Mario Strazzabosco

University of Florence, Florens, Tuscany, Italy

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Publications (241)1676.4 Total impact

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    Luca Fabris · Simone Brivio · Massimiliano Cadamuro · Mario Strazzabosco
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    ABSTRACT: Whether liver epithelial cells contribute to the development of hepatic scarring by undergoing epithelial-to-mesenchymal transition (EMT) is a controversial issue. Herein, we revisit the concept of EMT in cholangiopathies, a group of severe hepatic disorders primarily targeting the bile duct epithelial cell (cholangiocyte), leading to progressive portal fibrosis, the main determinant of liver disease progression. Unfortunately, therapies able to halt this process are currently lacking. In cholangiopathies, fibrogenesis is part of ductular reaction, a reparative complex involving epithelial, mesenchymal, and inflammatory cells. Ductular reactive cells (DRC) are cholangiocytes derived from the activation of the hepatic progenitor cell compartment. These cells are arranged into irregular strings and express a “reactive” phenotype, which enables them to extensively crosstalk with the other components of ductular reaction. We will first discuss EMT in liver morphogenesis and then highlight how some of these developmental programs are partly reactivated in DRC. Evidence for “bona fide” EMT changes in cholangiocytes is lacking, but expression of some mesenchymal markers represents a fundamental repair mechanism in response to chronic biliary damage with potential harmful fibrogenetic effects. Understanding microenvironmental cues and signaling perturbations promoting these changes in DRC may help to identify potential targets for new antifibrotic therapies in cholangiopathies.
    Preview · Article · Jan 2016 · Stem cell International
  • Simone Brivio · Massimiliano Cadamuro · Luca Fabris · Mario Strazzabosco
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    ABSTRACT: In addition to its well-established role in embryo development, epithelial-to-mesenchymal transition (EMT) has been proposed as a general mechanism favoring tumor metastatization in several epithelial malignancies. Herein, we review the topic of EMT in cholangiocarcinoma (CCA), a primary liver cancer arising from the epithelial cells lining the bile ducts (cholangiocytes) and characterized by an abundant stromal reaction. CCA carries a dismal prognosis, owing to a pronounced invasiveness and scarce therapeutic opportunities. In CCA, several reports indicate that cancer cells acquire a number of EMT biomarkers and functions. These phenotypic changes are likely induced by both autocrine and paracrine signals released in the tumor microenvironment (cytokines, growth factors, morphogens) and intracellular stimuli (microRNAs, oncogenes, tumor suppressor genes) variably associated with specific disease mechanisms, including chronic inflammation and hypoxia. Nevertheless, evidence supporting a complete EMT of neoplastic cholangiocytes into stromal cells is lacking, and the gain of EMT-like changes by CCA cells rather reflects a shift towards an enhanced pro-invasive phenotype, likely induced by the tumor stroma. This concept may help to identify new biomarkers of early metastatic behavior along with potential therapeutic targets.
    No preview · Article · Dec 2015 · Journal of Clinical Medicine
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    ABSTRACT: Congenital hepatic fibrosis (CHF) is a disease of the biliary epithelium characterized by bile duct changes resembling ductal plate malformations and by progressive peribiliary fibrosis, in the absence of overt necroinflammation. Progressive liver fibrosis leads to portal hypertension and liver failure; however, the mechanisms leading to fibrosis in CHF remain elusive. CHF is caused by mutations in PKHD1, a gene encoding for fibrocystin, a ciliary protein expressed in cholangiocytes. Using a fibrocystin-defective (Pkhd1del4/del4) mouse, which is orthologous of CHF, we show that Pkhd1del4/del4 cholangiocytes are characterized by a β-catenin-dependent secretion of a range of chemokines, including chemokine (C-X-C motif) ligands 1, 10, and 12, which stimulate bone marrow-derived macrophage recruitment. We also show that Pkhd1del4/del4 cholangiocytes, in turn, respond to proinflammatory cytokines released by macrophages by up-regulating αvβ6 integrin, an activator of latent local transforming growth factor-β1. While the macrophage infiltrate is initially dominated by the M1 phenotype, the profibrogenic M2 phenotype increases with disease progression, along with the number of portal myofibroblasts. Consistent with these findings, clodronate-induced macrophage depletion results in a significant reduction of portal fibrosis and portal hypertension as well as of liver cysts. Conclusion: Our results show that fibrosis can be initiated by an epithelial cell dysfunction, leading to low-grade inflammation, macrophage recruitment, and collagen deposition; these findings establish a new paradigm for biliary fibrosis and represent a model to understand the relationship between cell dysfunction, parainflammation, liver fibrosis, and macrophage polarization over time. © 2015 by the American Association for the Study of Liver Diseases.
    No preview · Article · Dec 2015 · Hepatology
  • Giulia Bonato · Laura Cristoferi · Mario Strazzabosco · Luca Fabris
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    ABSTRACT: Conclusions: PSC may be regarded as paradigmatic of the sequence leading from chronic inflammatory epithelial damage to neoplastic transformation. Understanding the molecular mechanisms regulating this pathogenetic sequence, may improve strategies of disease surveillance and cancer prevention and treatment. PSC is a chronic inflammatory cholangiopathy of unknown etiology but likely immune-mediated, characterized by peribiliary inflammation and fibrosis leading to strictures in any portion (intra- and/or extrahepatic) of the bile duct system. No effective medical treatments are currently available. A unique feature of PSC is the close association (about 80%) with IBD, mainly UC, often diagnosed before PSC (PSC/UC). As in other chronic inflammatory diseases, development of malignancies is a feared complication of PSC.
    No preview · Article · Dec 2015 · Digestive Diseases
  • S Conti · PA Cortesi · L Scalone · M Strazzabosco · G Cesana · LG Mantovani

    No preview · Article · Nov 2015 · Value in Health
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    ABSTRACT: Cystic fibrosis-associated liver disease is a chronic cholangiopathy that negatively affects the quality of life of cystic fibrosis patients. In addition to reducing biliary chloride and bicarbonate secretion, up-regulation of toll-like receptor 4/nuclear factor kappa light-chain-enhancer of activated B cells (NF-κB)-dependent immune mechanisms plays a major role in the pathogenesis of cystic fibrosis-associated liver disease and may represent a therapeutic target. Nuclear receptors are transcription factors that regulate several intracellular functions. Some nuclear receptors, including peroxisome proliferator-activated receptor-γ (PPAR-γ), may counterregulate inflammation in a tissue-specific manner. In this study, we explored the anti-inflammatory effect of PPAR-γ stimulation in vivo in cystic fibrosis transmembrane conductance regulator (Cftr) knockout mice exposed to dextran sodium sulfate and in vitro in primary cholangiocytes isolated from wild-type and from Cftr-knockout mice exposed to lipopolysaccharide. We found that in CFTR-defective biliary epithelium expression of PPAR-γ is increased but that this does not result in increased receptor activity because the availability of bioactive ligands is reduced. Exogenous administration of synthetic agonists of PPAR-γ (pioglitazone and rosiglitazone) up-regulates PPAR-γ-dependent genes, while inhibiting the activation of NF-κB and the secretion of proinflammatory cytokines (lipopolysaccharide-induced CXC chemokine, monocyte chemotactic protein-1, macrophage inflammatory protein-2, granulocyte colony-stimulating factor, keratinocyte chemoattractant) in response to lipopolysaccharide. PPAR-γ agonists modulate NF-κB-dependent inflammation by up-regulating nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha, a negative regulator of NF-κB. Stimulation of PPAR-γ in vivo (rosiglitazone) significantly attenuates biliary damage and inflammation in Cftr-knockout mice exposed to a dextran sodium sulfate-induced portal endotoxemia. Conclusion: These studies unravel a novel function of PPAR-γ in controlling biliary epithelium inflammation and suggest that impaired activation of PPAR-γ contributes to the chronic inflammatory state of CFTR-defective cholangiocytes. (Hepatology 2015;62:1551-1562) © 2015 by the American Association for the Study of Liver Diseases.
    No preview · Article · Nov 2015 · Hepatology
  • PA Cortesi · A Ciaccio · G Belleli · M Rota · S Conti · LG Mantovani · G Annoni · M Strazzabosco
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    ABSTRACT: Objectives: A relevant proportion of patients affected by Chronic Hepatitis C(CHC) is older than 65 years. These patients have been undertreated in the past two decades, due to poor eligibility to interferon-containing regimens. New all-oral, interferon-free antivirals may represent a valuable option for this population. Our aim was to assess the cost-effectiveness of sofosbuvir plus ledipasvir(SOF/LDV) therapy in genotype 1(G1) and 4(G4) CHC elderly patients. Methods: A Markov model of CHC natural history was built. The model focuses on CHC patients older than 65 years and assessed the impact of liver fibrosis (METAVIR F3 and F4), age and frailty phenotype, defined by Fried’s (not frail, pre-frail and frail), on the cost-effectiveness of SOF/LDV versus no treatment. The model estimated costs, Life Years and Quality-Adjusted Life Years (QALY) using the lifetime time horizon and the National Health System perspective. Results were presented as incremental cost-effectiveness ratios (ICERs) per QALY gained. Results: The cost-effectiveness of all-oral and IFN-free treatment regimen in HCV elderly patients is influenced by all three parameters assessed in our simulation. ICER was higher in lower fibrosis stages and increased with age and frailty phenotype. In F3 and F4 patients ICER was below 40,000 € /QALY up to age 83.3 and over 85 years in non-frail patients, up to age 79.5 and 82.5 in prefrail and up to age 76.5 and 79.5 in frail, respectively. The ICER was more sensitive to drug price and SVR probability. Further, the mortality rate not-liver related had a higher impact in the not-frail patients. Co nclusions: Age and fibrosis stage are not enough to assess the cost-effectiveness of anti-HCV treatment in elderly subjects. A careful assessment of the patient geriatric status should be mandatory, especially in patients older than 75 years, to better allocate the resources available and to prioritize the access to the treatment.
    No preview · Article · Nov 2015 · Value in Health
  • Source
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    ABSTRACT: Cholangiocarcinoma is an aggressive, strongly chemoresistant liver malignancy. Leukemia inhibitory factor (LIF), an IL-6 family cytokine, promotes progression of various carcinomas. To investigate the role of LIF in cholangiocarcinoma, we evaluated the expression of LIF and its receptor (LIFR) in human samples. LIF secretion and LIFR expression were assessed in established and primary human cholangiocarcinoma cell lines. In cholangiocarcinoma cells, we tested LIF effects on proliferation, invasion, stem cell-like phenotype, chemotherapy-induced apoptosis (gemcitabine+cisplatin), expression levels of pro-apoptotic (Bax) and anti-apoptotic (Mcl-1) proteins, with/without PI3K inhibition, and of pSTAT3, pERK1/2, pAKT. LIF effect on chemotherapy-induced apoptosis was evaluated after LIFR silencing and Mcl-1 inactivation. Results show that LIF and LIFR expression were higher in neoplastic than in control cholangiocytes; LIF was also expressed by tumor stromal cells. LIF had no effects on cholangiocarcinoma cell proliferation, invasion, and stemness signatures, whilst it counteracted drug-induced apoptosis. Upon LIF stimulation, decreased apoptosis was associated with Mcl-1 and pAKT up-regulation and abolished by PI3K inhibition. LIFR silencing and Mcl-1 blockade restored drug-induced apoptosis. In conclusion, autocrine and paracrine LIF signaling promote chemoresistance in cholangiocarcinoma by up-regulating Mcl-1 via a novel STAT3- and MAPK-independent, PI3K/AKT-dependent pathway. Targeting LIF signaling may increase CCA responsiveness to chemotherapy.
    Full-text · Article · Jul 2015 · Oncotarget
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    ABSTRACT: Preliminary studies on HCV-cirrhotics listed for transplant suggest that sofosbuvir in combination with ribavirin is very effective in promoting viral clearance and preventing disease recurrence. Unfortunately, the high cost of such treatment (€46 500 per 12 weeks of treatment) makes its cost-effectiveness questionable. A semi-Markov model was developed to assess the cost-effectiveness of sofosbuvir/ribavirin treatment in cirrhotic patients without HCC (HCV-CIRRH) and with HCC (HCV-HCC) listed for transplant. In the base-case analysis, the incremental cost-effectiveness ratio for 24 weeks of sofosbuvir/ribavirin was €44 875 per quality-adjusted life-year gained in HCV-CIRRH and €60 380 in HCV-HCC patients. Both results were above the willingness to pay threshold of €37 000 per quality-adjusted life-year. Our data also show that in order to remain cost-effective (with a 24-week treatment), any novel interferon-free treatment endowed with ideal efficacy should cost less than €67 224 or €95 712 in HCV-cirrhotics with and without HCC, respectively. The results shows that sofosbuvir/ribavirin therapy, given to patients listed for transplant, is not cost-effective at current prices despite being very effective, and new, more effective treatments will have little economic margins to remain cost-effective. New interferon-free combinations have the potential to revolutionize the treatment and prognosis of HCV-positive patients listed for transplant; however, without sustainable prices, this revolution is unlikely to happen. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
    Full-text · Article · Jul 2015 · American Journal of Transplantation
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    ABSTRACT: Female gender has been reported to be a risk factor for graft loss after liver transplantation for hepatitis C virus (HCV)-related cirrhosis but evidence is limited to retrospective studies. To investigate the impact of recipient gender and donor/recipient gender mismatch on graft outcome. We performed a survival analysis of a cohort of 1530 first adult transplants enrolled consecutively in Italy between 2007 and 2009 and followed prospectively. After excluding possible confounding factors (fulminant hepatitis, human immunodeficiency virus co-infection, non-viremic anti-HCV positive subjects), a total of 1394 transplant recipients (604 HCV-positive and 790 HCV-negative) were included. Five-year graft survival was significantly reduced in HCV-positive patients (64% vs 76%, p=0.0002); Cox analysis identified recipient female gender (HR=1.44, 95% CI 1.03-2.00, p=0.0319), Mayo clinic End stage Liver Disease score (every 10 units, HR=1.25, 95% CI 1.03-1.50; p=0.022), portal thrombosis (HR=2.40, 95% CI 1.20-4.79, p=0.0134) and donor age (every 10 years, HR=1.14, 95% CI 1.05-1.24, p=0.0024) as independent determinants of graft loss. All additional mortality observed among female recipients was attributable to severe HCV recurrence. This study unequivocally shows that recipient female gender unfavourably affects the outcome of HCV-infected liver grafts. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
    No preview · Article · Apr 2015 · Digestive and Liver Disease
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    ABSTRACT: Background and Aims: Primary sclerosing cholangitis (PSC) is an enigmatic disease with scarce therapeutic options, potentially evolving to severe and life-threatening complications, including malignancies like cholangiocarcinoma (CCA) or colon cancer. The clinical management of PSC remains challenging and may benefit from identification of outcome indicators to assess the quality of care. This study aims to: (A) identify Outcome Indicators (OIs) for PSC, and (B) validate OIs in a clinical context with a preliminary interim analysis. Methods: (A) A panel of experts generated a list of OIs using a modified version of the Delphi method. (B) OIs with the highest RAND/UCLA score were tested in an ongoing multicentric and prospective study (Value-based Medicine in Hepatology, VBMH). Results: Five OIs were identified on the basis of the highest rating values and disagreement indexes next to 0. They include: annual rate of acute cholangitis episodes (OI#1); mortality rate for patients not yet listed for liver transplantation (OI#2); rate of quality of life improvement, measured by EQ-VAS (a visual assessment scale ranging from 0 to 100 where the patient points out his present-day health status) and EQ-5D (assessment of 5 domains that measure daily performance according to 3 levels of severity) (OI#3); number of patients died for CCA and CRC (OI#4); incidence and/or worsening of osteoporosis, expressed as T-score differential over a 2-year interval (OI#5). In the validation study, 63 consecutive patients with PSC enrolled in 3 tertiary liver centres in Northern Italy were evaluated for a 24-month follow-up period. For each OI, the following values were reported: OI#1: cumulative incidence of 5.2%, resulting in 0.029 cholangitis/patient; OI#2, OI#4: no patients died without being listed for transplantation or because of cancer during study time; OI#3: 38.9% and 19.4% of patients showed an improvement in EQ-VAS and EQ-5D parameters, respectively; OI#5: 3% of patients developed or worsened osteoporosis. Conclusions: Five OIs for PSC were identified on a highly shared consensus. Albeit the study population is small (as in the case of rare diseases) and the follow-up time is short as compared to the long natural history of the disease, these OIs have proven to be easy to collect and to work appropriately. Therefore, they are suitable to be extended to specialized centres involved in PSC management to further validate their clinical usefulness.
    Full-text · Article · Apr 2015 · Journal of Hepatology
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    ABSTRACT: Background and Aims: A relevant proportion of patients affected by Chronic Hepatitis C (CHC) is older than 65 years. In the interferon era, comorbidities and a higher susceptibility to interferon/ribavirin adverse events have historically limited treatment in these patients. Recent approval of interferon-free regimens, characterized by high efficacy and limited toxicity, provide unprecedented chances for these patients to receive curative treatments. However, the costeffectiveness of all-oral Direct-Acting Antivirals (DAAs) has not been addressed in the elderly population. We have performed a cost-effectiveness analysis taking into account the severity of liver disease, the age of the patient and the geriatric (frailty) status. Methods: A semi-Markov model of CHC natural history was built. The study focuses on CHC patients older than 65 years, stratified according to liver fibrosis (METAVIR F3 and F4), age (65 to 85 years old) and frailty phenotype defined by Fried’s (not frail, pre-frail and frail) for a total of 30 cohorts simulated. Treatment with sofosbuvir plus simeprevir (SOF/SMV) combination versus no treatment was assessed for each cohort population. The model estimated costs, Life Years and Quality Adjusted Life Years (QALY) using a lifetime time horizon and the Health System perspective. Results are presented as incremental cost-effectiveness ratios (ICERs) per QALY gained. Cost-effectiveness was defined as an ICER under the willingness-to-pay threshold of €37,000 per QALY gained. Results: At each fibrosis score, ICER increased with age and frailty index. Among patients with F3 fibrosis, ICER ranged from €13,934/QALY in not-frail 65 years old and €79,354 in frail 85 years old patients. Among F4 patients ICER ranged from €13,873/QALY in not frail 65 years old and €115,965 in frail 85 years old patients. In both F3 and F4 cohorts ICER was below €37,000/QALY up to age 80 in non-frail pts, up to age 75 in pre-frail patients, up to age 70 in frail patients. Adopting an alternative scenario with a 20% discount of SOF/SMV treatment, the number of cohort population simulated with an ICER below € 37,000/QALY increased. Conclusions: SOF/SMV treatment is cost-effective in most CHC patients older than 65 years, however a careful assessment of the patient geriatric status is mandatory. This cost-effectiveness analysis should promote a prospective clinical study to verify efficacy and side effects in elderly HCV patients.
    No preview · Article · Apr 2015 · Journal of Hepatology
  • R. Fiorotto · A. Villani · R. Scirpo · C. Spirli · M. Strazzabosco

    No preview · Article · Feb 2015 · Digestive and Liver Disease
  • Source
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    ABSTRACT: Introduction: Primary sclerosing cholangitis (PSC) is an enigmatic disease with scarce therapeutic options. The clinical management of PSC remains challenging and may benefit from Outcome Indicators (OI) to assess the quality of care. Aims: This study aims to: (A) identify OIs for PSC, and (B) validate OIs in a clinical context. Methods: (A) A panel of experts generated a list of OIs by Delphi method. (B) OIs with the highest RAND/UCLA score were tested in an ongoing multicentric, prospective study (Value-based Medicine in Hepatology, VBMH). Results: Five OIs were identified having the highest rating values and low disagreement indexes: annual rate of acute cholangitis episodes (OI#1); mortality rate for patients not yet listed for liver transplantation (OI#2); rate of quality of life improvement, measured by EQ-VAS and EQ-5D (OI#3); number of patients died for cholangiocarcinoma and colo-rectal carcinoma (OI#4); incidence and/or worsening of osteoporosis (OI#5). In the validation study, 63 consecutive patients with PSC enrolled in 3 tertiary centres in Northern Italy were evaluated for a median 24-months follow-up period. For each OI, the following values were reported: (OI#1) cumulative incidence of 5.2%, resulting in 0.029 cholangitis/patient; (OI#2, OI#4) no patients died without being listed for transplantation or because of cancer during study time; (OI#3) 38.9 and 19.4% of patients showed an improvement in EQ-VAS and EQ-5D parameters, respectively; (OI#5) 3% of patients developed or worsened osteoporosis. Conclusions: Five OIs for PSC were identified reporting high consensus. Albeit the study population is small (as in the case of rare diseases) and the follow-up time is short as compared to the long natural history of the disease, these OIs have proven to be easy to collect and to work appropriately. Therefore, they are suitable to be extended to specialized centres involved in PSC management to further validate their clinical usefulness.
    Full-text · Article · Feb 2015 · Digestive and Liver Disease
  • Source
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    ABSTRACT: Background/aims: According to current guidelines on management of Chronic Hepatitis C (CHC), both interferon (IFN)-containing and IFN-free treatment combinations may be offered to patients, depending on viral genotype, previous treatment and contraindications to IFN. The past two decades of treatment have selected a large population of patients ineligible to IFN. Our aim is to characterize the current CHC population in order to best drive resource allocation. Patients and methods: we retrospectively retrieved the characteristics and outcomes of a cohort of 801 consecutive CHC outpatients followed-up at two tertiary Centers in Northern Italy. Baseline characteristics of never treated and treated CHC patients were compared by means of Chi-Square test for categorical and t-test for continuous variables. Results: fifty-three percent (426 out of 801) of patients had previously received treatment. Among them, 103 (24%) had achieved SVR; 323 (76%) had failed, of whom 74 (23%) did not complete and 249 (77%) did not respond to treatment. Adverse events were the main cause of treatment withdrawal (90%). Forty-seven percent (n = 375) of all participants had never received any treatment, mostly because of contraindications (27% overall, hematologic 11%, psychiatric 24%, cardiovascular 15%, autoimmune 7%, others 43%), advanced age (27%), personal choice (15%) or no fibrosis (10%). Never treated patients differed significantly (p < 0.01) from treated ones by age (61 vs 56 years) and gender (male 49 vs 65%). Six-hundred and ninety-eight patients (323 failed plus 375 never treated) are awaiting new antiviral therapy, of which 442 (63%) are candidate to all-oral combinations because of contraindications or past intolerance to IFN, while the remaining 256 (37%) may still receive an IFN-containing regimen. Conclusions: 37% of the CHC patients being followed in our clinics may receive IFN-containing protocols with newer DAAs, while about the two thirds of these patients are obligated candidates for the more costly, IFN-free regimens.
    Full-text · Article · Feb 2015 · Digestive and Liver Disease
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    ABSTRACT: Background and aim: A relevant proportion of patients affected by chronic hepatitis C (CHC) is older than 65 years. Comorbidities and a higher susceptibility to drugs toxicity have historically limited treatment in these patients. Recent approval of interferon-free regimens, characterized by high efficacy and limited toxicity, provides unprecedented chances for these patients to be cured. The aim of this study is to assess cost-effectiveness, taking into account the severity of liver disease, age, and the geriatric (frailty) status. Methods: A semi-Markov model of CHC natural history was built. The study focuses on CHC patients older than 65 years, stratified according to liver fibrosis (METAVIR F3 and F4), age (65–85 years old) and Fried’s frailty phenotype (not frail, pre-frail and frail) generating 30 simulated cohorts. Treatment with sofosbuvir plus simeprevir (SOF/SMV) versus no treatment was assessed for each cohort. The model estimated costs, Life Years and Quality Adjusted Life Years (QALY), with a lifetime time horizon and the Health System perspective. Results are presented as incremental costeffectiveness ratios (ICERs) per QALY gained. Cost-effectiveness was defined as an ICER under the 37,000D threshold. Results: At each fibrosis score, ICER increased with age and frailty index. Among F3 patients, ICER ranged from D13,934 in notfrail 65-years-old andD79,354 in frail 85-years-old patients. Among F4 patients ICER ranged from D13,873 in not frail 65-years-old and D115,965 in frail 85-years-old patients. In both F3 and F4 cohorts ICER was below D37,000/QALY up to age 80 in non-frail patients, up to age 75 in pre-frail patients, up to age 70 in frail patients. Conclusion: SOF/SMV treatment is cost-effective in most CHC patients older than 65 years, however a careful assessment of the patient geriatric status is mandatory. This cost-effectiveness analysis should promote a prospective clinical study to verify efficacy and side effects in elderly HCV patients.
    No preview · Article · Feb 2015 · Digestive and Liver Disease
  • M. Cadamuro · M. Vismara · S. Brivio · A. Furlanetto · M. Strazzabosco · L. Fabris

    No preview · Article · Feb 2015 · Digestive and Liver Disease
  • Roberto Scirpo · Romina Fiorotto · Ambra Villani · L. Fabris · Mario Strazzabosco
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    ABSTRACT: Cystic fibrosis-associated liver disease (CFLD) is a chronic cholangiopathy that negatively affects the quality of life of cystic fibrosis patients. In addition to reducing biliary chloride and bicarbonate secretion, up-regulation of TLR4/NF-kB-dependent immune mechanisms plays a major role in the pathogenesis of CFLD, and may represent a therapeutic target. Nuclear receptors (NRs) are transcription factors that regulate several intracellular functions. Some NRs, including peroxisome proliferator-activated receptor-γ (PPAR-γ), may counter-regulate inflammation in a tissue-specific manner. In this study, we explored the anti-inflammatory effect of PPAR-γ stimulation in vivo in Cftr-KO mice exposed to DSS, and in vitro in primary cholangiocytes isolated from wild type and from Cftr-KO mice exposed to LPS. We found that in CFTR-defective biliary epithelium, expression of PPAR-γ is increased, but does not result in increased receptor activity because the availability of bioactive ligands is reduced. Exogenous administration of synthetic agonists of PPAR-γ (pioglitazone and rosiglitazone) upregulates PPAR-γ-dependent genes, while inhibiting the activation of NF-kB and the secretion of proinflammatory cytokines (LIX, MCP-1, MIP-2, G-CSF, KC) in response to LPS. PPAR-γ agonists modulate NF-kB-dependent inflammation by upregulating IkBα, a negative regulator of NF-kB. Stimulation of PPAR-γ in vivo (rosiglitazone) significantly attenuates biliary damage and inflammation in Cftr-KO mice exposed to a DSS-induced portal endotoxemia. These studies unravel a novel function of PPAR-γ in controlling biliary epithelium inflammation and suggest that impaired activation of PPAR-γ contributes to the chronic inflammatory state of CFTR-defective cholangiocytes. This article is protected by copyright. All rights reserved. © 2015 by the American Association for the Study of Liver Diseases.
    No preview · Article · Feb 2015 · Digestive and Liver Disease
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    ABSTRACT: Results: PC2 protein expression, but not its gene expression, was significantly reduced in mouse livers with biliary damage (Mdr2(-/-) KO, bile duct ligation, DDC-treatment). Treatment of colangiocytes with pro-inflammatory cytokines, nitric oxide (NO) donors and ER stressors), increased ERK1/2 phosphorylation, HIF1α transcriptional activity, secretion of VEGF, VEGFR2 phosphorylation and downregulated PC2 protein expression without affecting PC2 gene expression. Expression of Herp and NEK, ubiquitin-like proteins that promote proteosomal PC2 degradation was increased. Pre-treatment with the proteasome inhibitor MG-132 restored the expression of PC2 in cells treated with cytokines but not in cells treated with NO donors or with ER stressors. In these conditions, PC2 degradation was instead inhibited by interfering with the autophagy pathway. Treatment of DDC-mice and of Mdr2(-/-) mice with the proteasome inhibitor bortezomib, restored PC2 expression and significantly reduced the ductular reaction, fibrosis and p-ERK1/2. In conclusion, in response to biliary damage, PC2 expression is modulated post-translationally by the proteasome or the autophagy pathways. PC2-dowregulation is associated with activation of ERK1/2 and increase of HIF1α-mediated VEGF secretion. Treatments able to restore PC2 expression and to reduce ductular reaction and fibrosis may represent a new therapeutic approach in biliary diseases. This article is protected by copyright. All rights reserved.
    No preview · Article · Feb 2015 · Digestive and Liver Disease
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    ABSTRACT: Background. Cholangiocarcinoma (CCA) is characterized by early and strong invasiveness. Nuclear expression of the S100A4 protein is a marker of increased CCA invasiveness and our preliminary data showed that Paclitaxel (PTX) could reduce S100A4 nuclearization. We aimed at studying if nuclear S100A4 promotes CAA invasiveness and may represent a therapeutic target. Methods and Results. CCA cells expressing nuclear S100A4 (EGI-1) were treated with increasing PTX doses to study its effects on nuclear S100A4 expression, S100A4 sumoylation (a mechanism of nuclear import of proteins), cytoskeletal integrity, cell proliferation/apoptosis, motility, invasiveness and Rho GTPases activity. PTX (1.5 and 15 nM) induced a marked reduction in nuclear S100A4. This decrement was linked with a significantly reduced sumoylated fraction and an attenuation of cell migration, invasiveness and Rho-A/Cdc42 activation, without affecting proliferation/apoptosis or cytoskeletal integrity. SCID mice xenografted with EGI-1 cells by spleen injection, were treated, after tumor engraftment, with low-dose metronomic regimen of PTX (2,6 mg/kg/die; n = 5) for 14 days, using untreated mice as controls (n = 5). After mice sacrifice, we evaluated PTX effects on tumor size, number of micrometastasis (MM) and isolated tumour cells (ITC) in liver and lung samples, along with proliferation, apoptosis and S100A4 expression of EGI-1. PTX induced a significant reduction in both the tumor size and number of lung MM/ITC. The primary CCA mass of PTX-treated mice, showed a significantly reduced number of EGI-1 cells expressing nuclear S100A4, whereas proliferation/apoptosis rate did not change. Conclusion. Down-regulation of nuclear S100A4 by PTX at doses below those commonly used in chemotherapy but able to interfere with the sumoylation process, results in a decreased CCA cell motility and invasiveness and in a reduction of hematogenous spread. These effects are not dependent upon changes in cell proliferation, apoptosis or cytoskeleton integrity, but upon down-modulation of Rho-A and Cdc42 activities by a reduced S100A4 nuclearization.
    No preview · Article · Feb 2015 · Digestive and Liver Disease

Publication Stats

4k Citations
1,676.40 Total Impact Points

Institutions

  • 2015
    • University of Florence
      • Dipartimento di Medicina Sperimentale e Clinica
      Florens, Tuscany, Italy
  • 2008-2015
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States
  • 1989-2015
    • Yale University
      • • Department of Internal Medicine
      • • Section of Digestive Diseases
      • • School of Medicine
      New Haven, Connecticut, United States
  • 2010-2014
    • Università degli Studi di Milano-Bicocca
      • Department of Surgery and Interdisciplinary Medicine
      Milano, Lombardy, Italy
  • 1985-2013
    • University of Padova
      • • Department of Industrial Engineering
      • • Department of Biology
      • • Department of Surgery, Oncology and Gastroenterology DISCOG
      • • Department of Medicine DIMED
      Padua, Veneto, Italy
  • 2007-2011
    • University of Rome Tor Vergata
      • Dipartimento di Biologia
      Roma, Latium, Italy
  • 2002-2007
    • Ospedali Riuniti di Bergamo
      Bérgamo, Lombardy, Italy
  • 2006
    • Sapienza University of Rome
      Roma, Latium, Italy
  • 2005
    • Istituto di Genetica Molecolare
      Ticinum, Lombardy, Italy
  • 2004
    • University of Bergamo
      Bérgamo, Lombardy, Italy
    • It-Robotics
      Vicenza, Veneto, Italy
  • 1998-2003
    • University of Milan
      • Department of Internal Medicine
      Milano, Lombardy, Italy
  • 1998-2002
    • University of Vienna
      Wien, Vienna, Austria
  • 2000
    • University-Hospital of Padova
      Padua, Veneto, Italy