Masatou Kawashima

Accumulation of 8-oxo-2'-deoxyguanosine and increased expression of hMTH1 protein in brain tumors.

Oxidative DNA damage generated by an attack of reactive oxygen species causes mutation or cell death that may lead to various diseases and may be related to initiation or progression of carcinogenesis. 8-Oxo-2-deoxyguanosine (8-oxo-dG) is a major oxidative DNA damage product that can result in mutation, and hMTH1, human MutT homolog protein 1, has been identified as an enzyme that hydrolyzes 8-oxo-dGTP to the monophosphate, thus preventing accumulation of 8-oxo-dG in DNA. With immunohistochemical approaches, we investigated accumulation of 8-oxo-dG and expression of hMTH1 in brain tumor tissues obtained from surgical and autopsy cases, including 42 neuroepithelial tumors, 5 meningiomas, 2 metastatic brain tumors, and 1 schwannoma. 8-Oxo-dG accumulation and hMTH1 expression were increased in various brain tumors. Nuclei of brain tumor cells were immunoreactive for 8-oxo-dG in all cases. In most cases, both nuclei and cytoplasm of the tumor cells were immunoreactive for hMTH1. Both 8-oxo-dG accumulation and hMTH1 expression were most evident in high-grade gliomas, indicating that oxidative stress was high in these gliomas. Thus, the defense mechanism against such oxidative stress may be enhanced as well. These results suggest that oxidative stress may play a role in tumor progression.

α-Synuclein is expressed in a variety of brain tumors showing neuronal differentiation

Abstractα-Synuclein is presynaptic nerve terminal protein and its immunoreactivity has been observed in such neurodegenerative structures as senile plaques of Alzheimer’s disease or Lewy bodies of Parkinson’s disease. The physiological role of α-synuclein is still unknown. It is speculated that α-synuclein may be expressed in brain tumors, especially in those showing neuronal differentiation. We examined the immunohistochemical localization of α-synuclein in 77 human brain tumors. α-Synuclein was widely distributed in the brain tumors showing neuronal differentiation. As a result, positive immunostaining for α-synuclein was observed in ganglioglioma, medulloblastoma, neuroblastoma, primitive neuroectodermal tumor, pineocytoma/pineoblastoma, and central neurocytoma. Compared with other neuronal markers, the positive ratio of α-synuclein was not as high as synaptophysin, microtubule-associacted protein 2, neuron-specific enolase and tau, but it was higher than neurofilament and chromogranin A. The expression of synaptophysin was diffusely observed in the cytoplasm, cellular processes and nucleus in tumors showing neuronal differentiation; however, the expression of α-synuclein was predominantly observed in the cytoplasm of the tumors as well as in the cellular processes. On the other hand, non-neuronal brain tumors such as astrocytic tumors or meningiomas were totally negative for α-synuclein. In conclusion, the appearance of an α-synuclein-positive structure was not limited to neurodegenerative diseases, but could also be detected in neoplastic cells showing neuronal differentiation.

CD9 Expression in Solid Non-neuroepithelial Tumors and Infiltrative Astrocytic Tumors

The tetraspan membrane protein CD9 is normally expressed in the mature myelin sheath and is believed to suppress the metastatic potential of certain human tumors. In this study we identified CD9 in a variety of brain tumors by immunohistochemical (IHC) and immunoblotting analyses. We examined 96 tumor samples and three glioma cell lines in addition to a murine brain tumor model of transplanted glioma cells in CD9-deficient mice and control mice. CD9 was expressed not only in solid non-neuroepithelial tumors but also in infiltrative malignant neuroepithelial tumors. Among the neuroepithelial tumors, high-grade astrocytic tumors, including glioblastomas and anaplastic astrocytomas, showed higher immunoreactivity than low-grade cerebral astrocytomas. Thus, CD9 expression in astrocytic tumors correlated with their malignancy. In the murine brain tumor model, transplanted glioma cells were shown to grow and spread through myelinated areas irrespective of the presence or absence of CD9 expression in the recipients brain. These results indicate that the CD9 expression of astrocytic tumors plays a significant role in the malignancy independent of CD9 expression in the surrounding tissue. This might be explained by the observation that the CD9 molecule is associated with a mitogenic factor, membrane-anchored heparin-binding epidermal growth factor, which is known to be upregulated in malignant gliomas.

Prostaglandin D synthase (beta-trace) in meningeal hemangiopericytoma.

The level of prostaglandin D synthase (PGDS), a major protein constituent of cerebrospinal fluid (CSF), is altered in various brain diseases, including meningitis. However, its role in the brain remains unclear. PGDS is mainly synthesized in the arachnoid cells, the choroid plexus and oligodendrocytes in the central nervous system. Among brain tumors, meningiomas showed intense immunoreactivity to PGDS in the perinuclear region. Thus, PGDS has been considered a specific cell marker of meningioma. In this study, we examined 25 meningeal hemangiopericytomas (HPCs) and found that 16 of the tumors (64%) showed immunoreactivity for PGDS in the perinuclear region. For comparison, 15 meningiomas, 14 soft-tissue HPCs, 1 mesenchymal chondrosarcoma, 3 choroid plexus papillomas, and 7 oligodendrogliomas were also examined. Meningiomas showed positive immunoreactivity for PGDS in 13 cases (80%). Except for one case located at the sacrum, none of the other soft-tissue HPCs showed immunostaining for PGDS. Mesenchymal chondrosarcoma arises in the bones of the skull, and its histological pattern resembles that of HPC; however, it showed no immunoreactivity for PGDS. Neither choroid plexus papillomas nor oligodendrogliomas were immunopositive for PGDS. These findings suggest that meningeal HPCs may have a unique molecular phenotype that is distinct from that of the soft-tissue HPCs. The origin of meningeal HPCs may be more closely related to the arachnoid cells.

Two surgical cases of internal carotid- ophthalmic artery aneurysms: Special reference to the usefulness of three-dimensional CT angiography

Abstract Three-dimensional computerized tomography angiography (3D-CTA) is a noninvasive tool for the diagnosis of cerebral aneurysms. 3D-CTA is helpful in the evaluation of the configuration of aneurysms and their surrounding vessels and anatomical structures. The aim of this study is to assess the usefulness of 3D-CTA for patients with unruptured internal carotid-ophthalmic artery aneurysms. We pre-operatively obtained surgical simulation images using 3D-CTA and 3D reconstruction and then compared them with magnetic resonance angiography (MRA), conventional cerebral angiography and operative findings in the patients. Two patients with unruptured internal carotid-ophthalmic artery aneurysm were selected. These patients underwent direct neck clipping after the optic canal was unroofed through a combined epidural-subdural approach. The cerebral aneurysm was detected by 3D-CTA, MRA and conventional cerebral angiography in each case. Only by 3D-CTA, however, could we easily detect the relationships among the aneurysm neck, ophthalmic artery and optic canal. Based on this information, direct clipping operations were performed safely without any complications. 3D-CTA is an excellent noninvasive diagnostic method not only for detecting cerebral aneurysms, but also for evaluating the relationships between the aneurysms and surrounding structures.

Different responses of benign and atypical meningiomas to gamma-knife radiosurgery: report of two cases with immunohistochemical analysis

Recent reports have shown that gamma-knife radiosurgery provides a safe and effective strategy for the management of brain tumors. To evaluate the role of stereotactic radiosurgery in the management of meningiomas, we investigated the histopathology of two patients. The patients, a 37-year-old man and a 54-year-old woman, presented with visual field disturbance or headache. Imaging studies demonstrated intracranial meningiomas-tentorial and sphenoid ridge, respectively. Each patient undewent subtotal surgical resection (more than 90% in both patients), followed by gamma-knife radiosurgery of the remnant tumor marginal doses of 15 Gy. Pathological examination of the original tumors revealed a meningothelial meningioma and an atypical meningioma, respectively. Enlargement of the remnant tumors 4 months after radiosurgery resulted in total surgical resection in both patients. Thirteen months later, the patient with the atypical meningioma underwent a third operation for early recurrence of the tumor. Histopathology was investigated, and MIB-1, p53, and bcl-2 labeling indexes (LI) were analyzed immunohistochemically. Histopathologically, the specimens showed necrosis and intratumoral vessel obliteration after radiosurgery in both cases. However, more remnant tumor cells survived in the atypical meningioma. Immunohistochemically, increased wild-type p53, decreased bcl-2 expression, and decreased MIB-1 LI were observed in the benign meningioma. In the atypical meningioma, on the contrary, MIB-1 LI was decreased and mutant-type p53 and bcl-2 expression were unchanged. The specimen from the third operation revealed an anaplastic meningioma, and MIB-1 LI was markedly increased. These findings suggest that the efficacy of radiosurgery may differ between benign and atypical meningiomas.