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Although anti-PD-1 antibody monotherapy (PD-1) is commonly used to treat advanced acral melanoma (AM), its efficacy is limited. Further, data on the efficacy of PD-1 plus anti-CTLA-4 antibody (PD-1+CTLA-4) for the treatment of AM are limited. Therefore, we compared the efficacy of PD-1+CTLA-4 and PD-1 in the treatment of Japanese patients with advanced AM.This retrospective study evaluated patients with advanced AM who were treated with PD-1 or PD-1+CTLA-4 as first-line immunotherapy in 24 Japanese institutions between 2014 and 2020. Treatment efficacy focussing on the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was compared between the two groups.In total, 254 patients (palm and sole melanoma [PSM], n = 180; nail apparatus melanoma [NAM], n = 74) were included. Among the patients with PSM, the ORR (19% vs. 31%; P = 0.44), PFS (5.9 vs. 3.2 months; P = 0.74), and OS (23.1 vs. not reached; P = 0.55) did not differ significantly between the PD-1 and PD-1+CTLA-4 groups. Among the patients with NAM, the ORR (61% vs. 10%; P 0.001) was significantly higher and PFS was longer (6.4 vs. 3.8 months; P = 0.10) in the PD-1+CTLA-4 group than in the PD-1 group. Cox multivariate analysis demonstrated that PD-1+CTLA-4 is an independent predictor of a favourable PFS in patients with NAM (P = 0.002).The efficacy of PD-1+CTLA-4 is not superior to that of PD-1 for the treatment of advanced PSM. However, PD-1+CTLA-4 may be more efficacious than PD-1 for the treatment of advanced NAM.

Sweat gland carcinoma with neuroendocrine differentiation (SCAND) is a newly proposed tumor entity of primary cutaneous apocrine/eccrine adnexal tumor with neuroendocrine differentiation. The histopathologic variations are not yet well known. In this article, we present a case of SCAND mimicking male breast cancer and syringocystadenocarcinoma papilliferum. A 68-year-old man presented with a reddish 12-mm nodule on his left areola. No lymph node or distant metastases were observed. The patient was disease free 1 year and 9 months after the tumor was surgically resected but died of cerebral hemorrhage. Histopathological examination revealed a predominantly intradermal tumor with marked syringotropism, mimicking a component of mammary ductal carcinoma in situ. In addition, another tissue section displayed a cup-shaped papillated tumor with syringocystadenocarcinoma papilliferum-like features, which were also seen because of marked syringotropism. Diffuse immunoexpression of cytokeratin 7, cytokeratin 19, chromogranin A, synaptophysin, INSM1, estrogen receptor, carcinoembryonic antigen, epithelial membrane antigen, and GATA3 was observed in the tumor, but no BRAF immunoexpression was seen. The present case would help us to understand the histopathological variation and differential diagnosis of SCAND. The histopathological diagnosis of male breast cancer or syringocystadenocarcinoma papilliferum should be made by ruling out SCAND.

In Japanese melanoma patients, the response rate of N/I was lower (35.1%) and the rate of adverse events was similar (60.4%) compared to those reported in previous clinical trials. No survival difference was observed with the use of N/I between clinical types. Patients who achieved a good response had better outcomes. Elevated LDH level and ≥3 metastatic sites were poor prognostic factors.

This study sought to reveal the clinicopathologic characteristics of large cell neuroendocrine carcinoma (LCNEC) of the skin/conjunctiva. The retrieved patients included 3 men and 3 women with a median age of 85 (63-95) years. All lesions occurred on the face, including the ears, with a median tumor size of 11.5 (7-65) mm. Lymph node metastasis was observed in 5 (83%) of 6 cases, and distant metastasis was noted in 2 (33%). One patient (17%) who had a 13-mm-sized tumor died of the tumor 13 months after excision. All tumors were mainly located in the dermis, and one of them also exhibited intraepithelial spreading. The cytology resembled that of an LCNEC in other organs. No adnexal differentiation was observed. Five cases were of the pure type, but one had a component of squamous cell carcinoma. Immunoreactivities for CAM5.2, CK7, CK19, BerEP4, epithelial membrane antigen, neuron-specific enolase, synaptophysin, c-KIT, GATA3, and bcl-2 were frequently present, but CK20, neurofilament, Merkel cell polyomavirus large T antigen, mammaglobin, estrogen receptor, HER2, and TTF1 were completely negative in all cases. Mutant-pattern immunostaining of p53, PTEN, and Rb was frequently observed. The Ki67 rate exceeded 70% in all cases. LCNEC of the skin/conjunctiva is a morphologically-defined group of primary cutaneous/conjunctival neuroendocrine neoplasm, although it may be heterogeneous similar to other-site LCNEC or Merkel cell carcinoma. This study highlighted the predominant location for the face, high metastatic and lethal potential, possible combination with other tumor components, and frequent mutant-type immunoexpressions of p53, PTEN, and Rb in this tumor group.

Background: Althoughpre-emptive therapy with oral tetracycline, moisturizer, sunscreen and topical corticosteroid isuseful for preventing acneiform eruption (AfE) due to epidermal growth factor receptor (EGFR) inhibitors, no studies have examinedthe efficacy of topical corticosteroids themselves, or investigated the optimal strength of the corticosteroid for treating facial AfE (FAfE).Patients and Methods: Screened patients with RAS wild-typecolorectal cancerstarted pre-emptive therapy with oral minocycline and moisturizeron initiation of cetuximab or panitumumab therapy. Patients who developed grade 1 or 2 FAfEwere randomly allocated to two groups:a ranking-down (RD) group,started with a very strong corticosteroid, and serially ranked down every 2 weeks unless FAfE exacerbated, and a ranking-up (RU) group, started with a weak corticosteroid and serially ranked up at exacerbation. FAfE grade, patient quality of life, and adverse events (AEs) with topical corticosteroid were evaluated every 2 weeks.The primary endpoint was the total number of times grade 2 or higher FAfEidentified in thecentral review of the 8-weektreatment period.Results: No significant differences in total numbers of grade 2 or higher FAfE and inAEs caused by topical corticosteroids were observedbetweengroups during the 8-week. Incidence of grade 2 or higher FAfEwas tended to lower inthe RD group during the first 2 weeks.Conclusion: Considering long-term care of FAfE, the RU regimen appears suitableand should be considered the standard treatment for FAfEdue to EGFR inhibitor therapy. Trial registration: UMIN Clinical Trials Registry (UMIN000024113)

Langerhans cell histiocytosis is a neoplastic condition of Langerhans cells, and can be associated with other neoplasms, especially BRAF-mutant hematological tumors and papillary thyroid carcinoma. Here, we present the first case of co-existing Langerhans cell histiocytosis and low cumulative sun damage (low-CSD) melanoma, both of which had a BRAF V600E mutation. A 49-year-old man had a 45 × 43 × 15 mm semi-pedunculated pigmented tumor in his back but had no other systemic symptoms. Histopathology revealed a 2 mm-sized incidental focus of Langerhans cell histiocytosis within a large lesion of low-CSD melanoma. Diffuse immunoexpression of CD1a, langerin/CD207, S100 protein, and BRAF (VE1) was observed in the focus of Langerhans cell histiocytosis. Sanger sequencing with microdissection confirmed BRAF V600E mutation in the component of Langerhans cell histiocytosis. Interestingly, the advanced melanoma also harbored the same BRAF V600E mutation, although the significance of this tumor combination is still unknown. This article is protected by copyright. All rights reserved.

Basal cell carcinoma is the most common type of skin cancer, and surgical excision with clear margins is the standard of care. Surgical margins are determined based on risk factors (high or low risk) for recurrence according to the National Comprehensive Cancer Network and Japanese basal cell carcinoma guidelines. The clarity of the clinical tumor border (well-defined or poorly defined) is considered a risk factor, and significant discrepancies in the judgment of clinical tumor borders among dermato-oncologists may occur. Therefore, we analyzed the dermato-oncologists' concordance in judging the clinical tumor border of basal cell carcinoma. Forty-seven dermato-oncologists (experts: 37; young trainees: 10) participated in this study. The datasets of clinical and dermoscopic photographs of 79 Japanese cases of head and neck basal cell carcinoma were used to determine the concordance in the judgment of clinical tumor border. The probability of the border that was selected more often was used to calculate the rater agreement rate for each dataset. Correct judgment was defined as a more frequently selected border, and the concordance rate of clarity of clinical tumor border for each dermato-oncologist was calculated based on the definition of the correct judgment. A median concordance rate of 85% or higher for all dermato-oncologists was predefined as an acceptable rate for clinical use. Of the 79 datasets, rater agreement rates were 80-100%, 60-79%, and 51-59% for 55, 19, and five datasets, respectively. The median concordance rate for all dermato-oncologists was 86% (interquartile range: 82-89%). There was no significant difference in the concordance rate between the experts and the trainees (median, 87% vs. 85.5%; p = 0.58). The concordance rates of dermato-oncologists for all datasets were relatively high and acceptable for clinical use.

Background. Carcinoid-like pattern in basal cell carcinoma is extremely rare and has only been documented in a textbook. The aim of this study is to reveal the characteristics of the carcinoid-like pattern in basal cell carcinoma as well as to establish the concept of the tumor pattern. Methods. Of 355 basal cell carcinoma cases (355 lesions of 308 patients), 11 tumors with histopathological features of carcinoid-like pattern were retrieved. Results. The patients included 5 males and 6 females with a median age of 73 years (range 38-86 years). Of the 11 lesions, 10 were observed on the head. Histopathologically, a carcinoid-like pattern with branching and anastomosing of trabecular structures was observed in 30% to 95% of the tumor area. No differentiation to sebocytes was observed in any of the tumors. The tumors were well-circumscribed, although 3 lesions contained an infiltrative-type component as well. The carcinoid-like pattern areas in all 11 lesions exhibited diffuse BerEP4 immunoexpression but no KIT, synaptophysin, or vimentin expression. Keratin 20-positive Merkel cells were not observed in the tumor areas. Conclusions. Basal cell carcinoma can show a carcinoid-like pattern cell arrangement. Based on the histopathological and immunohistochemical findings from our study, we collectively conclude that the carcinoid-like pattern in basal cell carcinoma does not seem to represent sebaceous mantle differentiation. Carcinoid-like pattern basal cell carcinoma can be distinguished from other tumors by the favorite site of the head, the co-existence of conventional basal cell carcinoma components, lack of sebaceous differentiation, and diffuse BerEP4 immunoexpression.

The multinational phase 3 CheckMate 238 trial compared adjuvant therapy with nivolumab versus ipilimumab among patients with resected stage III or IV melanoma (N = 906). In this Japanese subgroup analysis of CheckMate 238 (n = 28; nivolumab, n = 18; ipilimumab, n = 10), both the 12‐ and 18‐month recurrence‐free survival rates were 56% for nivolumab and 30% for ipilimumab (hazard ratio, 0.66; 97.56% confidence interval, 0.19–2.24; P = 0.4390). No new safety signals were reported for Japanese patients. Results were consistent with those from the CheckMate 238 global population, indicating that nivolumab has the potential to be a treatment option for Japanese patients with resected melanoma who are at high risk of recurrence.

Plaque-type blue nevus is a rare variant of blue nevi that was first described in 1954. This article presents clinical, macroscopic, histopathological, and genetic findings for a case of large plaque-type blue nevus expanding into the mammary gland tissue as well as the skin of the right breast. A 63-year-old woman presented with a congenital, large, blue-colored macule limited to the hypochondriac area of the right breast. A nodule 8 mm in diameter was also present in the mammary gland tissue. Magnetic resonance imaging was unable to detect diffuse melanin deposition in the mammary gland tissue, but pigmentation in the whole mammary parenchyma was observed in the cut surfaces of the mastectomy specimen. Histopathology revealed a sparse distribution of dendritic melanocytes in whole sections of the mammary fibrous tissue and partial sections of the dermis. The histopathological criteria for atypical cellular blue nevus were fulfilled for the mammary tumor. Nodal blue nevus was diagnosed in the sentinel lymph node. Sanger sequencing confirmed the GNAQ Q209P mutation, which was also identified in all 4 literature cases of plaque-type blue nevus, but rarely in conventional blue nevi and uveal melanoma. It should be noted that plaque-type blue nevus can expand into the mammary gland tissue, even if the pigmented lesion does not exist on the overlying breast skin. The mammary condition can be the origin of primary mammary melanocytic tumors. Mosaicism of the GNAQ Q209P mutation can be a characteristic genetic alteration to extensive blue nevi, including plaque-type blue nevus.

Background Immune checkpoint inhibitors (ICIs) have a lower efficacy in mucosal melanoma (MUM) than in cutaneous melanoma. The use of combination treatments with radiotherapy (RT) to improve the efficacy in MUM, however, requires further investigation. Methods We retrospectively evaluated 225 advanced MUM patients treated with anti-PD-1 monotherapy (PD1; 115) or anti-PD-1 + anti-CTLA-4 combination therapy (PD1+CTLA4; 42) with or without RT (56 and 12, respectively). Treatment efficacy was estimated by determining the objective response rate (ORR) and survival rate with the Kaplan–Meier analysis. Results The baseline characteristics between the two groups in each ICI cohort were similar, except for Eastern Cooperative Oncology Group performance status in the PD1 cohort. No significant differences in ORR, progression-free survival (PFS), and overall survival (OS) were observed between the PD1 alone and PD1+RT groups in the PD1 cohort (ORR 26% versus 27%, P > 0.99; median PFS 6.2 versus 6.8 months, P = 0.63; median OS 19.2 versus 23.1 months, P = 0.70) or between the PD1+CTLA alone and PD1+CTLA4+RT groups in the PD1+CTLA4 cohort (ORR 28% vs 25%, P = 0.62; median PFS 5.8 versus 3.5 months, P = 0.21; median OS 31.7 versus 19.8 months, P = 0.79). Cox multivariate analysis indicated that RT in addition to PD1 or PD1+CTLA4 did not have a positive impact on the PFS or OS. Conclusions A prolonged survival benefit with RT in combination with ICIs was not identified for advanced MUM patients, although RT may improve local control of the tumour and relieve local symptoms.

Background The American Joint Committee on Cancer (AJCC) 8th Edition Cancer Staging System was implemented in 2018; however, it has not been validated in an Asian melanoma population. Objective The purpose of this study was to validate the new system using a cohort of Japanese melanoma patients. Methods The AJCC 7th and 8th Editions were used for TNM classification of patients in a database established by the Japanese Melanoma Study Group. Patient data with sufficient information to be applicable to the AJCC 8th staging were selected. The Kaplan–Meier method was used to estimate disease-specific survival and relapse-free survival. Results In total, data for 3097 patients were analyzed. The 5-year disease-specific survival according to the 7th and 8th Edition staging system were as follows: IA = 98.5%/97.9%; IB = 95.4%/96.2%; IIA = 94.2%/94.1%; IIB = 84.6%/84.4%; IIC = 72.2%/72.2%; IIIA = 76.2%/87.5%; IIIB = 60.7%/72.6%; IIIC = 42.0%/55.3% and IIID = none/26.0%. The 5-year relapse-free survival according to the 7th and 8th Edition staging was as follows: IA = 94.5%/92.7%; IB = 85.4%/85.3%; IIA = 80.1%/79.4%; IIB = 71.4%/70.6%; IIC = 56.8%/55.7%; IIIA = 56.8%/69.4%; IIIB = 42.6%/56.8%; IIIC = 20.0%/33.3% and IIID = none/6.5%. Conclusion The results show that new staging system could efficiently classify our Japanese melanoma cohort. Although there was no difference in Stage I and II disease between the 7th and 8th Edition systems, we should be careful in managing Stage III disease since the survival curves of the 8th Edition staging were completely different from the 7th Edition. Moreover, our results indicate that adjuvant therapies for Stage IIB and IIC should be developed, since the relapse-free survival for these stages were equivalent to Stage IIIA and IIIB, respectively.

Background The incidence of melanoma among those of an Asian ethnicity is lower than in Caucasians; few large-scale Asian studies that include follow-up data have been reported. Objectives To investigate the clinical characteristics of Japanese patients with melanoma and to evaluate the prognostic factors. Methods Detailed patient information was collected from the database of Japanese Melanoma Study Group of the Japanese Skin Cancer Society. The American Joint Committee on Cancer seventh Edition system was used for TNM classification. The Kaplan-Meier method and Cox proportional hazards model were used to estimate the impact of clinical and histological parameters on disease-specific survival in patients with invasive melanoma. Results In total, 4594 patients were included in this analysis. The most common clinical type was acral lentiginous melanoma (40.4%) followed by superficial spreading melanoma (20.5%), nodular melanoma (10.0%), mucosal melanoma (9.5%), and lentigo maligna melanoma (8.1%). The 5-year disease-specific survival for each stage was as follows: IA = 98.0%, IB = 93.9%, IIA = 94.8%, IIB = 82.4%, IIC = 71.8%, IIIA = 75.0%, IIIB = 61.3%, IIIC = 41.7%, and IV = 17.7%. Although multivariate analysis showed that clinical classifications were not associated with survival across all stages, acral type was an independent poor prognostic factor in stage IIIA. Conclusions Our study revealed the characteristics of melanoma in the Japanese population. The 5-year disease-specific survival of each stage showed a similar trend to that of Caucasians. While clinical classification was not associated with survival in any stages, acral type was associated with poor survival in stage IIIA. Our result might indicate the aggressiveness of acral type in certain populations.

Recent advances in next-generation sequencing have enabled rapid and efficient evaluation of the mutational landscape of cancers. As a result, many cancer-specific neoantigens, which can generate antitumor cytotoxic T-cells inside tumors, have been identified. Previously, we reported a metastatic melanoma case with high tumor mutation burden, who obtained complete remission after anti-PD-1 therapy and surgical resection. The rib metastatic lesion, which was used for whole-exome sequencing and gene expression profiling in the HOPE project, showed upregulated expression of PD-L1 mRNA and a high single-nucleotide variants number of 2712. In the current study, we focused on a metastatic melanoma case and candidate epitopes among nonsynonymous mutant neoantigens of 1348 variants were investigated using a peptide-HLA binding algorithm, in vitro cytotoxic T-cell induction assay and HLA tetramer staining. Specifically, from mutant neoantigen data, a total of 21,066 9-mer mutant epitope candidates including a mutated amino acid anywhere in the sequence were applied to the NetMHC binding prediction algorithm. From in silico data, we identified the top 26 mutant epitopes with strong-binding capacity. A cytotoxic T-cell induction assay using 5 cancer patient-derived PBMCs revealed that the mutant ARMT1 peptide sequence (FYGKTILWF) with HLA-A*2402 restriction was an efficient neoantigen, which was detected at a frequency of approximately 0.04% in the HLA-A24 tetramer stain. The present success in identifying a novel mutant antigen epitope might be applied to clinical neoantigen screening in the context of an NGS-equipped medical facility for the development of the next-generation neoantigen cancer vaccines.

e21553 Background: The systemic treatment for advanced BRAF-mutant melanoma includes BRAF/MEK inhibitors (BRAF/MEKi), anti-PD-1 monotherapy (aPD1), and the combination of nivolumab plus ipilimumab (NIVO/IPI). Several studies have demonstrated favorable survival benefits for those treated with immunotherapy upfront. Most of these studies, however, were conducted among Caucasian-dominant cohorts; evidence for Asian patients is limited. Therefore, our objective was to assess the efficacy of first-line therapies for Asian patients in a real-world setting. Methods: We retrospectively collected the clinical data of Asian patients with advanced BRAF-mutant melanoma treated with first-line BRAF/MEKi, aPD1, or NIVO/IPI from 26 institutions in Japan. Clinical outcomes were determined by assessing the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) by first-line therapies. Kaplan‐Meier curves and log‐rank tests, as well as multivariable Cox proportional hazard models were used to estimate survival probabilities. Results: We identified 316 Asian patients treated with first-line BRAF/MEKi (n = 224), aPD1 (n = 59), or NIVO/IPI (n = 33) between 2016 and 2021. At baseline, the median age of the patients in each treatment arm was 63, 62, and 54, respectively (p = 0.053). The ORR in the first-line therapy was 69%, 29%, and 27%, respectively (p < 0.001). With a median follow-up of 18.9 months, the median PFS was 16.2, 5.6, and 6.4 months (p = 0.001); and the median OS was 36.9, 37.9 months, and not reached (p = 0.386), respectively. In a multivariable analysis, the predictive factors of short PFS were first-line therapy with aPD1 (HR, 2.44; 95%CI, 1.70-3.50, p < 0.001) or NIVO/IPI (1.73; 1.06–2.83, p = 0.029), BRAF V600K (p = 0.031), ECOG PS ≥2 (p = 0.011), elevated lactate dehydrogenase (LDH) levels (p = 0.001), and M1a/M1c/M1d stages (p = 0.036/ < 0.001/ < 0.001, respectively). Predictive factors of short OS were BRAF V600K (p = 0.042), ECOG PS ≥2 (p = 0.001), elevated LDH levels (p < 0.001), and M1c/M1d stages (both p < 0.001). The OS did not differ significantly by first-line therapies between BRAF/MEKi, aPD1 (1.52; 0.98–2.34, p = 0.061), and NIVO/IPI (0.63; 0.31–1.27, p = 0.194). Conclusions: Although upfront NIVO/IPI showed the longest OS numerically, its superiority over BRAF/MEKi in Asian patients seems to be modest compared with Caucasian patients. Because upfront BRAF/MEKi showed an OS that was comparable with that of aPD1, BRAF/MEKi remains an active first-line therapy option, especially for those who are not amenable to take the high risk of immune-related toxicities.

Aim The aim of the study was to evaluate the efficacy and safety of nivolumab combined with ipilimumab in treatment-naive Japanese patients with advanced melanoma. Methods In this multicentre, single-arm study, treatment-naive Japanese patients with unresectable stage III/IV or recurrent melanoma received nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for four doses, followed by biweekly doses of nivolumab (3 mg/kg). The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included overall survival (OS), progression-free survival (PFS), disease control rate and safety. Results The subtypes of the thirty patients enrolled were: 12, mucosal; eight, non-acral cutaneous; seven, acral; two, uveal and one, unknown primary melanoma. The ORR was 43.3% (95% confidence interval [CI]: 25.5, 62.6) with central and local assessment. The centrally and locally assessed disease control rate (95% CI) were 73.3% (54.1, 87.7) and 86.7% (69.3, 96.2), respectively. At the median follow-up period of 14.1 months (range 5.2–27.7), median OS and centrally assessed PFS were not reached. OS (95% CI) at 6, 12, 18 and 24 months was 93.3% (75.9, 98.3), 83.3% (64.5, 92.7), 72.9% (50.0, 86.5) and 65.6% (40.4, 82.2), respectively. Treatment-related adverse events (AEs) occurred in all patients. Grade III–IV and serious AEs occurred, mostly during the combination phase, in 23 (76.7%) and 20 (66.7%) patients, respectively. No treatment-related deaths occurred. Conclusions This study confirmed the efficacy and safety of nivolumab plus ipilimumab in treatment-naive Japanese patients with advanced melanoma including rare subtypes. Incidence rates for grade III–IV AEs were high but manageable with appropriate medical attention and treatment. Trial registration JapicCTI-152869.

This study aimed to identify the clinical and histopathological characteristics of secondary extramammary Paget disease (EMPD) with underlying anorectal adenocarcinoma so as to differentiate it from primary cutaneous EMPD. Seventeen and 8 cases of primary and secondary EMPD with anorectal adenocarcinoma, respectively, were retrieved from the pathology archive and the clinical and histopathological features reviewed. The tumor samples from 21 cases were totally resected specimens, whereas 3 and 1 of secondary and primary cases were punch biopsied, respectively. All 8 (100%) cases of secondary EMPD presented evenly distributed perianal lesions. By contrast, 4 of 17 (23.5%) primary EMPD cases had perianal skin lesions and displayed an uneven, asymmetrical distribution around the anus. Fibroepithelioma of Pinkus-like changes and subepidermal mucin deposits with no or few invasive tumor cells were observed in 6 (75%) and 3 (37.5%) of the 8 secondary EMPD cases, respectively, although 3 secondary case samples were small biopsy specimens. Both the histopathological changes were not observed in any of the 17 primary EMPD cases. Evenly circumferential perianal distribution, fibroepithelioma of Pinkus-like changes, and subepidermal mucin deposits without invasive tumor cells were characteristic to cases of secondary EMPD with anorectal adenocarcinoma. These clinicopathological features could be used to differentiate between secondary and primary EMPD.

Nivolumab plus ipilimumab combination is currently one of the preferred regimens for advanced melanoma in recently updated clinical practice guidelines. However, the evidence on the efficacy of the combination for acral or mucosal subtypes remains less robust. This is the final analysis of a multicenter, open‐label, uncontrolled phase II study that investigated the long‐term efficacy and safety in treatment‐naive Japanese patients with advanced melanoma, including acral or mucosal subtypes, and subsequent therapy after discontinuation of the investigational agents. Patients received four doses of nivolumab (1 mg/kg i.v.) in combination with ipilimumab (3 mg/kg i.v.) at 3‐week intervals, followed by doses of nivolumab (3 mg/kg i.v.) at 2‐week intervals. The median follow‐up period was 20.8 months (range, 5.2–35.0). The centrally and locally assessed objective response rates were both 43.3% (13/30; 95% confidence interval [CI], 25.5–62.6). Median progression‐free survival was not reached (95% CI, 3.02–not reached), and median overall survival was also not reached (95% CI, 19.52–not reached). The 30‐month progression‐free survival and overall survival rates were 50.3% and 54.2%, respectively. No new safety concerns were detected. After discontinuation of the investigational agents, 83.3% of patients received some form of subsequent therapy including 43.3% of patients who received nivolumab monotherapy and 26.7% of patients who received radiotherapy. Of the four patients who discontinued the investigational agents because of immune‐related adverse events, two received subsequent therapy (nivolumab and ipilimumab, respectively) and the other two showed long‐term treatment‐free survival (659 and 590 days, respectively). Long‐term survival with nivolumab plus ipilimumab was observed in Japanese patients with melanoma including acral and mucosal subtypes, which is consistent with the CheckMate 067 study. Many patients continued to receive some form of treatment safely after stopping treatment with nivolumab plus ipilimumab.

Immune-related adverse events (irAE) were reported to be associated with better outcomes in various cancers treated with the immune checkpoint inhibitor nivolumab. Considering that their development depends on host immune activation, irAE may reflect antitumor response in mucosal melanoma (MM). This single-center retrospective study including patients with advanced MM receiving nivolumab monotherapy between August 2014 and September 2018 investigated whether the development of irAE was associated with clinical efficacy. The study patients were divided into those with and without irAE, and treatment efficacy and safety were evaluated. The study cohort of 27 patients included 20 (74%), six (22%) and one (4%) patient with primary MM in the head and neck, genitourinary and anorectal regions, respectively. The irAE onset was not significantly associated with the objective response rate in patients while it was significantly associated with the disease control rate. The median progression-free survival in patients with and without irAE was 301 and 63 days, respectively. The median overall survival (OS) in patients with and without irAE was 723 and 199 days, respectively. According to the timing of irAE onset, the OS was better in seven patients who developed irAE after 180 days than in nine patients who developed irAE within 180 days. Although 16 patients (59%) experienced any grade irAE, including three (11%) with grade 3 or more irAE, there were no treatment-related deaths. These results indicated that the development of irAE may correlate with improved survival in patients with MM treated with nivolumab monotherapy. Further studies are necessary to confirm these findings.

Background This phase I dose-escalation study investigated the safety of the Smoothened inhibitor taladegib in Japanese patients with advanced solid tumors. Methods Patients received taladegib orally once daily for 28-day cycles, using a 3 + 3 dose-escalation method. The primary objective was the safety and tolerability of taladegib at doses up to the global recommended dose (400 mg). Secondary objectives included pharmacokinetics, changes in skin glioma-associated oncogene homolog 1 (Gli1) transcript levels, and antitumor activity. Results Nineteen patients received treatment (100 mg: 3; 200 mg: 3; 400 mg: 13). No dose-limiting toxicities (DLTs) were observed at doses of 100 mg or 200 mg; 3 of the 9 patients evaluable for DLTs at the 400 mg dose level experienced DLTs (thrombocytopenia: 1; decreased appetite: 2). The most commonly reported treatment-related adverse events were dysgeusia (13/19, 68.4%), decreased appetite (12/19, 63.2%), nausea (9/19, 47.4%), fatigue (9/19, 47.4%), and vomiting (6/19, 31.6%). The pharmacokinetic profile suggested that exposure to taladegib was higher in Japanese than non-Japanese patients, possibly related to differences in body weight and/or drug formulation. At all dose levels, a high level of inhibition of skin Gli1 transcript levels was observed after 15 and 30 days of exposure to taladegib. Partial response was achieved by 1 patient (basal cell carcinoma of the skin) and stable disease by 4 patients. Conclusions Taladegib doses of 100 mg and 200 mg, but not the global recommended dose of 400 mg, were well tolerated in this population of Japanese patients with advanced solid tumors.

Nail apparatus melanoma (NAM) is a rare subtype of malignant melanoma with a prevalence that varies among populations. Conservative surgical approaches for thin to intermediate NAMs have recently been reported, however, their adoption is controversial, and resulting long-term prognoses are unknown. The purpose of this study was to determine the prognosis of NAM in a sample Asian population, and to investigate whether there is a difference in the local control and overall survival (OS) rates according to the extent of resection of the primary tumour. We performed a retrospective study of NAM patients treated at five medical institutions in Japan between 2000 and 2013. Outcomes according to surgery (amputation vs. resection) and tumour thickness were compared. We identified 151 cases of NAM in 83 men and 68 women; the thumb (n = 50; 33.1%) and hallux (n = 55; 36.4%) were the most common sites. No local recurrence was detected following any of the surgical procedures; Kaplan-Meier survival analysis revealed that the surgical procedure type was not significantly associated with disease-free survival (p = 0.786) or OS (p = 0.997). Five-year OS rates according to tumour thickness were 100% for in situ, 94.4% for ≤1-mm, 91.7% for 1.01-2.0-mm, 72.7% for 2.01-4.0-mm, and 47.6% for ≥4.01-mm tumours. Surgical procedure type does not influence survival as long as total primary tumour resection is accomplished. The prognosis of NAM is comparable to that of other types of melanoma.

Background Dabrafenib is a BRAF inhibitor that has demonstrated clinical activity with a good tolerability profile in patients with BRAF V600E mutated metastatic melanoma. This study evaluated the safety and tolerability, pharmacokinetics and preliminary efficacy of dabrafenib in Japanese patients. Methods This phase I, open-label, dose escalation study was conducted in 12 Japanese patients with BRAF V600 mutation positive solid tumours. Primary endpoint was safety, assessed by monitoring and recording of all adverse events (AEs), serious AEs, drug-related AEs; secondary endpoints were pharmacokinetic profiles and efficacy measured by tumour response. This study is registered with ClinicalTrials.gov, number NCT01582997. Results Of the 12 patients enrolled, 3 each received 75 mg and 100 mg dabrafenib while 6 received 150 mg dabrafenib twice daily orally. Melanoma and thyroid cancer were the primary tumours reported in 11 (92%) and 1 (8%) patients respectively. Most AEs were grade 1 or 2 and considered related to study treatment. Most common AEs reported in the 12 patients were alopecia in 7 (58%); pyrexia, arthralgia and leukopenia in 6 (50%) each, hyperkeratosis and nausea in 4 (33%) each. Partial response as best overall response was reported in 7 of 12 (58%) patients and in 6 (55%) with malignant melanoma. No dose-limiting toxicity (DLTs) were reported during the DLT evaluation periods. Conclusions Dabrafenib was well tolerated and rapidly absorbed administered as single- or multiple dose. Comparable safety and pharmacokinetic profiles were observed compared with non-Japanese patients. Dabrafenib has promising clinical activity in Japanese patients with BRAF mutated malignant melanoma.

Randomized phase III trial (JCOG1309) has been started to confirm the superiority of adjuvant therapy with locoregional interferon beta over surgery alone in overall survival for patients with stage II/III cutaneous melanoma., The Dermatologic Oncology Group of Japan Clinical Oncology Group has started a randomized phase III trial to confirm the superiority of adjuvant therapy with locoregional interferon beta in overall survival over surgery alone for patients with pathological stage II/III cutaneous melanoma (JCOG1309). Patients in the interferon beta arm receive intra- or subcutaneous injections of interferon beta directly into the surgical site at a flat dose of 3 million units once per day. Treatment is repeated for 10 consecutive days every 8 weeks for a total of 3 courses during the induction phase, then 1-day injection every 4 weeks for 2.5 years. A total of 240 patients will be accrued from 17 Japanese institutions within 6.5 years. Primary endpoint is overall survival. Secondary endpoints are relapse-free survival, distant metastasis-free survival, pattern of recurrence, and adverse events. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000017494 [http://www.umin.ac.jp/ctr/index.htm].

Background Project HOPE (High-tech Omics-based Patient Evaluation) has been in progress since 2014 and uses whole-exome sequencing (WES) and gene expression profiling (GEP). Among a total of 1,685 patients with cancer, 13 with melanoma were registered and characterized using multi-omics analyses to investigate specific biomarkers in responders to programmed cell death-1 (PD-1) blockade. Materials and methods The patients with melanoma comprised of six males and seven females, and their mean age was 68 years. Five patients were treated with nivolumab, and two were responders. Results GEP analysis demonstrated that PD-L1 expression was positive in for cases, and melanoma-associated antigens and tumor signaling-associated genes were up-regulated in tumor compared with normal tissues. Additionally, WES analysis indicated more single nucleotide variants (SNVs) per melanoma tumor compared to other tumor types. Remarkably, a case of complete remission after nivolumab therapy showed high expression of PD-L1 protein and the highest number of SNVs. Conclusion The novel approach used in Project HOPE might be an efficient tool that facilitates identifying specific biomarkers predictive of good responders to anti-PD-1 therapy.

Objective Application of topical moisturizing preparations is important for the prevention and palliation of hand-foot skin reaction induced by multi-kinase inhibitor. Application adherence of topical moisturizing preparations in clinical practice has rarely been reported. This study investigated the factors affecting adherence to the application of topical moisturizing preparations in patients administered regorafenib. Methods The subjects were patients administered regorafenib ( n = 118). Consumption of a urea-based moisturizing ointment, hand-foot skin reaction grade (CTC-AE ver 3.0), treatment duration, and dose of regorafenib, factors that might affect the onset of symptoms and adherence, including age, sex, presence of a key person, working status, performance status, past use of capecitabine or epidermal growth factor receptor antibodies, and relative dose intensity were retrospectively investigated. The adherence to the topical moisturizing ointment (Results Working status was associated with poor adherence, showing a positive correlation (odds ratio; 3.024, p = 0.023). In contrast, symptom grade of hand-foot skin reaction and regorafenib relative dose intensity showed negative correlation with poor adherence (odds ratio; 0.971, p = 0.012, and 0.485, p Conclusions The results suggest that adherence decreases in patients with working. The relative dose intensity of regorafenib decreased when adherence to topical moisturizing ointments decreased. Severe hand-foot skin reaction could be associated with adherence. Patients consciously might not apply the ointment when hand-foot skin reaction did not become severe. It will be problematic for medical personnel to motivate patients for improving adherence to the use of moisturizing ointments.

To describe the treatment patterns of nivolumab and ipilimumab in Japan, a retrospective observational study was conducted in melanoma patients who received nivolumab and ipilimumab sequentially. Patients who received nivolumab and ipilimumab in combination were excluded from this study. Efficacy was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) in terms of the overall response rate (ORR), progression-free survival (PFS), and disease control rate (DCR). Overall survival (OS) was also evaluated. Safety was assessed by the Common Terminology Criteria for Adverse Events (CTCAE). The treatment for all 68 patients enrolled involved switching from nivolumab to ipilimumab in 61 patients and switching from ipilimumab to nivolumab in seven patients. Switching occurred because of progressive disease in 55 patients and adverse events in eight patients. The median number of ipilimumab doses was three. Ipilimumab treatment achieved an ORR and DCR of 4.9% and 21.3%, respectively, and the median OS from start of ipilimumab was 7.0 months. During the study period, no new safety signals were noted. Independent factors which were indicative of poor prognosis for PFS were high neutrophil-to-lymphocyte ratio (NLR) and high C-reactive protein (CRP) levels before ipilimumab treatment. An evaluation over a washout period indicated that no significant relationship existed with efficacy or safety. For the sequential administration of nivolumab and ipilimumab in Japanese melanoma patients, switch from nivolumab to ipilimumab was common, and the major reason for switching was progressive disease. The major prognostic factors for ipilimumab PFS after nivolumab were NLR and CRP before ipilimumab treatment.

9542 Background: Anti-PD-1 antibody monotherapy (PD1) has been commonly used for patients with advanced acral melanoma (AM). However, recent studies have demonstrated the limited clinical efficacy of PD1 in AM compared to non-acral cutaneous melanoma, particularly in nail apparatus melanoma. Although advanced AM patients are strong candidates for first-line anti-PD-1 and anti-CTLA-4 combination therapy (PD1+CTLA4), data on the clinical efficacy of PD1+CTLA4 in AM are lacking. Thus, we aimed to compare the clinical efficacies of PD1+CTLA4 and PD1 in Japanese advanced AM patients. Methods: We retrospectively reviewed the clinical records of advanced AM patients treated with PD1+CTLA4 or PD1 as first-line immunotherapy at 23 Japanese institutions. Clinical response was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Survival was estimated using Kaplan-Meier analysis. Toxicity was assessed according to CTCAE 4.0. Results: A total of 192 patients (median age, 72 years) with advanced AM (palm and sole melanoma, 135; nail apparatus melanoma, 57) were included in the study. PD1+CTLA4 and PD1 were used as first-line immunotherapy in 39 and 153 patients, respectively. The baseline demographics and characteristics were similar between the PD1+CTLA4 and PD1 groups, except for age (median age 67.3 vs. 73.2; P = 0.005). The objective response rate (ORR) in PD1+CTLA4 was significantly higher than that of the PD1 group (38.5% vs. 16.3%; P = 0.047). The median progression-free survival (PFS) and overall survival (OS) in the PD1+CTLA4 group tended to be longer than those of the PD1 group, but the differences were not significant (median PFS 7.3 months vs. 4.5 months; P = 0.19, median OS 43.6 months vs. 18.2 months; P = 0.19). In the subgroup analysis of the palm and sole melanoma cohorts, no significant differences in ORR, PFS, and OS were observed between the PD1+CTLA4 and PD1 groups (ORR 31% vs. 20.8%; P = 0.67, median PFS 5.3 months vs. 5.9 months; P = 0.87, median OS not reached vs. 22.3 months; P = 0.66). Meanwhile, the nail apparatus melanoma cohort in the PD1+CTLA4 group exhibited significantly higher ORR, and longer PFS and OS than the PD1 group (ORR 60% vs 6.1%; P < 0.001; median PFS 19.6 months vs 3.8 months; P = 0.008, median OS 43.6 months vs 13.5 months; P = 0.049). Due to immune-related adverse events in all cohorts, the treatment cessation rate was higher in the PD1+CTLA4 group than the PD1 group (59% vs. 11.8%). Conclusions: PD1+CTLA4 was clinically more efficacious than PD 1 in advanced AM patients. Notably, advanced nail apparatus melanoma patients were strong candidates for first-line PD1+CTLA4.

Skin grafting is a simple method for reconstruction of a large defect on the foot. Although skin grafting on the foot sometimes fails, it is not clear what factors influence the success rate of skin grafting. We analyzed data for 71 patients with skin cancer of the foot who underwent reconstruction of defects with skin grafting. The factors we evaluated were success rate of skin grafting, weight-bearing or non-weight-bearing area, immediate or delayed reconstruction, and whether a tie-over bolster was used or not. The success rates were higher in patients with lesions in non-weight-bearing areas than in patients with lesions in weight-bearing areas and in patients who underwent delayed reconstruction than in patients who received immediate reconstruction. On the other hand, the use of a tie-over bolster did not improve the success rate. In conclusion, delayed reconstruction is desirable if the lesion is located in a weight-bearing area.

Cutaneous adverse events are relatively common in patients being treated with molecular-targeted drugs. Paronychia is one of the cutaneous adverse events that influences the patient's quality of life because of pain, and it often affects anticancer treatments in severe cases. However, there are few effective treatments, especially for severe paronychia. Here, we present our experiences of treatment for paronychia due to oncology pharmacotherapy. Although we treated paronychia with various methods, only corticosteroid ointment and phenol chemical matricectomy significantly improved the paronychia. Dermatologists must perform appropriate and effective treatments for paronychia in order to enable patients to continue anticancer drug treatment without impairing their quality of life.

PurposeIpilimumab is designed to block cytotoxic T-lymphocyte antigen-4 to augment antitumor T cell responses. In studies of predominantly Caucasian patients with advanced melanoma, ipilimumab was associated with durable response, long-term survival benefit, and a manageable safety profile. This phase II study assessed the safety of ipilimumab in Japanese patients with unresectable stage III or IV melanoma.MethodsPatients received ipilimumab 3 mg/kg every 3 weeks for four doses. The database lock for the original analysis was in August 2014. Overall survival, progression-free survival, and data on deaths were based on an updated, follow-up analysis (database lock April 2015).ResultsData are reported from 20 patients. Fifteen patients (75 %) received all four doses of ipilimumab during induction. Twelve patients (60 %) had at least one drug-related adverse event (AE), and no patients discontinued due to a drug-related AE. There were no deaths related to study drug. The most common drug-related AEs were rash (n = 7), pyrexia (n = 3), increased aspartate aminotransferase (AST; n = 3), and increased alanine aminotransferase (ALT; n = 3). Twelve patients (60 %) reported immune-related AEs (irAEs); most frequent were skin (n = 9) and liver (n = 3) disorders. Grade 3 irAEs were ALT and AST elevation (n = 2) and diabetes mellitus (n = 1). Two patients had a partial response and two had stable disease, yielding a 20 % disease control rate. Median overall survival and progression-free survival were 8.71 and 2.74 months, respectively.ConclusionIpilimumab 3 mg/kg had a manageable AE profile in this Japanese patient population with clinical outcomes similar to that in Caucasian patients., Article, CANCER CHEMOTHERAPY AND PHARMACOLOGY.76(5):997-1004(2015)

A cutaneous metastatic tumor is relatively rare, and patients with such a tumor usually have a poor prognosis. Even if the metastases can be treated, the treatment cannot improve the prognosis. However, neglecting metastatic lesions sometimes results in a great deterioration of quality of life. Cutaneous metastatic foci are generally treated with chemotherapy and/or radiotherapy. On the other hand, surgical treatment is sometimes chosen for cutaneous metastases. In this study, we analyzed data for 40 patients with cutaneous metastatic tumors who received surgical treatment at Shizuoka Cancer Center between January 2009 and August 2014. Among these cases, lung cancer was the most common primary cancer and the craniocervical region was the most frequent metastatic site. Among the patients who died, the average duration to death after the operation was 186 days. We consider that resection of cutaneous metastatic tumors as palliative therapy is an appropriate therapeutic option if the patient's condition permits resection. Such treatment can improve quality of life for both the patients and their families.

The combination of dabrafenib and trametinib demonstrated encouraging antitumor activity and tolerability, at initial analysis, in Japanese patients with BRAF V600 mutant advanced melanoma warranting further investigation. This study evaluated the safety and tolerability, pharmacokinetics (PK) and preliminary efficacy of dabrafenib 150 mg b.i.d. plus trametinib 2 mg q.d. in Japanese patients with BRAF V600E/K mutant solid tumors (phase 1) and melanoma (phase 2). Phase 1 was primarily intended to assess safety and tolerability as assessed by adverse events (AE), and the primary end‐point in phase 2 was to assess confirmed overall response rate (ORR). The secondary end‐points in phase 1 included PK, confirmed/unconfirmed ORR and duration of response (DOR). The secondary end‐points in phase 2 were PK, unconfirmed ORR, DOR, safety and tolerability. A total of 12 cutaneous melanoma patients were enrolled in the study (six in phase 1 and six in phase 2) and received the combination therapy of dabrafenib and trametinib. Common AE (≥50.0%) included pyrexia (75%), increased aspartate aminotransferase (67%), peripheral edema (50%) and nasopharyngitis (50%). The investigator‐assessed ORR was reported in five patients (83%) in phase 1 and was also reported in five patients (83%; 95% confidence interval, 35.9–99.6; P

Project High-tech Omics-based Patient Evaluation (HOPE), including comprehensive whole-exome sequencing (WES) and gene expression profiling (GEP) using freshly resected tumor specimens, has been in progress since its implementation in 2014. Among a total of 1,685 cancer patients, 13 melanoma patients were registered in the HOPE Project and were characterized using multi-omics analyses. Among the 13 melanoma patients, 4 were deceased, and 9 were alive. The mean overall survival (OS) and relapse‑free survival (RFS) times of the melanoma patients were 16.9 and 14.7 months, respectively. Previously, we developed an immune response‑associated gene list, which consisted of 164 genes in Project HOPE, for evaluating the immunological status. In the present study, the association of immune response‑associated gene expression with immunological parameters, such as programmed death-ligand 1 (PD-L1) and CD8 expression levels, single nucleotide variant (SNV) number, and Vogelstein driver gene mutation number, was investigated. With respect to PD-L1 expression, both immuno-suppression and immuno-stimulation-related genes were upregulated in PD-L1-positive melanomas. In contrast, regarding Vogelstein driver mutations, several T-cell activation-related genes were significantly downregulated in the high driver gene mutation group. In addition, many T-cell activation-related genes were upregulated in the CD8-positive melanomas. The correlation of immune response-associated gene expression with the survival time of the melanoma patients was investigated. Eight specific genes were commonly identified as genes that were significantly correlated for both the overall OS and RFS time, which could be possible prognostic factors for melanoma patients. These results revealed that an immune response-associated gene panel could be an informative tool for evaluating the immunological status prior to clinical immunotherapy in the upcoming era of genomic cancer medicine.

Background Dabrafenib is a BRAF inhibitor that has demonstrated clinical activity with a good tolerability profile in patients with BRAF

A 70-year-old woman was diagnosed with a malignant melanoma of the occipital skin which was resected; however, multiple lung metastases were detected. Nivolumab therapy was initiated and partial response was obtained. However, the patient was diagnosed with grade 2 interstitial pneumonitis. Prednisolone administration was initiated and the interstitial pneumonitis shadow disappeared. However, then a right rib metastasis was noticed and given radiation therapy. After progressive disease was obtained, the metastatic lesion was resected, and no relapse occurred until skeletal muscle metastasis was found. According to whole-exome sequencing and gene expression profiling, the rib and skeletal muscle metastatic lesions showed an upregulated expression of programmed death-ligand 1 mRNA and a high single-nucleotide variant (SNV) number. The current melanoma case is representative of a patient who responded to nivolumab therapy, and showed typical immunological markers for responders such as high PD-L1 expression and high SNV.

9529 Background: Anti-PD-1 antibodies are used worldwide for patients (pts) with advanced melanoma. Clinical trials have demonstrated its efficacy and safety for nonacral cutaneous melanoma (NACM) in controlled settings. Since acral melanoma (AM) is epidemiologically and molecularly distinct from NACM, data on the real-world efficacy of anti-PD1 antibodies in advanced AM is still lacking. Thus, we aim to analyze the real-world efficacy and safety of anti-PD-1 antibodies in advanced AM. Methods: We retrospectively reviewed clinical records of advanced AM treated in any line with an anti-PD1 antibody at 21 Japanese institutions. Clinical response was assessed by (Response Evaluation Criteria in Solid Tumors) RECIST criteria. Survival was estimated using Kaplan-Meier analysis. Toxicity was assessed according to CTCAE 4.0. Results: A total of 193 pts (median age, 71 years) with advanced AM (subungual, 70; palm and sole, 123) were included in the study. Anti-PD-1 antibody was used as first-line therapy in 143 pts (74.1%). Nivolumab was used in 168 pts and pembrolizumab in 25 pts. Base-line lactate dehydrogenase (LDH) was within normal level in 102 pts (52.8%). The objective response rate (ORR) of all pts was 16.5% (complete response 3.1%, partial response 13.5%), and median overall survival (OS) was 18.1 months. Normal LDH level was significantly associated with better prognosis than abnormal level (median OS 24.9 vs 10.7 months; P < 0.001). Although baseline demographics and characteristics were almost similar between subungual group and palm and sole group, ORR was significantly lower in the subungual group than in palm and sole group (6/70 pts [8.6%] vs 26/123 pts [21.1%]; P = 0.026); median OS was significantly poorer as well (12.8 vs 22.3 months; P = 0.031). Immune-related adverse events of grades 3 to 5 occurred in 27 pts (14.0%). One patient (0.5%) died of grade 5 myasthenia gravis. Conclusions: Real-world efficacy of anti-PD-1 antibodies in AM pts is limited. Notably, pts with subungual melanoma showed poorer response and survival, making them strong candidates for further research of efficacy of anti-CTLA-4 and anti-PD-1 combination therapy.