Hiroo Amano

Four cases of Morbihan disease successfully treated with doxycycline

Morbihan disease (MD) is rosacea‐like disease characterized by persistent lymphedema on the upper half of the face. Currently, there is no established standard treatment for MD. Recently, MD has been reported to be associated with the infiltration of mast cells. The aim of this study was to investigate the association of treatment response and mast cell infiltration in MD. We report four cases of MD that were successfully treated with long‐term oral doxycycline therapy.

Successful treatment of erythematotelangiectatic rosacea with intense pulsed light: Report of 13 cases

Here, we describe the use of intense pulsed light (IPL) treatment for 13 cases of erythematotelangiectatic rosacea delivered in three sessions. For two‐step irradiation, after the whole face had been irradiated using conventional IPL equipment covering a wide area, localized IPL spot irradiation was performed for visibly dilated capillaries. The therapeutic effect was evaluated by image analysis using Image J and scored by 10 dermatologists using two IPL instruments in combination. This therapeutic approach was found to be much more effective than irradiation using a single instrument. Our findings demonstrate that IPL irradiation using the present method can deliver a sufficient therapeutic effect even with a small number of treatment sessions. Although rosacea is difficult to treat, we believe that IPL can be therapeutically useful in such cases.

Monitoring serum cytokeratin 19 fragment 21-1 to determine the efficacy of docetaxel chemotherapy in advanced extramammary Paget's disease

Dear Editor, Most Extramammary Paget’s disease (EMPD) tumors are limited to the epidermis. However, invasive EMPD tumors cause metastases to the regional lymph nodes or other organs. The treatments for metastatic EMPD include chemotherapy and radiotherapy, but it is necessary to evaluate the therapeutic effects. Previous research showed that serum cytokeratin (CK)19 fragment 21-1 (CYFRA) is a useful tumor marker and can be used to evaluate tumor progression and treatment efficacy in patients with EMPD. A 65-year-old Japanese woman presented to our hospital with a 5-month history of bilateral leg edema and genital bleeding. Physical examination revealed irregular erythema on both labia majora and an ulcerative tumor on the right labium (Fig. 1a). The right inguinal lymph nodes were enlarged. The serum carcinoembryonic antigen (CEA) level was mildly

Keratosis follicularis squamosa (Dohi) successfully treated with benzoyl peroxide 2.5% gel

Dear Editor, Keratosis follicularis squamosa (KFS), first described by Dohi in 1903, is a keratinizing disorder. KFS is particularly common in Asians. Irritation from clothing, bacterial infections, heredity and hormone imbalances have been proposed as pathogenic factors. However, the real pathogenesis of KFS is still unknown. We herein report a case of KFS successfully treated with topical benzoyl peroxide (BPO) 2.5% gel. A 10-year-old Japanese girl presented with a 6-month history of asymptomatic brownish scaly patches on her trunk and inguinal regions (Fig. 1a,b). Therapy with topical heparinoid ointment, corticosteroid ointment, oral vitamin C and tranexamic acid were not effective. Her medical history was unremarkable and she had no past history of atopic dermatitis. There was no family history of a similar condition. Physical examination revealed small scattered pityriatic round or oval patches with a brownish follicular plug in the center (Fig. 1c). This patch looked like lotus leaves on water as described by Dohi and Momose in their first report of this disease. Dermoscopic observation of the lesion with echo-jelly showed a typical brownish follicular plug in the center (Fig. 1d). Histological examination of her patch revealed dilated follicles with keratotic plugs and orthohyperkeratosis (Fig. 1e). The Gram stain showed Gram-positive cocci in the hair follicles (Fig. 1g). Based on the above findings, we diagnosed her as having KFS. After topical BPO gel was initiated once a day, she showed marked clinical improvement within 4 weeks. Eight weeks of therapy resulted in a marked improvement of the skin lesions (Fig. 1g). No serious adverse effects of topical BPO gel were noted during the course. Topical urea, salicylic acid and vitamin D ointment have been tried in the published work as treatments for KFS, however, no good therapeutic results were reported. To the best of our knowledge, this is the first report of KFS successfully treated with topical BPO gel. Benzoyl peroxide is known to be a powerful oxidizing agent. It reduces the number of microorganisms on the skin surface

In-frame Val 216 -Ser 217 deletion of KIT in mild piebaldism causes aberrant secretion and SCF response

BACKGROUNDnPiebaldism is a pigmentary disorder characterized by a white forelock and depigmented patches. Although the loss-of-function mutations in the KIT gene underlie the disease, the intracellular dynamics of the mutant KIT are largely unknown. We herein report a Japanese family with piebaldism in which the affected members showed a mild phenotype.nnnOBJECTIVEnThe objective of this study is to investigate the functions and intracellular dynamics of the mutant KIT protein.nnnMETHODSnWe performed genetic analyses of the KIT gene using peripheral blood cells. We analyzed the intracellular localization of the mutant KIT protein in HEK293T cells transfected with wild-type (Wt) and/or mutant KIT genes. Immunoprecipitation analyses, immunoblotting and immunofluorescence studies were performed using antibodies against KIT and downstream signaling proteins. Glycosidase digestion analysis was performed to clarify the intracellular localization of KIT protein.nnnRESULTSnA genetic analysis revealed a novel heterozygous mutation c.645_650delTGTGTC which results in the in-frame deletion of Val216 and Ser217 in the extracellular domain of KIT. Immunoprecipitation analyses confirmed that the wild and mutant KIT formed a heterodimer after treatment with stem cell factor (SCF); however, the phosphorylation of the downstream signaling factors was decreased. In an immunofluorescence study, the mutant KIT accumulated predominantly in the endoplasmic reticulum (ER) and was sparsely expressed on the cell surface. A glycosidase digestion study revealed that the mutant KIT is predominantly localized in the ER.nnnCONCLUSIONnThese data reveal an aberrant function and intracellular localization of mutant KIT protein in piebaldism.

Cross-sectional survey on disease severity in Japanese patients with harlequin ichthyosis/ichthyosis: Syndromic forms and quality-of-life analysis in a subgroup

BACKGROUNDnCongenital ichthyoses (CIs) adversely affect quality of life (QOL) in patients. However, the effects of CIs on patient QOL have not been studied sufficiently.nnnOBJECTIVEnTo investigate the association between disease severity and QOL in patients with harlequin ichthyosis (HI) and ichthyosis: syndromic forms (ISFs) METHODS: Clinical information of patients with HI and ISFs from 2010 to 2015 were obtained from 100 dermatology departments/divisions of principal institutes/hospitals throughout Japan. We examined the relationship between disease severity and QOL in patients with HI and ISFs. Patients who were aged 8 years or older and participated in a multicenter retrospective questionnaire survey in Japan were assessed by dermatology life quality index (DLQI, range of 0-30) and clinical ichthyosis score (range of 0-100).nnnRESULTSnNetherton syndrome patients had a significantly higher risk of allergy to food or environmental allergens than patients with other phenotypes. Keratitis-ichthyosis-deafness (KID) syndrome patients showed a significantly higher risk of skin infections than patients with other phenotypes. Complete data on DLQI were obtained from 13 patients, whose median age was 21 (8-71) years. Nine patients were male, and 4 were female. Systemic retinoids were administrated to 2 of the 3 HI patients. The Spearmans correlation coefficient between the clinical ichthyosis score and DLQI was 0.611 (Pu2009<u20090.05).nnnCONCLUSIONnWe confirmed that Netherton syndrome and KID syndrome patients have a higher risk of allergy to food or environmental allergens and of skin infections, respectively. QOL impairment correlates with disease severity in HI and ISFs patients.

Analysis of cancer-associated fibroblasts and the epithelial-mesenchymal transition in cutaneous basal cell carcinoma, squamous cell carcinoma and malignant melanoma

Activated cancer-associated fibroblasts (CAFs) and fibroblasts that have undergone the epithelial-mesenchymal transition (EMT) in cancer stroma contribute to tumor progression and metastasis. However, no reports have investigated the CAF phenotype and its clinicopathological relevance in cutaneous malignant tumors, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and malignant melanoma (MM). Here, we investigated the CAF phenotype in cutaneous malignant tumors based on their histology and immunohistochemical expression of CAF-related markers, including adipocyte enhancer-binding protein 1 (AEBP1), podoplanin, platelet-derived growth factor receptor α (PDGFRα), PDGFRβ, fibroblast activating protein (FAP), CD10, S100A4, α-smooth muscle actin (α-SMA), and EMT-related markers (Zeb1, Slug, and Twist). In addition, we assessed the role of the CAF phenotype in cutaneous malignant cancers using hierarchical cluster analysis. Consequently, 3 subgroups were stratified based on the expression pattern of CAF- and EMT-related markers. Subgroup 1 was characterized by low expression of AEBP1, PDGFRα, PDGFRβ, FAP and Slug, whereas subgroup 2 was closely associated with high expression of PDGFRβ, S100A4 and Twist. In addition, high expression levels of podoplanin, PDGFRβ, CD10, S100A4, α-SMA, Zeb1, Slug and Twist were observed in subgroup 3. High expression of CD10 was commonly found in all 3 subgroups. These subgroups were correlated with histologic subtypes, that is, subgroup 1, MM; subgroup 2, BCC; and subgroup 3, SCC. We suggest that the expression pattern of CAF- and EMT-related proteins plays crucial roles in the progression of BCC, SCC, and MM.

Carnosic acid, an inducer of NAD(P)H quinone oxidoreductase 1, enhances the cytotoxicity of β‑lapachone in melanoma cell lines

NAD(P)H quinone oxidoreductase 1 (NQO1)-dependent antitumor drugs such as β-lapachone (β-lap) are attractive candidates for cancer chemotherapy because several tumors exhibit higher expression of NQO1 than adjacent tissues. Although the association between NQO1 and β-lap has been elucidated, the effects of a NQO1-inducer and β-lap used in combination remain to be clarified. It has previously been reported that melanoma cell lines have detectable levels of NQO1 expression and are sensitive to NQO1-dependent drugs such as 17-allylamino-17-demethoxygeldanamycin. The present study was conducted to investigate the involvement of NQO1 in β-lap-mediated toxicity and the utility of combination treatment with a NQO1-inducer and β-lap in malignant melanoma cell lines. Decreased expression or inhibition of NQO1 caused these cell lines to become less sensitive to β-lap, indicating a requirement of NQO1 activity for β-lap-mediated toxicity. Of note was that carnosic acid (CA), a compound extracted from rosemary, was able to induce further expression of NQO1 through NF-E2 related factor 2 (NRF2) stabilization, thus significantly enhancing the cytotoxicity of β-lap in all of the melanoma cell lines tested. Taken together, the data presented in the current study indicated that the NRF2-NQO1 axis may have potential value as a therapeutic target in malignant melanoma to improve the rate of clinical response to NQO1-dependent antitumor drugs.