S.-M. Lin

Long-term outcome of hepatitis B e antigen–negative hepatitis B surface antigen carriers in relation to changes of alanine aminotransferase levels over time†

The baseline alanine aminotransferase (ALT) level was reported to have prognostic value in chronic hepatitis B virus (HBV) infection, during which ALT may change over time. Instead of baseline ALT, this study aimed to study the prognostic value of the height of ALT during the course of chronic HBV infection. A total of 4376 asymptomatic hepatitis B e antigen (HBeAg) negative, surface antigen (HBsAg) carriers with baseline ALT less than 2 times the upper limit of normal (ULN) were monitored with ALT measurement and ultrasonography every 3 to 12 month for over 3 years. Maximal ALT levels during follow‐up were correlated with long‐term outcomes using morbidity and mortality data from hospital records, cancer registration, and national mortality database. Baseline ALT level was normal in 3673 subjects and increased to abnormal level in 1720 (46.8%) during a mean follow‐up period of 13.4 ± 5.2 (3.0‐28.7) years. The incidence of liver cirrhosis, hepatocellular carcinoma (HCC), and mortality increased with increasing maximal ALT level during follow‐up, especially in those with maximal ALT of at least 2 times ULN, as compared with those who maintained normal ALT. Cox regression analysis indicated that age at entry, sex, and maximal ALT level during follow‐up were significant independent factors associated with the development of cirrhosis, HCC, and mortality whereas cirrhosis was also an independent factor for HCC development and mortality. Conclusion: Persistently normal ALT was associated with excellent long‐term prognosis, whereas increasing ALT levels of at least 2 times ULN during follow‐up was associated with increasing morbidity and mortality. ALT of at least 2 times ULN is therefore an appropriate threshold for anti‐HBV therapy, whereas those with ALT 1 to 2 times ULN require liver biopsy for decision. (HEPATOLOGY 2009.)

Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: A randomized phase III trial

Transarterial chemoembolization (TACE) is the current standard of treatment for unresectable intermediate‐stage hepatocellular carcinoma (HCC). Brivanib, a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor signaling, may improve the effectiveness of TACE when given as an adjuvant to TACE. In this multinational, randomized, double‐blind, placebo‐controlled, phase III study, 870 patients with TACE‐eligible HCC were planned to be randomly assigned (1:1) after the first TACE to receive either brivanib 800 mg or placebo orally once‐daily. The primary endpoint was overall survival (OS). Secondary endpoints included time to disease progression (TTDP; a composite endpoint based on development of extrahepatic spread or vascular invasion, deterioration of liver function or performance status, or death), time to extrahepatic spread or vascular invasion (TTES/VI), rate of TACE, and safety. Time to radiographic progression (TTP) and objective response rate were exploratory endpoints. The trial was terminated after randomization of 502 patients (brivanib, 249; placebo, 253) when two other phase III studies of brivanib in advanced HCC patients failed to meet OS objectives. At termination, median follow‐up was approximately 16 months. Intention‐to‐treat analysis showed no improvement in OS with brivanib versus placebo (median, 26.4 [95% confidence interval {CI}: 19.1 to not reached] vs. 26.1 months [19.0‐30.9]; hazard ratio [HR]: 0.90 [95% CI: 0.66‐1.23]; log‐rank P = 0.5280). Brivanib improved TTES/VI (HR, 0.64 [95% CI: 0.45‐0.90]), TTP (0.61 [0.48‐0.77]), and rate of TACE (0.72 [0.61‐0.86]), but not TTDP (0.94 [0.72‐1.22]) versus placebo. Most frequent grade 3‐4 adverse events included hyponatremia (brivanib, 18% vs. placebo, 5%) and hypertension (13% vs. 3%). Conclusions: In this study, brivanib as adjuvant therapy to TACE did not improve OS. (Hepatology 2014;60:1697–1707)

Acute hepatitis C virus superinfection followed by spontaneous HBeAg seroconversion and HBsAg elimination

SummaryAcute hepatitis C virus superinfection followed by spontaneous hepatitis B e antigen seroconversion and hepatitis B surface antigen clearance in a patient with chronic type B hepatitis is described. The observations suggests that HCV may exert a suppressive effect on hepatitis B virus.ZusammenfassungNach akuter Superinfektion mit dem Hepatitis C Virus trat bei einem Patienten mit chronischer B Hepatitis eine Serokonversion gegen das Hepatitis B Virus e- Antigen und Elimination des Hepatitis B Virus Oberflächenantigens ein. Nach dieser Beobachtung könnte HCV eine suppressive Wirkung gegen das Hepatitis B Virus haben.Acute hepatitis C virus superinfection followed by spontaneous hepatitis B e antigen seroconversion and hepatitis B surface antigen clearance in a patient with chronic type B hepatitis is described. The observations suggests that HCV may exert a suppressive effect on hepatitis B virus. Nach akuter Superinfektion mit dem Hepatitis C Virus trat bei einem Patienten mit chronischer B Hepatitis eine Serokonversion gegen das Hepatitis B Virus e- Antigen und Elimination des Hepatitis B Virus Oberflächenantigens ein. Nach dieser Beobachtung könnte HCV eine suppressive Wirkung gegen das Hepatitis B Virus haben.

Functional genomics identified a novel protein tyrosine phosphatase receptor type F-mediated growth inhibition in hepatocarcinogenesis.

It is unclear how proliferating cells elicit suppression on cell proliferation and how cancer cells evade this growth suppression. Using a loss‐of‐function screening of the human kinome and phosphatome to identify genes suppressing tumor initiation in human hepatocellular carcinoma (HCC), we identified 19 genes and characterized one of the top‐scoring tumor suppressor candidates, protein tyrosine phosphatase receptor type F (PTPRF). We found that PTPRF was induced during cell proliferation by cell‐cell contact. Ectopic expression of wild‐type PTPRF, but not the phosphatase‐inactive mutant, suppressed cell proliferation and colony formation in soft‐agar assays. In contrast, PTPRF silencing led to cell hyperproliferation, enhanced tumor colony formation in soft agar, and increased xenograft tumor growth in nude mice. Mechanistically, PTPRF silencing showed aberrant ERK‐dependent signaling including the phosphorylation/stabilization of v‐myc avian myelocytomatosis viral oncogene homolog (MYC) through the direct activation of v‐src avian sarcoma viral oncogene homolog (SRC) and suppression of PP2A. This PTPRF‐mediated growth suppression during cell proliferation functioned independently of the Hippo‐Yap pathway. Clinically, PTPRF was down‐regulated in 42% HCC (37/89), 67% gastric cancer (27/40), and 100% colorectal cancer (40/40). PTPRF up‐regulation was found in 24% HCC (21/89) and associated with better clinical outcomes. Conclusion: A novel PTPRF‐mediated growth suppression pathway was identified by way of a functional genomics screening in human hepatoma cells. Induction of PTPRF by cell‐cell contact during cell proliferation quenched the activated ERK‐dependent proliferation signaling to prevent cell hyperproliferation and tumor initiation. PTPRF down‐regulation in HCC facilitated tumor development. Our findings shed light on how cancer cells can evade growth suppression and open a new avenue for future development of anticancer therapies. (Hepatology 2014;59:2238–2250)

Increased regulatory T cells in patients with liver cirrhosis correlated with hyperbilirubinemia and predict bacterial complications.

Patients with liver cirrhosis (LC) were regarded as immunocompromised status with high incidence of bacterial infection. Regulatory T cell (Treg cell) is known as an immune suppressor and also plays an important role in patients with sepsis. This paper aims to study the role of Treg cells in patients with liver cirrhosis and their correlations to bacterial complications.