[MACULOPAPULAR CUTANEOUS MASTOCYTOSIS HARBORING A KIT MUTATION (ASP419DEL): A CASE REPORT].

A 2-year-old, male patient presented with an 18-month history of scattered, brown macules and nodules up to 2 cm in size on his trunk and extremities. These macules were accompanied by pruritus and were positive for Darier's sign. A skin biopsy of a brown macule on the left thigh revealed a dense accumulation of CD117-positive, round or oval cells with amphophilic cytoplasm within the upper to middle dermis. The patient was otherwise healthy and had normal laboratory and imaging test results. Sequence analysis of genomic DNA from a skin biopsy demonstrated the presence of an Asp419del mutation in exon 8 of the KIT gene. Based on these findings, maculopapular cutaneous mastocytosis (MPCM) was diagnosed. The patient received H 1-antihistamine. Although the pruritus resolved, the brown macules remained for one year after the initial treatment. To the best of our knowledge, only three cases of cutaneous mastocytosis (CM) with an Asp419del mutation, including the present case, have been reported in the Japanese literature to date; moreover, while the previous two cases were of DCM, the present case was the first instance of MPCM. Normally, the symptoms of childhood-onset MPCM are dormant until puberty. However, a recent study reported that many MPCM patients may experience persistent or exacerbated symptoms. The present study therefore evaluated 53 Japanese cases of childhood onset MPCM with a KIT gene mutation and discussed the patients' clinical outcomes.

Topical application of imatinib mesylate ameliorated psoriasis-like skin lesions in imiquimod-induced murine model via angiogenesis inhibition.

Psoriasis is a chronic skin disorder characterized by a skin rash with scaly patches. Microvascular abnormalities are a characteristic feature of psoriasis and play a crucial role in the pathogenesis of psoriatic lesions. Angiogenic factors are upregulated in psoriatic skin lesions and are thought to induce angiogenesis. Platelet-derived growth factor (PDGF) induces vascular endothelial growth factor (VEGF), and PDGF is upregulated in keratinocytes in psoriatic skin lesions. The present study aimed to investigate the effect of topical imatinib mesylate (IMT) in inhibiting the activation of PDGF signalling in the pathogenesis of psoriasis. When topically applied to the skin of mice with imiquimod (IMQ)-induced psoriasis, IMT ameliorated skin symptoms similar to those of human psoriasis. Hyperproliferation of keratinocytes, hyperkeratosis, inflammatory cell infiltration and hypervascularity were histologically suppressed by topical IMT. The expression of angiogenic factors including fibroblast growth factor (FGF) and VEGF was decreased. The expression of FGF and VEGF in a PDGF-stimulated fibroblast cell line was inhibited by IMT. PDGF is required for the signalling pathway producing angiogenic factors in fibroblast. Thus, topically applied IMT inhibits PDGFR activation in fibroblast and suppresses the production of angiogenic factors, thereby mitigating the symptoms of psoriasis. The inhibitory effect of IMT on angiogenesis suggests that topical application IMT may be a viable treatment option for psoriasis.

Topical application of imatinib mesylate suppresses vitamin D3 analog-induced dermatitis in Balb/c mice.

Atopic dermatitis (AD) is an allergic disease mediated by Th2 cells. In AD, externally stimulated keratinocytes release inflammatory cytokines, such as IL-33 and TSLP. Inflammatory cells infiltrate skin tissue and increase vascular permeability. Therefore, we hypothesized that imatinib mesylate (IMT), which suppresses vascular permeability, may be a candidate therapeutic agent for AD. A vitamin D3 analog (MC903) was administered daily to both ears of Balb/c mice to create a murine AD model to which IMT was applied. The skin lesions were evaluated histopathologically and by immunostaining. Cytokine expression in the skin was assessed by using real-time polymerase chain reaction (PCR) and immunostaining and was investigated using Evans Blue to determine whether IMT suppressed vascular permeability due to histamine. The suppressive effect of TNF-α/IL-4-induced TSLP expression in primary mouse keratinocytes (MKCs) treated with IMT was then investigated. Tslp gene and protein expression in the lesion was measured using real-time PCR and ELISA. The activation of signal transduction was analysed by western blotting. Topical application of IMT significantly reduced ear thickness, Evans blue leakage, and scratch onset. IMT suppressed the number of infiltrating cells (CD4+ T cells, eosinophils, and basophils), and the expression of IL-13, IL-33, and TSLP in a MC903-induced, murine AD model and inhibited TNF-α/IL-4-induced TSLP expression via downregulation of ERK phosphorylation in MKCs. IMT reduced the skin symptoms in a MC903-induced, murine AD model, suggesting that it may have potential as a new treatment for AD.

Efficacy and safety of ritlecitinib in adolescents with alopecia areata: Results from the ALLEGRO phase 2b/3 randomized, double-blind, placebo-controlled trial.

BACKGROUND/OBJECTIVES: This subgroup analysis of the ALLEGRO phase 2b/3 trial (NCT03732807) evaluated the efficacy and safety of ritlecitinib, an oral, selective dual JAK3/TEC family kinase inhibitor, for the treatment of alopecia areata (AA) in patients aged 12-17 years. METHODS: In ALLEGRO-2b/3, patients aged ≥12 years with AA and ≥50% scalp hair loss received once-daily ritlecitinib 50 or 30 mg (±4-week 200-mg loading dose) or 10 mg or placebo for 24 weeks. In a subsequent 24-week extension period, ritlecitinib groups continued their doses, and patients initially assigned to placebo switched to 200/50 or 50 mg daily. Clinician- and patient-reported hair regrowth outcomes and safety were assessed. RESULTS: In total, 105 adolescents were randomized. At Week 24, 17%-28% of adolescents achieved a Severity of Alopecia Tool (SALT) score ≤20 (≤20% scalp without hair) in the ritlecitinib 30 mg and higher treatment groups versus 0% for placebo. At Week 48, 25%-50% of patients had a SALT score ≤20 across ritlecitinib treatment groups (30 mg and higher). Adolescents reporting that their AA "moderately" or "greatly" improved were 45%-61% in the ritlecitinib groups (30 mg and higher) (vs. 10%-22% for placebo) at Week 24 and 44%-80% at Week 48. The most common adverse events in adolescents were headache, acne, and nasopharyngitis. No deaths, major adverse cardiovascular events, malignancies, pulmonary embolisms, opportunistic infections, or herpes zoster infections were reported. CONCLUSION: Ritlecitinib treatment demonstrated clinician-reported efficacy, patient-reported improvement, and an acceptable safety profile through Week 48 in adolescents with AA with ≥50% scalp hair loss.

Internal Transcribed Spacer Region Typing of Trichophyton interdigitale Isolated from Japanese Patients.

Trichophyton interdigitale, an anthropophilic species, is one of the main causative agents of tinea unguium and tinea pedis. T. interdigitale and the zoophilic species T. mentagrophytes are morphologically and physiologically very similar. Isolates of the T. interdigitale/T. mentagrophytes complex from around the world have been classified into more than 10 internal transcribed spacer (ITS) genotypes. In this study, we isolated T. interdigitale from Japanese patients and investigated which ITS type was more common. The ITS regions of 29 clinical isolates of T. interdigitale and one clinical isolate of T. mentagrophytes were sequenced. The phylogenetic analysis of the ITS region sequences revealed that the 29 isolates of T. interdigitale belong to ITS type II of T. interdigitale. The one clinical isolate of T. mentagrophytes was in the same cluster with ITS type II* of T. mentagrophytes. One terbinafine-resistant strain of T. interdigitale also belonged to ITS type II of T. interdigitale.

[ANALYSIS OF 201 PATIENTS WITH ATOPIC DERMATITIS RECEIVING DUPILUMAB AT TOKYO MEDICAL UNIVERSITY HOSPITAL].

OBJECTIVE: The present study aimed to assess the course of patients with atopic dermatitis (AD) receiving dupilumab treatment. METHODS: The present, retrospective survey enrolled 201 patients with AD between May 2018 and May 2022 to examine their previous treatment, skin score, percentage of self-injections, EASI improvement rate, treatment continuation rate, number of treatment interruptions, and reasons for the interruptions. RESULTS: The average EASI severity score was 39.5±18.1, and the self-injection rate was 83%. The percentage of improvement in patients with an EASI-75 was 63% at week 16 and EASI 100 was 15.9% at week 60. At week 16 of treatment, the patients were divided by their improvement rate into an EASI-75, < 50 group. The EASI-75 group maintained their improvement rate until week 60. In the EASI< 50% group achieved 73.4% at week 60. The treatment continuation rate was 82.6%, and 35 patients discontinued the treatment, in most cases shortly after commencement. CONCLUSION: Dupilumab has revolutionized AD treatment, markedly improving skin symptoms. The present study was the first in Japan to demonstrate a treatment continuation rate of 82.6% at week 60 at a single center. Clear guidelines on long-term, complete maintenance treatment with dupilumab await formulation.

[TWO CASES OF ALLERGY WITH MUNG BEAN SPROUTS].

Patient 1 was a female patient in her teens who presented with swelling of the lips and oral discomfort after consuming mung bean sprouts. She had a history of this reaction since the age of 6 years and showed positive on a prick-to-prick test for mung bean sprouts. Patient 2 was a male patient in his twenties who also showed positive for mung bean sprouts as well as soybean sprout. Both patients were positive for IgE specific to birch, Gly m4, and Bet v1.Mung beans belong to the PR-10 family because they contain the allergenic component, Vig r1. A cross reaction to mung bean may occur in a patient with birch allergy as in the present cases. Mung bean sprouts are a cheap and common dietary item in Japan where, however, only a few cases of mung bean sprouts allergy have been reported. Mung bean sprouts allergy should be diagnosed with appropriate testing; if the patient has allergic reactions for this food item, an allergologist should provide detailed dietary guidance for avoiding pollen-food allergy syndrome.

IL-25 contributes to development of chronic contact dermatitis in C57BL/6 mice, but not BALB/c mice.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by type 2 immune responses. Interleukin-25 (IL-25) is produced predominantly by epithelial cells. It can activate Th2 cells to produce type 2 cytokines such as IL-4, IL-5 and IL-13, contributing to host defense against nematodes. However, excessive/inappropriate production of IL-25 is considered to be involved in development of type 2 cytokine-associated allergic disorders such as asthma. On the other hand, the contribution of IL-25 to the pathogenesis of AD remains poorly understood. In the present study, we found that expression of Il25 mRNA was significantly increased in the skin of mice during oxazolone-induced chronic contact hypersensitivity (CHS), which is a mouse model of human AD. In addition, development of oxazolone-induced chronic CHS was significantly reduced in IL-25-deficient (Il25-/-) mice compared with wild-type mice on the C57BL/6, but not BALB/c, background, although IL-25 was not essential for IL-4 production by hapten-specific T cells. Therefore, IL-25 is crucial for development of chronic CHS, although that is partly dependent on the genetic background of the mice.

Low-Dose MST-16/VP-16 Combination Chemotherapy in 9 Patients with Tumor Stage Mycosis Fungoides.

BACKGROUND/AIM: MST-16 and VP-16, both of which are topoisomerase II inhibitors, are antitumor agents regularly used to treat malignant lymphoma and small cell lung carcinoma. New therapeutic agents for tumor stage mycosis fungoides (MF) have recently been developed, but their efficacy is limited. We herein retrospectively reported the use of MST-16/VP-16 combination therapy for tumor stage MF at multiple treatment centers and examined their antitumor effect. METHODS: Five male and four female patients with tumor stage MF were enrolled. Age at the start of therapy ranged from 33 to 80 years (average: 54.5 years), and the previous treatment consisted of R-CHOP, CAVOP-IFN, etc. The protocol for low-dose MST-16/VP-16 combination chemotherapy consisted of 800 mg MST-16 and 25 mg VP-16 administered 5 days per month. RESULTS: Three of the 9 patients died, but two of the three fatalities were unrelated to MF. A treatment effect was seen in three and 6 patients who showed a complete response and a partial response, respectively. The 5-year and 10-year overall survival rate was 85.7% and 57.1%, respectively. Adverse reactions consisted of 4 cases of nausea and 1 case of leukopenia. CONCLUSION: The present study demonstrated that the response rate to MST-16/VP-16 combination therapy was 100% and that the treatment effect was relatively long, suggesting that this therapy may be a viable option for treating tumor stage MF.

[A CHILD CASE OF DIFFUSE CUTANEOUS MASTOCYTOSIS].

Cutaneous mastocytosis (CM) usually appears in childhood and improves substantially before adolescence. The c-KIT mutation of D816V is present in 36% and 20% of patients with childhood-onset CM and diffuse cutaneous mastocytosis (DCM), respectively. In some cases of childhood-onset DCM, the disease can progress to systemic mastocytosis; in others, it resolves spontaneously. Thus, assessing the prognosis is difficult. Herein, we described a case of DCM in an 11-month-old, male patient without a c-KIT mutation. The patient presented with dark brown macules and sporadic erythema topped by bullous lesions. A skin biopsy of the macule on the abdomen revealed accumulation of mast cells which were round to oval-shaped with amphophilic cytoplasm within the upper dermis. The patient had received H1 inhibitor until age 3 years and continued to experience blisters on the trunk. However, no severe symptoms, such as anaphylaxis, occurred. Included in this manuscript is a review of previous reports of childhood-onset DCM in Japan and cases specifically seen at our dermatology clinic.

Histopathologic and dermoscopic features of 42 cases of folliculitis decalvans: A case series.

BACKGROUND: Folliculitis decalvans (FD) is a form of inflamed primary cicatricial alopecia (PCA). FD is classified as a neutrophilic PCA; however, only a few previous studies have described its histopathology, including the assessment of systematically evaluated and quantified follicular changes in horizontally sectioned biopsy specimens with clinical and dermoscopic findings of the early and advanced stages. OBJECTIVE: We aimed to clarify the histopathologic and dermoscopic features of early and advanced active stage FD. METHODS: We conducted a case series study of 42 patients with FD by dermoscopy and both horizontally and vertically sectioned biopsy specimens. RESULTS: The histopathologic findings of the early-stage lesions included loss of sebaceous glands; interfollicular acanthosis; and fibrosis with depressed, fused follicular infundibula showing thickened interfollicular keloid-like areas with tufted hairs on dermoscopy. Active lesions showed a greater number of hair clusters, clefting, and fused infundibula with dense inflammation predominantly in the upper follicles. Neutrophil-predominant infiltrates were observed in fewer than half of the patients, including those with early-stage lesions. LIMITATIONS: This was a retrospective study. CONCLUSION: FD has the features of mixed-cell PCA. The features of early-stage FD are thickened interfollicular keloid-like areas with tufted hairs and loss of sebaceous glands.

IL-17-positive mast cell infiltration in the lesional skin of lichen planopilaris: Possible role of mast cells in inducing inflammation and dermal fibrosis in cicatricial alopecia.

Lichen planopilaris (LPP) is a primary cicatricial alopecia characterized by the infiltration of lymphocytes in the upper portion of hair follicles. Inflammation around the bulge region of hair follicles induces destruction of hair follicle stem cells and tissue fibrosis, resulting in permanent hair loss. Treatment is still challenging, and the precise pathophysiology of this disorder is unknown. To clarify the pathogenesis of LPP, we performed histological and immunohistochemical analysis on specimens obtained from LPP patients. Formalin-fixed and paraffin-embedded samples were evaluated by staining with haematoxylin and eosin (HE), toluidine blue stain, immunohistochemistry and immunofluorescence. The immunohistochemical analysis demonstrated that CD4-positive T cells preferentially infiltrated into the follicular infundibulum in the LPP lesions. Toluidine blue stain detected a large number of mast cells in the inflammatory lesions of LPP. Interestingly, immunohistochemical analysis demonstrated that the mast cells harboured IL-17A- and IL-23-producing activity and expressed the IL-23 receptor. The number of IL-17A-positive mast cells was significantly higher in the LPP lesions than in normal scalp. Moreover, the IL-17 receptor was expressed exclusively in the follicular epithelial cells in the LPP lesions. These results suggested that mast cells infiltrating hair follicles might play a role in the pathogenesis of LPP via the IL-23/IL-17 axis.

Guinea pig seborrheic dermatitis model of Malassezia restricta and the utility of luliconazole.

Seborrheic dermatitis (SD) is a multifactorial disease in which Malassezia restricta has been proposed as the predominant pathogenic factor. However, experimental evidence supporting this hypothesis is limited. A guinea pig SD model using a clinical isolate of M. restricta was used to elucidate the pathogenicity of M. restricta. Also, the efficacy of 1% luliconazole (LLCZ) cream, a topical imidazole derivative, against M. restricta was compared with that of a 2% ketoconazole (KCZ) cream in the same guinea pig model. Dorsal skin hairs of guinea pig were clipped and treated with M. restricta by single or repeated inoculations without occlusion. Skin manifestations were examined macroscopically and histologically. A quantitative polymerase chain reaction (PCR) assay was also performed for mycological evaluation. An inflammatory response mimicking SD occurred after repeated as well as single inoculation but not in abraded skin. The inflammation score attained its maximum on day 11 and persisted until day 52. The yeast form of the fungal elements was distributed on the surface of stratum corneum and around the follicular orifices, and an epidermal and dermal histological reaction was observed. Application of 1% LLCZ or 2% KCZ cream significantly improved the skin manifestations and decreased the quantity of M. restricta rDNA in the skin lesions. The efficacy of topical antifungal drugs suggested that M. restricta is a pathogenic factor contributing to SD.

In vitro antifungal activity of luliconazole against nondermatophytic moulds.

In vitro antifungal activity of luliconazole against nondermatophytic moulds causing superficial infections was compared with that of five classes of 12 topical and systemic drugs. The minimum inhibitory concentration (MIC) of the drugs against the genera of Neoscytalidium, Fusarium, Aspergillus, Scedosporium, and Alternaria was measured via modified microdilution method. In results, the nondermatophytic moulds were found to be less susceptible to drugs to which Neoscytalidium spp. and Fusarium spp. were typically drug resistant. However, luliconazole was effective against all the genera tested, including afore-mentioned two species, and had the lowest MICs among the drugs tested.

Autologous cell-based therapy for male and female pattern hair loss using dermal sheath cup cells: A randomized placebo-controlled double-blinded dose-finding clinical study.

BACKGROUND: Few effective treatments are available for male pattern hair loss (MPHL) or, especially, for female pattern hair loss (FPHL). Recently, cell-based therapies using autologous or allogeneic cells have been used clinically. OBJECTIVE: We examined the safety and efficacy of autologous cell-based therapy using dermal sheath cup (DSC) cells to treat MPHL and FPHL. METHODS: DSCs dissected from occipital hair follicles were cultured to manufacture DSC cells. Participants with MPHL or FPHL received single injections of 7.5 × 106, 1.5 × 106, or 3.0 × 105 DSC cells or a placebo in 4 randomized separate regions on the scalp, and hair densities and diameters were measured for 3, 6, 9, and 12 months. RESULTS: Fifty men and 15 women aged 33 to 64 years were injected with DSC cells. Total hair density and cumulative hair diameter at the 3.0 × 105 DSC cells injection site was significantly increased compared with the placebo after 6 and 9 months. Men and women showed similar improvements, and there were no serious adverse events. LIMITATIONS: No lower cell numbers were tested, and the positive effect was temporary until 9 months. CONCLUSION: The results suggest that cell therapy with autologous DSC cells may be useful as a new therapeutic method for treating MPHL and FPHL.

Trichophyton indotineae sp. nov.: A New Highly Terbinafine-Resistant Anthropophilic Dermatophyte Species.

In this report, we describe the first isolation of two highly terbinafine (TRF)-resistant Trichophyton interdigitale-like strains from a Nepali patient and an Indian patient with tinea corporis in Japan. These strains (designated NUBS19006 and NUBS19007) exhibited a TRF minimal inhibitory concentration (MIC) of > 32 mg/L and contained a missense mutation (Phe397Leu) in squalene epoxidase (SQLE) gene. The internal transcribed spacer (ITS) region sequences amplified from the isolates (NUBS19006 and NUBS19007) were 99.5% identical to Japanese isolates of T. interdigitale and T. interdigitale strain CBS 428.63. The homology of region sequences were also 97.6% identical to T. mentagrophytes strain CBS 318.56. Moreover, the ITS sequences amplified from the isolates were 100% identical to highly TRF-resistant strains of T. interdigitale, which were isolated in Delhi, India, and harbored mutations in SQLE. The urease test on Christensen's urease agar was positive for T. mentagrophytes and T. interdigitale after 7 days of incubation. On the other hand, the type strain of T. rubrum CBS 100081 T and highly TRF-resistant strains (NUBS19006 and NUBS19007) were negative on Christensen urease agar after 7 and 14 days of incubation. Moreover, NUBS19006 and NUBS19007 were also negative reaction on the hair perforation test. To avoid confusion in the taxonomy of the T. mentagrophytes/T. interdigitale complex, we suggest that the highly TRF-resistant Indian strains be considered a new species independent of T. interdigitale, according to clinical and mycological features.

IL-36α is involved in hapten-specific T-cell induction, but not local inflammation, during contact hypersensitivity.

Levels of IL36α are known to be increased in specimens from patients with atopic dermatitis and psoriasis. In addition, it has been reported that IL-36α is crucial for development of imiquimod-induced psoriatic dermatitis in mice. On the other hand, the role of IL-36α in induction of allergic contact dermatitis/contact hypersensitivity (ACD/CHS) is poorly understood. We found that IL-36α was produced in keratinocytes of mice during imiquimod-induced psoriatic dermatitis, but it was hardly detectable in the skin of mice during either fluorescein isothiocyanate (FITC)- or 1-fluoro-2, 4-dinitrobenzene (DNFB)-induced CHS. Although IL-36α can enhance activation of dendritic cells (DCs) and T cells, in CHS, IL-36α was not essential for DC migration from the skin to draining LNs, but it was required for induction or activation of hapten-specific T cells such as Th/Tc1 or Th17 cells. However, local inflammation, assessed by measurement of ear skin thickness, was comparable between wild-type and IL-36α-deficient mice during both FITC- and DNFB-induced CHS. These observations indicate that IL-36α is involved in induction and/or activation of hapten-specific T-cell subsets in the sensitization phase of CHS, but not essential for induction of local inflammation in the elicitation phase.

A pulmonary metastatic model of murine melanoma assessed by magnetic resonance imaging.

Immune checkpoint inhibitors and kinase inhibitors have improved prognosis of malignant melanoma (MM) patients. However, these therapies cannot completely overcome the metastasis of MM. Thus, development of new therapy against metastasis should be required. A first step towards this goal, the aim of this study, is to establish a model of pulmonary metastasis from primary cutaneous MM and a monitoring system. B16-F10, a murine melanoma cell line, was subcutaneously injected into the pinna of mice. The pinna was excised when the lesion was detected. A metastatic nodule on T2-weighted imaging was detected 4 weeks after resection of the pinna. Lung metastases were observed in 37.5% (6/16) of the specimens. We established a novel murine model of the high pulmonary metastasis of MM. The MRI was useful for observations of the growth of the metastatic lesions in the lungs without dissection.