Upregulated expression of glucose transporter isoform 1 in invasive and metastatic extramammary Paget's disease.

Glucose transporter isoform 1 (GLUT1), which is upregulated in a variety of malignant tumors, facilitates cellular glucose uptake to boost rapid tumor growth and progression. In several types of cancer, inhibition of GLUT1 suppresses tumor proliferation and metastasis, indicating that GLUT1 is a potential target of anticancer therapy. The present study performed immunohistochemistry to analyze GLUT1 expression levels in 51 patients with extramammary Paget's disease (EMPD), including 23 with only intraepidermal lesions and 28 with dermal-invasive lesions. Of the 28 patients with dermal invasion, nine had available samples of lymph node metastasis. GLUT1 staining scores were significantly higher in dermal-invasive (P<0.0001) and metastatic lesions (P=0.0008) compared with in intraepidermal lesions. GLUT1 is upregulated during the transition from preinvasive to invasive or metastatic tumor in EMPD. Moreover, GLUT1 staining scores were statistically higher in intraepidermal tumor cells of dermal-invasive EMPD compared with tumor cells of only in situ EMPD (P=0.0338). GLUT1 is upregulated even during the preinvasive phase in patients with invasive EMPD, suggesting that GLUT1 immunostaining can predict the risk of dermal invasion. The present study provides novel evidence to pursue in vitro and in vivo studies to confirm that upregulated expression of GLUT1 enhances tumor aggressiveness in EMPD.

Involvement of the genus Corynebacterium in the pathogenesis of pigmented intratarsal keratinous cyst.

Intratarsal keratinous cyst (IKC) is a benign cystic lesion of the eyelid that retains keratin flakes. IKCs are usually yellow to white cystic lesions but rarely become brown or gray-blue, making clinical diagnosis difficult. The mechanisms by which dark brown pigments are generated in pigmented IKC are unclear. The authors report a case of pigmented IKC that had melanin pigments within the lining of the cyst wall and within the cyst. Focal infiltrates of lymphocytes were observed in the dermis, particularly beneath the cyst wall in areas with more melanocytes and intense melanin deposition. These pigmented parts faced bacterial colonies inside the cyst, which were identified to be Corynebacterium species in a bacterial flora analysis. The pathogenesis of pigmented IKC in relation to inflammation and bacterial flora is discussed.

Occupational ionizing radiation-induced skin injury among orthopedic surgeons: A clinical survey.

BACKGROUND: This study aimed to assess orthopedic surgeons' attitudes and behaviors toward occupational radiation exposure and investigate the prevalence of occupational radiation-induced skin injury among orthopedic surgeons. Similarly, risk factors for the presence of radiation-induced skin injury were investigated. METHODS: Overall, 108 orthopedic surgeons were administered self-reported questionnaires about occupational radiation exposure, and their hands were then photographed. Their fields of expertise were classified into spine, arthroplasty, sports medicine, hand, oncology, rheumatoid arthritis, pediatric orthopedic, and resident. Dermatologists evaluated the surgeons' skin conditions and classified into 3 grades of injury: grade 0, no clinical symptoms; grade 1, careful observation required; and grade 2, detailed examination required. Logistic regression analysis was performed to investigate the factors related to the presence of radiation-induced skin injury. Crude and adjusted logistic regression analysis using the backward stepwise selection method was similarly conducted. Receiver operating characteristic curve (ROC) analysis was performed to estimate the predictive power of exposure time, occupational period, and accumulated annual exposure time for radiation-induced skin injury. RESULTS: In total, 93.5% of the surgeons were careful about occupational radiation exposure, of which 76.8% used a dosimeter. Skin changes in the hands were self-reported by 42.5% of the surgeons, and radiation-induced skin injury was diagnosed in 31.4%. The accuracy of the self-reported skin changes was 100% for grade 2 and 61.5% for grade 1. Adjusted regression analysis showed that dermatologists' diagnosis-related factors were self-reported skin changes (odds ratio [OR] 3.1) and spine surgeons (OR 3.2). ROC analysis demonstrated that an occupational period >21 years and an accumulated exposure time >6696 min were considered risk factors, with ORs of 4.07 and 5.99, respectively. CONCLUSIONS: Orthopedic surgeons, particularly spine surgeons, should be regularly examined by dermatologists early in their careers for early detection of radiation-induced skin injury on the hands.

Significance of IL36RN mutation analyses in the management of impetigo herpetiformis: A case report and review of published cases.

Impetigo herpetiformis (IH) is a rare variant of generalized pustular psoriasis (GPP), which develops during pregnancy. GPP is associated with mutations of IL36RN, but it is still unclear whether the same is true of IH. A 20-year-old Japanese woman developed erythema and pustules on her trunk during the 27th week of her first pregnancy. Within 1 month, the skin lesions spread over her whole body, accompanied by fever. Skin biopsy revealed Kogoj's spongiform pustules in the epidermis and she was diagnosed with IH. Systemic administration of prednisolone failed to resolve the skin eruption, but it was partially improved by the addition of cyclosporin. The patient gave birth to a healthy female infant. After delivery, her erythema relapsed and the effect of granulocyte and monocyte adsorption apheresis was limited. Thus, secukinumab was administrated, and since then, she has maintained complete remission. Mutation analysis revealed a homozygous c.28C>T (p.Arg10X) mutation in IL36RN. Twelve cases of IH, including that presented here, have been reported together with the results of IL36RN genetic analyses, and 10 of the 12 cases occurred in East Asia (Japan and China) despite the fact that IL36RN mutations in GPP have been reported worldwide. Among 10 IH patients of East Asian descent, seven had IL36RN mutations, all of which were founder mutations causing GPP in East Asia: c.28C>T (p.Arg10X) or c.115+6T>C (p.Arg10ArgfsX1). Thus, East Asian founder mutations may play an important role in the pathogenesis of IH. IH patients with IL36RN mutations have a tendency to require biologics to resolve postpartum flare-ups or sustained psoriatic skin lesions. Because IL36RN mutation status may help predict postpartum flare-ups in IH patients, mutation analysis should be considered to enable preparation for biologic therapy of intractable flare-ups.

Deciphering UV-induced DNA Damage Responses to Prevent and Treat Skin Cancer.

Ultraviolet (UV) radiation is among the most prevalent environmental factors that influence human health and disease. Even 1 h of UV irradiation extensively damages the genome. To cope with resulting deleterious DNA lesions, cells activate a multitude of DNA damage response pathways, including DNA repair. Strikingly, UV-induced DNA damage formation and repair are affected by chromatin state. When cells enter S phase with these lesions, a distinct mutation signature is created via error-prone translesion synthesis. Chronic UV exposure leads to high mutation burden in skin and consequently the development of skin cancer, the most common cancer in the United States. Intriguingly, UV-induced oxidative stress has opposing effects on carcinogenesis. Elucidating the molecular mechanisms of UV-induced DNA damage responses will be useful for preventing and treating skin cancer with greater precision. Excitingly, recent studies have uncovered substantial depth of novel findings regarding the molecular and cellular consequences of UV irradiation. In this review, we will discuss updated mechanisms of UV-induced DNA damage responses including the ATR pathway, which maintains genome integrity following UV irradiation. We will also present current strategies for preventing and treating nonmelanoma skin cancer, including ATR pathway inhibition for prevention and photodynamic therapy for treatment.

Primary Amelanotic Rhabdoid Melanoma: A Case Report with Review of the Literature.

Primary rhabdoid melanoma (PRM) is a rare variant of melanoma. Herein, we describe a case of primary amelanotic rhabdoid melanoma and review the clinicopathological features of previously reported cases of PRMs. A 63-year-old Japanese man presented with a nonpigmented red granular tumor without peripheral pigmented macules on the left heel measuring 21 × 18 mm in size. Light microscopic examination revealed a tumor mass composed entirely of polygonal neoplastic cells resembling pulmonary alveoli. Tumor cells were also discohesive with bizarre nuclei, prominent nucleoli and large hyaline cytoplasmic inclusions. No melanin pigment was present. Tumor cells were strongly and diffusely positive for S-100, MART-1, HMB-45 and vimentin, while negative for desmin, αSMA and synaptophysin. According to previous reviews, PRM tends to be amelanotic and nodular. S-100 protein and vimentin stained in all cases contrary to low stainability for HMB-45, which was, by contrast, positive in our case. Prognosis of PRM remains controversial due to the very rare occurrence of this tumor and the small number of confirmed cases that have been reported. Recognition of this rare entity is important in clinical practice even for skillful dermatologists to avoid misdiagnosis with the other tumors and to determinate the subsequent treatment principles.

Multiple aplasia cutis congenita lesions located along Blaschko's lines in a patient with tetralogy of Fallot-A.

BACKGROUND: Aplasia cutis congenita (ACC) is a congenital absence of skin, and a single alopecic lesion on the scalp is the most common form. MAIN OBSERVATION: We present a case of ACC with tetralogy of Fallot-A. Differetial diagnosis included Adams-Oliver syndrome and nevus psiloliparus. Interestingly, our patient showed multiple ACC lesions, which were located along Blaschko's lines. CONCLUSIONS: As far as we know, our case is the third case of ACC with tetralogy of Fallot-A. Also, this is the first case of ACC associated with Blaschko's lines.

Characterization of retinoic acid-inducible gene-I (RIG-I) expression corresponding to viral infection and UVB in human keratinocytes.

BACKGROUND: Retinoic acid-inducible gene-I (RIG-I) is a cytoplasmic protein that recognizes viral double-stranded RNA to induce the type I interferon (IFN) response. In human keratinocytes, RIG-I is induced by IFN-γ and tumor necrosis factor-α stimulation, and is abundantly expressed in psoriatic keratinocytes of the spinous and basal layers. OBJECTIVE: This study investigated the effects of extraneous stimuli including viral infection and UVB exposure on RIG-I expression in human keratinocytes. METHODS: Human skin keratinocytes (HaCaT cells) were stimulated by polyinosinic-polycytidylic acid (poly(I:C)), which mimics viral infection, and UVB exposure. We assessed the expression of RIG-I and IFN-regulatory factor (IRF)-1 in HaCaT cells by RT-PCR and Western blot analysis. Moreover, we investigated the effect of IRF-1 binding site of RIG-I gene promoter on the regulation of RIG-I expression by luciferase promoter assay and electrophoretic mobility shift assay. RESULTS: Poly(I:C) induced RIG-I expression, while UVB inhibited basal RIG-I expression and the poly(I:C)-induced RIG-I overexpression in HaCaT cells. IRF-1, which binds to a regulatory element located on the RIG-I gene promoter, was required for both inductions of RIG-I expression. IRF-1 expression was enhanced three hours after the poly(I:C) stimulation, consistent with the RIG-I response to poly(I:C), and thereafter was suppressed. Moreover, UVB exposure promptly decreased IRF-1 expression, resulting in decreased IRF-1 protein binding to the RIG-I promoter, and consequently, decreased RIG-I expression. CONCLUSION: Thus, suppression of RIG-I and IRF-1 expression caused by UVB exposure may partly explain the inhibition of skin-based immune responses, leading to viral infection and recrudescence.