Cheng-Che E. Lan

Revised classification/nomenclature of vitiligo and related issues: the Vitiligo Global Issues Consensus Conference

During the 2011 International Pigment Cell Conference (IPCC), the Vitiligo European Taskforce (VETF) convened a consensus conference on issues of global importance for vitiligo clinical research. As suggested by an international panel of experts, the conference focused on four topics: classification and nomenclature; definition of stable disease; definition of Koebner’s phenomenon (KP); and ‘autoimmune vitiligo’. These topics were discussed in seven working groups representing different geographical regions. A consensus emerged that segmental vitiligo be classified separately from all other forms of vitiligo and that the term ‘vitiligo’ be used as an umbrella term for all non‐segmental forms of vitiligo, including ‘mixed vitiligo’ in which segmental and non‐segmental vitiligo are combined and which is considered a subgroup of vitiligo. Further, the conference recommends that disease stability be best assessed based on the stability of individual lesions rather than the overall stability of the disease as the latter is difficult to define precisely and reliably. The conference also endorsed the classification of KP for vitiligo as proposed by the VETF (history based, clinical observation based, or experimentally induced). Lastly, the conference agreed that ‘autoimmune vitiligo’ should not be used as a separate classification as published evidence indicates that the pathophysiology of all forms of vitiligo likely involves autoimmune or inflammatory mechanisms.

Rates of cutaneous metastases from different internal malignancies: Experience from a Taiwanese medical center

BACKGROUND Previous reports regarding the rates at which various internal tumors metastasize to the skin have been limited and have only included the Caucasian population. Moreover, the mechanisms that predispose certain internal malignancies to metastasize to the skin have rarely been discussed in the scientific literature. OBJECTIVES We determined the frequencies with which various internal malignancies metastasize to the skin in patients from a Taiwanese medical center. We also evaluated whether expressions of chemokine receptors CCR10 and CXCR4 by tumor cells correlate with cutaneous metastatic ability. METHODS Clinical records from Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, during 20 years (1986-2006) were reviewed and cases of biopsy-proven primary internal malignancies and cutaneous metastases were identified. Immunohistochemical staining with antibodies to CCR10 and CXCR4 was performed on a selected number of internal malignancies with and without skin metastases. RESULTS From 12,146 patients with internal malignancies, we found 124 cases (1.02%) with cutaneous metastases. The highest rates of skin metastases were found to occur from carcinoma of the breast, followed by the lung, oral mucosa, colon and rectum, stomach, and esophagus. However, the rate of cutaneous metastasis from breast cancer was much lower compared with previous studies involving Caucasians. In general, adenocarcinomas gave rise to cutaneous metastases at a higher frequency compared with other histologic subtypes. In addition, the expressions of CCR10 and CXCR4 by tumor cells did not correlate well with the presence or absence of skin metastases. LIMITATION This study is retrospective in nature. CONCLUSIONS Different internal malignancies metastasize to the skin with different frequencies, and the rates at which different malignancies metastasize to cutaneous sites differ between the Taiwanese and Caucasian populations. The mechanisms responsible for the cutaneous metastatic ability of certain malignancies likely involve factors other than chemokine receptors CCR10 and CXCR4, because their expressions by tumor cells are neither necessary nor sufficient for the formation of skin metastases.

Narrow-band ultraviolet-B stimulates proliferation and migration of cultured melanocytes.

Abstract:  Narrow‐band ultraviolet‐B (UVB) radiation is an effective treatment for vitiligo vulgaris. However, the mechanisms of narrow‐band UVB in inducing repigmentation of vitiligo lesions are not thoroughly clarified. The purpose of our study was to investigate the effects of narrow‐band UVB irradiation on melanocyte proliferation and migration in vitro. Our results showed that the cell counts as well as [3H]thymidine uptake of melanocytes were significantly enhanced by narrow‐band UVB‐irradiated keratinocyte supernatants. In these supernatants, a significant increase in basic fibroblast growth factor (bFGF) and in endothelin‐1 (ET‐1) release was observed. bFGF is a natural mitogen for melanocytes, whereas ET‐1 can stimulate DNA synthesis in melanocytes. This stimulatory effect of melanocyte proliferation by supernatants derived from narrow‐band UVB‐irradiated keratinocytes was significantly reduced by a selective endothelin‐B (ET‐B) receptor antagonist (BQ788), suggesting an essential role of ET‐1 on melanocyte proliferation. Our results of time‐lapse microphotography revealed a stimulatory effect of narrow‐band UVB irradiation on melanocyte migration. Focal adhesion kinase (FAK) plays a pivotal role in cell migration. Phosphorylated FAK (p125FAK) expression on melanocyte was enhanced by narrow‐band UVB irradiation. In this study, narrow‐band UVB irradiation stimulated a significant increase in matrix metalloproteinase‐2 (MMP‐2) activity in melanocyte supernatants. Narrow‐band UVB‐irradiation‐induced migration of melanocytes was significantly annihilated by the addition of p125FAK inhibitor (herbimycin‐A) or MMP‐2 inhibitor (GM6001). These results suggest that p125FAK and MMP‐2 activity play important roles in narrow‐band UVB‐induced migration of melanocytes. Our results provide a theoretical basis for the effectiveness of narrow‐band UVB irradiation in treating vitiligo.

High-glucose Environment Enhanced Oxidative Stress and Increased Interleukin-8 Secretion From Keratinocytes: New Insights Into Impaired Diabetic Wound Healing

Impaired wound healing frequently occurs in patients with diabetes. Interleukin (IL)-8 production by keratinocyte is responsible for recruiting neutrophils during healing. Intense inflammation is associated with diabetic wounds, while reduction of neutrophil infiltration is associated with enhanced healing. We hypothesized that increased neutrophil recruitment by keratinocytes may contribute to the delayed healing of diabetic wounds. Using cultured human keratinocytes and a diabetic rat model, the current study shows that a high-glucose environment enhanced IL-8 production via epidermal growth factor receptor (EGFR)–extracellular signal–regulated kinase (ERK) pathway in a reactive oxygen species (ROS)-dependent manner in keratinocytes. In addition, diabetic rat skin showed enhanced EGFR, ERK, and IL-8 expression compared with control rats. The dermal neutrophil infiltration of the wound, as represented by expression of myeloperoxidase level, was also significantly higher in diabetic rats. Treating diabetic rats with dapsone, an agent known to inhibit neutrophil function, was associated with improved healing. In conclusion, IL-8 production and neutrophil infiltration are increased in a high-glucose environment due to elevated ROS level and contributed to impaired wound healing in diabetic skin. Targeting these dysfunctions may present novel therapeutic approaches.

Hand eczema among University Hospital nursing staff: identification of high-risk sector and impact on quality of life.

Background:  Hand eczema is a commonly encountered occupational disease and has a negative impact on life quality.

Differential effects of arsenic on cutaneous and systemic immunity: focusing on CD4+ cell apoptosis in patients with arsenic-induced Bowen's disease

Bowens disease (BD), a carcinoma in situ of the skin, has been identified as an early lesion in arsenic carcinogenesis. Patients with arsenic-induced Bowens disease (As-BD) showed both cutaneous and systemic immune dysfunctions. We set out to evaluate the interactions between keratinocytes and lymphocytes in the context of As-BD carcinogenesis. Our results showed that As-BD lesions demonstrated a significant dermal CD4+ cell, an essential regulator of proper tumor immunity, undergoing apoptosis. In addition, it was found that the As-BD patients have lower percentage of peripheral CD4+ cells as compared with control subjects. However, the CD4+ cells from As-BD patients were less susceptible to arsenic-induced apoptosis, due to reduced tumor necrosis factor receptor 1 expression. Interestingly, arsenic was found to induce Fas expression on CD4+ cells and increase the soluble Fas ligand (sFasL) production from keratinocytes. This sFasL-containing keratinocyte supernatant was able to induce comparable CD4+ cell apoptosis for both patients and controls. Using immunofluorescent staining, increased FasL was observed in keratinocytes of As-BD lesions and Fas was expressed among infiltrating CD4+ cells. Our findings suggested that systemically, the percentage of CD4+ cells was decreased in the peripheral blood of As-BD patients. These residual CD4+ cells were less susceptible to arsenic-induced apoptosis. However, once infiltrated into the As-BD lesions, the selective CD4+ cell apoptosis might be mediated by FasL from keratinocytes. This additional tumor-anti-immune phenomenon present in the cutaneous environment provides a reasonable explanation for frequent occurrence of arsenic cancers in the skin.

Arthritis as an important determinant for psoriatic patients to develop severe vascular events in Taiwan: a nation-wide study.

Background  Psoriasis is an important systemic inflammatory disease that often leads to severe vascular diseases. This study was launched to determine if joint involvement affects incidence of vascular comorbidities in psoriatic patients. In addition, potential vasculo‐protective effects of methotrexate in psoriatic patients were also evaluated.

Neutrophil extracellular trap formation is increased in psoriasis and induces human β-defensin-2 production in epidermal keratinocytes

Neutrophil extracellular traps (NETs) have been implicated in the development of certain immune-mediated diseases, but their role in psoriasis has not been clearly defined. Human β-defensin-2 (HBD-2) is an important antimicrobial peptide overexpressed in psoriasis epidermis. We evaluated whether the amount of NETs is increased in psoriasis and determined the effect of NETs on HBD-2 production in epidermal keratinocytes. Using fluorescent microscopy, we found that patients with psoriasis (n = 48) had higher amount of NETotic cells in their peripheral blood compared to healthy controls (n = 48) and patients with eczema (n = 35). Psoriasis sera showed increased ability to induce NET formation in control neutrophils but normal NET degradation ability. The amount of NETs in the peripheral blood correlated with psoriasis disease severity. NETosis was also observed in the majority (18 of 20) of psoriasis skin specimens. Furthermore, NETs induced HBD-2 mRNA and protein production in keratinocytes, and immunohistochemical analysis confirmed strong expression of HBD-2 in psoriasis lesional skin. In summary, NET formation is increased in peripheral blood and lesional skin of psoriasis patients and correlates with disease severity. Additionally, NET-induced HBD-2 production may provide a novel mechanism for the decreased susceptibility of psoriasis plaques to microbial infections.

Low-Energy Helium-Neon Laser Therapy Induces Repigmentation and Improves the Abnormalities of Cutaneous Microcirculation in Segmental-Type Vitiligo Lesions

Segmental vitiligo (SV) is a special form of vitiligo occurring in a dermatomal distribution, and an abnormality involving the sympathetic nerves supplying the affected dermatome is known to underlie this disorder. Previously, we have shown that SV is associated with an abnormal increase in cutaneous blood flow and adrenoceptor responses in the affected areas. Since SV is resistant to conventional forms of therapy, its management represents a challenge for dermatologists. Low energy helium‐neon lasers (He‐Ne laser, wavelength 632.8nm) have been employed as a therapeutic instrument in many clinical situations, including vitiligo management and repair of nerve injury. The purpose of this study was to evaluate the effectiveness and safety of He‐Ne lasers in treating SV, and determine their effects on the repair of sympathetic nerve dysfunction. Forty patients with stable‐stage SV on the head and/or neck were enrolled in this study. He‐Ne laser irradiation was administered locally at 3.0J/cm2 with point stimulation once or twice weekly. Cutaneous microcirculatory assessments in six SV patients were performed using a laser Doppler flowmeter. The sympathetic adrenoceptor response of cutaneous microcirculation was determined by measuring cutaneous blood flow before, during and after iontophoresis with sympathomimetic drugs (phenylephrine, clonidine and propranolol). All measurements of microcirculation obtained at SV lesions were simultaneously compared with contralateral normal skin, both before and after He‐Ne laser treatment. After an average of 17 treatment sessions, initial repigmentation was noticed in the majority of patients. Marked repigmentation (> 50%) was observed in 60% of patients with successive treatments. Cutaneous blood flow was significantly higher at SV lesions compared with contralateral skin, but this was normalized after He‐Ne laser treatment. In addition, the abnormal decrease in cutaneous blood flow in response to clonidine was improved by He‐Ne laser therapy. Our study showed that He‐Ne laser therapy is an effective treatment for SV by normalizing dysfunctions of cutaneous blood flow and adrenoceptor responses in SV patients. Thus, the beneficial effects of He‐Ne laser therapy may be mediated in part by a reparative effect on sympathetic nerve dysfunction.

Pigmentation in Basal Cell Carcinoma Involves Enhanced Endothelin-1 Expression

Abstract:  Basal cell carcinoma (BCC) is the most prevalent malignant skin tumor. In Asian patients, marked pigmentation in BCC lesions is often observed. Recently, endothelins (ETs) have been implicated to participate in the pigmentation process of BCC. Therefore, we set out to investigate the involvement of ET in the pigmentation process of BCC and the potential regulators in the pigmentation pathway. We explored the effects of an established BCC cell line on melanocytes. The growth factor profiles of BCC culture supernatant and effects of supernatant on melanocytes were documented. Potential regulators involved in the pigmentation pathway were also studied. The immunohistochemical staining of pigmented and non‐pigmented BCC specimens was performed to confirm our in vitro findings. Our results showed that BCC supernatant contained significant amount of ET‐1, basic fibroblast growth factor, and nerve growth factor. Furthermore, BCC supernatant stimulated melanin formation of cultured melanocytes. Addition of ET‐receptor antagonist abrogated the melanogenic effect of BCC supernatant on melanocytes. Introduction of UVB irradiation decreased the ET‐1 secretion by BCC cells. Immunohistochemical staining of the pigmented facial BCC specimens showed prominent expression of ET‐1 on pigmented BCC, while the non‐pigmented facial BCC specimens showed little ET‐1 reactivity. Tumor necrosis factor‐alpha (TNF‐α) staining showed little expression on BCC specimens, regardless of pigmentation status. In summary, our results indicate that enhanced ET‐1 expression in pigmented BCC plays an important role in the hyperpigmentation of this tumor. Moreover, this enhanced ET‐1 cascade showed little correlation with UV irradiation and TNF‐α expression in our study.