Mutations in genes encoding for proteins along the RAS-RAF-MEK-ERK pathway have been detected in a variety of tumor entities, including malignant melanoma, thyroid, colonic and ovarian carcinomas, and some sarcomas. Thus, a number of inhibitors of this pathway have been developed, whose antitumor potential is currently being assessed in different clinical trials. Up to now one drug of this category (vemurafenib) has been approved by the FDA and the European Commission for late-stage melanoma. Although these new targeted anticancer therapies are generally considered to be safe and well tolerated, certain toxicities have been attributed to them, with cutaneous side effects being perhaps the most frequent amongst them. Based on results of clinical trials and on case series, a distinct profile of cutaneous toxicity has been observed, which is similar to that of EGFR and multikinase inhibitors. As exanthema, palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, xerosis, pruritus, photosensitivity, and paronychia, can be controlled in most cases with common conservative modalities, special attention should be given to the early detection of epithelial skin tumors (mainly keratoakanthomas) that can be induced during therapy with these agents. This report reviews all current published data on cutaneous side effects of RAS-RAF-MEK-ERK pathway inhibitors, and attempts to provide the clinician with clear hints for their management.

SummaryAlthough lichen planus is one of the most common dermatological entities, very few reviews on its management exist in the literature. Standard therapeutic approaches include various topical treatments (including topical corticosteroids, calcineurin inhibitors, vitamin D analogs) and phototherapy modalities, as well as systemic corticosteroids and systemic retinoids. While localized skin lesions are easily managed with standard modalities, generalized forms and in particular involvement of hair follicles, nails and mucosa, as well as eyes are often challenging. This review proposes an evidence-based and differential therapeutic regime, taking into account many new emerging systemic therapies to help clinicians optimize treatment according to the type, extent and severity of the disease. An individual therapeutic ladder has been developed for each location, starting with standard modalities and ranking alternative systemic treatments (mainly methotrexate and hydroxychloroquine, as well as cyclosporine, azathioprine and mycophenolate mofetil) according to efficacy, evidence level and side-effect profile.

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SummaryA multitude of surgical and non-surgical therapies are available to treat malignant epithelial tumors of the skin. The article summarizes the current treatment options for basal cell carcinoma, squamous cell carcinoma and keratoacanthoma. Moreover, the possibilities of primary and secondary prevention for high-risk patients are reviewed. The decision about the best therapeutic option depends on location, age, and general health of the patient as well as the risk of tumor recurrence.

Hidden low grade inflammation underlines various cardio-metabolic diseases. This type of inflammation is triggered by abnormal reaction to unwanted self products or deregulation of cellular response to cytokines. In the case of atherosclerosis hidden inflammation is induced by modified lipoproteins and develops under control of different cytokines including IL-4 and TGFβ. The key innate immune cells reacting on these factors are monocytes and macrophages. It is well established that monocytes represent a heterogeneous cell population that easily reacts to pathologic changes in the organism. The best studied marker which expression on monocytes is changed in inflammatory conditions is CD16. Although this marker was shown to be associated with various pathologic conditions its specificity is highly questionable. There is an urgent need of identification of new monocyte-expressed biomarkers that may help not only to detect hidden inflammation but also to determine its type. Our analysis of type 2 activation of human monocytes resulted in identification of 3 novel biomarkers for hidden type 2 inflammation. These include stabilin-1, FOXQ1 and IL17RB. These markers are expressed by monocytes/macrophages under stimulation with IL-4 or its combination with TGFβ - 2 cytokines playing important role in atherogenesis. Stabilin-1 was demonstrated on the monocytes in patients with hyperholisterolemia and in macrophages within atherosclerotic lesions. Association of FoxQ1 and IL17RB with atherosclerosis can be deduced from published data but requires experimental confirmation. Functions of all three proteins suggest that they are not only diagnostic markers, but also involved in atherogenesis and can be used as targets for novel therapeutic approaches.

Monocytes are actively recruited at sites of chronic inflammation. However, molecular factors involved in this process are not fully elucidated. Here, we show that cytokine IL-4 which is implicated in the development of chronic inflammatory disease atopic dermatitis (AD) induces expression of transcription factor FoxQ1 in human monocytes and macrophages. FoxQ1 mRNA levels were elevated in monocytes of AD patients compared to healthy donors. Overexpression of FoxQ1 in RAW 264.7 monocytic cells facilitated their migration towards MCP-1 and was associated with decreased expression of migration-regulating genes (claudin 11 and plexin C1). Furthermore, FoxQ1 overexpression in RAW cells accelerated TNFα secretion after LPS challenge. Overall, our results indicate that FoxQ1 stimulates monocyte motility, increases pro-inflammatory potential, and directs monocyte migration towards MCP-1 that is crucial for monocyte influx into inflammatory sites. This mechanism could contribute to the pathogenesis of chronic inflammatory disorders such as AD.

Although lichen planus is one of the most common dermatological entities, very few reviews on its management exist in the literature. Standard therapeutic approaches include various topical treatments (including topical corticosteroids, calcineurin inhibitors, vitamin D analogs) and phototherapy modalities, as well as systemic corticosteroids and systemic retinoids. While localized skin lesions are easily managed with standard modalities, generalized forms and in particular involvement of hair follicles, nails and mucosa, as well as eyes are often challenging. This review proposes an evidence-based and differential therapeutic regime, taking into account many new emerging systemic therapies to help clinicians optimize treatment according to the type, extent and severity of the disease. An individual therapeutic ladder has been developed for each location, starting with standard modalities and ranking alternative systemic treatments (mainly methotrexate and hydroxychloroquine, as well as cyclosporine, azathioprine and mycophenolate mofetil) according to efficacy, evidence level and side-effect profile.

Ein 13-jähriger Junge wurde in unsere Einrichtung überwiesen, da sich auf seinem Körper seit einigen Monaten, zunehmend und mit einer diskreten Hyperkeratose einhergehend, braune Maculae von ca. 1 cm bis 5 cm Durchmesser entwickelten (Abbildung 1). Der junge Patient war asymptomatisch und entzündliche Erkrankungen waren keine vorausgegangen. Die Maculae, die vor allem im Bereich der linken Schulter, des linken Arms und der rechten Brust auftraten, wiesen ein ungleichmäßiges und asymmetrisches Verteilungsmuster auf. Sie folgten in ihrer Anordnung weder Spalt-noch Blaschko-Linien und zeigten auch keine segmentale Verteilung. Eine lokale Therapie mit Antimykotika und Glucocorticoiden hatte zu keiner Verbesserung des Befundes geführt. DifferenzialdiagnosenArzneimittelexanthem, postentzündliche Hyperpigmentierung, Mastozytose, Lichen planus pigmentosus, Erythema dyschromicum perstans, Acanthosis nigricans, konfluierende retikuläre Papillomatose (Morbus Gougerot-Carteaud).Abbildung 2 Papillomatose mit basaler Hyperpigmentierung und begleitender Hyperkeratose ohne Zeichen einer Entzündung.Abbildung 1 Asymptomatische braune hyperkeratotische Maculae.Ihre Diagnose? PathologieIn der histopathologischen Untersuchung zeigte sich eine Papillomatose, Orthohyperkeratose und Akanthose. Die epidermale Basalzellschicht war moderat hyperpigmentiert, in der Dermis kamen vereinzelt Lymphozyten vor. Eine Proliferation dermaler oder epidermaler Melanozyten konnte nicht nachgewiesen werden (Abbildung 2).