BACKGROUND: Nemolizumab reduces pruritus and skin lesions in patients with atopic dermatitis (AD), yet some patients develop cutaneous adverse events (CAEs) with increased serum thymus- and activation-regulated chemokine (TARC); mechanisms are unclear. OBJECTIVE: Define systemic changes and the mechanism underlying TARC elevation after IL-31 receptor A (IL-31RA) blockade. METHODS: Serum proteomics (Olink), MC903 models ± anti-IL-31RA, skin single-cell RNA-seq of AD skin with in situ validation, functional assays using human dendritic cells (DCs), and human dorsal root ganglion analyses with ligand-receptor inference were integrated. RESULTS: In patients with CAEs, TARC levels increased and correlated with type 2 markers. In mice, IL-31RA blockade increased serum and dermal TARC without broad transcriptomic shifts. A Ccl17-T2A-GFP reporter localized TARC to dermal DCs, enriched in type 2 conventional dendritic cell (cDC2). In patients, CCL17 localized to LAMP3+ CD1c+ mature DCs in situ. Analyses supported calcitonin gene-related peptide (CGRP) signaling via the calcitonin receptor-like (CALCRL) signaling from IL-31RA/oncostatin M receptor (OSMR)-positive nociceptors to mature DCs; CGRP reduced DC maturation and TARC in vitro. CONCLUSION: Findings support an IL-31-dependent CGRP-CALCRL neuroimmune brake that restrains DC maturation and TARC. IL-31RA blockade disinhibits this circuit, linking antipruritic therapy to DC-driven chemokine programs and offering a rationale for stronger TARC responses in patients than in the MC903 model. Monitoring TARC and neuroimmune context may aid management of nemolizumab-treated patients with AD.

BACKGROUND: Data in East Asian patients and in other epithelial skin cancers, including extramammary Paget's disease (EMPD) and adnexal carcinomas, are scarce. Therefore, we conducted a phase II trial of nivolumab in Japanese patients with advanced non-melanoma skin cancers (NMSCs). PATIENTS AND METHODS: This multicentre, open-label, single-arm phase II study enrolled adults (≥ 20 years) with histologically confirmed unresectable or recurrent epithelial cutaneous malignancies, Eastern Cooperative Oncology Group performance status 0-1, and at least one measurable lesion (RECIST v1.1). Nivolumab 480 mg was administered intravenously every 4 weeks for up to 26 cycles. The primary endpoint was overall response rate (ORR), assessed by blinded independent central review (BICR; RECIST v1.1). Secondary endpoints included progression-free survival, overall survival, and safety. RESULTS: Thirty-one patients were enrolled (20 cSCC, 4 EMPD, 2 BCC, 5 other NMSCs); median age was 73 years (range 58-86), and 71% were male. ORR by BICR was 22.6% (7/31), and the disease control rate was 54.8% (17/31). Responses were durable, with a median duration of 21.3 months. In the cSCC cohort, median tumour mutational burden (TMB) was 9.0 mut/Mb, lower than in Western series; among three patients with TMB ≥ 30 mut/Mb, two achieved objective responses. Common adverse events included pyrexia, hypothyroidism, adrenal insufficiency, and pruritus. CONCLUSIONS: Nivolumab showed durable antitumour activity with manageable toxicity in Japanese patients with advanced NMSCs, including rare non-cSCC. The lower ORR compared with Western trials may reflect intrinsic biological differences and support biomarker-driven, region-specific immunotherapy. CLINICAL TRIAL REGISTRATION: jRCT2031190048; registered 2 July 2019.

Extramammary Paget disease (EMPD) is a rare skin cancer with an estimated incidence rate of 0.13 per 100 000 population/year in Caucasians and 0.28 in Asians. Although distant metastases have been reported in 10%-20% of EMPD cases, standardized systemic chemotherapy has not been established. Prospective clinical trials are essential to establish standard treatments for advanced EMPD. Therefore, this retrospective study examined a substantial number of patients with EMPD to assess the efficacy of systemic chemotherapy. This study included 164 patients with advanced EMPD who underwent treatment at 16 Japanese institutions. Treatment efficacy was evaluated in a cohort of 138 patients, after excluding 26 patients without lesions outside the radical irradiation field from the 164 patients. The efficacy of each treatment was evaluated by determining the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) using Kaplan-Meier analysis. Multivariate analysis was performed to account for potential confounding factors, such as age, sex, and performance status. The patients received the following treatments: docetaxel hydrate (DOC) (65.9%); tegafur/gimeracil/oteracil potassium, DOC (S-1/DOC) (9.8%); fluorouracil and cisplatin (FP) (15.9%); and other drugs (8.5%). DOC is the most commonly used in Japan. The ORRs in the DOC, S-1/DOC, and FP groups were 51.6%, 78.6%, and 27.8%, respectively. Logistic regression analysis revealed that, compared with the DOC group, the odds ratio for the ORR of the S-1/DOC group was 3.29 (95% CI: 1.49-7.25, p = 0.003). However, no significant differences in OS or PFS were observed between the treatment groups (p = 0.122 and p = 0.422, respectively). This study provides valuable information on EMPD and may serve as a useful historical control for the future evaluation of new treatments for EMPD.

Recent advances in generative artificial intelligence (AI) have expanded its applications in diagnostic support within dermatology, but its clinical accuracy requires ongoing evaluation. This study compared the diagnostic performance of three advanced AI models, ChatGPT-4o, Claude 3.5 Sonnet, and Gemini 1.5 Pro, with that of board-certified dermatologists, using a dataset of 30 cases encompassing a variety of dermatological conditions. The AI models demonstrated diagnostic accuracy comparable to, and sometimes exceeding, that of the specialists, particularly in rare and complex cases. Statistical analysis revealed no significant difference in accuracy rates between the AI models and dermatologists, indicating that AI may serve as a valuable supplementary diagnostic tool in dermatological practice. Limitations include a small sample size and potential selection bias. However, these findings underscore the progress in AI's diagnostic capabilities, supporting further validation with larger datasets and diverse clinical scenarios to confirm its practical utility.

BACKGROUND: Anti-programmed cell death 1 antibodies (anti-PD-1 Abs) are widely used for advanced melanoma, but the efficacy of an anti-PD-1 Abs is limited in the Asian population. There remains an unmet need to improve the therapeutic effects of anti-PD-1 Abs treatment, particularly in melanoma patients who are refractory to anti-PD-1 Abs. The aim was to evaluate anti-PD-1 Abs treatment in combination with TM5614 (plasminogen activator inhibitor-1: PAI-1 inhibitor) in patients with unresectable melanoma. METHODS: The TM5614-MM study was a multicentre, open-label, single-arm, phase 2 clinical trial to evaluate the efficacy and safety of nivolumab in combination with TM5614 in patients with advanced, unresectable malignant melanoma recruited at 7 Japanese institutes between 13 September 2021 and 31 March 2023. Patients with metastatic or unresectable melanoma previously treated with anti-PD-1 Abs were enrolled. Nivolumab 480 mg was administered intravenously every 4 weeks for 8 weeks, while TM5614 was administered orally at a dose of 120 mg (0-4 weeks) and 180 mg once daily (5-8 weeks). The primary endpoint was the overall response rate after 8 weeks of concomitant use of TM5614. RESULTS: Thirty nine patients were enrolled, and 34 patients in the anti-PD-1 Abs-refractory cohort. The overall response rate at 8 weeks was 25.9% (95% CI: 12.9-44.9%; P = .027) in 27 anti-PD-1-Abs refractory patients by investigator assessment in the protocol per set cohort. Seven patients discontinued treatment due to progressive disease or adverse events. Treatment-related grade 3 or higher adverse events occurred in 3 of 39 patients (7.7%) in the intention-to-treat cohort. CONCLUSIONS: TM5614 in combination with nivolumab is well-tolerated and effective in anti-PD-1 Abs-refractory, unresectable melanoma. TRIAL REGISTRATION: This trial was registered with Clinical Trial gov, jRCT2021210029.

The COVID-19 pandemic has increased mRNA vaccine usage and revealed various cutaneous adverse events, such as injection site reactions, urticaria, and morbilliform eruptions. Multiple centers have reported erythema multiforme (EM) as a COVID-19 vaccine-associated adverse event. Our center observed two cases of EM in patients receiving immune checkpoint inhibitors (ICI) after COVID-19 vaccination. Notably, ICI administration is known to cause cutaneous adverse events, including EM. A previous report indicated that administering COVID-19 vaccination to patients receiving ICI treatment could promote severe systemic symptoms. This raise concerns that COVID-19 vaccination might rapidly worsen skin rashes in these patients. Our report demonstrates that skin rash related to COVID-19 vaccine-induced EM in ICI-treated patients does not significantly differ from that of COVID-19 vaccine-related EM. Additionally, in both cases, the skin rash resolved without exacerbation. Further research is necessary to determine optimal management strategies. However, our findings provide reassurance that COVID-19 vaccination is safe in ICI-treated patients and should not be avoided.

Abstract CCR4 is a major trafficking receptor for Th2 cells and Th17 cells and is considered as a potential therapeutic target for atopic dermatitis (AD). The CCR4 ligands CCL17 and CCL22 have been reported to be upregulated in the skin lesions of AD patients. Of note, Thymic stromal lymphopoietin (TSLP), a master regulator of the Th2 immune response, promotes the expression of CCL17 and CCL22 in AD skin lesions. Here, we investigated the role of CCR4 in an AD mouse model induced by MC903, a TSLP inducer. Topical application of MC903 to ear skin increased the expression of not only TSLP but also CCL17, CCL22, the Th2 cytokine IL-4, and the Th17 cytokine IL-17A. Consistently, MC903 induced AD-like skin lesions as shown by increased epidermal thickness; increased infiltration of eosinophils, mast cells, type 2 innate lymphoid cells, Th2 cells, and Th17 cells; and elevated serum levels of total IgE. We also found increased expansion of Th2 cells and Th17 cells in the regional lymph nodes (LNs) of AD mice. Compound 22, a CCR4 inhibitor, ameliorated AD-like skin lesions with reduction of Th2 cells and Th17 cells in the skin lesions and regional LNs. We further confirmed that compound 22 diminished the expansion of Th2 cells and Th17 cells in the coculture of CD11c + dendritic cells and CD4 + T cells derived from the regional LNs of AD mice. Collectively, CCR4 antagonists may exhibit anti-allergic effects by inhibiting both the recruitment and expansion of Th2 cells and Th17 cells in AD.

Abstract In December 2019, a new infectious pathogen named severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was identified in Wuhan, China. Transmitted through respiratory droplets, SARS‐CoV‐2 is the causative pathogen of coronavirus disease 2019 (COVID‐19). Although this new COVID‐19 infection is known to cause primarily interstitial pneumonia and respiratory failure, it is often associated with cutaneous manifestations as well. These manifestations with COVID‐19 can be classified into seven categories: (i) chilblain‐like skin eruption (e.g., COVID toes), (ii) urticaria‐like skin eruption, (iii) maculopapular lesions, (iv) vesicular eruptions, (v) purpura, (vi) livedo reticularis and necrotic lesions, (vii) urticarial vasculitis, and others such as alopecia and herpes zoster. The pathogenesis of skin eruptions can be broadly divided into vasculitic and inflammatory skin eruptions. Various cutaneous adverse reactions have also been observed after COVID‐19 mRNA vaccination. The major cutaneous adverse reactions are type I hypersensitivity (urticaria and anaphylaxis) and type IV hypersensitivity (COVID arm and erythema multiform). Autoimmune‐mediated reactions including bullous pemphigus, vasculitis, vitiligo, and alopecia areata have also been reported. Several cases with chilblain‐like lesions and herpes zoster after COVID‐19 mRNA vaccination have been published. Various skin diseases associated with COVID‐19 and COVID‐19 vaccination have been reported, and the mechanism has been partly elucidated. In the process, for example, some papers have reported that it is not related to COVID‐19 infection, although it was initially called COVID‐toe and considered a COVID‐19‐associated cutaneous eruption. In fact, some COVID‐19‐associated skin reactions are indistinguishable from drug eruptions. In the future, the mechanisms of COVID‐19‐ or COVID‐19 vaccine‐associated skin reactions need to be elucidated and verification of causal relationships is required.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

To investigate the mechanism of autoimmunity and peripheral tolerance in the skin, several transgenic mouse strains expressing membrane-bound ovalbumin (mOVA) as an epidermal self-antigen under the control of keratinocyte-specific promotors, such as keratin 5 and keratin 14, were employed in combination with adoptive transfer of CD8+ T cells from OT-I mice (OT-I T cells) that recognize an ovalbumin-derived peptide. However, these strains showed bodyweight loss and required additional inflammatory stimuli, such as γ-irradiation and tape-stripping, to induce skin inflammation. In this study, we generated a mouse strain expressing mOVA under the control of human involucrin promoter (involucrin-mOVA mice). In contrast to previous strains, involucrin-mOVA mice spontaneously developed skin inflammation after the transfer of OT-I T cells in the absence of external stimuli without significant bodyweight loss. We focused on the skin infiltration process of OT-I T cells and found that transferred OT-I T cells accumulated around the hair follicles in the early phase of skin inflammation, and in the later phase, the skin inflammation spontaneously resolved despite the remaining OT-I T cells in the skin. Our involucrin-mOVA mice will provide a promising tool to investigate the pathogenesis and the tolerance mechanisms of cytotoxic skin autoimmunity.

Th17 cells express CCR4 and secrete cytokines such as IL-17A and GM-CSF, while dendritic cells (DCs) produce CCL22, a CCR4 ligand, upon stimulation with GM-CSF. Th17 cells are known to play a critical role in the pathogenesis of rheumatoid arthritis (RA). CCL22 has also been shown to be upregulated in the synovial tissues of RA patients. Here, we investigated the role of CCR4 in collagen-induced arthritis (CIA), a mouse model of RA. DBA/1J mice efficiently developed CIA as shown by erythema, paw swelling, joint rigidity, and joint destruction. Th17 cells were increased in the arthritic joints and regional lymph nodes (LNs) of CIA mice. A fraction of Th17 cells were also shown to produce GM-CSF. On the other hand, we observed no significant increases of Th2 cells or Treg cells, the T cell subsets also known to express CCR4, in these tissues. We further observed clusters of CCR4-expressing memory Th17 cells and CCL22-producing DCs in the regional LNs of CIA mice, supporting the role of the CCR4-CCL22 axis in the expansion of Th17 cells in the regional LNs. Compound 22, a CCR4 inhibitor, ameliorated the disease severity with reduction of Th17 cells in the arthritic joints and regional LNs and Th17-DC clusters in the regional LNs. We further confirmed that CCR4-deficient mice in the C57BL/6J background were highly resistant to CIA induction compared with wild-type mice. Collectively, CCR4 contributes to the pathogenesis of CIA and may thus represent a new therapeutic target for RA.

Atopic dermatitis (AD) is the most common inflammatory skin disease, which is characterized by excessive Th2 immune responses. In AD patients, the expression of the chemokines CCL17 and CCL22 is increased in skin lesions, leading to the infiltration of Th2 cells. In addition, typical pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6, have also been shown to be associated with the pathogenesis of AD. Recently, DDH-1, an ascorbic acid derivative, has been synthesized and demonstrated to have a more stabilized structure and better skin penetrability. Furthermore, DDH-1 has been shown to suppress pro-inflammatory cytokine expression in vitro and in vivo. Therefore, using an AD mouse model, we evaluated the effect of DDH-1 to reduce allergic skin inflammation. We found that cutaneous administration of DDH-1 significantly reduced the expression levels of TNF-α, IL-1β and IL-6 in the skin lesions of AD-like mice. Additionally, DDH-1 administration also significantly reduced the expression levels of CCL17 and CCL22, resulting in decreased skin infiltration of Th2 cells. Consequently, DDH-1 reduced ear and epidermal thickness, the serum IgE levels and the number of infiltrating inflammatory cells and mast cells into the AD-like skin lesions. Combination treatment with DDH-1 and corticosteroid more efficiently improved the skin lesions compared with corticosteroid alone. Collectively, our results suggest that DDH-1 has an anti-allergic effect in an AD mouse model by reducing not only the pro-inflammatory cytokine expression but also the Th2-associated chemokine expression. Thus, DDH-1 may be beneficial for AD treatment and prevention as a monotherapy or in combination with corticosteroids.

A decrease in the number of basophils in the peripheral blood, or basopenia, has been noted, reflecting the activity of chronic spontaneous urticaria (CSU). Infiltration of basophils into the skin has also been reported, but the mechanism of basopenia in CSU has not been clarified. The phenomenon of basopenia during the active phase of urticaria was confirmed, and basophil numbers increased following symptom improvement in 15 out of 17 patients treated with omalizumab and in 13 of 15 patients treated with antihistamines. Our examination by immunostaining also revealed basophil infiltration of the CSU lesions, as in previous reports, but since most of our patients were already taking oral steroids, it was not considered appropriate to examine the relationship between basophil numbers in tissue and peripheral blood. Then, we used mouse model of contact hypersensitivity with a single application of oxazolone, which is known to stimulate basophil infiltration, and investigated basophil counts in the skin, peripheral blood, and bone marrow. In this model, a decrease in peripheral blood basophil numbers was observed one day after challenge, but not after 2 days, reflecting supplementation from the bone marrow. Indeed, when cultured basophils expressing GFP were transplanted into the peripheral blood, GFP-positive basophil numbers in the peripheral blood remained low even after 2 days of challenge. Despite differences among species and models, these results suggest that one reason for the decrease of basophils in the peripheral blood in CSU may involve migration of circulating basophils into the skin.

Atopic dermatitis (AD) is characterized by chronic, eczematous, severe pruritic skin lesions. The knowledge on the pathogenesis of AD is driving the development of new drugs. From the research results, it has been revealed that Th2 cell-mediated immunity, skin barrier dysfunction, and pruritus cause a vicious cycle of AD. On the other hand, the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway are one of the essential signaling pathways in various inflammatory diseases including AD. In particular, TSLP, IL-4, IL-13 and IL-22 occupy an important position for Th2 cell-mediated immune reaction. Moreover, experimentally pan-JAK inhibitor suppress the STAT3 activation and improved the skin barrier function. Furthermore TSLP, IL-4, IL-13 and IL-31 contribute a lot to chronic pruritus of AD, and transmitted via JAK-STAT pathway. Therefore, JAK inhibitors are promising candidates for the treatment of severe AD. Here we review clinical trials of topical dergocitinib; a pan-JAK inhibitor, ruxolitinib; a JAK1 and JAK2 inhibitor, and tofacitinib; a JAK1, JAK2, and JAK3 inhibitor and oral baricitinib; a JAK1 and JAK2 inhibitor, abrocitinib and upadacitinib; JAK1 inhibitor. Significant improvements in the symptoms were obtained by each drug with low frequency of adverse events. In particular, oral JAK inhibitors have the ability to improve the pruritus and skin symptoms quickly. Therefore, the emergence of these topical and oral JAK inhibitors would be regarded as an innovation in the treatment of atopic dermatitis.

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibody monotherapy (PD1) has led to favorable responses in advanced non-acral cutaneous melanoma among Caucasian populations; however, recent studies suggest that this therapy has limited efficacy in mucosal melanoma (MCM). Thus, advanced MCM patients are candidates for PD1 plus anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) combination therapy (PD1 + CTLA4). Data on the efficacy of immunotherapy in MCM, however, are limited. We aimed to compare the efficacies of PD1 and PD1 + CTLA4 in Japanese advanced MCM patients. PATIENTS AND METHODS: We retrospectively assessed advanced MCM patients treated with PD1 or PD1 + CTLA4 at 24 Japanese institutions. Patient baseline characteristics, clinical responses (RECIST), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis, and toxicity was assessed to estimate the efficacy and safety of PD1 and PD1 + CTLA4. RESULTS: Altogether, 329 patients with advanced MCM were included in this study. PD1 and PD1 + CTLA4 were used in 263 and 66 patients, respectively. Baseline characteristics were similar between both treatment groups, except for age (median age 71 versus 65 years; P < 0.001). No significant differences were observed between the PD1 and PD1 + CTLA4 groups with respect to objective response rate (26% versus 29%; P = 0.26) or PFS and OS (median PFS 5.9 months versus 6.8 months; P = 0.55, median OS 20.4 months versus 20.1 months; P = 0.55). Cox multivariate survival analysis revealed that PD1 + CTLA4 did not prolong PFS and OS (PFS: hazard ratio 0.83, 95% confidence interval 0.58-1.19, P = 0.30; OS: HR 0.89, 95% confidence interval 0.57-1.38, P = 0.59). The rate of ≥grade 3 immune-related adverse events was higher in the PD1 + CTLA4 group than in the PD1 group (53% versus 17%; P < 0.001). CONCLUSIONS: First-line PD1 + CTLA4 demonstrated comparable clinical efficacy to PD1 in Japanese MCM patients, but with a higher rate of immune-related adverse events.

Schnitzler syndrome is characterized by chronic urticarial rash, neutrophilic dermal infiltrate, recurrent fever, bone pain, elevated C-reactive protein, and neutrophilic leukocytosis. The pathophysiology of Schnitzler syndrome is unknown, but it is considered to be an acquired form of an autoinflammatory disease because of the resemblance to clinical phenotypes of cryopyrin-associated periodic syndrome, in which a gain-of-function mutation in NLRP3 causes overexpression of interleukin (IL)-1β. Schnitzler syndrome is generally accompanied by a monoclonal immunoglobulin (Ig)M gammopathy with a long-term risk of lymphoproliferation that is possibly associated with an MYD88 mutation. Herein, we present the following four patients with Schnitzler syndrome: a 63-year-old woman; a 65-year-old man; a 43-year-old woman; and a 63-year-old woman. Each patient fulfilled the Strasbourg diagnostic criteria, but none of the patients had any mutation in NLRP3 or MYD88 detected in their peripheral blood. Although approved treatment options for Schnitzler syndrome are lacking, our patients were treated with IL-1-targeted therapy (anakinra or canakinumab) or anti-IL-6 (tocilizumab). The acute inflammatory clinical manifestations improved completely with canakinumab and partially with anakinra and tocilizumab, but the serum IgM levels were gradually increased in all patients, even during treatment. To determine whether treatment with anti-IL-1β or IL-6 prevents conversion to a hematopoietic disorder, further collection of cases and long-term follow-up will be needed.

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: Sensory nerves regulate cutaneous local inflammation indirectly through induction of pruritus and directly by acting on local immune cells. The underlying mechanisms for how sensory nerves influence cutaneous acquired immune responses remain to be clarified. OBJECTIVE: This study aimed to explore the effect of peripheral nerves on cutaneous immune cells in cutaneous acquired immune responses. METHODS: We analyzed contact hypersensitivity (CHS) responses as a murine model of delayed-type hypersensitivity in absence or presence of resiniferatoxin-induced sensory nerve denervation. We conducted ear thickness measurements, flow cytometric analyses, and mRNA expression analyses in CHS. RESULTS: CHS responses were attenuated in mice that were denervated during the sensitization phase of CHS. By screening neuropeptides, we found that pituitary adenylate cyclase-activating polypeptide (PACAP) mRNA expression was decreased in the dorsal root ganglia after denervation. Administration of PACAP restored attenuated CHS response in resiniferatoxin-treated mice, and pharmacological inhibition of PACAP suppressed CHS. Flow cytometric analysis of skin-draining lymph nodes showed that cutaneous dendritic cell migration and maturation were reduced in both denervated mice and PACAP antagonist-treated mice. The expression of chemokine receptors CCR7 and CXCR4 of dendritic cell s was enhanced by addition of PACAP in vitro. CONCLUSION: These findings indicate that a neuropeptide PACAP promotes the development of CHS responses by inducing cutaneous dendritic cell functions during the sensitization phase.

PURPOSE: Extramammary Paget disease (EMPD) is an uncommon skin malignancy whose genetic alterations are poorly characterized. Previous reports identified mutations in chromatin remodeling genes and PIK3CA. In order to unambiguously determine driver mutations in EMPD, we analyzed 87 EMPD samples using exome sequencing in combination with targeted sequencing. EXPERIMENTAL DESIGN: First, we analyzed 37 EMPD samples that were surgically resected using whole-exome sequencing. Based on several in silico analysis, we built a custom capture panel of putative driver genes and analyzed 50 additional formalin-fixed, paraffin-embedded samples using target sequencing. ERBB2 expression was evaluated by HER2 immunohisotochemistry. Select samples were further analyzed by fluorescence in situ hybridization. RESULTS: A median of 92 mutations/sample was identified in exome analysis. A union of driver detection algorithms identified ERBB2, ERBB3, KMT2C, TP53, PIK3CA, NUP93, AFDN, and CUX1 as likely driver mutations. Copy-number alteration analysis showed regions spanning CDKN2A as recurrently deleted, and ERBB2 as recurrently amplified. ERBB2, ERBB3, and FGFR1 amplification/mutation showed tendency toward mutual exclusivity. Copy-number alteration load was associated with likelihood to recur. Mutational signatures were dominated by aging and APOBEC activation and lacked evidence of ultraviolet radiation. HER2 IHC/fluorescence in situ analysis validated ERBB2 amplification but was underpowered to detect mutations. Tumor heterogeneity in terms of ERBB2 amplification status was observed in some cases. CONCLUSIONS: Our comprehensive, unbiased analysis shows EMPD is characterized by alterations involving the PI3K-AKT pathway. EMPD is distinct from other skin cancers in both molecular pathways altered and etiology behind mutagenesis.

BACKGROUND: The programmed cell death-1 (PD-1)/programmed death ligand 1 (PD-L1) pathway is known to inhibit the activation of effector CD8+ T cells. However, just how this regulatory pathway is involved in the pathophysiology of CD8+ T-cell-mediated inflammatory skin diseases remains unclear. OBJECTIVE: Our aim was to elucidate the mechanisms by which the PD-1/PD-L1 pathway exerts its regulatory roles in CD8+ T-cell-mediated cutaneous immune responses. METHODS: PD-L1-deficient (Pdl1-/-) mice were used for the murine contact hypersensitivity model. Inflammatory responses such as IFN-γ production from CD8+ T cells in the skin was evaluated by flow cytometry. RESULTS: Compared with wild-type mice, Pdl1-/- mice exhibited exacerbated ear swelling and increased numbers of IFN-γ+ CD8+ T cells in the skin. Adoptive T-cell transfer experiments revealed the involvement of the PD-1/PD-L1 pathway in the elicitation phase of contact hypersensitivity. Bone marrow chimera experiments showed that PD-L1 on radioresistant cells was responsible for this regulatory pathway. Flow cytometric analysis revealed that among the radioresistant cells in the skin, PD-L1 was most highly expressed on mast cells (MCs) before and after elicitation. Administration of anti-PD-L1 blocking antibody during the elicitation phase significantly enhanced ear swelling responses and increased the number of IFN-γ+CD8+ T cells in the skin of wild-type mice, whereas no significant effects were observed in MC-deficient (WBB6F1/J-KitW/KitW-v/J and C57BL/6-KitW-sh/W-sh) mice. The high level of expression of PD-L1 on human skin MCs was confirmed by database analysis and immunohistochemical analysis. CONCLUSION: PD-L1 on MCs negatively regulates CD8+ T-cell activation in the skin.

Schnitzler syndrome is characterized by a chronic urticarial rash with an intermittent fever, and is considered to be an acquired form of autoinflammatory syndrome because its clinical phenotypes are similar to cryopyrin-associated periodic syndrome with a gain-of-function mutation in NLRP3.1 Patients with Schnitzler syndrome also exhibit IgM monoclonal gammopathy, and 15-20% of patients eventually develop a lymphoproliferative disorder resembling Waldenström macroglobulinemia with an MYD88 mutation.2 At present, the precise pathogenesis of Schnitzler syndrome remains unknown.

INTRODUCTION: Malignant cutaneous epithelial tumors comprise various skin malignancies originating from the cutaneous epithelium, including cutaneous squamous cell carcinoma, basal cell carcinoma, and malignant cutaneous adnexal tumors. Treatment options are limited, as the rarity of these tumors, especially among Asians, renders well-controlled clinical trials extremely challenging to conduct. Thus, we designed a clinical trial to evaluate the efficacy and safety of the anti-programmed cell death-1 (PD-1) monoclonal antibody nivolumab in patients with metastatic cutaneous squamous cell carcinomas and other rare metastatic cutaneous epithelial tumors. METHODS AND ANALYSIS: This is an open-label, single-arm, multicenter, phase 2 clinical trial involving patients with metastatic malignant cutaneous epithelial tumors. Nivolumab (480 mg) will be administered intravenously every 4 weeks for a maximum of 26 doses. The primary outcome of the study will be the response rate based on response evaluation criteria in solid tumors, version 1.1. Assuming a null hypothesis of a response rate ≤5% and an alternative hypothesis of a 25% response rate, a minimum of 26 patients are required to achieve a 5% two-sided type I error and 80% power based on the exact binomial distribution. Finally, a target cohort size of 30 patients was determined as some patient dropout will be expected. DISCUSSION: This is the first phase 2 clinical trial evaluating the efficacy and safety of the PD-1 inhibitor nivolumab in Asian patients with metastatic malignant cutaneous epithelial tumors. The findings of the study will contribute to the development of novel treatment approaches for patients with rare cutaneous malignancies, which remains an unmet clinical need. TRIAL REGISTRATION: Registry number: jRCT 2031190048.

Blue nevus is a subset of benign melanocytic tumors typically located on the dorsal aspects of extremities, scalp, and buttocks. It is also reported to occur rarely even at the oral and genital mucosa. Herein, we report a case of blue nevus of the labium minus with atypical clinical manifestations, which was confirmed by whole-exome sequencing.

BACKGROUND: Insulin-like growth factor-2 messenger RNA-binding protein 3 (IGF2BP3 or IMP3) is an oncofetal protein that is expressed in various cancer types, and its expression is often associated with poor prognosis. IGF2BP3 expression has not been fully settled in vascular lesions. METHODS: We evaluated the expression of IGF2BP3 in malignant (angiosarcoma and epithelioid hemangioendothelioma [EHE]) and benign (hemangioma, granulation tissue cappilaries, and pyogenic granuloma) vascular lesions using immunohistochemistry. IGF2BP3 expression was scored as negative (0% of endothelial/neoplastic cells), equivocal (1-25%), or positive (> 26%). RESULTS: Eight of 30 (26.7%) cases of angiosarcoma and two of five (40%) cases of epithelioid hemangioendothelioma were positive for IGF2BP3. In contrast, hemangiomas (10 cases) and granulation tissue capillaries (12 cases) were all negative for IGF2BP3, and some cases of pyogenic granuloma (six of 14 cases) was scored as equivocal. In angiosarcoma, IGF2BP3 expression was independent of age, gender, location, morphological pattern, prognosis, presence of metastatic foci, and PD-L1 expression. CONCLUSIONS: IGF2BP3 is a useful marker to distinguish between malignant and benign vascular lesions.

Mast cells, eosinophils and basophils are central effector immune cells in allergic skin inflammation including atopic dermatitis (AD). Recent studies revealed that the bidirectional interaction between these three immune cell types (mast cells, eosinophils and basophils) and the nervous system is involved in the pathogenesis of neurogenic inflammation, pain and pruritus. Emerging evidence shows that these cells are the main source of pruritogens such as histamine, neuropeptides and cytokines, which are potential new therapeutic targets for drug development in chronic pruritus. For instance, many Th2 cytokines including interleukin (IL)-4, 13 and 31 have been recognized as some of the most promising targets for the treatment of chronic pruritus in AD. In this review, we highlight the link between these three immune cell subsets and peripheral nerves, with emphasis on the development of chronic pruritus such as AD. We present cytokines and receptors of these three immune cells and peripheral nerves, and discuss the therapeutic potential of targeting these neuro-immunological processes.

© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. 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

BACKGROUND: Atopic dermatitis (AD) is a common and chronic inflammatory skin disease of type 2 immunity. Keratinocyte-derived cytokines, including thymic stromal lymphopoietin (TSLP) and IL-33, are considered to induce the development of AD. Production of prostanoids, a family of lipid mediators, is increased in AD lesions. However, their physiologic functions remain to be clarified. OBJECTIVES: We sought to elucidate the functions of prostanoids in the development of AD. METHODS: The roles of prostanoids were investigated in a mouse model of AD induced by repeated application of hapten and PAM212, a keratinocyte cell line. RESULTS: Application of indomethacin, which blocks prostanoid synthesis, leads to enhanced TSLP and IL-33 production in the skin, increased serum IgE levels, and exacerbation of skin inflammation in this AD model. The skin inflammation was attenuated in TSLP receptor-deficient mice but not in IL-33-deficient mice, and the indomethacin-enhanced type 2 immune responses were abolished in TSLP receptor-deficient mice. Indomethacin increased protease-activated receptor 2-mediated TSLP production in keratinocytes in vitro, and prostaglandin E2 reversed the increase in TSLP levels through its receptor, the prostaglandin E2 receptor (EP2), by downregulating surface expression of protease-activated receptor 2. Administration of an EP2 agonist canceled indomethacin-enhanced TSLP production and type 2 immune responses in the skin, whereas an EP2 antagonist caused an enhancement of TSLP production and type 2 immune responses in the skin. CONCLUSION: Prostaglandin E2-EP2 signaling negatively regulates murine AD-like skin inflammation by suppressing TSLP expression.

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.

BACKGROUND: The objective of this study was to identify predictive markers, including inflammatory and nutritional status measures, of early progressive disease (EPD) in unresectable melanoma patients treated with nivolumab. METHODS: A retrospective review was performed on 39 consecutive patients with unresectable melanoma treated with nivolumab. EPD was defined as progressive disease within 60 days after starting nivolumab according to Response Evaluation Criteria in Solid Tumors version 1.1. The predictive index model [melanoma inflammation index (MII)] was determined by the number of predictive factors. RESULTS: Seventeen patients had cutaneous melanoma and 22 patients had mucosal melanoma. The overall response rate was 18.4%, and the response rates for cutaneous and mucosal melanoma were 29.4% and 9.5%, respectively. EPD was observed in 13 patients (34.2%). By multivariate analysis, body mass index (BMI) and C-reactive protein to albumin ratio (CAR) were independently and significantly associated with EPD, disease control rate, progression-free survival, and overall survival. Low BMI (cutoff 20) and high CAR (cutoff 0.0055) were predictive factors of EPD and were determined to be prognostic factors. MII, from 0 to 2, was determined by the number of these factors. The incidence of EPD was 0% in the low-risk group (MII = 0), 50% in the intermediate-risk group (MII = 1), and 83% in the high-risk group (MII = 2). CONCLUSIONS: An MII status of low BMI and high CAR may be used to predict EPD in unresectable melanoma patients treated with nivolumab.

Anti-programmed cell death protein 1 (PD1) antibodies are in wide use for the treatment of various cancers. PD1 antibody-based immunotherapy, co-administration of nivolumab and ipilimumab, is one of the optimal immunotherapies, especially in advanced melanoma with high tumor mutation burden. Since this combined therapy leads to a high frequency of serious immune-related adverse events (irAEs) in patients with advanced melanoma, biomarkers are needed to evaluate nivolumab efficacy to avoid serious irAEs caused by ipilimumab. This study analyzed baseline serum levels of CXCL5, CXCL10, and CCL22 in 46 cases of advanced cutaneous melanoma treated with nivolumab. Baseline serum levels of CXCL5 were significantly higher in responders than in non-responders. In contrast, there were no significant differences in baseline serum levels of CXCL10 and CCL22 between responders and non-responders. These results suggest that baseline serum levels of CXCL5 may be useful as a biomarker for identifying patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy.

BACKGROUND: Blocking the PD-1 pathway induces immune-related adverse events (irAEs) which often involve the thyroid gland (thyroid irAEs). Clinical features of a thyroid irAE including its predictability and relationship to prognosis remain to be elucidated. METHODS: Two hundred consecutive patients treated with nivolumab at Kyoto University Hospital between September 1, 2014 and August 31, 2017 were included in a retrospective cohort study. We systematically determined and classified subclinical and overt thyroid irAEs based on data collected of serum free T4 and TSH levels. Baseline characteristics and detailed clinical data were analyzed, and analyses of overall survival (OS) excluded patients censored within 1 month from the first administration of nivolumab. RESULTS: Sixty-seven patients (33.5%) developed thyroid irAEs and these were divided into a subclinical thyroid irAE group (n = 40, 20.0%) and an overt thyroid irAE group (n = 27, 13.5%). Patients with thyroid uptake of FDG-PET before treatment showed high incidences of overt thyroid irAE (adjusted odds ratio 14.48; 95% confidence interval [CI] 3.12-67.19), while the same relationship was not seen with subclinical thyroid irAE. Regarding the total cohort, the thyroid irAE (+) group had a significantly longer median OS than the thyroid irAE (-) group (16.1 versus 13.6 months, hazard ratio [HR] 0.61; 95% CI 0.39-0.93). In 112 non-excluded patients with lung cancer, the thyroid irAE (+) group similarly had a longer median OS than the thyroid irAE (-) group (not reached versus 14.2 months, HR 0.51; 95% CI 0.27-0.92). However, this observation was not seen in 41 non-excluded patients with malignant melanoma (12.0 versus 18.3 months, HR 1.54; 95% CI 0.67-3.43). CONCLUSIONS: By thyroid uptake of FDG-PET, overt thyroid irAEs could be predicted before nivolumab therapy. Thyroid irAEs related to good prognosis in lung cancer but might be inconclusive in malignant melanoma.

Immune checkpoint blockade (ICB) induces a remarkable response in patients with certain cancers. However, the response rate is not yet satisfactory. Biomarkers that help physicians identify patients who would benefit from ICB need to be developed. Killer immunoglobulin-like receptors (KIRs) are a class of receptors that are mainly expressed by natural killer cells. KIR genotypes have been shown to influence the outcomes of patients with neuroblastoma and hematopoietic malignancies. KIRs may thus influence the clinical outcomes of melanoma patients receiving nivolumab. We aimed to identify the KIR genotype, or KIR/KIR-ligand combinations, which influence the outcomes of melanoma patients receiving nivolumab. We genotyped 112 melanoma patients who were treated with nivolumab for KIR and human leukocyte antigen. The clinical records of the patients were analyzed to determine if they showed a response to nivolumab, and whether or not they experienced adverse events. Our analysis showed that no KIR gene was associated with a response to nivolumab. The KIR/KIR-ligand combination did not correlate with a response to nivolumab. KIR genes were not predictive of experiencing adverse events of grade 2 or greater. We conclude that the KIR genotype or KIR/KIR-ligand genotype do not show predictive value in melanoma patients receiving nivolumab.

The potential of omega-3 poly-unsaturated fatty acids (PUFAs) as a therapeutic target for psoriasis, a chronic inflammatory skin disease of IL-23/IL-17 axis, is a long-disputed question, since various epidemiological studies have suggested the association between high-intake of omega-3 PUFAs and the reduced frequency and severity of psoriasis. However, their actual significance and the molecular mechanisms remain largely unknown. To address these issues, we focused on resolvin E1 (RvE1), an omega-3 PUFAs-derived metabolite, and examined its effects on psoriatic dermatitis, using an imiquimod-induced mouse psoriasis model. RvE1 potently suppressed the inflammatory cell infiltration and epidermal hyperplasia in the psoriatic skin. RvE1 decreased the mRNA expression of IL-23 in the skin. Consistently, RvE1 inhibited IL-23 production by dendritic cells (DCs) in vitro. Furthermore, RvE1 exerted inhibitory effects on migration of cutaneous DCs and γδ T cells, a major IL-17-producing cell population in mouse, both in vivo and in vitro. These suppressive effects of RvE1 were mediated by its antagonistic function on BLT1, a receptor of leukotriene B4, and were also observed in human DCs, Th17 and Tc17 cells. Our results indicate a novel mechanism of omega-3 PUFA-mediated amelioration of psoriasis, and suggest a potential of RvE1 as a therapeutic target for psoriasis.

Although uveitis is reported as a rare adverse event (AE) associated with dabrafenib/trametinib therapy or nivolumab, the occurrence of severe uveitis is extremely rare. We describe two cases of Vogt-Koyanagi-Harada (VKH)-like uveitis developing after the sequential administration of nivolumab and dabrafenib/trametinib therapy. Interestingly, both cases had HLA-DRB1*04:05, which is strongly associated with VKH disease, and achieved biologically complete remission after the treatment for uveitis. Our cases suggest a possible correlation between VKH-like uveitis as an AE and the clinical outcomes of sequential administration of nivolumab and dabrafenib/trametinib therapy for the treatment of advanced melanoma.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. The human epidermal growth factor receptor 2 (HER2) is recognized as an oncogene as well as a therapeutic target in various cancers. Certain patients with advanced extramammary Paget’s disease (EMPD) have also been reported to express HER2, which is therefore considered a therapeutic target for EMPD. However, an accurate methodology to determine HER2-positive EMPD has not been established. To assess the optimal methods for detection of HER2-positive EMPD, 73 EMPD samples were analyzed by immunohistochemical (IHC) staining, fluorescence in situ hybridization (FISH), and the HER2 testing algorithm for breast cancer of the American Society of Clinical Oncology/College of American Pathologists, which combined the results of IHC staining and FISH. The results showed discordance in the rate of positive IHC staining and FISH results. While 68.6% (24/35) of the metastatic samples showed equivocal or positive IHC staining, only 37.1% (13/35) were positive by FISH. To assess the accuracy of these methods, the degree of HER2 expression detected by each method was correlated with the staining profiles of activated downst

BACKGROUND: Due to resistance and immune-related adverse events (irAE) some melanoma patients require ipilimumab after nivolumab therapy. However, little is known about the result of this switching. OBJECTIVE: Investigate the outcome of ipilimumab switching in Japanese patients. METHODS: We retrospectively collected 60 patients who were treated with ipilimumab after nivolumab from 9 institutes in Japan. Information of the primary tumor, treatment, response, irAE), and survival was collected. RESULTS: In our cohort, acral lentiginous and mucosal melanoma accounted for 53% of the cases. The most common reason for initiating ipilimumab was disease progression (93%). Median interval from the last nivolumab administration to first ipilimumab administration was 29days. Only 38% of patients completed 4 injections of ipilimumab. The best overall response was 3.6%. IrAE occurred in 78% of patients and 70% of those were of grade 3/4 (G3/4) and 31% of patients experienced 2 or more irAEs. An within interval of 28days or less between the last nivolumab administration and ipilimumab administration was correlated with the development of G3/4 pyrexia and 3 or more irAEs, but irAE occurrence did not affect survival. Multivariate analysis showed that endocrine irAE (relative risk=0.22, P=0.015) and skin irAE (relative risk=2.78, P=0.048) were significant factors associated with survival. CONCLUSION: In our study, the response ratio to ipilimumab after nivolumab was unsatisfactory and associated with a high frequency of severe irAEs. As there are few second-line treatment options for patients with BRAF wild-type advanced melanoma after nivolumab failure, patients should be closely monitored if ipilimumab is initiated.

Antibodies against programmed cell death protein 1, such as nivolumab and pembrolizumab, are widely used for treating various cancers, including advanced melanoma. Nivolumab significantly prolongs survival in patients with metastatic melanoma, and sequential administration with lipilimumab may improve outcomes when switched at the appropriate time. Biomarkers are therefore needed to evaluate nivolumab efficacy soon after first administration. This study analyzed serum levels of soluble cluster of differentiation 163 (sCD163) in 59 cases of advanced cutaneous melanoma and 16 cases of advanced mucosal melanoma treated using nivolumab. Serum levels of sCD163 were significantly increased after 6 weeks in responders compared to non-responders after initial administration of nivolumab for cutaneous melanoma. In contrast, no significant difference between responders and non-responders was seen among patients with non-cutaneous melanoma. These results suggest that sCD163 may be useful as a biomarker for selecting patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy.

Cutaneous angiosarcoma (CAS) is a malignant sarcoma with poor prognosis. Programmed cell death-1 (PD-1)/programmed cell death-1 ligand-1 (PD-L1) expression reflects antitumor immunity, and is associated with patient prognosis in various cancers. The purpose of this study is to investigate the relationship between PD-1/PD-L1 expression and CAS prognosis. CAS cases (n = 106) were immunohistochemically studied for PD-L1 and PD-1 expression, and the correlation with patient prognosis was analyzed. PD-L1 expression was assessed by flow cytometry on three CAS cell lines with or without IFNγ stimulation. A total of 30.2% of patients' samples were positive for PD-L1, and 17.9% showed a high infiltration of PD-1-positive cells. Univariate analysis showed a significant relationship between a high infiltration of PD-1-positive cells with tumor site PD-L1 expression and favorable survival in stage 1 patients (p = 0.014, log-rank test). Multivariable Cox-proportional hazard regression analysis also showed that patients with a high infiltration of PD-1-positive cells with tumor site PD-L1 expression were more likely to have favorable survival, after adjustment with possible confounders (hazard ratio (HR) = 0.38, p = 0.021, 95% confidence interval (CI) 0.16-0.86). Immunofluorescence staining of CAS samples revealed that PD-L1-positive cells were adjacent to PD-1-positive cells and/or tumor stroma with high IFNγ expression. In vitro stimulation with IFNγ increased PD-L1 expression in two out of three established CAS cell lines. Our results suggest that PD-1/PD-L1 expression is related to CAS progression, and the treatment with anti-PD-1 antibodies could be a new therapeutic option for CAS.

我が国には約40万人のアトピー性皮膚炎（atopic dermatitis；AD）の患者がいるとされる．ADは慢性的なかゆみを伴う皮膚疾患であり，その背景として湿疹ができやすい体質があると考えられている．その体質として皮膚の乾燥が候補因子であったが，十分な解析はなされていなかった．ところが，2006年にADの有病率とフィラグリン遺伝子の相関関係が指摘されたことで，皮膚のバリア機能と免疫とのクロストークが注目を集めることとなった．

Extramammary Paget's disease is a rare cutaneous malignant neoplasm. Previous studies indicated the efficacy of docetaxel in advanced cases. The common side effects of docetaxel are usually tolerable and seldom life-threatening. We experienced a case of severe pseudomembranous colitis and neutropenic fever that developed just after the first cycle of docetaxel chemotherapy. To the best of our knowledge, there are few reports of pseudomembranous colitis associated with docetaxel administration for skin cancers. The patient showed complete resolution of her symptoms within 2 weeks with an oral metronidazole therapy. During the second and third cycles, the patient received docetaxel safely with lower doses. The present case indicated that pseudomembranous colitis should be included in the differential diagnosis when assessing patients who develop severe diarrhea during systemic chemotherapy with docetaxel.

58-year-old female was admitted to our hospital complaining isolated proteinuria of 1.7 g/day. Abdominal echography showed right-sided unilateral hydronephrosis, and computed tomography pointed out a tumor of the right renal pelvis, suggesting cancer of renal pelvis. The right nephroureterectomy was carried out. Pathological diagnosis was urothelial carcinoma. Renal tissue revealed no apparent glomerulopathy with tubular atrophy, interstitial fibrosis, and mildly-to-moderately interstitial mononuclear cell infiltration. Immunofluorescence study showed no deposition of immunoreactanct, and electron microscopy showed almost normal glomerulus without electron dense deposit. Proteinuria disappeared within 6 days after the operation. Moderate amount of proteinuria in our patient was probably caused by secreted protein from urothelial carcinoma. This condition is rare but should be taken into account in patients with even moderate amount of proteinuria.

We report a case of recurring Merkel cell carcinoma on the nose of a 90-year-old man. A radical operation was performed on the red nodule on his nose. However, 1 month later a red nodule 30×30mm in diameter was found on his nose and another red nodule 6×7mm in diameter appeared on his right cheek. The biopsy specimen revealed cytokeratin20-positive tumor cells localized in the dermis to subcutaneous fatty tissue. We chose radiotherapy treatment of (5MeV) for both lesions. When the total amount of irradiation reached 66 Gy, the tumor completely disappeared. We reviewed 21 reported cases of radiotherapy treated Merkel cell carcinoma and found a 24% rate of local recurrence. The recurrence cases with prophylactic lymph node radiation were observed only in 10%, whereas the recurrence rate without radiotherapy revealed 45.5%. Local recurrence and lymph node involvement are important prognostic factors. We suggest that adjuvant radiotherapy is very effective for Merkel cell carcinoma. [Skin Cancer (Japan) 2005; 20: 84-88]

皮膚アレルギー疾患病態形成における末梢神経の関与が注目されている。皮膚末梢神経は神経軸索とその支持細胞であるシュワン細胞からなるが、これまでの研究は神経軸索にシュワン細胞が混在した状態での評価であった。シュワン細胞がケモカイン等を産生することを申請者はすでに見出しており、神経軸索とシュワン細胞を区別しその機能を解析することが重要である。 シュワン細胞特異的光刺激マウスを作成し基礎的な解析を行った。光刺激により皮膚毛細血管の拡張が見られ、また痒みが軽度誘発されることを確認した。このマウスを用いて、接触皮膚炎モデルでの解析を行う予定である。また、シングルセルRNAシークエンスの技術を用いて、表皮間近に存在するシュワン細胞の解析を行った。その結果、シュワン細胞はいくつかのサブセットが存在することが明らかとなった。 また、シュワン細胞の影響を除外した末梢神経の皮膚アレルギー疾患における役割の検討を行った。黄色ブドウ球菌による皮膚炎モデルの解析にて、好塩基球が多数皮膚に浸潤してくることを明らかとした。この系において、末梢神経及びシュワン細胞が重要な役割を担うことをRTX処置にて明らかとした。さらに、DRGよりシュワン細胞と神経軸索を分離しin vitroで検証した結果、ともにいくつかのケモカインを賛成することを見出した。これらの研究成果は、末梢神経だけでなくシュワン細胞が皮膚アレルギー疾患において病態に関与することを示唆する。

It is widely known that itching of the skin is mediated by the peripheral nerves. However, recent studies have shown that peripheral nerves interact with immune cells and may be involved in the pathogenesis of skin allergic diseases. In this research question, we investigated the role of peripheral nerves in cutaneous allergic diseases. The results showed that neuropeptides released from peripheral nerves are involved in contact dermatitis.
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IL-4遺伝子のイントロン2に存在するイントロニックエンハンサーは肥満細胞特異的にIL-4遺伝字発現を制御する領域であることが報告されている。上記の細胞特異的遺伝子発現システムを用いて、理研・久保允人博士らはDT-Rを挿入した肥満細胞特異的DT-R Tgマウス(Mast cell-specific enhancer mediated Toxin REceptor mediated Conditional cell Knock out(TRECK)systems、MaS TRECK)を作製した。 Mas TRECK TgマウスDT処理後、肥満細胞のみ除去された状態で接触皮膚炎を確認したところ野生型に比べ接触皮膚炎反応が減弱していることが明らかとなった。ハプテンの種類や濃度によってW/Wvマウスの接触皮膚炎反応が不変か減弱するか考えられていることから、異なる2つのハプテンを用いて検証したところ、どちらのハプテンでも接触皮膚炎反応が減弱することが明らかとなった。さらにoxazoloneの濃度を低濃度もしくは高濃度と変えて感作を行ったところ、どちらの濃度においても接触皮膚炎反応が減弱することが明らかとなった。これより肥満細胞が接触皮膚炎に関与しているということを新しいモデルマウスを用いて示すことが出来た。 W/WvとMas TRECK Tgマウスの実験結果の違いは、W/Wvマウスが肥満細胞の欠損のみならず、メラノサイトの欠損、また重度の貧血があることに加え、先天的に肥満細胞が欠損していることによる免疫細胞のホメオタシスの影響があることによるものと考えられる。今回、我々はconditionalかつspecificに肥満細胞を除去できるMas TRECK Tgマウスを用いて、肥満細胞が接触皮膚炎反応に大きな影響を与えていることを証明した。