Shin Nakano

Effects of cilostazol on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a multicenter prospective, randomized, open-label blinded end point trial

OBJECT Cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) is a major cause of subsequent morbidity and mortality. Cilostazol, a selective inhibitor of phosphodiesterase 3, may attenuate cerebral vasospasm because of its antiplatelet and vasodilatory effects. A multicenter prospective randomized trial was conducted to investigate the effect of cilostazol on cerebral vasospasm. METHODS Patients admitted with SAH caused by a ruptured anterior circulation aneurysm who were in Hunt and Kosnik Grades I to IV and were treated by clipping within 72 hours of SAH onset were enrolled at 7 neurosurgical sites in Japan. These patients were assigned to one of 2 groups: the usual therapy group (control group) or the add-on 100 mg cilostazol twice daily group (cilostazol group). The group assignments were done by a computer-generated randomization sequence. The primary study end point was the onset of symptomatic vasospasm. Secondary end points were the onset of angiographic vasospasm and new cerebral infarctions related to cerebral vasospasm, clinical outcome as assessed by the modified Rankin scale, and length of hospitalization. All end points were assessed for the intention-to-treat population. RESULTS Between November 2009 and December 2010, 114 patients with SAH were treated by clipping within 72 hours from the onset of SAH and were screened. Five patients were excluded because no consent was given. Thus, 109 patients were randomly assigned to the cilostazol group (n = 54) or the control group (n = 55). Symptomatic vasospasm occurred in 13% (n = 7) of the cilostazol group and in 40% (n = 22) of the control group (p = 0.0021, Fisher exact test). The incidence of angiographic vasospasm was significantly lower in the cilostazol group than in the control group (50% vs 77%; p = 0.0055, Fisher exact test). Multiple logistic analyses demonstrated that nonuse of cilostazol is an independent factor for symptomatic and angiographic vasospasm. The incidence of new cerebral infarctions was also significantly lower in the cilostazol group than in the control group (11% vs 29%; p = 0.0304, Fisher exact test). Clinical outcomes at 1, 3, and 6 months after SAH in the cilostazol group were better than those in the control group, although a significant difference was not shown. There was also no significant difference in the length of hospitalization between the groups. No severe adverse event occurred during the study period. CONCLUSIONS Oral administration of cilostazol is effective in preventing cerebral vasospasm with a low risk of severe adverse events. Clinical trial registration no. UMIN000004347, University Hospital Medical Information Network Clinical Trials Registry.

Down-regulation of transforming growth factor-β and interleukin-10 secretion from malignant glioma cells by cytokines and anticancer drugs

The effect of treatment with interleukin-1β (IL-1β), interferon-γ (IFN-γ), vincristine, and etoposide was evaluated on the secretion of transforming growth factor-β (TGF-β) and IL-10 and the expression of major histocompatibility complex (MHC) class I, intercellular adhesion molecule-1 (ICAM-1), and CD80 molecules by malignant glioma cells. Five malignant glioma cell lines were treated with IL-1β, IFN-γ, and/or anticancer agents (vincristine and etoposide). Combined treatment with IL-1β and IFN-γ caused greater inhibition of TGF-β secretion compared to treatment with IFN-γ, and almost the same levels of inhibition as treatment with vincristine and etoposide. The greatest inhibition of TGF-β secretion was achieved by treatment with all agents. Low levels of IL-10 secretion were determined in two out of five malignant glioma cell lines. This IL-10 secretion was inhibited by treatment with IL-1β, IFN-γ, vincristine, and/or etoposide. Treatment with both cytokines and anticancer agents increased the expression of MHC class I and ICAM-1 in all tumor cell lines. The mean increase of expression of MHC class I was 50% and that of ICAM-1 was 12-fold. No tumor cell lines expressed CD80 molecules on the cell surface, and no treatment caused CD80 expression. These results suggest that TGF-β and IL-10 secretion by malignant glioma cells can be suppressed by treatment with a combination of IL-1β, IFN-γ, vincristine, and etoposide, and the treatment up-regulates MHC class I and ICAM-1 expression on tumor cells. These results have implications for immunotherapy and chemotherapy in patients with malignant tumors.

Inhibition of Tumor Necrosis Factor‐α and β Secretion by Lymphokine Activated Killer Cells by Transforming Growth Factor‐β

Transforming growth factor‐β (TGF‐β) has a variety of immunosuppressive properties. We investigated the effect of TGF‐β secreted by glioblastoma (T98G) cells on the secretion of tumor necrosis factor‐α and ‐β (TNFs) by lymphokine activated killer (LAK) cells stimulated with tumor cells. The supernatant from T98G cells was preincubated with anti‐TGF‐βl and ‐β2 neutralizing antibodies or untreated, and added to a coculture of LAK and Daudi cells. The neutralizing antibodies were added to LAK/Daudi and LAK culture, and natural human TGF‐β and recombinant human TGF‐β were also added to the LAK/Daudi culture. LAK cells were also cultured with T98G cells, of which the supernatant contained both active and latent forms of TGF‐/β1 and TGF‐β2, and the neutralizing antibodies were added to the coculture. TNFs activity in the supernatants from LAK/ Daudi cultures was examined by a specific bioassay. Addition of the supernatant from T98G cells to LAK/Daudi culture resulted in the inhibition of TNFs secretion by LAK cells. The inhibition was abrogated by the pretreatment of the supernatants with the anti‐TGF‐β antibodies. Addition of TGF‐β and TGF‐β to LAK/Daudi culture inhibited TNFs secretion by LAK cells in a dose‐dependent manner. Addition of anti‐TGFβ‐ antibodies to LAK culture resulted in an increase of TNFs secretion. These results suggest that, if tumor cells have the capacity to convert TGF‐β from a latent to an active form, the active TGF‐β suppresses TNFs secretion by LAK cells stimulated with the tumor cells, and that TGF‐β secreted and activated by glioblastoma cells suppresses the propagation of immune reaction by inhibiting TNFs secretion by activated lymphocytes adjacent to tumor cells.

Long-term survival in a young patient with anaplastic glioma

A 26-year-old man with anaplastic glioma in the left frontoparietal lobe survived for 9 years and 9 months after combined therapy, including subtotal resection, postoperative irradiation, and chemotherapy. The tumor recurred and he received immunotherapy using lymphokine-activated killer (LAK) cells. At the last LAK cell infusion, infection of the Ommaya reservoir occurred, but subsided after antibiotics were administered. Follow-up neuroimaging showed no recurrence of the tumor. Review of the surgical specimens found that the original diagnosis of glioblastoma was inconclusive, although the tumor is considered to be a type of anaplastic glioma.

Bony carotid canal hypoplasia in patients with moyamoya disease.

OBJECT The natural history of moyamoya disease is not well known. We have observed that the bony carotid canal is hypoplastic in patients with adult onset moyamoya disease. Bony carotid canal development should represent internal carotid artery (ICA) development, and may stop with the beginning of ICA stenosis. The purpose of this study was to determine the onset of moyamoya disease by measuring the bony carotid canal. METHODS The normal diameter of the bony carotid canal was evaluated on 4-mm thick bone window CT scans of the skull base in 60 Japanese patients aged 20-80 years, who had minor head trauma or headache considered to be unrelated to the skull base or arterial systems. The relationship between age and bony carotid canal development was assessed in a second group of 50 patients aged 0-19 years, including 10 under 2 years, using CT scans with the same parameters. The diameter of the bony carotid canal in 17 Japanese patients with moyamoya disease was measured. RESULTS The normal diameter in adults was 5.27 +/- 0.62 mm (mean +/- SD). The bony carotid canal developed rapidly before approximately 2 years of age. After fusion of the bony suture, the bony carotid canal developed slowly. The mean diameter of the bony carotid canal was 3.31 +/- 0.44 mm in 11 adult patients with adult-onset moyamoya disease. According to the apparent curve of bony carotid canal development, ICA stenosis was assumed to start in early childhood. CONCLUSIONS Our findings suggest that most cases of Asian moyamoya disease may arise in childhood and that many Asian adult patients with moyamoya disease may develop occlusive vasculopathy in childhood.