EpiDex® Swiss field trial 2004-2008.

BACKGROUND: Approximately 20% of leg ulcers remain unresponsive to the best conservative standard of care. So far, these patients could either receive conventional skin grafts or had to accept their intractable wound. Skin substitutes from cell culture may represent a promising alternative to heal a major part of these patients on a non-surgical, potentially more cost-effective basis. OBJECTIVE: To systematically evaluate the first 68 patients treated in Switzerland (Swiss EpiDex® field trial 2004-2008). METHODS: Retrospective study on EpiDex treatment of a complete consecutive series of 68 patients with chronic wounds (66 chronic leg ulcers, 2 sores) unresponsive to best conservative standard of care. The primary end point was complete wound closure within 9 months after transplantation, the secondary end points change of wound surface area, pain reduction and overall judgement by the patient. Adverse effects were infection, dermatitis and others. Calculation of treatment costs was made. RESULTS: By the end of the study, 50/68 (74%) of patients had their wound completely healed [venous 29/37 (78%); mixed 7/9 (78%); others 14/22 (64%)]; 10/68 (15%) had the wound surface area reduced by >50%, and 8/68 (12%) did not respond to the EpiDex treatment. Wound pain disappeared completely in 78% and partially in 13%. Fifteen patients (22%) received antibiotics for wound infection, and 2 (3%) developed dermatitis (not related to the local therapy). Average treatment costs for venous ulcers amounted to EUR 5,357, compared to EUR 5,722-8,622 reimbursed according to the German DRG system (2010) for an in-patient skin graft. CONCLUSION: EpiDex may effectively heal up to three quarters of recalcitrant chronic leg ulcers. Thus, it represents an intermediate step to avoid costly in-patient split-skin mesh graft treatments. Patients remain mobilized, and a donor site is avoided. Large wound size or a necrotic wound bed limit the use of EpiDex. Otherwise, it offers the opportunity to avoid conventional skin grafts in a significant number of chronic leg ulcer patients.

[Cutaneous lymphomas]. / Kutane Lymphome.

Cutaneous lymphomas are a heterogenous group of lymphoproliferative disorders of the T- and B-lymphocytes with a low incidence of approximately 1:100000/year. They belong to the Non-Hodgkin lymphoma. The skin is the second most abundant site of extranodal lymphoma formation (after the GI tract). The new WHO/EORTC classification of cutaneous T- and B-cell lymphomas provides a widely accepted nomenclature for primary cutaneous lymphomas based primarily on clinical, but also on histologic, cytologic and molecular features. It has already proven to be an invaluable tool for international prospective clinical studies. The clear distinction of primary cutaneous from secondary cutaneous lymphoma will also be important to prevent overtreatment of the frequently benign primary cutaneous lymphoma. Treatment of primary cutaneous lymphoma is skin-directed in early disease stages, and uses as systemic approach in advanced stages. Skin-directed therapies encompass UV-light treatment such as UVB311nm, or PUVA, topical steroids class III and IV, or bexaroten gel. Systemic treatment options may be immunomodulatory, such as treatment with interferon alpha injection, or biologic response modifiers such as bexarotene. We recommend that advanced stages of cutaneous lymphoma should be treated in centers that offer clinical studies in this field, because prognosis of late stages is still dismal and there is so far no therapeutic approach that has led to an increase in overall survival. Hence, inclusion of patients in prospective controlled clinical studies should always be considered in patients with primary cutaneous lymphoma.

Mitogen-activated protein/extracellular signal-regulated kinase kinase inhibition results in biphasic alteration of epidermal homeostasis with keratinocytic apoptosis and pigmentation disorders.

PURPOSE: Raf/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway is constitutively activated in melanoma. AZD6244 blocks MEK1/2, inhibiting ERK phosphorylation. We focus on associated cutaneous toxicity and we attempt to understand the underlying pathophysiology and design treatment strategies. EXPERIMENTAL DESIGN: Dermatologic conditions of 22 patients with unresectable melanoma stage III/IV in a phase II trial were evaluated. Thirteen patients received AZD6244 initially, and nine patients were treated with AZD6244 following tumor progression with temozolomide. Biopsies were compared with matched controls in normal skin. Immunohistochemistry was performed. Half-side treatment of acute skin toxicity compared therapeutic options. RESULTS: Nineteen of 22 (86%) AZD6244-treated patients presented with cutaneous eruptions. Seventeen patients (77%) developed acute papulopustular rash. Chronic skin changes included xerosis, paronychia, and fissured fingertips, resembling cutaneous toxicity of epidermal growth factor receptor inhibition. In addition, we observed reduced pigmentation of hair and skin. Histology of acute skin lesions revealed a significant increase of apoptotic keratinocytes (P = 0.0008), focal neutrophilic infiltrates, destruction of the adnexal structures by neutrophils, and reduced cytokeratins. A significant proliferation shift from basal to suprabasal keratinocytes was shown in acute and chronic lesions. The number and viability of melanocytes was not affected. Corticosteroids plus antibacterial topical therapy ameliorate acute skin toxicity. CONCLUSIONS: AZD6244-associated skin reactions partly overlap with those observed upon epidermal growth factor receptor inhibition. Additionally, pigmentation of skin and hair is affected. The interruption of the MEK signaling pathway results in an acute keratinocyte stress response with disturbed epidermal homeostasis, inflammation, and tissue damage. Chronic adaptation controls inflammatory tissue damage but leads to cutaneous malfunctions that explain chronic skin toxicity.