The inhibition of the mitogen-activated protein kinases signalling pathway through combined use of BRAF and MEK inhibitors (BRAFi+MEKi) represents an established therapeutic option in patients with BRAF-mutated, advanced melanoma. These efficient therapies are well tolerated with mostly moderate and reversible side effects and a discontinuation rate due to adverse events of 11.5%–15.7%. Median duration of therapy ranges between 8.8 and 11.7 months. Based on data from confirmatory trials, safety profiles of three BRAFi+MEKi combinations were reviewed, that is, dabrafenib plus trametinib, vemurafenib plus cobimetinib and encorafenib plus binimetinib. Many adverse events are class effects, such as cutaneous, gastrointestinal, ocular, cardiac and musculoskeletal events; some adverse events are substance associated. Fever (dabrafenib) and photosensitivity (vemurafenib) are the most common and clinically prominent examples. Other adverse events are less frequent and the association to one substance is less strong such as anaemia, facial paresis (encorafenib), neutropenia (dabrafenib), skin rash, QTc prolongation and increased liver function tests (vemurafenib). This narrative review provides recommendations for monitoring, adverse event evaluation and management focusing on the clinically relevant side effects of the three regimens.

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BackgroundOver the past two decades, there has been a rising trend in malignant melanoma incidence worldwide. In 2008, Germany introduced a nationwide skin cancer screening program starting at age 35. The aims of this study were to analyse the distribution of malignant melanoma tumour stages over time, as well as demographic and regional differences in stage distribution and survival of melanoma patients.MethodsPooled data from 61 895 malignant melanoma patients diagnosed between 2002 and 2011 and documented in 28 German population-based and hospital-based clinical cancer registries were analysed using descriptive methods, joinpoint regression, logistic regression and relative survival.ResultsThe number of annually documented cases increased by 53.2% between 2002 (N = 4 779) and 2011 (N = 7 320). There was a statistically significant continuous positive trend in the proportion of stage UICC I cases diagnosed between 2002 and 2011, compared to a negative trend for stage UICC II. No trends were found for stages UICC III and IV respectively. Age (OR 0.97, 95% CI 0.97–0.97), sex (OR 1.18, 95% CI 1.11–1.25), date of diagnosis (OR 1.05, 95% CI 1.04–1.06), ‘diagnosis during screening’ (OR 3.24, 95% CI 2.50–4.19) and place of residence (OR 1.23, 95% CI 1.16–1.30) had a statistically significant influence on the tumour stage at diagnosis. The overall 5-year relative survival for invasive cases was 83.4% (95% CI 82.8–83.9%).ConclusionsNo distinct changes in the distribution of malignant melanoma tumour stages among those aged 35 and older were seen that could be directly attributed to the introduction of skin cancer screening in 2008.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2963-0) contains supplementary material, which is available to authorized users.

Cellular phenotypes are established and controlled by complex and precisely orchestrated molecular networks. In cancer, mutations and dysregulations of multiple molecular factors perturb the regulation of these networks and lead to malignant transformation. High-throughput technologies are a valuable source of information to establish the complex molecular relationships behind the emergence of malignancy, but full exploitation of this massive amount of data requires bioinformatics tools that rely on network-based analyses. In this report we present the Virtual Melanoma Cell, an online tool developed to facilitate the mining and interpretation of high-throughput data on melanoma by biomedical researches. The platform is based on a comprehensive, manually generated and expert-validated regulatory map composed of signaling pathways important in malignant melanoma. The Virtual Melanoma Cell is a tool designed to accept, visualize and analyze user-generated datasets. It is available at: https://www.vcells.net/melanoma. To illustrate the utilization of the web platform and the regulatory map, we have analyzed a large publicly available dataset accounting for anti-PD1 immunotherapy treatment of malignant melanoma patients.

IntroductionSeveral kinase inhibitors (KI) bear the potential to act as radiosensitizers. Little is known of the radiosensitizing effects of a wide range of other KI like palbociclib, which is approved in ER+/HER2- metastatic breast cancer.MethodIn our study, we used healthy donor fibroblasts and breast cancer and skin cancer cells to investigate the influence of a concomitant KI + radiation therapy. Cell death and cell cycle distribution were studied by flow cytometry after Annexin-V/7-AAD and Hoechst staining. Cellular growth arrest was studied in colony-forming assays. Furthermore, we used C12-FDG staining (senescence) and mRNA expression analysis (qPCR) to clarify cellular mechanisms.ResultsThe CDK4/6 inhibitor palbociclib induced a cell cycle arrest in the G0/G1 phase. Cellular toxicity (cell death) was only slightly increased by palbociclib and not enhanced by additional radiotherapy. As the main outcome of the colony formation assays, we found that cellular growth arrest was induced by palbociclib and improved by radiotherapy in an additive manner. Noticeably, palbociclib treatment clearly induced senescence not only in breast cancer and partly in melanoma cells, but also in healthy fibroblasts. According to these findings, the downregulation of senescence-related FOXM1 might be an involved mechanism of the senescence-induction potential of palbociclib.ConclusionThe effect on cellular growth arrest of palbociclib and radiotherapy is additive. Palbociclib induces permanent G0/G1 cell cycle arrest by inducing senescence in fibroblasts, breast cancer, and melanoma cells. Direct cell death induction is only a minor secondary mechanism of action. Concomitant KI and radiotherapy is a strategy worth studying in clinical trials.