A novel splicing variant of CADM2 as a protective transcript of psoriasis.

CADM2, a candidate gene for psoriasis, was identified by a genome-wide association study using microsatellites in the Japanese population (561 cases and 561 controls). Moreover, haplotype analysis included an additional 68 SNPs and indicated that a 110-kb haplotype block was detected for the protective risk haplotype of psoriasis. We also identified an initial exon of novel splicing variants in this haplotype block. A functional analysis by qRT-PCR using RNAs from the blood of 56 cases and 64 controls significantly demonstrated an inverse correlation between expression frequencies in a novel splicing variant and the number of alleles associated with psoriasis. To confirm these results, we must perform replication studies using other ethnic groups and more functional analysis particularly for skin tissues.

Thrombospondin 2 inhibits metastasis of human malignant melanoma through microenvironment-modification in NOD/SCID/gammaCnull (NOG) mice.

Thrombospondin (TSP) 2 interacts with matrix metalloproteinases (MMPs) and matrix serine proteases such as plasminogen activator (PA). Malignant melanoma is an aggressive human neoplasm showing aggressive metastatic features. We examined the effects of TSP2 gene introduction in the human malignant melanoma cell line A375. We established three clones transfected with human TSP2 (A375/TSP2). The in vitro invasiveness was remarkably suppressed (42-61%) in the TSP2-transfectants, while growth properties were preserved. The A375/TSP2 showed significantly decreased liver metastatic potential (liver weight: 3.88+/-0.30 g in A375/TSP2, 7.07+/-0.67 g in vector-transfectant (A375/V), p<0.01, Mann-Whitney U test) in super immuno-deficient mice (NOD/SCID/gammacnull, NOG). The PA inhibitor-1 (PAI-1) and PAI-2 mRNAs were significantly overexpressed in A375/TSP2. The increased activities of PAI-1 and PAI-2 were confirmed by reverse zymography. The vascularity of metastatic lesions was significantly decreased in A375/TSP2 (vascular density: 0.62+/-0.15% in A375/TSP2, 4.96+/-0.61% in A375/V, p<0.01, Welch test). These results suggest that TSP2 suppresses hematogenous metastasis through microenvironment-modification including PAI up-regulation and anti-vascularization in human malignant melanoma.

Pediatric case of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma forming a solitary skin tumor on the forearm.

A 5-year-old girl noticed a rapidly growing reddish nodule on her right forearm. Although oral antibiotics had been administrated for 2 weeks, the tumor enlarged. Skin biopsy revealed excessive infiltration of atypical neoplastic cells expressing CD4, CD30 and anaplastic lymphoma kinase (ALK). These histological and immunohistochemical findings were consistent with anaplastic large cell lymphoma (ALCL). Computed tomography showed multiple lymphadenopathy, but lymph node biopsy and bone marrow examination did not show any evidence of systemic dissemination. However, due to the positive results for ALK and multiple lymphadenopathy, we diagnosed ALK-positive ALCL forming a solitary skin tumor on the forearm. The patient received chemotherapy and presented marked improvement. This paper discusses the difficulty of diagnosing pediatric ALK-positive ALCL limited to the skin and reviews the medical published work.

S100A4 expression with reduced E-cadherin expression predicts distant metastasis of human malignant melanoma cell lines in the NOD/SCID/gammaCnull (NOG) mouse model.

Tumor xenografts in immune-deficient mice (athymic nude mice and SCID mice) are well-established animal models for the study of human cancer. Several human melanoma cell lines were reported to metastasize in the immune-deficient mice models. However, metastatic rates were extremely low in spite of large numbers of injections of cancer cells, more than 1 x 10(6) cells/mouse. The NOD/SCID/gamma(C)(null) (NOG) mouse shows multiple immunological dysfunctions, including cytokine production capability, in addition to the functional incompetence of T, B and natural killer (NK) cells. However, the immune-deficient mice, with preserved NK cell activity, might interfere with engraftment efficiency. We examined the distant metastasis of the human melanoma cell lines (A2058, A375, G361 and HMY-1, 1 x 10(4) cells/mouse) in the 6 weeks after intravenous inoculation. All four melanoma cell lines showed metastasis in the NOG mice, while no metastatic lesions were observed in the NOD/SCID mice. Metastatic lesions were noted in the liver and lung of 6/6 (100%) mice at A2058, 8/9 (89%) at A375, 2/6 (33%) at G361 and 2/8 (25%) at HMY-1. A2058 and A375 cell lines with high metastatic potentials show increased gene expression of S100A4. Western blot assay confirmed the increased protein levels of S100A4 in the A2058 and A375 cell lines. E-cadherin gene expression was conversely inhibited in these cell lines. The increased expression of S100A4 combined with inhibited E-cadherin expression resulted in high metastatic potentials of the human melanoma cell lines in vivo.

The modifier subunit of glutamate cysteine ligase relates to cisplatin resistance in human small cell lung cancer xenografts in vivo.

Glutamate cysteine ligase (GCL) plays an important role in the intracellular detoxification of cisplatin (CDDP). GCL is composed of a modifier or light chain subunit (GCLM) and a catalytic or heavy chain subunit (GCLC). Previously, we showed that the GCL subunits enhanced CDDP-resistance in non-small cell lung cancer (NSCLC) xenografts. In small cell lung cancer (SCLC), it is unclear whether the GCL subunits are essential to CDDP-resistance. We examined the gene expression of GCLM and GCLC in four human SCLC xenografts with the real-time polymerase chain reaction (PCR). An in vivo drug sensitivity test with CDDP was performed on the SCLC xenografts. CDDP-resistance was examined as the growth ratio of the relative volume of the treated xenografts to the controls (T/C%). The expression level of GCLM gene in SCLC was significantly lower than that in NSCLC (p=0.0026, Welch's t-test). One of four SCLC xenografts showed 62% of T/C and this was evaluated as CDDP-resistance, while the other three xenografts were sensitive to CDDP in vivo (Mann-Whitney U-test, p<0.01, one-sided). The expression level of the GCLM gene was significantly correlated to T/C% (Fisher's test, p=0.0289, correlations = 0.975), while the GCLC gene expression level was not associated with T/C%. These results suggest that the overexpression of GCLM is correlated with CDDP-resistance in SCLC xenografts in vivo.

A case of epidermal cyst with pilomatrical differentiation.

A 20-year-old Japanese woman with an epidermal cyst on the back is described. Physical examination revealed a deep blue and round shaped cystic lesion measuring 10 min in diameter. A comedo-like keratotic plug also could be seen at the center. Histologically, the inner surface of the cyst was clearly separated of two types of the cells. The one was layers of epidermal keratinocytes and the other looked like a basal layer of epidermis, which immunohistochemically stained by S-100, HMB-45, cytokeratin (CK19) and Fontana-Masson staining. We diagnosed this case as epidermal cyst with pilomatrical differentiation.

A case of atypical benign fibrous histiocytoma.

A case of atypical benign fibrous histiocytoma is reported. A 62-year-old Japanese female visited our clinic because of an asymptomatic solitary lesion on the skin of the left leg. Physical examination revealed a polypoid mass lesion (2.5 x 2.3 x 1.8 cm) with central erosion. The lesion began with a 1 mm-sized papule and slowly enlarged over the 20 years. Clinical diagnosis was a malignant tumor such as dermatofibrosarcoma protuberans, atypical fibroxanthoma or adnexal tumors. Biopsy of the polypoid lesion was carried out. Histopathological examination revealed a polypoid lesion consisting of proliferation of fibroblast-like spindle cells in the dermis. Large atypical cells with pleomorphic nuclei were occasionally observed but mitotic figures were rare. From immunohistochemical results (CD68, Factor-XIII, MIB-1 labeling index), we diagnosed this case as "atypical benign fibrous histiocytoma (ABFH)". Clear distinction has not been made between ABFH, a variant of benign fibrous histiocytoma, and atypical fibroxanthoma, which is a variant of malignant fibrous histiocytoma. Here we report a case of ABFH with a diagnosis of the neoplasm.

A Case of Delayed Flare-up Allergic Dermatitis Caused by Jellyfish Sting.

A 7-year-old boy, taking lessons at a yacht school at Enoshima in Kanagawa prefecture in Japan, recognized a linear eruption on his left lower leg during practice in August 2012. As it gradually enlarged, he visited a local medical clinic. The eruption initially improved with topical treatment but exacerbated in October of the same year. Although topical treatment was started again, there was minimal improvement, so the patient visited our hospital in December. At his first visit, he had a hard linear nodule on his left lower leg, and papules with excoriation were scattered over the lower limbs. Considering eczema, topical steroid treatment and occlusive dressing technique were started but the nodule remained. Based on the clinical course, clinical features, and laboratory findings, the lesion was considered to be delayed flare-up allergic dermatitis caused by a jellyfish sting [1].

Notch signaling may be involved in the abnormal differentiation of epidermal keratinocytes in psoriasis.

Localization of each keratin isoform differs among epidermal layers. Proliferating basal cells synthesize keratin 14 (K14) and suprabasal cells express keratin 10 (K10) in normal skin. Notch signaling is essential for keratinocyte differentiation. Notch1 is expressed in all epidermal layers, Notch2 in the basal cell layer and Notch3 in basal cell and spinous cell layers in normal epidermis. It has been poorly elucidated how localization and expression levels of Notch molecules are related to epidermal molecular markers K10 and K14 in psoriatic skin with abnormal differentiation of epidermal tissue. This study aimed to investigate the relationship between abnormal differentiation of epidermal cells in psoriatic skin and expression of Notch molecules. We investigated keratins (K14 and K10) and Notches (1, 2, 3 and 4) using immunohistochemistry in psoriatic skin (n=30) and normal skin (n=10). In normal skin, K14 and K10 were discretely observed in the basal cell layer and suprabasal layer, respectively. In psoriatic skin, K14 was expressed in the pan epidermal layer while it and K10 were co-expressed in some middle suprabasal layer cells. Notch1, 2, 3, and 4 localized in all epidermal layers in normal skin. In psoriatic skin, Notch1, 2, and 4 mainly localized in suprabasilar layers and Notch3 is lacalized in pan epidermal, suprabasilar, and basilar layers. Protein and mRNA of Notch1, 2, and 3 isoforms decreased in psoriatic epidermis compared with normal epidermis. These data suggest that decrements in these Notch molecules might cause aberrant expression of K10 and K14 leading to anomalous differentiation of the epidermis in psoriatic lesions.

A case of foreign body granuloma induced by subcutaneous injection of leuprorelin acetate─clinical analysis for 335 cases in our hospital─.

We experienced a case of granuloma formation by subcutaneous injection of leuprorelin acetate for treatment of prostate cancer. This patient was an 80-year-old man visiting the clinic of gastroenterological surgery as an outpatient after gastric cancer surgery with a one-week's history of rash on the abdomen. Based on the history of gastric cancer and prostate cancer, though ultrasonography and CT were performed, the possibility of metastatic skin tumor could still not be ruled out. Finally, finding of a foreign-body granuloma in the subcutaneous adipose tissue was recognized histological. Then, an interview with the patient revealed that he had received subcutaneous injection of a 3-month depot formulation of leupurorelin acetate at the site of the lesion about two months earlier. Among urologists, as side effects for treatment, foreign body granuloma induced by subcutaneous injection of leuprorelin maybe well known. Therefore, it is tried to analyze as to clinical findings, especially granuloma formation for 335 cases that received leuprorelin acetate treatment at our hospital. In this report, we analyzed reported case and 335 cases that received leuprorelin acetate treatment at our hospital and summarized the cases that developed the granuloma formation by it.

HLA-C*12:02 is a susceptibility factor in late-onset type of psoriasis in Japanese.

Psoriasis is thought to be a multifactorial disease triggered by both genetic and environmental factors. The HLA-C locus on chromosome 6p21.33 remains the strongest susceptibility candidate locus in psoriasis. The strong association between psoriasis and the HLA-Cw6 allele has been well documented in various races. It is known that psoriatic patients with early onset are more likely to be familial and associated with HLA-Cw6. Familial occurrence of Japanese psoriasis is smaller than other populations. Furthermore, males are predominant over females in Japanese psoriasis. We investigated the relation between HLA-C alleles and age of onset, and in each gender for Japanese psoriasis, and discuss male predominance in the incidence of psoriasis in Japan. Four hundred forty six unrelated Japanese patients with psoriasis vulgaris and 557 sex- and age-matched unrelated Japanese healthy controls were investigated by genotyping. We confirmed the association between early-onset type of psoriasis with HLA-C*06:02 allele in Japanese. In addition, we detected the association between the late-onset type of psoriasis and the HLA-C*12:02 allele in Japanese. No significant differences in allele frequency were observed between females and males. Our results suggest that there is no genetic factor effect on male predominance in Japanese. In contract, the effect of environmental risk factors on the onset of Japanese psoriatic patients is stronger in males than in females. As a result, male predominant in psoriasis may occur in Japan.

Case of generalized pustular psoriasis with end-stage renal disease successfully treated with granulocyte monocyte apheresis in combination with hemodialysis.

Granulocyte monocyte apheresis (GMA) is an extracorporeal apheresis instrument that removes activated neutrophils and monocytes. Generalized pustular psoriasis (GPP) is characterized by neutrophil infiltration into the epidermis that causes Kogoj's spongiotic pustule. Thus, GMA is one of the useful therapies for GPP, and it was approved for the treatment in 2012 in Japan. Herein, we report a case of GPP with end-stage renal disease (ESRD) successfully treated with GMA in combination with hemodialysis (HD). A 54-year-old Japanese female visited our outpatient clinic because of erythema with pustules on her trunk and extremities over the past 4 months. Histopathological examination showed an intraepidermal pustule filled with numerous neutrophils and spongiosis. These findings led to the diagnosis of GPP. She had ESRD and had been treated with HD twice a week for approximately 4 years. During maintenance HD twice a week, weekly GMA was started at Tokai University Hospital. The skin symptoms disappeared after five administrations of GMA. We suggest that GMA is an effective therapy for GPP patients with ESRD who are treated with HD.

A novel small compound accelerates dermal wound healing by modifying infiltration, proliferation and migration of distinct cellular components in mice.

BACKGROUND: Impaired wound healing in skin ulcer is one of the major medical issues in the aged society. Wound healing is a complex process orchestrated by a number of humoral factors and cellular components. TGF-ß is known to stimulate collagen production in dermal fibroblasts while inhibiting proliferation of epidermal keratinocyte. A screening of small compounds that suppress type I collagen production in fibroblasts has identified HSc025 that antagonizes the TGF-ß/Smad signal. OBJECTIVE: We examined the effects of HSc025 on dermal wound healing and elucidated the underlying mechanisms. METHODS: Effects of HSc025 on the wound closure process were evaluated in a murine full-thickness excisional wound healing model. Cell proliferation and migration were estimated using primary cultures of human keratinocytes and fibroblasts. Comprehensive analyses of gene expression profiles were performed using untreated and HSc025-treated fibroblasts. RESULTS: Oral HSc025 administration suppressed macrophage infiltration and accelerated wound closure as early as at day 2 after the dermal excision. Treatment of cultured keratinocytes with HSc025 counteracted the inhibitory effects of TGF-ß on cell proliferation and migration. On the other hand, HSc025 stimulated migration, but not proliferation, of dermal fibroblasts independently of TGF-ß. Experiments using an artificial dermis graft revealed that HSc025 stimulated migration of collagen-producing cells into the graft tissue. A cDNA microarray analysis of untreated and HSc025-treated fibroblasts identified pirin as a critical mediator accelerating fibroblast migration. CONCLUSION: HSc025 accelerates wound healing by modifying infiltration, proliferation and migration of distinct cellular components, which provides a novel insight into the therapy for intractable skin ulcer.

Case of exogenous insulin-derived acanthosis nigricans caused by insulin injections.

A 73-year-old male with diabetes mellitus had been treated with insulin for six years. He developed a solid mass on his left lateral of the abdomen at the insulin injection site. A firm subcutaneous mass with dark-red erythema was overlaid by dark-brown keratinized plaques. On histological examination of the mass, keratin proliferation and epidermal papilloma were observed. There were four previously reported cases of acanthosis nigricans that were considered to be caused by continuous injections of insulin. Using immunohistochemistry, in our case the findings were positive in the basal epithelial and prickle cell layers when the patient's lesion was dyed with insulin-like growth factor (IGF)-1 antibody. The coexistence of dermal IGF-1 receptor and acanthosis nigricans found in our patient has not been reported previously, to our knowledge.

Long-term efficacy of psoriasis vulgaris treatments: analysis of treatment with topical corticosteroid and/or vitamin D3 analog, oral cyclosporin, etretinate and phototherapy over a 35-year period, 1975-2010.

Various therapies have been tried for psoriasis. In Japan, biologics began to be used for psoriasis treatment in January 2010. Their clinical efficacy is well known, but biologics cannot be used in all psoriasis patients for reasons such as side-effects and cost. It is necessary to evaluate the effect of long-term psoriasis treatment, but there have been no reports evaluating long-term treatment. Therefore, the outcomes of patients who had been treated at the Tokai University Hospital for more than 5 years, before biological agents were released, were examined. Three categories, classified by initial severity, changes in severity by method of treatment and background characteristics, were investigated. In conclusion, cases of long-term treatment with a combination of topical corticosteroid and topical vitamin D3 analog or oral cyclosporin were found to be effective therapies. Patients with a history of diabetes mellitus or cardiovascular disease of psoriasis were likely to be treatment resistant.

Diagnostic usefulness of findings in Doppler sonography for amelanotic melanoma.

To evaluate the diagnostic usefulness of Doppler sonography for amelanotic melanoma (AM), the correspondence between the findings of dermoscopy and Doppler sonography was investigated in AM in comparison with other hypopigmented tumors. Seven cases with AM and 11 cases with squamous cell carcinoma (SCC), 10 cases with non- or hypopigmented basal cell carcinoma (NP-BCC) and six cases with eccrine poroma (EP) as hypopigmented tumors were investigated. EP is readily recognized by differences from AM and SCC based on a single vertical and non-torvtuous vessels. NP-BCC is distinguished from AM based on tortuosity running in a vertical direction. Though findings of tortuosity in vessels and heterogeneity of vessel size are recognized both in AM and SCC: (i) abundant blood flow was recognized more clearly in AM; (ii) total blood flow was more than 40% in most cases of AM (average, 60.9%); and (iii) more vessels which flow into a tumor are found in AM (85.7%). There is no relationship between dermoscopic findings of vessel types and Doppler sonography findings of vessels. In this study, the diagnostic usefulness of the above-mentioned specific findings in examination may suggest using Doppler sonography for AM as one non-invasive method.

Case of disseminated vesicles of herpes zoster developing one day before the onset of local eruption in a hospitalized immunocompromised patient.

Disseminated herpes zoster is not rare in immunocompromised patient. It is defined as at least 20 lesions in multiple dermatomes that occur within a week of the onset of local eruption. Herein, we report that a case of disseminated vesicles of herpes zoster (HZ) that developed one day before the onset of local eruption in an immunocompromised patient. A 44 year-old Japanese male, who had been in the hospital with acute myelocytic leukemia, developed disseminated hemorrhagic vesicles of 5 to 10 mm in diameter. The next day, grouped vesicles, including hemorrhagic vesicles erupted on the right side of the second to third cervical (C2-C3) dermatomes. At this point, the diagnosis was made as disseminated herpes zoster. The activation of varicella-zoster virus (VZV) is believed to be due to waning of VZV-specific memory T cell responses. In our case, the memory immunity to VZV which had been increased by last episode of HZ might affect on the appearance of skin eruptions.

Psoriasis affects patient's quality of life more seriously in female than in male in Japan.

OBJECTIVE: The aim of this study was to assess the quality of life (QOL) of patients with psoriasis in Japan using Dermatology Life Quality Index (DLQI). Furthermore, we had evaluated the correlation between DLQI and clinical severity of psoriasis. METHODS: The Japanese version of DLQI was used to assess the QOL of patients. Psoriasis area and severity index (PASI) and Itch visual analogue scale (VAS) were used to assess clinical severity of psoriasis. RESULTS: The subjects were 102 Japanese patients with mild to severe psoriasis (77 males, 25 females, mean age 55.2 ± 14.2). There were no statistically significant differences in age, PASI, and itch VAS between male and female. The mean DLQI scores in total were 3.6 ± 3.2 in male and 7.2 ± 1.2 in female. The mean total DLQI scores in female were higher than that in male (p = 0.0016). Significant correlation was observed between DLQI scores and PASI score (p < 0.001) or itch VAS score (p < 0.001). CONCLUSIONS: The mean total DLQI scores in female were significantly higher than that in male. Also, we confirmed the correlation between DLQI and clinical severity of psoriasis. These findings suggest that QOL assessment plays a greater role in females than in the males, when assessing the severity of psoriasis.

A case of chromomycosis treated by surgical therapy combined with preceded oral administration of terbinafine to reduce the size of the lesion.

Chromomycosis is a chronic fungal disease of the skin and subcutaneous tissues caused by a group of dematiaceous black fungi. Small lesions can be removed with excision, but other cases are difficult to treat. We report a case of chromomycosis caused by Fonsecaea pedrosoi (F. pedrosoi). The case involved a 74-year-old man, who had noted a lesion on the back of the right thigh, that was gradually enlarging and reaching up to 30 cm in diameter, in 20-years. From microscopic examination, sclerotic cells were seen. We diagnosed this case as chromomycosis caused by F. pedrosoi on mycological examination. The patient was initially treated with oral terbinafine (250 mg/day) as the lesion was very large. After the 18 months treatment, the size of the lesion reduced to 1 cm, then the remaining lesion was excised.

Random skin biopsy of intravascular large B-cell lymphoma: a case report.

A 72-year-old woman visited our clinic with fever of unknown origin above 38°C and arthralgia from 7 months before. Her symptoms recurred as oral steroid was reduced. Random skin biopsy was carried out from five points. One of the five specimens taken from abdomen revealed large atypical lymphoid cells in the vascular space of subcutaneous fat. Immunohistochemical analysis showed that these cells were positive for CD20, CD79a, bcl-2, bcl-6 and MUM-1. From these findings, a diagnosis of intravascular large B cell lymphoma was made.