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Palmoplantar pustulosis (PPP) is a chronic skin inflammatory disease characterized by sterile pustules on the palms and soles. Pustulotic arthro‐osteitis (PAO) is a major comorbidity of PPP, frequently affecting the anterior chest wall. PPP and PAO are thought to be closely associated with focal infection. We report a female in her 40s who developed pustules on her palms and soles with tenderness of both sternoclavicular and left sacroiliac joints, which were not improved with non‐steroidal anti‐inflammatory drugs. Of note, she showed a great response to amoxicillin, resulting in the almost complete resolution of her skin lesions and arthralgia. We also reviewed previous reports to learn more about the potential therapeutic options of antibiotics for PAO. [ABSTRACT FROM AUTHOR]

Objectives: Graft‐versus‐host disease (GVHD) is an important complication of bone marrow transplantation. Recent reports suggest the significance of T‐cell subsets (Th1, Th17, and cytotoxic CD8+ T cells) as well as CD163+ macrophages in the development of cutaneous GVHD. CD163+ macrophages produce various chemokines to establish the immunological microenvironment following stimulation by stromal factors in lesional skin. Thus, the purpose of this study is to determine the main source of IFN‐inducible chemokines in the lesional skin of GVHD. Methods: We employed immunohistochemical (IHC) staining for CD163 as well as interferon (IFN)‐inducible chemokines (CXCL9, CXCL10, CXCL11) to determine if the main source of IFN‐inducible chemokines in the lesional skin of GVHD was CD163+ macrophages. Moreover, we investigated the possible cytokine profiles of lesional skin in GVHD by evaluating phospho‐signal transducer and activator of transcription (pSTAT) expression in epidermal keratinocytes. Results: Immunohistochemical staining of serial sections for CD163 revealed that CXCL9‐expressing cells, CXCL10‐expressing cells, and CXCL11‐expressing cells were detected in adjacent to CD163+ TAMs in the dermis. In contrast, there were no CCL17‐expressing cells or CCL22‐expressing cells in the dermis. The nuclei of epidermal keratinocytes in GVHD expressed pSTAT1, pSTAT3, and pSTAT5B. Conclusions: The chemokine expression patterns on CD163+ macrophages matched the expected phosphorylation pattern of epidermal STATs. Our present study suggested that CD163 + macrophages may be a therapeutic target in GVHD. The significance of T‐cell subsets (Th1, Th17, and cytotoxic CD8+ T cells) as well as CD163+ macrophages in the development of cutaneous GVHD. ·IHC staining revealed that CXCL9‐expressing cells, CXCL10‐expressing cells, and CXCL11‐expressing cells were detected in adjacent to CD163+ TAMs in the dermis. ·The chemokine expression patterns on CD163+ macrophages matched the expected phosphorylation pattern of epidermal STATs. [ABSTRACT FROM AUTHOR]

Palmoplantar pustulosis (PPP) is a chronic skin inflammatory disease in which blisters and pustules repeatedly develop on palms and soles. PPP is often refractory to topical therapy, oral therapy, phototherapy, and biologics that are usually applied for PPP. We report a patient with PPP improved by vedolizumab (anti-α4β7 integrin antibody) treatment for ulcerative colitis, suggesting the possibility of a new molecular target for PPP therapy. [ABSTRACT FROM AUTHOR]

An active form of cathelicidin antimicrobial peptide, LL-37, has immunomodulatory and stimulatory effects, though the specific pathways are not clear. The purpose of this study was to identify the cellular pathways by which LL-37 amplifies the inflammation induced by damage-associated molecular patterns (DAMPs). We performed DNA microarray, reverse transcription polymerase chain reaction, immunoblotting, and proximity ligation assays using cultured keratinocytes treated with LL-37 and/or the DAMP poly(I:C), a synthetic double-stranded RNA. In contrast to the combination of LL-37 and poly(I:C), LL-37 alone induced genes related to biological metabolic processes such as VEGFA and PTGS2 (COX-2). Inhibition of FPR2, a known receptor for cathelicidin, partially suppressed the induction of VEGFA and PTGS2. Importantly, VEGFA and PTGS2 induced by LL-37 alone were diminished by the knockdown of scavenger receptors including SCARB1 (SR-B1), OLR1 (SR-E1), and AGER (SR-J1). Moreover, LL-37 alone, as well as the combination of LL-37 and poly(I:C), showed proximity to the scavenger receptors, indicating that LL-37 acts via scavenger receptors and intermediates between them and poly(I:C). These results showed that the broad function of cathelicidin is generally dependent on scavenger receptors. Therefore, inhibitors of scavenger receptors or non-functional mock cathelicidin peptides may serve as new anti-inflammatory and immunosuppressive agents. [ABSTRACT FROM AUTHOR]

Sensitization to galactose‐α‐1,3‐galactose (α‐Gal) leads to the development of α‐Gal syndrome, which includes red meat allergy and cetuximab‐induced anaphylaxis. Since tick bites represent the main cause of α‐Gal sensitization, it was speculated that sensitization to α‐Gal occurs throughout Japan. However, few cohort studies have investigated α‐Gal sensitization in Japan. Therefore, we aimed to elucidate the subclinical sensitization rate to α‐Gal in Japan. Sera were obtained from 300 participants without food or cetuximab allergy at Shimane University Hospital (Shimane prefecture), Tokyo Medical and Dental University Hospital (Tokyo metropolis), and Tohoku University Hospital (Miyagi prefecture). ImmunoCAP‐bovine thyroglobulin (BTG), ImmunoCAP‐beef, and IgE immunoblotting with cetuximab were performed to detect α‐Gal‐specific IgE. Clinical information was collected from participants using a questionnaire. The overall positivity rate of ImmunoCAP‐BTG was 4.0% without significant inter‐institute differences, whereas that for ImmunoCAP‐beef was 9.7% with a significant inter‐institute difference. Tokyo Medical and Dental University Hospital (19.0%) had the highest positivity rate. The positivity rate based on cetuximab IgE immunoblotting was 2.7%, without any significant inter‐institute differences. The overall positivity rate for both ImmunoCAP‐BTG and cetuximab immunoblotting was 2.0%, with a significant inter‐institute difference; 5.0% of Shimane University Hospital was the highest. Two cases showed sensitization against the non‐α‐Gal epitope of cetuximab. The overall positivity rate for both ImmunoCAP‐beef and cetuximab immunoblotting was 1.3%, without significant inter‐institute differences. Male sex was associated with positive beef‐specific IgE. The prevalence of subclinical sensitization to α‐Gal is estimated at 2.0%–4.0% in Japan and may be higher in rural areas, supporting an association between tick bites and α‐Gal sensitization. In contrast, the prevalence of subclinical sensitization to beef is 9.7% in Japan and is highest in Tokyo Metropolis, suggesting the presence of another IgE‐binding epitope apart from α‐Gal and another sensitization route in the sensitization to beef IgE. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by inflammation of various organs such as skin, kidneys, bones, and brain and the presence of autoantibodies. Although the cause of SLE is not completely understood, environmental factors, genetic susceptibility, hormone factors, and environmental factors are thought to play essential roles in the pathogenesis of SLE. Among environmental factors, the microbiota are linked to the development of different autoimmune diseases. The microbiota in the nasal cavity and gut are involved in SLE development, but the influence of skin microbiota is still unclear. Here, we demonstrated that epithelial cell–specific IκBζ-deficient (NfkbizΔK5) mice showed spontaneous skin inflammation with increased abundance of Staphylococcus aureus on the skin. When S. aureus was epicutaneously applied on NfkbizΔK5 mice, NfkbizΔK5 mice developed SLE-associated autoantibodies, anti-dsDNA antibodies, anti-Sm antibodies, and glomerulonephritis with IgG deposition. Epicutaneous S. aureus application significantly increased staphylococcal colonization on the skin of NfkbizΔK5 mice with reduced expression of several antimicrobial peptides in the skin. This staphylococcal skin colonization promoted caspase-mediated keratinocyte apoptosis and neutrophil activation, inducing the interleukin-23 (IL-23)/IL-17 immune response by activating dendritic cells and T cells. Furthermore, the subcutaneous administration of anti–IL-23p19 and anti–IL-17A antibodies alleviated the systemic autoimmune response. Together, these findings underscore epithelial-immune cross-talk disturbances caused by skin dysbiosis as an essential mediator inducing autoimmune diseases. Skin staph promotes lupus: Systemic lupus erythematosus (SLE) is an autoimmune disease that affects various organs, and the microbiota of the nasal cavity and gut are involved in SLE development. However, it is unclear how the skin microbiota influences SLE. Using an epithelial cell–specific IκBζ-deficient (NfkbizΔK5) mouse model of spontaneous skin inflammation, Terui et al. tested the impact of Staphylococcus aureus colonization of the skin on SLE-associated effects. The authors found that the spontaneous SLE-associated effects seen in the NfkbizΔK5 mice worsened with skin S. aureus colonization. These effects were associated with neutrophil extracellular trap (NET)–induced epidermal apoptosis via the increased production of IL-17A. Thus, skin S. aureus colonization potentially worsens SLE by mediating increased release of NETs. [ABSTRACT FROM AUTHOR]

Rosacea is a chronic inflammatory skin disease with facial redness and acne‐like papules and pustules. The characteristics and background of rosacea patients in Japan have not been well documented. In this study, we retrospectively collected the medical information of rosacea patients, and investigated the background, complications, exacerbating factors, and status of allergy. Between January 2010 and December 2020, 431 cases were diagnosed as rosacea or rosacea‐like dermatitis. We selected 340 patients, in which we could confirm telangiectasia on facial skin. Females and males numbered 266 and 74, respectively. The average age of the first visit was 51.5 years, and the youngest and oldest were 11 and 88 years old. Among 340 cases, 323 had erythematotelangiectatic rosacea, 97 papulopustular rosacea, 20 phymatous rosacea presenting as rhinophyma, and four had symptoms of ocular rosacea. The most common complication was hay fever (93 individuals, 27.4%), and 66 (19.4%) had a medical history of contact dermatitis. Temperature differences (141 individuals, 41.5%) were the most common exacerbating factor followed by sunlight exposure (60 individuals, 17.6%). Seventy‐eight individuals received allergen‐specific immunoglobulin (Ig)E tests, and IgE for cedar was the most frequently observed (46 individuals, 59.0%). High frequencies of IgE for Dermatophagoides pteronyssinus or D. farinae (33 individuals, 42.3%) and house dust I (31 individuals, 39.7%) suggested that environmental conditions at home would affect rosacea symptoms. Since the facial skin is exposed to environmental stimuli every moment, this retrospective observation suggested the importance of the daily lifestyle guidance as well as medical treatments. [ABSTRACT FROM AUTHOR]

Background: The Toll-like receptor signaling pathway contributes to the regulation of intestinal homeostasis through interactions with commensal bacteria. Although the transcriptional regulator IκB-ζ can be induced by Toll-like receptor signaling, its role in intestinal homeostasis is still unclear. Aims: To investigate the role of IκB-ζ in gut homeostasis. Methods: DSS-administration induced colitis in control and IκB-ζ-deficient mice. The level of immunoglobulins in feces was detected by ELISA. The immunological population in lamina propria (LP) was analyzed by FACS. Results: IκB-ζ-deficient mice showed severe inflammatory diseases with DSS administration in the gut. The level of IgM in the feces after DSS administration was less in IκB-ζ-deficient mice compared to control mice. Upon administration of DSS, IκB-ζ-deficient mice showed exaggerated intestinal inflammation (more IFN-g-producing CD4+ T cells in LP), and antibiotic treatment canceled this inflammatory phenotype. Conclusion: IκB-ζ plays a crucial role in maintaining homeostasis in the gut. [ABSTRACT FROM AUTHOR]

A novel COL3A1 variant was identified in a Japanese case of Ehlers–Danlos syndrome type IV (EDS‐IV) with a characteristic "Madonna" face, fragile uterus, and easy bruising in addition to a history of cavernous sinus fistula. We confirmed variable diameters of collagen fibrils in the dermis and decrease in type 3 collagen production from cultured fibroblasts. Genomic DNA sequencing of the COL3A1 region and COL3A1 cDNA sequence expressing in cultured fibroblasts identified that a nucleotide variation at c.951+2T>G on intron 14 leads to skipping of exon 14 in COL3A1 cDNA. The novel variation in the splice site of COL3A1 region g.IVS14+2T>G was not listed in the EDS‐IV pathogenic genetic databases including Human Gene Mutation Database, ClinVar, and Leiden Open Variation Database. Using the whole genome sequence database of 8380 Japanese individuals reported by the Tohoku Medical Megabank Organization (ToMMo) cohort study, we also confirmed that COL3A1 g.IVS14+2T>G was not a common single nucleotide variation in the Japanese population, although 13 EDS‐related COL3A1 variants were identified in the ToMMo database of 8380 Japanese individuals. These results demonstrated that our case of EDS‐IV was a result of the novel variation of COL3A1 g.IVS14+2T>G. These statistical genetics approaches with the combination of the ToMMo database of 8380 Japanese individuals and pathogenic genetic databases are a useful method to confirm the uniqueness of novel variation in Japanese. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic disease centered on tumor necrosis factor (TNF), interleukin (IL)‐23, and IL‐17 axis. While psoriasis patients benefit from biologics targeting TNF, IL‐17s, and IL‐23 nowadays, suppression of these molecules could modulate the balances of immune systems. However, the incidence of autoimmune disease and T‐helper 2 reaction during biologic treatments for psoriasis patients is not well documented. We retrospectively examined antinuclear antibody (ANA), eosinophil counts, and immunoglobulin E (IgE) levels for psoriasis patients who underwent biologic treatments in our dermatology clinic from June 10, 2010 to January 29, 2020. A cumulative total of 199 biologic treatments were performed for a total of 128 psoriasis patients. Compared to the non‐biologic group of 109 psoriasis patients who received non‐biologic treatment, patients treated with infliximab showed more incidents of high ANA (14%, p = 0.039) and high eosinophils (14%, p = 0.021). The use of brodalumab increased incidents of high eosinophils (21%, p = 0.005) but did not affect increase in ANA and IgE. The increase in high IgE level was observed significantly more during the use of risankizumab (15%, p = 0.011). Methotrexate was the most frequently used concomitant systemic treatment, but methotrexate did not affect ANA, eosinophil counts, and IgE levels. Since the biologics for psoriasis treatment modulate the balance of T‐helper cells, careful observation is required to detect unexpected changes of systemic immune conditions under biologic treatments. [ABSTRACT FROM AUTHOR]

Biologics has had a great impact on psoriasis treatment as well as the life of psoriasis patients. Infliximab (IFX), one of the biologics targeting tumor necrosis factor (TNF), is the first of the biologics introduced to Japanese psoriasis patients. Many patients had benefits of IFX from initial applications and sustained remission of skin lesions and arthritis. Some, however, fall into so‐called secondary failure, in which patients become less responsive to IFX when the treatment is repeated. The mechanism of secondary failure and the background of patients with secondary failure have not been completely elucidated. To address this issue, we retrospectively evaluated psoriasis patients treated with IFX in our department. In this retrospective, single‐center, case‐control study based on the clinical record, a total of 34 patients were enrolled. We excluded 7 patients who discontinued IFX because of adverse events of IFX. We divided other 27 patients into two groups; 16 patients who kept using IFX (Continuance group); and 11 patients who switched to other treatments (Discontinuance group). Among various clinical features, body mass index (BMI), HbA1c, and serum CRP level were significantly higher in the Discontinuance group than the Continuance group. The results indicated that these three clinical features of BMI, HbA1c and serum CRP level before treatment are the predictors of successful IFX treatment and suggest that improvement of metabolic conditions contributes to avoiding secondary failure and discontinuance of IFX. [ABSTRACT FROM AUTHOR]

Prurigo is a treatment‐resistant skin disease characterized by multiple isolated papules/nodules that cause severe itch. Prurigo papules/nodules occur either as primary lesions or as secondary lesions due to persistent scratching. The fundamental concepts and classifications of prurigo have not been sufficiently established, and considerable confusion remains regarding this topic. Clinical guidelines for chronic prurigo in Japan were published in 2012 in an attempt to reduce confusion regarding the concepts of prurigo and to standardize laboratory tests and treatments. However, the diagnostic terms for prurigo and associated concepts have changed over time, and new forms of treatment are under development. We have, thus, updated and revised the guidelines to classify prurigo based on clinical forms and causes, and disease name classifications based on the clinical form have been further simplified, such as prurigo nodularis, prurigo chronica multiformis, and prurigo (not otherwise specified). Expressions for acute, subacute, and chronic forms are not used. These guidelines outline the current concepts and specify treatments for prurigo. [ABSTRACT FROM AUTHOR]

The mechanisms underlying itch are not fully understood. Physicians usually encounter difficulty controlling itch in generalized pruritus. Since only a small percentage of patients with generalized pruritus respond to antihistamines (H1 receptor antagonists), a variety of itch mediators and mechanisms other than histaminergic signals are considered to be involved in itch for these non‐responsive patients. In 2012, we created guidelines for generalized pruritus. Those guidelines have been updated and revised to make some of the definitions, diagnostic terms, and classifications more applicable to daily clinical practice. Cutaneous pruritus as designated in these guidelines is a disease characterized by itch without an observable rash. Generalized pruritus (without skin inflammation) is defined as the presence of itch over a wide area, and not localized to a specific part of the body. This entity includes idiopathic pruritus, pruritus in the elderly, symptomatic pruritus, pregnancy‐associated pruritus, drug‐induced pruritus, and psychogenic pruritus. Localized pruritus (without skin inflammation) represents fixed itch localized to a specific part of the body, and includes anogenital pruritus, scalp pruritus, notalgia paresthetica, and brachioradial pruritus. These guidelines outline the current concepts and specify the diagnostic methods/treatments for cutaneous pruritus. [ABSTRACT FROM AUTHOR]

BRAF kinase inhibitors in combination with MEK kinase inhibitors are among the most promising chemotherapeutic regimens for the treatment of advanced BRAF‐mutant melanoma. Although the NCCN guideline for cutaneous melanoma recommended BRAF/MEK inhibitors as first‐line therapies for unresectable BRAF‐mutated melanoma, resistance to these drugs should be taken into account in real‐world practice. Therefore, development of a protocol for BRAF/MEK inhibitor‐resistant advanced melanoma is needed. In this report, a case of BRAF/MEK inhibitor‐resistant advanced cutaneous melanoma that was successfully treated with nivolumab plus ipilimumab combination therapy followed by intensity‐modulated radiotherapy (IMRT) is reported. In the present case, not only the locally irradiated lesion, but remote metastases including inguinal lymph nodes decreased after ipilimumab plus nivolumab followed by IMRT treatment leading to complete remission, suggesting that IMRT triggered an abscopal response. Moreover, immunohistochemical analysis showed increased CD3+, CD4+, and CD8+ T cells after radio‐immunotherapy (RIT). This case suggests that RIT might break the tolerance in the tumor microenvironment and induce a systemic anti‐melanoma immune response. [ABSTRACT FROM AUTHOR]

Genome‐wide association studies have identified more than 60 susceptibility loci for psoriasis, highlighting the role of genetics in psoriasis development. Although the HLA region is suggested as the most prominent susceptibility locus, the role of the HLA haplotype in the development of psoriasis is unclear. The aim of this study is to investigate how HLA haplotype changes affect the onset of psoriasis and which HLA haplotypes are associated with the development of psoriasis. A longitudinal, retrospective case series study of children was conducted at Tohoku University Hospital in Japan, between November 1981 and October 2020. We evaluated a total of 378 pediatric patients who underwent hematopoietic stem cell transplantation in the Department of Pediatrics. The background of these patients and their HLA haplotypes before and after transplantation was assessed. Among the 378 cases, aged 0–22 years old (median age 6) identified, 117 cases received autologous transplantation, 260 cases received allogeneic transplantation, and one case received syngeneic transplantation. Only two cases developed de novo psoriasis, and these cases had acquired HLA‐B46‐Cw1 after allogeneic transplantation. Others who had HLA‐B46‐Cw1 before and after allogeneic transplantation did not develop psoriasis. Our findings suggest that the HLA‐B46 and HLA‐Cw1 combination contributes to the development of psoriasis in this Asian population. [ABSTRACT FROM AUTHOR]

We have reported that the IL-2 Luc assay can detect the effects of chemicals on IL-2 promoter activity by using a dual reporter cell line, 2H4 cells that measure IL-2 promoter-driven luciferase activity (IL2LA) and GAPDH promoter-driven luciferase activity (GAPLA). Since the IL-2 Luc assay cannot detect immunosuppressive drugs that are antimitotic towards rapidly proliferating cells, we attempted to establish a new assay to detect these chemicals by taking advantage of the dual reporter cell properties of 2H4 cells. We first determined the optimal incubation time with drugs and the seeding cell density, and confirmed that the change in GAPLA and IL2LA levels reflects the change in cell count and IL-2 production of 2H4 cells after drug treatment. We designed the IL-2 luciferase lymphotoxicity test (IL-2 Luc LTT) to detect the antimitotic effects of chemicals by modifying the protocol and criteria of the IL-2 Luc assay. To determine the performance of the IL-2 Luc LTT and that of the combination of the IL-2 Luc LTT and the IL-2 Luc assay, we examined 46 drugs: 19 immunosuppressive drugs with different mechanisms of action, 12 anti-cancer drugs, and 15 non-immunosuppressive drugs. The performances of the IL-2 Luc LTT, the IL-2 Luc assay and their combination were 43.3%, 61.3%, and 93.3%, respectively, for sensitivity, 84.6%, 53.3%, and 50.0%, respectively, for specificity, and 55.8%, 58.7%, and 79.5%, respectively, for accuracy. These results demonstrated that the combination of these two assays is promising for the detection of immunosuppressive drugs with different mechanisms of action. [ABSTRACT FROM AUTHOR]

Systemic corticosteroid is indicated for vitiligo, especially for generalized and progressive vitiligo. However, no consensus exists yet for the dosages and modalities of systemic corticosteroid treatments for vitiligo. The purpose of this study is to validate the efficacy and safety of i.v. methylprednisolone pulse therapy (IVMP) for patients with progressive generalized vitiligo. We retrospectively reviewed the medical records of vitiligo patients treated in our institute for 10 years between January 2010 and December 2019. Among 525 vitiligo patients treated in 10 years, 33 vitiligo patients (aged, 8–78 years; 18 female and 15 males) received IVMP, a single course of daily 500 mg methylprednisolone application (8 mg/kg/day for children) for 3 consecutive days. We observed that 14 of 25 (56%) achieved stable condition without lesion progression, and 12 of 19 (63%) had more than 25% repigmentation at 6 months after IVMP. A group of Vitiligo Area Scoring Index over 10 included more patients with Vitiligo Disease Activity Score of +3 and +4 disease progression at 6 months after the IVMP. We did not observe any severe adverse events relating to the IVMP procedures. In conclusion, IVMP is a safe and effective treatment for progressive generalized vitiligo. [ABSTRACT FROM AUTHOR]

The most common adverse event of epidermal growth factor receptor inhibitors, used to treat colorectal, non‐small cell lung, and head and neck cancers, is acneiform eruption, with a profound effect on treatment continuation. Prolonged acneiform eruptions treated with topical corticosteroids, a standard management, may be associated with secondary bacterial infections, thus there is a need for new treatments. We conducted a multicenter, phase II trial to evaluate the efficacy and safety of topical benzoyl peroxide for epidermal growth factor receptor inhibitor‐induced prolonged acneiform eruptions. Patients with colorectal, non‐small lung cell, and head and neck cancers who received epidermal growth factor receptor inhibitors for >10 weeks and had persistent acneiform eruptions were eligible. Topical benzoyl peroxide was applied to the affected area of the face once daily for 8 weeks; a clinical evaluation was performed every 2 weeks. The primary endpoint was a change in acneiform eruption severity evaluated between disease onset and end of the treatment period. The quality of life of patients was assessed using the Dermatology Life Quality Index. Of the 14 enrolled patients, 11 completed the trial. The protocol‐specified grade of acneiform eruptions from baseline to week 8 improved from 2.0 to 1.0 (P < 0.01). The dermatology life quality index score from baseline to week 8 improved from 3.0 to 1.0 point (P < 0.01). No patient experienced severe adverse events. Overall, topical benzoyl peroxide may be effective for treating and managing prolonged acneiform eruptions induced by epidermal growth factor receptor inhibitors. [ABSTRACT FROM AUTHOR]

Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma that tends to show local recurrence and metastasis. Typically, MCC is polyomavirus (MCPyV)‐associated and cytokeratin 20 (CK20) positive. However, little is known about this tumor and its origins. Here, we aimed to determine the developmental origins of MCC and to identify prognostic clinicopathologic factors. Initial examinations revealed that CK20 and MCPyV expression (CK20+, MCPyV+ (60%); CK20+, MCPyV− (10%); CK20−, and MCPyV− (30%)) did not affect overall survival. With RB1 gene sequencing of FFPE specimens, which covered an entire exon, all RB1 mutation‐positive cases showed positive regional lymph node and/or distant metastases (8/8 cases, 100%), whereas the frequency of the metastasis was statistically significantly lower in RB1 mutation‐negative cases, (10/16 cases, 62%, P = 0.033). The results were also confirmed with immunohistochemistry, and either RB1 alterations, entire exon sequencing, or immunohistochemistry was associated with the metastasis (P = 0.007). RB1 alterations may be used to access the aggressive clinical course of MCC. [ABSTRACT FROM AUTHOR]

IL-1 functions as an essential pro-inflammatory mediator for the sensitisation of allergic contact dermatitis (ACD). However, studies conducted to date have typically used a limited number of haptens and examined their effects only on murine ACD or murine dendritic cells (DCs). It therefore remains unclear whether IL-1α and/or IL-1β is produced in ACD induced by haptens other than those commonly used in mouse ACD models, and whether they are essential for sensitisation leading to ACD in humans. In addition, it is unclear whether human DCs also produce IL-1α or IL-1β after stimulation by haptens in general. Here, we first demonstrated that 10 haptens (3 extreme, 1 strong, 3 moderate and 3 weak) increased both IL-1α mRNA and IL-1β mRNA expression by the human monocyte cell line THP-1, a commonly used surrogate of DCs in in vitro skin sensitisation tests. Next, we constructed an in vitro skin sensitisation test using a stable IL-1β reporter cell line, THP-G1b, and evaluated whether 88 haptens and 34 non-haptens increase IL-1β reporter activity. We found that 94% of 77 haptens evaluated after considering their applicability domain and solubility in the chosen media stimulated reporter activity. These studies demonstrated that most haptens, irrespective of their potency, increased IL-1β mRNA expression by THP-1 cells, confirming that human DCs also produce IL-1β after stimulation by most haptens. The luciferase assay using THP-G1b cells is thus another skin sensitisation test based on the adverse outcome pathway with reasonable performance. [ABSTRACT FROM AUTHOR]

CXCL13 recruits CXCR5+ follicular helper T (Tfh) cells in inflammatory lesions to develop secondary lymphoid organs. Tfh cells activate B cells to produce antibodies during humoral immune responses. Indeed, as previous reports suggested, CXCR5+ cell numbers were increased in the peripheral blood of bullous pemphigoid (BP) patients when compared with healthy donors, and the ratio of CXCR5+ cells was positively correlated with the anti‐BP180‐NC16A titers. From the above findings, in this report, we hypothesized that a chemokine related to CXCR5+ cells, namely CXCL13, may play a role in the development of BP. We performed immunohistochemical staining of CXCR5, CXCL13, LL37, CXCL10 and CCL20 for 10 cases of BP and 10 cases of pemphigus vulgaris (PV), and quantitatively analyzed the staining by digital microscopy. Moreover, we investigated the CXCL10 and CXCL13 production in BP and PV patients by enzyme‐linked immunosorbent assay. The immunomodulatory effects of LL37 on the production of T‐helper 17‐related chemokines were evaluated using monocyte‐derived M2 macrophages. Immunohistochemical staining and digital microscopic analysis showed that the ratios of CXCR5+, CXCL13+ and LL37+ cells in the dermis were significantly higher in BP patients than in PV patients. Notably, the ratio of CXCL13+ cells was positively correlated with the anti‐BP180‐NC16A titers. Moreover, the serum levels of CXCL13 were positively correlated with the anti‐BP180‐NC16A titers. Furthermore, CD163+ M2 macrophages stimulated by LL37 in vitro produced CXCL10 and CCL20. In the lesional skin of BP, CD163+ macrophages CXCL10 and CCL20 were produced. The serum levels of CXCL10 were negatively correlated with the anti‐BP180‐NC16A titers. The present study results indicate that the mechanism of the development of BP may involve the CXCL13/CXCR5‐mediated migration of Tfh cells. [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]

False-negative judgment due to poor chemical solubility is a problem with in vitro skin sensitisation tests. Water-insoluble chemicals are typically dissolved in DMSO in most sensitisation tests but precipitate when diluted with medium beyond their solubility in water. Such tests lack procedures to rule out false-negative judgments due to poor solubility. The IL-8 Luc assay (OECD442E) is unique in that if chemicals do not dissolve at 20 mg/mL in medium and have no effect on IL-8 luciferase activity (IL8LA), they are classified as indeterminate. The purpose of the present study was to reduce the number of indeterminate chemicals and improve assay performance. The IL-8 Luc assay can simultaneously examine glyceraldehyde 3-phosphate dehydrogenase luciferase activity (GAPLA) and IL8LA, and thus we examined the correlation between the reduction of GAPLA (defined as Inh-GAPLA) and the reduction of propidium iodide (PI)-excluding cells for three sensitizers and three non-sensitizers. We observed a significant correlation between luciferase activity driven by the GAPDH promoter of THP-G8 cells and the number of viable cells. Furthermore, chemicals providing an Inh-GAPLA value below 0.8 always reduced the ratio of PI-excluding cells to less than 0.6. Using the modified criteria, indeterminate chemicals are judged as negative if they provide Inh-GAPLA values below 0.8. This modification reduced the number of indeterminate chemicals and increased specificity, highlighting the unique advantage of the IL-8 Luc assay. [ABSTRACT FROM AUTHOR]

Skin pigmentation is associated with skin damages and skin cancers, and ultraviolet (UV) photography is used as a minimally invasive mean for the assessment of pigmentation. Since UV photography equipment is not usually available in general practice, technologies emphasizing pigmentation in color photo images are desired for daily care. We propose a new method using conditional generative adversarial networks, named UV-photo Net, to generate synthetic UV images from color photo images. Evaluations using color and UV photo image pairs taken by a UV photography system demonstrated that pigment spots were well reproduced in synthetic UV images by UV-photo Net, and some of the reproduced pigment spots were difficult to be recognized in color photo images. In the pigment spot detection analysis, the rate of pigment spot areas in cheek regions for synthetic UV images was highly correlated with the rate for UV photo images (Pearson's correlation coefficient 0.92). We also demonstrated that UV-photo Net was effective for floating up pigment spots for photo images taken by a smartphone camera. UV-photo Net enables an easy assessment of pigmentation from color photo images and will promote self-care of skin damages and early signs of skin cancers for preventive medicine. [ABSTRACT FROM AUTHOR]

Various adverse events (AEs) have been reported to occur at a high rate in patients treated with dabrafenib plus trametinib (D + T) combination therapy. Among such AEs, the incidence of pyrexia was highest among the series of AEs in patients treated with D + T combination therapy. Although little is known about the mechanisms of pyrexia caused by D + T combination therapy, a recent report suggested that sCD163, as well as interferon‐inducible chemokines (CXCL9, CXCL10, CXCL11), might correlate with pyrexia caused by encorafenib plus binimetinib combination therapy. In addition to these soluble factors, CXCL5 is a biomarker for predicting immune‐related AEs in melanoma patients treated with nivolumab. From the above findings, we hypothesized that these soluble factors might also correlate with the onset of AEs in D + T combination therapy. The serum levels of sCD163 were increased in patients with pyrexia in parallel with their severity, whereas the serum levels of CXCL5 were increased in patients without pyrexia. Moreover, increased levels of CXCL9, CXCL10, and CXCL11 were prominent in patients with AEs over G2 levels. As these chemokines recruit Th1, Th17, and activated CD8+ T cells, increased serum levels of these chemokines might correlate with the positive feedback of inflammatory reactions related to AEs. [ABSTRACT FROM AUTHOR]

Mogamulizumab is a humanized anti‐C‐C chemokine receptor type (CCR)4 antibody that shows cytotoxicity against CCR4+ lymphoma cells via antibody‐dependent cell‐mediated cytotoxicity in advanced cutaneous T cell lymphoma (CTCL) patients. The production levels of ligands for CCR4, that is, Chemokine (C‐C motif) ligand (CCL)17 and CCL22, are important for the assessment of the disease activity in CTCL patients. We evaluated the serum levels of CCL17, CCL19, CCL22, C‐X‐C motif chemokine ligand (CXCL)10, and CXCL13, which are ligands for CCR4, CCR7, CCR4, C‐X‐C Motif Chemokine Receptor (CXCR)3, and CXCR5, respectively, at baseline and 4 weeks after the administration of mogamulizumab in five patients with mycosis fungoides. The serum levels of CCL22 were significantly decreased in patients who responded to mogamulizumab, but no differences were identified in the serum levels of CCL17, CCL19, CXCL10, or CXCL13. Immunofluorescence staining revealed that the majority of CCL22‐producing cells were cluster of differentiation (CD)163+ tumor‐associated macrophages, and they were surrounded by CCR4+ CTCL cells. Our present data suggested that the serum CCL22 level may be a predictive marker of the efficacy of mogamulizumab for the treatment of CCR4+ CTCL. [ABSTRACT FROM AUTHOR]

A 66‐year‐old man with a 2‐year history of suspected scalp eczema with excessive dandruff developed painful swollen joints in the extremities. Four months after developing polyarthritis and polydactylitis, eczema gradually spread to the face. He was referred to our hospital for intractable scalp and facial eczema and polyarthritis. Based on the appearance of the head and facial skin lesions, psoriasis was suspected. Treatment with apremilast (a phosphodiesterase‐4‐inhibitor) was initiated, which swiftly alleviated the skin lesions. The joint deformities persisted, but the pain in the joints disappeared. This case implies that psoriatic arthritis should be suspected even if psoriatic skin lesions are localized to the scalp. [ABSTRACT FROM AUTHOR]

Since the cost of molecular biological methods for Spitzoid neoplasms is expensive, the number of institutes that employ these methods might be limited. Preferentially expressed antigen in melanoma (PRAME) is a tumor-associated antigen that is useful to distinguish melanoma from other melanocytic disorders, including pediatric Spitzoid tumors that are difficult to diagnose by conventional methods alone. In this report, we report a case of PRAME-expressing juvenile Spitzoid melanoma with lymph node metastasis. Unexpectedly, there were few PRAME-expressing cells in the primary tumor, whereas most metastatic tumors expressed PRAME in the metastatic lymph node. These observations might suggest that, in Spitzoid melanomas, a limited number of melanoma cells possess metastatic potential and that metastatic lesions possess clonality. [ABSTRACT FROM AUTHOR]

Mogamulizumab shows cytotoxicity against CCR4+ lymphoma cells by antibody‐dependent cell‐mediated cytotoxicity (ADCC) in advanced cutaneous T‐cell lymphoma (CTCL) patients. Although mogamulizumab is used as one of the anchor drugs for the treatment of advanced CTCL, its efficacy is unsatisfactory, especially in mycosis fungoides (MF). Therefore, additional drugs to enhance the antitumor effects of mogamulizumab are needed to further optimize its use for the treatment of MF. In this report, two cases of mogamulizumab‐resistant MF successfully treated with additional administration of etoposide are presented. Moreover, the possible mechanisms of mogamulizumab‐etoposide combined therapy for the treatment of MF were investigated based on the modulation of chemokine profiles in vivo using an EL‐4 mouse T‐cell lymphoma model. Intraperitoneal administration of etoposide significantly increased the mRNA expressions of CCL17, CXCL5, and CXCL10, suggesting that CCR4+ CTCL cells gather around the tumor‐associated macrophagess. Furthermore, the immunomodulatory effects of etoposide on the mRNA expressions of these chemokines were validated using monocyte‐derived M2 macrophages in vitro. Since mogamulizumab shows cytotoxicity against CCR4+ lymphoma cells by ADCC that depends on the contact between the lymphoma cells and the effector cells, these chemokines could enhance the therapeutic effect of mogamulizumab. [ABSTRACT FROM AUTHOR]

Various serious adverse events (AE) have been reported to occur at a high rate in patients treated with BRAF plus mitogen‐activated protein kinase kinase (MEK) inhibitor combination therapy, but their subtypes differ among the BRAF/MEK inhibitors. Pyrexia or a spike of fever are well‐known AE of BRAF inhibitors, with or without MEK inhibitors, and have been reported to have a high incidence after dabrafenib/trametinib, but not after encorafenib/binimetinib. In this report, we describe three cases of severe pyrexia in nivolumab‐resistant advanced melanoma after successful combined therapy with encorafenib plus binimetinib. Interestingly, in all cases, the serum levels of soluble CD163 C‐X‐C motif chemokine (CXCL)9, CXCL10 and CXCL11, which are known biomarkers for adult‐onset Still's disease (AOSD), increased in parallel with the development of pyrexia. Our present cases suggest that pyrexia caused by BRAF/MEK inhibitors may possess a similar pathophysiology as that of AOSD. [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]

Skin lesions, cataracts, and congenital anomalies have been frequently associated with inherited deficiencies in enzymes that synthesize cholesterol. Lanosterol synthase (LSS) converts (S)-2,3-epoxysqualene to lanosterol in the cholesterol biosynthesis pathway. Biallelic mutations in LSS have been reported in families with congenital cataracts and, very recently, have been reported in cases of hypotrichosis. However, it remains to be clarified whether these phenotypes are caused by LSS enzymatic deficiencies in each tissue, and disruption of LSS enzymatic activity in vivo has not yet been validated. We identified two patients with novel biallelic LSS mutations who exhibited congenital hypotrichosis and midline anomalies but did not have cataracts. We showed that the blockade of the LSS enzyme reaction occurred in the patients by measuring the (S)-2,3-epoxysqualene/lanosterol ratio in the forehead sebum, which would be a good biomarker for the diagnosis of LSS deficiency. Epidermis-specific Lss knockout mice showed neonatal lethality due to dehydration, indicating that LSS could be involved in skin barrier integrity. Tamoxifen-induced knockout of Lss in the epidermis caused hypotrichosis in adult mice. Lens-specific Lss knockout mice had cataracts. These results confirmed that LSS deficiency causes hypotrichosis and cataracts due to loss-of-function mutations in LSS in each tissue. These mouse models will lead to the elucidation of the pathophysiological mechanisms associated with disrupted LSS and to the development of therapeutic treatments for LSS deficiency. Author summary: Skin lesions, cataracts, and congenital anomalies have been frequently associated with inherited deficiencies of cholesterol synthetic enzymes. LSS encodes lanosterol synthase, an enzyme in the cholesterol biosynthesis pathway, and biallelic mutations in LSS have been reported in families with congenital cataracts and hypotrichosis. However, it remains to be clarified whether these phenotypes are caused by LSS enzymatic deficiency in each tissue, and disruption of LSS enzymatic activity in vivo has not yet been validated. We showed that LSS metabolic inhibition in patients with biallelic LSS mutations and congenital hypotrichosis in vivo by measuring metabolites of the LSS enzyme in the forehead sebum, which would be good biomarkers for the diagnosis of LSS deficiency. We recapitulated hypotrichosis and cataracts by creating tissue-specific Lss knockout mice. Our mouse studies confirmed that LSS deficiency causes hypotrichosis and cataracts due to loss-of-function mutations in LSS in each tissue. These mice will lead to the elucidation of the pathophysiological mechanisms associated with disrupted LSS and to the development of therapeutic treatments for LSS deficiency. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) significantly prolong survival in patients with metastatic melanoma but can lead to serious immune-related adverse events. In this report, we described a case of atypical neuropathy caused by nivolumab plus ipilimumab combination therapy before primary tumor resection. In our case, not only demyelinating neuropathy, but also muscle weakness and unilateral facial nerve palsy developed and manifested as severe and diverse symptoms. Moreover, unlike spontaneously developing demyelinating peripheral neuropathy, the present case suggested the therapeutic effects of high-dose methylprednisolone monotherapy for the treatment of ICIs-induced immune-related demyelinating peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Stewart-Treves syndrome (STS) is a rare cutaneous lymphangiosarcoma developing from chronic lymph edema as a consequence of radical mastectomy or surgical invasion of the groin for the treatment of cervical or penile cancer. Previous reports suggested possible mechanisms in the development of lymphangiosarcoma that correlate with the immunological background of STS patients. In this report, we described two cases of STS developing in patients who underwent radical dissection for cervical cancer, we employed immunohistochemical staining of IL-23 and IL-17. [ABSTRACT FROM AUTHOR]

Since the incidence of mucosal melanoma is higher in the Japanese population compared to Caucasians, and since mucosal melanoma possesses a lower mutation burden compared to cutaneous melanoma, the efficacy of anti-PD1 antibody (Ab) monotherapy for mucosal melanoma is limited. Therefore, other targeting molecules that enhance the anti-tumor effects of immune checkpoint inhibitors are needed. In this report, we present a case with anti-PD1 Ab-resistant recurrent malignant melanoma of the nasal cavity successfully treated with nivolu-mab, ipilimumab plus denosumab combination therapy. [ABSTRACT FROM AUTHOR]

Hidradenitis suppurativa (HS) is a follicular occlusive inflammatory skin disease that occurs in the axilla, groin, buttocks and vulval region. Control of the intractable inflammation is a primary goal of HS treatments. Benefit of anti‐tumor necrosis factor (TNF) antibodies against HS have been reported, and adalimumab has been approved for HS in Europe, the USA and Japan. However, the alternative therapies for anti‐TNF antibodies have not been established yet. We experienced a case of HS which developed during the infliximab treatment for Crohn's disease (CD) and was well managed by ustekinumab (UST). We reviewed the articles relating to ustekinumab treatments for HS. Twenty‐four HS patients, 16 women and eight men, have been treated with ustekinumab. The average age was 35.7 ± 10.8 years (mean ± SD). All were of Hurley stage II or III. Ten (10/24, 41.6%) had received anti‐TNF drugs including infliximab, adalimumab and etanercept prior to UST treatment for HS. Although the initial doses varied from 45 mg s.c. to 390 mg i.v., all cases were treated with 45 or 90 mg s.c. every 8 or 12 weeks at the regular dose, by following the regimen for psoriasis or CD. HS in most of the cases started to improve after 3–5 months of UST initiation, and some achieved complete remission. To our knowledge, our case is the first Asian HS patient improved by UST. Overall, UST is useful for HS and could be an alternative treatment if HS patients do not respond to other medications including anti‐TNF drugs. [ABSTRACT FROM AUTHOR]

The skin surface temperature reflects the physiological state of the human body. Quantitative methods of identification of skin cancers based on accurate measurement of effective thermal conductivity (ETC) are among the promising diagnostic tools for differentiating non‐invasive and invasive melanomas before surgical treatment. To validate these findings, in this report, the diagnostic methods for invasive and non‐invasive extramammary Paget's disease (EMPD) and squamous cell carcinoma (SCC) were further tested by measuring the absolute value of skin surface temperature and the ETC of the skin. In addition, to investigate the stromal factors that might affect ETC, immunohistochemical staining for LL37, periostin (POSTN), MMP12, and MMP28 was performed. The invasive SCC and EMPD group showed a relatively higher skin surface temperature compared to the in situ SCC group. The non‐invasive EMPD and SCC group showed significantly lower values of ETC at lesions, whereas the invasive EMPD group showed significantly higher ETC values at lesions compared to healthy skin. Immunohistochemical staining showed that the percentage of LL37‐producing cells was significantly increased in invasive EMPD and SCC compared to that in non‐invasive EMPD and SCC. Moreover, Spearman's rank correlation test showed a significant inverse correlation between the percentage of MMP12‐positive cells and increased levels of ETC‐expressing areas in EMPD and SCC (r = −.5997). The present study suggested that differences in ETC could be a novel high‐accuracy diagnostic technique for non‐melanoma skin cancer, especially for detecting dermal invasion of SCC and EMPD. [ABSTRACT FROM AUTHOR]

Patients with invasive extramammary Paget's disease have an increased risk of secondary malignancy, mostly occurring colorectal carcinoma. TP53 is a regulator of apoptosis, cell cycle arrest, and DNA damage response pathways, and has been reported as one of the genetic biomarkers for colorectal carcinoma. In this report, we describe a case of advanced invasive EMPD concomitant with cecal cancer with a rare variant of TP53 single nucleotide polymorphism (rs121912665). To our knowledge, there is no English report that presents EMPD concomitant with cecal carcinoma. [ABSTRACT FROM AUTHOR]

Nivolumab plus ipilimumab combined therapy is one of the promising drugs that enhance the anti- immune response in patients with advanced melanoma. Therefore, to increase its response rate is of great interest to dermatologists. Recent reports suggested that, since CD8+ T cells after the administration of ICIs increase the RANKL expression to induce an immunosuppressive tumor microenvironment in melanoma, denosumab might enhance the anti-tumor effects of immune checkpoint inhibitors, such as nivolumab and ipilimumab. In this report, we present a case of multiple metastatic melanoma with nivolumab, ipilimumab plus denosumab combined therapy. [ABSTRACT FROM AUTHOR]

Perifolliculitis capitis abscedens et suffodiens (PCAS) or dissecting cellulitis is a rare condition presenting deep follicular occlusions, follicular ruptures and follicular infections in the scalp area with unknown etiology, which consequently cause primary neutrophilic cicatricial alopecia by the repeated follicular inflammation. PCAS is categorized as one of the "follicular occlusion tetrad" along with hidradenitis suppurativa, acne conglobata and pilonidal cyst. In the pathogenesis of the follicular occlusion tetrad, the involvement of neutrophils and its activator tumor necrosis factor (TNF) have been discussed. Here, we report a case of PCAS that was successfully treated with adalimumab, a human anti‐TNF monoclonal antibody. This is the first Asian case of PCAS that was improved by a TNF inhibitor. [ABSTRACT FROM AUTHOR]

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]

Anti‐programmed death 1 antibody monotherapy is a first‐line and widely used immunotherapy for the treatment of advanced melanoma. However, its efficacy rate is lower in the Japanese population compared with the Caucasian population. Ipilimumab is another immune checkpoint inhibitor (ICI) that activates and increases T cells, which suppress the function of regulatory T cells. Previous reports have suggested that ipilimumab is useful for treating advanced melanoma, particularly in combination with radiation therapy. In this report, we described three cases of nivolumab‐resistant melanoma successfully controlled by ipilimumab with intensity‐modulated radiotherapy, which may enhance the therapeutic effects of the sequential administration of ICI. [ABSTRACT FROM AUTHOR]

Enfortumab vedotin (EV) is a novel, fully humanized monoclonal antibody–drug conjugate composed of an anti‐Nectin‐4 antibody joined to monomethyl auristatin E. In this report, we described a case of a severe eczematoid and lichenoid eruption with full‐thickness epidermal necrosis developing in patients with metastatic urothelial cancer treated with EV. Because phase II and phase III clinical studies are ongoing, in the future, substantial amounts of EV are expected to be used for the treatment of metastatic urothelial cancer. Therefore, understanding the mechanisms of drug eruption caused by EV is important for oncologists as well as dermatologists. [ABSTRACT FROM AUTHOR]

Dear Editor, A previous clinical study suggested that dabrafenib plus trametinib (D + T) combination therapy could cause a high rate of various AEs including skin disorders in BRAF SP V600E sp mutated advanced melanoma patients.1 Indeed, 24% (50/209) of patients treated with D + T combination therapy developed skin disorders.1 A 46-year-old woman visited our outpatient clinic with multiple erythematous nodules with pain on the extremities. Interim analysis for post-marketing surveillance of dabrafenib and trametinib combination therapy in Japanese patients with unresectable and metastatic melanoma with BRAF V600 mutation. [Extracted from the article]

From the above findings, our diagnosis was multiple angiolymphoid hyperplasia with eosinophilia showing unusual presentation. 4 Adler BL, Krausz AE, Minuti A, Silverberg JI, Lev-Tov H. Epidemiology and treatment of angiolymphoid hyperplasia with eosinophilia (ALHE): a systematic review. [Extracted from the article]