Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trial.

BACKGROUND: The role of interleukin 13 in airway inflammation and remodelling in asthma is unclear. Tralokinumab is a human monoclonal antibody that neutralises interleukin 13. We aimed to evaluate whether tralokinumab would have an effect on airway eosinophilic infiltration, blood and sputum eosinophil concentrations, eosinophil activation, and airway remodelling. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled phase 2 trial at 15 centres across the UK, Denmark, and Canada. We enrolled participants of either sex aged 18-75 years with inadequately controlled moderate-to-severe asthma for 12 months or more, requiring treatment with inhaled corticosteroids at a stable dose. We randomly assigned participants (1:1) to receive tralokinumab (300 mg) or placebo by an interactive web-based system or voice response system. Participants and study personnel were masked to treatment allocation. Both tralokinumab and placebo were administered subcutaneously every 2 weeks. The primary outcome measure was change from baseline to week 12 in bronchial biopsy eosinophil count. Secondary outcome measures included change in blood and sputum eosinophil counts. Exploratory outcomes included fractional exhaled nitric oxide (FENO) and blood IgE concentrations. Safety analyses were carried out in all participants who received study drug. This trial is registered with ClinicalTrials.gov, number NCT02449473, and with the European Clinical Trials Database, EudraCT 2015-000857-19. FINDINGS: Between Sept 25, 2015, and June 21, 2017, 224 participants were enrolled and screened. Of these participants, 79 were randomly assigned to receive tralokinumab (n=39) or placebo (n=40). Tralokinumab did not significantly affect bronchial eosinophil count compared with placebo at week 12 (treatment effect ratio 1·43, 95% CI 0·63-3·27; p=0·39). Compared with placebo, tralokinumab did not significantly affect blood eosinophil count (treatment effect ratio 1·21, 95% CI 1·00-1·48; p=0·055) or sputum eosinophil count (0·57, 0·06-6·00; p=0·63), but FENO concentration (0·78, 0·63-0·96; p=0·023) and total blood IgE concentration (0·86, 0·77-0·97; p=0·014) were significantly reduced. 33 (85%) of 39 patients receiving tralokinumab and 32 (80%) of 40 receiving placebo reported at least one adverse event during the treatment period. No deaths in either treatment group were observed. Treatment-related adverse events occurred more frequently in the tralokinumab group than in the placebo group (11 [28%] of 39 vs seven [18%] of 40). INTERPRETATION: Tralokinumab did not significantly affect eosinophilic inflammation in bronchial submucosa, blood, or sputum compared with placebo, but did reduce FENO and IgE concentrations. These results suggest interleukin 13 is not crucial for eosinophilic airway inflammation control in moderate-to-severe asthma. FUNDING: AstraZeneca.

Potential Risks Related to Modulating Interleukin-13 and Interleukin-4 Signalling: A Systematic Review.

INTRODUCTION: Interleukin-13 and interleukin-4 are type-II cytokines signalling through the shared type II interleukin-4 receptor. As a result of their structural similarity, interleukin-13 and interleukin-4 have overlapping functions in the mediation of type-II-driven diseases and are, therefore, promising targets of biologic drugs currently in development for the treatment of such diseases, including asthma and atopic dermatitis. OBJECTIVE: This systematic review was conducted to assess preclinical evidence of potential safety concerns related to blockade of interleukin-13 alone or interleukin-13 and interleukin-4 in combination. METHODS: We specifically examined risks related to infection, malignancy and the cardiovascular system. We systematically searched the BIOSIS, MEDLINE and EMBASE databases to identify preclinical studies published between January 2006 and October 2016 that addressed the effects of interleukin-13/interleukin-4 blockade and modulation on the risk of infection, malignancy and cardiovascular events. To provide a clinical context, we also performed a search for clinical trials targeting the interleukin-13/interleukin-4 pathways. Relevant data from preclinical and clinical trials were abstracted and presented descriptively. RESULTS: Aside from expected evidence that inhibition of interleukin-13 and interleukin-4 impaired host responses to helminth infections, we did not identify other preclinical evidence suggesting safety risks relating to infection, malignancy or cardiovascular events. We found no evidence in clinical trials suggesting serious safety concerns, i.e. increased risk for infections, malignancy or cardiovascular events from therapeutic modulation of the interleukin-13 pathway alone or the combined interleukin-13/interleukin-4 pathways. CONCLUSIONS: Although our findings are reassuring, long-term safety assessments of biologics that target the interleukin-13/interleukin-4 pathways currently in clinical development are needed.

Systematic Review with Network Meta-Analysis: Antidiabetic Medication and Risk of Hepatocellular Carcinoma.

Antidiabetic medication may modify the incidence of hepatocellular carcinoma (HCC). We aimed to compare the use of different antidiabetic strategies and the incidence of HCC. PubMed, Embase.com and Cochrane Library databases were searched up to 31 October 2015 and randomized controlled trials (RCTs), cohort studies or case-control studies were included for our analyses. A total of thirteen studies enrolling 481358 participants with 240678 HCC cases who received at least two different strategies were retrieved in this analysis. Direct comparisons showed that use of metformin (risk ratio [RR] 0.49, 95% CI 0.25-0.97) was associated with a significant risk reduction of HCC, while insulin (RR = 2.44, 95% CI 1.10- 5.56) may significantly increase the risk. Indirect evidence also suggested that insulin (RR = 2.37, 95% CI 1.21-4.75) was associated with a significantly increased risk of HCC. Additionally, metformin was effective in reducing the risk of HCC when compared with sulphonylurea (RR = 0.45, 95% CI 0.27-0.74) and insulin (RR = 0.28, 95% CI 0.17-0.47). Notably, metformin was hierarchically the best when compared with other antidiabetic therapies for the prevention of HCC. In summary, available evidence suggests that metformin was the most effective strategy to reduce HCC risk when compared with other antidiabetic interventions.

Targeting endoplasmic reticulum stress in liver disease.

INTRODUCTION: The accumulation of unfolded protein in the endoplasmic reticulum (ER) initiates an unfolded protein response (UPR) via three signal transduction cascades, which involve protein kinase RNA-like ER kinase (PERK), inositol requiring enzyme-1α (IRE1α) and activating transcription factor-6α (ATF6α). An ER stress response is observed in nearly all physiologies related to acute and chronic liver disease and therapeutic targeting of the mechanisms implicated in UPR signaling have attracted considerable attention. AREAS COVERED: This review focuses on the correlation between ER stress and liver disease and the possible targets which may drive the potential for novel therapeutic intervention. Expert Commentary: We describe pathways which are involved in UPR signaling and their potential correlation with various liver diseases and underlying mechanisms which may present opportunities for novel therapeutic strategies are discussed.

Toll-like receptors in hepatocellular carcinoma: potential novel targets for pharmacological intervention.

INTRODUCTION: Toll-like receptors (TLRs) are expressed by a wide variety of cell types including immune cells. They play a crucial role in the inflammatory and host defense response against microorganisms, and triggering TLRs can mediate the activation of innate immunity. Furthermore, research suggests that various TLRs may function differently on different tumor cells. The change in TLR activity may elicit an anti-tumor activity in hepatocellular carcinoma (HCC) cells and may serve as a novel therapeutic target for HCC therapy. AREAS COVERED: This review discusses the role of the TLR family in HCC and the underlying signaling pathway of TLRs as a form of pattern recognition receptor in mediating inflammation and HCC immunity responses. Agonists and antagonists of TLRs, which render TLRs as potential therapeutic targets, activate downstream molecules, subsequently causing HCC cell survival. The proliferation or protection against the development of HCC is also described. EXPERT OPINION: A series of studies have highlighted a crucial role of TLRs in HCC and consider TLR signaling pathways as potential therapeutic targets for HCC. However, the conclusions of these studies are in part paradoxical and controversial. Thus, it is necessary to extend further research to help determine the signaling pathways involved.

Preoperative platelet to lymphocyte ratio is a valuable prognostic biomarker in patients with colorectal cancer.

OBJECTIVES: Recent studies suggest that an elevated preoperative platelet to lymphocyte ratio (PLR) may be considered a poor prognostic biomarker in patients with colorectal cancer (CRC). The aim of this study was to evaluate the prognostic impact of PLR in patients with CRC. METHODS: We enrolled 1314 patients who underwent surgery for CRC between 2005 and 2011. Preoperative PLR level was stratified into quintiles for Kaplan-Meier analysis and multivariable Cox proportional hazard regression models. RESULTS: Higher PLR quintiles were significantly associated with poorer overall survival (P = 0.002). Multivariate analysis showed that PLR was an independent risk factor for overall survival (OS) (P = 0.034). Patients in PLR quintile 5 had lower overall survival than in quintile 1 (hazard ratio (HR) = 1.701, 95% confidence interval (CI): 1.267-2.282, P < 0.001). Although patients in PLR quintile 5 had significantly lower disease-free survival (DFS) than in quintile 1 (HR = 1.522, 95% CI: 1.114-2.080, P = 0.008), this association was not significant after multivariable adjustment (P = 0.075). In the subgroup analysis, PLR remained an independent factor in terms of advanced tumor stage (III, IV), male sex, carcinoembryonic antigen (≤ 5 ng/ml), age (> 65 years) and body mass index (≤ 25) (P < 0.05 for all measurements). The results remained unchanged when the PLR was analyzed as a dichotomous variable by applying different cut-off values of 150, 185, 220. CONCLUSIONS: Elevated preoperative PLR was independently associated with an increased risk of mortality in patients with CRC. The utility of PLR may help to improve prognostic predictors.

Atheroprotection through SYK inhibition fails in established disease when local macrophage proliferation dominates lesion progression.

Macrophages in the arterial intima sustain chronic inflammation during atherogenesis. Under hypercholesterolemic conditions murine Ly6C(high) monocytes surge in the blood and spleen, infiltrate nascent atherosclerotic plaques, and differentiate into macrophages that proliferate locally as disease progresses. Spleen tyrosine kinase (SYK) may participate in downstream signaling of various receptors that mediate these processes. We tested the effect of the SYK inhibitor fostamatinib on hypercholesterolemia-associated myelopoiesis and plaque formation in Apoe(-/-) mice during early and established atherosclerosis. Mice consuming a high cholesterol diet supplemented with fostamatinib for 8 weeks developed less atherosclerosis. Histologic and flow cytometric analysis of aortic tissue showed that fostamatinib reduced the content of Ly6C(high) monocytes and macrophages. SYK inhibition limited Ly6C(high) monocytosis through interference with GM-CSF/IL-3 stimulated myelopoiesis, attenuated cell adhesion to the intimal surface, and blocked M-CSF stimulated monocyte to macrophage differentiation. In Apoe(-/-) mice with established atherosclerosis, however, fostamatinib treatment did not limit macrophage accumulation or lesion progression despite a significant reduction in blood monocyte counts, as lesional macrophages continued to proliferate. Thus, inhibition of hypercholesterolemia-associated monocytosis, monocyte infiltration, and differentiation by SYK antagonism attenuates early atherogenesis but not established disease when local macrophage proliferation dominates lesion progression.

The role of lncRNAs in hepatocellular carcinoma: opportunities as novel targets for pharmacological intervention.

Long non-coding RNA (lncRNA) is commonly defined as an RNA with a length of greater than 200 nucleotides, frequently up to 100 kb. Numerous studies have shown that dysregulation of lncRNAs may directly relate to a number of human diseases, particularly in oncology where lncRNAs appear to play an important role. LncRNAs may also play a potentially novel and critical role in the development and progression of hepatocellular carcinoma (HCC). This article discusses lncRNAs as a new possibility for diagnostic and therapeutic approaches for HCC. The authors introduce the relationship between some lncRNAs and HCC, including carcinogenesis, development, metastasis and prognosis. In addition, the authors suggest that the discovery of lncRNAs may encourage the discovery and development of new therapeutic modalities for HCC and that their regulation may be a promising potential treatment for HCC. Clinical studies are required to determine the therapeutic effect of regulating lncRNA in humans with HCC.

Stratified neutrophil-to-lymphocyte ratio accurately predict mortality risk in hepatocellular carcinoma patients following curative liver resection.

OBJECTIVES: Neutrophil lymphocyte ratio (NLR) has been shown to predict prognosis of cancers in several studies. This study was designed to evaluate the impact of stratified NLR in patients who have received curative liver resection (CLR) for hepatocellular carcinoma (HCC). METHODS: A total of 1659 patients who underwent CLR for suspected HCC between 2007 and 2014 were reviewed. The preoperative NLR was categorized into quartiles based on the quantity of the study population and the distribution of NLR. Hazard ratios (HRs) and 95% confidence intervals (CIs) were significantly associated with overall survival (OS) and derived by Cox proportional hazard regression analyses. Univariate and multivariate Cox proportional hazard regression analyses were evaluated for association of all independent parameters with disease prognosis. RESULTS: Multivariable Cox proportional hazards models showed that the level of NLR (HR = 1.031, 95%CI: 1.002-1.060, P = 0.033), number of nodules (HR = 1.679, 95%CI: 1.285-2.194, P<0.001), portal vein thrombosis (HR = 4.329, 95%CI: 1.968-9.521, P<0.001), microvascular invasion (HR = 2.527, 95%CI: 1.726-3.700, P<0.001) and CTP score (HR = 1.675, 95%CI: 1.153-2.433, P = 0.007) were significant predictors of mortality. From the Kaplan-Meier analysis of overall survival (OS), each NLR quartile showed a progressively worse OS and apparent separation (log-rank P=0.008). The highest 5-year OS rate following CLR (60%) in HCC patients was observed in quartile 1. In contrast, the lowest 5-year OS rate (27%) was obtained in quartile 4. CONCLUSIONS: Stratified NLR may predict significantly improved outcomes and strengthen the predictive power for patient responses to therapeutic intervention.

In vitro pharmacological profiling of R406 identifies molecular targets underlying the clinical effects of fostamatinib.

Off-target pharmacology may contribute to both adverse and beneficial effects of a new drug. In vitro pharmacological profiling is often applied early in drug discovery; there are fewer reports addressing the relevance of broad profiles to clinical adverse effects. Here, we have characterized the pharmacological profile of the active metabolite of fostamatinib, R406, linking an understanding of drug selectivity to the increase in blood pressure observed in clinical studies. R406 was profiled in a broad range of in vitro assays to generate a comprehensive pharmacological profile and key targets were further investigated using functional and cellular assay systems. A combination of traditional literature searches and text-mining approaches established potential mechanistic links between the profile of R406 and clinical side effects. R406 was selective outside the kinase domain, with only antagonist activity at the adenosine A3 receptor in the range relevant to clinical effects. R406 was less selective in the kinase domain, having activity at many protein kinases at therapeutically relevant concentrations when tested in multiple in vitro systems. Systematic literature analyses identified KDR as the probable target underlying the blood pressure increase observed in patients. While the in vitro pharmacological profile of R406 suggests a lack of selectivity among kinases, a combination of classical searching and text-mining approaches rationalized the complex profile establishing linkage between off-target pharmacology and clinically observed effects. These results demonstrate the utility of in vitro pharmacological profiling for a compound in late-stage clinical development.

Safety and Efficacy of an Oral Inhibitor of the Purinergic Receptor P2X7 in Adult Patients with Moderately to Severely Active Crohn's Disease: A Randomized Placebo-controlled, Double-blind, Phase IIa Study.

BACKGROUND: AZD9056 is a selective orally active inhibitor of the purinergic receptor P2X7, which is a key player in the generation and secretion of several proinflammatory cytokines involved in the pathogenesis of Crohn's disease (CD). The aim of this phase IIa study was to assess the efficacy and safety of AZD9056 for the treatment of moderately to severely active CD. METHODS: We conducted a placebo-controlled, multicenter, double-blind phase IIa study in patients with moderately to severely active CD as defined by a CD Activity Index (CDAI) of at least 220. Patients were randomized in a 2:1 mode either to 200 mg of AZD9056 administered orally as a tablet once daily for 28 days or matching placebo. Primary endpoint was the change in CDAI from baseline at day 28, and secondary endpoints included clinical remission (CDAI < 150) and CDAI 70 response and improvement in the quality of life measures Short Form 36 and Inflammatory Bowel Disease Questionnaire. Changes in serum C-reactive protein and fecal calprotectin were assessed. RESULTS: In total, 34 patients were enrolled, 24 to AZD9056 and 10 to placebo. The CDAI dropped in AZD9056-treated subjects from a baseline mean of 311 to 242 and from 262 to 239 in placebo-treated subjects (P = 0.049). Remission and response rates were numerically higher with AZD9056 versus placebo, (n = 5, 24% versus n = 1, 11%, P = 0.43 and n = 11, 52% versus n = 2, 22%, P = 0.13, respectively). Marked decrease in disease activity was observed for the CDAI subcomponents, pain and general well-being. Apart from a statistically significant improvement in the Mental Component Score of Short Form 36 for AZD9056 versus placebo (P = 0.017), no other differences in measurements of quality of life could be observed. There was no decrease in concentrations of serum C-reactive protein and fecal calprotectin during treatment. AZD9056 was well-tolerated, and no serious adverse events were reported. CONCLUSIONS: Our data suggest that the purinergic receptor P2X7 antagonist AZD9056 has the potential to improve symptoms in patients with moderate-to-severe CD combined with a beneficial risk profile. Although the lack in change of inflammatory biomarkers questions its anti-inflammatory potential, the results obtained in this study rather suggest P2X7 antagonism for the treatment of chronic abdominal pain.

Combined AFP-CRUT with microvascular invasion accurately predicts mortality risk in patients with hepatocellular carcinoma following curative liver resection.

AIMS: To establish and validate an equation of α-fetoprotein (AFP) change rate over unit time (AFP-CRUT) as a potential predictor of survival after resection in patients with hepatocellular carcinoma (HCC). METHODS: The AFP-CRUT was constructed based on dynamic variation in AFP over time and then categorized into quintiles. The area under the receiver operating characteristic (ROC) curve showed the performance for survival prediction. RESULTS: As independent risk factors associated with mortality, microvascular invasion (MVI) (p = 0.003) and AFP-CRUT quintiles (p = 0.048) were combined to enhance the predictive effect. The highest 5-year overall survival rate following curative liver resection (93%) was observed in patients with MVI absent and AFP-CRUT in quintile 1 (49.64 to 209.61). In contrast, the lowest 5-year overall survival (7%) was obtained in quintile 5 (-469.29 to 6.45) with MVI present. In validation cohorts at both 12 and 24 months, AFP-CRUT performed well as a potential prognostic biomarker. CONCLUSIONS: Combining AFP-CRUT quintiles with MVI may predict significantly improved outcomes and enhance the predictive power for patient responses to therapeutic intervention.

Establishment and Validation of SSCLIP Scoring System to Estimate Survival in Hepatocellular Carcinoma Patients Who Received Curative Liver Resection.

BACKGROUND AND AIMS: There is no prognostic model that is reliable and practical for patients who have received curative liver resection (CLR) for hepatocellular carcinoma (HCC). This study aimed to establish and validate a Surgery-Specific Cancer of the Liver Italian Program (SSCLIP) scoring system for those patients. METHODS: 668 eligible patients who underwent CLR for HCC from five separate tertiary hospitals were selected. The SSCLIP was constructed from a training cohort by adding independent predictors that were identified by Cox proportional hazards regression analyses to the original Cancer of the Liver Italian Program (CLIP). The prognostic performance of the SSCLIP at 12 and 36-months was compared with data from existing models. The patient survival distributions at different risk levels of the SSCLIP were also assessed. RESULTS: Four independent predictors were added to construct the SSCLIP, including age (HR = 1.075, 95%CI: 1.019-1.135, P = 0.009), albumin (HR = 0.804, 95%CI: 0.681-0.950, P = 0.011), prothrombin time activity (HR = 0.856, 95%CI: 0.751-0.975, P = 0.020) and microvascular invasion (HR = 19.852, 95%CI: 2.203-178.917, P = 0.008). In both training and validation cohorts, 12-month and 36-month prognostic performance of the SSCLIP were significantly better than those of the original CLIP, model of end-stage liver disease-based CLIP, Okuda and Child-Turcotte-Pugh score (all P < 0.05). The stratification of risk levels of the SSCLIP showed an enhanced ability to differentiate patients with different outcomes. CONCLUSIONS: A novel SSCLIP to predict survival of HCC patients who received CLR based on objective parameters may provide a refined, useful prognosis algorithm.

Optimal adjuvant therapy for resected hepatocellular carcinoma: a systematic review with network meta-analysis.

OBJECTIVES: Major adjuvant therapies (ATs) for resected hepatocellular carcinoma (HCC) include chemotherapy, internal radiation therapy (IRT), interferon therapy (IFNT) and immunotherapy but the optimum regimen remains inconclusive. We aim to compare these therapies in terms of patient survival and recurrence rates. METHODS: We searched PubMed, EMBASE and Cochrane library databases for randomized trials comparing the above four therapies until 31 March 2014. We estimated the HRs for survival and ORs for overall recurrence among different therapies. Toxic effects were also evaluated. RESULTS: Fourteen eligible articles were included. IFNT improved 5-year survival greatly (HR 1.81, 95% CI 1.01-3.81, P = 0.034), whereas chemotherapy (HR 0.33, 95% CI 0.03-2.02), IRT (HR 0.31, 95% CI 0.02-3.33) and immunotherapy (HR 0.73, 95% CI 0.05-9.12) all provided a poorer survival outcome after 1-year. Similarly, for 5-year survival rates, although differing, IRT did not provide a significant improvement in survival (HR 1.38, 95% CI 0.34-5.19) compared with IFNT. Chemotherapy (HR 0.49, 95% CI 0.18-1.14) and immunotherapy (HR 0.56, 95% CI 0.17-1.59) did not appear to provide benefit over IFNT. Chemotherapy was ranked the worst in overall recurrence (OR 0.99, 95% CI 0.18-5.38) and most likely to cause toxic effects. CONCLUSIONS: IFNT was the most efficacious AT regimen both for short and long term survivals. Immunotherapy and IFNT were the most two effective in preventing overall relapse for resected HCC.

Metabolic syndrome contributes to an increased recurrence risk of non-metastatic colorectal cancer.

OBJECTIVES: Epidemiological data suggests a close link between metabolic syndrome (MetS) and non-metastatic colorectal cancer (NMCRC). However, the relationship between MetS and the outcome of NMCRC is less well understood. We aim to evaluate the impact of MetS on the prognosis in NMCRC patients. METHODS: We performed a large cohort study of 1069 NMCRC patients. The Kaplan-Meier method was used to calculate the cumulative survival rate. Cox proportional hazard regression models were used to analyze the prognosis associated with MetS adjusting for clinicopathologic variables. RESULTS: MetS was identified in 20.7% of NMCRC patients. Patients with MetS were more likely to be older, higher levels of blood glucose, triglycerides, high density lipoprotein, and uric acid than patients without MS (P < 0.05 for all). During a mean period of 59.6 months follow-up, patients with MetS had a statistically significantly lower rate of disease-free survival (DFS) than the patients without MetS (P = 0.014), especially local recurrence (P = 0.040). However, there was no difference in overall survival (P = 0.116). Multivariate analysis showed that the presence of MetS was an independent risk factor for DFS (HR = 0.733, 95%CI 0.545-0.987, P = 0.041), but not for OS (P = 0.118). CONCLUSIONS: MetS is associated with an increased recurrence risk of NMCRC.

Nonalcoholic fatty liver disease: a negative risk factor for colorectal cancer prognosis.

Nonalcoholic fatty liver disease (NAFLD) is known to be associated with an increased risk of colorectal cancer (CRC). However, the relationship between NAFLD and the prognosis of CRC remains unclear. The primary objective of this study was to evaluate the overall survival (OS) and disease-free survival (DFS) rates in patients with CRC and the secondary objective was to compare clinicopathologic variables which were stratified by NAFLD. We performed a large cohort study of 1314 patients who were first diagnosed with CRC between January 2006 and April 2011. Postoperative follow-up data were collected from out-patient medical records, telephone consultations, and social security death indices. The Kaplan-Meier method was used to calculate the cumulative survival rate. Clinicopathologic variables were analyzed by univariate analysis and multivariate analysis through a Cox proportional hazard regression model. The mean follow-up time was 52.7 ±â€Š25.3 months. Upon baseline comparison, the NAFLD group had significantly higher values of body mass index, triglycerides, and uric acid and significantly lower values of high-density lipoprotein, compared with the non-NAFLD group (P < 0.05 for all). There were no significant differences between the 2 groups with regard to tumor location, TNM staging, tumor differentiation, carcinoembryonic antigen, and vascular invasion. The cumulative 1-, 3-, and 5-year OS rates were 96.1%, 85.2%, and 80.6%, respectively, in the NAFLD group, which were statistically significantly higher than the OS rates of 91.6%, 76.2%, and 67.8%, respectively, in the non-NAFLD group (P = 0.075, P = 0.002, P = 0.030, respectively). There was no difference in DFS rates between the CRC patients with and without NAFLD (P = 0.267). Multivariate analysis showed that the presence of NAFLD was an independent negative risk factor for OS after adjusting for clinicopathologic covariates (hazard ratio = 0.593; 95% confidence interval 0.442, 0.921; P = 0.020), but not for DFS (P = 0.270). NAFLD may play a protective role in OS for CRC patients. Further studies are needed to elucidate the molecular mechanisms of putative protective effects in CRC patients with NAFLD.

Systematic review with network meta-analysis: adjuvant chemotherapy for resected colorectal liver metastases.

There are 5 major adjuvant chemotherapies (ACTs) for hepatic metastases for colorectal cancer; however, the optimal treatment regimen remains inconclusive. Here, we aim to compare these therapies in terms of patient survival rate, intrahepatic recurrence rate, and adverse events.Different databases were searched for controlled trials up to June 30, 2014. The pooled hazards ratios for death and odds ratios (ORs) for intrahepatic recurrence and adverse events were estimated. A mean ranking and the probability of optimal therapeutic regime was obtained for each treatment analyzed in the network meta-analysis.Eleven eligible articles were included. Systemic chemotherapy (SCT) was ranked the most efficacious intervention among ACTs in both 1-year and 5-year survival; however, no statistical difference could be determined. Combination of bevacizumab (BEV) and hepatic arterial infusion (HAI) plus SCT was the most effective in preventing intrahepatic recurrence when compared with HAI alone (OR 1.21, 95% confidence interval [CI] 0.01-131.12), SCT (OR 2.37, 95% CI 0.03-234.16), HAI plus SCT (OR 0.97, 95% CI 0.03-35.30), SCT plus irinotecan (OR 1.01, 95% CI 0.00-278.14) and observation alone (OR 0.83, 95% CI 0.01-59.53). BEV and HAI plus SCT provided the least survival benefit after both 1 and 5 years compared with remaining therapies, and also was ranked the regiment with the least favorable adverse event profile among ACTs.SCT may be the most efficacious intervention, however, the potential benefit should be carefully considered with the regime's associated toxicities. Combination of BEV and HAI plus SCT was effective in preventing intrahepatic relapse but was associated with the highest risk for adverse events in patients with resected hepatic metastases for colorectal cancer.

Targeting fibroblast growth factor 19 in liver disease: a potential biomarker and therapeutic target.

INTRODUCTION: Fibroblast growth factor 19 (FGF19) is a member of the hormone-like FGF family and has activity as an ileum-derived postprandial hormone. It shares high binding affinity with ß-Klotho and together with the FGF receptor (FGFR) 4, is predominantly targeted to the liver. The main function of FGF19 in metabolism is the negative control of bile acid synthesis, promotion of glycogen synthesis, lipid metabolism and protein synthesis. AREAS COVERED: Drawing on in vitro and in vivo studies, this review discusses FGF19 and some underlying mechanisms of action of FGF19 as an endocrine hormone in several liver diseases. The molecular pathway of the FGF19-FGFR4 axis in non-alcoholic liver disease and hepatocellular carcinoma are discussed. Furthermore, definition of function and pharmacological effects of FGF19 for liver disease are also presented. EXPERT OPINION: A series of studies have highlighted a crucial role of FGF19 in liver disease. However, the conclusions of these studies are partly paradoxical and controversial. An understanding of the underlying biological mechanisms which may explain inconsistent findings is especially important for consideration of potential biomarker strategies and an exploration of the putative therapeutic efficacy of FGF19 for human liver disease.

Targeting the P2X7 receptor in rheumatoid arthritis: biological rationale for P2X7 antagonism.

OBJECTIVES: This paper aims to explore the functional significance of the P2X7 receptor in preclinical models of rheumatoid arthritis. METHODS: Preclinical studies in vivo were performed using the rat streptococcal cell wall (SCW) arthritis model. Ex vivo cultures of lipopolysaccharide (LPS)/benzoylbenzoyl adenosine triphosphate (BzATP)-stimulated human monocytes were generated to test the activities of a novel, highly specific inhibitor of human P2X7, AZD9056, on interleukin (IL)-1 and IL-18 release. RESULTS: P2X7 receptor expression was detected in inflamed synovial tissue after onset of SCW-induced arthritis in rats. Inhibition of P2X7 therein led to reduced articular inflammation and erosive progression. No effect was noted on acute-phase responses. Ex vivo, AZD9056 inhibited IL-1 and IL-18 release to BzATP in LPS-primed human monocytes. CONCLUSIONS: P2X7 receptor inhibition could represent a novel approach to the treatment of inflammatory arthritis. However, confirmatory clinical studies are warranted to further explore this possibility.

The role of fibroblast growth factor 21 in the pathogenesis of liver disease: a novel predictor and therapeutic target.

INTRODUCTION: Fibroblast growth factor 21 (FGF21) is one of the FGF family members that is produced mainly by tissues with high metabolic activity such as liver, pancreas, muscle and adipose tissue. The major function of FGF21 is to improve insulin sensitivity, ameliorate hepatic steatosis and enhance energy expenditure. Recently, several studies have reported a correlation between FGF21 and liver disease with numerous cross-sectional studies demonstrating significant correlation. This review will focus on the role of FGF21 in the pathogenesis of liver disease and its potential role as a biomarker and a new target for therapeutic intervention. AREAS COVERED: This review discusses cross-sectional studies and underlying mechanisms of FGF21 as an endocrine hormone in several liver diseases. Two major theories of 'endoplasmic reticulum stress' and 'FGF21 resistance' in particular are explained. Moreover, early functional detection and pharmacological effect of FGF21 for liver disease are also described. EXPERT OPINION: FGF21 can be a promising treatment in liver disease. However, still several problems are needed to be answered. The most important are whether different liver disease share common underlying mechanisms and the pharmacological effect in human with limited studies. Further studies are needed to explain the underlying mechanisms and develop potential therapeutic effect for human liver disease.