廣瀬 雄一

BACKGROUND: Reports of genetic analyses on pediatric gliomas are few, and those tumors have been far less characterized than adult gliomas. OBJECTIVE: To characterize the genetic and biological features of pediatric gliomas. METHODS: We investigated 23 pediatric nonependymal, nonpilocytic gliomas for chromosomal copy number aberrations (CNAs) by comparative genomic hybridization (CGH), mutations of isocitrate dehydrogenase (IDH) genes by direct sequencing, and proliferative activity and expression of O(6)-methylguanine-DNA methyltransferase (MGMT) by immunohistochemistry. RESULTS: The most frequent CNA was single-copy gain of chromosome 1q, with 10 of 20 successfully investigated tumors showing the abnormality (50%). Other CNAs detected by CGH included gain on 7q (+ 7q) in 6, +9q in 5, +17q in 5, and + 7p in 4 cases. Gain of entire chromosome 7 was rare (2 cases), and codeletion of 1p and 19q was not detected. Gain of 1q was significantly predictive for shorter progression-free survival (PFS) and overall survival (OS), and even more closely associated with poor clinical outcome than histological grade (P = .0009 for PFS, P = .003 for OS by 1q status; P = .004 for PFS, P = .035 for OS by high-grade vs low-grade). Gain of 1q was also significantly correlated with proliferative activity (P = .0002), and tumors with 1q gain showed a trend toward higher MGMT expression (P = .27). Mutation of IDH1 gene was detected in only 2 of 17 tumors successfully analyzed. CONCLUSION: Single copy gain of 1q is associated with biological features of pediatric gliomas, and is a negative prognostic marker in patients with those tumors.

Objective: There are various options for the treatment of vertebral artery dissection aneurysms (VADA). Treatment with stents may be an effective method to treat VADA involving the posterior inferior cerebellar artery (PICA) and dissection of the dominant vertebral artery (VA). In this article, our personal experience of the treatment of VADAs by using stems and coils is reported. Methods: Since 1998, 26 cases of VADA have been treated by endovascular surgery by the first author. Of these cases, 6 cases were treated using stents, 3 of which were treated using stent and coils, 2 patients were treated using double overlapping stents, and the remaining one patient was treated using a single stent. Results: In all patients, dissection aneurysms were successfully covered by stents. There was one complication: an intraprocedural rupture during additional coil insertion without neurological deterioration. Follow-up angiography was performed in all 5 surviving patients except for one patient who died due to the severity of his original subarachnoid hemorrhage (mean duration of follow-up angiography 22.8 months, range 15-57 months). Total or subtotal disappearance of the VADA was achieved in all 5 cases. At one year after the treatment, all 5 surviving patients remained clinically stable without any neurological deficit. Conclusions: Treatment using stents is an effective alternative for the treatment of VA dissecting aneurysms, especially for lesions of the dominant VA or involving the PICA. However, additional coil insertion should be performed very carefully and may be avoided if stagnation of contrast material is achieved after overlapping stenting.

Meningiomas in identical twins are extremely rare. To our knowledge, only one previous report of meningiomas in identical twins has been published. We present identical twin sisters with meningiomas. The tumors were located at a similar, but not a common, position (the cerebellopontine angle) in both twins. Histologically, both tumors were diagnosed as meningothelial meningiomas with an angiomatous component. Immunohistochemically, the Ki-67 indices in the two cases were 1.0 and 1.1, and the p53 positive rates were 0.2 and 0.9. The specimens in both cases were reactive to neurofibromin 2 (NF2). A comparative genomic hybridization (CGH) assay revealed an aberration in the long arm of chromosome X, but no aberrations in the long arm of chromosome 22 in either case. These results strongly suggest that genetic aberrations other than NF2 are associated with tumorigenesis in some types of sporadic meningiomas.

Object. The introduction of temozolomide (TMZ) has advanced chemotherapy for malignant gliomas. A considerable number of glioblastoma cases are refractory to TMZ, however, and the development of novel chemotherapeutic regimens is needed. The authors of previous studies have revealed that hsp90 is expressed at higher levels in human neoplastic tissues, including gliomas, than in normal tissues. Heat shock protein 90 is involved in a cytoprotective mechanism against cellular stressors such as DNA damage, and the authors hypothesized that hsp90 inhibitors might act as antitumor agents against gliomas and potentiate the cytotoxicity of DNA-damaging agents. Methods. The authors examined the cytotoxicity of an hsp90 inhibitor, 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), both alone and in combination with I of 3 DNA-damaging agents (cisplatin, 1,3-bis(2-chloroethyl)-1-nitrosourea, and TMZ) in human glioma cell lines. The cytotoxicity of these agents to glioma cells was measured using a colony formation assay. The cell cycle phase distribution, protein expression, and number of apoptotic cells were measured using a fluorescence-activated cell sorting assay, immunoblot assays, and double staining with annexin V and propidium iodide. In an in vivo experiment, 17-AAG, cisplatin, or 17-AAG and cisplatin were administered intraperitoneally to mice with xenografted U87MG cells, and the resulting tumor volumes were measured. Results. The authors found that 17-AAG reduced the clonogenicity of U87MG cells, and at a low concentration (< 100 nM) potentiated the cytotoxicity of the DNA-crosslinking agents cisplatin and 1,3-bis(2-chloroethyl)-1-nitrosourea, but not that of the DNA-methylating agent TMZ. This 17-AAG-induced potentiation of DNA crosslinking agent-induced cytotoxicity was a consequence of prolonged G(2)-M arrest accompanied by the suppression of cdc2 and cdc25C and of increased apoptotic cell death accompanied by the degradation of the antiapoptosis proteins Akt and survivin. Similar effects were observed when cells were treated with radicicol, another hsp90 inhibitor. The 17-AAG-induced enhancement of DNA crosslinking agent-induced cytotoxicity was also observed in other cell lines. In addition, 17-AAG sensitized xenografted U87MG cells to cisplatin in nude mice. Conclusions. Heat shock protein 90-targeted therapy may be an effective strategy for potentiating chemotherapy using DNA-crosslinking agents for TMZ-refractory gliomas. (DOI: 10.3171/2009.3.JNS081146)

Previous studies have revealed that p38, a member of the family of stress-activated protein kinases (SAPKs), cooperates with the Chk1-pathway to bring about temozolomide (TMZ)-induced G2 arrest, and that the inhibition of either pathway alone is sufficient to sensitize U87MG glioma cells to TMZ-induced cytotoxicity. c-Jun N-terminal kinase (JNK), another SAPK, has been reported to have several roles of cell survival, oncogenesis, growth, differentiation and cell death. To elucidate the functions of JNK in glioma cells treated with TMZ, we analyzed alterations in JNK and the effect of modification of JNK in U87MG human glioma cells treated with TMZ. We found that JNK was phosphorylated 1-2 days after TMZ treatment and that pretreatment (for 24 h) and post-treatment (for 72 h) with a JNK inhibitor SP600125 at a concentration of 200 nM or higher remarkably reduced clonogenicity in the TMZ-treated cells. The phosphorylation of the JNK target protein c-Jun, but not of ATF-2, was inhibited by this concentration of SP600125. Therefore JNK was proved to have a role of survival in glioma cells treated with TMZ, and c-Jun-related responses were suggested to be more important in the JNK-mediated survival of glioma cells with DNA damage. SP600125 amplified the percentage of senescence-like cells and of mitotic catastrophe cells in TMZ-treated U87MG and U87MG-E6 cells, respectively, suggesting that the enhancement of TMZ-induced cytotoxicity by a JNK inhibitor in glioma cells is induced (at least in part) by the potentiation of cell death pathways induced by TMZ alone. Further investigation based on the present data may provide a viable approach for enhancing TMZ-induced cytotoxicity in human gliomas.

Although some authors have reported the malignant transformation of meningiomas, there has been no previous report describing that a meningothelial meningioma transformed into an atypical meningioma within 1 year. This report documents a 57-year-old woman who presented with right hearing disturbance. Magnetic resonance imaging revealed a right petroclival meningioma. The tumor was subtotally removed and was diagnosed to be a meningothelial meningioma. Seven months after surgery, a recurrence of the tumor was confirmed. The diagnosis of this recurrent tumor was an atypical meningioma. The MIB-1 index and the percent of p53 protein-positive cells in the primary tumor were 4.6% and 35.4%, respectively, whereas those of the recurrent tumor were 34.7% and 33.1%, respectively. A chromosomal DNA copy number loss was observed on 1p, 6q, 10, 14q, and -22q detected in both the primary and the recurrent tumors. These results suggest that the present case had a potentially malignant tumor in the early stage, although it had the histological features of benign meningiomas. An evaluation of the MIB-1 index, as well as the expression of p53 and chromosomal aberrations, may be useful for predicting the malignant transformation of meningiomas.

This 32-year-old woman, 27 weeks pregnant, harbored a cystic mass with a solid component in the left frontal lobe. Histologically, the lesion was hypercellular and contained a diffuse sheet of eosinophilic cells of various sizes. The cells were almost round and had a few prominent, eccentrically placed, hyperchromatic nuclei of various sizes. Immunohistochemically, the tumor was reactive for vimentin, epithelial membrane antigen, cytokeratin AE1/AE3, smooth muscle actin, and BAF47/INI-1, and negative for glial fibrillary acidic protein, neurofilament protein, S100 protein, CK7, CK20, HMB-45, MIC2, and Bcl-2. The Ki 67 labeling index was 4.2%. Comparative genomic hybridization analysis revealed aberrations of the chromosomal copy number of +7 and -10. This tumor could not be categorized according to the present World Health Organization classification. Results of staining with glial fibrillary acidic protein were not consistent with a glioma, and staining with INI-1 was inconsistent with atypical teratoid/rhabdoid tumor. The tumor was therefore designated as a "cerebral tumor with extensive rhabdoid features." (DOI: 10.3171/2008.11.JNS08776)

Adult infratentorial gliomas are rare and have not been well studied. We therefore conducted genetic analysis of those tumors to see if there was any characteristic that could be relevant in clinical management and understanding of tumorigenesis. Nineteen adult infratentorial gliomas were analyzed for chromosomal aberration by comparative genomic hybridization, and for expression of p53 and epidermal growth factor receptor (EGFR) by immunohistochemistry. The most frequent chromosomal aberration was the gain of 7p, and five of the seven cerebellar or fourth ventricle malignant gliomas had that aberration. However, the gain of 7q, the characteristic abnormality of supratentorial astrocytomas commonly associated with the gaining of 7p, was observed only in 1 of 11 adult infratentorial astrocytic tumors. Combined losses of 1p and 19q, the genetic hallmark of oligodendroglioma, were not observed. Results of immunohistochemistry of p53 and EGFR were comparable to those reported in supratentorial gliomas. Our findings might suggest the presence of distinct tumorigenic pathway in adult infratentorial gliomas.