Inhibition of interleukin‐12 and/or interleukin‐23 for the treatment of psoriasis: What is the evidence for an effect on malignancy?

Immune cells and cytokines play an important role in the pathogenesis of psoriasis. Interleukin‐12 (IL‐12) and IL‐23 promote cellular responses mediated by T cells, which contribute to an inflammatory loop responsible for the induction and maintenance of psoriatic plaques. Antibodies that inhibit IL‐12/23 or IL‐23 are key treatment options for patients with psoriasis. IL‐12 and IL‐23 also play a key role in immune responses to infections and tumors. A growing body of information from clinical trials, cohort studies, postmarketing reports, genetic studies and animal models provides insights into the potential biological relationships between IL‐12/23 inhibition and malignancies. We summarize this information in tables and provide some context for the interpretation of these data with the goal of informing dermatologists who are using IL‐12/23 or IL‐23 inhibitors to treat patients with psoriasis.     

Radiation‐induced cutaneous carcinoma of the head and neck: is there an early role for p53 mutations?

BACKGROUND: Little is known about the molecular mechanisms underlying ionizing radiation-induced carcinogenesis of the skin. AIMS: To investigate the possible role of p53 in radiodermatitis and in the development of radiation-induced cutaneous carcinomas. METHODS: The study group comprised six patients affected by cutaneous carcinomas arising in radiodermatitis (one squamous cell carcinoma and five basal cell carcinomas), and seven patients presenting only chronic radiodermatitis. Skin specimens were evaluated for p53 immunohistochemical expression. Using laser-assisted microdissection, areas with different p53 immunoreactivity were separately submitted to DNA isolation and p53 gene analysis. RESULTS: In the majority of cases (9/12, 75%), p53 immunoreactivity was detected in radiation-damaged epidermis. In carcinomas p53 oncoprotein was expressed by several neoplastic cells in one case (16.7%%), or by nearly all neoplastic cells in four (66.7%). SSCP band shifts were detected in 9/25 samples (36%) microdissected from irradiated epidermis and in 3/6 (50%) carcinomas. DNA sequencing demonstrated two repeatedly found mutations: a G deletion at codon 244 and an A-->G transition at codon 205, as well as hallmarks of ultraviolet mutagenic action, including a C-->T transition occurring at a dipyrimidine site and a CC-->TT tandem double-base transition. CONCLUSION: Our data indicate that irradiation induces significant p53 alterations that may be relevant in the modification of epithelial maturation processes and may be responsible for the high risk for development of carcinomas in radiodermatitis.     

Is occupational solar ultraviolet irradiation a relevant risk factor for basal cell carcinoma? A systematic review and meta‐analysis of the epidemiological literature

Summary Background The most important risk factor for basal cell carcinoma (BCC) is ultraviolet (UV) radiation. It is reasonable to assume that outdoor workers with a long history of work‐related UV exposure are at increased risk of developing BCC. Objectives To analyse systematically the epidemiological literature concerning the evidence of an association between occupational UV exposure and BCC risk in outdoor workers. Methods Systematic literature review of cohort studies and case–control studies providing data on occupational UV exposure and BCC occurrence. PubMed (up to 28 January 2011) was searched, supplemented by hand searching and consultation of experts in the field. The association between occupational UV exposure and BCC risk is presented as odds ratios (ORs). A random‐effects meta‐analysis and sensitivity analysis including meta‐regression on study‐specific covariates were performed. Results Twenty‐four relevant epidemiological studies (five cohort studies, 19 case–control studies) were identified. Twenty‐three studies reported sufficient data to be included in the meta‐analysis. The pooled OR for the association between outdoor work and BCC risk was 1·43 (95% confidence interval 1·23–1·66; P = 0·0001). Studies adjusting for sex (P < 0·0001) and individual nonoccupational UV exposure (P = 0·014) showed a significantly stronger association of occupational UV exposure and BCC risk. Meta‐regression revealed a significant inverse relationship between occupational UV radiation exposure and BCC risk with latitude (P = 0·015). Conclusions Published epidemiological literature indicates that outdoor workers are at significantly increased risk for BCC. This finding is highly relevant for health policy to stimulate the implementation of effective prevention strategies.     

Vulvar vitiligo-like depigmentation and multiple halos of hypomelanosis at the trunk following treatment with imiquimod 5% cream for vulvar condylomata: casual or related events?

A 25-year-old Caucasian female with multiple genital warts involving the vulvar areawas treated with imiquimod 5% cream. During follow-up the patient developed areas ofhypopigmentation at the site of application of imiquimod cream and areas ofhypomelanosis around multiple preexisting nevi of the trunk. At 18 months follow-upgenital depigmentation persisted and halo nevi of the trunk were still present.Different mechanisms of imiquimod-induced depigmentation have been reported. Halonevi are considered expression of an autoimmune response. In the case presented here,it might be conceivable that both vitiligo-like depigmentation at the site ofapplication and halo of hypomelanosis around melanocytic nevi have been induced bythe same immunologic mechanism elicited by topical application of imiquimod.     

Overexpression of the chemokine receptors CXCR4, CCR7, CCR9, and CCR10 in human primary cutaneous melanoma: a potential prognostic value for CCR7 and CCR10?

Multiple functional implications have been suggested for a limited number of chemokines and their cognate receptors in melanoma pathogenesis. The purpose of this study was to investigate the potential role of the chemokine receptors CXCR4, CCR7, CCR9, and CCR10 as prognostic markers in human primary cutaneous melanoma. Chemokine receptor expression was analyzed by immunohistochemistry in a total of 38 patients with cutaneous melanoma. Results were statistically correlated with melanoma features and clinical disease progression. No significant correlation between overexpression of CXCR4 or CCR9 and survival or prognosis was found. CCR7 overexpression was associated with significantly lower survival (0.005 log rank) and shorter time to progression (0.009 log rank)—similar to CCR10 overexpression (lower survival: 0.001 log rank, shorter time to progression: 0.002 log rank). In addition, CCR7 overexpression correlated with expression of metallothionein, while CCR10 seems to be associated with cerebral metastases. Two chemokine receptors permitting the identification of high-risk patients were identified: CCR7 and CCR10 overexpressions were found to be associated with a worse outcome of disease course independent of Breslow’s tumor thickness and Clark level, thus representing possible additional prognostic markers.     

Computer simulation of heterogeneous single nucleotide polymorphisms in the catalase gene indicates structural changes in the enzyme active site,NADPH‐binding and tetramerization domains: a genetic predisposition for an altered catalase in patients with vitiligo?

Abstract:  Patients with vitiligo have low levels/activities of catalase in their lesional and non-lesional epidermis as well as in their epidermal melanocytes under in vitro conditions while the levels of catalase mRNA are unaltered. This defect leads to a build-up of hydrogen peroxide (H₂O₂) in the 10⁻³  m range in the epidermis of these patients. In this context, it was realized that 10⁻³  m H₂O₂ deactivates catalase. Along this line, it was also suspected that catalase in patients with vitiligo possesses a special sensitivity to this reactive oxygen species (ROS), and indeed several heterozygous single nucleotide polymorphisms (SNPs) have been documented in the cat gene of these patients. Based on the 3D structure of human catalase monomer, we have modelled the influence of three selected SNPs on the enzyme active site, on the NADPH- as well as the tetramerization-binding domains. Our results show that these SNPs severely alter catalase structurally, which in turn should make the enzyme more susceptible to ROS compared with wild-type enzyme. Taken together, the work presented herein together with the earlier results on SNPs in the cat gene suggests a genetic predisposition for an altered catalase in patients with vitiligo.     

Towards the development of a pragmatic technique for isolating and differentiating nestin‐positive cells from human scalp skin into neuronal and glial cell populations: generating neurons from human skin?

Nestin+ hair follicle-associated cells of murine skin can be isolated and differentiated in vitro into neuronal and glial cells. Therefore, we have asked whether human skin also contains nestin+ cells, and whether these can be differentiated in vitro into neuronal and/or glial cell populations. In this methodological pilot study, we show that both are indeed the case - employing purposely only very simple techniques for isolating, propagating, and differentiating nestin+ cells from normal human scalp skin and its appendages that do not require selective microdissection and tissue compartment isolation prior to cell culture. We show that, it is in principle, possible to maintain and propagate human skin nestin+ cells for extended passage numbers and to differentiate them into both neuronal (i.e. neurofilament+ and/or PGP9.5+) and glial (i.e. GFAP+, MBP+ and/or O4+) cell populations. Therefore, human scalp skin can serve as a highly accessible, abundant, and convenient source for autologous adult stem cell-like cells that offer themselves to be exploited for neuroregenerative medicine purposes.