RASopathic comedone-like or cystic lesions induced by vemurafenib: a model of skin lesions similar but not identical to those induced by dioxins MADISH.

BACKGROUND: Patients treated with vemurafenib for metastatic melanoma often develop skin lesions similar to those observed after exposure to dioxin-like compounds. We previously called these lesions MADISH (metabolizing acquired dioxin-induced skin hamartoma) when analysing a case of acute dioxin poisoning. OBJECTIVE: We performed a clinical trial aimed at comparing the skin lesions observed under vemurafenib treatment with MADISH in order to bring to light a possible crosstalk between vemurafenib and dioxin pathways. METHODS: In this case series study, we explored the histological aspect of skin lesions in 10 cases treated with vemurafenib for malignant melanoma. We also analysed the ability of vemurafenib and tyrosine kinase inhibitors to induce dioxin-AhR pathway. RESULTS: All patients had skin lesions diagnosed as 'non-inflammatory acneiform eruption' by dermatologists. These were predominantly facial with notable retroauricular involvement and clinically compatible with chloracne/MADISH when assessed by dioxin expert. Histological analysis showed mostly comedone-like lesions and dermal cysts containing epithelial wall with basal or lateral epithelial projections and lamellar keratinization and alterations of remaining sebaceous glands. The expression of CYP1A1, a gene highly induced following dioxin exposure, was not observed in these lesions. Vemurafenib and the tyrosine kinase inhibitors erlotinib and gefitinib did not induce CYP1A1 activity. DISCUSSION: Although the skin lesions under vemurafenib treatment were morphologically similar to MADISH, the absence of CYP1A1 expression in dermal cysts of patients and the absence of CYP1A1 activation by vemurafenib led us consider that these skin lesions were different from true MADISH and not mediated by a crosstalk of AhR signalling, but rather to a hyperactivation of PI3K-Akt pathway as a consequence of vemurafenib treatment. A strong expression of CYP1A1 in the epithelial wall of dermal cysts must be required, parallel to the morphology of the lesions, to make the diagnosis of MADISH, the hallmark of an exposure to dioxin-like/chloracnegen compounds.

New treatments for cutaneous metastatic melanoma: MAPK pathway-targeted and immune based therapies.

Increasing knowledge on cellular biology has permitted rapid changes in the treatment of metastatic melanoma. Until 2011, dacarbazine was the gold standard treatment at our disposal. In 2011 the treatment landscape changed dramatically with the approval by the FDA of ipilimumab and vemurafenib. These drugs use two new therapeutic approaches: immunomodulation and the targeting of mutated cellular pathways in tumor cells. These two drugs, used as single agents have shown important increases in overall survival, unseen before in patients with advanced melanoma, but are limited by their toxicities and the appearance of acquired resistances. In this article, we review new therapeutic options in pathway-targeted -with the arrival of MEK inhibitors - and immune based melanoma therapies -with the arrival of anti-PD1 and anti-PDL1- as well as new therapeutic strategies developed to overcome acquired resistance and diminish drug toxicities.

[Aesthetic gluteal region reconstruction with a perforator artery flap]. / Reconstruction fessière esthétique fiabilisée par une artère perforante glutéale.

The gluteal region is an important pressure zone in every day life. Defects associated with bone exposure in the sacral region are more frequent among pressure sores. The gold standard treatment consists in a musculocutaneous gluteal flap; it can have as side effects functional deficits for walking and an important scar. In order to diminish the donor site morbidity muscle sparing flaps, as perforator flaps, have been described. The purpose of this article is to report the case of a 29-year-old patient with a median sacral defect with bone exposure after oncological resection, covered by a perforator gluteal flap. A superior gluteal artery perforator was researched using a Doppler flowmetry. The role of the perforator was to make the flap more reliable and to obtain a higher degree of mobilization of the flap devoid of tension or flap morbidity, without interfering with the gluteus maximus muscle integrity. Also, the aesthetic units of the gluteal region have been considered in order to obtain a better scar quality. At the 4 months follow-up, the result was stable with a discrete scar and no walking difficulties. In conclusion, the median defects associating bone exposure in the sacral region are difficult to treat, especially in young patients. The treatment should consist in a stable soft tissue coverage with minimal functional and aesthetic sequela. The perforator gluteal flap respects the aesthetic units and can be considered as an elegant and efficient solution to treat this type of defects.