glioma cell lines. These results suggest that the characteristics of p53 and EGFR expression in the malignant glioma cell lines were passed over from the original tumor tissues. These newly established malignant glioma cell lines can be used for further analysis of the mechanisms of tumor growth and progression.


Subject(s)
Biomarkers, Tumor/analysis , Brain Neoplasms/metabolism , Cell Line, Tumor , Gene Expression , Glioma/metabolism , Adult , Aged , Blotting, Western , Cell Cycle Proteins/biosynthesis , Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinase Inhibitor p15 , Cyclin-Dependent Kinase Inhibitor p16/biosynthesis , Cyclin-Dependent Kinases/biosynthesis , ErbB Receptors/biosynthesis , Female , Glial Fibrillary Acidic Protein/biosynthesis , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Male , Middle Aged , Proto-Oncogene Proteins/biosynthesis , S100 Proteins/biosynthesis , Tumor Suppressor Protein p53/biosynthesis , Tumor Suppressor Proteins/biosynthesis
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