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Mitsuto Hanihara, Tomoyuki Kawataki, Kyoko Oh-Oka, Kentaro Mitsuka, Atsuhito Nakao and Hiroyuki Kinouchi

OBJECT

Indoleamine 2,3-dioxygenase (IDO), a key enzyme of tryptophan (Trp) metabolism, is involved in tumor-derived immune suppression through depletion of Trp and accumulation of the metabolite kynurenine, resulting in inactivation of natural killer cells and generation of regulatory T cells (Tregs). It has been reported that high expression of IDO in cancer cells is associated with suppression of the antitumor immune response and is consistent with a poor prognosis. Thus, IDO may be a therapeutic target for malignant cancer. The authors have recently shown that IDO expression is markedly increased in human glioblastoma and secondary glioblastoma with malignant change, suggesting that IDO targeting may also have therapeutic potential for patients with glioma. The aim of this study was to investigate the antitumor effect of IDO inhibition and to examine the synergistic function of IDO inhibitor and temozolomide (TMZ) in a murine glioma model.

METHODS

Murine glioma GL261 cells and human glioma U87 cells were included in this study. The authors used 3 mouse models to study glioma cell growth: 1) a subcutaneous ectopic model, 2) a syngeneic intracranial orthotopic model, and 3) an allogenic intracranial orthotopic model. IDO inhibition was achieved via knockdown of IDO in GL261 cells using short hairpin RNA (shRNA) and through oral administration of the IDO inhibitor, 1-methyl-l-tryptophan (1-MT). Tumor volume in the subcutaneous model and survival time in the intracranial model were evaluated.

RESULTS

In the subcutaneous model, oral administration of 1-MT significantly suppressed tumor growth, and synergistic antitumor effects of 1-MT and TMZ were observed (p < 0.01). Mice containing intracranially inoculated IDO knockdown cells had a significantly longer survival period as compared with control mice (p < 0.01).

CONCLUSIONS

These results suggest that IDO expression is implicated in immunosuppression and tumor progression in glioma cells. Therefore, combining IDO inhibition with standard TMZ treatment could be an encouraging therapeutic strategy for patients with malignant glioma.

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Tomoyuki Kawataki, Eiji Sato, Tatsuya Kato, Takashi Sato, Toru Horikoshi and Hiroyuki Kinouchi

In this report, a rare case of dysembryoplastic neuroepithelial tumor (DNET) initially presented as a small white matter lesion with calcification adjacent to the lateral ventricle and extending to the frontal cortex after 7 years. This 1-year-old boy initially suffered from partial seizures. Initial CT revealed a small, low-density area surrounding a tiny calcified mass in the deep white matter of the left frontal lobe. Seven years later, his seizures had become intractable to antiepileptic agents, and MR imaging demonstrated a relatively large mass extending from the calcified lesion up to the adjacent cortical surface. He underwent surgery and the tumor was subtotally removed. Histological examination of the tumor verified it as a DNET consisting of clusters of small oligodendrocytes with floating neurons in the mucoid background. The pattern of the tumor progression in this case suggests that a DNET in the cortex originates from the subependymal germinal layer near the ventricle.

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Takashi Sato, Takeshi Sugiyama, Tomoyuki Kawataki, Eiji Sato, Toru Horikoshi, Kanji Sugita and Hiroyuki Kinouchi

This 11-year-old boy presented with a rare case of Castleman syndrome caused by a clear cell meningioma manifesting as persistent fever of unknown origin, 2 years after glomerulonephritis. Laboratory investigation of the patient showed an increased inflammatory reaction, as well as elevated polyclonal gamma globulin titer and serum level of C-reactive protein. Magnetic resonance imaging revealed a tumor at the cerebellopontine angle. Neurosurgical intervention was performed under the presumptive diagnosis of Castleman syndrome caused by intracranial tumor. Histological examination of the tumor verified that it was clear cell meningioma with infiltration of lymphoplasma cells, and surgical removal resulted in complete resolution of the patient's symptoms and biochemical abnormalities. The present case of clear cell meningioma manifesting as Castleman syndrome shows that the possibility of a brain tumor should be considered in patients presenting with fever of unknown origin, anemia, hypergammaglobulinemia, or other systemic illness.