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内容記述 |
Background and Purpose: Cytokine release syndrome (CRS) is a systemic inflammatory condition caused by a various factors, including infection and drug administration and can sometimes cause CNS symptoms in severe cases. However, there was few information about animal model with severe lethal symptoms induced by chemotherapy. We experienced CRS with CNS symptoms in a cynomolgus monkey treated with paclitaxel. To investigate CRS-related changes and their distribution in a whole brain, we conducted an ex vivo MRI with three-dimensional volume reconstruction evaluation, and histopathologic examination of the brain to compared the respective results and evaluate their correlations.Methods: A 3-years-old male monkey once treated with paclitaxel at 6 mg/kg showed symptom suggesting infusion reactions from end of dosing with prolonged CNS clinical sign and was sacrificed moribund on the day after administration. Serum samples were collected sequentially from 5 min to 24 hr after dosing and was submitted to blood cytokine level measurement (Milliplex MAP kit NHP Cytokine Magnetic Bead Panel). After necropsy, the brain was fixed with 10% neutral buffered formalin and ex vivo MRI was performed on the fixed brain. A Bruker 7 Tesla MRI system (Biospec 70/40) was used, with an 86 mm inner diameter birdcage coil (T12053V3) for transmission and reception. Microscopic examination by Hematoxylin-Eosin (HE) staining, Immunohistochemistry (IHC) staining for fibrinogen was performed on the brain following ex vivo MRI.Results: In the cytokine measurement, serum IL-10, IL-6, and MCP-1 increased, while IL-8 decreased from 30 min up to 24 hours after dosing, compared to levels in background control pool. In the ex vivo MRI, the T2-weighted images revealed hypointense signals around the vasculature in the brainstem region. In the histopathology, there was localized dilatation of arteries and veins in the brainstem region where hypointense signals in MRI, suggesting abnormalities in the circulation. There was focal and very slight neuronal necrosis in the superficial layers of the cerebral cortex adjacent to the cerebral sulci. In the pia mater, reactive infiltration of inflammatory cells was also observed. In the anti-fibrinogen IHC staining, there were perivascular fibrinogen-positive areas with indistinct boundaries around blood vessels in the medulla oblongata. Although no clear changes were seen in these regions in HE stained sections and MRI images, the IHC findings suggested brain edema due to leakage of plasma components out of the vasculature.Conclusions: In the monkey presenting CRS with CNS symptoms, MRI using T2-weighted sequences revealed vascular lesions in the midbrain. Histopathologic examination with HE staining showed localized dilatation of arteries and veins in the brainstem region where MRI abnormalities had been detected. In addition to the areas with MRI abnormality, focal and very slight neuronal necrosis, mild inflammatory cell infiltration, and perivascular fibrinogen-positive areas were also observed. In conclusion, combination of MRI and hisotopathologic examination could detect highly localized vasculature changes. It was considered that the brain edema caused by CRS contributed to CNS symptoms in this animal, suggested by MRI abnormalities, neuronal necrosis and fibrinogen-positive perivascular area. |
