Primary penile melanomas are rare tumors that represent less than 0.1% of all melanomas. We report a case of a 60-year-old Japanese male with a mucosal penile melanoma and describe an increased CD8+ T cell infiltration in brain after dacarbazine (DTIC) administration. After partial penectomy and left inguinal lymphadenectomy, he developed multiple lung, bone, spleen, brain and skin metastases. He was treated with interferon-β, DTIC and nivolumab. However, the metastases were not reduced in size. Immunohistochemistry showed an increase of CD8+ T cell infiltration and programmed death-ligand 1 (PD-L1) expression after the administration of DTIC, but the expression of programmed cell death protein 1 (PD-1) was negative. We speculate that DTIC exerted immunostimulatory effects, but nivolumab was ineffective due to the negative expression of PD-1 and/or an insufficient infiltration of CD8+ T cells. Although this is only one case, this case report could be the first step to discuss the development of effective therapies against melanoma to take advantage of the increased CD8+ T cell infiltration elicited by chemotherapeutic agents. It would be beneficial to pay more attention to the relationship between DTIC and immune checkpoint modulators.
The AMPK-related kinase NUAK2 is considered to play some role in melanoma development and progression. In our past studies, we showed that NUAK2 is a gene that has a prognostic significance in acral melanoma patients by verifying a public array comparative genomic hybridization (CGH) database and immunohistochemistry of 56 primary acral melanomas (PNAS, 2011) and that pharmacologic inhibition of CDK2 is sufficient to suppress the growth of NUAK2 amplified and PTEN-deficient melanoma cells (Cancer Res, 2015). This time, in order to validate the previous survival data with an increased number of cases, we performed immunohistochemical analyses using 87 specimens of acral melanomas. We also examined its relevance with DNA copy number gains revealed by metaphase CGH. We performed immunohistochemical analyses by using formalin-fixed, paraffin-embedded tissues from 87 acral melanomas and 40 Non-CSD melanomas, and performed metaphase CGH analyses from 12 acral melanomas and 6 Non-CSD melanomas. The Kaplan-Meier curves showed that both the relapse-free survival and the overall survival time of patients with acral melanomas expressing NUAK2 were significantly shorter than patients without the NUAK2 expression. The Cox regression model showed a significant difference in relapse-free survival in acral melanomas. All 6 cases with 1q32 gain, where NUAK2 resides, over-express NUAK2. These data demonstrate that over-expression of NUAK2 has a significant impact on the survival of acral melanoma patients.
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