✓The authors describe the case of a patient with a glioblastoma multiforme who showed remarkably good response to chemotherapy. A genetic analysis using comparative genomic hybridization (CGH) revealed that the tumor had a gain on the q arm of chromosome 1 (1q). Using CGH for a series of genetic analyses of more than 180 patients with gliomas, six were found to have a demonstrated 1q gain. Although the tumors in all six of these cases were histopathologically diagnosed as high-grade gliomas, compared with other malignant gliomas they demonstrated a good prognosis because of their favorable chemotherapeutic sensitivity. In immunohistochemical tests, most of the tumor cells in these cases were negative for O6-methylguanine–DNA methyltransferase, which antagonizes the effect of DNA-alkylating chemotherapeutic agents. The authors believed that a gain of 1q could be produced through the genetic events that cause loss of 1p, because these chromosomal aberrations have an imbalance of DNA copy number in common (1p <1q). A gain of 1q is an infrequent chromosomal aberration and its clinical importance should be investigated in a larger study; however, patients with malignant gliomas demonstrating a 1q gain possibly show longer survival and good response to chemotherapy similar to patients with tumors demonstrating 1p loss. The importance of using genetic analysis for gliomas is emphasized in this report because it may help in selecting cases responsive to chemotherapy and because appropriate treatment for these patients will lead to progress in the treatment of malignant gliomas.
Satoshi Takahashi, Yuichi Hirose, Eiji Ikeda, Raita Fukaya and Takeshi Kawase
Shigeo Ohba, Yuichi Hirose, Kazunari Yoshida, Takahito Yazaki and Takeshi Kawase
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.
The authors examined the cytotoxicity of an hsp90 inhibitor, 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), both alone and in combination with 1 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.
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 G2-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.
Heat shock protein 90–targeted therapy may be an effective strategy for potentiating chemotherapy using DNA-crosslinking agents for TMZ-refractory gliomas.
Shigeo Ohba, Kazunari Yoshida, Yuichi Hirose, Eiji Ikeda, Yoichi Nakazato and Takeshi Kawase
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.”
Hideki Murakami, Yuichi Hirose, Masachika Sagoh, Kazuhiro Shimizu, Masaru Kojima, Kazuhiro Gotoh, Yutaka Mine, Takuro Hayashi and Takeshi Kawase
Object. Thrombomodulin is a thrombin receptor on vascular endothelial cells that is highly expressed when these cells are injured, and it has anticoagulating activity. The authors investigated thrombomodulin expression to clarify why chronic subdural hematomas (CSDHs) continue to grow slowly, like a tumor, and are liquefied.
Methods. Burr hole craniotomy and drainage were performed in all 35 patients with CSDH who were included in the study. The plasma-soluble thrombomodulin and blood clotting factor values were determined in the hematoma and in peripheral blood. In the seven most recent cases, the plasma-soluble thrombomodulin values were determined in the residual hematoma collected from the drainage tube the day after surgery. The outer membranes of the CSDH that were obtained as specimens at operation were stained with monoclonal antibody against thrombomodulin for immunohistochemical studies. The plasma-soluble thrombomodulin values were higher (p < 0.0001), and conversely the values for factors V and VIII were lower in the hematoma than in peripheral blood (p < 0.0001). The plasma-soluble thrombomodulin values were lower in the residual hematomas than in the same lesions at operation (p = 0.018). The endothelial cells on the sinusoidal vessels exhibited immunoreactivity with thrombomodulin antibody in 28 (93%) of 30 cases.
Conclusions. The thrombomodulin is expressed on the sinusoidal vessels, and the blood coagulation system is inhibited in the hematoma. These findings indicate that these vessels are continuously injured and fail to heal. As a result, the bleeding from the sinusoidal vessels may persist, and the hematoma may grow slowly and fail to coagulate. It is suspected that transmitted pulsation variations in the hematoma cavity generate sinusoidal vessel injury.