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Melanoma: HELP
Articles by Giuseppe Palmieri
Based on 53 articles published since 2008
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Between 2008 and 2019, Giuseppe Palmieri wrote the following 53 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Editorial The role of BRAF V600 mutation in melanoma. 2012

Ascierto, Paolo A / Kirkwood, John M / Grob, Jean-Jacques / Simeone, Ester / Grimaldi, Antonio M / Maio, Michele / Palmieri, Giuseppe / Testori, Alessandro / Marincola, Francesco M / Mozzillo, Nicola. ·Department of Melanoma, Istituto Nazionale Tumori Fondazione G, Pascale, Naples, Italy. paolo.ascierto@gmail.com ·J Transl Med · Pubmed #22554099.

ABSTRACT: BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50 % of melanomas harbors activating BRAF mutations (over 90 % V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naïve patients (BRIM-3). The study results showed a relative reduction of 63 % in risk of death and 74 % in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas carrying the V600K mutation. In 2011, both FDA and EMA therefore approved vemurafenib for metastatic melanoma carrying BRAFV600 mutations. Some findings suggest that continuation of vemurafenib treatment is potentially beneficial after local therapy in a subset of patients with disease progression (PD). Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA-4 inhibitor mAb ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors.

2 Review Vitamin D in melanoma: Controversies and potential role in combination with immune check-point inhibitors. 2018

Stucci, Luigia Stefania / D'Oronzo, Stella / Tucci, Marco / Macerollo, Antonella / Ribero, Simone / Spagnolo, Francesco / Marra, Elena / Picasso, Virginia / Orgiano, Laura / Marconcini, Riccardo / De Rosa, Francesco / Di Guardo, Lorenza / Galli, Giulia / Gandini, Sara / Palmirotta, Raffaele / Palmieri, Giuseppe / Queirolo, Paola / Silvestris, Francesco / Anonymous4700950. ·Medical Oncology Unit, Department of Biomedical Sciences and Human Oncology, University of Bari 'Aldo Moro', Italy. · Medical Oncology Unit, Department of Biomedical Sciences and Human Oncology, University of Bari 'Aldo Moro', Italy. Electronic address: stella.doronzo@uniba.it. · Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, United Kingdom. · Department of Medical Sciences Section of Dermatology, University of Turin, Italy. · Department of Medical Oncology , Ospedale Policlinico San Martino, Genova, Italy. · Department of Medical Oncology, University of Cagliari, Cagliari, Italy. · Department of Oncology, Azienda Ospedaliero-Universitaria Pisana and University of Pisa, Istituto Toscano Tumori, Santa Chiara Hospital, Pisa, Italy. · Immunotherapy-Cell Therapy and Biobank Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. · Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy. · Unit of Cancer Genetics, ICB-CNR, Sassari, Italy. ·Cancer Treat Rev · Pubmed #29864718.

ABSTRACT: The role of vitamin D in melanoma is still controversial. Although several Authors described a correlation between vitamin D deficiency and poor survival in metastatic melanoma patients, clinical trials exploring the effects of vitamin D supplementation in this clinical setting were mostly inconclusive. However, recent evidence suggests that vitamin D exerts both anti-proliferative effects on tumor cells and immune-modulating activities, that have been widely explored in auto-immune disorders. On the one hand, vitamin D has been shown to inhibit T-helper17 lymphocytes, notoriously involved in the pathogenesis of immune-related adverse events (iAEs) which complicate immune-checkpoint inhibitor (ICI) treatment. On the other hand, vitamin D up-regulates PDL-1 expression on both epithelial and immune cells, suggesting a synergic effect in combination with ICIs, for which further investigation is needed.

3 Review Vitamin D status and risk for malignant cutaneous melanoma: recent advances. 2017

Ombra, Maria N / Paliogiannis, Panagiotis / Doneddu, Valentina / Sini, Maria C / Colombino, Maria / Rozzo, Carla / Stanganelli, Ignazio / Tanda, Francesco / Cossu, Antonio / Palmieri, Giuseppe. ·aInstitute of Food Sciences, National Research Council (CNR), Avellino bDepartment of Surgical, Microsurgical and Medical Sciences, University of Sassari cInstitute of Biomolecular Chemistry, National Research Council (CNR), Cancer Genetics Unit, Sassari dRomagna Scientific Institute for the Study and Cure of Tumors, Skin Cancer Unit, Meldola, Italy. ·Eur J Cancer Prev · Pubmed #28125434.

ABSTRACT: Cutaneous malignant melanoma, whose incidence is increasing steadily worldwide, is the result of complex interactions between individual genetic factors and environmental risk factors. Ultraviolet radiation represents the most important environmental risk factor for the development of skin cancers, including melanoma. Sun exposure and early sunburn during childhood are the principal causes of cutaneous melanoma insurgence in adults, with double the risk relative to a nonexposed population. Consequently, ultraviolet protection has long been recognized as an important measure to prevent such a malignancy. Biological and epidemiological data suggest that vitamin D status could affect the risk of cancer and play a role in cancer prevention by exerting antiproliferative effects. Solar radiations are critical for vitamin D synthesis in humans; however, uncontrolled and intensive sun exposure is dangerous to skin health and may contribute toward the development of cutaneous malignant melanoma. An optimum balance between sun protection and exposure is thus advocated. Additional research is required to confirm the preventive role of vitamin D in melanoma incidence or a positive influence on patient outcome.

4 Review NF-κB as potential target in the treatment of melanoma. 2012

Madonna, Gabriele / Ullman, Claudio Dansky / Gentilcore, Giusy / Palmieri, Giuseppe / Ascierto, Paolo Antonio. ·Unit of Medical Oncology and Innovative Therapy, Istituto Nazionale Tumori Fondazione, G, Pascale, Napoli, Italy. ·J Transl Med · Pubmed #22433222.

ABSTRACT: The RAS/MAP kinase pathway has attracted attention because activating mutations of the BRAF serine/threonine kinase was described in over 50% of melanomas. Very recently, selective and potent BRAF inhibitors have been developed. Several other signal transduction pathways have been found to be constitutively active or mutated in other subsets of melanoma tumors that are potentially targetable with new agents. Among these, NFκB is another pathway that melanoma tumors use to achieve survival, proliferation and resistance to apoptosis. Inhibition of NF-κB activation appears to be a very promising option for anti-cancer therapies.

5 Review Main roads to melanoma. 2009

Palmieri, Giuseppe / Capone, Mariaelena / Ascierto, Maria Libera / Gentilcore, Giusy / Stroncek, David F / Casula, Milena / Sini, Maria Cristina / Palla, Marco / Mozzillo, Nicola / Ascierto, Paolo A. ·Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche (CNR), Sassari, Italy. gpalmieri@yahoo.com ·J Transl Med · Pubmed #19828018.

ABSTRACT: The characterization of the molecular mechanisms involved in development and progression of melanoma could be helpful to identify the molecular profiles underlying aggressiveness, clinical behavior, and response to therapy as well as to better classify the subsets of melanoma patients with different prognosis and/or clinical outcome. Actually, some aspects regarding the main molecular changes responsible for the onset as well as the progression of melanoma toward a more aggressive phenotype have been described. Genes and molecules which control either cell proliferation, apoptosis, or cell senescence have been implicated. Here we provided an overview of the main molecular changes underlying the pathogenesis of melanoma. All evidence clearly indicates the existence of a complex molecular machinery that provides checks and balances in normal melanocytes. Progression from normal melanocytes to malignant metastatic cells in melanoma patients is the result of a combination of down- or up-regulation of various effectors acting on different molecular pathways.

6 Clinical Trial Phase III randomized study of fotemustine and dacarbazine versus dacarbazine with or without interferon-α in advanced malignant melanoma. 2013

Daponte, Antonio / Signoriello, Simona / Maiorino, Luigi / Massidda, Bruno / Simeone, Ester / Grimaldi, Antonio Maria / Caracò, Corrado / Palmieri, Giuseppe / Cossu, Antonio / Botti, Gerardo / Petrillo, Antonella / Lastoria, Secondo / Cavalcanti, Ernesta / Aprea, Pasquale / Mozzillo, Nicola / Gallo, Ciro / Comella, Giuseppe / Ascierto, Paolo Antonio / Anonymous230750. ·Department of Melanoma, Istituto Nazionale Tumori Fondazione Pascale, Via Mariano Semmola, 80131, Naples, Italy. ·J Transl Med · Pubmed #23402397.

ABSTRACT: BACKGROUND: The effect of the addition of fotemustine and/or interferon (IFN) to standard therapy with dacarbazine alone in patients with advanced malignant melanoma was investigated in a multicenter, randomized 2x2 factorial design trial. METHODS: A total of 260 patients were randomly assigned to one of four treatment groups: (A) fotemustine and dacarbazine repeated on 3-week cycle; (B) same treatment as (A) plus IFN-α2b three times per week; (C) dacarbazine alone repeated on 3-week cycle; (D) same treatment as (C) plus IFN-α2b three times per week. Two comparisons were planned to assess the efficacy of fotemustine (groups A+B vs. C+D) and IFN-α2b (groups A+C vs. B+D). RESULTS: Addition of fotemustine did not significantly improve overall survival (OS) (p=0.28) or progression-free survival (PFS) (p=0.55); Hazard ratio (HR) for OS was 0.93 (95% CI 0.71-1.21). Similarly, addition of IFN-α2b did not improve OS (p=0.68) or PFS (p=0.65); HR for OS was 0.92 (95% CI 0.70-1.20). Overall response rate was not improved by the addition of either fotemustine (p=0.87) or IFN-α2b (p=0.57). The combination of all three drugs resulted in the highest occurrence of adverse events. CONCLUSIONS: No significant improvement in outcomes were observed with the addition of either fotemustine or IFN-α2b to dacarbazine. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01359956.

7 Clinical Trial Regulatory T cell frequency in patients with melanoma with different disease stage and course, and modulating effects of high-dose interferon-alpha 2b treatment. 2010

Ascierto, Paolo A / Napolitano, Maria / Celentano, Egidio / Simeone, Ester / Gentilcore, Giusy / Daponte, Antonio / Capone, Mariaelena / Caracò, Corrado / Calemma, Rosa / Beneduce, Gerardo / Cerrone, Margherita / De Rosa, Vincenzo / Palmieri, Giuseppe / Castello, Giuseppe / Kirkwood, John M / Marincola, Francesco M / Mozzillo, Nicola. ·Unit of Medical Oncology and Innovative Therapy and Melanoma Cooperative Group, National Tumor Institute, Naples, Italy. paolo.ascierto@gmail.com ·J Transl Med · Pubmed #20712892.

ABSTRACT: BACKGROUND: High-dose interferon-alpha 2b (IFN-alpha 2b) is the only approved systemic therapy in the United States for the adjuvant treatment of melanoma. The study objective was to explore the immunomodulatory mechanism of action for IFN-alpha 2b by measuring serum regulatory T cell (Treg), serum transforming growth factor-beta (TGF-beta), interleukin (IL)-10, and autoantibody levels in patients with melanoma treated with the induction phase of the high-dose IFN-alpha 2b regimen. METHODS: Patients with melanoma received IFN-alpha 2b administered intravenously (20 MU/m2 each day from day 1 to day 5 for 4 consecutive weeks). Serum Treg levels were measured as whole lymphocytes in CD4+ cells using flow cytometry while TGF-beta, IL-10, and autoantibody levels were measured using enzyme-linked immunosorbent assays. RESULTS: Twenty-two patients with melanoma received IFN-alpha 2b treatment and were evaluated for Treg levels. Before treatment, Treg levels were significantly higher in patients with melanoma when compared with data from 20 healthy subjects (P = 0.001; Mann-Whitney test). Although a trend for reduction of Treg levels following IFN-α 2b treatment was observed (average decrease 0.29% per week), statistical significance was not achieved. Subgroup analyses indicated higher baseline Treg levels for stage III versus IV disease (P = 0.082), early recurrence versus no recurrence (P = 0.017), deceased versus surviving patients (P = 0.021), and preoperative neoadjuvant versus postoperative adjuvant treatment groups (not significant). No significant effects were observed on the levels of TGF-beta, IL-10, and autoantibodies in patients with melanoma treated with IFN-alpha 2b. CONCLUSIONS: Patients with melanoma in this study showed increased basal levels of Treg that may be relevant to their disease and its progression. Treg levels shifted in patients with melanoma treated with IFN-alpha 2b, although no firm conclusions regarding the role of Tregs as a marker of treatment response or outcome can be made at present.

8 Clinical Trial The role of spectrophotometry in the diagnosis of melanoma. 2010

Ascierto, Paolo A / Palla, Marco / Ayala, Fabrizio / De Michele, Ileana / Caracò, Corrado / Daponte, Antonio / Simeone, Ester / Mori, Stefano / Del Giudice, Maurizio / Satriano, Rocco A / Vozza, Antonio / Palmieri, Giuseppe / Mozzillo, Nicola. ·National Cancer Institute, Naples, Italy. paolo.ascierto@gmail.com ·BMC Dermatol · Pubmed #20707921.

ABSTRACT: BACKGROUND: Spectrophotometry (SPT) could represent a promising technique for the diagnosis of cutaneous melanoma (CM) at earlier stages of the disease. Starting from our experience, we further assessed the role of SPT in CM early detection. METHODS: During a health campaign for malignant melanoma at National Cancer Institute of Naples, we identified a subset of 54 lesions to be addressed to surgical excision and histological examination. Before surgery, all patients were investigated by clinical and epiluminescence microscopy (ELM) screenings; selected lesions underwent spectrophotometer analysis. For SPT, we used a video spectrophotometer imaging system (Spectroshade MHT S.p.A., Verona, Italy). RESULTS: Among the 54 patients harbouring cutaneous pigmented lesions, we performed comparison between results from the SPT screening and the histological diagnoses as well as evaluation of both sensitivity and specificity in detecting CM using either SPT or conventional approaches. For all pigmented lesions, agreement between histology and SPT classification was 57.4%. The sensitivity and specificity of SPT in detecting melanoma were 66.6% and 76.2%, respectively. CONCLUSIONS: Although SPT is still considered as a valuable diagnostic tool for CM, its low accuracy, sensitivity, and specificity represent the main hamper for the introduction of such a methodology in clinical practice. Dermoscopy remains the best diagnostic tool for the preoperative diagnosis of pigmented skin lesions.

9 Article Prognostic impact of regression in patients with primary cutaneous melanoma >1 mm in thickness. 2019

Ribero, Simone / Galli, Francesca / Osella-Abate, Simona / Bertero, Luca / Cattaneo, Laura / Merelli, Barbara / Tondini, Carlo / Ghilardi, Laura / De Giorgi, Vincenzo / Occelli, Marcella / Quaglino, Pietro / Cassoni, Paola / Palmieri, Giuseppe / Massi, Daniela / Mandala, Mario / Anonymous3041096. ·Section of Dermatology, Medical Sciences Department, University of Turin, Turin, Italy. · Methodology for Clinical Research Laboratory, Instituto di Ricovero e Cura a Carattere Scientifico, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. · Section of Surgical Pathology, Medical Sciences Department, University of Turin, Turin, Italy. · Unit of Pathology, Papa Giovanni XXIII Hospital, Bergamo, Italy. · Unit of Medical Oncology, Papa Giovanni XXIII Hospital, Bergamo, Italy. · Department of Dermatology, University of Florence, Florence, Italy. · Azienda Ospedaliera Santa Croce e Carle di Cuneo SC Oncologia, Cuneo, Italy. · Unit of Cancer Genetics, Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy. · Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy. · Unit of Medical Oncology, Papa Giovanni XXIII Hospital, Bergamo, Italy. Electronic address: mariomandala@tin.it. ·J Am Acad Dermatol · Pubmed #30447951.

ABSTRACT: BACKGROUND: The impact of histologic regression on sentinel lymph node biopsy (SLNB) status and on clinical outcome is uncertain. OBJECTIVE: To investigate whether and to what extent regression <75% is able to predict SLNB status and clinical outcome of patients with melanoma >1-mm thick. METHODS: The study included patients with diagnoses given at 4 centers of the Italian Melanoma Intergroup. Univariate and multivariate Cox proportional hazard models stratified by center were used to analyze the effect of regression on disease-free interval and melanoma-specific survival. RESULTS: Out of 1182 patients given primary cutaneous melanoma diagnoses during 1998-2015 with a Breslow thickness >1 mm, 954 (304 with and 650 without regression) were included in the analysis. The proportion of patients with a positive SLNB was lower in patients with regression than without (24.4% vs 31.6%, chi-squared test P = .0368). At multivariate analysis, no association was detected between regression and disease-free interval (hazard ratio 1.11, 95% confidence interval 0.85-1.46; P = .4509) or melanoma-specific survival (hazard ratio 1.05, 95% confidence interval 0.77-1.44; P = .7600). LIMITATION: Retrospective analysis. CONCLUSION: In our series, regression was not an independent prognostic factor in primary cutaneous melanoma patients with Breslow thickness >1 mm whereas it was associated with a lower incidence of SLNB positivity.

10 Article Effect of ABT-888 on the apoptosis, motility and invasiveness of BRAFi-resistant melanoma cells. 2018

Fratangelo, Federica / Camerlingo, Rosa / Carriero, Maria Vincenza / Pirozzi, Giuseppe / Palmieri, Giuseppe / Gentilcore, Giusy / Ragone, Concetta / Minopoli, Michele / Ascierto, Paolo Antonio / Motti, Maria Letizia. ·Istituto Nazionale Tumori -IRCCS- 'Fondazione G. Pascale', 80131 Naples, Italy. · Unit of Cancer Genetics, Institute of Biomolecular Chemistry, National Research Council, 07100 Sassari, Italy. ·Int J Oncol · Pubmed #29956724.

ABSTRACT: Melanoma is a molecularly heterogeneous disease with many genetic mutations and altered signaling pathways. Activating mutations in the BRAF oncogene are observed in approximately 50% of cutaneous melanomas and the use of BRAF inhibitor (BRAFi) compounds has been reported to improve the outcome of patients with BRAF-mutated metastatic melanoma. However, the majority of these patients develop resistance within 6-8 months following the initiation of BRAFi treatment. In this study, we examined the possible use of the poly(ADP-ribose) polymerase 1 (PARP1) inhibitor, ABT-888 (veliparib), as a novel molecule that may be successfully employed in the treatment of BRAFi-resistant melanoma cells. Sensitive and resistant to BRAFi dabrafenib A375 cells were exposed to increasing concentrations of ABT-888. Cell viability and apoptosis were assessed by MTT assay and Annexin V-FITC analysis, respectively. The cell migratory and invasive ability was investigated using the xCELLigence technology and Boyden chamber assays, respectively. ABT-888 was found to reduce cell viability and exhibited pro-apoptotic activity in melanoma cell lines, independently from the BRAF/NRAS mutation status, in a dose-dependent manner, with the maximal effect being reached in the 25-50 µM concentration range. Moreover, ABT-888 promoted apoptosis in both the sensitive and resistant A375 cells, suggesting that ABT-888 may be useful in the treatment of BRAFi-resistant subsets of melanoma cells. Finally, in accordance with the involvement of PARP1 in actin cytoskeletal machinery, we found that the cytoskeletal organization, motility and invasive capability of both the A375 and A375R cells decreased upon exposure to 5 µM ABT-888 for 24 h. On the whole, the findings of this study highlight the pivotal role of PARP1 in the migration and invasion of melanoma cells, suggesting that ABT-888 may indeed be effective, not only as a pro-apoptotic drug for use in the treatment of BRAFi-resistant melanoma cells, but also in suppressing their migratory and invasive activities.

11 Article Dermoscopy and confocal microscopy for metachronous multiple melanomas: morphological, clinical, and molecular correlations. 2018

Colombino, Maria / Paliogiannis, Panagiotis / Pagliarello, Calogero / Cossu, Antonio / Lissia, Amelia / Satta, Rosanna / Mazzoni, Laura / Magi, Serena / Sini, Maria Cristina / Manca, Antonella / Casula, Milena / Doneddu, Valentina / Palmieri, Giuseppe / Stanganelli, Ignazio. ·Unit of Cancer Genetics, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR), Traversa La Crucca 3, 07100, Sassari, Italy. · Experimental Pathology and Oncology, Department of Clinical and Experimental Medicine, University of Sassari, Via Padre Manzella 4, 07100, Sassari, Italy. · Dermatologic Unit, University of Parma, 43121 Parma, Italy. · Anatomic Pathology Unit, Department of Surgical, Microsurgical and Medical Sciences, University of Sassari, Via Matteotti 64, 07100, Sassari, Italy. · Dermatology Unit, Department of Clinical and Experimental Medicine, University of Sassari, V.le San Pietro 43, 07100, Sassari, Italy. · Skin Cancer Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, FC, Italy. · Experimental Pathology and Oncology, Department of Clinical and Experimental Medicine, University of Sassari, Via Padre Manzella 4, 07100, Sassari, Italy, Skin Cancer Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, FC, Italy. ·Eur J Dermatol · Pubmed #29180316.

ABSTRACT: Cutaneous melanoma is one of the most frequent malignancies of the skin in Caucasian populations. Patients who develop cutaneous melanoma are at increased risk of developing a second primary melanoma. The estimated incidence of multiple primary melanoma (MPM) ranges from 1.2% to 8.2% of cases, with a high preponderance of melanomas occurring metachronously. The aim of this study was to describe dermoscopic, microscopic, clinical, and molecular correlations between first and subsequent melanomas in patients with metachronous MPMs. Twenty-four paired melanomas from 12 MPM patients were evaluated for architectural characteristics based on dermoscopy and confocal microscopy, as well as for mutations in BRAF and NRAS genes by Sanger-based sequencing analysis. Specific scores used for classifying features of dermoscopy (global pattern; 7-point check list; ABCD Stolz score) and confocal microscopy (Segura and Pellacani) were compared with genetic and histological data. Consistency in dermoscopic patterns between the primary and subsequent cutaneous melanomas were observed in about two thirds of cases, whereas concordant features based on confocal microscopy were found in only about two fifths of cases. The majority of patients (7/12; 58%) presented consistent BRAF/NRAS mutation patterns between first and subsequent primary melanomas. A significant association between BRAF mutations and Pellacani score was evident. Similarities between the index melanoma and subsequent cutaneous melanomas were observed with regards to dermoscopic features and, to a much less extent, confocal microscopy findings. Our data further indicate that the Pellacani score may be used to predict BRAF mutations.

12 Article Clinicopathological predictors of recurrence in nodular and superficial spreading cutaneous melanoma: a multivariate analysis of 214 cases. 2017

Pizzichetta, Maria A / Massi, Daniela / Mandalà, Mario / Queirolo, Paola / Stanganelli, Ignazio / De Giorgi, Vincenzo / Ghigliotti, Giovanni / Cavicchini, Stefano / Quaglino, Pietro / Corradin, Maria T / Rubegni, Pietro / Alaibac, Mauro / Astorino, Stefano / Ayala, Fabrizio / Magi, Serena / Mazzoni, Laura / Manganoni, Maria Ausilia / Talamini, Renato / Serraino, Diego / Palmieri, Giuseppe / Anonymous1471021. ·Division of Oncology B, CRO Aviano National Cancer Institute, Via Franco Gallini 2, 33081, Aviano, Italy. pizzichetta@cro.it. · Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy. · Unit of Medical Oncology, Papa Giovanni XXIII Hospital, Bergamo, Italy. · Department of Medical Oncology, National Institute for Cancer Research, IRCCS San Martino, Genoa, Italy. · Skin Cancer Unit, Istituto Tumori Romagna (IRST), Meldola, Italy. · Department of Dermatology, University of Parma, Parma, Italy. · Department of Dermatology, University of Florence, Florence, Italy. · Clinic of Dermatology, IRCCS San Martino-IST, Genoa, Italy. · Department of Dermatology, Fondazione Ospedale Maggiore Policlinico IRCCS, Milan, Italy. · Dermatologic Clinic, Dept Medical Sciences, University of Torino, Turin, Italy. · Division of Dermatology, Pordenone Hospital, Pordenone, Italy. · Department of Dermatology, University of Siena, Siena, Italy. · Department of Dermatology, University of Padova, Padua, Italy. · Division of Dermatology, Celio Hospital, Rome, Italy. · National Cancer Institute, "Fondazione G. Pascale"-IRCCS, Naples, Italy. · Department of Dermatology, ASST degli Spedali Civili di Brescia, Brescia, Italy. · Unit of Epidemiology and Biostatistics, CRO Aviano National Cancer Institute, Aviano, Italy. · Unit of Cancer Genetics, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR), Sassari, Italy. ·J Transl Med · Pubmed #29115977.

ABSTRACT: BACKGROUND: Nodular melanoma (NM) accounts for most thick melanomas and because of their frequent association with ulceration, fast growth rate and high mitotic rate, contribute substantially to melanoma-related mortality. In a multicentric series of 214 primary melanomas including 96 NM and 118 superficial spreading melanoma (SSM), histopathological features were examined with the aim to identify clinicopathological predictors of recurrence. METHODS: All consecutive cases of histopathologically diagnosed primary invasive SSM and NM during the period 2005-2010, were retrieved from the 12 participating Italian Melanoma Intergroup (IMI) centers. Each center provided clinico-pathological data such as gender, age at diagnosis, anatomical site, histopathological conventional parameters, date of excision and first melanoma recurrence. RESULTS: Results showed that NM subtype was significantly associated with Breslow thickness (BT) at multivariate analysis: [BT 1.01-2 mm (OR 7.22; 95% CI 2.73-19.05), BT 2.01-4 mm (OR 7.04; 95% CI 2.54-19.56), and BT > 4 mm (OR 51.78; 95% CI 5.65-474.86) (p < 0.0001)]. Furthermore, mitotic rate (MR) was significantly correlated with NM histotype: [(MR 3-5 mitoses/mm CONCLUSIONS: We found that NM subtype was significantly associated with higher BT and MR but it was not a prognostic factor since it did not significantly correlate with melanoma recurrence rate. Conversely, increased BT and MR as well as SNLB positivity were significantly associated with a higher risk of melanoma recurrence.

13 Article Phenotype characterization of human melanoma cells resistant to dabrafenib. 2017

Cordaro, Fabiola Gilda / De Presbiteris, Anna Lisa / Camerlingo, Rosa / Mozzillo, Nicola / Pirozzi, Giuseppe / Cavalcanti, Ernesta / Manca, Antonella / Palmieri, Giuseppe / Cossu, Antonio / Ciliberto, Gennaro / Ascierto, Paolo A / Travali, Salvatore / Patriarca, Eduardo J / Caputo, Emilia. ·Institute of Genetics and Biophysics (IGB), A. Buzzati-Traverso, CNR, I-80131 Naples, Italy. · Istituto Nazionale Tumori Fondazione G. Pascale, I-80131 Naples, Italy. · Unit of Cancer Genetics, Institute of Biomolecular Chemistry, CNR, I-07100 Sassari, Italy. · Unit of Pathology, Hospital-University Health Unit (AOU), I-07100 Sassari, Italy. · Department of Biomedical and Biotechnological Sciences-BIOMETEC, University of Catania, I-95100 Catania, Italy. ·Oncol Rep · Pubmed #29048639.

ABSTRACT: In the present study, the phenotype of melanoma cells resistant to dabrafenib (a B-RAF inhibitor) was investigated, to shed more light on melanoma resistance to B-RAF inhibition. Melanoma cells resistant to dabrafenib were generated using 3 different cell lines, A375, 397 and 624.38, all carrying B-RAFV600E, and they were characterized by cytofluorometric analysis, Ion Torrent technology, immunofluorescence and biochemistry. All dabrafenib-resistant cells showed, in addition to a re-activation of MAPK signaling, morphological changes compared to their sensitive counterparts, accompanied by an increase in CD90 (mesenchymal marker) expression and a decrease in E-cadherin (epithelial marker) expression, suggesting an epithelial-to-mesenchymal-like phenotypic transition. However, melanoma cells with TGF-β1-induced epithelial-to-mesenchymal transition (EMT) were more sensitive to dabrafenib treatment compared to the sensitivity noted in the non-TGF‑β1‑induced EMT melanoma cells, suggesting that TGF-β1-induced EMT was not associated with dabrafenib resistance. Although dabrafenib-resistant cells exhibited increased cell motility and E-cadherin/vimentin reorganization, as expected in EMT, all of them showed unvaried E-cadherin mRNA and unchanged Snail protein levels, while Twist1 protein expression was decreased with the exception of A375 dabrafenib-resistant melanoma cells, where it was unaffected. These findings suggest a distinct active EMT-like process adopted by melanoma cells under drug exposure. Furthermore, dabrafenib-resistant cells exhibited stem cell-like features, with Oct4 translocation from the cytoplasm to peri-nuclear sites and nuclei, and increased CD20 expression. In conclusion, our data, in addition to confirming that resistance to dabrafenib is dependent on re-activation of MAPK signaling, suggest that this resistance is linked to a distinct active EMT-like process as well as stem-cell features adopted by melanoma cells.

14 Article Antitumoral effect of vanadium compounds in malignant melanoma cell lines. 2017

Rozzo, Carla / Sanna, Daniele / Garribba, Eugenio / Serra, Maria / Cantara, Alessio / Palmieri, Giuseppe / Pisano, Marina. ·Istituto CNR di Chimica Biomolecolare, Trav. La Crucca 3, I-07100 Sassari, Italy. · Dipartimento di Chimica e Farmacia, Università di Sassari, Via Vienna 2, I-07100 Sassari, Italy. · Istituto CNR di Chimica Biomolecolare, Trav. La Crucca 3, I-07100 Sassari, Italy. Electronic address: marina.pisano@icb.cnr.it. ·J Inorg Biochem · Pubmed #28558258.

ABSTRACT: In this study we evaluated the anticancer activity against malignant melanoma (MM) of four different vanadium species: the inorganic anion vanadate(V) (indicated with VN), and three oxidovanadium(IV) complexes, [V

15 Article Second primary melanoma on a patient undergoing vemurafenib therapy. A case report. 2017

Onnis, Giuliana / Palmieri, Giuseppe / Montesu, Maria Antonietta / Satta, Rosanna. ·Department of Surgical, Microsurgical and Medical Sciences, Dermatology Unit, University of Sassari, ICB-CNR, Sassari, Italy. · Unit of Cancer Genetics, ICB-CNR, Sassari, Italy. ·Int J Dermatol · Pubmed #28345133.

ABSTRACT: BACKGROUND: Several side effects have been reported during treatment with vemurafenib, including multiple benign lesions and, less frequently, atypical melanocytic proliferations and second primary melanomas. METHODS: A 46-year-old man undergoing vemurafenib therapy for metastatic malignant melanoma was clinically and dermoscopically monitored using total-body mapping. RESULTS: During BRAF inhibitor (BRAFi) treatment, the patient developed atypical melanocytic lesions and particularly secondary primary melanoma. CONCLUSIONS: Secondary melanomas are usually diagnosed during the early disease stage, and no case of advanced melanomas is reported in the literature, mostly due to careful surveillance in BRAFi-treated patients.

16 Article COX-2 expression positively correlates with PD-L1 expression in human melanoma cells. 2017

Botti, Gerardo / Fratangelo, Federica / Cerrone, Margherita / Liguori, Giuseppina / Cantile, Monica / Anniciello, Anna Maria / Scala, Stefania / D'Alterio, Crescenzo / Trimarco, Chiara / Ianaro, Angela / Cirino, Giuseppe / Caracò, Corrado / Colombino, Maria / Palmieri, Giuseppe / Pepe, Stefano / Ascierto, Paolo Antonio / Sabbatino, Francesco / Scognamiglio, Giosuè. ·Dipartimento di Patologia Diagnostica e di Laboratorio: SC di Anatomia Patologica e Citopatologia, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. · Struttura Complessa di Oncologia Medica e Terapie Innovative, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. · Genomica Funzionale, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. · Department of Pharmacy, University of Naples "Federico II", 80131, Naples, Italy. · Melanoma and Sarcoma Surgery Unit, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. · Unit of Cancer Genetics, Institute of Biomolecular Chemistry, National Research Council, 07100, Sassari, Italy. · Department of Medicine and Surgery, University of Salerno, Baronissi, 84081, Salerno, Italy. · Department of Medicine and Surgery, University of Salerno, Baronissi, 84081, Salerno, Italy. sabbatinof@gmail.com. · Dipartimento di Patologia Diagnostica e di Laboratorio: SC di Anatomia Patologica e Citopatologia, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. giosue.scognamiglio@istitutotumori.it. ·J Transl Med · Pubmed #28231855.

ABSTRACT: BACKGROUND: The resistance to PD-1/PD-L1 inhibitors for the treatment of melanoma have prompted investigators to implement novel clinical trials which combine immunotherapy with different treatment modalities. Moreover is also important to investigate the mechanisms which regulate the dynamic expression of PD-L1 on tumor cells and PD-1 on T cells in order to identify predictive biomarkers of response. COX-2 is currently investigated as a major player of tumor progression in several type of malignancies including melanoma. In the present study we investigated the potential relationship between COX-2 and PD-L1 expression in melanoma. METHODS: Tumor samples obtained from primary melanoma lesions and not matched lymph node metastases were analyzed for both PD-L1 and COX-2 expression by IHC analysis. Status of BRAF and NRAS mutations was analyzed by sequencing and PCR. Co-localization of PD-L1 and COX-2 expression was analyzed by double fluorescence staining. Lastly the BRAF RESULTS: BRAF CONCLUSIONS: COX-2 expression correlates with and modulates PD-L1 expression in melanoma cells. These findings have clinical relevance since they provide a rationale to implement novel clinical trials to test COX-2 inhibition as a potential treatment to prevent melanoma progression and immune evasion as well as to enhance the anti-tumor activity of PD-1/PD-L1 based immunotherapy for the treatment of melanoma patients with or without BRAF/NRAS mutations.

17 Article Epidemiology and genetic susceptibility of malignant melanoma in North Sardinia, Italy. 2017

Cossu, Antonio / Casula, Milena / Cesaraccio, Rosaria / Lissia, Amelia / Colombino, Maria / Sini, Maria C / Budroni, Mario / Tanda, Francesco / Paliogiannis, Panagiotis / Palmieri, Giuseppe. ·aUnit of Pathology, Azienda Ospedaliero Universitaria (AOU) bUnit of Cancer Genetics, Institute of Biomolecular Chemistry, CNR cSassari Cancer Registry, Azienda Sanitaria Locale (ASL) n. 1 dSurgical Pathology Unit, AOU Sassari, Sassari, Italy. ·Eur J Cancer Prev · Pubmed #26999380.

ABSTRACT: The aim of this report was to study the descriptive and genetic epidemiology of malignant melanoma in North Sardinia, Italy, in the period 1992-2011. Epidemiological data were obtained from the local tumor registry, which is part of the Italian Association for Tumor Registries. Among patients included in the North Sardinia tumor registry, 316 patients first evaluated for familial recurrence of melanoma were submitted to mutation analysis in CDKN2A and CDK4 genes. The overall number of cases registered was 532. The male-to-female ratio was 1 : 1 and the mean age was 56 years for men and 55 years for women. The standardized incidence rates were 4.9/100 000 and 4.4/100 000 and the standardized mortality rates were 1.7/100 000 and 1.3/100 000 for men and women, respectively. The relative 5-year survival was 77% for men and 79% for women. In our series, 24/316 (7.6%) patients had a familial occurrence of melanoma (presence of at least one additional family member affected). Among these, one variant (Gly23Asp), reported previously as a low-frequency disease-causing mutation, was detected by mutational screening in the p16 gene only. With the exception of polymorphisms, none of either the sporadic melanoma patients or healthy controls presented a germline mutation in candidate genes. An increase in incidence and a decrease in mortality rates of malignant melanoma were registered in North Sardinia, from 1992 to 2011, whereas survival was similar to that reported in recent international reports. The high-penetrance melanoma susceptibility genes (CDKN2A and CDK4) are not involved in predisposition to melanoma in North Sardinia.

18 Article Protein expression changes induced in a malignant melanoma cell line by the curcumin analogue compound D6. 2016

Pisano, Marina / Palomba, Antonio / Tanca, Alessandro / Pagnozzi, Daniela / Uzzau, Sergio / Addis, Maria Filippa / Dettori, Maria Antonietta / Fabbri, Davide / Palmieri, Giuseppe / Rozzo, Carla. ·Institute of Biomolecular Chemistry, National Research Council of Italy, Traversa la Crucca, 3, 07100, Sassari, Italy. · Proteomics Laboratory, Porto Conte Ricerche, Tramariglio, Alghero, Italy. · Biosistema Scrl, Sassari, Italy. · Institute of Biomolecular Chemistry, National Research Council of Italy, Traversa la Crucca, 3, 07100, Sassari, Italy. carla.rozzo@icb.cnr.it. ·BMC Cancer · Pubmed #27192978.

ABSTRACT: BACKGROUND: We have previously demonstrated that the hydroxylated biphenyl compound D6 (3E,3'E)-4,4'-(5,5',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-diyl)bis(but-3-en-2-one), a structural analogue of curcumin, exerts a strong antitumor activity on melanoma cells both in vitro and in vivo. Although the mechanism of action of D6 is yet to be clarified, this compound is thought to inhibit cancer cell growth by arresting the cell cycle in G2/M phase, and to induce apoptosis through the mitochondrial intrinsic pathway. To investigate the changes in protein expression induced by exposure of melanoma cells to D6, a differential proteomic study was carried out on D6-treated and untreated primary melanoma LB24Dagi cells. METHODS: Proteins were fractionated by SDS-PAGE and subjected to in gel digestion. The peptide mixtures were analyzed by liquid chromatography coupled with tandem mass spectrometry. Proteins were identified and quantified using database search and spectral counting. Proteomic data were finally uploaded into the Ingenuity Pathway Analysis software to find significantly modulated networks and pathways. RESULTS: Analysis of the differentially expressed protein profiles revealed the activation of a strong cellular stress response, with overexpression of several HSPs and stimulation of ubiquitin-proteasome pathways. These were accompanied by a decrease of protein synthesis, evidenced by downregulation of proteins involved in mRNA processing and translation. These findings are consistent with our previous results on gene expression profiling in melanoma cells treated with D6. CONCLUSIONS: Our findings confirm that the curcumin analogue D6 triggers a strong stress response in melanoma cells, turning down majority of cell functions and finally driving cells to apoptosis.

19 Article Antitumor Activity of BRAF Inhibitor and IFNα Combination in BRAF-Mutant Melanoma. 2016

Sabbatino, Francesco / Wang, Yangyang / Scognamiglio, Giosuè / Favoino, Elvira / Feldman, Steven A / Villani, Vincenzo / Flaherty, Keith T / Nota, Sjoerd / Giannarelli, Diana / Simeone, Ester / Anniciello, Anna M / Palmieri, Giuseppe / Pepe, Stefano / Botti, Gerardo / Ascierto, Paolo A / Ferrone, Cristina R / Ferrone, Soldano. · ·J Natl Cancer Inst · Pubmed #26851802.

ABSTRACT: BACKGROUND: BRAF(V600E)-mediated MAPK pathway activation is associated in melanoma cells with IFNAR1 downregulation. IFNAR1 regulates melanoma cell sensitivity to IFNα, a cytokine used for the adjuvant treatment of melanoma. These findings and the limited therapeutic efficacy of BRAF-I prompted us to examine whether the efficacy of IFNα therapy of BRAF(V600E) melanoma can be increased by its combination with BRAF-I. METHODS: BRAF/NRAS genotype, ERK activation, IFNAR1, and HLA class I expression were tested in 60 primary melanoma tumors from treatment-naive patients. The effect of BRAF-I on IFNAR1 expression was assessed in three melanoma cell lines and in four biopsies of BRAF(V600E) metastases. The antiproliferative, pro-apoptotic and immunomodulatory activity of BRAF-I and IFNα combination was tested in vitro and in vivo utilizing three melanoma cell lines, HLA class I-MA peptide complex-specific T-cells and immunodeficient mice (5 per group for survival and 10 per group for tumor growth inhibition). All statistical tests were two-sided. Differences were considered statistically significant when the P value was less than .05. RESULTS: The IFNAR1 level was statistically significantly (P < .001) lower in BRAF(V600E) primary melanoma tumors than in BRAF wild-type tumors. IFNAR1 downregulation was reversed by BRAF-I treatment in the three melanoma cell lines (P ≤ .02) and in three out of four metastases. The IFNAR1 level in the melanoma tumors analyzed was increased as early as 10 to 14 days following the beginning of the treatment. These changes were associated with: 1) an increased susceptibility in vitro of melanoma cells to the antiproliferative (P ≤ .04), pro-apoptotic (P ≤ .009) and immunomodulatory activity, including upregulation of HLA class I antigen APM component (P ≤ .04) and MA expression as well as recognition by cognate T-cells (P < .001), of BRAF-I and IFNα combination and 2) an increased survival (P < .001) and inhibition of tumor growth of melanoma cells (P < .001) in vivo by BRAF-I and IFNα combination. CONCLUSIONS: The described results provide a strong rationale for the clinical trials implemented in BRAF(V600E) melanoma patients with BRAF-I and IFNα combination.

20 Article Multiple primary melanomas (MPMs) and criteria for genetic assessment: MultiMEL, a multicenter study of the Italian Melanoma Intergroup. 2016

Bruno, William / Pastorino, Lorenza / Ghiorzo, Paola / Andreotti, Virginia / Martinuzzi, Claudia / Menin, Chiara / Elefanti, Lisa / Stagni, Camilla / Vecchiato, Antonella / Rodolfo, Monica / Maurichi, Andrea / Manoukian, Siranoush / De Giorgi, Vincenzo / Savarese, Imma / Gensini, Francesca / Borgognoni, Lorenzo / Testori, Alessandro / Spadola, Giuseppe / Mandalà, Mario / Imberti, Gianlorenzo / Savoia, Paola / Astrua, Chiara / Ronco, Anna Maria / Farnetti, Alessandra / Tibiletti, Maria Grazia / Lombardo, Maurizio / Palmieri, Giuseppe / Ayala, Fabrizio / Ascierto, Paolo / Ghigliotti, Giovanni / Muggianu, Marisa / Spagnolo, Francesco / Picasso, Virginia / Tanda, Enrica Teresa / Queirolo, Paola / Bianchi-Scarrà, Giovanna. ·Department of Internal Medicine, Medical Specialties and Surgical Science and Integrated Diagnostics, University of Genoa, Genoa, Italy; Genetics of Rare Cancers, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. · Department of Internal Medicine, Medical Specialties and Surgical Science and Integrated Diagnostics, University of Genoa, Genoa, Italy; Genetics of Rare Cancers, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. Electronic address: l.pastorino@unige.it. · Department of Internal Medicine, Medical Specialties and Surgical Science and Integrated Diagnostics, University of Genoa, Genoa, Italy. · Department of Internal Medicine, Medical Specialties and Surgical Science and Integrated Diagnostics, University of Genoa, Genoa, Italy; Department of Internal Medicine, Medical Specialties and Surgical Science and Integrated Diagnostics, University of Genoa, Genoa, Italy. · Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, Istituto Oncologico Veneto (IOV)-IRCCS, Padua, Italy. · Section of Oncology and Immunology, Department of Surgery, Oncology, and Gastroenterology, University of Padua, Padua, Italy. · Melanoma and Soft Tissue Sarcoma Unit, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy. · Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. · Melanoma and Sarcoma Surgery Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. · Medical Genetics Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. · Department of Dermatology, University of Florence, Florence, Italy. · Unit of Medical Genetics, Department of Biomedical Experimental and Clinical Sciences, University of Florence, Florence, Italy. · Plastic Surgery Unit, Regional Melanoma Referral Center, Santa Maria Annunziata Hospital, Florence, Italy. · Division of Dermatoncological Surgery, European Institute of Oncology, Milan, Italy. · Medical Oncology Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy. · Dermatology Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy. · Department of Medical Sciences, Dermatology Section, University of Turin, Turin, Italy. · Dermatoncological Surgery Unit, Presidio Sanitario Gradenigo, Turin, Italy. · Anatomopathology Unit, Università dell'Insubria, Ospedale di Circolo, Varese, Italy. · Dermatology Unit, Ospedale di Circolo, Varese, Italy. · Cancer Genetics Unit, Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy. · Department of Melanoma, National Cancer Institute Pascale Foundation, Naples, Italy. · Dermatology Unit, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. · Department of Plastic and Reconstructive Surgery, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. · Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera Universitaria (AOU) San Martino-Istituto Nazionale dei Tumori (IST) Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. ·J Am Acad Dermatol · Pubmed #26775776.

ABSTRACT: BACKGROUND: Multiple primary melanoma (MPM), in concert with a positive family history, is a predictor of cyclin-dependent kinase (CDK) inhibitor 2A (CDKN2A) germline mutations. A rule regarding the presence of either 2 or 3 or more cancer events (melanoma and pancreatic cancer) in low or high melanoma incidence populations, respectively, has been established to select patients for genetic referral. OBJECTIVE: We sought to determine the CDKN2A/CDK4/microphthalmia-associated transcription factor mutation rate among Italian patients with MPM to appropriately direct genetic counseling regardless of family history. METHODS: In all, 587 patients with MPM and an equal number with single primary melanomas and control subjects were consecutively enrolled at the participating centers and tested for CDKN2A, CDK4, and microphthalmia-associated transcription factor. RESULTS: CDKN2A germline mutations were found in 19% of patients with MPM versus 4.4% of patients with single primary melanoma. In familial MPM cases the mutation rate varied from 36.6% to 58.8%, whereas in sporadic MPM cases it varied from 8.2% to 17.6% in patients with 2 and 3 or more melanomas, respectively. The microphthalmia-associated transcription factor E318K mutation accounted for 3% of MPM cases altogether. LIMITATIONS: The study was hospital based, not population based. Rare novel susceptibility genes were not tested. CONCLUSION: Italian patients who developed 2 melanomas, even in situ, should be referred for genetic counseling even in the absence of family history.

21 Article Activating PIK3CA mutations coexist with BRAF or NRAS mutations in a limited fraction of melanomas. 2015

Manca, Antonella / Lissia, Amelia / Capone, Mariaelena / Ascierto, Paolo A / Botti, Gerardo / Caracò, Corrado / Stanganelli, Ignazio / Colombino, Maria / Sini, MariaCristina / Cossu, Antonio / Palmieri, Giuseppe. ·Institute of Biomolecular Chemistry, National Research Council (CNR), Traversa La Crucca 3 - Baldinca Li Punti, Sassari, 07100, Italy. gpalmieri@yahoo.com. ·J Transl Med · Pubmed #25627962.

ABSTRACT: BACKGROUND: Activated PI3K-AKT pathway may contribute to decrease sensitivity to inhibitors of key pathogenetic effectors (mutated BRAF, active NRAS or MEK) in melanoma. Functional alterations are deeply involved in PI3K-AKT activation, with a minimal role reported for mutations in PIK3CA, the catalytic subunit of the PI3K gene. We here assessed the prevalence of the coexistence of BRAF/NRAS and PIK3CA mutations in a series of melanoma samples. METHODS: A total of 245 tumor specimens (212 primary melanomas and 33 melanoma cell lines) was screened for mutations in BRAF, NRAS, and PIK3CA genes by automated direct sequencing. RESULTS: Overall, 110 (44.9%) samples carried mutations in BRAF, 26 (10.6%) in NRAS, and 24 (9.8%) in PIK3CA. All identified PIK3CA mutations have been reported to induce PI3K activation; those detected in cultured melanomas were investigated for their interference with the antiproliferative activity of the BRAF-mutant inhibitor vemurafenib. A reduced suppression in cell growth was observed in treated cells carrying both BRAF and PIK3CA mutations as compared with those presenting a mutated BRAF only. Among the analysed melanomas, 12/245 (4.9%) samples presented the coexistence of PIK3CA and BRAF/NRAS mutations. CONCLUSIONS: Our study further suggests that PIK3CA mutations account for a small fraction of PI3K pathway activation and have a limited impact in interfering with the BRAF/NRAS-driven growth in melanoma.

22 Article The immune-related role of BRAF in melanoma. 2015

Tomei, Sara / Bedognetti, Davide / De Giorgi, Valeria / Sommariva, Michele / Civini, Sara / Reinboth, Jennifer / Al Hashmi, Muna / Ascierto, Maria Libera / Liu, Qiuzhen / Ayotte, Ben D / Worschech, Andrea / Uccellini, Lorenzo / Ascierto, Paolo A / Stroncek, David / Palmieri, Giuseppe / Chouchane, Lotfi / Wang, Ena / Marincola, Francesco M. ·Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD 20892, USA; Department of Genetic Medicine, Weill Cornell Medical College in Qatar, PO Box 24144, Doha, Qatar; Sidra Medical and Research Center, P.O. Box 26999, Doha, Qatar. Electronic address: stomei@sidra.org. · Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD 20892, USA; Sidra Medical and Research Center, P.O. Box 26999, Doha, Qatar. · Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD 20892, USA. · Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD 20892, USA; Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy. · Cell Processing Section, Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD 20892, USA. · Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD 20892, USA; Department of Biochemistry, Biocenter, University of Wuerzburg, Wuerzburg 97074, Germany; Genelux Corporation, San Diego Science Center, San Diego 92109, USA. · Sidra Medical and Research Center, P.O. Box 26999, Doha, Qatar. · Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD 20892, USA; Center of Excellence for Biomedical Research (CEBR), University of Genoa, Italy. · Department of Biology, Northern Michigan University, Marquette, MI, USA. · Department of Genetic Medicine, Weill Cornell Medical College in Qatar, PO Box 24144, Doha, Qatar. · Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD 20892, USA; Institute of Infectious and Tropical Diseases, University of Milan, L. Sacco Hospital, Milan, Italy. · Istituto Nazionale Tumori Fondazione "G. Pascale", Via G. Semmola, Naples, Italy. · Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy. ·Mol Oncol · Pubmed #25174651.

ABSTRACT: BACKGROUND: The existence of a dichotomy between immunologically active and quiescent tumor phenotypes has been recently recognized in several types of cancer. The activation of a Th1 type of immune signature has been shown to confer better prognosis and likelihood to respond to immunotherapy. However, whether such dichotomy depends on the genetic make-up of individual cancers is not known yet. BRAF and NRAS mutations are commonly acquired during melanoma progression. Here we explored the role of BRAF and NRAS mutations in influencing the immune phenotype based on a classification previously identified by our group. METHODS: One-hundred-thirteen melanoma metastases underwent microarray analysis and BRAF and NRAS genotyping. Allele-specific PCR was also performed in order to exclude low-frequency mutations. RESULTS: Comparison between BRAF and NRAS mutant versus wild type samples identified mostly constituents or regulators of MAPK and related pathways. When testing gene lists discriminative of BRAF, NRAS and MAPK alterations, we found that 112 BRAF-specific transcripts were able to distinguish the two immune-related phenotypes already described in melanoma, with the poor phenotype associated mostly with BRAF mutation. Noteworthy, such association was stronger in samples displaying low BRAF mRNA expression. However, when testing NRAS mutations, we were not able to find the same association. CONCLUSION: This study suggests that BRAF mutation-related specific transcripts associate with a poor phenotype in melanoma and provide a nest for further investigation.

23 Article MC1R variants increased the risk of sporadic cutaneous melanoma in darker-pigmented Caucasians: a pooled-analysis from the M-SKIP project. 2015

Pasquali, Elena / García-Borrón, José C / Fargnoli, Maria Concetta / Gandini, Sara / Maisonneuve, Patrick / Bagnardi, Vincenzo / Specchia, Claudia / Liu, Fan / Kayser, Manfred / Nijsten, Tamar / Nagore, Eduardo / Kumar, Rajiv / Hansson, Johan / Kanetsky, Peter A / Ghiorzo, Paola / Debniak, Tadeusz / Branicki, Wojciech / Gruis, Nelleke A / Han, Jiali / Dwyer, Terry / Blizzard, Leigh / Landi, Maria Teresa / Palmieri, Giuseppe / Ribas, Gloria / Stratigos, Alexander / Council, M Laurin / Autier, Philippe / Little, Julian / Newton-Bishop, Julia / Sera, Francesco / Raimondi, Sara / Anonymous290797. ·Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy. ·Int J Cancer · Pubmed #24917043.

ABSTRACT: The MC1R gene is a key regulator of skin pigmentation. We aimed to evaluate the association between MC1R variants and the risk of sporadic cutaneous melanoma (CM) within the M-SKIP project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. Data included 5,160 cases and 12,119 controls from 17 studies. We calculated a summary odds ratio (SOR) for the association of each of the nine most studied MC1R variants and of variants combined with CM by using random-effects models. Stratified analysis by phenotypic characteristics were also performed. Melanoma risk increased with presence of any of the main MC1R variants: the SOR for each variant ranged from 1.47 (95%CI: 1.17-1.84) for V60L to 2.74 (1.53-4.89) for D84E. Carriers of any MC1R variant had a 66% higher risk of developing melanoma compared with wild-type subjects (SOR; 95%CI: 1.66; 1.41-1.96) and the risk attributable to MC1R variants was 28%. When taking into account phenotypic characteristics, we found that MC1R-associated melanoma risk increased only for darker-pigmented Caucasians: SOR (95%CI) was 3.14 (2.06-4.80) for subjects with no freckles, no red hair and skin Type III/IV. Our study documents the important role of all the main MC1R variants in sporadic CM and suggests that they have a direct effect on melanoma risk, independently on the phenotypic characteristics of carriers. This is of particular importance for assessing preventive strategies, which may be directed to darker-pigmented Caucasians with MC1R variants as well as to lightly pigmented, fair-skinned subjects.

24 Article AurkA inhibitors enhance the effects of B-RAF and MEK inhibitors in melanoma treatment. 2014

Caputo, Emilia / Miceli, Roberta / Motti, Maria Letizia / Taté, Rosarita / Fratangelo, Federica / Botti, Gerardo / Mozzillo, Nicola / Carriero, Maria Vincenza / Cavalcanti, Ernesta / Palmieri, Giuseppe / Ciliberto, Gennaro / Pirozzi, Giuseppe / Ascierto, Paolo Antonio. · ·J Transl Med · Pubmed #25074438.

ABSTRACT: BACKGROUND: Aurora kinase A (AurkA) is over-expressed in melanoma and its inhibition has been observed to limit tumor growth, suggesting a potential role in melanoma treatment. METHODS: A human melanoma cell line with the B-RAF (V600E) mutation (A375mel) was exposed to B-RAF inhibitor (GSK2118436), MEK inhibitor (GSK1120212) and AurkA inhibitor (MLN8054) as single agents or in various combinations (BRAF plus AurkA inhibitor, MEK plus AurkA inhibitor or triple combination BRAF plus MEK plus AurkA inhibitor). Cell proliferation was assessed using xCELLigence technology. Total protein extracts were examined for p53 and c-Myc protein expression by Western blot analysis. Drug anti-tumor effects were further assessed using a 3D-human melanoma skin reconstruction model, in which tissues were incubated with serum-free medium containing control, B-RAF plus MEK inhibitor, MEK plus AurkA inhibitor or the triple combination. RESULTS: AurkA inhibitor plus B-RAF inhibitor, AurkA inhibitor plus MEK inhibitor or triple combination had a markedly greater anti-proliferative effect on A375 (BRAFV600E) melanoma cells than single agents. In the 3D human skin model, the triple combination had a greater anti-tumor effect at the epidermal/dermal junction than control or either double combination. However, S-100 and Ki-67 positively stained spindle-shaped cells were detected in the dermal stratum, suggesting the presence of alive and proliferating melanoma cells. CONCLUSIONS: These findings provide new prospects for melanoma research, including combined B-RAF/AurkA inhibition for B-RAF mutated melanomas and MEK/AurkA inhibitor combination for patients without B-RAF mutations. Moreover, for the first time, we have shown that a B-RAF, MEK and AurkA inhibitor triple drug combination offers increased efficacy against melanoma cell growth and might be considered as a potential treatment strategy for enhancing clinical response in melanoma. However, although this triple drug combination was more effective at the epidermal/dermal junction, the suggested presence of alive and proliferating melanoma cells in the dermal stratum could result in drug resistance and disease recurrence. Molecular characterization of these dermal cells may be critical for the development of novel therapeutic strategies.

25 Article Discrepant alterations in main candidate genes among multiple primary melanomas. 2014

Colombino, Maria / Sini, MariaCristina / Lissia, Amelia / De Giorgi, Vincenzo / Stanganelli, Ignazio / Ayala, Fabrizio / Massi, Daniela / Rubino, Corrado / Manca, Antonella / Paliogiannis, Panagiotis / Rossari, Susanna / Magi, Serena / Mazzoni, Laura / Botti, Gerardo / Capone, Mariaelena / Palla, Marco / Ascierto, Paolo A / Cossu, Antonio / Palmieri, Giuseppe / Anonymous180796. ·Unit of Cancer Genetics, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR) - Traversa La Crucca 3, Baldinca Li Punti, 07100 Sassari, Italy. gpalmieri@yahoo.com. ·J Transl Med · Pubmed #24885594.

ABSTRACT: BACKGROUND: Alterations in key-regulator genes of disease pathogenesis (BRAF, cKIT, CyclinD1) have been evaluated in patients with multiple primary melanoma (MPM). METHODS: One hundred twelve MPM patients (96 cases with two primary melanomas, 15 with three, and 1 with four) were included into the study. Paired synchronous/asynchronous MPM tissues (N=229) were analyzed for BRAF mutations and cKIT/CyclynD1 gene amplifications. RESULTS: BRAF mutations were identified in 109/229 (48%) primary melanomas, whereas cKIT and CyclinD1 amplifications were observed in 10/216 (5%) and 29/214 (14%) tumor tissues, respectively. While frequency rates of BRAF mutations were quite identical across the different MPM lesions, a significant increase of cKIT (p<0.001) and CyclinD1 (p=0.002) amplification rates was observed between first and subsequent primary melanomas. Among the 107 patients with paired melanoma samples, 53 (49.5%) presented consistent alteration patterns between first and subsequent primary tumors. About one third (40/122; 32.8%) of subsequent melanomas presented a discrepant pattern of BRAF mutations as compared to incident primary tumors. CONCLUSIONS: The low consistency in somatic mutation patterns among MPM lesions from same patients provides further evidence that melanomagenesis is heterogeneous and different cell types may be involved. This may have implications in clinical practice due to the difficulties in molecularly classifying patients with discrepant primary melanomas.

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