How to diagnose and manage hepatic encephalopathy: a consensus statement on roles and responsibilities beyond the liver specialist

INTRODUCTION: Hepatic encephalopathy is defined as brain dysfunction caused by liver insufficiency and/or portosystemic shunting. Symptoms include nonspecific cognitive impairment, personality changes and changes in consciousness. Overt (symptomatic) hepatic encephalopathy is a common complication of cirrhosis that is associated with a poor prognosis. Patients with hepatic encephalopathy may present to healthcare providers who do not have primary responsibility for management of patients with cirrhosis. Therefore, we developed a series of 'consensus points' to provide some guidance on management. METHODS: Using a modified 'Delphi' process, consensus statements were developed that summarize our recommendations for the diagnosis and management of patients with hepatic encephalopathy. Points on which full consensus could not be reached are also discussed. RESULTS: Our recommendations emphasize the role of all healthcare providers in the identification of cognitive impairment in patients with cirrhosis and provide guidance on steps that might be considered to make a diagnosis of overt hepatic encephalopathy. In addition, treatment recommendations are summarized. Minimal hepatic encephalopathy can have a significant impact on patients; however, in most circumstances identification and management of minimal hepatic encephalopathy remains the responsibility of specialists in liver diseases. CONCLUSION: Our opinion statements aim to define the roles and responsibilities of all healthcare providers who at times care for patients with cirrhosis and hepatic encephalopathy. We suggest that these recommendations be considered further by colleagues in other disciplines and hope that future guidelines consider the management of patients with cirrhosis and with a 'suspicion' of cognitive impairment through to a formal diagnosis of hepatic encephalopathy.status: publishe

FGFR2, HER2 and cMet in gastric adenocarcinoma: detection, prognostic significance and assessment of downstream pathway activation

Receptor tyrosine kinase pathways are potential therapeutic targets in gastric adenocarcinoma patients. We evaluated HER2 and cMet protein expression, and FGFR2 gene amplification to assess their prognostic significance, and downstream mediators pS6 and pERK for their potential utility as pharmacodynamic biomarkers in patients with gastric adenocarcinoma. Tissue microarrays were constructed from resection samples of 184 patients who underwent surgery for gastric/gastro-oesophageal junction adenocarcinoma. Tissue cores were obtained from the tumour body (TB), luminal surface (LS) and invasive edge (IE), and immunohistochemical and fluorescence in situ hybridisation (FGFR2) analysis was performed. FGFR2 amplification was identified in 2 % of cases and associated with worse survival (P = 0.005). HER2 overexpression was observed in 10 % of cases and associated with increased survival (P = 0.041). cMet overexpression was observed in 4 % of cases and associated with worse survival (P <0.001). On multivariate analysis, only cMet retained significance (P = 0.006). pS6 and pERK expression were observed in 73 % and 30 % of tumours, respectively, with no association with survival. HER2 (P = 0.004) and pERK (P = 0.001) expression differed between tumour regions with HER2 expression increased in the LS compared with the TB and IE. These findings confirm subpopulations in gastric adenocarcinoma with poor outcome that may benefit from specific therapeutic strategies. However, we found heterogeneous HER2, pS6 and pERK overexpression, which presents challenges for their use as predictive biomarkers in gastric biopsies. The potential downstream pharmacodynamic markers pS6 and pERK were expressed across tumour regions, providing evidence that resections and biopsies would yield comparative results in clinical trials. © 2013 Springer-Verlag Berlin Heidelberg

Statin use is associated with a reduced incidence of colorectal cancer: a colonoscopy-controlled case-control study

Background: The aetiology of colorectal cancer (CRC) remains elusive in the majority of cases. There is experimental evidence to show that HMG-CoA reductase inhibitors (statins) may inhibit proliferation and induce cause apoptosis in CRC cells and although some clinical studies have suggested that statins may protect against the development of CRC, this has not been a consistent finding. Therefore we have examined any potential protective effects of statins by comparing statin use in patients with colorectal cancer against a control group. Methods: This was a case–control study examining statin use in symptomatic patients attending for diagnostic colonoscopy. Statin use was compared between patients with CRC and a control group, who had all had normal colonoscopy. Structured interviews and clinical records notes were used to determine drug exposure. Logistic regression was used to compare statin exposure and correct for confounding factors. Results: There was a significant inverse association between previous statin use and a diagnosis of CRC (OR = 0.43 (95% confidence interval 0.25 – 0.80), pyears: OR = 0.18 (0.06 – 0.55), p<0.01). Conclusions: Statins use was associated with a protective effect against the development of CRC. This effect is associated with a significant dose and duration response. These findings need to be repeated in other observational studies before an interventional study can be considered

Epigenetics: At the crossroads between genetic and environmental determinants of disease

Epigenetic modifications play an essential role in the functional regulation of genes, including their expression. In contrast to the relative stability of the genome, the epigenome varies in a very dynamic way, through what are known as epigenetic mechanisms. These epigenetic modifications are reversible and are conditioned by environmental pressures. The most well-known epigenetic DNA modifications are the methylation of the cytosines present in the context of cytosine-guanine dinucleotides and the posttranslational modification of histones. Several works have reported that events in the early environment are associated with changes in gene expression and biological function and that such changes persist beyond the immediate influence of the stimulus and into adulthood. While the exact molecular mechanisms underlying developmental programming are largely unknown, there is much epidemiological evidence and data from animal studies linking epigenetic modifications with parental lifestyle (e.g., alcohol or tobacco consumption), nutrition, and environmental factors (such as exposure to UV light or heavy metals and stress). Moreover, pre-existing pathologies in the parents (e.g., diabetes, obesity, or metabolic syndrome) can also increase the susceptibility of the offspring to developing certain diseases over the course of their lifetime.Peer reviewe

Therapeutic vaccines for cancer: an overview of clinical trials

Item does not contain fulltextThe therapeutic potential of host-specific and tumour-specific immune responses is well recognized and, after many years, active immunotherapies directed at inducing or augmenting these responses are entering clinical practice. Antitumour immunization is a complex, multi-component task, and the optimal combinations of antigens, adjuvants, delivery vehicles and routes of administration are not yet identified. Active immunotherapy must also address the immunosuppressive and tolerogenic mechanisms deployed by tumours. This Review provides an overview of new results from clinical studies of therapeutic cancer vaccines directed against tumour-associated antigens and discusses their implications for the use of active immunotherapy