Paolo Verderio

CRO Centro di Riferimento Oncologico di Aviano, Aviano, Friuli Venezia Giulia, Italy

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Publications (104)488.22 Total impact

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    ABSTRACT: Purpose: The influence of the androgen receptor (AR) CAG repeat polymorphism on breast cancer is controversial. We investigated the combined effects of CAG repeat length and estrogen receptor (ER) status on prognosis in 355 postmenopausal women with primary breast cancer. Methods: CAG repeat length was determined by the HUMARA test. Relapse-free survival (RFS) and overall survival (OS) according to the X-weighted CAG repeat biallelic mean (XWBM) were investigated by univariate and multivariate analysis. Results: XWBM was not associated with RFS or OS, but a significant interaction between XWBM and ER status (p = 0.002) was found for OS. ER-negative patients with median XWBM <20 showed lower OS than ER-negative/XWBM ≥20 patients (HR = 0.270; 95% Cl: 0.073-0.999). ER-negative/XWBM <20 patients also had significantly lower OS than ER-positive women, irrespective of CAG repeat length (p<0.001). Accordingly, estimated OS was lowest in ER-negative patients with XWBM <20 (OS: 0.63, 95% CI: 0.41-0.79) and highest in ER-positive patients with XWBM <20 (OS: 0.95, 95% CI: 0.90-0.97). Conclusions: Our data suggest that short CAG repeat length is associated with increased risk of death in ER-negative disease but is related to better survival when ER is expressed. These findings are in agreement with the hypothesis that AR may stimulate or inhibit breast cancer growth depending on ER status, AR transactivation, and the endocrine-metabolic environment of breast tumors. Evaluation of CAG repeat length together with ER status could help improve the estimation of the risk of death, with possible implications for the optimization of standard breast cancer treatment and implementation of prevention strategies.
    The International journal of biological markers 11/2015; DOI:10.5301/jbm.5000176 · 1.37 Impact Factor
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    ABSTRACT: Objective: Hepcidin-25 production is stimulated by systemic inflammation, and it interferes with iron utilization, leading to anemia. This study aimed to investigate the relationships between the plasma levels of hepcidin, interleukin-6 (IL-6), erythropoietin (EPO) and erythroferrone (ERFE) in patients with benign breast disease or cancer. Methods: Plasma samples from a cohort of 131 patients (47 with benign breast disease and 84 with breast cancer) were subjected to the evaluation of hepcidin, IL-6, EPO and ERFE using SELDI-TOF-MS or immunoassays. Results: An elevated hepcidin was observed in malignant breast tumors compared to benign ones. No correlation was observed between hepcidin and IL-6, EPO or ERFE. Conclusion: Since the study included a cohort of patients (87%) with breast cancers smaller than 2 cm, these results may support our previous evidence about the potential role of hepcidin in breast cancer disease.
    Expert Review of Proteomics 10/2015; 12(6):1-7. DOI:10.1586/14789450.2015.1099436 · 2.90 Impact Factor

  • Human pathology 10/2015; DOI:10.1016/j.humpath.2015.06.026 · 2.77 Impact Factor
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    ABSTRACT: Purpose: We report on feasibility of preoperative chemotherapy with or without radiation therapy (RT) in the context of a phase III randomized clinical trial involving localized, high-risk, soft tissue sarcomas. Patients and methods: Of 321 eligible patients, 161 were randomly assigned to three preoperative cycles of epirubicin 120 mg/m(2) plus ifosfamide 9 g/m(2), and 160 were randomly assigned to three preoperative plus two postoperative cycles. Among them, 303 patients were included in this analysis; 169 were male and 134 were female, with a median age of 48 years (range, 15 to 79 years). One hundred fifty-two patients received concurrent RT preoperatively at a total dose of 44 to 50 Gy. Preoperative chemotherapy-related hematologic toxicity and early postoperative complications were reported. The influence of RT, age, and sex on hematologic grade 3 or 4 toxicities and wound complications was analyzed. Chemotherapeutic dose intensity (DI) was analyzed. Results: Among the patients, 61.4%, 22.4%, and 23.8% experienced, grade 4 leucopenia, grade 3 or 4 anemia, and grade 3 or 4 thrombocytopenia, respectively. Respective rates were 66.4%, 24.3%, and 31.6% when RT was added preoperatively, and 56.3%, 20.5%, and 15.9% when preoperative chemotherapy was administered alone. Patient age affected grade 3 or 4 thrombocytopenia. Grade 4 leucopenia and grade 3 or 4 anemia presented 2.5 times more frequently in female patients than in male patients. Wound complications were observed in 13.5% of patients: 17% with preoperative RT and 10% without. Chemotherapeutic DI was greater than 90%, even in patients receiving preoperative RT and in patients age 65 years or older. Conclusion: This preoperative chemotherapy is feasible and can also be proposed for selected elderly patients. Grade 3 or 4 hematologic toxicity was common, but DI was excellent. Concurrent preoperative RT is safe, although an increased rate of grade 4 thrombocytopenia and limited increase in wound complications may be observed.
    Journal of Clinical Oncology 09/2015; DOI:10.1200/JCO.2015.62.9394 · 18.43 Impact Factor
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    ABSTRACT: Numerous genetic factors that influence breast cancer risk are known. However, approximately two thirds of the overall familial risk remains unexplained. To determine whether some of the missing heritability is due to rare variants conferring high to moderate risk, we tested for an association between the c.5791C>T nonsense mutation (p.Arg1931*; rs144567652) in exon 22 of FANCM gene and breast cancer. An analysis of genotyping data from 8,635 familial breast cancer cases and 6,625 controls from different countries yielded an association between the c.5791C>T mutation and breast cancer risk (odds ratio (OR)=3.93 (95% CI=1.28-12.11; P=0.017)). Moreover, we performed two meta-analyses of studies from countries with carriers in both cases and controls, and of all available data. These analyses showed breast cancer associations with OR=3.67 (95% CI=1.04-12.87; P=0.043) and OR=3.33 (95%CI=1.09-13.62, P=0.032), respectively. Based on information theory-based prediction, we established that the mutation caused an out-of-frame deletion of exon 22, due to the creation of a binding site for the pre-mRNA processing protein hnRNP A1. Furthermore, genetic complementation analyses showed that the mutation influenced the DNA repair activity of the FANCM protein. In summary, we provide evidence for the first time showing that the common p.Arg1931* loss-of-function variant in FANCM is a risk factor for familial breast cancer. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email:
    Human Molecular Genetics 06/2015; 24(18). DOI:10.1093/hmg/ddv251 · 6.39 Impact Factor
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    ABSTRACT: Circulating cell-free DNA (ccfDNA) has been confirmed as a useful biomarker in cancer and pre-natal clinical practice. One of the main critical points in using ccfDNA is a lack of standardisation for sample processing methods, storage conditions, procedures for extraction, and quantification that can affect ccfDNA quality and quantity. We report the results obtained from the SPIDIA-DNAplas, one of the EU SPIDIA (Standardisation and improvement of generic pre-analytical tools and procedures for in vitro diagnostics) subprojects based on the implementation of an External Quality Assessment scheme for the evaluation of the influence of the pre-analytical phase on ccfDNA. This is the first reported quality control scheme targeting ccfDNA for pre-analytical phase studies. Fifty-six laboratories throughout Europe were recruited. The participating laboratories received the same plasma sample and extracted ccfDNA by using their own procedures, at defined plasma storage conditions, and sent the isolated ccfDNA to the SPIDIA facility for analyses. Laboratory performance was evaluated by using specific quality parameters such as ccfDNA integrity (by multiplex PCR) and yield (by qPCR). The analysis of the ccfDNA extracted by the laboratories showed that most of them (53 of 56) were able to recover ccfDNA but only 12.5% recovered non-fragmented ccfDNA. Extraction methods specifically designed for ccfDNA preserved the integrity profile. The evidence-based results of the SPIDIA-DNAplas EQA have been proposed as a basis for the development of a Technical Specification by the European Committee for standardisation (CEN).
    Clinical Chemistry and Laboratory Medicine 04/2015; DOI:10.1515/cclm-2014-1161 · 2.71 Impact Factor
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    ABSTRACT: In this note we present an ad-hoc procedure that combines the qualitative (visual evaluation) and quantitative (ImageJ software) evaluation of Pulsed-Field Gel Electrophoresis (PGFE) images to assess the genomic DNA (gDNA) integrity of analyzed samples.This procedure could be suitable for the analysis of a large number of images by taking into consideration both the expertise of researchers and the objectiveness of the software.We applied this procedure on the 1(st) SPIDIA-DNA External Quality Assessment (EQA) samples. Results show that the classification obtained by this ad-hoc procedure allows a more accurate evaluation of gDNA integrity in respect to a single approach. Copyright © 2015. Published by Elsevier Inc.
    Analytical Biochemistry 03/2015; 479. DOI:10.1016/j.ab.2015.03.023 · 2.22 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs), small noncoding RNAs, are involved in tumorigenesis and in the development of various cancers. Quantitative real-time polymerase chain reaction (qPCR) is the most commonly used tool to investigate miRNA expression, and qPCR low-density arrays are increasingly being used as an experimental technique for both the identification of potentially relevant miRNAs and their subsequent validation. Due to the reduced number of microRNAs to be validated, this phase is generally performed on ad hoc customized cards for which a technical robustness is assumed similar to that of the high-throughput cards used during the identification phase. With the aim of investigating the degree of reproducibility between the 2 types of cards, we analyzed plasma-circulating miRNAs evaluated in 60 subjects enrolled in a colorectal cancer screening program. Our results showed a reproducibility between the 2 methods that was not fully satisfactory, with a concordance correlation coefficient equal to 0.69 (95% confidence interval, 0.12-0.92). This report highlights the need to add a technical validation step to the high-throughput-based miRNA identification workflow, after their discovery and before the validation step in an independent series.
    The International journal of biological markers 02/2015; 30(2). DOI:10.5301/jbm.5000135 · 1.37 Impact Factor
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    ABSTRACT: DNA integrity is a critical part of the definition of genomic DNA (gDNA) quality and can influence downstream molecular applications. Pre-analytical variables as sample storage and DNA extraction methods can influence quality and quantity of isolated DNA and affect molecular test performances. Aim of this paper is to investigate the role of blood samples storage and DNA extraction procedures on gDNA integrity and gDNA fragmentation impact on a molecular test. 157 DNA samples deriving from the Pan European 1st SPIDIA DNA External Quality Assesssment (EQA), aimed to investigate the influence of blood storage on gDNA quality and quantity, have been analyzed by Pulsed Field Gel Electrophoresis and ImageJ imaging software. In this EQA, no time or temperature limitations and extraction method procedures were imposed. To evaluate gDNA integrity impact on an analytical test, a subset of 26 DNA samples were analyzed by a multiplex PCR assay for the characterization of T cell receptor genes recombination. Our results demonstrate that blood sample storage and DNA extraction procedures influence gDNA integrity and that the same blood sample undergone to a long range multiplex PCR based analytical test can provide different results if the adopted pre-analytical procedures are not standardized. Copyright © 2014. Published by Elsevier B.V.
    Clinica Chimica Acta 12/2014; 440. DOI:10.1016/j.cca.2014.12.004 · 2.82 Impact Factor
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    ABSTRACT: Background Human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinomas (OSCCs) are two distinct entities. We defined the molecular profiles of druggable receptor tyrosine kinases (RTKs) in both groups.Materials and methodsE5 expression and RTK alterations were studied in 17 HPV-positive and 59 HPV-negative formalin-fixed OSCCs. RTK activation was explored in further 12 frozen OSCCs.ResultsThe HPV-positive OSCCs showed E5 expression and 33.3% expressed low level of HER2. The HPV-negative OSCCs showed HER2 expression (31.2%), increased HER2 gene copy number (46.51%, P = 0.045) and HER2 activation through HER2/EGFR heterodimerisation; HER3 (51.06%, P = 0.008) and neuregulin (65.63%; P = 0.03) expression, HER3 activation and HER3/EGFR heterodimerisation; and increased IGF-1R copy number (40.50%, P = 0.021), high IGF-1R cDNA values (P = 0.002), IGF-1R activation and expression of IGF1/2 and amphiregulin. PI3KCA mutations/expression/increased gene copy number and PTEN mutations were found in both groups, whereas PTEN gene loss was only observed in the HPV-positive cases.Conclusion Human papillomavirus-positive and HPV-negative OSCC showed different RTK profiles. In HPV-positive cases, it would be interesting to study the expression of E5, which may modulate EGFR turnover and activate VEGF and PDGFRβ. In HPV-negative cases, HER3 may be a promising druggable biomarker that deserves further investigation. PI3KCA and PTEN alterations encourage the promising clinical evaluation of PI3K/mTOR inhibitor activity in OSCC, particularly in HPV-positive/PI3KCA-mutated OSCCs because they may be driven by PI3KCA mutation alone.
    Journal of Oral Pathology and Medicine 12/2014; 44(9). DOI:10.1111/jop.12301 · 1.93 Impact Factor
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    ABSTRACT: One purpose of the EC funded project, SPIDIA, is to develop evidence-based quality guidelines for the pre-analytical handling of blood samples for RNA molecular testing. To this end, two pan-European External Quality Assessments (EQAs) were implemented. Here we report the results of the second SPIDIA-RNA EQA. This second study included modifications in the protocol related to the blood collection process, the shipping conditions and pre-analytical specimen handling for participants. Participating laboratories received two identical proficiency blood specimens collected in tubes with or without an RNA stabilizer. For pre-defined specimen storage times and temperatures, laboratories were asked to perform RNA extraction from whole blood according to their usual procedure and to return extracted RNA to the SPIDIA facility for further analysis. These RNA samples were evaluated for purity, yield, integrity, stability, presence of interfering substances, and gene expression levels for the validated markers of RNA stability: FOS, IL1B, IL8, GAPDH, FOSB and TNFRSF10c. Analysis of the gene expression results of FOS, IL8, FOSB, and TNFRSF10c, however, indicated that the levels of these transcripts were significantly affected by blood collection tube type and storage temperature. These results demonstrated that only blood collection tubes containing a cellular RNA stabilizer allowed reliable gene expression analysis within 48 h from blood collection for all the genes investigated. The results of these two EQAs have been proposed for use in the development of a Technical Specification by the European Committee for Standardization.
    PLoS ONE 11/2014; 9(11). DOI:10.1371/journal.pone.0112293 · 3.23 Impact Factor
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    ABSTRACT: There is an increasing need for proper quality control tools in the pre-analytical phase of the molecular diagnostic workflow. The aim of the present study was to identify biomarkers for monitoring pre-analytical mRNA quality variations in two different types of blood collection tubes, K2EDTA (EDTA) tubes and PAXgene Blood RNA Tubes (PAXgene tubes). These tubes are extensively used both in the diagnostic setting as well as for research biobank samples. Blood specimens collected in the two different blood collection tubes were stored for varying times at different temperatures, and microarray analysis was performed on resultant extracted RNA. A large set of potential mRNA quality biomarkers for monitoring post-phlebotomy gene expression changes and mRNA degradation in blood was identified. qPCR assays for the potential biomarkers and a set of relevant reference genes were generated and used to pre-validate a sub-set of the selected biomarkers. The assay precision of the potential qPCR based biomarkers was determined, and a final validation of the selected quality biomarkers using the developed qPCR assays and blood samples from 60 healthy additional subjects was performed. In total, four mRNA quality biomarkers (USP32, LMNA, FOSB, TNRFSF10C) were successfully validated. We suggest here the use of these blood mRNA quality biomarkers for validating an experimental pre-analytical workflow. These biomarkers were further evaluated in the 2nd ring trial of the SPIDIA-RNA Program which demonstrated that these biomarkers can be used as quality control tools for mRNA analyses from blood samples.
    PLoS ONE 11/2014; 9(11):e111644. DOI:10.1371/journal.pone.0111644 · 3.23 Impact Factor

  • Cancer Research 10/2014; 74(19 Supplement):1874-1874. DOI:10.1158/1538-7445.AM2014-1874 · 9.33 Impact Factor
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    ABSTRACT: The aim of our study was to evaluate the quality of histo- and cytomorphological features of PAXgene-fixed specimens and their suitability for histomorphological classification in comparison to standard formalin fixation. Fifteen colon cancer tissues were collected, divided into two mirrored samples and either formalin fixed (FFPE) or PAXgene fixed (PFPE) before paraffin embedding. HE- and PAS-stained sections were scanned and evaluated in a blinded, randomised ring trial by 20 pathologists from Europe and the USA using virtual microscopy. The pathologists evaluated histological grading, histological subtype, presence of adenoma, presence of lymphovascular invasion, quality of histomorphology and quality of nuclear features. Statistical analysis revealed that the reproducibility with regard to grading between both fixation methods was rather satisfactory (weighted kappa statistic (k w) = 0.73 (95 % confidence interval (CI), 0.41–0.94)), with a higher agreement between the reference evaluation and the PFPE samples (k w = 0.86 (95 % CI, 0.67–1.00)). Independent from preservation method, inter-observer reproducibility was not completely satisfactory (k w = 0.60). Histomorphological quality parameters were scored equal or better for PFPE than for FFPE samples. For example, overall quality and nuclear features, especially the detection of mitosis, were judged significantly better for PFPE cases. By contrast, significant retraction artefacts were observed more frequently in PFPE samples. In conclusion, our findings suggest that the PAXgene Tissue System leads to excellent preservation of histomorphology and nuclear features of colon cancer tissue and allows routine morphological diagnosis.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 08/2014; 465(5). DOI:10.1007/s00428-014-1624-4 · 2.65 Impact Factor
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    ABSTRACT: Target-specific agents used in melanoma are not curative, and chemokines are being implicated in drug-resistance to target-specific agents. Thus, the use of conventional agents in rationale combinations may result in optimization of therapy. Because histone deacetylases participate in tumor development and progression, the combination of the pan-inhibitor SAHA and temozolomide might provide a therapeutic advantage. Here, we show synergism between the two drugs in mutant BRAF cell lines, in association with decreased phosphorylation of cell survival proteins (e.g., C-Jun-N-terminal-kinase, JNK). In the spontaneous ret transgenic mouse melanoma model, combination therapy produced a significant disease onset delay and down-regulation of Chemokine (C-C motif) ligand 2 (CCL2), JNK, and of Myeloid-derived suppressor cell recruitment. Co-incubation with a CCL2-blocking-antibody enhanced in vitro cell sensitivity to temozolomide. Conversely, recombinant CCL2 activated JNK in human tumor melanoma cells. In keeping with these results, the combination of a JNK-inhibitor with temozolomide was synergistic. By showing that down-regulation of CCL2-driven signals by SAHA and temozolomide via JNK contributes to reduce melanoma growth, we provide a rationale for the therapeutic advantage of the drug combination. This combination strategy may be effective because of interference both with tumor cell and tumor microenvironment.
    Oncotarget 06/2014; 5(12). DOI:10.18632/oncotarget.2065 · 6.36 Impact Factor
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    Neuro-Oncology 06/2014; 16(suppl 1):i137-i145. DOI:10.1093/neuonc/nou082 · 5.56 Impact Factor
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    ABSTRACT: In this note we propose an R function named NqA (Normalization qPCR Array), suitable for the identification of a set of microRNAs (miRNAs) to be used for data normalization in view of subsequent validation studies with qPCR data. NqA is available through the web-site of the Fondazione IRCCS Istituto Nazionale dei Tumori of Milan at: with a dedicated user-guide. We applied our function on a qPCR dataset downloaded from the Gene Expression Omnibus (GEO) database. Results show that NqA provides a functional subset of reference miRNAs and a set of promising significantly modulated miRNAs for subsequent validations studies.
    Analytical Biochemistry 05/2014; 461. DOI:10.1016/j.ab.2014.05.020 · 2.22 Impact Factor

  • International Journal of Cancer 04/2014; 134(8). DOI:10.1002/ijc.28530 · 5.09 Impact Factor
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    ABSTRACT: Aims and background: The quantification and molecular characterization of circulating free DNA (cfDNA) have attracted much interest as new and promising, noninvasive means of detecting and monitoring the presence of surgical resectable colorectal cancer (CRC). Instead, the role of cfDNA in the early detection of malignant and premalignant colorectal lesions is still unclear. The aim of this study was to evaluate the predictive power of the quantification and KRAS status of cfDNA in detecting early colorectal lesions in plasma from healthy high-risk subjects. Methods: The study population consisted of 170 consecutive healthy high-risk subjects aged >50 years who participated in the screening program promoted by the Local Health Service (ASL-Milano) for early CRC detection and who underwent endoscopic examination after being found positive at fecal occult blood test (FOBT). Thirty-four participants had malignant lesions consisting of 12 adenocarcinomas (at an early stage in half of the cases) and 22 instances of high-grade intraepithelial neoplasia (HGIN) in adenomas; 73 participants had premalignant lesions (adenomas and hyperplasia), and 63 participants had no lesions. Plasma cfDNA was quantified by quantitative real-time PCR and analyzed for KRAS mutations by a mutant-enriched PCR. KRAS status was assessed also in matched adenocarcinoma and HGIN tissues. The distribution of cfDNA concentrations among FOBT-positive subjects with diagnosed lesion (cases) was compared with that of FOBT-positive subjects without lesions (controls) and its predictive capability (AUC) was assessed. Results: The predictive capability of cfDNA levels was satisfactory in predicting adenocarcinomas (AUC 0.709; 95% CI, 0.508-0.909) but not HGIN and premalignant lesions. The rate of KRAS mutations in plasma was low (5/170 = 3%) compared with the rate observed in the matched adenocarcinoma and HGIN tissues (45%). Conclusions: The use of cfDNA quantification to predict adenocarcinoma at an early stage in high-risk (aged >50 years and FOBT positive) subjects seems to be promising but needs more sensitive methods to improve cfDNA detection.
    Tumori 03/2014; 100(2):115-21. DOI:10.1700/1491.16389 · 1.27 Impact Factor
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    ABSTRACT: Purpose: Monoallelic germ-line deleterious mutations of PALB2 (partner and localizer of BRCA2) are associated with breast cancer risk and have been found in several populations, with carrier frequencies of ~1-2%. Initially, these mutations were considered to have moderate penetrance, but accumulating evidence now indicates that they are associated with much higher risk. Methods: In this study, we sequenced the PALB2 coding regions unlinked to BRCA (breast cancer) genes in 575 probands from Italian breast cancer families recruited in Milan. Results: We found 12 carriers (2.1%) of deleterious mutations, and none of the mutations was found in 784 controls collected in Milan. One of these mutations, the c.1027C>T (p.Gln343X), was found to be recurrent in the province of Bergamo in northern Italy, being detected in 6/113 (5.3%) familial breast cancer cases and 2/477 (0.4%) controls recruited in this area (Fisher's exact test: P < 0.01). Conclusions: Our data provide confirmatory findings that, in the Italian population also, deleterious mutations of PALB2 are relatively frequent predisposing factors for breast cancer and may be associated with high risk of the disease.
    Genetics in medicine: official journal of the American College of Medical Genetics 02/2014; 16(9). DOI:10.1038/gim.2014.13 · 7.33 Impact Factor

Publication Stats

2k Citations
488.22 Total Impact Points


  • 2009-2015
    • CRO Centro di Riferimento Oncologico di Aviano
      • Division of Experimental Oncology 1
      Aviano, Friuli Venezia Giulia, Italy
  • 1999-2015
    • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
      • s.c. Medicina Oncologica 1
      Milano, Lombardy, Italy
  • 2014
    • Technische Universität München
      München, Bavaria, Germany
    • INRCA Istituto Nazionale di Ricovero e Cura per Anziani
      Ancona, The Marches, Italy
  • 2005-2006
    • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
      Meldola, Emilia-Romagna, Italy
  • 2000
    • Istituto Nazionale Tumori "Fondazione Pascale"
      Napoli, Campania, Italy
  • 1994-1997
    • University of Milan
      • Institute of Medical Statistics and Biometry "G. A. Maccacaro" IBSUM
      Milano, Lombardy, Italy
    • San Bortolo Hospital
      Vicenza, Veneto, Italy