Kou Nakagawa

Meningioangiomatosis Not Associated with von Recklinghausen's Disease

We report a rare case of meningioangiomatosis unassociated with von Recklinghausens disease. The patient was a 30-year-old woman with a 25-year history of seizures. The lesion was confined to the right temporal cortex and consisted of a proliferation of angiomatous blood vessels and meningocytic cells. Her seizures have been well controlled after excision of the lesion.

Introduction of wild-type p53 enhances thrombospondin-1 expression in human glioma cells

Malignant gliomas are distinguished from low-grade gliomas by their intense angiogenesis. In gliomas, p53 is the most frequently altered gene and is involved in the early phase of glioma development. In contrast, homozygous p16 gene deletion is more common in high-grade gliomas. In order to understand the mechanism by which gliomas become more angiogenic during the malignant transformation, we examined the relationship between thrombospondin-1, a negative regulator in angiogenesis, and these tumor suppressor genes in malignant gliomas. Human glioma cell line U-251 MG, which has mutated p53 and deleted p16, was transduced with recombinant replication-defective adenovirus vectors containing the cDNA of wild-type p53, p16, and p21. Only the induction of wild-type p53 enhanced expression of thrombospondin-1 mRNA and the protein in U-251 MG cells. Furthermore, thrombospondin-1 that was secreted in the culture medium was significantly increased (3.8-fold) as compared with that of the viral control 36 h after infection with Ad5CMV-p53. In the presence of wild-type p53 plasmid DNA, the promoter activity was increased 7.4-fold as compared with an empty expression vector control. These studies may suggest that mutation of p53 gene endows gliomas with an angiogenic phenotype by reducing thrombospondin-1 production as well as enhancing the angiogenesis inducers in the early phase of malignant progression.

Endothelial nitric oxide synthase expression in tumor vasculature is correlated with malignancy in human supratentorial astrocytic tumors

OBJECTIVE Endothelial nitric oxide synthase (eNOS) may play an important role in the regulation of tumor blood flow and vascular permeability. However, there have been no reports describing alterations of eNOS expression in relation to malignant progression in human astrocytic tumors. We immunohistochemically studied the relationship between eNOS expression in tumor vasculature and malignancy in supratentorial astrocytic tumors. METHODS Tissue samples were obtained from 12 patients with low-grade astrocytomas, 10 with anaplastic astrocytomas, and 17 with glioblastomas. Normal brain tissue samples were obtained from four patients with other brain diseases. Immunohistochemical staining was performed using the avidin-biotin complex method, with polyclonal anti-eNOS antibody, and the levels of eNOS expression in endothelial cells were evaluated as slight, moderate, or intense on the basis of eNOS immunoreactivity. The proliferative potential was assessed as the MIB-1 staining index for tumor cells. RESULTS The expression of eNOS was slight in all specimens of normal brain tissue, slight in 7 and moderate in 5 specimens of low-grade astrocytoma, slight in 2, moderate in 6, and intense in 2 specimens of anaplastic astrocytoma, and moderate in 5 and intense in 12 specimens of glioblastoma. The MIB-1 staining index (mean+/-standard deviation) was 0.2+/-0.2% for normal specimens, 1.8+/-0.6% for low-grade astrocytomas, 9.6+/-6.9% for anaplastic astrocytomas, and 18.5+/-7.7% for glioblastomas. The MIB-1 staining indices for slight, moderate, and intense eNOS expression were 2.0+/-2.3%, 10.8+/-9.8%, and 16.9+/-7.7%, respectively. CONCLUSION Expression of eNOS in tumor vessels was significantly correlated with histological grade and proliferative potential. These findings suggest that astrocytic tumor vessels possess higher activity for nitric oxide production than do normal vessels.

Intracranial meningiomas in infancy

We report on two infants with meningioma under the age of 1 year. One is an 11-month old male infant with a fibroblastic meningioma without dural attachment to the right frontal lobe. The other is an 8-month-old male infant with a hemangiopericytic meningioma in the posterior fossa arising from the right petrous ridge. Both tumors were totally removed. Twenty-four infant meningiomas reported in the literature, including our two cases, were reviewed.

Downregulation of laminin α4 chain expression inhibits glioma invasion in vitro and in vivo

The laminin family is a structural constituent of the extracellular matrix that plays an essential role in promoting the motility of infiltrative tumor cells. We investigated the role of laminin α4 chain, a subset of laminin‐8, ‐9 and ‐14, in the motile and invasive activities of human glioma cells. All malignant glioma cell lines examined expressed more mRNA for the laminin α4 and β1 chains than for the β2 chain, indicating that these cells predominantly express the laminin‐8 isoform. Introducing an antisense oligonucleotide for laminin α4 chain (AS‐Ln‐α4) into the glioma cells resulted in downregulation of laminin α4 expression. AS‐Ln‐α4 also significantly suppressed glioma cell adhesion and migration. Furthermore, invasiveness was significantly reduced in cells transfected with AS‐Ln‐α4 compared to those transfected with the sense oligonucleotide (S‐Ln‐α4). Indeed, when glioma spheroids were implanted into rat brain slices, AS‐Ln‐α4‐transfected cells failed to invade surrounding normal brain tissues. In addition, intracerebral injection of glioma cells transfected with AS‐Ln‐α4 into nude mice resulted in the formation of a noninvasive tumor, whereas injection of cells transfected with S‐Ln‐α4 resulted in diffuse invasion of brain tissue. These results suggest that mainly laminin‐8 is essential for the invasive activity of human glioma cells; thus, a novel therapeutic strategy could target this molecule to treat patients with malignant glioma.

Downregulation of laminin alpha4 chain expression inhibits glioma invasion in vitro and in vivo.

The laminin family is a structural constituent of the extracellular matrix that plays an essential role in promoting the motility of infiltrative tumor cells. We investigated the role of laminin α4 chain, a subset of laminin‐8, ‐9 and ‐14, in the motile and invasive activities of human glioma cells. All malignant glioma cell lines examined expressed more mRNA for the laminin α4 and β1 chains than for the β2 chain, indicating that these cells predominantly express the laminin‐8 isoform. Introducing an antisense oligonucleotide for laminin α4 chain (AS‐Ln‐α4) into the glioma cells resulted in downregulation of laminin α4 expression. AS‐Ln‐α4 also significantly suppressed glioma cell adhesion and migration. Furthermore, invasiveness was significantly reduced in cells transfected with AS‐Ln‐α4 compared to those transfected with the sense oligonucleotide (S‐Ln‐α4). Indeed, when glioma spheroids were implanted into rat brain slices, AS‐Ln‐α4‐transfected cells failed to invade surrounding normal brain tissues. In addition, intracerebral injection of glioma cells transfected with AS‐Ln‐α4 into nude mice resulted in the formation of a noninvasive tumor, whereas injection of cells transfected with S‐Ln‐α4 resulted in diffuse invasion of brain tissue. These results suggest that mainly laminin‐8 is essential for the invasive activity of human glioma cells; thus, a novel therapeutic strategy could target this molecule to treat patients with malignant glioma.

A cerebral neuroblastoma with extracranial metastases

A rare case of cerebral neuroblastoma with extracranial metastases is reported. This patient was followed for over ten years. The biopsy specimen of the brain tumor taken at the first operation revealed the architecture of a poorly differentiated ependymoma having perivascular rosettes. The histological pattern of the second biopsy taken eight years after the first operation was highly cellular and vascular with abundant mitoses, showing Homer-Wright rosettes. The histological diagnosis of this second specimen was a cerebral neuroblastoma. The problem of the multipotentiality of the brain tumor is discussed.

Aneurysm of the anterior inferior cerebellar artery at the internal auditory meatus.

An aneurysm of the anterior inferior cerebellar artery extending into the internal auditory meatus is reported. The patient developed headache and vomiting caused by a subarachnoid hemorrhage, and rapidly showed signs and symptoms of a lesion in the cerebellopontine angle soon after the onset. At operation, a clip was successfully applied to the neck of the aneurysm. The characteristic clinical findings are briefly reviewed.

Vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay for platelet response to cilostazol.

Recent clinical trials have demonstrated that cilostazol, an antiplatelet drug competent to inhibit phosphodiesterase 3, is effective in secondary prevention of atherothrombosis including ischemic stroke, myocardial infarction, and peripheral arterial disease. However, there is no reliable assay for detection of the platelet response to cilostazol. We attempted to establish such an assay for clinical use. Phosphorylation of vasodilator-stimulated phosphoprotein (VASP) subsequent to the pharmacological action of cilostazol was measured by a platelet VASP assay kit that has been widely used for monitoring platelet response to ADP receptor antagonists in clinical settings. We modified the kit and found the optimal conditions for detection of cilostazol-dependent VASP phosphorylation. The assay could detect the in vitro and in vivo platelet responses to cilostazol effectively in the presence of 50 nM PGE1. ROC analysis showed that our assay had 97% sensitivity and 75% specificity when blood drawn between 3 and 9 h after cilostazol ingestion was subjected to the assay. The assay results were verified by immunoblotting specific for VASP phosphorylation. Standard light transmission platelet aggregometry could not detect significant inhibition of agonist-induced platelet aggregation by cilostazol except for the in vitro effect of high concentrations of cilostazol. These results demonstrate that the platelet VASP assay can detect the platelet response to cilostazol with high sensitivity and specificity.

Intracranial nonspecific inflammatory granuloma

A case of nonspecific inflammatory granuloma arising from the dura mater near the hypoglossal canal is reported. A 38-year-old woman developed an isolated left hypoglossal nerve palsy. Computed tomography and magnetic resonance imaging demonstrated an enhanced tumorous lesion at the inner orifice of the left hypoglossal canal. Skull x-ray was normal, and cerebral angiography showed no vascular abnormalities. Examination of the cerebrospinal fluid showed mild pleocytosis with a predominance of lymphocytes. Systemic examination revealed no abnormalities. The tumor was removed completely and pathologic investigation revealed that it was an inflammatory granuloma. The patients history and laboratory data, however, failed to suggest the underlying disease, and histopathologic examination did not indicate any special type of granuloma. Therefore, the lesion was diagnosed as a nonspecific inflammatory granuloma.