Pei-Chang Lee

Beneficial effects of dual vascular endothelial growth factor receptor/fibroblast growth factor receptor inhibitor brivanib alaninate in cirrhotic portal hypertensive rats.

Vascular endothelial (VEGF) and fibroblast growth factor (FGF)‐induced hepatic stellate (HSCs) and liver endothelial cells (LECs) activation accelerates hepatic fibrogenesis and angiogenesis, and hemodynamic dysarrangements in cirrhosis. VEGF targeting agents had been reported as potential drugs for cirrhosis. However, the evaluation of effects of dual VEGF/FGF targeting agent in cirrhosis is still limited.

Long-term cannabinoid type 2 receptor agonist therapy decreases bacterial translocation in rats with cirrhosis and ascites.

BACKGROUND & AIMS Intestinal hyperpermeability, impaired peritoneal macrophages (PMs) phagocytosis, and bacterial translocation (BT), resulting in increased systemic and local infection/inflammation such as spontaneous bacterial peritonitis (SBP) together with increased tumor necrosis factor-α (TNFα) levels, are all implicated in the pathogenesis of cirrhosis-related complications. Manipulation of the cannabinoid receptors (CB1R and CB2R), which are expressed on the gut mucosa and PMs, has been reported to modulate intestinal inflammation and systemic inflammatory cytokine release. Our study aims to explore the effects of chronic CB1R/CB2R agonist/antagonist treatments on relevant abnormalities in cirrhotic ascitic rats. METHODS Vehicle, archidonyl-2-chloroethylamide (ACEA, CB1R agonist), JWH133 (CB2R agonist), and AM630 (CB2R antagonist) were given to thioacetamide (TAA) and common bile duct ligation (BDL) cirrhotic rats with ascites for two weeks and various measurement were performed. RESULTS Compared to sham rats, CB2Rs were downregulated in cirrhotic rat intestines and PMs. The two-week JWH133 treatment significantly decreased systemic/intestinal oxidative stress, TNFα and inflammatory mediators, infection, intestinal mucosal damage and hyperpermeability; the JWH133 treatment also decreased bacterial overgrowth/adhesion, BT and SBP, upregulated intestinal tight junctions and downregulated the PM TNFα receptor/NFκBp65 protein expression in cirrhotic rats. Acute and chronic JWH133 treatment corrected the TNFα-induced suppression of phagocytosis of cirrhotic rat PMs, which then could be reversed by concomitant AM630 treatment. CONCLUSIONS Our study suggests that CB2R agonists have the potential to treat BT and various relevant abnormalities through inhibition of systemic/intestinal oxidative stress, inflammatory cytokines and TNFα release in cirrhosis. Overall, the chronic CB2R agonist treatment affects multiple approach mechanisms, and its direct effect on the hyperdynamic circulation is only minor.

Anti-VEGFR agents ameliorate hepatic venous dysregulation/microcirculatory dysfunction, splanchnic venous pooling and ascites of NASH-cirrhotic rat

Antivascular endothelial growth factor receptor (VEGFR) agents improve hepatic fibrosis and portal hypertension in cirrhosis. Detail interactions among recruited/activated leucocytes, hepatic angiogenesis and fibrogenesis, splanchnic blood pooling, decreased hepatic veins to fluctuated splanchnic blood volume (hepatic venous dysregulation), portal hypertensive syndrome and ascites have never explored in cirrhosis. Our study used two anti‐VEGFR agents – brivanib and sorafenib – to elucidate the relationship between above abnormalities of nonalcoholic steatohepatitis (NASH)‐cirrhotic rats.

The Risk of Cancer in Patients with Benign Anal Lesions: A Nationwide Population-based Study

OBJECTIVE To evaluate the risk of cancer among patients diagnosed with hemorrhoids and benign anal inflammatory lesions. METHODS A population-based, retrospective cohort study was conducted that included patients diagnosed with hemorrhoids or benign inflammatory anal lesions (eg, anal fissure, fistula, and perianal abscesses) that were registered in the National Health Insurance Research Database in Taiwan between January 1, 2000 and December 31, 2010. Standardized incidence ratios (SIRs) were calculated to compare the cancer incidence of these patients to the general population. RESULTS During a median observation period of 6.23 years, 3080 cancers developed among 70,513 hemorrhoid patients, with a follow-up period of 438,425.6 person-years, entailing the SIR of 1.52 (95% confidence interval [CI], 1.47-1.58). Increased cancer risk (SIR 1.16; 95% CI, 1.11-1.21) was still noted even after excluding the first year of observation. Significant long-term risk for colorectal cancer (SIR 1.50; 95% CI, 1.35-1.66) and prostate cancer (SIR 1.40; 95% CI, 1.17-1.66) was observed after corrections were made for multiple comparisons. In contrast, there was no remarkable increase in cancer risk for patients with inflammatory anal lesions when cancers detected within the first year of diagnosis were excluded. CONCLUSION The presence of hemorrhoids is associated significantly with a long-term risk of developing colorectal cancer or prostate cancer. In contrast, benign inflammatory anal lesions do not appear to increase the risk of malignancy.

Concomitant inhibition of oxidative stress and angiogenesis by chronic hydrogen-rich saline and N-acetylcysteine treatments improves systemic, splanchnic and hepatic hemodynamics of cirrhotic rats.

In cirrhosis, increased oxidative stress leads to systemic and splanchnic hyperdynamic circulation, splanchnic angiogenesis, portosystemic collateral formation, hepatic endothelial dysfunction, increased intrahepatic resistance and the subsequent portal hypertension. Like N‐acetylcysteine, hydrogen‐rich saline is a new documented antioxidant with the potential to treat the complications of liver diseases.

Risk of Cancer in Patients with Cholecystitis: A Nationwide Population-based Study

OBJECTIVE The objective of this study was to evaluate the risk of cancer in patients diagnosed with cholecystitis and possible interactions between cholecystitis and cholecystectomy. METHODS A retrospective population-based cohort study was conducted among patients diagnosed with cholecystitis that were registered in the National Health Insurance Research Database in Taiwan between January 1, 2000 and December 31, 2010. Standardized incidence ratios (SIRs) were calculated to compare the incidence of cancer in these patients to that of the general population. Adjusted hazard ratios (HRs) were also calculated to investigate whether cholecystitis increased the risk for specific cancers. RESULTS During a median observation period of 5.4 years, 1541 cancers occurred in 20,431 patients with cholecystitis, yielding a SIR of 1.97 (95% confidence interval [CI], 1.88-2.07). A significantly greater risk of biliary tract cancer (adjusted HR 1.72; 95% CI, 1.08-2.75) was observed after adjusting for potential risk factors. In contrast, cholecystectomy was found to attenuate the cancer risk, with the reduction of adjusted HR from 2.34 (95% CI, 1.62-3.37) to 1.28 (95% CI, 0.76-2.14). CONCLUSION Cholecystitis is an independent risk factor to extrahepatic biliary tract cancers, whereas cholecystectomy can attenuate the cancer risk of cholecystitis.

Mechanisms of the prevention and inhibition of the progression and development of NASH by genetic and pharmacological DcR3 supplementation.

Treatment of non‐alcoholic steatohepatitis (NASH) is difficult due to the absence of a proven treatment and its comprehensive mechanisms. In the NASH animal model, upregulated hepatic inflammation and oxidative stress, with the resultant M1 polarization of macrophages as well as imbalanced adipocytokines, all accelerate NASH progression. As a member of the tumor necrosis factor receptor superfamily, decoy receptor 3 (DcR3) not only neutralizes the death ligands, but also performs immune modulations. In this study, we aimed to investigate the possible non‐decoy effects of DcR3 on diet‐induced NASH mice.

Mechanisms of the prevention and inhibition of the progression and development of non-alcoholic steatohepatitis by genetic and pharmacological decoy receptor 3 supplementation.

Treatment of non‐alcoholic steatohepatitis (NASH) is difficult due to the absence of a proven treatment and its comprehensive mechanisms. In the NASH animal model, upregulated hepatic inflammation and oxidative stress, with the resultant M1 polarization of macrophages as well as imbalanced adipocytokines, all accelerate NASH progression. As a member of the tumor necrosis factor receptor superfamily, decoy receptor 3 (DcR3) not only neutralizes the death ligands, but also performs immune modulations. In this study, we aimed to investigate the possible non‐decoy effects of DcR3 on diet‐induced NASH mice.

Validation of the ALBI Grade-based Integrated Model as a Predictor for Sorafenib-failed Hepatocellular Carcinoma

Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC) but is challenging after treatment failure. Appropriate criteria for enrolling patients into second‐line trials are still limited. In this study, we aimed to establish more objective criteria based on Albumin‐Bilirubin (ALBI) grade to select patients with better post‐progression survival (PPS) for second‐line treatment.

The Prognosis of Single Large Hepatocellular Carcinoma Was Distinct from Barcelona Clinic Liver Cancer Stage A or B: The Role of Albumin-Bilirubin Grade

Background/Aims: Whether single large hepatocellular carcinoma (SLHCC) is classified as Barcelona Clinic Liver Cancer (BCLC) stage A or B is still controversial. We aimed to compare the clinical manifestations, treatment modalities, and prognoses among patients with SLHCC and those in BCLC stage A and B. Methods: We enrolled 2,285 treatment-naive hepatocellular carcinoma (HCC) patients with BCLC stage A or B from October 2007 to December 2015. Factors in terms of prognoses were analyzed by multivariate analysis. Results: We enrolled 1,210, 466, and 609 patients in a BCLC-A, SLHCC, and BCLC-B group, respectively. After a median follow-up duration of 21.2 months, 898 patients had died. The cumulative 5-year survival rates were 57.0, 42.6, and 27.3% for patients in the BCLC-A, SLHCC, and BCLC-B groups, respectively, which were significantly different (p < 0.001). Multivariate analysis indicated that the following independent risk factors were associated with poor prognosis: age > 65 years, alkaline phosphatase > 100 U/L, creatinine > 1.0 mg/dL, alpha-fetoprotein > 20 mg/mL, noncurative treatment, albumin-bilirubin (ALBI) grade, and HCC staging. Subgroup analysis also confirmed that patients in the SLHCC group had a survival rate intermediate to those in the BCLC-A and BCLC-B groups. However, for patients in the SLHCC group and with ALBI grade 1, outcomes were close to those in the BCLC-A group, especially in the setting of curative treatment. For those with ALBI grades 2 or 3, the prognoses were similar to those of the SLHCC and BCLC-B groups. Conclusion: Patients in the SLHCC group had an overall survival rate intermediate to those of the BCLC-A and BCLC-B groups. It is suggested that the SLHCC group could be classified as occupying a different stage from the BCLC stages A and B. The ALBI grade could help to stratify SLHCC into a different prognostic group. However, the results need to be validated externally in other regions of the world.