Research studies suggest that tumor-related angiogenesis contributes to the phenotype of malignant gliomas. We assessed the effect of local delivery of the angiogenesis inhibitor endostatin on human glioma cell line (U-87MG) xenografts. Baby hamster kidney (BHK) cells were stably transfected with a human endostatin (hES) expression vector and were encapsulated in alginate-poly L-lysine (PLL) microcapsules for long-term delivery of hES. The release of biologically active endostatin was confirmed using assays of bovine capillary endothelial (BCE) proliferation and of tube formation. Human endostatin released from the microcapsules brought about a 67. 2% inhibition of BCE proliferation. Furthermore, secreted hES was able to inhibit tube formation in KDR/PAE cells (porcine aortic endothelial cells stably transfected with KDR, a tyrosine kinase) treated with conditioned U-87MG medium. A single local injection of encapsulated endostatin-secreting cells in a nude mouse model resulted in a 72.3% reduction in subcutaneous U87 xenografts' weight 21 days post treatment. This inhibition was achieved by only 150.8 ng/ml human endostatin secreted from 2 x 10(5) encapsulated cells. Encapsulated endostatin-secreting cells are effective for the treatment of human glioblastoma xenografts. Continuous local delivery of endostatin may offer an effective therapeutic approach to the treatment of a variety of tumor types.
Several reports of clinical trials of immunotherapy using dendritic cells have been published to date. In this study, we investigated the safety and clinical response of immunotherapy with fusions of dendritic and glioma cells for the treatment of patients with malignant glioma. Eight patients with malignant glioma, ranging in age from 4 to 63 years old, participated in this study. Dendritic cells were generated from peripheral blood. Cultured autologous glioma cells were established from surgical specimens in each case. Fusion cells of dendritic and glioma cells were prepared with polyethylene glycol, and the fusion efficiency ranged from 9.2 to 35.3% (mean, 21.9%). All patients received the fusion cells every three weeks for a minimum of 3, and a maximum of 7, immunizations. Fusion cells were injected intradermally, close to a cervical lymph node. The percentage of CD16- and CD56-positive cells in peripheral blood lymphocytes slightly increased after immunization in 4 out of 5 cases investigated. Peripheral blood mononuclear cells were incubated with irradiated autologous glioma or U87MG cells and supernatants were harvested. In 6 cases analyzed, the concentration of interferon-gamma in the supernatant increased after immunization. Clinical results showed that there were no serious adverse effects and two partial responses. Although the results of the phase I clinical trial of fusion cells indicated that this treatment safely induced immune responses. we were unable to establish a statistically significant treatment-associated response rate, due to the limited sample population. Therefore, further evaluation of the role of adjuvant cytokines is necessary.
Background and Purpose-We evaluated several hemodynamic parameters for the prediction of rupture in a data set of initially unruptured aneurysms, including aneurysms that ruptured during follow-up observation. Methods-Aneurysm geometry was extracted from CT angiographic images and analyzed using a mathematical formula for fluid flow under pulsatile blood flow conditions. Fifty side-wall internal carotid posterior communicating artery aneurysms and 50 middle cerebral artery bifurcation aneurysms of medium size were investigated for energy loss, pressure loss coefficient, wall shear stress, and oscillatory shear index. During follow-up observation, 6 internal carotid posterior communicating artery and 7 middle cerebral artery aneurysms ruptured (44 and 43 remained unruptured, respectively, with the same location and a similar size as the ruptured cases). Results-A significant difference in the minimum wall shear stress between aneurysms that ruptured and those that remained unruptured was noted only in internal carotid artery aneurysms (PϽ0.001). Energy loss showed a higher tendency in ruptured aneurysms but statistically not significant. For pressure loss coefficient, a significant difference was noted in both internal carotid artery (Pϭ0.0046) and middle cerebral artery (PϽ0.001) aneurysms. Conclusions-Pressure loss coefficient may be a potential parameter to predict future rupture of unruptured aneurysms. (Stroke.
Despite aggressive treatment, the median survival of patients with high-grade malignant astrocytoma is about 1 year. The authors investigated the safety and clinical response to immunotherapy using fusions of dendritic and glioma cells combined with recombinant human interleukin 12 (rhIL-12) for the treatment of malignant glioma. Fifteen patients with malignant glioma participated in this study. Dendritic cells were generated from peripheral blood. Cultured autologous glioma cells were established from surgical specimens in each case. Fusion cells were prepared from dendritic and glioma cells using polyethylene glycol. All patients received fusion cells intradermally on day 1. rhIL-12 was injected subcutaneously at the same site on days 3 and 7. Response to the treatment was evaluated by clinical observations and radiologic findings. No serious adverse effects were observed. In four patients, magnetic resonance imaging showed a greater than 50% reduction in tumor size. One patient had a mixed response. These results show that administration of fusion cells and rhIL-12 safely induces clinical antitumor effects in some patients with malignant glioma.
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