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Turajlic S.,Institute of Cancer Research | Furney S.J.,Institute of Cancer Research | Lambros M.B.,Institute of Cancer Research | Mitsopoulos C.,Institute of Cancer Research | And 12 more authors.
Genome Research | Year: 2012

Next generation sequencing has enabled systematic discovery of mutational spectra in cancer samples. Here, we used whole genome sequencing to characterize somatic mutations and structural variation in a primary acral melanoma and its lymph node metastasis. Our data show that the somatic mutational rates in this acral melanoma sample pair were more comparable to the rates reported in cancer genomes not associated with mutagenic exposure than in the genome of a melanoma cell line or the transcriptome of melanoma short-term cultures. Despite the perception that acral skin is sunprotected, the dominant mutational signature in these samples is compatible with damage due to ultraviolet light exposure. A nonsense mutation in ERCC5 discovered in both the primary and metastatic tumors could also have contributed to the mutational signature through accumulation of unrepaired dipyrimidine lesions. However, evidence of transcription-coupled repair was suggested by the lower mutational rate in the transcribed regions and expressed genes. The primary and the metastasis are highly similar at the level of global gene copy number alterations, loss of heterozygosity and single nucleotide variation (SNV). Furthermore, the majority of the SNVs in the primary tumor were propagated in the metastasis and one nonsynonymous coding SNV and one splice site mutation appeared to arise de novo in the metastatic lesion. © 2012 by Cold Spring Harbor Laboratory Press.

Sznol M.,Melanoma Unit
Seminars in Oncology | Year: 2012

Antibodies targeting ligandreceptor interactions that control activation and function of immune cell subsets such as dendritic cells (DCs) and in particular T cells have shown substantial promise for the treatment of unresectable or metastatic melanoma. The furthest in development, the antagonist antiCTLA-4 antibodies, which block a key negative regulator of T-cell activation, have been shown to produce durable clinical responses in a small subset of patients. One of these antibodies, ipilimumab, also prolonged overall survival in two randomized phase III studies, leading to regulatory approval for marketing by the US Food and Drug Administration (FDA). Consistent with its mechanism of action, the major adverse events from antiCTLA4 stem from immune-mediated inflammatory reactions. Paradigms for the administration of antiCTLA-4 and newer immunomodulatory agents have evolved to effectively manage the adverse events and also to consider unique patterns and kinetics of tumor response. Early clinical studies of another antagonist antibody, which blocks the co-inhibitory receptor PD-1 on activated T cells, also are showing promising activity in metastatic melanoma. The clinical efficacy of cancer vaccines, which in broad terms also includes intratumorally administered agents designed to increase tumor immunogenicity, is being investigated in ongoing phase III trials, and various new agents are in earlier development, including newer cytokines and T-cell or DC co-stimulatory antibodies, some of which have already demonstrated clinical activity in advanced disease. Current data suggest that focusing development on agents countering immune suppression in the tumor microenvironment or blocking regulatory checkpoints to T-cell activation may have the greatest clinical yield. Combinations of immunomodulatory agents also may improve clinical activity, although possibly at a cost of greater toxicity. A major challenge for the field will be to develop predictive biomarkers of response, and to identify mechanisms of resistance to existing agents that can be addressed in subsequent clinical trials. © 2012 Elsevier Inc.

Goulart J.M.,Sloan Kettering Cancer Center | Malvehy J.,Melanoma Unit | Puig S.,Melanoma Unit | Marghoob A.A.,Sloan Kettering Cancer Center
Archives of Dermatology | Year: 2011

Background: Education for patients on the technique of skin self-examination is important for improving the rate of early detection of melanoma. Strategies to improve skills in skin self-examination include the use of mnemonics to facilitate the recognition of melanoma features and photography to assist in the detection of change. Observation: We describe 2 patients who used dermoscopy on their own initiative to help identify suspicious pigmented lesions during skin self-examination. Conclusions: Dermoscopy has not yet been evaluated for patient use. We were intrigued by this concept and suggest that dermoscopy, with appropriate training, may improve the ability for early detection of melanoma in skin self-examination for select patients. ©2011 American Medical Association. All rights reserved.

Puig S.,Melanoma Unit | Malvehy J.,Melanoma Unit
Dermatologic Clinics | Year: 2013

Early recognition is the most effective intervention to improve melanoma mortality. Early diagnosis of melanoma in atypical mole syndrome patients, however, may be challenging. Skin self-examination and periodic physician-based total-body skin examinations are recommended in atypical mole patients but dermoscopy, total-body photography, and digital dermatoscopy have been proved to improve accuracy in early detection of melanoma in these high-risk patients. Digital follow-up in atypical mole syndrome patients allows detection of new lesions and changes in preexisting lesions. © 2013.

Spain L.,Melanoma Unit | Larkin J.,Melanoma Unit
Expert Opinion on Biological Therapy | Year: 2016

Introduction: The use of immune checkpoint inhibitors for the treatment of advanced melanoma has evolved beyond monotherapies such as ipilimumab and nivolumab to combination strategies involving both. This combination approach results in response rates around 60% and superior progression-free survival compared with ipilimumab monotherapy (median 11.5 versus 2.9 months).Areas covered: A comprehensive literature search was undertaken including search terms of ipilimumab and nivolumab and combination immune checkpoint therapy. Relevant information contained in abstracts and conference presentations was included. This article summarizes the mechanism of action, efficacy and safety of combination ipilimumab and nivolumab across Phase I, II and III clinical trials. It also describes the place of combination therapy in the current market of advanced melanoma treatment options.Expert Opinion: Efficacy for the combination approach is seen across a wide array of subgroups and occurs regardless of BRAF mutation status. Counterbalancing the apparent advantages, combination ipilimumab with nivolumab is associated with a high rate (55%) of grade 3/4 adverse events leading to discontinuation in a third of those treated. Most of these are manageable and do not appear to compromise durability of response. Overall survival information is currently immature but appears promising. © 2016 Taylor & Francis.

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