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Immune checkpoint inhibitors (ICIs) bring prognostic benefits to patients with malignancies. However, there is a substantial number of patients whose lesions are not improved by ICIs. In addition, ICIs may cause immune‐related adverse events (irAEs), which could lead to an unfavorable prognosis with fatal consequences. Therefore, we conducted a retrospective study to evaluate the utility of circulating sPD‐L1 (soluble programmed cell death 1 ligand 1) as a biomarker in patients with advanced melanoma treated with anti–PD‐1 (programmed cell death 1 protein) antibodies. Sera from 31 consecutive patients were prospectively collected before and after anti–PD‐1 antibody treatment and the serum level of sPD‐L1 was evaluated. We found that high sPD‐L1 levels before treatment were associated with better prognosis, and this association was observed only in patients with a low tumor burden. We also found that sPD‐L1 levels were elevated in patients who developed severe irAEs after treatment, and the patients with severe irAEs had significantly higher fluctuations in sPD‐L1 (delta sPD‐L1) than those without severe irAEs. Our study suggests that serum sPD‐L1 level is a useful biomarker to predict tumor response and irAE development in patients with advanced melanoma treated with anti–PD‐1 antibodies. [ABSTRACT FROM AUTHOR]

Pembrolizumab demonstrated an acceptable safety profile and promising antitumor activity in Japanese patients with advanced melanoma in the phase 1b KEYNOTE‐041 (Study of Pembrolizumab [MK‐3475] in Participants With Advanced Melanoma) trial. To evaluate the long‐term efficacy and safety of pembrolizumab in Japanese patients with advanced melanoma in KEYNOTE‐041. The current analysis reports results of additional follow‐up of approximately 12 months since the initial analysis. Eligible patients had locally advanced (unresectable stage III) or metastatic (stage IV) melanoma not amenable to local therapy and had received two or fewer prior systemic therapies. Pembrolizumab 2 mg/kg was given every 3 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Primary end points included safety, tolerability, and overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 by independent central review. The data cutoff for this analysis was August 30, 2017. Forty‐two patients were followed up for a median of 22.3 months (range, 2.63–30.82 months). The ORR was 24.3% (nine of 37 evaluable patients [95% confidence interval (CI), 11.8%–41.2%]). Two patients with partial response at the time of the initial analysis achieved complete response. The median overall survival (OS) was 25.1 months (95% CI, 13.1–not reached] and the 30‐month OS rate was 46.3% (95% CI, 29.8%–61.3%). The median duration of response was not reached. Treatment‐related adverse events (TRAEs) were reported in 78.6% of patients; the incidence of grade 3 to 5 TRAEs was 23.8%. No additional treatment‐related deaths occurred since the initial analysis. Pembrolizumab provided durable antitumor activity and an acceptable safety profile in Japanese patients with advanced melanoma. [ABSTRACT FROM AUTHOR]

Since anti‐PD‐1 Abs can cause irreversible immune‐related adverse events (irAEs), the associations between their efficacies and the incidence of irAEs are important to evaluate the use of anti‐PD‐1Abs for the treatment of melanoma, especially in the adjuvant setting. The purpose of this post hoc analysis study was to retrospectively analyze the associations between recurrence‐free survival (RFS) at 12 months and the onset of any irAEs in 31 non‐acral cutaneous and 30 acral melanoma cases treated with anti‐PD‐1 Abs therapy at the adjuvant setting in Asians. There were 20 cases with greater than grade 1 AEs in both the acral and non‐acral cutaneous groups. Of the acral melanoma, 10 cases were nails or toes, and 20 cases were soles and heels. The log‐rank test showed that RFS was better in cases with AEs than in cases without AEs. The present study suggested that the different profiles of irAEs between non‐acral cutaneous and acral melanoma might correlate with the different response to anti‐PD1 Abs of melanoma in the adjuvant setting. [ABSTRACT FROM AUTHOR]

Cutaneous angiosarcoma (CAS) is an endothelial cell‐derived, highly aggressive type of vascular tumour. Although chemoradiotherapy with paclitaxel (PTX) is recognized as a first‐line therapy for CAS, second‐line therapy for CAS remains controversial, and there is no standard therapy for taxane‐resistant CAS. Plasminogen activator inhibitor‐1 (PAI‐1) is associated with poor clinical outcomes, and elevated levels of PAI‐1 in both tissue and serum are correlated with poor response to therapy in various cancers, including skin cancers. Since PAI‐1 protects endothelial cells from Fas ligand‐mediated apoptosis, PAI‐1 inhibition might induce apoptosis of endothelial cell‐derived tumours such as CAS. This is a single‐arm, open‐label, multi‐institutional, Phase 2 clinical trial to assess the efficacy and safety of PTX in combination with TM5614 (PAI‐1 inhibitor) in patients with PTX‐resistant CAS. PTX will be administered for 28 weeks, with oral administration of TM5614. The primary endpoint of this study will be the overall response rate (ORR) at 28 weeks after starting treatment (central image evaluation). The secondary endpoint will include the ORR at 28 weeks after starting treatment (investigator evaluation), ORR at 8 weeks and 16 weeks after initiation of treatment (central and investigator evaluation), progression‐free survival, overall survival, disease control rate and safety profiles. Assuming the null hypothesis of a response rate of 13.6% and an alternative hypothesis of 45%, a minimum of 15 patients are required to achieve a two‐sided, Type I error of 5% and power of 70% based on the exact binomial distribution. Data quality control will be conducted by a combination of centralized (remote) and on‐site monitoring. This study will contribute to the development of novel combination therapy for PTX‐resistant CAS patients, which remains an unmet clinical need. [ABSTRACT FROM AUTHOR]

Background: Anti‐PD‐1‐based immunotherapy is considered a preferred first‐line treatment for advanced BRAF V600‐mutant melanoma. However, a recent international multi‐center study suggested that the efficacy of immunotherapy is poorer in Asian patients in the non‐acral cutaneous subtype. We hypothesized that the optimal first‐line treatment for Asian patients may be different. Methods: We retrospectively collected data of Asian patients with advanced BRAF V600‐mutant melanoma treated with first‐line BRAF/MEK inhibitors (BRAF/MEKi), anti‐PD‐1 monotherapy (Anti‐PD‐1), and nivolumab plus ipilimumab (PD‐1/CTLA‐4) between 2016 and 2021 from 28 institutions in Japan. Results: We identified 336 patients treated with BRAF/MEKi (n = 236), Anti‐PD‐1 (n = 64) and PD‐1/CTLA‐4 (n = 36). The median follow‐up duration was 19.9 months for all patients and 28.6 months for the 184 pa tients who were alive at their last follow‐up. For patients treated with BRAF/MEKi, anti‐PD‐1, PD‐1/CTLA‐4, the median ages at baseline were 62, 62, and 53 years (p = 0.03); objective response rates were 69%, 27%, and 28% (p < 0.001); median progression‐free survival (PFS) was 14.7, 5.4, and 5.8 months (p = 0.003), and median overall survival (OS) was 34.6, 37.0 months, and not reached, respectively (p = 0.535). In multivariable analysis, hazard ratios (HRs) for PFS of Anti‐PD‐1 and PD‐1/CTLA‐4 compared with BRAF/MEKi were 2.30 (p < 0.001) and 1.38 (p = 0.147), and for OS, HRs were 1.37 (p = 0.111) and 0.56 (p = 0.075), respectively. In propensity‐score matching, BRAF/MEKi showed a tendency for longer PFS and equivalent OS with PD‐1/CTLA‐4 (HRs for PD‐1/CTLA‐4 were 1.78 [p = 0.149]) and 1.03 [p = 0.953], respectively). For patients who received second‐line treatment, BRAF/MEKi followed by PD‐1/CTLA‐4 showed poor survival outcomes. Conclusions: The superiority of PD‐1/CTLA‐4 over BRAF/MEKi appears modest in Asian patients. First‐line BRAF/MEKi remains feasible, but it is difficult to salvage at progression. Ethnicity should be considered when selecting systemic therapies until personalized biomarkers are available in daily practice. Further studies are needed to establish the optimal treatment sequence for Asian patients. [ABSTRACT FROM AUTHOR]

Cutaneous angiosarcoma (CAS) is a rare and highly aggressive type of vascular tumor. Although chemoradiotherapy with taxanes is recognized as a first‐line therapy for CAS, second‐line therapy for CAS remains controversial. From the above findings, the efficacy and safety profiles of taxane‐switch (change paclitaxel to docetaxel or vise), eribulin methylate, and pazopanib regimens in second‐line chemotherapy were evaluated retrospectively in 50 Japanese taxane‐resistant CAS patients. Although there was no significant difference in progression‐free survival (P = 0.3528) among the regimens, the incidence of all adverse events (AEs) (P = 0.0386), as well as severe G3 or more AEs (P = 0.0477) was significantly higher in the eribulin methylate group and pazopanib group than in the taxane‐switch group. The present data suggest that switching to another taxane should be considered for the treatment of taxane‐resistant CAS in second‐line therapy based on the safety profiles. [ABSTRACT FROM AUTHOR]

Several studies have demonstrated the usefulness of negative pressure closure (NPC) for the stabilization of skin grafts because it provides a uniform pressure to the graft. The results of our previous retrospective study also suggested the superiority of NPC over tie‐over methods for the stabilization of split‐thickness skin graft (STSG) in large or muscle‐exposing defects. However, the usefulness of NPC for graft stabilization is yet to be fully established. This prospective, phase II clinical study was conducted to investigate the safety and efficacy of NPC for the stabilization of STSG in large or muscle‐exposing defects. Patients who would require STSG for reconstruction of defects in the trunk and extremities other than hands and feet measuring >10 cm in the longest diameter or with muscle exposure were enrolled. NPC was applied for skin graft stabilization. Seven patients who had received wide excision of malignant tumors and resulted in muscle‐exposed skin defects were included. All patients underwent meshed STSG. The mean size of the defect was 94.5 cm2 (range 63.6–164.9). The mean time from the skin graft harvesting to the NPC stabilization was 15.6 min (range 10.7–19.5). The mean survival rate of the skin graft at postoperative day 7 and 10 was 98.7% (range 97–100) and 96.5% (range 89.4–98.4), respectively. No adverse events associated with the procedure were observed. This prospective study provided further evidence of the safety and efficacy of NPC for STSG stabilization in patients with large or muscle‐exposing skin defects. [ABSTRACT FROM AUTHOR]

We report the 5‐year follow‐up results from a single‐arm, open‐label, multicenter phase II study (ONO‐4538‐08) conducted in Japan. Twenty‐four patients with treatment‐naïve, recurrent, or unresectable stage III/IV malignant melanoma received 3 mg/kg nivolumab every 2 weeks until progressive disease or unacceptable toxicity occurred. The 5‐year overall survival (OS) rate was 26.1%. Five years after the start of nivolumab treatment, there were six survivors. The 5‐year OS rate was 66.7% for patients with a superficial spreading type, 14.3% for acral lentiginous type, and 16.7% for mucosal type. The 5‐year progression‐free survival rate was 17.2%. No new cases of partial response or complete response were observed after 3 years, and overall response and disease control rates were similar to those reported at 3 years. The treatment‐related adverse events reported between the 3‐ and 5‐year follow‐up periods were anemia (grade 2), white blood cell count decrease (grade 2), and psoriasiform dermatitis (grade 2) in one patient each. No new grade 3 or higher treatment‐related adverse events occurred in this period. In conclusion, first‐line treatment with nivolumab in Japanese patients with unresectable or metastatic melanoma resulted in confirmed long‐term survival. No new safety signals were reported in the studied population. [ABSTRACT FROM AUTHOR]

Surgical‐site infection (SSI) is one of the major postoperative complications in surgery, which can cause significant morbidity. However, factors associated with SSI in dermatological surgery are not well understood. Here, we retrospectively investigated 512 patients who underwent outpatient surgery for skin tumors at the University of Tsukuba Hospital to analyze factors associated with postoperative SSI. The overall incidence of SSI was 28 (5.5%). Univariate logistic regression analysis revealed that SSI was significantly associated with invasive squamous cell carcinoma (iSCC), Bowen's disease (BD), actinic keratosis (AK), longer diameter of defects, presence of ulcer, reconstruction with full‐thickness skin graft and local skin flaps, medical history of diabetes mellitus, and use of immunosuppressive agents. However, in the multivariate analysis only iSCC, BD, and AK retained significance. The frequencies of SSI in iSCC, BD, and AK were 22% (13/58 patients), 15.6% (5/32), and 25% (2/8), respectively; however, the frequency of other non‐SCC tumors was only 1.9% (8/414). χ2‐Tests revealed that the frequency of SSI in iSCC, BD, and AK were all significantly higher than in non‐SCC tumors, with the frequencies being more than eight times higher. These results suggest that invasive and in situ lesions of SCC are independent risk factors of SSI development after outpatient skin surgery. [ABSTRACT FROM AUTHOR]

The efficacy of encorafenib plus binimetinib (E + B) combination therapy for BRAF‐mutated advanced melanoma as second‐line therapy and beyond is still unknown. In this report, we investigated 22 cases of BRAF‐mutated advanced melanoma treated with E + B combination therapy. The objective response rate (ORR) for the total cohort was 68.4%. Notably, the ORR for the second‐line and beyond cohort was 73.3%, suggesting that the therapeutic effect of E + B combination therapy is comparable with that of first‐line targeted therapy. In contrast, overall survival and progress‐free survival in our present cohort was worse than that in a previous clinical trial. Notably, although the incidence rate of severe adverse events was higher than that in a previous report, our present study suggested that E + B combination therapy is a well‐tolerated antimelanoma regimen. Our present study suggested that the efficacy and safety profile of E + B combination therapy as a second‐line therapy and beyond is comparable with that of first‐line targeted therapy. [ABSTRACT FROM AUTHOR]

Recent clinical trials revealed that both immune checkpoint inhibitors (ICI) and BRAF/MEK inhibitors significantly prolonged survival in melanoma patients when used for both advanced stage disease and postoperative adjuvant therapy. Although BRAF/MEK inhibitors are associated with a higher objective response rate than ICI, most patients relapse during treatment. However, progression patterns during treatment with BRAF/MEK inhibitors have not been extensively investigated. Here, we retrospectively collected the data of melanoma patients initially treated with BRAF/MEK inhibitors or anti‐programmed death 1 (PD‐1) antibody monotherapy at the University of Tsukuba Hospital and compared their results. The χ2‐test revealed that frequency of brain metastasis (BM) development was significantly higher in cases treated with BRAF/MEK inhibitors compared with those with anti‐PD‐1 antibody monotherapy. In addition, BM‐free survival in cases treated with BRAF/MEK inhibitors was significantly shorter than those treated with anti‐PD‐1 antibody monotherapy. Our results indicate that BM development during treatment with BRAF/MEK inhibitors may be more frequent than anti‐PD‐1 antibody monotherapy, even though the extracranial metastases are well controlled. Therefore, we recommend frequent brain examinations during treatment with BRAF/MEK inhibitors to detect BM at an early stage and to promptly administrate ICI with local radiation therapy. [ABSTRACT FROM AUTHOR]

Vitiligo is an autoimmune disorder resulting from the destruction of melanocytes. Several reports indicate the association between vitiligo and treatment response in advanced melanoma during immunotherapy. It has not been investigated, however, if an increase of vitiligo while on treatment with anti‐programmed death 1 (PD‐1) antibodies is associated with more durable responses. The aim of this study is to evaluate the correlation between the vitiligo dynamics and clinical efficacy of anti‐PD‐1 antibodies. This study included advanced melanoma patients who were treated with nivolumab or pembrolizumab and developed vitiligo thereafter. Correlation between vitiligo expansion (defined as an increase of lesion size at two separate time points at least 4 weeks apart) as well as vitiligo extent (body surface area [BSA] affected) and clinical efficacy based on response rate, progression‐free survival and overall survival was assessed. We retrospectively reviewed 29 patients. The median time from the initiation of anti‐PD‐1 antibody to vitiligo onset was 4.3 months in patients who showed a response and 5.5 months in patients who showed no response (P = 0.31). Twelve patients showed vitiligo expansion, and in nine of these patients, vitiligo increased to grade 2 (covering ≥ 10% BSA). Vitiligo expansion and grade 2 vitiligo showed no improvement in treatment response (P = 0.59 and 0.25) but were associated with prolonged progression‐free survival (P = 0.019 and 0.04). Grade 2 vitiligo also showed a trend for prolonged overall survival (P = 0.07). Trend of expansion and larger vitiligo extent may be predictive factors of prolonged survival during anti‐PD‐1 antibody in melanoma patients. [ABSTRACT FROM AUTHOR]

Bexarotene is useful for both early and advanced cutaneous T‐cell lymphoma (CTCL), and is sometimes applied to ultraviolet‐tolerant early CTCL patients as one of the first‐line therapies in the real world. However, continuous administration of bexarotene is sometimes difficult because of its adverse events (AE). Development of an appropriate protocol for bexarotene that can induce a consistent response for CTCL without severe AE (SAE) is needed. We retrospectively investigated 29 Japanese cases of CTCL and evaluated the efficacy of treatment and incident ratios of all AE and SAE. Objective response rate (ORR) for the overall cohort was 65.5%. ORR of the 300 mg/m2 cohort (conventional dose) was 76.2%, while that of the 150–300 mg/body (low dose) with narrowband ultraviolet B light (NBUVB) cohort was 37.5%. Mean event‐free survival was 10.0 months for all patients, 6.7 months for the bexarotene conventional‐dose cohort and 19.1 months for the low‐dose with NBUVB cohort. The incident ratio of total SAE for all patients was 20.7%. The incident ratio of total SAE was 23.8% for the conventional‐dose cohort and 12.5% for the low‐dose with NBUVB cohort. Our present study suggests that low‐dose bexarotene plus NBUVB therapy is well‐tolerated and could be one of the optimal therapies for advanced CTCL. [ABSTRACT FROM AUTHOR]

Angiomatoid Spitz nevus (ASN) is a rare histological variant of Spitz nevus (SN) that is characterized by prominent blood vessel proliferation around the intradermal melanocytes of SN. In contrast, SN may have pagetoid components, which are characterized by epidermal proliferation of single melanocytes. However, cases of ASN with predominant pagetoid melanocytic proliferation in the epidermis have not been reported. Here, we report a case of ASN with surrounding pagetoid melanocytic proliferation without formation of tumor nests in the epidermis in the plantar region. A 12‐year‐old girl presented with a bright red nodule surrounded by a brown macule on the sole of her right foot. Histologically, the nodule showed tumor nests in the dermis, composed of spindle or epithelioid melanocytes containing abundant cytoplasm and large nuclei. Around the nests, numerous blood vessels were seen. In the overlying epidermis of the nodule, numerous eosinophilic Kamino bodies were found along the dermal–epidermal interface. In the macule, proliferation of oval melanocytes was present as single‐cell units in the epidermis. Theses melanocytes had abundant cytoplasm with large nuclei, which were larger than those of the surrounding keratinocytes. From these findings, a diagnosis of ASN with surrounding pagetoid melanocytic proliferation was made. Vascular endothelial growth factor and fibroblast growth factor 2 were strongly expressed in the melanocytes as well as in the endothelial cells in our case. Therefore, angiogenic factors produced by the melanocytes of SN might have played important roles in the surrounding angiogenesis of this case. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors have improved the prognosis of advanced melanoma. Although anti–programmed death ligand‐1 (PD‐L1) is a well‐studied biomarker for response to anti–programmed death‐1 PD‐1 therapy in melanoma, its clinical relevance remains unclear. It has been established that the high expression of indoleamine 2,3‐dioxygenase (IDO) is correlated to a response to anti–CTLA‐4 treatment in melanoma. However, it is still unknown whether the IDO expression is associated with response to anti–PD‐1 therapy in advanced melanoma. In addition, acral and mucosal melanomas, which comprise a great proportion of all melanomas in Asians, are genetically different subtypes from cutaneous melanomas; however, they have not been independently analyzed due to their low frequency in Western countries. To evaluate the association of IDO and PD‐L1 expression with response to anti–PD‐1 antibody in acral and mucosal melanoma patients, we analyzed 32 Japanese patients with acral and mucosal melanomas treated with anti–PD‐1 antibody from the perspective of IDO and PD‐L1 expression levels by immunohistochemistry (IHC). Multivariate Cox regression models showed that the low expression of IDO in tumors was associated with poor progression‐free survival (HR = 0.33, 95% CI = 0.13‐0.81, P = 0.016), whereas PD‐L1 expression on tumors was not associated with progression‐free survival. Significantly lower expression of IDO in tumors was found in non–responders compared to responders. Assessment of the IDO expression could be useful for the identification of suitable candidates for anti–PD‐1 therapy among acral and mucosal melanomas patients. Further validation study is needed to estimate the clinical utility of our findings. [ABSTRACT FROM AUTHOR]

Immune microenvironment controls the outcome of PD-1 blockade in cutaneous immune response The introduction of immune checkpoint inhibitors (ICI) targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway or cytotoxic T-lymphocyte antigen 4 (CTLA-4) has brought about a revolution in anticancer therapy by embodying the concept that the host's exhausted pre-existing antitumor immunity can be reactivated. In line with the fact that the PD-1/PD-L1 pathway promotes T-cell exhaustion at the periphery and thereby prevents pathological consequences in various mouse models of infection or autoimmune diseases,[2] we have shown the exaggerated allergic response in the skin. [Extracted from the article]

Malassezia yeast play a role in the pathogenesis of chronic dermatitis, especially in apocrine areas, by polarizing the local immunologic background to a Th2/Th17 state through aryl hydrocarbon receptor (AhR)‐dependent pathways. Extra‐mammary Paget's disease (EMPD) is an adenocarcinoma of apocrine origin, and except for cases associated with Malassezia yeast and their metabolites, the lesions typically develop in areas not exposed to environmental material. The purpose of this study was to investigate (a) the immunomodulatory effects of Malassezia metabolites on normal human keratinocytes (NHKCs), focusing on interleukin (IL)‐17 and related cytokines/chemokines (IL‐23, IL‐36γ, CCL20), (b) the expression of these factors in lesion‐affected skin in EMPD and (c) the activation of tumor‐associated macrophages (TAMs) by these factors. Malassezia metabolites augmented the expression of cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1), CCL20 and IL‐36γ mRNA in NHKCs in vitro. In lesion‐affected skin of patients with EMPD, epidermal keratinocytes expressed CYP1A1 and CCL20. In addition, Paget cells expressed CCL20 and IL‐23. IL‐17–producing cells were distributed adjacent to Paget cells. Compared to healthy donors, patients with EMPD exhibited significantly increased serum levels of soluble (s)CD163, CXCL5, CXCL10 and CCL20. In addition, serum levels of sCD163 decreased significantly following tumor resection. Our study demonstrates a possible mechanism for the development of EMPD involving AhR‐mediated signalling by epidermal keratinocytes and RANKL‐induced recruitment of Th17 cells and TAMs. [ABSTRACT FROM AUTHOR]

Pyrexia is the most common adverse event in patients with melanoma or other solid organ malignancies that are treated with the combination of dabrafenib and trametinib (combi‐DT). Given the expanded indication for combi‐DT, management of pyrexia is a high priority. No previous case series has revealed which blood markers reflect the course of pyrexia and there is no consensus on the management strategy for pyrexia. The current case series study describes the utility of neutrophil count (NC), neutrophil ratio (NR) and C‐reactive protein (CRP) in 11 patients with metastatic melanoma and BRAF V600 mutations who experienced pyrexia during combi‐DT in our department. We also described the clinical course of pyrexia episodes that were managed with the concomitant use of oral prednisolone and immediate withdrawal of combi‐DT. Consequently, the analysis of 37 pyrexia episodes in 11 patients showed that the differences in NC, NR and CRP at the onset of pyrexia were significantly different from those at pyretolysis (P = 0.01, 0.006 and 0.03, respectively). Additionally, in the 24 pyrexia episodes treated with the concomitant use of oral prednisolone and the immediate withdrawal of combi‐DT, the mean duration of pyrexia and the mean time to restart combi‐DT were 3 and 6 days, respectively. Therefore, the blood markers that reflect the course of pyrexia during combi‐DT may be helpful for the appropriate management of pyrexia; also, our management strategy for pyrexia successfully reduced the duration of pyrexia and did not require a long‐term drug holiday. Further large‐scale studies are required to verify our results. [ABSTRACT FROM AUTHOR]

The immune checkpoint inhibitor nivolumab inhibits the programmed death 1 receptor and suppresses the immune resistance of cancer cells. This is a long‐term follow up of a single‐arm, open‐label, multicenter, phase II study of nivolumab in untreated Japanese patients with stage III/IV or recurrent melanoma. In addition, a post–hoc subgroup analysis stratified by melanoma types was performed. Nivolumab was administered intravenously at a dose of 3 mg/kg every 2 weeks. The primary endpoint was the overall response rate (ORR), and secondary endpoints included overall survival (OS), progression‐free survival (PFS), best overall response, the disease control rate and change in tumor diameter. Safety was assessed by recording treatment‐related adverse events (TRAE), including select immune‐related adverse events. Of the 24 patients initially included in the primary phase II study, 10 survived for over 3 years (41.7%). The ORR was 34.8% (90% confidence interval [CI]: 20.8, 51.9) for all patients. When analyzing by melanoma type, the ORR was 66.7% (90% CI: 34.7, 88.3) for superficial spreading, 33.3% (90% CI: 11.7, 65.3) for mucosal, and 28.6% (90% CI: 10.0, 59.1) for acral lentiginous tumors. The median OS was 32.9 months, the 3‐year OS rate was 43.5%, and the 3‐year PFS rate was 17.2%. A long‐term response was observed in all the tumor types. The most common TRAE included skin toxicity (45.8%) and endocrine disorders (29.2%). This study demonstrated the long‐term efficacy and tolerability of nivolumab in patients with advanced or recurrent melanoma, irrespective of melanoma type. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Morphea profunda refers to inflammatory and sclerotic lesions that start primarily from the deep dermis, subcutaneous fat and fascia. Its pediatric case published work is limited. Here, we report the case of an 8‐year‐old girl with a 5‐year history of multiple subcutaneous nodules on her extremities and a right wrist joint contracture who had been previously diagnosed with juvenile idiopathic arthritis and treated with salazosulfapyridine, low‐dose prednisolone (PSL) and methotrexate. We performed biopsies of two subcutaneous nodules, which revealed the typical morphology of morphea profunda. She was administrated a tapered course of oral PSL then cyclosporin A (CyA) for 20 weeks which completely resolved her joint contracture and subcutaneous nodules. We reviewed 11 previously reported cases of morphea profunda and found that some include circumscribed/linear morphea that develop into subcutaneous tissues, indicating that "classical" morphea profunda arising within the deep tissues has rarely been reported. Our report is the first to demonstrate the efficacy of CyA for treatment of morphea profunda, and the possibility of CyA as a treatment option to reduce oral steroid doses in juvenile cases. [ABSTRACT FROM AUTHOR]

Abstract: Skin grafts are frequently used for the reconstruction of skin defects, and optimal stabilization of the graft is essential for successful reconstruction. Although the tie‐over technique has been widely used as a standard method in Japan, we sometimes encounter cases with significant graft loss due to suboptimal stabilization of the graft. Reported risk factors for increased graft loss include the following: defects of a large size, with muscle exposure, and located in the trunk and extremities. Recent studies have demonstrated the usefulness of negative‐pressure closure (NPC) for the stabilization of skin grafts due to the uniform pressure it provides across the graft. Therefore, since March 2017, we have used NPC for skin graft stabilization in patients with defects in the trunk and extremities of more than 10 cm in size or with muscle exposure. We carried out a retrospective comparative study of the outcome of the conventional tie‐over technique versus NPC. Mann–Whitney U‐test revealed that NPC showed significantly higher graft survival rate than tie‐over method (P = 0.0012). In addition, NPC showed a tendency toward shorter operative times (from skin graft harvest to the completion of the graft stabilization) than the tie‐over method (P = 0.0931). These results suggest that NPC may be superior to the tie‐over method for stabilization of skin grafts especially in large or muscle‐exposing defects in the trunk or extremities. [ABSTRACT FROM AUTHOR]

Pyoderma gangrenosum ( PG) is a chronic inflammatory disease of unknown cause that presents as an inflammatory and ulcerative disorder of the skin. PG is often associated with an underlying systemic disease. However, the frequencies of the underlying diseases are unclear in Japanese patients. In this retrospective, observational study, all patients diagnosed with PG who visited dermatology departments of nine regional hospitals in and around Ibaraki Prefecture were collected from 1982 to 2011 or 2014. The diagnoses of PG were based on the characteristic clinical and histological appearances and ruling out of infection. Sixty-two PG patients, including 29 males and 33 females, were identified. The ages of onset were 16-89 years, and the mean age was 50.2 years. Fifty (80%) of the 62 patients presented with an ulcerative PG, and the lower leg was the most common site (74%). Forty-six (74%) PG patients had underlying diseases. The most frequent was ulcerative colitis (32%), followed by myelodysplastic syndrome (11%), rheumatoid arthritis (6%) and aortitis syndrome (5%). For treatment, 54 cases (87%) received systemic corticosteroids and 10 received additional treatment with cyclosporin. There was no significant correlation between underlying diseases and response to the initial treatment. Multivariate analysis revealed that the number of affected sites negatively correlated with successful initial treatment. Fifteen (24%) of the 62 cases relapsed. In conclusion, ulcerative colitis and hematological disorders were frequently associated with PG while approximately a quarter of the cases were idiopathic. [ABSTRACT FROM AUTHOR]

Background The number of very elderly patients who require surgery for cutaneous tumors is increasing. However, there is limited information on the safety of cutaneous surgery in such patients. Methods To evaluate the safety of cutaneous surgery in patients 90 years of age and older, we retrospectively reviewed the elderly patients who underwent surgery for cutaneous tumors under local anesthesia. Consecutive patients 90 years of age and older and 75-80 years old were included in the elderly group and the control group. Results The elderly and control groups included 104 and 106 patients, respectively. The mean age of the patients was 93.4 years (range, 90-101 years) in the elderly group and 77.4 years (range, 75-80 years) in the control group. The preoperative performance status was significantly worse in the elderly group than in the control group ( P < 0.001). The surgical time was not significantly different between the two groups ( P = 0.09). The occurrences of intraoperative and postoperative complications were not significantly different between the two groups ( P = 0.19 and P = 0.07, respectively). Conclusions The result of the present study indicates that cutaneous surgery for very elderly patients 90 years of age and older is as safe as for patients ranging in age from 75-80 years old. [ABSTRACT FROM AUTHOR]

Promising antitumor activities of nivolumab, a fully humanized IgG4 inhibitor antibody against the programmed death-1 protein, were suggested in previous phase 1 studies. The present phase 2, single-arm study ( JAPIC- CTI #111681) evaluated the antitumor activities of nivolumab and explored its predictive correlates in advanced melanoma patients at 11 sites in Japan. Intravenous nivolumab 2 mg/kg was given repeatedly at 3-week intervals to 35 of 37 patients enrolled from December 2011 to May 2012 until they experienced unacceptable toxicity, disease progression, or complete response. Primary endpoint was objective response rate. Serum levels of immune modulators were assessed at multiple time points. As of 21 October 2014, median response duration, median progression-free survival, and median overall survival were 463 days, 169 days, and 18.0 months, respectively. The overall response rate and 1- and 2-year survival rates were 28.6%, 54.3%, and 42.9%, respectively. Thirteen patients remained alive at the end of the observation period and no deaths were drug related. Grade 3-4 drug-related adverse events were observed in 31.4% of patients. Pretreatment serum interferon-γ, and interleukin-6 and -10 levels were significantly higher in the patients with objective tumor responses than in those with tumor progression. In conclusion, giving repeated i.v. nivolumab had potent and durable antitumor effects and a manageable safety profile in advanced melanoma patients, strongly suggesting the usefulness of nivolumab for advanced melanoma and the usefulness of pretreatment serum cytokine profiles as correlates for predicting treatment efficacy. [ABSTRACT FROM AUTHOR]

Cutaneous squamous cell carcinoma is the second common cutaneous cancer, especially in the elderly. Sentinel lymph node biopsy is generally performed in breast cancers and cutaneous melanomas to detect occult nodal metastases. The benefit of sentinel lymph node biopsy in improving cutaneous squamous cell carcinoma prognosis is doubtful. One hundred and sixty-nine patients who underwent treatment for cutaneous squamous cell carcinoma between 2004 and 2015, and who were followed up for at least 6 months or developed metastases within the follow-up period were included. Forty-nine patients underwent sentinel lymph node biopsy, whereas 120 patients did not, including 13 who exhibited clinical lymph node metastases before treatment. Of these 49 patients, nine (18.4%) presented with sentinel lymph node metastasis, which occurred after treatment in three (6.1%) of them (false-negative). Among the 107 patients who did not undergo lymph node biopsy, 12 (11.2%) developed post-treatment metastases. The metastasis-free and disease-specific survival rates were not significantly different in those who did or did not undergo sentinel lymph node biopsy. Patients with clinical lymph node metastases had a higher risk compared with those without. Patients with T2-T4 tumors had a higher risk compared with those with T1 tumors. When selecting for those with T2 tumors or greater, the same lack of relationship was observed. In conclusion, in this small retrospective cohort, in patients with cutaneous squamous cell carcinoma, there were no significant differences in metastasis-free and disease-specific survival rates between those who did or did not undergo sentinel lymph node biopsy, regardless of T staging. [ABSTRACT FROM AUTHOR]

Vitiligo is occasionally seen in melanoma patients. Although several studies indicate a correlation between vitiligo occurrence and clinical response in melanoma patients receiving immunotherapy, most studies have included heterogeneous patient and treatment settings. The aim of this study is to investigate the correlation between the occurrence of vitiligo and clinical benefit of nivolumab treatment in advanced melanoma patients. We retrospectively reviewed unresectable stage III or IV melanoma patients treated with nivolumab. Of 35 melanoma patients treated with nivolumab, 25.7% (9/35) developed vitiligo during treatment. The time from the start of nivolumab treatment to occurrence of vitiligo ranged 2-9 months (mean, 5.2). Of nine patients who developed vitiligo, two (22.2%) had a complete response to nivolumab and two (22.2%) had a partial response. The objective response rate was significantly higher in patients with vitiligo than in patients without vitiligo (4/9 [44.4%] vs 2/26 [7.7%]; P = 0.027). The mean time to vitiligo occurrence in patients achieving an objective response was significantly less than that in patients who showed no response (3.1 vs 6.8 months, P = 0.004). Vitiligo occurrence was significantly associated with prolonged progression-free and overall survival (hazard ratio, 0.24 and 0.16; 95% confidence interval, 0.11-0.55 and 0.03-0.79; P = 0.005, and 0.047, respectively). At the 20-week landmark analysis, however, vitiligo was not associated with a statistically significant overall survival benefit ( P = 0.28). The occurrence of vitiligo during nivolumab treatment may be correlated with favorable clinical outcome. [ABSTRACT FROM AUTHOR]

Although recent clinical trials have revealed that immune checkpoint inhibitors significantly improved the overall survival (OS) of patients with advanced melanoma, these previous studies comprised mainly white populations, in which superficial spreading melanoma (SSM) and lentigo maligna melanoma are the major clinical types of melanoma. In contrast, Asians manifest a distinct clinicopathological type of melanoma from that of whites and show much higher frequencies of acral lentiginous melanoma (ALM) and mucosal melanoma, which have been shown to be less susceptible to immune checkpoint inhibitors. Because no comparative studies have been published showing improvement of OS by immune checkpoint inhibitors in Asian melanoma patients, we retrospectively collected the data for 45 melanoma patients treated with checkpoint inhibitors and 24 melanoma patients treated with chemotherapy alone before immune checkpoint inhibitors became available, and compared their OS. The results showed that the patients treated with immune checkpoint inhibitors had significantly better OS than did those treated with chemotherapy alone (P < 0.0001). Improved OS was observed in both the SSM and the ALM patients. In addition, multivariate Cox regression analyses revealed that use of immune checkpoint inhibitors was associated with favorable prognosis (P = 0.0001), indicating that use of immune checkpoint inhibitors is an independent factor for favorable survival. Our study showed that immune checkpoint inhibitors may also improve the prognosis of Asian melanoma patients. [ABSTRACT FROM AUTHOR]

In invasive extramammary Paget's disease ( EMPD), distant metastases may develop and the condition may become fatal; however, no standardized treatment has been established. Although based on only a few cases, several chemotherapy regimens were reported to be promising. We conducted a multicenter, retrospective study to evaluate the efficacy of docetaxel for metastatic EMPD. We retrospectively collected data on 18 metastatic EMPD patients treated using docetaxel from 1998 to 2012 in 12 institutes in Japan. The following clinical data were collected: tumor response, time to progression, overall survival and adverse effects. Of those, three patients treated combined with S-1, one patient treated with weekly schedule and one patient treated combined with radiotherapy were excluded from the further analysis. All 13 patients received monthly docetaxel as the first-line treatment. The average number of treatment cycles was 9.1. Among the 12 patients with a confirmed response, seven (58%) showed a partial response, three (25%) stable disease and two (17%) progressive disease. The disease control rate (partial response + stable disease) was as high as 83%. The time to progression and median overall survival were 7.1 and 16.6 months, respectively. The 1-year overall survival rate determined by the Kaplan-Meier method was 75.0%. All adverse effects were manageable and no treatment-related deaths were observed. The high disease control rate and overall survival shown by this study suggest that first-line use of docetaxel may be a promising treatment for metastatic EMPD. A prospective clinical trial is required to confirm our results. [ABSTRACT FROM AUTHOR]

Subungual melanomas ( SUM) are rare, and amputation is often required. Non-amputative wide local excision ( WLE) of the nail unit with the periosteum of the distal phalanx, followed by skin graft, has been accepted for in situ or SUM of 0.5 mm or less thickness. However, previous reports have included a limited number of cases, and not all more than 0.5-mm thick SUM exhibit invasion or attachment to the distal phalanx. The aim of the present study was to investigate the local recurrence and prognosis for in situ, minimally invasive and invasive SUM that were treated using WLE. We retrospectively reviewed 50 patients with in situ ( n = 48) or minimally invasive SUM ( n = 2) ( in situ or minimally invasive group) and 12 patients with more than 0.5-mm thick invasive SUM (invasive group) who were treated using WLE. All patients survived the follow-up period (24-207 months), although four patients with in situ SUM experienced local recurrence at the lateral margin and re-excision was required. In the invasive group, no patients experienced local recurrence, although one patient (8.3%) developed nodal metastasis at 86 months and regional lymph node dissection was required. WLE may provide acceptable local control for in situ and intermediate thickness SUM, without compromising the vital prognosis. However, a larger randomized prospective study with long-term follow up is required to evaluate adequately the risks associated with a non-amputative WLE for in situ and invasive SUM. [ABSTRACT FROM AUTHOR]

Basal cell carcinoma ( BCC) is a common malignant skin tumor. However, BCC that arise at the umbilicus is rare. We present three cases of umbilical BCC. Each BCC was excised at a different depth level, and all deep surgical margins were negative. All patients had no evidence of local recurrence or metastasis during the follow-up periods (12, 24, and 52 months). Reviewing the reported cases of umbilical BCC, the BCC cells did not seem to invade into the umbilical scar in most cases, and the deepest invasion levels of tumor cells were up to the middle layer of the subcutaneous tissue. However, the dermatological surgeons have to consider the possibility of surgical excision down to and including the umbilical attachment to the peritoneum, and intraoperative margin assessment should be necessary to avoid the risk of excessive or incomplete excision. [ABSTRACT FROM AUTHOR]

Subungual melanoma ( SUM) is rare and represents approximately 2-3% and 20% of all cutaneous melanomas in Caucasians and Asians, respectively. Amputation has usually been performed for invasive SUM; however, not all invasive SUMs invade or attach to the distal phalanx. To investigate the possibility of non-amputative surgery for patients with invasive SUM, the distances between the deepest base of the melanoma cells and the bony surface in the surgical specimens of invasive SUM were measured. Thirty surgical specimens of invasive SUM were retrospectively reviewed. The contents of the specimens were as follows: 14 first toes, 10 thumbs, three second fingers, two third fingers, and one fifth finger. Four specimens showed bone invasion, and the tumor was attached to the bone in four specimens. The tumor-to-bone distance exceeded 0.9 mm in all the specimens with thicknesses <4 mm. In the non-ulcerated SUMs (nine specimens), only one SUM specimen showed bone attachment. There was a higher likelihood of bone attachment or invasion when tumor thickness (TT) exceeded 4 mm (Pearson chi-square test, P = 0.009; Fisher exact test, P = 0.004; student t test, 0.033). Univariate and multivariate analysis also revealed that thick TT had a statistically significant affect (odds ratio 1.807 and 1.865, 95% CI 1.11-3.01 and 1.11-3.13, P = 0.023 and 0.018). Non-amputative surgery may be possible for SUM tumors that are of intermediate-thickness. However, there has been little evidence demonstrating survival with non-amputative surgery for invasive SUM. A large, randomized, prospective clinical study is required to address this issue. [ABSTRACT FROM AUTHOR]

Lipomas are common, benign, small-sized, soft-tissue tumors. However, giant lipomas are uncommon and the tumor size can cause pain and nerve compression syndrome. The axilla is an extremely rare location for development of giant lipomas. We report two cases of axillary giant lipoma. A 47-year-old man (case 1) and a 42-year-old woman (case 2) presented with a large mass in the axillary region. Case 2 had tenderness in the shoulder and numbness in the upper arm. Magnetic resonance imaging of each tumor showed a homogenous soft-tissue mass in the axillary region, suggestive of lipoma. In case 2, the tumor extended from the axilla to the supraclavicular region and split and compressed the neurovascular bundle. Each lesion was successfully excised surgically without serious complications and recurrence. In case 2, the tenderness and numbness disappeared. Histologically, each lesion was composed of multilobulated, mature adipose cells, which led to a diagnosis of benign lipoma. Axillary giant lipoma is preferably excised surgically to avoid damage caused by tumor compression to the major vessels or nerves, to offer better local control and to establish a correct final diagnosis. [ABSTRACT FROM AUTHOR]

Mucoepidermoid carcinoma ( MEC) usually originates from the salivary glands. However, there has been no report on mucoepidermoid carcinoma of the columella. In this study, we report the case of a high-grade MEC of the columella that was successfully reconstructed after surgical resection with bilateral nasolabial flaps set up in a sandwich shape and an auricular cartilage graft. A 66-year-old man presented with a nodule on the columella. Histological findings were suggestive of a high-grade mucoepidermoid carcinoma. Wide excision was performed, and the defects of the columella and the nasal floor were reconstructed with bilateral nasolabial flaps set up in a sandwich shape and an auricular cartilage graft. The postoperative cosmetic result was good with excellent tissue texture. The reconstructed columella had an appropriate, not bulky, width as well as satisfactory height and depth. This reconstructive technique is particularly useful for correcting the large defect of the columella with nasal septum and/or nasal floor defects. [ABSTRACT FROM AUTHOR]