Kazuhide Adachi, Takeshi Kawase, Kazunari Yoshida, Takahito Yazaki and Satoshi Onozuka
Surgery for skull base meningiomas (SBMs) can lead to complications because these lesions are difficult to approach and can involve cranial nerves and arteries. The authors propose a scoring system to evaluate the relative risks and benefits of surgical treatment of SBMs.
The authors used a 2-step process to construct their scale. First, they derived significant predictive variables from retrospective data on 132 SBM cases treated surgically (primary surgeries only) between May 2000 and December 2005. Next, they validated the predictive accuracy of their scoring system in 60 consecutive cases treated surgically between January 1995 and April 2000, including both primary and repeated surgeries. Finally, they investigated the effect of the surgery on the patients' preoperative symptoms for consecutive cases treated surgically between January 1995 and December 2005, including both primary surgeries and retreatments.
Five items that predicted surgical risk were identified: 1) tumor attachment size; 2) arterial involvement; 3) brainstem contact; 4) central cavity location; and 5) cranial nerve group involvement. The authors named their scoring system the ABC Surgical Risk Scale, after the initial letters of these items. Each factor was assigned a score of 0–2 points, and an additional point was added for previous surgical treatment or for radiation, giving a possible total score of 12 points. On average, the scoring system allocated 2 points for gross-total resections, 6.1 points for near-total resections, and 9 points for subtotal resections, with significant differences between groups. For cases scoring ≥ 8 points, the percentage of cases showing neurological deterioration postoperatively exceeded the percentage showing improvement.
The authors conclude that this scoring system can be used to predict the extent of tumor removal and that the scores reflect the surgical risk.
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.