BACKGROUND: Sorafenib has become the standard first-line treatment for patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the efficacy and safety of sorafenib in advanced HCC patients and explore its true value for specific subgroups.
DATA SOURCES: A computer-based systematic search from January 2005 to June 2011 with "sorafenib" and "advanced hepatocellular carcinoma" as search terms was performed for possible clinical trials. Hazard ratios (HR) and their 95% confidence intervals (CI) for overall survival (OS) and time to progression (TTP), rates of partial response (PR), rates of toxicity effects, and details of subgroup analysis were extracted. Meta-analyses were done using the software Review Manager (version 5.0).
RESULTS: Six trials with 1164 patients were included. Based on three randomized controlled trials, the pooled HR (sorafenib/placebo) was 0.66 for OS (95% CI: 0.56-0.78; P<0.00001) and 0.57 for TTP (95% CI: 0.47-0.68; P<0.00001). The pooled odds ratio (OR) for PR was 2.96 (95% CI: 0.96-9.15; P=0.06). For three single-arm trials, the pooled HR was 0.69 for OS (95% CI: 0.56-0.84; P=0.0002) and 0.64 for TTP (95% CI: 0.52-0.78; P<0.00001). The pooled OR for PR in three single-arm trials was 3.56 (95% CI: 1.22-10.39; P=0.02). Subgroup analysis indicated that sorafenib was less effective in patients with extrahepatic spread (with: P=0.13 vs without: P<0.0001), with normal alpha-fetoprotein level (AFP) (P=0.15 vs elevated: P=0.0006), and with elevated level of serum bilirubin (P=0.06 vs normal: P=0.0009). Sorafenib-based therapy significantly increased the risk of grade 3/4 hand-foot skin reaction, diarrhea, fatigue, and rash/desquamation.
CONCLUSIONS: Sorafenib-based therapy benefits advanced HCC patients. Meanwhile, sorafenib is less effective for patients with extrahepatic spread, with normal AFP level and with elevated level of bilirubin.

BACKGROUND: Organ fibrosis has been viewed as one of the major medical problems, which can lead to progressive dysfunction of the liver, lung, kidney, skin, heart, and eventually death of patients. Fibrosis is initiated by a variety of pathological, physiological, biochemical, and physical factors. Regardless of their different etiologies, they all share a common pathogenetic process: excessive activation of the key profibrotic cytokine, transforming growth factor-β (TGF-β). Peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated transcription factor of the nuclear receptor superfamily, has received particular attention in recent years, because the activation of PPARγ by both natural and synthetic agonists could effectively inhibit TGF-β-induced profibrotic effects in many organs.
DATA SOURCES: The English-language medical databases, PubMed, Elsevier and SpringerLink were searched for articles on PPARγ, TGF-β, and fibrosis, and related topics.
RESULTS: TGF-β is recognized as a key profibrotic cytokine. Excessive activation of TGF-β increases synthesis of extracellular matrix proteins and decreases their degradation, associated with a gradual destruction of normal tissue architecture and function, whereas PPARγ agonists inhibit TGF-β signal transduction and are effective antifibrogenic agents in many organs including the liver, lung, kidney, skin and heart.
CONCLUSIONS: The main antifibrotic activity of PPARγ agonists is to suppress the TGF-β signaling pathway by so-called PPARγ-dependent effect. In addition, PPARγ agonists, especially 15d-PGJ2, also exert potentially antifibrotic activity independent of PPARγ activation. TGF-β1/Smads signaling not only plays many essential roles in multiple developmental processes, but also forms cross-talk networks with other signal pathways, and their inhibition by PPARγ agonists certainly affects the cytokine networks and causes non-suspected side-effects. Anti-TGF-β therapies with PPARγ agonists may have to be carefully tailored to be tissue- and target gene-specific to minimize side-effects, indicating a great challenge to the medical research at present.

BACKGROUND: Hemosuccus pancreaticus (HP) is defined as upper gastrointestinal (GI) hemorrhage from the papilla of Vater via the pancreatic duct and is a rare cause of digestive bleeding.
DATA SOURCE: A PubMed search of relevant articles published from January 1967 to September 2011 was performed to identify current information about HP in terms of its etiology, pathophysiology, clinical presentation, diagnosis and management. 
RESULTS: A variety of etiological factors, most commonly chronic pancreatitis but also tumors and vascular diseases, can lead to this condition. Appropriate endoscopic or radiologic procedures should be chosen to establish a precise diagnosis for patients, especially those with a known history of pancreatic disorders, who present with abdominal pain, GI hemorrhage and hyperamylasemia. There are two main therapeutic options for this condition: angiographic embolotherapy and surgery. Both treatments can stop bleeding, but angiographic embolotherapy is the treatment of choice for stable patients. Recently, new and less invasive treatments have emerged to treat this condition.
CONCLUSIONS: Because of its rarity and broad spectrum of causes, HP is difficult to diagnose accurately. However, appropriate endoscopic and radiologic procedures are extremely helpful for establishing a correct diagnosis. Both angiographic embolotherapy and surgery are reliable treatment options for this condition, and transcatheter intervention is the treatment of choice for clinically stable patients. Additional innovative treatments have emerged, but their effectiveness and safety must be confirmed.

BACKGROUND: Whether splenectomy can be performed simultaneously during liver transplantation in patients with end-stage liver diseases complicated by hypersplenism remains controversial. This study aimed to compare the impact of simultaneous splenectomy on high- and low-risk liver transplant patients with end-stage liver diseases and severe hypersplenism.
METHODS: Forty-two patients with end-stage liver diseases complicated by severe hypersplenism who had undergone orthotopic liver transplantation were enrolled in this study. Splenectomy was performed in 19 of the patients. The 42 patients were grouped according to the risk of liver diseases and operations they received. Patients were considered to be at high-risk if they had at least one of the following conditions: preoperative prothrombin time >5 seconds, portal vein thrombosis, and severe perisplenitis. High-risk patients who had undergone splenectomy were classified into group A, whereas high-risk patients who had not undergone splenectomy were classified into group B. Low-risk patients who had undergone splenectomy were classified into group C, and low-risk patients who had spleen preservation were classified into group D. Operative time, intraoperative blood loss, postoperative bleeding, pulmonary infection, perioperative mortality, and postoperative platelet recovery were analyzed.
RESULTS: Operative time and intraoperative blood loss were greater in group A than in groups B-D (P<0.01), but there was no significant difference between groups C and D (P>0.05). In group A, 3 patients had postoperative bleeding, 5 had pulmonary infection, and 2 had perioperative mortality, which was higher than any other group, but postoperative bleeding, pulmonary infection, and perioperative mortality were similar to those in groups C and D. In patients undergoing simultaneous splenectomy, platelet counts recovered within 6 months after surgery. Thrombocytopenia was sustained in 3 of the 23 patients who did not undergo simultaneous splenectomy.
CONCLUSION: Splenectomy should be avoided during orthotopic liver transplantation in high-risk patients, but this procedure does not increase the operative risk in low-risk patients and may be a valuable method to ensure good postoperative platelet recovery.

BACKGROUND: A major barrier to the clinical application of xenotransplantation as a treatment option for patients is T cell-mediated rejection. Studies based on experimental rodent models of xenograft tolerance or rejection in vivo have provided useful information about the role of T cell immune response in xenotransplantation. However not all observations seen in rodents faithfully recapitulate the human situation. This study aimed to establish a humanized mouse model of xenotransplantation, which mimics xenograft rejection in the context of the human immune system.
METHODS: NOD-SCID IL2rγ-/- mice were transplanted with neonatal porcine islet cell clusters (NICC) followed by reconstitution of human peripheral blood mononuclear cells (PBMC). Human leukocyte engraftment and islet xenograft rejection were confirmed by flow cytometric and histological analyses. 
RESULTS: In the absence of human PBMC, porcine NICC transplanted into NOD-SCID IL2rγ-/- mice revealed excellent graft integrity and endocrine function. Human PBMC demonstrated a high level of engraftment in NOD-SCID IL2rγ-/- mice. Reconstitution of NICC recipient NOD-SCID IL2rγ-/- mice with human PBMC led to the rapid destruction of NICC xenografts in a PBMC number-dependent manner.
CONCLUSIONS: Human PBMC-reconstituted NOD-SCID IL2rγ-/- mice provide an ideal model to study human immune responses in xenotransplantation. Studies based on this humanized mouse model will provide insight for improving the outcomes of clinical xenotransplantation.

BACKGROUND: The relationship between cytokines and responses to peginterferon α-2a treatment in chronic hepatitis B patients has not yet been fully elucidated. We analyzed the serum levels of interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, vascular endothelial growth factor, interferon-γ, tumor necrosis factor-α, monocyte chemotactic protein-1 (MCP1) and epidermal growth factor during the treatment with peginterferon α-2a.
METHODS: Ninety-three serum samples from 20 chronic hepatitis B patients were collected before, during and after 48 weeks of peginterferon therapy and were assayed for 12 cytokines. The patients were categorized as either virologic responders (VRs) or non-responders (NRs) according to their HBV DNA levels taken at 6th month during treatment. The Evidence Investigator (Randox, Antrim, UK), a protein chip analyzer, was used to quantify cytokines.
RESULTS: Among the 12 cytokines, the levels of MCP1 were increased and the levels of IL-4 were decreased during the treatment in VRs. However these cytokines were not significantly changed in NRs in the treatment phases. Area under the receiver operating characteristic curve (AUROC) value of HBV DNA measured before the treatment was 0.81 in predicting VRs, and that of the baseline MCP1 was 0.76. IL-6 levels at 3rd and 6th months during the treatment also showed AUROC values 0.85 and 0.78 respectively in predicting sustained VRs.
CONCLUSION: Serum cytokine levels reflect the pathological differences of individual treatment phases and could also be useful in monitoring responses to peginterferon treatment in chronic hepatitis B patients.

BACKGROUND: Postoperative hepatic failure is a dreadful complication after major hepatectomy and carries high morbidity and mortality rates. In this study, we assessed the accuracy of the 50/50 criteria (bilirubin >2.9 mg/dL and international normalized ratio >1.7 on postoperative day 5) and the Mullen criteria (bilirubin peak >7 mg/dL on postoperative days 1-7) in predicting death from hepatic failure in patients undergoing right hepatectomy only. In addition, we identified prognostic factors linked to intra-hospital morbidity and mortality in these patients.
METHODS: One hundred seventy consecutive patients underwent major right hepatectomy at a tertiary medical center from 2000 to 2008. Nineteen (11.2%) patients suffered from liver cirrhosis. Univariate and multivariate analyses were performed to identify predictors of intra-hospital mortality, morbidity and death from hepatic failure.
RESULTS: The intra-hospital mortality was 6.5% (11/170). Of the six patients who died from hepatic failure, one was positive for the 50/50 criteria, but all six patients were positive for the Mullen criteria. Multivariate analysis showed that male gender, hepatitis C (HCV), hepatocellular carcinoma, postoperative bilirubin >7 mg/dL and ALT<188 U/L on postoperative day 1 were predictive of death from hepatic failure in the postoperative period. Age >65 years, HCV, reoperation, and renal failure were significant predictors of overall intra-hospital mortality on multivariate analysis.
CONCLUSIONS: The Mullen criteria were more accurate than the 50/50 criteria in predicting death from hepatic failure in patients undergoing right hepatectomy. A bilirubin peak >7 mg/dL in the postoperative period, HCV positivity, hepatocellular carcinoma, and an ALT level <188 U/L on postoperative day 1 were associated with death from hepatic failure in our patient population.

BACKGROUND: Controversy exists about the correlation between liver ultrasonography and serum parameters for evaluating the severity of liver involvement in non-alcoholic fatty liver disease (NAFLD). This study was designed to determine the association between liver ultrasonography staging in NAFLD and serum parameters correlated with disease severity in previous studies; and set optimal cut-off points for those serum parameters correlated with NAFLD staging at ultrasonography, in order to differentiate ultrasonographic groups (USGs).
METHODS: This cross-sectional study evaluated outpatients with evidence of NAFLD in ultrasonography referred to a general hospital. Those with positive viral markers, abnormal serum ceruloplasmin or gamma-globulin concentrations were excluded. A radiologist performed the ultrasonography staging and stratified the patients into mild, moderate, and severe groups. Fasting serum alanine aminotransferase (ALT), aspartate aminotransferase, alkaline phosphatase, triglyceride (TG), high and low density lipoprotein (HDL, LDL), and cholesterol were checked.
RESULTS: Two hundred and forty-five patients with a mean age (±standard deviation) of 41.63(±11.46) years were included. There were no significant differences when mean laboratory concentrations were compared between moderate and severe USGs. Therefore, these groups were combined to create revised USGs ("mild" versus "moderate or severe"). There were associations between the revised USGs, and ALT, TG, HDL levels, and diabetes mellitus [odds ratios=2.81 (95% confidence interval (CI): 1.37-5.76), 2.48 (95% CI: 1.29- 4.78), 0.36 (95% CI: 0.18-0.74), and 5.65 (95% CI: 2.86-11.16) respectively; all P values <0.01]. A cut-off value of 32.5 mg/dL for ALT gave a sensitivity of 70% and a specificity of 62%, for differentiating between the revised USGs.
CONCLUSIONS: Serum ALT, TG, and HDL concentrations seem to be associated with the staging by liver ultrasonography in NAFLD. They might be used to predict the staging of liver ultrasonography in these patients.

BACKGROUND: Ischemia/reperfusion (I/R) injury is an important barrier to liver surgery and transplantation because it impairs remnant liver/reduced-size-graft regeneration. Ischemic preconditioning (IPC), as an effective measure to overcome I/R injury, has been shown to enhance the regenerative capacity of hepatocytes. However, investigations have always focused on regeneration in the late phase after reperfusion. This study aimed to investigate whether IPC enhances hepatocyte proliferation in the early phase after reperfusion and possible underlying mechanisms.
METHODS: A total of 90 rats were divided into three groups: hemi-hepatectomy alone (PHx group), 60 minutes of ischemia plus hemi-hepatectomy (I/R group), and a cycle of 10 minutes of alternating I/R prior to 60 minutes of ischemia plus hemi-hepatectomy (IPC group). Each group was divided into five subgroups sacrificed after 0.5, 2, 6, 12 or 24 hours (n=6/subgroup). Subsequently, serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) were measured; caspase-3 and proliferating cell nuclear antigen (PCNA) proteins were also determined by Western blotting. Furthermore, PCNA was detected by immunohistochemistry to identify the expression site.
RESULTS: Serum ALT and AST levels after 2-24 hours of reperfusion in the PHx and IPC groups were remarkably decreased compared to the I/R group, and the serum TNF-α was relatively lower. A significant increase of serum IL-6 levels was found in the PHx and IPC groups compared with the I/R group at each time point. Furthermore, PCNA expression was remarkably increased in the IPC group after 6-12 hours of reperfusion, and in the earlier 0.5 and 6 hours time points after reperfusion have shown the massive PCNA-positive hepatocytes. At the same time, the expression of liver p-JNK was higher in the IPC group in the early phase after reperfusion than that of the I/R group and its expression was consistent with the PCNA.
CONCLUSION: IPC can initiate hepatocyte proliferation in the early phase after ischemia under hemi-hepatectomy, and may be associated with p-JNK expression and triggered by TNF-α/IL-6 signals.

BACKGROUND: Gastrin has a cholecystokinetic action on gallbladder motility, and cholecystokinin and gastrin act directly on the smooth muscle of the gallbladder. The aim of this study was to investigate the effect of endogenous hypergastrinemia on gallbladder motility in patients with autoimmune gastritis.
METHODS: Forty-one patients (29 females, 12 males; mean age, 46 years) with autoimmune gastritis and 29 healthy subjects (17 females, 12 males; mean age, 44.8 years) were enrolled in the study. Fasting and postprandial gallbladder volumes were measured ultrasonographically with the ellipsoid technique and the ejection fraction of the gallbladder was calculated from fasting and postprandial volumes. All subjects were investigated after 12 hours of fasting and 30 minutes after a standard test meal.
RESULTS: The gallbladder ejection fraction (%) of the patients with autoimmune gastritis was lower than that of the control group (46.06±18.28% vs 55.03±14.67%, P=0.032). There was no difference between patients with autoimmune gastritis and the control group in terms of the mean fasting gallbladder volume (30.38±12.85 vs 29.27±9.91 cm3, P=0.189) and the mean postprandial gallbladder volume (15.67±8.32 vs 13.44±7.69 cm3, P=0.258). Logistic regression analysis of baseline parameters revealed that "abdominal bloating" was a risk factor for the low gallbladder ejection fraction in autoimmune gastritis patients (P=0.045, F=4.40). In addition, logistic regression analysis of baseline parameters revealed that smoking (n=5, P=0.025, F=5.44) is a predictor of low gallbladder ejection fraction in patients with autoimmune gastritis.
CONCLUSIONS: Patients with endogenous hypergastrinemia have a low gallbladder ejection fraction compared with healthy controls. This study shows that at least part of upper gastrointestinal symptoms observed in this patient population may be due to altered gallbladder motility.

BACKGROUND: Hepatitis B virus (HBV) is an etiological factor of intrahepatic cholangiocarcinoma (ICC), but the pathogenic mechanisms remain unclear. This study aimed to investigate the expression and possible role of HBx, an HBV-encoded potentially oncogenic protein, in HBV-infected ICC.
METHODS: Tissue samples were obtained from 54 specimens of HBV-infected ICC. Forty-four specimens were of peripheral type and 10  hilar type. Formalin-fixed, paraffin-embedded sections of the specimens were immunohistochemically stained for HBx and p53.
RESULTS: HBx expression was found in 70.4% (38/54) of the specimens, and it was more frequently seen in the peripheral type than in the hilar type (79.5% vs 30.0%, P=0.002). All three well-differentiated ICCs expressed HBx, whereas 76.9% (30/39) moderately-differentiated and 41.7% (5/12) poorly-differentiated ICCs had HBx expression (P=0.033). Patients with HBx expression had a significantly higher prevalence of elevated serum alpha-fetoprotein (P=0.033). p53 protein expression was found in 18 of 54 cases (33.3%), and was not correlated with that of HBx.
CONCLUSIONS: HBx may contribute to the pathogenesis of ICC, particularly the peripheral type. p53 abnormality may not play a significant role in HBx-mediated oncogenicity during ICC carcinogenesis.

BACKGROUND: The indications for laparoscopic spleen-preserving distal pancreatectomy (LSPDP) and its morbidity compared with laparoscopic distal pancreatectomy with splenectomy (LDPS) are ill-defined. This study aimed to share the indications for spleen-preservation and investigate the safety and outcome of LSPDP at our institution.
METHODS: A retrospective review of patients who were scheduled to receive laparoscopic surgery for distal pancreatic lesions was conducted. The indications, surgical procedures, intra-operative data, and outcomes of the two procedures were collected and compared by statistical analysis.
RESULTS: LDPS and LSPDP were successfully performed in 16 and 21 patients respectively, whereas they were converted to open surgery in 9 patients. There were no significant differences in age, gender, operation time, blood loss, and conversion rate between the LDPS and LSPDP groups. The mean tumor size showed an inter-group difference (5.05 vs 2.53 cm, P<0.001). There were no significant differences in complication and morbidity rates between the two groups. All patients remained alive without recurrence during a follow-up of 9 to 67 months (median 35).
CONCLUSION: LSPDP has a morbidity and outcome comparable to LDPS.

The scarcity of liver grafts in Asia leads to a significant dropout of patients from liver transplant waiting lists, particularly patients with hepatocellular carcinoma and a low model for end-stage liver disease score. In order to reduce dropping out, different bridging therapies are employed. We report the use of high-intensity focused ultrasound ablation as a bridging therapy for a patient with hepatocellular carcinoma of stage two and an extremely low platelet count (20×10⁹/L). The ablation was successful. Blood tests showed that his liver function was similar before and after the treatment. No adhesion was encountered in the liver transplantation performed six months later.

BACKGROUND: Crigler-Najjar syndrome type I (CNS I) is a very rare autosomal recessive inherited disease that liver transplantation can properly deal with.
METHODS: We present one case of an 18-month-old child with CNS I diagnosed by clinical findings and genetic detecting. LTx was performed 5 days after kernicterus broke out and neurological symptoms were successfully reversed.
RESULT: Magnetic resonance imaging and magnetic resonance spectroscopy showed encouraging results that brain pathology had a trend to return to normal in 1-year follow-up, combined with electroencephalogram and motor development estimate studies.
CONCLUSIONS: Liver transplantation can cure CNS I with reversible neurological symptoms to some extent in time. Magnetic resonance spectroscopy may be a future option of predicting brain conditions and selecting suitable patients with CNS I for transplantation.

BACKGROUND: Xanthogranulomatous cholecystitis (XGC) is a destructive inflammatory disease of the gallbladder that can mimic gallbladder carcinoma.
METHODS: We present the case of a 35-year-old Hispanic male complaining of right upper quadrant pain and jaundice for 2 months prior to admission. He denied a history of fever, nausea/vomiting, and weight loss. The past medical history was relevant only for diabetes. He had no previous history of jaundice or previous operations.
RESULTS: CA19-9 was slightly elevated (52 U/mL). Abdominal ultrasonography showed an irregular thickening of the gallbladder wall and no gallstones were detected. CT scan also revealed an irregular thickening of the wall of the gallbladder body suggestive of malignancy. At laparotomy, the mass was adherent to the duodenum and colon, and although the frozen section biopsy was negative, the intraoperative findings were suggestive of malignancy, and the patient underwent left liver trisegmentectomy, resection of the common bile duct and Roux-en-Y hepaticojejunostomy. Pathological examination unexpectedly revealed XGC without malignancy.
CONCLUSIONS: Preoperative and intraoperative differential diagnosis of XGC from gallbladder carcinoma remains a challenge when it is associated with inflammatory involvement of surrounding tissues. Since gallbladder carcinoma and XGC may coexist, radical resection is justified when malignancy cannot be completely ruled out.

BACKGROUND: Gallstone ileus is a heterogeneous and highly morbid condition that suffers from a lack of consensus regarding the timing and approach to management of the biliary tree and associated fistula.
METHODS: We report three cases that demonstrate the spectrum of gallstone ileus with classical examples of both Barnard's and Bouveret's syndromes. Clinical presentation, diagnostic imaging, surgical technique and outcome are discussed.
RESULTS: One patient with Barnard's syndrome presented with recurrent gallstone ileus. To minimize the risks of complex, definitive biliary surgery and avoid further recurrent episodes, a cholecystolithotomy was performed with effect. Two cases of Bouveret's syndrome were successfully managed with enterolithotomy/cholecystectomy and multivisceral resection respectively, thus highlighting the diverse nature of this disease and management options.
CONCLUSIONS: Following enterolithotomy, potentially morbid, definitive one-stage surgery in typically compromised, elderly patients needs to be weighed against the risk of recurrence and ongoing biliary pathology. We suggest the use of open cholecystolithotomy for the removal of residual gallstones when the patient is not suitable for definitive biliary surgery.