Paola Muti

McMaster University, Hamilton, Ontario, Canada

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Publications (219)1055.49 Total impact

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    ABSTRACT: Malignant pleural mesothelioma is a poorly treated neoplasia arising from the pleural mesothelial lining. Here we document that the leaf extract of Cynara scolymus exerts broad antitumoral effects both in vitro and in vivo on mesothelioma cell lines. We found that Cynara scolymus treatment affects strongly cell growth, migration and tumor engraftment of mesothelioma cell lines. Strikingly, dietary feeding with Cynara scolymus leaf extract reduces the growth of mesothelioma xenografted tumors similarly to pemetrexed, a commonly employed drug in the treatment of mesothelioma. In aggregate our findings suggest that leaf extract of Cynara scolymus holds therapeutic potential for the treatment of mesothelioma.
    Oncotarget 06/2015; · 6.63 Impact Factor
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    ABSTRACT: Aspirin, the pro-drug of salicylate, is associated with reduced incidence of death from cancers of the colon, lung and prostate and is commonly prescribed in combination with metformin in individuals with type 2 diabetes. Salicylate activates the AMP-activated protein kinase (AMPK) by binding at the A-769662 drug binding site on the AMPK β1subunit, a mechanism, that is distinct from metformin which disrupts the adenylate charge of the cell. A hallmark of many cancers is high rates of fatty acid synthesis and AMPK inhibits this pathway through phosphorylation of acetyl-CoA carboxylase (ACC). It is currently unknown whether targeting the AMPK-ACC-lipogenic pathway using salicylate and/or metformin may be effective for inhibiting cancer cell survival. Salicylate suppresses clonogenic survival of prostate and lung cancer cells at therapeutic concentrations achievable following the ingestion of aspirin (<1.0mM); effects not observed in prostate (PNT1A) and lung (MRC-5) epithelial cell lines. Salicylate concentrations of 1mM increased the phosphorylation of ACC and suppressed de novo lipogenesis and these effects were enhanced with the addition of clinical concentrations of metformin (100 mM) and eliminated in mouse embryonic fibroblasts (MEFs) deficient in AMPK b1. Supplementation of media with fatty acids and/or cholesterol reverses the suppressive effects of salicylate and metformin on cell survival indicating the inhibition of de novo lipogenesis is likely important. Pre-clinical studies evaluating the use of salicylate based drugs alone and in combination with metformin to inhibit de novo lipogenesis and the survival of prostate and lung cancers are warranted.
    Biochemical Journal 05/2015; DOI:10.1042/BJ20150122 · 4.78 Impact Factor
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    PLoS ONE 04/2015; 10(4):e0124894. DOI:10.1371/journal.pone.0124894 · 3.53 Impact Factor
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    ABSTRACT: Background: Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide with a high rate of recurrence. MicroRNAs (miRNAs) are gene regulators playing an important role in oral carcinogenesis. We aimed to identify and functionally characterize miRNAs that predict recurrence in OSCC.Methods: We collected 92 OSCC with their normal tissue counterparts and we performed miRNAs expression profiling on 74 OSCC and 38 normal tissues. The association between the expression of microRNAs and clinical outcome was evaluated in 69 followed-up patients.Results: Four of the miRNAs deregulated between OSCC and normal tissues. areprognostic for recurrence either when considered individually or as a group. Depletion of the expression of prognostic miRNAs inhibits the proliferation of OSCC cells Conclusions: MicroRNAs are differentially expressed in OSCC versus normal samples. The expression of 4 prognostic microRNAs signature is able to predict recurrence risk independently from other clinical factors in OSCC. This article is protected by copyright. All rights reserved.
    Head & Neck 12/2014; DOI:10.1002/hed.23969 · 3.01 Impact Factor
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    ABSTRACT: Epidemiological studies have examined breast cancer risk in relation to sex hormone concentrations measured by different methods: "extraction" immunoassays (with prior purification by organic solvent extraction, with or without column chromatography), "direct" immunoassays (no prior extraction or column chromatography), and more recently with mass spectrometry-based assays. We describe the associations of estradiol, estrone and testosterone with both body mass index and breast cancer risk in postmenopausal women according to assay method, using data from a collaborative pooled analysis of 18 prospective studies. In general, hormone concentrations were highest in studies that used direct assays and lowest in studies that used mass spectrometry-based assays. Estradiol and estrone were strongly positively associated with body mass index, regardless of the assay method; testosterone was positively associated with body mass index for direct assays, but less clearly for extraction assays, and there were few data for mass spectrometry assays. The correlations of estradiol with body mass index, estrone and testosterone were lower for direct assays than for extraction and mass spectrometry assays, suggesting that the estimates from the direct assays were less precise. For breast cancer risk, all three hormones were strongly positively associated with risk regardless of assay method (except for testosterone by mass spectrometry where there were few data), with no statistically significant differences in the trends, but differences may emerge as new data accumulate. Future epidemiological and clinical research studies should continue to use the most accurate assays that are feasible within the design characteristics of each study.
    Steroids 10/2014; DOI:10.1016/j.steroids.2014.09.001 · 2.72 Impact Factor
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    ABSTRACT: Background: MicroRNAs (miRNAs) have been implicated in the regulation of key metabolic, inflammatory and malignant pathways, hence they might be considered both predictors and players of cancer development. Methods: Using a case-control study design nested in the ORDET prospective cohort study, we addressed the possibility that specific microRNAs can serve as early predictors of breast cancer incidence in postmenopausal women. We compared leucocyte miRNA profiles of 133 incident postmenopausal breast cancer cases and profiles of 133 women who remained healthy over a follow-up period of twenty years. Results: The analysis identified 20 differentially expressed miRNAs, 15 of them were down-regulated. Among the 20 miRNAs, miRNA-145-5p and miRNA-145-3p, each derived from another arm of the respective pre-miRNA, were consistently and significantly down-regulated in all databases we surveyed. For example, analysis of more than 1,500 patients (the UK Metabric cohort) indicated that high abundance of miRNA 145-3p and miRNA-145-5p was associated with longer, and for miRNA-145-3p also statistically significant, survival. The experimental data attributed different roles to the identified microRNAs: while the 5p isoform was associated with invasion and metastasis the other isoform appears related to cell proliferation. Conclusions: These observations and the prospective design of our study lend support to the hypothesis that down-regulation of specific microRNAs constitutes an early event in cancer development. This finding might be utilized for breast cancer prevention. Impact: The identification of the miRNAs as long-term biomarkers of breast cancer may have an impact of breast cancer prevention and early detection.
    Cancer Epidemiology Biomarkers & Prevention 07/2014; DOI:10.1158/1055-9965.EPI-14-0398 · 4.32 Impact Factor
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    ABSTRACT: Chemoresistance is one of the main problems in the therapy of cancer. There are a number of different molecular mechanisms through which a cancer cell acquires resistance to a specific treatment, such as alterations in drug uptake, drug metabolism and drug targets. There are several lines of evidence showing that miRNAs are involved in drug sensitivity of cancer cells in different tumor types and by different treatments. In this review, we provide an overview of the more recent and significant findings on the role of miRNAs in cancer cell drug resistance. In particular, we focus on specific miRNA mechanisms of action that in various steps lead from drug cell sensitivity to drug cell resistance. We also provide evidence on how miRNA profiling may unveil relevant predictive biomarkers for therapy outcomes.
    06/2014; 2. DOI:10.1186/2052-8426-2-16
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    ABSTRACT: Increasing evidence witnesses that cancer metabolism alterations represent a critical hallmark for many types of human tumors. There is a strong need to understand and dissect the molecular mechanisms underlying cancer metabolism to envisage specific biomarkers and underpin critical molecular components that might represent novel therapeutic targets. One challenge, that is the focus of this review, is the reprogramming of the altered metabolism of a cancer cell toward that of un-transformed cell. The anti-hyperglicemic agent, metformin has proven to be effective in reprogramming the metabolism of cancer cells even from those subpopulations endowed with cancer stem like features and very high chemoresistenace to conventional anticancer treatments. A functional interplay involving selective modulation of microRNAs (miRNAs) takes place along the anticancer metabolic effects exerted by metformin. The implications of this interplay will be also discussed in this review.
  • Value in Health 05/2014; 17(3):A72. DOI:10.1016/j.jval.2014.03.421 · 2.89 Impact Factor
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    ABSTRACT: There is growing evidence that 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) plays a role in breast cancer prevention and survival. It elicits a variety of antitumor activities like controlling cellular differentiation, proliferation and angiogenesis. Most of its biological effects are exerted via its nuclear receptor which acts as a transcriptional regulator. Here, we carried out a genome-wide investigation of the primary transcriptional targets of 1α,25(OH)2D3 in breast epithelial cancer cells using RNA-Seq technology. We identified early transcriptional targets of 1α,25(OH)2D3 involved in adhesion, growth regulation, angiogenesis, actin cytoskeleton regulation, hexose transport, inflammation and immunomodulation, apoptosis, endocytosis and signaling. Furthermore, we found several transcription factors to be regulated by 1α,25(OH)2D3 that subsequently amplify and diversify the transcriptional output driven by 1α,25(OH)2D3 leading finally to a growth arrest of the cells. Moreover, we could show that 1α,25(OH)2D3 elevates the trimethylation of histone H3 lysine 4 at several target gene promoters. Our present transcriptomic analysis of differential expression after 1α,25(OH)2D3 treatment provides a resource of primary 1α,25(OH)2D3 targets that might drive the antiproliferative action in breast cancer epithelial cells.
    The Journal of steroid biochemistry and molecular biology 04/2014; 143. DOI:10.1016/j.jsbmb.2014.03.007 · 4.05 Impact Factor
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    ABSTRACT: Tumor initiation and progression are the outcomes of a stepwise accumulation of genetic alterations. Among these, gene amplification and aberrant expression of oncogenic proteins, as well as deletion or inactivation of tumor suppressor genes, represent hallmark steps. Mounting evidence collected over the last few years has identified different populations of non-coding RNAs as major players in tumor suppression in almost all cancer types. Elucidating the diverse molecular mechanisms underlying the roles of non-coding RNAs in tumor progression might provide illuminating insights, potentially able to assist improved diagnosis, better staging and effective treatments of human cancers. Here we focus on several groups of tumor suppressor microRNAs, whose downregulation exerts a profound oncologic impact and might be harnessed for the benefit of cancer patients.
    FEBS letters 03/2014; 588(16). DOI:10.1016/j.febslet.2014.03.033 · 3.34 Impact Factor
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    ABSTRACT: Metabolic remodeling is a hallmark of cancer progression and may affect tumor chemoresistance. Here we investigated by 1H-NMR/PCA analysis the metabolic profile of chemoresistant breast cancer cell subpopulations (ALDHbright cells) and their response to metformin, a promising anticancer metabolic modulator. The purified ALDHbright cells exhibited a different metabolic profile as compared to their chemosensitive ALDHlow counterparts. Metformin treatment strongly affected the metabolism of the ALDHbright cells thereby affecting, among the others, the glutathione metabolism, whose upregulation is a feature of progenitor-like, chemoresistant cell subpopulations. Globally, metformin treatment reduced the differences between ALDHbright and ALDHlow cells, making the former more similar to the latter. Metformin broadly modulated microRNAs in the ALDHbright cells, with a large fraction of them predicted to target the same metabolic pathways experimentally identified by 1H-NMR. Additionally, metformin modulated the levels of c-MYC and IRS-2, and this correlated with changes of the microRNA-33a levels. In summary, we observed, both by 1H-NMR and microRNA expression studies, that metformin treatment reduced the differences between the chemoresistant ALDHbright cells and the chemosensitive ALDHlow cells. This works adds on the potential therapeutic relevance of metformin and shows the potential for metabolic reprogramming to modulate cancer chemoresistance.
    Oncotarget 03/2014; 5(12). · 6.63 Impact Factor
  • Paola Muti
    Nature Reviews Cancer 01/2014; DOI:10.1038/nrc3518-c1 · 29.54 Impact Factor
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    ABSTRACT: Cancer metabolism is the focus of intense research, which witnesses its key role in human tumors. Diabetic patients treated with metformin exhibit a reduced incidence of cancer and cancer-related mortality. This highlights the possibility that the tackling of metabolic alterations might also hold promising value for treating cancer patients. Here, we review the emerging role of metformin as a paradigmatic example of an old drug used worldwide to treat patients with type II diabetes which to date is gaining strong in vitro and in vivo anticancer activities to be included in clinical trials. Metformin is also becoming the focus of intense basic and clinical research on chemoprevention, thus suggesting that metabolic alteration is an early lesion along cancer transformation. Metabolic reprogramming might be a very efficient prevention strategy with a profound impact on public health worldwide.
    12/2013; 3(4):1051-75. DOI:10.3390/metabo3041051
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    ABSTRACT: We identified a discrete number of microRNAs differentially expressed in benign or malignant mesothelial tissues. We focused on mir-145 whose levels were significantly downregulated in malignant mesothelial tissues and malignant pleural mesothelioma (MPM) cell lines as compared to benign tissues (pleura, peritoneum or cysts). We show that promoter hyper-methylation caused very low levels in MPM cell lines and specimens. Treatment of MPM cell lines with mir-145 agonists negatively modulated some protumorigenic properties of MPM cells, such as clonogenicity, cell migration and resistance to pemetrexed treatment. The main effector mechanism of the clonogenic death induced by mir-145 was that of accelerated senescence. We found that mir-145 targeted OCT4 via specific binding to its 3'-UTR. Increased intracellular levels of mir-145 decreased the levels of OCT4 and its target gene ZEB1, thereby counteracting the increase of OCT4 induced by pemetrexed treatment which is known to favor the development of chemoresistant cells. In line with this, reintroduction of OCT4 into mimic-145 treated cells counteracted the effects on clonogenicity and replicative senescence. This further supports the relevance of the mir-145-OCT4 interaction for the survival of MPM cells. The potential use of mir-145 expression levels to classify benign vs malignant mesothelial tissues and the differences between pemetrexed-induced senescence and that induced by the re-expression of mir-145 are discussed.Oncogene advance online publication, 18 November 2013; doi:10.1038/onc.2013.476.
    Oncogene 11/2013; DOI:10.1038/onc.2013.476 · 8.56 Impact Factor
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    ABSTRACT: TP53 mutation is associated with decreased survival rate in head and neck squamous cell carcinoma (HNSCC) patients. We set out to identify microRNAs (miRNAs) whose expression associates with TP53 mutation and survival in HNSCC. We analyzed TP53 status by direct sequencing of exons 2 through 11 of a prospective series of 121 HNSCC samples and assessed its association with outcome in 109 followed-up patients. We carried out miRNA expression profiling on 121 HNSCC samples and 66 normal counterparts. miRNA associations with TP53 mutations and outcome were evaluated. A TP53 mutation was present in 58% of the tumors and TP53 mutations were significantly associated with a shorter recurrence-free survival. This association was stronger in the clinical subgroup of patients subjected to adjuvant therapy after surgery.The expression of 49 miRNAs was significantly associated with TP53 status. Among these 49, we identified a group of 12 miRNAs whose expression correlates with recurrence-free survival and a group of 4 miRNAs that correlates with cancer-specific survival. The two groups share three miRNAs. Importantly, miRNAs that correlate with survival are independent prognostic factors either when considered individually or as signatures. miRNAs expression associates with TP53 status and with reduced survival after surgical treatment of squamous cell carcinoma of the head and neck.
    Annals of Oncology 10/2013; 24(12). DOI:10.1093/annonc/mdt380 · 6.58 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) are characterized as small RNA molecules that modulate gene transcription in a posttranslational manner. Functionally, miRNAs play important roles in a diverse number of biological processes, including cell development, differentiation, proliferation, and apoptosis. Consequently, changes in the expression pattern of miRNAs have been associated with multiple human pathologies, including cancer. Based on these alterations, distinct miRNAs can be utilized as markers for cancer risk evaluation or used in tumour detection. Recent evidence has indicated that lifestyle factors, such as nutrition, physical activity, and glycemic control provide health benefits through regulation of miRNA expression. In this review, we provide a concise overview of miRNA regulation, biosynthesis, and their expression patterns in normal and malignant tissue. We then summarize the emerging knowledge of how lifestyle factors, including nutrients, exercise, and hypoglycemic agents modify miRNAs and are involved in cancer prevention. Finally, we conclude by providing recommendation for future investigations into novel agents that can modulate miRNAs and act as chemotherapeutic agents against cancer.
    09/2013; 2(2):82-90. DOI:10.2174/22115366113029990013
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    ABSTRACT: Objective Chronic lung disease is exacerbated by comorbid psychiatric issues and treatment of depression may improve disease symptoms. We sought to add to the literature as to whether depression is associated with pulmonary function in healthy adults.Methods In 2551 healthy adults from New York State, we studied the association of depression via the Center for Epidemiologic Studies Depression scale (CES-D) scale score and forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) using general linear models and a cross-sectional design.ResultsWe identified statistically significant inverse trends in FEV1, FVC, FEV1%, and FVC% by CES-D category, especially in ever-smokers and men. When adjusted for covariates, the difference in FEV1 and FEV1% for smokers with more than 18.5 lifetime pack-years from CES-D scores 0 to 3 to 16 or more (depressed) is approximately 0.25 l and 5.0% (adjusted p values for trend are <.001 and .019, respectively). In men, we also observed statistically significant inverse trends in pulmonary function with increasing CES-D.Conclusions We identified an inverse association of depressive symptoms and pulmonary function in healthy adults, especially in men and individuals with a heavy smoking history. Further studies of these associations are essential for the development and tailoring of interventions for the prevention and treatment of chronic lung disease.
    Psychosomatic Medicine 08/2013; 75(8). DOI:10.1097/PSY.0b013e3182a15672 · 4.09 Impact Factor
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    ABSTRACT: Introduction Previous studies showed that higher testosterone levels are associated with greater risk of breast cancer in premenopausal women, but the literature is scant and inconsistent. Methods In a prospective nested case-control study of 104 premenopausal women with incident breast cancer and 225 matched controls, all characterized by regular menstrual cycles throughout their lifetime, we measured the concentration of estradiol, total and free testosterone (FT), progesterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in blood samples collected on days 20 through 24 of their cycles. Results In logistic regression models, the multivariate odds ratios (ORs) of invasive breast cancer for women in the highest tertile of circulating FT compared with the lowest was 2.43 (95% confidence interval (95% CI), 1.15 to 5.10; Ptrend = 0.03), whereas for total testosterone, the association had the same direction but was not statistically significant (OR, 1.27; 95% CI, 0.62 to 2.61; Ptrend = 0.51). Endogenous progesterone was not statistically associated with breast cancer (OR, 1.16; 95% CI, 0.60 to 2.27; Ptrend = 0.75), nor were the other considered hormones. Conclusions Consistent with previous prospective studies in premenopausal women and our own earlier investigation, we observed that higher levels of FT are positively associated with breast cancer risk in women with regular menstrual cycles throughout their lifetimes. No evidence of risk was found associated with the other endogenous sex steroids.
    Breast cancer research: BCR 06/2013; 15(3):R46. DOI:10.1186/bcr3438 · 5.88 Impact Factor
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    ABSTRACT: High circulating glucose has been associated with increased risk of breast cancer (BC). There may also be a link between serum glucose and prognosis in women treated for BC. We assessed the effect of peridiagnostic fasting blood glucose and body mass index (BMI) on long-term BC prognosis. We retrospectively investigated 1,261 women diagnosed and treated for stage I-III BC at the National Cancer Institute, Milan, in 1996, 1999 and 2000. Data on blood tests and follow-up were obtained by linking electronic archives, with follow-up to end of 2009. Multivariate Cox modelling estimated hazard ratios (HR) with 95 % confidence intervals (CI) for distant metastasis, recurrence and death (all causes) in relation to categorized peridiagnostic fasting blood glucose and BMI. Mediation analysis investigated whether blood glucose mediated the BMI-breast cancer prognosis association. The risks of distant metastasis were significantly higher for all other quintiles compared to the lowest glucose quintile (reference <87 mg/dL) (respective HRs: 1.99 95 % CI 1.23-3.24, 1.85 95 % CI 1.14-3.0, 1.73 95 % CI 1.07-2.8, and 1.91 95 % CI 1.15-3.17). The risk of recurrence was significantly higher for all other glucose quintiles compared to the first. The risk of death was significantly higher than reference in the second, fourth and fifth quintiles. Women with BMI ≥ 25 kg/m(2) had significantly greater risks of recurrence and distant metastasis than those with BMI < 25 kg/m(2), irrespective of blood glucose. The increased risks remained invariant over a median follow-up of 9.5 years. Mediation analysis indicated that glucose and BMI had independent effects on BC prognosis. Peridiagnostic high fasting glucose and obesity predict worsened short- and long-term outcomes in BC patients. Maintaining healthy blood glucose levels and normal weight may improve prognosis.
    Breast Cancer Research and Treatment 04/2013; 138(3). DOI:10.1007/s10549-013-2519-9 · 4.20 Impact Factor

Publication Stats

7k Citations
1,055.49 Total Impact Points

Institutions

  • 2010–2015
    • McMaster University
      • • Department of Oncology
      • • Juravinski Cancer Centre
      Hamilton, Ontario, Canada
  • 2014
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 2013
    • NYU Langone Medical Center
      • Department of Cardiothoracic Surgery
      New York City, New York, United States
  • 2012–2013
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2005–2013
    • Istituto Regina Elena - Istituti Fisioterapici Ospitalieri
      Roma, Latium, Italy
  • 1998–2011
    • University at Buffalo, The State University of New York
      • • Department of Medicine
      • • Department of Social and Preventive Medicine
      • • School of Public Health and Health Professions
      • • School of Medicine and Biomedical Sciences
      Buffalo, NY, United States
  • 1990–2011
    • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
      Milano, Lombardy, Italy
  • 2008
    • Sapienza University of Rome
      Roma, Latium, Italy
  • 2004–2007
    • Roswell Park Cancer Institute
      • Department of Epidemiology
      Buffalo, New York, United States
    • New York University
      • Department of Obstetrics and Gynecology
      New York City, NY, United States
  • 1990–2007
    • CRO Centro di Riferimento Oncologico di Aviano
      Aviano, Friuli Venezia Giulia, Italy
  • 2006
    • Cornell University
      Итак, New York, United States
  • 2003–2005
    • State University of New York
      New York City, New York, United States
  • 1988–2003
    • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
      Meldola, Emilia-Romagna, Italy
  • 2002
    • University of Vermont
      Burlington, Vermont, United States
  • 1996
    • Istituto Nazionale Tumori "Fondazione Pascale"
      Napoli, Campania, Italy