Yasuhiko Kaku

BACKGROUND AND PURPOSE: About one half of those who develop adult-onset moyamoya disease experience intracranial hemorrhage. Despite the extremely high frequency of rebleeding attacks and poor prognosis, measures to prevent rebleeding have not been established. The purpose of this study is to determine whether extracranial-intracranial bypass can reduce incidence of rebleeding and improve patient prognosis. METHODS: This study was a multicentered, prospective, randomized, controlled trial conducted by 22 institutes in Japan. Adult patients with moyamoya disease who had experienced intracranial hemorrhage within the preceding year were given either conservative care or bilateral extracranial-intracranial direct bypass and were observed for 5 years. Primary and secondary end points were defined as all adverse events and rebleeding attacks, respectively. RESULTS: Eighty patients were enrolled (surgical, 42; nonsurgical, 38). Adverse events causing significant morbidity were observed in 6 patients in the surgical group (14.3%) and 13 patients in the nonsurgical group (34.2%). Kaplan-Meier survival analysis revealed significant differences between the 2 groups (3.2%/y versus 8.2%/y; P=0.048). The hazard ratio of the surgical group calculated by Cox regression analysis was 0.391 (95% confidence interval, 0.148-1.029). Rebleeding attacks were observed in 5 patients in the surgical group (11.9%) and 12 in the nonsurgical group (31.6%), significantly different in the Kaplan-Meier survival analysis (2.7%/y versus 7.6%/y; P=0.042). The hazard ratio of the surgical group was 0.355 (95% confidence interval, 0.125-1.009). CONCLUSIONS: Although statistically marginal, Kaplan-Meier analysis revealed the significant difference between surgical and nonsurgical group, suggesting the preventive effect of direct bypass against rebleeding. CLINICAL TRIAL REGISTRATION URL: http://www.umin.ac.jp/ctr/index.htm. Unique identifier: C000000166.

The authors have recently performed a fluorescence-guided tumor resection procedure by using high-dose fluorescein sodium without any special surgical microscopes for the intraoperative visualization of glioblastoma multiforme (GBM), and they report on the actual procedure and clinicopathological findings. Thirty-two patients with GBMs underwent tumor resection during which this fluorescence-guided procedure was used. Fluorescein sodium (20 mg/kg) was intravenously injected after dural opening at the craniotomy site. The tumor was stained almost homogeneously yellow and the color was intense enough to be readily perceived for resection. The center of the solid lesion was stained a deep yellow and surrounded by a transition zone that was faintly stained. The colored lesion was clearly distinguishable from the unstained zone outside the GBM, particularly in the white matter. Both the deeply and faintly stained regions included endothelial proliferation and dense tumor cells. In the unstained region, less dense tumor cells were consistently revealed; however, no endothelial proliferation could be seen. Gross-total resection (GTR) was successful in 84.4% of the patients who received an injection of fluorescein sodium, which accounted for 100% of those in whom all the visible yellow color (both the deeply and faintly stained regions) was judged to have been resected during operation. Gross-total resection was performed in 100% of the patients who underwent the fluorescence-guided procedure and assigned to Stage I, a GBM stage in which, as a therapeutic policy, the tumor should be resected as radically as possible. The GTR rates in patients who received fluorescein sodium were significantly higher than those in patients who did not (73 patients with GBMs who underwent tumor resection without the fluorescence-guided procedure). Although the extent of surgery was revealed to be one of the significant and independent prognostic factors for GBM, the fluorescein sodium-guided resection procedure was not a significant or independent prognostic factor in this series. This surgical procedure does not require any special surgical microscopic equipment and is simple, safe, useful, readily accomplished, and universally available for resection of GBMs. Its efficacy simplifies the surgical procedure of navigating the stained lesion from the unstained area to achieve GTR of GBMs, which can be demonstrated on magnetic resonance images.

BACKGROUND AND PURPOSE: The primary results of the Japan Adult Moyamoya Trial revealed the statistically marginal superiority of bypass surgery over medical treatment alone in preventing rebleeding in moyamoya disease. The purpose of this analysis is to test the prespecified subgroup hypothesis that the natural course and surgical effects vary depending on the hemorrhagic site at onset. METHODS: The hemorrhagic site, classified as either anterior or posterior, was the only stratifying variable for randomization. Statistical analyses were focused on the assessment of effect modification according to the hemorrhagic site and were based on tests of interaction. RESULTS: Of 42 surgically treated patients, 24 were classified as anterior hemorrhage and 18 as posterior hemorrhage; of 38 medically treated patients, 21 were classified as anterior and 17 as posterior. The hazard ratio of the primary end points (all adverse events) for the surgical group relative to the nonsurgical group was 0.07 (95% confidence interval, 0.01-0.55) for the posterior group, as compared with 1.62 (95% confidence interval, 0.39-6.79) for the anterior group (P=0.013 for interaction). Analysis within the nonsurgical group revealed that the incidence of the primary end point was significantly higher in the posterior group than in the anterior group (17.1% per year versus 3.0% per year; hazard ratio, 5.83; 95% confidence interval, 1.60-21.27). CONCLUSIONS: Careful interpretation of the results suggests that patients with posterior hemorrhage are at higher risk of rebleeding and accrue greater benefit from surgery, subject to verification in further studies. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/index.htm. Unique identifier: C000000166.