Patients with end-stage liver disease (ESLD) have a compromised nutritional status because of the liver crucial role in regulating metabolic homeostasis and energy balance.

A systematic review of literature based on extensive relevant articles published from 2001 to 2017 in English in PubMed database was performed by searching keywords such as liver disease, non-alcoholic liver disease, alcoholic liver disease, malnutrition, epigenetics, gut microbiota, and probiotics.

Liver transplantation would be one eligible therapy for ESLD patients, even if, the clinical outcome is negatively influenced by malnutrition and/or infections. The malnutrition is a condition of nutrient imbalance with a high incidence in ESLD patients. An accurate evaluation of nutritional status could be fundamental for reducing complications and prolonging the survival of ESLD patients including those undergoing liver transplantation. In addition, the interaction among nutrients, diet and genes via epigenetics has emerged as a potential target to reduce the morbidity and mortality in ESLD patients. The malnutrition induces changes in gut microbiota causing dysbiosis with a probable translocation of bacteria and/or pathogen-derived factors from the intestine to the liver. Gut microbiota contribute to the progression of chronic liver diseases as well as hepatocellular carcinoma. The administration of probiotics modulating gut microbiota could improve all chronic liver diseases.

This review provides an update on malnutrition status linked to epigenetics and the potential benefit of some probiotics on the management of ESLD patients. In support of this view and to reveal the constant and growing interest in this field, some clinical trials are reported.

BACKGROUND: Chimeric antigen receptor-engineered T-cell (CAR-T) therapy is a newly developed immunotherapy used in the treatment of cancers. Because CAR-T therapy has shown great success in treating CD19-positive hematological malignancies, its application has been explored in the treatment of solid tumors, such as liver cancer. In this review, we discuss the immune characteristics of liver cancer, the obstacles encountered during the application of CAR-T therapy, and preclinical and clinical progress in the use of CAR-T therapy in patients with liver cancer.

DATA SOURCES: The data on CAR-T therapy related to liver cancers were collected by searching PubMed and the Web of Science databases prior to December 2017 with the keywords "chimeric antigen receptor", "CAR-T", "liver cancer", "hepatocellular carcinoma", and "solid tumor". Additional articles were identified by manual search of references found in the primary articles. The data for clinical trials were collected by searching ClinicalTrials.gov.

RESULTS: The liver has a tolerogenic nature in the intrahepatic milieu and its tumor microenvironment significantly affects tumor progression. The obstacles that reduce the efficacy of CAR-T therapy in solid tumors include a lack of specific tumor antigens, limited trafficking and penetration of CAR-T cells to tumor sites, and an immunosuppressive tumor microenvironment. To overcome these obstacles, several strategies have emerged. In addition, several strategies have been developed to manage the side effects of CAR-T, including enhancing the selectivity of CARs and controlling CAR-T activity. To date, no clinical trials of CAR-T therapy against HCC have been completed. However, preclinical studies in vitro and in vivo have shown potent antitumor efficacy. Glypican-3, mucin-1, epithelial cell adhesion molecule, carcinoembryonic antigen, and other targets are currently being studied.

CONCLUSIONS: The application of CAR-T therapy for liver cancer is just beginning to be explored and more research is needed. However, we are optimistic that CAR-T therapy will offer a new approach for the treatment of liver cancers in the future.

New-onset hyperglycemia (NOH) is a common phenomenon after liver transplantation (LT), but its impact on clinical outcomes has not yet been fully assessed. We aimed to evaluate the etiology and prognosis of NOH within 1 month after LT.

The data of 3339 adult patients who underwent primary LT from donation after citizen death between January 2010 and June 2016 were extracted from China Liver Transplant Registry database and analyzed. NOH was defined as fasting blood glucose ≥7.0?mmol/L confirmed on at least two occasions within the first post-transplant month with or without hypoglycemic agent.

Of 3339 liver recipients, 1416 (42.4%) developed NOH. Recipients with NOH had higher incidence of post-transplant complications such as graft and kidney failure, infection, biliary stricture, cholangitis, and tumor recurrence in a glucose concentration-dependent manner as compared to non-NOH recipients (P < 0.05). The independent risk factors of NOH were donor warm ischemic time >10?min, cold ischemic time >10?h, anhepatic time >60?min, recipient model for end-stage liver disease score >30, moderate ascites and corticosteroid usage (P?<?0.05). Liver enzymes (alanine aminotransferase and gamma-glutamyltranspeptidase) on post-transplant day 7 significantly correlated with NOH (P?<?0.001).

NOH leads to increased morbidity and mortality in liver recipients. Close surveillance and tight control of blood glucose are desiderated immediately following LT particularly in those with delayed graft function and receiving corticosteroid. Strategic targeting graft ischemic injury may help maintain glucose homeostasis.

Laparoscopic anatomic hepatectomy remains challenging because of the complex interior structures of the liver. Our novel strategy includes the Glissonian approach and the major hepatic vein first, which serves to define the external and internal landmarks for laparoscopic anatomic hepatectomy.

Eleven cases underwent laparoscopic anatomic hepatectomy, including three right hepatectomies, three left hepatectomies, three right posterior hepatectomies, and two mesohepatectomies. The Glissonian approach was used to transect the hepatic pedicles as external demarcation. The major hepatic vein near the hepatic portal was exposed and served as the internal landmark for parenchymal transection. The liver parenchyma below and above the major hepatic vein was transected along the major hepatic vein. Fifty-nine subjects were used to compare the distance between the major hepatic vein and secondary Glisson pedicles among different liver diseases.

The average operative time was 327 min with an estimated blood loss of 554.55 mL. Only two patients received three units of packed red blood cells. The others recovered normally and were discharged on postoperative day 7. The distance between right posterior Glissonian pedicle and right hepatic vein was shorter in the patients with cirrhosis than that without cirrhosis, and this distance was even shorter in patients with hepatocellular carcinoma.

The Glissonian approach with the major hepatic vein first is easy and feasible for laparoscopic anatomic hepatectomy, especially in patients with hepatocellular carcinoma and cirrhosis.

BACKGROUND: Postoperative complications may adversely affect oncological outcomes. The aim of this study was to evaluate the impact of postoperative complications on early-phase recurrence after curative resection for hepatocellular carcinoma (HCC).

METHODS: We included 145 HCC patients who underwent initial and curative resection between January 2004 and December 2013. Postoperative complications of grade III or higher based on Clavien-Dindo classification were defined as clinically relevant postoperative complications. Recurrence within two years after hepatectomy was defined as early-phase recurrence.

RESULTS: Thirty-eight patients (26%) developed postoperative complications. The only predictive factor for postoperative complication was longer operative duration (P?=?0.037). The disease-specific survival rate of patients with complication was lower than that of patients without complications (P?=?0.015). Early-phase recurrence was observed in 20/38 (53%) patients who suffered postoperative complications and 36/107 (34%) patients with no complications, which was statistically significant (P?=?0.039). Multivariate analysis identified four factors contributing to early-phase recurrence: high serum AFP level (P?=?0.042), multiple tumors (P?<?0.001), poor differentiation (P?=?0.036) and presence of postoperative complication (P?=?0.039).

CONCLUSIONS: Postoperative complication is an independent prognostic factor for early-phase recurrence after curative resection of HCC. Close observation of patients with postoperative complications may be a necessary treatment strategy for HCC.

Oxidative stress has been implicated in the progression of severe forms of non-alcoholic fatty liver disease (NAFLD). NADPH oxidase produces reactive oxygen species. In the present study, we investigated for the first time two single nucleotide polymorphisms (SNPs) in the regulatory region of genes encoding NADPH oxidase 4 (NOX4) and p22phox (CYBA) in NAFLD.

A total of 207 biopsy-proven NAFLD patients [simple steatosis (n?=?27); nonalcoholic steatohepatitis (NASH) (n?=?180)] were evaluated. Genomic DNA was extracted from peripheral blood cells, and polymorphisms in CYBA (unregistered) and NOX4 (rs3017887) were determined by direct sequencing of PCR.

Associations of CYBA-675 T/A with high-density lipoprotein (HDL) (TT vs TA vs AA; P?<?0.01) and triglycerides (TGL) (TT vs XA; P?<?0.01) were observed only in NASH patients. For polymorphisms in the NOX4 gene, NOX4 (rs3017887) CA?+?AA genotypes was significant associated with alanine aminotransferase (ALT) (CA?+?AA vs CC; P?=?0.02). However, there was no association of SNPs in the CYBA and NOX4 genes encoding the NADPH oxidase system proteins and the presence of NASH. Regarding the clinical results, it was observed that the most advanced degrees of fibrosis occurred in patients diagnosed with type 2 diabetes mellitus (66.9% vs 37.5%, P?<?0.01) and those who were more obese (32.2 vs 29.0?kg/m², P?<?0.01). In addition, serum glucose and insulin levels increased significantly in the presence of NASH.

There were associations between the presence of the allele A in the NOX4 SNP and a higher concentration of ALT in the NAFLD population; between the presence of the AA genotype in the polymorphism of the CYBA-675 T/A CYBA gene and a higher level of TGL and lower HDL in NASH patients. The presence of metabolic syndrome was associated with advanced degrees of fibrosis in NAFLD patients.

Accumulating evidence demonstrates that microRNAs (miRNAs) play essential roles in tumorigenesis and cancer progression of hepatocellular carcinoma (HCC). Average targets of a miRNA were more than 100. And one miRNA may act in tumor via regulating several targets. The present study aimed to explore more potential targets of miR-449a by proteomics technology and further uncover the role of miR-449a in HCC tumorigenesis.

Technologies such as iTRAQ-based quantitative proteomic were used to investigate the effect of miR-449a on HCC. The expression of c-Met and miR-449a was detected by qRT-PCR in HCC samples. Gain- and loss-of-function experiments were performed to identify the function and potential target of miR-449a in HCC cells.

In HCC, miR-449a was significantly downregulated, while c-Met was upregulated concurrently. Quantitative proteomics and luciferase reporter assay identified c-Met as a direct target of miR-449a. Moreover, miR-449a inhibited HCC growth not only by targeting CDK6 but also by suppressing c-Met/Ras/Raf/ERK signaling pathway. Furthermore, the inhibition of c-Met expression with a specific siRNA significantly inhibited cells growth and deregulated the ERK pathway in HCC.

The tumor suppressor miR-449a suppresses HCC tumorigenesis by repressing the c-Met/ERK pathway.

The histopathological examination of cholecystectomy specimens has not been standardized with a debate concerning the routine and the selective approach. The aim of this study was to assess the information obtained from routine histopathological examination of cholecystectomy specimens.

All histopathological reports of cholecystectomy specimens between January 2003 and December 2016 were analyzed, including a clinical diagnosis of benign gallstone disease or cholecystitis.

A total of 20,584 reports were examined. The mean age of patients was 54.2 years. Patients aged more than 60 years represent 37.6% of the study population. Of all patients, 15,973 (77.6%) were females. Incidental gallbladder cancers (GBC) were present in 155 cholecystectomies specimens (0.8%). 67.1% of GBC are at T2 and T3 stage. Granulomatous cholecystitis was diagnosed in only 19 cases (0.1%). GBC were more prevalent in older patients (P < 10^-6) and cholesterolosis was more prevalent in young patients (P < 10^-6). There was no gender predilection for GBC (P = 0.739).

The rate of incidental gallbladder carcinoma in our study is low, yet, we found a higher proportion of T2 and T3 carcinomas stage. Granulomatous cholecystitis may need further investigations and treatments. When a selective approch of histopathological examination of cholecystectomy specimens is used, it is important to take into account that clinical parameters are significantly associated with gallbladder cancer.

The International Study Group of Pancreatic Surgery (ISGPS) has defined two periods of postpancreatectomy hemorrhage, early (<24 h) and late (>24 h). A previously published Blood Usage Risk Score (BURS) aimed to predict early and late blood transfusion. The primary aim of this study was to define risk factors for early and late blood transfusion after pancreaticoduodenectomy. Secondary aims were to assess the predictive accuracy of the BURS.

In this retrospective observational study, multivariable analyses were used to identify independent risk factors for both early and late blood transfusion. The predictive ability of the BURS was then assessed using a receiver operating characteristic (ROC) curve analysis.

Among 628 patients, 99 (15.8%) and 144 (22.9%) received early and late blood transfusion, respectively. Risk factors for blood transfusion differed between early and late periods. Preoperative anemia and venous resection were associated with early blood transfusion whilst Whipple's resection (as opposed to pylorus preserving pancreaticoduodenectomy), lack of biliary stent and a narrow pancreatic duct were predictors of late blood transfusion. The BURS was significantly predictive of early blood transfusion, albeit with a modest degree of accuracy (AUROC: 0.700, P < 0.001), but not of late blood transfusion (AUROC: 0.525, P = 0.360). Late blood transfusion was independently associated with increasing severity of postoperative pancreatic fistula (POPF) (OR: 1.85, 3.18 and 9.97 for biochemical, types B and C POPF, respectively, relative to no POPF).

Two largely different sets of variables are related to early and late blood transfusion following pancreaticoduodenectomy. The BURS was significantly associated with early, albeit with modest predictive accuracy, but not late blood transfusion. An understanding of POPF risk allows assessment of the need for late blood transfusion.

We read with great interest the article by Yang et al.[1] evaluating the effects of postoperative serum total cholesterol (sTC) changes on early allograft dysfunction and survival after living donor liver transplantation (LDLT). By multivariate regression analysis, they showed that patients with sTC <1.42 mmol/L on postoperative day 3 had 4.08-fold and 2.72-fold greater risks of developing allograft dysfunction and 90-day mortality, and patients with sTC <1.42 mmol/L had poorer overall recipient and graft survival rates at 1-, 3-, and 5-year compared with those with sTC ≥1.42 mmol/L. Thus, they concluded that postoperative sTC <1.42 mmol/L is an independent risk factor of short- and long-term adverse outcomes after LDLT. However, this is a retrospective study, which can introduce a number of potential confounders. Other than the limitations described in discussion section, we noted that some methodological issues seem important to avoid any optimistic interpretation or misinterpretation of results.

We thank Dr. Fu-Shan Xue et al. for the opportunity to discuss the article we recently published in Hepatobiliary Pancreat Dis Int  [1] . They claim that the study setting is not strong enough to prove the statistical association between a low postoperative sTC and increased postoperative adverse outcome. It is true that many different factors can affect outcomes after living donor liver transplantation (LDLT). Recipient and donor characteristics as well as intraoperative and postoperative complications may lead to adverse short- and long-term outcomes. Actually, we have taken well-known risk factors affecting postoperative outcome including recipient, donor and intraoperative aspects in our univariate analysis. Eight of the examined variables related to postoperative early allograft dysfunction (EAD) based on the univariate analysis were entered into the multivariate analysis. And in this study setting, postoperative complications set as the outcome parameters were not taken into the univariate analysis and multivariate analysis model.