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ERICA VILLA
SENIOR PROFESSOR
Dipartimento Chirurgico, Medico, Odontoiatrico e di Scienze Morfologiche con interesse Trapiantologico, Oncologico e di Medicina Rigenerativa
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Pubblicazioni
2023
- Angiogenesis: the Yin and Yang in intrahepatic cholangiocarcinoma
[Articolo su rivista]
Romanzi, A.; Villa, E.
abstract
The tumor microenvironment (TME) constitutes a complex structure comprising different cell types and soluble factors that surround the tumor and promote its progression. Primarily for its pivotal role in malignant growth, TME has become a potential therapeutic objective for developing new targeted therapy and a marker for assessing therapeutic response. In intrahepatic cholangiocarcinoma (iCCA), the second most common primary liver malignancy, TME has also gained a central role in understanding the mechanisms underlying tumor progression. In this review, we focused on the role of angiogenic factors and their pathway in iCCA and analyzed possible therapeutic and prognostic implications.
2023
- Feasibility, safety, and outcome of second-line nivolumab/bevacizumab in liver transplant patients with recurrent hepatocellular carcinoma
[Articolo su rivista]
Di Marco, Lorenza; Pivetti, Alessandra; Foschi, Francesco Giuseppe; D'Amico, Roberto; Schepis, Filippo; Caporali, Cristian; Casari, Federico; Lasagni, Simone; Critelli, Rosina Maria; Milosa, Fabiola; Romanzi, Adriana; Marcelli, Gemma; De Maria, Nicola; Romagnoli, Dante; Catellani, Barbara; Scianò, Filippo; Magistri, Paolo; Colecchia, Antonio; Sighinolfi, Pamela; Di Benedetto, Fabrizio; Martinez-Chantar, Maria-Luz; Villa, Erica
abstract
2023
- Flow-dependent shear stress affects the biological properties of pericyte-like cells isolated from human dental pulp
[Articolo su rivista]
Bertani, Giulia; Di Tinco, Rosanna; Bertoni, Laura; Orlandi, Giulia; Pisciotta, Alessandra; Rosa, Roberto; Rigamonti, Luca; Signore, Michele; Bertacchini, Jessika; Sena, Paola; De Biasi, Sara; Villa, Erica; Carnevale, Gianluca
abstract
Background: Human dental pulp stem cells represent a mesenchymal stem cell niche localized in the perivascular area of dental pulp and are characterized by low immunogenicity and immunomodulatory/anti-inflammatory properties. Pericytes, mural cells surrounding the endothelium of small vessels, regulate numerous functions including vessel growth, stabilization and permeability. It is well established that pericytes have a tight cross talk with endothelial cells in neoangiogenesis and vessel stabilization, which are regulated by different factors, i.e., microenvironment and flow-dependent shear stress. The aim of this study was to evaluate the effects of a pulsatile unidirectional flow in the presence or not of an inflammatory microenvironment on the biological properties of pericyte-like cells isolated from human dental pulp (hDPSCs). Methods: Human DPSCs were cultured under both static and dynamic conditions with or without pre-activated peripheral blood mononuclear cells (PBMCs). Pulsatile unidirectional flow shear stress was generated by using a specific peristaltic pump. The angiogenic potential and inflammatory properties of hDPSCs were evaluated through reverse phase protein microarrays (RPPA), confocal immunofluorescence and western blot analyses. Results: Our data showed that hDPSCs expressed the typical endothelial markers, which were up-regulated after endothelial induction, and were able to form tube-like structures. RPPA analyses revealed that these properties were modulated when a pulsatile unidirectional flow shear stress was applied to hDPSCs. Stem cells also revealed a downregulation of the immune-modulatory molecule PD-L1, in parallel with an up-regulation of the pro-inflammatory molecule NF-kB. Immune-modulatory properties of hDPSCs were also reduced after culture under flow-dependent shear stress and exposure to an inflammatory microenvironment. This evidence was strengthened by the detection of up-regulated levels of expression of pro-inflammatory cytokines in PBMCs. Conclusions: In conclusion, the application of a pulsatile unidirectional flow shear stress induced a modulation of immunomodulatory/inflammatory properties of dental pulp pericyte-like cells.
2023
- GALAD outperforms aMAP and ALBI for predicting HCC in patients with compensated advanced chronic liver disease: A 12-year prospective study
[Articolo su rivista]
Villa, Erica; Donghia, Rossella; Baldaccini, Valentina; Tedesco, Calogero C; Shahini, Endrit; Cozzolongo, Raffaele; Ascari, Sara; Pesole, Pasqua Letizia; Coletta, Sergio; Critelli, Rosina Maria; Lasagni, Simone; Schepis, Filippo; Semellini, Filippo; Giannelli, Gianluigi
abstract
Background and aims: Surveillance programs are strongly recommended in patients with liver cirrhosis for early detection of HCC development. Six-monthly ultrasound sonography is the most reliable and commonly used technique, especially when associated with serum determination of α-fetoprotein, but different score systems have been proposed to overcome the unsatisfactory diagnostic accuracy of α-fetoprotein. The aim of this 12-year prospective study is to compare the gender, age, AFP-L3, AFP, des-gamma-carboxy prothrombin (GALAD) versus age, gender, bilirubin, albumin, and platelets and albumin-bilirubin scores in predicting HCC onset. Approach and results: A cohort of 545 consecutive patients with compensated advanced chronic liver disease without suspected focal lesions was followed up every 6 months by liver imaging and α-fetoprotein to detect HCC occurrence. Harrell's C-index for censored data was employed to evaluate the performance of any parameters or scores helping to predict HCC development. ROC curve analysis showed that the GALAD score was more accurate in evaluating HCC development than albumin-bilirubin and age, gender, bilirubin, albumin, and platelets. The AUC ranged from 0.7268 to 0.6851 at 5 and 10 years, both in the total cohort and in the sub-cohorts (viral hepatitis, NASH, and alcohol). The HCC Risk model was constructed using univariate and multivariate Cox proportional hazard regression analysis, showing a strong association of GALAD with HR > 1, p < 0.05, in the total and sub-cohorts, and a better risk prediction in the alcohol cohort, both alone and standardized with other blood parameters. Conclusions: GALAD is the most reliable and accurate score system to detect HCC risk of development in patients with compensated advanced chronic liver disease.
2023
- Hepatic encephalopathy increases the risk for mortality and hospital readmission in decompensated cirrhotic patients: a prospective multicenter study
[Articolo su rivista]
Riggio, O.; Celsa, C.; Calvaruso, V.; Merli, M.; Caraceni, P.; Montagnese, S.; Mora, V.; Milana, M.; Saracco, G. M.; Raimondo, G.; Benedetti, A.; Burra, P.; Sacco, R.; Persico, M.; Schepis, F.; Villa, E.; Colecchia, A.; Fagiuoli, S.; Pirisi, M.; Barone, M.; Azzaroli, F.; Soardo, G.; Russello, M.; Morisco, F.; Labanca, S.; Fracanzani, A. L.; Pietrangelo, A.; Di Maria, G.; Nardelli, S.; Ridola, L.; Gasbarrini, A.; Camma, C.
abstract
Introduction: Hepatic encephalopathy (HE) affects the survival and quality of life of patients with cirrhosis. However, longitudinal data on the clinical course after hospitalization for HE are lacking. The aim was to estimate mortality and risk for hospital readmission of cirrhotic patients hospitalized for HE. Methods: We prospectively enrolled 112 consecutive cirrhotic patients hospitalized for HE (HE group) at 25 Italian referral centers. A cohort of 256 patients hospitalized for decompensated cirrhosis without HE served as controls (no HE group). After hospitalization for HE, patients were followed-up for 12 months until death or liver transplant (LT). Results: During follow-up, 34 patients (30.4%) died and 15 patients (13.4%) underwent LT in the HE group, while 60 patients (23.4%) died and 50 patients (19.5%) underwent LT in the no HE group. In the whole cohort, age (HR 1.03, 95% CI 1.01–1.06), HE (HR 1.67, 95% CI 1.08–2.56), ascites (HR 2.56, 95% CI 1.55–4.23), and sodium levels (HR 0.94, 95% CI 0.90–0.99) were significant risk factors for mortality. In the HE group, ascites (HR 5.07, 95% CI 1.39–18.49) and BMI (HR 0.86, 95% CI 0.75–0.98) were risk factors for mortality, and HE recurrence was the first cause of hospital readmission. Conclusion: In patients hospitalized for decompensated cirrhosis, HE is an independent risk factor for mortality and the most common cause of hospital readmission compared with other decompensation events. Patients hospitalized for HE should be evaluated as candidates for LT.
2023
- Hydroxypropyl-β-Cyclodextrin Depletes Membrane Cholesterol and Inhibits SARS-CoV-2 Entry into HEK293T-ACEhi Cells
[Articolo su rivista]
Alboni, Silvia; Secco, Valentina; Papotti, Bianca; Vilella, Antonietta; Pia Adorni, Maria; Zimetti, Francesca; Schaeffer, Laurent; Tascedda, Fabio; Zoli, Michele; Leblanc, Pascal; Villa, Erica
abstract
2023
- Long-Term SARS-CoV-2 Antibody Seroprevalence in Blood Donors, Italy
[Articolo su rivista]
Ferrari, Martina; Di Marco, Lorenza; Pivetti, Alessandra; Paduano, Stefania; Vecchi, Chiara; Bernabucci, Veronica; Critelli, Rosina Maria; Lasagni, Simone; De Maria, Monica; Venturelli, Donatella; Pecorari, Monica; Boaretto, Giorgia; Serpini, Giulia Fregni; Romagnoli, Dante; Mantovani, Roberto; Ceccherelli, Giovanni Battista; Villa, Erica
abstract
: We evaluated SARS-CoV-2 antibody response in voluntary blood donors in Italy at different timepoints. Immediately after lockdown easing, 908/25,657 donors (3.5%) had low IgG titers against nucleocapsid. In the next 2 years, titers increased despite few COVID-19 symptoms. On multivariate analysis, allergic rhinitis was associated with reduced risk for symptomatic COVID-19.
2022
- Abstract PO008: Aggressive hepatocellular carcinoma and intrahepatic cholangiocarcinoma cell lines share similar response to proangiogenic priming
[Abstract in Rivista]
Milosa, Fabiola; Romanzi, Adriana; Marcelli, Gemma; Critelli, Rosina Maria; Lasagni, Simone; Cadamuro, Massimiliano; Fabris, Luca; Villa, Erica
abstract
2022
- Diagnosi di crioproteinemia: preziosa collaborazione tra laboratorio e clinica
per la corretta gestione di una patologia rara
[Articolo su rivista]
Natali, Patrizia; Debbia, Daria; Sheldon, Joanna; Bari, Alessia; Basile, Umberto; Lavatelli, Francesca; Patel, Dina; Galli, Massimo; Villa, Erica; Salvarani, Carlo; Palladini, Giovanni; Mascia, Maria Teresa; Sandri, Gilda
abstract
Cryoglobulinemia is a rare pathologic condition that can be difficult to diagnose both clinically and in the laboratory,
which is why close collaboration between the clinic and laboratory is essential. The laboratory needs the skills and
experience to interpret the laboratory tests and the clinician should not hesitate to contact the laboratory when the
result is not supported by the clinical signs. To strengthen this collaboration, the Protein Study Group of the Italian
Society of Clinical Biochemistry (SIBioC) in collaboration with the Italian Association for the Fight against
Cryglobulinemia (ALCRI) under the patronage of the University of Modena and Reggio Emilia, organised a
conference in Modena on September 2021 entitled "Cryoglobulinemia: laboratory and clinic, a virtuous collaboration
for the correct management of a rare pathology". This collective paper is aimed to summarize the topics discussed
during the meeting. The conference consisted of two parts: the first aimed at highlighting the critical components of
the pre-, intra- and post-analytical phases of cryoglobulin investigation. Cryoprotein testing remains totally manual
and operator dependent so it was important to identify areas where best practice guidance or even harmonisation of
the laboratory investigation would be beneficial. The second part of the conference focused on clinical aspects and
the effects of therapies, including antiviral drugs with direct action against HCV. These drugs are able to eradicate the
virus, but the elimination of HCV-related cryoglobulins is seen in only about half of cases. Finally, the clinical
consequences of the diagnosis of cryoglobulinemia and the multidisciplinary implications that this entails were
highlighted, underlining how the continuous dialogue between the laboratory and clinic is crucial for the correct
management of the patient.
2022
- Dynamic Angiopoietin-2 Serum Level as Endothelial Damage Marker and Potential Therapeutic Target
[Articolo su rivista]
Melegari, Gabriele; Critelli, Rosina M; Lasagni, Simone; Romagnoli, Dante; Bertellini, Elisabetta; Villa, Erica
abstract
2022
- Endothelial angiopoietin-2 overexpression in explanted livers identifies subjects at higher risk of recurrence of hepatocellular carcinoma after liver transplantation
[Articolo su rivista]
Lasagni, Simone; Leonardi, Filippo; Pivetti, Alessandra; Di Marco, Lorenza; Ravaioli, Federico; Serenari, Matteo; Gitto, Stefano; Critelli, Rosina Maria; Milosa, Fabiola; Romanzi, Adriana; Mancarella, Serena; Dituri, Francesco; Riefolo, Mattia; Catellani, Barbara; Magistri, Paolo; Romagnoli, Dante; Celsa, Ciro; Enea, Marco; de Maria, Nicola; Schepis, Filippo; Colecchia, Antonio; Cammà, Calogero; Cescon, Matteo; D'Errico, Antonietta; di Benedetto, Fabrizio; Giannelli, Gianluigi; Martinez-Chantar, Maria Luz; Villa, Erica
abstract
Background Though the precise criteria for accessing LT are consistently being applied, HCC recurrence (HCC-R_LT) still affects more than 15% of the patients. We analyzed the clinical, histopathological, and biological features of patients with HCC to identify the predictive factors associated with cancer recurrence and survival after LT.Methods We retrospectively analyzed 441 patients with HCC who underwent LT in our center. Overall, 70 (15.8%) of them developed HCC-R_LT. We matched them by age at transplant and etiology with 70 non-recurrent patients. A comparable cohort from the Liver Transplant Centre of Bologna served as validation. The clinical and biochemical characteristics and pre-LT criteria (Milan, Metroticket, Metroticket_AFP, and AFP model) were evaluated. Histological analysis and immunohistochemistry for angiopoietin-2 in the tumor and non-tumor tissue of explanted livers were performed. Patients' follow-up was until death, last clinical evaluation, or 31 December 2021. In patients with HCC-R_LT, the date of diagnosis of recurrence and anatomical site has been reported; if a biopsy of recurrence was available, histologic and immunohistochemical analyses were also performed.Results Patients were followed up for a mean period of 62.7 54.7 months (median, 39 months). A higher risk of HCC-R_LT was evident for factors related indirectly (AFP) or directly (endothelial angiopoietin-2, microvascular invasion) to biological HCC aggressiveness. In multivariate analysis, only angiopoietin-2 expression was independently associated with recurrence. Extremely high levels of endothelial angiopoietin-2 expression were also found in hepatic recurrence and all different metastatic locations. In univariate analysis, MELD, Metroticket_AFP Score, Edmondson-Steiner grade, microvascular invasion, and endothelial angiopoietin-2 were significantly related to survival. In multivariate analysis, angiopoietin-2 expression, Metroticket_AFP score, and MELD (in both training and validation cohorts) independently predicted mortality. In time-dependent area under receiver operating characteristic curve analysis, the endothelial angiopoietin-2 expression had the highest specificity and sensitivity for recurrence (AUC 0.922, 95% CI 0.876-0.962, p < 0.0001).Conclusions Endothelial angiopoietin-2 expression is a powerful independent predictor of post-LT tumor recurrence and mortality, highlighting the fundamental role of tumor biology in defining the patients' prognosis after liver transplantation. The great advantage of endothelial angiopoietin-2 is that it is evaluable in HCC biopsy before LT and could drive a patient's priority on the waiting list.
2022
- Predictors of solid extra-hepatic non-skin cancer in liver transplant recipients and analysis of survival: a long-term follow-up study
[Articolo su rivista]
Gitto, Stefano; Magistri, Paolo; Marzi, Luca; Mannelli, Nicolò; De Maria, Nicola; Mega, Andrea; Vitale, Giovanni; Valente, Giovanna; Vizzutti, Francesco; Villa, Erica; Marra, Fabio; Andreone, Pietro; Di Benedetto, Fabrizio; Falcini, Margherita; Catellani, Barbara; Guerrini, Gian Piero; Serra, Valentina; Di Sandro, Stefano; Ballarin, Roberto; Piai, Guido; Schepis, Filippo; Margotti, Marzia; Cursaro, Carmela; De Simone, Paolo; Petruccelli, Stefania; Carrai, Paola; Forte, Paolo; Campani, Claudia; Zoller, Heinz
abstract
Introduction and objectives: De novo malignancies represent an important cause of death for liver transplant recipients. Our aim was to analyze predictors of extra-hepatic non-skin cancer (ESNSC) and the impact of ESNSC on the long-term outcome. Patients: We examined data from patients transplanted between 2000 and 2005 and followed-up in five Italian transplant clinics with a retrospective observational cohort study. Cox Regression was performed to identify predictors of ESNSC. A 1:2 cohort sub-study was developed to analyze the impact of ESNSC on 10-year survival. Results: We analyzed data from 367 subjects (median follow-up: 15 years). Patients with ESNSC (n=47) more often developed post-LT diabetes mellitus (DM) (57,4% versus 35,9%, p=0,004). At multivariate analysis, post-LT DM independently predicted ESNSC (HR 1.929, CI 1.029-3.616, p=0.040). Recipients with ESNSC showed a lower 10-year survival than matched controls (46,8% versus 68,1%, p=0,023). Conclusions: Post-LT DM seems to be a relevant risk factor for post-LT ESNSC. ESNSC could have a noteworthy impact on the long-term survival of LT recipients.
2022
- Quality of life in liver transplant recipients during the Corona virus disease 19 pandemic: A multicentre study
[Articolo su rivista]
Gitto, S.; Golfieri, L.; Mannelli, N.; Tame, M. R.; Lopez, I.; Ceccato, R.; Montanari, S.; Falcini, M.; Vitale, G.; De Maria, N.; Presti, D. L.; Marzi, L.; Mega, A.; Valente, G.; Borghi, A.; Foschi, F. G.; Grandi, S.; Forte, P.; Cescon, M.; Di Benedetto, F.; Andreone, P.; Arcangeli, G.; De Simone, P.; Bonacchi, A.; Sofi, F.; Morelli, M. C.; Petranelli, M.; Lau, C.; Marra, F.; Chiesi, F.; Vizzutti, F.; Vero, V.; Di Donato, R.; Berardi, S.; Pianta, P.; D'Anzi, S.; Schepis, F.; Gualandi, N.; Miceli, F.; Villa, E.; Piai, G.; Valente, M.; Campani, C.; Lynch, E.; Magistri, P.; Cursaro, C.; Chiarelli, A.; Carrai, P.; Petruccelli, S.; Dinu, M.; Pagliai, G.
abstract
Background: Liver transplant recipients require specific clinical and psychosocial attention given their frailty. Main aim of the study was to assess the quality of life after liver transplant during the current pandemic. Methods: This multicentre study was conducted in clinically stable, liver transplanted patients. Enrollment opened in June and finished in September 2021. Patients completed a survey including lifestyle data, quality of life (Short Form health survey), sport, employment, diet. To examine the correlations, we calculated Pearson coefficients while to compare subgroups, independent samples t-tests and ANOVAs. To detect the predictors of impaired quality of life, we used multivariable logistic regression analysis. Results: We analysed data from 511 patients observing significant associations between quality of life’s physical score and both age and adherence to Mediterranean diet (p <.01). A significant negative correlation was observed between mental score and the sedentary activity (p <.05). Female patients scored significantly lower than males in physical and mental score. At multivariate analysis, females were 1.65 times more likely to report impaired physical score than males. Occupation and physical activity presented significant positive relation with quality of life. Adherence to Mediterranean diet was another relevant predictor. Regarding mental score, female patients were 1.78 times more likely to show impaired mental score in comparison with males. Sedentary activity and adherence to Mediterranean diet were further noteworthy predictors. Conclusions: Females and subjects with sedentary lifestyle or work inactive seem to show the worst quality of life and both physical activity and Mediterranean diet might be helpful to improve it.
2022
- Translational Value of Tumor-Associated Lymphangiogenesis in Cholangiocarcinoma
[Articolo su rivista]
Cadamuro, Massimiliano; Romanzi, Adriana; Guido, Maria; Sarcognato, Samantha; Cillo, Umberto; Gringeri, Enrico; Zanus, Giacomo; Strazzabosco, Mario; Simioni, Paolo; Villa, Erica; Fabris, Luca
abstract
The prognosis of cholangiocarcinoma remains poor in spite of the advances in immunotherapy and molecular profiling, which has led to the identification of several targetable genetic alterations. Surgical procedures, including both liver resection and liver transplantation, still represent the treatment with the best curative potential, though the outcomes are significantly compromised by the early development of lymph node metastases. Progression of lymphatic metastasis from the primary tumor to tumor-draining lymph nodes is mediated by tumor-associated lymphangiogenesis, a topic largely overlooked until recently. Recent findings highlight tumor-associated lymphangiogenesis as paradigmatic of the role played by the tumor microenvironment in sustaining cholangiocarcinoma invasiveness and progression. This study reviews the current knowledge about the intercellular signaling and molecular mechanism of tumor-associated lymphangiogenesis in cholangiocarcinoma in the hope of identifying novel therapeutic targets to halt a process that often limits the success of the few available treatments.
2022
- Upregulation of the oestrogen target gene SIX1 is associated with higher growth speed and decreased survival in HCV-positive women with hepatocellular carcinoma
[Articolo su rivista]
Critelli, Rosina Maria; Milosa, Fabiola; Romanzi, Adriana; Lasagni, Simone; Marcelli, Gemma; Di Marco, Lorenza; Pivetti, Alessandra; Schepis, Filippo; Romagnoli, Dante; Mancarella, Serena; Dituri, Francesco; Martinez-Chantar, Maria-Luz; Giannelli, Gianluigi; Villa, Erica
abstract
The male/female ratio of patients with hepatocellular carcinoma (HCC) is often unbalanced towards the male sex, indicating a sex predisposition for HCC development. A possible explanation may be attributed to different hormonal statuses, including the pro-inflammatory action of androgens in men and the protective effects of oestrogen against excessive inflammation in women. Although several studies have studied gene expression in patients with HCC, very few have attempted to identify features that could be distinctive between male and female patients. The present study aimed to identify distinctive signalling mechanisms between men and women that may be associated with HCC progression. The present study analysed a detailed microarray database that was obtained from the prospective study of 78 patients with HCC to study gene expression according to sex. In addition, the present study aimed to evaluate whether the differentially expressed genes were known oestrogen targets. Moreover, RNAs from the HCC cohort were evaluated for microRNA (miRNA/miR) expression, and a relationship between miRNA and gene expression according to sex was investigated. One gene, sineoculis homeobox homolog 1 (SIX1), which is known to be an oestrogen target gene, was revealed to be highly upregulated in hepatitis virus C (HCV)-positive female patients with HCC but not in HCV-positive male patients. In addition, SIX1 upregulation had a significant relationship with tumour growth speed (assessed as tumour doubling time in two CTs performed 6 weeks apart) and survival (P=0.009 and P=0.042, respectively) in female patients only. Furthermore, SIX1 upregulation was related with miR-421 and miR-9-5p only in male patients; however, in female patients, SIX1 upregulation had a direct relationship with miR-181b, miR-503-5p and miR-125b (miRNAs with potential oncogenic capacity), and an inverse correlation with miR139-5p, miR-26b, let7c-3p and let7c-5p (putatively oncosuppressive microRNAs). These data suggested a distinctive model for liver carcinogenesis in HCV-positive women, with downregulation of protective mechanisms against tumour progression and the activation of potential oncogenes, in relation to the oestrogen target gene SIX1. (IRB10/08_CE_UniRer; ClinicalTrials ID: NCT01657695).
2021
- Anti-miR-518d-5p overcomes liver tumor cell death resistance through mitochondrial activity
[Articolo su rivista]
Fernandez-Tussy, P.; Rodriguez-Agudo, R.; Fernandez-Ramos, D.; Barbier-Torres, L.; Zubiete-Franco, I.; Davalillo, S. L.; Herraez, E.; Goikoetxea-Usandizaga, N.; Lachiondo-Ortega, S.; Simon, J.; Lopitz-Otsoa, F.; Juan, V. G. -D.; Mccain, M. V.; Perugorria, M. J.; Mabe, J.; Navasa, N.; Rodrigues, C. M. P.; Fabregat, I.; Boix, L.; Sapena, V.; Anguita, J.; Lu, S. C.; Mato, J. M.; Banales, J. M.; Villa, E.; Reeves, H. L.; Bruix, J.; Reig, M.; Marin, J. J. G.; Delgado, T. C.; Martinez-Chantar, M. L.
abstract
Dysregulation of miRNAs is a hallmark of cancer, modulating oncogenes, tumor suppressors, and drug responsiveness. The multi-kinase inhibitor sorafenib is one of the first-line drugs for advanced hepatocellular carcinoma (HCC), although the outcome for treated patients is heterogeneous. The identification of predictive biomarkers and targets of sorafenib efficacy are sorely needed. Thus, selected top upregulated miRNAs from the C19MC cluster were analyzed in different hepatoma cell lines compared to immortalized liver human cells, THLE-2 as control. MiR-518d-5p showed the most consistent upregulation among them. Thus, miR-518d-5p was measured in liver tumor/non-tumor samples of two distinct cohorts of HCC patients (n = 16 and n = 20, respectively). Circulating miR-518d-5p was measured in an independent cohort of HCC patients receiving sorafenib treatment (n = 100), where miR-518d-5p was analyzed in relation to treatment duration and patient’s overall survival. In vitro and in vivo studies were performed in human hepatoma BCLC3 and Huh7 cells to analyze the effect of miR-518d-5p inhibition/overexpression during the response to sorafenib. Compared with healthy individuals, miR-518d-5p levels were higher in hepatic and serum samples from HCC patients (n = 16) and in an additional cohort of tumor/non-tumor paired samples (n = 20). MiR-518d-5p, through the inhibition of c-Jun and its mitochondrial target PUMA, desensitized human hepatoma cells and mouse xenograft to sorafenib-induced apoptosis. Finally, serum miR-518d-5p was assessed in 100 patients with HCC of different etiologies and BCLC-stage treated with sorafenib. In BCLC-C patients, higher serum miR-518d-5p at diagnosis was associated with shorter sorafenib treatment duration and survival. Hence, hepatic miR-518d-5p modulates sorafenib resistance in HCC through inhibition of c-Jun/PUMA-induced apoptosis. Circulating miR-518d-5p emerges as a potential lack of response biomarker to sorafenib in BCLC-C HCC patients.
2021
- Clinical features and comorbidity pattern of HCV infected migrants compared to native patients in care in Italy: A real-life evaluation of the PITER cohort
[Articolo su rivista]
Quaranta, M. G.; Ferrigno, L.; Tata, X.; D'Angelo, F.; Massari, M.; Coppola, C.; Biliotti, E.; Giorgini, A.; Laccabue, D.; Ciancio, A.; Blanc, P. L.; Margotti, M.; Ieluzzi, D.; Brunetto, M. R.; Barbaro, F.; Russo, F. P.; Beretta, I.; Morsica, G.; Verucchi, G.; Saracino, A.; Galli, M.; Kondili, L. A.; Mazzaro, C.; Bertola, M.; Benedetti, A.; Schiada, L.; Cucco, M.; Giacometti, A.; Brescini, L.; Castelletti, S.; Fiorentini, A.; Angarano, G.; Milella, M.; Leo, A. D.; Rendina, M.; Salvatore D'ABRAMO, F.; Lillo, C.; Iannone, A.; Piazzolla, M.; Badia, L.; Piscaglia, F.; Benevento, F.; Serio, I.; Castelli, F.; Zaltron, S.; Spinetti, A.; Odolini, S.; Bruno, R.; Mondelli, M.; Chessa, L.; Loi, M.; Torti, C.; Costa, C.; Mazzitelli, M.; Pisani, V.; Scaglione, V.; Trecarichi, E. M.; Zignego, A. L.; Monti, M.; Madia, F.; Attala, L.; Pierotti, P.; Salomoni, E.; Mariabelli, E.; Santantonio, T. A.; Bruno, S. R.; Cela, E. M.; Bassetti, M.; Mazzarello, G.; Alessandrini, A. I.; Biagio, A. D.; Nicolini, L. A.; Raimondo, G.; Filomia, R.; Aghemo, A.; Meli, R.; Lazzarin, A.; Salpietro, S.; Fracanzani, A. L.; Fatta, E.; Lombardi, R.; Lampertico, P.; Borghi, M.; D'Ambrosio, R.; Degasperi, E.; Puoti, M.; Baiguera, C.; D'Amico, F.; Vinci, M.; Rumi, M. G.; Zuin, M.; Zermiani, P.; Andreone, P.; Caraceni, P.; Guarneri, V.; Villa, E.; Bernabucci, V.; Bristot, L.; Paradiso, M. L.; Migliorino, G.; Gambaro, A.; Lapadula, G.; Spolti, A.; Soria, A.; Invernizzi, P.; Ciaccio, A.; Luca, M.; Malinverno, F.; Ratti, L.; Amoruso, D. C.; Pisano, F.; Scarano, F.; Staiano, L.; Morisco, F.; Cossiga, V.; Gentile, I.; Buonomo, A. R.; Foggia, M.; Zappulo, E.; Federico, A.; Dallio, M.; Coppola, N.; Sagnelli, C.; Martini, S.; Monari, C.; Nardone, G.; Sgamato, C.; Chemello, L.; Cavalletto, L.; Sterrantino, D.; Zanetto, A.; Zanaga, P.; Brancaccio, G.; Craxi, A.; Petta, S.; Calvaruso, V.; Crapanzano, L.; Madonia, S.; Cannizzaro, M.; Bruno, E. M.; Licata, A.; Amodeo, S.; Capitano, A. R.; Ferrari, C.; Negri, E.; Orlandini, A.; Pesci, M.; Gulminetti, R.; Pagnucco, L.; Parruti, G.; Stefano, P. D.; Coco, B.; Corsini, R.; Garlassi, E.; Andreoni, M.; Teti, E.; Cerva, C.; Baiocchi, L.; Grassi, G.; Gasbarrini, A.; Pompili, M.; Siena, M. D.; Taliani, G.; Spaziante, M.; Persico, M.; Masarone, M.; Aglitti, A.; Calvanese, G.; Anselmo, M.; Leo, P. D.; Marturano, M.; Saracco, G. M.
abstract
Background: Direct-acting antivirals are highly effective for the treatment of hepatitis C virus (HCV) infection, regardless race/ethnicity. We aimed to evaluate demographic, virological and clinical data of HCV-infected migrants vs. natives consecutively enrolled in the PITER cohort. Methods: Migrants were defined by country of birth and nationality that was different from Italy. Mann-Whitney U test, Chi-squared test and multiple logistic regression were used. Results: Of 10,669 enrolled patients, 301 (2.8%) were migrants: median age 47 vs. 62 years, (p < 0.001), females 56.5% vs. 45.3%, (p < 0.001), HBsAg positivity 3.8% vs. 1.4%, (p < 0.05). Genotype 1b was prevalent in both groups, whereas genotype 4 was more prevalent in migrants (p < 0.05). Liver disease severity and sustained virologic response (SVR) were similar. A higher prevalence of comorbidities was reported for natives compared to migrants (p < 0.05). Liver disease progression cofactors (HBsAg, HIV coinfection, alcohol abuse, potential metabolic syndrome) were present in 39.1% and 47.1% (p > 0.05) of migrants and natives who eradicated HCV, respectively. Conclusion: Compared to natives, HCV-infected migrants in care have different demographics, HCV genotypes, viral coinfections and comorbidities and similar disease severity, SVR and cofactors for disease progression after HCV eradication. A periodic clinical assessment after HCV eradication in Italians and migrants with cofactors for disease progression is warranted.
2021
- Clinical impact of sexual dimorphism in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)
[Articolo su rivista]
Burra, P.; Bizzaro, D.; Gonta, A.; Shalaby, S.; Gambato, M.; Morelli, M. C.; Trapani, S.; Floreani, A.; Marra, F.; Brunetto, M. R.; Taliani, G.; Villa, E.
abstract
NAFLD/NASH is a sex-dimorphic disease, with a general higher prevalence in men. Women are at reduced risk of NAFLD compared to men in fertile age, whereas after menopause women have a comparable prevalence of NAFLD as men. Indeed, sexual category, sex hormones and gender habits interact with numerous NAFLD factors including cytokines, stress and environmental factors and alter the risk profiles and phenotypes of NAFLD. In the present review, we summarized the last findings about the influence of sex on epidemiology, pathogenesis, progression in cirrhosis, indication for liver transplantation and alternative therapies, including lifestyle modification and pharmacological strategies. We are confident that an appropriate consideration of sex, age, hormonal status and sociocultural gender differences will lead to a better understanding of sex differences in NAFLD risk, therapeutic targets and treatment responses and will aid in achieving sex-specific personalized therapies.
2021
- Correction: Phase 1b/2 trial of tepotinib in sorafenib pretreated advanced hepatocellular carcinoma with MET overexpression (British Journal of Cancer, (2021), 10.1038/s41416-021-01334-9)
[Articolo su rivista]
Decaens, T.; Barone, C.; Assenat, E.; Wermke, M.; Fasolo, A.; Merle, P.; Blanc, J. -F.; Grando, V.; Iacobellis, A.; Villa, E.; Trojan, J.; Straub, J.; Bruns, R.; Berghoff, K.; Scheele, J.; Raymond, E.; Faivre, S.
abstract
The original version of this article unfortunately contained a mistake. Due to a typesetting error ‘sorafenib pretreated’ was changed to ‘sorafenibpretreated’ throughout the article. The correct spelling is ‘sorafenib pretreated. There were also minor errors in Fig. 1 and Fig. 3. The original article has been corrected
2021
- Dynamic angiopoietin-2 assessment predicts survival and chronic course in hospitalized patients with COVID-19
[Articolo su rivista]
Villa, E.; Critelli, R.; Lasagni, S.; Melegari, A.; Curatolo, A.; Celsa, C.; Romagnoli, D.; Melegari, G.; Pivetti, A.; Di Marco, L.; Casari, F.; Arioli, D.; Turrini, F.; Zuccaro, V.; Cassaniti, I.; Riefolo, M.; de Santis, E.; Bernabucci, V.; Bianchini, M.; Lei, B.; de Maria, N.; Carulli, L.; Schepis, F.; Gozzi, C.; Malaguti, S.; Del Buono, M.; Brugioni, L.; Torricelli, P.; Trenti, T.; Pinelli, G.; Bertellini, E.; Bruno, R.; Camma, C.; D'Errico, A.
abstract
This study examined the association between dynamic angiopoietin-2 assessment and COVID-19 short- and long-term clinical course. We included consecutive hospitalized patients from 1 February to 31 May 2020 with laboratory-confirmed COVID-19 from 2 Italian tertiary referral centers (derivation cohort, n 5 187 patients; validation cohort, n 5 62 patients). Serum biomarker levels were measured by sandwich enzyme-linked immunosorbent assay. Lung tissue from 9 patients was stained for angiopoietin-2, Tie2, CD68, and CD34. Cox model was used to identify risk factors for mortality and nonresolving pulmonary condition. Area under the receiver operating characteristic curve (AUROC) was used to assess the accuracy of 3- and 10-day angiopoietin-2 for in-hospital mortality and nonresolving pulmonary condition, respectively. Three-day angiopoietin-2 increase of at least twofold from baseline was significantly associated with in-hospital mortality by multivariate analysis (hazard ratio [HR], 6.69; 95% confidence interval [CI], 1.85-24.19; P 5 .004) with AUROC 5 0.845 (95% CI, 0.725-0.940). Ten-day angiopoietin-2 of at least twofold from baseline was instead significantly associated with nonresolving pulmonary condition by multivariate analysis (HR, 5.33; 95% CI, 1.34-11.77; P # .0001) with AUROC 5 0.969 (95% CI, 0.919-1.000). Patients with persistent elevation of 10-day angiopoietin-2 levels showed severe reticular interstitial thickening and fibrous changes on follow-up computed tomography scans. Angiopoietin-2 and Tie2 were diffusely colocalized in small-vessel endothelia and alveolar new vessels and macrophages. Angiopoietin-2 course is strongly associated with COVID-19 in-hospital mortality and nonresolving pulmonary condition. Angiopoietin-2 may be an early and useful predictor of COVID-19 clinical course, and it could be a relevant part of disease pathogenesis. Angiopoietin-2 blockade may be a COVID-19 treatment option.
2021
- Effectiveness and safety of glecaprevir/pibrentasvir in chronic hepatitis C patients: Results of the Italian cohort of a post-marketing observational study
[Articolo su rivista]
Aghemo, A.; Alberti, A.; Andreone, P.; Angelico, M.; Brunetto, M. R.; Chessa, L.; Ciancio, A.; Craxi, A.; Gaeta, G. B.; Galli, M.; Gasbarrini, A.; Giorgini, A.; Grilli, E.; Lampertico, P.; Lichtner, M.; Milella, M.; Morisco, F.; Persico, M.; Pirisi, M.; Puoti, M.; Raimondo, G.; Romano, A.; Russello, M.; Sangiovanni, V.; Schiavini, M.; Serviddio, G.; Villa, E.; Vinci, M.; De Michina, A.; Gallinaro, V.; Gualberti, G.; Roscini, A. S.; Zignego, A. L.
abstract
Background and Aims: The MARS post-marketing, observational study evaluates glecaprevir/pibrentasvir in a large population of Italian patients who are infected with HCV. Patients and Methods: Achievement of SVR12 was the primary endpoint in the overall population and by subpopulations of interest (treatment-naïve and treatment-experienced patients, subjects infected with different HCV genotype/sub-genotype, cirrhotic and non-cirrhotic patients, patients with different severity of fibrosis, patients with an APRI score ≥1, subjects with comorbidities, HIV-coinfected patients, elderly patients and people who use drugs). Safety and quality of life (assessed by SF-36 and Work Productivity and Activity Impairment) were also evaluated. Results: The SVR12 rate was 99.4% (319/321; 95% CI: 97.8–99.8%) in the core population with sufficient follow-up (n = 321), 99.7% (318/319) in 8-week treated patients, and high (>96%) across subgroups. Only three patients (0.9%) had treatment-related adverse events that led to treatment discontinuation. In total, 30.1% of patients showed an improvement of ≥2.5 points in the Physical Component Summary of the SF-36 from baseline to the end of treatment, and this figure raised to 37.5% with the achievement of SVR12. Corresponding values for MCS were 42.2% and 42.8%, respectively. Conclusion: Glecaprevir/pibrentasvir is safe and effective across subpopulations who are underserved in clinical trials.
2021
- HCV cirrhotic patients treated with direct-acting antivirals: Detection of tubular dysfunction and resolution after viral clearance
[Articolo su rivista]
Biliotti, E.; Palazzo, D.; Tinti, F.; D'Alessandro, M. D.; Esvan, R.; Labriola, R.; Cappoli, A.; Umbro, I.; Volpicelli, L.; Bachetoni, A.; Villa, E.; Mitterhofer, A. P.; Rucci, P.; Taliani, G.
abstract
Background/Aims: Hepatitis C virus (HCV) has been identified in tubular epithelial cells of infected patients; however, the presence of tubular dysfunction, which is a risk factor for chronic kidney disease (CKD), has never been examined in vivo. The present prospective longitudinal study aimed to estimate the prevalence of tubular dysfunction alone or with glomerular damage and its evolution after HCV clearance in cirrhotic patients. Methods: One hundred and thirty-five consecutive Child-Pugh A cirrhotic patients were evaluated before antiviral treatment and 6 months after the end of therapy. Tubular dysfunction was evaluated by urinary alpha1-microglobulin to creatinine ratio (α1-MCR), and glomerular damage was assessed by urinary albumin to creatinine ratio (ACR). Results: Almost all the patients (93.3%) showed a normal or mildly decreased e-GFR (KDIGO-G1/G2-categories). Tubular dysfunction was found in 23.7% (32/135) of patients, co-occurring with glomerular damage in 37.5% (12/32) of cases, while glomerular damage was found in 16.3% (22/135) of patients. In multiple logistic regression, glomerular damage and the concomitant presence of diabetes and hypertension were the only predictors significantly associated with tubular dysfunction. After HCV clearance, patients experienced a significant reduction of α1-MCR levels (21.0 vs 10.5 μg/mg, P =.009) and tubular dysfunction resolved in 57.1% of subjects. Conclusions: Tubular dysfunction is an unrecognized feature of HCV-related kidney disease in cirrhotic patients and its presence should be primarily investigated in subjects with glomerular damage, diabetes and hypertension, despite normal e-GFR. Tubular dysfunction resolves in the majority of cases after HCV clearance; however, it may persist after antiviral treatment and further studies should evaluate its long-term impact on kidney function.
2021
- Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via the DEPTOR-mTOR axis
[Articolo su rivista]
Serrano-Macia, M.; Simon, J.; Gonzalez-Rellan, M. J.; Azkargorta, M.; Goikoetxea-Usandizaga, N.; Lopitz-Otsoa, F.; De Urturi, D. S.; Rodriguez-Agudo, R.; Lachiondo-Ortega, S.; Mercado-Gomez, M.; Gutierrez de Juan, V.; Bizkarguenaga, M.; Fernandez-Ramos, D.; Buque, X.; Baselli, G. A.; Valenti, L. V. C.; Iruzubieta, P.; Crespo, J.; Villa, E.; Banales, J. M.; Avila, M. A.; Marin, J. J. G.; Aspichueta, P.; Sutherland, J.; Barrio, R.; Mayor, U.; Elortza, F.; Xirodimas, D. P.; Nogueiras, R.; Delgado, T. C.; Martinez-Chantar, M. L.
abstract
Objective: Neddylation is a druggable and reversible ubiquitin-like post-translational modification upregulated in many diseases, including liver fibrosis, hepatocellular carcinoma, and more recently, non-alcoholic fatty liver disease (NAFLD). Herein, we propose to address the effects of neddylation inhibition and the underlying mechanisms in pre-clinical models of NAFLD. Methods: Hepatic neddylation measured by immunohistochemical analysis and NEDD8 serum levels measured by ELISA assay were evaluated in NAFLD clinical and pre-clinical samples. The effects of neddylation inhibition by using a pharmacological small inhibitor, MLN4924, or molecular approaches were assessed in isolated mouse hepatocytes and pre-clinical mouse models of diet-induced NAFLD, male adult C57BL/6 mice, and the AlfpCre transgenic mice infected with AAV-DIO-shNedd8. Results: Neddylation inhibition reduced lipid accumulation in oleic acid-stimulated mouse primary hepatocytes and ameliorated liver steatosis, preventing lipid peroxidation and inflammation in the mouse models of diet-induced NAFLD. Under these conditions, increased Deptor levels and the concomitant repression of mTOR signaling were associated with augmented fatty acid oxidation and reduced lipid content. Moreover, Deptor silencing in isolated mouse hepatocytes abolished the anti-steatotic effects mediated by neddylation inhibition. Finally, serum NEDD8 levels correlated with hepatic neddylation during the disease progression in the clinical and pre-clinical models Conclusions: Overall, the upregulation of Deptor, driven by neddylation inhibition, is proposed as a novel effective target and therapeutic approach to tackle NAFLD.
2021
- Overview of prognostic systems for hepatocellular carcinoma and ITA.LI.CA external validation of MESH and CNLC classifications
[Articolo su rivista]
Vitale, A.; Farinati, F.; Finotti, M.; Di Renzo, C.; Brancaccio, G.; Piscaglia, F.; Cabibbo, G.; Caturelli, E.; Missale, G.; Marra, F.; Sacco, R.; Giannini, E. G.; Trevisani, F.; Cillo, U.; Bhoori, S.; Borzio, M.; Burra, P.; Casadei Gardini, A.; Carrai, P.; Conti, F.; Cozzolongo, R.; Cucchetti, A.; D'Ambrosio, R.; Dell'Unto, C.; De Matthaeis, N.; Di Costanzo, G. G.; Di Sandro, S.; Famularo, S.; Foschi, F. G.; Fucilli, F.; Galati, G.; Gambato, M.; Gasbarrini, A.; Giuliante, F.; Ghinolfi, D.; Grieco, A.; Gruttadauria, S.; Guarino, M.; Iavarone, M.; Kostandini, A.; Lai, Q.; Lenci, I.; Levi Sandri, G. V.; Losito, F.; Lupo, L. G.; Marasco, G.; Manzia, T. M.; Mazzocato, S.; Masarone, M.; Melandro, F.; Mescoli, C.; Miele, L.; Morisco, F.; Muley, M.; Nicolini, D.; Pagano, D.; Persico, M.; Pompili, M.; Ponziani, F. R.; Pravisani, R.; Rapaccini, G. L.; Rendina, M.; Renzulli, M.; Romano, F.; Rossi, M.; Rreka, E.; Russo, F. P.; Sangiovanni, A.; Sessa, A.; Simonetti, N.; Sposito, C.; Tortora, R.; Vigano, L.; Vigano, M.; Villa, E.; Vincenzi, V.; Violi, P.; Azzaroli, F.; Brunetto, M. R.; Di Marco, A.; Gasbarrini, A.; Foschi, F. G.; Guarino, M.; Masotto, A.; Mega, A.; Morisco, F.; Nardone, G.; Oliveri, F.; Raimondo, G.; Rapaccini, G. L.; Svegliati Baroni, G.; Vidili, G.; Zoli, M.
abstract
Prognostic assessment in patients with HCC remains an extremely difficult clinical task due to the complexity of this cancer where tumour characteristics interact with degree of liver dysfunction, patient general health status, and a large span of available treatment options. Several prognostic systems have been proposed in the last three decades, both from the Asian and European/North American countries. Prognostic scores, such as the CLIP score and the recent MESH score, have been generated on a solid statistical basis from real life population data, while staging systems, such as the BCLC scheme and the recent CNLC classification, have been created by experts according to recent HCC prognostic evidences from the literature. A third category includes combined prognostic systems that can be used both as prognostic scores and staging systems. A recent example is the ITA.LI.CA prognostic system including either a prognostic score and a simplified staging system. This review focuses first on an overview of the main prognostic systems for HCC classified according to the above three categories, and, second, on a comprehensive description of the methodology required for a correct comparison between different systems in terms of prognostic performance. In this second section the main studies in the literature comparing different prognostic systems are described in detail. Lastly, a formal comparison between the last prognostic systems proposed for each of the above three categories is performed using a large Italian database including 6882 HCC patients in order to concretely apply the comparison rules previously described.
2021
- Phase 1b/2 trial of tepotinib in sorafenibpretreated advanced hepatocellular carcinoma with MET overexpression
[Articolo su rivista]
Decaens, T.; Barone, C.; Assenat, E.; Wermke, M.; Fasolo, A.; Merle, P.; Blanc, J. -F.; Grando, V.; Iacobellis, A.; Villa, E.; Trojan, J.; Straub, J.; Bruns, R.; Berghoff, K.; Scheele, J.; Raymond, E.; Faivre, S.
abstract
Background: This Phase 1b/2 study evaluated tepotinib, a highly selective MET inhibitor, in US/European patients with sorafenibpretreated advanced hepatocellular carcinoma (aHCC) with MET overexpression. Methods: Eligible adults had aHCC, progression after ≥4 weeks of sorafenib, and, for Phase 2 only, MET overexpression. Tepotinib was administered once daily at 300 or 500 mg in Phase 1b (‘3 + 3’ design), and at the recommended Phase 2 dose (RP2D) in Phase 2. Primary endpoints were dose-liming toxicities (DLTs; Phase 1b) and 12-week investigator-assessed progression-free survival (PFS; Phase 2). Results: In Phase 1b (n = 17), no DLTs occurred and the RP2D was confirmed as 500 mg. In Phase 2 (n = 49), the primary endpoint was met: 12-week PFS was 63.3% (90% CI: 50.5–74.7), which was significantly greater than the predefined null hypothesis of ≤15% (one-sided binomial exact test: P < 0.0001). Median time to progression was 4 months. In Phase 2, 28.6% of patients had treatment-related Grade ≥3 adverse events, including peripheral oedema and lipase increase (both 6.1%). Conclusions: Tepotinib was generally well tolerated and the RP2D (500 mg) showed promising efficacy and, therefore, a positive benefit–risk balance in sorafenibpretreated aHCC with MET overexpression. Trial Registration: ClinicalTrials.gov: NCT02115373.
2021
- Prognostic significance of hypoxic and metabolic gene profiling in hepatocellular carcinoma
[Articolo su rivista]
Milosa, Fabiola; Critelli, Rosina Maria; Lasagni, Simone; Pivetti, Alessandra; DI MARCO, Lorenza; Romagnoli, Dante; Carulli, Lucia; Dituri, Francesco; Mancarella, Serena; Giannelli, Gianluigi; Martinez‐chantar, Maria‐luz; Fabris, Luca; Villa, Erica
abstract
2021
- Proximal Splenic Artery Embolization to Treat Refractory Ascites in a Patient With Cirrhosis
[Articolo su rivista]
Caporali, C.; Turco, L.; Prampolini, F.; Quaretti, P.; Bianchini, M.; Saltini, D.; Miceli, F.; Casari, F.; Felaco, D.; Garcia-Pagan, J. C.; Trebicka, J.; Senzolo, M.; Guerrini, G. P.; Di Benedetto, F.; Torricelli, P.; Villa, E.; Schepis, F.
abstract
2021
- Subjects with blood group O are not at lower risk to acquire SARS-CoV-2 infection
[Articolo su rivista]
Gamal, N.; Villa, E.; Rolli, M.; Pecorari, M.; Mirabella, G.; Bertellini, E.; Ceccherelli, G.; Venturelli, D.
abstract
2021
- That’s the sex, baby, and there’s nothing you can do about it!
[Articolo su rivista]
De Maria, N.; Villa, E.
abstract
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2020
- Commentary on: Comparison of three transfusion protocols prior to central venous catheterization in patients with cirrhosis: A randomized controlled trial
[Articolo su rivista]
Intagliata, N. M.; Villa, E.
abstract
2020
- Influence of donor and recipient gender on liver transplantation outcomes in Europe
[Articolo su rivista]
Germani, G.; Zeni, N.; Zanetto, A.; Adam, R.; Karam, V.; Belli, L. S.; O'Grady, J.; Mirza, D.; Klempnauer, J.; Cherqui, D.; Pratschke, J.; Jamieson, N.; Salizzoni, M.; Hidalgo, E.; Lerut, J.; Paul, A.; Garcia-Valdecasas, J. C.; Rodriguez, F. S. J.; Villa, E.; Burra, P.
abstract
Background & Aims: The impact of gender and donor/recipient gender mismatch on LT outcomes is controversial. The aim of this study was to compare outcomes of LT in Europe, using the ELTR database, between male and female recipients, including donor/recipient gender mismatch. Methods: Recipient, donor and transplant characteristics were compared between male and female patients. Patient survival was compared between groups, and the impact of donor/recipient gender matching as well as donor and recipient anthropometric characteristics were evaluated as potential risk factors for post-LT death/graft loss. Results: A total of 46,334 LT patients were evaluated (70.5% men and 29.5% women). Ten-year survival rate was significantly higher in female than in male recipients (66% vs 59%, P <.0001). At multivariate analysis, adjusted for indication to LT and type of graft, donor/recipient gender mismatch (HR 1.12, 95% CI 1.04-1.2; P =.003), donor age > 60 years (HR 1.09, 95% CI 1.01-1.18; P =.027) and recipient age (HR 1.02, 95% CI 1.1-1.02; P <.0001) were significantly associated with post-LT lower survival rate in men. Conversely in female recipients, donor BMI > 30 (HR 1.32, 95% CI 1.09-1.6; P =.005), donor age > 60 years (HR 1.15, 95% CI 1.01-1.32; P =.027) and recipient age (HR 1.02, 95% CI 1.01-1.02; P <.0001) were significantly associated with lower post-LT survival rate. Conclusions: Donor/recipient gender mismatch in male recipients and the use of obese donor in female recipients are associated with reduced survival after LT. Therefore, the incorporation of donor and recipient anthropometric quantities in the allocation process should be a matter of further studies, as their matching can significantly influence long-term outcomes.
2020
- Pre-transplant diabetes predicts atherosclerotic vascular events and cardiovascular mortality in liver transplant recipients: a long-term follow-up study
[Articolo su rivista]
Gitto, S.; De Maria, N.; Marzi, L.; Magistri, P.; Falcini, M.; Vitale, G.; Olivieri, T.; Guerrini, G. P.; Serra, V.; Forte, P.; Carrai, P.; De Simone, P.; Mega, A.; Zoller, H.; Piai, G.; Schepis, F.; Marocchi, M.; Villa, E.; Marra, F.; Andreone, P.; Di Benedetto, F.; Vizzutti, F.; Laffi, G.; Borelli, E.; Ballarin, R.; Tarantino, G.; Di Sandro, S.; Puntili, R.; Petruccelli, S.; Valente, G.; Turco, L.
abstract
Background Early after surgery, liver transplant (LT) recipients often develop weight gain. Metabolic disorders and cardiovascular disease represent main drivers of morbidity and mortality. Our aim was to identify predictors of atherosclerotic vascular events (AVE) and to assess the impact of AVE on the long-term outcome. Methods We retrospectively analyzed data from patients transplanted between 2000 and 2005 and followed-up in five Italian transplant clinics. Cox Regression analysis was performed to identify predictors of AVE, global mortality, and cardiovascular mortality. Survival analysis was performed using the Kaplan-Meier method. Results We analyzed data from 367 subjects during a median follow-up of 14 years. Thirty-seven post-LT AVE were registered. Patients with AVE more frequently showed pre-LT diabetes mellitus (DM) (48.6 vs 13.9%, p=0.000). In the post-LT period, patients with AVE satisfied criteria of metabolic syndrome in 83.8% vs. 36.7% of subjects without AVE (p=0.000). At multivariate analysis, pre-LT DM independently predicted AVE (HR 2.250, CI 4.848-10.440, p=0.038). Moreover, both pre-LT DM and AVE strongly predicted cardiovascular mortality (HR 5.418, CI 1.060-29.183, p=0.049, and HR 86.097, CI 9.510-779.480, p=0.000, respectively). Conclusions Pre-LT DM is the main risk factor for post-LT AVE. Pre-LT DM and post-LT AVE are strong, long-term predictors of cardiovascular mortality. Patients with pre-LT DM should obtain a personalized follow-up for prevention or early diagnosis of AVE.
2020
- Proteoglycan-4 is correlated with longer survival in HCC patients and enhances sorafenib and regorafenib effectiveness via CD44 in vitro
[Articolo su rivista]
Dituri, F.; Scialpi, R.; Schmidt, T. A.; Frusciante, M.; Mancarella, S.; Lupo, L. G.; Villa, E.; Giannelli, G.
abstract
Sorafenib and regorafenib administration is among the preferential approaches to treat hepatocellular carcinoma (HCC), but does not provide satisfactory benefits. Intensive crosstalk occurring between cancer cells and other multiple non-cancerous cell subsets present in the surrounding microenvironment is assumed to affect tumor progression. This interplay is mediated by a number of soluble and structural extracellular matrix (ECM) proteins enriching the stromal milieu. Here we assess the HCC tumor expression of the ECM protein proteoglycan 4 (PRG4) and its potential pharmacologic activity either alone, or in combination with sorafenib and regorafenib. PRG4 mRNA levels resulted strongly correlated with increased survival rate of HCC patients (p = 0.000) in a prospective study involving 78 HCC subjects. We next showed that transforming growth factor beta stimulates PRG4 expression and secretion by primary human HCC cancer-associated fibroblasts, non-invasive HCC cell lines, and ex vivo specimens. By functional tests we found that recombinant human PRG4 (rhPRG4) impairs HCC cell migration. More importantly, the treatment of HCC cells expressing CD44 (the main PRG4 receptor) with rhPRG4 dramatically enhances the growth-limiting capacity of sorafenib and regorafenib, whereas not significantly affecting cell proliferation per se. Conversely, rhPRG4 only poorly potentiates drug effectiveness on low CD44-expressing or stably CD44-silenced HCC cells. Overall, these data suggest that the physiologically-produced compound PRG4 may function as a novel tumor-suppressive agent by strengthening sorafenib and regorafenib effects in the treatment of HCC.
2020
- Targeting Hepatic Glutaminase 1 Ameliorates Non-alcoholic Steatohepatitis by Restoring Very-Low-Density Lipoprotein Triglyceride Assembly
[Articolo su rivista]
Simon, J.; Nunez-Garcia, M.; Fernandez-Tussy, P.; Barbier-Torres, L.; Fernandez-Ramos, D.; Gomez-Santos, B.; Buque, X.; Lopitz-Otsoa, F.; Goikoetxea-Usandizaga, N.; Serrano-Macia, M.; Rodriguez-Agudo, R.; Bizkarguenaga, M.; Zubiete-Franco, I.; Gutierrez-de Juan, V.; Cabrera, D.; Alonso, C.; Iruzubieta, P.; Romero-Gomez, M.; van Liempd, S.; Castro, A.; Nogueiras, R.; Varela-Rey, M.; Falcon-Perez, J. M.; Villa, E.; Crespo, J.; Lu, S. C.; Mato, J. M.; Aspichueta, P.; Delgado, T. C.; Martinez-Chantar, M. L.
abstract
Non-alcoholic steatohepatitis (NASH) is characterized by the accumulation of hepatic fat in an inflammatory/fibrotic background. Herein, we show that the hepatic high-activity glutaminase 1 isoform (GLS1) is overexpressed in NASH. Importantly, GLS1 inhibition reduces lipid content in choline and/or methionine deprivation-induced steatotic mouse primary hepatocytes, in human hepatocyte cell lines, and in NASH mouse livers. We suggest that under these circumstances, defective glutamine fueling of anaplerotic mitochondrial metabolism and concomitant reduction of oxidative stress promotes a reprogramming of serine metabolism, wherein serine is shifted from the generation of the antioxidant glutathione and channeled to provide one-carbon units to regenerate the methionine cycle. The restored methionine cycle can induce phosphatidylcholine synthesis from the phosphatidylethanolamine N-methyltransferase-mediated and CDP-choline pathways as well as by base-exchange reactions between phospholipids, thereby restoring hepatic phosphatidylcholine content and very-low-density lipoprotein export. Overall, we provide evidence that hepatic GLS1 targeting is a valuable therapeutic approach in NASH.
2020
- Undefined/non-malignant hepatic nodules are associated with early occurrence of HCC in DAA-treated patients with HCV-related cirrhosis
[Articolo su rivista]
Sangiovanni, A.; Alimenti, E.; Gattai, R.; Filomia, R.; Parente, E.; Valenti, L.; Marzi, L.; Pellegatta, G.; Borgia, G.; Gambato, M.; Terreni, N.; Serio, I.; Belli, L.; Oliveri, F.; Maimone, S.; Brunacci, M.; D'Ambrosio, R.; Forzenigo, L. V.; Russo, F. P.; Rumi, M.; Barone, M.; Fracanzani, A. L.; Raimondo, G.; Giannini, E. G.; Brunetto, M. R.; Villa, E.; Biganzoli, E.; Colombo, M.; Lampertico, P.
abstract
Background & Aim: An unexpected early increase in incidence, recurrence and clinical aggressiveness of hepatocellular carcinoma (HCC) has been reported (and refuted) in patients with HCV-related cirrhosis following direct-acting antiviral (DAA) treatment. To address this controversy, we performed a prospective multicenter study on consecutively enrolled cirrhotic patients, with or without a history of HCC, undergoing DAA therapy. Patients and methods: A total of 1,161 HCC-free cirrhotics (group 1) and 124 cirrhotics who had received a curative treatment for an HCC (group 2) were enrolled. Clinical features, including presence of undefined/non-malignant liver nodules (UNMNs), were analyzed with respect to HCC incidence and recurrence. Results: During a median study time of 17 months in group 1 and 16 months in group 2, de novo HCC developed in 48 patients (yearly incidence 3.1/100 patient-years, 75% BCLC 0-A) and recurred in 40 (mean yearly incidence 29.9/100 patient-years, 83% BCLC 0-A). A peak of HCC instant incidence was observed at 4.2 months in group 1 patients with UNMNs, and at 7.7 months in group 2. By multivariable Cox regression models, UNMNs (hazard ratio [HR] 3.11; 95% CI 1.47–6.57: p = 0.003), ascites detected any time before enrolment (HR 3.04; 95% CI 1.23–7.51; p = 0.02), and alpha-fetoprotein log-value (HR 1.90; 95% CI 1.05–3.44; p = 0.03) were the variables independently associated with the incidence of de novo HCC, while history of alcohol abuse (HR 2.10; 95% CI 1.08–4.09; p = 0.03) and history of recurrence of HCC (HR 2.87; 95% CI 1.35–6.09; p = 0.006) were associated with HCC recurrence. Conclusion: An early high incidence of both de novo HCC, in patients with UNMNs, and recurrent HCC was observed in DAA-treated patients; this was not accompanied by increased tumor aggressiveness. Lay summary: This prospective study focuses on the risk of developing de novo or recurrent hepatocellular carcinoma (HCC) after direct-acting antiviral (DAA) treatment in patients with hepatitis C-related cirrhosis. We found that DAA treatment was associated with an early high HCC incidence in patients with undefined or non-malignant nodules, as well as in those with a history of complete response to HCC treatment. Whether this is related to the presence of clinically undetectable nests of cancer cells or to precancerous lesions that may progress to overt HCC upon DAA treatment remains unanswered. No evidence of increased clinical aggressiveness was reported in de novo or recurrent HCC.
2019
- Angiopoietin-2/Tie2 Inhibition by Regorafenib Associates With Striking Response in a Patient With Aggressive Hepatocellular Carcinoma
[Articolo su rivista]
Todesca, P.; Marzi, L.; Critelli, R. M.; Cuffari, B.; Caporali, C.; Turco, L.; Pinelli, G.; Schepis, F.; Carulli, L.; de Maria, N.; Casari, F.; Scaglioni, R.; Villa, E.
abstract
2019
- Anticoagulation in the cirrhotic patient
[Articolo su rivista]
Turco, L.; de Raucourt, E.; Valla, D. -C.; Villa, E.
abstract
In the past, patients with liver cirrhosis were thought to be prone to increased bleeding risk. However, those with compensated liver cirrhosis actually have normal coagulative balance, which can become altered when liver function worsens, or infection, bleeding, or acute kidney insufficiency occur. When this happens, it is now recognized that patients with liver cirrhosis are at higher risk of thrombotic rather than haemorrhagic complications. Anticoagulation plays a favourable role both when used therapeutically or prophylactically. Successful anticoagulation is associated with a lower rate of decompensation and with improved survival. To date, treatment has involved the use of low molecular weight heparins and vitamin K antagonists. Preliminary data suggest that novel non-vitamin K antagonist oral anticoagulants can be used safely in patients with liver cirrhosis.
2019
- Daclatasvir-based regimens in HCV cirrhosis: experience from the Italian early access program
[Articolo su rivista]
Calvaruso, Vincenza; Mazzarelli, Chiara; Milazzo, Laura; Badia, Lorenzo; Pasulo, Luisa; Guaraldi, Giovanni; Lionetti, Raffaella; Villa, Erica; Borghi, Vanni; Carrai, Paola; Alberti, Alfredo; Biolato, Marco; Piai, Guido; Persico, Marcello; Santantonio, Teresa; Felder, Martina; Angelico, Mario; Montalbano, Marzia; Mancusi, Rossella Letizia; Grieco, Antonio; Angeli, Elena; D'Offizi, Gianpiero; Fagiuoli, Stefano; Belli, Luca; Verucchi, Gabriella; Puoti, Massimo; Craxì, Antonio
abstract
We reported the efficacy and safety data for daclatasvir (DCV)-based all-oral antiviral therapy in patients treated in the Italian compassionate-use program. 275 patients were included (202 male-73.5%, mean age: 57.4 years, 62 HIV-coinfected, 94 with recurrence of hepatitis C post-OLT). Forty-nine patients (17.8%) had Child-Pugh B, Genotype(G) distribution was: G1a:72 patients (26.2%), G1b:137 (49.8%); G3:40 (14.5%) and G4:26 (9.5%). Patients received DCV with sofosbuvir(SOF) (n = 221, 129 with ribavirin(RBV) or with simeprevir (SMV) or asunaprevir (ASU) (n = 54, 19 with RBV) for up to 24 weeks. Logistic regression was used to identify baseline characteristics associated with sustained virological response at week 12 post-treatment (SVR12). Liver function changes between baseline and follow up were assessed in 228 patients. 240 patients achieved SVR12 (87.3%), post transplant and HIV co-infected patients were equally distributed among SVR and no SVR (35% vs 34.3%; p = 0.56 and 24.2% vs 11.4%, p = 0.13, respectively). SVR rate was significantly higher with the combination DCV + SOF compared with DCV + SIM or ASU (93.2% vs 63.0%, p < 0.0001). Bilirubin value (OR: 0.69, CI95%: 0.54-0.87, p = 0.002) and regimen containing SOF (OR: 9.99, CI95%: 4.09-24.40; p < 0.001) were independently related with SVR. Mean albumin and bilirubin values significantly improved between baseline and follow-up week 12. DCV-based antiviral therapy was well tolerated and resulted in a high SVR when combined with SOF either in pre-transplant and in OLT patients and in "difficult to treat" HCV genotypes. Regimens containing DCV in combination with NS3 protease inhibitors obtained suboptimal results.
2019
- Economic Consequences of Investing in Anti-HCV Antiviral Treatment from the Italian NHS Perspective: A Real-World-Based Analysis of PITER Data
[Articolo su rivista]
Marcellusi, A.; Viti, R.; Kondili, L. A.; Rosato, S.; Vella, S.; Mennini, F. S.; Kondili, L. A.; Vella, S.; Quaranta, M. G.; Rosato, S.; Tosti, M. E.; Weimer, L. E.; Ferrigno, L.; D'Angelo, F.; Falzano, L.; Benedetti, A.; Schiada, L.; Cucco, M.; Giacometti, A.; Brescini, L.; Castelletti, S.; Drenaggi, D.; Mazzaro, C.; Angarano, G.; Milella, M.; Dileo, A.; Rendina, M.; Contaldo, A.; Iannone, A.; La Fortezza, F.; Rizzi, M.; Cologni, G.; Bolondi, L.; Benevento, F.; Serio, I.; Andreone, P.; Caraceni, P.; Guarneri, V.; Margotti, M.; Simonetti, G.; Mazzella, G.; Verucchi, G.; Donati, V.; Mian, P.; Rimenti, G.; Rossini, A.; Contessi, G. B.; Castelli, F.; Zaltron, S.; Spinetti, A.; Odolini, S.; Leandro, G.; Cozzolongo, R.; Zappimbulso, M.; Russello, M.; Benigno, R.; Coco, C.; Torti, C.; Costa, C.; Greco, G.; Mazzitelli, M.; Pisani, V.; Cosco, L.; Quintieri, F.; Desiena, M.; Giancotti, F.; Vecchiet, J.; Falasca, K.; Mastroianni, A.; Apuzzo, G.; Chidichimo, L.; Foschi, F. G.; Dall'Aglio, A. C.; Libanore, M.; Segala, D.; Sighinolfi, L.; Bartolozzi, D.; Salomoni, E.; Blanc, P.; Baragli, F.; Delpin, B.; Mariabelli, E.; Mazzotta, F.; Poggi, A.; Zignego, A. L.; Monti, M.; Madia, F.; Xheka, A.; Cela, E. M.; Santantonio, T. A.; Bruno, S. R.; Viscoli, C.; Alessandrini, A. I.; Curti, C.; Dibiagio, A.; Nicolini, L. A.; Balletto, E.; Mastroianni, C.; Blerta, K.; Prati, D.; Raffaele, L.; Andreoletti, M.; Perboni, G.; Costa, P.; Manzini, L.; Raimondo, G.; Filomia, R.; Lazzarin, A.; Morsica, G.; Salpietro, S.; Puoti, M.; Baiguera, C.; Vassalli, S.; Rumi, M. G.; Labanca, S.; Zuin, M.; Giorgini, A.; Orellana, D.; D'Arminiomonforte, A.; Debona, A.; Solaro, S.; Fargion, S.; Valenti, L.; Periti, G.; Pelusi, S.; Galli, M.; Calvi, E.; Milazzo, L.; Peri, A.; Lampertico, P.; Borghi, M.; D'Ambrosio, R.; Degasperi, E.; Vinci, M.; Villa, E.; Bernabucci, V.; Bristot, L.; Pereira, F.; Chessa, L.; Pasetto, M. C.; Loi, M.; Gori, A.; Beretta, I.; Pastore, V.; Soria, A.; Strazzabosco, M.; Ciaccio, A.; Gemma, M.; Borgia, G.; Foggia, A.; Zappulo, E.; Gentile, I.; Buonomo, A. R.; Abrescia, N.; Maddaloni, A.; Caporaso, N.; Morisco, F.; Camera, S.; Donnarumma, L.; Coppola, C.; Amoruso, D. C.; Staiano, L.; Saturnino, M. R.; Coppola, N.; Martini, S.; Monari, C.; Federico, A.; Dallio, M.; Loguercio, C.; Gaeta, G. B.; Brancaccio, G.; Nardone, G.; Sgamato, C.; D'Adamo, G.; Alberti, A.; Gonzo, M.; Piovesan, S.; Chemello, L.; Buggio, A.; Cavalletto, L.; Barbaro, F.; Castelli, E.; Floreani, A.; Cazzagon, N.; Franceschet, I.; Russo, F. P.; Zanetto, A.; Franceschet, E.; Madonia, S.; Cannizzaro, M.; Montalto, G.; Licata, A.; Capitano, A. R.; Craxi, A.; Petta, S.; Calvaruso, V.; Rini, F.; Ferrari, C.; Negri, E.; Orlandini, A.; Pesci, M.; Bruno, R.; Lombardi, A.; Zuccaro, V.; Gulminetti, R.; Asti, A.; Villaraggia, M.; Mondelli, M.; Ludovisi, S.; Baldelli, F.; Di Candilo, F.; Parruti, G.; Di Stefano, P.; Sozio, F.; Gizzi, M. C.; Brunetto, M. R.; Colombatto, P.; Coco, B.; Surace, L.; Foti, G.; Pellicano, S.; Fornaciari, G.; Schianchi, S.; Vignoli, P.; Massari, M.; Corsini, R.; Garlassi, E.; Ballardini, G.; Andreoni, M.; Cerva, C.; Angelico, M.; Gasbarrini, A.; Siciliano, M.; De Siena, M.; Nosotti, L.; Taliani, G.; Biliotti, E.; Santori, M.; Spaziante, M.; Tamburini, F.; Vullo, V.; D'Ettorre, G.; Cavallari, E. N.; Gebremeskel, T. S.; Pavone, P.; Cauda, R.; Cingolani, A.; Lamonica, S.; D'Offizi, G.; Lionetti, R.; Visco Comandini, U.; Grieco, A.; D'Aversa, F.; Picardi, A.; De Vincentis, A.; Galati, G.; Gallo, P.; Dell'Unto, C.; Aghemo, A.; Gatti Comini, A.; Persico, M.; Masarone, M.; Anselmo, M.; De Leo, P.; Marturano, M.; Brunelli, E.; Ridolfi, F.; Schimizzi, A. M.; Ayoubi Khajekini, M.; Framarin, L.; Di Perri, G.; Cariti, G.; Boglione, L.; Cardellino, C.; Marinaro, L.; Saracco, G. M.; Ciancio, A.; Toniutto, P.; Alterini, G.; Capra, F.; Ieluzzi, D.
abstract
Objective: We estimated the cost consequence of Italian National Health System (NHS) investment in direct-acting antiviral (DAA) therapy according to hepatitis C virus (HCV) treatment access policies in Italy. Methods: A multistate, 20-year time horizon Markov model of HCV liver disease progression was developed. Fibrosis stage, age and genotype distributions were derived from the Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. The treatment efficacy, disease progression probabilities and direct costs in each health state were obtained from the literature. The break-even point in time (BPT) was defined as the period of time required for the cumulative costs saved to recover the Italian NHS investment in DAA treatment. Three different PITER enrolment periods, which covered the full DAA access evolution in Italy, were considered. Results: The disease stages of 2657 patients who consecutively underwent DAA therapy from January 2015 to December 2017 at 30 PITER clinical centres were standardized for 1000 patients. The investment in DAAs was considered to equal €25 million, €15 million, and €9 million in 2015, 2016, and 2017, respectively. For patients treated in 2015, the BPT was not achieved, because of the disease severity of the treated patients and high DAA prices. For 2016 and 2017, the estimated BPTs were 6.6 and 6.2 years, respectively. The total cost savings after 20 years were €50.13 and €55.50 million for 1000 patients treated in 2016 and 2017, respectively. Conclusions: This study may be a useful tool for public decision makers to understand how HCV clinical and epidemiological profiles influence the economic burden of HCV.
2019
- Effectiveness and safety of switching to entecavir hepatitis B patients developing kidney dysfunction during tenofovir
[Articolo su rivista]
Vigano, M.; Loglio, A.; Labanca, S.; Zaltron, S.; Castelli, F.; Andreone, P.; Messina, V.; Ganga, R.; Coppola, N.; Marrone, A.; Russello, M.; Marzano, A.; Tucci, A.; Taliani, G.; Fasano, M.; Fagiuoli, S.; Villa, E.; Bronte, F.; Santantonio, T.; Brancaccio, G.; Occhipinti, V.; Facchetti, F.; Grossi, G.; Rumi, M.; Lampertico, P.
abstract
Background and Aims: Tenofovir disoproxil fumarate (TDF) is recommended for chronic hepatitis B (CHB) treatment, but it may induce kidney dysfunction whose management is not yet known. This Italian, multicentre, retrospective study aimed to assess the efficacy and safety of switching to entecavir (ETV) patients who developed TDF-associated glomerular and/or tubular dysfunction. Methods: A total of 103 TDF-treated patients were included as follows: age 64 years, 83% male, 49% cirrhotics, 98% with undetectable HBV DNA, 47% with previous lamivudine resistance (LMV-R) and 71% previously treated with adefovir. Twenty-nine (28%) were switched to ETV because estimated glomerular filtration rate (eGFR MDRD ) was <60 mL/min, 37 (36%) because blood phosphate (P) levels were <2.5 mg/dL and 37 (36%) for both reasons. Kidney, liver and virological parameters were recorded every 4 months thereafter. Results: During 46 (4-115) months of ETV treatment, all patients’ renal parameters significantly improved as follows: creatinine from 1.30 to 1.10 mg/dL (P < 0.0001), eGFR MDRD from 54 to 65 mL/min (P = 0.002), P from 2.2 to 2.6 mg/dL (P < 0.0001) and maximal tubule phosphate reabsorption (TmPO4/eGFR) from 0.47 to 0.62 mmol/L (P < 0.0001). Thirteen patients (52%) improved their eGFR MDRD class, P levels were normalised in 13 (35%), and eight (22%) showed improvements in both parameters. Viral suppression was maintained in all but five patients (5%), all of whom had been LMV-R. The 5-year cumulative probability of ETV-R was 0% in LMV-naïve patients, and 11% in LMV-R patients (P = 0.018). Conclusions: Entecavir is an effective and safe rescue strategy for CHB patients who develop renal dysfunction during long-term TDF treatment.
2019
- Gender differences in chronic alcoholic and viral liver diseases
[Articolo su rivista]
Carulli, L.; Romagnoli, D.; Turco, L.; Bernabucci, V.; Villa, E.
abstract
Chronic liver disease progresses in men and women at different rates, regardless of the etiology of the disease itself. In general, the natural history of chronic liver disease is more favorable in women than in men. The biological basis of these marked differences, in an organ that is not considered a classical hormone-dependent organ, is the presence in the liver of receptors both for estrogens and for androgens, which make the liver susceptible to changes in hormone levels during the various stages of reproductive life. In the literature, there are several studies that demon-strate, both in experimental animal models and in humans, that the presence of estrogens, at levels similar to those of the fertile period, is in principle protective against the develop-ment of a more severe disease, while on the contrary the effect of androgenic modulation has negative effects. Estrogen protection disappears when a woman goes into menopause. As estrogen levels decrease, the tendency to develop a more pronounced fibrosis increases. Most impor-tantly, there is a marked propensity to develop primary liver cancer, which in women over 65 has a similar incidence to that of men.
2019
- Glecaprevir/Pibrentasvir in Patients with Chronic HCV Genotype 3 Infection: An Integrated Phase 2/3 Analysis
[Articolo su rivista]
Flamm, Steven; Mutimer, David; Asatryan, Armen; Wang, Stanley; Rockstroh, Jurgen; Horsmans, Yves; Kwo, Paul Y; Weiland, Ola; Villa, Erica; Heo, Jeong; Gane, Edward; Ryder, Stephen D; Welzel, Tania M; Ruane, Peter J; Agarwal, Kosh; Ng, Teresa I; Xue, Zhenyi; Lovell, Sandra S; Krishnan, Preethi; Kopecky-Bromberg, Sarah; Trinh, Roger; Mensa, Federico J; Wyles, David L
abstract
Glecaprevir coformulated with pibrentasvir (G/P) is approved to treat hepatitis C virus (HCV) infection and was highly efficacious in phase 2 and 3 studies. Treating HCV genotype (GT) 3 infection remains a priority, as these patients are harder to cure and at a greater risk for liver steatosis, fibrosis progression, and hepatocellular carcinoma. Data were pooled from five phase 2 or 3 trials that evaluated 8-, 12-, and 16-week G/P in patients with chronic HCV GT3 infection. Patients without cirrhosis or with compensated cirrhosis were either treatment-naïve or experienced with interferon- or sofosbuvir-based regimens. Safety and sustained virologic response 12 weeks post-treatment (SVR12) were assessed. The analysis included 693 patients with GT3 infection. SVR12 was achieved by 95% of treatment-naïve patients without cirrhosis receiving 8-week (198/208) and 12-week (280/294) G/P. Treatment-naïve patients with cirrhosis had a 97% (67/69) SVR12 rate with 12-week G/P. Treatment-experienced, non-cirrhotic patients had SVR12 rates of 90% (44/49) and 95% (21/22) with 12- and 16-week G/P, respectively; 94% (48/51) of treatment-experienced patients with cirrhosis treated for 16 weeks achieved SVR12. No serious adverse events (AEs) were attributed to G/P; AEs leading to study drug discontinuation were rare (<1%). G/P was well-tolerated and efficacious for patients with chronic HCV GT3 infection, regardless of cirrhosis status or prior treatment experience. Eight- and 12-week durations were efficacious for treatment-naïve patients without cirrhosis and with compensated cirrhosis, respectively; 16-week G/P was efficacious in patients with prior treatment experience irrespective of cirrhosis status. This article is protected by copyright. All rights reserved.
2019
- Impact of a Multidisciplinary Team on Alcohol Recidivism and Survival After Liver Transplant for Alcoholic Disease
[Articolo su rivista]
Magistri, P.; Marzi, L.; Guerzoni, S.; Vandelli, M.; Mereu, F.; Ascari, F.; Guidetti, C.; Tarantino, G.; Serra, V.; Guerrini, G. P.; Ballarin, R.; Moscara, M.; De Maria, N.; Villa, E.; Di Benedetto, F.
abstract
Background: Alcohol use disorders have a prevalence of 10% among the population of the United States and Europe and are one of the most frequent causes of liver cirrhosis in the Western world. Currently, alcohol-related liver cirrhosis represents one of the most frequent indications to liver transplant (LT), both as independent cause or associated with hepatitis C virus or hepatitis B virus infections. Starting from 2014, a multidisciplinary team involving surgeons, gastroenterologists, clinical toxicologists, psychiatrists, and psychologists was developed within the Modena Liver Transplant Center. Methods: We retrospectively reviewed our prospectively maintained institutional database of liver transplants in order to identify cirrhotic patients eligible for LT with a diagnosis of alcohol use disorder. Results: A total of 756 liver transplants were performed at Policlinico University Hospital, University of Modena, and Reggio Emilia, MO, Italy, between November 2000 and November 2017; 102 patients who underwent LT were considered eligible for inclusion in the study. Conclusions: The multidisciplinary approach, together with blood, urinary, and hair tests, allows identification of early recurrences and improves survival. Further studies are necessary to understand how multidisciplinary teams can change the 6-month rule in patient selection.
2019
- Nabilone administration in refractory chronic diarrhea: A case series
[Articolo su rivista]
Pellesi, L.; Verga, M. C.; De Maria, N.; Villa, E.; Pini, L. A.; Guerzoni, S.
abstract
Background: Daily cannabis assumption is currently associated with several physical and mental health problems, however in the past it was prescribed for a multitude of symptoms, including vomiting, abdominal pain and diarrhea. Through the years, the endocannabinoid system has been recognized in the homeostatic mechanisms of the gut, as well as in the physiological control of intestinal motility and secretion. Accordingly, cannabinoids may be a promising therapy against several gastrointestinal conditions, such as abdominal pain and motility-related disorders. Case presentation: We retrospectively analysed the efficacy and safety of a CB1-receptor agonist administered in six patients with refractory chronic diarrhea, between April 2008 and July 2016. After three months of therapy, oral nabilone improved the health of nearly all patients, with visible improvements in reducing diarrheal symptoms and weight gain. Most of the benefits persisted through the three-month follow-up. Only one patient interrupted the treatment after one month, due to severe fatigue and mental confusion; the symptoms disappeared in the follow-up period. Conclusions: These findings encourage the study of cannabinoids acting on CB1 receptors in chronic gastrointestinal disorders, especially in refractory chronic diarrhea, offering a chance for a substantial improvement in the quality of life of selected patients, with a reasonable safety profile.
2019
- New Direct-Acting Antivirals for the Treatment of Patients With Hepatitis C Virus Infection: A Systematic Review of Randomized Controlled Trials
[Articolo su rivista]
Pecoraro, V.; Banzi, R.; Cariani, E.; Chester, J.; Villa, E.; D'Amico, R.; Bertele', V.; Trenti, T.
abstract
Background: New direct-acting antiviral agents (DAAs) approved for the treatment of patients infected by Hepatitis C virus (HCV) are well tolerated and increase sustained virological response (SVR) rate. We summarize current evidence on the efficacy and safety from comparative randomized controlled trials (RCTs) of DAAs. Methods: We systematically searched MEDLINE, Embase, Scopus, CENTRAL, and Lilacs as well as a list of reference literature. We included RCTs comparing DAAs with placebo or active control and reporting response rates and adverse events according to antiviral regimens. Risk ratios (RRs) were pooled as appropriate. We assessed the risk of bias of included studies and graded the quality of evidence according to the GRADE method. Results: We included 28 RCTs, enrolling more than 7000 patients. The quality of evidence was generally low. Twelve-week treatment with DAAs in naïve patients significantly increased SVR12 and SVR24 compared with placebo (RR 1.4, 95% CI 1.3–1.6; RR 1.5, 95% CI 1.4–1.6, respectively). This means that for every 1000 patients, 240 or 260 more patients experienced SVR12 or SVR24 if treated with any DAAs. We could not find RCTs assessing progression of liver disease or development of hepatocellular carcinoma. DAAs were not associated with higher incidence of serious adverse events or discontinuation due to adverse events. Conclusions: This systematic review confirms that new DAAs are more effective in inducing SVR than placebo. Outside clinical trials, in real word, HCV cure with DAA regimens occurs in less than 90% of patients, so further comparative evaluations are needed to establish their long-term effects.
2019
- Nonalcoholic steatohepatitis before and after liver transplant: keeping up with the times
[Articolo su rivista]
Gitto, S.; Marra, F.; De Maria, N.; Bihl, F.; Villa, E.; Andreone, P.; Burra, P.
abstract
Introduction: In the last years, nonalcoholic steatohepatitis (NASH) has become a leading indication for liver transplant (LT). After transplant, both recurrent and de novo nonalcoholic fatty liver disease (NAFLD) can be commonly diagnosed. However, dedicated surveillance programs for patients with pre- or post-transplant NAFLD are not available. Areas covered: Patients waiting for LT for NASH show specific peculiarities and would deserve targeted stratification of mortality risk. Obesity, hyperlipidemia, and diabetes mellitus can be often found after transplant. These conditions, together with immunosuppressive regimen, make LT recipients a high-risk population for both recurrent and de novo NAFLD. Development of fatty liver disease after LT has a relevant impact on both morbidity and mortality. Expert commentary: A targeted stratification of neoplastic and cardiovascular risk for patients with NASH waiting for LT would be mandatory. In both pre- and post-transplant period, NAFLD should be considered not only a liver disease but also a cardiovascular risk factor. Patients within Transplant Program, especially those with known metabolic risk factors, should be followed with personalized diagnostic and life-style interventions before and after LT.
2019
- Occurrence of hepatocellular carcinoma after direct-acting antiviral therapy for hepatitis C virus infection: literature review and risk analysis
[Articolo su rivista]
Galati, G.; Muley, M.; Vigano, M.; Iavarone, M.; Vitale, A.; Dell'Unto, C.; Lai, Q.; Cabibbo, G.; Sacco, R.; Villa, E.; Trevisani, F.
abstract
Introduction: Concerns were raised about a high occurrence of hepatocellular carcinoma (HCC) after successful treatment of chronic hepatitis C (CHC) by direct-acting antivirals (DAAs). Areas covered: The authors summarize the clinical studies reporting the occurrence rate and risk factors of HCC after DAAs in CHC. Expert opinion: The recent introduction of all-oral DAAs has substantially changed the scenario of CHC, achieving a sustained virological response (SVR) in >90% of cases. Earlier concerns raised about an increasing incidence of HCC post-DAAs were flawed by large heterogeneity of patients, the limited number of well-designed prospective studies (only nine, up to date) and the inclusion of a large number of patients with advanced liver disease, previously excluded from interferon-based studies. Current data on DAAs have shown a lower risk of HCC development; however, they were unable to identify patients at greater risk for HCC occurrence after SVR. Surveillance strategy, likely lifelong, is mandatory in these patients according to general expert opinion.
2019
- Platelets and Hepatocellular Cancer: Bridging the Bench to the Clinics
[Articolo su rivista]
Lai, ; Q., aEmail Author; Vitale, ; A., bEmail Author; Manzia, ; T. M., cEmail Author; Foschi, ; F. G., dEmail Author; Sandri, ; G. B. L., eEmail Author; Gambato, ; M., bEmail Author; Melandro, ; F., fEmail Author; Russo, ; F. P., bEmail Author; Miele, ; L., gEmail Author; Viganò, ; L., hEmail Author; Burra, ; P., bEmail Author; Giannini, ; E. G., iEmail Author; Aliberti, C.; Baccarani, U.; Bhoori, S.; Borzio, M.; Brancaccio, G.; Cabibbo, G.; Casadei, Gardini; A., Carrai; P., Cillo; U., Conti; F., Cucchetti; A., D’Ambrosio; R., Dell’Unto; C., Dematthaeis; Di, Costanzo; G., G.; Di Sandro, S.; Fucilli, F.; Galati, G.; Gasbarrini, A.; Giuliante, F.; Ghinolfi, D.; Grieco, A.; Gruttaduria, S.; Guarino, M.; Kostandini, A.; Iavarone, M.; Lenci, I.; Losito, F.; Lupo, L. G.; Mazzocato, S.; Mescoli, C.; Miele, L.; Morisco, F.; Muley, M.; Nicolini, D.; Persico, M.; Pompili, M.; Ponziani, F. R.; Pravisani, R.; Rapaccini, G. L.; Rendina, M.; Renzulli, M.; Rossi, M.; Rreka, E.; Sacco, R.; Sangiovanni, A.; Sessa, A.; Simonetti, N.; Sposito, C.; Tortora, R.; Trevisani, F.; Viganò, M.; Villa, E.; Vincenzi, V.; Violi, P.; Associazione Italiana per lo Studio del Fegato (AISF) HCC Special Interest, Group
abstract
Growing interest is recently being focused on the role played by the platelets in favoring hepatocellular cancer (HCC) growth and dissemination. The present review reports in detail both the experimental and clinical evidence published on this topic. Several growth factors and angiogenic molecules specifically secreted by platelets are directly connected with tumor progression and neo-angiogenesis. Among them, we can list the platelet-derived growth factor, the vascular endothelial growth factor, the endothelial growth factor, and serotonin. Platelets are also involved in tumor spread, favoring endothelium permeabilization and tumor cells' extravasation and survival in the bloodstream. From the bench to the clinics, all of these aspects were also investigated in clinical series, showing an evident correlation between platelet count and size of HCC, tumor biological behavior, metastatic spread, and overall survival rates. Moreover, a better understanding of the mechanisms involved in the platelet-tumor axis represents a paramount aspect for optimizing both current tumor treatment and development of new therapeutic strategies against HCC.
2019
- Predictors of hepatocellular carcinoma in HCV cirrhotic patients treated with direct acting antivirals
[Articolo su rivista]
Lleo, Ana; Aglitti, Andrea; Aghemo, Alessio; Maisonneuve, Patrick; Bruno, Savino; Persico, Marcello; Villa, Erica; Andreone, Pietro
abstract
BACKGROUND:
Despite the dramatic improvement in viral eradication rates that has been reached with direct antiviral agents (DAAs), the real benefit of viral eradication after DAAs on hepatocellular carcinoma (HCC) development is still controversial.
AIM:
To prospectively assess the risk of HCC occurrence and early recurrence in a large cohort of DAA-treated HCV-cirrhotic patients and to identify potential predictors of HCC development.
METHODS:
We analyzed data prospectively collected from 1927 consecutive HCV-infected cirrhotic patients treated with DAA from January to December 2015 in 10 tertiary liver centers in Italy and followed-up for one year after therapy. 161 patients had a previous HCC.
RESULTS:
38/161 subjects developed tumor recurrence during the follow-up (recurrence rate = 24.8 per 100-year), patients with SVR had a significantly lower rate of recurrence. Lack of SVR and alpha-fetoprotein (AFP) were independent predictors of HCC recurrence. 50/1766 patients without a previous HCC history developed HCC during follow-up (incidence rate = 2.4 per 100-year). Lack of SVR was the strongest predictor of HCC development. Furthermore, patients with SVR and no stigmata of portal hypertension have a lower incidence rate of HCC (1.0 per 100-year).
CONCLUSIONS:
SVR is associated with a significant decrease of recurrent or de novo HCC. Baseline AFP and signs of portal hypertension can help to stratify the risk of HCC.
2019
- Reply to: “It takes two “eyes” to see in depth”
[Articolo su rivista]
Turco, L.; Garcia-Tsao, G.; Rossi, R.; Villa, E.; Schepis, F.
abstract
2019
- Retraction: The OMICs Window into Nonalcoholic Fatty Liver Disease (NAFLD) (Metabolites 2019, 9(2), 25)
[Articolo su rivista]
Carulli, L.; Zanca, G.; Schepis, F.; Villa, E.
abstract
As the authors of the title paper [1], it is with great regret that we inform the readership of Metabolites that we have asked the journal’s publisher, MDPI, to retract the paper from the scientific literature. Due to human error, we included contents similar to article [2], which has already been published by Pirola et al. We apologize to the readership of Metabolites and to the authors of [2] for any inconvenience caused. MDPI is a member of the Committee on Publication Ethics (COPE) and takes the responsibility to enforce strict ethical policies and standards very seriously. To ensure the integrity of the publication record, [1] is retracted and shall be marked accordingly.
2019
- SUMOylation regulates LKB1 localization and its oncogenic activity in liver cancer
[Articolo su rivista]
Zubiete-Franco, Imanol; García-Rodríguez, Juan L.; Lopitz-Otsoa, Fernando; Serrano-Macia, Marina; Simon, Jorge; Fernández-Tussy, Pablo; Barbier-Torres, Lucía; Fernández-Ramos, David; Gutiérrez-de-Juan, Virginia; López de Davalillo, Sergio; Carlevaris, Onintza; Beguiristain Gómez, Adolfo; Villa, Erica; Calvisi, Diego; Martín, César; Berra, Edurne; Aspichueta, Patricia; Beraza, Naiara; Varela-Rey, Marta; Ávila, Matias; Rodríguez, Manuel S.; Mato, José M.; Díaz-Moreno, Irene; Díaz-Quintana, Antonio; Delgado, Teresa C.; Martínez-Chantar, María L.
abstract
Background: Even though liver kinase B1 (LKB1) is usually described as a tumor suppressor in a wide variety of tissues, it has been shown that LKB1 aberrant expression is associated with bad prognosis in Hepatocellular Carcinoma (HCC). Methods: Herein we have overexpressed LKB1 in human hepatoma cells and by using histidine pull-down assay we have investigated the role of the hypoxia-related post-translational modification of Small Ubiquitin-related Modifier (SUMO)ylation in the regulation of LKB1 oncogenic role. Molecular modelling between LKB1 and its interactors, involved in regulation of LKB1 nucleocytoplasmic shuttling and LKB1 activity, was performed. Finally, high affinity SUMO binding entities-based technology were used to validate our findings in a pre-clinical mouse model and in clinical HCC. Findings: We found that in human hepatoma cells under hypoxic stress, LKB1 overexpression increases cell viability and aggressiveness in association with changes in LKB1 cellular localization. Moreover, by using site-directed mutagenesis, we have shown that LKB1 is SUMOylated by SUMO-2 at Lys178 hampering LKB1 nucleocytoplasmic shuttling and fueling hepatoma cell growth. Molecular modelling of SUMO modified LKB1 further confirmed steric impedance between SUMOylated LKB1 and the STe20-Related ADaptor cofactor (STRADα), involved in LKB1 export from the nucleus. Finally, we provide evidence that endogenous LKB1 is modified by SUMO in pre-clinical mouse models of HCC and clinical HCC, where LKB1 SUMOylation is higher in fast growing tumors. Interpretation: Overall, SUMO-2 modification of LKB1 at Lys178 mediates LKB1 cellular localization and its oncogenic role in liver cancer. Fund: This work was supported by grants from NIH (US Department of Health and Human services)-R01AR001576-11A1 (J.M.M and M.L.M-C.), Gobierno Vasco-Departamento de Salud 2013111114 (to M.L.M.-C), ELKARTEK 2016, Departamento de Industria del Gobierno Vasco (to M.L.M.-C), MINECO: SAF2017–87301-R and SAF2014–52097-R integrado en el Plan Estatal de Investigación Cientifica y Técnica y Innovación 2013–2016 cofinanciado con Fondos FEDER (to M.L.M.-C and J.M.M., respectively), BFU2015–71017/BMC MINECO/FEDER, EU (to A.D.Q. and I.D.M.), BIOEF (Basque Foundation for Innovation and Health Research): EITB Maratoia BIO15/CA/014; Instituto de Salud Carlos III:PIE14/00031, integrado en el Plan Estatal de Investigación Cientifica y Técnica y Innovacion 2013–2016 cofinanciado con Fondos FEDER (to M.L.M.-C and J.M.M), Asociación Española contra el Cáncer (T.C.D, P·F-T and M.L.M-C), Daniel Alagille award from EASL (to T.C.D), Fundación Científica de la Asociación Española Contra el Cancer (AECC Scientific Foundation) Rare Tumor Calls 2017 (to M.L.M and M.A), La Caixa Foundation Program (to M.L.M), Programma di Ricerca Regione-Università 2007–2009 and 2011–2012, Regione Emilia-Romagna (to E.V.), Ramón Areces Foundation and the Andalusian Government (BIO-198) (A.D.Q. and I.D.M.), ayudas para apoyar grupos de investigación del sistema Universitario Vasco IT971–16 (P.A.), MINECO:SAF2015–64352-R (P.A.), Institut National du Cancer, FRANCE, INCa grant PLBIO16–251 (M.S.R.), MINECO - BFU2016–76872-R to (E.B.). Work produced with the support of a 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (M.V-R). Finally, Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III. We thank MINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644). Funding sources had no involvement in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
2019
- The OMICs window into nonalcoholic fatty liver disease (NAFLD)
[Articolo su rivista]
Carulli, L.; Zanca, G.; Schepis, F.; Villa, E.
abstract
Nonalcoholic fatty liver disease (NAFLD) is a common cause of hepatic abnormalities worldwide. Nonalcoholic steatohepatitis (NASH) is part of the spectrum of NAFLD and leads to progressive liver disease, such as cirrhosis and hepatocellular carcinoma. In NASH patient, fibrosis represents the major predictor of liver-related mortality; therefore, it is important to have an early and accurate diagnosis of NASH. The current gold standard for the diagnosis of NASH is still liver biopsy. The development of biomarkers able to predict disease severity, prognosis, as well as response to therapy without the need for a biopsy is the focus of most up-to-date genomic, transcriptomic, proteomic, and metabolomic research. In the future, patients might be diagnosed and treated according to their molecular signatures. In this short review, we discuss how information from genomics, proteomics, and metabolomics contribute to the understanding of NAFLD pathogenesis.
2019
- Transjugular intrahepatic portosystemic shunt does not affect the efficacy and safety of direct-acting antivirals in patients with advanced cirrhosis: a real-life, case-control study
[Articolo su rivista]
Gitto, Stefano; Vizzutti, Francesco; Schepis, Filippo; Turco, Laura; Aspite, Silvia; Vitale, Giovanni; Arena, Umberto; Villa, Erica; Laffi, Giacomo; Debernardi-Venon, Wilma; Fanelli, Fabrizio; Andreone, Pietro; Marra, Fabio
abstract
Background: Transjugular Intrahepatic Portosystemic Shunt (TIPS) is a well-established treatment
for complications of portal hypertension. Aims: To analyze the impact of TIPS on virologic
response and safety profile in patients treated with direct-acting antivirals (DAA). Methods: We
analyzed data from HCV-positive cirrhotic patients treated with DAAs. Twenty-one patients with previous TIPS placement were compared with 42 matched subjects without TIPS. Logistic
regression was used to identify predictors of hepatic function worsening and adverse events.
Results: No differences were found between the two groups in particular regarding sustained
virologic response (92.5 and 97.6% in TIPS vs no-TIPS, p=0.559). Model for End-stage Liver
Disease (MELD) of both TIPS and no-TIPS groups declined from baseline to week 24 of follow-up
(from 12.5±3.5 to 10.8±3.4 and from 11.1±3.5 to 10.3±3.4, p=0.044 and 0.025). There were no
differences in adverse event rates. At univariate analysis, age was associated with MELD increase
from baseline to week 24 (OR 1.111, 95% CI 1.019-1.211, p=0.017), and patients with higher
baseline MELD developed serious adverse events more frequently (OR 0.815, 95% CI 0.658-1.010,
p=0.062). Patients with or without TIPS did not show differences in transplant-free survival.
Conclusion: TIPS placement does not affect virologic response and clinical outcome of patients
receiving DAAs.
2018
- Cardiopulmonary hemodynamics and c-reactive protein as prognostic indicators in compensated and decompensated cirrhosis
[Articolo su rivista]
Turco, Laura; Garcia-Tsao, Guadalupe; Magnani, Ilenia; Bianchini, Marcello; Costetti, Martina; Caporali, Cristian; Colopi, Stefano; Simonini, Emilio; De Maria, Nicola; Banchelli, Federico; Rossi, Rosario; Villa, Erica; Schepis, Filippo
abstract
The main stages of cirrhosis (compensated and decompensated) have been substaged based on clinical, endoscopic, and portal pressure (determined by the hepatic venous pressure gradient, HVPG) features. Vasodilatation leading to a hyperdynamic circulatory state is central in the development of a late decompensated stage with inflammation being currently considered a key driver. We aimed to assess hepatic/systemic hemodynamics and inflammation (by C reactive protein, CRP) among the different substages of cirrhosis and to investigate their interrelationship and prognostic relevance.
2018
- Concepts and Controversies in Haemostasis and Thrombosis Associated with Liver Disease: Proceedings of the 7th International Coagulation in Liver Disease Conference
[Articolo su rivista]
Intagliata, N. M.; Argo, C. K.; Stine, J. G.; Lisman, T.; Caldwell, S. H.; Violi, F.; Villa, E
abstract
Peer evaluation of coagulation in chronic liver disease
2018
- Correction: The Role of Anticoagulation in Treating Portal Hypertension
[Articolo su rivista]
Turco, Laura; Schepis, Filippo; Villa, Erica
abstract
: [This corrects the article DOI: 10.1007/s11901-018-0406-x.].
2018
- Corrigendum to “Premature ovarian senescence and a high miscarriage rate impair fertility in women with HCV” [J Hepatol 68 (2018) 33–41](S0168827817322596)(10.1016/j.jhep.2017.08.019)
[Articolo su rivista]
Karampatou, Aimilia; Han, Xue; Kondili, Loreta A.; Taliani, Gloria; Ciancio, Alessia; Morisco, Filomena; Critelli, Rosina Maria; Baraldi, Enrica; Bernabucci, Veronica; Troshina, Giulia; Guarino, Maria; Tagliavini, Simonetta; D'Ambrosio, Federica; Bristot, Laura; Turco, Laura; Rosato, Stefano; Vella, Stefano; Trenti, Tommaso; Neri, Isabella; La Marca, Antonio; Manthena, Shivaji; Goldstein, Andrea S.; Bruno, Savino; Bao, Yanjun; Gonzalez, Yuri Sanchez; Villa, Erica
abstract
It has come to our attention that the PITER framework investigator, Alessandro Federico, was incorrectly listed as F. Alessandro in the original manuscript. Please note that the correct name of this author is Alessandro Federico (2nd University of Naples). The correct list of PITER investigators is in the footnote below.
2018
- Current and future challenges in HCV: insights from an Italian experts panel
[Articolo su rivista]
Andreoni, Massimo; Babudieri, Sergio; Bruno, Savino; Colombo, Massimo; Zignego, Anna L.; Di Marco, Vito; Di Perri, Giovanni; Perno, Carlo F.; Puoti, Massimo; Taliani, Gloria; Villa, Erica; Craxì, Antonio
abstract
Background: The recent availability of direct acting antiviral drugs (DAAs) has drastically changed hepatitis C virus (HCV) treatment scenarios, due to the exceedingly high rates of sustained virological response (SVR) and excellent tolerability allowing for treatment at all disease stages. Methods: A panel of Italian experts was convened twice, in November 2016 and January 2017, to provide further support on some open issues and provide guidance for personalized HCV care, also in light of forthcoming regimens. Results and conclusions: Treatment recommendations issued by international and national liver societies to guide clinicians in the management of HCV infection are constantly updated due to accumulating new data. Such recommendations may not be applicable to all healthcare settings for a variety of reasons. Moreover, some gaps still remain and the spectrum of patients to be treated is also evolving.
2018
- De-novo nonalcoholic steatohepatitis is associated with long-term increased mortality in liver transplant recipients
[Articolo su rivista]
Gitto, Stefano; de Maria, Nicola; di Benedetto, Fabrizio; Tarantino, Giuseppe; Serra, Valentina; Maroni, Lorenzo; Cescon, Matteo; Pinna, Antonio D; Schepis, Filippo; Andreone, Pietro; Villa, Erica
abstract
Patients who have undergone transplantation often develop metabolic syndrome (MetS) and de-novo nonalcoholic fatty liver disease (NAFLD). Our aim was to evaluate the impact of metabolic disease on cardiovascular and neoplastic risk and survival.
2018
- Direct-acting antivirals and hepatocellular carcinoma in chronic hepatitis C: A few lights and many shadows
[Articolo su rivista]
Guarino, Maria; Sessa, Anna; Cossiga, Valentina; Morando, Federica; Caporaso, Nicola; Morisco, Filomena; Luca, Viganó; Romana, Ponziani Francesca; Maurizio, Pompili; Cillo, Umberto; Burra, Patrizia; Mescoli, Claudia; Gambato, Martina; Paolo, Russo Francesco; Alessandro, Vitale; Giuseppe, Cabibbo; Mauro, Vigano'; Giovanni, Galati; Villa, Erica; Lupo, Luigi G.; Maria, Rendina; Losito, Francesco; Fucilli, Fabio; Persico, Marcello; D'Ambrosio, Roberta; Sangiovanni, Angelo; Massimo, Iavarone; Giuseppina, Brancaccio; Cucchetti, Alessandro; Renzulli, Matteo; Franco, Trevisani; Miele, Luca; Grieco, Antonio; Rapaccini, Gianlodovico; Gasbarrini, Antonio; Sandri, Giovanni Battisa Levi; Melandro, Fabio; Rossi, Massimo; Quirino, Lai; Lenci, Ilaria; Manzia, Tommaso Maria; Tortora, Raffaella; Di Costanzo, Giovan Giuseppe; Ghinolfi, Davide; Rreka, Erion; Carrai, Paola; Simonetti, Natalia; Rodolfo, Sacco; Sposito, Carlo; Bhoori, Sherrie; Di Sandro, Stefano; Foschi, Francesco Giuseppe; Gardini, Andrea Casadei; Nicolini, Daniele; Mazzocato, Susanna; Alba, Kostandini; Violi, Paola; Baccarani, Umberto; Pravisani, Riccardo; Vincenzi, Valter
abstract
With the introduction of direct-acting antiviral agents (DAA), the rate of sustained virological response (SVR) in the treatment of hepatitis C virus (HCV) has radically improved to over 95%. Robust scientific evidence supports a beneficial role of SVR after interferon therapy in the progression of cirrhosis, resulting in a decreased incidence of hepatocellular carcinoma (HCC). However, a debate on the impact of DAAs on the development of HCC is ongoing. This review aimed to analyse the scientific literature regarding the risk of HCC in terms of its recurrence and occurrence after the use of DAAs to eradicate HCV infection. Among 11 studies examining HCC occurrence, the de novo incidence rate ranged from 0 to 7.4% (maximum follow-up: 18 mo). Among 18 studies regarding HCC recurrence, the rate ranged from 0 to 54.4% (maximum "not well-defined" followup: 32 mo). This review highlights the major difficulties in interpreting data and reconciling the results of the included studies. These difficulties include heterogeneous cohorts, potential misclassifications of HCC prior to DAA therapy, the absence of an adequate control group, short follow-up times and different kinds of follow-up. Moreover, no clinical feature-based scoring system accounts for the molecular characteristics and pathobiology of the tumours. Nonetheless, this review does not suggest that there is a higher rate of de novo HCC occurrence or recurrence after DAA therapy in patients with previous HCV infection.
2018
- Efficacy and Safety of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir With or Without Ribavirin in Patients With Chronic Hepatitis C Virus Genotype 1 Infection Receiving Opioid Substitution Therapy: A Post Hoc Analysis of 12 Clinical Trials
[Articolo su rivista]
Grebely, Jason; Puoti, Massimo; Wedemeyer, Heiner; Cooper, Curtis; Sulkowski, Mark S; Foster, Graham R; Berg, Thomas; Villa, Erica; Rodriguez-Perez, Federico; Wyles, David L; Schnell, Gretja; Alami, Negar N; Zhang, Zhenzhen; Dumas, Emily; Dore, Gregory J
abstract
We evaluated the impact of opioid substitution therapy (OST) on the completion, adherence, efficacy, and safety of the 3-direct-acting antiviral regimen of ombitasvir, paritaprevir (identified by AbbVie and Enanta) co-dosed with ritonavir, and dasabuvir ± ribavirin among patients infected with hepatitis C virus (HCV) genotype (GT) 1, with or without compensated cirrhosis.
2018
- High efficacy of direct-acting anti-viral agents in hepatitis C virus-infected cirrhotic patients with successfully treated hepatocellular carcinoma
[Articolo su rivista]
Persico, M.; Aglitti, A.; Aghemo, A.; Rendina, M.; Lleo, A.; Ciancio, A.; Di Marco, V.; Lampertico, P.; Brunetto, M. R.; Zuin, M.; Andreone, P.; Villa, E.; Troshina, G.; Calvaruso, V.; Degasperi, E.; Coco, B.; Giorgini, A.; Conti, F.; Di Leo, A.; Marzi, L.; Boccaccio, V.; Bollani, S.; Maisonneuve, P.; Bruno, S.
abstract
Background: The efficacy of direct-acting anti-viral (DAA) therapy in patients with a history of hepatocellular carcinoma (HCC) is unknown. Aim: We prospectively evaluated whether previously treated HCC affects DAA efficacy in a large real-life cohort of cirrhotic patients. Methods: From January to December 2015 all consecutive HCV mono-infected patients with cirrhosis and/or history of HCC attending 10 Italian tertiary liver centres were enrolled. Baseline characteristics and response to therapy were recorded. 1927 patients were enrolled (mean age: 62.1 ± 10.9 years; 1.205 males). Genotype 1 was the most frequent (67.9%) followed by genotypes 3 (12.4%), 2 (11.2%) and 4 (8.6%). 88.4% and 10.9% of cases were classified Child A and B, respectively, and 14 (<1%) cases were classified Child C. Ascites and hepatic encephalopathy occurred in 10.7% and 3.2% of patients, respectively. Varices were detected in 39.3% of patients. Suboptimal and optimal treatment was prescribed: 15.9% of patients received sofosbuvir/simeprevir, 33.4% sofosbuvir/ledipasvir, 20.2% a Viekirax + Exviera regimen, 15.7% sofosbuvir/ribavirin, 9.9% sofosbuvir/daclatasvir and 3.4% Viekirax; 1.3% of patients received an interferon-based regimen. Results: The sustained virologic response (SVR) rate at intention-to-treat analysis was 95.1%. It differed significantly across Child classes, that is, 96.3%, 86.1% and 71.4% Child A, B and C, respectively (P < 0.0001) and across genotypes (P = 0.002). The SVR rate did not differ between patients with (95.0%) and those without previous HCC (95.1%). At multivariable analysis, SVR was significantly associated with HCV genotype, Child class. Conclusion: This large real-life study proves that the efficacy of DAA in cirrhotic patients is not impaired by successfully treated HCC.
2018
- Liver Angiopoietin-2 is a key predictor of de novo or recurrent hepatocellular cancer after HCV direct-acting antivirals
[Articolo su rivista]
Faillaci, Francesca; Marzi, Luca; Critelli, Rosina; Milosa, Fabiola; Schepis, Filippo; Turola, Elena; Andreani, Silvia; Vandelli, Gabriele; Bernabucci, Veronica; Lei, Barbara; D'Ambrosio, Federica; Bristot, Laura; Cavalletto, Luisa; Chemello, Liliana; Sighinolfi, Pamela; Manni, Paola; Maiorana, Antonino; Caporali, Cristian; Bianchini, Marcello; Marsico, Maria; Turco, Laura; de Maria, Nicola; Del Buono, Mariagrazia; Todesca, Paola; di Lena, Luca; Romagnoli, Dante; Magistri, Paolo; di Benedetto, Fabrizio; Bruno, Savino; Taliani, Gloria; Giannelli, Gianluigi; Martinez-Chantar, Maria-Luz; Villa, Erica
abstract
Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC).In Study 1,we studied the proangiogenic liver microenvironment in 242 DAAs-treated chronic Hepatitis C patients with advanced fibrosis.Angiopoietin-2 expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent,de novo,non-recurrent HCC or patients never developing HCC.Circulating Angiopoietin-2,vascular-endothelial growth factor (VEGF),and C-reactive protein were also measured. In Study 2,we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical,clinical,hemodynamic,endoscopic, elastographic,and echo-Doppler work-up was performed in both studies.In Study 1,none without cirrhosis developed HCC.Of 183 patients with cirrhosis,14/28 (50.0%) with previous HCC recurred while 21/155 (13.5%) developed de novo HCC.Recurrent and de novo HCCs had significantly higher liver fibrosis scores,portal pressure,and systemic inflammation than non-recurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients,tumor and non-tumor Angiopoietin-2 showed an inverse relationship with portal vein velocity (r=-0.412,p=0.037 and r= -0.409,p=0.047,respectively) and a positive relationship with liver stiffness (r=0.526,p=0.007;r=0.525,p=0.003,respectively).Baseline circulating VEGF and cirrhotic liver Angiopoietin-2 were significantly related (r=0.414,p=0.044).VEGF increased during DAAs, remaining stably elevated at 3 months follow-up, when it significantly related with serum Angiopoietin-2 (r=0.531,p=0.005).Angiopoietin-2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with the risk of HCC recurrence (OR 1.137,95%CI 1.044-1.137,p=0.003) or occurrence (OR 1.604,95% CI 1.080-2.382;p=0.019).In Study 2,DAA treatment (OR 4.770,95%CI 1.395-16.316,p=0.013) and large varices (OR 3.857,95%CI 1.127-13.203,p=0.032) were independent predictors of de novo HCC.
2018
- Low molecular weight heparin does not increase bleeding and mortality post endoscopic variceal band ligation in cirrhotic patients
[Articolo su rivista]
Bianchini, Marcello; Cavani, Giulia; Bonaccorso, Ambra; Turco, Laura; Vizzutti, Francesco; Sartini, Alessandro; Gitto, Stefano; Merighi, Alberto; Banchelli, Federico; Villa, Erica; Schepis, Filippo
abstract
Anticoagulants are commonly indicated in cirrhotic patients due to high rate of (pro)thrombotic conditions. Low molecular weight heparin (LMWH) is safe in patients with esophageal varices. However, the safety of LMWH is unknown in patients undergoing prophylactic endoscopic variceal ligation (EVL).
2018
- MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis
[Articolo su rivista]
Fernández-Ramos, David; Fernández-Tussy, Pablo; Lopitz-Otsoa, Fernando; Gutiérrez-de-Juan, Virginia; Navasa, Nicolás; Barbier-Torres, Lucía; Zubiete-Franco, Imanol; Simón, Jorge; Fernández, Agustín F.; Arbelaiz, Ander; Aransay, Ana M.; Lavín, José Luis; Beraza, Naiara; Perugorria, María J.; Banales, Jesus M.; Villa, Erica; Fraga, Mario F.; Anguita, Juan; Avila, Matias A.; Berasain, Carmen; Iruzibieta, Paula; Crespo, Javier; Lu, Shelly C.; Varela-Rey, Marta; Mato, José M.; Delgado, Teresa C.; Martínez-Chantar, María L.
abstract
Glycine N-methyltransferase (GNMT) is the most abundant methyltransferase in the liver and a master regulator of the transmethylation flux. GNMT downregulation leads to loss of liver function progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Moreover, GNMT deficiency aggravates cholestasis-induced fibrogenesis. To date, little is known about the mechanisms underlying downregulation of GNMT levels in hepatic fibrosis and cirrhosis. On this basis, microRNAs are epigenetic regulatory elements that play important roles in liver pathology. In this work, we aim to study the regulation of GNMT by microRNAs during liver fibrosis and cirrhosis. Luciferase assay on the 3ʹUTR-Gnmt was used to confirm in silico analysis showing that GNMT is potentially targeted by the microRNA miR-873-5p. Correlation between GNMT and miR-873-5p in human cholestasis and cirrhosis together with miR-873-5p inhibition in vivo in different mouse models of liver cholestasis and fibrosis [bile duct ligation and Mdr2 (Abcb4)-/- mouse] were then assessed. The analysis of liver tissue from cirrhotic and cholestatic patients, as well as from the animal models, showed that miR-873-5p inversely correlated with the expression of GNMT. Importantly, high circulating miR-873-5p was also detected in cholestastic and cirrhotic patients. Preclinical studies with anti-miR-873-5p treatment in bile duct ligation and Mdr2-/- mice recovered GNMT levels in association with ameliorated inflammation and fibrosis mainly by counteracting hepatocyte apoptosis and cholangiocyte proliferation. In conclusion, miR-873-5p emerges as a novel marker for liver fibrosis, cholestasis, and cirrhosis and therapeutic approaches based on anti-miR-873-5p may be effective treatments for liver fibrosis and cholestatic liver disease.
2018
- Non-alcoholic fatty liver disease phenotypes in patients with inflammatory bowel disease
[Articolo su rivista]
Sartini, Alessandro; Gitto, Stefano; Bianchini, Marcello; Chiara Verga, Maria; Di Girolamo, Maria; Bertani, Angela; Del Buono, Mariagrazia; Schepis, Filippo; Lei, Barbara; De Maria, Nicola; Villa, Erica
abstract
Non-alcoholic fatty liver disease (NAFLD) can be detected in up to 33.6% of inflammatory bowel disease (IBD) patients, often in absence of metabolic risk factors. Nevertheless, most of previous studies on such issue were conducted within the IBD population only. The primary aim of this study was to compare clinical and metabolic features of NAFLD in patients with and without IBD (w/o IBD) and to identify specific NAFLD phenotypes within the IBD population. Among 223 NAFLD patients, 78 patients with IBD were younger compared to 145 without (w/o) IBD, were less likely to have altered liver enzymes, had lower mean body weight, smaller waist circumference and lower body mass index (BMI); at the same time, MetS was more prevalent among patients w/o IBD (56.6 vs. 23.1%, p < 0.001). Within IBD population, patients with severe IBD showed more often severe steatosis (S3) at ultrasound (US) (32.1 vs. 16.6%, p = 0.01), compared to mild-to-moderate disease. Independent risk factors for S3 US steatosis in IBD patients at the multivariate logistic regression analysis were: more than 1 IBD relapse per year during disease history (OR 17.3, 95% CI 3.6-84), surgery for IBD (OR 15.1, 95% CI 3.1-73.7) and more extensive intestinal involvement (OR 19.4, 95% CI 3.4-110.9); the ongoing anti-Tumor Necrosis Factor alpha (antiTNFα) therapy was the only independent factor which protect toward the presence of altered liver enzymes (OR 0.15, 95% CI 0-0.8, p = 0.02). In conclusion, NAFLD in IBD patients is different from that in patients w/o IBD, who seem to develop different NAFLD phenotypes according to intestinal disease clinical course. More severe IBD seem to predict the presence of more severe steatosis. Therapy with antiTNFα antibodies could prevent alteration of liver enzymes in such population.
2018
- Obese zebrafish: A small fish for a major human health condition
[Articolo su rivista]
Faillaci, Francesca; Milosa, Fabiola; Critelli, Rosina Maria; Turola, Elena; Schepis, Filippo; Villa, Erica
abstract
Obesity is becoming a silent worldwide epidemic, with a steady increase in both adults and children. To date, even though several drugs have been licensed for long‐term obesity treatment, none of them are yet used in routine clinical practice. So far the only successful intervention has been behavioral therapy. A suitable and economic experimental model mimicking the human condition would therefore be extremely useful to evaluate preventive measures and novel treatments. Zebrafish are emerging as an important model system to study obesity and related metabolic disease. Remarkable similarities have been reported in lipid metabolism and the adipogenic pathway between zebrafish and mammals. Moreover, the zebrafish possesses a number of features—the relative inexpensiveness of animal husbandry, its optical transparency and the ability to produce a large number of offspring at low cost—that make it ideal for large‐scale screening and for testing drugs and intervention. In this review, we summarize recent progress in using zebrafish as a model system to study obesity and obesity‐related metabolic disorders. We describe several zebrafish models (in both larvae and adult animals) that develop obesity and non‐alcoholic fatty liver disease (NAFLD) using different approaches, including gene manipulation, diet manipulation and modification of microbiota composition. For these models, we have outlined the specific aspects related to obesity and its development and we have summarized their advantages and limitations.
2018
- Premature ovarian senescence and a high miscarriage rate impair fertility in women with HCV
[Articolo su rivista]
Karampatou, Aimilia; Han, Xue; Kondili, Loreta A; Taliani, Gloria; Ciancio, Alessia; Morisco, Filomena; Critelli, Rosina Maria; Baraldi, Enrica; Bernabucci, Veronica; Troshina, Giulia; Guarino, Maria; Tagliavini, Simonetta; D'Ambrosio, Federica; Bristot, Laura; Turco, Laura; Rosato, Stefano; Vella, Stefano; Trenti, Tommaso; Neri, Isabella; LA MARCA, Antonio; Manthena, Shivaji; Goldstein, Andrea S; Bruno, Savino; Bao, Yanjun; Gonzalez, Yuri Sanchez; Villa, Erica; Andreone, Pietro
abstract
Premenopausal women who are HCV positive (HCV+) have failing ovarian function, which is likely to impact their fertility. Thus, we investigated the reproductive history, risk of infertility, and pregnancy outcomes in women of childbearing age who were HCV+.
2018
- Prevention and Management of Bleeding Risk Related to Invasive Procedures in Cirrhosis
[Articolo su rivista]
Schepis, Filippo; Turco, Laura; Bianchini, Marcello; Villa, Erica
abstract
Cirrhosis represents the end stage of chronic liver disease and its transition from a compensated to a decompensated status is mainly driven by portal hypertension and systemic inflammation. Although relevant modifications in the evaluation of the coagulative balance in cirrhosis across its natural history have occurred and alterations in routine indices of hemostasis have lost their role as indicators of the hemorrhagic risk of patients with liver cirrhosis, these are still perceived as prone to bleed when admitted to invasive procedures. This view, which is still present in guidelines addressing the management of bleeding risk, makes preprocedural transfusion of plasma and platelets still an ongoing clinical practice. In this review, we describe the limitations of both bleeding risk assessment in cirrhotic patients admitted to radiologic and endoscopic invasive procedures and evaluate whether preventive strategies indicated by current guidelines can affect the procedure-related hemorrhagic events.
2018
- Recurrence of hepatocellular carcinoma after direct acting antiviral treatment for hepatitis C virus infection: Literature review and risk analysis
[Articolo su rivista]
Guarino, Maria; Viganò, Luca; Ponziani, Francesca Romana; Giannini, Edoardo Giovanni; Lai, Quirino; Morisco, Filomena; Vitale, Alessandro; Russo, Francesco Paolo; Cillo, Umberto; Burra, Patrizia; Mescoli, Claudia; Gambato, Martina; Sessa, Anna; Cabibbo, Giuseppe; Viganò, Mauro; Galati, Giovanni; Villa, Erica; Iavarone, Massimo; Brancaccio, Giuseppina; Rendina, Maria; Lupo, Luigi G.; Losito, Francesco; Fucilli, Fabio; Persico, Marcello; D'Ambrosio, Roberta; Sangiovanni, Angelo; Cucchetti, Alessandro; Trevisani e Matteo Renzulli, Franco; Miele, Luca; Grieco, Antonio; Lodovico Rapaccini, Gian; Pompili, Maurizio; Gasbarrini, Antonio; Battisa Levi Sandri, Giovanni; Melandro, Fabio; Rossi, Massimo; Lenci, Ilaria; Manzia, Tommaso Maria; Tortora, Raffaella; Di Costanzo, Giovan Giuseppe; Sacco, Rodolfo; Ghinolfi, Davide; Rreka, Erion; Carrai, Paola; Simonetti, Natalia; Sposito, Carlo; Bhoori, Sherrie; di Sandro, Stefano; Foschi, Francesco Giuseppe; CASADEI GARDINI, Andrea; Nicolini, Daniele; Mazzocato, Susanna; Kostandini, Alba; Violi, Paola; Baccarani, Umberto; Pravisani, Riccardo; Vincenzi, Valter
abstract
Although studies suggest decreased incident hepatocellular carcinoma (HCC) after treatment with direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection, data are conflicting regarding risk and aggressiveness of recurrence in patients who have a history of treated HCC. This review analyses data available in literature in order to elucidate the impact of DAAs on the risk of HCC recurrence after successful treatment of the tumor. Overall 24 papers were identified. The available data cannot be considered definitive, but the initial alarmist data indicating an increased risk of recurrence have not been confirmed by most subsequent studies. The suggested aggressive pattern (rapid growth and vascular invasion) of tumor recurrence after DAAs still remains to be confirmed. Several limitations of the available studies were highlighted, and should drive future researches. The time-to-recurrence should be computed since the last HCC treatment and results stratified for cirrhosis and sustained viral response. Any comparison with historical series is of limited interest because of a number of biases affecting these studies and differences between enrolled patients. Prospective intention-to-treat analyses will be probably the best contribution to drive clinical practice, provided that a randomized trial can be difficult to design.
2018
- Reply to: “Relationship of hyperdynamic circulation and cardiodynamic states in cirrhosis”
[Articolo su rivista]
Turco, Laura; Garcia-Tsao, Guadalupe; Rossi, Rosario; Villa, Erica; Schepis, Filippo
abstract
N/A
2018
- Safety and efficacy of ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in patients over 65 years with HCV genotype 1 cirrhosis
[Articolo su rivista]
Ascione, Antonio; De Luca, Massimo; Melazzini, Mario; Montilla, Simona; Trotta, Maria Paola; Petta, Salvatore; Puoti, Massimo; Sangiovanni, Vincenzo; Messina, Vincenzo; Bruno, Savino; Izzi, Antonio; Villa, Erica; Aghemo, Alessio; Zignego, Anna Linda; Orlandini, Alessandra; Fontanella, Luca; Gasbarrini, Antonio; Marzioni, Marco; Giannini, Edoardo G.; Craxì, Antonio; Abbati, Giuseppe; Alberti, Alfredo; Andreone, Pietro; Andreoni, Massimo; Angeli, Paolo; Angelico, Mario; Angarano, Gioacchino; Angrisani, Debora; Antinori, Andrea; Antonini, Cinzia; Avancini, Ivo; Barone, Michele; Bruno, Raffaele; Benedetti, Antonio; Bernabucci, Veronica; Blanc, Pier; Boarini, Chiara; Boffa, Nicola; Boglione, Lucio; Borghi, Vanni; Borgia, Guglielmo; Brancaccio, Giuseppina; Brunetto, Maurizia; Cacciola, Irene; Calabrese, Paolo; Calvaruso, Vincenza; Campagnolo, Davide; Canovari, Benedetta; Caporaso, Nicola; Capra, Franco; Carolo, Giada; Cassola, Giovanni; Castelli, Francesco; Cauda, Roberto; Silberstein, Francesca Ceccherini; Cecere, Roberto; Chessa, Luchino; Chiodera, Alessandro; Chirianni, Antonio; Ciancio, Alessia; Cima, Serena; Coco, Barbara; Colombo, Massimo; Coppola, Nicola; Corti, Giampaolo; Cosco, Lucio; Corradori, Silvia; Cozzolongo, Raffaele; Cristaudo, Antonio; Danieli, Elena; Monforte, Antonella D’Arminio; Monache, Marco delle; Del Poggio, Paolo; de Luca, Andrea; Dentone, Chiara; Di Biagio, Antonio; Di Leo, Alfredo; Di Perri, Giovanni; Di Stefano, Marco; D’Offizi, Giampiero; Donato, Francesca; Durante, Emanuele; Erne, Elke; Fagiuoli, Stefano; Falasca, Katia; Federico, Alessandro; Felder, Martina; Ferrari, Carlo; Gaeta, Giovanni Battista; Ganga, Roberto; Gatti, Pietro; Giacomet, Vania; Giacometti, Andrea; Gianstefani, Alice; Giordani, Maria; Giorgini, Alessia; Grieco, Antonio; Guerra, Michele; Gulminetti, Roberto; Ieluzzi, Donatella; Imparato, Michele; Iodice, Valentina; La Monica, Silvia; Lazzarin, Adriano; Lenzi, Marco; Levrero, Massimo; Lichtner, Myriam; Lionetti, Raffaella; Guercio, Carmela Lo; Madonna, Salvatore; Magnani, Silvia; Maida, Ivana; Marignani, Massimo; Marrone, Aldo; Marsetti, Fabio; Martini, Silvia; Masarone, Mario; Maserati, Renato; Mastroianni, Claudio Maria; Memoli, Massimo; Menzaghi, Barbara; Merli, Manuela; Miele, Luca; Milella, Michele; Mondelli, Mario; Montalbano, Marzia; Monti, Monica; Morelli, Olivia; Morisco, Filomena; Nardone, Gaetano; Novara, Sergio; Onnelli, Giovanna; Onofrio, Mirella; Paganin, Simona; Pani, Luca; Parisi, Maria Rita; Parruti, Giustino; Pasquazzi, Caterina; Pasulo, Luisa; Perno, Carlo Federico; Persico, Marcello; Piai, Guido; Picciotto, Antonino; Pigozzi, Grazielle Marie; Piovesan, Sara; Piras, Maria Chiara; Pirisi, Massimo; Piscaglia, Anna Maria; Ponti, Laura; Potenza, Domenico; Pravadelli, Cecilia; Quartini, Mariano; Quirino, Tiziana; Raimondo, Giovanni; Rapaccini, Gian Ludovico; Rendina, Maria; Rizzardini, Giuliano; Rizzetto, Mario; Rizzo, Salvatore; Romagnoli, Dante; Romano, Antonietta; Rossi, Cristina; Rumi, Maria Grazia; Russello, Maurizio; Russo, Francesca Paolo; Russo, Maria Luisa; Sansonno, Domenico Ettore; Santantonio, Teresa Antonia; Saracco, Giorgio; Schimizzi, Anna Maria; Serviddio, Gaetano; Simeone, Filomena; Solinas, Attilio; Soria, Alessandro; Tabone, Marco; Taliani, Gloria; Tarantino, Giuseppe; Tarquini, Pierluigi; Tavio, Marcello; Termite, Antonio; Teti, Elisabetta; Toniutto, Pierluigi; Torti, Carlo; Tundi, Paolo; Vecchiet, Giacomo; Verucchi, Gabriella; Gentilucci, Umberto Vespasiani; Vinci, Maria; Vullo, Vincenzo; Zolfino, Teresa; Zuin, Massimo
abstract
Purpose: To analyse safety and efficacy of treatment based on ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in the sub-group of GT1 patients older than 65 years. Methods: We collected data extracted from the ABACUS compassionate-use nationwide Italian programme, in patients with cirrhosis due to hepatitis C virus (HCV) Genotype-1 (GT1) or 4 and at high risk of decompensation. GT1-HCV-infected patients received once-daily ombitasvir/paritaprevir, with the pharmacokinetic enhancer ritonavir (25/150/100 mg) and twice-daily dasabuvir (250 mg) plus Ribavirin (RBV) (OBV/PTV/r + DSV + RBV) for 12 (GT1b) or 24 (GT1a) weeks. Endpoints were to evaluate safety and efficacy, the latter defined as HCV RNA negative 12 weeks after the end of treatment (SVR12). Results: Patients who suffered any adverse event (AE) were 74/240 (30.8%); 13/240 (5.4%) discontinued the treatment. A multivariate analysis found albumin < 3.5 g/dL (OR 2.04: 95% CI 1.0–4.2, p < 0.05) and hypertension (OR 4.6: 95% CI 2.3–9.2, p < 0.001) as variables independently associated with AE occurrence. The SVR12 was 95% (228/240). Multivariate analysis identified baseline bilirubin < 2 mg/dL (OR 4.9: 95% CI 1.17–20.71, p = 0.029) as the only variable independently associated with SVR12. Conclusion: Our findings suggest that OBV/PTV/r + DSV + RBV is safe and effective in real-life use in patients with compensated cirrhosis, HCV-GT1 infection, and age over 65.
2018
- Study of the Serum Metabolomic Profile in Nonalcoholic Fatty Liver Disease: Research and Clinical Perspectives
[Articolo su rivista]
Gitto, Stefano; Schepis, Filippo; Andreone, Pietro; Villa, Erica
abstract
In recent years, metabolomics has attracted great scientific attention. The metabolomics methodology might permit a view into transitional phases between healthy liver and nonalcoholic steatohepatitis. Metabolomics can help to analyze the metabolic alterations that play a main role in the progression of nonalcoholic steatohepatitis. Lipid, glucose, amino acid, and bile acid metabolism should be widely studied to understand the complex pathogenesis of nonalcoholic steatohepatitis. The discovery of new biomarkers would be important for diagnosis and staging of liver disease as well as for the assessment of efficacy of new drugs. Here, we review the metabolomics data regarding nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. We analyzed the main studies regarding the application of metabolomics methodology in the complex context of nonalcoholic steatohepatitis, trying to create a bridge from the basic to the clinical aspects.
2018
- The Role of Anticoagulation in Treating Portal Hypertension
[Articolo su rivista]
Turco, Laura; Schepis, Filippo; Villa, Erica
abstract
Purpose of review: To revise experimental and clinical data supporting a less traditional role of anticoagulation for treating portal hypertension in patients with cirrhosis. Recent findings: Portal hypertension is the main driver of complications such as ascites, variceal hemorrhage, and hepatic encephalopathy, with inflammation as a key component. The traditional view of cirrhosis as a pro-hemorrhagic condition has recently changed, prothrombotic complications being recognized as frequently as the hemorrhagic ones. Several data indicate a close relationship between inflammation, prothrombotic status, worsening of hepatic fibrosis, and portal hypertension both in animal models and in patients with chronic liver disease. These findings indicate that anticoagulation may represent a potent tool to act on fibrogenesis and therefore consequently to treat portal hypertension. All anticoagulants have good to optimal safety profiles and can be used in patients with advanced chronic liver disease with confidence. Summary: Anticoagulation has a role as a pleiotropic treatment of portal hypertension in cirrhosis.
2018
- The prevalence of asymptomatic early sacroiliitis in Crohn’s disease patients: The single experience of an Italian tertiary care centre
[Abstract in Atti di Convegno]
DI GIROLAMO, Maria; Campomori, F; Spinella, A; Sartini, A; Sandri, G; Bertani, A; Verga, C; Merighi, A; Villa, E
abstract
Background
The inflammatory involvement of sacroiliac joint is one of the most frequent and underestimated extra-intestinal manifestation in patients with inflammatory bowel disease. The early recognition of a sacroiliitis can prevent their progression to definite spondyloarthritis with worsening of quality of patients’ life. The use of magnetic resonance imaging might be useful to detect early and asymptomatic sacroiliitis. The aim of this study is to assess the prevalence of early sacroiliitis in asymptomatic patients affected by Crohn’s disease who undergo to abdominal magnetic resonance imaging for the staging of bowel disease.
Methods
The retrospective study included 121 patients affected by Crohn’s disease who refer to the Department of Gastroenterology and undergo consecutively to the abdominal magnetic resonance imaging for the staging of the bowel disease, enrolled from January 2012 to January 2017. The assessment of sacroiliitis and Crohn’s disease by magnetic resonance imaging was made using T1-weighted spin-echo [TISE], short tau inversion recovery [STIR] and fat-saturated T2-weighted sequences.
Results
At the abdominal magnetic resonance imaging, 35 (28.9 %) of patients have an asymptomatic bone marrow oedema of the sacroiliac joint. At the logistic regression, the previous surgical therapy is a statistical significant predictive factor of sacroiliitis (OR 3.27, 95% CI 1.45–7.41, p = 0.004) and the previous biological therapy with anti-TNF seems to be a protective factor (OR 0.79, 95% CI 0.26 - 2.36, p = 0.67).Conclusions
Our study underlines the presence of an asymptomatic and early sacroilitiis in patients affected by Crohn's disease and the need for tight control of Crohn's patients using also cross-sectional methods for a complete control of disease and an integrated multidisciplinary approach in order to identify a therapeutic strategy, especially in the era of the new biologic therapies.
2018
- Under-dilated TIPS Associate With Efficacy and Reduced Encephalopathy in a Prospective, Non-randomized Study of Patients With Cirrhosis
[Articolo su rivista]
Schepis, Filippo; Vizzutti, Francesco; Garcia-Tsao, Guadalupe; Marzocchi, Guido; Rega, Luigi; De Maria, Nicola; Di Maira, Tommaso; Gitto, Stefano; Caporali, Cristian; Colopi, Stefano; De Santis, Mario; Arena, Umberto; Rampoldi, Antonio; Airoldi, Aldo; Cannavale, Alessandro; Fanelli, Fabrizio; Mosconi, Cristina; Renzulli, Matteo; Agazzi, Roberto; Nani, Roberto; Quaretti, Pietro; Fiorina, Ilaria; Moramarco, Lorenzo; Miraglia, Roberto; Luca, Angelo; Bruno, Raffaele; Fagiuoli, Stefano; Golfieri, Rita; Torricelli, Pietro; Di Benedetto, Fabrizio; Saverio Belli, Luca; Banchelli, Federico; Laffi, Giacomo; Marra, Fabio; Villa, Erica
abstract
Portosystemic encephalopathy (PSE) is a major complication of trans-jugular intrahepatic porto-systemic shunt (TIPS) placement. Most devices are self-expandable polytetrafluoroethylene-covered stent grafts (PTFE-SGs) that are dilated to their nominal diameter (8 or 10 mm). We investigated whether PTFE-SGs dilated to a smaller caliber (under-dilated TIPS) reduce PSE yet maintain clinical and hemodynamic efficacy. We also studied whether under-dilated TIPS self-expand to nominal diameter over time.
METHODS:
We performed a prospective, non-randomized study of 42 unselected patients with cirrhosis who received under-dilated TIPS (7 and 6 mm) and 53 patients who received PTFE-SGs of 8 mm or more (controls) at referral centers in Italy. After completion of this study, dilation to 6 mm became the standard and 47 patients were included in a validation study. All patients were followed for 6 months; Doppler ultrasonography was performed 2 weeks and 3 months after TIPS placement and every 6 months thereafter. Stability of PTFE-SG diameter was evaluated by computed tomography analysis of 226 patients with cirrhosis whose stent grafts increased to 6, 7, 8, 9, or 10 mm. The primary outcomes were incidence of at least 1 episode of PSE grade 2 or higher during follow up, incidence of recurrent variceal hemorrhage or ascites (based on need for at least 1 large-volume paracentesis by 4 weeks after TIPS placement), incidence of shunt dysfunction requiring TIPS recanalization, and reduction in porto-caval pressure gradient.
RESULTS:
PSE developed in a significantly lower proportion of patients with under-dilated TIPS (46%) than controls (73%) during the first year after the procedure (P=.015), but the proportions of patients with recurrent variceal hemorrhage or ascites did not differ significantly between groups. No TIPS occlusions were observed. These results were confirmed in the validation cohort. In an analysis of self-expansion of stent grafts, during a mean follow-up period of 252 days after placement, none of the PTFE-SGs self-expanded to the nominal diameter in hemodynamically relevant sites (such as portal and hepatic vein vascular walls).
CONCLUSION:
In prospective, non-randomized study of patients with cirrhosis, we found under-dilation of PTFE-SGs during TIPS placement to be feasible, associated with lower rates of PSE, and effective
2017
- A morphological method for ammonia detection in liver
[Articolo su rivista]
Gutiérrez-De-Juan, Virginia; De Davalillo, Sergio López; Fernández-Ramos, David; Barbier-Torres, Lucía; Zubiete-Franco, Imanol; Fernández-Tussy, Pablo; Simon, Jorge; Lopitz-Otsoa, Fernando; De Las Heras, Javier; Iruzubieta, Paula; Arias-Loste, María Teresa; Villa, Erica; Crespo, Javier; Andrade, Raúl; Lucena, M. Isabel; Varela-Rey, Marta; Lu, Shelly C.; Mato, José M.; Delgado, Teresa Cardoso; Martínez-Chantar, María-Luz
abstract
Hyperammonemia is a metabolic condition characterized by elevated levels of ammonia and a common event in acute liver injury/failure and chronic liver disease. Even though hepatic ammonia levels are potential predictive factors of patient outcome, easy and inexpensive methods aiming at the detection of liver ammonia accumulation in the clinical setting remain unavailable. Thus, herein we have developed a morphological method, based on the utilization of NessleÅs reagent, to accurately and precisely detect the accumulation of ammonia in biological tissue. We have validated our method against a commercially available kit in mouse tissue samples and, by using this modified method, we have confirmed the hepatic accumulation of ammonia in clinical and animal models of acute and chronic advanced liver injury as well as in the progression of fatty liver disease. Overall, we propose a morphological method for ammonia detection in liver that correlates well with the degree of liver disease severity and therefore can be potentially used to predict patient outcome.
2017
- A summary of the 6th international conference on coagulation in liver disease: Discussion, debate, deliberations
[Articolo su rivista]
Caldwell, S.; Intagliata, N.; Gatt, A.; Reuben, A.; Farias, A.; Lackner, C.; Eby, C.; Greenberg, C.; Jenne, C.; Leveille-Webster, C. R.; Kleiner, D.; Rijken, D.; Valla, D.; Gabriel, D.; Giannini, E.; Villa, E.; Deangelis, G.; Cortez-Pinto, H.; Wanless, I.; Gorham, J.; Luyendyk, J.; Garcia-Pagan, J. C. C.; Senzolo, M.; Magnussen, M.; Hoffman, M.; Englesbee, M.; Mendez-Sanchez, N.; Shah, N.; Intagliata, N.; Key, N.; Simioni, P.; Northup, P.; Rautou, P. -E.; Chowdary, P.; Steadman, R.; Porte, R.; Sabri, S.; Lee, S.; Pelletier, S.; Caldwell, S.; Mallet, S.; Stravitz, T.; Lisman, T.; Ikura, Y.; Henry, Z.
abstract
2017
- Anticoagulation in cirrhosis: a new paradigm?
[Articolo su rivista]
Leonardi, Filippo; Maria, Nicola De; Villa, Erica
abstract
The liver plays a crucial role in coagulation cascade. Global hemostatic process is profoundly influenced by the presence of liver disease and its complications. Patients with cirrhosis have impaired synthesis of most of the factors involved in coagulation and fibrinolysis process due to a reduced liver function and altered platelet count secondary to portal hypertension. Altered routine tests and thrombocytopenia were considered in the past as associated with increased risk of bleeding. These concepts explain both the routine use of plasma and/or platelets transfusion in patients with liver cirrhosis, especially before invasive procedures, and why these patients were considered "auto-anticoagulated". New recent evidences show that patients with liver cirrhosis have a more complex hemostatic alteration. Despite the presence of altered levels of factors involved in primary hemostasis, coagulation and fibrinolysis, patients with stable cirrhosis have a rebalanced hemostatic, which however can easily be altered by decompensation or infection, both in hemorrhagic or thrombotic direction. Patients with cirrhosis have an increased risk of venous thrombotic events (namely portal vein thrombosis) while bleeding seems to be related to the grade of portal hypertension rather than to a hemostatic imbalance. The use of anticoagulants both as treatment or prophylaxis is safe, reduces the rate of portal vein thrombosis and decompensation, and improves survival. Standard laboratory coagulation tests are unable to predict bleeding and are inadequate for the assessment of hemostatic status in these patients, hence more comprehensive tests are required to guide the management of thrombotic and bleeding complications.
2017
- Deregulated neddylation in liver fibrosis
[Articolo su rivista]
Zubiete-Franco, Imanol; Fernández-Tussy, Pablo; Barbier-Torres, Lucía; Simon, Jorge; Fernández-Ramos, David; Lopitz-Otsoa, Fernando; Gutiérrez-de Juan, Virginia; de Davalillo, Sergio López; Duce, Antonio Martín; Iruzubieta, Paula; Taibo, Daniel; Crespo, Javier; Caballeria, Juan; Villa, Erica; Aurrekoetxea, Igor; Aspichueta, Patricia; Varela-Rey, Marta; Lu, Shelly C; Mato, José M.; Beraza, Naiara; Delgado, Teresa C.; Martínez-Chantar, María L
abstract
Hepatic fibrosis is a global health problem currently without effective therapeutic approaches. Even though the ubiquitin-like posttranslational modification of neddylation, that conjugates Nedd8 (neural precursor cell expressed developmentally downregulated) to specific targets, is aberrant in many pathologies, its relevance in liver fibrosis (LF) remained unexplored. Our results show deregulated neddylation in clinical fibrosis and both in mouse bileductligationâ and CCl4-induced fibrosis. Importantly, neddylation inhibition, by using the pharmacological inhibitor, MLN4924, reduced liver injury, apoptosis, inflammation, and fibrosis by targeting different hepatic cell types. On one hand, increased neddylation was associated with augmented caspase 3 activity in bile-acidâ induced apoptosis in mouse hepatocytes whereas neddylation inhibition ameliorated apoptosis through reduction of expression of the Cxcl1 and Ccl2 chemokines. On the other hand, chemokine receptors and cytokines, usually induced in activated macrophages, were reduced after neddylation inhibition in mouse Kupffer cells. Under these circumstances, decreased hepatocyte cell death and inflammation after neddylation inhibition could partly account for reduction of hepatic stellate cell (HSC) activation. We provide evidence that augmented neddylation characterizes activated HSCs, suggesting that neddylation inhibition could be important for resolving LF by directly targeting these fibrogenic cells. Indeed, neddylation inhibition in activated HSCs induces apoptosis in a process partly mediated by accumulation of c-Jun, whose cullin-mediated degradation is impaired under these circumstances. Conclusion: Neddylation inhibition reduces fibrosis, suggesting neddylation as a potential and attractive therapeutic target in liver fibrosis. (Hepatology 2017;65:694-709).
2017
- Does Metabolic Syndrome and Not the Inflammatory Load Predict Nonalcoholic Fatty Liver Disease Severity in Inflammatory Bowel Disease Patients?
[Articolo su rivista]
Sartini, Alessandro; Gitto, Stefano; Villa, Erica
abstract
Does Metabolic Syndrome and Not the Inflammatory Load Predict Nonalcoholic Fatty Liver Disease Severity in Inflammatory Bowel Disease Patients?
2017
- Focal adhesion kinase depletion reduces human hepatocellular carcinoma growth by repressing enhancer of zeste homolog 2
[Articolo su rivista]
Gnani, Daniela; Romito, Ilaria; Artuso, Simona; Chierici, Marco; De Stefanis, Cristiano; Panera, Nadia; Crudele, Annalisa; Ceccarelli, Sara; Carcarino, Elena; D'Oria, Valentina; Porru, Manuela; Giorda, Ezio; Ferrari, Karin; Miele, Luca; Villa, Erica; Balsano, Clara; Pasini, Diego; Furlanello, Cesare; Locatelli, Franco; Nobili, Valerio; Rota, Rossella; Leonetti, Carlo; Alisi, Anna
abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer in humans. The focal adhesion tyrosine kinase (FAK) is often over-expressed in human HCC and FAK inhibition may reduce HCC cell invasiveness. However, the anti-oncogenic effect of FAK knockdown in HCC cells remains to be clarified. We found that FAK depletion in HCC cells reduced in vitro and in vivo tumorigenicity, by inducing G2/M arrest and apoptosis, decreasing anchorage-independent growth, and modulating the expression of several cancer-related genes. Among these genes, we showed that FAK silencing decreased transcription and nuclear localization of enhancer of zeste homolog 2 (EZH2) and its tri-methylation activity on lysine 27 of histone H3 (H3K27me3). Accordingly, FAK, EZH2 and H3K27me3 were concomitantly upregulated in human HCCs compared to non-tumor livers. In vitro experiments demonstrated that FAK affected EZH2 expression and function by modulating, at least in part, p53 and E2F2/3 transcriptional activity. Moreover, FAK silencing downregulated both EZH2 binding and histone H3K27me3 levels at the promoter of its target gene NOTCH2. Finally, we found that pharmacological inhibition of FAK activity resembled these effects although milder. In summary, we demonstrate that FAK depletion reduces HCC cell growth by affecting cancer-promoting genes including the pro-oncogene EZH2. Furthermore, we unveil a novel unprecedented FAK/EZH2 crosstalk in HCC cells, thus identifying a targetable network paving the way for new anticancer therapies.
2017
- Incidence of DAA failure and the clinical impact of retreatment in real-life patients treated in the advanced stage of liver disease: Interim evaluations from the PITER network
[Articolo su rivista]
Kondili, Loreta A.; Gaeta, Giovanni Battista; Brunetto, Maurizia Rossana; Di Leo, Alfredo; Iannone, Andrea; Santantonio, Teresa Antonia; Giammario, Adele; Raimondo, Giovanni; Filomia, Roberto; Coppola, Carmine; Amoruso, Daniela Caterina; Blanc, Pierluigi; Del Pin, Barbara; Chemello, Liliana; Cavalletto, Luisa; Morisco, Filomena; Donnarumma, Laura; Rumi, Maria Grazia; Gasbarrini, Antonio; Siciliano, Massimo; Massari, Marco; Corsini, Romina; Coco, Barbara; Madonia, Salvatore; Cannizzaro, Marco; Zignego, Anna Linda; Monti, Monica; Russo, Francesco Paolo; Zanetto, Alberto; Persico, Marcello; Masarone, Mario; Villa, Erica; Bernabucci, Veronica; Taliani, Gloria; Biliotti, Elisa; Chessa, Luchino; Pasetto, Maria Cristina; Andreone, Pietro; Margotti, Marzia; Brancaccio, Giuseppina; Ieluzzi, Donatella; Borgia, Guglielmo; Zappulo, Emanuela; Calvaruso, Vincenza; Petta, Salvatore; Falzano, Loredana; Quaranta, Maria Giovanna; Weimer, Liliana Elena; Rosato, Stefano; Vella, Stefano; Giannini, Edoardo Giovanni
abstract
Background: Few data are available on the virological and clinical outcomes of advanced liver disease patients retreated after first-line DAA failure. Aim: To evaluate DAA failure incidence and the retreatment clinical impact in patients treated in the advanced liver disease stage. Methods: Data on HCV genotype, liver disease severity, and first and second line DAA regimens were prospectively collected in consecutive patients who reached the 12-week post-treatment and retreatment evaluations from January 2015 to December 2016 in 23 of the PITER network centers. Results: Among 3,830 patients with advanced fibrosis (F3) or cirrhosis, 139 (3.6%) failed to achieve SVR. Genotype 3, bilirubin levels >1.5mg/dl, platelet count <120,000/mm3 and the sofosbuvir+ribavirin regimen were independent predictors of failure by logistic regression analysis. The failure rate was 7.6% for patients treated with regimens that are no longer recommended or considered suboptimal (sofosbuvir+ribavirin or simeprevir+sofosbuvir±ribavirin), whereas 1.4% for regimens containing sofosbuvir combined with daclatasvir or ledipasvir or other DAAs. Of the patients who failed to achieve SVR, 72 (51.8%) were retreated with a second DAA regimen, specifically 38 (52.7%) with sofosbuvir+daclatasvir, 27 (37.5%) with sofosbuvir+ledipasvir, and 7 (9.7%) with other DAAs ±ribavirin. Among these, 69 (96%) patients achieved SVR12 and 3 (4%) failed. During a median time of 6 months (range: 5â14 months) between failure and the second DAA therapy, the Child-Pugh class worsened in 12 (16.7%) patients: from A to B in 10 patients (19.6%) and from B to C in 2 patients (10.5%), whereas it did not change in the remaining 60 patients. Following the retreatment SVR12 (median time of 6 months; range: 3â12 months), the Child-Pugh class improved in 17 (23.6%) patients: from B to A in 14 (19.4%) patients, from C to A in 1 patient (1.4%) and from C to B in 2 (2.9%) patients; it remained unchanged in 53 patients (73.6%) and worsened in 2 (2.8%) patients. Of patients who were retreated, 3 (4%) had undergone OLT before retreatment (all reached SVR12 following retreatment) and 2 (2.8%) underwent OLT after having achieved retreatment SVR12. Two (70%) of the 3 patients who failed to achieve SVR12 after retreatment, and 2 (2.8%) of the 69 patients who achieved retreatment SVR12 died from liver failure (Child-Pugh class deteriorated from B to C) or HCC complications. Conclusions: Failure rate following the first DAA regimen in patients with advanced disease is similar to or lower than that reported in clinical trials, although the majority of patients were treated with suboptimal regimens. Interim findings showed that worsening of liver function after failure, in terms of Child Pugh class deterioration, was improved by successful retreatment in about one third of retreated patients within a short follow-up period; however, in some advanced liver disease patients, clinical outcomes (Child Pugh class, HCC development, liver failure and death) were independent of viral eradication.
2017
- Microenvironment inflammatory infiltrate drives growth speed and outcome of hepatocellular carcinoma: a prospective clinical study
[Articolo su rivista]
Critelli, Rosina; Milosa, Fabiola; Faillaci, Francesca; Condello, Rosario; Turola, Elena; Marzi, Luca; Lei, Barbara; Dituri, Francesco; Andreani, Silvia; Sighinolfi, Pamela; Manni, Paola; Maiorana, Antonino; Caporali, Cristian; di Benedetto, Fabrizio; Del Buono, Mariagrazia; De Maria, Nicola; Schepis, Filippo; Martinez-Chantar, Maria-Luz; Giannelli, Gianluigi; Villa, Erica
abstract
In HCC, tumor microenvironment, heavily influenced by the underlying chronic liver disease, etiology and stage of the tissue damage, affects tumor progression and determines the high heterogeneity of the tumor. Aim of this study was to identify the circulating and tissue components of the microenvironment immune-mediated response affecting the aggressiveness and the ensuing clinical outcome. We analyzed the baseline paired HCC and the surrounding tissue biopsies from a prospective cohort of 132 patients at the first diagnosis of HCC for immunolocalization of PD-1/PD-L1, FoxP3, E-cadherin, CLEC2 and for a panel of 82 microRNA associated with regulation of angiogenesis, cell proliferation, cell signaling, immune control and autophagy. Original microarray data were also explored. Serum samples were analyzed for a panel of 19 cytokines. Data were associated with biochemical data, histopathology and survival. Patients with a more aggressive disease and shorter survival, who we named fast-growing accordingly to the tumor doubling time, at presentation had significantly higher AFP levels, TGF-β1 and Cyphra 21-1 levels. Transcriptomic analysis evidenced a significant downregulation of CLEC2 and upregulation of several metalloproteinases. A marked local upregulation of both PD-1 and PD-L1, a concomitant FoxP3-positive lymphocytic infiltrate, a loss of E-cadherin, gain of epithelial-mesenchymal transition (EMT) phenotype and extreme poor differentiation at histology were also present. Upregulated microRNA in fast-growing HCCs are associated with TGF-β signaling, angiogenesis and inflammation. Our data show that fast HCCs are characterized not only by redundant neo-angiogenesis but also by unique features of distinctively immunosuppressed microenvironment, prominent EMT, and clear-cut activation of TGFβ1 signaling in a general background of long-standing and permanent inflammatory state.
2017
- Modeling cost-effectiveness and health gains of a âuniversalâ versus âprioritizedâ hepatitis C virus treatment policy in a real-life cohort
[Articolo su rivista]
Kondili, Loreta A.; Romano, Federica; Rolli, Francesca Romana; Ruggeri, Matteo; Rosato, Stefano; Brunetto, Maurizia Rossana; Zignego, Anna Linda; Ciancio, Alessia; Di Leo, Alfredo; Raimondo, Giovanni; Ferrari, Carlo; Taliani, Gloria; Borgia, Guglielmo; Santantonio, Teresa Antonia; Blanc, Pierluigi; Gaeta, Giovanni Battista; Gasbarrini, Antonio; Chessa, Luchino; Erne, Elke Maria; Villa, Erica; Ieluzzi, Donatella; Russo, Francesco Paolo; Andreone, Pietro; Vinci, Maria; Coppola, Carmine; Chemello, Liliana; Madonia, Salvatore; Verucchi, Gabriella; Persico, Marcello; Zuin, Massimo; Puoti, Massimo; Alberti, Alfredo; Nardone, Gerardo; Massari, Marco; Montalto, Giuseppe; Foti, Giuseppe; Rumi, Maria Grazia; Quaranta, Maria Giovanna; Cicchetti, Americo; Craxì, Antonio; Vella, Stefano
abstract
We evaluated the cost-effectiveness of two alternative direct-acting antiviral (DAA) treatment policies in a real-life cohort of hepatitis C virusâinfected patients: policy 1, âuniversal,â treat all patients, regardless of fibrosis stage; policy 2, treat only âprioritizedâ patients, delay treatment of the remaining patients until reaching stage F3. A liver disease progression Markov model, which used a lifetime horizon and health care system perspective, was applied to the PITER cohort (representative of Italian hepatitis C virusâinfected patients in care). Specifically, 8,125 patients naive to DAA treatment, without clinical, sociodemographic, or insurance restrictions, were used to evaluate the policiesâ cost-effectiveness. The patientsâ age and fibrosis stage, assumed DAA treatment cost of â¬15,000/patient, and the Italian liver disease costs were used to evaluate quality-adjusted life-years (QALY) and incremental cost-effectiveness ratios (ICER) of policy 1 versus policy 2. To generalize the results, a European scenario analysis was performed, resampling the study population, using the mean European country-specific health states costs and mean treatment cost of â¬30,000. For the Italian base-case analysis, the cost-effective ICER obtained using policy 1 was â¬8,775/QALY. ICERs remained cost-effective in 94%-97% of the 10,000 probabilistic simulations. For the European treatment scenario the ICER obtained using policy 1 was â¬19,541.75/QALY. ICER was sensitive to variations in DAA costs, in the utility value of patients in fibrosis stages F0-F3 postâsustained virological response, and in the transition probabilities from F0 to F3. The ICERs decrease with decreasing DAA prices, becoming cost-saving for the base price (â¬15,000) discounts of at least 75% applied in patients with F0-F2 fibrosis. Conclusion: Extending hepatitis C virus treatment to patients in any fibrosis stage improves health outcomes and is cost-effective; cost-effectiveness significantly increases when lowering treatment prices in early fibrosis stages. (Hepatology 2017;66:1814â1825).
2017
- Ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin for patients with hepatitis C virus genotype 1 or 4 infection with cirrhosis (ABACUS): a prospective observational study
[Articolo su rivista]
Petta, Salvatore; Marzioni, Marco; Russo, Pierluigi; Aghemo, Alessio; Alberti, Alfredo; Ascione, Antonio; Antinori, Andrea; Bruno, Raffaele; Bruno, Savino; Chirianni, Antonio; Gaeta, Giovanni Battista; Giannini, Edoardo G; Merli, Manuela; Messina, Vincenzo; Montilla, Simona; Perno, Carlo Federico; Puoti, Massimo; Raimondo, Giovanni; Rendina, Maria; Silberstein, Francesca Ceccherini; Villa, Erica; Zignego, Anna Linda; Pani, Luca; Craxì, Antonio; Tabone, Marco; Andreoni, Massimo; Teti, Elisabetta; Angelico, Mario; Persico, Marcello; Masarone, Mario; Chiodera, Aledssandro; Solinas, Attilio; delle Monache, Marco; Cecere, Roberto; Maria Schimizzi, Anna; Piovesan, Sara; Campagnolo, Davide; Chiara Piras, Maria; Zolfino, Teresa; Paolo Russo, Francesca; Morelli, Olivia; Sangiovanni, Vincenzo; Onofrio, Mirella; Iodice, Valentina; Izzi, Antonio; Pirisi, Massimo; Danieli, Elena; Vinci, Maria; Rizzardini, Giuliano; Fagiuoli, Stefano; Pasulo, Luisa; D'Arminio Monforte, Antonella; Zuin, Massimo; Giorgini, Alessia; Simeone, Filomena; Piali, Guido; Lo Guercio, Carmela; Federico, Alessandro; Brancaccio, Giuseppina; Marrone, Aldo; Abbati, Giuseppe; Boarini, Chiara; Borghi, Vanni; Bernabucci, Veronica; Corti, Giampaolo; Monti, Monica; Rizzetto, Mario; Martini, Silvia; Andreone, Pietro; Gianstefani, Alice; Lenzi, Marco; Verucchi, Gabriella; Toniutto, Pierluigi; Borgia, Guglielmo; Caporaso, Nicola; Morisco, Filomena; Nardone, Gaetano; Angrisani, Debora; Giacometti, Andrea; Benedetti, Antonio; Tarantino, Giuseppe; Marsetti, Fabio; Tavio, Marcello; Novara, Sergio; Antonia Santantonio, Teresa; Serviddio, Gaetano; Brunetto, Maurizia; Coco, Barbara; Angarano, Gioacchino; Milella, Michele; Barone, Michele; Di Leo, Alfredo; Ettore Sansonno, Domenico; Cacciola, Irene; Boffa, Nicola; Saracco, Giorgio; Di Biagio, Antonio; Picciotto, Antonino; de Luca, Andrea; Calvaruso, Vincenza; Corradori, Silvia; Ferrari, Carlo; Orlandini, Alessandra; Maida, Ivana; Torti, Carlo; Chessa, Luchino; Felder, Martina; Vespasiani Gentilucci, Umberto; Angeli, Paolo; Romano, Antonietta; Ludovico Rapaccini, Gian; Miele, Luca; Cima, Serena; Luisa Russo, Maria; Cozzolongo, Raffaele; Onnelli, Giovanna; D'Offizi, Giampiero; Lionetti, Raffaella; Montalbano, Marzia; Guerra, Michele; Di Perri, Giovanni; Boglione, Lucio; Capra, Franco; Carolo, Giada; Ieluzzi, Donatella; Antonini, Cinzia; Termite, Antonio; Madonia, Salvatore; Tarquini, Pierluigi; Parruti, Giustino; Vecchiet, Giacomo; Falasca, Katia; Menzaghi, Barbara; Quirino, Tiziana; Dentone, Chiara; Maria Piscaglia, Anna; Rossi, Cristina; Giordani, Maria; Fontanella, Luca; Cassola, Giovanni; Russello, Maurizio; Cristaudo, Antonio; Giacomet, Vania; Colombo, Massimo; Donato, Francesca; Durante, Emanuele; Cosco, Lucio; Marignani, Massimo; Quartini, Mariano; Memoli, Massimo; Ganga, Roberto; Ponti, Laura; Soria, Alessandro; Grazia Rumi, Maria; Gulminetti, Roberto; Maserati, Renato; Mondelli, Mario; Lazzarin, Adriano; Rita Parisi, Maria; Canovari, Benedetta; Avancini, Ivo; Pravadelli, Cecilia; Blanc, Pier; Pasquazzi, Caterina; Maria Mastroianni, Claudio; Lichtner, Myriam; Distefano, Marco; Magnani, Silvia; Paganin, Simona; Erne, Elke; Gatti, Pietro; Tundi, Paolo; Calabrese, Paolo; Gasbarrini, Antonio; Grieco, Antonio; Coppola, Nicola; Del Poggio, Paolo; Levrero, Massimo; Talliani, Gloria; Vullo, Vincenzo; Cauda, Roberto; La Monica, Silvia; Potenza, Domenico; Rizzo, Salvatore; Castelli, Francesco; Marie Pigozzi, Grazielle; Ciancio, Alessia; Romagnoli, Dante; Barchetti, Federica; Ivanovic, Jelena; Longo, Olimpia; Petraglia, Sandra; Paola Trotta, Maria
abstract
Background We ran a compassionate use nationwide programme (ABACUS) to provide access to ombitasvir, paritaprevir, and ritonavir, with dasabuvir, plus ribavirin for hepatitis C virus (HCV) genotype 1 infection and ombitasvir, paritaprevir, and ritonavir, plus ribavirin for HCV genotype 4 infection in patients with cirrhosis at high risk of decompensation while approval of these regimens was pending in Italy. Methods In this prospective observational study, we collected data from a compassionate use nationwide programme from March 17, 2014, to May 28, 2015. Patients with HCV genotype 1 infection and cirrhosis at high risk of decompensation were given coformulated ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once daily and dasabuvir (250 mg) twice daily for 12 weeks (patients with HCV genotype 1b infection) or 24 weeks (patients with HCV genotype 1a infection). Patients with HCV genotype 4 infection were given coformulated ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once per day for 24 weeks. All patients were given weight-based ribavirin. The primary efficacy endpoint was sustained virological response at week 12 after the end of treatment (SVR12), analysed by intention-to-treat. Univariate and multivariate logistic regression analyses were used to identify baseline characteristics associated with SVR12. Adverse events were recorded throughout the study. Findings 728 (96%) of 762 patients with cirrhosis who were given ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin therapy for 12 or 24 weeks achieved SVR12. Logistic regression analyses identified that bilirubin concentrations of less than 2 mg/dL were associated with SVR12 (odds ratio [OR] 4·76 [95% CI 1·83–12·3]; p=0·001). 166 (23%) of 734 patients included in safety analyses had an adverse event. 25 (3%) patients discontinued treatment because of adverse events. Asthenia was the most commonly reported adverse event, occurring in 36 (5%) patients. Interpretation Our findings suggest that the safety and effectiveness of ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin in patients with HCV genotype 1 or 4 infection and cirrhosis at high risk of decompensation in a real-life setting are similar to those reported in clinical trials. The concordance with clinical trials provides reassurance that the reported efficacy of this treatment in clinical trials will translate to its use in routine clinical practice. Funding Dipartimento Biomedico di Medicina Interna e Specialistica dell'Universita di Palermo.
2017
- Reply
[Articolo su rivista]
Bianchini, M.; Pietri, L. D.; Garcia-Tsao, G.; Villa, E.
abstract
2017
- The mitochondrial negative regulator MCJ is a therapeutic target for acetaminophen-induced liver injury
[Articolo su rivista]
Barbier-Torres, Lucía; Iruzubieta, Paula; Fernández-Ramos, David; Delgado, Teresa C.; Taibo, Daniel; Guitiérrez-De-Juan, Virginia; Varela-Rey, Marta; Azkargorta, Mikel; Navasa, Nicolas; Fernández-Tussy, Pablo; Zubiete-Franco, Imanol; Simon, Jorge; Lopitz-Otsoa, Fernando; Lachiondo-Ortega, Sofia; Crespo, Javier; Masson, Steven; Mccain, Misti Vanette; Villa, Erica; Reeves, Helen; Elortza, Felix; Lucena, Maria Isabel; Hernández-Alvarez, Maria Isabel; Zorzano, Antonio; Andrade, Raúl J.; Lu, Shelly C.; Mato, José M.; Anguita, Juan; Rincón, Mercedes; Martínez-Chantar, María Luz
abstract
Acetaminophen (APAP) is the active component of many medications used to treat pain and fever worldwide. Its overuse provokes liver injury and it is the second most common cause of liver failure. Mitochondrial dysfunction contributes to APAP-induced liver injury but the mechanism by which APAP causes hepatocyte toxicity is not completely understood. Therefore, we lack efficient therapeutic strategies to treat this pathology. Here we show that APAP interferes with the formation of mitochondrial respiratory supercomplexes via the mitochondrial negative regulator MCJ, and leads to decreased production of ATP and increased generation of ROS. In vivo treatment with an inhibitor of MCJ expression protects liver from acetaminophen-induced liver injury at a time when N-acetylcysteine, the standard therapy, has no efficacy. We also show elevated levels of MCJ in the liver of patients with acetaminophen overdose. We suggest that MCJ may represent a therapeutic target to prevent and rescue liver injury caused by acetaminophen.
2017
- Treatment of Hepatitis C virus infection in Italy: A consensus report from an expert panel
[Articolo su rivista]
Viganò, Mauro; Perno, Carlo Federico; Craxì, Antonio; Aghemo, Alessio; Alberti, Alfredo; Andreone, Pietro; Andreoni, Massimo; Bonora, Stefano; Brunetto, Maurizia Rossana; Bruno, Raffaele; Bruno, Savino; Calvaruso, Vincenza; Caporaso, Nicola; Ceccherini-Silberstein, Francesca; Cento, Valeria; Ciancio, Alessia; Colombatto, Piero; Degasperi, Elisabetta; DI MARCO, Vito; Di Perri, Giovanni; D'Offizi, Gianpiero; Fagiuoli, Stefano; Ferrari, Carlo; Gaeta, Giovanni Battista; Pellicelli, Adriano; Petta, Salvatore; Piovesan, Sara; Puoti, Massimo; Raimondo, Giovanni; Russo, Francesco Paolo; Taliani, Gloria; Trama, Ugo; Villa, Erica; Zignego, Anna Linda
abstract
Hepatitis C virus (HCV) infection remains one of the main causes of chronic liver disease worldwide. The advent of direct-acting antivirals (DAAs) has significantly improved the course of patients with chronic HCV infection (CHC), due to the ability of these drugs to achieve high rates of sustained virological response (SVR). These exceedingly high rates of SVR and the excellent safety data have been confirmed in real life practice. Evolving guidelines have been issued by national and international scientific societies in accordance with the progression of clinical knowledge and the availability of new DAAs. These recommendations, however, may not be applied universally because of delays in drugs reimbursability in different countries and because some National Health Systems identify only patients with advanced disease as a treatment priority. Italy in this regard is a prototype about DAAs treatment of CHC patients. With the aim to assess the Italian treatment experience with DAAs and to respond to unmet needs in treatment optimization of antiviral therapy in specific settings of CHC patients, a group of Italian experts met in Stresa in February 2017. The summary of the considerations arising from this two-day meeting and some statements regarding a few open issues are reported in this position paper.
2017
- Validating, deconstructing and refining Baveno criteria for ruling out high-risk varices in patients with compensated cirrhosis
[Articolo su rivista]
Jangouk, Parastoo; Turco, Laura; De Oliveira, Ana; Schepis, Filippo; Villa, Erica; Garcia-Tsao, Guadalupe
abstract
Background: Guidelines recommend variceal screening in patients with cirrhosis to identify varices at high risk of bleeding requiring primary prophylaxis. Non-invasive criteria to rule out high-risk varices will avoid unnecessary endoscopies. Recent Baveno VI criteria define patients with compensated cirrhosis in whom endoscopy can be avoided as those with a liver stiffness by transient elastography <20 kPa and a platelet count >150Â 000/mm3. Aims: To validate Baveno criteria in two cohorts with a different prevalence of high-risk varices and to determine whether alternate parameters not including liver stiffness would be equal/more accurate in ruling out high-risk varices. Methods: Retrospective study evaluating patients with liver stiffness >10 kPa who had liver stiffness and endoscopy within 1Â year of each other. Results: This study included 161 patients from the US cohort (14 [9%] with high-risk varices) and 101 patients from an Italian cohort (17 [17%] with high-risk varices). Of patients meeting Baveno criteria (41 in the US, 16 in Italy), none had high-risk varices and therefore 26% (US) and 16% (Italy) endoscopies could have been avoided. Sensitivity and negative predictive value were 100%. A stepwise strategy using platelet count >150Â 000 and MELD=6, increased the number of endoscopies avoided to 54% (US) while maintaining a sensitivity and negative predictive value of 100%. Excellent sensitivity and negative predictive value were validated in the Italian cohort and in another cohort of patients with a clinical diagnosis of cirrhosis. Conclusions: This study validates Baveno VI criteria, particularly in sites with a low prevalence of high-risk varices and describes a new accurate strategy that does not include liver stiffness.
2017
- What to start with in first line treatment of chronic hepatitis B patients: an Italian multicentre observational cohort, HBV-RER study group
[Articolo su rivista]
Cuomo, Gianluca; Borghi, Vanni; Giuberti, Tiziana; Andreone, Pietro; Massari, Marco; Villa, Erica; Pietrangelo, Antonello; Verucchi, Gabriella; Levantesi, Fabio; Ferrari, Carlo
abstract
Treatment options for chronic hepatitis B (CHB) are pegylated interferon (Peg-IFN) in minimal-mild liver fibrosis and nucleot(s)ide analogues (NUC) in more advanced disease. Since little is known about their use in daily clinical practice, we conducted a multicentre prospective study to investigate treatment regimens applied to naïve CHB patients in real life. HBV-RER is an observational multicentre Italian network that collect clinic and virologic data of patients with CHB. Among the 2527 CHB patients seen during the study period (2009 - 2012), 502 patients started a first line antiviral treatment. Liver biopsy was performed in 30.9% of the patients, with high levels of fibrosis being detected in 19.4% of them. In 216 patients (43%) Peg-IFN was used as first-line therapy while the remaining patients started NUC therapy (entecavir and tenofovir in 75%, lamivudine in 15%, telbivudine and adefovir 10%). By multivariate logistic regression, an age under 40 (OR 0.92, 95%IC 0.90-0.94; p <0.001) and the execution of liver biopsy (OR 3.83; 95%IQR 1.76-8.36; p <0.001) were the only determinants of choice between Peg-IFN vs NUC. Peg-IFN was expected to be used in first-line treatment for CHB in 70% of the patients based on Italian recommendations, but a much lower proportion of patients were actually treated with Peg-IFN with a limited use of the biopsy. Thus, in daily clinical practice physicians prefer to use NUCs, presumably because of their optimal tolerability and anti-viral efficacy, even if they frequently require life-long treatment as opposed to the short duration of Peg-IFN.
2016
- AISF position paper on liver disease and pregnancy
[Articolo su rivista]
Morisco, Filomena; Bruno, Raffaele; Bugianesi, Elisabetta; Burra, Patrizia; Calvaruso, Vincenza; Cannoni, Alice; Caporaso, Nicola; Caviglia, Gian Paolo; Ciancio, Alessia; Fargion, Silvia; Federico, Alessandro; Floreani, Annarosa; Gaeta, Giovanni Battista; Guarino, Maria; Invernizzi, Pietro; Licata, Anna; Loguercio, Carmela; Mazzella, Giuseppe; Petraglia, Felice; Primignani, Massimo; Rodriguez Castro, Kryssia; Smedile, Antonina; Valenti, Luca; Vanni, Ester; Vannuccini, Silvia; Voltolini, Chiara; Villa, Erica; Italian Assoc Study Liver, Aisf
abstract
The relationship between liver disease and pregnancy is of great clinical impact. Severe liver disease in pregnancy is rare; however, pregnancy-related liver disease is the most frequent cause of liver dysfunction during pregnancy and represents a severe threat to foetal and maternal survival. A rapid differential diagnosis between liver disease related or unrelated to pregnancy is required in women who present with liver dysfunction during pregnancy. This report summarizes the recommendation of an expert panel established by the Italian Association for the Study of the Liver (AISF) on the management of liver disease during pregnancy. The article provides an overview of liver disease occurring in pregnancy, an update on the key mechanisms involved in its pathogenesis, and an assessment of the available treatment options. The report contains in three sections: (1) specific liver diseases of pregnancy; (2) liver disease occurring during pregnancy; and (3) pregnancy in patients with pre-existing chronic liver disease. Each topic is discussed considering the most relevant data available in literature; the final statements are formulated according to both scientific evidence and clinical expertise of the involved physicians, and the AISF expert panel recommendations are reported.
2016
- AISF position paper on liver transplantation and pregnancy: Women in Hepatology Group, Italian Association for the Study of the Liver (AISF)
[Articolo su rivista]
Alisi, Anna; Balsano, Clara; Bernabucci, Veronica; Berzigotti, Annalisa; Brunetto, Maurizia; Bugianesi, Elisabetta; Burra, Patrizia; Calvaruso, Vincenza; Cariani, Elisabetta; Coco, Barbara; Colle, Isabelle; Critelli, Rosina; De Martin, Eleonora; Del Buono, Mariagrazia; Fabregat, Isabel; Faillaci, Francesca; Fattovich, Giovanna; Floreani, Annarosa; Garcia-Tsao, Guadalupe; Housset, Chantal; Karampatou, Aimilia; Lei, Barbara; Mangia, Alessandra; Martinez-Chantar, Maria Luz; Milosa, Fabiola; Morisco, Filomena; Nasta, Paola; Ozben, Tomris; Pollicino, Teresa; Ponti, Maria Laura; Pontisso, Patrizia; Reeves, Helen; Rendina, Maria; Rodríguez-Castro, Kryssia Isabel; Sagnelli, Caterina; Sebastiani, Giada; Smedile, Antonella; Taliani, Gloria; Vandelli, Carmen; Vanni, Ester; Villa, Erica; Vukotic, Ranka; Zignego, Anna Linda; Rodríguez-Castro, Kryssia; GUARINO LO BIANCO, Maria; Morisco, Filomena; Villa, Erica; Mazzella, Giuseppe
abstract
After the first successful pregnancy in a liver transplant recipient in 1978, much evidence has accumulated on the course, outcomes and management strategies of pregnancy following liver transplantation. Generally, liver transplantation restores sexual function and fertility as early as a few months after transplant. Considering that one third of all liver transplant recipients are women, that approximately one-third of them are of reproductive age (18â49 years), and that 15% of female liver transplant recipients are paediatric patients who have a >70% probability of reaching reproductive age, the issue of pregnancy after liver transplantation is rather relevant, and obstetricians, paediatricians, and transplant hepatologists ever more frequently encounter such patients. Pregnancy outcomes for both the mother and infant in liver transplant recipients are generally good, but there is an increased incidence of preterm delivery, hypertension/preeclampsia, foetal growth restriction, and gestational diabetes, which, by definition, render pregnancy in liver transplant recipients a high-risk one. In contrast, the risk of congenital anomalies and the live birth rate are comparable to those of the general population. Currently there are still no robust guidelines on the management of pregnancies after liver transplantation. The aim of this position paper is to review the available evidence on pregnancy in liver transplant recipients and to provide national Italian recommendations for clinicians caring for these patients.
2016
- Akt1/Akt2 inhibition and development of hepatocellular carcinoma
[Articolo su rivista]
Critelli, R. M.; Schepis, F.; Villa, E.
abstract
2016
- Antimicrobial stewardship in a Gastroenterology Department: Impact on antimicrobial consumption, antimicrobial resistance and clinical outcome
[Articolo su rivista]
Bedini, Andrea; De Maria, Nicola; Del Buono, Mariagrazia; Bianchini, Marcello; Mancini, Mauro; Binda, Cecilia; Brasacchio, Andrea; Orlando, Gabriella; Franceschini, Erica; Meschiari, Marianna; Sartini, Alessandro; Zona, Stefano; Paioli, Serena; Villa, Erica; Gyssens, Inge C.; Mussini, Cristina
abstract
Background A major cause of the increase in antimicrobial resistance is the inappropriate use of antimicrobials. Aims To evaluate the impact on antimicrobial consumption and clinical outcome of an antimicrobial stewardship program in an Italian Gastroenterology Department. Methods Between October 2014 and September 2015 (period B), a specialist in infectious diseases (ID) controlled all antimicrobial prescriptions and decided about the therapy in agreement with gastroenterologists. The defined daily doses of antimicrobials (DDDs), incidence of MDR-infections, mean length of stay and overall in-hospital mortality rate were compared with those of the same period in the previous 12-months (period A). Results During period B, the ID specialist performed 304 consultations: antimicrobials were continued in 44.4% of the cases, discontinued in 13.8%, not recommended in 12.1%, de-escalated 9.9%, escalated in 7.9%, and started in 4.0%. Comparing the 2 periods, we observed a decreased of antibiotics consumption (from 109.81 to 78.45 DDDs/100 patient-days, p = 0.0005), antifungals (from 41.28 to 24.75 DDDs/100pd, p = 0.0004), carbapenems (from 15.99 to 6.80 DDDsx100pd, p = 0.0032), quinolones (from 35.79 to 17.82 DDDsx100pd, p = 0.0079). No differences were observed in incidence of MDR-infections, length of hospital stay (LOS), and mortality rate. Conclusions ASP program had a positive impact on reducing the consumption of antimicrobials, without an increase in LOS and mortality.
2016
- BactDNA as an Independent Risk Factor for Short-Term Crohn's Disease Recurrence
[Articolo su rivista]
Sartini, Alessandro; Verga, Maria Chiara; Marzi, Luca; De Maria, Nicola; Villa, Erica
abstract
BactDNA as an Independent Risk Factor for Short-Term Crohn's Disease Recurrence
2016
- Complete resolution of non-necrotizing lung granuloma and pyoderma gangrenosum after restorative proctocolectomy in a woman with severe ulcerative colitis and cytomegalovirus infection
[Articolo su rivista]
Sartini, Alessandro; Bianchini, Marcello; Schepis, Filippo; Marzi, Luca; De Maria, Nicola; Villa, Erica
abstract
Here, we report the unusual case of an ulcerative colitis female patient presenting together with cytomegalovirus infection, pyoderma gangrenosum and a noncaseating lung granuloma, both resistant to immunomodulatory drugs which dramatically obtained a clinical stable remission after restorative proctocolectomy.
2016
- Efficacy of a Novel Granulocyte Monocyte Apheresis Adsorber Device in the Treatment of Inflammatory Bowel Diseases: A Pilot Study
[Articolo su rivista]
Di Girolamo, Maria; Sartini, Alessandro; Critelli, Rosina Maria; Bertani, Angela; Merighi, Alberto; Villa, Erica
abstract
Granulocyte monocyte apheresis (GMA) is a non-pharmacological treatment for inflammatory bowel disease. In our study, we tested a novel GMA adsorber device in terms of clinical efficacy and safety in patientsâ non-response to pharmacological therapy. Secondary outcomes were the evaluation of adsorber's technical performance, the reduction of inflammatory markers and the improvement of patients' life quality. The prospective study included 18 patients enrolled from 2011 to 2012 with a monitoring of 48 weeks. All patients with Crohn's disease achieved a clinical remission after GMA treatments, sustained until the end of follow up, while 80% of ulcerative colitis patients obtained a clinical benefit, maintained after 48 weeks of monitoring. Leukocytes, neutrophils, monocytes and platelets, compared to erythrocytes and lymphocytes, were effectively removed from peripheral blood. There was no statistically significant result about serological markers of inflammation. A consistent improvement of the patients' quality of life was observed up to the end of follow up. No significant side-effects were recorded. Our study underlines the efficacy and the safety of this novel GMA adsorber device; a prospective randomized clinical trial with adequate sample size should be performed.
2016
- From current status to optimization of HCV treatment: Recommendations from an expert panel
[Articolo su rivista]
Craxì, Antonio; Perno, Carlo Federico; Viganò, Mauro; Ceccherini-Silberstein, Francesca; Petta, Salvatore; Aghemo, Alessio; Alberti, Alfredo; Andreone, Pietro; Andreoni, Massimo; Bonora, Stefano; Brunetto, Maurizia Rossana; Bruno, Savino; Caporaso, Nicola; Chirianni, Antonio; Ciancio, Alessia; Degasperi, Elisabetta; Di Perri, Giovanni; Fagiuoli, Stefano; Ferrari, Carlo; Gaeta, Giovanni Battista; Pellicelli, Adriano; Puoti, Massimo; Raimondo, Giovanni; Taliani, Gloria; Villa, Erica; Zignego, Anna Linda
abstract
Chronic hepatitis C virus (HCV) infection is a major public health problem at a global level, causing an enormous burden of hepatic and extra-hepatic morbidity and mortality. Treatment of chronic HCV (CHC) has been revolutionized in the last few years by the introduction of highly effective and well tolerated direct acting antiviral agents (DAAs) able to achieve >90% rates of sustained virological response (SVR) in many groups of patients, including those previously excluded from interferon-based regimens. For such reason interferon-free regimens are now the treatments of choice for all patients. Successful anti-HCV treatment can stop liver disease progression and can solve the HCV-related extra hepatic manifestations, eventually reducing both liver-related and overall mortality. Together with the rapidly accumulating data about the evolution of treatment landscape, different guidelines from national and international Liver Scientific Societies have been published until today. However, these recommendations may not be applied worldwide as, due to high treatment costs, most of them identify as priority groups only patients with advanced liver disease. Moreover some types of patients pose clinical management problems for which even the guidelines do not always provide useful answers. With the aim of treatment optimization by filling some of the gaps of the current guidelines and addressing the remaining unmet needs in practice, a group of Italian experts, experienced on treatment of HCV infection, met in Stresa in February 2016. The summary of all the considerations arising from this two-day meeting and the final statements are reported in this position paper.
2016
- Hemostatic balance in patients with liver cirrhosis: Report of a consensus conference
[Articolo su rivista]
Andriulli, Angelo; Tripodi, Armando; Angeli, Paolo; Senzolo, Marco; Primignani, Massimo; Giannini, Edoardo G.; Riggio, Oliviero; Colli, Agostino; Prati, Daniele; Sacerdoti, David; Merkel, Carlo; Basili, Stefania; Ferro, Domenico; Villa, Erica; Di Minno, Giovanni; Caraceni, Paolo; Marzioni, Marco; Mannucci, Pier Mannuccio; Violi, Francesco; Piscaglia, Fabio; Calvaruso, Vincenza; De Pietri, Lesley; Falcone, Marco; Feltracco, Paolo; Grandone, Elvira; La Mura, Vincenzo; Licata, Anna; Lucidi, Cristina; Maimone, Sergio; Marietta, Marco; Morisco, Filomena; Napoleone, Laura; Piano, Salvatore; Raparelli, Valeria; Rebulla, Paolo; Ribero, Dario; Sartori, Maria Teresa; Scalera, Antonella; Schepis, Filippo; Sicilianom, Massimo; Baroni, Gianluca Svegliati; Tufano, Antonella; Vitale, Alessandro; Zuin, Massimo
abstract
Patients with cirrhosis present with hemostatic alterations secondary to reduced availability of pro-coagulant and anti-coagulant factors. The net effect of these changes is a rebalanced hemostatic system. The Italian Association of the Study of the Liver (AISF) and the Italian Society of Internal Medicine (SIMI) promoted a consensus conference on the hemostatic balance in patients with cirrhosis. The consensus process started with the review of the literature by a scientific board of experts and ended with a formal consensus meeting in Rome in December 2014. The statements were graded according to quality of evidence and strength of recommendations, and approved by an independent jury. The statements presented here highlight strengths and weaknesses of current laboratory tests to assess bleeding and thrombotic risk in cirrhotic patients, the pathophysiology of hemostatic perturbations in this condition, and outline the optimal management of bleeding and thrombosis in patients with liver cirrhosis.
2016
- Inflammatory bowel disease patients seem to develop non-alcoholic steatohepatitis (NASH) independently from an altered metabolic profile or active bowel disease
[Abstract in Atti di Convegno]
Sartini, A.; Bianchini, M.; Gitto, S.; Di Girolamo, M.; Bertani, A.; Merighi, A.; Villa, E.
abstract
IBD patients with NAFLD seem to be younger than the general population is, and they develop it independently from the presence of an altered metabolic profile/metabolic syndrome or of active gut disease; indeed, only the presence of elevated GGT seems to predict the presence of NASH in such group. This could be possibly due to the altered composition of gut microbiota, which characterises IBD itself and/or of a leak in the barrier function, leading in a breakdown of the gut/liver axis.
2016
- Interleukin 28B polymorphisms as predictors of sustained virological response in chronic hepatitis C: Systematic review and meta-analysis
[Articolo su rivista]
Cariani, E.; Roli, L.; Missale, G.; Villa, E.; Ferrari, C.; Trenti, T.
abstract
Polymorphism of interleukin 28B gene represents a powerful outcome predictor for interferon-based regimens in hepatitis C virus infection. However, some studies report conflicting results. The predictive value of interleukin 28B genotype over the outcome interferon-α/ribavirin treatment was thoroughly evaluated and compared with virological predictors of response. Literature revision was performed on PubMed. Pooled odds ratios (ORs) were calculated by fixed- or random-effects models. Heterogeneity and publication bias were also assessed. Sixty-two eligible papers including 20 290 patients were retrieved. Both polymorphisms (rs12979860 and rs8099917) were strongly associated with response (OR=4.09 and 4.00, respectively), however, the association was weaker for subjects infected with viral genotypes 2 and 3 (OR=1.52 and 1.49, respectively). Compared with interleukin 28B genotype, the association with response was lower for baseline viremia (OR=2.15) and higher for rapid virological response (OR=13.86). These results provide a critical evaluation of interleukin 28B genotype as a pharmacogenetic predictor in hepatitis C patients.
2016
- LOW MOLECULAR WEIGHT HEPARIN TREATMENT DOES NOT INCREASE THE RISK OF BLEEDING AFTER PROPHYLACTIC ENDOSCOPIC VARICEAL BAND LIGATION IN PATIENTS WITH CIRRHOSIS
[Abstract in Atti di Convegno]
Bianchini, M; Cavani, G; Bonaccorso, A; Turco, L; Merighi, A; Villa, E; Schepis, F
abstract
Introduction. Anticoagulants are commonly indicated in cirrhotics due to their high rate of thrombotic events. It’s not known if anticoagulants are safe in cirrhotics undergoing elective Endoscopic Variceal band Ligation (EVL).
Aim. to define the short-term risk of bleeding after prophylactic EVL in cirrhotics treated with LMWH.
Materials and Methods. All primary and secondary prophylactic EBL performed from January 2009 to September 2015 were restrospectively analyzed. Inclusion criteria: diagnosis of cirrhosis, age 18-85, EVL procedures started and completed at the same Institution during the observation period. Exclusion criteria: active bleeding at first endoscopy. Patients treated with LMWH were classified as Cases, the remaining as Controls. Clinical characteristics including ascites, hepatic encephalopathy and MELD, endoscopic features at the beginning and at the end of EVL treatment, number of EVL sessions, mean number of bands per session were recorded. EVL related bleeding was defined as endoscopic evidence of hemorrhage within 30 days from the procedure.
Results. Among 26742 upper endoscopies, 542 were prophylactic EVLs performed in 245 (200 primary and 45 secondary prophylaxis) cirrhotics. 197 EVL sessions were performed in 76 Cases (4.81±0.92 bands/session) and 345 in 169 Controls (4.80±1.03; p=ns). 48 Cases (63%) were treated with 100 U/Kg/bid while the remaining with 70 U/Kg/bid. Clinical and endoscopic features were similar between the groups at the time of the first EVL and at the last treatment. Overall 5 patients bled (2%), 3 Cases (3.9%) and 2 Controls (1.2%, Log-Rank test 0.161). F2 and F3 varices with red marks (100% vs 54,7%, p 0.044) and the number of bands used at index EVL (5.8±0.4 vs 4.6±1.1, p=0.003) were different between bleeders and non-bleeders, respectively.
Conclusions. Anticoagulation with LMWH does not increase the risk of post-procedural bleeding in cirrhotic patients undergoing prophylactic EBL.
2016
- Missed treatment in an Italian HBV infected patients cohort: HBV RER
[Articolo su rivista]
Cuomo, Gianluca; Borghi, Vanni; Andreone, Pietro; Massari, Marco; Villa, Erica; Pietrangelo, Antonello; Verucchi, Gabriella; Ferrari, Carlo
abstract
Very little is known about the access to treatment for Chronic Hepatitis B in the real clinical practice and the characteristics of the patients who do not receive antiviral therapy.
2016
- Neoangiogenesis-related genes are hallmarks of fast-growing hepatocellular carcinomas and worst survival. Results from a prospective study
[Articolo su rivista]
Villa, Erica; Critelli, Rosina Maria; Lei, Barbara; Marzocchi, Guido; Cammà, Calogero; Giannelli, Gianluigi; Pontisso, Patrizia; Cabibbo, Giuseppe; Enea, Marco; Colopi, Stefano; Caporali, Cristian; Pollicino, Teresa; Milosa, Fabiola; Karampatou, Aimilia; Todesca, Paola; Bertolini, Elena; Maccio, Livia; Martinez Chantar, Maria Luz; Turola, Elena; Del Buono, Mariagrazia; De Maria, Nicola; Ballestri, Stefano; Schepis, Filippo; Loria, Paola; Gerunda, Giorgio Enrico; Losi, Luisa; Cillo, Umberto
abstract
Objective: The biological heterogeneity of hepatocellular carcinoma (HCC) makes prognosis difficult. We translate the results of a genome-wide highthroughput analysis into a tool that accurately predicts at presentation tumour growth and survival of patients with HCC. Design: Ultrasound surveillance identified HCC in 78 (training set) and 54 (validation set) consecutive patients with cirrhosis. Patients underwent two CT scans 6 weeks apart (no treatment in-between) to determine tumour volumes (V0 and V1) and calculate HCC doubling time. Baseline-paired HCC and surrounding tissue biopsies for microarray study (Agilent Whole Human Genome Oligo Microarrays) were also obtained. Predictors of survival were assessed by multivariate Cox model. Results: Calculated tumour doubling times ranged from 30 to 621 days (mean, 107±91 days; median, 83 days) and were divided into quartiles: ≤53 days (n=19), 54-82 days (n=20), 83-110 days (n=20) and ≥111 days (n=19). Median survival according to doubling time was significantly lower for the first quartile versus the others (11 vs 41 months, 42, and 47 months, respectively) (p<0.0001). A five-gene transcriptomic hepatic signature including angiopoietin-2(ANGPT2), delta-like ligand 4(DLL4), neuropilin (NRP)/tolloid (TLL)-like 2(NETO2), endothelial cell-specific molecule-1(ESM1), and nuclear receptor subfamily 4, group A, member 1 (NR4A1) was found to accurately identify rapidly growing HCCs of the first quartile (ROC AUC: 0.961; 95% CI 0.919 to 1.000; p<0.0001) and to be an independent factor for mortality (HR: 3.987; 95% CI 1.941 to 8.193, p<0.0001). Conclusions: The hepatic five-gene signature was able to predict HCC growth in individual patient and the consequent risk of death. This implies a role of this molecular tool in the future therapeutic management of patients with HCC. Trial registration number ClinicalTrials.gov Identifier: NCT01657695.
2016
- Non-Alcoholic Fatty Liver Disease and Metabolic Syndrome after Liver Transplant
[Articolo su rivista]
Gitto, Stefano; Villa, Erica
abstract
Liver transplant is the unique curative therapy for patients with acute liver failure or end-stage liver disease, with or without hepatocellular carcinoma. Increase of body weight, onset of insulin resistance and drug-induced alterations of metabolism are reported in liver transplant recipients. In this context, post-transplant diabetes mellitus, hyperlipidemia, and arterial hypertension can be often diagnosed. Multifactorial illnesses occurring in the post-transplant period represent significant causes of morbidity and mortality. This is especially true for metabolic syndrome. Non-alcoholic steatosis and steatohepatitis are hepatic manifestations of metabolic syndrome and after liver transplant both recurrent and de novo steatosis can be found. Usually, post-transplant steatosis shows an indolent outcome with few cases of fibrosis progression. However, in the post-transplant setting, both metabolic syndrome and steatosis might play a key role in the stratification of morbidity and mortality risk, being commonly associated with cardiovascular disease. The single components of metabolic syndrome can be treated with targeted drugs while lifestyle intervention is the only reasonable therapeutic approach for transplant patients with non-alcoholic steatosis or steatohepatitis.
2016
- Non-alcoholic steatohepatitis and liver transplantation
[Articolo su rivista]
Gitto, Stefano; Vukotic, Ranka; Vitale, Giovanni; Pirillo, Martina; Villa, Erica; Andreone, Pietro
abstract
Non-alcoholic steatohepatitis is a growing liver-related health problem. In Europe, non-alcoholic fatty liver disease is the most usual reason of chronic liver illness while steatohepatitis, its progressive form, affects 1% of Europeans and North Americans. In the United States steatohepatitis-related cirrhosis is one of the main indications for liver transplant. A targeted stratification for patients waiting for transplant and affected by this disease is mandatory especially because of their increased cardiovascular and cancer risk. The adequate treatment of NAFLD is crucial for the reduction of the disease related morbidity and mortality. In post-transplant setting, the recurrent or de novo steatosis might seriously affect the allograft short- and long-term outcome. Many conditions can represent the basis of the post-transplant steatohepatitis: obesity, hyperlipidaemia, diabetes mellitus, arterial hypertension, immunosuppressant treatment, alcoholic habit and liver graft steatosis. Today, the only consolidated therapy is represented by a deep life-style intervention since the use of drug-based alternative strategies is still limited and a very few data are available for the post-transplant period. Targeted and personalized behaviour and pharmacological interventions have to be developed for both the pre- and post-transplant phase.
2016
- Optimisation of triple therapy for patients with chronic hepatitis C: a systematic review
[Articolo su rivista]
Pecoraro, Valentina; Cariani, Elisabetta; Villa, Erica; Trenti, Tommaso
abstract
Background: Triple therapy with Pegylated-Interferon α (PEG-IFNα)/Ribavirin (RBV) and Boceprevir (Boc) or Telaprevir (Tel) significantly improved sustained virological response (SVR) rates for patients with genotype 1 HCV infection compared to PEG-IFNα/RBV alone (dual therapy). However, less is known about factors associated with rates of SVR and of adverse events (AEs). Material and Methods: The aim of this systematic review was to evaluate the evidence regarding the factors affecting response and rate of AEs associated with triple therapy. We performed systematic electronic searches in Medline, Embase, Scopus and Central as well as a list of reference literature. We included randomised controlled trials examining triple therapy compared with dual therapy and reporting data according to patients features and about AEs. Odds ratios (OR) were pooled using either fixed or random effect model, as appropriate. Results: We included data from 14 studies. Treatment with triple therapy increased SVR rate compared to dual therapy especially in patients previously treated with PEG-IFNα/RBV and with increased pretreatment alanine aminotransferase (ALT) levels. Higher rate of serious AEs and treatment discontinuation due to AEs was also observed particularly in treatment-experienced patients. Conclusions: The present study shows how improved results of triple therapy are mainly observed in some patientsâ subsets and are accompanied by increased risk of AEs compared to dual therapy. These results might be useful for optimising treatment of chronic hepatitis C when IFN-free regimens are unavailable.
2016
- PROGRESSIVE ALTERATIONS IN SYSTEMIC AND CARDIOPULMONARY HEMODYNAMICS OCCUR IN PATIENTS WITH CIRRHOSIS AND PREDICT DEATH IN DECOMPENSATED CIRRHOSIS
[Abstract in Atti di Convegno]
Turco, L; Garcia-Tsao, G; Magnani, I; Bianchini, M; Costetti, M; Rossi, R; Villa, E; Schepis, F
abstract
Background and Aims: The main stages of cirrhosis (compensated and decompensated) have been substaged based on clinical, endoscopic, and portal pressure (determined by the hepatic venous pressure gradient, HVPG) features. Vasodilation leading to a hyperdynamic circulatory state is central in the development of a late decompensated stage with inflammation being currently considered a key driver. We aimed to assess hepatic/systemic hemodynamics and inflammation (by C reactive protein, CRP) among the different substages of cirrhosis and to investigate their interrelationship and prognostic relevance.
Methods: Single center, prospective cohort of patients with cirrhosis undergoing per protocol hepatic and right-heart catheterization and CRP measurement, classified into recently defined prognostic stages (PS) of compensated (PS1: HVPG ≥6mmHg but <10mmHg; PS2: HVPG ≥10 mmHg without gastroesophageal varices; PS3: patients with gastroesophageal varices) and decompensated (PS4: diuretic-responsive ascites; PS5: refractory ascites) disease. Cardiodynamic states based on cardiac index (L/min/m2) were created: relatively-hypodynamic (<3.2), normodynamic (3.2-4.2) and hyperdynamic (>4.2).
Results: 238 patients, 151 compensated (PS1=25; PS2=36; PS3=90), 87 decompensated (PS4=48; PS5=39). Mean arterial pressure decreased progressively from PS1 to PS5, cardiac index increased progressively from PS1-to-PS4 but decreased in PS5. HVPG, MELD, and CRP increased progressively from PS1-to-PS5. Among compensated patients, age, HVPG, relatively-hypodynamic/hyperdynamic state and CRP were predictive of decompensation. Among patients with ascites, MELD, relatively-hypodynamic/hyperdynamic state, post-capillary pulmonary hypertension, and CRP were independent predictors of death/liver transplant.
Conclusions: Our study demonstrates that, in addition to known parameters, cardiopulmonary hemodynamics and CRP are predictive of relevant outcomes in patients with both compensated and decompensated cirrhosis.
2016
- Reply
[Articolo su rivista]
De Pietri, L.; Bianchini, M.; Garcia-Tsao, G.; Villa, E.
abstract
2016
- Reply
[Articolo su rivista]
De Pietri, L.; Bianchini, M.; Garcia-Tsao, G.; Villa, E.
abstract
2016
- Role of metabolic, atherogenic and psychological factors in patients with colorectal adenomas
[Abstract in Rivista]
Boarino, Valentina; Merighi, Alberto; Mancini, Stefano; Bertani, Angela; Marocchi, Margherita; Marsico, Maria; Olivetti, Giampiero; Primerano, Anna Maria; Mattei, Giorgio; Ferrari, Silvia; Roncucci, Luca; Villa, Erica
abstract
Some metabolic, atherogenic, and psychological risk factors are related to the growth of colorectal adenomas
2016
- Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy: A randomized, controlled trial
[Articolo su rivista]
De Pietri, Lesley; Bianchini, Marcello; Montalti, Roberto; De Maria, Nicola; DI MAIRA, Tommaso; Begliomini, Bruno; Gerunda, Giorgio Enrico; DI BENEDETTO, Fabrizio; GARCIA TSAO, Guadalupe; Villa, Erica
abstract
Bleeding is a feared complication of invasive procedures in patients with cirrhosis and significant coagulopathy (as defined by routine coagulation tests), and is used to justify pre-procedure use of fresh frozen plasma (FFP) and/or platelets (PLT). Thromboelastography (TEG) provides a more comprehensive global coagulation assessment than routine tests (INR and platelet count) and its use may avoid unnecessary blood product transfusion in patients with cirrhosis and significant coagulopathy (defined in this study as INR>1.8 and/or platelet count <50x10(3) /µl) who will be undergoing an invasive procedure. Sixty patients were randomly allocated to TEG-guided transfusion strategy or standard of care (SOC)(1:1 TEG:SOC). TEG group would receive FFP if the reaction time (r) >40mm and/or PLT if maximum amplitude (MA) <30mm. All SOC patients received FFP and/or PLT per hospital guidelines. Endpoints were blood product use and bleeding complications. Baseline characteristics of the two groups were similar. Per protocol, all subjects in the SOC group received blood product transfusions vs. 5 in the TEG group (100% vs. 16.7%, p<0.0001). Sixteen SOC (53.3%) received FFP, 10 (33.3%) PLT, and 4 (13.3%) both FFP and PLT. In the TEG group, none received FFP alone (p<0.0001 vs. SOC), 2 received PLT (6.7%)(p=0.009 vs. SOC), and 3 both FFP and PLT (NS). Post-procedure bleeding occurred in only 1 patient (SOC group) after large-volume paracentesis.
2015
- "Blindly" ADA Dose Escalation to 80 mg Weekly in Crohn's Disease Patients with LOR: Is It Cost Effective or Not?
[Articolo su rivista]
Sartini, Alessandro; Di Girolamo, Maria; Bertani, Angela; Villa, Erica
abstract
Reply to an article
2015
- Acute hepatitis B caused by a vaccine-escape HBV strain in vaccinated subject: sequence analysis and therapeutic strategy
[Articolo su rivista]
Luongo, Monica; Critelli, Rosina Maria; Grottola, Antonella; Gitto, Stefano; Bernabucci, Veronica; Bevini, Mirco; Vecchi, Chiara; Montagnani, Giuliano; Villa, Erica
abstract
HBV vaccine contains the 'a' determinant region, the major immune-target of antibodies (anti-HBs). Failure of immunization may be caused by vaccine-induced or spontaneous 'a' determinant surface gene mutants. Here, we evaluate the possible lack of protection by HBV vaccine, describing the case of an acute hepatitis B diagnosed in a 55-year-old Caucasian male unpaid blood donor, vaccinated against HBV. Sequencing data for preS-S region revealed multiple point mutations. Of all the substitutions found, Q129H, located in the "a" determinant region of HBsAg, can alter antigenicity, leading to mutants. This mutant may cause vaccine failure especially when associated with high viremia of infecting source.
2015
- Biology of hepatocellular carcinoma
[Articolo su rivista]
Critelli, Rosina Maria; De Maria, Nicola; Villa, Erica
abstract
This chapter focuses on the identification of hepatocellular carcinoma (HCC) molecular signatures and the potentials of these signatures in prediction of HCC prognosis and driving of HCC therapeutic treatments. Progress in molecular profiling studies using DNA-microarray-based gene expression profiling has provided new insight about HCC pathogenesis, and gene signatures that can distinguish tumor subtypes assist clinical staging and predict patient outcomes. This provides the possibility to improve the stratification of HCC patients at a molecular level and, in the near future, will be potential in paving the way for tailored medicine in HCC patients.
2015
- Framingham score, renal dysfunction, and cardiovascular risk in liver transplant patients
[Articolo su rivista]
Di Maira, Tommaso; Rubin, Angel; Puchades, Lorena; Aguilera, Victoria; Vinaixa, Carmen; Garcia, Maria; De Maria, Nicola; Villa, Erica; Lopez Andujar, Rafael; San Juan, Fernando; Montalva, Eva; Perez, Judith; Prieto, Martin; Berenguer, Marina
abstract
Cardiovascular (CV) events represent major impediments to the long-term survival of liver transplantation (LT) patients. The
aim of this study was to assess whether the Framingham risk score (FRS) at transplantation can predict the development
of post-LT cardiovascular events (CVEs). Patients transplanted between 2006 and 2008 were included. Baseline features,
CV risk factors, and CVEs occurring after LT (ischemic heart disease, stroke, heart failure, de novo arrhythmias, and peripheral
arterial disease) were recorded. In total, 250 patients (69.6% men) with a median age of 56 years (range, 18-68 years)
were included. At transplantation, 34.4%, 34.4%, and 33.2% of patients, respectively, had a low, moderate, and high FRS
with a median FRS of 14.9 (range, 0.09-30); 14.4% of LT recipients developed at least 1 CVE at a median of 2.619 years
(range, 0.006-6.945 years). In the univariate analysis, factors associated with the development of CVEs were the continuous
FRS at LT (P50.003), age (P50.007), creatinine clearance [estimated glomerular filtration rate (eGFR); P50.020], and
mycophenolate mofetil use at discharge (P50.011). In the multivariate analysis, only the eGFR [hazard ratio (HR), 0.98;
95% confidence interval (CI), 0.97-1.00; P50.009] and FRS (HR, 1.06; 95% CI, 1.02-1.10; P50.002) remained in the
model. Moreover, an association was also found between the FRS and overall survival (P50.004) with 5-year survival rates
of 82.5%, 77.8%, and 61.4% for the low-, moderate-, and high-risk groups, respectively. Continuous FRS, eGFR, and hepatitis
C virus infection were independent risk factors for overall mortality. In our series, the FRS and eGFR at LT were able to
predict the development of post-LT CVEs and poor outcomes
2015
- Histone deacetylase 4 promotes cholestatic liver injury in the absence of prohibitin-1
[Articolo su rivista]
Barbier-Torres, L.; Beraza, N.; Fernandez-Tussy, P.; Lopitz-Otsoa, F.; Fernandez-Ramos, D.; Zubiete-Franco, I.; Varela-Rey, M.; Delgado, T. C.; Gutierrez, V.; Anguita, J.; Pares, A.; Banales, J. M.; Villa, E.; Caballeria, J.; Alvarez, L.; Lu, S. C.; Mato, J. M.; Martinez-Chantar, M. L.
abstract
Prohibitin-1 (PHB1) is an evolutionarily conserved pleiotropic protein that participates in diverse processes depending on its subcellular localization and interactome. Recent data have indicated a diverse role for PHB1 in the pathogenesis of obesity, cancer, and inflammatory bowel disease, among others. Data presented here suggest that PHB1 is also linked to cholestatic liver disease. Expression of PHB1 is markedly reduced in patients with primary biliary cirrhosis and biliary atresia or with Alagille syndrome, two major pediatric cholestatic conditions. In the experimental model of bile duct ligation, silencing of PHB1 induced liver fibrosis, reduced animal survival, and induced bile duct proliferation. Importantly, the modulatory effect of PHB1 is not dependent on its known mitochondrial function. Also, PHB1 interacts with histone deacetylase 4 (HDAC4) in the presence of bile acids. Hence, PHB1 depletion leads to increased nuclear HDAC4 content and its associated epigenetic changes. Remarkably, HDAC4 silencing and the administration of the HDAC inhibitor parthenolide during obstructive cholestasis in vivo promote genomic reprogramming, leading to regression of the fibrotic phenotype in liver-specific Phb1 knockout mice. Conclusion: PHB1 is an important mediator of cholestatic liver injury that regulates the activity of HDAC4, which controls specific epigenetic markers; these results identify potential novel strategies to treat liver injury and fibrosis, particularly as a consequence of chronic cholestasis.
2015
- Interferon lambda-3 is not associated with clinical outcome in patients with HCV-induced compensated cirrhosis: a long-term cohort study
[Articolo su rivista]
Bruno, Savino; Thompson, Alex J; Critelli, Rosina Maria; Crosignani, Andrea; Rossi, Sonia; De Lisi, Stefania; Cariani, Elisabetta; Zermiani, Paola; Vaira, Valentina; Boccaccio, Vincenzo; Maisonneuve, Patrick; Villa, Erica
abstract
Background: Interferon Lambda-3 (IFN-λ3) gene polymorphism is associated with spontaneous clearance of hepatitis C virus (HCV) and response to IFN-based therapy (IFN). However, very few data are available about its value in predicting sustained virologic response (SVR) in patients with cirrhosis, and whether IFN-λ3 genotype influences liver disease progression remains unclear. Methods: We determined IFN-λ3 genotype by PCR in a cohort of patients with compensated HCV-related cirrhosis, enrolled between 1989 and 1992. Person-years follow-up was calculated for each individual from the date of enrolment to the development of first episode of decompensation, HCC, liver transplant, death or end of follow-up. The follow-up of patients who achieved SVR was censored at the time of IFN initiation. Kaplan-Meier curves and Cox regression analyses were used to assess the association between IFN-λ3 genotype and clinical outcome. Results: IFN-λ3 was determined in 264 patients (52% males, mean age 57 ± 8 years, 67% HCV genotype (G)1, while CC, CT and TT genotypes were 36%, 50% and 14%, respectively. During a median follow-up of 14.8 years, 149 (56%) patients received IFN. Overall, SVR was achieved in 31 (21%) patients, 40% among those with CC genotype (22% in G1 and 61% in G2, respectively) compared to 10% and 13% among patients with CT and TT genotypes (p < 0.0001). Univariate and multivariate analyses found no association between IFN-λ3 (CC vs. non-CC genotype) and disease progression. Conclusion: IFN-λ3 determination is fundamental for allocating cirrhotic patients to be treated with IFN, while it has no value in predicting the outcome of the disease.
2015
- Letter: TNFα inhibitors and prevalence of fatty liver disease in chronic inflammatory diseases
[Articolo su rivista]
Sartini, A.; Leonardi, F.; Gitto, S.; Di Girolamo, M.; Villa, E.
abstract
2015
- Methylprednisolone-induced toxic hepatitis after intravenous pulsed therapy for multiple sclerosis relapses
[Articolo su rivista]
Ferraro, Diana; Mirante, Vincenzo G.; Losi, Luisa; Villa, Erica; Simone, ANNA MARIA; Vitetta, Francesca; Federzoni, Lucia; Nichelli, Paolo Frigio; Sola, Patrizia
abstract
High-dose, intravenous methylprednisolone (MP) is the only recommended first-line treatment for multiple sclerosis relapses. However, there are increasing reports on liver toxicity induced by this treatment regimen. We report of 4 multiple sclerosis patients with no history of viral/metabolic liver disorders or alcohol/hepatotoxic drug intake, who developed hypertransaminasaemia following intravenous MP. In 2 of the patients, liver biopsy showed periportal fibrosis, piecemeal necrosis, and inflammatory cell infiltrates. A rechallenge test confirmed a causal association in 1 case. MP-induced liver toxicity may be more frequent than commonly thought and it is important to report this adverse reaction, which is potentially lethal, and to raise awareness on the potential hepatotoxicity of corticosteroid pulses.
2015
- Ovarian senescence increases liver fibrosis in humans and zebrafish with steatosis
[Articolo su rivista]
Turola, Elena; Petta, Salvatore; Vanni, Ester; Milosa, Fabiola; Valenti, Luca; Critelli, Rosina Maria; Miele, Luca; Maccio, Livia; Calvaruso, Vincenza; Fracanzani, Anna L.; Bianchini, Marcello; Raos, Nazarena; Bugianesi, Elisabetta; Mercorella, Serena; Di Giovanni, Marisa; Craxì, Antonio; Fargion, Silvia; Grieco, Antonio; Cammà, Calogero; Cotelli, Franco; Villa, Erica
abstract
Contrasting data exist on the effect of gender and menopause on the susceptibility, development and liver damage progression in non-alcoholic fatty liver disease (NAFLD). Our aim was to assess whether menopause is associated with the severity of liver fibrosis in individuals with NAFLD and to explore the issue of ovarian senescence in experimental liver steatosis in zebrafish. In 244 females and age-matched males with biopsy-proven NAFLD, we assessed anthropometric, biochemical and metabolic features, including menopausal status (self-reported); liver biopsy was scored according to ‘The Pathology Committee of the NASH Clinical Research Network’. Young and old male and female zebrafish were fed for 24 weeks with a high-calorie diet. Weekly body mass index (BMI), histopathological examination and quantitative real-time PCR analysis on genes involved in lipid metabolism, inflammation and fibrosis were performed. In the entire cohort, at multivariate logistic regression, male gender [odds ratio (OR): 1.408, 95% confidence interval (95% CI): 0.779-2.542, P=0.25] vs women at reproductive age was not associated with F2-F4 fibrosis, whereas a trend was observed for menopause (OR: 1.752, 95% CI: 0.956-3.208, P=0.06). In women, menopause (OR: 2.717, 95% CI: 1.020-7.237, P=0.04) was independently associated with F2-F4 fibrosis. Similarly, in overfed zebrafish, old female fish with failing ovarian function [as demonstrated by extremely low circulating estradiol levels (1.4±0.1 pg/µl) and prevailing presence of atretic follicles in the ovaries] developed massive steatosis and substantial fibrosis (comparable with that occurring in males), whereas young female fish developed less steatosis and were totally protected from the development of fibrosis. Ovarian senescence significantly increases the risk of fibrosis severity both in humans with NAFLD and in zebrafish with experimental steatosis.
2015
- Ramucirumab (RAM) as Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma (HCC) Following First-Line Therapy with Sorafenib: Analyses from the Randomized Phase III REACH Study
[Articolo su rivista]
Barone, C.; Brandi, G.; Daniele, B.; Villa, Erica; Leo, S.; Di Fabio, F.; Aprile, G.; Colombo, M.; Sobrero, A.; Giannelli, G.; Porta, C.; Cabibbo, G.; Zhu, A.; Blanc, J.; Okusaka, T.; Chau, I.; Abada, P.; Yang, L.; Pastorelli, D.
abstract
Background: REACH was a global, multicenter, double-blind, phase 3 study evaluating the efficacy and safety of RAM as a single agent for patients (pts) with advanced HCC after prior sorafenib.
Methods: Eligible intention-to-treat (ITT) population included: Child-Pugh (CP) A; advanced HCC; Barcelona Clinic Liver Cancer stage C or B refractory or not amenable to locoregional therapy; Eastern Cooperative Oncology Group performance status 0–1; prior sorafenib; and adequate hematologic and biochemical parameters. Pts were randomized 1:1 to receive RAM (8mg/kg IV) or placebo (PBO) every 2 weeks until progression, unacceptable toxicity, or death. CP B pts were enrolled initially; analyses in this population are exploratory. RAM treatment efficacy and safety data are presented for the ITT (CP A) and CP score 7 + 8 (CP B) populations, and for the pre-specified subgroup of pts with baseline alpha-fetoprotein (AFP) 3 or <400 ng/mL. Analyses compared overall survival (OS) using stratified or unstratified log-rank tests. Hazard ratios (HR) were generated using a corresponding Cox regression model.
Results: The OS HR for the ITT population (RAM 283; PBO 282) was 0.866 (95%CI 0.72–1.05; p = 0.1391); median OS was 9.2m for RAM vs 7.6m for PBO. The observed safety profile of RAM in the ITT population was consistent with advanced HCC and the previously demonstrated safety profile for single-agent RAM. In ITT (CP A) pts with baseline AFP ≥400 ng/mL (RAM 119; PBO 131), OS HR was 0.674 (95%CI 0.508–0.895; p = 0.0059); median OS was 7.8m for RAM vs 4.2m for PBO. In CP B pts (RAM 39; PBO 39), OS HR was 0.998 (95%CI 0.623–1.599; p = 0.9946). In CP B pts with AFP ≥400 ng/mL, OS HR was 0.674 (0.332–1.368; p = 0.2756). The safety profile in ITT pts with baseline AFP ≥ or <400 ng/mL was consistent with the overall ITT safety population. Detailed quality-of-life (QoL) analyses and safety results will be presented.
Conclusions: A statistically significant improvement in OS was not met in REACH using single-agent RAM. However, a consistent and clinically meaningful improvement in OS was observed in pts with baseline AFP levels ≥400ng/mL who received RAM, warranting further investigation. In the ITT population with baseline AFP ≥400ng/mL, a trend for delay in symptoms and performance status deterioration was observed. The safety profile of RAM in the ITT population is considered manageable, regardless of baseline AFP.
2015
- Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer
[Articolo su rivista]
Barbier Torres, Lucía; Delgado, Teresa C; García Rodríguez, Juan L; Zubiete Franco, Imanol; Fernández Ramos, David; Buqué, Xabier; Cano, Ainara; Gutiérrez de Juan, Virginia; Fernández Domínguez, Itziar; Lopitz Otsoa, Fernando; Fernández Tussy, Pablo; Boix, Loreto; Bruix, Jordi; Villa, Erica; Castro, Azucena; Lu, Shelly C; Aspichueta, Patricia; Xirodimas, Dimitris; Varela Rey, Marta; Mato, José M; Beraza, Naiara; Martínez Chantar, María L.
abstract
The current view of cancer progression highlights that cancer cells must undergo through a post-translational regulation and metabolic reprogramming to progress in an unfriendly environment. In here, the importance of neddylation modification in liver cancer was investigated. We found that hepatic neddylation was specifically enriched in liver cancer patients with bad prognosis. In addition, the treatment with the neddylation inhibitor MLN4924 in Phb1-KO mice, an animal model of hepatocellular carcinoma showing elevated neddylation, reverted the malignant phenotype. Tumor cell death in vivo translating into liver tumor regression was associated with augmented phosphatidylcholine synthesis by the PEMT pathway, known as a liver-specific tumor suppressor, and restored mitochondrial function and TCA cycle flux. Otherwise, in protumoral hepatocytes, neddylation inhibition resulted in metabolic reprogramming rendering a decrease in oxidative phosphorylation and concomitant tumor cell apoptosis. Moreover, Akt and LKB1, hallmarks of proliferative metabolism, were altered in liver cancer being new targets of neddylation. Importantly, we show that neddylation-induced metabolic reprogramming and apoptosis were dependent on LKB1 and Akt stabilization. Overall, our results implicate neddylation/signaling/metabolism, partly mediated by LKB1 and Akt, in the development of liver cancer, paving the way for novel therapeutic approaches targeting neddylation in hepatocellular carcinoma.
2015
- The Coiled-Coil Domain Containing 80 (ccdc80) gene regulates gadd45β2 expression in the developing somites of zebrafish as a new player of the hedgehog pathway
[Articolo su rivista]
Della Noce, Isabella; Carra, Silvia; Brusegan, Chiara; Critelli, Rosina Maria; Frassine, Andrea; De Lorenzo, Carlo; Giordano, Antonio; Bellipanni, Gianfranco; Villa, Erica; Cotelli, Franco; Pistocchi, Anna; Schepis, Filippo
abstract
The Coiled-Coil Domain Containing 80 (CCDC80) gene has been identified as strongly induced in rat thyroid PC CL3 cells immortalized by the adenoviral E1A gene. In human, CCDC80 is a potential oncosoppressor due to its down-regulation in several tumor cell lines and tissues and it is expressed in almost all tissues. CCDC80 has homologous in mouse, chicken, and zebrafish. We cloned the zebrafish ccdc80 and analyzed its expression and function during embryonic development. The in-silico translated zebrafish protein shares high similarity with its mammalian homologous, with nuclear localization signals and a signal peptide. Gene expression analysis demonstrates that zebrafish ccdc80 is maternally and zygotically expressed throughout the development. In particular, ccdc80 is strongly expressed in the notochord and it is under the regulation of the Hedgehog pathway. In this work we investigated the functional effects of ccdc80-loss-of-function during embryonic development and verified its interaction with gadd45β2 in somitogenesis.
2015
- Therapeutic decisions and treatment with sorafenib in hepatocellular carcinoma: Final analysis of GIDEON study in Italy
[Articolo su rivista]
D'Angelo, S.; Germano, D.; Zolfino, T.; Sansonno, D.; Giannitrapani, L.; Benedetti, A.; Montesarchio, V.; Attili, A.; Buonadonna, A.; Barni, S.; Gasbarrini, A.; Burlone, M. E.; Cillo, U.; Marenco, S.; Villa, E.; Giovanis, P.; Proserpio, I.; Saitta, C.; Magini, G.; Cengarle, R.; Fava, G.; Cuttone, F.; Calvani, N.; Angelico, M.; Di Costanzo, F.; Noto, A.; Poggi, G.; Marignani, M.; Cascinu, S.; Amoroso, D.; Palmieri, V.; Massa, E.; Croce, L. S.; Picardi, A.; Tumulo, S.; Erminero, C.; Lencioni, R.; Lorusso, V.
abstract
Introduction. Sorafenib, an oral multikinase inhibitor, is the only targeted agent approved for the treatment of patients with hepatocellular carcinoma (HCC) after demonstration to increase overall survival compared to placebo in two randomized phase III study. GIDEON (Global Investigation of therapeutic DEcisions in HCC and Of its treatment with sorafeNib) is the largest, global, non-interventional, prospective study of patients with uHCC (n>3200) treated with sorafenib in real-life clinical practice conditions. Here we report the final analysis of safety and efficacy in the Italian cohort of patients. Methods. Patients with unresectable HCC who are candidates for systemic therapy, and for whom a decision has been made to treat with sorafenib, are eligible for inclusion. Patients demographics disease characteristics and treatment history were recorded at baseline visit. Sorafenib dose, concomitant medications, performance status, liver function, adverse events and efficacy (survival and response rate) were collected throughout the study. Results. In the Italian cohort of the GIDEON study 278 patients were included in 36 centers. The global rate of adverse events was 81%. Drug-related events accounted for 67%, mostly of grade 1 and 2, and only 8% were classified as serious. The most common were diarrhea (24%), fatigue (23%), dermatological (14%), rash/exfoliation (10%), hypertension (9%), hemorrage/bleeding of gastrointestinal tract (6%). Overall survival was 14.4 months and time to progression 6.2 months. Objective responses were observed in 14 patients (5%) with 3 complete responses (1%). Stable diseases of at least 6 weeks were observed in 113 patients (41%) with a 30% of disease control rate. Discussion. The safety profile of sorafenib in terms of rate and type of adverse events is similar to that emerged in the global international GIDEON study as well as in the pivotal registration studies.
2015
- Thrombophilic genetic risk factors for liver fibrosis: To screen or not to screen?
[Articolo su rivista]
Schepis, Filippo; Villa, Erica
abstract
Invited Editorial
2015
- Treatment of nonalcoholic steatohepatitis in adults: present and future
[Articolo su rivista]
Gitto, S; Vitale, G; Villa, Erica; Andreone, P.
abstract
Nonalcoholic steatohepatitis has become one of the most common liver-related health problems. This condition has been linked to an unhealthy diet and weight gain, but it can also be observed in nonobese people. The standard of care is represented by the lifestyle intervention. However, because this approach has several limitations, such as a lack of compliance, the use of many drugs has been proposed. The first-line pharmacological choices are vitamin E and pioglitazone, both showing a positive effect on transaminases, fat accumulation, and inflammation. Nevertheless, vitamin E has no proven effect on fibrosis and on long-term morbidity and mortality and pioglitazone has a negative impact on weight. Other drugs have been studied such as metformin, ursodeoxycholic acid, statins, pentoxiphylline, and orlistat with only partially positive results. Among the emerging treatments, telmisartan is particularly interesting as it seems to have an impact on insulin resistance, liver steatosis, inflammation, and fibrosis. However, the pathogenesis of steatohepatitis is highly complex and is determined by different parallel hits; indeed, the association of different drugs that act on various levels has been suggested. In conclusion, lifestyle intervention should be optimised and the associations of different drugs should be tested in large studies with long-term outcomes.
2014
- Boceprevir is highly effective in treatment-experienced hepatitis C virus-positive genotype-1 menopausal women
[Articolo su rivista]
Bernabucci, Veronica; Ciancio, Alessia; Petta, Salvatore; Karampatou, Aimilia; Turco, Laura; Strona, Silvia; Critelli, Rosina Maria; Todesca, Paola; Cerami, Caterina; Sagnelli, Caterina; Rizzetto, Mario; Cammà, Calogero; Villa, Erica
abstract
To investigate the safety/efficacy of Boceprevir-based triple therapy in hepatitis C virus (HCV)-G1 menopausal women who were historic relapsers, partial-responders and null-responders.
2014
- Circulating TGF-β1-related biomarkers in patients with hepatocellular carcinoma and their association with HCC staging scores
[Articolo su rivista]
Dituri, Francesco; Serio, Gabriella; Filannino, Doriana; Mascolo, Antonella; Sacco, Rodolfo; Villa, Erica; Giannelli, Gianluigi
abstract
TGF-β1 was inversely correlated with E-cadherin but significantly correlated with VEGF. VEGF and AFP had a low coefficient value but statistically significant. A significant correlation was found between E-cadherin and MMP2. In conclusion, TGF-β and E-cadherin are inversely correlated in HCC patients' sera and not related to the BCLC classification nor survival but rather to the biological properties of the tumor.
2014
- Coagulopathy in liver diseases: complication or therapy?
[Articolo su rivista]
Bianchini, Marcello; De Pietri, Lesley; Villa, Erica
abstract
Coagulopathy in cirrhosis is a composite condition where liver synthetic deficit rebalances coagulation to a parallel reduction of both pro- and anticoagulant factors. Cirrhosis is therefore no longer considered a hypocoagulable state but rather a more unstable hemostatic balance with a lower threshold for tipping toward thrombosis or bleeding. Tendency to bleeding in cirrhosis is due to the reduction in the synthesis of procoagulants and a low platelet count as well as hyperfibrinolysis. Variceal hemorrhage is a frequent bleeding complication in decompensated cirrhosis. However, the possible contribution of coagulopathy as a precipitant or an aggravating factor is poorly documented and further data are required to clarify its real contributing role. Moreover, apart from the gastrointestinal tract, the occurrence of spontaneous and procedure-related bleeding elsewhere in the body, whilst not uncommon, is less than would be expected. By contrast, a large-scale population-based study has shown the propensity towards venous thrombosis in patients with liver diseases. Portal vein thrombosis (PVT) is a critical but frequent event occurring in up to 40% of patients with liver cirrhosis. PVT causes deterioration of the clinical course, the complications of portal hypertension and an increase in post-transplant mortality. The pathogenesis of PVT includes both local alterations, like blood flow reduction and endothelial activation, and systemic derangement. Systemic prohemostatic alterations include high von Willebrand factor, low ADAMTS-13, low levels of anticoagulants (antithrombin, proteins C and S) and increases in procoagulants like factor VIII. Low-molecular-weight heparin such as enoxaparin has proven to be safe and effective in both the treatment and prevention of PVT. In addition, patients in prophylaxis with enoxaparin showed a lower rate of decompensation and a better survival without bleeding complications. In such patients, circulating bacterial DNA, endotoxemia and markers of inflammation were attenuated compared to controls. These results therefore suggest a possible connection between enoxaparin, decrease of endotoxemia and reduction of portal hypertension. The approach to the coagulopathy in patients with liver diseases is changing: while the main goal for clinicians so far has been to reduce the risk of bleeding, the results of these new studies highlight the importance of preventing or treating thrombophilic disorders like PVT to avoid microcirculatory damage and eventually liver decompensation.
2014
- Expression profiling of hepatocellular carcinoma
[Capitolo/Saggio]
Critelli, R. M.; Cariani, E.; Villa, E.
abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the world. The molecular mechanism of HCC onset involves a complex interplay of both genetic and epigenetic factors. Hepatic carcinogenesis is characterized by an increase in allelic losses, chromosomal aberrations, gene mutations, epigenetic alterations, changes of gene expression and alterations in molecular cellular pathways. The integration of genetic, epigenetic, genomic, and proteomic data provides insight into the molecular mechanisms underlying hepatocarcinogenesis and is revealing promising clinical approaches. Resulting findings offer the possibility for the identification of relevant biomarkers, useful for the detection, molecular diagnosis, prediction of recurrence and prognosis of HCC as well as for the improved identification of novel therapeutic targets. This will be of utmost importance in the near future as more and more new targeted drugs will become available.
2014
- Female gender in the setting of liver transplantation
[Articolo su rivista]
Rodríguez Castro, Kryssia Isabel; De Martin, Eleonora; Gambato, Martina; Lazzaro, Silvia; Villa, Erica; Burra, Patrizia
abstract
The evolution of liver diseases to end-stage liver disease or to acute hepatic failure, the evaluation process for liver transplantation, the organ allocation decision-making, as well as the post-transplant outcomes are different between female and male genders. Women's access to liver transplantation is hampered by the use of model for end-stage liver disease (MELD) score, in which creatinine values exert a systematic bias against women due to their lower values even in the presence of variable degrees of renal dysfunction. Furthermore, even when correcting MELD score for gender-appropriate creatinine determination, a quantifiable uneven access to transplant prevails, demonstrating that other factors are also involved. While some of the differences can be explained from the epidemiological point of view, hormonal status plays an important role. Moreover, the pre-menopausal and post-menopausal stages imply profound differences in a woman's physiology, including not only the passage from the fertile age to the non-fertile stage, but also the loss of estrogens and their potentially protective role in delaying liver fibrosis progression, amongst others. With menopause, the tendency to gain weight may contribute to the development of or worsening of pre-existing metabolic syndrome. As an increasing number of patients are transplanted for non-alcoholic steatohepatitis, and as the average age at transplant increases, clinicians must be prepared for the management of this particular condition, especially in post-menopausal women, who are at particular risk of developing metabolic complications after menopause.
2014
- Letter: TNFα blockers and psoriasis: A 'reasonable paradox' - The role of TH-17 cells
[Articolo su rivista]
Sartini, A.; Di Girolamo, M.; Scarcelli, A.; Bertani, A.; Marzi, L.; Lasagni, C.; Merighi, A.; Villa, E.
abstract
2014
- The role played by gender in viral hepatitis
[Articolo su rivista]
Bernabucci, Veronica; Villa, Erica
abstract
Although not a classical target for estrogens, the liver is a target for their action and is sensitive to their deprivation. The occurrence of menopause is accompanied by a chain of events depending on the progressive estrogen deprivation that eventually leads to a shift from a low inflammatory to a high inflammatory state. This has a series of well-known consequences in many different organs and tissues (bone, heart, brain, body fat etc.) among which the liver is particularly interesting. The consequences are extremely evident in HCV-positive women in whom HCV infection and menopause cooperate to induce higher necro-inflammatory features, increased hepatic steatosis and eventually faster progression of fibrosis. In addition, menopause is the strongest negative factor for sustained viral response (SVR) in HCV-positive females, especially HCV genotype 1 (in whom menopause was the only independent factor for failure of antiviral therapy). This suggests that HCV-positive women should be treated early during fertile age to obtain maximal response to antiviral therapy.
2014
- Transforming growth factor-β as a therapeutic target in hepatocellular carcinoma
[Articolo su rivista]
Giannelli, Gianluigi; Villa, Erica; Lahn, Michael
abstract
Hepatocellular carcinoma arises in patients as a consequence of long-standing preexisting liver illnesses, including viral hepatitis, alcohol abuse, or metabolic disease. In such preexisting liver diseases, TGF-β plays an important role in orchestrating a favorable microenvironment for tumor cell growth and promoting epithelial-mesenchymal transition (EMT). TGF-β signaling promotes hepatocellular carcinoma progression by two mechanisms: first, via an intrinsic activity as an autocrine or paracrine growth factor and, second, via an extrinsic activity by inducing microenvironment changes, including cancer-associated fibroblasts, T regulatory cells, and inflammatory mediators. Although there is an increasing understanding on how TGF-β signaling is associated with tumor progression in hepatocellular carcinoma, it is not clear whether TGF-β signaling is limited to a certain subgroup of patients with hepatocellular carcinoma or is a key driver of hepatocellular carcinoma during the entire tumorigenesis of hepatocellular carcinoma. Inhibitors of the TGF-β signaling have been shown to block hepatocellular carcinoma growth and progression by modulating EMT in different experimental models, leading to the clinical investigation of the TGF-β inhibitor LY2157299 monohydrate in hepatocellular carcinoma. Preliminary results from a phase II clinical trial have shown improved clinical outcome and also changes consistent with a reduction of EMT.
2014
- Update on Alcohol and Viral Hepatitis
[Articolo su rivista]
Gitto, Stefano; Vitale, Giovanni; Villa, Erica; Andreone, Pietro
abstract
Alcohol consumption is often associated with viral hepatitis. Although alcohol is known to worsen viral liver disease, the interactions between alcohol and viral hepatitis are not fully understood. Molecular alterations in the liver due to alcohol and viral hepatitis include effects on viral replication, increased oxidative stress, cytotoxicity, and a weakened immune response. Clinically, alcohol enhances disease progression and favors induction of primitive liver neoplasm. The use of new antivirals for hepatitis C and well-established drugs for hepatitis B will determine how viral hepatitis can be controlled in a large percentage of these patients. However, alcohol-related liver disease continues to represent a barrier for access to antivirals, and it remains an unresolved health issue.
2013
- Cost-effectiveness of sorafenib treatment in field practice for patients with hepatocellular carcinoma
[Articolo su rivista]
Cammà, Calogero; Cabibbo, Giuseppe; Petta, Salvatore; Enea, Marco; Iavarone, Massimo; Grieco, Antonio; Gasbarrini, Antonio; Villa, Erica; Zavaglia, Claudio; Bruno, Raffaele; Colombo, Massimo; Craxì, Antonio
abstract
The purpose was to assess the cost-effectiveness of sorafenib in the treatment of hepatocellular carcinoma (HCC) patients incorporating current prices and the results of the recent published field practice SOraFenib Italian Assessment (SOFIA) study. We created a Markov Decision Model to evaluate, in a hypothetical cohort of Caucasian male patients, aged 67 years with Barcelona Clinic Liver Cancer (BCLC) C HCC, or BCLC B HCC who were unfit or failed to respond to locoregional therapies, well compensated cirrhosis, and with performance status 0-1 according to Eastern Cooperative Oncology Group (ECOG), the cost-effectiveness of the following strategies: (1) full or dose-adjusted sorafenib for BCLC B and C patients together; (2) full or dose-adjusted sorafenib for BCLC B patients; (3) full or dose-adjusted sorafenib for BCLC C patients. Outcomes include quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratio (ICER). In the base-case analysis dose-adjusted sorafenib was the most effective of the evaluated strategies. For dose-adjusted sorafenib, QALY was 0.44 for BCLC B and C patients together, 0.44 for BCLC C patients, and 0.38 for BCLC B patients. The ICER of dose-adjusted sorafenib compared with BSC was €34,534 per QALY gained for BCLC B and C patients together, €27,916 per QALY gained for BCLC C patients, and €54,881 per QALY gained for BCLC B patients. Results were sensitive to BSC survival rate, and sorafenib treatment duration.
2013
- EFFICACY AND SAFETY OF ENTECAVIR (ETV) PROPHYLAXIS IN INACTIVE HBV CARRIERS WHO UNDERWENT CHEMOTHERAPY FOR SOLID OR HAEMATOLOGICAL CANCER: INTERIM ANALYSIS OF A COHORT STUDY.
[Abstract in Rivista]
V., Di Marco; E., Angelucci; Pietrangelo, Antonello; F., Salerno; G. A., Niro; B., Daniele; M., Vinci; Villa, Erica
abstract
-
2013
- Influence of age and gender before and after liver transplantation
[Articolo su rivista]
Burra, Patrizia; De Martin, Eleonora; Gitto, Stefano; Villa, Erica
abstract
Women constitute a particular group among patients with chronic liver disease and in the post-liver transplantation (LT) setting: they are set apart not only by traditional differences with respect to men (ie, body mass index, different etiologies of liver disease, and accessibility to transplantation) but also in increasingly evident ways related to hormonal changes that characterize first the fertile age and subsequently the postmenopausal period (eg, disease course variability and responses to therapy). The aim of this review is, therefore, to evaluate the role of the interplay of factors such as age, gender, and hormones in influencing the natural history of chronic liver disease before and after LT and their importance in determining outcomes after LT. As the population requiring LT ages and the mean age at transplantation increases, older females are being considered for transplantation. Older patients are at greater risk for nonalcoholic steatohepatitis, osteoporosis, and a worse response to antiviral therapy. Female gender per se is associated with a greater risk for osteoporosis because of metabolic changes after menopause, the bodily structure of females, and, in the population of patients with chronic liver disease, the greater prevalence of cholestatic and autoimmune liver diseases. With menopause, the fall of protective estrogen levels can lead to increased fibrosis progression, and this represents a negative turning point for women with chronic liver disease and especially for patients with hepatitis C. Therefore, the notion of gender as a binary female/male factor is now giving way to the awareness of more complex disease processes within the female gender that follow hormonal, social, and age patterns and need to be addressed directly and specifically.
2013
- Reply: To PMID 22819864
[Articolo su rivista]
Villa, Erica; Cammà, Calogero; Valla, Dominique
abstract
na
2013
- Sex-oriented diagnosis and therapy of hepatitis C
[Articolo su rivista]
Villa, E.
abstract
Chronic liver disease progresses at unequal rates in the 2 sexes both in viral hepatitis and in liver injury of different etiology. Fibrosis and/or cirrhosis develop earlier and are more severe in men than they are in women. Estrogens are supposed to have a protective role in preventing progression of liver injury toward fibrosis. This has been shown to be true in experimental models and in clinical studies. The experimental and clinical data also support the view that the course of hepatitis C and the response to therapy are heavily influenced by sex. In designing future clinical trials, this should be taken into account as the sustained response rate cannot be expected to be comparable between the 2 sexes, and for that matter within the female sex (ie, in fertile vs menopausal women). Care should be taken to enroll a suitable number of women and to stratify them by reproductive status. © 2013 FBCommunication s.r.l. a socio unico.
2013
- Successful liver transplantation in a patient with splanchnic vein thrombosis and pulmonary embolism due to polycythemia vera with Jak2v617f mutation and heparin-induced thrombocytopenia.
[Articolo su rivista]
Biagioni, E; Pedrazzi, Paola; Marietta, M; DI BENEDETTO, Fabrizio; Villa, Erica; Luppi, Mario; Girardis, Massimo
abstract
Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin
treatment resulting in a severe acquired thrombophilic condition with an
associated mortality of about 10 %. We report the first case of successful urgent
liver transplantation (LT) in a patient with end-stage liver disease due to a
Budd-Chiari syndrome, portal vein thrombosis and pulmonary embolism due to
acquired thrombophilia associated to polycythemia vera carrying JAK2V617F gene
mutation and HIT in the acute phase. Lepirudin was used to provide
anticoagulation in the LT perioperative period that was performed without
haemorrhagic and thrombotic complications despite the donor received heparin
during liver explantation.
2012
- Anticoagulation in cirrhosis.
[Articolo su rivista]
Villa, Erica; N., De Maria
abstract
The Authors review and comment a recent publication by Senzolo et al. on this topic published in Liver International
2012
- Enoxaparin prevents portal vein thrombosis and liver decompensation in patients
with advanced cirrhosis
[Articolo su rivista]
Villa, Erica; C., Cammà; M., Marietta; Luongo, Monica; Critelli, Rosina Maria; S., Colopi; C., Tata; Zecchini, Ramona; S., Gitto; S., Petta; B., Lei; Bernabucci, Veronica; Vukotic, Ranka; N., De Maria; Schepis, Filippo; A., Karampatou; C., Caporali; L., Simoni; M., Del Buono; B., Zambotto; Turola, Elena; G., Fornaciari; S., Schianchi; A., Ferrari; D., Valla
abstract
BACKGROUND & AIMS: We performed a randomized controlled trial to evaluate the safety and efficacy of enoxaparin, a low-molecular-weight heparin, in preventing portal vein thrombosis (PVT) in patients with advanced cirrhosis.
METHODS: In a nonblinded, single-center study, 70 outpatients with cirrhosis (Child-Pugh classes B7-C10) with demonstrated patent portal veins and without hepatocellular carcinoma were assigned randomly to groups that were given enoxaparin (4000 IU/day, subcutaneously for 48 weeks; n = 34) or no treatment
(controls, n = 36). Ultrasonography (every 3 months) and computed tomography
(every 6 months) were performed to check the portal vein axis. The primary
outcome was prevention of PVT. Radiologists and hepatologists that assessed
outcomes were blinded to group assignments. Analysis was by intention to treat.
RESULTS: At 48 weeks, none of the patients in the enoxaparin group had developed
PVT, compared with 6 of 36 (16.6%) controls (P = .025). At 96 weeks, no patient
developed PVT in the enoxaparin group, compared with 10 of 36 (27.7%) controls (P
= .001). At the end of the follow-up period, 8.8% of patients in the enoxaparin
group and 27.7% of controls developed PVT (P = .048). The actuarial probability
of PVT was lower in the enoxaparin group (P = .006). Liver decompensation was
less frequent among patients given enoxaparin (11.7%) than controls (59.4%) (P <
.0001); overall values were 38.2% vs 83.0%, respectively (P < .0001). The
actuarial probability of liver decompensation was lower in the enoxaparin group
(P < .0001). Eight patients in the enoxaparin group and 13 controls died. The
actuarial probability of survival was higher in the enoxaparin group (P = .020).
No relevant side effects or hemorrhagic events were reported.
CONCLUSIONS: In a small randomized controlled trial, a 12-month course of
enoxaparin was safe and effective in preventing PVT in patients with cirrhosis
and a Child-Pugh score of 7-10. Enoxaparin appeared to delay the occurrence of
hepatic decompensation and to improve survival.
2012
- Menopause, and not age, is a critical factor associated with a worse response to antiviral therapy in women affected by chronic hepatitis C
[Articolo su rivista]
Gitto, S; Karampatou, A; Andreone, P; Villa, Erica
abstract
Letter commenting the fact that menopause and not age is a key factor for resistance to IFN
2012
- Peginterferon-Α_2B plus ribavirin is more effective than peginterferon-Α_2A plus ribavirin in menopausal women with chronic hepatitis C
[Articolo su rivista]
Villa, Erica; Cammà, C; Di Leo, A; Karampatou, A; Enea, M; Gitto, S; Bernabucci, Veronica; Losi, L; De Maria, N; Lei, B; Ferrari, A; Vukotic, Ranka; Vignoli, P; Rendina, M; Francavilla, A.
abstract
Under-enrolment of women to randomized clinical trials, including chronic hepatitis C, has long been recognized. The aim of this study was to identify factors predictive of sustained virological response (SVR) to PEG IFN/Ribavirin antiviral therapy in relation to gender and reproductive status of female patients involved. Seven hundred and forty-six treatment-naïve patients (431 men, 315 women) treated with Peg-IFNα-2a (180 μg/week) or Peg-IFNα-2b (1.5 μg/kg/week) plus ribavirin (800-1400 mg/day) for 24 or 48 weeks were studied between 2006 and 2010. Differences in SVR rate, overall and by gender were assessed after adjustment and propensity score matching. SVR was obtained in 44.2% of Peg-IFNα-2a-treated patients and in 51.2% of Peg-IFNα-2b-treated patients (intention-to-treat; P = 0.139). Age, fibrosis stage and genotype 2 and 3 were independently associated with SVR by multivariate analysis. Analysing by gender, the difference in SVR between PEG-IFNα types was not significant in men but highly significant in women (Peg-IFNα-2a:39.1%vs Peg-IFNα-2b:54.4%, P = 0.007). This was attributable to a higher SVR rate with Peg-IFNα-2b in the difficult postmenopausal population (26.9% Peg-IFNα-2a vs 46.0% Peg-IFNα-2b, P = 0.040). In women, absence of menopause, genotype 2 hepatitis C virus infection and use of Peg-IFNα-2b were independently associated with SVR. In conclusion, predictive factors for SVR are different in men and women. Factors differing between genders are menopause, severe steatosis and peg-interferon used. The higher SVR rate with Peg-IFNα-2b in menopausal women is likely attributable to more favourable pharmacokinetics that allows Peg-IFNα-2b to reach visceral fat and oppose the increased cytokine production and enhanced inflammatory status in menopause
2012
- Reproductive status is associated with the severity of fibrosis in women with hepatitis C.
[Articolo su rivista]
Villa, Erica; Vukotic, Ranka; Cammà, C; Petta, S; DI LEO, Antonino; Gitto, S; Turola, E; Karampatou, A; Losi, L; Bernabucci, Veronica; Cenci, A; Tagliavini, S; Baraldi, E; De Maria, N; Gelmini, Roberta; Bertolini, Elena; Rendina, M; Francavilla, A.
abstract
INTRODUCTION:
Chronic hepatitis C is the main cause of death in patients with end-stage liver disease. Prognosis depends on the increase of fibrosis, whose progression is twice as rapid in men as in women. Aim of the study was to evaluate the effects of reproductive stage on fibrosis severity in women and to compare these findings with age-matched men.
MATERIALS AND METHODS:
A retrospective study of 710 consecutive patients with biopsy-proven chronic hepatitis C was conducted, using data from a clinical database of two tertiary Italian care centers. Four age-matched groups of men served as controls. Data about demographics, biochemistry, liver biopsy and ultrasonography were analyzed. Contributing factors were assessed by multivariate logistic regression analysis.
RESULTS:
Liver fibrosis was more advanced in the early menopausal than in the fully reproductive (P<0.0001) or premenopausal (P = 0.042) group. Late menopausal women had higher liver fibrosis compared with the other groups (fully reproductive, P<0.0001; premenopausal, P = <0.0001; early menopausal, P = 0.052). Multivariate analyses showed that male sex was independently associated with more severe fibrosis in the groups corresponding to premenopausal (P = 0.048) and early menopausal (P = 0.004) but not late menopausal pairs. In women, estradiol/testosterone ratio decreased markedly in early (vs. reproductive age: P = 0.002 and vs. premenopausal: P<0.0001) and late menopause (vs. reproductive age: P = 0.001; vs. premenopausal: P<0.0001). In men age-matched with menopausal women, estradiol/testosterone ratio instead increased (reproductive age group vs. early: P = 0.002 and vs. late M: P = 0.001).
CONCLUSIONS:
The severity of fibrosis in women worsens in parallel with increasing estrogen deprivation and estradiol/testosterone ratio decrease. Our data provide evidence why fibrosis progression is discontinuous in women and more linear and severe in men, in whom aging-associated estradiol/testosterone ratio increase occurs too late to noticeably influence the inflammatory process leading to fibrosis.
2012
- SCCA-IC serum levels are predictive of clinical response in HCV chronic hepatitis to antiviral therapy: A multicentric prospective study
[Articolo su rivista]
Fransvea, E.; Trerotoli, P.; Sacco, R.; Bernabucci, V.; Milella, M.; Napoli, N.; Mazzocca, A.; Renna, E.; Quaranta, M.; Angarano, G.; Villa, E.; Antonaci, S.; Giannelli, G.
abstract
The combination of pegylated interferon (Peg-IFN) and ribavirin is currently the gold standard therapy in patients with HCV chronic infection. The duration of therapy, as well as the therapeutic dosage, depend on the genotype. Identification of the genotype and rapid virological response (RVR) are widely accepted as the most important predictors of clinical outcome during antiviral therapy but to optimize cost-benefits and to reduce possible side effects, further prognostic factors are needed. Squamous cell carcinoma antigens immunocomplex (SCCA-IC) has been reported to be increased in the serum of patients with liver cancer. In this multicentric prospective study, we investigated the serum levels of SCCA-IC in 103 patients with HCV chronic infection. Serum HCV-RNA was detected before the beginning of treatment, after 4, 12, 24 or 48 weeks, and at week 24 during follow-up. RVR, early virological response and sustained virological response (SVR) were assessed following the international guidelines. SCCA-IC levels were higher in responders (238 AU, interquartile difference 130-556 AU) and decreased significantly to 125 AU (70-290 AU). The mean baseline value in nonresponders was 149 AU (86.5-306.5 AU), but after 4 weeks of treatment the serum levels decreased to 115 AU (80-280 AU): the profile of reduction was different between patients with or without a positive SVR. Logistic regression with SVR as dependent variable identified as significant independent variables: the reduction in SCCA-IC after 1 month (OR = 4.82; 95% CI 1.39-16.67; P = 0.131) and a genotype other than 1 (OR = 0.094; 95% CI 0.21-0.42; P = 0.002); sex and age were also significant factors influencing SVR. SCCA-IC seems to be a reliable independent prognostic marker of therapeutic effectiveness in anti-HCV positive patients undergoing antiviral therapy. © 2012 Blackwell Publishing Ltd.
2011
- A SIMPLIFIED REAL-TIME PCR-BASED METHOD FOR INTERLEUKIN (IL)28B GENOTYPING FROM DIFFERENT BIOLOGICAL SPECIMENS
[Abstract in Atti di Convegno]
Cariani, E.; Trenti, T.; Rota, C.; Critelli, Rosina Maria; Villa, Erica
abstract
Description of a simplified method for IL28 genotyping
2011
- Chronic viral hepatitis: Its characteristics and management
[Articolo su rivista]
Brunetto, M. R.; Balsano, C.; Burra, P.; Cariani, E.; Taliani, G.; Villa, E.
abstract
Although most patients with liver disease remain asymptomatic throughout their life, chronic viral hepatitis is a major health problem because of the signifi cant mortality rates of its complications-cirrhosis and hepatocellular carcinoma. Recent knowledge in the understanding of viral pathogenesis and the introduction of new, directly acting antivirals and new diagnostics aimed to assess both viral and host genetic heterogeneity will bring significant improvement in clinical practice. The faculty of experts of "Women in Hepatology" provided the state-of-the-art review of the impact of some new approaches to clinical decision-making. One key issue from these presentations concerned the management of patients with chronic hepatitis B and C who undergo antiviral therapy and liver transplantation. Also included in this chapter are the differences and relation between hepatitis C virus infection and nonalcoholic fatty liver disease. © FBCommunication - Modena (Italy).
2011
- ENOXAPARIN PREVENTS PORTAL VEIN THROMBOSIS (PVT) AND DECOMPENSATION IN ADVANCED CIRRHOTIC PATIENTS: FINAL REPORT OF A PROSPECTIVE RANDOMIZED CONTROLLED STUDY
[Abstract in Atti di Convegno]
Villa, E; Zecchini, R; Marietta, M; Bernabucci, V; Lei, B; Vukotic, R; Ferrari, A; De Maria, N; Schepis, F; Fornaciari, G; Schianchi, S
abstract
BACKGROUND & AIMS:
We performed a randomized controlled trial to evaluate the safety and efficacy of enoxaparin, a low-molecular-weight heparin, in preventing portal vein thrombosis (PVT) in patients with advanced cirrhosis.
METHODS:
In a nonblinded, single-center study, 70 outpatients with cirrhosis (Child-Pugh classes B7-C10) with demonstrated patent portal veins and without hepatocellular carcinoma were assigned randomly to groups that were given enoxaparin (4000 IU/day, subcutaneously for 48 weeks; n = 34) or no treatment (controls, n = 36). Ultrasonography (every 3 months) and computed tomography (every 6 months) were performed to check the portal vein axis. The primary outcome was prevention of PVT. Radiologists and hepatologists that assessed outcomes were blinded to group assignments. Analysis was by intention to treat.
RESULTS:
At 48 weeks, none of the patients in the enoxaparin group had developed PVT, compared with 6 of 36 (16.6%) controls (P = .025). At 96 weeks, no patient developed PVT in the enoxaparin group, compared with 10 of 36 (27.7%) controls (P = .001). At the end of the follow-up period, 8.8% of patients in the enoxaparin group and 27.7% of controls developed PVT (P = .048). The actuarial probability of PVT was lower in the enoxaparin group (P = .006). Liver decompensation was less frequent among patients given enoxaparin (11.7%) than controls (59.4%) (P < .0001); overall values were 38.2% vs 83.0%, respectively (P < .0001). The actuarial probability of liver decompensation was lower in the enoxaparin group (P < .0001). Eight patients in the enoxaparin group and 13 controls died. The actuarial probability of survival was higher in the enoxaparin group (P = .020). No relevant side effects or hemorrhagic events were reported.
CONCLUSIONS:
In a small randomized controlled trial, a 12-month course of enoxaparin was safe and effective in preventing PVT in patients with cirrhosis and a Child-Pugh score of 7-10. Enoxaparin appeared to delay the occurrence of hepatic decompensation and to improve survival.
2011
- Early menopause is associated with lack of response to antiviral therapy in women with chronic hepatitis C.
[Articolo su rivista]
Villa, Erica; Karampatou, A; Cammà, C; Di Leo, A; Luongo, Monica; Ferrari, A; Petta, S; Losi, L; Taliani, G; Trande, P; Lei, B; Graziosi, Amalia; Bernabucci, Veronica; Critelli, Rosina Maria; Pazienza, P; Rendina, M; Antonelli, A; Francavilla, A.
abstract
Chronic hepatitis C (CHC) and liver fibrosis progress more rapidly in men and menopausal women than in women of reproductive age. We investigated the associations among menopause, sustained virologic response (SVR), and liver damage in patients with CHC.METHODS:We performed a prospective study of 1000 consecutive, treatment-naïve patients 18 years of age and older with compensated liver disease from CHC. Liver biopsy samples were analyzed (for fibrosis, inflammation, and steatosis) before patients received standard antiviral therapy. From women (n = 442), we collected data on the presence, type, and timing of menopause; associated hormone and metabolic features; serum levels of interleukin-6; and hepatic tumor necrosis factor (TNF)-α.RESULTS:Postmenopausal women achieved SVRs less frequently than women of reproductive age (46.0% vs 67.5%; P < .0001) but as frequently as men (51.1%; P = .283). By multivariate regression analysis, independent significant predictors for women to not achieve an SVR were early menopause (odds ratio [OR], 8.055; 95% confidence interval [CI], 1.834-25.350), levels of γ-glutamyl transpeptidase (OR, 2.165; 95% CI, 1.364-3.436), infection with hepatitis C virus genotype 1 or 4 (OR, 3.861; 95% CI, 2.433-6.134), and cholesterol levels (OR, 0.985; 95% CI, 0.971-0.998). Early menopause was the only independent factor that predicted lack of an SVR among women with genotype 1 hepatitis C virus infection (OR, 3.933; 95% CI, 1.274-12.142). Baseline levels of liver inflammation, fibrosis, steatosis, serum interleukin-6 (P = .04), and hepatic TNF-α (P = .007) were significantly higher among postmenopausal women than women of reproductive age.CONCLUSIONS:Among women with CHC, early menopause was associated with a low likelihood of SVR, probably because of inflammatory factors that change at menopause
2011
- Editorial - Women in hepatology: Who and why
[Articolo su rivista]
Villa, E.; Bassendine, M.; Garcia-Tsao, G.
abstract
2011
- Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy.
[Articolo su rivista]
Iavarone, M; Cabibbo, G; Piscaglia, F; Zavaglia, C; Grieco, A; Villa, Erica; Cammà, C; Colombo, M.
abstract
A multicenter randomized controlled trial established sorafenib as a standard of care for patients with advanced hepatocellular carcinoma (HCC). Because the study was prematurely interrupted due to survival benefits in the sorafenib arm, we conducted an observational study to adequately assess risks and benefits of this regimen in field practice. Starting in 2008, all clinically compensated patients with advanced HCC and those with an intermediate HCC who were unfit or failed to respond to ablative therapies were consecutively evaluated in six liver centers in Italy, for tolerability as well as radiologic and survival response to 800-mg/d sorafenib therapy. Treatment was down-dosed or interrupted according to drug label. Two hundred ninety-six patients (88% Child-Pugh A, 75% Barcelona Clinic Liver Cancer [BCLC]-C, and 25% BCLC-B) received sorafenib for 3.8 months (95% CI 3.3-4.4). Two hundred sixty-nine (91%) patients experienced at least one adverse event (AE), whereas 161 (54%) had to reduce dosing. Treatment was interrupted in 103 (44%) for disease progression, in 95 (40%) for an AE, and in 38 (16%) for liver deterioration. The median survival was 10.5 months in the overall cohort, 8.4 months in BCLC-C versus 20.6 months in BCLC-B patients (P < 0.0001), and 21.6 months in the 77 patients treated for >70% of the time with a half dose versus 9.6 months in the 219 patients treated for >70% of the time with a full dose. At month 2 of treatment, the overall radiologic response was 8%. Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic spread of the tumor, radiologic response at month 2, and sorafenib dosing were independent predictors of shortened survival. Conclusion: Overall, safety, effectiveness, and generalizability of sorafenib therapy in HCC was validated in field practice. The effectiveness of half-dosed sorafenib may have implications for tailored therapy.
2011
- Interleukin 28B genotype determination using DNA from different sources: A simple and reliable tool for the epidemiological and clinical characterization of hepatitis C.
[Articolo su rivista]
Cariani, E; Critelli, Rosina Maria; Rota, C; Luongo, Monica; Trenti, T; Villa, Erica
abstract
Recent studies reported a close correlation between polymorphisms in the Interleukin (IL)28B gene and rates of resolution of hepatitis C virus infection occurring spontaneously or induced by treatment. The diagnostic utility of IL28B genotype, however, is not understood completely. For rapid data collection on the natural history of HCV infection in patients with different IL28B genotype, simple, sensitive and rapid methods suitable for non-invasive and archival clinical samples are needed urgently. A real-time polymerase chain reaction (PCR) method for IL28B typing (rs12979860) was developed using very small DNA quantities extracted from different biological specimens. Consistent IL28B genotyping of at least two DNA samples obtained from different sources such as whole blood, buccal swab, serum, and formalin fixed paraffin-embedded liver tissue was obtained from 58 patients with liver disease of mixed etiology. IL28B genotype prevalence in 170 patients with liver disease in this region of Italy was consistent with data reported in Caucasian populations. Differential distribution of genotypes was observed according to response to treatment in 68 patients infected with HCV, with higher prevalence of CC genotype in responders (50%) compared to non-responders (17.85%; p=0.015). These results indicate that the possibility of reliable IL28B genotyping using different DNA sources may represent a useful tool for both clinical research and characterization of patients with hepatitis C.
2011
- Natural history of chronic HBV infection: special emphasis on the prognostic implications of the inactive carrier state versus chronic hepatitis.
[Articolo su rivista]
Villa, Erica; Fattovich, G; Mauro, Antonella; Pasino, M.
abstract
The evaluation of the natural history of chronic hepatitis B virus (HBV) infection requires the precise definition of the various clinical conditions that can be encountered (i.e. inactive carrier state or subject with liver disease activity). This can be achieved by repeat monitoring of ALT, serum HBV-DNA levels (over a period of at least 1 year, according to international guidelines) and/or evaluation of HBsAg titre. Liver biopsy may offer additional information although it is not mandatory. Overall, the natural history of the true inactive carrier is benign: reactivation of hepatitis, especially in Western countries, is rare and is usually due to co-factors (like alcohol or drugs); spontaneous HBsAg loss is frequent (around 1% per year) and HCC development rare. On the other hand, in patients with chronic hepatitis B or cirrhosis, the risk of reactivation, of HCC development and of liver-related mortality is much higher, especially in Eastern countries, and should therefore lead to antiviral therapy.
2011
- Translating pharmacogenetics into clinical practice: interleukin (IL)28B and inosine triphosphatase (ITPA) polymophisms in hepatitis C virus (HCV) infection.
[Articolo su rivista]
Cariani, E; Villa, Erica; Rota, C; Critelli, Rosina Maria; Trenti, T.
abstract
Hepatitis C virus (HCV) infection is frequently characterized by evolution to chronicity and by a variable clinical course of the disease. The clinical heterogeneities of HCV infection and the imperfect predictability of the response to interferon (IFN) have suggested the need to search for a genetic basis of clinical features. This led to the discovery of genetic polymorphisms playing a major role in the evolution of infection, as well as on treatment response and adverse effects. This review will cover recent reports on the subject, focusing on the potential use of the new genetic markers in the diagnostic algorithm for the stratification of patients for personalized antiviral regimens.
2010
- ANTICOAGULANT THERAPY IS SAFE AND EFFECTIVE IN PREVENTING PORTAL VEIN THROMBOSIS (PVT) IN ADVANCED CIRRHOTIC PATIENTS: A PROSPECTIVE RANDOMIZED CONTROLLED STUDY
[Abstract in Atti di Convegno]
Zecchini, R; Ferrari, A; Bernabucci, V; Lei, B; Vukotic, R; De Maria, N; Schepis, F; Marietta, M; Fornaciari, G; Schianchi, S; Villa, E
abstract
BACKGROUND & AIMS:
We performed a randomized controlled trial to evaluate the safety and efficacy of enoxaparin, a low-molecular-weight heparin, in preventing portal vein thrombosis (PVT) in patients with advanced cirrhosis.
METHODS:
In a nonblinded, single-center study, 70 outpatients with cirrhosis (Child-Pugh classes B7-C10) with demonstrated patent portal veins and without hepatocellular carcinoma were assigned randomly to groups that were given enoxaparin (4000 IU/day, subcutaneously for 48 weeks; n = 34) or no treatment (controls, n = 36). Ultrasonography (every 3 months) and computed tomography (every 6 months) were performed to check the portal vein axis. The primary outcome was prevention of PVT. Radiologists and hepatologists that assessed outcomes were blinded to group assignments. Analysis was by intention to treat.
RESULTS:
At 48 weeks, none of the patients in the enoxaparin group had developed PVT, compared with 6 of 36 (16.6%) controls (P = .025). At 96 weeks, no patient developed PVT in the enoxaparin group, compared with 10 of 36 (27.7%) controls (P = .001). At the end of the follow-up period, 8.8% of patients in the enoxaparin group and 27.7% of controls developed PVT (P = .048). The actuarial probability of PVT was lower in the enoxaparin group (P = .006). Liver decompensation was less frequent among patients given enoxaparin (11.7%) than controls (59.4%) (P < .0001); overall values were 38.2% vs 83.0%, respectively (P < .0001). The actuarial probability of liver decompensation was lower in the enoxaparin group (P < .0001). Eight patients in the enoxaparin group and 13 controls died. The actuarial probability of survival was higher in the enoxaparin group (P = .020). No relevant side effects or hemorrhagic events were reported.
CONCLUSIONS:
In a small randomized controlled trial, a 12-month course of enoxaparin was safe and effective in preventing PVT in patients with cirrhosis and a Child-Pugh score of 7-10. Enoxaparin appeared to delay the occurrence of hepatic decompensation and to improve survival.
2010
- Impact of menopause on the clinical management of chronic hepatitis c in women
[Articolo su rivista]
Villa, E.; Bernabucci, V.
abstract
The liver, although not a classical target for estrogens, is sensitive to their effects, particularly in cases of deprivation. Menopause is a key event in the life of a woman: apart from the hormonal changes, it determines a shift from a low-inflammatory to a proinflammatory state. This has a series of well-known consequences on many different organs and tissues, including bone, heart, brain, adipose tissue, and, among others, liver. The consequences are extremely evident in hepatitis C virus (HCV)-positive women: in these, HCV infection and menopause cooperate to induce higher necroinflammatory activity, increased hepatic steatosis, and eventually faster progression of fibrosis. Furthermore, menopause is the strongest negative factor for sustained viral response (SVR) in HCV-positive females, especially HCV genotype 1 patients (in whom this is the only independent factor for failure of antiviral therapy). This suggests that HCV-positive women should be treated early during fertile age to obtain maximal response to antiviral therapy. © 2010 FBCommunication s.r.l. a socio unico.
2010
- Interleukin-1beta, C-X-C Motif Ligand 10, and Interferon-Gamma Serum Levels in Mixed Cryoglobulinemia With or Without Autoimmune Thyroiditis.
[Articolo su rivista]
A., Antonelli; Ferri, Clodoveo; Ferrari, Silvia Martina; S., De Marco; A., Di Domenicantonio; M., Centanni; C., Pupilli; Villa, Erica; F., Menichetti; P., Fallahi
abstract
The aim of this study was to evaluate serum levels of interleukin-1beta; (IL-1beta), chemokine (C-X-C motif) ligand 10 (CXCL10), and interferon-gamma (IFN-gamma;) in a series of patients with "mixed cryoglobulinemia and hepatitis C virus chronic infection" (MC+HCV) in the presence or absence of autoimmune thyroiditis (AT) and to relate them to the clinical phenotype of these patients. Serum IL-1beta, IFN-gamma, and CXCL10 were assayed in 30 patients with MC+HCV without AT, in 30 patients with MC+HCV and AT, and in 30 sex- and age-matched controls. Cryoglobulinemic patients showed significantly higher mean IL-1beta; and CXCL10 levels than controls (P<0.01). Moreover, CXCL10 was significantly increased in patients with AT patients with respect to those without AT (P<0.01). Serum IFN-gamma; levels were not significantly higher in MC+HCV patients than in controls. In conclusion, our study demonstrates significantly high serum levels of IL-1beta; in patients with MC+HCV with and without AT compared with healthy controls. Further, significantly high serum levels of CXCL10 in patients with MC+HCV compared with healthy controls were confirmed, overall in the presence of AT. Moreover, a pathophysiological association between high circulating levels of IL-1beta; and CXCL10 has been suggested. A possible therapeutic role of the anti-IL-1 receptor antagonist (Anakinra) in MC remains to be evaluated.
2010
- Massive GI bleeding due to accidental ASA inhalation.
[Articolo su rivista]
Bianchini, M; Cavina, Maurizio; Boarino, V; Begliomini, Bruno; De Maria, N; Villa, Erica
abstract
This report describes a 38-year-old man admitted to hospital for a massive rectal bleeding and syncope. He was known to have idiopathic thrombocytopenia but he had never complained of bleeding until he was admitted to hospital with uncontrolled hemorrhage. Upper and lower endoscopic examination, performed 6 hours after occurrence of bleeding, were negative for ulcers or other bleeding lesions. However, capsule endoscopy did detect diffuse areas of petechial hemorrhage and erosions in the small bowel. Thromboelastography performed on the day of admission showed a marked decrease in platelet aggregation rate, that normalized two days after. The patient recovered with conservative treatment only. Thorough questioning did not evidence relevant events apart from inhalation of a massive quantity of acetylsalicylic acid: the patient, working as a farmer, had prepared, without protection, fodder for the animals containing a great amount of acetylsalicylic acid. Bleeding had started few hours thereafter. After recovery, bleeding did not recur despite persistent thrombocytopenia.
2010
- No inflammation? No cancer! Clear HBV early and live happily.
[Articolo su rivista]
Villa, Erica; Fattovich, G.
abstract
COMMENTARY ON: Clearance of Hepatitis B Surface Antigen and Risk of Hepatocellular Carcinoma in a cohort Chronically Infected with Hepatitis B Virus. Simonetti J, Bulkow L, McMahon BJ, Homan C, Snowball M, Negus S, Williams J, Livingston SE. Hepatology. 2009 Nov 30. [Epub ahead of print]. Copyright 2009. Reprinted with permission of John Wiley and Sons, Inc. Abstract: Some individuals who are chronically infected with hepatitis B virus (HBV) eventually lose hepatitis B surface antigen (HBsAg). Hepatocellular carcinoma (HCC) has been demonstrated to occur in a few patients after loss of HBsAg. Neither factors associated with loss of HBsAg nor the incidence of HCC thereafter have been clearly elucidated. We performed a prospective population-based cohort study in 1271 Alaska native persons with chronic HBV infection followed for an average of 19.6 years to determine factors associated with loss of HBsAg and risk of developing HCC thereafter. HBsAg loss occurred in 158 persons for a rate of HBsAg clearance of 0.7%/year. Older age, but not sex, was associated with clearance of HBsAg, and loss of HBsAg was not associated with any particular HBV genotypes (A-D, and F) found in this population. Participants were followed for an average of 108.9 months after HBsAg loss. Six patients, two with cirrhosis and four without, developed HCC a mean of 7.3 years after HBsAg clearance (range, 2.0-15.5 years). The incidence of HCC after clearance of HBsAg was 36.8 per 100,000 per year (95% CI 13.5-80.0) which was significantly lower than the rate in those who remained HBsAg-positive (195.7 cases per 100,000 person-years of follow-up [95% CI 141.1-264.5; P<0.001). After loss of HBsAg, HBV DNA was detected in the sera of 28 (18%) of those who cleared a median of 3.6 years after clearance. Conclusion: HCC can occur in persons with chronic hepatitis B who have lost HBsAg, even in the absence of cirrhosis. These persons should still be followed with periodic liver ultrasound to detect HCC early
2010
- PROCALCITONIN IS THE BEST DIAGNOSTIC AND PROGNOSTIC MARKER OF SEPSIS IN DECOMPENSATED CIRRHOTIC PATIENTS
[Abstract in Atti di Convegno]
Schepis, F; Bianchini, M; Ferretti, I; Marino, M; Bonfreschi, Silvia; Dattomo, G; Agnello, F; Wratten, Ml; De Maria, N; Villa, E
abstract
PROCALCITONIN IS THE BEST DIAGNOSTIC AND PROGNOSTIC MARKER OF SEPSIS IN DECOMPENSATED CIRRHOTIC PATIENTS
2010
- Retrospective, observational, multicentre study on an Italian population affected by chronic hepatitis C who failed to clear HCV-RNA after the combined therapy (PEG-IFN and ribavirin): NADIR study
[Articolo su rivista]
Morisco, F; Stroffolini, T; Medda, E; Amoruso, Dc; Almasio, Pl; Villa, Erica; Zuin, M; Paris, B; Stanzio, H; Caporaso, N; NADIR Study, Group*
abstract
Summary. There is a lack of information on the characteristics of patients with chronic hepatitis C virus infection (HCV) who fail to respond to antiviral treatment. We studied HCV-positive subjects with chronic liver diseases treated with pegylated-interferon (PEG-IFN) and ribavirin (RBV) who failed to clear HCV in routine clinical practice. A total of 2150 consecutive adult patients treated with PEG-IFN plus RBV therapy in 46 Italian centres between 1 July 2004, and 30 June 2005, were studied. Of the 2150 patients, 923 (42.9%) (M/F 585/335, mean age 54.8 years) failed to achieve a serum HCV-RNA clearance. Of these 923 patients, 429 (46.5%) were nonresponders, 298 (32.3%) relapsers, 168 (18.2%) drop-outs for noncompliance or adverse events and 28 (3.0%) were lost during follow-up. Overall, 642 (70.6%) patients received adequate therapy (defined as more than 80% of the drug doses for >80% of the time). Genotypes 1-4 were observed in 76.9% of cases; genotypes 2-3 in 21.2% and mixed in 1.9%, respectively. Multiple logistic regression analysis identified genotypes 1 and 4 as the sole independent predictors of the likelihood of nonresponse to therapy compared with relapse (OR: 4.38; 95% CI = 2.28-8.4). Age older than 65 years was the sole independent factor associated with no adherence to therapy (OR: 2.22; 95% CI = 1.36-3.62). Patients who fail to respond to treatment are a nonhomogeneous population with different features, and the sole factor that discriminates nonresponse from relapse is the distribution of genotypes 1-4. Co-morbidities are unable to determine the type of treatment failure and inadequate adherence to therapy mostly affects patients older than 65 years of age.
2009
- Androgen receptor alterations in hepatocarcinogenesis.
[Articolo su rivista]
Villa, Erica
abstract
Definition of the role of androgens in hepatocercionogeneiss
2009
- Pretreatment with pegylated interferon prevents emergence of lamivudine mutants in lamivudine-naive patients: a pilot study.
[Articolo su rivista]
Villa, Erica; Lei, B; Taliani, G; Graziosi, Amalia; Critelli, Rosina Maria; Luongo, Monica; Gennari, W; Bianchini, M; Ferretti, Ilva
abstract
BACKGROUND: In patients with advanced fibrosis, primary end points of long-term or possibly indefinite antiviral therapy are sustained inhibition of viral replication and avoidance of emergence of resistance. In lamivudine-treated patients, the strongest predictor of emergence of YMDD mutations is baseline hepatitis B virus (HBV) DNA viral load. We aimed to verify whether abatement of viraemia by a short course of pegylated interferon (PEG-IFN-alpha2a) treatment before lamivudine treatment could prevent the emergence of lamivudine-associated mutations during long-term therapy. METHODS: A total of 14 patients with hepatitis B e antigen (HBeAg)-negative infection (3 lamivudine-experienced and 11 lamivudine-naive), with moderate/high viraemia (>10(6) copies/ml) and with Ishak stage 4-6 at liver biopsy were sequentially treated with 180 microg PEG-IFN-alpha2a for a period long enough to reach HBV DNA levels < or =10(3) copies/ml or have a decrease of 3 log(10) copies/ml from baseline. Lamivudine was then added to PEG-IFN-alpha2a treatment for 1 month and finally continued as monotherapy for 2 years or until viral breakthrough. RESULTS: Baseline HBV DNA (mean +/-se 2.3 x 10(7) +/-7.2 x 10(7) copies/ml) decreased with PEG-IFN-alpha2a treatment to target value in mean +/-se 3.7 +/-1.3 months. None of the 11 lamivudine-naive patients developed genotypic resistance and were still HBV-DNA-negative after a mean +/-se observation period of 23 +/-2 months, whereas the three lamivudine-experienced patients developed YMDD mutations after 6, 9 and 12 months of lamivudine monotherapy (P=0.003, Fisher's exact test). CONCLUSIONS: In lamivudine-naive patients, abatement of HBV DNA<10(3) copies/ml by pretreatment with PEG-IFN-alpha2a completely prevents the emergence of YMDD mutants after 24 months of lamivudine monotherapy. This sequential schedule can optimize the use of a well tolerated, effective and inexpensive drug, such as lamivudine, in highly viraemic HBV patients.
2008
- Experimental hepatology applied to stem cells
[Articolo su rivista]
Burra, P; Tomat, S; Villa, Erica; Gasbarrini, A; Costa, An; Conconi, Mt; Forbes, Sj; Farinati, F; Cozzi, E; Alison, Mr; Russo, Fp
abstract
Transplantation is an accepted treatment today for many people suffering from organ failure. More and more patients are referred for transplant surgery, and the waiting lists are growing longer because not enough organs and tissues are donated for transplantation. This has led to several potentially viable alternatives being considered, including bio-artificial support devices, the transplantation of mature cells or stem/progenitor cells and the potential transplantation of xenogenic organs and cells [Burra P, Samuel D, Wendon J, Pietrangelo A, Gupta S. Strategies for liver support: from stem cells to xenotransplantation. J Hepatol 2004;41:1050-9]. Numerous investigators around the world are engaged in these investigations and the pace of discovery has begun to accelerate in recent years. To take stock of the achievements of recent years, the AISF sponsored a Single-Topic Conference, held in Padua on 26-27 May, 2006, with the participation of many leading investigators from various parts of Italy and Europe. This present paper summarizes the content of the Conference. Different issues were analysed, from the biology of stem cells to the possible use of gene therapy. The speakers were clinicians and scientists interested in diseases not only of the liver but also of other organs such as the kidney or heart. The fact that numerous specialties were represented helped the audience to understand the stem cell research area from different standpoints, and what research has achieved so far.
2008
- Role of estrogen in liver cancer
[Articolo su rivista]
Villa, Erica
abstract
Liver cancer is the fifth most common cancer worldwide and despite increasing implementation of ultrasonographic surveillance strategies, its incidence is rising, especially in western countries. A universal characteristic of hepatocellular carcinoma is the striking male prevalence that is found, with few exceptions, both in animals and in humans. Many different hypotheses have been put forward in an attempt to explain this finding, which is not a simple epidemiological oddity but could also have pathogenetic implications. An obvious trail to follow, as gender susceptibility is implicated, is the role played by sex hormones, namely estrogens. Estrogens are not simply involved in reproductive mechanisms; instead, it is increasingly evident that they have a role in such an enormous variety of cellular processes that their implication in liver carcinogenesis may be manifold. The purpose of this review is to provide an overview of the available data, with a special focus on the hormonal mechanisms potentially implicated in the development of liver cancer.
2008
- Statements from the Taormina expert meeting on occult hepatitis B virus infection.
[Articolo su rivista]
Raimondo, G; Allain, Jp; Brunetto, Mr; Buendia, Ma; Chen, Ds; Colombo, M; Craxì, A; Donato, F; Ferrari, C; Gaeta, Gb; Gerlich, Wh; Levrero, M; Locarnini, S; Michalak, T; Mondelli, Mu; Pawlotsky, Jm; Pollicino, T; Prati, D; Puoti, M; Samuel, D; Shouval, D; Smedile, A; Squadrito, G; Trépo, C; Villa, Erica; Will, H; Zanetti, Ar; Zoulim, F.
abstract
Report of the meeting of HBV experts to set up diagnostic and therapeutic guidelines
2007
- Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: Final long-term results
[Articolo su rivista]
Schiff, E.; Lai, C. -L.; Hadziyannis, S.; Nuehaus, P.; Terrault, N.; Colombo, M.; Tillmann, H.; Samuel, D.; Zuezem, S.; Villenueve, J. -P.; Arteburn, S.; Borroto-Esoda, K.; Brosgart, C.; Chuck, S.; Shakil, A. O.; Fung, J.; Alberti, A.; Lok, A.; Picciotto, A.; Torre, F.; Riely, C.; Trepo, C.; Bizollon, T.; Bottaa-Fridlund, D.; Gerolami, R.; Douglas, D.; Ranjan, D.; Faust, D.; Trojan, J.; Gane, E.; Villa, E.; Boarino, M.; Sokal, E.; Starkel, P.; Bonino, F.; Maurizio, B.; Gordon, F.; Pratt, J.; Berr, F.; Schiefke, I.; McCaughan, G.; Strasser, S.; Dusheiko, G.; Pageaux, G. P.; Larrey, D.; Pastore, G.; Santantonio, T.; Alexander, G.; Woodall, T.; Van Vlierberghe, H.; Colle, I.; Harley, H.; Guggenheim, J.; Myx-Staccini, A.; Metreau, J. M.; Mavier, P.; Vierling, J.; Tran, T.; Girgrah, N.; Nyberg, L.; Yuen, M. -F.; Ma, M.; Balnco, M. D.; Merli, M.; Tanzilli, P.; Angelico, M.; Di Paolo, D.; Rizzetto, M.; Marzano, A.; Lampertico, P.; Prieto, M.; Berenguer, M.; Felder, M.; Sterneck, M.; Willems, M.; Charlton, M.; Gunneson, T.; Ritter, M.; Voight, M.; Swift, J.; Shiffman, M.; Tassopoulos, N.; Klissas, I.; Naourmov, N.; Chamouard, P.; Marcellin, P.; Durand, F.; Angus, P.; Nathan, C.; Toniutto, P.; Fumo, E.; Andreone, P.; Cursaro, C.; Barcena, R.; Hoz, F. G.; Zachoval, R.; Christina, M.; De Man, R. A.; Metselaar, H.
abstract
Wait-listed (n = 226) or post-liver transplantation (n = 241) chronic hepatitis B (CHB) patients with lamivudine-resistant hepatitis B virus (HBV) were treated with adefovir dipivoxil for a median of 39 and 99 weeks, respectively. Among wait-listed patients, serum HBV DNA levels became undetectable (
2006
- Rectal amputation sparing by haemostatic therapy with recombinant factor Vlla in a patient with cytomegalovirus-related colitis
[Articolo su rivista]
Girardis, Massimo; Marietta, M; Busani, S; Codeluppi, M; Villa, Erica; Pasetto, A.
abstract
The use of rFVIIa allowed to rescue the integrity of intestinal tract
2005
- Outcomes after adult isolated small bowel transplantation: experience from a single European centre.
[Articolo su rivista]
DI BENEDETTO, Fabrizio; A., Lauro; M., Masetti; Cautero, Nicola; Quintini, Cristiano; A., Dazzi; N. D., Ruvo; T. D., Uso; Begliomini, Bruno; A., Siniscalchi; Bagni, Alessandra; M., Codeluppi; G., Ramacciato; Villa, Erica; A. D., Pinna
abstract
BACKGROUND: Adult isolated small bowel transplantation is considered the standard treatment for patients with life-threatening parenteral nutrition-related complications. Here, we report a 3-year experience in a single European centre between December 2000 and December 2003. AIMS: To evaluate and discuss pre-transplant and post-transplant factors that influenced survival rates in our series. PATIENTS: Fourteen patients, with a mean parenteral nutrition course of 27 months, were transplanted. In eight cases they had not experienced any major complication from parenteral nutrition. METHODS: We described pre-transplant evaluation and inclusion criteria, surgical technique and clinical management after transplant. Immunosuppressive therapy was based on induction drugs and Tacrolimus. We reported survival rates, major complications and rejection events. RESULTS: One-year actuarial survival rate was of 92.3\% with a mean 21-month follow-up (range 3-36 months). We had no intraoperative deaths. One patient (7.2\%) died of sepsis following cytomegalovirus enteritis. One patient underwent graftectomy (7.2\%) for intractable severe acute rejection. One-year actuarial graft survival rate of 85.1\%. One patient (7.2\%) affected by post-transplant lymphoproliferative disease is alive and disease-free after 8 months. CONCLUSION: We believe candidate selection, induction therapy, donor selection and short ischemia time play an important role in survival after small bowel transplantation.
2005
- Topical treatment of distal active ulcerative colitis with beclomethasone dipropionate or mesalamine: A single-blind randomized controlled trial
[Articolo su rivista]
Gionchetti, P.; D'Arienzo, A.; Rizzello, F.; Manguso, F.; Maieron, R.; Lecis, P. E.; Valpiani, D.; Iaquinto, G.; Annese, V.; Balzano, A.; Varoli, G.; Campieri, M.; Bennato, R.; Zilli, M.; Biedo, F. C.; Germana, B.; Bove, A.; Lombardi, G.; Pasquale, L.; Andriulli, A.; D'Albasio, G.; Bagnoli, S.; Adamo, S.; Desideri, S.; Benedetti, G.; Sablich, R.; Riegler, G.; Caserta, L.; Belletta, M.; Benedetti, A.; Ridolfi, F.; Blasi, A.; Inserra, G.; Prada, A.; Ferrau, O.; Turiano, S.; Loriga, P.; Muscas, A.; Murgia, R.; Colombo, E.; Canevelli, E.; Menardo, G.; Dagnino, F.; Monica, F.; Giordano, M.; Torelli, I.; Cuoco, D. L.; Villa, E.; Rigo, G.; Bertani, A.; Cremonini, C.; Minoli, G.; Meucci, G.; Cattoni, M.
abstract
Goals: Therapy for active ulcerative colitis (UC) usually involves rectal formulations of corticosteroids (CS), which are characterized by the risk of systemic steroid-related adverse effects. Background: To compare the efficacy and safety of the topically acting CS beclomethasone dipropionate (BDP) versus mesalamine (5-ASA) in the treatment of active UC. Study: Patients with mild to moderate distal active UC were randomized to a 6-week treatment with BDP 3 mg enema o.d. or 5-ASA 1 g enema daily in a single-blind, multicenter, parallel-group, controlled study. The primary efficacy variable was the decrease in Disease Activity Index (DAI) score. Safety variables were adrenal function, monitoring of adverse events, vital signs, and laboratory parameters. Results: A total of 217 patients were enrolled and treated with BDP (n = 111) or 5-ASA (n = 106). A significant decrease in the DAI score (P < 0.05) was observed in both treatment groups, with a clinical remission rate of 36.7% in the BDP group and of 29.2% in the 5-ASA group. Both treatments were well tolerated. No changes from baseline in morning cortisol levels were observed in the BDP group. Conclusions: BDP administered as a rectal enema over a 6-week treatment period was efficacious and safe in patients with active UC, without interference with pituitary adrenal axis. Copyright © 2005 by Lippincott Williams & Wilkins.
2004
- Characterization of mutations in ATP8B1 associated with hereditary cholestasis
[Articolo su rivista]
Lwj, Klomp; Jc, Vargas; SWC Van, Mil; L., Pawlikowska; Ss, Strautnieks; MJT Van, Eijk; Jj, Juijn; C., Pabon Pena; Lb, Smith; Ja, Deyoung; Ja, Byrne; J., Gombert; G., Van der Brugge; R., Berger; I., Jankowska; J., Pawlowska; Villa, Erica; As, Knisely; Rj, Thompson
abstract
Progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC) are clinically distinct hereditary disorders. PFIC patients suffer from chronic cholestasis and develop liver fibrosis. BRIC patients experience intermittent attacks of cholestasis that resolve spontaneously. Mutations in ATP8B1(previously FIC1) may result in PFIC or BRIC. We report the genomic organization of ATP8B1 and mutation analyses of 180 families with PFIC or BRIC that identified 54 distinct disease mutations, including 10 mutations predicted to disrupt splicing, 6 nonsense mutations, 11 small insertion or deletion mutations predicted to induce frameshifts, 1 large genomic deletion, 2 small inframe deletions, and 24 missense mutations. Most mutations are rare, occurring in 1-3 families, or are limited to specific populations. Many patients are compound heterozygous for 2 mutations. Mutation type or location correlates overall with clinical severity: missense mutations are more common in BRIC (58% vs. 38% in PFIC), while nonsense, frameshifting, and large deletion mutations are more common in PFIC (41% vs. 16% in BRIC). Some mutations, however, lead to a wide range of phenotypes, from PFIC to BRIC or even no clinical disease. ATP8B1 mutations were detected in 30% and 41%, respectively, of the PFIC and BRIC patients screened. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.comljpages/0270-9139/suppmat/index.html) and at www.atp8b1-primers.nl.
2004
- Hepatic allograft salvage with early Doppler ultrasound diagnosis of acute vena cava thrombosis
[Articolo su rivista]
Bertani, H; Pinna, Ad; DI BENEDETTO, Fabrizio; Quintini, Cristiano; Miller, C; Villa, Erica
abstract
Postoperative inferior vena cava obstruction is an uncommon complication after liver transplantation. Outflow obstruction, if not rapidly corrected, can lead to graft failure and the patient's death. We report a case in which Doppler ultrasound showed the thrombus inside the vessel, excluding extrahepatic causes of venous outflow obstruction, and permitted early surgical correction of the complication without graft loss.
2004
- Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection
[Articolo su rivista]
T., Pollicino; G., Squadrito; G., Cerenzia; I., Cacciola; G., Raffa; A., Craxi; F., Farinati; G., Missale; A., Smedile; C., Tiribelli; Villa, Erica; G., Raimondo
abstract
Background & Aims: Occult hepatitis B virus (HBV) infection is characterized by persistence of HBV DNA into the tissue of hepatitis B surface antigen-negative individuals. The clinical relevance of this peculiar infection is still under debate. In particular, the impact of occult HBV infection in cases of hepatocellular carcinoma (HCC) is uncertain. We investigated the prevalence and molecular status of occult HBV in patients with HCC. Methods: We tested tumor tissues from 107 patients with HCC and the corresponding nontumor liver tissue from 72 of these patients for HBV DNA. We also examined, liver specimens from :192 patients with chronic hepatitis. All cases were hepatitis B surface antigen negative. Covalently closed circular HBV genomes, HBV transcripts, and viral integrated forms were investigated in cases of HCC found positive for occult HBV. Results: Viral DNA was detected in 68 of 107 cases of HCC (63.5%) and in 63 of 192 cases of chronic hepatitis (32.8%) (P < 0.0001; odds ratio, 3.6; 95% confidence interval, 2.2-5.9). The significant association of occult HBV with HCC was irrespective of age, sex, and contemporary hepatitis C virus infection. Both integrated viral DNA and covalently closed circular HBV genomes were detected in patients with occult HBV. Moreover, the presence of free HBV genomes was associated with persistence of viral transcription and replication. Conclusions: Our findings provide clear evidence that occult HBV is a risk factor for development of HCC and show that the potential mechanisms whereby overt HBV might induce tumor formation are mostly maintained in cases of occult infection.
2004
- Natural history of chronic HBV in northern Italy: Morbidity and morality after 30 years
[Articolo su rivista]
M., Manno; C., Camma; Schepis, Filippo; F., Bassi; Gelmini, Roberta; F., Giannini; F., Miselli; Grottola, Antonella; I., Ferretti; C., Vecchi; M., De Palma; Villa, Erica
abstract
Background & Aims: Increased morbidity and mortality from liver disease have been reported in chronic hepatitis B surface antigen (HBsAg) carriers, but data on survival are equivocal. To assess the impact of hepatitis B virus (HBV) infection on survival and liver-related complications, we re-evaluated, after a mean follow-up of 30 years, a cohort of 296 blood donors excluded from donation 30 years ago when HBsAg screening became mandatory. Methods: Clinical and ultrasound examination and biochemical and virologic tests were performed. The cause of death was recorded and survival was compared with a control population of 157 HBV-negative blood donors selected at baseline. Results: Thirty-two (10.8%) cases and 14 controls (8.9%) (P = 0.625) had died; 3 of 32 (9.3%) and 1 of 14 (7.1%) deaths were liver-related. Hepatocellular carcinoma (HCC) caused death in 2 of 296 and 1 of 157 subjects (0.6% in each group). Alcohol-induced cirrhosis occured in the remaining subject. By Cox regression analysis, survival was independently predicted by older age, abnormal gamma-glutamyl transpeptidase (GGT) levels, and presence of medical comorbidities at baseline. Unequivocal liver disease was found in 4 carriers only. No disease decompensation occurred during follow-up. Fifty-nine (32.2%) carriers cleared HBsAg (yearly incidence, 1.0%). Full-length serum HBV DNA was present in 32.2% of persistently HBsAg-positive individuals (average titer always <10(5) copies/mL). Conclusions: Over a 30-year period, chronic HBV carrier blood donors from Northern Italy did not develop clinically significant liver disease, hepatocellular cancer, or other liver-related morbidity or mortality at a higher rate than uninfected controls. The presence of medical comorbidities, older age at diagnosis, and abnormal GGT levels were independent predictors of death among chronic HBV carriers.
2003
- Bioartificial liver support with human hepatocytes and MARS in fulminant hepatic failure: comparison with standard therapy
[Abstract in Atti di Convegno]
R., Balugani; H., Bertani; M., del Buono; R., Iemmolo; Gelmini, Roberta; Girardis, Massimo; Villa, Erica
abstract
x
2003
- Capsule enteroscopy in small bowel transplantation
[Articolo su rivista]
R., de Franchis; E., Rondonotti; C., Abbiati; G., Beccari; A., Merighi; A., Pinna; Villa, Erica
abstract
Background. Enteroscopy plays a key role in the post-operative monitoring of patients with small bowel transplantation for the early detection of post-transplant complications and for the assessment of the graft's integrity. Routine surveillance enteroscopies (trans-stomal terminal ileoscopy or jejunoscopy) are invasive, may be unsafe in frail patients, and only allow incomplete exploration of the transplanted graft, which may be unsatisfactory, since the distribution of the lesions is often patchy or segmental. Aims. To evaluate the potential of capsule enteroscopy, a new, minimally invasive technique which allows complete exploration of the small bowel, in small bowel transplant recipients. Methods. Five small bowel transplanted patients underwent capsule enteroscopy with the GIVEN(R) endoscopy system. The results of capsule enteroscopy were compared with those of trans-stomal ileoscopy. Results. Capsule enteroscopy was better tolerated than ileoscopy and good quality images of the small bowel were obtained in four patients. The terminal ileum was normal both on ileoscopy and capsule enteroscopy. Mucosal changes in segments not reached by ileoscopy were detected by capsule enteroscopy in three of four patients. Conclusions. Capsule enteroscopy is better tolerated than ileoscopy, allows complete exploration of the transplanted graft and can detect mucosal changes in segments not reached by ileoscopy. (C) 2003 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
2003
- Clinical staging systems for hepatocellular carcinoma: Comparison with estrogen receptor classification
[Abstract in Rivista]
Villa, Erica; Colantoni, Alessandra; Camma, C; Grottola, Antonella; Ferretti, Ilva; Gelmini, Roberta; De Maria, N; Manenti, Federico
abstract
Clinical staging systems for hepatocellular carcinoma: Comparison with estrogen receptor classification
2003
- Estrogen receptor classification for hepatocellular carcinoma: Comparison with clinical staging systems
[Articolo su rivista]
Villa, Erica; A., Colantoni; C., Camma; Grottola, Antonella; Gelmini, Roberta; P., Buttafoco; I., Ferretti; Manenti, Federico
abstract
Purpose: Several scoring systems to evaluate patients with hepatocellular carcinoma (HCC) exist. A good scoring system should provide information on prognosis and guide therapeutic decisions. The presence of variant liver estrogen receptor (ER) transcripts in the tumor has been shown to be the strongest negative predictor of survival in HCC. The aim of this study was to compare the predictive value of the commonly applied clinical scoring systems for survival of patients with HCC with that of the evaluation of ER in patients with HCC (molecular scoring system). Materials and Methods: HCC was staged according to the Okuda classification, Barcelona Clinic Liver Cancer classification, Italian classification system (CLIP), French classification, and ER status in 96 patients. Analysis of survival was performed according to the Kaplan-Maier test and was made for each classification system and ER. A comparison between classifications was made by univariate and multivariate analysis. Results: Among the clinical classification systems, only the CLIP was able to identify patient populations with good, intermediate, and poor prognosis. On multivariate analysis, ER classification was shown to be the best predictive classification for survival of patients with HCC (P < .0001). This difference was the result of a better allocation of patients with ominous prognosis (variant ER) having nevertheless good clinical score. Conclusion: The evaluation of the presence of wild-type or variant ER transcripts in the tumor is the best predictor of survival in patients with HCC. Its accuracy in discriminating patients with good or unfavorable prognosis is significantly greater than that of the commonly used scoring systems for the staging of HCC.
2003
- Genetic analysis of HAV strains recovered from patients with acute hepatitis from southern Italy
[Articolo su rivista]
M., Chironna; Grottola, Antonella; C., Lanave; Villa, Erica; S., Barbuti; M., Quarto
abstract
Southern Italy is an endemic area for HAV infection contributing to the majority of Italian hepatitis A cases. Using molecular analysis, HAV strains have been classified in distinct genotypes and subgenotypes. To characterize HAV wildtype strains circulating in Southern Italy, sequence analysis of VP3-VP1 and VP1/2A junction regions of HAV isolates recovered from 25 patients with acute hepatitis during 2000 and 2001 was carried out. HAV isolates showed a degree of identity, after pairwise comparison with one another, ranging from 91.9-100% in the VP3-VP1 junction region and 89.9-100% in the VP1/2A junction region. All strains belonged to genotype 1, with 84% (21/25) of samples clustering in subgenotype IA and 16% (4/25) in subgenotype IB. Cocirculation of subgenotypes IA and IB was observed among isolates from 2000, whereas all strains from 2001 were subgenotype IA. In addition,the subgenotype IA strains formed different clusters, one of which was related closely to some Cuban strains, showing a percent similarity of 98.8% in the 168-base pair segment encompassing the VP1/2A junction and the same amino acid substitution. The latter finding suggests that this subgenotype variant circulates also in the Mediterranean area. The results of the phylogenetic analysis confirm the genetic heterogeneity among HAV strains in Western Europe.
2003
- Predominance of pre-S1 mutated hepatitis B virus in a patient following treatment with adefovir dipivoxil
[Articolo su rivista]
Villa, Erica; V., Boarino; Grottola, Antonella; Gelmini, Roberta; Ng, Lama
abstract
A liver transplant recipient reinfected with a lamivudine-resistant mixed wild-type/pre-S1-deleted hepatitis B virus (HBV) strain and rescued with adefovir dipivoxil was still HBV DNA positive after more than 1 year of therapy. Analysis of serum HBV DNA, amplified by polymerase chain reaction and directly sequenced by dideoxy nucleotide chain-termination method, showed that adefovir inhibited the wild type, but not the pre-S1-deleted HBV. Predominance of the pre-S1-deleted strain over wild type after adefovir treatment suggests that either adefovir inhibited the wild type more effectively or the pre-S1 mutant replicates more efficiently. The normality of liver condition confirms that to exert its pathogenic effect, the pre-S1-deleted strain requires the presence of wild-type virus.
2003
- [Living donor liver transplantation, adult to adult].
[Articolo su rivista]
A., Pinna; M., Masetti; C., Miller; A., Dazzi; B., Begliomini; A., Siniscalchi; N., Cautero; F. D., Benedetto; A., Lauro; Girardis, Massimo; Villa, Erica; G., Ramacciato
abstract
Since living donor liver transplantation (LDLT) can offer a viable response to the lack of transplantable cadaveric organs, our center instituted an LDLT program in 2001.The authors report their experience with the first 35 LDLT procedures successfully completed at the Liver and Multiorgan Transplant Center of the University of Modena between 9 May 2001 and 21 May 2003. The case series comprised 35 patients, 7 of which received a left-half liver and 1 a left lobe.The global survival rate was 77.2\% (27 out of 35 patients), with a mean follow-up period of 295 days; the survival rate at 1 year was 81\%. In 4 cases (11\%) retransplantation was performed. The donor demographics are described; all donors returned to their normal activities before transplantation, after a mean follow-up period of 373 days. No intraoperative complications were experienced by the donors, whereas during the postoperative period, 2 donors (5.7\%) developed major complications (1 biliary fistula on the cut surface, 1 stenosis of the main bile duct).Our study shows that LDLT can be safely completed in the donor, with good results achieved in the recipient as well. Underlying these results is the accurate pretransplant assessment that continued into the operation itself. Even more important was the demonstrated ability and experience of the surgical team to attain results in the donor which we believe are necessary for carrying forth a LDLT program.
2002
- Does any medical intervention modify outcome in patients with hepatic failure
[Relazione in Atti di Convegno]
C., Bassi; A., Borghi; N., De Maria; Girardis, Massimo; A., Liberati; V., Solfrini; Villa, Erica
abstract
x
2002
- Estrogen receptor alpha mRNA variant lacking exon 5 is co-expressed with the wild-type in endometrial adenocarcinoma
[Articolo su rivista]
Cobellis, L; Reis, Fm; Driul, L; Vultaggio, G; Ferretti, Ilva; Villa, Erica; Petraglia, F.
abstract
Background: Endometrial adenocarcinoma is a typical estrogen-dependent neoplasia. The molecular mechanisms underlying carcinogenesis in the endometrium are still largely unknown. Recently, estrogen receptor (ER) mRNA splicing variants have been investigated in several normal and neoplastic human tissues. It has been suggested that the variant receptors compete with the wild-type receptors and thereby modulate the effects of estrogens and related steroids. Objective: To investigate the possible expression of the ER alpha mRNA variant-type lacking, exon 5 (ERDelta5) in endometrial adenocarcinoma and peritumoral tissues, non-neoplastic endometrium of healthy women served as control. Study design: The studs included 16 patients divided in two groups. The first group (n = 6) was submitted to hysteroscopy and endometrial biopsy for metrorrhage, showing normal proliferative (n = 2) or secretory (n = 4) endometrium, the second group (n = 10) included patients submitted to hysterectomy for endometrial adenocarcinoma (stages Ib-IIIb), In this latter group, specimens from peritumoral tissues were also analyzed (n = 31). Characterization of the variant and wild-type alpha estrogen receptor transcripts was performed by RT-PCR with primers located in exons 4 and 6. followed by southern hybridization with probes directed to a specific 29 nucleotide sequence of exon 6. internal to the amplified fragments. Results: The ER alpha mRNA variant was co-expressed with the wild-type ER in five or six samples of non-neoplastic endometrium and in 10/10 cases of adenocarcinoma, with a more intense hybridization signal corresponding to the wild-type 439 bp band compared to the variant-type 300 bp band. Specimens from peritumoral tissue also expressed the variant EPDelta5 along with wild-type ER. Conclusion: The presence of alpha mRNA variant lacking exon 5 in both normal and endometrial adenocarcinoma do not support a major role of variant estrogens receptors in the biology of endometrial cancer. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
2002
- Estrogens receptors and oxidative damage in the liver
[Articolo su rivista]
Farinati, F; Cardin, R; Bortolami, M; Grottola, Antonella; Manno, M; Colantoni, A; Villa, Erica
abstract
There is considerable evidence that reactive oxygen species (ROS) have a causative role in chronic hepatic injury and cancer development via direct and indirect mechanisms. Estrogens produce free oxygen radicals through redox cycling and affect cell proliferation, also in the liver. We are presently involved in evaluating the possible relationship between estrogens receptor expression, type of receptor, oxidative DNA damage and c-myc in chronic liver disease. The data on DNA adducts, c-myc mRNA and variant estrogen receptor in patients with HCV- or HBV-related chronic liver disease are suggesting that those positive for variant liver estrogen receptor present higher genomic oxidative damage, as reflected in 8-OHdG levels. We are also observing that patients with chronic hepatitis and cirrhosis, when positive for variant estrogen receptor, present higher c-myc m-RNA expression, a factor reportedly associated with increased genomic instability, augmented cytoproliferation and carcinogenesis. Our own and other author's data are shedding new light on estrogen pathophysiology, liver damage and hepatic cancer. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
2002
- Haemodinamic changes in living-related liver transplant: a colour-doppler ultrasound study. .
[Relazione in Atti di Convegno]
Bertani, H; Cremonini, C; DEL BUONO, Mg; Primerano, A; Gelmini, Roberta; Cautero, N; Jovine, Elio; Pinna, Antonio Daniele; Manenti, Federico; Villa, Erica
abstract
Haemodinamic changes in living-related liver transplant: a colour-doppler ultrasound study
2002
- Hepatic estrogen receptors and alcohol intake
[Articolo su rivista]
Colantoni, A; Emanuele, Ma; Kovacs, Ej; Villa, Erica; Van Thiel, Dh
abstract
Human liver contains estrogen receptors (ER) which render it sensitive to estrogen. Chronic ethanol ingestion in humans and rats results in alterations of circulating sex steroid levels and expression of sex hormone-dependent phenotype. The analysis and quantitation of hepatic estrogen receptor (ER) activity and sex hormone-responsive proteins have been performed over the past two decades. Alcohol abuse appears to induce an increase in ER content of human liver, especially in patients with alcoholic hepatitis actively drinking. This observation is reproduced in an experimental model of chronic alcohol feeding of rats. In male rat liver, the increased ER expression induced by alcohol is associated with an elevated proliferation rate of the hepatocytes. In female liver, the ER content is not affected by alcohol intake and apoptosis prevails over proliferation. The feminization of the liver in males may protect the liver from the severe alcohol-induced liver injury seen in females. (C) 2002 Published by Elsevier Science Ireland Ltd.
2002
- Hepatocellular carcinoma - Role of estrogen receptors in the liver
[Articolo su rivista]
Villa, Erica; Grottola, Antonella; Colantoni, A; De Maria, N; Buttafoco, Paola; Ferretti, Ilva; Manenti, Federico
abstract
Experimental and clinical evidence indicates that estrogens have a relevant role in the pathogenesis of cancer of hormone-sensitive organs. Estrogen receptors (ERs) are present in liver cells. Normal liver expresses almost exclusively wild-type ERs derived from the full-length transcript of the gene. During progression of liver disease to hepatocellular carcinoma, variant forms of ERs have been demonstrated that greatly influence the course of the disease and the possibility of palliative treatment. Peritumoral cirrhotic tissue of patients with hepatocellular carcinoma, especially males, expresses a variant form of ER (vER) with an exon 5 deletion. In hepatocellular carcinoma, vER largely predominates and sometimes becomes the only form expressed. That the occurrence of vER alone is limited almost exclusively to males suggests that it could be one of the molecular events that eventually lead to the preferential development of hepatocellular carcinoma in males. In addition, the presence of vER appears most frequently in patients infected with the hepatitis B virus. The growth rate of hepatocellular carcinoma in patients with vER is also significantly higher than that in patients with tumors expressing wtER.
2002
- Intestinal/multivisceral transplantation: University of Modena experience
[Articolo su rivista]
Masetti, Michele; Jovine, Elio; Begliomini, Bruno; Cautero, Nicola; DI BENEDETTO, Fabrizio; Gelmini, Roberta; Villa, Erica; A., Merighi; A., Bagni; L., Bezer; Ad, Pinna
abstract
N/A
2002
- Literature overview on artificial liver support in fulminant hepatic failure: A methodological approach
[Articolo su rivista]
H., Bertani; Gelmini, Roberta; MG Del, Buono; N., De Maria; Girardis, Massimo; Villa, Erica; V., Solfrini
abstract
Artificial liver support is a therapeutic option for subjects with fulminant hepatic failure. Results of these studies suggest a possible favourable effect on this condition. The aim of the present review is to evaluate not the results of the different artificial systems available but the methodology used to achieve these results. A computer and manual search of the literature was performed, 832 pertinent references were retrieved. Seventy-seven were full papers reporting the application of artificial liver support in animals or humans (15 RCTs (3 in humans, 12 in animals), 53 uncontrolled phase I trials, 9 case reports)., The results of this review indicate that, although the rationale of artificial liver support as shown by animal studies is acceptable, the widespread use in clinical practice is not justified and a controlled design for the studies on artificial liver support systems is mandatory.
2002
- Orthogonal polarization spectral imaging: A new tool in morphologic surveillance in intestinal transplant recipients
[Articolo su rivista]
Cautero, Nicola; Gelmini, Roberta; Villa, Erica; A., Bagni; A., Merighi; Masetti, Michele; DI BENEDETTO, Fabrizio; F., Di Francesco; L., Bezer; Begliomini, Bruno; Jovine, Elio; Ad, Pinna
abstract
Intestinal transplantation (ITx) can be considered a lifesaving procedure in patients with intestinal failure. However, despite improvements in the surgical technique and in patient selection, as well as in immunosuppressive therapy, successful ITx requires an early diagnosis of graft rejection. Acute cellular rejection (ACR) remains the most common and serious complication in clinical ITx. In this scenario frequent endoscopic and histologic surveillance are mandatory to achieve an early diagnosis of rejection and to tailor an effective immunosuppressive regimen. We compared zoom video endoscope (ZVE)[1] and orthogonal polarization spectral (OPS) imaging as techniques to predict qualitative modifications of microscopic architecture and villi microcirculation for the diagnosis of acute cellular rejection in small bowel transplant patients.
2002
- Phytoestrogens and liver disease
[Articolo su rivista]
Lei, B; Roncaglia, V; Vigano, R; Cremonini, C; De Maria, N; Del Buono, Mg; Manenti, Federico; Villa, Erica
abstract
Phytoestrogens are plant substances that are similar to 17-beta-estradiol and produce estrogenic effects. A protective role in the development of breast and prostate cancer has been hypothesized. Estrogen receptors and their variant forms play a significant role in the pathogenesis of hepatocellular carcinoma (HCC); therefore weak estrogenic substances in the diet may play a role in its development. To investigate the role of phytoestrogens in HCC an investigation of dietary intake of these substances has been performed. Cases, patients at first diagnosis of cirrhosis or HCC were chosen. Questionnaire was built up using indications from previously published papers, extending the registration of details of the diet to reconstruct intake of nutrients for the last year. Interviews were always performed by the same dietician. Quantities determined with the help of photos of servings. Data were analyzed with Winfood(R) database completed with data regarding content in phytoestrogens of food, beverages and seasonings. So far 92 cirrhotic patients and 32 HCCs have been interviewed. No significant difference was registered among the two groups regarding total caloric intake or single nutrients (lipids, carbohydrates, proteins). A significant lower intake of genistein was evidenced in patients at first diagnosis of HCC in comparison with cirrhotics; no significant difference was found in daidzein intake. Lignans intake was strictly related with wine intake; intake was significantly lower in cases only when wine was taken into account otherwise it was similar. Results can be summarized as follows: (1) there are no clear-cut differences (both qualitative or quantitative) between cirrhotics and HCC patients in the overall daily caloric intake while; (2) definite differences exist in the intake of some of the phytoestrogens (genistein, SEC, MAT); (3) differences between cases and controls in SEC and MAT are mainly attributable to lower alcohol intake in cases while; (4) significantly lower genistein intake in HCC only seems due to personal preferences of patients. In conclusion, these differences that we have evidenced in the diet in regard to estrogen-like substances may be relevant in modulating the risk of developing HCC in cirrhotic patients. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
2002
- Pretransplantation pre-S2 and S protein heterogeneity predisposes to hepatitis B virus recurrence after liver transplantation
[Articolo su rivista]
GROTTOLA, Antonella; BUTTAFOCO, Paola; MG Del, Buono; C., Cremonini; COLANTONI, Alessandra; GELMINI, Roberta; C., Morelli; MASETTI, Michele; JOVINE, Elio; F., Fruet; PINNA, Antonio Daniele; MANENTI, Federico; VILLA, Erica
abstract
Abstract Liver transplantation (LT) in patients with hepatitis B virus (HBV) infection often is complicated by recurrence of infection despite immunoglobulin treatment. To evaluate whether variability in HBV genomic sequences and the target of antibody to hepatitis B surface antigen action in pre-LT samples may be associated with a high recurrence rate, HBV pre-S/S regions of 14 HBV-positive candidates for LT (in 9 of these patients, HBV infection subsequently recurred) were amplified and sequenced. Two hundred ninety-one mutations in 1,167 sequenced nucleotides (24.9%) were found. Of these, 120 mutations (10.2%) led to an amino-acid change. The only significant difference between patients with and without recurrent disease was in the number of mutations in the pre-S2 region (total mutations, P = .042; missense mutations, P = .012) of pre-LT HBV DNA. In addition, a difference in amino-acid level was present in the pre-S2 region (P = .030). The delay in HBV infection recurrence was proportional to the number of pre-LT HBV mutations in the pre-S2 and S genes: the higher the number, the longer the interval between LT and recurrence of infection (pre-S2, P = .0124; S, P = .0060; total number of mutations in S protein, P = .0421). In conclusion, pre-LT determination of pre-S/S gene sequence variability showed that heterogeneity of the pre-S2 and, to a lesser extent, S genes was associated with a greater chance for HBV recurrence. Modification of B-cell epitopes of S, but especially of pre-S2, protein leading to conformational changes and alterations in the viral encapsidation and secretion process may facilitate HBV recurrence and contribute to the failure of immune globulin therapy.
2002
- Sex hormones and liver cancer
[Articolo su rivista]
De Maria, N; Manno, M; Villa, Erica
abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancy in the world and it usually occurs in individuals with chronic liver disease. The neoplasm is predominant in the male gender, where it is characterized also by a worst prognosis than in females. The pathogenesis of HCC is obscure. Because of its striking male predominance, androgens have been investigated as potential factors able to induce or at least promote hepatic carcinogenesis; this hypothesis has been also supported by the ability of androgens of inducing liver neoplasms in experimental models. On the other hand, due to the fact that HCC occurs predominantly in male cirrhotics who present a characteristic hormone imbalance with a relative hyperestrogenic state, the potential role of estrogen in liver cancer has been studied as well. In this paper, the potential role of sex hormones in liver carcinogenesis has been reviewed. (C) 2002 Published by Elsevier Science Ireland Ltd.
2002
- Small intestine microflora after intestinal/multivisceral transplantation: Preliminary results
[Articolo su rivista]
Amarri, S.; Masetti, M.; Benatti, F.; Callegari, M. L.; Morelli, L.; Villa, E.; Balli, F.; Jovine, E.; Pinna, A. D.
abstract
2002
- Special issue - Proceedings of the Congress 'Estrogen 2001' - Estrogens: Molecular and Clinical Aspects in Health and Disease - Modena, Italy, May 21-22, 2001 - Preface
[Articolo su rivista]
Villa, Erica; Carani, Cesare
abstract
Editorial
2002
- Variant estrogen receptors and their role in liver disease
[Articolo su rivista]
Villa, Erica; Colantoni, A; Grottola, Antonella; Ferretti, Ilva; Buttafoco, Paola; Bertani, H; De Maria, N; Manenti, Federico
abstract
The liver presents estrogen receptors alpha and beta. As for breast cancer, a variant form of estrogen receptor alpha transcript (ER) has been described in hepatocellular carcinoma (HCC). It is derived by an exon 5-deleted transcript (vER), which lacks the hormone-binding domain of the receptor but, being intact in the DNA-binding domain, maintains constitutive transcriptional activity. HCCs presenting vER have an extremely aggressive clinical course and are unresponsive to the antiestrogen tamoxifen. On the other hand, megestrol, a drug able to block both the wild type and the variant form of ER, influence the clinical course of HCC presenting vER. The presence of vER is associated with elevated cancer cell proliferation rate. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
2001
- Haemodinamic changes in living-related liver transplant: a colour-doppler ultrasound study. .
[Relazione in Atti di Convegno]
Bertani, H; Cremonini, C; DEL BUONO, Mg; Primerano, A; Gelmini, Roberta; Cautero, N; Jovine, Elio; Pinna, Antonio Daniele; Manenti, Federico; Villa, Erica
abstract
color-doppler ultrasound study: haemodynamic changes in living-ralated liver transplant
2001
- High doses of alpha-interferon are required in chronic hepatitis due to coinfection with hepatitis B virus and hepatitis C virus: Long term results of a prospective randomized trial
[Articolo su rivista]
Villa, Erica; Grottola, Antonella; Buttafoco, P; Colantoni, A; Bagni, A; Ferretti, Ilva; Cremonini, C; Bertani, H; Manenti, Federico
abstract
OBJECTIVE: Coinfection with hepatitis B (HBV) and hepatitis C (HCV) viruses is associated with a more severe liver disease, increased frequency in the development of hepatocellular carcinoma, and resistance to interferon (IFN) therapy when performed with the standard dosages used in single infections. In the attempt to verify whether the outcome of IFN therapy in patients with hepatitis B and hepatitis C coinfection can be improved, we have planned a prospective, randomized trial with medium to high dosages of interferon three times a week for 6 months. METHODS: Thirty patients with HBV-HCV coinfection, and chronic hepatitis were randomized to receive either 6 or 9 MU a-interferon three times a week for 6 months. Patients were HBsAg positive, anti-HBe positive, HBV DNA negative by dot blot (6/30 positive by polymerase chain reaction), and anti-HCV-positive, HCV RNA positive. Pretreatment and posttreatment liver biopsies were performed. RESULTS: Five patients treated with 9 MU IFN consistently cleared HCV RNA and HBV DNA, whereas none of those treated with 6 MU reacted in a similar fashion (p = 0.045). Responders showed significant improvement of histological activity index in comparison with nonresponders (mean Ishak score pretreatment versus posttreatment p = 0.002). Long term follow-up showed that none of the patients treated with high doses developed cirrhosis whereas 4/14 treated with low doses did develop cirrhosis. CONCLUSION: Even though the percentage was not very high, the sustained response, the striking histological improvement, and the lack of development of cirrhosis achieved in these patients, indicate that with HBV-HCV coinfection, a trial with high doses of interferon is strongly recommended. (Am J Gastroenterol 2001;96:2973-2977.
2001
- Hormonal therapy with megestrol in inoperable hepatocellular carcinoma characterized by variant oestrogen receptors
[Articolo su rivista]
Villa, Erica; I., Ferretti; Grottola, Antonella; P., Buttafoco; M. G., Del Buono; F., Giannini; M., Manno; H., Bertani; A., Dugani; F., Manenti
abstract
Variant liver oestrogen receptor transcripts in hepatocellular carcinoma are associated with aggressive clinical course and unresponsiveness to tamoxifen. To evaluate the impact on survival and on tumour growth of megestrol (progestin drug acting at post-receptorial level) we enrolled 45 patients with HCC characterized by variant liver oestrogen receptors in a prospective, randomized study with megestrol vs. placebo. Presence of Variant oestrogen receptors was determined by RT/PCR. 24 patients were randomized to no treatment and 21 to therapy with megestrol 160 mg day(-1). Results were analysed by Kaplan-Meier and Cox methods. Survival of hepatocellular carcinoma characterized by variant oestrogen receptors was extremely poor (median survival 7 months); megestrol significantly improved survival (18 months) (P = 0.0090). Tumour growth at one year was significantly slowed down in megestrol-treated patients (P = 0.0212). Bilirubin levels, presence of portal thrombosis, HBV aetiology and treatment were identified at univariate analysis as factors significantly associated with survival; at multivariate analysis, only megestrol therapy (P = 0.0003), presence of HBV infection (P = 0.0009) and presence of portal vein thrombosis (P = 0.0051) were factors independently related with survival. (1) Megestrol slows down the aggressive tumour growth of patients with hepatocellular carcinoma characterized by variant estrogen receptors and (2) is also able to favourably influence the course of disease, more than doubling median survival.
2001
- Orthogonal Polarization Spectral (OPS) Imaging: A New Tool in Morphologic Surveillance in Intestinal Transplant Recipients
[Relazione in Atti di Convegno]
N., Cautero; Gelmini, Roberta; Villa, Erica; A., Bagni; A., Merighi; M., Masetti; DI BENEDETTO, Fabrizio; F., DI FRANCESCO; L., Bezer; Begliomini, Bruno; Jovine, Elio; Pinna, Antonio Daniele
abstract
Orthogonal Polarization Spectral (OPS) Imaging: A New Tool in Morphologic Surveillance in Intestinal Transplant Recipients
2001
- Prognostic features and survival of hepatocellular carcinoma in Italy: impact of stage of disease
[Articolo su rivista]
R., Lerose; R., Molinari; Rocchi, Emilio; Manenti, Federico; Villa, Erica
abstract
The aim of this study was to evaluate the prognostic factors at presentation and survival in Italian patients with hepatocellular carcinoma (HCC). Clinical and demographic data of 176 patients consecutively observed from 1993 to 1997 were evaluated by univariate and multivariate analyses. Overall median survival was 18 months. At univariate analysis, low albumin, high bilirubin, high alkaline phosphatase, high alpha-fetoprotein (AFP); high platelet count, hepatitis B surface antigen (HBsAg)-positivity, the presence of ascites, of encephalopathy, of portal vein thrombosis (PVT), male sex, no treatment, poor differentiation, untreatable tumours and incidental diagnosis were each associated with shorter survival. HBsAg-positive subjects more often presented with untreatable lesions or diffuse tumours (P = 0.001 and P = 0.007, respectively) and had significantly worse survival (P = 0.0057). By multiple regression analysis, low albumin, high bilirubin, abnormal AFP, presence of PVT and of untreatable lesions were independent risk factors for worse survival. Thus, the most important factors influencing survival are the degree of functional impairment of the liver, the presence of hepatitis B viral (HBV) infection, the type of diagnosis and the aggressiveness of the tumour. (C) 2001 Elsevier Science Ltd. All rights reserved.
2001
- Reply to: A cut-off serum creatinine value of 1.5mg/dl for AKI To be or not to be
[Articolo su rivista]
Villa, E.; De Maria, N.; Colantoni, A.; Manno, M.; Bertani, H.
abstract
2001
- Ten-year combination treatment with colchicine and ursodeoxycholic acid for primary biliary cirrhosis: a double-blind, placebo-controlled trial on symptomatic patients
[Articolo su rivista]
Battezzati, Pm; Zuin, M; Crosignani, A; Allocca, M; Invernizzi, P; Selmi, C; Villa, Erica; Podda, M.
abstract
Background: Combined medical treatment may provide further benefit to primary biliary cirrhosis (PBC) patients administered ursodeoxycholic acid (UDCA). Aim: To evaluate the long-term effects of colchicine and UDCA in symptomatic PBC patients. Patients/methods: We extended up to 10 years the double-blind treatment of 44 symptomatic PBC patients originally included in a 3-year multicentre study comparing UDCA and colchicine (U + C) versus UDCA and placebo (U + P). Outcome measures were death or liver transplantation; incidence of clinically relevant events; clinical and quantitative variables retaining prognostic information. Results: Mean follow-up was 7 +/- 3 years. One patient was lost, three withdrew because of jaundice (U + P); two patients stopped colchicine but remained on UDCA. Eleven patients (two for liver-unrelated reasons, U + P) and six patients (U + C) died, three and two patients, respectively, were transplanted (incidence rate difference, five cases per 100 patient-years; 95% CI, -1 to 11). Hepatocellular carcinoma developed in one (U + P) and four (U + C) patients (difference, -2; CI, -5 to 1), portal hypertension complications in nine patients from each group (difference, 1; CI, -5 to 6). Trends of serum bilirubin, Mayo score, antipyrine clearance were similar among treatment groups. Conclusions: In cirrhotic PBC patients, colchicine does not offer additional benefits to UDCA. In this population, UDCA does not obviate disease progression.
2000
- Molecular screening for colon cancer detection.
[Articolo su rivista]
Villa, Erica
abstract
Molecular detection of kris can improve CRC screening
2000
- Natural history of inoperable hepatocellular carcinoma: Estrogen receptors' status in the tumor is the strongest prognostic factor for survival
[Articolo su rivista]
Villa, Erica; A., Moles; Ferretti, Ilva; P., Buttafoco; Manenti, Federico; Grottola, Antonella; M., Del Buono; M., De Santis
abstract
Clinical course in hepatocellular carcinoma may be very different. We prospectively evaluated 96 patients with hepatocellular carcinoma unsuitable For radical therapy to investigate Factors that could influence survival. Clinical, pathologic, and molecular data of patients were analyzed by univariate and multivariate analysis. The overall actuarial probability of survival at year 1, 2, 3, 4, 5, and 6 was 72%, 41%, 38%, 24%, 20%, and 9%. At univariate analysis, alphafetoprotein (AFP) (P = .0082); alkaline phosphatase (P = .0281); bilirubin (P = .0076); etiology (P = .0001); increment of turner mass at month 3 (P = .0051); type of estrogen receptor (ER) in the tumor (P = .0000); prothrombin time (P = .0003); and portal vein thrombosis (P = .0000) had prognostic significance. At multivariate analysis, only type of ER (P = .0000) and bilirubin (P = .0030) showed independent predictive value for mortality. Survival was significantly longer in patients with wild-type estrogen receptors (P = .0000). Cumulative probability of survival at year 1, 2, 3, 4, 5, and 6 was 94%, 66%, 52%, 43%, 35%, and 18% for wild-type and 51%, 21%, 16%, and 9% for variant estrogen receptors (no patients alive after 4 years). Hepatitis B surface antigen (HBsAg)-positive patients with variant ERs had a median survival of 8 months versus 45 months in antihepatitis C virus-positive patients with wild-type ERs (P = .0001). In conclusion, (1) the presence of variant liver ER transcripts in the tumor was the strongest negative predictor of survival in inoperable hepatocellular carcinoma; (2) their presence was associated with spontaneous survival significantly worse than in patients with wild-type estrogen receptors; and (3) HBsAg-positive patients with variant receptors were characterized by the worst survival.
1999
- Fine-resolution mapping by haplotype evaluation: the examples of PFIC1 and BRIC
[Articolo su rivista]
L. N., Bull; J. A., Juijn; M., Liao; M. J. T., van Eijk; R. J., Sinke; N. L., Stricker; J. A., Deyoung; V. E. H., Carlton; S., Baharloo; L. W. J., Klomp; D., Abukawa; D. E., Barton; N. M., Bass; B., Bourke; B., Drumm; I., Jankowska; P., Lovisetto; S., Mcquaid; J., Pawlowska; Y., Tazawa; Villa, Erica; Tyg,
abstract
Loci for two inherited liver diseases, benign recurrent intrahepatic cholestasis (BRIC) and progressive familial intrahepatic cholestasis type 1 (PFIC1), have previously been mapped to 18q21 by a search for shared haplotypes in patients in two isolated populations. This paper describes the use of further haplotype evaluation with a larger sample of patients for both disorders, drawn from several different populations. Our assessment places both loci in the same interval of less than 1 cM and has led to the discovery of the PFIC1/BRIC gene, FIC1; this discovery permits retrospective examination of the general utility of haplotype evaluation and highlights possible caveats regarding this method of genetic mapping.
1999
- Gross pathologic types of hepatocellular carcinoma in Italy.
[Articolo su rivista]
Stroffolini, T; Andreone, P; Andriulli, A; Ascione, A; Craxì, A; Chiaramonte, M; Galante, D; Manghisi, Og; Mazzanti, R; Medaglia, C; Pilleri, G; Rapaccini, Gl; Albanese, M; Taliani, G; Tosti, Me; Villa, Erica; Gasbarrini, G.
abstract
The prevalence and independent predictors of the different macroscopic types of hepatocellular carcinoma (HCC) were assessed in 1,073 unselected patients of 14 hospitals in Italy from May 1996 to May 1997. Solitary HCC was the most common cancer type (44.6%), followed by multinodular (44.2%), diffuse (8.4%) and massive (2.8%) types. After adjustment for the influence of confounders by multiple logistic regression analysis, Child-Pugh grades B and C were found to be independent predictors of multinodular (odds ratio, OR, 2.0; 95% confidence interval (CI) = 1.5-2.6) and diffuse (OR 2.6; 95% CI = 1.6-4.4) HCC types. These findings indicate that the majority of HCC cases are not detected at a potentially treatable stage. Delayed detection of HCC is associated with a higher likelihood of the multinodular or diffuse gross pathologic type.
1998
- Beneficial hemodynamic effects of dipyridamole on portal circulation in cirrhosis
[Articolo su rivista]
G., Sansoe; Ferrari, Alberto; P., D'Alimonte; T., Trenti; P., Zoboli; R., Romagnoli; Villa, Erica; Manenti, Federico
abstract
Objective: Dipyridamole is a vasodilator that inhibits the cellular uptake of adenosine, which physiologically reduces the resistance to hepatic arterial flow inside the liver. This study aims at assessing the acute effect of dipyridamole on functional liver plasma flow (measured as the extrarenal sorbitol clearance) and on the Doppler US Congestion Index of the portal vein (the ratio between the cross-sectional area of this vein and the mean velocity of portal flow), which correlates with the severity of portal hypertension. Methods: We have determined the extrarenal sorbitol clearance (14 cases) and the Congestion Index (seven cases) before and at 30, 60, and 90 min after the oral administration of 25 mg dipyridamole in patients with liver cirrhosis. We also measured the effect of dipyridamole on functional liver plasma flow in six healthy subjects. Results: Dipyridamole increased the extrarenal sorbitol clearance in controls (+17%, p < 0.01) and in cirrhotic patients (+15%, p < 0.01). The drug decreased the portal Congestion Index in all patients, averaging -24% (p < 0.05) 90 min after its oral administration. Conclusions: This result was due both to a mean decrease of the portal sectional area and to a mean increase in portal flow velocity. In conclusion, these data suggest that dipyridamole should decrease the vascular resistance to portal flow in cirrhosis; this effect may be mediated by an adenosine-dependent vasodilation in the intrahepatic site or along the portosystemic collaterals.
1998
- Characteristics of hepatocellular carcinoma in Italy
[Articolo su rivista]
Stroffolini, T; Andreone, P; Andriulli, A; Ascione, A; Craxì, A; Chiaramonte, M; Galante, D; Villa, Erica
abstract
This study aimed to assess the main features of hepatocellular carcinoma at the time of diagnosis in Italy, particularly in relation to the presence or absence of underlying cirrhosis, hepatitis virus marker patterns, age of the subjects and alpha-foetoprotein values.METHODS:A total of 1148 patients with hepatocellular carcinoma seen at 14 Italian hospitals in the 1-year period from May 1996 to May 1997 were the subjects of this prevalence study. Both newly diagnosed cases (incident cases) and cases diagnosed before May 1996 but still attending the hospitals during the study period (prevalent cases) were included.RESULTS:We found that 71.1% of cases were positive for hepatitis C virus antibodies but negative for HBsAg; in contrast, 11.5% were negative for anti-HCV but positive for HBsAg; 5.3% were positive for both markers; and 12.1% were negative for both viruses. The mean age of detection was over 60 years, with a younger mean age in HBsAg-positive compared to anti-HCV-positive patients (59.3 years vs. 65.6 years, p<0.01). The male-to-female ratio among HBsAg-positive patients was 10.4:1, in contrast to 2.8:1 among anti-HCV-positive patients (p<0.01). The majority of cases (93.1%) had underlying cirrhosis. Cirrhotic patients were more likely to be anti-HCV positive than non-cirrhotic cases (73.2% vs 43.9%; p<0.01); conversely, absence of hepatitis virus markers was more frequently observed in the non-cirrhotic than in the cirrhotic population (40.9% vs. 10.0%; p<0.01). Overall, the alpha-foetoprotein level was altered (>20 ng/ml) in 57.9% of patients; only 18% of cases presented diagnostic (>400 ng/ml) values. Anti-HCV positivity (O.R. 2.0; CI 95%=1.3-3.1) but not HBsAg positivity (O.R. 1.0; CI 95%=0.6-1.8) was shown to be an independent predictor of the likelihood of altered alpha-foetoprotein values by multivariate analysis.CONCLUSIONS:These findings point to differences in the characteristics of the populations infected by hepatitis B and hepatitis C. Factors other than the hepatitis viruses are important in non-cirrhotic patients. A change in the relative prevalence of hepatitis virus markers among hepatocellular carcinoma cases was demonstrated, reflecting a significant change in the rate of HBV endemicity in the Italian population. Finally, the increased trend in the mortality rate from liver cancer in Italy from 4.8 per 100,000 in 1969 to 10.9 in 1994 may reflect the large cohort of subjects infected with HCV via the iatrogenic route during 1950s and 1960s when glass syringes were commonly used for medical treatment
1998
- Variant liver estrogen receptor transcripts already occur at an early stage of chronic liver disease
[Articolo su rivista]
Villa, Erica; A., Dugani; A., Moles; L., Camellini; Grottola, Antonella; P., Buttafoco; A., Merighi; I., Ferretti; P., Esposito; L., Miglioli; A., Bagni; R., Troisi; B., De Hemptinne; M., Praet; F., Callea; Manenti, Federico
abstract
Variant estrogen receptors may be found in hepatocellular carcinoma and may influence its natural history Because it is not known whether their occurrence is an early or a late event during the course of chronic liver disease or whether they cluster in some subgroups of patients, we investigated a series of patients in different stages of chronic liver disease, One hundred eleven consecutive patients were studied for variant estrogen receptor transcripts by reverse-transcription polymerase chain reaction of RNA extracted from liver biopsy specimens. In chronic active hepatitis, variant estrogen receptor transcripts were coexpressed with wild-type significantly more often in men than in women (P = .029) and in hepatitis B surface antigen (HBsAg)-positive subjects than in subjects positive for antibody to hepatitis C virus (P = .0006). In hepatocellular carcinoma, again in men (P = .004) and in HBsAg-positive patients (P = .0015), the variant estrogen receptor transcript was overexpressed or remained the only one expressed, Patients with liver cell dysplasia presented with the same estrogen receptor pattern than patients with hepatocellular carcinoma, This further reinforces the significance of liver cell dysplasia as a preneoplastic condition. The significantly higher occurrence of variant estrogen receptor in men (especially in HBsAg-positive men) already at an early stage of disease, like chronic active hepatitis, suggests that the alteration of estrogen receptors, favoring uncontrolled proliferation and development of hyperplasia, might constitute a prominent mechanism facilitating neoplastic transformation especially in men.
1997
- Ki-ras mutations in stool and whole-gut lavage fluid - Reply
[Articolo su rivista]
Villa, Erica; Rebecchi, A; Dugani, A; Grottola, Antonella; Buttafoco, P; Trande, P; Manenti, F.
abstract
Demonstration of better results of molecular screening
1997
- Molecular diagnostics in hepatitis C virus infection: Clinical applications
[Articolo su rivista]
Alberti, A.; Bonino, F.; Brunetto, M.; Cariani, E.; Farci, E.; Ferrari, C.; Levrero, M.; Mondelli, M.; Pontisso, P.; Raimondo, G.; Rumi, M.; Smedile, A.; Villa, E.; Zignego, A. L.
abstract
1997
- Molecular screening: Why haven't we started yet?
[Articolo su rivista]
Villa, E.; Zetterman, R. K.
abstract
1997
- Molecular screening: why haven't we started yet? [editorial].
[Articolo su rivista]
Villa, Erica
abstract
Dissertation on the value of molecular screening for CRC
1996
- A survey of adverse events in 11 241 patients with chronic viral hepatitis treated with alfa interferon
[Articolo su rivista]
Fattovich, G.; Giustina, G.; Favarato, S.; Ruol, A.; Macarri, G.; Orlandi, E.; Iaquinto, G.; Ambrosone, L.; Francavilla, A.; Pastore, G.; Santantonio, M. T.; Romagno, D.; Bolondi, L.; Sofia, S.; Marchesini, A.; Pisi, E.; Mazzella, G.; Roda, E.; Attaro, L.; Chiodo, E.; Mori, E.; Verucchi, G.; Lanzini, A.; Salmi, A.; Calvi, B.; Bozzetti, E.; Radaeli, E.; Bernasconi, M.; Pilleri, G.; Bacca, D.; Romano, G.; Mastrapasqua, G.; Cozzolongo, R.; Cacopardo, B.; Nunnari, A.; Blasi, A.; Sala, L. O.; Minoli, G.; Sangiovanni, A.; Spinzi, G. C.; Colombo, A.; Camassa, M.; Riva, D.; Maggi, G.; Boccia, S.; Gualandi, G.; Nucci, A.; Pacini, F.; Marino, N.; Mazzotta, E.; La Mura, A.; Pompei, A. G.; Casinelli, K.; Petrosillo, N.; Giacchino, R.; Timitilli, A.; Spiga, E.; Corsetti, M.; Menicagli, V.; Tucci, A.; Bissoli, E.; Raimondo, G.; Rodino, G.; Bellobuono, A.; Ideo, G.; Colombo, M.; Pacchetti, S.; Rumi, M. R.; Battezzati, P. M.; Bruno, S.; Podda, M.; Zuin, M.; Fargion, S.; Fiorelli, G.; Gellmann, E.; Vandelli, C.; Ventura, E.; Manenti, F.; Villa, E.; Caporaso, N.; Coltorti, M.; Morisco, E.; Del Vecchio-Blanco, C.; di Santolo, S. S.; Di Nunzio, S.; Ruggiero, G.; Zampino, R.; Ascione, A.; De Luca, M.; Galeota-Lanza, A.; Aprea, L.; Sagnelli, E.; Felaco, E. M.; Piccinino, E.; Ballare, M.; Monteverde, A.; Tappero, G.; Sanna, G.; Alberti, A.; Bonetti, P.; Casarin, C.; Diodati, G.; Tremolada, E.; Naccarato, R.; Chiaramonte, M.; Floreani, M. R.; Almasio, P.; Craxi, A.; Loiacono, O.; Pagliaro, L.; Fiaccadori, E.; Giuberti, T.; Belloni, G.; Bernardini, E.; Buscarini, L.; Sbolli, G.; Giudici-Cipriani, A.; Marenco, G.; Mazzaro, C.; Massari, M.; Fornaciari, G.; Plancher, A.; Gasbarrini, G.; Grieco, A.; Luchetti, R.; Rapaccini, G. L.; Bombardieri, G.; Di Virgilio, D.; Bruno, G.; Ricci, G. L.; Hassan, G.; Mari, T.; Scalisi, I.; Colloredo, G.; Frunzio, A.; Tabone, M.; Costa, C.; Rosina, E.; Saracco, G.; Verme, G.; Frezza, M.; Urban, E.; Capra, E.; Casaril, M.; Corrocher, R.; Benetti, G. P.
abstract
Aims: The aim of this study was to assess the incidence of fatal, life-threatening side effects and the de novo appearance of non-hepatic morbidity during interferon alfa therapy for chronic viral hepatitis. The relationship of these adverse events to actual total dose and duration of interferon was also evaluated. Methods: We conducted a retrospective study at 73 Italian centers of 11 241 consecutive patients with chronic viral hepatitis who underwent interferon alfa treatment. Results: Five patients died during interferon therapy due to liver failure (n=4) or complications arising from sepsis. Life-threatening side effects were observed in eight patients: two cases where depression developed and led to a suicide attempt and six patients with bone marrow suppression (granulocytes <500/ mm3 or platelets <25 000/mm3). These symptoms and signs completely disappeared after interferon withdrawal. During interferon treatment, 131 patients developed the following de novo non-hepatic disorders: symptomatic thyroid disease (n=71), impotence (n= 5), systemic autoimmune disease (n=5), immune-mediated dermatologic disease (n=14), diabetes mellitus (n=10), cardiovascular disease (n=7), psychosis n=10), seizures (n=4), peripheral neuropathy (n=3) and hemolytic anemia (n=2). Most of these complications are reversible or can be ameliorated. Fatal or life-threatening side effects were not related to actual total dose or duration of interferon alfa, while the majority of patients with de novo non-hepatic morbidity received medium/high doses (>200 million units) of interferon alfa or were treated for periods longer than 16 weeks (68% and 80%, respectively). Conclusions: Treatment with interferon alfa may have fatal or life-threatening side effects, their incidence in this study being low (0.04% and 0.07%, respectively) and perhaps no different than in untreated patients with chronic viral hepatitis. Moreover de novo non-hepatic morbidity occurred in 1.2% of patients, and the dose and duration of interferon therapy seem important in determining the frequency of this complication. The development of clinically-overt thyroid disease was most common.
1996
- Alpha but not beta interferon is useful in chronic active hepatitis due to hepatitis C virus - A prospective, double-blind, randomized study
[Articolo su rivista]
Villa, Erica; P., Trande; Grottola, Antonella; Manenti, Federico; P., Buttafoco; Am, Rebecchi; T., Stroffolini; F., Callea; A., Merighi; L., Camellini; P., Zoboli; R., Cosenza; Loria, Paola; L., Miglioli; Carulli, Nicola; R., Iori
abstract
Interferon-alpha has been widely used in chronic hepatitis C, but controlled studies with intramuscular interferon-beta are lacking. We therefore performed a prospective, double-blind, randomized study comparing intramuscular IFN-alpha and -beta in patients with chronic hepatitis C. Sixty patients were randomly assigned to receive 3 MU thrice weekly intramuscularly of either recombinant IFN-alpha or leukocyte IFN-alpha or fibroblast IFN-beta for six months. Nine of 20 patients (45.0%) in the recombinant IFN, 5/19 (26.3%) in the leukocyte IFN, and none in the IFN-beta group had a complete response during therapy (recombinant IFN vs IFN-beta: P < 0.01). Only in IFN-alpha-treated patients, was infection with a single HCV genotype (type 2a or 2b) associated with significantly better long-term outcome. IFN-alpha is useful in chronic hepatitis C while intramuscular IFN-beta interferon does not exert any beneficial effect. This is probably due to an insufficient bioavailability of IFN-beta when given intramuscularly.
1996
- Identification of subjects at risk for colorectal carcinoma through a test based on K-ras determination in the stool
[Articolo su rivista]
Villa, Erica; A., Dugani; Am, Rebecchi; A., Vignoli; Grottola, Antonella; P., Buttafoco; Losi, Lorena; M., Perini; P., Trande; A., Merighi; R., Lerose; Manenti, Federico
abstract
Background & Aims: The gold standard for screening for colorectal carcinoma is colonoscopy. The aim of this study was to compare endoscopic results with those obtained using the noninvasive screening test of K-ras determination in the stool in a large population of patients undergoing colonoscopy. Methods: Two hundred thirty consecutive patients were studied by K-ras amplification on stool-derived DNA using polymerase chain reaction and oligomer-specific hybridization. Results: Wild-type K-ras was amplified in 103 of 230 patients (44.8%), the rate of amplification being directly proportional to the presence of an organic disease of the intestine characterized by hyperproliferating mucosa. In 30 of these 103 patients (29.1%), a K-ras mutation was found. Four of 5 with early colorectal carcinoma, all who had K-ras mutations in the tumor, were identified. In first-degree relatives of patients with colorectal carcinoma, all subjects either carrying adenomas >1 cm in diameter or multiple smaller adenomas were identified. In patients with inflammatory bower disease, the test identified the only patient with neoplastic transformation. Conclusions: The sensitivity and specificity of K-ras determination on stool-derived DNA in patients with colorectal carcinoma, in first-degree relatives of patients with colorectal carcinoma, and in patients with inflammatory bowel disease support the opportunity of a large-scale trial to validate its use as a screening test.
1996
- Type of estrogen receptor determines response to antiestrogen therapy
[Articolo su rivista]
Villa, Erica; A., Dugani; E., Fantoni; L., Camellini; P., Buttafoco; Grottola, Antonella; G., Pompei; M., Desantis; Ferrari, Alberto; Manenti, Federico
abstract
Failure of tamoxifen treatment for unresectable hepatocellular carcinomas (HCCs) might be caused by variant estrogen receptors (ERs) in some of these tumors. We therefore planned a study in which antihormonal therapy was done with 80 mg/day tamoxifen or 160 mg/day megestrol according to the presence of wild-type or exon 5-deleted variant ER transcripts. Growth rate (evaluated by MRI) of HCCs characterized by variant ER transcripts was 4 times more rapid than that of HCCs with wild-type ERs. Tumor volume in all patients with wild-type ERs was halved after 9 months of tamoxifen treatment, whereas megestrol in patients with variant ERs only slowed down tumor growth. Choosing antihormonal treatment according to the presence of wild-type or variant ERs in the tumor definitely improves the response rate to tamoxifen; in patients with tumors bearing variant ERs, megestrol causes only a temporary inhibition of tumor growth.
1996
- Variant liver estrogen and response to tamoxifen
[Articolo su rivista]
Villa, Erica; Camellini, L; Dugani, A; Buttafoco, P; Grottola, Antonella; Manenti, F.
abstract
Patients with hepatic variant ER do not response to tamoxifen
1995
- EVIDENCE FOR HEPATITIS-B VIRUS-INFECTION IN PATIENTS WITH CHRONIC HEPATITIS-C WITH AND WITHOUT SEROLOGICAL MARKERS OF HEPATITIS-B
[Articolo su rivista]
Villa, Erica; Grottola, Antonella; Buttafoco, Paola; P., Trande; A., Merighi; N., Fratti; Y., Seium; G., Cioni; Manenti, Federico
abstract
To assess the influence of HBV infection on anti-HCV-positive chronic liver disease, we performed a prospective case-control study comparing 19 HBsAg-positive, anti-HCV-positive patients with 38 HBsAg-negative, anti-HCV-positive patients, pair-matched for age, sex, and ALT levels. HBV and HCV infections were investigated by standard serology and polymerase chain reaction. HCV RNA was found in all patients with CAH and in 90.0% with cirrhosis (33% HBsAg-positive). HBV DNA sequences were found, in the HBsAg-positive subjects, in 71.4% of CAH and in 83.3% of cirrhotics; in the HBsAg-negative ones, only 10% of CAH but 77.7% of cirrhotics had demonstrable HBV DNA sequences. Consequently, 80.0% of cirrhotics had evidence of both HBV and HCV infection. Conventional serology gives partial information on the true occurrence of HBV infection in HBsAg-negative patients, while PCR defines more accurately the HBV status. When the rate of double infection is defined in this way, it correlates with the presence of cirrhosis.
1995
- Long-term follow-up of hepatitis C virus (HCV) infection in liver transplant patients
[Articolo su rivista]
Villa, Erica; Grottola, Antonella; Buttafoco, Paola; A., Merighi; Ferretti, Ilva; P., Trande; P., Zoboli; L., Camellini; F., Callea; M., Depalma; C., Vecchi; R., Troisi; M., Camisasca; S., Rossi; G., Tordato; B., Dehemptinne; M., Podda; Manenti, Federico
abstract
Chronic hepatitis represents a frequent event after orthotopic liver transplantation (OLT). To ascertain the influence of HCV infection on the clinical and histological, outcome of these patients, we have investigated the long-term outcome of 22 patients with end-stage chronic liver disease undergoing liver transplant focusing the attention on the role of different HCV genotypes in determining recurrence and severity of post-OLT liver disease. For all patients blood samples taken before OLT and 3 months, 1, 2 and 3 years after OLT were tested for antiHCV antibodies by two different enzyme-linked immune-assays and by recombinant immune-blot II and for the presence and type of HCV RNA by nested PCR (5' untranslated region and core gene primers). Of the 16 pre-OLT antiHCV-positive patients, 14 (87.5%) had recurrence of HCV infection while 2 cleared HCV Pre-OLT genotype recurred in 11 of these 14 patients (2 genotype I, 8 genotype II - in 1 case associated with genotype III and 1 genotype IV). Of the 6 pre-OLT antiHCV-negative patients, only 1 (16.6%) became persistently HCV-infected, with genotypes I and II. The recurrence of genotype II strictly related with development of severe chronic hepatitis while genotype I and IV were associated with milder forms of liver disease and were more easily cleared.
1995
- Selection of more pathogenic hepatitis C virus genotype II during long-term follow-up of interferon-treated patients.
[Articolo su rivista]
Villa, Erica; P., Buttafoco; A., Merighi; Manenti, Federico; Grottola, Antonella; I., Ferretti; Ferrari, Alberto; F., Callea; P., Trande; Am, Rebecchi
abstract
The behavior of hepatitis C virus (HCV) infection with regards to type and number of HCV genotypes (tested with genotype-specific nested polymerase chain reaction) was evaluated in 60 patients with anti HCV-positive chronic active hepatitis without cirrhosis [17 untreated and 43 subjects undergoing single or repeat courses of interferon (IFN) therapy] during a mean follow-up period of 76+/-18 months. In untreated patients (2 genotype I, 6 genotype II, 9 mixed infections) 4 out of 9 mixed infections selected for genotype II at the end of follow-up. Of the 43 treated patients 10 were long-term responders with histological remission, 6 were shortterm responders, and 22 did not respond. Fifteen of the latter patients received another course of IFN therapy, and only 3 patients responded. Eight of the 10 responders had infection with a single genotype (4 gt I, 3 gt II, 3 gt III). After IFN therapy, all but 2 patients cleared the HCV infection. The responders to the second IFN course (1 gt I, 1 gt II, 1 gt III) remained viremic. Of the shortterm responders, 2/6 patients had genotype II and 4 had a mixed infection (3 gt II+/-I and 1 gt II+/-III); gt III became prevalent in the latter in al but one patient. Of the nonresponders 18/24 had more than one genotype, 5 were genotype II at baseline and one had genotype I. At the end of the follow-up period 15/18 with mixed infection had selected for gt II (P<0.01 vs. untreated patient). Thirteen of 18 nonresponders who selected genotype II during follow-up developed cirrhosis, compared with none among the four untreated which also selected for genotype II (P<0.01) and with none of the patients maintaining their baseline genotype (P<0.01). In conclusion, patients with single HCV genotype, other than gt II, respond better to IFN, which seems to easily suppress HCV genotypes other than II. Genotype II is scarcely inhibited and becomes predominant during follow-up. In the patients selecting for genotype II, cirrhosis develops more rapidly than in untreated patients, where the selection for genotype II occurs at much slower rate.
1995
- The polymerase chain reaction (PCR). Its significance and limits
[Articolo su rivista]
Villa, E.; Buttafoco, P.; Grottola, A.; Merighi, A. L.; Ferretti, I.
abstract
1995
- Variant estrogen receptor messenger RNA species detected in human primary hepatocellular carcinoma
[Articolo su rivista]
Villa, Erica; L., Camellini; A., Dugani; F., Zucchi; Grottola, Antonella; A., Merighi; P., Buttafoco; Losi, Lorena; Manenti, Federico
abstract
The development of hepatocellular carcinoma (HCC) in addition to cirrhosis affects males in a significantly higher proportion than females. Liver estrogen receptors increase when HCC develops in males; however, these tumors usually respond poorly to antiestrogens. We have, therefore, hypothesized that, similar to breast cancer, estrogen receptors in males with HCC may be mutated. Variant estrogen receptor transcripts (lacking exon 5 of the hormone binding domain) were investigated by reverse transcription-PCR in 14 patients (7 males and 7 females) with HCC. While females mostly displayed the wild-type transcript (both in peritumoral and in tumor Liver tissue), males showed both transcripts in the cirrhotic tissue and almost only the variant in the tumor. ris the variant ER transcripts when translated could give rise to truncated receptors still able to constitutively activate transcription, they may be key factors in favoring deregulated proliferation in the male liver.
1994
- NORMAL AMINOTRANSFERASE CONCENTRATIONS IN PATIENTS WITH ANTIBODIES TO HEPATITIS-C VIRUS
[Articolo su rivista]
Bruno, S; Rossi, S; Petroni, Ml; Villa, Erica; Zuin, M; Podda, M.
abstract
HCV RNA helps distinguishes carrier with normal liver condition
1993
- Reactivation of hepatitis B virus infection induced by interferon (IFN) in HBsAg-positive, antiHCV-positive patients.
[Articolo su rivista]
Villa, Erica; Grottola, Antonella; Trande, P; Seium, Y; Rebecchi, Am; Dugani, A; Manenti, F.
abstract
Doses of IFN suitable for HCV may lead to reactivation of HBV infection
1992
- HEPATITIS-B VIRUS SPECIFIC TRANSCRIPTS IN PERIPHERAL-BLOOD MONONUCLEAR-CELLS
[Articolo su rivista]
Melegari, M; Scaglioni, Pp; Pasquinelli, C; Manenti, Federico; Villa, Erica
abstract
We report on the analysis of HBV transcription in peripheral blood mononuclear cells of chronically infected patients by polymerase chain reaction amplification. Our results suggest that in these cells gene expression occurs either as pregenomic or subgenomic transcripts.
1992
- HEPATITIS-C VIRUS TESTING IN PRIMARY BILIARY-CIRRHOSIS
[Articolo su rivista]
Bertolini, E; Battezzati, Pm; Zermiani, P; Bruno, S; Moroni, Ga; Marelli, F; Villa, Erica; Manenti, Federico; Zuin, M; Crosignani, A; Podda, M.
abstract
We retrospectively investigated anti-HCV prevalence in a series of 160 consecutive patients with primary biliary cirrhosis who presented between 1980 and 1989. Of these, 19 (12%) were positive for anti-HCV by C-100 ELISA. Serum IgG levels were significantly higher in anti-HCV-positive patients and correlated to optical density values. A serum sample was again collected from all the patients from the same series who were seen in 1990 for follow-up, after a median period of 32 months. Anti-HCV positivity was found to be substantially unchanged in this subgroup of patients when the freshly drawn blood samples were retested with C-100 ELISA, while it increased from 10% to 17% when second generation ELISA was used. Three of the C-100 ELISA positive samples were C-100 RIBA reactive, and six of the second generation ELISA positive samples were 4-RIBA reactive. The HCV genome was not detected in any of the seven anti-HCV C-100 ELISA and second generation ELISA positive sera which were studied by polymerase chain reaction, including four cases confirmed by 4-RIBA. Life expectancy, as determined by survival analysis, did not differ significantly between anti-HCV-positive and -negative patients. These findings suggest that anti-HCV positivity does not influence the clinical presentation and course of primary biliary cirrhosis.
1992
- Hepatitis C virus infection, HBsAg carrier state and hepatocellular carcinoma: relative risk and population attributable risk from a case-control study in Italy.
[Articolo su rivista]
T., Stroffolini; M., Chiaramonte; C., Tiribelli; Villa, Erica; Rg, Simonetti; M., Rapicetta; Ma, Stazi; T., Bertin; Sl, Croce; P., Trande; A., Magliocco; P., Chionne
abstract
In 1990, a case-control study was conducted in Italy to investigate the possible association between HCV infection and hepatocellular carcinoma (HCC). Serum samples from 65 subjects with newly diagnosed hepatocellular carcinoma and 99 hospital control subjects were tested for the presence of anti-HCV by second-generation ELISA test; positive sera were assayed by RIBA anti-HCV second-generation test. In addition, samples were tested for hepatitis B surface antigen (HBsAg), antibodies to the hepatitis B core antigen (anti-HBc), and antibodies to HBsAg (anti-HBs). The presence of HCV and/or HBsAg serologic markers was significantly associated with hepatocellular carcinoma risk: the relative risk (RR) of HCC was 21.3 (95% CI=8.8-51.5) for anti-HCV positivity in the absence of HBsAg; the relative risk of HCC was 13.3 (95% CI=5.5-32.2) for the presence of HBsAg in the absence of anti-HCV. A higher risk (77.0) was observed when both markers were present. These findings indicate that HCV and HBsAg are independent risk factors for HCC. The results of multivariate analysis showed that the adjusted RR linking anti-HCV and HCC was 26.9 (95% CI=9.9-72.5), the adjusted RR linking HBsAg and HCC was 11.4 (95% CI=3.1-41.4), whereas no association (RR 1.5; 95% CI=0.6-3.6) was found to link HCC with anti-HBc and/or anti-HBs positivity. Through the computation of population attributable risk we estimate that 25% of HCC cases occurring in Italy could be attributed to anti-HCV positivity alone and 20% to HBsAg carrier state alone. These data provide evidence that HCV infection plays a major role in the development of HCC in Italy.
1992
- Immunogenicity and safety of a recombinant hepatitis B vaccine produced in mammalian cells and containing the S and the preS2
[Articolo su rivista]
Corradi, M. P.; Tata, C.; Marchegiano, P.; Villa, E.; De Palma, M.; Trianni, G.; Fuiano, L.; Rompianesi, P.; Scacchetti, T.
abstract
A group of 273 health care workers, at risk of HBV infection, underwent vaccination with recombinant HBsAg produced in mammalian cells and containing protein sequences coded by both the S and pre-S2 regions (Genhevac B). Preliminary results show that a very early pre-S2 response occurred which may be useful in post-exposure prophylaxis. This observation, in addition to reduced influence by the vaccination protocol, provides grounds for optimism in spite of the fact that the efficiency spectrum of this vaccine was not superior to that of recombinant vaccines produced in yeast.
1992
- PRESENCE OF HCV RNA IN SERUM OF ASYMPTOMATIC BLOOD-DONORS INVOLVED IN POSTTRANSFUSION HEPATITIS (PTH)
[Articolo su rivista]
Villa, Erica; Melegari, M; Ferretti, Ilva; Vecchi, C; Scaglioni, Pp; Depalma, M; Manenti, Federico
abstract
To study the causes of residual posttransfusion hepatitis, serum from implicated donors was tested by PCR for the presence of HCV RNA. Of 20 anti HCV negative donors, 4 were HCV RNA positive and thus, infective. The results suggest that higher-level investigations are necessary for prospective donors who present blood enzyme abnormalities or other questionable characteristics.
1992
- The epidemiology of hepatitis delta infection in Italy
[Articolo su rivista]
Sagnelli, E.; Stroffolini, T.; Ascione, A.; Bonino, F.; Chiaramonte, M.; Colombo, M.; Crax, A.; Giusti, G.; Manghisi, O. G.; Pastore, G.; Piccinino, F.; Rizzetto, M.; Stazi, M. A.; Toti, M.; Verme, G.; Almi, E.; Amitrano, L.; Bartoletti, L.; Belmonte, A.; Borgia, G.; Broilo, L.; Budillon, G.; Buongiorno, G.; Buzzelh, G.; Cancellieri, C.; Caredda, F.; Cavallaro, C.; Chibbaro, G.; Ciampi, R.; Cimino, L.; Colella, F.; Coppin, P.; Di Giacomo, C.; Di Virgiho, D.; Fattovich, G.; Felaco, F. M.; Filippini, P.; Fornaciari, G.; Freni, M.; Frezza, M.; Gigliotti, T.; Ibba, M.; Madia, D.; Magnani, G.; Maio, G.; Manno, G.; Manzillo, E.; Marcelli, R.; Marinucci, G.; Marrazzi, M.; Marrone, A.; Mastropasqua, G.; Mele, A.; Messina, V.; Miglio, F.; Milella, M.; Mocci, G.; Naccrarato, R.; Nardiello, S.; Okoliksanyi, L.; Orlando, R.; Pasetti, G.; Pasquini, P.; Peinetti, P.; Plancher, A. C.; Raimondo, G.; Resta, M. L.; Rodino, G.; Romanelli, R. G.; Romeo, F.; Rosina, F.; Ruggiero, G.; Russo, M.; Spataro, G.; Terpin, M. M.; Vigano, P.; Villa, E.; Visco, G.
abstract
The epidemiology of HDV infection in Italy was assessed in a retrospective study involving 1556 HBsAg chronic carriers on their first presentation at one of the 35 Liver Units in 1987. Total anti-HD was detected in 23.4% of HBsAg carriers and was significantly more frequent in southern than in northern Italy (26.6% vs. 19.1%, p < 0.01). Age distribution showed that 73% of the anti-HD-positive subjects, but only 56% of the anti-HD-negative subjects, were under 40 years of age (p < 0.01). Anti-HD prevalence increased with the severity of the liver disease from 3.8% in healthy carriers to 42.5% in cirrhosis. No geographical statistical difference was found among HBsAg healthy carriers or subjects with chronic persistent hepatitis (CPH), while among patients with chronic active hepatitis (CAH) or cirrhosis anti-HD prevalence was much higher in the south (p < 0.01). The various potential risk factors were evaluated by multiple logistic regression analysis. HDV infection was independently related to young age, residence in the south, i.v. drug abuse, a large family and household contact with an anti-HD-positive carrier. No association was found with blood transfusion or male homosexuality. These findings confirm that HDV infection is endemic in Italy, particularly in some southern areas, where intrafamily contact probably at a young age may favour the spread of the infection. © 1992.
1991
- ANTIBODIES TO HEPATITIS-C VIRUS IN PATIENTS WITH HEPATOCELLULAR-CARCINOMA
[Articolo su rivista]
M., Levrero; A., Tagger; C., Balsano; E., Demarzio; Ml, Avantaggiati; G., Natoli; D., Diop; Villa, Erica; G., Diodati; A., Alberti
abstract
To study the potential relationship between the hepatitis C virus (HCV), the major etiologic agent of parenterally transmitted non-A, non-B hepatitis, and the development of hepatocellular carcinoma (HCC), we tested the presence of anti-HCV antibodies in sera from a large panel of HCC patients of different racial and geographical origins. Anti-HCV antibodies were detected in 82 out of 114 (71.9%) HBsAg-negative HCC patients and in 15 our of 53 (28.3%) HBsAg-positive patients. No significant difference in the prevalence of anti-HCV antibodies was found in the HBsAg-negative HCC patients when they were divided according to presence of anti-HBs and/or anti-HBc antibodies, or absence of all hepatitis B virus (HBV) serological markers. The prevalence of anti-HCV antibodies was similar in HCC patients of Caucasian and African origin. No differences were noted when the patients were grouped according to sex. The mechanisms by which HCV might contribute to the development of HCC need to be further investigated. As for HBV infection, the necro-inflammation associated with HCV infections may induce cirrhosis, regeneration and eventually malignant transformation. The finding that few anti-HCV patients had HCC which is not superimposed on cirrhosis suggest that HCV could, however, exert some direct effect on the development of HCC.
1991
- CONSERVED CORE PROTEIN SEQUENCES IN HEPATITIS-B VIRUS-INFECTED PATIENTS WITHOUT ANTI-HBC
[Articolo su rivista]
Melegari, M; Jung, Mc; Schneider, R; Santantonio, T; Bagnulo, S; Luchena, N; Pastore, G; Pape, G; Scaglioni, Pp; Villa, Erica; Will, H.
abstract
The absence of detectable anti-HBc antibodies in some hepatitis B virus (HBV) infected patients may be due to altered core-protein (HBc) sequences. To investigate this possibility we sequenced the pre-C/C-region of HBV isolated from 12 juvenile cancer patients who incurred a nosocomial infection of HBV during chemotherapy but did not develop anti-HBc antibodies or acute cytolytic episodes. The sequences demonstrated the highest sequence homology to the pre-C/C region of a previously cloned HBV genome (subtype ayw) and no deletions or striking mutations were detected. Up to 7 years after infection almost all the survivors developed low titers of anti-HBc antibodies but no clinical signs of hepatic damage. These results suggest that chemotherapy may induce a tolerance status to HBcAg, the most immunogenic HBV protein.
1991
- HCV RNA IN SERUM OF ASYMPTOMATIC BLOOD-DONORS INVOLVED IN POSTTRANSFUSION HEPATITIS (PTH)
[Articolo su rivista]
Villa, Erica; Ferretti, Ilva; Depalma, M; Melegari, M; Scaglioni, Pp; Trande, P; Vecchi, C; Fratti, N; Manenti, Federico
abstract
A group of blood donors involved in post-transfusion hepatitis was investigated for the presence of the anti-HCV antibody and of HCV RNA as a more direct infection marker. RNA was extracted from serum, reverse transcribed and amplified using primers which belonged to the non structural region. The amplified product of the PCR reaction was 582 base pairs. Seven (25.9%) of the 27 blood donors examined were found anti-HCV-positive by ELISA; five (71.4%) of these were HCV RNA positive. Among the 20 anti-HCV-negative blood donors, four (20.0%) were HCV RNA positive. ALT levels were below 45 UI/l in 18 donors, while the other nine had ALTs over the limit accepted for transfusion. The anti-HCV-negative HCV RNA-positive blood donors had normal ALTs. Our study offers a direct explanation for the substantial proportion of residual cases of anti-HCV-positive post-transfusion hepatitis and suggests the necessity of creating a register of blood donors who have at some time presented blood enzyme abnormalities and for whom second level investigations such as HCV RNA should be used.
1991
- HEPATOCELLULAR-CARCINOMA - RISK-FACTORS OTHER THAN HBV
[Articolo su rivista]
Villa, Erica; M., Melegari; P. P., Scaglioni; P., Trande; P., Cesaro; Manenti, Federico
abstract
The putative risk factors for hepatocellular carcinoma (HCC) are several, even in countries endemic for hepatitis B virus (HBV) infection. Cirrhosis characterizes more than 90% of HCC cases. The phases of inflammation, necrosis and regeneration, present for long periods in cirrhosis, might be most relevant in hepatocarcinogenesis. It is not clear what role is played by sex hormones while alcohol probably has a promoter role. Aflatoxins are known carcinogenins in the experimental animal: however it is difficult to evaluate the impact in human carcinogenesis due to the lack of reliable methods of measuring aflatoxin exposure in population studies. In conclusion, the aetiology of HCC is multifactorial and the main risk factor resides in the presence of underlying chronic liver disease.
1991
- Hepatitis-C virus infection in Italy: A multicentric sero-epidemiological study. (A report from the HCV study group of the Italian Association for the Study of the Liver)
[Articolo su rivista]
Chiaramonte, M.; Stroffolini, T.; Caporaso, N.; Coppola, R.; Craxi, A.; Gaeta, G. B.; Sagnelli, E.; Zanetti, A. R.; Baldi, M.; Manzini, P.; Crovari, P.; Bonanni, P.; Grasso, A.; Calcagno, G.; Tanzi, E.; Vigano, P.; Gubertini, G.; Puoti, M.; Pizzocolo, G.; Rodella, A.; Delaito, M.; Alberti, A.; Casarin, C.; Mastrapasqua, G.; Madia, D.; Mazzaro, C.; Crovato, M.; Fornaciari, G.; Giovannini, A. G.; Villa, E.; De Palma, M.; Mazzotta, F.; Mazzotta, F.; Meli, M.; Rapicetta, M.; Albertoni, F.; Biondi, B.; De Pisi, C.; Colarussi, M.; Colucci, M.; Coltorti, M.; Morisco, F.; Utili, R.; Marrone, A.; Piccinino, F.; Felaco, Fm.; Petruzziello, A.; Sardaro, C.; Dentico, P.; Schiraldi, O.; Pastore, G.; Mauro, G. F.; Geremicca, W.; Freni, M. A.; Resta, M. L.; Simonetti, R. G.; Di Marco, V.; Camma, C.; Fiorello, F.; Scifo, G.; Risicato, R.; Pilleri, G. P.; Bernasconi, M.
abstract
To assess possible geographical differences in the spread of hepatitis-C virus (HCV), the prevalence of antibodies against HCV (anti-C-100-3) was investigated in various adult population groups in 29 centres in Italy. Anti-HCV was positive in 375 out of 28,433 voluntary blood donors (1.3%): prevalence was higher in southern Italy (1.51%) than in the northern regions (1.28%), but the difference was not statistically significant. Anti-HCV prevalence was similar in the north and south in post-tranfusion chronic hepatitis (91%), haemophiliacs (73%), intravenous drug users (70%), and haemodialysis patients (28%), where parenteral contacts are obvious, and in HBsAg carriers (14%), a group with evidence of previous parenteral contamination. In contrast, anti-HCV prevalences were found to be significantly higher in the south than in the north and central Italy among patients with hepatocellular carcinoma (HCC) (73 vs 59%), cryptogenic liver disease (67 vs 58%), autoimmune chronic hepatitis (72 vs 44%) and alcoholic liver disease (51 vs 34%). These results indicate a very high circulation of HCV in Italy, with maximum incidence in the south and in the islands. They suggest that its spread in the community can occur through inapparent parenteral routes as observed for hepatitis-B (HBV) and hepatitis-delta viruses (HDV) and possibly facilitated by poorer social-demographic and lifestyle factors.
1991
- LACK OF ASSOCIATION BETWEEN CIRCULATING HCV-RNA AND ANTI-HCV POSITIVITY IN PRIMARY BILIARY-CIRRHOSIS
[Articolo su rivista]
Bertolini, E; Zermiani, P; Battezzati, Pm; Bruno, S; Villa, Erica; Manenti, F; Marelli, F; Moroni, Ga; Zuin, M; Podda, M.
abstract
PAtients with PBC have often false antiHCV-positivity
1991
- SIGNIFICANCE OF ANTI-HBX ANTIBODIES IN HEPATITIS-B VIRUS-INFECTION
[Articolo su rivista]
Levrero, M; Stemler, M; Pasquinelli, C; Alberti, A; Jeanjean, O; Franco, A; Balsano, C; Diop, D; Brechot, C; Melegari, M; Villa, Erica; Barnaba, V; Perricaudet, M; Will, H.
abstract
Serological responses to hepatitis B virus-X determinants have been noted in human sera, but conflicting findings concerning the correlation of anti-HBx antibodies with different stages of hepatitis B virus infection or pathological sequelae have been reported. Using an adenovirus-based eukaryotic vector, the 17 kD X protein was efficiently expressed in 293 cells. Cellular extracts containing the eukaryotic X protein have been used to screen for anti-HBx antibodies by immunoblot analysis in a large panel of sera from patients affected by hepatitis B virus chronic hepatitis, hepatocellular carcinoma and acute viral hepatitis. Sera from 32 of 171 (19%) chronic hepatitis virus patients were positive for anti-HBx antibodies. Only one of thirty-two (3%) HBsAg-negative, anti-HBs/anti-HBc-positive chronic hepatitis serum was anti-HBx positive. Very few sera from primary hepatocellular carcinoma patients showed positivity for anti-HBX (8 of 149 or 5%). Anti-HBx were also detected in 8 of 48 (17%) acute viral hepatitis patients. In the four cases that were followed up weekly, anti-HBx antibodies appeared 3 to 4 wk after the onset of the clinical signs. To compare the X protein expressed in eukaryotic and prokaryotic cells as a substrate for anti-HBx antibody detection, 171 sera were screened with HBx fusion proteins expressed in Escherichia coli. The prokaryotic cell extract test seems to be more sensitive. During the chronic phase of hepatitis B virus infection, the presence of anti-HBx antibodies detected with the eukaryotic cell extract correlates with the presence of well-established markers of ongoing viral replication: serum hepatitis B virus-DNA (p < 0.001) and intrahepatic HBcAg expression (p < 0.001).
1990
- Detection of hepatitis B virus transcripts in patients with chronic liver disease.
[Articolo su rivista]
C., Pasquinelli; M., Melegari; Villa, Erica; M., Seidenari; Pp, Scaglioni; C., Tiribelli; Ls, Croce; F., Manenti
abstract
Hepatitis B virus (HBV) transcription was studied by Northern blot analysis on total cellular RNA purified from liver biopsies in 70 patients with chronic liver disease (24 HBsAg positive, 15 antiHBs and/or antiHBc positive, 31 HBV negative). No transcripts were found in the HBV negative and in the antiHBs and/or antiHBc positive patients. In the others, three major RNA species were identified: i. a 3.5 kb transcript corresponding to the RNA pregenome; ii. 2.4-2.1 kb transcript corresponding to the s and preS1 gene RNA; iii. lower molecular weight species. All three forms were present simultaneously only in patients with active viral replication, with a strict relation between the presence of the 3.5 kb RNA in the liver and serum HBV-DNA. In conclusion, Northern blot analysis can easily be performed to study viral replication and it can contribute to a better understanding of the molecular processes underlying HBV infection and leading to liver disease in man.
1990
- Hepatitis B virus infection of peripheral blood mononuclear cells is common in acute and chronic hepatitis.
[Articolo su rivista]
Pasquinelli, C; Melegari, M; Villa, Erica; Scaglioni, Pp; Seidenari, M; Mongiardo, N; DE RIENZO, Bruno; Manenti, Federico
abstract
Hepatitis B virus (HBV) infection of peripheral blood mononuclear cells (PBMCs) has been observed in all stages of liver disease. Thus far all information about the physical state of HBV in mononuclear blood cells comes from Southern blot analysis and in situ hybridization. In this study we focused our attention on the presence of HBV DNA sequences in PBMCs of 30 patients with acute type B hepatitis and 6 patients with chronic active hepatitis by utilizing both Southern blot analysis and the polymerase chain reaction (PCR). Southern blot analysis showed no HBV DNA sequences in PBMCs of the acute hepatitis patients, although the sensitivity of our method enabled us to detect as little as 1 pg of cloned HBV insert. As far as the chronic hepatitis patients are concerned Southern blot analysis revealed the presence of HBV DNA sequences in 5 out of 6 patients but intermittently at successive follow-up times. On the other hand we were able to demonstrate the presence of HBV related sequences in 14 out of 30 acute hepatitis patients (5 HBeAg positive, 9 antiHBe positive) and in all 6 chronic hepatitis patients by PCR. Our results indicate that the involvement of PBMCs with HBV during acute HBV infection occurs at a very low level, often below the detection limit of the Southern blot technique.
1989
- Characterization of estrogen receptor from human liver.
[Articolo su rivista]
Rossini, Gian Paolo; Baldini, Gm; Villa, Erica; Manenti, F.
abstract
Characterization of the estrogen receptor in cytosol from human male liver was undertaken to further understanding of the molecular basis of estrogen action in this tissue. By analysis of estrogen binding data of crude cytosol, saturable estrogen binding showed a Kd = 4.7 X 10(-10) M. High levels of nonsaturable binding were also detected. The estrogen-binding activities detected could be distinguished by their steroid specificity, hydrodynamic parameters, ionic properties, and sensitivity to proteolytic attack. Our findings also confirmed that the moderate-affinity estrogen binders found in rodent liver cannot be detected in human tissue. We concluded that the properties of estrogen receptor of human liver cytosol allow its separation from nonsaturable estrogen-binding components.
1989
- Effect of ursodeoxycholic acid treatment on alanine aminotransferase and gamma-glutamyltranspeptidase serum levels in patients with hypertransaminasemia. Results from a double-blind controlled trial.
[Articolo su rivista]
Bellentani, S; Tabarroni, G; Barchi, T; Ferretti, Ilva; Fratti, N; Villa, Erica; Manenti, Federico
abstract
The ability of ursodeoxycholic acid (UDCA, 600 mg/day) to lower alanine aminotransferase (ALT) blood levels in blood donors rejected for donation because of fluctuating hypertransaminasemia was evaluated in a randomized, controlled, double-blind clinical trial vs. placebo. All subjects with ALT values at least twice the normal upper limit in at least two out of three previous checks (the last one not more than 1 month previously) were admitted to the study. Checks were carried out 1, 2 and 3 months after the admission. 59 out of 65 patients completed the study. Although all patients were asked to abstain from alcohol, more than 50% of them in both groups had basal gamma-glutamyltransferase (gamma-GT) values higher than normal. After 1 month of treatment and throughout its duration, UDCA was effective in lowering ALT in all patients (30% decrease with respect to the basal value) and, especially, in lowering gamma-GT in those patients with elevated levels (50% decrease with respect to the basal value). This decrease was significantly different from the spontaneous 10% decrease of the ALT and gamma-GT levels observed in the placebo group. 3 months after suspension of therapy a rebound of both ALT and gamma-GT to values comparable to the basal ones or even higher was found only in UDCA-treated patients. We conclude that the short-term administration of UDCA is free of hepatotoxic effects and could be useful in lowering ALT and gamma-GT serum levels. The real significance of UDCA treatment in the natural history of chronic liver diseases deserves further investigation.
1988
- Ethanol-induced increase in cytosolic estrogen receptors in human male liver: a possible explanation for biochemical feminization in chronic liver disease due to alcohol.
[Articolo su rivista]
Villa, Erica; G. M., Baldini; Rossini, Gian Paolo; C., Pasquinelli; M., Melegari; E., Cariani; C., Tata; S., Bellentani; Ferrari, Alberto; Manenti, Federico
abstract
Abstract The hepatic cytosolic estrogen receptor content was measured in liver samples from patients with normal livers and from patients with nonalcoholic cirrhosis, alcoholic cirrhosis and alcoholic hepatitis. The estrogen receptor content of normal liver was 5.2 ± 3.5 fmoles per mg of cytosolic protein. Levels which were not significantly different from this were found in the samples from patients with nonalcoholic cirrhosis (2.1 ± 2.0 fmoles per mg of cytosolic protein). The cytosolic estrogen receptor content in the livers of patients with alcoholic cirrhosis who were abstaining was 4.2 ± 3.6 fmoles per mg of cytosolic protein, but it increased to 10.4 ± 4.9 fmoles per mg of protein in the livers of patients with alcoholic cirrhosis who were drinking, to 17.3 ± 8.7 fmoles per mg of protein in the livers of patients with alcoholic hepatitis with cirrhosis and to 22.7 ± 15.7 fmoles per mg of protein in the livers of patients with alcoholic hepatitis without cirrhosis. Alcohol abuse appeared, therefore, to induce an increase in the estrogen receptor content of human liver, especially in patients who were drinking and had histological evidence of acute liver damage (alcoholic hepatitis). The increase in hepatic estrogen receptor which we have observed may be involved in the molecular mechanisms underlying the feminization of the liver in alcoholic males.
1988
- Risk factors for hepatocellular carcinoma in Italy. Male sex, hepatitis B virus, non-A non-B infection, and alcohol.
[Articolo su rivista]
Villa, Erica; Baldini, Gm; Pasquinelli, C; Melegari, M; Cariani, E; DI CHIRICO, G; Manenti, F.
abstract
To investigate risk factors for hepatocellular carcinoma (HCC) in Italy--a country with medium (south: 5% to 10%) to low (north: 1% to 2%) incidence of hepatitis B virus (HBV) infection--we studied 646 consecutive patients: 58 chronic active hepatitis (CAH), 428 cirrhosis, and 160 HCC, 49% from Southern and 51% from Northern Italy. Hepatitis B surface antigen (HBsAg) was positive in 41.4% of the CAH, in 23.1% of cirrhotic patients, and in 26.2% of HCC. In the latter, HBV DNA assay increased the number of subjects with active HBV infection by about 12%. Alcohol abuse was evenly distributed in all three categories of HBV markers. Males were preferentially affected. The HCC was superimposed on cirrhosis in more than 90% of patients. Our data suggest that, in our epidemiologic setting, different factors (HBV, non-A, non-B agents, alcohol) may cooperate in the development of HCC, mainly through their potential for causing cirrhosis.
1986
- Amineptine induced cholestatic hepatitis: A case with drug rechallenge
[Articolo su rivista]
Fornaciari, G.; Villa, E.; Tinterri, N.
abstract
1986
- Multicenter trial on the efficacy of HBIG and vaccine in preventing perinatal hepatitis B. Final report.
[Articolo su rivista]
Zanetti, Ar; Dentico, P; Del Vecchio Blanco, C; Sagnelli, E; Villa, Erica; Ferroni, P; Bergamini, F.
abstract
In an attempt to interrupt perinatal transmission of hepatitis B, 92 infants born to HBsAg carrier mothers (49 to HBeAg-positive mothers, 30 to anti-HBe-positive with abnormally elevated ALT levels, and 13 to HBeAg/anti-HBe-negative mothers) received 0.5 ml/kg BW of HBIG at birth and at 1 month of age. Three IM injections of hepatitis B vaccine were given at 3, 4, and 9 months of life. All babies who were given the three doses of vaccine developed an active anti-HBs response: of these, 53 (62.3%) had antibody titers higher than 1,000 mIU/ml, 29 (34.2%) had levels between 100 and 1,000 mIU/ml, and the other three (3.5%) were below 100 mIU/ml. At the end of the 2-year follow-up, these three poor responders became anti-HBs negative, whereas the others still had antibody. All but three babies were protected by HBIG plus vaccine treatment. Two chronic HBV infections occurred within 6 months of life presumably because the babies were already infected when prophylaxis started. The third baby became an HBsAg carrier at 9 months of age in spite of a previous response to the vaccine. Simultaneous presence of HBsAg of y specificity and anti-HBs (anti-a) was still detectable at 24 months of age. The vaccine was well tolerated. Passive plus active immunization is an effective procedure for preventing perinatally transmitted HBV infection.
1985
- Alcohol and Hepatitis B Virus Infection
[Capitolo/Saggio]
Villa, Erica; G., Baldini; S., Di Stabile; Plessi, Maria; C., Pasquinelli; A., Antonioli; Braghiroli, Daniela; T., Barchi; Monzani, Agar; Manenti, Federico
abstract
We have studied the metabolims of ethanol in 4 cronic asymtomatic HBsAg-positive subjects. Ethanol and acetaldehyde levels were estimated by an enzymatic method
1985
- Presence of HBV DNA in spermatozoa: a possible vertical transmission of HBV via the germ line.
[Articolo su rivista]
Hadchouel, M; Scotto, J; Huret, Jl; Molinie, C; Villa, Erica; Degos, F; Brechot, C.
abstract
Using molecular hybridization we studied the presence and state of HBV DNA in sperm samples obtained from 17 patients with HBV infection (eight HBsAg chronic carrier, nine acute hepatitis B). Presence of HBV DNA was detected in three samples of seminal fluid from three patients with acute hepatitis. Restriction enzyme patterns of cellular DNA were consistent with presence of integrated HBV DNA sequences in spermatozoa from two of these three patients. The results indicate that HBV DNA may be present in the semen, at least during the acute phase of HBV infection. The presence of HBV DNA in seminal fluid confirms the possibility of venereal transmission. The presence of integrated sequences in spermatozoa suggests the possibility of true vertical transmission of HBV via the germ line.
1984
- Gastrointestinal endoscopy and HBV infection: no evidence for a causal relationship. A prospective controlled study.
[Articolo su rivista]
Villa, Erica; Pasquinelli, C; Rigo, G; Ferrari, Alberto; Perini, Mario; Ferretti, Ilva; Gandolfo, Marco; Rubbiani, L; Antonioli, A; Barchi, T.
abstract
The importance of the different endoscopic procedures in the transmission of hepatitis B was investigated prospectively by following up for 6 months all HBV-negative patients endoscoped from April to October 1981. A group of patients admitted in the same period to our unit constituted the control group. Controls were obtained after 1, 3, and 6 months from endoscopy. Infection rate was 1% for the control group and 0.45% for the endoscopy group. The difference is not statistically significant. These results strongly support the view, already present on an uncontrolled basis in the literature, that transmission of hepatitis B is not associated with gastrointestinal endoscopy.
1983
- Fulminant onset of spontaneous bacterial peritonitis.
[Articolo su rivista]
Villa, Erica; Rubbiani, L; Barchi, T; Ferretti, Ilva; Manenti, Federico
abstract
Risk of spontaneous bacterial peritonitis in cirrhosis
1983
- Post nephectomy arteriovenous fistula: A reversible cause of hypertension and cardiac failure. Report of a case
[Articolo su rivista]
Pompei, G.; Romani, F.; Torricelli, P.; Villa, E.
abstract
1982
- Fatal outcome in a case of benign lymphangioma of the spleen: a case report
[Articolo su rivista]
Pompei, G.; Villa, E.; Pantusa, M.
abstract
1982
- Susceptibility of chronic symptomless HBsAg carriers to ethanol-induced hepatic damage.
[Articolo su rivista]
Villa, Erica; Rubbiani, L; Barchi, T; Ferretti, Ilva; Grisendi, A; De Palma, M; Bellentani, S; Manenti, Federico
abstract
To investigate the susceptibility of chronic symptomless HBsAg carriers to the hepatotoxic effect of ethanol 296 such carriers were followed up for 3 1/2 years with repeated biochemical and clinical examinations. A control group of HBsAg-negative blood donors matched by age, sex, occupation, duration and type of ethanol intake, and state of nutrition were followed up for the same period. Chronic symptomless HBsAg carriers seemed to be at risk of hepatic abnormalities when drinking an amount of ethanol which was harmless for HBsAg-negative subjects (less than 80 g). It may therefore be advisable to suggest complete abstinence from ethanol for HBsAg carriers.
1981
- Hepatitis B virus markers on dried blood spots. A new tool for epidemiological research.
[Articolo su rivista]
Villa, Erica; Cartolari, R; Bellentani, S; Rivasi, P; Casolo, G; Manenti, Federico
abstract
A tool for spidemiolgical research
1981
- Reactivation of hepatitis B virus infection in two patients: immunofluorescence studies of liver tissue.
[Articolo su rivista]
Villa, Erica; Theodossi, A; Portmann, B; Eddleston, Al; Williams, R.
abstract
Two patients, 1 with chronic active hepatitis, the other with Goodpasture's syndrome, became HBsAg-positive after the start of immunosuppressive drug therapy. At the same time of presentation, sera contained anti-HBc antibodies of IgM and IgG class in the absence of HBsAg or anti-HBs and immunofluorescent studies of liver biopsy specimens showed core antigen in the nuclei of liver cells. It is suggested that these findings reflected an unusual pattern of hepatitis B virus infection with a very low level of viral replication and that the appearance of HBsAg in both serum and liver cells after immunosuppressive drug therapy was due to reactivation of this infection, possibly as a result of changes in levels of antibodies which suppress viral replication. In 1 patients, the change in viral replication was associated with continuing liver cell necrosis and progressive deterioration in liver function
1981
- Study of the long-term effects of selective biliary obstruction (SBO).
[Articolo su rivista]
Bellentani, S; Ferrari, Alberto; Villa, Erica; Manenti, Federico
abstract
Selective biliary obstruction (SBO) is a model of partial cholestasis in the rat in which the bile duct draining the median lobe is ligated and transected; the remaining biliary tree remains intact. Other authors introduced this experimental model and studied morphological and biochemical modifications in the liver after 2 days from surgery. They suggest that an adaptation may occur. Choosing some markers of cholestasis and some other markers of various cytoplasmic organelles, we studied the long-term effects that occur in serum and in total liver homogenate of selectively obstructed rats as compared to controls. Alkaline phosphatase activity and bile acids content, which were significantly higher than controls in serum and in total liver homogenate of the median lobe after 2 and 8 days from SBO, returned to normal range values after 30 days. Cytochrome-oxidase and glucose-6-phosphatase activity in total homogenate of the SBO median lobe remains perfectly similar to the control values in time. Results, together with morphological observations, suggest that cholestasis is present immediately after operation, then decreases gradually and disappears finally. The obstructed median lobe seems to cope with cholestasis.
1981
- Thin needle percutaneous cholangiography in jaundiced patients with biliary-enteric anastomosis
[Articolo su rivista]
Pompei, G.; Villa, E.
abstract
1980
- 'Spontaneous' bacterial peritonitis in cirrhosis. Report of 10 cases
[Articolo su rivista]
Villa, E.; Rubbiani, L.; Ferrari, A.; Manenti, F.
abstract
1980
- Complications in laparoscopy: a survey of 6 563 cases
[Articolo su rivista]
Manenti, A.; Manenti, F.; Villa, E.; Ferrari, A.; Malagoli, M.; Cortesi, N.
abstract
Les auteurs décrivent leur expérience sur les complications de 6 563 laparoscopies. Au total la mortalité a été de 0,045 % et la morbidité de 1,23%. Il a été démontré que la laparoscopie seule est un procédé simple et sûr, avec une morbidité faible (1,33%) et sans mortalité. L'association à d'autres procédés, comme la biopsie et la cholangiographie, a fait augmenter le risque des accidents graves. Les complications mortelles ont eu lieu après biopsies hépatiques à l'aiguille en cas de foie cirrhotique ou néoplasique, avec une mortalité de 0,26% sur un total de 1 147 biopsies. © 1980, Springer-Verlag. All rights reserved.
1980
- Evidence for hepatitis B and other virus infection in HBsAg-negative chronic active hepatitis.
[Articolo su rivista]
Villa, Erica; Jenkins, P; Portmann, B; Eddleston, Al; Williams, R.
abstract
Antibody to the hepatitis B core antigen (anti-HBc) was detected in sera from 6 (19%) of 32 patients with HBsAg-negative chronic active hepatitis. In three cases with the highest anti-HBc titers, core antigen was detected in liver cell nuclei and in one case HBsAg was also present in hepatocytes, suggesting continuing hepatitis B virus infection. During follow-up, anti-HBc titers fell slowly in those with no viral antigens in liver tissue, and in two cases with virus in the liver at presentation, viral antigens were no longer demonstrable four and eight years later. In one case, clearance of virus was preceded by the appearance of HBsAg in liver and serum, suggesting reactivation of viral replication. In three of the anti-HBc-negative cases a nuclear antigen unrelated to the hepatitis B virus was detected by immunofluorescence, and it is possible that liver disease in these patients may be related to persistent non-A, non-B virus infection.
1976
- The part played by biliary salts in tolbutamide metabolism
[Articolo su rivista]
Ferrari, A.; Manenti, F.; Ponz De Leon, M.; Carulli, N.; Rosi, S.; Villa, E.
abstract
1974
- Recurrent intrahepatic cholestasis
[Articolo su rivista]
Manenti, F.; Ferrari, A.; Villa, E.
abstract
Intrahepatic recurrent cholestasis (IRC), after its first description in 1959, has been sporadically reported from all parts of the world. In total, less than 50 cases have been published, 4 of them in Italy. In the present report, six new patients are described: their age ranged between 16 and 51 yr; two were women. Four of them had several attacks of cholestatic jaundice, ranging from 4 to more than 10; two patients had, up to now, only one episode of jaundice: they are reported because they presented with all the features of the syndrome and had close familial relationship with the other patients. Clinically, they were characterized by pruritus and in the cases of longest duration, by steatorrhea and loss of weight. The peak of serum bilirubin, mainly in the conjugated form, ranged from 15 to over 50 mg/100 ml; alkaline phosphatases and serum cholesterol were very high during the attack, while serum transaminases were constantly normal or near normal. In all patients, the biliary tree was normal as proved either by direct cholangiography obtained during laparotomy or laparoscopy, or by intravenous cholangiogram performed in the interval between the attacks. Histology was obtained in all patients and in all, it showed heavy pigment deposition, normal liver structure, slight increase of fibrous tissue in portal spaces, where inflammatory infiltrates were present. In the interval between the attacks of jaundice, all patients showed complete remission of clinical and biochemical signs. The most striking feature of these cases is that all are natives of a very small area of the Appennines and all but one are more or less closely related. In particular, the two patients who had only one episode of jaundice are respectively sister and first cousin of one of the more typical cases. Moreover one patient has two brothers now living in England, already described as having IRC.