Melanoma accounts for ∼ 79% of skin cancer-related deaths, and the receptor activator of NF-κB (RANK)-receptor activator of NF-κB ligand (RANKL) pathway has been shown to be involved in the migration and metastasis of epithelial tumor cells. In this study, we demonstrate that RANK was significantly increased in peripheral circulating melanoma cells, primary melanomas, and metastases from stage IV melanoma patients compared with tumor cells from stage I melanoma patients. However, upregulated RANK expression was not found in stage IV melanoma patients with bone metastases compared with stage IV melanoma patients without bone metastases, providing a possible explanation for the clinical observation that melanoma cells do not preferentially metastasize to bone tissue. Strikingly, RANK-expressing melanoma cells from peripheral blood, primary tumors, or metastases of stage IV patients coexpressed ATP-binding cassette (ABC) B5 and CD133, both markers characteristic of melanoma-initiating cells, suggesting a tumor stem cell-like phenotype. In support of this hypothesis, RANK-expressing melanoma cells showed a reduced Ki67 proliferation index compared with RANK(-) melanoma cells from the same patient and are able to induce tumor growth in immunodeficient mice. Together, our data demonstrate that RANK expression is increased in metastatic melanoma and highly upregulated on melanoma-initiating cells, suggesting that RANK might be involved in the development and maintenance of melanoma-initiating cells and possibly in metastatic spreading.

Proopiomelanocortin (POMC)-derived peptides and their receptors have been identified in many peripheral organs including the skin in which they exert a diversity of biological actions. We investigated the expression and potential role of the POMC system in human dermal papilla cells (DPCs), a specialized cutaneous mesenchymal cell type regulating hair follicle activity. In culture, these cells expressed POMC and displayed immunoreactivity for ACTH, alphaMSH, and beta-endorphin. Among the prohormone convertases (PCs) tested, only PC2, its chaperone 7B2, and furin convertase but not PC1 and paired basic amino acid cleaving enzyme 4 gene were detected. Human DPCs in vitro expressed both the melanocortin-1 receptor (MC-1R) and MC-4R, and immunoreactivity for these receptors was also present in cells of the human dermal papilla in situ. In contrast to the dermal papilla of agouti mice, agouti signaling protein, a natural and highly selective MC-1R and MC-4R antagonist, was undetectable in human DPCs. The MC-Rs detected in human DPCs were functionally active because alphaMSH increased intracellular cAMP and calcium. Preincubation of the cells with a synthetic peptide corresponding to the C-terminal domain of agouti signaling protein abrogated cAMP induction by alphaMSH. Furthermore, alphaMSH was capable of antagonizing the expression of intercellular adhesion molecule-1 induced by the proinflammatory cytokine interferon-gamma. Our data suggest a regulatory function of alphaMSH within the dermal papilla whose disruption may lead to deregulation of immune and inflammatory responses of the hair follicle, thereby possibly contributing to the development of inflammatory forms of alopecia.

Leprosy is usually well-controlled by multidrug therapy (MDT). However, in case of noncompliance or leprosy reactions, it may present a therapeutically challenge. A 33-year-old Brazilian woman with lepromatous leprosy was treated with MDT for one year, but then discontinued therapy because she wanted to have children. Eight weeks after stopping her medications, she developed a severe and recalcitrant erythema (nodosum) leprosum (ENL) which presented histologically with thrombosed small veins and neutrophilic inflammation in fat septa, but without arteritis. During her pregnancy and ensuing lactation period, glucocorticoids were the only suitable drug. With the use of the shortened WHO/MDT regimen (one year vs. two years of treatment), ENL will probably be seen more often after the end of leprosy therapy. It needs to be rapidly recognized and treated to avoid damage to eyes or kidneys.

As soon as uveal melanoma has metastasized to the liver, response rates to systemic chemotherapy are low. It can be improved by development of special locoregional procedures. A 24-year-old woman suffered from inoperable hepatic metastases which grew to life-endangering size despite both systemic chemotherapy with gemcitabine/treosulfan and conventional intrahepatic chemoembolization with fotemustine and starch particles. We subsequently performed two angiographic C-arm CT-guided, superselective chemoembolizations of the hepatic arteries feeding the tumor, using cisplatin, starch microspheres and ethiodized oil. Following this treatment, no vital tumor tissue was detectable by MRI. This remission lasted for more than 6 months and the patient's quality of life was good. A subsequent local relapse could not be treated with chemoembolization because of thrombosis of the portal vein due to tumor compression. And the patient died 20 months after first detection of metastases. However, the selective angiographic C-arm CT-guided chemoembolization resulted in prolongation of life with good quality despite the advanced stage of the disease.

UV-exposition is considered as the main reason for the development of cancers of the skin. However, 90 to 100% of the Vitamin-D reqirement is formed within the skin through the action of sunlight. Considering the results of epidemiological studies, that have detected an association of Vitamin-D deficiency with various types of cancer (e.g. colon-, prostate-and breast cancer), this is a real dilema. The cancer protective effect of vitamin-D is contributed to the extra renal, local production of 1a,25(OH) 2 D 3 by the 25-hydroxyvitamin D-1a-hydroxylase, which has been detected in various tissues. In respect of the novel functions of vitamin-D and the risk of adverse consequences in case of deficiency we have screened sun deprived risk groups (A: patients with genodermatoses connected with defects in sun-induced DNA repair: n ¼ 4: 3 patients with xeroderma pigmentosum and 1 patient with basal cell nevus syndrome; and B: non vitamin-D substituted renal transplant recipients under immunosuppressants: n ¼ 33) for their vitamin-D status. As measure of the vitamin-D store and as substrate for the 25-hydroxyvitamin D-1a-hydroxylase basal 25(OH)D 3 serum levels (Nichols Institute Diagnostika GmbH, Bad Nauheim, Germany) have been analysed. In both groups decreased basal 25(OH)D 3 serum levels were detected. Therefore we demand a monitoring of vitamin-D status in patients practising sun protection, in case of vitamin-D deficiency an oral substitution should be recommended.Effect of UVB radiation emitted from the narrowband TL-01 lamp (311 nm) on the calcitriol synthesis in organotypic cultures of keratinocytesThe skin is the only tissue yet known in which the complete UVB-induced pathway from 7-dehydrocholesterol (7-DHC) to hormonally active calcitriol (1a,25-dihydroxyvitamin D 3 ) occurs under physiological conditions. It is well known that both calcitriol and UVB radiation exert potent antipsoriatic effects. We speculate that the therapeutic effect of UVB radiation can be