PMC8547604_01
Time course of the clinical parameters, diagnosis, and treatment for this subject. Firstly, about 4 weeks after starting nivolumab monotherapy for malignant melanoma, he suffered from destructive thyroiditis, and so we started replacement therapy with levothyroxine. Secondly, about 4 weeks after starting combination therapy of nivolumab and ipilimumab, he suffered from aseptic meningitis. Thereafter, we stopped both drugs and started steroid therapy with prednisolone. Finally, about 9 months after starting nivolumab, he suffered from isolated adrenocorticotropic hormone (ACTH) deficiency, and so we started replacement therapy with hydrocortisone.
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However, since multiple lung and liver metastases were found during the Feron maintenance therapy after the operation, this subject was treated with nivolumab in July 2018 (week 0) ( Figure 1 ). T4 (FT4) = 3.67 ng/dl, thyroid-stimulating hormone (TSH) < 0.01 muU/ml], and about 10 weeks later, hypothyroidism was observed (FT4 = 0.55 ng/dl, TSH = 22.10 muU/ml) ( Figure 1 ). Therefore, we diagnosed him with nivolumab-induced destructive thyroiditis and started replacement therapy with 50 mug/day of levothyroxine, increasing up to 100 mug/day ( Figure 1 ). In November 2018, nivolumab monotherapy was changed to a combination therapy of nivolumab and ipilimumab in order to enhance the antitumor effect of such medication ( Figure 1 ). Thereby, he was diagnosed with aseptic meningitis induced by the combination therapy of nivolumab and ipilimumab ( Figure 1 ). At that time, we started nivolumab together with prednisolone, just in case, in order to reduce the possibility of recurrence of the adverse effects triggered by nivolumab ( Figure 1 ). Also, the percentage of eosinophils gradually increased up to 10.5% ( Figure 1 ).
In the corticotropin-releasing hormone (CRH) load test, both the adrenocorticotropic hormone (ACTH) and cortisol levels were not increased at all. In the growth hormone-releasing peptide 2 (GHRP2) load test, the GH level was normally increased, but the ACTH level was not increased at all. In the thyrotropin-releasing hormone (TRH) load test, both the thyroid-stimulating hormone (TSH) and prolactin levels were increased. In the gonadotropin-releasing hormone (GnRH) load test, both the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were normally increased. All load tests were performed in the morning in a fasting state.
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As shown in  Figure 2 , in the corticotropin-releasing hormone (CRH) stimulation test, there was no reaction in both the ACTH and cortisol levels, which was compatible with ACTH deficiency. In addition, as shown in  Figure 2 , in the thyrotropin-releasing hormone (TRH) load test, excess reaction of TSH and normal reaction of prolactin were observed.