Papers by Antonio Marchetti
Cancer Chemotherapy and Pharmacology, Feb 1, 1990
The effects of fructose-1,6-diphosphate, an intermediate metabolite of glycolysis, on acute and c... more The effects of fructose-1,6-diphosphate, an intermediate metabolite of glycolysis, on acute and chronic cardiotoxicity of doxorubicin were investigated in rats. In the acute study, urethane-anaesthetized Wistar female rats treated with 10 mg/kg i.v. doxorubicin developed a widening of the S alpha T segment, an impairment of +dP/dtmax, and tachycardia. Pretreatment with 375 and 750 mg/kg i.p. fructose-1,6-diphosphate prevented the S alpha T segment from widening, whereas only 750 mg/kg i.p. significantly attenuated the heart rate increase. Chronic cardiomyopathy was induced over a 6-week period by weekly doses of 3 mg/kg i.v. doxorubicin, being characterized in vivo by the progressive enlargement of the S alpha T segment and the occurrence of histological alterations and in vitro by a marked impairment of the inotropic response elicited by adrenaline in isolated hearts from treated rats. Concurrent treatment with 150 and 300 mg/kg i.p. fructose-1,6-diphosphate thrice a week for 6 weeks did not lessen the chronic heart damage, whereas 600 mg/kg given i.p. significantly reduced the widening of the S alpha T segment and the severity of histological damage in vivo, as well as significantly improving the contractile responses of hearts in vitro. These findings suggest that the administration of fructose-1,6-diphosphate plays a protective role in the acute and chronic cardiotoxicity of doxorubicin in the rat.
Asco Meeting Abstracts, May 20, 2012
Background: Gefitinib was approved in Italy for treatment of pts with advanced NSCLC carrying mut... more Background: Gefitinib was approved in Italy for treatment of pts with advanced NSCLC carrying mutant EGFR in May 2010. Methods: The EGFR FASTnet program was designed to facilitate the exchange of biological material, clinico-pathological data and reports between medical oncologists, primary pathologists and referral laboratories. EGFR mutational analysis was carried by Sanger sequencing, Real Time PCR, Pyrosequencing, Fragment Analysis and High resolution melting. The Italian Association of Medical Oncology (AIOM) ...
Clinical Cancer Research, Jun 1, 2006
Purpose: The a 6 h 4 integrin, a laminin receptor, has been implicated from many studies in tumor... more Purpose: The a 6 h 4 integrin, a laminin receptor, has been implicated from many studies in tumor progression and invasion. We showed that the h 4 integrin subunit associates with the ErbB-2 tyrosine kinase in human mammary carcinoma cell lines and that its overexpression in NIH3T3/ ErbB-2^transformed cells causes a constitutive activation of phosphatidylinositol 3-kinase (PI3K), inducing a strong increase of their invasive capacity. In this study, we investigated the biological consequences of interference with the endogenous h 4 integrin subunit expression. Experimental Design: In vitro and in vivo tumor growth and the biochemical consequences of h 4 integrin inactivation were studied in mammary tumor cells by using short hairpin RNA approach. Results: Our data show that tumor growth of mammary tumor cells strictly depends on h 4 expression, confirming the relevance of h 4 protein in these cells. Moreover, interference with h 4 expression significantly reduces endogenous PI3K activity and AKT and mammalian target of rapamycin phosphorylation. Accordingly, with these results and considering that PI3K activity in mammary tumor plays a relevant role in hormone resistance, we asked whether h 4 expression might be relevant for hormone responsiveness in these cells. Data reported indicate that the interference with endogenous h 4 expression, upon hormone deprivation, induces caspase-9 and cytochrome c^mediated apoptosis, which is enhanced upon tamoxifen treatment. On the other hand, the expression of myr-AKT in MCF7 h 4^s hort hairpin RNA cells rescues the cells from apoptosis in the absence of hormones and upon tamoxifen treatment. Conclusions: Overall, these results confirm the relevance of h 4 expression in mammary tumors and indicate this integrin as a relevant target for tumor therapy.
Journal of Thoracic Oncology Official Publication of the International Association For the Study of Lung Cancer 2014 9 1675 84, Nov 1, 2014
The Lungscape project was designed to address the impact of clinical, pathological, and molecular... more The Lungscape project was designed to address the impact of clinical, pathological, and molecular characteristics on outcome in resected non-small- cell lung cancer (NSCLC). A decentralized biobank with fully annotated tissue samples was established. Selection criteria for participating centers included sufficient number of cases, tissue microarray building capability, and documented ethical approval. Patient selection was based on availability of comprehensive clinical data, radical resection between 2003 and 2009 with adequate follow-up, and adequate quantity and quality of formalin-fixed tissue. Fifteen centers contributed 2449 cases. The 5-year overall survival (OS) was 69.6% and 63.6% for stages IA and IB, 51.6% and 47.7% for stages IIA and IIB, and 29.0% and 13.0% for stages IIIA and IIIB, respectively (p < 0.001). Median and 5-year relapse-free survival (RFS) were 52.8 months and 47.3%, respectively. Distant relapse was recorded for 44.4%, local for 26.0%, and both for 16.9% of patients. Based on multivariate analysis for the OS, RFS, and time to relapse, the factors significantly associated with all of them are performance status and pathological stage. The aim of this report is to present the results from Lungscape, the first large series reporting on NSCLC surgical outcome measured not only by OS but also by RFS and time to relapse and including multivariate analysis by significant clinical and pathological prognostic parameters. As tissue from all patients is preserved locally and is available for detailed molecular investigations, Lungscape provides an excellent basis to evaluate the influence of molecular parameters on the disease outcome after radical resection, besides providing an overview of the molecular landscape of stage I to III NSCLC.
Cancer Research, May 1, 2002
90K, also known as Mac-2 binding protein, is a secreted glycoprotein that binds galectins, 1-int... more 90K, also known as Mac-2 binding protein, is a secreted glycoprotein that binds galectins, 1-integrins, collagens, and fibronectin, and has some relevance in cell-cell and cell-extracellular matrix adhesion. Previous studies have shown that serum levels of 90K have prognostic value in several neoplasms. In the present study, the role of the expression of 90K as an adverse prognostic indicator in 72 pathological stage I non-small cell lung cancer patients was investigated immunohistochemically. All of the patients underwent complete surgical removal of the tumor. The median length of follow-up care was 54 months. High level of 90K expression (90K staining of >50% of the neoplastic cells) was observed in 20 of the 72 (28%) tumors. Expression of 90K was confirmed by ELISA. The results showed that a high expression of 90K correlates with adverse prognosis. Among patients with high 90K expression, the disease-free and overall survival rates were significantly lower than the same rates of those with low expression (P ؍ 0. 0001 and P ؍ 0. 0003, respectively). The incidence of distant metastases in the patients with high 90K expression (60%; 12 of 20 patients) was significantly higher than that of in the patients with low expression (21%; 11 of 53 patients; P ؍ 0.0038). The results of multivariate analysis confirmed that a high 90K expression was a significant factor to predict poor prognosis. We suggest that 90K expression could be a useful prognostic factor in patients with stage I non-small cell lung cancer, likely as an indicator of the metastatic propensity of the tumor.
Journal of Thoracic Oncology, 2015
The potential to accurately quantify epidermal growth factor receptor (EGFR) mutations in plasma ... more The potential to accurately quantify epidermal growth factor receptor (EGFR) mutations in plasma from non-small-cell lung cancer patients would enable more rapid and more frequent analyses to assess disease status; however, the utility of such analyses for clinical purposes has only recently started to explore. Plasma samples were obtained from 69 patients with EGFR-mutated tumors and 21 negative control cases. EGFR mutations in plasma were analyzed by a standardized allele-specific polymerase chain reaction (PCR) test and ultra-deep next-generation sequencing (NGS). A semiquantitative index (SQI) was derived from dilutions of known EGFR mutation copy numbers. Clinical responses were evaluated by Response Evaluation Criteria in Solid Tumors 1.1 criteria and expressed as percent tumor shrinkage. The sensitivity and specificity of the PCR test and NGS assay in plasma versus tissue were 72% versus 100% and 74% versus 100%, respectively. Quantitative indices by the PCR test and NGS were significantly correlated (p < 0.001). EGFR testing at baseline and serially at 4 to 60 days during tyrosine kinase inhibitor therapy revealed a progressive decrease in SQI, starting from day 4, in 95% of cases. The rate of SQI decrease correlated with percent tumor shrinkage at 2 months (p < 0.0001); at 14 days, it was more than 50% in 70% of patients (rapid responders). In two patients with slow response, an early increase in the circulating levels of the T790M mutation was observed. No early T790M mutations were seen in plasma samples of rapid responders. Quantification of EGFR mutations from plasma with a standardized PCR test is feasible. To our knowledge, this is the first study showing a strong correlation between the EGFR SQI in the first days of treatment and clinical response with relevant implications for patient management.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2014
The prevalence of anaplastic lymphoma kinase (ALK) gene fusion (ALK positivity) in early-stage no... more The prevalence of anaplastic lymphoma kinase (ALK) gene fusion (ALK positivity) in early-stage non-small-cell lung cancer (NSCLC) varies by population examined and detection method used. The Lungscape ALK project was designed to address the prevalence and prognostic impact of ALK positivity in resected lung adenocarcinoma in a primarily European population. Analysis of ALK status was performed by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) in tissue sections of 1,281 patients with adenocarcinoma in the European Thoracic Oncology Platform Lungscape iBiobank. Positive patients were matched with negative patients in a 1:2 ratio, both for IHC and for FISH testing. Testing was performed in 16 participating centers, using the same protocol after passing external quality assessment. Positive ALK IHC staining was present in 80 patients (prevalence of 6.2%; 95% CI, 4.9% to 7.6%). Of these, 28 patients were ALK FISH positive, corresponding to a lower bound for the ...
Journal of Thoracic Oncology, 2014
The Lungscape project was designed to address the impact of clinical, pathological, and molecular... more The Lungscape project was designed to address the impact of clinical, pathological, and molecular characteristics on outcome in resected non-small- cell lung cancer (NSCLC). A decentralized biobank with fully annotated tissue samples was established. Selection criteria for participating centers included sufficient number of cases, tissue microarray building capability, and documented ethical approval. Patient selection was based on availability of comprehensive clinical data, radical resection between 2003 and 2009 with adequate follow-up, and adequate quantity and quality of formalin-fixed tissue. Fifteen centers contributed 2449 cases. The 5-year overall survival (OS) was 69.6% and 63.6% for stages IA and IB, 51.6% and 47.7% for stages IIA and IIB, and 29.0% and 13.0% for stages IIIA and IIIB, respectively (p < 0.001). Median and 5-year relapse-free survival (RFS) were 52.8 months and 47.3%, respectively. Distant relapse was recorded for 44.4%, local for 26.0%, and both for 16.9% of patients. Based on multivariate analysis for the OS, RFS, and time to relapse, the factors significantly associated with all of them are performance status and pathological stage. The aim of this report is to present the results from Lungscape, the first large series reporting on NSCLC surgical outcome measured not only by OS but also by RFS and time to relapse and including multivariate analysis by significant clinical and pathological prognostic parameters. As tissue from all patients is preserved locally and is available for detailed molecular investigations, Lungscape provides an excellent basis to evaluate the influence of molecular parameters on the disease outcome after radical resection, besides providing an overview of the molecular landscape of stage I to III NSCLC.
Journal of Thoracic Oncology, 2014
The Italian Association of Medical Oncology and the Italian Society of Anatomic Pathology and Dia... more The Italian Association of Medical Oncology and the Italian Society of Anatomic Pathology and Diagnostic Cytopathology organized an external quality assessment (EQA) scheme for anaplastic lymphoma kinase (ALK) rearrangement by florescence in situ hybridization (FISH) analysis in non-small-cell lung cancer (NSCLC). Methods: Sections from tissue microarrays, each including 10 NSCLC samples with known ALK status, were first validated in five referral laboratories and then provided to 37 participating centers. The laboratories were requested to perform the FISH test, using their usual protocols, and to complete the analysis within 3 weeks. By using a predefined scoring system, two points were assigned in case of correct genotype and zero points to false-negative or false-positive results. The threshold value to pass the EQA scheme was set at 18 points. Two rounds were planned. Results: Thirty-four centers submitted the results within the established deadline. Several errors in the evaluation of genotype (n = 18) were reported, with both false-positive (n = 7) and false-negative (n = 11) results. Test failure occurred in seven cases. Two samples were found to be critical by two referral laboratories and seven participating centers. Twenty-six (70%) laboratories passed the first round and six the second round. Overall, 32 (86%) laboratories passed the ALK EQA scheme.
Clinical Lung Cancer, 2014
ABSTRACT Lung adenocarcinoma harboring the c-ros oncogene 1 (ROS1) translocations represents a ne... more ABSTRACT Lung adenocarcinoma harboring the c-ros oncogene 1 (ROS1) translocations represents a newly discovered molecular subset of non small cell lung cancer (NSCLC. Just as with anaplastic lymphoma receptor tyrosine kinase (ALK)-rearranged NSCLC, early phase clinical trials have shown a high response rate to crizotinib in these patients. Fluorescent in situ hybridization (FISH) is considered the reference standard for detecting ROS1 translocations and ALK rearrangements. Several anti-ROS1 antibodies are in Use, and the first results have suggested that immunohistochemistry (IHC) Mild, be a suitable tool for identifying ROS1 rearrangement. The results from this small series suggest that IHC is a valuable tool, for identifying ROS1 rearrangement and have confirmed that this Subset of patients can benefit from crizotinib-based treatment.
PLoS ONE, 2014
Introduction: Assessment of EGFR mutation in non-small cell lung cancer (NSCLC) patients is manda... more Introduction: Assessment of EGFR mutation in non-small cell lung cancer (NSCLC) patients is mandatory for optimization of pharmacologic treatment. In this respect, mutation analysis of circulating tumor cells (CTCs) may be desirable since they may provide real-time information on patient's disease status.
PLoS ONE, 2011
Background: Monoclonal antibodies directed against the epidermal growth factor receptor (EGFR) ha... more Background: Monoclonal antibodies directed against the epidermal growth factor receptor (EGFR) have been approved for the treatment of patients with metastatic colorectal carcinoma (mCRC) that do not carry KRAS mutations. Therefore, KRAS testing has become mandatory to chose the most appropriate therapy for these patients.
Lung Cancer, 2009
The number of resected lymph-nodes (#RNs) has proven prognostic in breast and colorectal cancer. ... more The number of resected lymph-nodes (#RNs) has proven prognostic in breast and colorectal cancer. Here we evaluated its prognostic impact in a series of resected NSCLC patients. A panel of established prognostic factors plus (1) #RNs or (2) the ratio between the number of metastatic nodes and #RNs (NR) were correlated to overall- (OS), cancer-specific- (CSS), and disease-free-survival (DFS), using the Cox-model. Risk-classes according to hazard ratios (HR) were generated. Internal and external validation was accomplished. A dataset of 415 resected NSCLC patients was retrieved. At multivariate analysis, #RNs and NR were independent factor for longer OS, CSS and DFS (p<0.0001). Patients with a #RNs>10 (identified optimal cut-off) had a statistically significant OS (p=0.02) and DFS (p=0.0005) benefit. In node-positive patients, a NR<9% significantly correlated with better outcome. Stratification into High-, Medium-, and Low-Risk classes, based on High- (HRFs: stage, N-status, age, #RNs) and Intermediate-Risk Factors (IRFs: sex, grading, histology), efficiently predicted outcomes (p<0.0001). The risk class model performance was externally validated in and independent dataset of 297 patients. These results contribute to complete the panel of prognostic factors for resected NSCLC. A prospective larger validation and comparison with molecular prognostic tools is warranted.
Virchows Archiv, 2013
Molecular pathology is an integral part of daily diagnostic pathology and used for classification... more Molecular pathology is an integral part of daily diagnostic pathology and used for classification of tumors, for prediction of prognosis and response to therapy, and to support treatment decisions. For these reasons, analyses in molecular pathology must be highly reliable and hence external quality assessment (EQA) programs are called for. Several EQA programs exist to which laboratories can subscribe, but they vary in scope, number of subscribers, and execution. The guideline presented in this paper has been developed with the purpose to harmonize EQA in molecular pathology. It presents recommendations on how an EQA program should be organized, provides criteria for a reference laboratory, proposes requirements for EQA test samples, and defines the number of samples needed for an EQA program. Furthermore, a system for scoring of the results is proposed as well as measures to be taken for poorly performing laboratories. Proposals are made regarding the content requirements of an EQA report and how its results should be communicated. Finally, the need for an EQA database and a participant manual are elaborated. It is the intention of this guideline to improve EQA for molecular pathology in order to provide more reliable molecular analyses as well as optimal information regarding patient selection for treatment.
PLoS ONE, 2012
Microdeletions at exon 19 are the most frequent genetic alterations affecting the Epidermal Growt... more Microdeletions at exon 19 are the most frequent genetic alterations affecting the Epidermal Growth Factor Receptor (EGFR) gene in non-small cell lung cancer (NSCLC) and they are strongly associated with response to treatment with tyrosine kinase inhibitors. A series of 116 NSCLC DNA samples investigated by Sanger Sequencing (SS), including 106 samples carrying exon 19 EGFR deletions and 10 without deletions (control samples), were subjected to deep next generation sequencing (NGS). All samples with deletions at SS showed deletions with NGS. No deletions were seen in control cases. In 93 (88%) cases, deletions detected by NGS were exactly corresponding to those identified by SS. In 13 cases (12%) NGS resolved deletions not accurately characterized by SS. In 21 (20%) cases the NGS showed presence of complex (double/multiple) frameshift deletions producing a net in-frame change. In 5 of these cases the SS could not define the exact sequence of mutant alleles, in the other 16 cases the results obtained by SS were conventionally considered as deletions plus insertions. Different interpretative hypotheses for complex mutations are discussed. In 46 (43%) tumors deep NGS showed, for the first time to our knowledge, subpopulations of DNA molecules carrying EGFR deletions different from the main one. Each of these subpopulations accounted for 0.1% to 17% of the genomic DNA in the different tumors investigated. Our findings suggest that a region in exon 19 is highly unstable in a large proportion of patients carrying EGFR deletions. As a corollary to this study, NGS data were compared with those obtained by immunohistochemistry using the 6B6 anti-mutant EGFR antibody. The immunoreaction was E746-A750del specific. In conclusion, NGS analysis of EGFR exon 19 in NSCLCs allowed us to formulate a new interpretative hypothesis for complex mutations and revealed the presence of subpopulations of deletions with potential pathogenetic and clinical impact.
Journal of Thoracic Oncology, 2013
Recent clinical trials led to the approval of crizotinib (PF-02341066; Pfizer) by the U.S. Food a... more Recent clinical trials led to the approval of crizotinib (PF-02341066; Pfizer) by the U.S. Food and Drug Administration for the treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) patients whose tumors are positive for anaplastic lymphoma kinase (ALK) alterations. The European Medicines Agency accepted the regulatory submission of crizotinib for the treatment of these patients. Therefore, ALK gene testing has become mandatory to choose the most appropriate therapy. To help physicians, involved in the management of NSCLC patients to be treated with ALK inhibitors in Italy, the Italian Association of Medical Oncology and the Italian Society of Pathology and Cytopathology identified a large panel of Italian medical oncologists and pathologists that outlined recommendations for ALK testing in NSCLC patients. The guidelines produced include specific information on the target patient population, the biological material for molecular analysis, a section dedicated to the histocytopathologic diagnosis of NSCLC, and the methods for the assessment of ALK alterations that are summarized in this article. Clinicopathologic recommendations were produced to guide the management of NSCLC patients who need to be tested for ALK rearrangements before treatment with ALK inhibitors.
Journal of Thoracic Oncology, 2012
The optimal use of epidermal growth factor receptor (EGFR)-related molecular markers to prospecti... more The optimal use of epidermal growth factor receptor (EGFR)-related molecular markers to prospectively identify tyrosine kinase inhibitor (TKI)-sensitive patients, particularly after a previous chemotherapy treatment, is currently under debate. We designed a prospective phase II study to evaluate the activity of EGFR-TKI in four different patient groups, according to the combination of molecular (EGFR gene mutations, EGFR gene copy number and protein expression, and phosphorylated AKT expression, pAKT) and clinicopathological (histology and smoking habits) factors. Correlations between molecular alterations and clinical outcome were also explored retrospectively for first-line chemotherapy and EGFR-TKI treatment. Patients who had progressed during or after first-line chemotherapy were prospectively assigned to EGFR-TKI treatment as follows: (G1) EGFR mutation (n = 12); (G2) highly polysomic/amplified EGFR (n = 18); (G3) EGFR and/or pAKT positive (n = 41); (G4) adenocarcinoma/bronchoalveolar carcinoma and no smoking history (n = 15). G1 and G4 had the best and second-best overall response rate (25% and 20%, respectively), whereas the worst outcome was observed in G2 (ORR, 6%; p = 0.05). Disease control was highest in G1 and G4 (>50%) and lowest in G3 (<20%) (p = 0.02). Patients selected by EGFR mutation or clinical parameters (G1 and G4) also had significantly better progression-free survival and overall survival (p = 0.02 and p = 0.01, respectively). Multivariate analysis confirmed the impact of sex, smoking history, EGFR/KRAS mutation, and pAKT on outcomes and allowed us to derive an efficient predictive model. Histology, EGFR mutations, and pAKT were independent predictors of response to first-line chemotherapy at retrospective analysis, whereas pAKT and human epidermal growth factor receptor 2 expression were the only independent predictors of progression-free survival and overall survival. Selection of patients based on either EGFR mutation or clinical characteristics seems an effective approach to optimize EGFR-TKI treatment in chemotherapy-pretreated non-small-cell lung cancer patients.
The Journal of Pathology, 1997
The status of the P16 gene was investigated by Southern blot, polymerase chain reaction-single st... more The status of the P16 gene was investigated by Southern blot, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP), and DNA sequencing analyses in 30 primary resected non-small cell lung carcinomas (NSCLCs) with metastatic involvement of thoracic lymph nodes and 33 NSCLCs without node metastases. Direct sequencing of tumour DNA samples scored positive by PCR-SSCP showed five somatic mutations of the P16 gene: four nonsense and one frameshift. The Southern blot analysis revealed the presence of a homozygous deletion of the P16 locus in one tumour. All of the six NSCLCs with somatic aberrations of the P16 gene belonged to the series of tumours with metastatic diffusion to thoracic lymph nodes. In each of these six cases, the genetic aberration was seen in both the primary tumour and the node metastasis. No P16 alteration was found in tumours without metastatic lymph nodes. This difference was statistically significant (P = 0.02). No correlation was present between P16 alterations and other clinicopathological parameters including age of patients, tumour size, histological type, and grade. In three tumours with genetic aberration of P16, there was a concomitant alteration of the p53 gene. Our results indicate that the P16 gene is infrequently mutated (10 per cent of the cases examined) in primary resected NSCLC. However, since P16 mutations were found only in metastatic tumours, they may be important events in late phases of tumour progression and could represent useful markers of tumour aggressiveness in NSCLC.
The Journal of Pathology, 1996
Bronchioloalveolar carcinoma (BAC) is a form of peripheral lung adenocarcinoma growing as a singl... more Bronchioloalveolar carcinoma (BAC) is a form of peripheral lung adenocarcinoma growing as a single layer of malignant cells along the walls of terminal airways. The existence of BAC as a separate clinico-pathological entity has been a matter of controversy, mainly because its histogenesis is uncertain and it is not easily distinguishable from conventional lung adenocarcinoma (CLA). Three subtypes of BAC have been described using histological and cytological criteria: mucinous, non-mucinous, and sclerosing. The clinical behaviour of BAC appears to be dependent on the histological subtype. The different morphological patterns and clinical outcome of the subtypes of BAC suggest that their biological behaviour may be different from one another and from CLA. This study has investigated 58 BACs (10 mucinous, 40 non-mucinous, and 8 sclerosing) and 50 control CLAs for mutations at codon 12 of the K-ras oncogene. Twenty-one (36 per cent) BACs and 13 (26 per cent) CLAs showed K-ras mutations. A clear association (P < 0.0001) between K-ras mutations and the mucinous type of BAC was observed: all 10 mucinous tumours examined were scored positive for mutations in the K-ras gene, while only 9 (23 per cent) of the 40 non-mucinous and 2 (25 per cent) of the 8 sclerosing BACs were found to be positive. The frequency of ras mutations in non-mucinous BAC, sclerosing BAC, and CLA was not statistically different. Our data indicate that BACs are a heterogeneous group of lung tumours and that the mucinous form might represent a biological entity separate from both the other two BAC types and CLA.
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Papers by Antonio Marchetti