Association between neutrophil–lymphocyte ratio, socioeconomic status, and ethnic minority with treatment outcome in hepatocellular carcinoma Abstract Background Patients with lower socioeconomic status (SES), ethnic minorities and elevated neutrophil–lymphocyte ratio (NLR) have been suggested to have worse outcomes in hepatocellular carcinoma (HCC). However, how changes in NLR after intervention relate to survival has not been elucidated. Objectives We evaluated the association of NLR with overall survival (OS) and progression-free survival (PFS) in a large institutional cohort of HCC. Methods We reviewed all patients diagnosed with HCC between 2005–2016. The association between elevated NLR (> 4) and survival was examined with univariable and multivariable Cox regression. Results We identified 991 patients diagnosed with HCC. Lower SES and Hispanic and non-Hispanic Black ethnicity were significantly associated with lower NLR (p = 0.015 and 0.019, respectively). Elevated NLR, but not SES or ethnicity, was an independent predictor of worse OS (HR = 1.66, p < 0.001) and PFS (HR = 1.25, p = 0.032). The median OS in patients with elevated NLR was 8 months, compared to 42 months in patients with normal NLR. Patients with elevated NLR unresponsive to treatment and those with NLR that became elevated after treatment had significantly worse 3-year OS (47% and 44%, respectively), compared to patients whose NLR remained normal or normalized after treatment (72% and 80%, respectively; p < 0.01). Conclusions Our study showed that elevated NLR, but not SES or ethnicity, is an independent prognostic marker for OS and PFS in patients with HCC. NLR trends following intervention were highly predictive of outcome. NLR is easy to obtain and would provide valuable information to clinicians in evaluating prognosis and monitoring response after procedures.

Reversal of NASH fibrosis with pharmacotherapy Abstract NAFLD is a spectrum of liver disease starting with fatty liver at one end of the spectrum and cirrhosis or liver cancer at the other end. Worldwide, NAFLD has become one of the most common liver diseases and it has also become one of the leading indications for liver transplantation. Our understanding of the NAFLD epidemiology, pathogenesis and its progression to cirrhosis has improved over the last 2 decades. Currently, however, there are no FDA-approved treatment options for fibrosis resulting from NAFLD. A number of compounds targeting multiple pathways involved in the progression of NAFLD are currently in phase 2–3 trials. In this review, we will briefly discuss the epidemiology, the pathogenesis and the current status of treatment of NAFLD.

Clinical immunology and immunotherapy for hepatocellular carcinoma: current progress and challenges Abstract At the time of hepatocellular carcinoma (HCC) diagnosis, patients are most often at an advanced stage; however, the current treatment regimens remain unsatisfactory. Thus, novel and more powerful therapeutic approaches for advanced HCC are urgently required. Exacerbation of immunotolerant signals and/or escaping immunosurveillance leads to the development of HCC, which appears to be a rational reason to use immunotherapy to restore anticancer immunity. Several novel immunotherapeutic methods, including the use of immune checkpoint inhibitors, new types of immune cell adoption [e.g., chimeric antigen receptor T cell (CAR-T), TCR gene-modified T cells and stem cells], and microRNAs have been used in clinical trials for the treatment of HCC. However, some crucial issues remain to be addressed for such novel immunotherapy techniques. Finally, immunotherapy is now standing on the threshold of great advances in the fight against HCC.

An imbalance between stellate cells and γδT cells contributes to hepatocellular carcinoma aggressiveness and recurrence Abstract Purpose The diagnostic potential of hepatic stellate cells (HSCs) and γδT cells for patients with hepatocellular carcinoma (HCC) and their synergistic contributions to the prognosis of these patients have not yet been investigated. The aim of this study was to elucidate the prognostic value of these cells in HCC. Methods The prognostic significance of the ratio of HSCs to γδT cells (SGR) was assessed in a total of 339 HCC patients undergoing resection. The correlation between the circulating tumor cell (CTC) level and SGR in 71 HCC patients was determined using the CellSearch system. In vitro experiments were performed to validate the synergistic effects of HSCs and γδT cells on hepatoma cells. Results Peritumoral SGR was closely associated with overall survival (OS) and recurrence-free survival (RFS) of HCC patients after resection. In the testing cohort, two nomograms incorporating the SGR were constructed for the prediction of OS and RFS. The predictive accuracy of the two nomograms was verified by the validation cohort. CTC levels were positively correlated with SGR (r = 0.479, p < 0.001). Among the patients with CTCs > 2/7.5 ml, those with a high SGR exhibited higher early recurrence rates than those with a low SGR. In vitro experiments revealed that the secretion of INF-γ, IL-17, and TNF-α from γδT cells was increased after culture with HSC-conditioned medium. In addition, γδT cells cultured with HSC-conditioned medium decreased the proliferative and invasive abilities of hepatoma cells. Conclusions The peritumoral SGR is related to aggressive tumor behavior and has a powerful predictive value in HCC. Early recurrence in patients with a high peritumoral SGR might be associated with high CTC levels.

Identification and validation of a prognostic four-genes signature for hepatocellular carcinoma: integrated ceRNA network analysis Abstract Background Hepatocellular carcinoma (HCC) is one of the most aggressive malignant tumors, with a poor long-term prognosis worldwide. The functional deregulations of global transcriptome were associated with the genesis and development of HCC, but lacks systematic research and validation. Methods A total of 519 postoperative HCC patients were included. We built an interactive and visual competing endogenous RNA network. The prognostic signature was established with the least absolute shrinkage and selection operator algorithm. Multivariate Cox regression analysis was used to screen for independent prognostic factors for HCC overall survival. Results In the training set, we identified a four-gene signature (PBK, CBX2, CLSPN, and CPEB3) and effectively predicted the overall survival. The survival times of patients in the high-score group were worse than those in the low-score group (p = 0.0004), and death was also more likely in the high-score group (HR 2.444, p < 0.001). The results were validated in internal validation set (p = 0.0057) and two external validation cohorts (HR 2.467 and 2.6). The signature (AUCs of 1, 2, 3 years were 0.716, 0.726, 0.714, respectively) showed high prognostic accuracy in the complete TCGA cohort. Conclusions In conclusion, we successfully built a more extensive ceRNA network for HCC and then identified a four-gene-based signature, enabling prediction of the overall survival of patients with HCC.

Ascitic fluid infection in children with liver disease: time to change empirical antibiotic policy Abstract Background and aims Recent years have shown a rise in occurrence of multidrug resistant ascitic fluid infection (AFI) including resistant to third generation cephalosporins. Our aim was to find the prevalence, antibiotics resistance and outcome of AFI in children with liver disease. Methods Children (≤ 18 years) with liver disease-related ascites were prospectively enrolled from April 2015 to October 2017. Based on the results of ascitic fluid examination and culture, patients were classified as having AFI [spontaneous bacterial peritonitis (SBP), culture negative neutrocytic ascites (CNNA) and monomicrobial non-neutrocytic bacterascites (MNB)] and no-AFI. AFI diagnosed after 48 h of index hospitalization was considered as nosocomial. Results We enrolled 194 children with a median age of 85 [2–216] months. Chronic liver disease was the commonest etiology (153, 79%). AFI was present in 60 (31%) children [SBP (n = 13), CNNA (n = 39), MNB (n = 8)] of which 53% were nosocomial and resulted in high in-hospital mortality. Gram-negative bacilli dominated the ascitic fluid culture (12/21, 57%) and 10/12 (83%) of them were extended spectrum beta-lactamases (ESBL) producers. Six (60%) ESBL producers were sensitive to cefoperazone–sulbactam and 70% to carbapenems. Child–Pugh-Turcotte (CPT) score of ≥ 11 independently determined in-hospital mortality in children with AFI. Conclusions AFI was found in 31% children with liver disease and almost half of them were nosocomial resulting in high mortality. ESBL producing Gram-negative bacteria were the most frequently isolated organisms. Cefoperazone–sulbactam or carbapenems may be useful empirical antibiotics in nosocomial setting. Children with AFI and CPT score ≥ 11 should be evaluated for liver transplantation.

Relationship between relative skeletal muscle mass and nonalcoholic fatty liver disease: a systematic review and meta-analysis Abstract Background and Aim Nonalcoholic fatty liver disease (NAFLD) has gradually become one of the most common chronic liver diseases in the world. More and more evidence shows that low skeletal muscle mass index (SMI) may play a role in the development of NAFLD. Our aim was to quantify the association between SMI, sarcopenia and the presence and severity of NAFLD. Methods We systematically searched English relevant studies from PubMed, Embase, the Web of Science and the Cochrane Library updated to December 20th, 2018. Studies in which SMI was compared between NAFLD cases and controls were included. So were studies concerning the odds ratio (OR) of NAFLD, non-alcoholic steatohepatitis (NASH) and significant fibrosis in sarcopenia patients. Pooled weighted mean differences and ORs were calculated. Results Of the 1331 retrieved studies, 19 articles were included. SMI level in NAFLD patients was 1.77 (95% CI 1.15, 2.39) lower than that in normal controls. We also found a significantly higher occurrence risk of NAFLD (OR = 1.33, 95% CI 1.20 to 1.48), NASH (OR = 2.42, 95% CI 1.27 to 3.57) and NAFLD-related significant fibrosis (OR = 1.56, 95% CI 1.34, 1.78) in sarcopenia subjects. Conclusions SMI level in patients with NAFLD was lower than healthy people, and patients with sarcopenia have higher occurrence risk of NAFLD, as well as its advanced stages including NASH or NAFLD-related significant fibrosis. Further well-designed prospective studies are required to strengthen the arguments.

The prognostic role of liver stiffness in patients with chronic liver disease: a systematic review and dose–response meta-analysis Abstract Background and aims Liver stiffness measurement (LSM) by transient elastography (TE) has been assessed for the evaluation of clinically relevant outcomes in patients with chronic liver diseases (CLDs) while with variable results. This systematic review and meta–analysis aims to investigate the relationship between baseline LSM by TE and the development of clinically relevant outcomes. Methods The systematic review identified eligible cohorts reporting the association between baseline LSM by TE and risk of hepatic carcinoma (HCC), hepatic decompensation (HD), all–cause and/or liver–related mortality and liver–related events (LREs) in CLD patients. Summary relative risks (RRs) with 95% confidence intervals (CIs) were estimated using a random–effect model. The dose–response association was evaluated by generalized least squares trend (Glst) estimation and restricted cubic splines. Commands of GLST, MKSPLINE, MVMETA were applied for statistical analysis. Results 62 cohort studies were finally included, reporting on 43,817 participants. For one kPa (kilopascal) increment in baseline liver stiffness (LS), the pooled RR (95% CI) was 1.08 (1.05–1.11) for HCC, 1.08 (1.06–1.11) for all–cause mortality, 1.11 (1.05–1.17) for liver-related mortality, 1.08 (1.06–1.10) for HD and 1.07 (1.04–1.09) for LREs. Furthermore, the nonlinear dose–response analysis indicated that the significant increase in the risk of corresponding clinically relevant outcomes turned to a stable increase or a slight decrease with increasing baseline LS changing primarily in the magnitude of effect rather than the direction. Conclusions The dose–response meta-analysis presents a combination between the levels of baseline LS and RRs for each clinically relevant outcome. TE, which is noninvasive, might be a novel strategy for risk stratification and identification of patients at high risk of developing these outcomes.

New treatment-induced adverse effects we need to learn as modern hepatologists

Hepatology through the crystal ball Abstract The rapidity of the increase in the global burden of liver disease covered in this review with estimates worldwide of 2 million deaths from cirrhosis and with no signs of effective controls being introduced for two of the main causes, namely, excess alcohol consumption and obesity, is of great concern. The 25% prevalence of non-alcoholic fatty liver disease in many population groups and the recent description of primary hepatocellular cancer (HCC) in obese subjects without underlying severe fibrosis/cirrhosis also raises many questions. In addition, covered in this review are more encouraging areas including techniques for machine preservation of donor organs enabling previously marginal organs to be used for transplantation. Greater knowledge of gut microbiome and gut bacterial translocation is defining the inflammatory reaction underlying multi-organ failure in decompensated cirrhosis. The gut microbiome also influences the response of HCC patients to the new check-point inhibitor drugs which restore immunological responses of its host.