Application and Impact of Antiviral Therapy for Patients with HBV-Related Hepatocellular Carcinoma Receiving Sorafenib and Lenvatinib Treatment.

Overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC) has improved in the era of multi-line sequential therapy. The application of antiviral therapy and its impact on survival for patients with HBV-related HCC needs to be reassessed. The aim of this study was to evaluate the application and impact of antiviral therapy on survival for patients with HBV-related HCC receiving tyrosine kinase inhibitor (TKI) therapy. Patients with advanced HBV-related HCC treated with sorafenib or lenvatinib as first-line therapy with (n = 377) and without (n = 182) nucleos(t)ide analogue (NUC) therapy were retrospectively enrolled. Prognostic factors of OS were evaluated. Secular trends in the increased application of NUC therapy and improved survival were observed in the last decade. The HBV reactivation rate in patients without NUC therapy was 6.6%. By multivariate analysis, baseline low HBV viral load, achieving undetectable HBV DNA after TKI therapy, and ability to receive second-line therapy were found to be independent predictors of OS. In subgroup patients with NUC therapy, starting NUC before TKI was associated with a better OS. In conclusion, the application of antiviral therapy for patients with HBV-related HCC receiving TKI therapy has increased over time. Achieving complete virological suppression may contribute to a better OS in patients with advanced HBV-related HCC.

Upregulation of USP22 and ABCC1 during Sorafenib Treatment of Hepatocellular Carcinoma Contribute to Development of Resistance.

Sorafenib is a small molecule that blocks tumor proliferation by targeting the activity of multi-kinases for the treatment of advanced hepatocellular carcinoma (HCC). Increasing sorafenib resistance following long-term treatment is frequently encountered. Mechanisms underlying sorafenib resistance remain not completely clear. To further understand the mechanism of sorafenib resistance in HCC, we established sorafenib-resistant cell lines by slowly increasing sorafenib concentration in cell culture medium. Upregulation of USP22 and ABCC1 were found in Sorafenib-resistant cells. Sorafenib-resistant cells treated with USP22 siRNA showed significant reduction in endogenous mRNA and protein levels of ABCC1. During sorafenib treatment, upregulation of USP22 increases ABCC1 expression and subsequently contributes to sorafenib resistance in HCC cells. Immunohistochemical analysis revealed a positive correlation between USP22 and ABCC1 expression in tissue samples from sorafenib-resistant patients (Pearson's correlation = 0.59, p = 0.03). Our findings indicate that upregulation of USP22 and ABCC1 expression during treatment contribute to sorafenib resistance in HCC cells and that USP22 has strong potential as a therapeutic target for overcoming sorafenib resistance in HCC patients.

Less barium enema, more colonoscopy: A 12-year nationwide population-based study in Taiwan.

BACKGROUND: Colorectal cancer (CRC) is the second most common and third most fatal cancer in Taiwan. To reduce incidence and mortality rates from cancer, including CRC, the Health Promotion Administration in Taiwan initiated the National Program on Cancer Prevention in 2005. For patients who have a positive fecal occult blood test, colonoscopy is recommended, and double-contrast barium enema (BE) is reserved as an alternative for those who cannot receive colonoscopy. In addition, single-contrast BE is sometimes used in pediatrics to evaluate colonic condition. This study evaluated the usage trends of BE and colonoscopy in Taiwan. METHODS: Data from the National Health Insurance Research Database from 2001 to 2013 were used in this study. Patients who received BE and colonoscopy were identified using the procedure codes of the National Health Insurance program. Age-standardized, yearly rates of BE and colonoscopy procedures were calculated. RESULTS: According to the data, the total number of colonoscopies increased 3.7-fold from 2001 to 2013. The compound annual growth rates for BE and colonoscopy were -5.36% and 10.47%, respectively, during the same period. The compound annual growth rates for BE and colonoscopy were -3.89% and 11.64% from 2005 to 2009, and -11.36% and 9.82% from 2010 to 2013, respectively. BE was conducted significantly more frequently than colonoscopy in patients who were aged <12 years and in female patients. CONCLUSION: Professional association guidelines, national cancer prevention programs, patient and physician preferences, and increasing awareness and knowledge of CRC may all contribute to the increasing use of colonoscopy and the dramatic decline in the use of BE in Taiwan.

Validation of the albumin-bilirubin grade-based integrated model as a predictor for sorafenib-failed hepatocellular carcinoma.

BACKGROUND & AIMS: 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. METHODS: Consecutive 404 advanced HCC patients receiving sorafenib were retrospectively enrolled. All patients were in Child-Pugh class A and BCLC stage C with either portal vein invasion or extrahepatic metastasis at the beginning of sorafenib treatment. Radiological evaluation based on mRECIST criteria and clinical assessments with compliance were performed on schedule. RESULTS: During the median follow-up period of 5.8 months, 310 patients developed progressive disease (PD) and 350 deaths occurred. The PD patients were randomized into derivation and validation cohorts by a 1:1 ratio. The independent predictors of poor PPS in derivation cohort were ALBI grade 3 at PD (hazard ratio [HR]=3.24, P = .002), new extrahepatic lesions (NEH) (HR=1.75, P = .011), and early PD within 4 months (HR=1.88, P = .037). ALBI-PD criteria were proposed by incorporating these three risk factors. In the validation cohort, PPS could be independently predicted by presence of early PD, NEH as well as ALBI grade 3 at PD. Patients within ALBI-PD criteria had significant longer median PPS than those beyond it even in Child-Pugh A (9.7 vs 4.9 months, P = .005) subpopulations. CONCLUSIONS: The ALBI-PD criteria can differentiate PPS and stratify the patients with advanced HCC for the second-line trials or salvage therapy.

Hepatocellular Carcinoma: Nomograms Based on the Albumin-Bilirubin Grade to Assess the Outcomes of Radiofrequency Ablation.

Purpose To construct a nomogram with the albumin-bilirubin (ALBI) grade to assess the long-term outcomes of patients with early-stage hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA). Materials and Methods This retrospective study was approved by the institutional review board, and informed consent was waived. We studied 622 treatment-naïve patients with HCC according to the Milan criteria who subsequently underwent RFA from 2002 to 2013. Baseline characteristics were collected to identify the risk factors for determination of poor overall survival after RFA. The multivariate Cox proportional hazards model based on significant prognostic factors of overall survival was used to construct the nomogram. Results After a median follow-up time of 35.7 months, 190 patients had died. The cumulative 5- and 10-year overall survival rates were 63.1% and 48.7%, respectively. Stratified according to ALBI grade, the cumulative 5- and 10-year survival rates were 80.0% and 67.9% for patients with grade 1, respectively, and 48.6% and 35.1% for those with grades 2-3, respectively (P < .001). Multivariate analysis results showed that patient age older than 65 years, a prothrombin time international normalized ratio greater than 1.1, α-fetoprotein level greater than 20 ng/mL, multiple tumors, and ALBI grade 2 or 3 were associated with overall mortality. A nomogram was developed on the basis of these five variables. Internal validation with 200 bootstrapped sample sets had a good concordance index of 0.770 (95% confidence interval: 0.633, 0.876). Conclusion This simple nomogram based on the ALBI grade offers personalized long-term survival data for patients with early-stage HCC who undergo RFA. © RSNA, 2017 Online supplemental material is available for this article.

Clinical efficacy of Rong-Yang-Jyh-Gan-Tang on patients with chronic hepatitis C: A double-blinded randomized placebo-controlled crossover study.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine (TCM) has been widely used by the Chinese population for treatment of chronic hepatitis. However, the efficacy of TCM for patients with chronic hepatitis has not been confirmed, mostly due to the lack of available scientific parameters such as serum viral load to evaluate treatment response. AIM OF THE STUDY: We evaluated the efficacy of Rong-Yang-Jyh-Gan-Tang (RYJGT, composed of Long-Dan-Xie-Gan-Tang, Jia-Wei-Xia-Yao-San, Dan-Shen, and Hou-Po) on patients with chronic hepatitis C. MATERIALS AND METHODS: Thirty-six patients with chronic hepatitis C who had no response to or had contraindications to interferon-ribavirin therapy were randomly allocated to receive RYJGT 15g/day or placebo for 12 weeks. After a 2-week washout period, patients were crossed over to receive placebo or RYJGT for another 12 weeks. Evaluation parameters included liver biochemistries, serum HCVRNA, side effects of RYJGT/placebo, and TCM symptoms. RESULTS: Of the patients who had 12-week RYJGT treatment, 51.7% had decreased serum HCVRNA levels, whereas only 25.8% patients had decreased levels in the placebo group (p=0.036). TCM patterns of "Damp-Heat" and "Liver Qi Depression" had significantly improved after RYJGT treatment in comparison with the placebo. Logistic analyses showed that RYJGT treatment, and pre-treatment values of TCM symptoms of "Damp-Heat" and "Liver Qi Depression", were statistically significant factors in predicting the decrease in serum HCVRNA. CONCLUSION: Chronic hepatitis C patients who received a 12-week RYJGT treatment had significantly higher HCVRNA decrease ratio, and improved TCM symptoms of "Damp-Heat" and "Liver Qi Depression", than those who received the placebo. Our results require further larger scale clinical trials.

Determinants of survival after sorafenib failure in patients with BCLC-C hepatocellular carcinoma in real-world practice.

Sorafenib may improve progression-free survival (PFS) and overall survival (OS) of advanced hepatocellular carcinoma (HCC). However, the survival benefit is short lived and survivals after progressive disease (PD) have not been well characterized. This study aimed to evaluate the survival predictors of OS and postprogression survival (PPS) in advanced HCC patients receiving sorafenib treatment. Consecutive 149 HCC patients receiving sorafenib under National Health Insurance were retrospectively enrolled. All patients fulfilled the reimbursement criteria: Barcelona Clinic Liver Cancer stage C HCC with macroscopic vascular invasion or extrahepatic metastasis (Mets), and Child-Pugh class A. Radiologic assessment was performed at a 2-month interval using modified Response Evaluation Criteria in Solid Tumors. Patients who maintained Eastern Cooperative Oncology Group ≤2 and Child-Pugh class A at PD were assumed to be candidates for second-line treatment. During the median follow-up period of 7.5 months (range, 1.1-18.5), PD developed in 120 (80.5%) patients and 96 (64.4%) deaths occurred. The median PFS, OS, and PPS were 2.5, 8.0, and 4.6 months, respectively. In general, patients with Mets only had better OS and PPS than those with portal vein invasion. Independent predictors of OS include baseline performance status (hazard ratio [HR] = 1.956), tumor size (HR = 1.597), alpha-fetoprotein (HR = 1.869), discontinuation of sorafenib due to liver function deterioration (LD) (HR = 6.142), or concurrent PD and LD (HR = 2.661) and PD within 4 months (HR = 5.164). Independent predictors of PPS include deteriorated performance status (HR = 7.680), deteriorated liver functions (HR = 5.603), bilirubin (HR = 2.114), early PD (HR = 6.109), and new extrahepatic lesion (HR = 1.804). In 46 candidates for second-line trials, development of new extrahepatic lesion independently predicts poorer PPS (HR = 3.669). In conclusion performance status, liver functions, early disease progression, and progression pattern are important determinants of survival after sorafenib failure. These factors should be considered in clinical practice and second-line trial designs for patients with sorafenib failure.