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Hepatocellular adenoma (HCA) is a rare benign liver tumour associated with the use of oral contraceptives or other steroid medications which occurs predominantly in young and middle-aged women. Unlike other benign liver tumours, an HCA may be complicated by bleeding and malignant transformation. HCAs have been divided into four subtypes based on molecular and pathological features: hepatocyte nuclear factor 1 alpha-mutated HCA, inflammatory HCA, beta-catenin-mutated HCA, and unclassified HCA. beta-catenin-mutated HCA has the highest risk of haemorrhage or malignant transformation. In the latest upgrade of the guidelines regarding the management of benign liver tumours published in 2016 by the European Association for the Study of the Liver, magnetic resonance imaging (MRI) was recognized to be superior to all other imaging modalities in detecting HCAs and in being able to subtype HCAs up to 80%, with positive identification of 1 alpha-mutated HCA or inflammatory HCA achievable with > 90% specificity. This review analyzed the imaging features of HCA using MRI with hepato-specific contrast agents, focusing on the limitations in the HCA characterization.

Background CPFA is an extracorporeal treatment used in severe sepsis to remove circulating proinflammatory cytokines. Limited evidence exists on the effectiveness of bilirubin adsorption by the hydrophobic styrenic resin, the distinctive part of CPFA. The aim of this study is to validate CPFA effectiveness in liver detoxification. Methods In this prospective observational study, we enrolled patients with acute or acute-on-chronic liver failure (serum total bilirubin > 20 mg/dL or MELD Score > 20) hospitalized from June 2013 to November 2017. CPFA was performed using the Lynda (Bellco/MedTronic, Mirandola, Italy) or the Amplya (Bellco/MedTronic, Mirandola, Italy) machines. Anticoagulation was provided with unfractionated heparin or citrate. Bilirubin and bile acids reduction ratios per session (RRs) were the main parameters for hepatic detoxification. Results Twelve patients with acute (n = 3) or acute-on-chronic (n = 9) liver failure were enrolled. Alcohol was the main cause of liver disease. Thirty-one CPFA treatments of 6 h each were performed, 19 with heparin and 12 with citrate. RRs was 28.8% (range 2.2–40.5) for total bilirubin, 32.7% (range 8.3–48.9) for direct bilirubin, 29.5% (range 6.5–65.4) for indirect bilirubin and 28.9% (16.7- 59.7) for bile acids. One patient received liver transplantation and 8/9 were alive at 1 year of follow-up. Three patients (25%) died: 2 during hospitalization and 1 for a cardiac event at 4 months of follow up with restored liver function. Conclusions CPFA resulted to be effective in liver detoxification. Thus, it may be considered as a “bridge technique” both to the liver transplant and to the recovery of the basal liver function.

The current epidemic of non-alcoholic fatty liver disease (NAFLD) is reshaping the field of hepatology all around the world. The widespread diffusion of metabolic risk factors such as obesity, type2-diabetes mellitus, and dyslipidemia has led to a worldwide diffusion of NAFLD. In parallel to the increased availability of effective anti-viral agents, NAFLD is rapidly becoming the most common cause of chronic liver disease in Western Countries, and a similar trend is expected in Eastern Countries in the next years. This epidemic and its consequences have prompted experts from all over the word in identifying effective strategies for the diagnosis, management, and treatment of NAFLD. Different scientific societies from Europe, America, and Asia-Pacific regions have proposed guidelines based on the most recent evidence about NAFLD. These guidelines are consistent with the key elements in the management of NAFLD, but still, show significant difference about some critical points. We reviewed the current literature in English language to identify the most recent scientific guidelines about NAFLD with the aim to find and critically analyse the main differences. We distinguished guidelines from 5 different scientific societies whose reputation is worldwide recognised and who are representative of the clinical practice in different geographical regions. Differences were noted in: the definition of NAFLD, the opportunity of NAFLD screening in high-risk patients, the non-invasive test proposed for the diagnosis of NAFLD and the identification of NAFLD patients with advanced fibrosis, in the follow-up protocols and, finally, in the treatment strategy (especially in the proposed pharmacological management). These difference have been discussed in the light of the possible evolution of the scenario of NAFLD in the next years.

Background: A gluten-free diet (GFD) is known to be associated with altered macronutrient intake and metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD) is the hepatic hallmark of metabolic syndrome. The risk of NAFLD in patients with coeliac disease (CD) adhering to a GFD remains to be fully investigated; in particular, data from real-life clinical settings are lacking. Aim: To assess the prevalence and relative risk of NAFLD in CD patients treated with a GFD. Methods: Case–control study, with prospective enrolment of CD outpatients following a GFD and controls. Patients were matched for demographic characteristics (age and gender) and metabolic risk factors (overweight, diabetes mellitus, total cholesterol, and triglycerides) using a 1:1 ratio. NAFLD was diagnosed according to the European Association for the Study of the Liver criteria. Results: 202 CD patients and 202 controls were compared. The raw prevalence of NAFLD was 34.7% and 21.8% in the CD and control group, respectively (P = 0.006). Binary logistic regression confirmed an increased risk of NAFLD in the CD group (adjusted odds ratio = 2.90, 95% confidence interval: 1.64-5.15, P < 0.001). Additionally, the relative risk for NAFLD was notably higher in non-overweight CD patients (adjusted odds ratio = 5.71, 95% confidence interval: 2.30-14.19, P < 0.001). Conclusions: More than one-third of CD patients adhering to a GFD had concurrent NAFLD, accounting for a three-fold increased risk compared to the general population. Dietary advice provided using a patient-tailored approach should assist CD patients with NAFLD in achieving an appropriate nutritional intake whilst reducing the risk of long-term liver-related events.

International audience; BACKGROUND: Tivantinib (ARQ 197), a selective, oral MET inhibitor, improved overall survival and progression-free survival compared with placebo in a randomised phase 2 study in patients with high MET expression (MET-high) hepatocellular carcinoma previously treated with sorafenib. The aim of this phase 3 study was to confirm the results of the phase 2 trial. METHODS: We did a phase 3, randomised, double-blind, placebo-controlled study in 90 centres in Australia, the Americas, Europe, and New Zealand. Eligible patients were 18 years or older and had unresectable, histologically confirmed, hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0-1, high MET expression (MET-high; staining intensity score >=2 in >=50% of tumour cells), Child-Pugh A cirrhosis, and radiographically-confirmed disease progression after receiving sorafenib-containing systemic therapy. We randomly assigned patients (2:1) in block sizes of three using a computer-generated randomisation sequence to receive oral tivantinib (120 mg twice daily) or placebo (twice daily); patients were stratified by vascular invasion, extrahepatic spread, and α-fetoprotein concentrations (

none 7 no Background & Aims: Pain management in cirrhosis is a clinical challenge. Most analgesics are metabolized in the liver and cirrhosis may deeply alter their concentration, favouring the appearance of side effects. We aimed to assess the efficacy and safety of oral prolonged-release association of oxycodone/naloxone tablets (OXN) in the treatment of moderate/severe cancer pain in cirrhotic patients with metastatic hepatocellular carcinoma (HCC). Methods: We enrolled n = 32 HCC patients with moderate/severe cancer pain unresponsive to paracetamol alone or associated with codeine or tramadol. All patients received an initial OXN dose of 5 mg bid to be gradually increased in case of insufficient analgesia. At baseline and follow-up visits, we evaluated: pain intensity (using the Numerical Rating Scale, NRS), patients' autonomy in daily activities (Barthel Functioning Index); bowel dysfunction (Bowel Function Index, BFI), signs of hepatic encephalopathy (HE) and other opioid-induced side effects. Results: No clinically significant adverse effects were reported (median follow-up 122 days). No significant worsening of the BFI score was noted and no cases of HE were detected. Two patients (6.3%) discontinued treatment before T14 because of mild nausea and dizziness. The remaining n = 30 patients were assessed for efficacy. Treatment led to a significant reduction in the mean of pain scores both at T14 (-37.1 ± 16.3%, P < .001) and at T28 (-55.6 ± 21.5%, P < .001); Barthel scores showed gradual and significant increase from T0 (81.6 ± 13.0) to T14 (86.5 ± 11.4, P = .001) and to T28 (88.3 ± 13.6, P = .009). Conclusions: OXN may be considered a safe and effective option in the fragile population of cirrhotic patients. Tovoli, Francesco; De Lorenzo, Stefania; Samolsky Dekel, Boaz G.; Piscaglia, Fabio; Benevento, Francesca; Brandi, Giovanni; Bolondi, Luigi Tovoli, Francesco; De Lorenzo, Stefania; Samolsky Dekel, Boaz G.; Piscaglia, Fabio; Benevento, Francesca; Brandi, Giovanni; Bolondi, Luigi

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Summary Underlying liver cirrhosis is present in most patients with hepatocellular carcinoma, and liver transplantation is the only treatment strategy to cure both diseases. All other hepatocellular carcinoma treatment strategies have to take into account residual liver function that concurs with the patient's prognosis and might limit their feasibility. In patients with hepatocellular carcinoma and Child-Pugh-Turcotte class B (CPT-B), owing to borderline liver function, any intervention might be offset by liver function deterioration. In this setting, the decision for hepatocellular carcinoma treatment requires a comprehensive assessment of liver function, not restricted to the CPT classification, in addition to a careful evaluation of the prognostic effect of hepatocellular carcinoma compared with cirrhosis. In this Review, we provide an overview of the literature regarding the benefits and harms of non-transplant therapies in patients with hepatocellular carcinoma and CPT-B cirrhosis.

Background: Diagnosis of hepatocellular carcinoma can be achieved by imaging in cirrhotic patients. Combined hepatocellular-cholangiocarcinoma is a primary liver tumor and its imaging patterns have been poorly investigated. Misdiagnosis for either hepatocellular carcinoma or benign lesions can occur. We aimed to evaluate the enhancement pattern of combined hepatocellular-cholangiocarcinoma in cirrhosis with imaging techniques and to estimate the risk of misdiagnosis for hepatocellular carcinoma. Methods: All histology-confirmed combined hepatocellular-cholangiocarcinoma in cirrhosis seen in two Italian centers between 2003 and 2016, in which at least one imaging technique had been performed, was retrospectively collected. The enhancement pattern was analyzed for all available imaging modalities. Results: A total of 37 combined hepatocellular-cholangiocarcinoma nodules were identified. Contrast-enhanced ultrasound, computed tomography, and magnetic resonance imaging had been performed in 27, 34, and 17 nodules, respectively. Contrast-enhanced ultrasound was at higher risk of misdiagnosis for pure hepatocellular carcinoma than computed tomography (p = 0.005) or magnetic resonance imaging (p = 0.040). Only six of 24 combined hepatocellular-cholangiocarcinoma lesions submitted to both contrast-enhanced ultrasound and computed tomography showed coincident patterns; contrast-enhanced ultrasound correctly suggested a condition of malignancy in a higher number of cases than computed tomography (p < 0.001) and magnetic resonance imaging (p = 0.002). Conclusions: Contrast-enhanced ultrasound misdiagnosed a higher number of combined hepatocellular-cholangiocarcinoma as hepatocellular carcinoma than computed tomography and magnetic resonance imaging. However, the latter techniques were able to identify features of malignancy less often.

Background Unexpectedly high occurrence or recurrence rate of hepatocellular carcinoma (HCC) has been observed in patients with chronic hepatitis C receiving direct-acting antivirals (DAAs) therapy. Aims We evaluated the predictive value of albumin-bilirubin (ALBI) score and immune-inflammation indicators to identify the risk of occurrence or recurrence of HCC in patients treated with DAAs in a real life setting. Methods In this retrospective cohort study, we analysed data from 514 patients with cirrhosis who were prospectively enrolled for treatment with DAAs. We assessed baseline neutrophil to lymphocyte ratio (NLR), systemic immune-inflammation index (SII), platelet to lymphocyte ratio (PLR), aspartate aminotransferase-lymphocyte ratio (ALRI) index and ALBI score. Results In patients with no history of HCC (N = 416), increased AST, bilirubin, ALRI, and ALBI score, and decreased albumin and platelets were significantly associated with an increased risk of HCC development, at univariate analysis. At multivariate analysis, increase in ALBI grade (p = 0.038, HR: 2.35, 95% CI: 1.05–5.25) and decrease in platelets (p = 0.048, HR: 0.92, 95% CI: 0.85–1.0) were independently associated with HCC development. In patients with previous HCC (N = 98), adjusting for the time from HCC treatment, increased ALRI (p = 0.008, HR: 1.05, 95% CI: 1.01–1.09) was significantly associated with a risk of recurrence. Conclusion ALBI score, platelet count and ALRI are promising, easy to perform and inexpensive tools for identifying patients with higher risk of HCC after treatment with DAAs.

Background: Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme - arginine deiminase - conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and Patients: Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2:1 to ADI-PEG 20 18 mg/m2 vs. placebo intramuscular (IM) injection weekly. The primary endpoint was overall survival (OS), with 93% power to detect a 4 to 5.6 months increase in median OS (1-sided α = 0.025). Secondary endpoints included progression-free survival (PFS), safety, and arginine correlatives. Results: 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 vs 7.4 for placebo (p = 0.88, HR = 1.02) and median PFS 2.6 months vs. 2.6 (p = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in less than 5% of patients. Two patients on ADI-PEG 20 had ≥ grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 vs. 10.4% on placebo, none related to therapy. Post-hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion: ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway. Clinical Trial number: www.clinicaltrials (NCT 01287585).

Background: There is no standard of care for adjuvant therapy for patients with hepatocellular carcinoma. This trial was designed to assess the efficacy and safety of sorafenib versus placebo as adjuvant therapy in patients with hepatocellular carcinoma after surgical resection or local ablation. Methods: We undertook this phase 3, double-blind, placebo-controlled study of patients with hepatocellular carcinoma with a complete radiological response after surgical resection (n=900) or local ablation (n=214) in 202 sites (hospitals and research centres) in 28 countries. Patients were randomly assigned (1:1) to receive 400 mg oral sorafenib or placebo twice a day, for a maximum of 4 years, according to a block randomisation scheme (block size of four) using an interactive voice-response system. Patients were stratified by curative treatment, geography, Child-Pugh status, and recurrence risk. The primary outcome was recurrence-free survival assessed after database cut-off on Nov 29, 2013. We analysed efficacy in the intention-to-treat population and safety in randomly assigned patients receiving at least one study dose. The final analysis is reported. This study is registered with ClinicalTrials.gov, number NCT00692770. Findings: We screened 1602 patients between Aug 15, 2008, and Nov 17, 2010, and randomly assigned 1114 patients. Of 556 patients in the sorafenib group, 553 (>99%) received the study treatment and 471 (85%) terminated treatment. Of 558 patients in the placebo group, 554 (99%) received the study treatment and 447 (80%) terminated treatment. Median duration of treatment and mean daily dose were 12.5 months (IQR 2.6-35.8) and 577 mg per day (SD 212.8) for sorafenib, compared with 22.2 months (8.1-38.8) and 778.0 mg per day (79.8) for placebo. Dose modification was reported for 497 (89%) of 559 patients in the sorafenib group and 206 (38%) of 548 patients in the placebo group. At final analysis, 464 recurrence-free survival events had occurred (270 in the placebo group and 194 in the sorafenib group). Median follow-up for recurrence-free survival was 8.5 months (IQR 2.9-19.5) in the sorafenib group and 8.4 months (2.9-19.8) in the placebo group. We noted no difference in median recurrence-free survival between the two groups (33.3 months in the sorafenib group vs 33.7 months in the placebo group; hazard ratio [HR] 0.940; 95% CI 0.780-1.134; one-sided p=0.26). The most common grade 3 or 4 adverse events were hand-foot skin reaction (154 [28%] of 559 patients in the sorafenib group vs four [

The intermediate stage of hepatocellular carcinoma (HCC) comprises a highly heterogeneous patient population and therefore poses unique challenges for therapeutic management, different from the early and advanced stages. Patients classified as having intermediate HCC by the Barcelona Clinic Liver Cancer (BCLC) staging system present with varying tumor burden and liver function. Transarterial chemoembolization (TACE) is currently recommended as the standard of care in this setting, but there is considerable variation in the clinical benefit patients derive from this treatment.In April 2012, a panel of experts convened to discuss unresolved issues surrounding the application of current guidelines when managing patients with intermediate HCC. The meeting explored the applicability of a subclassification system for intermediate HCC patients to tailor therapeutic interventions based on the evidence available to date and expert opinion. The present report summarizes the proposal of the expert panel: four substages of intermediate HCC patients, B1 to B4.

Introduction: The classic histopathological features of hepatocellular carcinoma (HCC) are still inadequate in determining patient’s prognosis. Aims: (i) To improve HCC classification, including a better definition of advanced HCCs, with amultidisciplinary approach Beyond morphology; (ii) to identify the radiological features distinctive of the “histologically-advanced” HCCs. Materials and methods: Histopathological analysis, immunohistochemistry for CD34 and Nestin, and reverse transcriptasepolymerase chain reaction (RT-PCR) for TGF1 and IGF1R mRNA were performed on 96 HCCs for the identification of different morpho-vascular patterns; 740 miRNAs were analyzed on 22 HCCs by means of microfluidic cards; histopathological and magnetic resonance imaging (MRI) data of 39 liver nodules were correlated. Results: Four distinct morpho-vascular HCC patterns had been identified at pathology: (A) microtrabecular with CD34-positive Nestin-negative sinusoids; (B) microtrabecular with CD34-positive Nestin-positive sinusoids; (C) with macrotrabeculae covered by CD34-positive Nestin-positive endothelium; (D) solid HCCs with CD34-positive Nestin-positive new-formed arteries. At RT-PCR a significant increase in TGF1 and IGF1R mRNA was found between pattern A and the other patterns. Moreover, each pattern correlated with a peculiar miRNA expressions. On MRI, pattern A HCCs were isointense in 50% of cases on T1-weighted images (WI) and in 57% on T2-WI. Pattern B HCCs were hyperintense on T1-WI in two-third of cases, radiological features of “glycogen nodules”, without hyperintensity on T2-WI. Pattern D HCCs were isointense on T1-WI in 83% of cases and hyperintense on T2-WI in 50%, all detected by typical vascular pattern on MRI. Pattern C HCCs showed the highest heterogeneity. Conclusions: Our multidisciplinary approach allowed us to identify different morphological and vascular HCC types, each of them characterized by different expression of growth factors and miRNAs, and with peculiar MRI features too. While pattern A HCCs represent the “early” phase of hepatocarcinogenesis, pattern D could be recognized as advanced malignancies that skip the regenerative-dysplastic-neoplastic pathway.

Lysosomal acid lipase (LAL) is a key enzyme in lipid metabolism. Initial reports have suggested a role for a relative acquired LAL deficiency in non-alcoholic fatty liver disease (NAFLD)—however, it is still unclear whether this mechanism is specific for NAFLD. We aimed to determine LAL activity in a cohort of NAFLD subjects and in a control group of hepatitis C virus (HCV)-infected patients, investigating the role of liver cirrhosis. A total of 81 patients with a diagnosis of NAFLD, and 78 matched controls with HCV-related liver disease were enrolled. For each patient, LAL activity was determined on peripheral dried blood spots (DBS) and correlated with clinical and laboratory data. A subgroup analysis among cirrhotic patients was also performed. LAL activity is significantly reduced in NAFLD, compared to that in HCV patients. This finding is particularly evident in the pre-cirrhotic stage of disease. LAL activity is also correlated with platelet and white blood cell count, suggesting an analytic interference of portal-hypertension-induced pancytopenia on DBS-determined LAL activity. NAFLD is characterized by a specific deficit in LAL activity, suggesting a pathogenetic role of LAL. We propose that future studies on this topic should rely on tissue specific analyses, as peripheral blood tests are also influenced by confounding factors.

Background and aims Blood lysosomal acid lipase (LAL) is reduced in non-alcoholic steatohepatitis, which is the major cause of cryptogenic cirrhosis (CC); few data on LAL activity in CC do exist. We investigated LAL activity in a cohort of patients with liver cirrhosis. Methods This is a multicentre cohort study including 274 patients with liver cirrhosis of different aetiology from 19 centres of Internal Medicine, Gastroenterology and Hepatology distributed throughout Italy. Blood LAL activity (nmol/spot/h) was measured with dried blood spot extracts using Lalistat 2. Results Overall, 133 patients had CC, and 141 patients had cirrhosis by other causes (61 viral, 53 alcoholic, 20 alcoholic + viral, 7 autoimmune). Mean age was 64.2 ± 13.4 years, and 28.5% were women. Patients with CC were older compared to other aetiology-cirrhosis, with a lower Child-Turcotte-Pugh (CTP, p=0.003) and MELD (p=0.009) score, and a higher prevalence of cardio-metabolic risk factors and previous ischemic events. In the whole cohort, median LAL activity value was 0.58 nmol/spot/h, 0.49 and 0.65 in the groups of CC and known-aetiology cirrhosis, respectively (p=0.002). The difference remained significant after adjustment for white blood cells count (p=0.001). Multivariable linear regression analysis showed that CC (vs. known aetiology, Beta = −0.144, p=0.018), platelet count (Beta = 0.398, p < 0.001) and CTP score (Beta = −0.133, p=0.022) were associated with log-LAL activity. Similar results were found using MELD as covariate. Conclusions We found a marked reduction of LAL activity in patients with cryptogenic cirrhosis compared to the other known aetiologies. A prospective study will clarify the role of LAL in chronic liver diseases.

Background Few data exist on real-life adherence to international guidelines for the treatment of hepatocellular carcinoma. We analysed the rate of adherence to American Association for the Study of Liver Diseases guidelines, to identify reasons for discrepancy with treatments performed in our centre. Methods 227 consecutive cirrhotics with a first hepatocellular carcinoma diagnosis (2005–2010) were retrospectively evaluated and stratified based on Barcelona Clinic Liver Cancer system: 126 early, 50 intermediate, 40 advanced, and 11 end stage. Results Early hepatocellular carcinomas were theoretically eligible for resection ( n = 27), liver transplantation ( n = 36), and percutaneous treatment ( n = 63). In practice, 15/27 (55.5%), 31/36 (86.1%), and 22/63 (34.9%) respectively were treated as recommended. Reasons for discrepancy were age/comorbidity, tumour location, ultrasound visibility, surgical contraindications. Transarterial chemoembolisation was performed in 25/126 early hepatocellular carcinomas (19.8%), resection in 11/63 early hepatocellular carcinomas eligible for percutaneous treatment (17.5%). Transarterial chemoembolisation was excluded in 16/50 intermediate hepatocellular carcinomas (32%). Resection or transarterial chemoembolisation was performed in 6/40 advanced hepatocellular carcinomas (15%). Conclusion Overall, 60% of patients were treated according to American Association for the Study of Liver Diseases guidelines. Approximately 28% of hepatocellular carcinomas were “under-treated” and 7% treated more aggressively than recommended. Peculiarities of individual patients can lead the multidisciplinary team to personalise real-life treatments.

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a b s t r a c t Background: The frequency with which patients in Child-Pugh B having hepatocellular carcinoma are treated following the international guidelines according to the Barcelona Clinic Liver Cancer stages is unknown. Aims: To investigate treatment allocation for Child-Pugh B patients in different tumour stages, with particular interest in the intermediate stage. Methods: Patients were retrospectively identified from a consecutively collected series. Treatment was carried out primarily according to the guidelines. Results: Of 86 Child-Pugh B patients, 45 were Barcelona early stage, of which the Child-Pugh scores were 46.7% B7, 33.3% B8, 20.0% B9; 27 patients were intermediate stage (B7 59.3%, B8 37.0% and B9 3.7% respectively), 12 were advanced (41.7% B7, 25.0% B8 and 33.3% B9) and 2 were terminal (both B9). In the intermediate stage, transarterial chemoembolization (or ablation) was performed in 68.8% of the Child- Pugh B7 patients, 50% of the B8 patients and 0% of the B9 patients. Median survival of the intermediate patients was 8.0 months (9.0 in B7 vs. 6.0 in -B8/B9, P = 0.048). Survival of the intermediate stage patients undergoing chemoembolisation was 22.0 months in Child-Pugh B7 and 6.0 in B8. Conclusions: Approximately half of the intermediate stage patients can undergo locoregional treatment with good survival when in the Child-Pugh B7. The Child-Pugh numeric score impacts survival, suggesting that this tumour stage be refined. © 2013 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.

Acute liver failure and acute-on-chronic liver failure still show a poor prognosis. The molecular adsorbent recirculating system (MARS) has been extensively used as the most promising detoxifying therapy for patients with these conditions. Sixty-four patients with life-threatening liver failure were selected, and 269 MARS treatments were carried out as a bridge for orthotopic liver transplantation (OLT) or for liver function recovery. All patients were grouped according to the aim of MARS therapy. Group A consisted of 47 patients treated for liver function recovery (median age 59 years, range 23-82). Group B consisted of 11 patients on the waiting list who underwent OLT (median age 47 years, range 32-62). Group C consisted of 6 patients on the waiting list who did not undergo OLT (median age 45.5 years, range 36-54, P = 0.001). MARS depurative efficiency in terms of liver toxins, cytokines, and growth factors was assessed together with the clinical outcome of the patients during a 1-year follow-up. Total bilirubin reduction rate per session (RRs) for each MARS session was 23% (range 17-29); direct bilirubin RRs was 28% (21-35), and indirect bilirubin RRs was 8% (3-21). Ammonia RRs was 34% (12-86). Conjugated cholic acid RRs was 58% (48-61); chenodeoxycholic acid RRs was 34% (18-48). No differences were found between groups. Hepatocyte growth factor (HGF) values on starting MARS were 4.1 ng/mL (1.9-7.9) versus 7.9 ng/mL (3.2-14.1) at MARS end (P

Background and aims Whether Fibroscan thresholds can be immediately adopted for none, some or all other shear wave elastography techniques has not been tested. The aim of the present study was to test the concordance of the findings obtained from 7 of the most recent ultrasound elastography machines with respect to Fibroscan. Methods Sixteen hepatitis C virus-related patients with fibrosis ≥2 and having reliable results at Fibroscan were investigated in two intercostal spaces using 7 different elastography machines. Coefficients of both precision (an index of data dispersion) and accuracy (an index of bias correction factors expressing different magnitudes of changes in comparison to the reference) were calculated. Results Median stiffness values differed among the different machines as did coefficients of both precision (range 0.54–0.72) and accuracy (range 0.28–0.87). When the average of the measurements of two intercostal spaces was considered, coefficients of precision significantly increased with all machines (range 0.72–0.90) whereas of accuracy improved more scatteredly and by a smaller degree (range 0.40–0.99). Conclusions The present results showed only moderate concordance of the majority of elastography machines with the Fibroscan results, preventing the possibility of the immediate universal adoption of Fibroscan thresholds for defining liver fibrosis staging for all new machines.

Sorafenib is the standard treatment for patients with hepatocellular carcinoma (HCC) with advanced stage disease. Although its effectiveness has been demonstrated by randomized clinical trials and confirmed by field practice studies, reliable markers predicting therapeutic response have not yet been identified. Like other tyrosine kinase inhibitors, treatment with sorafenib is burdened by the development of adverse effects, the most frequent being cutaneous toxicity, diarrhoea, arterial hypertension and fatigue. In recent years, several studies have analysed the correlation between off-target effects and sorafenib efficacy in patients with HCC. In this review, an overview of the studies assessing the prognostic significance of sorafenib-related adverse events is provided.

AIM: We tested the relationship between hepatic haemodynamics assessed by Doppler ultrasonography and liver stiffness assessed by Transient Elastography in hepatitis C related chronic liver disease. METHODS: Three liver Doppler ultrasound parameters (hepatic artery resistance index, splenic artery resistance index and waveform pattern in hepatic veins) and liver stiffness measured by Transient Elastography were analysed in one hundred consecutive patients affected by hepatitis C related chronic liver disease. RESULTS: Hepatic and splenic arteries resistance indexes correlate significantly (p13 kPa, whereas a splenic artery resistance index cut-off value of 0.56 provided sensitivity and specificity respectively of 81.3% and 48.5%. The coincidental finding of both resistance indexes above the respective cut-off values showed a good accuracy in identifying patients with liver stiffness values >13 kPa (accuracy=78%, +LR=2.90, -LR=0.31). A significant difference in liver stiffness values was evident between patients with triphasic and bi- or monophasic waveform pattern (p=0.005). CONCLUSIONS: Hepatic and splenic arteries resistance indexes and the hepatic veins waveform pattern assessed by Doppler ultrasound may provide information similar to that of Transient Elastography in hepatitis C related chronic liver disease.

Background: Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) proteomic signature might be of interest for the early detection and staging of hepatocellular carcinoma (HCC). However, published procedures have been criticized for the lack of data about analytical reproducibility, and the use of inadequate data processing. Methods: MALDI-TOF profiling of peptides bound to serum albumin (“albuminome”) was performed using 90 μL of serum from 45 study subjects (HCV-related cirrhosis, small, unifocal HCCs and advanced HCCs). To overcome the large intra-sample variability, a Quality Assurance protocol was implemented, and 4–8 samples for each subject were processed and analyzed. Overall, 522 subject samples and 299 quality-control spectra were analyzed. A machine-learning approach (Random Forest) was applied to analyze the data sets. Results: Mean intra-sample coefficient of variation (CV) of the analytical procedure was 17.6%–30.0%; inter-subject CV was in the range 48.8%–71.3% among the three study groups. The Random Forest procedure correctly classified 433/522 “patient samples” and 295/299 “reference samples”; 43/45 patients were correctly classified following this approach. Conclusions: Our data suggest that, notwithstanding the large analytical variability found, multiple proteomic profiles obtained from each subject can differentiate cirrhosis with and without HCC, and HCCs with and without vascular invasion, warranting further investigation in a prospective setting. Clin Chem Lab Med 2010;48:1319–26.

Noninvasive criteria for the diagnosis of hepatocellular carcinoma (HCC) in cirrhosis, recommended by the European Association for the Study of Liver (EASL) in 2001 and by the American Association for the Study of Liver Diseases (AASLD) in 2005, have left a number of small liver neoplastic nodules undefined. We designed this prospective study in 2003 with the aims of assessing the diagnostic contribution of vascular contrast-enhanced techniques and investigating the possible additional contribution of superparamagnetic iron oxide magnetic resonance (SPIO-MR) in this setting.Between 2003 and 2005, 75 consecutive small (10-30 mm) liver nodules detected at ultrasonography in 60 patients with cirrhosis were prospectively submitted to contrast-enhanced ultrasound (CEUS), helical-computed tomography (helical-CT), and gadolinium magnetic resonance (gad-MR), each blinded to the other. A total of 68 nodules were also studied with SPIO-MR at the same time as gad-MR.Using the EASL noninvasive criteria, the diagnosis of HCC was established in 44 of 55 (80%) nodules with a final diagnosis of HCC. Gad-MR was the most sensitive technique for detecting the typical vascular pattern. SPIO-MR showed a pattern consistent with HCC in 5 of 10 HCCs, not satisfying the EASL noninvasive criteria, and was negative in 17 of 18 (94.4%) nonmalignant nodules. The review of the present case series according to the AASLD criteria for the noninvasive diagnosis of HCC yielded a sensitivity rate of 81.8%.This study shows that both EASL and AASLD noninvasive recall strategies for nodules of 10-30 mm in the cirrhotic liver, based on the vascular pattern of nodules, have a false-negative rate of approximately 20%. SPIO-MR may increase the diagnostic potential of noninvasive techniques, contributing to the diagnosis of HCC lacking a typical vascular pattern.

The caliber of the splenic and hepatic arteries, the hepatic to splenic artery ratio and the spleen size (area of widest spleen section) were evaluated by real time ultrasonography (US) in 88 patients affected by liver cirrhosis of different etiology (26 alcoholic cirrhosis, 43 hepatitis B virus (HBV) related cirrhosis, 8 cryptogenic cirrhosis and 11 primary biliary cirrhosis) and in a control group of 21 normal subjects, in order to assess the possible influence of the etiology of the disease on these morphological parameters. The mean caliber of the hepatic artery was larger, and the mean caliber of the splenic artery smaller in alcoholic than in HBV-related, cryptogenic and in primary biliary cirrhosis. This difference is emphasized when considering the hepatic to splenic artery ratio: this parameter was never greater than 0.9 in all cases of primary biliary cirrhosis, in 38 out of 43 patients with HBV-related cirrhosis and in 6 out of 8 cryptogenic cirrhosis, while in the alcoholic group only in one out of 26 was it less than 0.9. The sensitivity, specificity and accuracy of this ratio in differentiating alcoholic from non-alcoholic cirrhosis was 96%, 88% and 91%, respectively. Splenomegaly resulted more in primary biliary cirrhosis, in HBV-related cirrhosis and in cryptogenic cirrhosis than in the alcoholic form. Finally, a significant correlation was found in all groups of cirrhotic patients between the diameter of the splenic artery and the spleen size. These results show that some ultrasonographic morphological features of liver cirrhosis differ according to its varied etiology, probably reflecting different pathophysiological mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Conventional criteria for liver transplantation for patients with hepatocellular carcinoma are single HCC

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

none 12 no Background & Aims Hepatocellular carcinoma (HCC) represents a serious complication of HCV-related cirrhosis. New direct-acting antivirals (DAA) cure HCV infection in over 90% of patients. The aim of this study was to evaluate the early occurrence and recurrence of HCC in cirrhotic patients treated with DAA. Methods We analysed 344 consecutive cirrhotic patients, without HCC, who were treated with DAA, and followed for 24 weeks. Fifty-nine patients had previous HCC. Results DAA therapy induced sustained virological response in 91% of patients. During 24-week follow-up, HCC was detected in 26 patients (7.6%, 95% CI: 4.99–10.84): 17 of 59 patients (28.81%, 95% CI: 17.76–42.07) with previous HCC and 9 of 285 patients (3.16%, 95% CI: 1.45–5.90) without previous HCC. Child-Pugh Class B, more severe liver fibrosis, lower platelet count, and previous HCC were significantly associated with HCC development, at univariate analysis. At multivariate analysis, Child-Pugh class (p = 0.03, OR: 4.18, 95% CI: 1.17–14.8) and history of HCC (p

The best prioritization of patients with hepatocellular carcinoma (HCC) waiting for liver transplantation under the model for end-stage liver disease (MELD) allocation system is still being debated. We analyzed the impact of a MELD adjustment for HCC, which consisted of the addition of an extra score (based on the HCC stage and waiting time) to the native MELD score. The outcome was analyzed for 301 patients with chronic liver disease listed for liver transplantation between March 1, 2001 and February 28, 2003 [United Network for Organ Sharing (UNOS)-Child-Turcotte-Pugh (CTP) era, 163 patients, 28.8% with HCC] and between March 1, 2003 and February 28, 2004 (HCC-MELD era, 138 patients, 29.7% with HCC). In the HCC-MELD era, the cumulative dropout risk at 6 months was 17.6% for patients with HCC versus 22.3% for those patients without HCC (P = NS), similar to that in the UNOS-CTP era. The cumulative probability of transplantation at 6 months was 70.3% versus 39.0% (P = 0.005), being higher than that in the UNOS-CTP era for patients with HCC (P = 0.02). At the end of the HCC-MELD era, 12 patients with HCC (29.3%) versus 57 without HCC (58.8%) were still on the list (P = 0.001). Both native and adjusted MELD scores were higher (P < 0.05) and progressed more in patients with HCC who dropped out than in those who underwent transplantation or remained on the list (the initial-final native MELD scores were 17.3-23.1, 15.5-15.6, and 12.8-14.1, respectively). The patients without HCC remaining on the list showed stable MELD scores (initial-final: 15.1-15.4). In conclusion, the present data support the strategy of including the native MELD scores in the allocation system for HCC. This model allows the timely transplantation of patients with HCC without severely affecting the outcome of patients without HCC. Liver Transpl 13:857–866, 2007. © 2007 AASLD.

Background Since the incidence of myocardial infarction and other cardiovascular ischaemic events is highest in early morning, on account of a relative hypercoagulable state occurring in this time period, an attempt was made to test whether reperfusion of the hepatic artery at this time of the day, at liver transplantation, produces an increased risk of early thrombosis. Methods The records of 255 consecutive patients receiving a first transplant for chronic liver disease were retrospectively analysed. As possible risk factors, for early post-operative thrombosis ( Results Logistic regression identified donor age (OR for age >60: P = 0.017), bench reconstruction of the artery (OR: 5.06, P = 0.013) and time of high coagulability at reperfusion (OR 2.93, P = 0.087), as independently associated with early hepatic artery thrombosis. Conclusions The present findings identified three independent predictors of early hepatic thrombosis, warranting stricter post-surgical follow-up of patients presenting such conditions. Interestingly, these factors are consistent with arterial reperfusion in the early morning being associated with an increased risk of early hepatic artery thrombosis, suggesting relative coagulative imbalances to provide a contribution in the pathogenesis of this severe complication of liver transplantation.

Serum interleukin-6 (sIL6) is an acknowledged predictor of all-cause mortality in older age. A common G/C polymorphism has been identified at position −174 of the IL6 gene promoter (IL6−174G>C), but its associations with sIL6 and mortality are still unclear. Data from a population-based elderly cohort (n = 824) were used to study the associations of baseline sIL6 with the IL6−174 C-allele (C+) carrier status and all-cause mortality at 4 years, in the presence and absence of preexisting major diseases (PMD). Analyses were adjusted for socio-demographic factors and body-mass-index. Three-hundred-eighty-eight participants (47.1%) had PMD. Compared to the bottom sIL6 quartile, mortality increased both in presence [Hazard Ratio (HR) = 3.04; 95% confidence interval (CI): 1.48–6.25] and absence of PMD [HR = 3.91; 95%CI: 1.42–10.72] for the third higher sIL6 quartile, but only in presence of PMD for the top sIL6 quartile [HR = 2.30; 95%CI: 1.09–4.83]. In absence of PMD, C+ carrier status did not affect both sIL6 and mortality. In presence of PMD, C+ carrier status was associated with increased baseline sIL6 [odds ratio 2.01; 95%CI: 1.25–3.22, for all sIL6 quartiles above the bottom] but not with increased mortality risk. A survival advantage was even found for C+ carriers with PMD and sIL6 in the top quartile [HR = 0.31, 95%CI: 0.13–0.76]. In conclusion, although associated with increased sIL6 levels in presence of major diseases, the IL6−174 C-allele does not seem to have direct detrimental effects on survival in older age.

To confirm recent observations about the relationship between immunosuppression and the recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT), we retrospectively analyzed 70 consecutive HCC patients who underwent LT and received cyclosporine (CsA)-based immunosuppression. CsA trough blood levels, measured with the same technique (fluorescence polarization immunoassay), were analyzed at different time points after transplantation. The exposure to the drug was calculated with the trapezoidal rule in each patient. CsA was associated with steroids in 26 patients and steroids and azathioprine in 44 patients. HCC recurred in 7 patients (10.0%). Different immunosuppressive schedules (CsA and steroids vs. CsA, steroids, and azathioprine) or the cumulative dosage of steroids and azathioprine did not influence HCC recurrence that was associated instead with CsA exposure (278.3 +/- 86.4 ng/mL in recurrent vs. 169.9 +/- 33.3 in tumor-free patients; P < 0.001); CsA exposure above 189.6 ng/mL was related to HCC recurrence at the receiver operating characteristic analysis (ROC). The relationship between CsA exposure; various clinical (sex, age, viral- vs. non-viral-related cirrhosis, preoperative vs. incidental diagnosis of HCC, alpha-fetoprotein [AFP] blood level), pathologic (pathologic tumor staging [pT] stage, presence of Milan criteria), and histologic (grading, presence of microvascular tumor invasion) parameters; and tumor recurrence were assessed. AFP (P = 0.032), microvascular tumor invasion (P = 0.044), and CsA exposure (P < 0.001) influenced recurrence-free survival at the univariate analysis; CsA exposure was the only independent prognostic determinant at multivariate analysis (P < 0.001). High CsA exposure favors tumor recurrence; CsA blood levels should be kept to the effective minimum in HCC patients. In the presence of pathologic and histologic risk factors, specific immunosuppressive protocols should be considered.

Background. Ascites is one of the most frequent severe complications in patients with liver cirrhosis. The treatment of this chronic disease usually requires the prolonged use of albumin, frequently continued even after patients’ discharge from the hospital. Aims. Aim of the study was to define a consensus among Italian physicians with regard to the use of albumin in patients with decompensated cirrhosis and ascites. Methods. The study adopted the Delphi technique to conduct the consensus activities. All controversial issues related to the use of albumin were identified by the experts’ board and proposed to the 68 participating hepatology centres through two subsequent questionnaires. The questionnaires, returned by the specialists involved, were collected and the answers classified to verify the elements on which a consensus was reached. Results. The home use of albumin can help to improve the patient’s general conditions and well-being. About 77% of the experts involved considered likely that albumin administration could shorten hospital stays or could reduce the number of hospital admissions. The results of the study, along with a socioeconomic analysis, were presented to the Italian Drug Commission, which subsequently removed the specific hypoalbuminemia level as a prerequisite for having the drug reimbursed by the National Health Service. Conclusions. For an outpatient prescription, the hypoalbuminemia limit of 2.5 g/dl or less is not sufficient, while the decision whether to administer the drug requires the evaluation of patient’s overall clinical conditions as an essential criterion for the prescription of a home treatment with albumin.

Background: Brain edema and increased intracranial pressure worsen prognosis in patients with end-stage chronic cirrhosis. Objective: To use diffusion-weighted imaging (DWI) to quantify water apparent diffusion coefficient (ADC) in different brain regions of patients with chronic liver failure with or without hepatic encephalopathy. Methods: The authors studied 14 patients with viral liver cirrhosis and 12 sex- and age-matched healthy volunteers. Seven patients had no clinical evidence of hepatic encephalopathy; six had grade I hepatic encephalopathy; and one had grade II hepatic encephalopathy. Brain DWI was obtained using a single-shot echo-planar imaging sequence, and four gradient strengths ( b values = 0, 300, 600, and 900 s/mm 2 ) were applied to calculate the average diffusivity maps. Results: Mean ADC values in the brains of patients with cirrhosis were significantly increased in all selected regions of interest (caudate, putamen, and pallidus nuclei; occipital, parietal, and frontal lobe white matter) except in the thalamus. Venous ammonia was linearly related to ADC values in deep gray and white matter regions of interest. Conclusions: Brain water apparent diffusion coefficient is increased in patients with chronic liver disease and may be useful in monitoring patients with hepatic encephalopathy.

In early stage hepatocellular carcinoma (HCC), liver transplantation, surgical resection and percutaneous techniques are classified as radical treatments, and may be offered to about 25% of all patients with HCC evaluated in referral centres. The restricted inclusion criteria for surgical resection and the shortage of liver donors for transplantation have stimulated an increasing demand for minimally invasive treatments able to achieve effective and reproducible percutaneous tumour ablation, with less associated morbidity and lower cost than other interventions. Among percutaneous techniques, ethanol injection has proven to be highly effective in single HCC up to 3 cm, with a rate of complete response of 80%, being well tolerated and with a limited risk of minor complication. In larger and/or multinodular HCC the efficacy is reduced to 50% of complete response in nodules between 3 and 5 cm, and to lower rate in larger tumours. Alternative options to ethanol injection have been recently proposed, including radiofrequency, microwave and laser thermal ablation, aimed to extend the necrotic area thus improving the rate of complete response. To date, radiofrequency is the most used technique, with a reported rate of complete response of 90-98% in nodules smaller than 3 cm, and with the advantage of fewer sessions, otherwise counteracted by a higher rate of side-effects. Microwave and laser are promising technologies, but only few clinical data are available. Randomized controlled trials are needed in order to assess treatment response, long-term survival, rate of complication and cost-efficacy of newer technologies in comparison to ethanol injection.

The most widely adopted criteria to admit and maintain patients with HCC and cirrhosis in the waiting list for liver transplantation are the Milano criteria, consisting in the presence of a single tumour ≤ 5 cm in diameter or up to three tumours, none exceeding 3 cm in diameter. Since the average time to transplantation has become longer than 10-12 months in most European and American Centers, the exclusion from the list during the waiting period due to increase of the neoplasm over the established criteria is not uncommon at present. It is mandatory, therefore, to seek an effective therapeutic strategy for patients with HCC waiting for transplantation. Surgical resection and eventual subsequent salvage transplantation seems a cost-effective strategy in resectable HCC. In unresectable neoplasms both transarterial chemoembolization and percutaneous ablation techniques are currently used and one or the other are chosen according to individual applicability, limitations and specific risks. However, although positive trends were reported, no definitive evidence has been produced so far about their efficacy in increasing patient's survival and decreasing tumour recurrence rates after transplantation. Adult-to-adult living donor liver transplantation is one possible way to shorten the waiting list, but this strategy involves important ethical implications. At present it appears justified to take it into consideration only if the waiting time for cadaveric OLT is expected to exceed 7 months. A more general and definitive attempt to overcome problems related to long waiting times for patients with HCC and relatively preserved hepatic function has been introduced in the USA very recently and consists in prioritizing patients with HCC. However, the overall efficacy of this approach will be established only in some years.

207 Background: C, an inhibitor of MET, VEGFR, and AXL, has previously shown clinical activity in pts with advanced HCC. This phase 3 trial (NCT01908426) evaluated C vs P in previously treated pts with advanced HCC. Methods: In this double-blind, global, phase 3 trial, pts were randomized 2:1 to receive C (60 mg qd) or matched P stratified by disease etiology (HBV, HCV, other), geographic region (Asia, other), and presence of extrahepatic spread and/or macrovascular invasion (EHS/MVI). Eligible pts had pathologic diagnosis of HCC, Child-Pugh score A, ECOG PS ≤1, and must have received prior sorafenib. Pts received up to two lines of prior systemic therapy for HCC and must have progressed following at least one. The primary endpoint was overall survival (OS). Secondary endpoints were investigator-assessed progression-free survival (PFS) and objective response rate (ORR) per RECIST 1.1. The study was designed to detect a hazard ratio (HR) for OS of 0.76 (90% power, 2-sided α = 0.05) at the final analysis with two prespecified interim analyses at 50% and 75% of the planned 621 events. Results: As of 1 Jun 2017, 707 pts were randomized, and 484 deaths had occurred (317 out of 470 for C; 167 out of 237 for P). Baseline characteristics were balanced between the two arms: median age was 64 years, 82% were male, 38% had HBV, 24% had HCV, 25% enrolled in Asia, 78% had EHS, 30% had MVI, 85% had EHS/MVI, and 27% had received two prior systemic therapy regimens for advanced HCC. The study met the primary endpoint at the second planned interim analysis with median OS 10.2 mo for C vs 8.0 mo for P (HR 0.76, 95% CI 0.63-0.92; p = 0.0049). Median PFS was 5.2 mo for C vs 1.9 mo for P (HR 0.44, 95% CI 0.36-0.52; p < 0.001), and ORR was 4% vs 0.4% (p = 0.0086). The most common grade 3/4 adverse events (predominantly grade 3) with higher incidence in the C vs P arm included hand-foot skin reaction (17% vs 0%), hypertension (16% vs 2%), increased aspartate aminotransferase (12% vs 7%), fatigue (10% vs 4%), and diarrhea (10% vs 2%). Conclusion: C significantly improved OS and PFS vs P in previously treated pts with advanced HCC. Adverse events were consistent with the known safety profile of C. Clinical trial information: NCT01908426.

The list of indications for liver transplantation (LT) includes irreversible causes of end-stage liver disease which are curable by the procedure. More than a decade ago, the American Association for the Study of the Liver Disease (AASLD) established minimal listing criteria for patients with end-stage liver disease. To qualify for waiting list, the 1 year expected survival should be

OBJECTIVES: The aim of the present investigation was to study the endogenous circadian clock phase rhythm in cirrhotic patients. METHODS: The study population comprised 13 patients with cirrhosis (seven in Child-Pugh class A and six in classes B/C) and nine healthy controls. Plasma melatonin, tissue plasminogen activator antigen, and plasminogen activator inhibitor 1 antigen were measured at 4-h intervals over a 24-h period. Multiple-components rhythmometry using population mean cosinor methods were employed to analyze the findings. RESULTS: All three variables were characterized in both patients and controls by a statistically significant circadian rhythm, with similar profiles. The peak times of tissue plasminogen activator and plasminogen activator inhibitor 1 antigens were practically identical in controls and cirrhotic patients, irrespective of Child-Pugh class (calculated peak at times 6:52, 6:56, and 7:20 for the inhibitor in controls and Child-Pugh class A and classes B/C patients, respectively; p = ns), whereas the peak of melatonin was delayed in classes B/C patients (at times 2:08, 1:56, and 4:00, respectively; p CONCLUSION: The similar circadian phases of plasminogen activator inhibitor antigen in controls and cirrhotic patients in the present investigation indicates that the output rhythm of the internal timekeeping system is not shifted in this pathological condition.

Background No standard second-line treatments are available for hepatocellular carcinoma patients who fail sorafenib therapy. We assessed the safety and efficacy of metronomic capecitabine after first-line sorafenib failure. Methods Retrospective analysis of consecutive hepatocellular carcinoma patients receiving metronomic capecitabine between January 2012 and November 2014. The primary end-point was safety, secondary end-point was efficacy, including time-to-progression and overall survival. Results Twenty-six patients (80% Child–Pugh A, 80% Barcelona Clinic Liver Cancer stage C) received metronomic capecitabine (500 mg/bid). Median treatment duration was 3.2 months (range 0.6–31). Fourteen (53%) patients experienced at least one adverse event. The most frequent drug-related adverse events were bilirubin elevation (23%), fatigue (15%), anaemia (11%), lymphoedema (11%), and hand–foot syndrome (7.6%). Treatment was interrupted in 19 (73%) for disease progression, in 4 (15%) for liver deterioration, and in 1 (3.8%) for adverse event. Disease control was achieved in 6 (23%) patients. Median time-to-progression was 4 months (95% confidence interval 3.2–4.7). Median overall survival was 8 months (95% confidence interval 3.7–12.3). Conclusions Metronomic capecitabine was well tolerated in hepatocellular carcinoma patients who had been treated with sorafenib. Preliminary data show potential anti-tumour activity with long-lasting disease control in a subgroup of patients that warrants further evaluation in a phase III study.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, mainly occurring in cirrhotic livers (in 80–90% of cases) after years of chronic inflammation [1,2]. The pathogenesis of HCC is a multistep process associated with changes in the host gene expression of multiple redundant negative-growth regulatory pathways that protect cells against transformation. An imbalance between the proliferation and apoptosis of liver cells is thought to promote tumor development [3]. Annually, 3–6% of cirrhotic patients will develop HCC, mainly men with advanced liver disease. Recent trends in the USA show that men are affected three-times more frequently than women, Asians are affected twice as often as blacks and Hispanics, and blacks are affected twice as often as whites [4]. One explanation for the disproportionate effects of HCC in men may be due to the higher estrogen concentrations present in women, which suppress IL-6 production and inhibit chemically induced liver carcinogenesis [1]. Epidemiology & etiology HCC is the principal cause of death in patients with compensated cirrhosis worldwide. It is largely a problem of less developed regions, where 83% (50% in China alone) of the estimated 782,000 new cases of liver cell cancer worldwide occur (based on 2012 data) [5]. HCC is the fifth most common cancer in men (554,000 cases; 7.5% of the total) and the ninth in women (228,000 cases; 3.4% of the total) [5]. Regions of high incidence (age adjusted rates per 100,000 inhabitants per year in men) are eastern and south-eastern Asia (31.9 and 22.2, respectively). Intermediate rates occur in southern Europe (9.5) and North America (9.3), and the lowest rates are in northern Europe (4.6) and south-central Asia (3.7) [5]. The global age distribution of HCC cases is related to the dominant viral hepatitis in the underlying population and the age at which it was acquired. For example, the disease burden is highest in areas with endemic hepatitis B virus (HBV) infection, such as in sub-Saharan Africa, where the virus is mainly transmitted at birth (with >90% of these cases becoming chronic HBV carriers). However, the diagnosis of HCC often occurs later in North America and southern Europe, where the most common etiology is HBV or hepatitis C virus (HCV) acquired later in life [2]. Several factors have been reported to increase HCC risk among HBV carriers, including male sex, older age, Asian or African ethnicity, family history of HCC, viral (higher levels of HBV repli cation, HBV genotype, longer duration of infection or coinfection with HCV, HIV or hepatitis D virus), clinical (cirrhosis) and environmental or lifestyle factors (exposure to aflatoxin, chronic excessive alcohol consumption or tobacco smoking). Other risk factors that increase the risk in HCV-infected patients include coinfection with HIV, HBV, HCV genotype 1b, old age, the presence of diabetes and obesity and a high level of chronic alcohol consumption. However, both HBV and HCV are highly amenable to preventive measures with antivirals or vaccination (for HBV). In Italy, for example, the Italian Liver Cancer (ITA.LI.CA) database reveals a decline in HCV infection with a concomitant increase in alcohol consumption as the primary etiology for HCC [6].