Search

Background Radiological imaging such as computed tomography (CT) is used frequently for disease staging and therapy monitoring in advanced skin cancer patients. Detected lesions of unclear dignity are a common challenge for treating physicians. The aim of this study was to assess the frequency and outcome of CT-guided biopsy (CTGB) of radiologically unclear, suspicious lesions and to depict its usefulness in different clinical settings. Methods This retrospective monocentric study included advanced skin cancer patients (melanoma, Merkel cell carcinoma, squamous cell carcinoma, angiosarcoma, cutaneous lymphoma) with radiologically unclear lesions who underwent CTGB between 2010 and 2018. Results Of 59 skin cancer patients who received CTGB, 47 received CTGB to clarify radiologically suspicious lesions of unclear dignity. 32 patients had no systemic therapy (cohort A), while 15 patients received systemic treatment at CTGB (cohort B). In both cohorts, CTGB revealed skin cancer metastasis in a large proportion of patients (37.5%, 40.0%, respectively), but benign tissue showing inflammation, fibrosis or infection in an equally large percentage (37.5%, 46.7%, respectively). Additionally, a significant number of other cancer entities was found (25.0%, 13.3%, respectively). In patients receiving BRAF/MEK inhibitors, CTGB confirmed suspicious lesions as skin cancer metastasis in 83.3%, leading to treatment change. In immune checkpoint inhibitor-treated patients, skin cancer metastasis was confirmed in 11.1% of patients only, whereas benign tissue changes (inflammation/fibrosis) were found in 77.8%. Conclusions Our results highlight the relevance of clarifying radiologically unclear lesions by CTGB before start or change of an anti-tumour therapy to exclude benign alterations and secondary malignancies.

Cutaneous lymphomas are a group of rare and distinct diseases that present varying clinical manifestations, histopathology and prognosis. Optimal and early management relies on accurate diagnosis. Unfortunately, clinical diagnosis in early stages is difficult due to the clinical overlap with other dermatologic conditions. In numerous cases, several consultations and multiple biopsies are required. Dermoscopy is frequently used for the evaluation of melanocytic skin tumors, but its value has been recognized for non-melanocytic neoplasms and inflammatory skin diseases, and in the last few years it has assisted with the diagnosis of cutaneous lymphoproliferative disorders (LPD). Studies have shown that dermoscopy may be useful in the evaluation of cutaneous lymphomas, offering a link between clinical and histopathological examination, but the features are not diagnostic and histopathological confirmation is mandatory. However, dermoscopy can raise suspicion of cancer, leading to a skin biopsy. Furthermore, larger and prospective studies are required to define the exact dermoscopic features of every subtype of cutaneous lymphoma.

Background: For patients with early American Joint Committee on Cancer (AJCC)-stage melanoma the combined loss of the autophagy regulatory protein AMBRA1 and the terminal differentiation marker loricrin in the peritumoral epidermis is associated with a significantly increased risk of metastasis.\ud \ud Objectives: The aim of the present study was to evaluate the potential contribution of melanoma paracrine transforming growth factor (TGF)-β signalling to the loss of AMBRA1 in the epidermis overlying the primary tumour and disruption of epidermal integrity.\ud \ud Methods: Immunohistochemistry was used to analyse AMBRA1 and TGF-β2 in a cohort of 109 AJCC all-stage melanomas, and TGF-β2 and claudin-1 in a cohort of 30 or 42 AJCC stage I melanomas, respectively, with known AMBRA1 and loricrin (AMLo) expression. Evidence of pre-ulceration was analysed in a cohort of 42 melanomas, with TGF-β2 signalling evaluated in primary keratinocytes.\ud \ud Results: Increased tumoral TGF-β2 was significantly associated with loss of peritumoral AMBRA1 (P < 0·05), ulceration (P < 0·001), AMLo high-risk status (P < 0·05) and metastasis (P < 0·01). TGF-β2 treatment of keratinocytes resulted in downregulation of AMBRA1, loricrin and claudin-1, while knockdown of AMBRA1 was associated with decreased expression of claudin-1 and increased proliferation of keratinocytes (P < 0·05). Importantly, we show loss of AMBRA1 in the peritumoral epidermis was associated with decreased claudin-1 expression (P < 0·05), parakeratosis (P < 0·01) and cleft formation in the dermoepidermal junction (P < 0·05).\ud \ud Conclusions: Collectively, these data suggest a paracrine mechanism whereby TGF-β2 causes loss of AMBRA1 overlying high-risk AJCC early-stage melanomas and reduced epidermal integrity, thereby facilitating erosion of the epidermis and tumour ulceration.

Changes in melanocytic naevi and development of new naevi have been reported in pregnant women. The association between pregnancy and melanoma is a controversial topic. We conducted this systematic review to identify the dermatoscopic changes that occur in naevi during pregnancy that could facilitate in distinguishing benign from suspicious lesions. Medline, Scopus and Embase datasets were reviewed for clinical studies on dermatoscopic characteristics of melanoma and naevus in pregnancy. Six cohort studies with a total of 258 patients with 1167 skin lesions that were examined fulfilled the conditions to be included in the systematic review. None of the patients developed melanoma. Development of new naevi, when reported, was observed in less than half of the participants. The most frequent observed dermatoscopic change among the studies was the increase in the number of dots. Development of new vessels, hypo- and hyperpigmentations and changes in the pigment network were common described changes. The included studies were heterogeneous not allowing head-to-head comparisons between them. Robust and larger studies of dermatoscopic evaluation of naevi in pregnant women are needed to determine high-risk dermatoscopic characteristics.

Der extramammare Morbus Paget (EMP) ist ein seltenes, langsam wachsendes, kutanes Adenokarzinom mit einer Inzidenz von 0,1–2,4/1.000.000 Einwohner. Histologisch ist der EMP – ahnlich wie der mammare Morbus Paget – durch epidermale Paget-Zellen gekennzeichnet. Der EMP wird in einen primaren EMP (Typ I) und sekundaren EMP (Typ II – assoziiert mit einem kolorektalen Karzinom – und Typ III – assoziiert mit einem urogenitalen Karzinom) unterteilt. Das klinische Bild ist nicht charakteristisch und imitiert chronisch entzundliche Dermatosen. Dies kann eine fruhe Diagnosestellung erschweren und hinauszogern. Die mikrographisch kontrollierte Exzision ist die Therapie der Wahl. Bei geplantem Einsatz von topischen Therapien wie Imiquimod bzw. oberflachlichen ablativen Therapien sollte das Ausmas einer Adnexinfiltration histologisch untersucht werden. Die komplette Exzision des Tumors stellt aufgrund der pathologischen Charakteristika bei schlecht definierbaren Wundrandern eine Herausforderung dar. Im metastasierten Stadium hat der EMP eine schlechte Prognose. Kontrollierte klinische Studien zur Systemtherapie liegen bisher nicht vor.

Accurate classification of melanocytic proliferations has important implications for prognostic prediction, treatment and follow-up. Although most melanocytic proliferations can be accurately classified using clinical and pathological criteria, classification (specifically distinction between nevus and melanoma) can be challenging in a subset of cases, including those with spitzoid morphology. Genetic studies have shown that mutation profiles differ between primary melanoma subtypes and Spitz nevi. These differences may aid in distinguishing benign from malignant in some melanocytic tumours. Here, we present a selection of melanocytic proliferations with equivocal histopathological criteria, wherein genetic analysis was requested to help guide classification. In two of four cases, the genetic results offered valuable insights, allowing a definitive diagnosis, indicating the diagnostic value of mutation profiling in a real-world routine clinical setting. Although histopathological assessment remains decisive in melanocytic proliferation classification, we recommend including genetic profiling in cases of borderline or atypical lesion to support accurate classification.

Autophagy is required for normal skin homeostasis and its disordered regulation is implicated in a range of cutaneous diseases. Several well-characterized biomarkers of autophagy are used experimentally to quantify autophagic activity or clinically to correlate autophagy with disease progression. This article discusses the advantages and limitations of different approaches for measuring autophagy as well as the techniques for modulating autophagy. These include analysis of endogenous LC3, a central autophagy regulatory protein, and measurement of LC3 flux using a dual-fluorescent reporter, which provides a quantitative readout of autophagy in cell culture systems in vitro and animal models in vivo. Degradation of SQSTM1/p62 during autophagy is proposed as an alternative biomarker allowing the analysis of autophagy both experimentally and clinically. However, the complex regulation of individual autophagy proteins and their involvement in multiple pathways means that several proteins must be analyzed together, preferably over a time course to accurately interpret changes in autophagic activity. Genetic modification of autophagy proteins can be used to better understand basic autophagic mechanisms contributing to health and disease, whereas small molecule inhibitors of autophagy regulatory proteins, lysosomal inhibitors, or activators of cytotoxic autophagy have been explored as potential treatments for skin disorders where autophagy is defective. [Abstract copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.]

Patients with melanoma have an increased risk of having other neoplasms, and particularly other melanomas and non-melanoma skin cancers. The study aimed to describe multiple primary melanomas in a large medical university centre from Romania (Cluj-Napoca) from 2004 to 2020. Out of 699 patients with melanoma included in the study, 26 (3.71%) developed multiple tumours. The 26 patients developed a total of 59 melanomas, corresponding to a mean of 2.3 melanomas per patient. The site and histological subtype of the first and second melanomas were not consistent. The proportion of subsequent melanomas that were in situ (51.5%) or thin melanomas (

Background Conjunctival melanoma is a potentially deadly eye tumour. Despite effective local therapies, tumour recurrence and metastasis remain frequent. The genetics of conjunctival melanomas remain incompletely understood. Methods A large cohort of 63 conjunctival melanomas was screened for gene mutations known to be important in other melanoma subtypes by targeted next-generation sequencing. Mutation status was correlated with patient prognosis. Results Frequent mutations in genes activating the MAP kinase pathway were identified. NF1 mutations were most frequent (n = 21, 33%). Recurrent activating mutations were also identified in BRAF (n = 16, 25%) and RAS genes (n = 12, 19%; 11 NRAS and 1 KRAS). Conclusions Similar to cutaneous melanomas, conjunctival melanomas can be grouped genetically into four groups: BRAF-mutated, RAS-mutated, NF1-mutated and triple wild-type melanomas. This genetic classification may be useful for assessment of therapeutic options for patients with metastatic conjunctival melanoma

The identification of targetable molecules in cellular signaling pathways represents a milestone in the treatment of melanoma. Selective inhibitors of these molecules, known as phosphokinases, allow for individual signaling pathways to be "switched off". This is of particular importance for tumors in which these pathways are constitutively activated by mutations in genes encoding said molecules. Especially patients with BRAF-mutated melanomas significantly benefit from kinase inhibitor therapies, with the current standard of combined BRAF and MEK inhibition providing very good long-term disease control. Such regimens have been shown to achieve a progression-free survival of more than ten months and an overall survival of more than two years, along with good quality of life. Given that the majority of patients develop secondary resistance during long-term kinase inhibitor therapy, current clinical trials are geared towards finding suitable drug combinations including inhibitors of other signaling pathways as well as immune checkpoint inhibitors. The present review highlights targeted therapies for melanoma currently available as well as potential future options presently under clinical investigation.

Die Behandlungsstrategie beim metastasierten Melanom hat sich mit der Identifizierung therapeutisch angreifbarer molekularer Zielstrukturen innerhalb zellularer Signalwege radikal geandert. Durch die Zulassung von Substanzen, die gezielt an den zentralen Schaltmolekulen, den Phosphokinasen, angreifen, konnen diese Signalwege selektiv abgeschaltet werden. Dies ist insbesondere bei denjenigen Tumoren von Interesse, deren Signalwege durch aktivierende Mutationen der fur die Schaltmolekule kodierenden Gene konstitutiv aktiviert sind. Aktuell ist diese therapeutische Strategie insbesondere fur Patienten bedeutsam, deren Melanome eine Mutation im BRAF-Gen aufweisen. Diese Patienten konnen durch eine Kombinationstherapie aus Inhibitoren der Phosphokinasen BRAF und MEK langfristig mit sehr guter Krankheitskontrolle behandelt werden. Unter dieser Kombinationstherapie wird aktuell ein progressionsfreies Uberleben von uber zehn Monaten und ein Gesamtuberleben von mehr als zwei Jahren bei guter Lebensqualitat erzielt. Da unter langerfristiger Therapie mit Kinaseinhibitoren jedoch bei einem Grosteil der Patienten eine Resistenzbildung auftritt, sind aktuelle klinische Therapiestudien auf die Suche nach geeigneten Kombinationspartnern unter Blockierung anderer Signalwege oder unter Aktivierung der T-Zell-vermittelten Immunantwort ausgerichtet. Der vorliegende Ubersichtsartikel stellt sowohl die aktuell verfugbaren als auch die in der klinischen Testung befindlichen zukunftigen Optionen der zielgerichteten Therapie des Melanoms dar.

Background Mucosal melanoma (MM) is a rare but diverse cancer entity. Prognostic factors are not well established for Caucasians with MM. Patients and methods We analysed the disease course of 444 patients from 15 German skin cancer centres. Disease progression was determined with the cumulative incidence function. Survival times were estimated with the Kaplan–Meier method. Prognostic parameters were identified with multivariate Cox regression analysis. Results Common anatomic sites of primary tumours were head and neck (MMHN, 37.2%), female genital tract (MMFG, 30.4%) and anorectal region (MMAN, 21.8%). MMAN patients showed the highest vertical tumour thickness (p = 0.001), had a more advanced nodal status (p = 0.014) and a higher percentage of metastatic disease (p = 0.001) at diagnosis. Mutations of NRAS (13.8%), KIT (8.6%) and BRAF (6.4%) were evenly distributed across all tumour site groups. Local relapses were observed in 32.4% and most commonly occurred in the MMHN group (p = 0.016). Male gender (p = 0.047), advanced tumour stage (p = 0.001), nodal disease (p = 0.001) and incomplete resection status (p = 0.001) were independent risk factors for disease progression. Overall survival (OS) was highest in the MMFG group (p = 0.030) and in patients without ulceration (p = 0.004). Multivariate risk factors for OS were M stage at diagnosis (p = 0.002) and incomplete resection of the primary tumour (p = 0.001). Conclusion In this large series of MM patients in a European population, anorectal MM was associated with the poorest prognosis.

Blue nevi are melanocytic tumors originating in the cutaneous dermis. Malignant tumors may arise in association with or resembling blue nevi, so called ‘blue nevus-like melanoma’, which can metastasize and result in patient death. Identifying which tumors will behave in a clinically aggressive manner can be challenging. Identifying genetic alterations in such tumors may assist in their diagnosis and prognostication. Blue nevi are known to be genetically related to uveal melanomas (eg, both harboring GNAQ and GNA11 mutations). In this study, we analyzed a large cohort (n=301) of various morphologic variants of blue nevi and related tumors including tumors diagnosed as atypical blue nevi (n=21), and blue nevus-like melanoma (n=12), screening for all gene mutations known to occur in uveal melanoma. Similar to published reports, we found the majority of blue nevi harbored activating mutations in GNAQ (53%) or GNA11 (15%). In addition, rare CYSLTR2 (1%) and PLCB4 (1%) mutations were identified. EIF1AX, SF3B1, and BAP1 mutations were also detected, with BAP1 and SF3B1 R625 mutations being present only in clearly malignant tumors (17% (n=2) and 25% (n =3) of blue nevus-like melanoma, respectively). In sequencing data from a larger cohort of cutaneous melanomas, this genetic profile was also identified in tumors not originally diagnosed as blue nevus-like melanoma. Our findings suggest that the genetic profile of coexistent GNAQ or GNA11 mutations with BAP1 or SF3B1 mutations can aid the histopathological diagnosis of blue nevus-like melanoma and distinguish blue nevus-like melanoma from conventional epidermal-derived melanomas. Future studies will need to further elucidate the prognostic implications and appropriate clinical management for patients with tumors harboring these mutation profiles.

Background GNAQ and GNA11 mutant nonuveal melanoma represent a poorly characterized rare subgroup of melanoma with a gene mutation profile similar to uveal melanoma. Objectives To characterize these tumours in terms of clinical behaviour and genetic characteristics. Methods Patients with nonuveal GNAQ/11 mutated melanoma were identified from the prospective multicentre tumour tissue registry ADOREG, Tissue Registry in Melanoma (TRIM) and additional cooperating skin cancer centres. Extensive data on patient, tumour and treatment characteristics were collected retrospectively. Targeted sequencing was used to determine tumour mutational burden. Immunohistochemistry staining was performed for programmed death-ligand 1 and BRCA1-associated protein (BAP)1. Existing whole-exome cutaneous and uveal melanoma data were analysed for mutation type and burden. Results We identified 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma. Tumours had a lower tumour mutational burden and fewer ultraviolet signature mutations than cutaneous melanomas. In addition to GNAQ and GNA11 mutations (nine each), six splicing factor 3b subunit 1 (SF3B1), three eukaryotic translation initiation factor 1A X-linked (EIF1AX) and four BAP1 mutations were detected. In contrast to uveal melanoma, GNAQ/11 mutant nonuveal melanomas frequently metastasized lymphatically and concurrent EIF1AX, SF3B1 and BAP1 mutations showed no apparent association with patient prognosis. Objective response to immunotherapy was poor with only one partial response observed in 10 treated patients (10%). Conclusions Our findings suggest that GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is both clinically and genetically distinct from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed. What is already known about this topic? The rare occurrence of GNAQ/11 mutations in nonuveal melanoma has been documented. GNAQ/11 mutant nonuveal melanomas also harbour genetic alterations in EIF1AX, SF3B1 and BAP1 that are of prognostic relevance in uveal melanoma. What does this study add? GNAQ/11 mutant nonuveal melanomas show metastatic spread reminiscent of cutaneous melanoma, but not uveal melanoma. GNAQ/11 mutant nonuveal melanomas have a low tumour mutational burden that is higher than uveal melanoma, but lower than cutaneous melanoma. What is the translational message? Primary GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is clinically and genetically distinct from both cutaneous and uveal melanoma. As metastatic GNAQ/11 mutant nonuveal melanomas respond poorly to available systemic therapies, including immune checkpoint inhibition, novel therapeutic approaches for these tumours are urgently needed. Linked Comment: Rafei-Shamsabadi. Br J Dermatol 2020; 183:806-807.

Inflammatory bowel disease (IBD) is defined as a chronic condition characterized by unpredictable relapsing episodes of gastrointestinal inflammation. IBD is not limited to the gastrointestinal tract and should be considered a systemic disease which can involve any organ. Cutaneous manifestations in IBD are frequent and comprise a broad spectrum of diseases, ranging from mild to severe and sometimes debilitating lesions. Some of the cutaneous manifestations can present signs of an underlying intestinal disease, leading to the screening for non-detected IBD even in the absence of symptoms. Cutaneous EIMs are divided into 4 categories: i) Disease-specific lesions that show the same histopathologic findings as the underlying gastrointestinal disease, ii) reactive lesions which are inflammatory lesions that share a common pathogenetic mechanism but do not share the same pathology with the gastrointestinal disease, iii) associated conditions are more frequently observed in the context of IBD, without sharing the pathogenetic mechanism or the histopathological findings with the underlying disease and iv) drug-related skin reactions.

Study aim Melanomas arising in acral sites are associated with a poorer prognosis than other melanoma subtypes. The aim of this study was to evaluate clinical-pathological and genetic characteristics as well as therapeutic responses of a larger cohort of patients with melanomas arising in acral sites. Methods Clinical data of 134 patients with melanomas arising in acral sites from the Dept. of Dermatology Essen were collected and analysed with regard to clinicopathological characteristics and treatment responses. Genetic analysis with targeted next-generation sequencing was done on 50 samples. Results In our cohort, BRAF (30%), NRAS (28%), TERT promoter (26%), NF1 (14%) and KIT (6%) were frequently identified mutations. Comparing tumours situated on palms and soles with melanomas arising on dorsal acral sites, a higher frequency of NRAS (39.1% versus 25%) and NF1 (17.3% versus 0%) and lower frequencies of BRAF (21.7% versus 75%) and TERT promoter (8.6% versus 50%) mutations were observed. MAPK activating mutations were identified in 64% of tumours. Overall survival was longer in patients treated with immune checkpoint inhibitors as first-line treatment than in patients receiving other systemic therapies (i.e. BRAF/MEK inhibitors and chemotherapy). Conclusion Our data suggest that the genetics of melanomas arising in acral sites varies by tumour location and may influence biological behaviour.

Atypical fibroxanthomas and pleomorphic dermal sarcomas are tumors arising in sun-damaged skin of elderly patients. They have differing prognoses and are currently distinguished using histological criteria, such as invasion of deeper tissue structures, necrosis and lymphovascular or perineural invasion. To investigate the as-yet poorly understood genetics of these tumors, 41 atypical fibroxanthomas and 40 pleomorphic dermal sarcomas were subjected to targeted next-generation sequencing approaches as well as DNA copy number analysis by comparative genomic hybridization. In an analysis of the entire coding region of 341 oncogenes and tumor suppressor genes in 13 atypical fibroxanthomas using an established hybridization-based next-generation sequencing approach, we found that these tumors harbor a large number of mutations. Gene alterations were identified in more than half of the analyzed samples in FAT1, NOTCH1/2, CDKN2A, TP53, and the TERT promoter. The presence of these alterations was verified in 26 atypical fibroxanthoma and 35 pleomorphic dermal sarcoma samples by targeted amplicon-based next-generation sequencing. Similar mutation profiles in FAT1, NOTCH1/2, CDKN2A, TP53, and the TERT promoter were identified in both atypical fibroxanthoma and pleomorphic dermal sarcoma. Activating RAS mutations (G12 and G13) identified in 3 pleomorphic dermal sarcoma were not found in atypical fibroxanthoma. Comprehensive DNA copy number analysis demonstrated a wide array of different copy number gains and losses, with similar profiles in atypical fibroxanthoma and pleomorphic dermal sarcoma. In summary, atypical fibroxanthoma and pleomorphic dermal sarcoma are highly mutated tumors with recurrent mutations in FAT1, NOTCH1/2, CDKN2A, TP53, and the TERT promoter, and a range of DNA copy number alterations. These findings suggest that atypical fibroxanthomas and pleomorphic dermal sarcomas are genetically related, potentially representing two ends of a common tumor spectrum and distinguishing these entities is at present still best performed using histological criteria.Modern Pathology advance online publication, 3 November 2017; doi:10.1038/modpathol.2017.146.

Background Around 90% of melanomas are caused by ultraviolet (UV) exposure and are therefore eminently preventable. Unhealthy tanning behavior is mostly initiated in early adolescence, often with the belief that it increases attractiveness; the problems related to skin atrophy and malignant melanoma are too far in the future to fathom. Photoaging desktop programs, in which an image is altered to predict future appearance, have been successful in positively influencing behavior in adiposity or tobacco prevention settings. Objective To develop and test a photoaging app designed for melanoma prevention. Methods We harnessed the widespread availability of mobile phones and adolescents’ interest in appearance to develop a free mobile app called Sunface. This app has the user take a self-portrait (ie, a selfie), and then photoages the image based on Fitzpatrick skin type and individual UV protection behavior. Afterward, the app explains the visual results and aims at increasing self-competence on skin cancer prevention by providing guideline recommendations on sun protection and the ABCDE rule for melanoma self-detection. The underlying aging algorithms are based on publications showing UV-induced skin damage by outdoor as well as indoor tanning. To get a first impression on how well the app would be received in a young target group, we included a total sample of 25 students in our cross-sectional pilot study with a median age of 22 (range 19-25) years of both sexes (11/25, 44% female; 14/25, 56% male) attending the University of Essen in Germany. Results The majority of enrolled students stated that they would download the app (22/25, 88%), that the intervention had the potential to motivate them to use sun protection (23/25, 92%) and that they thought such an app could change their perceptions that tanning makes you attractive (19/25, 76%). Only a minority of students disagreed or fully disagreed that they would download such an app (2/25, 8%) or that such an app could change their perceptions on tanning and attractiveness (4/25, 16%). Conclusions Based on previous studies and the initial study results presented here, it is reasonable to speculate that the app may induce behavioral change in the target population. Further work is required to implement and examine the effectiveness of app-based photoaging interventions within risk groups from various cultural backgrounds.

The identification of targetable molecules in cellular signaling pathways represents a milestone in the treatment of melanoma. Selective inhibitors of these molecules, known as phosphokinases, allow for individual signaling pathways to be "switched off". This is of particular importance for tumors in which these pathways are constitutively activated by mutations in genes encoding said molecules. Especially patients with BRAF-mutated melanomas significantly benefit from kinase inhibitor therapies, with the current standard of combined BRAF and MEK inhibition providing very good long-term disease control. Such regimens have been shown to achieve a progression-free survival of more than ten months and an overall survival of more than two years, along with good quality of life. Given that the majority of patients develop secondary resistance during long-term kinase inhibitor therapy, current clinical trials are geared towards finding suitable drug combinations including inhibitors of other signaling pathways as well as immune checkpoint inhibitors. The present review highlights targeted therapies for melanoma currently available as well as potential future options presently under clinical investigation.

Die Behandlungsstrategie beim metastasierten Melanom hat sich mit der Identifizierung therapeutisch angreifbarer molekularer Zielstrukturen innerhalb zellulärer Signalwege radikal geändert. Durch die Zulassung von Substanzen, die gezielt an den zentralen Schaltmolekülen, den Phosphokinasen, angreifen, können diese Signalwege selektiv abgeschaltet werden. Dies ist insbesondere bei denjenigen Tumoren von Interesse, deren Signalwege durch aktivierende Mutationen der für die Schaltmoleküle kodierenden Gene konstitutiv aktiviert sind. Aktuell ist diese therapeutische Strategie insbesondere für Patienten bedeutsam, deren Melanome eine Mutation im BRAF-Gen aufweisen. Diese Patienten können durch eine Kombinationstherapie aus Inhibitoren der Phosphokinasen BRAF und MEK langfristig mit sehr guter Krankheitskontrolle behandelt werden. Unter dieser Kombinationstherapie wird aktuell ein progressionsfreies Überleben von über zehn Monaten und ein Gesamtüberleben von mehr als zwei Jahren bei guter Lebensqualität erzielt. Da unter längerfristiger Therapie mit Kinaseinhibitoren jedoch bei einem Großteil der Patienten eine Resistenzbildung auftritt, sind aktuelle klinische Therapiestudien auf die Suche nach geeigneten Kombinationspartnern unter Blockierung anderer Signalwege oder unter Aktivierung der T-Zell-vermittelten Immunantwort ausgerichtet. Der vorliegende Übersichtsartikel stellt sowohl die aktuell verfügbaren als auch die in der klinischen Testung befindlichen zukünftigen Optionen der zielgerichteten Therapie des Melanoms dar.

Using inbred BN and LE/Stm rats susceptible and resistant, respectively, to chemically induced cutaneous cyst development we were able to further unveil the genetic architecture of inherited multiple cyst formation. N-methyl-N-nitrosourea-treated (BN x LE) F2 intercross rats proved to develop differential numbers of cutaneous cysts, demonstrating epidermal, trichilemmal and verrucous keratinization types. Male rats developed significantly more cysts per animal than females. QTL interval mapping yielded three loci on rat chromosomes 1, 8 and 11 (Ccd1, Ccd2, Ccd3) linked to cutaneous cyst formation. Ccd2 proved to be homologous to the human TRICY1 region which could further be narrowed down by genome comparison in both species. It contains 11 genes with evidence of expression in human keratinocytes.

Blue nevi are common melanocytic tumors arising in the dermal layer of the skin. Similar to uveal melanomas, blue nevi frequently harbor GNAQ and GNA11 mutations. Recently, recurrent CYSLTR2 and PLCB4 mutations were identified in uveal melanomas not harboring GNAQ or GNA11 mutations. All four genes (GNAQ, GNA11, CYSLTR2, and PLCB4) code for proteins involved in the same signaling pathway, which is activated by mutations in these genes. Given the related functional consequences of these mutations and the known genetic similarities between uveal melanoma and blue nevi, we analyzed a cohort of blue nevi to investigate whether CYSLTR2 and PLCB4 mutations occur in tumors lacking GNAQ or GNA11 mutations (as in uveal melanoma). A targeted next-generation sequencing assay covering known activating mutations in GNAQ, GNA11, CYSLTR2, PLCB4, KIT, NRAS, and BRAF was applied to 103 blue nevi. As previously reported, most blue nevi were found to harbor activating mutations in GNAQ (59%, n = 61), followed by less frequent mutations in GNA11 (16%, n = 17). Additionally, one BRAF (1%) and three NRAS (3%) mutations were detected. In three tumors (3%) harboring none of the aforementioned gene alterations, CYSLTR2 mutations were identified. All three CYSLTR2 mutations were the same c.386T > A, L129Q mutation previously identified in uveal melanoma that has been shown to lead to increased receptor activation and signaling. In summary, our study identifies CYSLTR2 L129Q alterations as a previously unrecognized activating mutation in blue nevi, occuring in a mutually exclusive fashion with known GNAQ and GNA11 mutations. Similar to GNAQ and GNA11 mutations, CYSLTR2 mutations, when present, are likely defining pathogenetic events in blue nevi.

IntroductionMost smokers start smoking during their early adolescence, often with the idea that smoking is glamorous; the dramatic health consequences are too far in the future to fathom. We recently designed and tested an intervention that takes advantage of the broad availability of mobile phones as well as adolescents’ interest in their appearance. A free photoageing mobile app (Smokerface) was implemented by medical students in secondary schools via a novel method called mirroring. The pupils’ altered three-dimensional selfies on tablets were ‘mirrored’ via a projector in front of their whole grade. This is the first randomised trial to measure the effectiveness of the mirroring approach on smoking behaviour in secondary schools.Methods and analysisThe mirroring intervention, which lasts 45 min, is implemented by Brazilian medical students in at least 35 secondary school classes with 21 participants each (at least 35 classes with 21 participants for control) in February 2018 in the city of Itauna, Brazil. External block randomisation via computer is performed on the class level with a 1:1 allocation. In addition to sociodemographic data, smoking behaviour is measured via a paper–pencil questionnaire before, 3 and 6 months postintervention plus a random carbon monoxide breathing test at baseline and end line. The primary outcome is cigarette smoking in the past week at 6 months follow-up. Smoking behaviour (smoking onset, quitting) and effects on the different genders are studied as secondary outcomes. Analysis is by intention to treat.Ethics and disseminationEthical approval is obtained from the ethics committee of the University of Itauna in Brazil. Results will be disseminated at conferences, in peer-reviewed journals, throughout the Education Against Tobacco network social media channels and on our websites.Trial registration numberNCT03178227.

// Ioana Cosgarea 1 , Selma Ugurel 1 , Antje Sucker 1 , Elisabeth Livingstone 1 , Lisa Zimmer 1 , Mirjana Ziemer 2 , Jochen Utikal 3 , Peter Mohr 4 , Christiane Pfeiffer 5 , Claudia Pfohler 6 , Uwe Hillen 1 , Susanne Horn 1 , Dirk Schadendorf 1 , Klaus G. Griewank 1, * and Alexander Roesch 1, * 1 Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), University of Duisburg-Essen, Duisburg/Essen, Germany 2 Department of Dermatology, Venereology and Allergology, University Hospital Leipzig, Germany 3 Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany 4 Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude, Germany 5 Department of Dermatology, Klinikum Augsburg, Augsburg, Germany 6 Department of Dermatology, Saarland University Medical School, Homburg/Saar, Germany * These authors have contributed equally to this work Correspondence to: Klaus G. Griewank, email: klaus.griewank@uk-essen.de Alexander Roesch, email: alexander.roesch@uk-essen.de Keywords: mucosal melanoma, NF1 , RAS , sequencing, melanoma Received: December 28, 2016 Accepted: February 15, 2017 Published: March 24, 2017 ABSTRACT Purpose: Mucosal melanoma represents ~1% of all melanomas, frequently having a poor prognosis due to diagnosis at a late stage of disease. Mucosal melanoma differs from cutaneous melanoma not only in terms of poorer clinical outcome but also on the molecular level having e.g. less BRAF and more frequent KIT mutations than cutaneous melanomas. For the majority of mucosal melanomas oncogenic driver mutations remain unknown. Experimental Design and Results: In our study, 75 tumor tissues from patients diagnosed with mucosal melanoma were analyzed, applying a targeted next generation sequencing panel covering 29 known recurrently mutated genes in melanoma. NF1 and RAS mutations were identified as the most frequently mutated genes occurring in 18.3% and 16.9% of samples, respectively. Mutations in BRAF were identified in 8.4% and KIT in 7.0% of tumor samples. Conclusions: Our study identifies NF1 as the most frequently occurring driver mutation in mucosal melanoma. RAS alterations, consisting of NRAS and KRAS mutations, were the second most frequent mutation type. BRAF and KIT mutations were rare with frequencies below 10% each. Our data indicate that in mucosal melanomas RAS / NF1 alterations are frequent, implying a significant pathogenetic role for MAPK and potentially PI3K pathway activation in these tumors.

The majority of human tumours can be easily and correctly diagnosed based on clinical information and pathological assessment. In some cases however, correct diagnosis can prove difficult. In such cases, molecular approaches can be of significant diagnostic value. In recent years, the understanding of genetic alterations has greatly increased. In cutaneous melanoma, it is now well recognised, that 70-80% of tumours harbour BRAF and NRAS mutations. These mutations never occur in uveal melanoma. On the other hand activating GNAQ and GNA11 mutations are found in ∼90% of uveal melanomas, and are exceptionally rare in other melanomas (

We have previously demonstrated an impact of the BRAF inhibitor vemurafenib on patient lymphocyte counts. In the current study, the extent to which concomitant use of corticosteroids in BRAF inhibitor treated patients affects lymphocyte counts and predisposes to infection was investigated. A cohort of 102 patients receiving either the selective BRAF inhibitor vemurafenib or dabrafenib was analyzed. The amount of patients receiving either medication with or without systemic corticosteroids (dexamethasone) was determined and lymphocyte counts before and under therapy assessed. Additionally, the number and severity of infections occurring in these groups was analyzed. Vemurafenib treatment led to a considerable decrease in lymphocyte cell counts, with 62.3% of patients having lymphopenia. Dabrafenib treated patients only rarely demonstrated lymphopenia (12.5%). Dexamethasone co-administration further diminished lymphocyte counts. Lymphopenias were observed in 84.6% of patients receiving vemurafenib and dexamethasone. In our cohort, infections were noted in 9 patients, 4 of these were severe and 2 eventually fatal. All 9 cases with infections demonstrated lymphopenia, 8 of these had received dexamethasone and 7 of these a therapy with vemurafenib. Our findings demonstrate a significant lymphopenia in patients treated with the BRAF inhibitor vemurafenib, which is further augmented by dexamethasone and predisposes to infection. If validated in other studies, risk of infection should be considered when applying corticosteroids in combination with BRAF inhibitors, in particular vemurafenib.