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Targeted therapies with MAPK inhibitors ( MAPKi) are faced with severe problems of resistance in BRAF-mutant melanoma. In parallel to the acquisition of genetic mutations, melanoma cells may also adapt to the drugs through phenotype switching. The ZEB1 transcription factor, a known inducer of EMT and invasiveness, is now considered as a genuine oncogenic factor required for tumor initiation, cancer cell plasticity, and drug resistance in carcinomas. Here, we show that high levels of ZEB1 expression are associated with inherent resistance to MAPKi in BRAF V 600-mutated cell lines and tumors. ZEB1 levels are also elevated in melanoma cells with acquired resistance and in biopsies from patients relapsing while under treatment. ZEB1 overexpression is sufficient to drive the emergence of resistance to MAPKi by promoting a reversible transition toward a MITFlow/p75high stem-like and tumorigenic phenotype. ZEB1 inhibition promotes cell differentiation, prevents tumorigenic growth in vivo, sensitizes naive melanoma cells to MAPKi, and induces cell death in resistant cells. Overall, our results demonstrate that ZEB1 is a major driver of melanoma cell plasticity, driving drug adaptation and phenotypic resistance to MAPKi. [ABSTRACT FROM AUTHOR]

Background Reflectance confocal microscopy ( RCM)'s interest has been well established for the non-invasive diagnosis of skin cancers, especially melanocytic, and in the differential diagnosis between benign and malignant cutaneous lesions. However, its diagnostic interest in inflammatory skin diseases still needs to be demonstrated. Our purpose was to evaluate the correlation between RCM and conventional histopathology in a series of pustular eruptions of different pathogeny. Methods Reflectance confocal microscopy analysis was performed in eight consecutive unselected patients in whom the diagnoses of pustular psoriasis, bacterial sur-infection, herpes-type virus skin sur-infection, Sneddon-Wilkinson subcorneal putulosis and Hailey-Hailey disease have been made and images were compared to conventional histopathology. Results Neutrophils within the epidermis exhibited never reported earlier specific features, with either a shiny granular sludge or polylobated particules with a bright granular content. Moreover, some specific etiologies could be identified, such as acantholysis and herpes-type virus-infected keratinocytes. Conclusion Our studies show a good correlation between RCM and conventional histopathology in pustular eruptions. Reflectance confocal microscopy may play an important role in the differential diagnosis of pustular eruptions; as most of the pathologic clues are epidermal, narrow thickness of the field of imaging, its main technical limitation, is indeed of lesser importance. [ABSTRACT FROM AUTHOR]

Eosinophilic angiocentric fibrosis is a rare fibro inflammatory lesion of unknown etiology which occurs usually in the upper respiratory tract mucosa of middle-aged adults. The histologic features show an eosinophilic vasculitis and an angiocentric fibrosis with onion-skin pattern. Firstly described as a mucosal variant of the granuloma facial, which is a rare cutaneous vasculitis with eosinophils, it is considerated by some authors as separated entities. Four cases have been described in the orbit and three of them were in fact an extension of a sinusal lesion. We report the first case affecting a 69-years-old male patient who showed an isolated orbital involvement in association with granuloma facial, extra facial. This observation illustrates the relationship between these two pathologies and consolidates the first hypothesis of a single disease with cutaneous or mucosal involvement., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)