Tadateru Fukami

Immunohistochemical study for O6-methylguanine-DNA methyltransferase in the non-neoplastic and neoplastic components of gliomas.

Although the expression O6-methylguanine-DNA methyltransferase (MGMT) is an important hallmark for decision of nitrosourea chemotherapy for glioma patients, no immunohistochemical method for analysis of MGMT has been standardized yet. Gliomas usually contain non-neoplastic cells even deep in the tumor. It is not known which of these components expresses MGMT. To clarify this point, we investigated MGMT expression in the non-neoplastic cells in autopsy and surgical specimens by immuno-histochemistry. High grade gliomas were also studied to find a cut-off point for treatment decision. MGMT immunohistochemistry in the normal brain or brain with non-neoplastic disease revealed nuclear staining in some endothelial cells, inflammatory cells, ependymal cells, astrocytes and oligodendroglias. Some cells were double stained with CD68 (macrophages or microglias). The neurons were consistently MGMT-negative. High grade gliomas always contained an MGMT-positive non-neoplastic component. Although the endothelial cells were easily distinguished from the neoplastic cells, other cells were often mistaken for tumor cells. The population of MGMT-positive non-neoplastic cells was usually less than 10%. We set a cut off-point at 10% between the positive and negative groups because the statistical difference in the overall survival was most distinct at this value. In 51 high grade glioma patients, who received both radiotherapy and chemotherapy with nimustine (ACNU), the median overall survival of the MGMT-negative group (23months) was significantly longer than that of the MGMT-positive group (14months) (P<0.009). Multivariate analysis revealed that the negative MGMT expression was a significant prognostic variable next to the degree of surgical removal for the overall survival. In the MGMT-positive group, addition of platinum-based chemotherapy did not improve the survival.

Recurrence and regrowth of benign meningiomas

The World Health Organization (WHO) grading system for meningioma is helpful for predicting aggressive subtypes. However, even benign meningiomas sometimes show relatively rapid growth and may recur after total removal. We attempted to find histopathological features that would be valuable for predicting recurrence or regrowth of WHO grade I meningiomas. We investigated 135 benign meningiomas, of which 120 were totally removed (Simpson’s grade I–III). The median follow-up period was 9.7 years (1–21 years). The recurrence rate in the patients with total removal was 7.5% at 10 years and 9.3% at 20 years. The univariate analysis revealed that MIB-1 index (≥2%), existence of mitosis, absence of calcification, and paucity of fibrosis significantly correlated with recurrence. On the other hand, the histological features of sheet-like growth, prominent nucleoli, and necrosis did not correlate with recurrence, because they were relatively rare in grade I tumors. Multivariate analysis revealed that high MIB-1 index and absence of calcification significantly correlated with recurrence. The patients with recurrent or residual tumors did not always receive adjuvant treatment. Including subtotally treated tumors, the retreatment rate was 9.8% at 10 years and 25.6% at 20 years. MIB-1 index and Simpson’s grade significantly correlated with retreatment in both univariate and multivariate analyses.

Maturational changes in diffusion anisotropy in the rat corpus callosum: Comparison with quantitative histological evaluation

To determine the main histological components that affect fractional anisotropy (FA) in postnatal development of the rat corpus callosum and compare FA values with histological changes evaluated quantitatively.

Hyperthermia induces translocation of apoptosis-inducing factor (AIF) and apoptosis in human glioma cell lines

In the hyperthermal treatment, the wild type (wt) p53 plays an important role in apoptosis induction in the tumor cells. In human gliomas, p53 frequently has some form of mutation. The mutant type (mt) p53 does not work properly as a tumor suppressor and this may result in poor responses during treatment. We investigated the relationship between apoptosis-inducing factor (AIF) and apoptosis under various thermal conditions (43, 45, and 47 °C for 1 h) using four p53-wild or -mutant human glioma cell lines (A172, T98G, U251MG, and YKG-1). AIF translocation from the mitochondria to the nucleus under hyperthermal conditions was demonstrated by confocal laser microscopy. The percentage of AIF-positive nuclei increased significantly in comparison with the control in all cell lines and in all temperature groups except for YKG-1 at 47 °C. Immunoblot analyses of the nuclear fraction of each cell line revealed temperature-dependent increases in AIF. A simultaneous release of cytochrome c from the mitochondria to the cytosol was noted. A flow cytometric analysis showed that apoptosis induction occurred more often in a temperature-dependent manner in the 45 and 47 °C groups than in the control group. These findings indicate that the hyperthermal conditions can lead to AIF translocation and apoptotic cell death in the p53-mutant human glioma cells. The present report is the first description of AIF-induced apoptosis in hyperthermia.

Microscopic anatomy of the brain-meningioma interface.

We analyzed the relation between meningioma and the brain in 50 surgical cases. So-called capsule formation was seen in 20 meningiomas, of which 13 were categorized as thin and 7 as thick. In 21 meningiomas the arachnoid membrane was intact, and 10 meningiomas had no underlying arachnoid membrane. The other 19 tumors showed partial disruption of the arachnoid membrane. The degree of arachnoid disruption correlated with the tumor grade, perifocal edema, pial blood supply on angiography, and tumor size. The existence of brain invasion correlated with the tumor grade and partially with tumor size. In case of invasive tumor, GFAP-positive cells were found deep in the tumor, usually in contact with blood vessels. The axons in gliotic brain often showed degenerative changes such as ballooning or varicose swelling. Meningiomas were usually demarcated by a basement membrane that was collagen type 4 (Col4)-positive. However, atypical and anaplastic meningiomas usually lacked Col4 staining at the interface. In two benign meningiomas that looked like an invasive growth, Col4 staining was seen above the brain. A pia mater-like structure covered the tumor surface in both cases. We could not demonstrate a relation between the expression of matrix metalloproteinase (MMP)-2 or MMP-9 and arachnoid disruption or brain invasion.

Germinoma in Two Brothers: Case Report

We present a third reported case of intracranial germinomas occurring in two brothers. They underwent chemotherapy and radiotherapy after biopsy and are doing well for 10 years and 20 months, respectively. The pertinent literatures are reviewed, and the possible role of heredity in the pathogenesis of familial occurrence of germinomas is discussed.

Treatment of spontaneous intradural vertebral artery dissections.

Spontaneous intradural vertebral artery dissections may cause subarachnoid hemorrhage and often result in devastating damage. Increased use of noninvasive imaging studies has allowed larger numbers of patients to be diagnosed. In addition, intracranial vertebral artery dissection tends to induce multiple lesions affecting both intracranial vertebral arteries recurrently. Although unruptured dissections in this area usually have a benign nature, some authors have reported on the incidence of rupture from this lesion. Once hemorrhage from a dissecting vessel wall has occurred, it needs to be treated in the acute phase because of the high risk of rebleeding resulting in high morbidity and mortality. From December 2004 to July 2010, we managed 47 patients with spontaneous vertebral artery dissection, 31 patients were ruptured and 16 were unruptured. All patients who suffered from subarachnoid hemorrhage were treated with endovascular procedures. Most of the patients with unruptured dissection received medical therapy, but if the aneurysmal dilatation persisted or grew, surgical interventions were performed. Stenting with or without coils was deployed for 13 patients with posterior inferior cerebellar artery involvement at the site of dissection and/or were affected on the dominant side. In some patients, stenting was performed even if they were in the acute phase. For other ruptured patients, internal coil trappings were performed. Six patients died due to severe initial subarachnoid hemorrhage and one patient, who underwent stent deployment with coils for the dominant vertebral artery, with bilateral dissection continuing to the basilar artery died due to rerupture while the next additional coiling was planning. There were two cases of complications related to the intervention. During the follow-up period no bleeding occurred in any of the patients except for the previously mentioned patient. In conclusion, internal coil trapping or stent placement with or without coils was effective in preventing rebleeding of ruptured vertebral artery dissection. If the dissection is unruptured, it is necessary to detect the risk of bleeding with careful watching and when progress appears to be made, patients should be treated promptly. Stent-assisted therapy for preserving the patency of the parent artery and major branches is a promising treatment for vertebral artery dissection, even in the acute stage of subarachnoid hemorrhage. However, the risk of acute rerupture and recurrence remains even with the porous stent placement with or without coils.

Arsenic trioxide sensitizes glioblastoma to a myc inhibitor.

Glioblastoma multiforme (GBM) is associated with high mortality due to infiltrative growth and recurrence. Median survival of the patients is less than 15 months, increasing requirements for new therapies. We found that both arsenic trioxide and 10058F4, an inhibitor of Myc, induced differentiation of cancer stem-like cells (CSC) of GBM and that arsenic trioxide drastically enhanced the anti-proliferative effect of 10058F4 but not apoptotic effects. EGFR-driven genetically engineered GBM mouse model showed that this cooperative effect is higher in EGFRvIII-expressing INK4a/Arf-/- neural stem cells (NSCs) than in control wild type NSCs. In addition, treatment of GBM CSC xenografts with arsenic trioxide and 10058F4 resulted in significant decrease in tumor growth and increased differentiation with concomitant decrease of proneural and mesenchymal GBM CSCs in vivo. Our study was the first to evaluate arsenic trioxide and 10058F4 interaction in GBM CSC differentiation and to assess new opportunities for arsenic trioxide and 10058F4 combination as a promising approach for future differentiation therapy of GBM.

Discrepancies of MRI findings between recumbent and upright positions in atlantoaxial lesion. Report of two cases

Two cases of atlantoaxial (A-A) instability that showed different MRI findings between supine and upright positions are presented. The upright MRI represented the findings corresponding to their symptoms. In A-A lesions, conventional MR images taken in the supine position do not always explain the pathophysiological consequences. The MR images taken in the upright position disclose the actual spinal pathophysiology with gravitational effects.

Primary pericranial Ewing's sarcoma on the temporal bone: A case report

Background: Primary Ewings sarcoma originating in the pericranium is an extremely rare disease entity. Case Description: A 9-year-old female patient was admitted to our department due to a left temporal subcutaneous mass. The mass was localized under the left temporal muscle and attached to the surface of the temporal bone. Head computed tomography revealed a mass with bony spicule formation on the temporal bone, however, it did not show bone destruction or intracranial invasion. F-18 fluorodeoxyglucose positron emission tomography showed no lesions other than the mass on the temporal bone. Magnetic resonance imaging showed that the mass was located between the temporal bone and the pericranium. The mass was completely resected with the underlying temporal bone and the overlying deep layer of temporal muscle, and was diagnosed as primary Ewings sarcoma. Because the tumor was located in the subpericranium, we created a new classification, “pericranial Ewings sarcoma,” and diagnosed the present tumor as pericranial Ewings sarcoma. Conclusion: We herein present an extremely rare case of primary pericranial Ewings sarcoma that developed on the temporal bone.