Publications

Scholarly Journals--Published

  • Frenette CT, Morelli G, Shiffman ML, Frederick RT, Rubin RA, Fallon MB, Cheng JT, Cave M, Khaderi SA, Massoud O, Pyrsopoulos N, Park JS, Robinson JM, Yamashita M, Spada AP, Chan JL, Hagerty DT.Emricasan Improves Liver Function in Patients With Cirrhosis and High Model for End-stage Liver Disease Scores Compared With Placebo.  Clin Gastroenterol Hepatol. 2018 Jun 15. pii: S1542-3565(18)30622-0. PMID:  29913280 DOI:10.1016/j.cgh.2018.06.012 Abstract BACKGROUND & AIMS: Caspase-mediated apoptosis and inflammation contribute to progression of liver disease. Emricasan is a pan-caspase inhibitor that reduced serum markers of apoptosis and liver inflammation in patients with hepatitis C and non-alcoholic steatohepatitis (NASH). METHODS: We performed a multicenter study of 86 patients with cirrhosis (Child-Pugh class A or B; mean score, 6.9; 38% with alcohol-associated cirrhosis, 29% with HCV-associated cirrhosis, and 23% with NASH) and model for end-stage liver disease (MELD) scores of 11-18 (mean, 12.8). Patients were randomly assigned to groups given placebo (n=42) or emricasan (25 mg, n=44), twice daily for 3 months; subjects then received open-label emricasan (25 mg) twice-daily for 3 months. The primary endpoint was the change from baseline in serum levels of cleaved keratin 18 (CK-18) at month 3. RESULTS: Seventy-four patients completed the 3-month study period (40 given emricasan and 34 given placebo); 69 patients received open-label emricasan for 3 months afterward. At the 3-month timepoint, emricasan significantly reduced mean MELD (P=.003) and Child-Pugh (P=.003) scores in subjects with high MELD scores (15 or more), compared with placebo, with significant reductions in INR (95% CI, -0.2882 to -0.0866) and total bilirubin (95% CI, -1.5069 to -0.0823) vs placebo. There were no significant differences between emricasan and placebo groups in mean MELD (P=.466) or Child-Pugh (P=.124) scores overall at 3 months compared to placebo. Of patients with high MELD scores, 6/9 given emricasan (67%) had a reduction of 2 points or more at month 3, compared with 2/10 given placebo (20%). Serum levels of full-length CK-18 (P=.02) and caspase 3/7 (P<.001), but not cleaved CK-18 (P=.092), decreased significantly at 3 months in the emricasan vs placebo group. Emricasan was well tolerated, and adverse events were balanced between groups. Emricasan's effects were generally maintained or increased after 6 months of treatment. CONCLUSIONS: In a randomized trial of patients with cirrhosis, we found 3 months treatment with emricasan to improve liver function, compared with placebo, reducing MELD and Child-Pugh scores, INR, and total bilirubin in patients with MELD scores ≥15. (06/2018)
  • Bush DA, Smith JC, Slater JD, Volk ML, Reeves ME, Cheng J, Grove R, de Vera ME.  Randomized Clinical Trial Comparing Proton Beam Radiation therapy with transarterial chemoembolization for hepatocellular carcinoma: Results of an interim analysis.  Int J Radiation Oncol Biol Phys 2016;95:477–482.  PMID: 27084661  DOI: 10.1016/j.ijrobp.2016.02.027 PURPOSE:  To describe results of a planned interim analysis of a prospective, randomized clinical trial developed to compare treatment outcomes among patients with newly diagnosed hepatocellular carcinoma (HCC).METHODS AND MATERIALS:  Eligible subjects had either clinical or pathologic diagnosis of HCC and met either Milan or San Francisco transplant criteria. Patients were randomly assigned to transarterial chemoembolization (TACE) or to proton beam radiation therapy. Patients randomized to TACE received at least 1 TACE with additional TACE for persistent disease. Protonbeam radiation therapy was delivered to all areas of gross disease to a total dose of 70.2 Gy in 15 daily fractions over 3 weeks. The primary endpoint was progression-free survival, with secondary endpoints of overall survival, local tumor control, and treatment-related toxicities as represented by posttreatment days of hospitalization.RESULTS:  At the time of this analysis 69 subjects were available for analysis. Of these, 36 were randomized to TACE and 33 to proton. Total days of hospitalization within 30 days of TACE/proton was 166 and 24 days, respectively (P<.001). Ten TACE and 12 proton patients underwent liver transplantation after treatment. Viable tumor identified in the explanted livers after TACE/protonaveraged 2.4 and 0.9 cm, respectively. Pathologic complete response after TACE/proton was 10%/25% (P=.38). The 2-year overall survival for all patients was 59%, with no difference between treatment groups. Median survival time was 30 months (95% confidence interval 20.7-39.3 months). There was a trend toward improved 2-year local tumor control (88% vs 45%, P=.06) and progression-free survival (48% vs 31%, P=.06) favoring the proton beam treatment group.CONCLUSIONS:  This interim analysis indicates similar overall survival rates for proton beam radiation therapy and TACE. There is a trend toward improved local tumor control and progression-free survival with proton beam. There are significantly fewer hospitalization days after proton treatment, which may indicate reduced toxicity with proton beam therapy. (05/2016) (link)
  • Tong MJ, Blatt LM, Kao JH, Cheng JT, Corey WG.  Basal core promoter T1762/A1764 and precore A1896 gene mutations in hepatitis B surface antigen-positive hepatocellular carcinoma: a comparison with chronic carriers.  Liver Int  2007;27:1356–63.  PMID: 17900245 DOI: 10.1111/j.1478-3231.2007.01585.x BACKGROUND:  Chronic hepatitis B virus (HBV) infection is associated with hepatocellular carcinoma (HCC), and specific viral factors have been identified that may increase the risk for HCC development. However, the differences in these viral factors in chronic carriers who seldom develop HCC compared with HCC patients have not been adequately evaluated.  METHODS:  From 1989 to 2005, 101 hepatitis B surface antigen-positive patients presented to our clinic with HCC. Baseline basalcore promoter (BCP) T1762/A1764 mutants, precore (PC) A1896 mutants, HBV genotypes and HBV DNA in HCC patients were compared with 67 chronic carriers who had been followed for a mean of 112.1+/-77.7 standard deviation months.RESULTS:  At baseline, HCC patients had lower levels of serum albumin, but higher values of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, bilirubin and alpha-foetoprotein than those of chronic carriers (P<0.001 for all comparisons). The presence of genotype C, higher frequencies of PC A1896 mutants, BCP T1762/A1764 mutants and higher circulating levels of HBV DNA were more frequently detected in HCC patients than that in chronic carriers (P<0.001 for all observations). Logistic regression analysis revealed that BCP T1762/A1764 mutants [odds ratio (OR) 11.14, 95% confidence interval (CI) 3.05-40.72; P<0.001] and PC A1896 mutants (OR 3.75, 95% CI 1.14-12.34; P<0.05) were significantly associated with HCC development.CONCLUSION:  Our results indicate that the presence of BCP and PC mutations significantly increases the risk for HCC in chronic hepatitis B patients. These mutations were less often detected in chronic carriers who seldom develop HCC. (12/2007) (link)
  • Cheng JT, Hsien C, Sun HJ, Tong MJ. The emerging importance of chronic hepatitis C infection in Asian Americans. Am J Gastroenterol 2006;101:2737–2743.  PMID: 17227521 OBJECTIVES:  To study the demographics, epidemiology, and natural history of chronic hepatitis C in Asian Americans.METHODS:  This retrospective survey describes 260 Asian Americans with chronic hepatitis C referred to one tertiary center.RESULTS:  Ninety-two percent of patients were born in Asia. Fifty-one percent reported a history of unsafe therapeutic injections, which was a risk factor only in those with exposure outside the United States (p < 0.0001). A history of transfusion was reported in 41% of patients and was more frequent in those with exposure within the Unites States (p < 0.0001). Only 3.8% reported a history of intravenous drug abuse, which was more frequent in those with exposure within the United States (p < 0.0001). Hepatitis C genotype 1 was detected in 64.2% of patients, genotype 2 in 18.3%, and genotype 6 in 11.3%. Genotype 1 had a significantly lower sustained virologic response rate (32.8%) to interferon treatment, compared with genotype 2 (77.8%) or 6 (69.2%). During a mean follow-up of 6 yr, 26 patients developed hepatocellular carcinoma (HCC). Logistic regression model revealed fibrosis stage 4 (odds ratio [OR] 8.87, 95% confidence interval [CI] 2.97-26.48, p < 0.0001), age at presentation (55 vs 35 yr--OR 3.45, 95% CI 1.22-9.75, p= 0.0194), and baseline albumin level (3.0 vs 4.0 mg/dL--OR 3.47, 95% CI 1.02-11.76, p= 0.0464) were independent predictive factors for HCC development.CONCLUSIONS:  Asian Americans with a history of unsafe therapeutic injections must be screened for chronic hepatitis C. Antiviral treatment should be initiated prior to development of cirrhosis. Surveillance for HCC must be routinely performed in cirrhosis patients. (12/2006) (link)
  • Tong MJ, Blatt LM, Kao JH, Cheng JT, Corey WG. Precore/basal core promoter mutants and hepatitis B viral DNA levels as predictors for liver deaths and hepatocellular carcinoma. World J Gastroenterol 2006;12:6620–26. PMID: 17075974 AIM:  To conduct a retrospective study in 400 chronic hepatitis B patients in order to identify hepatitis B viral factors associated with complications of liver disease or development of hepatocellular carcinoma.METHODS:  The mean follow-up time was 83.6+/-39.6 mo. Alpha-fetoprotein test and abdominal ultrasound were used for cancer surveillance. Hepatitis B basal core promoter mutants, precore mutants, genotypes, hepatitis B viral DNA (HBV DNA) level and hepatitis B e antigen (HBeAg) were measured. Univariate analysis and logistic regression were used to assess odds ratios for viral factors related to liver deaths and hepatocellular carcinoma development.RESULTS:  During follow-up, 38 patients had liver deaths not related to hepatocellular carcinoma. On multivariate analysis, older age [odds ratio: 95.74 (12.13-891.31); P<0.0001], male sex [odds ratio: 7.61 (2.20-47.95); P=0.006], and higher log10 HBV DNA [odds ratio: 4.69 (1.16-20.43); P<0.0001] were independently predictive for these liver related deaths. Also, 31 patients developed hepatocellular carcinoma. Multivariate analysis showed that older age [odds ratio: 26.51 (2.36-381.47); P=0.007], presence of precore mutants [odds ratio: 4.23 (1.53-19.58); P=0.02] and presence of basal core promoter mutants [odds ratio: 2.93 (1.24-7.57); P=0.02] were independent predictors for progression to hepatocellular carcinoma.CONCLUSION:  Our results show that high levels of baseline serum HBV DNA are associated with non-hepatocellular carcinoma-related deaths of liver failure, while genetic mutations in the basal core promoter and precore regions are predictive for development of hepatocellular carcinoma. (11/2006) (link)

Abstract

  • Cheng JT, Sun HJ, Hsien C, Tong MJ.  Demographics, epidemiology, mode of transmission and treatment response in chronic hepatitis C genotype 2 patients.  [Abstract]  Gastroenterology 2007;132, suppl. S1:787. (04/2007)
  • Tong MJ, Blatt LM, Kao JH, Cheng JT, Corey WG.  Basal Core Promoter T1762/A1764 and precore A1896 gene mutations in HBsAg-positive hepatocellular carcinoma:  A comparison to chronic carriers.  [Abstract]  Gastroenterology 2007;132, suppl. S1:760 (04/2007)
  • Tong MJ, Tu S, Cheng JT, Blatt LM.  Development of HCC in patients who achieve SVR to IFN-based therapies is associated with cirrhosis and prior HBV exposure.  [Abstract]  Hepatology 2006;44, suppl. 1:323A. (10/2006)
  • Cheng JT, Hsien C, Sun HJ, Tong MJ.  Emerging importance of chronic hepatitis C in Asian Americans.  [Abstract]  Gastroenterology 2006;130, suppl. S2:779. (04/2006)
  • Tong MJ, Blatt LM, Kao JH, Cheng JT, Corey WG.  Viral factors which predicted liver-related deaths and development of hepatocellular carcinoma in patients with chronic hepatitis B.  [Abstract]  Hepatology 2005;42, suppl. 1:722A. (10/2005)