Mario Strazzabosco

University of Florence, Florens, Tuscany, Italy

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Publications (224)1525.91 Total impact

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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.
    Oncotarget 07/2015; · 6.63 Impact Factor
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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.
    American Journal of Transplantation 07/2015; 15(7):1817-26. DOI:10.1111/ajt.13320 · 6.19 Impact Factor
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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.
    Digestive and Liver Disease 04/2015; DOI:10.1016/j.dld.2015.04.006 · 2.89 Impact Factor
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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.
    Journal of Hepatology 04/2015; 62(Suppl 2):S791. DOI:10.1016/S0168-8278(15)31365-9 · 10.40 Impact Factor
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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.
    Journal of Hepatology 04/2015; 62(Suppl 2):S639. DOI:10.1016/S0168-8278(15)31014-X · 10.40 Impact Factor
  • R. Fiorotto · A. Villani · R. Scirpo · C. Spirli · M. Strazzabosco
    Digestive and Liver Disease 02/2015; 47. DOI:10.1016/j.dld.2015.01.010 · 2.89 Impact Factor
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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.
    Digestive and Liver Disease 02/2015; 47(Supplement 1):e16. DOI:10.1016/j.dld.2015.01.037 · 2.89 Impact Factor
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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.
    Digestive and Liver Disease 02/2015; 47(Supplement 1):e58. DOI:10.1016/j.dld.2015.01.126 · 2.89 Impact Factor
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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.
    Digestive and Liver Disease 02/2015; 47(Supplement 1):e15-e16. DOI:10.1016/j.dld.2015.01.036 · 2.89 Impact Factor
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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.
    Digestive and Liver Disease 02/2015; 47:e21. DOI:10.1016/j.dld.2015.01.049 · 2.89 Impact Factor
  • M. Cadamuro · M. Vismara · S. Brivio · A. Furlanetto · M. Strazzabosco · L. Fabris
    Digestive and Liver Disease 02/2015; 47:e22-e23. DOI:10.1016/j.dld.2015.01.052 · 2.89 Impact Factor
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    ABSTRACT: Polycystin-2 (PC2/TRPP2), a member of the transient receptor potential channels (TRP) family, is a non-selective calcium channel. Mutations in PC2/TRPP2 are associated with Polycystic Liver Diseases. PC2-defective cholangiocytes shows increased production of cAMP, PKA-dependent activation of the ERK1/2 pathway, HIF1α-mediated VEGF production, and stimulation of cyst growth and progression. Activation of the ERK/HIF1α/VEGF pathway in cholangiocytes plays a key role during repair from biliary damage. We hypothesized that PC2 levels are modulated during biliary damage/repair, resulting in activation of the ERK/HIF1α/VEGF pathway. 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. © 2015 by the American Association for the Study of Liver Diseases.
    Digestive and Liver Disease 02/2015; 47:e26. DOI:10.1016/j.dld.2015.01.059 · 2.89 Impact Factor
  • 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.
    Digestive and Liver Disease 02/2015; 47:e43-e44. DOI:10.1016/j.dld.2015.01.096 · 2.89 Impact Factor
  • Fabian Geisler · Mario Strazzabosco
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    ABSTRACT: This review critically discusses the most recent advances on the role of Notch signaling in liver development, homeostasis and disease. It is now clear that the significance of Notch in determining mammalian cell fates and functions extends beyond development, and Notch is a major regular of organ homeostasis. Moreover, Notch signaling is reactivated upon injury and regulates the complex interactions between the distinct cellular types involved in the repair process. Notch is also involved in the regulation of liver metabolism, inflammation and cancer. The net effects of Notch signaling are highly variable and finely regulated at multiple levels, but also depend on the specific cellular context in which Notch is activated. Persistent activation of Notch signaling is associated with liver malignancies, such as hepatocellular carcinoma with stem cell features and intrahepatic cholangiocarcinoma. The complexity of the pathway provides several possible targets for agents able to inhibit Notch. However, further cell- and context-specific in depth understanding of Notch signaling in liver homeostasis and disease will be essential to translate these concepts into the clinical practice and be able to predict benefits and risks of evolving therapies. (Hepatology 2014;).
    Hepatology 01/2015; 61(1). DOI:10.1002/hep.27268 · 11.19 Impact Factor
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    P.A. Cortesi · L. Mantovani · A. Ciaccio · M. Rota · G. Cesana · M. Strazzabosco · L.S. Belli
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    ABSTRACT: Objectives: Sofosbuvir in combination with ribavirin (SOF/RBV) is a novel treatment able to suppress HCV viremia when applied to HCV patients listed for transplant, preventing HCV recurrence. Aim of this study was to assess the costeffectiveness of this regimen in HCV patients listed for transplant for cirrhosis (HCVcirrhosis) or for hepatocellular carcinoma (HCV-HCC). Methods: a semi-Markov model was developed. The model simulates the progression of HCV-cirrhosis or HCV-HCC patients from the time of listing until death considering the risk of HCV recurrence post-transplant. The model compared 2 different strategies: 1) SOF/RBV up to a maximum of 24 weeks or until OLT if performed before the 24th week, 2) No antiviral treatment. The model estimated the costs related to the treatment with SOF/RBV, the costs associated to each health state, the life-years (LYSs), the quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) expressed as € per QALY gained. The analysis was performed from the Italian National Health System perspective with a lifetime time horizon and one-month Markov cycles. Future costs and clinical benefits, expressed as QALYs, were discounted at 3% per year. Results: in the base-case analysis the ICER for 24 weeks of SOF/RBVR was € 30,518 per QALY gained in HCV-cirrhosis patients and € 41,610 in HCV-HCC patients. The reliability of our results was confirmed by the one way sensitivity-analysis and by the cost-effectiveness acceptability curve. Further, SOF/RBV cost-effectiveness was clearly sensitive to the duration of treatment; assuming 12 weeks SOF/RBV treatment duration, the ICER decreased to € 19,317 in HCVCirrhosis and € 29,540 in HCV-HCC. Conclusions: our study shows that treating patients with HCV-cirrhosis or HCV-HCC listed for transplant with SOF/RBV is cost-effective and may become the new standard of care for these patients. However a well-defined prospective study is needed to confirm the value of the parameters assumed in the model and the results.
    Value in Health 11/2014; 17(7-7):A367-A368. DOI:10.1016/j.jval.2014.08.826 · 2.89 Impact Factor
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    ABSTRACT: Objectives: the impact of liver diseases (LDs) on health-related quality of life (HRQoL) is an important aspect to understand the burden of these conditions and improve their management. A well characterized impact of the major LDs on HRQoL of the general population is still lacking. The aim of our study was to fill this GAP. Methods: a dataset with HRQoL data of a representative sample of the general population of most populated Italian region was matched with the dataset from a multicenter study conducted in the same region and time period to generate and validate a set of health care outcomes indicators for the major LDs (hepatitis B (HBV), hepatitis C (HCV), compensated cirrhosis (CC), decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), NAFLD/NASH and patients listed for liver transplant (LTL)). Within both datasets, HRQoL data were collected using the EQ-5D-3L. Multivariate logistic and Tobit regressions were then performed adjusting for possible confounders (age, sex, education and working status). Results: a total of 6,800 “healthy subjects” and 3,105 subjects with LDs were included in the analyses. Multivariate logistic analyses showed that DC, HCC, and LTL had significantly (p< 0.05) higher risk to have problems in mobility, self-care, and usual activities compared to “healthy subjects”. AIH had significantly higher risk to have problems in self-care; while HCV, CC, DC, and NAFLD/NASH in Anxiety/depression. Similar results were obtained with the Tobit model performed using VAS and Utility-index. DC, HCC, AIH and LTL reported the highest decrease in VAS and Utility score. Conclusions: HRQoL decreased in advanced LDs (DC, HCC, LTL) and AIH. This study provides an actual true estimate of the impact of major LDs on the patients’ HRQoL compare to the general population, and therefore is a key tool for decision-making in care delivery for liver diseases.
    Value in Health 11/2014; 17(7-7):A369. DOI:10.1016/j.jval.2014.08.835 · 2.89 Impact Factor
  • Mario Strazzabosco · Luca Fabris
    Hepatology 11/2014; 60(5). DOI:10.1002/hep.27291 · 11.19 Impact Factor
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    ABSTRACT: Development of complications in liver cirrhosis (LC) is associated with increased mortality, hospital admissions and costs. Management of LC complications in clinical practice is well established, but the real value and effectiveness of care provided are still difficult to assess. Measurement of outcome indicators (OIs) together with patients-health related quality of life (p-HRQoL) could assist both clinicians and administrators in the process of care, in order to ensure greater quality in patients with LC. Aim of our study was to validate specific OIs, coupled with p-HRQoL scales, and apply them in the clinical assessment of compensated (CC) and decompensated cirrhosis (DC) management. A panel of hepatologists identified a set of OIs using published evidence, a modified Delphi method and a standard 9-point RAND appropriateness scale. These OIs were part of a larger effort, included in a prospective multicenter observational study (Value Based Medicine in Hepatology Study), involving three European tertiary clinical centers. P-HRQoL collected using the EQ-5D questionnaire, generated an health profile, by means of five utility domains (mobility, self care, anxiety/ depression, usual activities and pain/discomfort), and a visual analogue scale (VAS), which measured overall p-HRQoL in a range from 0 to 100. During 18 months we enrolled 1772 patients with LC: 1015 CC and 757 DC; the median follow-up time was 2 years. Results: the OIs chosen by the panelist were meant to evaluate the efficacy of care of major complications of LC: variceal bleeding occurred with an annual incidence of 3,1%, with 1-year survival of 76% of patients, and hepatocellular carcinoma (HCC) developed in a rate of 3,5% per year, with 83% CC patients diagnosed at early stage HCC. The strongest OIs according to the experts were decompensation rate in CC, which was 6.6% per year in our study, and overall survival in DC patients. The 1-year survival after the first decompensation episode (ascites in 73% of cases) was 96% for CPTA, 82% for CPT-B, 56% CPT-C, whereas it was 94% and 57% for MELD score respectively below or above 15. Furthermore, no significant changes in p-HRQoL between baseline and after 2 years follow-up were found in CC and CPT-A patients, while p-HRQoL progressively decreased in DC and CPT B-C patients. In conclusion, combined measurements of specific OIs and p-HRQoL scales provide the methodological bases to implement a value-based approach to the care of patients with LC. In fact, these outcomes combined with measurements of direct and indirect costs could guide future decision-making process and improve value of care in cirrhosis.
    Hepatology 10/2014; 60(Suppl 1):942A-943A. · 11.19 Impact Factor
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    ABSTRACT: The impact of liver diseases (LDs) on health-related quality of life (HRQoL) is an important aspect to understand the burden of these conditions and to improve their management. A well characterized impact of the major LDs on HRQoL of the general population is still lacking. The aim of our study was to fill this gap. A dataset with HRQoL data of a representative sample of the general population of most populated Italian region was matched with the dataset from a multicenter study conducted in the same region and time period to generate and validate a set of health care outcomes indicators for the major LDs (hepatitis B (HBV), hepatitis C (HCV), compensated cirrhosis (CC), decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), NAFLD/ NASH and patients listed for liver transplant (LTL)). Within both datasets, HRQoL data were collected using the EQ-5D-3L, a generic instrument that enables HRQoL to be compared within and between clinical conditions and with the general population. It generates a health profile made up of 5 domains (Mobility, Self-care, Usual activities, Pain/discomfort, Anxiety/ depression). It also consists of a visual analogue scale (EQ-5D VAS) which measures overall HRQoL. Further, results from the EQ-5D health profile can be converted to utility index, useful to conduct economic evaluations. Multivariate logistic and linear regressions were then performed adjusting for possible confounders (age, sex, education and working status). A total of 6,800 nullhealthy subjectsnull and 3,105 subjects with LDs (625 HCV, 287 HBV, 614 CC, 531 DC, 647 HCC, 59 LTL, 229 NAFLD/NASH, 68 PBC, 55 PSC, and 49 AIH) were included in the analyses. Multivariate logistic analyses showed that DC, HCC, and LTL had significantly (p<0.05) higher risk to have problems in mobility, self-care, and usual activities compared to nullhealthy subjectednull. AIH had significantly higher risk to have problems in self-care while HCV, CC, DC, and NAFLD/NASH in Anxiety/depression. Similar results were obtained with multivariate linear analyses performed using VAS and Utility-index. DC, HCC, AIH and LTL reported the highest decrease in VAS and Utility score. In conclusion, our results show that HRQoL of asymptomatic liver conditions are comparable to the general population except for the Anxiety/depression dimension. The HRQoL decreased in advanced LDs (DC, HCC, LTL) and AIH. This study provides an actual true estimate of the impact of major LDs on the patients' HRQoL compare to the general population, and therefore is a key tool for decision-making in care delivery for liver diseases.
    Hepatology 10/2014; 60(Suppl 1):948A-949A. · 11.19 Impact Factor
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    ABSTRACT: Complications in liver cirrhosis (LC) are associated with increased mortality and costs. Management of LC complications is well established in clinical practice, but their real effectiveness is difficult to measure. Assessment of outcome indicators (OIs) together with patients-health related quality of life (p-HRQoL) could help decision-making process for clinicians and administrators. Aim: The aim of our study was to identify a set of OIs, and apply them in the clinical assessment of compensated (CC) and decompensated cirrhosis (DC), together with p-HRQoL scales. Specific OIs chosen by a panel of hepatologists with a modified Delphi method, were tested in a prospective multicenter observational study. P-HRQoL collected using the EQ-5D questionnaire, generated an health profile with five utility domains (mobility, self care, anxiety/depression, usual activities and pain), and a visual analogue scale, which measured overall p-HRQoL in a range from 0 to 100. We enrolled 1772 patients with LC in 18 months: 1015 CC and 757 DC; median follow-up time was 2 years. Results: Variceal bleeding had an annual incidence of 3.1% with 1-year survival of 76%. Hepatocellular carcinoma occurred in a rate of 3.5% per year, and 83% CC patients were diagnosed at early stage. The strongest OIs according to the experts were decompensation rate in CC, which was 6.6% per year, and overall survival in DC patients. The 1-year survival after the first decompensation episode (ascites in 73% of cases) was 96% for CPT-A, 82% CPT-B, 56% CPT-C, whereas it was 94% and 57% for MELD score respectively below or above 15. Interestingly, no significant changes in p-HRQoL between baseline and after 2 years were found in CC and CPT-A patients, while p-HRQoL progressively decreased in DC and CPT B-C. Conclusions: Systematic measurement and comparison of objective OIs and p-HRQoL scales could increase value-based care in liver cirrhosis patients.
    Digestive and Liver Disease 10/2014; 46(Suppl 4):e129. DOI:10.1016/j.dld.2014.08.005 · 2.89 Impact Factor

Publication Stats

3k Citations
1,525.91 Total Impact Points

Institutions

  • 2015
    • University of Florence
      • Dipartimento di Medicina Sperimentale e Clinica
      Florens, Tuscany, Italy
  • 2010–2015
    • Università degli Studi di Milano-Bicocca
      • Department of Surgery and Interdisciplinary Medicine
      Milano, Lombardy, 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
  • 1983–2013
    • University of Padova
      • • Department of Industrial Engineering
      • • Department of Biology
      • • Department of Surgery, Oncology and Gastroenterology DISCOG
      • • Department of Medicine DIMED
      Padua, Veneto, Italy
  • 2008–2011
    • University of Rome Tor Vergata
      Roma, Latium, Italy
  • 2001–2007
    • Ospedali Riuniti di Bergamo
      Bérgamo, Lombardy, Italy
  • 2006
    • Sapienza University of Rome
      Roma, Latium, Italy
  • 2004
    • University of Bergamo
      Bérgamo, Lombardy, Italy
    • It-Robotics
      Vicenza, Veneto, Italy
  • 1998–2002
    • University of Vienna
      Wien, Vienna, Austria
  • 2000
    • University-Hospital of Padova
      Padua, Veneto, Italy
  • 1988
    • Università degli studi di Parma
      Parma, Emilia-Romagna, Italy