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Mycosis fungoides is recognized as an indolent cutaneous malignant T-cell lymphoma. In contrast, there are few therapeutic options for advanced forms of mycosis fungoides. Since immunotherapy is desirable as an alternative therapeutic option, identifying candidate molecules is an important goal for clinicians. Although tumor-derived negative immunomodulatory molecules, such as PD-1/PD-L1, have been identified in various malignancies, the useful positive immunological drivers of mycosis fungoides are largely unknown. We found that the stimulator of interferon (IFN) genes (STING) was highly upregulated in early-stage mycosis fungoides. Immunohistochemical examination revealed different STING staining patterns in patients with mycosis fungoides. Although there were no significant differences in clinical factors’ characteristics, STING expression was associated with the survival of patients with mycosis fungoides. The survival rate was significantly poor in patients with low STING-expressing mycosis fungoides. Univariate and multivariate analyses revealed that low STING expression was associated with an increased hazard ratio. Our results indicate that STING expression independently influences the prognosis of mycosis fungoides.

Background A previous study revealed that matrin-3 is an essential component in maintaining fibroblast growth factor 2 (FGF2)-mediated undifferentiation of neural stem cells (NSCs) using a proteomics approach. Malignant melanoma (MM) arises from melanocytes that originate from neural crest stem cells during development. Additionally, it has been reported that the expression of FGF2 is positively correlated with the progression of MM. Objective We expected that matrin-3, as a downstream component of FGF2, might be associated with the aggressiveness or differentiation of MM. Methods Matrin-3 expression was measured in human melanoma patient tissues and human MM cell lines. We analyzed the effect of matrin-3 siRNA on the proliferation of human MM cell lines and focused on cell cycle progression and apoptosis. We carried out in vivo xenograft tumor experiments by implanting A375 cells transfected with matrin-3 shRNA. Results Matrin-3 was highly expressed in MM, and matrin-3 knockdown inhibited the proliferation of melanoma cellsin vivo and in vitro. Furthermore, we found that matrin-3 knockdown led to an accumulation of cells in the G1 phase and an increase in apoptotic cell number. Conclusion Our results suggest that matrin-3 could be a new therapeutic target for the treatment of MM.

Psoriasis is a chronic inflammatory skin disease that involves various systemic organs and tissues and is characterized by scaly erythematous skin. Among the different types of psoriasis, psoriatic arthritis (PsA) is frequently reported, and occasionally develops into severe arthritis leading to joint dysfunction. There are various tools, especially questionnaires, to identify the presence of PsA in European and American populations; however, little is known about the utility of these tools in the Asian population. In this study, we investigated the utility of a representative tool, the psoriasis epidemiology screening tool (PEST) questionnaire, to identify PsA among Japanese patients with psoriasis. A total of 143 patients with psoriasis were enrolled in this study. Among them, 29 patients were diagnosed with PsA. The frequency of PsA was significantly increased in patients with PEST scores > 3, with a sensitivity of 93.1% and a specificity of 78.9%. Among the questions in the PEST questionnaire, “Have you ever had a swollen joint?” showed the highest frequency to answer “Yes” among patients with PsA. Univariate and multivariate analyses revealed that high PEST scores (> 3) was an independent variable in PsA patients. Taken together, our study suggests that the PEST questionnaire is a useful tool to identify PsA among Japanese patients with psoriasis.

Telaprevir used as a protease inhibitor against hepatitis C virus is frequently associated with cutaneous adverse reactions. To explore a histological biomarker of cutaneous adverse events induced by telaprevir, we systematically searched for genes that were dysregulated by telaprevir in normal human epidermal keratinocytes (NHEKs). Microarray analysis and real-time polymerase chain reaction (PCR) revealed the significant increase in the expression of S100 calcium-binding protein A2 (S100A2) gene following treatment of NHEKs with telaprevir. Immunohistochemical analysis demonstrated that the expression of S100A2 was dominant in the spinous layer of the epidermis in patients with telaprevir-mediated severe-type drug eruptions and limited to the basal layer of the epidermis in healthy subjects. Furthermore, S100A2 expression increased after treatment with trichloroethylene and other medications, and the degree of S100A2 expression correlated with the severity of cutaneous adverse events. S100A2 expression also significantly increased in the skin of patients with atopic dermatitis and psoriasis. Taken together, S100A2 is highly expressed in the epidermis under inflammatory conditions and drug eruptions and may serve as a marker for keratinocyte damage in response to any inflammatory or toxic condition.

Melanoma is a malignant tumor of the melanocytes with an unfavorable clinical behavior. Nivolumab, a representative anti-programmed death 1 (PD-1) antibody, has recently been used for the treatment of metastatic malignant melanoma. However, there have been few appropriate biomarkers predicting the effect of nivolumab before the administration. Furthermore, the detailed characteristics of peripheral blood mononuclear cell (PBMC) profiles during nivolumab treatment remains unclear. In this study, we investigated fluctuations of PBMC profile during nivolumab treatment. PBMC analysis showed T-helper (Th)2-dominant conditions after a first course of nivolumab treatment. In a favorable case treated with nivolumab, a Th1/T-cytotoxic 1 shift was observed after nivolumab was administrated. These results suggest that flow cytometric analysis of PBMC may be helpful for the treatment of nivolumab.

Leg ulcers are often complicated in patients with rheumatoid arthritis (RA), however, the etiology is multifactorial. We examined the cases of leg ulceration or gangrene in seven RA patients who were hospitalized over the past 3 years. One patient was diagnosed as having pyoderma gangrenosum. Although vasculitis was suspected in three patients, no histological evidence was obtained from the skin specimens. In these patients, angiography revealed the stenosis or occlusion of digital arteries. In the remaining three patients, leg ulcers were considered to be due to venous insufficiency. Treatment should be chosen depending on the causes of leg ulcers.

Enzalutamide is an androgen receptor inhibitor. We report a new cutaneous eruption to this drug and review cases of drug eruptions caused by androgen receptor inhibitors.

Arteriovenous malformation (AVM) is a structural vascular abnormality with no proliferation of cellular components. We report on a 53-year-old man who presented with a 15-year history of a progressively enlarging nodule on his lower lip. A dark-reddish, easy-bleeding nodule diagnosed as AVM was resected to reduce the volume and troublesome bleeding. Histologically, the nodule revealed that the proliferating cellular area was composed of endothelial cells and pericytes in addition to the area of dilated vessels. We speculated that the cell proliferation developed secondary to AVM. We also discuss the histological differential diagnosis of spindle cell hemangioma and pseudo-Kaposi's sarcoma.

The treatment of severe lymphedema is a difficult challenge. We performed lymphaticovenular anastomosis on two patients with secondary skin lesions of chronic lymphedema; one patient exhibited acquired lymphangioma circumscriptum of the vulva and the other presented elephantiasis nostras verrucosa of the lower leg. Both patients obtained a remarkable improvement in skin lesions and also in the reduction of lymphedema of the lower extremity. During a 6-month-follow-up period, constant reduction in the circumference of the lower extremities without exacerbation of skin lesions was achieved in both patients. Lymphaticovenular anastomosis is a useful surgical treatment for secondary lymphedema in the lower extremities. In addition, this surgical treatment is effective for secondary lesions of lymphedema, including acquired lymphangioma circumscriptum and elephantiasis nostras verrucosa.

Background A novel polyomavirus, the Merkel cell polyomavirus (MCPyV) has been implicated in the pathogenesis of Merkel cell carcinoma (MCC); however, the prevalence of MCPyV in Japan has not been extensively investigated. Objective To clarify the prevalence of MCPyV in Japanese patients with MCC. Methods MCPyV DNA was examined by polymerase chain reaction (PCR) in formalin-fixed paraffin-embedded (FFPE) or frozen tissue samples from 26 patients with MCC diagnosed in four medical centers in Japan. Immunohistochemistry was simultaneously performed using a monoclonal antibody against the viral large T (LT) antigen. FFPE samples from basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) were also analyzed as controls. Results Twenty-three out of 26 cases (88.5%) were positive for MCPyV DNA by PCR. The amplified products harbored 4 patterns of mutations. Phylogenetic analysis demonstrated that one of our strains was closely related to the other Japanese strains previously reported. The LT antigen was expressed in various degrees in 20 of 26 cases (76.9%) by immunohistochemistry. Histological type had little relation to CM2B4 positivity, whereas 3 of 5 trabecular-type tumors showed no staining. The immunoreactivity for CM2B4 did not correlate with the relative viral DNA load. In BCC and SCC, the LT antigen was immunohistochemically positive, but MCPyV DNA was not detected by PCR. The cells around some MCC and non-MCC tumors were stained with CM2B4 with a distribution similar to CD20- and CD45RO- (especially CD8-) positive lymphocytes. Conclusion MCPyV was highly positive in Japanese patients with MCC. It is of note that the positive rate differs depending upon the detection method.

Eighteen patients with adult-onset Still's disease have been followed up for 3-22 years in our department. Initial manifestations were fever with skin rash in 14 patients, fever, skin rash and sore throat in two, skin rash in one and arthralgia in one. During the follow-up period, typical skin rash was seen in all patients, of them five patients (29%) revealed atypical skin rash simultaneously. Atypical rash included persistent erythema with pigmentation in two, persistent plaques and papules with linear erythema in two and edema of the eyelids mimicking dermatomyositis in one. Persistent papules and plaques revealed histologically characteristic features, such as dyskeratotic keratinocyte and liquefaction degeneration as well as a sparse superficial dermal infiltrate containing scattered neutrophils. In patients of chronic articular type and polycyclic systemic type, atypical skin rash, lymphadenopathy and hyperferritinemia were noted to be significantly higher than those of monocyclic type. These factors might be prognostic factors of adult-onset Still's disease in our study.

We report an autopsy case of delayed anaphylactic shock due to contrast medium. A 17-year-old Japanese man underwent angiography using non-ionic contrast medium under the suspected diagnosis of Buerger's disease. Initial symptoms appeared 6 h after the administration of the contrast medium, and death was confirmed 11 h later. Considering the clinical course and the results of the autopsy, we concluded that the direct cause of the patient's death was severe acute circulatory failure due to a delayed allergic reaction to the contrast medium. The reported incidence of serious delayed reactions or biphasic reactions to non-ionic contrast medium is extremely low; however, we should be aware of such rare adverse reactions.

Recurrent digital ulcers are manifestations of vascular disease in patients with systemic sclerosis (SSc). We report six patients with severe digital ulcers who were treated with bosentan administered p.o., 62.5-125 mg daily. The mean duration from the diagnosis of SSc to the initiation of bosentan was 9.5 years, and the observation period after bosentan administration was from 7 months to 4.5 years. In case 1, neither new digital ulcers nor Raynaud's phenomenon developed for 4.5 years. In case 2, digital ulcers recurred after the discontinuation of bosentan; however, re-administration of bosentan lead to the improvement. In cases 3-5 with recurrent digital ulcers, no new lesions have developed. In these five patients, pain evaluated by visual analog scale was significantly reduced. In three patients, bosentan was discontinued because of severe liver dysfunction. These results suggest that bosentan is an effective treatment for refractory digital ulcers associated with SSc; however, liver function should be carefully monitored. Compared to the doses of bosentan used to treat pulmonary hypertension, relatively lower doses may effectively control painful digital ulcer/gangrene in patients with SSc.

Background Recent studies have suggested that there is a close association between the administration of gadolinium (Gd)-based contrast agents and the development of nephrogenic systemic fibrosis (NSF), an acquired disorder characterized by systemic fibrosis and abnormal calcification in patients with severe renal dysfunction. However, the causative roles of Gd remain unknown. Objective The aim of this in vitro study was to investigate the effect of Gd on the development of fibrosis and calcification in cultured cells. Methods MC3T3-E1 cells (pre-osteoblastic cells), human adipose tissue-derived mesenchymal stem cells (HAMSCs), human subcutaneous preadipocytes, and human dermal fibroblasts (HDFs) were each cultured in differentiation medium with or without gadolinium chloride. Calcium deposition of MC3T3-E1 cells, HAMSCs, and HDFs was determined by alzarin red S staining. Adipogenic differentiation of human subcutaneous preadipocytes and HAMSCs was determined by oil red O staining. Fibrogenesis of HDFs was determined by real-time PCR to measure the mRNA expression of type I collagen. Cell proliferation was determined by MTS assay. Results Gd induced calcium deposition in MC3T3-E1 cells, HAMSCs and HDFs in osteogenic differentiation media. Gd did not induce adipogenic differentiation in human subcutaneous preadipocytes and HAMSCs. Gd did not increase the mRNA expression of type I collagen in HDFs, but did promote cell proliferation. Conclusions We have demonstrated a direct effect of Gd on calcium deposition in cultured cells. The result will help us to understand the mechanism of abnormal calcification in NSF.

BACKGROUND Based on the fact that combination chemotherapy with cisplatin, ifosfamide, and bleomycin generated a 69% response rate in patients with recurrent cervical cancer; that 254-S (a cisplatin analogue) monotherapy generated a 46.3% response rate for cervical cancer, which was higher than those generated by cisplatin and carboplatin in historic comparison; and that peplomycin is a bleomycin analogue with improved pulmonary toxic effects, a combination regimen with 254-S, ifosfamide, and peplomycin was evaluated in an animal experiment and a clinical study in patients with advanced or recurrent cervical cancer with an expectation that the regimen might show a higher efficacy than 254-S monotherapy and the combination regimen including cisplatin. METHODS In the clinical testing, 254-S was administered intravenously (IV) at 80-100 mg/m2, ifosfamide was administered IV at 1500 mg/patient for 5 days, and peplomycin was administered intramuscularly at 5 mg/patient for 6 days. This treatment was repeated every 4 weeks. RESULTS As a result, this regimen showed additive or synergistic antitumor effects in mice receiving B16 melanoma transplants. In the clinical study, 83.8% and 60.9% response rates were obtained in 37 previously untreated patients with Stage III or IV cervical cancer and 23 with recurrent cervical cancer, respectively. The dose-limiting factor was bone marrow toxic effects, which were tolerable. The other toxic effects were mild, and there were no deaths. CONCLUSIONS From these results, this combination regimen was thought worthy of evaluation in a Phase III comparative study in patients with advanced or recurrent cervical cancer.

The surgical treatment of large, deep defects on the midline of the lower back or lumbar area comprises difficult reconstructive challenges. Various flaps have been designed to reconstruct the defect area. We herein report a 70-year-old Japanese woman with a large, deep ulcer in the midline of the lower back, caused by postoperative radiation therapy for eccrine porocarcinoma. The ulcer was successfully treated with surgical debridement followed by reverse latissimus dorsi musculocutaneous flap. This flap is reliable and useful for reconstruction of a large, deep midline defect of the lower back, having large and bulky tissue with a sufficient blood supply.

Mantle cell lymphoma (MCL) is a distinct type of non-Hodgkin's lymphoma that commonly affects extranodal sites. The most commonly affected sites are bone marrow, gastrointestinal tract and Waldeyer's ring, however, skin is rarely involved. We reported a 62-year-old Japanese patient with MCL, exhibiting multiple small dome-shaped red nodules and skin ulcers. Histopathological examination demonstrated numerous atypical lymphoid cells in the dermis and subcutis. Immunohistochemically, tumor cells were positive for CD20 (L26), CD5, CD43 and cyclin D1, but negative for CD45RO (UCHL-1), CD3, CD10 and CD23. Our patient showed a significant improvement of skin lesions and lymphadenopathy with a combination chemotherapy. Awareness of skin manifestations of MCL is essential for dermatologists to establish an early diagnosis and perform appropriate treatment.

The detection of fusion transcripts of the collagen type 1α1 (COL1A1) and platelet-derived growth factor-BB (PDGFB) genes by genetic analysis has recognized as a reliable and valuable molecular tool for the diagnosis of dermatofibrosarcoma protuberans (DFSP). To detect the COL1A1-PDGFB fusion, almost previous reports performed reverse transcription polymerase chain reaction (RT-PCR) using multiplex forward primers from COL1A1. However, it has possible technical difficulties with respect to the handling of multiple primers and reagents in the procedure. The objective of this study is to establish a rapid, easy, and efficient one-step method of PCR using only a single primer pair to detect the fusion transcripts of the COL1A1 and PDGFB in DFSP. To validate new method, we compared the results of RT-PCR in five patients of DFSP between the previous method using multiplex primers and our established one-step RT-PCR using a single primer pair. In all cases of DFSP, the COL1A1-PDGFB fusion was detected by both previous method and newly established one-step PCR. Importantly, we detected a novel COL1A1 breakpoint in exon 5. The newly developed method is valuable to rapidly identify COL1A1-PDGFB fusion transcripts in DFSP.