Individual Keratinocyte Necroses in the Epidermis Are Apoptotic Keratinocytes in the Skin.

The patient was a 44-year-old woman with Stevens-Johnson syndrome due to receiving Baktar® (sulfamethoxazole trimethoprim) medication at our outpatient dermatology clinic. The epidermis, dermis, and subcutaneous adipose tissue samples showed numerous necrotic keratinocytes in the epidermis. Apoptotic nuclei were visualized as diaminobenzidine brown deposits with immunoperoxidase staining for cleaved caspase-3. The cleaved caspase-3-positive findings were consistent with eosinophilic material that appeared to be necrotic cells within the epidermis. Therefore, these eosinophilic materials may be apoptotic bodies. Generally speaking, eosinophilic cells are considered necrotic keratinocytes, especially in Japan. To the best of our knowledge, no studies have used apoptotic immunohistochemical markers to examine whether these structures are apoptotic in a human specimen.

Correlation between cutaneous adverse events and prognosis in patients with melanoma treated with nivolumab: A single institutional retrospective study.

Treatment for patients with unresectable melanoma has been dramatically changed by the use of immunocheckpoint inhibitors (ICI). In this study, we reviewed patients with unresectable stage III/IV melanoma, who were treated with nivolumab between July 2014 and March 2017 at the Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, and retrospectively recorded cutaneous adverse events (cAE), development of vitiligo, clinical characteristics and clinical responses. We identified 128 patients, 61 (47.7%) of whom showed cAE, including 30 (23.4%) with development or exacerbation of vitiligo. The prognosis of patients with melanoma treated with ICI correlated with cAE, including development of vitiligo. Patients with cAE showed better objective responses (41.0% vs 6.0%, P < 0.001), progression-free survival (PFS) (377 vs 61 days, P < 0.001) and overall survival (OS) (763 vs 209 days, P < 0.001) than did patients without cAE. Patients who developed vitiligo showed better objective responses (53.3% vs 29.0% vs 6.0%, P < 0.001), PFS (median, not reached vs 317 vs 65 days, P < 0.001) and OS (not reached vs 689 vs 209 days, P < 0.001) than did patients with other cAE and patients without cAE. Landmark analysis showed development of vitiligo starting 20 weeks after starting nivolumab correlated with better OS. In multivariate analysis, OS correlated with performance status, number of metastasized organs, cAE other than vitiligo and development of vitiligo. Despite the fact that the correlation between other cAE and OS was less than that of vitiligo, cAE may be a simple marker of favorable prognosis.

Nivolumab for patients with metastatic uveal melanoma previously untreated with ipilimumab: a single-institution retrospective study.

We evaluated the efficacy of nivolumab in patients with metastatic uveal melanoma previously untreated with ipilimumab. We performed a retrospective study at the National Cancer Center Hospital in Tokyo, Japan, where nivolumab was approved 1 year earlier than ipilimumab. Clinical efficacy outcomes were determined by assessing best overall response according to the Response Evaluation Criteria in Solid Tumors (version 1.1), progression-free survival and overall survival. Fourteen patients were analyzed; none had received any prior systemic therapies although eight had undergone transarterial chemoembolization. The median follow-up period was 15 months. The objective response and disease control rates were 7.1% and 42.9%, respectively (one partial response and five stable diseases). The median progression-free survival and overall survival were 10 (range, 4-105) and 60 (range, 5-105) weeks, respectively. Liver metastases in three patients were all programmed cell death-1 ligand negative. Lower lactate dehydrogenase, development of vitiligo, and a neutrophil-to-lymphocyte ratio less than 5 at week 6 were associated with favorable progression-free survival and overall survival; of these, only a neutrophil-to-lymphocyte ratio less than 5 at week 6 was statistically significant. Even with the use of nivolumab before ipilimumab, metastatic uveal melanoma appears to remain refractory to nivolumab monotherapy. However, because one patient in our cohort achieved an objective response, and the median overall survival exceeded 1 year, treatment strategies that incorporate anti-PD1 antibody should be further investigated. Whether a neutrophil-to-lymphocyte ratio less than 5 at week 6 is a favorable early on-treatment marker should be validated in larger cohorts.