Downstaging for hepatocellular cancer: Harm or benefit?

Downstaging of hepatocellular carcinoma (HCC) to enable liver transplantation has become an area of intense interest and research. It may allow a curative option in patients outside widely accepted transplantation criteria, with outcomes that, in some studies, are comparable to transplantation for patients within criteria. There have been conflicting opinions on the best downstaging protocols, criteria for downstaging eligibility and for assessment of response. We therefore aimed to review the literature and evidence for downstaging, as well as considering its drawbacks. Conclusion: Pooled analyses have suggested success in down staging in about half of patients treated, but with higher recurrence rates than patients initially within transplantation criteria. Studies with strict inclusion criteria and mandatory waiting time before transplantation reported survival equivalent to patients who did not require downstaging. In carefully selected patients, there is a role for down staging to provide the chance of transplantation and cure, with acceptable outcomes. Further multi center, well-designed studies are required to clarify who will mostly benefit. Until such data is available, downstaging criteria should be stated within transplantation programs and relevant decisions should be discussed by multidisciplinary teams

Report of an inter-laboratory comparison from the European Union Reference Laboratory for Food Contact Materials: ILC01 2015 – Temperature control during migration tests by article filling

This report presents the results of an inter-laboratory comparison (ILC) on the temperature control during migration tests by article filling organised by the EURL-FCM, Ispra (Italy). Participants carried out a migration test by article filling in provided polypropylene cups (volume 0.3 L) with food simulant D1 (ethanol 50 %, v/v) at 70°C for 2 h and monitored the temperature of the food simulant inside one of the test specimen during the contact phase and provide details for the operating procedure. The participation to the ILC was satisfactory. The results show that 30% of the 53 migration experiments performed by the 45 laboratories were successful (scoring 100%) meaning that the temperature of the food simulant was in the desired range during the full contact time. It is clear that this result will trigger further discussion to improve the temperature control during a migration test. The information provided by the laboratories through the questionnaire gives a first insight in the factors that can be important to reach a satisfactory score. This discussion should lead to the selection of one or more methods for temperature control during migration testing. These selected methods need to be compared in a future ILC.JRC.F.7-Knowledge for Health and Consumer Safet

Intestinal hormones, gut microbiota and nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and has a complex pathophysiology with multiple pathways of development and progression implicated. Intestinal hormones regulate multiple biological functions and may play a role in the pathogenesis of non alcoholic fatty liver disease (NAFLD) by affecting food intake, body weight and insulin resistance. Bacterial products can affect the secretion of these hormones and thus have an effect on metabolism. Gut microbiota are normally involved in the intestinal energy harvest and their role has been increasingly been implicated in the pathogenesis of obesity and NAFLD. The intestinal hormone pathways as well as in the intestinal microbiota populations are potential therapeutic targets in the management of NAFLD. We review the evidence on the associations of the intestinal hormones and gut microbiota in the development, progression and treatment of NAFLD

Ursodeoxycholic acid improves bilirubin but not albumin in primary biliary cirrhosis: further evidence for nonefficacy.

BACKGROUND/AIM: In randomised controlled trials (RCTs) of ursodeoxycholic acid (UDCA), although serum bilirubin is frequently reduced, its effect on disease progression and mortality is unclear. As serum albumin is an established independent prognostic marker, one might expect less deterioration of serum albumin values in a UDCA-treated group. We therefore modelled the typical evolution of serum bilirubin and albumin levels over time in UDCA-untreated patients and compared it with the observed levels in UDCA RCTs. METHODS: Multilevel modelling was used to relate the evolution of serum albumin to serum bilirubin and time since patient referral. For each considered RCT, the derived model was used to predict the relationship between final mean serum albumin and bilirubin concentration, adjusted for mean serum albumin at referral and followup duration. RESULTS: Five RCTs were eligible in terms of available data, of which two had long followup. In all trials, serum albumin did not significantly differ between UDCA- and placebo-treated patients, despite the UDCA effect on serum bilirubin. Therefore, there is no evidence over time for changes or maintenance of albumin levels for UDCA-treated patients above the levels predicted for placebo-treated patients. CONCLUSIONS: Our findings suggest that UDCA does not alter serum albumin in a way that is consistent with its effect on serum bilirubin. Therefore, reductions in serum bilirubin of UDCA-treated PBC do not parallel another validated and independent prognostic marker, further questioning the validity of serum bilirubin reduction with UDCA as a surrogate therapeutic marker

The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)

Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. Despite its high prevalence, only a small minority of affected patients develops inflammation and subsequently fibrosis and chronic liver disease, while most of them only exhibit simple steatosis. In this context, the full understanding of the mechanisms underlying the development of NAFLD and non-alcoholic steatohepatitis (NASH) is of extreme importance; despite advances in this field, knowledge on the pathogenesis of NAFLD is still incomplete. The 'two-hit' hypothesis is now obsolete, as it is inadequate to explain the several molecular and metabolic changes that take place in NAFLD. The "multiple hit" hypothesis considers multiple insults acting together on genetically predisposed subjects to induce NAFLD and provides a more accurate explanation of NAFLD pathogenesis. Such hits include insulin resistance, hormones secreted from the adipose tissue, nutritional factors, gut microbiota and genetic and epigenetic factors. In this article, we review the factors that form this hypothesis

Loss of histone macroH2A1 in hepatocellular carcinoma cells promotes paracrine-mediated chemoresistance and CD4+CD25+FoxP3+ regulatory T cells activation

Rationale: Loss of histone macroH2A1 induces appearance of cancer stem cells (CSCs)-like cells in hepatocellular carcinoma (HCC). How CSCs interact with the tumor microenvironment and the adaptive immune system is unclear. Methods: We screened aggressive human HCC for macroH2A1 and CD44 CSC marker expression. We also knocked down (KD) macroH2A1 in HCC cells, and performed integrated transcriptomic and secretomic analyses. Results: Human HCC showed low macroH2A1 and high CD44 expression compared to control tissues. MacroH2A1 KD CSC-like cells transferred paracrinally their chemoresistant properties to parental HCC cells. MacroH2A1 KD conditioned media transcriptionally reprogrammed parental HCC cells activated regulatory CD4+/CD25+/FoxP3+ T cells (Tregs). Conclusions: Loss of macroH2A1 in HCC cells drives cancer stem-cell propagation and evasion from immune surveillance

Report of an inter-laboratory comparison from the European Union Reference Laboratory for Food Contact Materials: ILC02 2015 – Specific migration from a multilayer in food simulant A

This report presents the results of an inter-laboratory comparison on the specific migration of caprolactam (CAP) and 2,4-di-tert butyl phenol (2,4-DTBP) from a plastic food contact material in food simulant A (ethanol 10 %, v/v) organised by the EURL-FCM, Ispra (Italy). Homogeneity and stability studies were conducted. Participants had to carry out a migration test by immersion with food simulant A for 10 days at 60oC, to quantify the migration of caprolactam (CAP) in food simulant A, and to provide details of the analytical and sample extraction procedure. In addition a by-product 2,4-di-tert butyl phenol (2,4-DTBP) was also present and had to be quantified. The assigned values of the migration of the migrant were calculated as the robust mean of the results reported by the participants by applying the Q/Hampel method robust statistics. The participation to the ILC was satisfactory with 28 out of 29 participating laboratories submitting results. The z-score values of the laboratories for each substance were calculated based on the assigned value. In the case of CAP and also for the more challenging non intentionally added substances 2,4-DTBP more than 82% of the results were fully satisfactory (|z-score|<2). This percentage rose to close to 90% for z-scores <3 in the compliance evaluation of the regulated substance CAP.JRC.F.7-Knowledge for Health and Consumer Safet