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      Future perspectives in melanoma research. Meeting report from the “Melanoma Bridge. Napoli, December 2nd-4th 2012”

      meeting-report
      1 , , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 1 , 1 , 37 , 38
      Journal of Translational Medicine
      BioMed Central

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          Abstract

          Recent insights into the genetic and somatic aberrations have initiated a new era of rapidly evolving targeted and immune-based treatments for melanoma. After decades of unsuccessful attempts to finding a more effective cure in the treatment of melanoma now we have several drugs active in melanoma. The possibility to use these drugs in combination to improve responses to overcome the resistance, to potentiate the action of immune system with the new immunomodulating antibodies, and identification of biomarkers that can predict the response to a particular therapy represent new concepts and approaches in the clinical management of melanoma. The third “Melanoma Research: “A bridge from Naples to the World” meeting, shortened as “Bridge Melanoma Meeting” took place in Naples, December 2 to 4 th, 2012. The four topics of discussion at this meeting were: advances in molecular profiling and novel biomarkers, combination therapies, novel concepts toward integrating biomarkers and therapies into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage, and the knowledge gained from the biology of tumor microenvironment across different tumors as a bridge to impact on prognosis and response to therapy in melanoma. This international congress gathered more than 30 international faculty members who in an interactive atmosphere which stimulated discussion and exchange of their experience regarding the most recent advances in research and clinical management of melanoma patients.

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          Most cited references70

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          Final version of 2009 AJCC melanoma staging and classification.

          To revise the staging system for cutaneous melanoma on the basis of data from an expanded American Joint Committee on Cancer (AJCC) Melanoma Staging Database. The melanoma staging recommendations were made on the basis of a multivariate analysis of 30,946 patients with stages I, II, and III melanoma and 7,972 patients with stage IV melanoma to revise and clarify TNM classifications and stage grouping criteria. Findings and new definitions include the following: (1) in patients with localized melanoma, tumor thickness, mitotic rate (histologically defined as mitoses/mm(2)), and ulceration were the most dominant prognostic factors. (2) Mitotic rate replaces level of invasion as a primary criterion for defining T1b melanomas. (3) Among the 3,307 patients with regional metastases, components that defined the N category were the number of metastatic nodes, tumor burden, and ulceration of the primary melanoma. (4) For staging purposes, all patients with microscopic nodal metastases, regardless of extent of tumor burden, are classified as stage III. Micrometastases detected by immunohistochemistry are specifically included. (5) On the basis of a multivariate analysis of patients with distant metastases, the two dominant components in defining the M category continue to be the site of distant metastases (nonvisceral v lung v all other visceral metastatic sites) and an elevated serum lactate dehydrogenase level. Using an evidence-based approach, revisions to the AJCC melanoma staging system have been made that reflect our improved understanding of this disease. These revisions will be formally incorporated into the seventh edition (2009) of the AJCC Cancer Staging Manual and implemented by early 2010.
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            Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation.

            Activating B-RAF(V600E) (also known as BRAF) kinase mutations occur in ∼7% of human malignancies and ∼60% of melanomas. Early clinical experience with a novel class I RAF-selective inhibitor, PLX4032, demonstrated an unprecedented 80% anti-tumour response rate among patients with B-RAF(V600E)-positive melanomas, but acquired drug resistance frequently develops after initial responses. Hypotheses for mechanisms of acquired resistance to B-RAF inhibition include secondary mutations in B-RAF(V600E), MAPK reactivation, and activation of alternative survival pathways. Here we show that acquired resistance to PLX4032 develops by mutually exclusive PDGFRβ (also known as PDGFRB) upregulation or N-RAS (also known as NRAS) mutations but not through secondary mutations in B-RAF(V600E). We used PLX4032-resistant sub-lines artificially derived from B-RAF(V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumours and tumour-matched, short-term cultures from clinical trial patients. Induction of PDGFRβ RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sub-lines, patient-derived biopsies and short-term cultures. PDGFRβ-upregulated tumour cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRβ or N-RAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRβ or N-RAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, MAPK reactivation predicts MEK inhibitor sensitivity. Thus, melanomas escape B-RAF(V600E) targeting not through secondary B-RAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.
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              Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia.

              Vulvar intraepithelial neoplasia is a chronic disorder caused by high-risk types of human papillomavirus (HPV), most commonly HPV type 16 (HPV-16). Spontaneous regression occurs in less than 1.5% of patients, and the rate of recurrence after treatment is high. We investigated the immunogenicity and efficacy of a synthetic long-peptide vaccine in women with HPV-16-positive, high-grade vulvar intraepithelial neoplasia. Twenty women with HPV-16-positive, grade 3 vulvar intraepithelial neoplasia were vaccinated three or four times with a mix of long peptides from the HPV-16 viral oncoproteins E6 and E7 in incomplete Freund's adjuvant. The end points were clinical and HPV-16-specific T-cell responses. The most common adverse events were local swelling in 100% of the patients and fever in 64% of the patients; none of these events exceeded grade 2 of the Common Terminology Criteria for Adverse Events of the National Cancer Institute. At 3 months after the last vaccination, 12 of 20 patients (60%; 95% confidence interval [CI], 36 to 81) had clinical responses and reported relief of symptoms. Five women had complete regression of the lesions, and HPV-16 was no longer detectable in four of them. At 12 months of follow-up, 15 of 19 patients had clinical responses (79%; 95% CI, 54 to 94), with a complete response in 9 of 19 patients (47%; 95% CI, 24 to 71). The complete-response rate was maintained at 24 months of follow-up. All patients had vaccine-induced T-cell responses, and post hoc analyses suggested that patients with a complete response at 3 months had a significantly stronger interferon-gamma-associated proliferative CD4+ T-cell response and a broad response of CD8+ interferon-gamma T cells than did patients without a complete response. Clinical responses in women with HPV-16-positive, grade 3 vulvar intraepithelial neoplasia can be achieved by vaccination with a synthetic long-peptide vaccine against the HPV-16 oncoproteins E6 and E7. Complete responses appear to be correlated with induction of HPV-16-specific immunity. Copyright 2009 Massachusetts Medical Society.
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                Author and article information

                Contributors
                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central
                1479-5876
                2013
                3 June 2013
                : 11
                : 137
                Affiliations
                [1 ]Istituto Nazionale Tumori, Fondazione “G. Pascale”, Naples, Italy
                [2 ]Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MA, USA
                [3 ]Plastic and Reconstructive Surgery, Regional Melanoma Refferral Center – S.M. Annunziata Hospital, Florence, Italy
                [4 ]Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy
                [5 ]WHO Melanoma Program, Milan, Italy
                [6 ]Nodality Inc, South San Francisco, USA
                [7 ]Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
                [8 ]Cancer Institute Gustave Roussy, Villejuif, Paris-Sud, France
                [9 ]John Wayne Cancer Institute, Santa Monica, CA, USA
                [10 ]Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
                [11 ]Laboratory of Molecular and Tumor Immunology, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, OR, USA
                [12 ]Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, USA
                [13 ]University of Chicago, Chicago, IL, USA
                [14 ]INSERM, U872, Laboratory of Integrative Cancer Immunology, Paris F-75006, France
                [15 ]Université Paris Descartes, Paris, France
                [16 ]Centre de Recherche des Cordeliers, Université Pierre et Marie Curie Paris 6, Paris, France
                [17 ]Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
                [18 ]1st Department of Medicine, Medical School, University of Athens, Athens, Greece
                [19 ]Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, CA, USA
                [20 ]Rush University, Chicago, IL, USA
                [21 ]Royal Marsden NHS Foundation Trust, London, UK
                [22 ]Dermatology/Medicine, UCLA Geffen School of Medicine and Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
                [23 ]Humanitas Clinical and Research Institute, Rozzano, Italy
                [24 ]Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, University of Washington, Seattle, WA, USA
                [25 ]Leiden University Medical Center and ISA Pharmaceuticals, Leiden, The Netherlands
                [26 ]Peter MacCallum Cancer Centre, East Melbourne, Australia
                [27 ]Unit of Cancer Genetics, Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy
                [28 ]Vanderbilt University Medical Center, Nashville, TN, USA
                [29 ]Tumor Immunology Program, Jonsson Comprehensive Cancer Center (JCCC), David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA
                [30 ]Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany
                [31 ]Vanderbilt-Ingram Comprehensive Cancer Center, Nashville, TN, USA
                [32 ]Global Early Clinical Development, Clinical Immunotherapeutics, Immunotherapeutics, GlaxoSmithKline Vaccines, Rixensart, Belgium
                [33 ]University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
                [34 ]Cancer and Inflammation Program, Center for Cancer Research, NCI, NIH, Frederick, MD, USA
                [35 ]Institute of Applied Molecular Medicine (IMMA), CEU-San Pablo University and HM-Hospitals School of Medicine, Boadilla del Monte, 28668, Madrid, Spain
                [36 ]Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Center for Human Immunology (CHI), NIH, Bethesda, MD, USA
                [37 ]Sidra Medical and Research Centre, Doha, Qatar
                [38 ]Cancer Diagnosis Program. NCI, NIH, Bethesda, MD, USA
                Article
                1479-5876-11-137
                10.1186/1479-5876-11-137
                3681569
                23731854
                b4951f8c-826e-4634-84a9-4308a204ddb1
                Copyright ©2013 Ascierto et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 May 2013
                : 19 May 2013
                Categories
                Meeting Report

                Medicine
                Medicine

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