BACKGROUND: Hepatocellular carcinoma (HCC) is a complex and heterogeneous malignancy, frequently occurs in the setting of a chronically diseased organ, with multiple confounding factors making its management challenging. HCC represents one of the leading causes of cancer-related mortality globally with a rising trend of incidence in some of the developed countries, which indicates the need for better surgical and nonsurgical management strategies.
DATA SOURCES: PubMed database was searched for relevant articles in English on the issue of HCC management.
RESULTS: Surgical resection represents a potentially curative option for appropriate candidates with tumors detected at earlier stages and with well-preserved liver function. The long-term outcome of surgery is impaired by a high rate of recurrence. Surgical approaches are being challenged by local ablative therapies such as radiofrequency ablation and microwave ablation in selected patients. Liver transplantation offers potential cure for HCC and also correction of underlying liver disease, and minimizes the risk of recurrence, but is reserved for patients within a set of criteria proposed for a prudent allocation in the shortage of donor organs. Transcatheter locoregional therapies have become the palliative standard allowing local control for intermediate stage patients with noninvasive multinodular or large HCC who are beyond the potentially curative options. The significant survival benefit with the multikinase inhibitor sorafenib for advanced HCC has shifted the direction of research regarding systemic treatment toward molecular therapies targeting the disregulated pathways of hepatocarcinogenesis. Potential benefit is suggested from simultaneous or sequential multimodal therapies, and optimal combinations are being investigated. Despite the striking progress in preclinical studies of HCC immunotherapy and gene therapy, extensive clinical trials are required to achieve successful clinical applications of these innovative approaches.
CONCLUSION: Treatment decisions have become increasingly complex for HCC with the availability of multiple surgical and nonsurgical therapeutic options and require a comprehensive, multidisciplinary approach.

BACKGROUND: Bone marrow mesenchymal stem cells (BMMSCs) exert immunosuppressive activities in transplantation. This study aimed to determine whether BMMSCs reduce acute rejection and improve outcomes of liver transplantation in rats.
METHODS: Orthotopic liver transplantation from Lewis to Brown Norway rats was performed, which was followed by the infusion of BMMSCs through the penile superficial dorsal vein. Normal saline infusion was used as a control. Animals were sacrificed at 0, 24, 72, or 168 hours after BMMSCs infusion. Liver grafts, and recipient serum and spleen tissues were obtained. Histopathology, apoptosis, serum liver enzymes, serum cytokines, and circulating regulatory T (Treg), Th1, Th2 and Th17 cells were assessed at each time point.
RESULTS: BMMSCs significantly attenuated acute rejection and improved the survival rate of allogeneic liver transplantation recipients. Liver enzymes and liver apoptosis were significantly alleviated. The levels of the Th1/Th2 ratio-associated cytokines such as IL-2 and IFN-γ were significantly reduced and IL-10 was significantly increased. The levels of the Th17/Tregs axis-associated cytokines such as IL-6, IL-17, IL-23, and TNF-α were significantly reduced, whereas TGF-β concentration was significantly increased. Moreover, flow cytometry analysis showed that the infusion of BMMSCs significantly increased Th2 and Treg cells and decreased Th1 and Th17 cells.
CONCLUSION: BMMSCs had immunomodulatory effects, attenuated acute rejection and improved outcomes of allogeneic liver transplantation in rats by regulating the levels of cytokines associated with Th1/Th2 and Th17/Treg ratios.

BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) after curative resection remains a major cause of treatment failure and tumor-related death. Patterns of HCC recurrence can be categorized into early recurrence and late recurrence which have different underlying mechanisms. In this study, we investigated if simple inflammation-based clinical markers can distinguish patterns of recurrence after curative resection of HCC.
METHODS: A retrospective analysis of 223 patients who underwent curative hepatectomy for HCC was performed. Preoperative inflammation-based factors including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio, γ-glutamyl transferase/alanine aminotransferase ratio, aspartate aminotransferase/platelet ratio index (APRI) and prognostic nutritional index together with other clinicopathologic parameters were evaluated by univariate analysis and multivariate analysis to identify independent prognostic factors. By combining risk factors, predictive models were established to distinguish populations at high risk of early or late recurrence.
RESULTS: Age ≤50 years, resection margin ≤1 cm, TNM stage III-IV, NLR>2.75, APRI>0.23 and positive alpha-fetoprotein were independent adverse prognostic factors for early recurrence. Patients with three or more risk factors were at significant higher risk of early recurrence. APRI>0.23 and positive hepatitis B e antigen (HBeAg) were independent risk factors of late recurrence, the coexistence of high APRI and positive HBeAg increased the risk of late recurrence.
CONCLUSIONS: Preoperative inflammation-based prognostic factors predict early and late recurrence of HCC after curative resection. Different prognostic factor combinations distinguish high-risk populations of early or late HCC recurrence.

BACKGROUND: Plasma exchange (PE)-centered artificial liver support system reduced the high mortality rate of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). But the data were diverse in different medical centers. The present prospective nationwide study was to evaluate the effects of PE on patients with HBV-ACLF at different stages.
METHODS: From December 2009 to December 2011, we evaluated 250 patients at different stages of HBV-ACLF from 10 major medical centers in China. All the laboratory parameters were collected at admission, before and after PE.
RESULTS: Among the 250 patients who underwent 661 rounds of PE, one-month survival rate was 61.6%; 141 (56.4%) showed improvement after PE. Variables such as age (P=0.000), levels of total bilirubin (TB, P=0.000), direct bilirubin (P=0.000), total triglycerides (P=0.000), low-density lipoprotein (P=0.022), Na+ (P=0.014), Cl– (P=0.038), creatinine (Cr, P=0.007), fibrinogen (P=0.000), prothrombin time (PT, P=0.000), white blood cell (P=0.000), platelet (P=0.003) and MELD (P=0.000) were significantly related to prognosis. Multivariate logistic regression analysis showed that age, disease stage, TB, Cr and PT levels were independent risk factors of mortality among HBV-ACLF patients.
CONCLUSIONS: PE can improve the clinical outcome of patients with HBV-ACLF. Levels of TB, Cr and PT, age and disease stage help to predict prognosis.

BACKGROUND: Increasing evidence indicates that downregulation of cell adhesion molecule 1 (CADM1) contributes to tumorigenesis in various cancers. The present study was undertaken to investigate the CADM1 expression pattern in human hepatocellular carcinoma (HCC), and to elucidate the mechanism underlying CADM1-mediated tumor suppression.
METHODS: CADM1 expression in HCC cell lines was measured by quantitative real-time PCR. The function of CADM1 in the context of tumor suppression in HCC cells was determined using proliferation assays, cell cycle analysis, EdU incorporation assays, in vitro colony formation analysis, and in vivo tumorigenicity assays. The mechanism by which CADM1 acts as a tumor suppressor gene in HCC was investigated using Western blotting analysis.
RESULTS: Downregulation of CADM1 expression is frequently detected in both HCC cells and clinical samples. Restoration of CADM1 expression in HCC cell lines significantly inhibits cell growth and negatively regulates the G1/S transition. CADM1 overexpression can inhibit the tumorigenicity of HCC cells both in vitro and in vivo. Western blotting analysis revealed that ectopic expression of CADM1 in HCC cells is associated with increased expression of Retinoblastoma (Rb) protein.
CONCLUSIONS: Our results showed that suppression of tumorigenesis by CADM1 may be mediated by the Rb-E2F pathway, involving upregulation of Rb protein levels. This pathway could therefore represent an attractive target for HCC therapy.

BACKGROUND: Mannose-binding lectin 2 (MBL2) plays a key role in the host immune response, but whether it is associated with hepatocellular carcinoma (HCC) is not clear. The present study aimed to identify the association between MBL2 gene polymorphisms and HCC in patients with hepatitis B virus (HBV)-related cirrhosis in the Chinese population.
METHODS: A single-nucleotide polymorphism of MBL2, rs11003123, was genotyped and analyzed in a case-control study of HBV-related cirrhotic patients with HCC (n=77) and without HCC (n=40).
RESULTS: We found that Child-Pugh profiles, model for end-stage liver disease score, and the incidence of encephalopathy were all higher in the non-HCC group (P<0.05). A significant association between allele mutants and HCC occurrence was demonstrated by allele comparison (A vs G) (OR=0.34; 95% CI: 0.15-0.76; P=0.006). Heterozygous comparison (GA vs GG) revealed that the individuals with GA mutants had a reduced risk of HCC occurrence compared with those with GG wild type (adjusted OR=0.28; 95% CI: 0.10-0.80; P=0.004). In a dominant model (GA+AA vs GG), a decreased risk of HCC occurrence was observed in individuals with variant genotypes (GA and AA) compared with those with the wild type (adjusted OR=0.30; 95% CI: 0.11-0.85; P=0.004). However, no statistically significant associations were observed between rs11003123 and prognosis of patients with HCC after liver transplantation in both recurrence-free survival and overall survival (P=0.449 and P=0.384, respectively).
CONCLUSION: MBL2 rs11003123 polymorphism may be a marker for the risk of HCC occurrence in patients with HBV-related cirrhosis in the Chinese population.

BACKGROUND: Definitive therapy for gallstone pancreatitis requires eradication of gallstones with cholecystectomy and common bile duct (CBD) clearance. Current guidelines recommend this be done within the same admission and preferably by laparoscopic cholecystectomy and CBD exploration. We report our experience of laparoscopic single-stage management with cholecystectomy and intraoperative cholangiogram followed by laparoscopic bile duct exploration (LBDE) when necessary performed at three different stages.
METHODS: From January 1998 to December 2012, 134 patients (100 females and 34 males) underwent single-stage laparoscopic management of gallstone pancreatitis. Patients were classified according to the timing of surgery: “A”,  ≤7 days from symptom onset (n=27); “B”, 8 to 30 days (n=58) and “C”, >30 days (n=49).
RESULTS: LBDE was performed in 30 patients with a success rate of 100%. CBD stones were found in 25 patients (A: 22.2%, B: 22.4%, C: 12.2%). CBD stones were more common in patients undergoing surgery within 30 days of presentation than after this time point (P=0.35). Multiple choledocholithiasis was more frequent in patients treated within 7 days (P=0.04). The 30-day mortality after surgery was 0, with no conversion to an open approach. Overall complication rate was 11.9%, which did not differ significantly between patients treated within 7 days or after this time point (P=0.83).
CONCLUSIONS: This study demonstrated the feasibility and reproducibility of single-stage laparoscopic management of acute gallstone pancreatitis, which has a low complication rate at any stage. Patients undergoing early treatment have a higher incidence of choledocholithiasis and multiple stones than those treated after 30 days, supporting the passage of stones with time.

BACKGROUND: Early diagnosis of postoperative pancreatic fistula (POPF) is important for proper interventions. The preoperative, intraoperative and early postoperative biochemical markers have predictive value of POPF. The present study was to evaluate several simple biochemical parameters in the prediction of POPF.
METHODS: Patients who underwent pancreaticoduodenectomy in our center between 2006 and 2015 were reviewed retrospectively. Preoperative and early postoperative biochemical parameters were evaluated. Additionally, the relationship between POPF and pH and lactate level at the end of surgery were analyzed, and neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and red cell distribution width-to-platelet ratio (RPR) were calculated for postoperative days (PODs) 1 and 3. Diagnosis and grading of POPF were performed according to the standards of the International Study Group on Pancreatic Fistula. The patients were divided into two groups: Group 1 with no fistula or grade-A fistula; group 2 with grade-B or -C fistula. These simple biochemical markers were then compared between the two groups.
RESULTS: Serum amylase level was significantly higher at POD3, and pH level was significantly lower at the end of operation in group 2 compared with those in group 1. However, the serum amylase was below the upper limit of normal serum level and therefore, the difference was not significant in clinical practice. Receiver operating charecteristic curve analysis showed that pH level was a reliable predictor of POPF (area under the curve: 0.713; 95% CI: 0.573-0.853).
CONCLUSIONS: A low pH level at the end of pancreaticoduodenectomy was a risk factor of POPF. NLR, PLR, and RPR had no predictive value of POPF after pancreaticoduodenectomy.

BACKGROUND: The Atlanta criteria for acute pancreatitis (AP) has been revised recently. This study was to evaluate its practical value in classification of AP, the severity assessment and management.
METHODS: The clinical features, severity classification, outcome and risk factors for mortality of 3212 AP patients who had been admitted in Ruijin Hospital from 2004 to 2011 were analyzed based on the revised Atlanta criteria (RAC) and the original Atlanta criteria (OAC).
RESULTS: Compared to the OAC group, the incidence of severe acute pancreatitis (SAP) was decreased by approximately one half (13.9% vs 28.2%) in the RAC group. The RAC presented a lower sensitivity but higher specificity, and its predictive value for severity and poor outcome was higher than those of the OAC. The proportion of SAP diagnosis and ICU admission in the early phase in the RAC group was significantly lower than that in the OAC group (P<0.05). Based on the RAC, the risk factors for death among SAP patients were older age, high CT severity index (CTSI), renal failure, cardiovascular failure, acute necrotic collection and walled-off necrosis. Compared to the OAC, the acute physiology and chronic health evaluation II (APACHE II) score, Ranson score, idiopathic etiology, respiratory failure and laparotomy debridement were not risk factors of death in contrast to walled-off necrosis. Interestingly, hypertriglyceridemia-related SAP had good outcomes in both groups.
CONCLUSIONS: The RAC showed a higher predictive value for severity and poorer outcome than the OAC. However, the RAC resulted in fewer ICU admissions in the early phase due to its lower sensitivity for diagnosis of SAP. Among SAP cases, older age, high CTSI, renal and cardiovascular failure, complications of acute necrotic collection and walled-off necrosis were independent risk factors for mortality.

Anti-virus prophylactic therapy may be not necessary for the prevention of hepatitis B virus (HBV) recurrence after HBV-related liver transplantation (LT). However, studies on completely stopping the hepatitis B immune globulin (HBIG) and nucleos(t)ide analogs (NUC) after LT are few. The aim of the current study was to evaluate the safety of anti-virus prophylaxis withdrawal in liver recipients whose serum hepatitis B e antigen (HBeAg) and HBV DNA are negative. We analyzed 190 patients undergone LT for HBV-related liver disease from 2006 to 2012 and found that 10 patients completely stopped the HBIG and NUC due to poor compliance. These patients were liver biopsied and checked monthly with serum HBV markers, HBV DNA and liver function. Among the 10 patients, 9 did not show the signs of HBV recurrence after a mean follow-up of 51.6 months (range 20-73) after withdrawal of the HBIG and NUC. The average time from LT to the withdrawal of the anti-virus drug was 23.8 (13-42) months; one patient showed hepatitis B surface antigen-positive and detectable HBV DNA after stopping anti-virus drugs and this patient was successfully treated with entecavir. Our data suggested that complete withdrawal of anti-virus prophylaxis was safe and feasible for patients whose serum HBeAg and HBV DNA were negative at the time of LT.

Patients with hepatocellular carcinoma have a very short life expectancy if they receive no surgical intervention. A relatively new surgical technique termed “Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy” (ALPPS) has been employed for inducing rapid hypertrophy of the future liver remnant for patients waiting for hepatectomy. As portal vein embolization may not result in satisfactory hypertrophy before tumor progression occurs, ALPPS can be an alternative for patients with advanced hepatocellular carcinoma. Herein we describe an ALPPS procedure with tumor thrombectomy for a patient who had a small left liver lobe and a large hepatocellular carcinoma involving the whole right liver lobe and the middle hepatic vein and extending into the inferior vena cava. In the first-stage operation, the right portal vein was controlled and divided with a Hemolock. The right hepatic artery was well protected. Hepatic transection was performed with a 1-cm margin from the tumor. The middle hepatic vein trunk was preserved. Ten days afterwards, there was significant hypertrophy of the left lateral section of the liver, and the second-stage operation was conducted. Extended right hepatectomy and tumor thrombectomy were performed under sternotomy and total vascular exclusion. The patient had good recovery and was free of disease 10 months after the operation. ALPPS may be a good treatment option even for patients with advanced disease if carried out at high-volume centers.

Pancreatico-jejunal anastomosis after pancreatoduodenectomy still represents the Achilles’ heel of the procedure: the failure of this anastomosis is relatively common and it is the main cause of post-operative morbidity and mortality. Studies have described different reconstruction strategies for the control of the development of post-operative pancreatic fistula, but the strategy to obtain a safer pancreatico-jejunal anastomosis is still far from satisfaction. We report a novel variation of the invagination technique based on preliminary clinical experience in 8 patients who underwent pancreatico-jejunal anastomosis after pancreatoduodenectomy in our hepatobiliopancreatic center from 2008 to 2014. The variation could obtain a safer intestinal invagination for a solid pancreatico-jejunal anastomosis even in the presence of soft pancreatic remnant.

Intrahepatic portosystemic shunts (IPSS) are rare congenital anomalies arising from disordered portal vein embryogenesis. It has been described in both children and adults and may be asymptomatic or be associated with a variety of neurophysiological and pulmonary complications. When recognized, early intervention to occlude the shunt will reverse the associated complications. Literature review reports of surgical and radiological occlusion of the shunt, but due to its rarity, a standard therapeutic protocol has not been established. A case of a 38-year-old woman with abdominal pain and low grade encephalopathy, diagnosed with an IPSS and treated by right hepatectomy was reported.