Takashi Kokunai

Congenital brain tumors in Japan (ISPN Cooperative Study): specific clinical features in neonates.

The authors present specific clinical features of brain tumors occurring in immature brain in comparison with those of older infants and children. Twenty-six neonatal brain tumors, which accounted for 11.3% of 231 brain tumors diagnosed in the 1st year of life collected in a cooperative study in Japan, were analyzed. Although astrocytomas were invariably common tumors in each age group, comprising 25.0% for all pediatric brain tumors, teratomas were the most common type of neonatal brain tumors and accounted for 33.4% in this age group. Location of tumors in the immature brain was more striking, involving the posterior fossa region less commonly, as in 11.1% in neonatal, 29.5% in infantile, and 41.4% in all pediatric age groups. Surgical intervention was performed in 97.4% of the infantile and 79.1% of the neonatal cases, but total or subtotal resection of the mass was achieved only in 58.9% in the infants and 73.7% in the neonates. There was more strict limitation in performing the adjuvant therapies in the immature age groups. Radiation therapy and chemotherapy were given only in 32.0% and 27.6%, respectively, in the neonatal cases. The prognosis was extremely poor in the immature cases: 1-year, 5-year, and 10-year survivial rates were 59.3%, 26.1%, 11.5% in the infants, and 43.5%, 23.8%, 7.1% in the neonates, respectively. Of the neonates, 76% and of the infants 73.1% were retarded. The present study delineates the characteristic clinical features of tumors involving immature brain and emphasized that establishment of more specific therapeutic modalities is urgent.

Overexpression of p21WAF1/CIP1 induces cell differentiation and growth inhibition in a human glioma cell line.

p21WAF1/CIP1 is a downstream mediator of p53 and mediates growth arrest by inhibiting the action of G1 cyclin‐dependent kinases. Since cellular differentiation is frequently characterized by G1 arrest, we examined whether p21WAF1/CIP1 overexpression would induce growth suppression and differentiation in p53‐defective human glioma cells. Overexpression of p21WAF1/CIP1 resulted in an accumulation of cells in G1, altered morphology, growth arrest and cell differentiation. The extent of cell differentiation correlated with the level of p21WAF1/CIP1 as well as of proliferating cell nuclear antigen, cyclin E, and cdk 2, which associates with p21WAF1/CIP1. Our data suggest that gene transfer of p21WAF1/CIP1 may arrest glioma cell growth in vivo by committing malignant glioma cells to a pathway of terminal differentiation. Int. J. Cancer 75:643–648, 1998.

Quantitative analysis of glutathione in rat central nervous system: comparison of GSH in infant brain with that in adult brain

Reduced glutathione (GSH) plays an important role in cellular protection against damage from free radicals and other electrophiles. GSH in the rat central nervous system was quantitatively analyzed. In adult brain, tissue from the cerebellum and cerebrum had higher GSH levels than that from the brainstem and spinal cord. Infant cerebrum and cerebellum contained lower levels of GSH than adult cerebrum and cerebellum. These data seem to suggest that the brainstem and spinal cord in adults, and the cerebrum and cerebellum in infants, are more vulnerable to injury by free radical-like radiation than the cerebrum and cerebellum in adults.

Intrasellar Pituitary Gangliocyto-Adenoma Presenting with Acromegaly: Case Report

OBJECTIVE AND IMPORTANCE A gangliocytoma in the sellar region is extremely rare. We describe a rare case of intraseller gangliocytoma coexisting with a growth hormone-producing pituitary adenoma, which presented with acromegaly. CLINICAL PRESENTATION AND INTERVENTION A 64-year-old woman was admitted to our hospital with headache and acromegaly. Endocrinological studies revealed an elevated serum level of growth hormone (GH). Magnetic resonance imaging showed a tumor at the intrasellar and suprasellar regions. The tumor was totally removed via a transsphenoidal approach. RESULTS A histological examination of the resected specimen showed areas of ganglionic cells and adenomatous cells. Immunohistochemical examination demonstrated GH-releasing hormone-positive ganglionic cells and GH-positive pituitary adenoma. CONCLUSION Based on these immunohistochemical findings, we hypothesized that the intrasellar gangliocytoma promoted the growth of the pituitary adenoma, which had been transformed from a region of pituitary hyperplasia by chronic overstimulation from excess GH-releasing hormone produced by the intrasellar gangliocytoma.

Cerebellar pilocytic astrocytoma with leptomeningeal dissemination: Case report

The authors present an extremely rare case of histologically benign cerebellar pilocytic astrocytoma that had already disseminated to the leptomeninges at the initial presentation.

ECTOPIC PITUITARY ADENOMA IN THE SUPRASELLAR CISTERN : CASE REPORT

The case of a 56-year-old man with an ectopic pituitary adenoma is reported. Neurological examinations, neurodiagnostic imaging, surgical observation, endocrinological evaluation, histological examination, and immunohistological study demonstrated evidence of ectopic prolactinoma in the suprasellar cistern and the presence of a normal pituitary in the sella turcica. The patient underwent total removal of the suprasellar mass by a pterional approach, leading to a surgical and endocrinological cure.

Bromocriptine-induced apoptosis in pituitary adenoma cells: relationship to p53 and bcl-2 expression

In an attempt to understand the roles of the tumour suppressor gene p53 and the proto-oncogene bcl-2 in cell death and survival in pituitary adenomas, we investigated the relationship of their expression to the apoptotic response of two pituitary adenoma cell lines (GH3 and AtT-20) to bromocriptine. An MTT (3-4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrasolium bromide) assay was performed after treatment with bromocriptine for various periods of time over a range of concentrations to determine the effect of this drug on cell growth. Bromocriptine inhibited growth of GH3 and AtT-20 cells in a dose dependent manner. DNA fragmentation was assessed in GH3 and AtT-20 cells exposed to 10 ug/ml bromocriptine- for 48 h and 72 h. The DNA of GH3 and AtT-20 cells showed nucleosomal fragmentation, indicative of apoptosis. When assayed 2 days after adding bromocriptine, approximately 60% of GH3 and 58% of AtT-20 cells treated with bromocriptine displayed typical apoptotic morphology, including condensed chromatin and fragmented nuclei. There was a time dependent increase in the proportion of all tumour cells undergoing apoptosis. Decreased expression of bcl-2 and accumulation of wild-type p53 were associated with bromocriptine induced apoptosis in pituitary adenoma cells. DNA analysis confirmed the results obtained by the protein study. Different expression of p53 and bcl-2 genes is consistent with the expression of these gene products. These findings show that bromocriptine activated wild-type p53 and suppressed bcl-2 favouring occurrence of apoptosis in pituitary adenoma cells. Copyright 1999 Harcourt Publishers Ltd.

Blood-brain barrier formation of grafted human umbilical vein endothelial cells in athymic mouse brain.

Human umbilical vein endothelial cells (HUVECs) were transplanted in athymic mouse brain and neovascularization of grafted endothelial cells was studied. HUVECs were transfected by a reporter gene pEGFPE-N1 in vitro and grafted stereotactically in unilateral striatum of adult nude mice. Histological studies in 4 weeks revealed that grafted HUVECs newly formed microvessels in brain, which were migrated and fused with host vessels. Intravenous injection of Evans blue before sacrificing animals resulted in no extravasation of dye, indicating that a blood-brain barrier (BBB) was formed by the grafted HUVECs. Immunohistochemistry demonstrated that host astrocytes extended glial feet on the grafted endothelial cells and a part of the newly formed vessels was positive with glucose transporter-1. These results indicate that endothelial cells from an ectopic origin have the potential to form a BBB after grafting in the central nervous system.

Relationship between expression of p21WAF1/CIP1 and radioresistance in human gliomas.

The role of p21WAF1/CIP1 (p21) in DNA repair and apoptosis following γ‐irradiation remains controversial. In this study the influence of p21 on the radiosensitivity of human brain tumors was investigated. Resected tumors were stained immunohistochemically for p21. Expression of p21 in astrocytic tumors was high, but it was low in medulloblastomas, germinomas, and primary malignant lymphomas. Glioma and medulloblastoma cell lines were transfected with pcDNA/p21 to cause p21 overexpression, then tumor‐cell colony formation and apoptosis were assessed following γ‐irradiation of the transfected and nontransfected cells. Overexpression of p21 enhanced clono‐genic survival and suppressed apoptosis after γ‐irradiation in human brain tumor cell lines with or without p53 protein deficiency. Radioresistance was acquired when p21 was overproduced in the glioma cell lines irrespective of p53 status.

Overcoming of Radioresistance in Human Gliomas by p21WAF1/CIP1 Antisense Oligonucleotide

Malignant gliomas are highly resistant tumors against γ-irradiation and contained overexpression of p21WAF1/CIP1 (p21). Overexpression of p21 enhanced clonogenic survival and suppressed apoptosis after γ-irradiation in human brain tumor cell lines with or without p53 protein deficiency. The effect of antisense oligonucleotide to p21 against the γ-irradiation-induced apoptosis and cytotoxicity in malignant glioma cell lines was examined. Antennapedia homeodomain internalization peptide was used as an insertion vector. The high transfection efficiency of Antennapedia homeodomain internalization peptide joined with antisense oligonucleotide was observed. The pretreatment with antisense oligonucleotide enhanced the γ-irradiation-induced apoptosis and cytotoxicity in radioresistant glioma cells. p21 may represent an important new target for radiosensitization protocols, possibly involving antisense oligonucleotide directed against.