Prenylation Inhibition-Induced Cell Death in Melanoma: Reduced Sensitivity in BRAF Mutant/PTEN Wild-Type Melanoma Cells.

While targeted therapy brought a new era in the treatment of BRAF mutant melanoma, therapeutic options for non-BRAF mutant cases are still limited. In order to explore the antitumor activity of prenylation inhibition we investigated the response to zoledronic acid treatment in thirteen human melanoma cell lines with known BRAF, NRAS and PTEN mutational status. Effect of zoledronic acid on proliferation, clonogenic potential, apoptosis and migration of melanoma cells as well as the activation of downstream elements of the RAS/RAF pathway were investigated in vitro with SRB, TUNEL and PARP cleavage assays and videomicroscopy and immunoblot measurements, respectively. Subcutaneous and spleen-to-liver colonization xenograft mouse models were used to evaluate the influence of zoledronic acid treatment on primary and disseminated tumor growth of melanoma cells in vivo. Zoledronic acid more efficiently decreased short-term in vitro viability in NRAS mutant cells when compared to BRAF mutant and BRAF/NRAS wild-type cells. In line with this finding, following treatment decreased activation of ribosomal protein S6 was found in NRAS mutant cells. Zoledronic acid demonstrated no significant synergism in cell viability inhibition or apoptosis induction with cisplatin or DTIC treatment in vitro. Importantly, zoledronic acid could inhibit clonogenic growth in the majority of melanoma cell lines except in the three BRAF mutant but PTEN wild-type melanoma lines. A similar pattern was observed in apoptosis induction experiments. In vivo zoledronic acid did not inhibit the subcutaneous growth or spleen-to-liver colonization of melanoma cells. Altogether our data demonstrates that prenylation inhibition may be a novel therapeutic approach in NRAS mutant melanoma. Nevertheless, we also demonstrated that therapeutic sensitivity might be influenced by the PTEN status of BRAF mutant melanoma cells. However, further investigations are needed to identify drugs that have appropriate pharmacological properties to efficiently target prenylation in melanoma cells

Melanoma incidence and mortality in Europe: new estimates, persistent disparities

Background Melanoma incidence and mortality in Europe are high but there are significant gaps in the epidemiological information available across the continent. Objectives With the aim of enhancing the planning of educational programmes for reducing the melanoma burden in Europe, we analysed the most recent incidence and mortality data for Europe with a new focus on the regional disparities of melanoma reporting. Methods GLOBOCAN 2008, the standard set of worldwide estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer for 2008, was used to provide the estimated age-standardized rates (world standard population) of melanoma incidence and mortality in European countries and regions. Results The estimated age-standardized incidence of melanoma (measured per 100 000 person-years) varies widely from 19 2 in Switzerland to 2 2 in Greece. The incidence rate of 4 3 of Central and Eastern Europe (CEE) is less than half of that of Western Europe. Melanoma mortality rates of 1 5 are similar in CEE and Western Europe, although rates vary with a high of 3 2 in Norway and a low of 0 9 in Greece. Over 20 000 deaths from melanoma were estimated in Europe in 2008, with CEE having the larg Conclusions The most recent estimates of melanoma incidence and mortality in Europe reveal sharp differences between European countries, possibly related to missed opportunities for early diagnosis and incomplete reporting of melanoma in Eastern Europe

The status of dermoscopy in Germany - results of the cross-sectional Pan-Euro-Dermoscopy Study.

BACKGROUND: Survey on the current status of dermoscopy in Germany. METHODS: In the context of a pan-European internet-based study (n = 7,480) conducted by the International Dermoscopy Society, 880 German dermatologists were asked to answer questions with respect to their level of training as well as their use and perceived benefit of dermoscopy. RESULTS: Seven hundred and sixty-two (86.6 %) participants practiced dermatology in a publicly funded health care setting; 98.4 % used a dermoscope in routine clinical practice. About 93 % (n = 814) stated to have had more than five years of experience in the use of dermoscopy. Dermoscopy was considered useful in the diagnosis of melanoma by 93.6 % (n = 824); for pigmented skin tumors, by 92.4 % (n = 813); in the follow-up of melanocytic lesions, by 88.6 % (n = 780); for non-pigmented lesions, by 71.4 % (n = 628), in the follow-up of non-melanocytic lesions, by 52.7 % (n = 464); and for inflammatory skin lesions, by 28.5 % (n = 251). Overall, 86.5 % (n = 761) of participants felt that - compared to naked-eye examination - dermoscopy increased the number of melanomas diagnosed; 77,7 % (n = 684) considered the number of unnecessary excisions of benign lesions to be decreased. Participants who personally felt that dermoscopy improved their ability to diagnose melanoma were significantly i) younger, ii) had been practicing dermatology for a shorter period of time, iii) were less commonly employed by an university-affiliated dermatology department, iv) were more frequently working in an office-based public health care setting, and v) had more frequently been trained in dermoscopy during their dermatology residency. CONCLUSIONS: The findings presented herein ought to be integrated into future residency and continuing medical education programs with the challenge to improve dermato-oncological care and to expand the diagnostic spectrum of dermoscopy to include inflammatory skin diseases

Euromelanoma: a dermatology-led European campaign against nonmelanoma skin cancer and cutaneous melanoma. Past, present and future

Euromelanoma is a dermatologist-led skin cancer prevention programme conducting an annual screening and public education campaign in over 20 European countries. Within its 10-year history, Euromelanoma has screened over 260,000 individuals across Europe, detecting a significant number of cutaneous melanomas and nonmelanoma skin cancers, identifying high-risk individuals for further surveillance and promoting awareness on the suspicious features of melanoma and the hazardous effects of ultraviolet exposure. In this review article, we summarize the history of the Euromelanoma campaign, present its organizational structure and discuss the results of the campaign in individual countries and on a European scale. Euromelanoma has had a significant impact on melanoma prevention and early diagnosis in participating countries and, despite many challenges, has positively influenced public health attitudes towards regular mole examination and the implementation of preventive measures against skin cancer