Rose Bengal - Phototoxicity versus Intrinsic Cytotoxicity

Question: Mutant BRAF inhibitors such as vemurafenib and dabrafenib have achieved unprecedented responses in the treatment of melanoma, but the benefits are often of limited duration. On the other hand, durable tumor repression can be achieved by a variety of immunological agents such as the anti-CTLA4 antibody ipilimumab (Yervoy) and antibodies against PD1 in a small proportion of melanoma patients. Combinations of BARF inhibitors and immunological agents are emerging as promising therapeutic approaches. However, the mechanism(s) responsible for the enhanced efficacy remains to be determined. Methods: Here we show that inhibition of BRAFV600E induces programmed necrosis of high immunogenicity in melanoma cells. Results: Although exposure of sensitive BRAFV600E melanoma cells to the BRAF inhibitor PLX4720 triggered strong activation of the caspase cascade, it appeared dispensable for induction of cell death. Instead, PLX4720-induced killing was characterized by early rupture of the cell membrane and release of intracellular contents, indicative of programmed necrosis. Strikingly, killing of sensitive cells by PLX4720 was associated with exposure of calreticulin, characteristic of immunogenic cell death. In contrast, PLX4720 did not cause calreticulin exposure in resistant BRAFV600E melanoma cells, supporting that immunogenicity of melanoma cells triggered by PLX4720 is the consequence of cell death. Indeed, PLX4720 stimulated IFN ® production by autologous lymphocytes in mixed lymphocyte tumor cell culture (MLTC) with sensitive BRAFV600E melanoma cells, but not those resistant to PLX4720 induced killing. Conclusion: Collectively, these results provide a strong rationale for combinations of mutant BRAF inhibitors and immunological agents in the treatment of melanoma, and suggest that induction of immunogenic cell death may be a useful biomarker for prediction of responses of mutant BRAF melanomas to such combinations.2 page(s

Differences in clinicopathological features and distribution of risk factors in italian melanoma patients.

No studies are available in the literature on the distribution of different melanoma features and risk factors in the Italian geographical areas. OBJECTIVE: To identify the differences in clinical-pathological features of melanoma, the distribution of risk factors and sun exposure in various Italian macro-areas. METHODS: Multicentric-observational study involving 1,472 melanoma cases (713 north, 345 centre, 414 south) from 26 referral centres belonging to the Italian Multidisciplinary Group for Melanoma. RESULTS: Melanoma patients in northern regions are younger, with thinner melanoma, multiple primaries, lower-intermediate phototype and higher counts of naevi with respect to southern patients; detection of a primary was mostly connected with a physician examination, while relatives were more involved in the south. Northern patients reported a more frequent use of sunbeds and occurrence of sunburns before melanoma despite sunscreen use and a lower sun exposure during the central hours of the day. CONCLUSIONS: The understanding of differences in risk factors distribution could represent the basis for tailored prevention programmes