Ryuhei Kitai

Induction of radioresistance by a nitric oxide-mediated bystander effect.

Abstract Matsumoto, H., Hayashi, S., Hatashita, M., Ohnishi, K., Shioura, H., Ohtsubo, T., Kitai, R., Ohnishi, T. and Kano, E. Induction of Radioresistance by a Nitric Oxide-Mediated Bystander Effect. To elucidate whether nitric oxide secreted from irradiated cells affects cellular radiosensitivity, we examined the accumulation of inducible nitric oxide synthase, TP53 and HSP72, the concentration of nitrite in the medium of cells after X irradiation, and cellular radiosensitivity using two human glioblastoma cell lines, A-172, which has a wild-type TP53 gene, and a transfectant of A-172 cells, A-172/mp53, bearing a mutated TP53 gene. Accumulation of inducible nitric oxide synthase was caused by X irradiation of the mutant TP53 cells but not of the wild-type TP53 cells. Accumulation of TP53 and HSP72 in the wild-type TP53 cells was observed by cocultivation with irradiated mutant TP53 cells, and the accumulation was abolished by the addition of an inhibitor for inducible nitric oxide synthase, aminoguanidine, to the medium. Likewise, accumulation of these proteins was observed in the wild-type TP53 cells after exposure to conditioned medium from irradiated mutant TP53 cells, and the accumulation was abolished by the addition of a specific nitric oxide scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide, to the medium. The radiosensitivity of wild-type TP53 cells was reduced when the cells were cultured in conditioned medium from irradiated mutant TP53 cells compared to conventional fresh growth medium. Collectively, these findings indicate the potential importance of an intercellular signal transduction pathway initiated by nitric oxide in the cellular response to ionizing radiation.

Prognostic value of vascular endothelial growth factor and its receptors Flt-1 and Flk-1 in astrocytic tumours.

Summary Background. Vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) is an important regulator of angiogenesis and vascular permeability. Method. We examined immunohistochemically expressions of VEGF and its corresponding receptors Flt-1 and Flk-1 in a series of 50 astrocytic tumours, and correlated their expressions with the degree of angiogenesis, brain edema and prognosis. Findings. There were significant relationships between VEGF, Flk-1 expressions and glioma malignancy grading, intratumoural vascularity and peritumoural brain edema, respectively. Patients with VEGF positive low grade astrocytoma and glioblastoma multiforme had a significantly shorter mean overall survival time than those with negative tumours (P=0.0010 and 0.0180, respectively). Flk-1 is also a significant prognostic factor within each tumour grade, which has a negative impact on overall survival. Additionally, overexpression of VEGF and Flk-1 were significantly associated with earlier recurrence in patients with low grade astrocytomas (P=0.0018 and 0.0240, respectively). Interpretation. It is possible to subcategorize each grade of astrocytic tumours based on their VEGF and Flk-1 staining pattern, which may be crucial in predicting the biological behavior of tumours and thus provide useful information with regard to adequate treatment.

Experimental and clinical study of detection of glioma at surgery using fluorescent imaging by a surgical microscope after fluorescein administration.

Total resection is the optimal treatment for malignant gliomas. However, an unexpected residual tumor mass is sometimes found on magnetic resonance imaging performed after an operation because of a macroscopically unclear margin of the tumor at surgery. This study was designed to evaluate the effectiveness of fluorescent imaging by a surgical microscope after fluorescein administration for the detection of gliomas at surgery. For this study, we produced two filters for the excitation and emission of fluorescein that can be easily fitted to and removed from a surgical microscope manually during the operation. For the experimental study, Wistar rat brains bearing C6 glioma were removed at appropriate intervals after intravenous administration of 10-20 mg kg-1 body weight of sodium fluorescein, and their surface and coronal section through the tumor were observed using a surgical microscope with the filters. In clinical cases, 1000 mg of sodium fluorescein was intravenously administered to five patients with glioma before tumor resection. In the experimental study, the C6 glioma itself and the edematous brain adjacent to the tumor (within 2-3 mm of the gross surface of the tumor) were well stained a brilliant yellowish green for a few hours. The normal brain was not stained. In clinical cases, the tumors were stained a brilliant yellowish green under fluorescent observation at surgery. The patients had no side effects. At all times the fluorescent observation could be quickly changed to ordinary observation by removing the filters from the surgical microscope. The tumor was also stained a faint yellow under ordinary nonfluorescent observation. Although this contributed to detection of the tumor, the fluorescent staining demarcated the tumor more clearly than nonfluorescent staining. These results suggest that this imaging technique by a surgical microscope with special filters at surgery may be practical and useful for detection of gliomas and warrants further clinical evaluations.

Meningeal Rosai-Dorfman disease: report of three cases and literature review.

Rosai-Dorfman disease is a well-recognized clinicopathological entity, which in rare cases affects the central nervous system, where it mimics meningioma. We describe three cases and review the literature. Histological and immunohistochemical confirmation is essential for definitive diagnosis. In addition to emperipolesis (lymphophagocytosis), reactivity for S-100 and CD68 and nonreactivity for CD-1a immunostaining are characteristic features of this histioproliferative disease. In contrast to meningioma, this tumor usually occurs in young males and infiltrates the brain parenchyma.

Astroblastoma: Immunohistochemical and ultrastructural study of distinctive epithelial and probable tanycytic differentiation

We report the clinicopathological findings of astroblastoma found in an 8‐year‐old girl who was subsequently treated for 11 years. The primary superficially circumscribed tumor was located in the frontoparietal lobe, while the recurrent and the second recurrent tumor were restricted to the same region 11 years later. The tumors obtained on these three occasions showed fundamentally the same histological, immunohistochemical and fine structural features. They exhibited astrocytic as well as ependymal tanycytic features with apparent epithelial cell lineage. The tumor cells showed typical features of astroblastoma comprising prominent perivascular pseudorosettes with remarkable vascular sclerosis. The immunohistochemical study revealed intensive positivity of GFAP, vimentin, epithelial membrane antigen (EMA), cytokeratin, connexin 26 and 32, desmocollin 1 and neuronal cadherin. The fine structure revealed divergent types of junctional complexes, some of which were connected with tonofilament bundles. Numerous microvilli protruded and basal lamina abutted on the tumor cell surface. We report these unique histological features, and stress that astroblastoma should be categorized as a specific type of neuroepithelial tumor.

Nestin expression in astrocytic tumors delineates tumor infiltration

Nestin is an intermediate filament protein expressed in undifferentiated cells during central nervous system development, and glioma is known to be a highly infiltrative tumor. We determined whether nestin was expressed in astrocytic tumors and could identify infiltrating tumor cells. We screened 65 archival, paraffin-embedded adult astrocytic tumors using immunohistochemical staining and computerized overlaid photographs. Normal biopsied brains and metastatic brain tumors were also examined. The intensity of nestin expression corresponded to the tumor grade. All 33 glioblastoma cases showed positive and extensive staining, which was less positive in diffuse astrocytoma. Overlaid images showed that nestin immunostaining delineated tumor invasion into adjacent gray and white matter. Nestin is a useful marker for examining the infiltration of malignant cells into surrounding tissue.

Suppression of heat-induced HSF activation by CDDP in human glioblastoma cells

PURPOSE The kinetics of the accumulation of inducible 72-kD heat shock protein (hsp72) and the activation of heat shock transcriptional factor (HSF) after hyperthermia and/or CDDP treatment in two human glioblastoma cell lines, A-172 having the wild-type p53 gene and T98G having the mutated p53 gene were evaluated. METHODS AND MATERIALS Western blot analysis of hsp72, gel-mobility shift assay of HSF, cell survival, and development of thermotolerance were examined. RESULTS The prominent suppression of heat-induced hsp72 accumulation by CDDP was seen in A-172 cells, but not in T98G cells. This was due to the p53-dependent inhibition of heat-induced HSF activation by CDDP. The interactive hyperthermic enhancement of CDDP cytotoxicity was observed in A-172 cells, but not in T98G cells. In addition, the heat-induced thermotolerance was suppressed by the presence of CDDP in the pretreatment. CONCLUSION Suppression of heat-induced hsp72 accumulation by CDDP contributes to an interactive hyperthermic enhancement of CDDP cytotoxicity in the cells bearing the wild-type p53 gene.

Linear sebaceous nevus syndrome (sebaceous nevus of Jadassohn) associated with abnormal neuronal migration and optic glioma : case report

A case of linear sebaceous nevus syndrome (sebaceous nevus of Jadassohn) in an infant is reported. The clinical manifestation and the radiological features of the central nervous system abnormalities associated with this neurocutaneous syndrome are presented. We believe that this is the first reported case of this syndrome in combination with optic glioma.

Lymphomatosis cerebri: clinical characteristics, neuroimaging, and pathological findings

Lymphomatosis cerebri is a rare variant of primary central nervous system lymphoma. We present a case involving a 56-year-old immunocompetent woman who complained of rapid deterioration of her higher brain function over a 4-month period. Magnetic resonance imaging showed extensive white-matter lesions. During brain biopsy, a diffusely infiltrating lymphoma with distinctive immunohistochemical features was detected. Awareness of this unique presentation and early tissue diagnosis provide the best hope for instituting appropriate treatments.

Clival chordoma manifesting as nasal bleeding. A case report.

Chordoma is a rare cartilaginous tumor, for which bleeding presentation is unusual. We report a case of rare hemorrhaged clival chordoma, which was diagnosed correctly by magnetic resonance imaging. A 32-year-old man presented with nasal bleeding. The tumor was totally removed via a trans-sphenoidal approach, from which the surgical specimen confirmed chordoma. Epistaxis seemed to be caused by the spreading of the intratumoral hemorrhage into the sphenoid sinus. This case demonstrates the importance of an exact differential diagnostic evaluation, including chordoma, by use of modern imaging techniques for nasal bleeding.