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Object Local invasiveness of malignant glioma is a major reason for the failure of current treatments including surgery and radiation therapy. Tetraarsenic oxide (As4O6 [TAO]) is a trivalent arsenic compound that has potential anticancer and antiangiogenic effects in selected cancer cell lines at a lower concentration than arsenic trioxide (As2O3 [ATO]), which has been more widely tested in vitro and in vivo. The authors tried to determine the cytotoxic concentration of TAO in malignant glioma cell lines and whether TAO would show anti-invasive effects under conditions independent of cell death or apoptosis. Methods The human phosphatase and tensin homolog (PTEN)-deficient malignant glioma cell lines U87MG, U251MG, and U373MG together with PTEN-functional LN428 were cultured with a range of micromolar concentrations of TAO. The invasiveness of the glioma cell lines was analyzed. The effect of TAO on matrix metalloproteinase (MMP) secretion and membrane type 1 (MT1)-MMP expression was measured using gelatin zymography and Western blot, respectively. Akt, or protein kinase B, activity, which is a downstream effector of PTEN, was assessed with a kinase assay using glycogen synthesis kinase-3β (GSK-3β) as a substrate and Western blotting of phosphorylated Akt. Results Tetraarsenic oxide inhibited 50% of glioma cell proliferation at 6.3–12.2 μM. Subsequent experiments were performed under the same TAO concentrations and exposure times, avoiding the direct tumoricidal effect of TAO, which was confirmed with apoptosis markers. An invasion assay revealed a dose-dependent decrease in invasiveness under the influence of TAO. Both the gelatinolytic activity of MMP-2 and MT1-MMP expression decreased in a dose-dependent manner in all cell lines, which was in accordance with the invasion assay results. The TAO decreased kinase activity of Akt on GSK-3β assay and inhibited Akt phosphorylation in a dose-dependent manner in all cell lines regardless of their PTEN status. Conclusions These results showed that TAO effectively inhibits proliferation of glioblastoma cell lines and also exerts an anti-invasive effect via decreased MMP-2 secretion, decreased MT1-MMP expression, and the inhibition of Akt phosphorylation under conditions devoid of cytotoxicity. Further investigations using an in vivo model are needed to evaluate the potential role of TAO as an anti-invasive agent.

Object Surgical spillage has been one of the causative factors for the development of leptomeningeal seeding (LMS) after resection of brain metastases. In this paper, the authors' goal was to define the factors related to the development of LMS and to evaluate the difference according to tumor location. Methods The authors retrospectively analyzed 242 patients who had undergone resection for brain metastases. The factors investigated included tumor location with proximity to the CSF pathway (that is, contacting, involved with, or separated from the CSF pathway), the method of resection, and the use of the Cavitron Ultrasonic Surgical Aspirator (CUSA). Results A total of 39 patients (16%) developed LMS at a median of 6.0 months (range 1–42 months) after resection. The risk of developing LMS was significantly higher in patients whose tumors were resected piecemeal than in those whose tumors were removed en bloc, with a hazard ratio (HR) of 4.08 (p < 0.01). The incidence of LMS was significantly higher in patients in whom the CUSA was used, and the HR was 2.64 (p < 0.01). The proximity of tumor to the CSF pathway in the involved group conferred an increased risk of LMS compared with the separated group (HR 11.36, p < 0.01). The risk of piecemeal resection for LMS was significant only in involved lesions (p < 0.01), and the use of the CUSA in both contact and involved lesions increased the incidence of LMS (p < 0.01 and p < 0.03, respectively). Conclusions The authors suggest that piecemeal resection using the CUSA should be limited because of the risk of postsurgical LMS, especially when the tumor is in contact with the CSF pathway.

Local invasiveness of malignant glioma is a major reason for the failure of current treatments including surgery and radiation therapy. Tetraarsenic oxide (As4O6 [TAO]) is a trivalent arsenic compound that has potential anticancer and antiangiogenic effects in selected cancer cell lines at a lower concentration than arsenic trioxide (As2O3 [ATO]), which has been more widely tested in vitro and in vivo. The authors tried to determine the cytotoxic concentration of TAO in malignant glioma cell lines and whether TAO would show anti-invasive effects under conditions independent of cell death or apoptosis.The human phosphatase and tensin homolog (PTEN)-deficient malignant glioma cell lines U87MG, U251MG, and U373MG together with PTEN-functional LN428 were cultured with a range of micromolar concentrations of TAO. The invasiveness of the glioma cell lines was analyzed. The effect of TAO on matrix metalloproteinase (MMP) secretion and membrane type 1 (MT1)-MMP expression was measured using gelatin zymography and Western blot, respectively. Akt, or protein kinase B, activity, which is a downstream effector of PTEN, was assessed with a kinase assay using glycogen synthesis kinase-3β (GSK-3β) as a substrate and Western blotting of phosphorylated Akt.Tetraarsenic oxide inhibited 50% of glioma cell proliferation at 6.3-12.2 μM. Subsequent experiments were performed under the same TAO concentrations and exposure times, avoiding the direct tumoricidal effect of TAO, which was confirmed with apoptosis markers. An invasion assay revealed a dose-dependent decrease in invasiveness under the influence of TAO. Both the gelatinolytic activity of MMP-2 and MT1-MMP expression decreased in a dose-dependent manner in all cell lines, which was in accordance with the invasion assay results. The TAO decreased kinase activity of Akt on GSK-3β assay and inhibited Akt phosphorylation in a dose-dependent manner in all cell lines regardless of their PTEN status.These results showed that TAO effectively inhibits proliferation of glioblastoma cell lines and also exerts an anti-invasive effect via decreased MMP-2 secretion, decreased MT1-MMP expression, and the inhibition of Akt phosphorylation under conditions devoid of cytotoxicity. Further investigations using an in vivo model are needed to evaluate the potential role of TAO as an anti-invasive agent.

Object. The authors conducted an analysis of prognostic factors for patient survival and local control of brain metastases after gamma knife radiosurgery. Methods. In the survival analysis, 53 consecutive patients with 121 lesions treated in the last 2 years were examined. Common primary sites were lung (26 patients), kidney (seven), breast (three), and colon (three). Patient age ranged from 28 to 75 years (median 58 years) and the female/male ratio was 1:0.9. The median tumor volume was 2.1 cm3 (range 0.02–45.5cm3) and the average prescription dose was 15.4 Gy to the 50% isodose. The median follow up was 12 months (range 1–23 months) and the median survival was 46 weeks. Six-month and 1-year survival rates were 63% and 39%, respectively. Karnofsky Performance Scale score, tumor volume, and presence of extracranial disease were statistically significant prognostic factors (p < 0.05) for survival in multivariate analysis. Number of lesions, patient age, and adjuvant whole-brain radiation therapy were not statistically significant. Ninety-one of 121 lesions with follow-up images were included in the local control analysis. The 1-year actuarial local control rate was 48%. In multivariate analysis smaller volume was associated with better control (p = 0.0043), and, control period of renal cell carcinoma was shorter than that of the other tumor types (p = 0.0070). Conclusions. Karnofsky Performance Scale score, tumor volume, controlled primary cancer, and absence of extracranial metastases were associated with longer survival in the present study. For local control, tumor volume was a statistically significant factor.

Surgical spillage has been one of the causative factors for the development of leptomeningeal seeding (LMS) after resection of brain metastases. In this paper, the authors' goal was to define the factors related to the development of LMS and to evaluate the difference according to tumor location.The authors retrospectively analyzed 242 patients who had undergone resection for brain metastases. The factors investigated included tumor location with proximity to the CSF pathway (that is, contacting, involved with, or separated from the CSF pathway), the method of resection, and the use of the Cavitron Ultrasonic Surgical Aspirator (CUSA).A total of 39 patients (16%) developed LMS at a median of 6.0 months (range 1-42 months) after resection. The risk of developing LMS was significantly higher in patients whose tumors were resected piecemeal than in those whose tumors were removed en bloc, with a hazard ratio (HR) of 4.08 (p0.01). The incidence of LMS was significantly higher in patients in whom the CUSA was used, and the HR was 2.64 (p0.01). The proximity of tumor to the CSF pathway in the involved group conferred an increased risk of LMS compared with the separated group (HR 11.36, p0.01). The risk of piecemeal resection for LMS was significant only in involved lesions (p0.01), and the use of the CUSA in both contact and involved lesions increased the incidence of LMS (p0.01 and p0.03, respectively).The authors suggest that piecemeal resection using the CUSA should be limited because of the risk of postsurgical LMS, especially when the tumor is in contact with the CSF pathway.

✓ The authors present a case of postoperative spinal seeding of papillary craniopharyngioma. This 27-year-old man who had previously undergone subtotal removal of a suprasellar craniopharyngioma was admitted because of low-back and right leg pain. Results of neurological examination showed a limitation in straight-leg raising in the right side with no sensorimotor changes. Magnetic resonance imaging of the lumbar spine demonstrated multiple enhanced intradural extramedullary masses causing spinal cord compression. Pathological examination of the tumor tissue obtained via laminectomy revealed papillary craniopharyngioma, which had the same histological features as those of the previous suprasellar tumor. Several ectopic recurrences of craniopharyngioma have been reported; however, the authors believe that this is the first published report of the spinal seeding of craniopharyngioma.