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Mesothelioma: HELP
Articles from Genoa
Based on 48 articles published since 2008
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These are the 48 published articles about Mesothelioma that originated from Genoa during 2008-2019.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Advances in treatment of mesothelioma. 2016

Maggioni, C / Barletta, G / Rijavec, E / Biello, F / Gualco, E / Grossi, F. ·a IRCCS San Martino-IST Istituto Nazionale per la Ricerca sul Cancro , UOS Tumori Polmonari , Genova , Italy. ·Expert Opin Pharmacother · Pubmed #27055148.

ABSTRACT: INTRODUCTION: Malignant pleural mesothelioma (MPM) is an uncommon, aggressive cancer, derived from pleural mesothelial cells, that has a close relationship to asbestos exposure. To date, MPM prognosis is poor and very few treatment options are available for both localized and advanced MPM. AREAS COVERED: The standard of care is still chemotherapy with platinum derivates and antifolate agents. In the last few years, several new agents have been studied on the basis of mesothelioma carcinogenesis and invasiveness mechanisms; however, the recent results are poor and few drugs have been tested in phase III trials because of toxicity or because they did not improve patient outcomes. The aim of this review is to focus on the current available treatment for MPM through the analysis of the results comes from the phase III trials and to discuss the future perspectives in the pathogenesis, diagnosis and treatment. EXPERT OPINION: Many compounds are currently under investigation in different subsets of patients. Interesting data have come from preliminary studies on immunotherapy, but randomized studies are needed to confirm the preliminary positive results of this new strategy. A better comprehension of MPM pathogenesis should be obtained to improve and develop new diagnostic tools and target therapies.

2 Review Prognostic and Therapeutic Implications of MicroRNA in Malignant Pleural Mesothelioma. 2016

Truini, Anna / Coco, Simona / Genova, Carlo / Mora, Marco / Dal Bello, Maria G / Vanni, Irene / Alama, Angela / Rijavec, Erika / Barletta, Giulia / Biello, Federica / Maggioni, Claudia / Grossi, Francesco. ·Lung Cancer Unit, IRCCS AOU San Martino-IST, L. go R. Benzi 10, 16132 Genova, Italy. ·Microrna · Pubmed #26817512.

ABSTRACT: Malignant Pleural Mesothelioma (MPM) is an aggressive disease characterized by a dismal prognosis, mainly due to late diagnosis. To date, there are very few treatment options available and the refractoriness to the majority of therapeutic strategies, leading to consider MPM a relevant problem in public health. Therefore, the identification of novel prognostic markers and alternative therapeutic strategies remain a top priority. Several efforts have been made in this direction and to date a number of studies have investigated the role of microRNA as biomarkers in MPM, identifying the potential prognostic role of miR-29c* and miR-31. Very recently, the first microRNA signature able to discriminate poor or and good prognosis of MPM patients underwent surgery has been published. Very interestingly, several microRNA such as miR-1, miR-16, and miR-34b/c have been identified as potential therapeutic agents. Indeed, the forced expression of these microRNA resulted in anti-tumor effects both in vitro and in vivo. Besides, the introduction of microRNA mimic, some agents such as EphrinA1 and Onconase, seemed to exert anti-tumor effects through specific microRNA. Moreover, microRNA have also been reported to play a role in chemoresistance enhancing the sensitivity to specific drug such as pemetrexed. In this review the most relevant and updated data about the role of microRNA as prognostic markers and therapeutic agents in MPM will be presented, opening new avenues towards improved management of this aggressive disease.

3 Review Molecular Pharmacology of Malignant Pleural Mesothelioma: Challenges and Perspectives From Preclinical and Clinical Studies. 2016

Thellung, Stefano / Favoni, Roberto E / Würth, Roberto / Nizzari, Mario / Pattarozzi, Alessandra / Daga, Antonio / Florio, Tullio / Barbieri, Federica. ·Section of Pharmacology, Department of. Internal Medicine (Di.M.I.), University of Genova, Viale Benedetto XV, 2 16132 Genova, Italy. federica.barbieri@unige.it. ·Curr Drug Targets · Pubmed #26240051.

ABSTRACT: Malignant pleural mesothelioma (MPM) is one of the deadliest and most heterogeneous tumors, highly refractory to multimodal therapeutic approach, including surgery, chemo- and radiotherapy. Preclinical and clinical studies exploring the efficacy of drugs targeting tyrosine kinases, angiogenesis and histone deacetylases, did not fulfil the expected clinical benefits. Thus, novel molecular targets should be identified from a definite knowledge of the unique biology and most relevant transduction pathways of MPM cells. Cancer stem cells (CSCs) are a subset of malignant precursors responsible for initiation, progression, resistance to cytotoxic drugs, recurrence and metastatic diffusion of tumor cells. CSCs are putative driving factors for MPM development and contribute to its clinical and biological heterogeneity; hence, targeted eradication of CSCs represents an ineludible goal to counteract MPM aggressiveness. In this context, innovative preclinical models could be exploited to identify novel intracellular pathway inhibitors able to target CSC viability. Novel drug targets have been identified among key factors responsible for the oncogenic transformation of mesothelial cells, often directly induced by asbestos. These include mitogenic and anti-apoptotic signaling that may also be activated by autocrine and paracrine cytokine pathways controlling cell plasticity. Both signaling pathways affecting proto-oncogene and transcription factor expression, or genetic and epigenetic alterations, such as mutations in cell cycle genes and silencing of tumor suppressor genes, represent promising disease-specific targets. In this review we describe current knowledge of MPM cell biology, focusing on potential targets to be tested in pharmacological studies, and highlighting results and challenges of clinical translation.

4 Review Role of microRNAs in malignant mesothelioma. 2014

Truini, A / Coco, S / Alama, A / Genova, C / Sini, C / Dal Bello, M G / Barletta, G / Rijavec, E / Burrafato, G / Boccardo, F / Grossi, F. ·Lung Cancer Unit, IRCCS A.O.U. San Martino IST-Istituto Nazionale per la Ricerca sul Cancro, L.go Rosanna Benzi 10, 16132, Genova, Italy, anna.truini@hsanmartino.it. ·Cell Mol Life Sci · Pubmed #24562347.

ABSTRACT: Malignant mesothelioma (MM) is an aggressive tumor, mainly derived from the pleura, which is predominantly associated with exposure to asbestos fibers. The prognosis of MM patients is particularly severe, with a median survival of approximately 9-12 months and latency between exposure and diagnosis ranging from 20-50 years (median 30 years). Emerging evidence has demonstrated that tumor aggressiveness is associated with genome and gene expression abnormalities; therefore, several studies have recently focused on the role of microRNAs (miRNAs) in MM tumorigenesis. miRNAs are small non-protein coding single-stranded RNAs (17-22 nucleotides) involved in numerous cellular processes that negatively regulate gene expression by modulating the expression of downstream target genes. miRNAs are often deregulated in cancer; in particular, the differential miRNA expression profiles of MM cells compared to unaffected mesothelial cells have suggested potential roles of miRNAs as either oncogenes or tumor suppressor genes in MM oncogenesis. In this review, the mechanism of MM carcinogenesis was evaluated through the analysis of the published miRNA expression data. The roles of miRNAs as diagnostic biomarkers and prognostic factors for potential therapeutic strategies will be presented and discussed.

5 Review Preclinical studies identify novel targeted pharmacological strategies for treatment of human malignant pleural mesothelioma. 2012

Favoni, Roberto E / Daga, Antonio / Malatesta, Paolo / Florio, Tullio. ·IRCCS A.O.U. San Martino-IST, Laboratory of Gene Transfer, Genoa, Italy. roberto.favoni@istge.it ·Br J Pharmacol · Pubmed #22289125.

ABSTRACT: The incidence of human malignant pleural mesothelioma (hMPM) is still increasing worldwide. hMPM prognosis is poor even if the median survival time has been slightly improved after the introduction of the up-to-date chemotherapy. Nevertheless, large phase II/III trials support the combination of platinum derivatives and pemetrexed or raltitrexed, as preferred first-line schedule. Better understanding of the molecular machinery of hMPM will lead to the design and synthesis of novel compounds targeted against pathways identified as crucial for hMPM cell proliferation and spreading. Among them, several receptors tyrosine kinase show altered activity in subsets of hMPM. This observation suggests that these kinases might represent novel therapeutic targets in this chemotherapy-resistant disease. Over these foundations, several promising studies are ongoing at preclinical level and novel molecules are currently under evaluation as well. Yet, established tumour cell lines, used for decades to investigate the efficacy of anticancer agents, although still the main source of drug efficacy studies, after long-term cultures tend to biologically diverge from the original tumour, limiting the predictive potential of in vivo efficacy. Cancer stem cells (CSCs), a subpopulation of malignant cells capable of self-renewal and multilineage differentiation, are believed to play an essential role in cancer initiation, growth, metastasization and relapse, being responsible of chemo- and radiotherapy refractoriness. According to the current carcinogenesis theory, CSCs represent the tumour-initiating cell (TIC) fraction, the only clonogenic subpopulation able to originate a tumour mass. Consequently, the recently described isolation of TICs from hMPM, the proposed main pharmacological target for novel antitumoural drugs, may contribute to better dissect the biology and multidrug resistance pathways controlling hMPM growth.

6 Review Combined chemotherapy with cytotoxic and targeted compounds for the management of human malignant pleural mesothelioma. 2011

Favoni, Roberto E / Florio, Tullio. ·Department of Translational Oncology Research, Gene Transfer Laboratory, National Cancer Institute, Largo Rosanna Benzi, 10 16132 Genoa, Italy. roberto.favoni@istge.it ·Trends Pharmacol Sci · Pubmed #21620489.

ABSTRACT: Human malignant pleural mesothelioma (hMPM) is an aggressive asbestos-associated cancer, the incidence of which is increasing and which, despite progress in diagnosis and therapy, continues to have a poor prognosis. Asbestos fibers induce aberrant cell signaling, leading to proto-oncogene activation and chemoresistance. In this review, we discuss the evolution of pharmacological management of hMPM up to the most recent advances. Monotherapy with single cytotoxic drugs achieves modest objective response rates, seldom reaching 30%. However, combination regimens using novel drugs and standard molecules are showing gradually improving responses and clinical benefits. Phase II/III studies have identified pemetrexed, a multitarget folate pathway inhibitor in combination with platinum derivatives, and the cisplatin/gemcitabine association as front-line chemotherapy for hMPM. Detailed knowledge of molecular mechanisms of signal transduction and neoangiogenesis in hMPM should aid in the design and screening of other promising compounds such as more efficacious receptor tyrosine kinase inhibitors.

7 Review alpha7-Nicotinic receptor antagonists at the beginning of a clinical era for NSCLC and Mesothelioma? 2009

Paleari, Laura / Cesario, Alfredo / Fini, Massimo / Russo, Patrizia. ·Lung Cancer Unit, National Cancer Research Institute, Genoa, Italy. laura.paleari@istge.it ·Drug Discov Today · Pubmed #19616116.

ABSTRACT: Of the human solid cancers, Non-Small Cell Lung Cancer (NSCLC) and Malignant Pleural Mesothelioma (MPM) display a natural history supporting the concept that they develop from multiple preneoplastic pathways. Recently, new evidence suggested that nicotinic Acetylcholine Receptors (nAChRs) play a significant role in lung cancer predisposition and natural history. This review is based on some translational research aimed at evaluating the potential therapeutic effect of nAChR antagonists on NSCLC and MPM. The background and rationale of this approach are based on the experimental observations that: (a) NSCLC and MPM cells express nAChRs and (b) the activation of these receptors by agonists, namely nicotine, inhibits apoptosis, whereas receptor antagonists have a pro-apoptotic effect.

8 Review Multiple roles of nicotine on cell proliferation and inhibition of apoptosis: implications on lung carcinogenesis. 2008

Catassi, A / Servent, D / Paleari, L / Cesario, A / Russo, P. ·Cancer Unit, National Cancer Research Institute, Genoa, Italy. ·Mutat Res · Pubmed #18495523.

ABSTRACT: The genotoxic effects of tobacco carcinogens have long been recognized, the contribution of tobacco components to cancerogenesis by cell surface receptor signaling is relatively unexplored. Nicotine, the principal tobacco alkaloid, acts through nicotinic acetylcholine receptor (nAChR). nAChR are functionally present on human lung airway epithelial cells, on lung carcinoma [SCLC and NSCLC] and on mesothelioma and build a part of an autocrine-proliferative network that facilitates the growth of neoplastic cells. Different nAChR subunit gene expression patterns are expressed between NSCLC from smokers and non-smokers. Although there is no evidence that nicotine itself could induce cancer, different studies established that nicotine promotes in vivo the growth of cancer cells and the proliferation of endothelial cells suggesting that nicotine might contribute to the progression of tumors already initiated. These observations led to the hypothesis that nicotine might be playing a direct role in the promotion and progression of human lung cancers. Here, we briefly overview the role and the effects of nicotine on pulmonary cell growth and physiology and its feasible implications in lung carcinogenesis.

9 Review Genetic susceptibility to malignant pleural mesothelioma and other asbestos-associated diseases. 2008

Neri, Monica / Ugolini, Donatella / Dianzani, Irma / Gemignani, Federica / Landi, Stefano / Cesario, Alfredo / Magnani, Corrado / Mutti, Luciano / Puntoni, Riccardo / Bonassi, Stefano. ·Unit of Molecular Epidemiology, National Cancer Research Institute, Genoa, Italy. monica.neri@istge.it ·Mutat Res · Pubmed #18420450.

ABSTRACT: Exposure to asbestos fibers is a major risk factor for malignant pleural mesothelioma (MPM), lung cancer, and other non-neoplastic conditions, such as asbestosis and pleural plaques. However, in the last decade many studies have shown that polymorphism in the genes involved in xenobiotic and oxidative metabolism or in DNA repair processes may play an important role in the etiology and pathogenesis of these diseases. To evaluate the association between diseases linked to asbestos and genetic variability we performed a review of studies on this topic included in the PubMed database. One hundred fifty-nine citations were retrieved; 24 of them met the inclusion criteria and were evaluated in the review. The most commonly studied GSTM1 polymorphism showed for all asbestos-linked diseases an increased risk in association with the null genotype, possibly linked to its role in the conjugation of reactive oxygen species. Studies focused on GSTT1 null and SOD2 Ala16Val polymorphisms gave conflicting results, while promising results came from studies on alpha1-antitrypsin in asbestosis and MPO in lung cancer. Among genetic polymorphisms associated to the risk of MPM, the GSTM1 null genotype and two variant alleles of XRCC1 and XRCC3 showed increased risks in a subset of studies. Results for the NAT2 acetylator status, SOD2 polymorphism and EPHX activity were conflicting. Major limitations in the study design, including the small size of study groups, affected the reliability of these studies. Technical improvements such as the use of high-throughput techniques will help to identify molecular pathways regulated by candidate genes.

10 Clinical Trial NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial. 2018

Gregorc, Vanesa / Gaafar, Rabab M / Favaretto, Adolfo / Grossi, Francesco / Jassem, Jacek / Polychronis, Andreas / Bidoli, Paolo / Tiseo, Marcello / Shah, Riyaz / Taylor, Paul / Novello, Silvia / Muzio, Alberto / Bearz, Alessandra / Greillier, Laurent / Fontana, Floriana / Salini, Giulia / Lambiase, Antonio / O'Brien, Mary. ·Ospedale San Raffaele, Milan, Italy. Electronic address: vanesa.gregorc@hsr.it. · National Cancer Institute, University, Cairo, Egypt. · Istituto Oncologico Veneto, Padua, Italy. · Ospedale Policlinico San Martino, Genoa, Italy. · Medical University, Gdansk, Poland. · Mount Vernon Cancer Centre, Northwood, UK. · Ospedale San Gerardo, Monza, Italy. · Azienda Ospedaliero-Universitaria, Parma, Italy. · Kent Oncology Centre, Maidstone, UK. · Wythenshawe Hospital, Manchester, UK. · University of Turin, AOU San Luigi, Orbassano, Turin, Italy. · Ospedale S Spirito, Casale Monferrato, Italy. · Centro di Riferimento Oncologico, Aviano, Italy. · Assistance Publique Hôpitaux de Marseille, Aix Marseille University, Marseille, France. · MolMed, Milan, Italy. · The Royal Marsden Hospital, Sutton, UK. ·Lancet Oncol · Pubmed #29753703.

ABSTRACT: BACKGROUND: Malignant pleural mesothelioma is an aggressive cancer with highly vascularised tumours. It has poor prognosis and few treatment options after failure of first-line chemotherapy. NGR-hTNF is a vascular-targeting drug that increases penetration of intratumoral chemotherapy and T-cell infiltration by modifying the tumour microenvironment. In this trial, we aimed to investigate the efficacy and safety of NGR-hTNF in patients with malignant pleural mesothelioma who had progressed during or after a first-line treatment. METHODS: NGR015 was a randomised, double-blind, placebo-controlled phase 3 trial done in 41 centres in 12 countries. Eligible participants had malignant pleural mesothelioma of any histological subtype (epithelial, sarcomatoid, or mixed), were aged 18 years or older, and had an Eastern Cooperative Oncology Group performance status of 0-2 and radiologically documented progressive disease after one pemetrexed-based chemotherapy regimen. Participants were randomly assigned to receive weekly NGR-hTNF 0·8 μg/m FINDINGS: Between April 12, 2010 and Jan 21, 2013, we enrolled 400 eligible participants. 381 (95%) of 400 patients were selected to receive chemotherapy before all participants were randomly assigned to receive NGF-hTNF plus best investigator choice (n=200) or placebo plus best investigator choice (n=200). At the cutoff date (April 29, 2014), the median follow-up was 18·7 months (IQR 15·1-24·4), and overall survival did not differ between the two treatment groups (median 8·5 months [95% CI 7·2-9·9] in the NGR-hTNF group vs 8·0 months [6·6-8·9] in the placebo group; hazard ratio 0·94, 95% CI 0·75-1·18; p=0·58). Grade 3 or worse study-emergent adverse events occurred in 136 (70%) of patients receiving NGR-hTNF versus 118 (61%) of patients receiving placebo, with the most common being neutropenia (35 [18%] of 193 patients vs 36 [19%] of 193 patients), pain (11 [6%] vs 16 [8%]), dyspnoea (nine [5%] vs seven [4%]), and chills (nine [5%] vs none). 50 (26%) patients in the NGR-hTNF group had a serious adverse event, compared with 47 (24%) in the placebo group. Treatment-related serious adverse events occurred in 17 (9%) patients in the NGR-hTNF group and 20 patients (10%) in the placebo group. There were 12 deaths in the NGR-hTNF group and 13 deaths in the placebo group, but none were treatment related. INTERPRETATION: The study did not meet its primary endpoint. The hypothesis-generating findings from the subgroup analyses deserve a confirmatory randomised trial because patients who rapidly progress after first-line treatment have a poor prognosis. FUNDING: MolMed.

11 Article Deregulation of miRNAs in malignant pleural mesothelioma is associated with prognosis and suggests an alteration of cell metabolism. 2017

De Santi, Chiara / Melaiu, Ombretta / Bonotti, Alessandra / Cascione, Luciano / Di Leva, Gianpiero / Foddis, Rudy / Cristaudo, Alfonso / Lucchi, Marco / Mora, Marco / Truini, Anna / Tironi, Andrea / Murer, Bruno / Boldorini, Renzo / Cipollini, Monica / Gemignani, Federica / Gasparini, Pierluigi / Mutti, Luciano / Landi, Stefano. ·Respiratory Research Division, Department of Medicine, Education and Research Centre, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland. · Immuno-Oncology Laboratory, Department of Paediatric Haematology/Oncology, Ospedale Pediatrico Bambino Gesù, Viale di S. Paolo 15, 00146, Rome, Italy. · Preventive and Occupational Medicine, University Hospital of Pisa, Pisa, Italy. · Lymphoma and Genomics Research Program, Institute of Oncology Research, Bellinzona, Switzerland. · School of Environment and Life Sciences, University of Salford, Manchester, United Kingdom. · Department of Translational Research and of new Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. · Division of Thoracic Surgery, Cardiac and Thoracic Department, University of Pisa, Pisa, Italy. · IRCCS H, San Martino-IST Genova, Genova, Italy. · Section of Anatomic Pathology, Oncology and Experimental Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy. · Azienda ULSS 12 Veneziana, Venice, Italy. · Department of Health Sciences, School of Medicine, University Hospital Maggiore della Carità, Novara, Italy. · Department of Biology, University of Pisa, Pisa, Italy. · Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Columbus, Ohio, USA. · Department of Biology, University of Pisa, Pisa, Italy. slandi@biologia.unipi.it. ·Sci Rep · Pubmed #28600498.

ABSTRACT: Malignant pleural mesothelioma (MPM) is an aggressive human cancer and miRNAs can play a key role for this disease. In order to broaden the knowledge in this field, the miRNA expression was investigated in a large series of MPM to discover new pathways helpful in diagnosis, prognosis and therapy. We employed nanoString nCounter system for miRNA profiling on 105 MPM samples and 10 healthy pleura. The analysis was followed by the validation of the most significantly deregulated miRNAs by RT-qPCR in an independent sample set. We identified 63 miRNAs deregulated in a statistically significant way. MiR-185, miR-197, and miR-299 were confirmed differentially expressed, after validation study. In addition, the results of the microarray analysis corroborated previous findings concerning miR-15b-5p, miR-126-3p, and miR-145-5p. Kaplan-Meier curves were used to explore the association between miRNA expression and overall survival (OS) and identified a 2-miRNA prognostic signature (Let-7c-5p and miR-151a-5p) related to hypoxia and energy metabolism respectively. In silico analyses with DIANA-microT-CDS highlighted 5 putative targets in common between two miRNAs. With the present work we showed that the pattern of miRNAs expression is highly deregulated in MPM and that a 2-miRNA signature can be a new useful tool for prognosis in MPM.

12 Article The inhibition of FGF receptor 1 activity mediates sorafenib antiproliferative effects in human malignant pleural mesothelioma tumor-initiating cells. 2017

Pattarozzi, Alessandra / Carra, Elisa / Favoni, Roberto E / Würth, Roberto / Marubbi, Daniela / Filiberti, Rosa Angela / Mutti, Luciano / Florio, Tullio / Barbieri, Federica / Daga, Antonio. ·Department of Internal Medicine (DiMI) and Centre of Excellence for Biomedical Research (CEBR), University of Genova, Viale Benedetto XV, 2, 16132, Genova, Italy. · Department of Experimental Medicine (DIMES), University of Genova, Via L.B. Alberti, 2, 16132, Genova, Italy. · IRCCS-AOU San Martino-IST, Largo R. Benzi, 10, 16132, Genova, Italy. · Biomedical Research Centre, University of Salford, The Crescent, Salford, Manchester, M5 4WT, UK. · Department of Internal Medicine (DiMI) and Centre of Excellence for Biomedical Research (CEBR), University of Genova, Viale Benedetto XV, 2, 16132, Genova, Italy. tullio.florio@unige.it. · Department of Internal Medicine (DiMI) and Centre of Excellence for Biomedical Research (CEBR), University of Genova, Viale Benedetto XV, 2, 16132, Genova, Italy. federica.barbieri@unige.it. ·Stem Cell Res Ther · Pubmed #28545562.

ABSTRACT: BACKGROUND: Malignant pleural mesothelioma is an aggressive cancer, characterized by rapid progression and high mortality. Persistence of tumor-initiating cells (TICs, or cancer stem cells) after cytotoxic drug treatment is responsible for tumor relapse, and represents one of the main reasons for the poor prognosis of mesothelioma. In fact, identification of the molecules affecting TIC viability is still a significant challenge. METHODS: TIC-enriched cultures were obtained from 10 human malignant pleural mesotheliomas and cultured in vitro. Three fully characterized tumorigenic cultures, named MM1, MM3, and MM4, were selected and used to assess antiproliferative effects of the multi-kinase inhibitor sorafenib. Cell viability was investigated by MTT assay, and cell cycle analysis as well as induction of apoptosis were determined by flow cytometry. Western blotting was performed to reveal the modulation of protein expression and the phosphorylation status of pathways associated with sorafenib treatment. RESULTS: We analyzed the molecular mechanisms of the antiproliferative effects of sorafenib in mesothelioma TIC cultures. Sorafenib inhibited cell cycle progression in all cultures, but only in MM3 and MM4 cells was this effect associated with Mcl-1-dependent apoptosis. To investigate the mechanisms of sorafenib-mediated antiproliferative activity, TICs were treated with epidermal growth factor (EGF) or basic fibroblast growth factor (bFGF) causing, in MM3 and MM4 cells, MEK, ERK1/2, Akt, and STAT3 phosphorylation. These effects were abolished by sorafenib only in bFGF-treated cells, while a modest inhibition occurred after EGF stimulation, suggesting that sorafenib effects are mainly due to FGF receptor (FGFR) inhibition. Indeed, FGFR1 phosphorylation was inhibited by sorafenib. Moreover, in MM1 cells, which release high levels of bFGF and showed autocrine activation of FGFR1 and constitutive phosphorylation/activation of MEK-ERK1/2, sorafenib induced a more effective antiproliferative response, confirming that the main target of the drug is the inhibition of FGFR1 activity. CONCLUSIONS: These results suggest that, in malignant pleural mesothelioma TICs, bFGF signaling is the main target of the antiproliferative response of sorafenib, acting directly on the FGFR1 activation. Patients with constitutive FGFR1 activation via an autocrine loop may be more sensitive to sorafenib treatment and the analysis of this possibility warrants further clinical investigation.

13 Article Pleurectomy-decortication in malignant pleural mesothelioma: are different surgical techniques associated with different outcomes? Results from a multicentre study. 2017

Marulli, Giuseppe / Breda, Cristiano / Fontana, Paolo / Ratto, Giovanni Battista / Leoncini, Giacomo / Alloisio, Marco / Infante, Maurizio / Luzzi, Luca / Paladini, Piero / Oliaro, Alberto / Ruffini, Enrico / Benvenuti, Mauro Roberto / Pariscenti, Gianluca / Spaggiari, Lorenzo / Casiraghi, Monica / Rusca, Michele / Carbognani, Paolo / Ampollini, Luca / Facciolo, Francesco / Leuzzi, Giovanni / Mucilli, Felice / Camplese, Pierpaolo / Romanello, Paola / Perissinotto, Egle / Rea, Federico. ·Thoracic Surgery Unit, University of Padova, Padova, Italy. · Thoracic Surgery Unit, ULSS 12 Veneziana, Venice-Mestre, Italy. · Thoracic Surgery Unit, IRCCS Azienda Ospedaliera Universitaria San Martino, Genova, Italy. · Thoracic Surgery Unit, Humanitas Research Hospital, Rozzano, Italy. · Thoracic Surgery Unit, University of Siena, Siena, Italy. · Thoracic Surgery Unit, University of Torino, Torino, Italy. · Thoracic Surgery Unit, ASST Spedali Civili, Brescia, Italy. · Thoracic Surgery Unit, European Institute of Oncology, Milan, Italy. · Thoracic Surgery Unit, University of Parma, Parma, Italy. · Thoracic Surgery Unit, Regina Elena National Cancer Institute, Rome, Italy. · Thoracic Surgery Unit, University of Chieti, Pescara, Italy. ·Eur J Cardiothorac Surg · Pubmed #28419212.

ABSTRACT: OBJECTIVES: The potential benefit of surgery for malignant pleural mesothelioma (MPM), especially concerning pleurectomy/decortication (P/D), is unclear from the literature. The aim of this study was to evaluate the outcome after multimodality treatment of MPM involving different types of P/D and to analyse the prognostic factors. METHODS: We reviewed 314 patients affected by MPM who were operated on in 11 Italian centres from 1 January 2007 to 11 October 2014. RESULTS: The characteristics of the population were male/female ratio: 3.7/1, and median age at operation was 67.8 years. The epithelioid histotype was observed in 79.9% of patients; neoadjuvant chemotherapy was given to 57% of patients and Stage III disease was found following a pathological analysis in 62.3% of cases. A total of 162 (51.6%) patients underwent extended P/D (EP/D); 115 (36.6%) patients had P/D and 37 (11.8%) received only a partial pleurectomy. Adjuvant radiotherapy was delivered in 39.2% of patients. Median overall survival time after surgery was 23.0 [95% confidence interval (CI): 19.6-29.1] months. On multivariable (Cox) analysis, pathological Stage III-IV [ P  = 0.004, hazard ratio (HR):1.34; 95% CI: 1.09-1.64], EP/D and P/D ( P  = 0.006, HR for EP/D: 0.46; 95% CI: 0.29-0.74; HR for P/D: 0.52; 95% CI: 0.31-0.87), left-sided disease ( P  = 0.01, HR: 1.52; 95% CI: 1.09-2.12) and pathological status T4 ( P  = 0.0003, HR: 1.38; 95% CI: 1.14-1.66) were found to be independent significant predictors of overall survival. CONCLUSIONS: Whether the P/D is extended or not, it shows similarly good outcomes in terms of early results and survival rate. In contrast, a partial pleurectomy, which leaves gross tumour behind, has no impact on survival.

14 Article Comparison of the Diagnostic Performance of Fibulin-3 and Mesothelin in Patients with Pleural Effusions from Malignant Mesothelioma. 2017

Battolla, Enrico / Canessa, Pier Aldo / Ferro, Paola / Franceschini, Maria Cristiana / Fontana, Vincenzo / Dessanti, Paolo / Pinelli, Valentina / Morabito, Anna / Fedeli, Franco / Pistillo, Maria Pia / Roncella, Silvio. ·Division of Clinical Pathology, Azienda Sanitaria Locale n°5, La Spezia, Italy. · Division of Pneumology, Azienda Sanitaria Locale n°5, La Spezia, Italy. · Division of Histopathology and Cytopathology, Azienda Sanitaria Locale n°5, La Spezia, Italy. · Unit of Clinical Epidemiology, Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. · Unit of Tumor Epigenetics, Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. · Division of Histopathology and Cytopathology, Azienda Sanitaria Locale n°5, La Spezia, Italy silvio.roncella@asl5.liguria.it. ·Anticancer Res · Pubmed #28314308.

ABSTRACT: BACKGROUND: In the literature, there exist conflicting data on the value of fibulin-3 (FBLN3) for the diagnosis of pleural effusion (PE) in malignant pleural mesothelioma (MPM). Therefore we compared the diagnostic performance of FBLN3 against that of soluble mesothelin-related peptide (SMRP) in a cohort of Italian patients. MATERIALS AND METHODS: FBLN3 and SMRP were detected in PE from 33 patients with MPM, 64 with pleural benign lesions and 23 with non-MPM pleural metastases using a commercial enzyme-linked-immunosorbent(ELISA)-assay kit according to manufacturers' instructions. RESULTS: Levels of FBLN3 were similar in PE from MPM and PE from other pathologies (geometric mean=68.1 vs. 66.2 ng/ml; p=0.872) in contrast to SMRP levels, which were significantly higher in PE from MPM (geometric mean=14.6 vs. 3.2 nM; p<0.001). Receiver operating characteristic analysis confirmed that SMRP showed a good performance (area under the curve=0.79, p<0.001), whereas FBLN3 was not able to discriminate MPM from other pathologies (area under the curve=0.44, p=0.838). CONCLUSION: FBLN3 detection in PE, in contrast to SMRP detection, is not useful as a biomarker for the diagnosis of PE from MPM.

15 Article [Possible health risks from asbestos in drinking water]. 2016

Di Ciaula, Agostino / Gennaro, Valerio. ·UO medicina interna, PO Bisceglie, ASL BAT, Bisceglie. agostinodiciaula@tiscali.it. · International Society of Doctors for Environment (ISDE) Italia. · COR Liguria, Registro nazionale mesoteliomi (ReNaM), IRCCS Azienda ospedaliera universitaria San Martino, Genova. · Istituto nazionale per la ricerca sul cancro (IST), Genova. ·Epidemiol Prev · Pubmed #27919155.

ABSTRACT: The recent finding of asbestos fibres in drinking water (up to 700.000 fibres/litres) in Tuscany (Central Italy) leads to concerns about health risks in exposed communities. Exposure to asbestos has been linked with cancer at several levels of the gastrointestinal tract, and it has been documented, in an animal model, a direct cytotoxic effect of asbestos fibres on the ileum. It has been recently described a possible link between asbestos and intrahepatic cholangiocarcinoma, and asbestos fibres have been detected in humans in histological samples from colon cancer and in gallbladder bile. Taken together, these findings suggest the possibility of an enterohepatic translocation of asbestos fibres, alternative to lymphatic translocation from lungs. In animal models, asbestos fibres ingested with drinking water act as a co-carcinogen in the presence of benzo(a) pyrene and, according to the International Agency for Research on Cancer (IARC ), there is evidence pointing to a causal effect of ingested asbestos on gastric and colorectal cancer. The risk seems to be proportional to the concentration of ingested fibres, to the extent of individual water consumption, to exposure timing, and to the possible exposure to other toxics (i.e., benzo(a)pyrene). Furthermore, the exposure to asbestos by ingestion could explain the epidemiological finding of mesothelioma in subjects certainly unexposed by inhalation. In conclusion, several findings suggest that health risks from asbestos could not exclusively derive from inhalation of fibres. Health hazards might also be present after ingestion, mainly after daily ingestion of drinking water for long periods. In Italy, a systemic assessment of the presence of asbestos fibres in drinking water is still lacking, although asbestos-coated pipelines are widely diffused and still operating. Despite the fact that the existence of a threshold level for health risks linked to the presence of asbestos in drinking water is still under debate, the precautionary principle should impose all possible efforts in order to revise health policies concerning this topic, and a systematic monitoring of drinking water to quantify the presence of asbestos is certainly needed in all regions. Further epidemiological studies aimed to the identification of exposed communities and to an adequate health risk assessment in their specific geographical areas are urgently needed.

16 Article Whole exome sequencing of independent lung adenocarcinoma, lung squamous cell carcinoma, and malignant peritoneal mesothelioma: A case report. 2016

Vanni, Irene / Coco, Simona / Bonfiglio, Silvia / Cittaro, Davide / Genova, Carlo / Biello, Federica / Mora, Marco / Rossella, Valeria / Dal Bello, Maria Giovanna / Truini, Anna / Banelli, Barbara / Lazarevic, Dejan / Alama, Angela / Rijavec, Erika / Barletta, Giulia / Grossi, Francesco. ·aLung Cancer Unit, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genova bCentre for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, Milan cDepartment of Internal Medicine and Medical Specialties (DIMI), Università di Genova IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genova dDepartment of Pathology, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genova eLaboratory of Tumor Epigenetics, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro and Department of Health Sciences, Università di Genova, Genova, Italy. ·Medicine (Baltimore) · Pubmed #27902597.

ABSTRACT: The presence of multiple primary tumors (MPT) in a single patient has been identified with an increasing frequency. A critical issue is to establish if the second tumor represents an independent primary cancer or a metastasis. Therefore, the assessment of MPT clonal origin might help understand the disease behavior and improve the management/prognosis of the patient.Herein, we report a 73-year-old male smoker who developed 2 primary lung cancers (adenocarcinoma and squamous cell carcinoma) and a malignant peritoneal mesothelioma (PM).Whole exome sequencing (WES) of the 3 tumors and of germline DNA was performed to determine the clonal origin and identify genetic cancer susceptibility.Both lung cancers were characterized by a high mutational rate with distinct mutational profiles and activation of tumor-specific pathways. Conversely, the PM harbored a relative low number of genetic variants and a novel mutation in the WT1 gene that might be involved in the carcinogenesis of nonasbestos-related mesothelioma. Finally, WES of the germinal DNA displayed several single nucleotide polymorphisms in DNA repair genes likely conferring higher cancer susceptibility.Overall, WES did not disclose any somatic genetic variant shared across the 3 tumors, suggesting their clonal independency; however, the carcinogenic effect of smoke combined with a deficiency in DNA repair genes and the patient advanced age might have been responsible for the MPT development. This case highlights the WES importance to define the clonal origin of MPT and susceptibility to cancer.

17 Article CTLA-4 in mesothelioma patients: tissue expression, body fluid levels and possible relevance as a prognostic factor. 2016

Roncella, Silvio / Laurent, Stefania / Fontana, Vincenzo / Ferro, Paola / Franceschini, Maria Cristiana / Salvi, Sandra / Varesano, Serena / Boccardo, Simona / Vigani, Antonella / Morabito, Anna / Canessa, Pier Aldo / Giannoni, Ugo / Rosenberg, Ilan / Valentino, Alessandro / Fedeli, Franco / Merlo, Domenico Franco / Ceppi, Marcello / Riggio, Salvatore / Romani, Massimo / Saverino, Daniele / Poggi, Alessandro / Pistillo, Maria Pia. ·Division of Histopathology and Cytopathology, ASL5, La Spezia, Italy. · Department of Internal Medicine (DIMI), University of Genoa, Genoa, Italy. · Unit of Clinical Epidemiology, IRCCS AOU San Martino-IST, Genoa, Italy. · Division of Histopathology and Cytopathology, IRCCS AOU San Martino-IST, Genoa, Italy. · Unit of Clinical Oncology, ASL5, La Spezia, Italy. · Unit of Tumor Epigenetics, IRCCS AOU San Martino-IST, Genoa, Italy. · Division of Pneumology, ASL5, La Spezia, Italy. · Unit of Radiodiagnostic, ASL5, La Spezia, Italy. · Blood Transfusion Centre, IRCCS AOU-San Martino-IST, Genoa, Italy. · Department of Experimental Medicine, University of Genoa, Genoa, Italy. · Unit of Molecular Oncology and Angiogenesis, IRCCS AOU San Martino-IST, Genoa, Italy. · Unit of Tumor Epigenetics, IRCCS AOU San Martino-IST, Genoa, Italy. mariapia.pistillo@hsanmartino.it. ·Cancer Immunol Immunother · Pubmed #27207606.

ABSTRACT: CTLA-4 function as a negative regulator of T cell-mediated immune response is well established, whereas much less is known about the immunoregulatory role of its soluble isoform (sCTLA-4). No data are available on CTLA-4 expression and prognostic impact in malignant pleural mesothelioma (MPM). We investigated, by immunohistochemistry, CTLA-4 expression in tumor tissues and, by ELISA, sCTLA-4 levels in sera and matched pleural effusions from 45 MPM patients. Prognostic effect of CTLA-4 expression on overall survival (OS) was assessed through Cox regression and prognostic significance expressed as death rate ratio (HR). We found that 56.0 % of MPM tissues expressed CTLA-4 with variable intensity and percentage of positive cells estimated by the immunoreactive score. sCTLA-4 levels were significantly higher in sera (S-sCTLA-4) than in pleural effusions (PE-sCTLA-4) (geometric mean ratio = 2.70, P value = 0.020). CTLA-4 expression at the tissue level was higher in the epithelioid histological subtype than in the sarcomatoid, whereas at the serum level, it was higher in the sarcomatoid subtype. A homogeneous favorable prognostic effect was found for CTLA-4 overexpression in tissue, serum and pleural effusion. Interestingly, only the PE-sCTLA-4 was found to be a statistically significant positive prognostic factor (HR = 0.37, 95 % CI = 0.18-0.77, P value = 0.007). Indeed, PE-sCTLA-4 correlated with CTLA-4 expression in tissues, whereas this latter expression showed a weak association with OS. To confirm our findings, further experimental evidences obtained from a larger cohort of MPM patients are required. However, our results would indicate a positive correlation of PE-sCTLA-4 levels and OS in MPM patients.

18 Article SIRT1 at the crossroads of AKT1 and ERβ in malignant pleural mesothelioma cells. 2016

Pinton, Giulia / Zonca, Sara / Manente, Arcangela G / Cavaletto, Maria / Borroni, Ester / Daga, Antonio / Jithesh, Puthen V / Fennell, Dean / Nilsson, Stefan / Moro, Laura. ·Department of Pharmaceutical Sciences, University of Piemonte Orientale "A. Avogadro", 28100 Novara, Italy. · Department of Sciences and Technological Innovation, University of Piemonte Orientale "A. Avogadro", 15121 Alessandria, Italy. · Department of Health Sciences, University of Piemonte Orientale "A. Avogadro", 28100 Novara, Italy. · Department of Integrated Oncological Therapies, IRCCS San Martino-IST, 16132 Genova, Italy. · Division of Biomedical Informatics Research, Sidra Medical and Research Center, 26999 Doha, Qatar. · Department of Cancer Studies, Cancer Research UK Leicester Centre, University of Leicester, LE1 7RH Leicester, UK. · Department of Biosciences and Nutrition, Karolinska Institutet, S-141 57 Huddinge, Sweden. · Karo Bio AB, Novum, S-141 57 Huddinge, Sweden. ·Oncotarget · Pubmed #26885609.

ABSTRACT: In this report, we show that malignant pleural mesothelioma (MPM) patients whose tumors express high levels of AKT1 exhibit a significantly worse prognosis, whereas no significant correlation with AKT3 expression is observed. We provide data that establish a phosphorylation independent role of AKT1 in affecting MPM cell shape and anchorage independent cell growth in vitro and highlight the AKT1 isoform-specific nature of these effects.We describe that AKT1 activity is inhibited by the loss of SIRT1-mediated deacetylation and identify, by mass spectrometry, 11 unique proteins that interact with acetylated AKT1.Our data demonstrate a role of the AKT1/SIRT1/FOXM1 axis in the expression of the tumor suppressor ERβ. We further demonstrate an inhibitory feedback loop by ERβ, activated by the selective agonist KB9520, on this axis both in vitro and in vivo.Our data broaden the current knowledge of ERβ and AKT isoform-specific functions that could be valuable in the design of novel and effective therapeutic strategies for MPM.

19 Article Resveratrol induces intracellular Ca(2+) rise via T-type Ca(2+) channels in a mesothelioma cell line. 2016

Marchetti, Carla / Ribulla, Stefania / Magnelli, Valeria / Patrone, Mauro / Burlando, Bruno. ·Istituto di Biofisica, Consiglio Nazionale delle Ricerche, via De Marini 6, 16149 Genova, Italy. Electronic address: marchetti@ge.ibf.cnr.it. · Dipartimento di Scienze e Innovazione Tecnologica (DISIT), Università del Piemonte Orientale, viale T. Michel 11, 15121 Alessandria, Italy. · Istituto di Biofisica, Consiglio Nazionale delle Ricerche, via De Marini 6, 16149 Genova, Italy; Dipartimento di Scienze e Innovazione Tecnologica (DISIT), Università del Piemonte Orientale, viale T. Michel 11, 15121 Alessandria, Italy. ·Life Sci · Pubmed #26845536.

ABSTRACT: AIMS: Intracellular calcium (Ca(2+)) is known to play an important role in cancer development and growth. Resveratrol (Res) is a stilbene polyphenol occurring in several plant species and known for various possible beneficial effects, including its ability to inhibit proliferation and to induce apoptosis in cancer cells. This study was designed to determine whether Res affects Ca(2+) signaling in cancer cells. MAIN METHODS: We used the REN human mesothelioma cell line, as an in vitro cancer cell model, and the non-malignant human mesothelial MeT5A cell line, as normal cell model. Cytosolic Ca(2+) concentration was measured by the fluorescent indicator Fura-2. Immunofluorescence, Western blot, and siRNA technique were employed to assess the involvement of T-type Ca(2+) channels. Cell viability was determined by the calcein assay. KEY FINDINGS: REN cells transiently exposed to 1-10μM Res showed increasing peaks of Ca(2+) that were absent in Ca(2+)-free medium and were reduced by non-selective (Ni(2+)), and highly selective (NNC 55-0396) T-type Ca(2+) channels antagonist, and by siRNA knockout of Cav3.2T-type Ca(2+) channel gene. Dose-dependent curve of Res-induced Ca(2+) peaks showed a rightward shift in normal MeT-5A mesothelial cells (EC50=4.9μM) with respect to REN cells (EC50=2.7μM). Moreover, incubation with 3 and 10μM Res for 7days resulted in cell growth inhibition for REN, but not for MeT-5A cells. SIGNIFICANCE: Res induces Ca(2+) influx, possibly mediated through T-type Ca(2+) channels, with significant selectivity towards mesothelioma cells, suggesting a possible use as an adjuvant to chemotherapy drugs for mesothelioma clinical treatment.

20 Article Imaging of mesothelioma of tunica vaginalis testis. 2016

Bertolotto, M / Boulay-Coletta, I / Butini, R / Dudea, S M / Grenier, N / Oltmanns, G / Ramchandani, P / Stein, M W / Valentino, M / Derchi, Lorenzo E. ·Department of Radiology, University of Trieste, Trieste, Italy. · Service d'Imagerie Medical, Fondation Hopital Saint Joseph, Paris, France. · Department of Radiology, Ospedale S. Giacomo, Castelfranco Veneto, TV, Italy. · Department of Radiology, Univ. Med. Pharm. "Iuliu Hatieganu", Cluj-Napoca, Romania. · Department of Radiology, Pellegrin Hospital, Place Amelie Raba Leon, 33076, Bordeaux, France. · Department of Radiology, University Hospital of North Norway, Tromsø, N9038, Norway. · Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA. · Department of Radiology, Albert Einstein College of Medicine, Montefiore Medical Center, 111 E. 210th Street, Bronx, NY, 10467, USA. · Department of Radiology, Sant'Antonio Hospital, Tolmezzo, UD, Italy. · Department of Health Sciences, University of Genoa, Largo R. Benzi, 10, Genova, Italy. derchi@unige.it. · Radiologia d'Urgenza, IRCCS Azienda Ospedaliera Universitaria San Martino IST, Largo R. Benzi, 10, I-16122, Genova, Italy. derchi@unige.it. ·Eur Radiol · Pubmed #26115654.

ABSTRACT: OBJECTIVES: To describe the imaging findings in a series of patients with mesothelioma of the tunica vaginalis testis. METHODS: We reviewed clinical data, imaging findings and follow-up information in a series of 10 pathology-proven cases of mesothelioma (all had US; 2 had MR) of the tunica vaginalis. RESULTS: A variety of patterns could be observed, the most common (5/10) being a hydrocele with parietal, solid and hypervascular vegetations; one patient had a septated hydrocele with hypervascular walls; one had multiple, solid nodules surrounded by a small, physiological quantity of fluid; one a cystic lesion with thick walls and vegetations compressing the testis; two had a solid paratesticular mass. MR showed multiple small nodules on the surface of the tunica vaginalis in one case and diffuse thickening and vegetations in the other one; lesions had low signal intensity on T2-w images and were hypervascular after contrast injection. CONCLUSIONS: A preoperative diagnosis of mesotheliomas presenting as solid paratesticular masses seems very difficult with imaging. On the contrary, the diagnosis must be considered in patients in whom a hydrocele with parietal vegetations is detected, especially if these show high vascularity. KEY POINTS: Mesotheliomas of the tunica vaginalis are rare, often challenging to diagnose preoperatively. Most common finding is a complex hydrocele with hypervascular parietal vegetations. Septated hydrocele, nodules without hydrocele, a thick-walled paratesticular cyst are less common. Preoperative diagnosis may allow aggressive surgical approach and, possibly, a better prognosis.

21 Article MDM2 and HIF1alpha expression levels in different histologic subtypes of malignant pleural mesothelioma: correlation with pathological and clinical data. 2015

Pasello, Giulia / Urso, Loredana / Mencoboni, Manlio / Grosso, Federica / Ceresoli, Giovanni Luca / Lunardi, Francesca / Vuljan, Stefania Edith / Bertorelle, Roberta / Sacchetto, Valeria / Ciminale, Vincenzo / Rea, Federico / Favaretto, Adolfo / Conte, PierFranco / Calabrese, Fiorella. ·Department of Clinical and Experimental Oncology, Medical Oncology 2, Istituto Oncologico Veneto IRCCS Padova, Italy. · Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. · Oncology Unit, Villa Scassi Hospital, Genova, Italy. · Oncohematologic Department, Mesothelioma Unit, Oncology, SS Antonio e Biagio General Hospital, Alessandria, Italy. · Oncology, Cliniche Humanitas Gavazzeni, Bergamo, Italy. · Department of Cardio-Thoracic and Vascular Sciences, University of Padova, Padova, Italy. · Department of Clinical and Experimental Oncology, Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IRCCS, Padova, Italy. ·Oncotarget · Pubmed #26544728.

ABSTRACT: Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited treatment options. Sarcomatoid/biphasic mesotheliomas are characterized by more aggressive behaviour and a poorer prognosis compared with the epithelioid subtype. To date prognostic and tailored therapeutic biomarkers are lacking. The present study analyzed the expression levels of MDM2 and HIF1alpha in different histologic subtypes from chemonaive MPM patients. Diagnostic biopsies of MPM patients from four Italian cancer centers were centrally collected and analyzed. MDM2 and HIF1alpha expression levels were investigated through immunohistochemistry and RT-qPCR. Pathological assessment of necrosis, inflammation and proliferation index was also performed. Molecular markers, pathological features and clinical characteristics were correlated to overall survival (OS) and progression free survival (PFS). Sixty MPM patients were included in the study (32 epithelioid and 28 non-epithelioid). Higher levels of MDM2 (p < 0.001), HIF1alpha (p = 0.013), necrosis (p = 0.013) and proliferation index (p < 0.001) were seen mainly in sarcomatoid/biphasic subtypes. Higher levels of inflammation were significantly associated with epithelioid subtype (p = 0.044). MDM2 expression levels were correlated with HIF1alpha levels (p = 0.0001), necrosis (p = 0.008) and proliferation index (p = 0.009). Univariate analysis showed a significant correlation of non-epithelioid histology (p = 0.04), high levels of necrosis (p = 0.037) and proliferation index (p = 0.0002) with shorter PFS. Sarcomatoid/biphasic and epithelioid mesotheliomas showed different MDM2 and HIF1alpha expression levels and were characterized by different levels of necrosis, proliferation and inflammation. Further studies are warranted to confirm a prognostic and predictive role of such markers and features.

22 Article Intracellular lactate-mediated induction of estrogen receptor beta (ERβ) in biphasic malignant pleural mesothelioma cells. 2015

Manente, Arcangela G / Pinton, Giulia / Zonca, Sara / Cilli, Michele / Rinaldi, Maurizio / Daga, Antonio / Nilsson, Stefan / Moro, Laura. ·Department of Pharmaceutical Sciences, University of Piemonte Orientale "A. Avogadro", 28100, Novara, Italy. · IRCCS San Martino-IST, 16132, Genova, Italy. · Karo Bio AB, Novum, S-141 57, Huddinge, Sweden. · Department of Biosciences and Nutrition, Karolinska Institutet, Novum, S-141 57, Huddinge, Sweden. ·Oncotarget · Pubmed #26208479.

ABSTRACT: Biphasic malignant pleural mesothelioma (MPM) is the second most common histotype of MPM. It is histologically characterized by the concomitant presence of epithelioid and sarcomatoid features, the latter associated with worse prognosis. In this report we describe that silencing of AKT1 in spindle-shaped biphasic MPM cells promotes the shift toward an epithelioid phenotype. Furthermore, AKT1 silencing resulted in decreased expression of the lactate/H+ symporter MCT4 and its chaperone CD147/Basigin, and in the induction of estrogen receptor β (ERβ) expression. We provide evidence that ERβ expression is induced by increased intracellular lactate concentration. Spheroid culturing and tumor growth of ERβ negative biphasic MPM in nude mice resulted in the induction of ERβ expression and response to the selective agonist KB9520. In both models, the treatment with the ERβ agonist results in reduced cell proliferation, decreased expression of MCT4 and CD147/Basigin and increased acetylation and inactivation of AKT1. Collectively, in response to metabolic changes, ERβ expression is induced and exerts an anti-tumor effect through selective agonist activation. The possibility to reverse the more aggressive biphasic mesothelioma histotype by targeting ERβ with a selective agonist could represent a new effective treatment strategy.

23 Article Prognostic Score of Long-Term Survival After Surgery for Malignant Pleural Mesothelioma: A Multicenter Analysis. 2015

Leuzzi, Giovanni / Rea, Federico / Spaggiari, Lorenzo / Marulli, Giuseppe / Sperduti, Isabella / Alessandrini, Gabriele / Casiraghi, Monica / Bovolato, Pietro / Pariscenti, Gianluca / Alloisio, Marco / Infante, Maurizio / Pagan, Vittore / Fontana, Paolo / Oliaro, Alberto / Ruffini, Enrico / Ratto, Giovanni Battista / Leoncini, Giacomo / Sacco, Rocco / Mucilli, Felice / Facciolo, Francesco. ·Department of Surgical Oncology, Thoracic Surgery Unit, Regina Elena National Cancer Institute, Rome, Italy. Electronic address: gio.leuzzi@yahoo.it. · Department of Cardiologic, Thoracic and Vascular Sciences, University of Padua, Padua, Italy. · Thoracic Surgery Division, European Institute of Oncology, University of Milan, Milan, Italy. · Scientific Direction, Regina Elena National Cancer Institute, Rome, Italy. · Department of Surgical Oncology, Thoracic Surgery Unit, Regina Elena National Cancer Institute, Rome, Italy. · Thoracic Surgery Unit, Community Hospital, Brescia, Italy. · Division of Thoracic Surgery, Humanitas Research Hospital-Rozzano, Milan, Italy. · Division of Thoracic Surgery, Ospedale di Mestre, Venezia-Mestre, Italy. · Department of Thoracic Surgery, University of Turin, San Giovanni Battista Hospital, Turin, Italy. · Division of Thoracic Surgery, IRCCS AOU "San Martino" IST, Genoa, Italy. · Division of Surgery, Università-ASL, Chieti, Italy. ·Ann Thorac Surg · Pubmed #26163973.

ABSTRACT: BACKGROUND: Despite ongoing efforts to improve therapy in malignant pleural mesothelioma, few patients undergoing extrapleural pneumonectomy experience long-term survival (LTS). This study aims to explore predictors of LTS after extrapleural pneumonectomy and to define a prognostic score. METHODS: From January 2000 to December 2010, we retrospectively reviewed clinicopathologic and oncological factors in a multicenter cohort of 468 malignant pleural mesothelioma patients undergoing extrapleural pneumonectomy. LTS was defined as survival longer than 3 years. Associations were evaluated using χ(2), Student's t, and Mann-Whitney U tests. Logistic regression, Cox regression hazard model, and bootstrap analysis were applied to identify outcome predictors. Survival curves were calculated by the Kaplan-Meier method. Receiver operating characteristic analyses were used to estimate optimal cutoff and area under the curve for accuracy of the model. RESULTS: Overall, 107 patients (22.9%) survived at least 3 years. Median overall, cancer-specific, and disease-free survival times were 60 (95% confidence interval [CI], 51 to 69), 63 (95% CI, 54 to 72), and 49 months (95% CI, 39 to 58), respectively. At multivariate analysis, age (odds ratio, 0.51; 95% CI, 0.31 to 0.82), epithelioid histology (odds ratio, 7.07; 95% CI, 1.56 to 31.93), no history of asbestos exposure (odds ratio, 3.13; 95% CI, 1.13 to 8.66), and the ratio between metastatic and resected lymph nodes less than 22% (odds ratio, 4.12; 95% CI, 1.68 to 10.12) were independent predictors of LTS. According to these factors, we created a scoring system for LTS that allowed us to correctly predict overall, cancer-specific, and disease-free survival in the total sample, obtaining two different groups with favorable or poor prognosis (area under the curve, 0.74; standard error, 0.04; p < 0.0001). CONCLUSIONS: Our prognostic model facilitates the prediction of LTS after surgery for malignant pleural mesothelioma and can help to stratify the outcome and, eventually, tailor postoperative treatment.

24 Article Gene-asbestos interaction in malignant pleural mesothelioma susceptibility. 2015

Tunesi, Sara / Ferrante, Daniela / Mirabelli, Dario / Andorno, Silvano / Betti, Marta / Fiorito, Giovanni / Guarrera, Simonetta / Casalone, Elisabetta / Neri, Monica / Ugolini, Donatella / Bonassi, Stefano / Matullo, Giuseppe / Dianzani, Irma / Magnani, Corrado. ·Department of Translational Medicine, Unit of Medical Statistics and Cancer Epidemiology, CPO Piemonte and University of Piemonte Orientale, Novara, Italy, Center for Cancer Epidemiology and Prevention, City of Health and Science Hospital, Turin, Italy, sara.tunesi@med.uniupo.it. · Department of Translational Medicine, Unit of Medical Statistics and Cancer Epidemiology, CPO Piemonte and University of Piemonte Orientale, Novara, Italy. · Center for Cancer Epidemiology and Prevention, City of Health and Science Hospital, Turin, Italy, Interdepartmental Center "G. Scansetti", University of Turin, Turin, Italy. · Department of Health Sciences, University of Piemonte Orientale, Novara, Italy. · Genomic Variation in Human Population and Complex Diseases Unit, Human Genetics Foundation, Turin, Italy, Department of Medical Sciences, University of Turin, Turin, Italy. · Unit of Clinical and Molecular Epidemiology, IRCCS San Raffaele Pisana, Rome, Italy. · Department of Internal Medicine, University of Genoa and IRCSS AOU San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. · Department of Translational Medicine, Unit of Medical Statistics and Cancer Epidemiology, CPO Piemonte and University of Piemonte Orientale, Novara, Italy, Interdepartmental Center "G. Scansetti", University of Turin, Turin, Italy. ·Carcinogenesis · Pubmed #26139392.

ABSTRACT: Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, on average less than 10% of subjects highly exposed to asbestos develop MPM, suggesting the possible involvement of other risk factors. To identify the genetic factors that may modulate the risk of MPM, we conducted a gene-environment interaction analysis including asbestos exposure and 15 single nucleotide polymorphisms (SNPs) previously identified through a genome-wide association study on Italian subjects. In the present study, we assessed gene-asbestos interaction on MPM risk using relative excess risk due to interaction and synergy index for additive interaction and V index for multiplicative interaction. Generalized multifactor dimensionality reduction (GMDR) analyses were also performed. Positive deviation from additivity was found for six SNPs (rs1508805, rs2501618, rs4701085, rs4290865, rs10519201, rs763271), and four of them (rs1508805, rs2501618, rs4701085, rs10519201) deviated also from multiplicative models. However, after Bonferroni correction, deviation from multiplicative model was still significant for rs1508805 and rs4701085 only. GMDR analysis showed a strong MPM risk due to asbestos exposure and suggested a possible synergistic effect between asbestos exposure and rs1508805, rs2501618 and rs5756444. Our results suggested that gene-asbestos interaction may play an additional role on MPM susceptibility, given that asbestos exposure appears as the main risk factor.

25 Article Malignant mesothelioma due to non-occupational asbestos exposure from the Italian national surveillance system (ReNaM): epidemiology and public health issues. 2015

Marinaccio, Alessandro / Binazzi, Alessandra / Bonafede, Michela / Corfiati, Marisa / Di Marzio, Davide / Scarselli, Alberto / Verardo, Marina / Mirabelli, Dario / Gennaro, Valerio / Mensi, Carolina / Schallemberg, Gert / Merler, Enzo / Negro, Corrado / Romanelli, Antonio / Chellini, Elisabetta / Silvestri, Stefano / Cocchioni, Mario / Pascucci, Cristiana / Stracci, Fabrizio / Ascoli, Valeria / Trafficante, Luana / Angelillo, Italo / Musti, Marina / Cavone, Domenica / Cauzillo, Gabriella / Tallarigo, Federico / Tumino, Rosario / Melis, Massimo / Anonymous3700832. ·Italian Workers' Compensation Authority (INAIL), Department of Occupational and Environmental Medicine, Epidemiology and Hygiene, Unit of Occupational and Environmental Epidemiology, Italian Mesothelioma Register, Rome, Italy. · Valle d'Aosta Health Local Unit, Regional Operating Centre of Valle d'Aosta (COR Valle d'Aosta), Aosta, Italy. · COR Piedmont, Unit of Cancer Prevention, University of Turin and CPO-Piemonte, Torino, Italy. · COR Liguria, UO Epidemiology, IRCCS Azienda Ospedaliera Universitaria San Martino, National Cancer Research Institute (IST), Genova, Italy. · COR Lombardy, Department of Preventive Medicine, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico and University of Milan, Milan, Italy. · COR Province of Trento, Provincial Unit of Health, Hygiene and Occupational Medicine, Trento, Italy. · COR Veneto, Occupational Health Unit, Department of Prevention, Padua, Italy. · Clinical Unit of Occupational Medicine, COR Friuli-Venezia Giulia, University of Trieste-Trieste General Hospitals, Trieste, Italy. · COR Emilia-Romagna, Health Local Unit, Public Health Department, Reggio Emilia, Italy. · Unit of Environmental and Occupational Epidemiology, COR Tuscany, Cancer Prevention and Research Institute, Florence, Italy. · Environmental and Health Sciences Department, COR Marche, University of Camerino, Hygiene, Camerino, Italy. · Department of Hygiene and Public Health, COR Umbria, University of Perugia, Perugia, Italy. · Department of Experimental Medicine, COR Lazio, University La Sapienza, Rome, Italy. · COR Abruzzo, Health Local Unit, Occupational Medicine Unit, Pescara, Italy. · Department of Experimental Medicine, COR Campania, Second University of Naples, Naples, Italy. · Department of Internal Medicine and Public Medicine, Section of Occupational Medicine ''B.Ramazzini'', COR Puglia, University of Bari, Bari, Italy. · COR Basilicata, Epidemiologic Regional Centre, Potenza, Italy. · COR Calabria, Public Health Unit, Crotone, Italy. · Ragusa Cancer Register Unit, COR Sicily, 'Civile-M.P. Arezzo' Hospital, Ragusa, Italy. · COR Sardegna, Regional Epidemiological Centre, Cagliari, Italy. ·Occup Environ Med · Pubmed #26045315.

ABSTRACT: INTRODUCTION: Italy produced and imported a large amount of raw asbestos, up to the ban in 1992, with a peak in the period between 1976 and 1980 at about 160,000 tons/year. The National Register of Mesotheliomas (ReNaM, "Registro Nazionale dei Mesoteliomi" in Italian), a surveillance system of mesothelioma incidence, has been active since 2002, operating through a regional structure. METHODS: The Operating Regional Center (COR) actively researches cases and defines asbestos exposure on the basis of national guidelines. Diagnostic, demographic and exposure characteristics of non-occupationally exposed cases are analysed and described with respect to occupationally exposed cases. RESULTS: Standardised incidence rates for pleural mesothelioma in 2008 were 3.84 (per 100,000) for men and 1.45 for women, respectively. Among the 15,845 mesothelioma cases registered between 1993 and 2008, exposure to asbestos fibres was investigated for 12,065 individuals (76.1%), identifying 530 (4.4%) with familial exposure (they lived with an occupationally exposed cohabitant), 514 (4.3%) with environmental exposure to asbestos (they lived near sources of asbestos pollution and were never occupationally exposed) and 188 (1.6%) exposed through hobby-related or other leisure activities. Clusters of cases due to environmental exposure are mainly related to the presence of asbestos-cement industry plants (Casale Monferrato, Broni, Bari), to shipbuilding and repair activities (Monfalcone, Trieste, La Spezia, Genova) and soil contamination (Biancavilla in Sicily). CONCLUSIONS: Asbestos pollution outside the workplace contributes significantly to the burden of asbestos-related diseases, suggesting the need to prevent exposures and to discuss how to deal with compensation rights for malignant mesothelioma cases induced by non-occupational exposure to asbestos.

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