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Background & Aims Assessment of long-term outcome is required in hepatitis C virus (HCV)-infected patients with cirrhosis, who have been successfully treated for Barcelona Clinic Liver Cancer (BCLC) stage A hepatocellular carcinoma (HCC). However, problems arise due to the lack of models accounting for early changes during follow-up. The aim of this study was to estimate the impact of early events (HCC recurrence or hepatic decompensation within 12Âmonths of complete radiological response) on 5-year overall survival (OS) in a large cohort of patients with HCV and cirrhosis, successfully treated HCC. Methods A total of 328 consecutive Caucasian patients with HCV-related cirrhosis and BCLC stage 0/A HCC who had complete radiological response after curative resection or thermal ablation were prospectively recruited to this study. Primary endpoint of the study was 5-year OS. Independent baseline and time-dependent predictors of 5-year OS were identified by Cox model. Results The observed 5-year survival rate was 44%. The observed HCC early recurrence and early hepatic decompensation rate were 21% and 10%, respectively. Early hepatic decompensation (Hazard Ratio [HR] 7.52; 95% confidence intervals (CI): 1.23–13.48) and HCC early recurrence as time-dependent covariates (HR 2.50; 95%CI: 1.23–5.05), presence of esophageal varices at baseline (HR 1.66; 95% CI: 1.02–2.70) and age (HR 1.04; 95% CI: 1.02–1.07) were significantly associated with the 5-year OS. Conclusion Survival in HCV-infected patients with cirrhosis and successfully treated HCC is influenced by early hepatic decompensation. Our study indirectly suggests that direct-acting antiviral agents could improve OS of HCC patients through long-term preservation of liver function, resulting in a lower cirrhosis-related mortality and a greater change of receiving curative treatments. Lay summary Survival in hepatitis C virus (HCV) infected patients with cirrhosis and successfully treated hepatocellular carcinoma (HCC), is mainly influenced by early hepatic decompensation. HCV eradication after treatment with new direct-acting antiviral agents could improve overall survival of HCC patients through long-term preservation of liver function.

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.

Sorafenib is associated with multiple adverse events (AEs), potentially causing its permanent interruption. The impact of the physicians experience on the management of these AEs and the relative implications on clinical outcomes are unknown. We verified if the AEs management changed over time and if these modifications impacted on treatment duration and overall survival (OS). Background & Aims: Sorafenib is associated with multiple adverse events (AEs), potentially causing its permanent interruption. It is unknown how physicians’ experience has impacted on the management of these AEs and consequently on clinical outcomes. We aimed to assess whether AE management changed over time and if these modifications impacted on treatment duration and overall survival (OS). Methods: We analysed the prospectively collected data of 338 consecutive patients who started sorafenib between January 2008 and December 2017 in 3 tertiary care centres in Italy. Patients were divided according to the starting date: Group A (2008–2012; n = 154), and Group B (2013–2017, n = 184). Baseline and follow-up data were compared. In the OS analysis, patients who received second-line treatments were censored when starting the new therapy. Results: Baseline characteristics, AEs, and radiological response were consistent across groups. Patients in Group B received a lower median daily dose (425 vs. 568 mg/day, p

Screening strategies to detect celiac disease (CD) in at-risk subjects are of paramount importance to prevent the possible long-term complications of this condition. It is therefore of strategic relevance to understand whether patients diagnosed through screening follow a strict gluten-free diet (GFD), as the non-compliance to this diet can make screening efforts pointless. Currently, no studies have verified whether CD patients diagnosed in their adulthood are adhering to the GFD years after the diagnosis. We retrospectively evaluated the medical records of 750 CD patients diagnosed in our center during January 2004&ndash, December 2013 to verify differences between screening detected and clinically diagnosed patients. The groups shared a similar adherence to the GFD (91.2 versus 89.8%, p = 0.857). Moreover, the rates of non-responsive CD, GFD-induced metabolic alterations, and persistence in controls were also similar. Instead, screening-detected patients had a significantly lower rate of osteopenia/osteoporosis at diagnosis (31.3 versus 46%, p &lt, 0.001). In conclusion, screening strategies for CD in at-risk groups should be encouraged even in the adult population. Patients diagnosed through these strategies had no additional problems compared to those diagnosed for clinical suspicion and might benefit from a protective effect against metabolic bone disease.

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

Sorafenib has been the only approved systemic treatment of hepatocellular carcinoma (HCC) for almost a decade. Recently, two new drugs showed positive results in two Phase III studies. The RESORCE trial identified regorafenib as a valid second-line treatment for patients progressing to sorafenib, the REFLECT trial showed that lenvatinib is noninferior to sorafenib as front-line treatment. Following these trials, the therapeutic scenario will be dominated by anti-VEGFR drugs, with three different molecules showing a proven anticancer activity. Some open problems still remain and different immunotherapy trials are underway, following promising preliminary results. In this review we analyze: the most recent advancements about patients treated with sorafenib; the results of RESORCE and REFLECT trials; and the ongoing Phase III clinical trials. Finally, we discuss how they could address the current problems and possibly reshape the future of the systemic treatments for HCC.

Information about the clinical outcome of patients with non-celiac wheat sensitivity (NCWS) treated with gluten-free diet (GFD) derive from studies assessing the symptom response in the first few weeks of treatment. We aimed to evaluate the clinical response to the GFD and the quality of life (QoL) of NCWS patients in the long term.Forty-four NCWS (diagnosed according to the Salerno criteria) participated in the study. Participants rated their symptoms according to a 0-10 scale patients and filled in a QoL questionnaire (CDQ) before the beginning of the GFD and during a follow-up evaluation performed after at least one year. To assess the reliability of the questionnaire we also included a control group of 43 matched patients with celiac disease (CD).Upon diagnosis, NCWS patients had a high prevalence of intestinal and extraintestinal symptoms. Also, most symptoms were described as severe and the QoL questionnaire showed high scores. On follow-up, both prevalence and severity of the most common symptoms were significantly reduced. However, persistent intestinal and extraintestinal symptoms of mild severity were found in 65.9 and 72.7% of NCWS patients. In comparison, in the CD group, the prevalence was lower (32.6 and 23.2% respectively) and consistent with previous studies. The analyses of the determinant of QoL showed that, upon diagnosis, NCWS patients had higher scores in the CDQ "gastrointestinal symptoms" (p 0.001), "emotional aspects" (p 0.001) and "social problems" (p 0.001) subclasses compared to CD patients. After the GFD, NCWS and CD patients shared similar scores in all of the subclasses.A significant proportion of NCWS patients still complains of intestinal and extraintestinal symptoms, even if significantly attenuated by the GFD, even years after the diagnosis. A comprehensive nutritional evaluation of these patients is required to further improve their symptoms and their QoL.

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.

Purpose In 2015, we published a study on a small series of patients with hepatocellular carcinoma (HCC) treated chronically with metformin for type II diabetes mellitus (DM2) who showed a poorer response to sorafenib. The aim of the present study was to validate the prognostic significance of metformin in HCC patients treated with sorafenib, providing a biological rationale for the mechanism of resistance to sorafenib in patients on chronic metformin therapy, and to clarify the role of sirtuin-3 (SIRT-3), a protein involved in metabolic diseases and acknowledged as a tumour suppressor in HCC, in this resistance. Patients and methods We analysed 279 patients consecutively treated with sorafenib for the clinical analysis. Of the 86 (30%) patients with DM2, 52 (19%) were on chronic treatment with metformin and 34 (12%) with insulin. We included 43 patients with HCC for the biological study: 19 (44.1%) were diabetic and 14 (73.7%) of these received metformin for DM2. SIRT-3 expression was investigated by immunohistochemistry (IHC) in formalin-fixed and paraffin-embedded (FFPE) samples. Results In HCC patients undergoing chronic treatment with metformin, the use of sorafenib was associated with poor progression-free survival (PFS) and overall survival (OS) (1.9 and 6.6 months, respectively) compared to 3.7 months and 10.8 months, respectively, for patients without DM2 and 8.4 months and 16.6 months, respectively, for patients on insulin (P

Due to the ability to detect the typical contrast-imaging pattern for hepatocellular carcinoma (HCC), that is hyperenhancement in the arterial phase and hypoenhancement in the late phase on a cirrhotic background, contrast-enhanced ultrasonography (CEUS) was included in the American diagnostic algorithm for HCC in 2005. However, its role has been questioned because of the possibility of misdiagnosis of cholangiocarcinoma. The present review aims to describe the advantages and disadvantages of CEUS applications using Sonovue® for HCC. In particular there is focus on the accuracy of CEUS in detecting the typical HCC pattern, the CEUS patterns of intrahepatic cholangiocarcinoma (ICC), the risk of misdiagnosis with HCC, the diagnostic use of CEUS in cases of locoregional and systemic treatments, and the evaluation of response to antiangiogenic treatment using dedicated software.

Hepatocellular carcinoma is one of the most common malignancies and represents a unique challenge for physicians and patients. Treatment patterns are not uniform between areas despite efforts to promote a common protocol. Even if most hepatologists worldwide adopt the Barcelona Clinic Liver Cancer staging system, Asian and North American physicians are also independently making an effort to expand the indications of each treatment, combining therapies for better outcomes. Also, new therapeutic techniques have emerged and an increasing number of studies are trying to include these paradigm shifts into newer treatment guidelines. Controversial and diverging points in the current international guidelines are emphasized and discussed. Unanswered questions are also analyzed to identify the most needed and promising future perspectives.

In 2001, the European Association for the Study of the Liver (EASL) endorsed the possibility of achieving a non-invasive diagnosis of Hepatocellular Carcinoma (HCC) for the first time. Since then, various refinements of the criteria and techniques capable of achieving this diagnosis and the role of plasma and tissue oncomarkers have been reported in the literature and have been accepted to different extents in various geographical areas. Such tools can also potentially imply prognostic significance. The present article critically discusses some of the most relevant and debated challenges which have emerged in this field, including the role of contrast-enhanced ultrasound, and of hepatocyte-specific magnetic resonance contrast agents, the pitfall of transient hepatic attenuation differences, the reliability of biopsy and the status of biomarkers.

Gluten is one of the most abundant and widely distributed components of food in many areas. It can be included in wheat, barley, rye, and grains such as oats, barley, spelt, kamut, and triticale. Gluten-containing grains are widely consumed; in particular, wheat is one of the world's primary sources of food, providing up to 50% of the caloric intake in both industrialized and developing countries. Until two decades ago, celiac disease (CD) and other gluten-related disorders were believed to be exceedingly rare outside of Europe and were relatively ignored by health professionals and the global media. In recent years, however, the discovery of important diagnostic and pathogenic milestones led CD from obscurity to global prominence. In addition, interestingly, people feeding themselves with gluten-free products greatly outnumber patients affected by CD, fuelling a global consumption of gluten-free foods with approximately $2.5 billion in United States sales each year. The acknowledgment of other medical conditions related to gluten that has arisen as health problems, providing a wide spectrum of gluten-related disorders. In February 2011, a new nomenclature for gluten-related disorders was created at a consensus conference in London. In this review, we analyse innovations in the field of research that emerged after the creation of the new classification, with particular attention to the new European Society for Paediatric Gastroenterology, Hepatology and Nutrition guidelines for CD and the most recent research about non-celiac gluten sensitivity.