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Background and aims: In patients with hepatocellular carcinoma (HCC), macrovascular invasion (MaVI) limits treatment options and decreases survival. Detailed data on the relationship between MaVI extension and patients' characteristics, and its impact on patients' outcome are limited. We evaluated the prevalence and extension of MaVI in a large cohort of consecutive HCC patients, analysing its association with liver disease and tumour characteristics, as well as with treatments performed and patients' survival. Methods: We analysed data of 4774 patients diagnosed with HCC recorded in the Italian Liver Cancer (ITA.LI.CA) database (2008-2018). Recursive partition analysis (RPA) was performed to evaluate interactions between MaVI, clinical variables and treatment, exploring the inter-relationship determining overall survival. Results: MaVI prevalence was 11.1%, and median survival of these patients was 6.0months (95% CI, 5.1-7.1). MaVI was associated with younger age at diagnosis, presence of symptoms, worse Performance Status (PS) and liver function, high alphafetoprotein levels and large HCCs. MaVI extension was associated with worse PS, ascites and greater impairment in liver function. RPA identified patients' categories with different treatment indications and survival, ranging from 2.4months in those with PS>1 and ascites, regardless of MaVI extension (receiving best supportive care in 90.3% of cases), to 14.1months in patients with PS 0-1, no ascites and Vp1-Vp2 MaVI (treated with surgery in 19.1% of cases). Conclusions: MaVI presence and extension, together with PS and ascites, significantly affect patients' survival and treatment selection. The decision tree based on these parameters may help assess patients' prognosis and inform therapeutic decisions.

none 31 no Nonalcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of metabolic syndrome and may evolve into hepatocellular carcinoma (HCC). Only scanty clinical information is available on HCC in NAFLD. The aim of this multicenter observational prospective study was to assess the clinical features of patients with NAFLD-related HCC (NAFLD-HCC) and to compare them to those of hepatitis C virus (HCV)-related HCC. A total of 756 patients with either NAFLD (145) or HCV-related chronic liver disease (611) were enrolled in secondary care Italian centers. Survival was modeled according to clinical parameters, lead-time bias, and propensity analysis. Compared to HCV, HCC in NAFLD patients had a larger volume, showed more often an infiltrative pattern, and was detected outside specific surveillance. Cirrhosis was present in only about 50% of NAFLD-HCC patients, in contrast to the near totality of HCV-HCC. Regardless of tumor stage, survival was significantly shorter (P = 0.017) in patients with NAFLD-HCC, 25.5 months (95% confidence interval 21.9-29.1), than in those with HCV-HCC, 33.7 months (95% confidence interval 31.9-35.4). To eliminate possible confounders, a propensity score analysis was performed, which showed no more significant difference between the two groups. Additionally, analysis of patients within Milan criteria submitted to curative treatments did not show any difference in survival between NAFLD-HCC and HCV-HCC (respectively, 38.6 versus 41.0 months, P = nonsignificant) CONCLUSIONS: NAFLD-HCC is more often detected at a later tumor stage and could arise also in the absence of cirrhosis, but after patient matching, it has a similar survival rate compared to HCV infection; a future challenge will be to identify patients with NAFLD who require more stringent surveillance in order to offer the most timely and effective treatment. Fabio Piscagliaxxx; Gianluca Svegliati-Baroni; Andrea Barchetti; Anna Pecorellixxx; Sara Marinellixxx; Claudio Tiribelli; and; Stefano Bellentani; on behalf of the HCC-NAFLD Italian Study Group [;Mauro Bernardi; Maurizio Biselli; Paolo Caraceni; Marco Domenicali; Francesca Garuti; Annagiulia Gramenzi; Barbara Lenzi; Donatella Magalotti; Matteo Cescon; Matteo Ravaioli; Emanuela Giampalma; Rita Golfieri; Cristina Mosconi; Luigi Bolondi; Marco Zoli; Alessandro Granito; Francesco Tovoli; Franco Trevisani; Laura Venerandi; Giovanni Brandi; Alessandro Cucchetti;] Fabio Piscagliaxxx; Gianluca Svegliati-Baroni; Andrea Barchetti; Anna Pecorellixxx; Sara Marinellixxx; Claudio Tiribelli; and; Stefano Bellentani; on behalf of the HCC-NAFLD Italian Study Group [;Mauro Bernardi; Maurizio Biselli; Paolo Caraceni; Marco Domenicali; Francesca Garuti; Annagiulia Gramenzi; Barbara Lenzi; Donatella Magalotti; Matteo Cescon; Matteo Ravaioli; Emanuela Giampalma; Rita Golfieri; Cristina Mosconi; Luigi Bolondi; Marco Zoli; Alessandro Granito; Francesco Tovoli; Franco Trevisani; Laura Venerandi; Giovanni Brandi; Alessandro Cucchetti;]

Background and aims the Barcelona Clinic Liver Cancer intermediate stage (BCLC-B) of hepatocellular carcinoma (HCC) includes extremely heterogeneous patients in terms of tumor burden and liver function. Transarterial-chemoembolization (TACE) is the first-line treatment for these patients although it may be risky/useless for someone, while others could undergo curative treatments. This study assesses the treatment type performed in a large cohort of BCLC-B patients and its outcome. Methods retrospective analysis of 485 consecutive BCLC-B patients from the ITA.LI.CA database diagnosed with naive HCC after 1999. Patients were stratified by treatment. Results 29 patients (6%) were lost to follow-up before receiving treatment. Treatment distribution was: TACE (233, 51.1%), curative treatments (145 patients, 31.8%), sorafenib (18, 3.9%), other (39, 8.5%), best supportive care (BSC) (21, 4.6%). Median survival (95% CI) was 45 months (37.4-52.7) for curative treatments, 30 (24.7-35.3) for TACE, 14 (10.5-17.5) for sorafenib, 14 (5.2-22.7) for other treatments and 10 (6.0-14.2) for BSC (p

// Filomena Morisco 1 , Silvia Camera 1 , Maria Guarino 1 , Raffaella Tortora 2 , Valentina Cossiga 1 , Anna Vitiello 1 , Gabriella Cordone 2 , Nicola Caporaso 1 , Giovan Giuseppe Di Costanzo 2 and Italian Liver Cancer (ITA.LI.CA) group 1 Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples, Italy 2 Hepatology Unit, “Cardarelli” Hospital, Naples, Italy Correspondence to: Filomena Morisco, email: filomena.morisco@unina.it Keywords: large HCC; laser ablation; TACE Received: December 13, 2017 Accepted: February 27, 2018 Published: April 03, 2018 ABSTRACT Background: Limited therapies are available for large (≥40 mm) unresectable hepatocellular carcinoma (HCC). Currently, the standard treatment with transarterial chemoembolisation (TACE) is unsatisfactory with high recurrence rate and limited effect on survival. Laser Ablation (LA) has emerged as a relatively new technique characterized by high efficacy and good safety. This study is aimed to evaluate the efficacy of LA in comparison to TACE in patients with large HCC. Methods: Eighty-two patients with a single HCC nodule ≥40 mm (BCLC stage A or B) were enrolled in this case-control study. Forty-one patients were treated with LA and 41 patients were treated with TACE. Response to therapy was evaluated according to the mRECIST criteria. Survival was calculated with Kaplan-Meier from the time of cancer diagnosis to death with values censored at the date of the last follow-up. Results: Twenty-six (63.4%) and 8 (19.5%) patients had a complete response after LA and TACE, respectively ( p 60 mm. LA resulted superior to TACE especially in nodules ranging between 51 and 60 mm in diameter, with a complete response rate post-LA and post-TACE of 75% and 14.3%, respectively ( p = 0.0133). The 36 months cumulative survival rate in patients treated with LA and TACE was 55.4% and 48.8%, respectively. The disease recurrence rates after LA and TACE were 19.5% and 75.0%, respectively. Conclusions: LA is a more effective therapeutic option than TACE in patients with solitary large HCC.

Background: Metabolic disorders are well-known risk factors for HCC. Conversely, their impact on the natural history of HCC is not established. This study aimed at evaluating the impact of metabolic disorders on clinical features, treatment and survival of HCC patients regardless of its aetiology. Methods: We analysed the ITA.LI.CA database regarding 839 HCC patients prospectively collected. The following metabolic features were analysed: BMI, diabetes, arterial hypertension, hypercholesterolaemia and hypertriglyceridaemia. According to these features, patients were divided into 3 groups: 0-1, 2 and 3-5 metabolic features. Results: As compared with patients with 0-1 metabolic features, patients with 3-5 features showed lower percentage of HCC diagnosis on surveillance (P=.021), larger tumours (P=.038), better liver function (higher percentage of Child-Pugh class A [P=.007] and MELD&nbsp

The emergence of drug-resistant virus in hepatitis B virus patients treated with lamivudine is well documented. However. its clinical impact in the long-term treatment of anti-HBe positive compensated cirrhotic patients is not well known. In this study, we treated 22 consecutive patients with anti-HBe compensated cirrhosis with lamivudine for a median period of 42 months. All patients responded to lamivudine, but viral breakthrough occurred in 13 patients (59%) between 9 and 42 months of therapy due to the emergence of a mutant strain. During the follow-up, 11 developed hepatocellular carcinoma. Of these, 10 occurred soon after the emergence of viral resistance, generally showing aggressive behaviour, and one in the nine long-term responder patients (P = 0.013). Lamivudine resistance was the only independent predictor of hepatocellular carcinoma development (risk ratio: 10.4; 95% CI: 1.3-84.9). Our study suggests that the occurrence of lamivudine resistance increases the risk of hepatocellular carcinoma in anti-HBe positive cirrhosis and warrants further research.

Lead-time is the time by which diagnosis is anticipated by screening/surveillance with respect to the symptomatic detection of a disease. Any screening program, including surveillance for hepatocellular carcinoma (HCC), is subject to lead-time bias. Data regarding lead-time for HCC are lacking. Aims of the present study were to calculate lead-time and to assess its impact on the benefit obtainable from the surveillance of cirrhotic patients. Background & Aims: Lead-time is the time by which diagnosis is anticipated by screening/surveillance with respect to the symptomatic detection of a disease. Any screening program, including surveillance for hepatocellular carcinoma (HCC), is subject to lead-time bias. Data regarding lead-time for HCC are lacking. Aims of the present study were to calculate lead-time and to assess its impact on the benefit obtainable from the surveillance of cirrhotic patients. Methods: One-thousand three-hundred and eighty Child–Pugh class A/B patients from the ITA.LI.CA database, in whom HCC was detected during semiannual surveillance (n = 850), annual surveillance (n = 234) or when patients came when symptomatic (n = 296), were selected. Lead-time was estimated by means of appropriate formulas and Monte Carlo simulation, including 1000 patients for each arm. Results: The 5-year overall survival after HCC diagnosis was 32.7% in semiannually surveilled patients, 25.2% in annually surveilled patients, and 12.2% in symptomatic patients (p

Background & Aims: Transcatheter arterial chemoembolization (TACE) currently is used as a palliative treatment for patients with unresectable hepatocellular carcinoma (HCC), but its efficacy still is debated. Our aim was to assess the impact of TACE on patient survival and to identify prognostic factors for survival. Methods: Fifty-six cirrhotic patients with unresectable HCC undergoing at least :1 course of TACE were matched 1:1. for sex, age (in 5-year periods), parameters of Child-Pugh score, Okuda stage, and tumor type with a control group who had received only supportive care. Results: The 2 groups were comparable for cause of cirrhosis, alpha-fetoprotein serum levels, and Cancer of the Liver Italian Program (CLIP) score. The 56 patients in the TACE group received a total of 123 treatment courses. The median follow-up period was 16 months (range, 1-67 mo) in the TACE group and 5 months (range, 1-77 mo) in the supportive care group. Survival rates at 12, 24, and 30 months in patients receiving TACE were 74.3%, 52.1%, and 38.8% respectively, with a median survival time of 25 month whereas in supportive care patients the rates we 39.4%, 25.4%, and 19%, respectively, with a median survival time of 7 months (P =.0004). At univariate analysis, TACE, tumor type, presence of ascites, alpha-fetoprotein serum level, CLIP score, and Okuda stage were associated significantly with survival. Only TACE and CLIP score proved to be independent predictors of survival at multivariate analysis. Conclusions: TACE is an effective therapeutic option for cirrhotic patients with unresectable HCC and a CLIP score of 3 or less.

INTRODUCTION: Hepatocellular carcinoma (HCC) is an established indication for liver transplantation (LT), but the selection criteria and priority are still debated. AIMS: To ascertain the number and features of patients with HCC who undergo transplantation in a Western country, the number of patients eligible for LT according to the American Association for the Study of Liver Diseases (AASLD) guidelines, the number of patients who actually undergo transplantation and whether adherence affects survival. METHODS: This is a retrospective analysis from a multicentre Italian database of 2042 cases of HCC, recruited prospectively and consecutively. Kaplan-Meier (log rank) and Cox multivariate analysis estimated survival. RESULTS: Patients who had undergone transplantation (50, 2.5%, with no change over time) had a median survival of 133 months, significantly influenced by the number of lesions and alpha-fetoprotein levels, which were found to be independent predictors of survival on multivariate analysis. Milan criteria were fulfilled in 68%, impacting on survival, whereas 48% fulfilled AASLD guidelines, without such an impact. Two hundred and twenty-eight (11%) patients were eligible for LT according to AASLD; in this group, alpha-fetoprotein levels and Child-Pugh class were independent predictors of survival. CONCLUSION: Among patients with HCC, those undergoing LT represent a small minority; even fewer (1%) are those who undergo transplantation according to AASLD guidelines, adherence to which only marginally affects survival. Overall, LT impact on HCC patients' treatment is very limited

Background Treatment of hepatitis C virus (HCV) recurrence after liver transplantation (LT) is difficult with low response rates. Aim To assess the safety and efficacy of pegylated-interferon (PEG-IFN) alfa-2b + ribavirin (RBV) in patients with post-LT recurrent genotype-1 HCV and to establish stopping rules according to response. Methods Fifty-three patients with post-LT HCV recurrence were enrolled. Patients received PEG-IFN alfa-2b 1.0 μ/kg/week plus RBV 8–10 mg/kg/day for 24 weeks. Those with ‘early virological response at week 24’ (EVR24) continued treatment for 24 weeks (group A). Patients without EVR24 were randomized to continue (group B) or to discontinue (group C). Results Overall sustained virological response (SVR) was 26% (14/53). Alanine aminotransferase, rapid virological response, EVR12, EVR24, undetectable serum HCV-RNA at weeks 12 (cEVR12) and 24 (cEVR24) were related to SVR. cEVR12 and cEVR24 (OR: 14.7; 95% CI: 2.02–106.4) were independent predictors of SVR. All patients with SVR, had cEVR12. No patient in groups B and C achieved end-of-treatment response. One patient in group B had SVR. Conclusions Pegylated-interferon alfa-2b was effective in one of four of patients with HCV genotype 1 after LT. Treatment should be discontinued in patients with no virological response at week 12. Further studies are needed to evaluate whether a longer treatment period may be beneficial in patients with ≥2 log10 drop in HCV-RNA at week 24

Objectives: This study investigates the diagnostic performance of a new T1 imaging series, generated by the digital subtraction of the opposed phase from in phase T 1 weighted images, in MRI for renal angiomyolipoma (AML) evaluation. Methods: This retrospective study involved 96 patients, 63 (65.6%) with at least one renal AML and 33 (34.4%) healthy patients. Two radiologists having different experience retrospectively reviewed two MR imaging series, starting with in and out-phase T 1 weighted images and then the new subtracted T1 images, in which AML appeared white on black background. The presence, number, location, and dimensions of the AMLs, and reading time were collected separately for the two kidneys. Statistical analysis was carried out using the appropriate tests. Results: The number of lesions identified and the evaluation of lesion dimension did not statistically differ between the different MR imaging series evaluated, without interobserver variability. Both percentage agreement of the total number of observations and the κ coefficient showed very good agreement between the radiologists. The median time for the diagnosis was statistically lower when using the subtracted T1 imaging series for both observers with a median gain from 6.5 to 15 s per identified lesion, resulting in a total time-saving of more than half (52.9%), in both patients with and without AMLs, and in patients with a single or with more than one AML (p < 0.001). Conclusions: The new subtracted T1 imaging series proved to be reliable in identifying fat-containing renal lesions, by both expert and non-expert radiologists, resulting in a saving of both time and money. Moreover, this new subtracted T1 imaging series could be an effective tool in non-dedicated kidney examinations in which a faster reading is advisable. Advances in knowledge: The opportunity of using a single set of MRI images in kidney evaluation for identifying fat-containing lesions, considerably reducing reading time, resulting in cost-effectiveness.

We aimed to evaluate whether pelvic magnetic resonance imaging (MRI) could play a role in better assessing chronic pelvic pain syndrome. We evaluated 44 male patients (median 41 aged) with a clinical history of painful pelvic symptoms, lasting for at least three of the previous 6 months, associated with urinary, anorectal and sexual disorders in the absence of bacterial prostate infection. All these patients underwent ultrasound (US) and MRI evaluation of the pelvis. Prostate imaging findings, such as gland morphology evaluated by US and prostatic signal intensity on MRI, appeared normal in the majority of patients (38/44; 82%). Extraparenchymal alterations were found in 28 patients (63.6%); the most frequent was the dilatation of periprostatic vein plexus (20/28; 71.4%), significantly correlated to chronic pelvic pain syndrome (p = 0.0013), regardless of different clinical presentations. This finding was tested in a control group of 90 patients, demonstrating an excellent specificity (97%), good positive predictive value (87%) and diagnostic accuracy (80%). MRI confirmed its high capability in evaluating prostatic and extraprostatic structures. Periprostatic vein dilatation, which identified approximately two-thirds of the patients with chronic pelvic pain syndrome using pelvic MRI, significantly correlated to chronic pelvic pain syndrome, independently of patient age, symptoms and prostatic volume.

Summary Background Hepatocellular carcinoma (HCC) causes premature death and loss of life expectancy worldwide. Its primary and secondary prevention can result in a significant number of years of life saved. Aim To assess how many years of life are lost after HCC diagnosis. Methods Data from 5346 patients with first HCC diagnosis were used to estimate lifespan and number of years of life lost after tumour onset, using a semi-parametric extrapolation having as reference an age-, sex- and year-of-onset-matched population derived from national life tables. Results Between 1986 and 2014, HCC lead to an average of 11.5 years-of-life lost for each patient. The youngest age-quartile group (18–61 years) had the highest number of years-of-life lost, representing approximately 41% of the overall benefit obtainable from prevention. Advancements in HCC management have progressively reduced the number of years-of-life lost from 12.6 years in 1986–1999, to 10.7 in 2000–2006 and 7.4 years in 2007–2014. Currently, an HCC diagnosis when a single tumour

Background & Aims The model for end-stage liver disease (MELD) is used for organ allocation in liver transplantation (LT), but its prognostic performance is less accurate in patients with low score. We assess the outcome of patients with MELD 15.9. Conclusions In patients with low MELD (

Background: The number of elderly patients diagnosed with hepatocellular carcinoma (HCC) is progressively increasing. The aim of this study was to determine the safety and efficacy of conventional transarterial chemoembolization (TACE) in elderly HCC patients compared with younger adults. Methods: A consecutive cohort of unresectable HCC patients treated with TACE as a first-line treatment was retrospectively analyzed. Patients were categorized into “elderly” (≥ 70years, 80 patients) and “younger” (< 70years, 145 patients). Liver-related death and progression-free survival after TACE were compared before and after propensity score matching. A competing risk regression analysis was used for univariate/multivariate survival data analysis. Results: cTACE was well tolerated in both groups. The cumulative risk of both liver-related death and progression-free survival after cTACE was comparable between “elderly” and “younger” (death: 73.8% vs 69.4%, P = 0.505; progression-free survival: 48.2% vs 44.8%, P = 0.0668). Propensity model matched 61 patients in each group for gender and Barcelona Clinic Liver Cancer staging. Even after matching, the cumulative risk of liver-related death and of progression-free survival did not differ between the two groups. At multivariate analysis, Child–Pugh class, tumor gross pathology and alpha-fetoprotein were independently associated with the liver-related mortality risk. Conclusions: This study confirms that TACE is well tolerated and effective in patients aged 70years or more with unresectable HCC as it is for their younger counterparts (< 70years). Liver-related mortality was not associated with age ≥ 70years and primarily predicted by tumor multifocality, Child–Pugh class B and an increased alpha-fetoprotein value (> 31ng/ml).

Background An enhanced surveillance schedule has been proposed for cirrhotics with viral etiology, who are considered at extremely high-risk of hepatocellular carcinoma (HCC). Aims We compared the 3- and 6-months surveillance interval, evaluating cancer stage at diagnosis and patient survival. Methods Data of 777 HBV and HCV cirrhotic patients with HCC diagnosed under a 3-months (n = 109, 3MS group) or a 6-months (n = 668, 6MS group) surveillance were retrieved from the Italian Liver Cancer database. Survival in the 3MS group was considered as observed and adjusted for lead-time bias, and survival analysis was repeated after a propensity score matching. Results The 3-months surveillance interval neither reduced the share of patients diagnosed outside the Milano criteria, nor increased their probability to receive curative treatments. The median survival of 6MS patients (55.0 months [45.9–64.0]) was not significantly different from the observed (47.0 months [35.0–58.9]; p = 0.43) and adjusted (44.9 months [33.4–56.4]; p = 0.30) survival of 3MS patients. A propensity score analysis confirmed the absence of a survival advantage for 3MS patients. Conclusions A tightening of surveillance schedule does not increase the diagnosis of early-stage tumors, the feasibility of curative treatments and the survival. Therefore, we should maintain the 6-months interval in the surveillance of viral cirrhotics.

Aim: To identify, in vitro, the best fruit juice to use as oral contrast agent in magnetic resonance cholangiopancreatography (MRCP) and to test, in vivo, the best natural juice and the new parameters in MRCP sequences identified in vitro. Materials and methods: The in vitro evaluations consisted of measuring the T2 values of a pure solution of manganese (Mn) and iron (Fe) at different concentrations, measuring the content of Mn and Fe in five commercial juices and their T2 relaxation times, and identifying the optimal juice dilution for suppressing the gastrointestinal fluid signal. The new parameters of MRCP sequences were tested in vivo. Results: Manganese alone strongly influenced the shortening of the T2 values (p=0.004). The T2 value with an echo time (TE) of ≥1,000 ms enabled sufficient intestinal fluid suppression in the case of high juice dilution. A flip angle of 90° maximised the differences between the high signal from static fluids, such as the bile and the fluid in the gastrointestinal tract, using fast imaging employing steady-state acquisition (FIESTA) sequences (p

Background & Aims: According to the Barcelona Clinic Liver Cancer (BCLC) staging system, monofocal hepatocellular carcinoma (HCC) is classified as early (BCLC A) irrespective of its size, even though controversies still exist regarding staging and treatment of large tumours. We aimed at evaluating the appropriate staging and treatment for large (>5cm) monofocal (HCC). Methods: From the Italian Liver Cancer database, we selected 924 patients with small early monofocal HCC (2-5cm; SEM-HCC), 163 patients with larger tumours (>5cm; LEM-HCC) and 1048 intermediate stage patients (BCLC B). Results: LEM-HCC patients had a worse overall survival (OS) than SEM-HCC (31.0 vs 49.0months; P&nbsp

Background Bacterial and fungal infections (BFIs) are frequent in patients with cirrhosis and often trigger acute-on-chronic liver failure (ACLF). This prospective observational study aims to describe the interactions between BFI and ACLF in terms of mortality and related risk factors. Methods We performed a 2-center prospective observational study enrolling hospitalized patients with cirrhosis admitted for acute decompensation. Data were recorded at admission and during hospitalization. Survival was recorded up to 1 year. Results Among the 516 patients enrolled, 108 (21%) were infected at admission, while an additional 61 patients (12%) developed an infection during hospital stay. In the absence of ACLF, the 1-year mortality rate of patients with BFI did not differ from that of patients without BFI (33% vs 31%; P = .553). In contrast, those with ACLF triggered or complicated by BFI had a significantly higher mortality rate than those who remained free from BFI (75% vs 54%; P = .011). Competing risk analysis showed that the negative impact of ACLF-related BFI on long-term prognosis was independent from Model for End-stage Liver Disease (MELD) incorporating serum sodium concentration score, comorbidity, and basal C-reactive protein level. Finally, multivariable logistic regression showed that higher MELD score (P, The adverse prognosis of bacterial or fungal infections in patients with decompensated cirrhosis is linked to the development of acute-on-chronic liver failure. Severity, type and microbiological features of infections are main predictors of the development of acute-on-chronic liver failure.

Beside the regulation of fluid distribution, human serum albumin (HSA) carries other activities, such as binding, transport, and detoxification of many molecules. In patients with cirrhosis, HSA exhibits posttranscriptional alterations that likely affect its functions. This study aimed at identifying the structural HSA alterations occurring in cirrhosis and determining their relationship with specific clinical complications and patient survival. One hundred sixty-eight patients with cirrhosis, 35 with stable conditions and 133 hospitalized for acute clinical complications, and 94 healthy controls were enrolled. Posttranscriptional HSA molecular changes were identified and quantified by using a high-performance liquid chromatography/electrospray ionization mass spectrometry technique. Clinical and biochemical parameters were also recorded and hospitalized patients were followed for up to 1 year. Seven HSA isoforms carrying one or more posttranscriptional changes were identified. Altered HSA isoforms were significantly more represented in patients than in healthy controls. Conversely, the native, unchanged HSA isoform was significantly reduced in cirrhosis. Native HSA and most altered isoforms correlated with both Child-Pugh and Model for End-Stage Liver Disease scores. In hospitalized patients, oxidized and N-terminal truncated isoforms were independently associated with ascites, renal impairment, and bacterial infection. Finally, the native HSA and cysteinylated/N-terminal truncated isoforms were predictors of 1-year survival, with greater prognostic accuracy than total serum albumin concentration. Conclusions: Extensive posttranscriptional changes of HSA, involving several molecular sites and increasing in parallel with disease severity, occur in patients with cirrhosis. Altered isoforms are independently associated with specific clinical complications, whereas the residual, native HSA isoform independently predicts patient survival. These findings support the concept of the “effective albumin concentration,” which implies that the global HSA function is related not only to its serum concentration, but also to the preservation of its structural integrity. (Hepatology 2014;60:1850–1859)

Background & Aims: Determining risk for recurrence or survival after curative resection or ablation in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) is important for stratifying patients according to expected outcomes in future studies of adjuvant therapy in the era of direct-acting antivirals (DAAs). The aims of this meta-analysis were to estimate the recurrence and survival probabilities of HCV-related early HCC following complete response after potentially curative treatment and to identify predictors of recurrence and survival. Methods: Studies reporting time-dependent outcomes (HCC recurrence or death) after potentially curative treatment of HCV-related early HCC were identified in MEDLINE through May 2016. Data on patient populations and outcomes were extracted from each study by three independent observers and combined using a distribution-free summary survival curve. Primary outcomes were actuarial probabilities of recurrence and survival. Results: Eleven studies met the inclusion criteria. Pooled estimates of actuarial recurrence rates were 7.4% at 6months and 47.0% at 2years. Pooled estimates of actuarial survival rates were 79.8% at 3years and 58.6% at 5years. Heterogeneity among studies was highly significant for all outcomes. By univariate meta-regression analyses, lower serum albumin, randomized controlled trial study design and follow-up were independently associated with higher recurrence risk, whereas tumour size and alpha-foetoprotein levels were associated with higher mortality. Conclusions: This meta-analysis showed that recurrence risk and survival are extremely variable in patients with successfully treated HCV-related HCC, providing a useful benchmark for indirect comparisons of the benefits of DAAs and for a correct design of randomized controlled trials in the adjuvant setting.

none 48 no Background: In HCV-infected cirrhotic patients with successfully treated early hepatocellular carcinoma (HCC), the time to HCC recurrence and the effects of sustained viral eradication (SVR) by interferon (IFN)-based or IFN-free regimens on HCC recurrence remain unclear. Aim: To perform an indirect comparison of time to recurrence (TTR) in patients with successfully treated early HCC and active HCV infection with those of patients with SVR by IFN-based and by IFN-free regimens. Methods: We evaluated 443 patients with HCV-related cirrhosis and Barcelona Clinic Liver Cancer Stage A/0 HCC who had a complete radiological response after curative resection or ablation. Active HCV infection was present in 328, selected from the Italian Liver Cancer group cohort; 58 patients had SVR achieved by IFN-free regimens after HCC cure, and 57 patients had SVR achieved by IFN-based regimens after HCC cure. Individual data of patients in the last two groups were extracted from available publications. Results: TTR by Kaplan–Meier curve was significantly lower in patients with active HCV infection compared with those with SVR both by IFN-free (P = 0.02) and by IFN-based (P < 0.001) treatments. TTR was similar in patients with SVR by IFN-free or by IFN-based (P = 0.49) strategies. Conclusion: In HCV-infected, successfully treated patients with early HCC, SVR obtained by IFN-based or IFN-free regimens significantly reduce tumour recurrence without differences related to the anti-viral strategy used. Petta, S.; Cabibbo, G.; Barbara, M.; Attardo, S.; Bucci, L.; Farinati, F.; Giannini, E.G.; Tovoli, F.; Ciccarese, F.; Rapaccini, G.L.; Di Marco, M.; Caturelli, E.; Zoli, M.; Borzio, F.; Sacco, R.; Virdone, R.; Marra, F.; Felder, M.; Morisco, F.; Benvegnù, L.; Gasbarrini, A.; Svegliati-Baroni, G.; Foschi, F.G.; Olivani, A.; Masotto, A.; Nardone, G.; Colecchia, A.; Persico, M.; Boccaccio, V.; Craxì, A.; Bruno, S.; Trevisani, F.; Cammà, C; the Italian Liver Cancer (ITALICA) Group [ ; Maurizio Biselli; Paolo Caraceni; Alessandro Cucchetti; Marco Domenicali; Fabio Piscaglia; Annagiulia Gramenzi; Alessandro Granito; Donatella Magalotti; Carla Serra; Giulia Negrini; Lucia Napoli; Veronica Salvatore; Francesca Benevento;] Petta, S.; Cabibbo, G.; Barbara, M.; Attardo, S.; Bucci, L.; Farinati, F.; Giannini, E.G.; Tovoli, F.; Ciccarese, F.; Rapaccini, G.L.; Di Marco, M.; Caturelli, E.; Zoli, M.; Borzio, F.; Sacco, R.; Virdone, R.; Marra, F.; Felder, M.; Morisco, F.; Benvegnù, L.; Gasbarrini, A.; Svegliati-Baroni, G.; Foschi, F.G.; Olivani, A.; Masotto, A.; Nardone, G.; Colecchia, A.; Persico, M.; Boccaccio, V.; Craxì, A.; Bruno, S.; Trevisani, F.; Cammà, C; the Italian Liver Cancer (ITALICA) Group [ ; Maurizio Biselli; Paolo Caraceni; Alessandro Cucchetti; Marco Domenicali; Fabio Piscaglia; Annagiulia Gramenzi; Alessandro Granito; Donatella Magalotti; Carla Serra; Giulia Negrini; Lucia Napoli; Veronica Salvatore; Francesca Benevento;]

Background and aims Epidemiology of hepatocellular carcinoma is changing worldwide. This study aimed at evaluating the changing scenario of etiology, presentation, management and prognosis of hepatocellular carcinoma in Italy during the last 15 years. Methods Retrospective analysis of the ITA.LI.CA (Italian Liver Cancer) database including 5192 hepatocellular carcinoma patients managed in 24 centers from 2000 to 2014. Patients were divided into three groups according to the date of cancer diagnosis (2000-2004, 2005-2009 and 2010-2014). Results The main results were: 1) progressive patient aging; 2) progressive expansion of non-viral cases and, namely, of “metabolic” hepatocellular carcinomas; 3) increasing proportion of hepatocellular carcinoma diagnosed during a correct (semiannual) surveillance program; 4) favourable cancer stage migration; 4) increased use of radiofrequency ablation to the detriment of percutaneous ethanol injection; 5) improved outcomes of ablative and transarterial treatments; 6) improved overall survival (adjusted for the lead time in surveyed patients), particularly after 2009, of both viral and non-viral patients presenting with an early or intermediate stage hepatocellular carcinoma. Conclusions During the last 15 years several etiological and clinical features of hepatocellular carcinoma patients have changed, as their management. The observed improvement of overall survival was due both to the wider use of semiannual surveillance, expanding the proportion of tumors that qualified for curative treatments, and to the improved outcome of locoregional treatments. This article is protected by copyright. All rights reserved.

Decompensated cirrhosis is associated to extensive post-transcriptional changes of human albumin (HA). This study aims to characterize the occurrence of HA homodimerization in a large cohort of patients with decompensated cirrhosis and to evaluate its association with clinical features and prognosis. HA monomeric and dimeric isoforms were identified in peripheral blood by using a HPLC-ESI-MS technique in 123 cirrhotic patients hospitalized for acute decompensation and 50 age- and sex-comparable healthy controls. Clinical and biochemical parameters were recorded and patients followed up to one year. Among the monomeric isoforms identified, the N- and C-terminal truncated and the native HA underwent homodimerization. All three homodimers were significantly more abundant in patients with cirrhosis, acute-on-chronic liver failure and correlate with the prognostic scores. The homodimeric N-terminal truncated isoform was independently associated to disease complications and was able to stratify 1-year survival. As a result of all these changes, the monomeric native HA was significantly decreased in patients with cirrhosis, being also associated with a poorer prognosis. In conclusion homodimerization is a novel described structural alteration of the HA molecule in decompensated cirrhosis and contributes to the progressive reduction of the monomeric native HA, the only isoform provided of structural and functional integrity.

Background/Aims Orthotopic liver transplantation (OLT) is an important therapeutic option for HBV-related end-stage-liver disease, yet it is often hampered by a scarcity of organ availability. One option to increase organ availability is the use of virologically compromised organs from HBV-infected donors. Transplantation of anti-HBcore positive grafts has been associated with a low risk of HBV recurrence if adequately treated with nucleoside analogs, irrespective of concomitant HBV-specific immunoglobulin therapy. Experience using HBsAg positive grafts is, however, very limited. Methods Here, the analysis of the cellular and humoral HBV-specific immunity of a subject with past HBV infection (anti-HBs and anti-HBc positive) receiving an HBsAg positive liver graft is reported. Results Nine months post-OLT, the patient experienced a spontaneous anti-HBs re-seroconversion allowing the discontinuation of HBIG. The data show a concurrent increase in the cellular and humoral immunity at times of reduced viral antigenemia, demonstrating effective immune control of HBV post-OLT. Conclusions These data support the use of marginal organs in this setting, providing a potential strategy to further alleviate organ shortage.

Summary Background Hepatitis C virus (HCV) and alcohol abuse are the main risk factors for hepatocellular carcinoma (HCC) in Western countries. Aim To investigate the role of alcoholic aetiology on clinical presentation, treatment and outcome of HCC as well as on each Barcelona Clinic Liver Cancer (BCLC) stage, as compared to HCV-related HCCs. Methods A total of 1642 HCV and 573 alcoholic patients from the Italian Liver Cancer (ITA.LI.CA) database, diagnosed with HCC between January 2000 and December 2012 were compared for age, gender, type of diagnosis, tumour burden, portal vein thrombosis (PVT), oesophageal varices, liver function tests, alpha-fetoprotein, BCLC, treatment and survival. Aetiology was tested as predictor of survival in multivariate Cox regression models and according to HCC stages. Results Cirrhosis was present in 96% of cases in both groups. Alcoholic patients were younger, more likely male, with HCC diagnosed outside surveillance, in intermediate/terminal BCLC stage and had worse liver function. After adjustment for the lead-time, median (95% CI) overall survival (OS) was 27.4 months (21.5–33.2) in alcoholic and 33.6 months (30.7–36.5) in HCV patients (P = 0.021). The prognostic role of aetiology disappeared when survival was assessed in each BCLC stage and in the Cox regression multivariate models. Conclusions Alcoholic aetiology affects survival of HCC patients through its negative effects on secondary prevention and cancer presentation but not through a greater cancer aggressiveness or worse treatment result. In fact, survival adjusted for confounding factors was similar in alcoholic and HCV patients.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide, and in most cases it develops in a cirrhotic liver (Kamangar et al, 2006). Surveillance of patients at risk for developing HCC can detect tumours amenable to curative therapies, with positive impact on survival (Trevisani et al, 2002; Zhang et al, 2004). The α-fetoprotein (AFP) is a serum marker still used for the diagnosis and surveillance of HCC. A value of 20 ng ml−1 is considered as best cutoff (BC) to suspect the development of HCC in the setting of chronic liver disease (Trevisani et al, 2001). However, about 32–59% of patients with HCC have normal AFP levels and, conversely, non-tumour-related AFP elevations may occur in patients with cirrhosis or chronic hepatitis, making AFP inadequate as a surveillance test (Gupta et al, 2003; Colli et al, 2006; Lok et al, 2010). To detect HCC at an early stage, it has been proposed to lower the AFP cutoff to 10.9 ng ml−1, obtaining a sensitivity of 66% and a specificity of 82% (Marrero et al, 2009). However, even with this cutoff, about 30% of HCC escape from an early diagnosis. Therefore, Western guidelines consider AFP as inadequate to survey patients at risk of HCC and recommend the use of ultrasound (US) alone (Bruix and Sherman, 2011; European Association for the Study of the Liver; European Organization for Research and Treatment of Cancer, 2012). Nevertheless, being an operator-dependent imaging technique, US has been shown to suffer from a limited sensitivity (63%) for an early detection of HCC (Singal et al, 2009). Thus, some authors as well as Eastern guidelines suggest maintaining the use of AFP in HCC surveillance (Poon et al, 2009; Lee et al, 2013). Waiting for the new reliable biomarkers to complement US in detecting early HCC, our retrospective case–control study aimed at optimising the efficiency of AFP as a surveillance test in cirrhotic patients, considering both its value at the time of HCC diagnosis and its changes overtime before the diagnosis.

The prognosis of untreated patients with hepatocellular carcinoma (HCC) is heterogeneous, and survival data were mainly obtained from control arms of randomized studies. Clinical practice data on this topic are urgently needed, so as to help plan studies and counsel patients. We assessed the prognosis of 600 untreated patients with HCC managed by the Italian Liver Cancer Group. Prognosis was evaluated by subdividing patients according to the Barcelona Clinic Liver Cancer (BCLC) classification. We also assessed the main demographic, clinical, and oncological determinants of survival in the subgroup of patients with advanced HCC (BCLC C). Advanced (BCLC C: n = 138; 23.0%) and end-stage HCC (BCLC D; n = 210; 35.0%) represented the majority of patients. Overall median survival was 9 months, and the principal cause of death was tumor progression (n = 279; 46.5%). Patients' median survival progressively and significantly decreased as BCLC stage worsened (BCLC 0: 38 months; BCLC A: 25 months; BCLC B: 10 months; BCLC C: 7 months; BCLC D: 6 months; P 3) HCC (HR = 1.79; 95% CI = 1.21-2.63; P = 0.003) were independent predictors of survival in patients with advanced HCC (BCLC C). CONCLUSION: BCLC adequately predicts the prognosis of untreated HCC patients. In untreated patients with advanced HCC, female gender, clinical decompensation of cirrhosis, and multinodular tumor are independent prognostic predictors and should be taken into account for patient stratification in future therapeutic studies.

Background & Aims Significant proportion of Hepatocellular Carcinoma (HCC) cases are diagnosed in stage B of Barcelona Clinic Liver Cancer (BCLC) algorithm, in which the standard of care is Transcatheter Arterial ChemoEmbolization (TACE). We aimed to ascertain adherence to current guidelines, survival and prognostic factors in BCLC stage B patients. Methods From 3027 HCC cases recruited from 1986 to 2008 by the Italian Liver Cancer group (2430 with data allowing a correct allocation in the BCLC system), a retrospective analysis was conducted on those diagnosed in BCLC stage B (405 patients, 17%). Statistics were performed with Kaplan–Meier (log rank) method and Cox multivariate analysis. Results Median overall survival in BCLC stage B patients was 25 months (Confidence Interval - C.I. - 22–28 months) with a 5-year survival of 18%. Child–Pugh class, oesophageal varices and Alpha-foetoprotein (AFP) were the independent predictors of survival. TACE was applied in 40% of cases and did not offer the longest survival in comparison with surgical or percutaneous treatments (median 27 months vs. 37 and 36 months, respectively) (P

Background Hepatitis C virus recurrence after liver transplantation is universal, leading to chronic hepatitis and cirrhosis. Aims and patients We evaluated the efficacy and safety of pegylated interferon and ribavirin in 20 patients with recurrent Hepatitis C virus after liver transplantation (10 naive and 10 non-responders to a previous interferon course). Methods Treatment consisted of pegylated interferon alfa-2b (1.0 μg/kg once weekly) and ribavirin (600 mg/daily) for at least 6 months. Therapy continued for an additional 6 months only in patients with undetectable serum Hepatitis C virus-RNA or >2 log drop from baseline levels. Results Eleven out of 20 patients (55%) completed 1 year of treatment. Nine patients (45%) had undetectable Hepatitis C virus-RNA at the end of treatment, six of them were naives and three non-responders. In all of them, virological response persisted 6 months after discontinuation of therapy, so the sustained virological response rate was 60% in naive patients and 30% in non-responders. Conclusions Our results suggest that pegylated interferon plus ribavirin combination therapy may be effective in patients with post-liver transplantation recurrent chronic Hepatitis C, even in those previously non-responders to interferon plus ribavirin. These results need to be confirmed by large studies.

In this pilot study, we evaluated the efficacy of interferon-alpha (IFN) plus Thymosin-alpha 1 (TA1) to that of IFN alone in naive patients with chronic hepatitis C. Twenty-two patients were randomized to receive interferon-alpha 2b (3 million units three times a week) plus thymosin-alpha l (900 microg/m2 body surface area) and 19 received interferon-alpha 2b alone at the same dose. Patients were treated for 6 months and followed up for another 6 months. Biochemical (alanine aminotransferase values) and virological (hepatitis C virus-RNA) responses to treatment were determined. Combination treatment showed significantly higher efficacy than monotherapy in achieving virological end-of-treatment response (P = 0.03). At 6-month follow up, the sustained biochemical and virological response was not different between the two groups. Our results indicate that the immune modulator TA1 may enhance the end-of-treatment response in naive patients with chronic hepatitis C. Higher doses and/ore more prolonged courses as well as the association with new interferon formulation such as pegylated interferons could improve the sustained response rates to this treatment.

Background & Aims The role of hepatic resection for hepatocellular carcinoma (HCC) in different Barcelona Clinic Liver Cancer (BCLC) stages is controversial. We aimed at measuring the survival benefit of resection vs. non-surgical-therapies in each BCLC stage. Methods Using the ITA.LI.CA database, we identified 2090 BCLC A, B, and C HCC patients observed between 2000 and 2012: 550 underwent resection, 1046 loco-regional therapy (LRT), and 494 best supportive care (BSC). A multivariate log-logistic model was chosen to predict median survival (MS) after resection vs. MS after LRT or BSC. The results were expressed as net survival benefit of resection: (MS resection - MS LRT)/MS BSC. Results After stratifying for BCLC stage, the median net survival benefit of resection over LRT was: BCLC 0 = 62% (40%, 82%), A = 45% (13%, 65%), B = 46% (9%, 76%), C = -16% (-55%, 33%). Model for end-stage liver disease (MELD) score >9, Child B class, and performance status (PST) = 2 were the main risk factors for liver resection. 1181 Child A patients (57%) with MELD ≤9 and PST 9 or PST = 2 or Child B class), resection did not prove any survival benefit over LRT. Conclusions Resection could result in survival benefit over LRT for HCC patients regardless of their BCLC stage, provided that liver dysfunction (Child B or MELD >9) and PST >1 are absent.

Alpha-fetoprotein is a tumor marker that has been used for surveillance and diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis. The prognostic capability of this marker in patients with HCC has not been clearly defined. In this study our aim was to evaluate the prognostic usefulness of serum alpha-fetoprotein in patients with well-compensated cirrhosis, optimal performance status, and small HCC identified during periodic surveillance ultrasound who were treated with curative intent. Among the 3,027 patients included in the Italian Liver Cancer study group database, we selected 205 Child-Pugh class A and Eastern Cooperative Group Performance Status 0 patients with cirrhosis with a single HCC ≤3 cm of diameter diagnosed during surveillance who were treated with curative intent (hepatic resection, liver transplantation, percutaneous ethanol injection, radiofrequency thermal ablation). Patients were subdivided according to alpha-fetoprotein serum levels (i.e., normal ≤20 ng/mL; mildly elevated 21-200 ng/mL; markedly elevated >200 ng/mL). Patient survival, as assessed by the Kaplan-Meier method, was not significantly different among the three alpha-fetoprotein classes (P = 0.493). The same result was obtained in the subgroup of patients with a single HCC ≤2 cm (P = 0.714). An alpha-fetoprotein serum level of 100 ng/mL identified by receiver operating characteristic curve had inadequate accuracy (area under the curve = 0.536, 95% confidence interval = 0.465-0.606) to discriminate between survivors and deceased patients. Conclusion: Alpha-fetoprotein serum levels have no prognostic meaning in well-compensated cirrhosis patients with single, small HCC treated with curative intent. (HEPATOLOGY 2012)

End-stage alcoholic liver disease is a recognised indication for liver transplantation but some questions on the matter remain open. It is difficult to quantify alcohol consumption, and a single definition of post-transplant relapse is lacking. Moreover, there are no internationally accepted criteria for the selection of candidates for liver transplantation and the eligibility parameters for these patients are controversial. Additional clinical and psychological evaluations are necessary in this setting, especially to establish the risk of alcohol relapse. Nevertheless, patient and graft survival rates after liver transplantation in alcoholic liver disease are comparable to those after transplant for other aetiologies, alcohol consumption relapse being one of the most important problems in the post-transplant phase. In conclusion, alcohol-related liver disease is a good indication for liver transplantation. The main future goals are to formulate a well-defined pre-transplant approach and a single definition of alcohol relapse and to improve prevention strategies.

Background: Alcoholic liver cirrhosis (ALC) is a leading indication for orthotopic liver transplantation (OLT). Goals: To investigate the long-term outcome of OLT for ALC compared with patients transplanted for hepatitis C virus (HCV) infection. Study: From 1987 to 2001, 49 OLT were performed for ALC and 173 for HCV. From these contemporary groups we matched 1:2 ALC patients (cases) to 98 HCV (controls). The following variables were analyzed: survival, retransplantation, rejection, primary nonfunction, infections, de novo tumors, cardiovascular and neurologic complications, and alcoholic recurrence. Results: Actuarial survival rate at 9 years was comparable for cases and controls. Actuarial graft survival rate at 9 years was significantly higher in cases (78% vs. 60%; P = 0.026). The retransplantation rate was higher in controls (21 % vs. 4%; P = 0.007). Post-OLT complications were not significantly different. The alcoholic recidivism rate was 28% without influence on patients or graft survival, whereas relapse of HCV caused the majority of death in controls (30%; P = 0.042). At multivariate analysis retransplantation was the only predictor of patient survival (odds ratio: 4.35; 95% confidence interval: 2.16-8.74; P < 0.001), whereas HCV was associated with a 2-fold probability of graft failure (odds ratio: 1.97; 95% confidence interval: 1.02-3.81; P = 0.032). Conclusions: The long-term outcome of OLT for ALC is comparable to that for HCV, even if graft survival is significantly better among ALC. These data support ALC as an excellent indication for OLT.

Given the lack of donors, a correct organ allocation system for candidates to liver transplantation is essential to increase graft and patient survival. The most used organ allocation tools are Child–Turcotte–Pugh and model for end-stage liver disease. It is generally accepted that model for end-stage liver disease score is superior to the Child–Turcotte–Pugh classification in predicting the short-term survival of cirrhotic patients awaiting liver transplantation. Since 2002, model for end-stage liver disease is widely used for liver allocation. In recent years, to overcome limitations of the consolidated scores, some adjustments to the original model for end-stage liver disease formula and new scoring systems have been proposed. Published data suggest that integrating serum sodium and model for end-stage liver disease may improve the score prognostic accuracy but further studies are necessary to confirm this issue. The updated model for end-stage liver disease, obtained through a revision of traditional model for end-stage liver disease parameters and tested in a large cohort of patients, is of great interest at the moment. In conclusion, several scoring systems have been described for organ allocation, but today, none is definitely able to overcome the limitations of the Child–Turcotte–Pugh and model for end-stage liver disease systems.

Background: Efficacy and safety of interferon induction therapy alone or in combination with ribavirin or ribavirin plus amantadine were evaluated in chronic hepatitis C patients who were nonresponders to primary antiviral treatment. Methods: The study was designed to have 225 HCV nonresponder patients, but at an interim analysis the response rate difference between groups was lower than expected and the enrollment was stopped when 75 patients had been randomized to receive interferon-α2a (group A, n = 26), interferon-αa plus 15 mg/kg per day of ribavirin (group B, n = 24), or interferon-α2a plus ribavirin plus 200 mg/day of amantadine hydrochloride (group C, n = 25). Treatment duration was 48 weeks. The dose of interferon was 6 MU/day for 4 weeks followed by 3 MU/ day for the remaining 44 weeks. Results: On intention-to-treat, the sustained virological response at 24 weeks of follow-up was 11.5% in group A, 12.5% in group B, and 12% in group C. Therapy was discontinued because of adverse effects in three patients in group A (11.5%), three in group B (12.5%), and two in group C (8%). Conclusions: Nonresponders with chronic hepatitis C may achieve a sustained virological response rate of approximately 12% if retreated with interferon induction treatment followed by administration of a daily dose. The addition of ribavirin or amantadine did not seem to improve the response rates

Background: Interferon may trigger autoimmune disorders, including autoimmune hepatitis, in immunocompetent patients. To date, no such disorders have been described in liver transplanted patients. Methods: 9 of 44 liver transplanted patients who had been receiving pegylated-interferon alpha-2b and ribavirin for at least 6 months for hepatitis C virus (HCV) recurrence, developed graft dysfunction despite on-treatment HCV-RNA clearance in all but one case. Laboratory, microbiological, imaging and histological evaluations were performed to identify the origin of graft dysfunction. The International Autoimmune Hepatitis scoring system was also applied. Results: In all cases infections, anastomoses complications and rejection were excluded, whereas the autoimmune hepatitis score suggested a “probable autoimmune hepatitis” (score from 10 to 14). Three patients developed other definite autoimmune disorders (overlap anti-mitochondrial antibodies (AMA)-positive cholangitis, autoimmune thyroiditis and systemic lupus erythematosus, respectively). In all cases, pre-existing autoimmune hepatitis was excluded. Anti-lymphocyte antibodies in immunosuppressive induction treatment correlated with the development of the disorder, whereas the use of granulocyte colony-stimulating factor to treat interferon-induced neutropenia showed a protective role. Withdrawal of antiviral treatment and treatment with prednisone resulted in different outcomes (five remissions and four graft failures with two deaths). Conclusions: De novo autoimmune hepatitis should be considered in differential diagnosis along with rejection in liver transplanted patients developing graft dysfunction while on treatment with interferon.

SUMMARY: The relationship between the balance of helper T-cell type 1 (Th1) or type 2 (Th2) cytokines and the clinical course of hepatitis C virus (HCV) infection is unclear. We evaluated Th1 [interleukin (IL)-2, interferon-gamma (IFN-gamma)] and Th2 cytokine (IL-4, IL-10) and 2,5-oligoadenylate synthetase (OAS, an IFN-induced antiviral protein) production by peripheral blood mononuclear cells from 10 healthy anti-HCV-positive individuals (group A), 10 HCV-RNA-positive with persistently normal alanine aminotransferase (ALT) levels (group B), 10 HCV-RNA-positive with abnormal ALT (group C) and 10 uninfected healthy controls. IL-2 production was significantly increased in group B when compared with all the other groups. No difference was found for IFN-gamma. IL-4 was significantly higher in group C than in both group B (P = 0.0006) and controls (P = 0.004). Compared with controls, IL-10 was significantly decreased in group A (P = 0.013) and B (P = 0.004). The production of 2,5-OAS was significantly higher in group B than in A (P = 0.04) and in C (P = 0.004). Finally, in all HCV-RNA-positive patients, a significant correlation was found between ALT and both IL-2 (r = -0.78; P = 0.0008) and IL-4 (r = 0.75; P = 0.0008). IN CONCLUSION: (i) subjects who cleared HCV showed a cytokine profile similar to controls; (ii) a preferential shift towards a Th1 profile seems associated with a more favourable clinical outcome in chronic hepatitis C; and (iii) a prevalent Th2 profile seems implicated in HCV pathogenesis and severity of liver disease.

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Current evidences suggest that non-steroidal anti-inflammatory drugs could enhance the antiviral activity of interferon-alpha in chronic HCV infection. In this study, we investigated the effect of indomethacin, a non-steroidal anti-inflammatory drug, and interferon-alpha on cytokine production by peripheral blood mononuclear cells from 12 untreated patients with chronic hepatitis C. We evaluated the effect of incubation with indomethacin, interferon-alpha or both on synthesis of Th1- (interleukin-2, interferon-gamma) and Th2-associated cytokines (interleukin-4, interleukin-10), and of the antiviral protein 2',5'-oligoadenylate synthetase. Interferon-alpha induced a significant increase in production of interleukin-2. Smaller increases were also seen in the presence of indomethacin, while incubation with both indomethacin and interferon-alpha leads to a synergistic effect. Incubation with indomethacin decreased both interleukin-4 and interleukin-10, whereas interferon-alpha increased these cytokines. The addition of indomethacin to interferon-alpha significantly reversed this interferon-induced increase. Finally, both indomethacin and the association interferon-alpha plus indomethacin determined a significant increase in 2',5'-oligoadenylate synthetase production compared to both baseline and interferon-alpha alone. In conclusion, indomethacin was able to enhance the antiviral activity of interferon-alpha and to modulate the interferon-induced Th1 and Th2 cytokine response by increasing the Th1-response, fundamental for sustained clearance of HCV, and by decreasing the Th-2 type response, associated with HCV persistence.