Francesco Lo-Coco

University of Rome Tor Vergata, Roma, Latium, Italy

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Publications (146)1058.75 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The analyses carried out using two different bioinformatics pipelines (SomaticSniper and MuTect) on the same set of genomic data from 133 Acute Myeloid Leukemia (AML) patients, sequenced inside the Cancer Genome Atlas project, gave discrepant results. We subsequently tested these two variant-calling pipelines on 20 leukemia samples from our series (19 primary AMLs and one secondary AML). By validating many of the predicted somatic variants (variant allele frequencies ranging from 100% to 5%), we observed significantly different calling efficiencies. In particular, despite relatively high specificity, sensitivity was poor in both pipelines resulting in a high rate of false negatives. Our findings raise the possibility that landscapes of AML genomes might be more complex than previously reported and characterized by the presence of hundreds of genes mutated at low variant allele frequency, suggesting that the application of genome sequencing to the clinic requires a careful and critical evaluation. We think that improvements in technology and workflow standardization, through the generation of clear experimental and bioinformatics guidelines, are fundamental to translate the use of Next generation sequencing from research to the clinic and to transform genomic information into better diagnosis and outcomes for the patient. Copyright © 2014 American Society of Hematology.
    Blood 12/2014; · 9.78 Impact Factor
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    ABSTRACT: Olaparib (AZD-2281, Ku-0059436) is an orally bioavailable and well-tolerated poly(ADP-ribose) polymerase (PARP) inhibitor currently under investigation in patients with solid tumors. To study the clinical potential of olaparib as a single-agent for the treatment of Acute Myeloid Leukemia (AML) patients, we analyzed the in vitro sensitivity of AML cell lines and primary blasts. Clinically achievable concentrations of olaparib were able to induce cell death in the majority of primary AML case samples (88%) and tested cell lines. At these concentrations, olaparib preferentially killed leukemic blasts sparing normal lymphocytes derived from the same patient and did not substantially affect the viability of normal bone marrow and CD34-enriched peripheral blood cells obtained from healthy donors. Most primary AML analyzed were characterized by low BRCA1 mRNA level and undetectable protein expression that likely contributed to explain their sensitivity to olaparib. Noteworthy, while PARP1 over-expression was detected in blasts not responsive to olaparib, phosphorylation of the histone H2AFX (γH2AX) was associated with drug sensitivity. As to genetic features of tested cases the highest sensitivity was shown by a patient carrying a 11q23 deletion. The high sensitivity of AML blasts and the identification of biomarkers potentially able to predict response and/or resistance may foster further investigation of olaparib monotherapy for AML patients unfit to conventional chemotherapy. Copyright © 2014. Published by Elsevier B.V.
    Biochimica et biophysica acta. 12/2014;
  • Leukemia Research. 11/2014;
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    ABSTRACT: We assessed by flow cytometry minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) given standard-dose (SDAC) and high-dose ARA-C (HDAC) regimens. Of 163 patients enrolled, 130 (median age, 45 years; range, 18-59 years) qualified for analysis, all achieving complete remission after treatment with SDAC (n=78) or HDAC (n=52) plus etoposide and daunorubicin. Consolidation consisted of intermediate-dose ARA-C and daunorubicin. MRD negativity was significantly more frequent in the SDAC vs. HDAC arm after both induction (37% vs 15%, p=0.007) and consolidation (44% vs. 18%, p=0.002). Respective median residual leukemic cell counts with SDAC and HDAC use were 1.5 × 10-3 and 4 × 10-3 (p=0.033) after induction and 5.7 × 10-4 and 2.9 × 10-3 (p=0.008) after consolidation. Based on ARA-C schedule and post-consolidation MRD status, the four patient groups (SDAC-MRD- , HDAC-MRD- , SDAC-MRD+ , and HDAC-MRD+ ) displayed 5-year overall survival rates of 60%, 33%, 24%, and 42% (p=0.007), respectively, with 24%, 35%, 74%, and 48% (p<0.0001) respective cumulative incidence of relapse estimates. MRD may serve as a biomarker for optimal biologic dosing of ARA-C, and SDAC regimen appears to yield more frequent MRD negativity.
    American Journal of Hematology 11/2014; · 4.00 Impact Factor
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    ABSTRACT: In adult patients with acute lymphoblastic leukemia (ALL), Central Nervous System (CNS) involvement is associated with a very poor prognosis. The diagnostic assessment of this condition relies on the use of neuroradiology, conventional cytology (CC) and flow cytometry (FCM). Among these approaches, which is the gold standard it is still a matter of debate. Neuroradiology and CC have a limited sensitivity with a higher rate of false negative results. FCM demonstrated a superior sensitivity over CC, particularly when low levels of CNS infiltrating cells are present. Although prospective studies of a large series of patients are still awaited, a positive finding by FCM appears to anticipate an adverse outcome even if CC shows no infiltration. Current strategies for adult ALL CNS-directed prophylaxis or therapy involve systemic and intrathecal chemotherapy and radiation therapy. An early and frequent intrathecal injection of cytostatic combined with systemic chemotherapy is the most effective strategy to reduce the frequency of CNS involvement. In patients with CNS overt ALL, at diagnosis or upon relapse, allogeneic hematopoietic stem cell transplantation might be considered. This review discusses risk factors, diagnostic techniques for identification of CNS infiltration and modalities of prophylaxis and therapy to manage it.
    Mediterranean Journal of Hematology and Infectious Diseases 11/2014; 6(1):e2014075.
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    ABSTRACT: Somatic mutations of the spliceosome machinery have been recently identified by whole genome analysis in hematologic diseases, such as myelodysplastic syndrome, chronic lymphocytic leukemia, myeloproliferative neoplasms, acute myeloid leukemia, and advanced forms of mastocytosis, and also in nonhematologic conditions. SRSF2 is a member of the serine/arginine–rich family pre-mRNA splicing factors that plays a role in mRNA export from the nucleus and translation. We describe a high-resolution melting (HRM) curve analysis to screen for SRSF2 hotspot mutations in a fast, sensitive, and reliable way. Fifty bone marrow samples from patients with myelodysplastic syndrome were analyzed by the HRM assay and by direct sequencing. HRM screening identified four melting patterns corresponding to a negative (wild-type) group and three different mutated groups. Each mutated group was identified according to the positive control used: P95H, P95L, and P95R, respectively. An HRM mutated pattern was identified in seven patients. Positive and negative results from HRM were compared with direct sequencing results with a sensitivity and specificity of 100% (95% CI, 0.56–1, and 95% CI, 0.89–1, respectively). Analytical sensitivity analysis revealed a detection threshold of up to 1:9 (mutated/wild type) dilution. This rapid screening method may provide useful information for clinical decision making and be helpful to optimize laboratory resources and reduce turnaround time.
    The Journal of Molecular Diagnostics. 10/2014;
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    ABSTRACT: A randomized clinical trial compared efficacy and toxicity of standard all-trans-retinoic acid (ATRA) plus chemotherapy versus ATRA plus arsenic trioxide in patients with newly diagnosed, low- or intermediate-risk acute promyelocytic leukemia (APL). Here, we report health-related quality-of-life (HRQOL) results.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 09/2014;
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    ABSTRACT: All-trans retinoic acid (ATRA) has made acute promyelocytic leukemia (APL) a very curable disease also in patients aged >60 years; however, there are only few case reports in very elderly APL patients. To address this issue, we reviewed treatment results in 13 patients aged >70 years with newly diagnosed APL followed at our institution from January 1991 to December 2008. According to Sanz score, seven patients were at low risk, five at intermediate risk, and one at high risk. Induction therapy consisted of ATRA + idarubicin in nine patients (3/9 with reduced idarubicin dosage) and ATRA alone in four patients; in this latter group, however, 2/4 needed to add chemotherapy (CHT) due to hyperleukocytosis during ATRA treatment. All patients achieved both morphological and molecular complete remission (CR) after a median time of 51 [interquartile range (IR) 43-55] and 114 (IR 74-155) days, respectively. Infective complications were observed in 10/13 patients, APL differentiation syndrome in 3/13 patients. Twelve patients received consolidation therapy, followed by maintenance treatment in nine patients. Five patients relapsed after 7, 8, 11, 35, and 56 months. At present, seven patients are still alive, five died due to disease progression (four) or senectus while in CR (one), and one was lost to follow-up while in CR. The 5-year event-free survival was 56.1 % (95 % CI, 26.0-86.2); the 5-year overall survival (OS) was 64.5 % (95 % CI, 35.6-93.4). ATRA-based treatment of APL is safe and effective also in very elderly patients, with long-lasting disease-free OS.
    Annals of Hematology 09/2014; · 2.87 Impact Factor
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    ABSTRACT: Activating internal tandem duplication (ITD) mutations in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) are associated with poor outcome in acute myeloid leukemia, but their prognostic impact in acute promyelocytic leukemia (APL) remains controversial. Here, we screened for FLT3-ITD mutations in 171 APL patients, treated with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. We identified FLT3-ITD mutations in 35 patients (20 %). FLT3-ITD mutations were associated with higher white blood cell counts (P < 0.0001), relapse-risk score (P = 0.0007), higher hemoglobin levels (P = 0.0004), higher frequency of the microgranular morphology (M3v) subtype (P = 0.03), and the short PML/RARA (BCR3) isoform (P < 0.0001). After a median follow-up of 38 months, FLT3-ITD(positive) patients had a lower 3-year overall survival rate (62 %) compared with FLT3-ITD(negative) patients (82 %) (P = 0.006). The prognostic impact of FLT3-ITD on survival was retained in multivariable analysis (hazard ratio: 2.39, 95 % confidence interval [CI] 1.17-4.89; P = 0.017). Nevertheless, complete remission (P = 0.07), disease-free survival (P = 0.24), and the cumulative incidence of relapse (P = 0.94) rates were not significantly different between groups. We can conclude that FLT3-ITD mutations are associated with several hematologic features in APL, in particular with high white blood cell counts. In addition, FLT3-ITD may independently predict a shorter survival in patients with APL treated with ATRA and anthracycline-based chemotherapy.
    Annals of Hematology 07/2014; · 2.87 Impact Factor
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    ABSTRACT: Dear Editor,Retinoic acid receptors (RARs) are nuclear hormone receptors functioning as ligand-activated transcription factors which interact specifically in order to modulate transcription DNA elements. RARs include alpha (RARA), beta (RARB), and gamma (RARG) receptor types. They function as heterodimers with retinoid X receptors (RXRs). Heterodimers formed by RXRA-RARG are necessary for growth arrest and visceral and primitive endodermal differentiation [1, 2]. The RARA is known to be involved in the t(15;17) chromosome translocation uniquely associated with acute promyelocytic leukemia (APL) which generates the RARA/PML fusion [1]. In a few APL cases, RARA is rearranged with partner genes other than PML as a result of variant translocations [3, 4]. In a previous report, we described a novel fusion protein generated by a translocation t(11;12)(p15;q13) that involved the genes NUP98 and RARG in a patient with acute myeloid leukemia (AML) [5]. The involvement of RARG in a chimeric fusi
    Annals of Hematology 04/2014; · 2.87 Impact Factor
  • Francesco Lo-Coco, Laura Cicconi
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    ABSTRACT: Modern guidelines based on a large international consensus indicate that treatment of newly diagnosed acute promyelocytic leukemia (APL) requires distinguishing at presentation low-intermediate (<10 × 10(9)/L WBC) from high-risk (>10 × 10(9)/L WBC) disease. The concomitant use of all-trans retinoic acid (ATRA) and anthracycline based chemotherapy, with inclusion of AraC in consolidation for hyperleucocytic patients, has remained the standard of care for the past two decades. The advent of arsenic trioxide (ATO) and results from a large randomized trial, have recently challenged the standard ATRA-chemotherapy approach suggesting that at least patients in the low-intermediate category may be cured without chemotherapy using the ATRA-ATO combination.
    Current Hematologic Malignancy Reports 04/2014;
  • Francesco Lo-Coco, Syed Khizer Hasan
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    ABSTRACT: Acute promyelocytic leukemia (APL) is a distinct subset of acute myeloid leukemia (AML) associated with peculiar biologic and clinical features and requiring specific management. At the genetic level, APL is featured by a unique chromosome translocation t(15;17) which results in the PML-RARα gene fusion and chimeric protein. APL is the first example of differentiation therapy targeted to a defined genetic target i.e PML-RARα. PML-RARα behaves as an altered retinoic acid receptor with an ability of transmitting oncogenic signaling leading to accumulation of undifferentiated promyelocytes. All-trans-retinoic acid (ATRA) induces disease remission in APL patients by triggering terminal differentiation of leukemic promyelocytes. More recently, arsenic trioxide (ATO) has been shown to contribute degradation of the PML-RARα oncoprotein through bonding the PML moiety and has shown excellent synergism with ATRA in clinical trials. Elucidating the oncogenic signaling of PML-RARα through various transcription factors and the study of APL mouse models have greatly helped to understand the molecular pathogenesis of APL. However, the precise molecular mechanism by which t(15;17) is formed and initiates leukemia remains unknown. While transforming oncogenic potential of PML-RARα has been described extensively, the mechanistic events important for the formation of t(15;17) have been taken from the model of t-APL.
    Bailli&egrave re s Best Practice and Research in Clinical Haematology 03/2014; · 2.81 Impact Factor
  • Massimo Breccia, Laura Cicconi, Francesco Lo-Coco
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    ABSTRACT: Arsenic trioxide (ATO) has been shown to be the most effective single agent in acute promyelocytic leukaemia (APL) and has been approved for the treatment of relapsed patients both in the US and Europe. The role of ATO in front-line therapy of APL is under investigation. Pilot studies using ATO with or without all-trans retinoic acid (ATRA) have been carried out in newly diagnosed APL patients with the aim to reduce the short and long-term toxic effects of chemotherapy and to improve clinical outcome. Especially in patients with non-high-risk APL, the ATRA + ATO approach allowed significant increase in event-free survival and overall survival rates compared to standard ATRA and chemotherapy. This has been demonstrated by pilot studies and, more recently, by a randomized comparative multi-centre study conducted in Italy and Germany. The ATO + ATRA strategy for APL may provide the first paradigm of acute leukaemia curability by targeted agents and without chemotherapy. However, longer follow-up of available studies and independent confirmation of the Italian-German findings are awaited to firmly establish this paradigm. Finally, extension of this approach to other patient categories such as high-risk, elderly and children will need to be explored in the near future.
    Current opinion in hematology 01/2014; · 5.19 Impact Factor
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    ABSTRACT: Genomic characterization of translocation breakpoints is relevant to identify possible mechanisms underlying their origin. The consistent association of anthracylines (e.g., epirubicin and idarubicin) in inducing therapy-related acute leukemias (t-AL) with mixed lineage leukemia (MLL) gene rearrangement suggests that MLL translocations are causative events for t-AL. Using asymmetric multiplex PCR strategy followed by direct DNA sequencing, we characterized the genomic breakpoints of the MLL and AFF1 genes in two patients who developed t-AL with t(4;11)(q21;q23). Chemotherapeutic treatment of the primary disease in both patients included topoisomerase II (topo II) targeting agents. In one case, the MLL breakpoint was located in intron 9 at nucleotide position chr11:118354284 while the AFF1 breakpoint was in intron 3 at nucleotide position chr4:87992070. The breakpoint junction sequences revealed an insertion of two nucleotides at the MLL-AFF1 junction. In the other patient, the MLL breakpoint was located in intron 11 at nucleotide position chr11:118359130-32 and the AFF1 break was in intron 3 at nucleotide position chr4:87996215-17. The MLL breakpoint found in the latter patient was identical to that of two previously reported cases, strongly suggesting the presence of a preferential site of DNA cleavage in the presence of topo II inhibitor. In addition, microhomologies at the breakpoint junctions were indicative of DNA repair by the non-homologous end joining (NHEJ) pathway. This study further supports the evidence that MLL breakpoints in therapy-related acute leukemia with MLL-AFF1 are clustered in the telomeric half of the breakpoint cluster region that contains topo II recognition sites. © 2013 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 12/2013; · 3.55 Impact Factor
  • American Journal of Hematology 12/2013; · 4.00 Impact Factor
  • Haematologica 12/2013; 98(12):e161-3. · 5.94 Impact Factor
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    ABSTRACT: Background All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity. Methods We conducted a phase 3, multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell count, ≤10×10(9) per liter). Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA. The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival at 2 years in the two groups was not greater than 5%. Results Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P=0.12). The median follow-up was 34.4 months. Two-year event-free survival rates were 97% in the ATRA-arsenic trioxide group and 86% in the ATRA-chemotherapy group (95% confidence interval for the difference, 2 to 22 percentage points; P<0.001 for noninferiority and P=0.02 for superiority of ATRA-arsenic trioxide). Overall survival was also better with ATRA-arsenic trioxide (P=0.02). As compared with ATRA-chemotherapy, ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity. Conclusions ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL. (Funded by Associazione Italiana contro le Leucemie and others; ClinicalTrials.gov number, NCT00482833 .).
    New England Journal of Medicine 11/2013; 369(2):112-21. · 54.42 Impact Factor
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    ABSTRACT: In Ph- myeloproliferative neoplasms, the quantification of the JAK2V617F transcripts may provide some advantages over the DNA allele burden determination. We developed a q-RT-PCR to assess the JAK2WT and JAK2V617F mRNA expression in 105 cases (23 donors, 13 secondary polycythemia, 22 polycythemia vera (PV), 38 essential thrombocythemia (ET), and 9 primary myelofibrosis (PMF)). Compared with the standard allele-specific oligonucleotide (ASO)-PCR technique, our assay showed a 100 % concordance rate detecting the JAK2V617F mutation in 22/22 PV (100 %), 29/38 (76.3 %) ET, and 5/9 (55.5 %) PMF cases, respectively. The sensitivity of the assay was 0.01 %. Comparing DNA and RNA samples, we found that the JAK2V617F mutational ratios were significantly higher at the RNA level both in PV (p = 0.005) and ET (p = 0.001) samples. In PV patients, JAK2WT expression levels positively correlated with the platelets (PLTs) (p = 0.003) whereas a trend to negative correlation was observed with the Hb levels (p = 0.051). JAK2V617F-positive cases showed the lowest JAK2WT and ABL1 mRNA expression levels. In all the samples, the expression pattern of beta-glucoronidase (GUSB) was more homogeneous than that of ABL1 or β2 microglobulin (B2M). Using GUSB as normalizator gene, a significant increase of the JAK2V617F mRNA levels was seen in two ET patients at time of progression to PV. In conclusion, the proposed q-RT-PCR is a sensitive and accurate method to quantify the JAK2 mutational status that can also show clinical correlations suggesting the impact of the residual amount of the JAK2WT allele on the Ph- MPN disease phenotype. Our observations also preclude the use of ABL1 as a housekeeping gene for these neoplasms.
    Annals of Hematology 10/2013; · 2.87 Impact Factor
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    ABSTRACT: Therapy-related acute promyelocytic leukemia (t-APL) has been increasingly reported after exposure to cytotoxic and/or immunosuppressive agents given for prior malignancies or autoimmune diseases. t-APL represents both a model for better understanding human leukemogenesis and an interesting therapeutic subset which requires specific adaptations for optimal management. We discuss here potential risk factors for t-APL development and the main biologic and clinical characteristics of t-APL as compared to de-novo APL.In addition, we review therapeutic results obtained in patients with t-APL receiving conventional retinoic acid and chemotherapy and discuss new treatment opportunities with minimal or no exposure to conventional cytotoxic agents. Genomic studies in patients at risk of t-APL are relevant to better adapt treatment for the primary disease and to implement monitoring during follow-up and early diagnosis of t-APL. Improved molecular characterization of t-APL may include next generation sequencing approaches to better identify distinguishing features as compared to de-novo APL. Early diagnosis of t-APL through careful monitoring of patients at higher risk, coupled to incorporation in the therapeutic armamentarium of novel effective agents such as arsenic trioxide could result in improved clinical outcome for these patients.
    Current opinion in oncology 09/2013; · 4.09 Impact Factor

Publication Stats

5k Citations
1,058.75 Total Impact Points

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Institutions

  • 2003–2014
    • University of Rome Tor Vergata
      • • Department of Biomedicine and Prevention
      • • Dipartimento di Biopatologia e Diagnostica per Immagini
      Roma, Latium, Italy
  • 2013
    • University of São Paulo
      San Paulo, São Paulo, Brazil
    • University of Valencia
      Valenza, Valencia, Spain
  • 2001–2013
    • Sapienza University of Rome
      • • Department of Medico-Surgical Sciences and Biotechnologies
      • • Department of Cellular Biotechnology and Hematology BCE
      • • Unit of Histology and Medical Embryology
      • • Department of Experimental Medicine
      Roma, Latium, Italy
  • 2012
    • Rosario National University
      Rosario, Santa Fe, Argentina
  • 2011–2012
    • Foundation Santa Lucia
      Roma, Latium, Italy
    • Cairo University
      • Department of Medical Oncology (NCI)
      Cairo, Muhafazat al Qahirah, Egypt
  • 2009–2012
    • Istituto Regina Elena - Istituti Fisioterapici Ospitalieri
      Roma, Latium, Italy
  • 2006–2011
    • Istituto Superiore di Sanità
      • Department of Haematology, Oncology and Molecular Medicine
      Roma, Latium, Italy
  • 2004–2011
    • Hospital Universitari i Politècnic la Fe
      • Department of Hematology
      Valencia, Valencia, Spain
    • Campus IFOM-IEO
      Milano, Lombardy, Italy
  • 2002–2011
    • LIUCBM Libera Università Campus Bio-Medico di Roma
      Roma, Latium, Italy
  • 2010
    • Policlinico Tor Vergata
      Roma, Latium, Italy
  • 2002–2010
    • IEO - Istituto Europeo di Oncologia
      • Department of Experimental Oncology
      Milano, Lombardy, Italy
  • 2008
    • Università degli Studi di Torino
      • Dipartimento di Scienze Cliniche e Biologiche
      Torino, Piedmont, Italy