Yoshimasa Nobeyama

Silencing of tissue factor pathway inhibitor‐2 gene in malignant melanomas

To identify tumor‐suppressor genes inactivated by aberrant methylation of promoter CpG islands (CGIs) in human malignant melanomas, genes upregulated by treatment of cells with a demethylating agent, 5‐aza‐2′‐deoxycytidine (5‐aza‐dC), were searched for using oligonucleotide microarrays in melanoma cell lines, HMV‐I, MeWo and WM‐115. Seventy‐nine known genes with CGIs were identified as being upregulated (≥16‐fold), and 18 of them had methylation of their putative promoter CGIs in 1 or more of 8 melanoma cell lines. Among the 18 genes, TFPI‐2, which is involved in repression of the invasive potential of malignant melanomas, was further analyzed. Its expression was repressed in a melanoma cell line with its complete methylation, and was restored by 5‐aza‐dC treatment. It was unmethylated in cultured neonatal normal epidermal melanocyte, and was induced by ultraviolet B. In surgical melanoma specimens, TFPI‐2 methylation was detected in 5 of 17 metastatic site specimens (29%), while it was not detected in 20 primary site specimens (0%) (p = 0.009). By immunohistochemistry, the 5 specimens with promoter methylation lacked immunoreactivity for TFPI‐2. The results showed that TFPI‐2 is silenced in human malignant melanomas by methylation of its promoter CGI and suggested that its silencing is involved in melanoma metastasis.

Sweet's syndrome with neurologic manifestation: case report and literature review

Background Sweets syndrome with involvement of the central nervous system (CNS) is rarely reported.

Novel IL36RN gene mutation revealed by analysis of 8 Japanese patients with generalized pustular psoriasis

[2] Tarutani M, Itami S, Okabe M, Ikawa M, Tezuka T, Yoshikawa K, et al. Tissuespecific knockout of the mouse Pig-a gene reveals important roles for GPIanchored proteins in skin development. Proc Natl Acad Sci U S A 1997;94:7400– 5. [3] Vasioukhin V, Degenstein L, Wise B, Fuchs E. The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. Proc Natl Acad Sci U S A 1999;96:8551–6. [4] Sano S, Itami S, Takeda K, Tarutani M, Yamaguchi Y, Miura H, et al. Keratinocytespecific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. EMBO J 1999;18:4657–68. [5] Tarutani M, Nakajima K, Takaishi M, Ohko K, Sano S. Epidermal hyperplasia induced by Raf-MAPK signaling requires Stat3 activation. J Dermatol Sci 2013;72:110–5. [6] Ramirez A, Page A, Gandarillas A, Zanet J, Pibre S, Vidal M, et al. A keratin K5Cre Yujin Nakagawa, Gyohei Egawaa,*, Yoshiki Miyachi, Kenji Kabashima Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; PRESTO, Japan Science and Technology Agency, 7 Gobancho, Chiyoda-ku, Tokyo 102-0075, Japan

Successful treatment of ustekinumab in a severe psoriasis patient with human immunodeficiency virus infection.

myeloma, the diagnosis of AL amyloidosis was initially made by dermatological evaluation and skin biopsy. Among patients with multiple myeloma, 15% may develop some form of amyloidosis. Dermatologists should be aware that periorbital papules, purpura/ecchymosis and macroglossia are suggestive for systemic amyloidosis and require biopsy. First priority in handling amyloidosis is to identify and treat underlying disease.

Switching of biologics in psoriasis: Reasons and results.

Efficacy and safety profiles of biologics have been established for moderate to severe psoriasis. However, inefficacy or adverse events sometimes require changing the treatment to other biologics. Here, we examine the effectiveness of this strategy. We retrospectively investigated cases requiring switching biologics. We enrolled 275 psoriatic patients treated with biologics between January 2010 and December 2014 in our hospital. Of these, 51 required a switch to another biologic. First‐line therapies were infliximab (IFX, n = 26), adalimumab (ADA, n = 18) and ustekinumab (UST, n = 7), and second‐line therapies were IFX (n = 5), ADA (n = 21) and UST (n = 25). Reasons for switching were inefficacy (n = 38), adverse events (n = 11) and others (n = 2). The details were primary failure (n = 15), secondary failure (n = 23) and infusion reactions (n = 8). In 49 patients who switched biologics due to inefficacy and adverse events, the mean Psoriasis Area and Severity Index (PASI) score at week 16 was 4.3 for first‐line therapies and 2.9 for second‐line therapies (P < 0.05). Switching to a second biologic therapy to address the firsts inefficacy or adverse events often results in significant improvement in moderate to severe psoriasis.

Xeroderma pigmentosum complementation group F: Report of a case and review of Japanese patients

Xeroderma pigmentosum (XP) is an autosomal recessive genetic disorder characterized by extraordinary sensitivity to sunlight, resulting in cutaneous malignant tumors. Among XP, XP‐F presents relatively uniquely in Japanese. To clarify the characteristics of this group, we describe a case of XP‐F and review Japanese cases previously reported. A 50‐year‐old Japanese woman was referred to us with multiple, variously sized, light‐ or dark‐brown macules on the face and sunlight‐exposed extremities. She had experienced bulla formation with approximately 10 min of sunlight exposure during her elementary school years. Her parents had been first cousins, and her mother and sister had photosensitivity. She showed no neurological or developmental abnormalities. Ultraviolet (UV) irradiation testing revealed normal levels for minimal erythema dose with UV‐A and UV‐B. Sensitivity to UV‐C and DNA repair ability in the patients fibroblasts were indicated between that in normal individuals and that in an XP‐A patient. Complementation assay revealed that transfection of the XPF gene led most efficient DNA repair compared with the other XP genes. Therefore, the patient was diagnosed with XP‐F. Twenty‐three cases of Japanese patients (six males, 17 females) with XP‐F have been reported, including the present case. Our review suggested a relatively high prevalence of 50% (11/22) for cutaneous malignant tumors. A significant difference was evident in the mean age at first medical consultation between patients with cutaneous malignant tumors (53.6 years) and patients without such tumors (30.8 years). This suggests that cutaneous malignant tumors could occur in the age range of 30–50 years in XP‐F patients.

Tumor-suppressive effects of natural-type interferon-β through CXCL10 in melanoma.

INTRODUCTION Type 1 interferon is in widespread use as adjuvant therapy to inhibit melanoma progression. Considering the tumor-suppressive effects of local administration of interferon-β (IFN-β) on lymphatic metastasis, the present study was conducted to identify melanoma-suppressive molecules that are up-regulated by IFN-β treatment of lymphatic endothelial cells. MATERIALS AND METHODS Lymphatic endothelial cells, fibroblasts, and melanoma cells were treated with natural-type IFN-β, and melanoma cells were treated with CXCL10. Genome-wide oligonucleotide microarray analysis was performed using lymphatic endothelial cells with or without IFN-β treatment. Quantitative real-time reverse transcription-PCR and an enzyme-linked immunosorbent assay were performed to examine CXCL10 expression. A proliferation assay was performed to examine the effects of IFN-β and CXCL10 in melanoma cells. RESULTS Genome-wide microarray analyses detected CXCL10 as a gene encoding a secretory protein that was up-regulated by IFN-β in lymphatic endothelial cells. IFN-β treatment significantly induced CXCL10 in dermal lymphatic endothelial cells and melanoma cells that are highly sensitive to IFN-β. CXCL10 reduced melanoma cell proliferation in IFN-β-sensitive cells as well as resistant cells. Melanoma cells in which CXCL10 was knocked down were sensitive to IFN-β. CXCR3-B, which encodes the CXCL10 receptor, was up-regulated in melanoma cells with high sensitivity to IFN-β and down-regulated in melanoma cells with medium to low sensitivity. CONCLUSIONS Our data suggest that IFN-β suppresses proliferation and metastasis from the local lymphatic system and melanoma cells via CXCL10. Down-regulation of CXCR3-B by IFN-β may be associated with resistance to IFN-β.

Case of metastatic malignant melanoma associated with hypertrophic osteoarthropathy.

tumor on the thigh. A 30-year-old woman had a subcutaneous nodule on the inner aspect of her left thigh. The nodule had gradually enlarged over the previous 4 years. On examination, it was a solitary, oval, non-tender, subcutaneous nodule, 5 mm in diameter, with normal-appearing overlying skin (Fig. 1a). There was no adhesion to the surrounding tissue. Echography showed a round lesion beneath the dermis without rich blood circulation. With the tentative diagnosis of epidermal cyst, the tumor was totally excised. Histopathologically, it was an infundibular cyst-like structure surrounded by collagen bundles (Fig. 1b). The cyst contained horny materials, but not hair shafts. Multiple, hypertrophic, sebaceous lobules were radially connected to the cyst wall and consisted of maturated sebaceous cells. The individual sebaceous glands were opened to the cyst. Vascular vessels were hyperplastic in the surrounding stroma (Fig. 1c). Continuity of the cyst to the epidermis was unlikely. We thus diagnosed the nodule as FSCH. The histopathological relationship between FSCH and trichofolliculoma (TF), especially its variant termed sebaceous TF, remains controversial. Ansai et al. proposed that FSCH is distinct from sebaceous TF in its mesenchymal changes. In FSCH, double clefts exist between the fibroepithelial units and the surrounding altered stroma, as seen in our case. In addition, while sebaceous TF often contains numerous terminal hairs and vellus hairs, FSCH shows only focal follicular differentiation. Deparaffinized sections were immunohistochemically stained by using the avidin–biotin complex method. Consistent with the previous case of FSCH, K1 (Fig. 2a) and K10 (Fig. 2b) was found in the suprabasal layer of the infundibulosebaceous structures of the tumor, and K14 was found in the basal cells of the infundibulosebaceous structures of the tumor (Fig. 2c) similarly to the normal skin. K15 and K19 are potential markers of hair follicle stem cells in the hair bulge. Consistent with the previous case of FSCH, K15 (Fig. 2d), but not K19 (data not shown), was expressed in the basal cells of the infundibulosebaceous structures of our case. The lack of K19 may result from the absence of the isthmus/bulge region of the hair follicles. The tumor cells of FSCH are postulated to be proliferating K15-positive hair follicle stem cells with sebaceous differentiation. Although the nestin-positive spindle stromal cells are present around adipocytes in some cases of FSCH, they were not detected in our case using an antibody (1:200, 10C2; Abcam, Cambridge, UK). The staining with D2-40 reactive to podoplanin exhibited the presence of not only lymphatic vessel endothelial cells but also germinative cells in the most outer layer of the sebaceous lobules. Folliculosebaceous cystic hamartoma is located most frequently on the face (71%), followed by the scalp (14%), whereas 17 cases (11%) occur on other sites in Japanese patients. Lesions on the auris, nipple, back, axilla and extremities are rare and generally uncommon at the non-hair-bearing sites. Only two cases of FSCH on the lower extremities have previously been reported. FSCH usually exhibits a sessile or pedunculated nodule, and there has been no report of FSCH histologically located in the subcutaneous fat. Our case is characterized by both the lesional site and histopathological location.

Case of engraftment syndrome appearing as scratch dermatitis

Dear Editor, Scratch dermatitis, or flagellate erythema, is characterized by linear erythematous/hyperpigmented streaks, and can be caused by shiitake mushroom, bleomycin, dermatomyositis and Still’s disease. Engraftment syndrome (ES) presents with pyrexia, maculopapular eruption and edema during neutrophil recovery following hematopoietic stem cell transplantation. Here, we describe a case with scratch dermatitis encountered as a clinical manifestation of ES. A 44-year-old Japanese woman was referred to us with a 2day history of distinct scratch marks due to severe pruritus 18 days after unrelated allogeneic bone marrow transplantation (BMT) from an unrelated donor to treat blast crisis of chronic myeloid leukemia. Human leukocyte antigens between patient and donor were matched at eight of eight loci serologically, and seven of eight loci by DNA typing (mismatch for DRB1). The patient denied having eaten shiitake mushrooms recently. Neither bleomycin nor peplomycin had been administrated. Physical examination showed severe pruritus and erythematous streaks on the trunk on post-BMT day 18 (Fig. 1a). Maculopapular eruptions appeared on the trunk and extremities on day 19 (Fig. 1b). No diarrhea or jaundice was observed. Bodyweight was 56.0 kg, 57.2 kg and 56.2 kg on day 16, 18–21 and 22, respectively. Maximum daily axillary temperature was 37.9°C on day 16, 39.5°C on day 17, 39.1°C on day 18, 39.5°C on day 19 and 38.0°C on day 20. Neutrophil counts were 400/lL on day 16, 1300/lL on day 18 and 3500/lL on day 19. Aspartate transaminase and alanine transaminase concentrations were 173 IU/mL and 340 IU/mL, respectively, on day 18. Histopathological examination of the streaks on the

Case of ecthyma gangrenosum in which only methicillin-resistant Staphylococcus epidermidis was detected.

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