Vincenzo Mazzaferro

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

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Publications (268)1692.9 Total impact

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    ABSTRACT: Neoadjuvant chemotherapy (NACT) prior to liver resection is advantageous for patients with colorectal cancer liver metastases (CLM). Bevacizumab- or cetuximab-based NACT may affect patient outcome and curative resection rate, but comparative studies on differential tumour regression grade (TRG) associated with distinct antibodies-associated regimens are lacking. Ninety-three consecutive patients received NACT plus bevacizumab (n = 46) or cetuximab (n = 47) followed by CLM resection. Pathological response was determined in each resected metastasis as TRG rated from 1 (complete) to 5 (no response). Except for KRAS mutations prevailing in bevacizumab versus cetuximab (57 vs. 21 %, p = 0.001), patients characteristics were well balanced. Median follow-up was 31 months (IQR 17-48). Bevacizumab induced significantly better pathological response rates (TRG1-3: 78 vs. 34 %, p < 0.001) as well as complete responses (TRG1: 13 vs. 0 %, p = 0.012) with respect to cetuximab. Three-year progression-free survival (PFS) and overall survival (OS) were not significantly different in the two cohorts. At multivariable analysis, significant association with pathological response was found for number of resected metastases (p = 0.015) and bevacizumab allocation (p < 0.001), while KRAS mutation showed only a trend. Significant association with poorer PFS and OS was found for low grades of pathological response (p = 0.009 and p < 0.001, respectively), R2 resection or presence of extrahepatic disease (both p < 0.001) and presence of KRAS mutation (p = 0.007 and p < 0.001, respectively). Bevacizumab-based regimens, although influenced by the number of metastases and KRAS status, improve significantly pathological response if compared to cetuximab-based NACT. Possible differential impact among regimens on patient outcome has still to be elucidated.
    Medical Oncology 07/2015; 32(7):638. DOI:10.1007/s12032-015-0638-3 · 2.06 Impact Factor
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    ABSTRACT: The aim of this study was to optimize the dosimetric approach and to review the absorbed doses delivered, taking into account radiobiology, in order to identify the optimal methodology for an individualized treatment planning strategy based on (99m)Tc-macroaggregated albumin (MAA) single photon emission computed tomography (SPECT) images. We performed retrospective dosimetry of the standard TheraSphere® treatment on 52 intermediate (n = 17) and advanced (i.e. portal vein thrombosis, n = 35) hepatocarcinoma patients with tumour burden < 50 % and without obstruction of the main portal vein trunk. Response was monitored with the densitometric radiological criterion (European Association for the Study of the Liver) and treatment-related liver decompensation was defined ad hoc with a time cut-off of 6 months. Adverse events clearly attributable to disease progression or other causes were not attributed to treatment. Voxel dosimetry was performed with the local deposition method on (99m)Tc-MAA SPECT images. The reconstruction protocol was optimized. Concordance of (99m)Tc-MAA and (90)Y bremsstrahlung microsphere biodistributions was studied in 35 sequential patients. Two segmentation methods were used, based on SPECT alone (home-made code) or on coregistered SPECT/CT images (IMALYTICS™ by Philips). STRATOS™ absorbed dose calculation was validated for (90)Y with a single time point. Radiobiology was used introducing other dosimetric variables besides the mean absorbed dose D: equivalent uniform dose (EUD), biologically effective dose averaged over voxel values (BEDave) and equivalent uniform biologically effective dose (EUBED). Two sets of radiobiological parameters, the first derived from microsphere irradiation and the second from external beam radiotherapy (EBRT), were used. A total of 16 possible methodologies were compared. Tumour control probability (TCP) and normal tissue complication probability (NTCP) were derived. The area under the curve (AUC) of the receiver-operating characteristic (ROC) curve was used as a figure of merit to identify the methodology which gave the best separation in terms of dosimetry between responding and non-responding lesions and liver decompensated vs non-decompensated liver treatment. MAA and (90)Y biodistributions were not different (71 % of cases), different in 23 % and uncertain in 6 %. Response correlated with absorbed dose (Spearman's r from 0.48 to 0.69). Responding vs non-responding lesion absorbed doses were well separated, regardless of the methodology adopted (p = 0.0001, AUC from 0.75 to 0.87). EUBED gave significantly better separation with respect to mean dose (AUC = 0.87 vs 0.80, z = 2.07). Segmentation on SPECT gave better separation than on SPECT/CT. TCP(50 %) was at 250 Gy for small lesion volumes (<10 cc) and higher than 1,000 Gy for large lesions (>10 cc). Apparent radiosensitivity values from TCP were around 0.003/Gy, a factor of 3-5 lower than in EBRT, as found by other authors. The dose-rate effect was negligible: a purely linear model can be applied. Toxicity incidence was significantly larger for Child B7 patients (89 vs 14 %, p < 0.0001), who were therefore excluded from dose-toxicity analysis. Child A toxic vs non-toxic treatments were significantly separated in terms of dose averaged on whole non-tumoural parenchyma (including non-irradiated regions) with AUC from 0.73 to 0.94. TD50 was ≈ 100 Gy. No methodology was superior to parenchyma mean dose, which therefore can be used for planning, with a limit of TD15 ≈ 75 Gy. A dosimetric treatment planning criterion for Child A patients without complete obstruction of the portal vein was developed.
    European Journal of Nuclear Medicine 06/2015; DOI:10.1007/s00259-015-3068-8 · 5.22 Impact Factor
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    ABSTRACT: Background & Aims: Hepatocellular carcinoma (HCC) has become a major cause of liver related death and indication to liver transplantation (LT) in patients with chronic hepatitis B virus (HBV) infection following the widespread adoption of antiviral therapy with nucleos(t)ide analogs (NUCs). Yet, the long-term outcome of patients undergoing liver transplantation for an HCC developed during effective NUC treatment is unknown. Methods: We evaluated 101 patients with persistently compensated cirrhosis who were consecutively transplanted for HCC in two centers in Milan. At LT, 91 (90%) patients had undetectable serum HBV DNA (<12 IU/mL) and 90 (89%) were within Milan criteria(MC).All patients received post transplant HBV prophylaxis with specific immunoglobulins (HBIgs) and NUCs. End-points were long-term patient survival and recurrence of HCC and HBV. Results: During 106 (range 3-165) months following LT, HCC recurred in 11 (11%) patients (9 beyond MC at explant, 2 within MC with HBV recurrence). Age (HR 1.1, 95%CI 1.0-1.2, p=0.04) and exceeding MC (HR 9.6, 95%CI 2.9-32, p<0.0001) were the only independent pretransplant predictors of tumor recurrence. The 10-year cumulative rate of HCC recurrence was 7% among patients transplanted within MC compared to 45% among those beyond MC al LT (p=0.004). Overall, 18 patients (18%, 9 HCC, 9 non liver-related events) died with a 10-year cumulative probability of overall and liver-related survival of 79% and 89%, respectively. Conclusions: Extended survival of HBV cirrhotics transplanted for HCC can be achieved by coupling MC at listing with persistent pharmacological suppression of HBV.
    Liver international: official journal of the International Association for the Study of the Liver 05/2015; DOI:10.1111/liv.12835 · 4.41 Impact Factor
  • Renato Romagnoli, Vincenzo Mazzaferro, Jordi Bruix
    Hepatology 04/2015; DOI:10.1002/hep.27831 · 11.19 Impact Factor
  • Journal of Hepatology 04/2015; 62:S405-S406. DOI:10.1016/S0168-8278(15)30481-5 · 10.40 Impact Factor
  • Journal of Hepatology 04/2015; 62(1S):S144-S156. DOI:10.1016/j.jhep.2015.02.007 · 10.40 Impact Factor
  • Journal of Hepatology 04/2015; 62:S458. DOI:10.1016/S0168-8278(15)30599-7 · 10.40 Impact Factor
  • Journal of Hepatology 04/2015; 62:S189. DOI:10.1016/S0168-8278(15)30006-4 · 10.40 Impact Factor
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    ABSTRACT: Genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. Analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereas FGF3, FGF4, FGF19 or CCND1 amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (FDA)-approved drugs. In conclusion, we identified risk factor-specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy.
    Nature Genetics 03/2015; 47(5). DOI:10.1038/ng.3252 · 29.65 Impact Factor
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    Journal of Hepatology 02/2015; 57(6). DOI:10.1016/j.jhep.2015.01.033 · 10.40 Impact Factor
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    ABSTRACT: Epigenetic deregulation has emerged as a driver in human malignancies. There is no clear understanding of the epigenetic alterations in hepatocellular carcinoma and of the potential role of DNA methylation markers as prognostic biomarkers. The analysis of tumor tissue from 304 patients with hepatocellular carcinoma treated with surgical resection allowed us to generate a methylation-based prognostic signature using a training-validation scheme. Methylome profiling was done with the Illumina HumanMethylation450 array, which covers 96% of known CpG islands and 485,000 CpG, and transcriptome profiling was performed with Affymetrix Human Genome U219 Plate and miRNA Chip 2.0. Random Survival Forest enabled us to generate a methylation signature based on 36 methylation probes. We computed a risk score of mortality for each individual that accurately discriminated patient's survival both in the training set (221 patients; 47% hepatitis C-related hepatocellular carcinoma) and validation sets (n=83; 47% alcohol-related hepatocellular carcinoma). This signature correlated with known predictors of poor outcome and retained independent prognostic capacity of survival along with multinodularity and platelet count. The subset of patients identified by this signature was enriched in the molecular subclass of proliferation with progenitor cell features. The study confirmed a high prevalence of genes known de-regulated by aberrant methylation in hepatocellular carcinoma (e.g. RASSF1, IGF2, APC) and other solid tumors (e.g. NOTCH3), and describe potential candidate epidrivers (e.g. SEPT9, EFNB2). Conclusions: A validated signature of 36 DNA methylation markers accurately predicts poor survival in patients with hepatocellular carcinoma. Patients with this methylation profile harbor mRNA-based signatures indicating tumors with progenitor cell features. This article is protected by copyright. All rights reserved.
    Hepatology 02/2015; 61(6). DOI:10.1002/hep.27732 · 11.19 Impact Factor
  • Digestive and Liver Disease 02/2015; 47:e54. DOI:10.1016/j.dld.2015.01.118 · 2.89 Impact Factor
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    ABSTRACT: Intrahepatic cholangiocarcinoma (iCCA) is a fatal bile duct cancer with dismal prognosis and limited therapeutic options. By performing RNA- and exome-sequencing analyses, we report a novel fusion event, FGFR2-PPHLN1 (16%), and damaging mutations in the ARAF oncogene (11%). Here we demonstrate that the chromosomal translocation t(10;12)(q26;q12) leading to FGFR2-PPHLN1 fusion possesses transforming and oncogenic activity, which is successfully inhibited by a selective FGFR2 inhibitor in vitro. Among the ARAF mutations, N217I and G322S lead to activation of the pathway and N217I shows oncogenic potential in vitro. Screening of a cohort of 107 iCCA patients reveals that FGFR2 fusions represent the most recurrent targetable alteration (45%, 17/107), while they are rarely present in other primary liver tumours (0/100 of hepatocellular carcinoma (HCC); 1/21 of mixed iCCA-HCC). Taken together, around 70% of iCCA patients harbour at least one actionable molecular alteration (FGFR2 fusions, IDH1/2, ARAF, KRAS, BRAF and FGF19) that is amenable for therapeutic targeting.
    Nature Communications 01/2015; 6:6087. DOI:10.1038/ncomms7087 · 10.74 Impact Factor
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    ABSTRACT: Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer that develops in children and young adults without cirrhosis. Little is known about its pathogenesis, and it can only be treated with surgery. We performed an integrative genomic analysis of a large series of patients with FLC to identify associated genetic factors. Using 78 clinically annotated FLC samples, we performed whole-transcriptome (n=58), single-nucleotide polymorphism array (n=41), and next-generation sequencing (n=48) analyses; we also assessed the prevalence of the DNAJB1-PRKACA fusion transcript associated with this cancer (n=73). We performed class discovery using non-negative matrix factorization, and functional annotation using gene set enrichment analyses, nearest template prediction, ingenuity pathway analyses, and immunohistochemistry. The genomic identification of significant targets in cancer algorithm was used to identify chromosomal aberrations, MuTect and VarScan2 were used to identify somatic mutations, and the random survival forest was used to determine patient prognoses. Findings were validated in an independent cohort. Unsupervised gene expression clustering revealed 3 robust molecular classes of tumors: the proliferation class (51% of samples) had altered expression of genes that regulate proliferation and mTOR signaling activation; the inflammation class (26% of samples) had altered expression of genes that regulate inflammation and cytokine production; and the unannotated class (23% of samples) had a gene expression signature not previously associated with liver tumors. Expression of genes that regulate neuroendocrine function, as well has histologic markers of cholangiocytes and hepatocytes, were detected in all 3 classes. FLCs had few copy number variations; the most frequent were focal amplification at 8q24.3 (in 12.5% of samples) and deletions at 19p13 (in 28% of samples) and 22q13.32 (in 25% of samples). The DNAJB1-PRKACA fusion transcript was detected in 79% of samples. FLC samples also contained mutations in cancer-related genes such as BRCA2 (in 4.2% of samples), which are uncommon in liver neoplasms. However, FLCs did not contain mutations most commonly detected in liver cancers. We identified an 8-gene signature that predicted survival of patients with FLC. In a genomic analysis of 78 FLC samples, we identified 3 classes based on gene expression profiles. FLCs contain mutations and chromosomal aberrations not previously associated with liver cancer, and almost 80% contain the DNAJB1-PRKACA fusion transcript. Using this information, we identified a gene signature that is associated with patient survival time. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
    Gastroenterology 12/2014; 148(4). DOI:10.1053/j.gastro.2014.12.028 · 13.93 Impact Factor
  • European Journal of Cancer 11/2014; 50:152. DOI:10.1016/S0959-8049(14)70592-1 · 4.82 Impact Factor
  • Vincenzo Mazzaferro, Riccardo Lencioni, Pietro Majno
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    ABSTRACT: In the treatment of early hepatocellular carcinoma (HCC), resection ablation and transplantation have had excellent initial success. Choices have to be based on a broad and long-term vision integrating-besides patients' interests-the community's needs and resources. In this scenario, guidelines such as the Barcelona Clinic Liver Cancer (BCLC) staging system can be viewed as a hideous frame (symbolized by the myth of Procrustes, Poseidon's son who stretched or maimed travelers to fit into his bed), or as a useful structure against which personalized or innovative treatments must be reality checked. In this article, the latter view is taken: For resection, portal hypertension must still represent a powerful caveat, particularly because of poor long-term results. Expansion of the criteria may instead be explored for multiple tumors and vascular invasion, where good indications can consistently be selected in expert surgical centers. For ablation, competitive results can be obtained although a small, but appreciable proportion of patients with early vascular invasion (∼ 10%), as they could probably benefit from anatomical resections. Conversely, ablative techniques overcoming the location and size limitations are developing and may prove competitive. For transplantation, several equivalent careful expansions of Milan's Criteria can be accepted, but as more patients have access to the waiting list-often prioritized on non-HCC indications-current allocation models prove to be insufficient, if not plainly inequitable, and should be revised.
    Seminars in Liver Disease 11/2014; 34(4):415-26. DOI:10.1055/s-0034-1394365 · 5.12 Impact Factor
  • Jordi Bruix, Gregory Gores, Vincenzo Mazzaferro
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    ABSTRACT: We appreciate the opportunity to comment on the controversial issues surrounding treatment options for patients with hepatocellular carcinoma. In the field of surgery or interventional radiology it is common to emphasise technical feasibility and early morbidity/mortality rather than medium/long-term survival. Expanding life expectancy of the patients in comparison with that offered by other treatments, or even no treatment, is the goal of therapy. In our review1 and in practice guidelines2 ,3 the recommendations were based on robust data from prospective studies, preferably randomised, in the target population that had the option of being investigated. In the setting of surgical resection there are now several studies showing that presence of vascular invasion, multifocal disease and portal hypertension are associated with a … [Full text of this article]
    Gut 10/2014; 64(3). DOI:10.1136/gutjnl-2014-308381 · 13.32 Impact Factor
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  • Sherrie Bhoori, Vincenzo Mazzaferro
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    ABSTRACT: Liver transplantation (LT) is the best option of cure for hepatocellular carcinoma (HCC). Notwithstanding several alternatives, Milan Criteria remain the cornerstone for patient selection. Currently, expanded criteria patients are unsuitable for LT without taking downstaging approaches and response to therapies into consideration. Relative weight of HCC as indication to LT is increasing and that generates competition with MELD-described non-cancer indications. Allocation policies should be adjusted accordingly, considering principles of urgency and utility in the management of the waiting list and including transplant benefit to craft equitable criteria to deal with the limited resource of donated grafts. Maximization of cost-effectiveness of LT in HCC can be also pursued through changes in immunosuppression policies and multimodal management of post-transplant recurrences. This review is focused on those constantly mutating challenges that have to be faced by anyone dealing with the management of HCC in the context of liver transplantation.
    Baillière&#x027 s Best Practice and Research in Clinical Gastroenterology 10/2014; 28(5). DOI:10.1016/j.bpg.2014.08.001 · 3.28 Impact Factor
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    ABSTRACT: In some countries where the Model for End-Stage Liver Disease (MELD) score is used for graft allocation, selected patients with hepatocellular carcinoma (HCC) receive a fixed number of exception points at listing, and increasing priority on the list by accruing additional exception points at regular time intervals. This system originally aimed at balancing the risks of HCC patients of developing contraindications and of non-HCC patients of dying before transplantation, is not ideal because it appears to offer an advantage to HCC patients, regardless of tumor characteristics and response to loco-regional treatment. Scores modulated by HCC characteristics have been proposed. They are based on a more refined estimate of the risk of pretransplant drop-out or of the posttransplant transplant benefit expressed as the life-years gained for each graft. This review describes the newly proposed systems, and discusses their advantages and drawbacks. We believe that the current exception points allocation should be revised and that drop-out-equivalent or transplant benefit-equivalent models should be studied further. As with all policy changes, these should be done under close monitoring that allows subsequent revisions.
    American Journal of Transplantation 09/2014; 14(10). DOI:10.1111/ajt.12923 · 6.19 Impact Factor

Publication Stats

14k Citations
1,692.90 Total Impact Points

Institutions

  • 1993–2015
    • CRO Centro di Riferimento Oncologico di Aviano
      • • Department of Surgery
      • • Division of Experimental Oncology 1
      • • Division of Radiology
      Aviano, Friuli Venezia Giulia, Italy
  • 2014
    • Hospital Clínic de Barcelona
      Barcino, Catalonia, Spain
  • 1992–2014
    • Istituto Nazionale Tumori "Fondazione Pascale"
      Napoli, Campania, Italy
  • 1990–2014
    • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
      • • s.c. Pediatria Oncologica
      • • s.c. Medicina Oncologica 1
      Milano, Lombardy, Italy
  • 2013
    • Università degli Studi di Milano-Bicocca
      • Department of Health Science
      Milano, Lombardy, Italy
    • Mount Sinai Hospital
      New York City, New York, United States
  • 2012
    • University of California, San Diego
      San Diego, California, United States
    • Istituto di Cura e Cura a Carattere Scientifico Basilicata
      Rionero in Vulture, Basilicate, Italy
  • 2011
    • University of Rome Tor Vergata
      Roma, Latium, Italy
  • 1988–2010
    • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
      Meldola, Emilia-Romagna, Italy
  • 2008
    • McGill University
      Montréal, Quebec, Canada
    • Dana-Farber Cancer Institute
      • Department of Pediatric Oncology
      Boston, Massachusetts, United States
  • 1988–2008
    • University of Pittsburgh
      • Department of Surgery
      Pittsburgh, Pennsylvania, United States
  • 1997–2007
    • University of Milan
      • Department of Internal Medicine
      Milano, Lombardy, Italy
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2005
    • IDIBAPS August Pi i Sunyer Biomedical Research Institute
      Barcino, Catalonia, Spain
  • 2003
    • Università degli Studi di Modena e Reggio Emilia
      Modène, Emilia-Romagna, Italy
  • 2002–2003
    • Ospedale di San Raffaele Istituto di Ricovero e Cura a Carattere Scientifico
      Milano, Lombardy, Italy
  • 2000
    • Shanghai Medical University
      Shanghai, Shanghai Shi, China