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Melanoma: HELP
Articles by Giuseppe Palmieri
Based on 67 articles published since 2010
(Why 67 articles?)
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Between 2010 and 2020, Giuseppe Palmieri wrote the following 67 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Editorial What is changing in the adjuvant treatment of melanoma? 2017

Ascierto, Paolo A / Palmieri, Giuseppe / Gogas, Helen. ·Paolo A. Ascierto: Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Napoli, Italy. ·Oncotarget · Pubmed #29340009.

ABSTRACT: -- No abstract --

2 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.

3 Review New paradigm for stage III melanoma: from surgery to adjuvant treatment. 2019

Ascierto, Paolo Antonio / Borgognoni, Lorenzo / Botti, Gerardo / Guida, Michele / Marchetti, Paolo / Mocellin, Simone / Muto, Paolo / Palmieri, Giuseppe / Patuzzo, Roberto / Quaglino, Pietro / Stanganelli, Ignazio / Caracò, Corrado. ·Unit Melanoma, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Naples, Italy. paolo.ascierto@gmail.com. · Ospedale Santa Maria Annunziata and University of Florence, Florence, Italy. · Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Naples, Italy. · Unit Melanoma and Rare Tumors, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy. · Oncologia Medica B Policlinico Umberto I di Roma, Rome, Italy. · Surgical Oncology Unit, IOV-IRCCS of Padova and Dept. Surgery Oncology Gastroenterology, University of Padova, Padua, Italy. · Unit of Cancer Genetics, ICB-CNR, Sassari, Italy. · Research Director CNR, Italian Melanoma Intergroup (IMI), Unit of Cancer Genetics, Head Institute of Biomolecular Chemistry (ICB), National Research Council (CNR), Sassari, Italy. · IRCCS Fondazione Istituto Nazionale dei Tumori di Milano, Milan, Italy. · Dermatologic Clinic, Department of Medical Sciences, University of Turin Medical School, Turin, Italy. · Skin Cancer Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, FC, Italy. · University of Parma, Parma, Italy. ·J Transl Med · Pubmed #31412885.

ABSTRACT: BACKGROUND: Recently the 8th version of the American Joint Committee on Cancer (AJCC) classification has been introduced, and has attempted to define a more accurate and precise definition of prognosis in line with the major progresses in understanding the biology and pathogenesis of melanoma. This new staging system introduces major changes in the stage III staging system. Indeed, surgical practice is changing in stage III patients, since, according to recent evidence, there is no survival benefit in radical lymph node dissection following a positive sentinel lymph node dissection. Therefore, some patients currently staged IIIB-C after dissection could be downgraded to IIIA (as in the case of patients with metastatic non-sentinel lymph nodes) since many completion lymph node dissections will no longer be performed. Moreover, new and effective targeted and immune strategies are being introduced in the pharmacological armamentarium in the adjuvant setting, showing major efficacy. CONCLUSIONS: This article provides the authors' personal view on the above-mentioned topics.

4 Review Dietary compounds and cutaneous malignant melanoma: recent advances from a biological perspective. 2019

Ombra, Maria Neve / Paliogiannis, Panagiotis / Stucci, Luigia Stefania / Colombino, Maria / Casula, Milena / Sini, Maria Cristina / Manca, Antonella / Palomba, Grazia / Stanganelli, Ignazio / Mandalà, Mario / Gandini, Sara / Lissia, Amelia / Doneddu, Valentina / Cossu, Antonio / Palmieri, Giuseppe / Anonymous310992. ·1Institute of Food Sciences, National Research Council, Avellino, Italy. · 0000 0001 1940 4177 · grid.5326.2 · 2Department of Medical, Surgical and Experimental Sciences, University of Sassari, Viale San Pietro 43, 07100 Sassari, Italy. · 0000 0001 2097 9138 · grid.11450.31 · 3Department of Biomedical Sciences and Human Oncology, University of Bari 'Aldo Moro', Bari, Italy. · 0000 0001 0120 3326 · grid.7644.1 · 4Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy. · 5Istituto Scientifico Romagnolo per Studio e Cura Tumori (IRST-IRCCS), Meldola, Italy. · 0000 0004 1755 9177 · grid.419563.c · 6Medical Oncology, "Papa Giovanni XXIII" Hospital, Bergamo, Italy. · 0000 0004 1757 8431 · grid.460094.f · 7Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy. · 0000 0004 1757 0843 · grid.15667.33 ·Nutr Metab (Lond) · Pubmed #31139235.

ABSTRACT: Cutaneous malignant melanoma is a heterogeneous disease, being the consequence of specific genetic alterations along several molecular pathways. Despite the increased knowledge about the biology and pathogenesis of melanoma, the incidence has grown markedly worldwide, making it extremely important to develop preventive measures. The beneficial role of correct nutrition and of some natural dietary compounds in preventing malignant melanoma has been widely demonstrated. This led to numerous studies investigating the role of several dietary attitudes, patterns, and supplements in the prevention of melanoma, and ongoing research investigates their impact in the clinical management and outcomes of patients diagnosed with the disease. This article is an overview of recent scientific advances regarding specific dietary compounds and their impact on melanoma development and treatment.

5 Review Molecular Pathways in Melanomagenesis: What We Learned from Next-Generation Sequencing Approaches. 2018

Palmieri, Giuseppe / Colombino, Maria / Casula, Milena / Manca, Antonella / Mandalà, Mario / Cossu, Antonio / Anonymous6000961. ·Unit of Cancer Genetics, National Research Council (CNR), Institute of Biomolecular Chemistry (ICB), Traversa La Crucca 3, Baldinca Li Punti, 07100, Sassari, Italy. gpalmieri@yahoo.com. · Unit of Cancer Genetics, National Research Council (CNR), Institute of Biomolecular Chemistry (ICB), Traversa La Crucca 3, Baldinca Li Punti, 07100, Sassari, Italy. · PAPA GIOVANNI XXIII Cancer Center Hospital, Bergamo, Italy. · Institute of Pathology, Azienda Ospedaliero Universitaria (AOU), Sassari, Italy. ·Curr Oncol Rep · Pubmed #30218391.

ABSTRACT: PURPOSE OF REVIEW: Conventional clinico-pathological features in melanoma patients should be integrated with new molecular diagnostic, predictive, and prognostic factors coming from the expanding genomic profiles. Cutaneous melanoma (CM), even differing in biological behavior according to sun-exposure levels on the skin areas where it arises, is molecularly heterogeneous. The next-generation sequencing (NGS) approaches are providing data on mutation landscapes in driver genes that may account for distinct pathogenetic mechanisms and pathways. The purpose was to group and classify all somatic driver mutations observed in the main NGS-based studies. RECENT FINDINGS: Whole exome and whole genome sequencing approaches have provided data on spectrum and distribution of genetic and genomic alterations as well as allowed to discover new cancer genes underlying CM pathogenesis. After evaluating the mutational status in a cohort of 686 CM cases from the most representative NGS studies, three molecular CM subtypes were proposed: BRAF

6 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 / Anonymous2790950. ·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.

7 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.

8 Review Epidemiological and genetic factors underlying melanoma development in Italy. 2015

Palmieri, Giuseppe / Colombino, Maria / Casula, Milena / Budroni, Mario / Manca, Antonella / Sini, Maria Cristina / Lissia, Amelia / Stanganelli, Ignazio / Ascierto, Paolo A / Cossu, Antonio. ·Institute of Biomolecular Chemistry, National Research Council (CNR), Sassari, Italy. · Department of Pathology, Hospital-University Health Unit (AOU), Sassari, Italy. · Skin Cancer Unit, Istituto Scientifico Romagnolo Tumori (IRST), Meldola, Italy. · Istituto Nazionale Tumori (INT), Fondazione G. Pascale, Naples, Italy. ·Melanoma Manag · Pubmed #30190844.

ABSTRACT: Among human cancers, melanoma remains one of the malignancies with an ever-growing incidence in white populations. Recent advances in biological and immunological therapeutic approaches as well as increased efforts for secondary prevention are contributing to improve the survival rates. It is likely that a significant fall in mortality rates for melanoma will be achieved by further increase of the early detection through a more accurate selection of the higher-risk individuals (i.e., carriers of predisposing genetic alterations). A similar scenario occurs in Italy. In the present review, we have considered data on incidence, survival and mortality rates of melanoma in Italian population, including evaluation of the main risk factors and genetic mutations underlying disease susceptibility.

9 Review Multiple Molecular Pathways in Melanomagenesis: Characterization of Therapeutic Targets. 2015

Palmieri, Giuseppe / Ombra, MariaNeve / Colombino, Maria / Casula, Milena / Sini, MariaCristina / Manca, Antonella / Paliogiannis, Panagiotis / Ascierto, Paolo Antonio / Cossu, Antonio. ·Unità di Genetica dei Tumori, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche , Sassari , Italy. · Istituto di Scienze dell'Alimentazione, Consiglio Nazionale delle Ricerche , Avellino , Italy. · Dipartimento di Scienze Chirurgiche, Microchirurgiche e Mediche, Università di Sassari , Sassari , Italy. · Istituto Nazionale Tumori "Fondazione Pascale" , Naples , Italy. ·Front Oncol · Pubmed #26322273.

ABSTRACT: Molecular mechanisms involved in pathogenesis of malignant melanoma have been widely studied and novel therapeutic treatments developed in recent past years. Molecular targets for therapy have mostly been recognized in the RAS-RAF-MEK-ERK and PI3K-AKT signaling pathways; small-molecule inhibitors were drawn to specifically target key kinases. Unfortunately, these targeted drugs may display intrinsic or acquired resistance and various evidences suggest that inhibition of a single effector of the signal transduction cascades involved in melanoma pathogenesis may be ineffective in blocking the tumor growth. In this sense, a wider comprehension of the multiple molecular alterations accounting for either response or resistance to treatments with targeted inhibitors may be helpful in assessing, which is the most effective combination of such therapies. In the present review, we summarize the known molecular mechanisms underlying either intrinsic and acquired drug resistance either alternative roads to melanoma pathogenesis, which may become targets for innovative anticancer approaches.

10 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.

11 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 / Anonymous250750. ·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.

12 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.

13 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.

14 Article The density and spatial tissue distribution of CD8 2019

Massi, Daniela / Rulli, Eliana / Cossa, Mara / Valeri, Barbara / Rodolfo, Monica / Merelli, Barbara / De Logu, Francesco / Nassini, Romina / Del Vecchio, Michele / Di Guardo, Lorenza / De Penni, Roberta / Guida, Michele / Sileni, Vanna Chiarion / Di Giacomo, Anna Maria / Tucci, Marco / Occelli, Marcella / Portelli, Francesca / Vallacchi, Viviana / Consoli, Francesca / Quaglino, Pietro / Queirolo, Paola / Baroni, Gianna / Carnevale-Schianca, Fabrizio / Cattaneo, Laura / Minisini, Alessandro / Palmieri, Giuseppe / Rivoltini, Licia / Mandalà, Mario / Anonymous1811191. ·Section of Pathological Anatomy, Department of Health Sciences, University of Florence, Florence, Italy. · Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy. · Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. · Unit of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy. · Unit of Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · Department of Oncology, Hematology, and Respiratory Diseases, University Hospital of Modena, Modena, Italy. · Department of Medical Oncology and Molecular Genetics Laboratory, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy. · Melanoma and Esophageal Cancer Unit, Istituto Oncologico Veneto-IRCCS, Department of Medical Oncology, Padua, Italy. · Medical Oncology and Immunotherapy, Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. · Medical Oncology Unit, Department of Biomedical Sciences and Human Oncology, University of Bari 'Aldo Moro', Bari, Italy. · Azienda Ospedaliera Santa Croce e Carle di Cuneo SC Oncologia, Cuneo, Italy. · Department of Oncology, ASST Spedali Civili, Brescia, Italy. · Department of Medical Sciences, Section of Dermatology, University of Turin, Turin, Italy. · Unit of Medical Oncology, Ospedale Policlinico San Martino, Genoa, Italy. · Medical Oncology Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy. · Division of Pathological Anatomy, Papa Giovanni XXIII Hospital, Bergamo, Italy. · Department of Oncology, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy. · Unit of Cancer Genetics, Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy. · Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. licia.rivoltini@istitutotumori.mi.it. ·J Immunother Cancer · Pubmed #31730502.

ABSTRACT: BACKGROUND: Clinical response to MAPK inhibitors in metastatic melanoma patients is heterogeneous for reasons still needing to be elucidated. As the patient immune activity contributes to treatment clinical benefit, the pre-existing level of immunity at tumor site may provide biomarkers of disease outcome to therapy. Here we investigated whether assessing the density and spatial tissue distribution of key immune cells in the tumor microenvironment could identify patients predisposed to respond to MAPK inhibitors. METHODS: Pretreatment tumor biopsies from a total of 213 patients (158 for the training set and 55 for the validation set) treated with BRAF or BRAF/MEK inhibitors within the Italian Melanoma Intergroup were stained with selected immune markers (CD8, CD163, β-catenin, PD-L1, PD-L2). Results, obtained by blinded immunohistochemical scoring and digital image analysis, were correlated with clinical response and outcome by multivariate logistic models on response to treatment and clinical outcome, adjusted for American Joint Committee on Cancer stage, performance status, lactate dehydrogenase and treatment received. RESULTS: Patients with high intratumoral, but not peritumoral, CD8 CONCLUSIONS: Analysis of the spatially constrained distribution of CD8

15 Article BRAF Mutations and Dysregulation of the MAP Kinase Pathway Associated to Sinonasal Mucosal Melanomas. 2019

Colombino, Maria / Paliogiannis, Panagiotis / Cossu, Antonio / De Re, Valli / Miolo, Gianmaria / Botti, Gerardo / Scognamiglio, Giosuè / Ascierto, Paolo Antonio / Santeufemia, Davide Adriano / Fraggetta, Filippo / Manca, Antonella / Sini, Maria Cristina / Casula, Milena / Palomba, Grazia / Pisano, Marina / Doneddu, Valentina / Lissia, Amelia / Fedeli, Maria Antonietta / Palmieri, Giuseppe. ·Institute of Biomolecular Chemistry, National Research Council (CNR), Traversa La Crucca 3, 07100 Sassari, Italy. colombinom@yahoo.it. · Department of Medical, Surgical and Experimental Sciences, University of Sassari, Viale S., 07100 Sassari, Italy. panospaliogiannis@gmail.com. · Anatomia Patologica, Azienda Ospedaliero Universitaria (AOU), 07100 Sassari, Italy. cossu@uniss.it. · Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico (CRO), 33081 Pordenone, Italy. vdere@cro.it. · Department of Medical Oncology, Centro di Riferimento Oncologico (CRO), 33081 Pordenone, Italy. gmiolo@cro.it. · Istituto Nazionale Tumori "Fondazione Pascale", 80131 Naples, Italy. g.botti@istitutotumori.na.it. · Istituto Nazionale Tumori "Fondazione Pascale", 80131 Naples, Italy. giosco80@gmail.com. · Istituto Nazionale Tumori "Fondazione Pascale", 80131 Naples, Italy. paolo.ascierto@gmail.com. · Oncologia Medica, Ospedale Civile, 07041 Sassari, Italy. davidesanteufemia@gmail.com. · Anatomia Patologica, Azienda Ospedaliera Cannizzaro, Via Messina 829, 95126 Catania, Italy. filippofra@hotmail.com. · Institute of Biomolecular Chemistry, National Research Council (CNR), Traversa La Crucca 3, 07100 Sassari, Italy. antonella.manca@cnr.it. · Institute of Biomolecular Chemistry, National Research Council (CNR), Traversa La Crucca 3, 07100 Sassari, Italy. mariacristina.sini@cnr.it. · Institute of Biomolecular Chemistry, National Research Council (CNR), Traversa La Crucca 3, 07100 Sassari, Italy. casulam@yahoo.it. · Institute of Biomolecular Chemistry, National Research Council (CNR), Traversa La Crucca 3, 07100 Sassari, Italy. graziap68@yahoo.it. · Institute of Biomolecular Chemistry, National Research Council (CNR), Traversa La Crucca 3, 07100 Sassari, Italy. marina.pisano@cnr.it. · Anatomia Patologica, Azienda Ospedaliero Universitaria (AOU), 07100 Sassari, Italy. valentinadoneddu@gmail.com. · Anatomia Patologica, Azienda Ospedaliero Universitaria (AOU), 07100 Sassari, Italy. a_lissia@yahoo.it. · Anatomia Patologica, Azienda Ospedaliero Universitaria (AOU), 07100 Sassari, Italy. mariaant.fedeli@hotmail.it. · Institute of Biomolecular Chemistry, National Research Council (CNR), Traversa La Crucca 3, 07100 Sassari, Italy. gpalmieri@yahoo.com. ·J Clin Med · Pubmed #31581559.

ABSTRACT: Sinonasal mucosal melanoma (SNM) is a rare and aggressive type of melanoma, and because of this, we currently have a limited understanding of its genetic and molecular constitution. The incidence among SNMs of somatic mutations in the genes involved in the main molecular pathways, which have been largely associated with cutaneous melanoma, is not yet fully understood. Through a next-generation sequencing (NGS) approach using a panel of 25 genes involved in melanoma pathogenesis customized by our group, we performed a mutation analysis in a cohort of 25 SNM patients. Results showed that pathogenic mutations were found in more than 60% of SNM cases at a somatic level, with strikingly 32% of them carrying deleterious mutations in the BRAF gene. The identified mutations mostly lack the typical UV signature associated with cutaneous melanomas and showed no significant association with any histopathological parameter. Oncogenic activation of the BRAF-depending pathway, which may induce immune tolerance into the tumour microenvironment (i.e., by increasing the VEGF production) was poorly associated with mutations in genes that have been related to diminished clinical benefit of the treatment with BRAF inhibitors. Screening for mutations in BRAF and other MAPK genes should be included in the routine diagnostic test for a better classification of SNM patients.

16 Article Mutational concordance between primary and metastatic melanoma: a next-generation sequencing approach. 2019

Manca, Antonella / Paliogiannis, Panagiotis / Colombino, Maria / Casula, Milena / Lissia, Amelia / Botti, Gerardo / Caracò, Corrado / Ascierto, Paolo A / Sini, Maria Cristina / Palomba, Grazia / Pisano, Marina / Anonymous1651197 / Anonymous1661197 / Doneddu, Valentina / Cossu, Antonio / Palmieri, Giuseppe / Anonymous1671197. ·Unit of Cancer Genetics, Institute of Biomolecular Chemistry, National Research Council, Traversa La Crucca 3, 07100, Sassari, Italy. · Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, Italy. · Istituto Nazionale Tumori "Fondazione Pascale", Via Mariano Semmola, 53, 80131, Naples, Italy. · Unit of Cancer Genetics, Institute of Biomolecular Chemistry, National Research Council, Traversa La Crucca 3, 07100, Sassari, Italy. gpalmieri@yahoo.com. ·J Transl Med · Pubmed #31455347.

ABSTRACT: BACKGROUND: Cutaneous malignant melanoma (CMM) is one of the most common skin cancers worldwide. Limited information is available in the current scientific literature on the concordance of genetic alterations between primary and metastatic CMM. In the present study, we performed next-generation sequencing (NGS) analysis of the main genes participating in melanoma pathogenesis and progression, among paired primary and metastatic lesions of CMM patients, with the aim to evaluate levels of discrepancies in mutational patterns. METHODS: Paraffin-embedded tumor tissues of the paired lesions were retrieved from the archives of the institutions participating in the study. NGS was performed using a specific multiple-gene panel constructed by the Italian Melanoma Intergroup (IMI) to explore the mutational status of selected regions (343 amplicons; amplicon range: 125-175 bp; coverage 100%) within the main 25 genes involved in CMM pathogenesis; sequencing was performed with the Ion Torrent PGM System. RESULTS: A discovery cohort encompassing 30 cases, and a validation cohort including eleven Sardinian patients with tissue availability from both the primary and metachronous metastatic lesions were identified; the global number of analyzed tissue specimens was 90. A total of 829 genetic non-synonymous variants were detected: 101 (12.2%) were pathogenic/likely pathogenic, 131 (15.8%) were benign/likely benign, and the remaining 597 (72%) were uncertain/unknown significance variants. Considering the global cohort, the consistency in pathogenic/pathogenic like mutations was 76%. Consistency for BRAF and NRAS mutations was 95.2% and 85.7% respectively, without statistically significant differences between the discovery and validation cohort. CONCLUSIONS: Our study showed a high level of concordance in mutational patterns between primary and metastatic CMM, especially when pathogenic mutations in driver genes were considered.

17 Article Germline and somatic mutations in patients with multiple primary melanomas: a next generation sequencing study. 2019

Casula, Milena / Paliogiannis, Panagiotis / Ayala, Fabrizio / De Giorgi, Vincenzo / Stanganelli, Ignazio / Mandalà, Mario / Colombino, Maria / Manca, Antonella / Sini, Maria Cristina / Caracò, Corrado / Ascierto, Paolo Antonio / Satta, Rosanna Rita / Anonymous1911035 / Lissia, Amelia / Cossu, Antonio / Palmieri, Giuseppe / Anonymous1921035. ·Unit of Cancer Genetics, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR), Traversa La Crucca 3, Baldinca Li Punti, 07100, Sassari, Italy. · Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Italy. · National Tumor Institute "Fondazione G. Pascale", Napoli, Italy. · Department of Surgery and Translational Medicine, University of Florence, Florence, Italy. · Department of Dermatology, University of Parma, Parma, Italy. · Unit of Medical Oncology, "Papa Giovanni XXIII" Hospital of Bergamo, Bergamo, Italy. · 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. ·BMC Cancer · Pubmed #31382929.

ABSTRACT: INTRODUCTION: Multiple primary melanomas (MPM) occur up to 8% of patients with cutaneous malignant melanoma (CMM). They are often sporadic harbouring several somatic mutations, but also familial cases harbouring a CDKN2A germline mutation have been describe in Caucasian populations. The aim of this study was to investigate the incidence, the distribution patterns and the impact of known and unknown germline and somatic mutations in patients with MPM from Italy. MATERIALS AND METHODS: One-hundred and two MPM patients were enrolled for germline mutation analysis, and five patients with at least four MPMs were identified for somatic mutation analysis. The demographic, pathologic and clinical features were retrieved from medical records. Molecular analysis for both germline and somatic mutations was performed in genomic DNA from peripheral blood and tissue samples, respectively, through a next generation sequencing approach, using a specific multiple-gene panel constructed by the Italian Melanoma Intergroup for somatic analysis and a commercial cancer hotspot panel for somatic analysis. RESULTS: CDKN2A mutations were detected in 6/16 (37.5%) and 3/86 (3.5%) MPM cases with and without family history for melanoma, respectively. Furthermore, multiple MC1R and, to a lesser extent, ATM variants have been identified. BAP1 variants were found only in MPM patients from southern Italy. The most frequent somatic variants were the pathogenic BRAF CONCLUSIONS: CDNK2A mutation is the most relevant susceptibility mutation in Italian patients with MPM, especially those with a family history for CMM. The prevalence of this mutation and other sequence variants identified in this study varies among specific sub-populations. Furthermore, some heterogeneity in driver somatic mutations between sporadic MPMs has been observed, as well as in a number of associated sequence variants the clinical impact of which needs to be further elucidated.

18 Article Perspectives in melanoma: meeting report from the Melanoma Bridge (November 29th-1 December 1st, 2018, Naples, Italy). 2019

Ascierto, Paolo A / Agarwala, Sanjiv S / Botti, Gerardo / Budillon, Alfredo / Davies, Michael A / Dummer, Reinhard / Ernstoff, Marc / Ferrone, Soldano / Formenti, Silvia / Gajewski, Thomas F / Garbe, Claus / Hamid, Omid / Lo, Roger S / Luke, Jason J / Michielin, Oliver / Palmieri, Giuseppe / Zitvogel, Laurence / Marincola, Francesco M / Masucci, Giuseppe / Caracò, Corrado / Thurin, Magdalena / Puzanov, Igor. ·Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. paolo.ascierto@gmail.com. · Medical Oncology and Hematology, St. Luke's University Hospital and Temple University, Bethlehem, PA, USA. · Istituto Nazionale Tumori-IRCCS Fondazione "G. Pascale", Naples, Italy. · Experimental Pharmacology Unit, Department of Translational Research, Istituto Nazionale Tumori-IRCCS Fondazione "G. Pascale", Naples, Italy. · Department of Melanoma Medical Oncology, Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Dermatology, University of Zurich Hospital, Zurich, Switzerland. · Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. · Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA. · Department of Pathology and Department of Medicine, Section of Hematology/Oncology, The University of Chicago Medicine, Chicago, IL, USA. · Division of Dermatologic Oncology, Department of Dermatology, Eberhard Karls University, Tuebingen, Germany. · The Angeles Clinic, Experimental Therapeutics Cedars Sinai Foundation, Los Angeles, CA, USA. · Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · University of Chicago Medical Center, Chicago, IL, USA. · Oncology Department, UNIL-CHUV, Lausanne, Switzerland. · Unit of Cancer Genetics, Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy. · Institut de Cancérologie, Gustave Roussy Cancer Campus, Villejuif, Paris, France. · Refuge Biotechnologies, Menlo Park, CA, USA. · Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden. · Division of Surgery of Melanoma and Skin Cancer, Istituto Nazionale Tumori-IRCCS Fondazione "G. Pascale", Naples, Italy. · Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, NCI, 9609 Medical Center Drive, Bethesda, MD, 20892-7420, USA. thurinm@mail.nih.gov. · Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. ·J Transl Med · Pubmed #31331337.

ABSTRACT: Diagnosis of melanocytic lesions, correct prognostication of patients, selection of appropriate adjuvant and systemic therapies, and prediction of response to a given therapy remain very real challenges in melanoma. Recent studies have shown that immune checkpoint blockade that represents a forefront in cancer therapy, provide responses but they are not universal. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers they have yet to be fully characterized and implemented clinically. For example, advancements in sequencing and the understanding of the tumor microenvironment in melanoma have led to the use of genome sequencing and gene expression for development of multi-marker assays that show association with inflammatory state of the tumor and potential to predict response to immunotherapy. As such, melanoma serves as a model system for understanding cancer immunity and patient response to immunotherapy, either alone or in combination with other treatment modalities. Overall, the aim for the translational and clinical studies is to achieve incremental improvements through the development and identification of optimal treatment regimens, which increasingly involve doublet as well as triplet combinations, as well as through development of biomarkers to improve immune response. These and other topics in the management of melanoma were the focus of discussions at the fourth Melanoma Bridge meeting (November 29th-December 1st, 2018, Naples, Italy), which is summarised in this report.

19 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 / Anonymous23290969. ·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.

20 Article Baseline neutrophil-to-lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab. 2018

Capone, Mariaelena / Giannarelli, Diana / Mallardo, Domenico / Madonna, Gabriele / Festino, Lucia / Grimaldi, Antonio Maria / Vanella, Vito / Simeone, Ester / Paone, Miriam / Palmieri, Giuseppe / Cavalcanti, Ernesta / Caracò, Corrado / Ascierto, Paolo Antonio. ·Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. · Statistical Unit, Regina Elena National Cancer Institute, Rome, Italy. · Unit of Cancer Genetics, Institute of Biomolecular Chemistry, CNR, I-07100, Sassari, Italy. · Department of Diagnostic Pathology and Laboratory, Istituto Nazionale Tumori- IRCCS -Fondazione G. Pascale, Napoli, Italy. · Melanoma and Skin Cancers Surgery Unit, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Napoli, Italy. · Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. p.ascierto@istitutotumori.na.it. ·J Immunother Cancer · Pubmed #30012216.

ABSTRACT: BACKGROUND: Previous studies have suggested that elevated neutrophil-to-lymphocyte ratio (NLR) is prognostic for worse outcomes in patients with a variety of solid cancers, including those treated with immune checkpoint inhibitors. METHODS: This was a retrospective analysis of 97 consecutive patients with stage IV melanoma who were treated with nivolumab. Baseline NLR and derived (d) NLR were calculated and, along with other characteristics, correlated with progression-free survival (PFS) and overall survival (OS) in univariate and multivariate analyses. The best cutoff values for NLR and dNLR were derived using Cutoff Finder software based on an R routine which optimized the significance of the split between Kaplan-Meier survival curves. RESULTS: In univariate analysis, increasing absolute neutrophil count (ANC), NLR, dNLR and lactate dehydrogenase (LDH) (continuous variables) were all significantly associated with OS. Only NLR (hazard ratio [HR] = 2.85; 95% CI 1.60-5.08; p < 0.0001) and LDH (HR = 2.51; 95% CI 1.36-4.64; p < 0.0001) maintained a significant association with OS in multivariate analysis. Patients with baseline NLR ≥5 had significantly worse OS and PFS than patients with NLR < 5, as did patients with baseline dNLR ≥3 versus < 3. Optimal cut-off values were ≥ 4.7 for NLR and ≥ 3.8 for dNLR. Using this ≥4.7 cut-off for NLR, the values for OS and PFS were overlapping to the canonical cut-off for values, and dNLR< 3.8 was also associated with better OS and PFS. CONCLUSION: Both Neutrophil-to-lymphocyte ratio (NLR) and derived (d) NLR were associated with improved survival when baseline levels were lower than cut-off values. NLR and dNLR are simple, inexpensive and readily available biomarkers that could be used to help predict response to immunotherapy in patients with advanced melanoma.

21 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.

22 Article Genetic alterations in main candidate genes during melanoma progression. 2018

Sini, Maria Cristina / Doneddu, Valentina / Paliogiannis, Panagiotis / Casula, Milena / Colombino, Maria / Manca, Antonella / Botti, Gerardo / Ascierto, Paolo A / Lissia, Amelia / Cossu, Antonio / Palmieri, Giuseppe. ·Unit of Cancer Genetics, Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy. · Department of Surgical, Microsurgical and Medical Sciences, University of Sassari, Sassari, Italy. · Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy. · Istituto Nazionale Tumori, Fondazione Pascale, Napoli, Italy. ·Oncotarget · Pubmed #29492214.

ABSTRACT: Cutaneous melanoma is a common and aggressive human skin cancers. Much is actually known about the molecular mechanisms underlying melanoma pathogenesis. The aim of the study was to evaluate any possible correlation between mutations in main growth-controlling genes (

23 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.

24 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 / Anonymous1830926. ·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.

25 Article The anti-apoptotic BAG3 protein is involved in BRAF inhibitor resistance in melanoma cells. 2017

Guerriero, Luana / Palmieri, Giuseppe / De Marco, Margot / Cossu, Antonio / Remondelli, Paolo / Capunzo, Mario / Turco, Maria Caterina / Rosati, Alessandra. ·BIOUNIVERSA s.r.l., 84084 Baronissi, Italy. · Unit of Cancer Genetics, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR), 07100 Sassari, Italy. · Unit of Pathology, Azienda Ospedaliero Universitaria (AOU), University di Sassari, 07100 Sassari, Italy. · Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana" University of Salerno, 84084 Baronissi, Italy. ·Oncotarget · Pubmed #29113311.

ABSTRACT: BAG3 protein, a member of BAG family of co-chaperones, has a pro-survival role in several tumour types. BAG3 anti-apoptotic properties rely on its characteristic to bind several intracellular partners, thereby modulating crucial events such as apoptosis, differentiation, cell motility, and autophagy. In human melanomas, BAG3 positivity is correlated with the aggressiveness of the tumour cells and can sustain IKK-γ levels, allowing a sustained activation of NF-κB. Furthermore, BAG3 is able to modulate BRAFV600E levels and activity in thyroid carcinomas. BRAFV600E is the most frequent mutation detected in malignant melanomas and is targeted by Vemurafenib, a specific inhibitor found to be effective in the treatment of advanced melanoma. However, patients with BRAF-mutated melanoma may result insensitive

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