Teng-Yu Lee

Association between nucleos(t)ide analog and tumor recurrence in hepatitis B virus–related hepatocellular carcinoma after radiofrequency ablation

Radiofrequency ablation (RFA) is the best choice for curative treatment of hepatocellular carcinoma (HCC) cases not suitable for surgical intervention, but efforts should be made to reduce the risk of tumor recurrence. We aimed to investigate the association between nucleos(t)ide analog (NA) therapy for hepatitis B virus (HBV) and the risk of HCC recurrence post‐RFA. Using the Taiwan National Health Insurance Research Database between July 1, 2004 and December 31, 2012, we screened 48,807 patients with newly diagnosed HBV‐related HCC. We identified 850 patients (200 patients who used NAs for more than 90 days and 650 who never used NA post‐RFA) who received RFA as a potentially curative treatment for HCC. Patients in the NA‐treated cohort were randomly matched 1:2 with patients in the untreated cohort by age, sex, cirrhosis, and the time period between RFA and initiation of NA therapy. Finally, 133 patients were recruited in the NA‐treated group and 266 in the untreated group for analysis. Cumulative incidences of and hazard ratios (HRs) for HCC recurrence were analyzed after adjusting for competing mortality. The HCC recurrence rate of the NA‐treated group was significantly lower than that of the untreated group (2‐year recurrence rate: 41.8%; 95% confidence interval [CI]: 32.9‐50.6 vs. 54.3%; 95% CI: 48.0‐60.6; modified log‐rank test: P < 0.05). In modified Coxs regression analysis, NA therapy was independently associated with a decreased risk of HCC recurrence (HR, 0.69; 95% CI: 0.50‐0.95; P < 0.05). Multivariate stratified analyses verified the association of NA therapy and decreased HCC recurrence in almost all patient subgroups. Conclusion: NA therapy was associated with a decreased risk of HCC recurrence among patients with HBV‐related HCC post‐RFA. (Hepatology 2016;63:1517‐1527)

Association between nucleos(t)ide analogue and tumor recurrence in HBV-related hepatocellular carcinoma after radiofrequency ablation

Radiofrequency ablation (RFA) is the best choice for curative treatment of hepatocellular carcinoma (HCC) cases not suitable for surgical intervention, but efforts should be made to reduce the risk of tumor recurrence. We aimed to investigate the association between nucleos(t)ide analog (NA) therapy for hepatitis B virus (HBV) and the risk of HCC recurrence post‐RFA. Using the Taiwan National Health Insurance Research Database between July 1, 2004 and December 31, 2012, we screened 48,807 patients with newly diagnosed HBV‐related HCC. We identified 850 patients (200 patients who used NAs for more than 90 days and 650 who never used NA post‐RFA) who received RFA as a potentially curative treatment for HCC. Patients in the NA‐treated cohort were randomly matched 1:2 with patients in the untreated cohort by age, sex, cirrhosis, and the time period between RFA and initiation of NA therapy. Finally, 133 patients were recruited in the NA‐treated group and 266 in the untreated group for analysis. Cumulative incidences of and hazard ratios (HRs) for HCC recurrence were analyzed after adjusting for competing mortality. The HCC recurrence rate of the NA‐treated group was significantly lower than that of the untreated group (2‐year recurrence rate: 41.8%; 95% confidence interval [CI]: 32.9‐50.6 vs. 54.3%; 95% CI: 48.0‐60.6; modified log‐rank test: P < 0.05). In modified Coxs regression analysis, NA therapy was independently associated with a decreased risk of HCC recurrence (HR, 0.69; 95% CI: 0.50‐0.95; P < 0.05). Multivariate stratified analyses verified the association of NA therapy and decreased HCC recurrence in almost all patient subgroups. Conclusion: NA therapy was associated with a decreased risk of HCC recurrence among patients with HBV‐related HCC post‐RFA. (Hepatology 2016;63:1517‐1527)

Association between ultrasonography screening and mortality in patients with hepatocellular carcinoma: a nationwide cohort study

Objective Current guidelines recommend screening for hepatocellular carcinoma (HCC) in high-risk populations. However, the effectiveness of screening in reducing mortality has been challenged. In addition, it is unclear which subgroups benefit most from HCC screening. Design This nationwide cohort study identified a total of 52 823 newly diagnosed HCC patients between 1 January 2002 and 31 December 2007. These HCC patients were classified into the following cohorts according to the time intervals in which they received ultrasonography screening: 0–6 months (6M), 7–12 months (12M), 13–24 months (24M), 25–36 months (36M) and not screened within 3 years (never screened). The chance to receive curative therapy and 5-year cumulative mortalities were calculated after adjusting for lead-time bias. Results Chances to receive curative therapy among the 6M, 12M, 24M, 36M and never screened cohorts were 24.3% (95% CI 23.7% to –24.9%), 26.9% (95% CI 25.7% to 28.2%), 22.9% (95% CI 21.8% to 24.1%), 21.3% (95% CI 19.9% to 22.8%) and 18.3% (95% CI 17.8% to 18.8%), respectively. Compared with the 6M cohort, adjusted HRs of mortality for the 12M, 24M, 36M and never screened cohorts were 1.11 (95% CI 1.07 to 1.15), 1.23 (95% CI 1.19 to 1.28), 1.31 (95% CI 1.26 to 1.37) and 1.47 (95% CI 1.43 to 1.51) (all p Conclusions Shorter ultrasonography screening intervals are associated with reduced overall mortality in HCC patients in a dose-dependent manner.

Lower serum folate is associated with development and invasiveness of gastric cancer

AIM To evaluate the associations of serum folate level with development, invasiveness and patient survival of gastric cancer. METHODS In this nested case-control study, patients with newly diagnosed gastric cancer undergoing gastrectomy were enrolled, and patients receiving chemotherapy prior to surgery, with other concurrent malignancy, or of the aboriginal and alien populations were excluded. In total, 155 gastric cancer patients and 149 healthy controls were enrolled for determination of serum folate levels and their correlation with gastric cancer. Using the median value of serum folate computed among the overall population as the cutoff value, the associations between serum folate and gastric cancer in all cases and different age and gender subgroups were analyzed by multivariate logistic regression analysis. In the patient cohort of gastric cancer, receiver-operating characteristic analyses were performed to calculate the best cutoff values of serum folate, and the associations between serum folate levels and clinicopathological features were further analyzed by multivariate regression analysis. Survival analyses were conducted using the Cox proportional hazards model. RESULTS The mean serum folate level was significantly lower in gastric cancer patients than that in controls (3.71 ± 0.30 ng/mL vs 8.00 ± 0.54 ng/mL, P < 0.01), and folate levels were consistently lower in gastric cancer patients regardless of age and gender (all P < 0.01). Using the median serum folate value as the cutoff value, low serum folate was significantly associated with gastric cancer risk in the whole population (OR = 19.77, 95%CI: 10.54-37.06, P < 0.001) and all strata (age < 60 years OR = 17.39, 95%CI: 7.28-41.54, age ≥ 60 years (OR = 21.67, 95%CI: 8.27-56.80), males (OR = 17.95, 95%CI: 7.93-40.62), and females (OR = 20.95, 95%CI: 7.66-57.31); all P < 0.001. In the patient cohort of gastric cancer, the respective cutoff values showed that low serum folate levels were significantly associated with serosal invasion (OR = 2.54, 95%CI: 1.23-5.23), lymphatic invasion (OR = 2.23, 95%CI: 1.17-4.26), and liver metastasis (OR = 6.67, 95%CI: 1.28-34.91) of gastric cancer (all P < 0.05). Serum folate level below 1.90 ng/mL was associated with poor patient survival (HR = 1.84, 95%CI: 1.04-3.27, P < 0.05) in univariate analysis. CONCLUSION Lower serum folate levels were significantly associated with gastric cancer development and invasive phenotypes. The role of folate depletion in gastric cancer invasion warrants further study.

Osteopontin promoter polymorphisms are associated with susceptibility to gastric cancer.

Goals: To evaluate the significance of osteopontin (OPN) genotypes in the susceptibility to gastric cancer. Background: The expression of OPN has been correlated with development, invasiveness, metastasis, and survival of gastric cancer, but the role of polymorphisms in the OPN promoter has not been investigated. Study: We enrolled 146 gastric cancer patients and 128 controls. DNA was extracted from peripheral blood leucocytes. Single-nucleotide polymorphisms (SNPs) in the OPN promoter (−66, −156, −443, −616, −1748, and −1776) were analyzed by pyrosequencing and direct sequencing methods. Logistic regression analyses were used to evaluate the associations between SNPs and development of gastric cancer. Results: SNP −443 C/C and −616 T/T of the OPN promoter were significantly associated with gastric cancer [odds ratio (OR)=2.88; 95% confidence interval (CI), 1.16-7.12 and OR=1.95; 95% CI, 1.35-2.82, respectively]. Analysis of the combined effect of OPN promoter SNPs revealed that the combination of SNP −443 (T/C or C/C) and SNP −616 (T/T or T/G) had the most significant association with gastric cancer (OR=3.95; 95% CI, 1.58-9.90). Conclusions: Our results suggest that polymorphisms in the OPN promoter are associated with the development of gastric cancer, and the combination of SNP −443 (T/C or C/C) and −616 (T/T or T/G) most significantly increases susceptibility to gastric cancer.

The Incidence of Gastric Adenocarcinoma Among Patients With Gastric Intestinal Metaplasia: A Long-term Cohort Study.

Background and Aims: Gastric intestinal metaplasia (IM) has been known as a premalignant condition, but estimates of its cancer risk vary widely. We aimed to analyze cancer risk of gastric IM by a long-term cohort study. Methods: We conducted a hospital-based study that included all patients with gastric IM between 1992 and 2010, and the development of gastric adenocarcinoma was evaluated until July 2011. Patients developing gastric cancer ⩽180 days after the index diagnosis of IM were excluded. The incidence rate, the cumulative incidence, and the standardized incidence ratio (SIR) of gastric cancer were determined, and hazard ratios (HRs) of risk factors were calculated. Results: We identified 7059 patients with a median follow-up duration of 5.1 years, and 81 patients developed gastric adenocarcinoma during the study period. The 5-, 10-, and 15-year cumulative incidences of gastric cancer were 0.9% [95% confidence interval (CI), 0.6-1.1), 2.0% (95% CI, 1.5-2.6), and 3.0% (95% CI, 2.0-4.0), respectively. On multivariate analysis, older age (eg, 75 y and above; HR=7.4; 95% CI, 2.8-19.6), low-grade dysplasia (HR=4.0; 95% CI, 2.1-7.9), and high-grade dysplasia (HR=18.8; 95% CI, 9.0-39.5) were independent risk factors. As compared with the risk in the general population, the SIR of gastric cancer among patients with gastric IM was 2.5 (95% CI, 2.0-3.1). However, the SIR was only 2.0 (95% CI, 1.5-2.6) in the nondysplasia subgroup, but was up to 35.2 (95% CI, 15.2-69.4) in the high-grade dysplasia subgroup. Conclusions: Gastric IM is an important risk factor for gastric cancer, but surveillance should be arranged only for those at an especially high risk.

The occurrence of hepatocellular carcinoma in different risk stratifications of clinically noncirrhotic nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) may be a cause of hepatocellular carcinoma (HCC), but its high prevalence challenges current surveillance strategies. We aimed to evaluate HCC incidences in different risk stratifications for noncirrhotic NAFLD. Using Taiwans National Health Insurance Research Database, we located 31,571 patients with NAFLD between the years 1998 and 2012. After excluding other causes of hepatitis, underlying cirrhosis or malignancy, 18,080 patients were recruited for final analysis. Cumulative incidences of HCC were analyzed after adjusting for competing mortality. With a median follow‐up duration of 6.32 years in the study cohort, the 10‐year cumulative incidence of HCC was 2.73% [95% confidence interval (CI): 1.69–3.76%]. Hepatoprotectant was used as a surrogate marker for elevated serum alanine transaminase (ALT). After adjusting for age, gender, hypertension, hypercholesterolemia, diabetes mellitus, gout, statin use, metformin use and aspirin use, elevated ALT was independently associated with an increased HCC risk [hazard ratio (HR) 6.80, 95% CI: 3.00–15.42; p < 0.001]. Multivariate stratified analysis verified this association in all subgroups (HR> 1.0). Moreover, increased age (HR 1.08 per year, 95% CI: 1.05–1.11) and statin use (HR 0.29, 95% CI: 0.12–0.68) were also identified as independent risk factors. The 10‐year cumulative HCC incidence was highest in older (age >55 years) patients with ALT elevation (12.41%, 95% CI: 5.99–18.83%), but lowest in younger patients without ALT elevation (0.36%, 95% CI: 0–1.08%). The incidence of HCC was relatively low in patients with clinically noncirrhotic NAFLD, however, HCC risk was significantly increased in older patients experiencing an elevated serum ALT.

Evaluation of the Effect of Cumulative Operator Experience on Hepatocellular Carcinoma Recurrence after Primary Treatment with Radiofrequency Ablation

PURPOSE To investigate the association between cumulative operator volume and the risk of hepatocellular carcinoma (HCC) recurrence after potentially curative radiofrequency ablation (RFA). MATERIALS AND METHODS This study was approved by the Research Ethics Committee. By using the Taiwan National Health Insurance Research Database, 52 096 patients with HCC were identified between July 1, 2004, and December 31, 2011. In total, 2827 patients were selected who underwent potentially curative RFA for newly diagnosed HCC. These patients were grouped into quintiles according to the cumulative operator volumes. Patients in the lowest or the highest quintiles were 1:1 matched according to their propensity scores. Finally, two separate groups, each containing 406 patients, were recruited in the high- and low-volume groups (cumulative operator volume of ≥79 cases and ≤10 cases, respectively). Cumulative incidences of and hazard ratios for HCC recurrence were analyzed after adjusting for competing mortality. RESULTS The HCC recurrence rate of the high-volume group was significantly lower than that of the low-volume group (high-volume group 5-year recurrence rate of 65.8%, 95% confidence interval [CI]: 59.5%, 72.1%; low-volume group 5-year recurrence rate of 71.4%, 95% CI: 66.2%, 76.5%; P < .05). In modified Cox regression analysis, the highest cumulative operator volume was independently associated with a decreased risk of HCC recurrence (hazard ratio, 0.80; 95% CI: 0.67, 0.97; P < .05). Multivariable stratified analyses verified the association between the highest cumulative operator volume and decreased HCC recurrence in almost all subgroups. CONCLUSION The risk of HCC recurrence could be significantly decreased by experienced RFA operators. Further studies based on cumulative operator volume may be helpful in improving the quality of RFA for HCC.

Effect of Nucleos(t)ide Analogue Therapy on Risk of Intrahepatic Cholangiocarcinoma in Patients With Chronic Hepatitis B

BACKGROUND & AIMS: Chronic infection with hepatitis B virus (HBV) increases risk of intrahepatic cholangiocarcinoma (ICC), but it is not clear whether antiviral therapy reduces risk. We investigated the association between nucleos(t)ide analogue therapy and ICC risk. METHODS: We performed a nationwide long‐term cohort study using Taiwan’s National Health Insurance Research Database to obtain data on 185,843 patients with chronic HBV infection from October 1, 2003 through December 31, 2012. We excluded patients with confounding disorders such as infection with hepatitis C virus, HIV, or other hepatitis‐associated viruses; liver flukes; biliary stone diseases; cholangitis; congenital biliary anomalies; biliary tract surgeries; or cancer. We identified 10,062 patients who received nucleos(t)ide analogue therapy (the treated group), and used propensity scores to match them (1:1) with patients who received hepatoprotectants (the untreated group). Cumulative incidences of and hazard ratios (HRs) for ICC development were analyzed. RESULTS: The cumulative incidence of ICC was significantly lower in the treated group after 3 years of therapy (1.28%; 95% CI, 0.56–2.01) than in the untreated group (3.14%; 95% CI, 2.02–4.27) and after 5 years of therapy (1.53%; 95% CI, 0.73–2.33 vs 4.32% in untreated group; 95% CI, 2.96–5.6869). In multivariable regression analysis, nucleos(t)ide analogue therapy was independently associated with a reduced risk of ICC (HR, 0.44; 95% CI, 0.25–0.78; P = .005). Older age (HR 1.05 per year; 95% CI, 1.03–1.07) and cirrhosis (HR, 2.80; 95% CI, 1.52–5.1415) were independently associated with an increased risk of ICC. Sensitivity analyses verified the association between nucleos(t)ide analogue therapy and a reduced ICC risk. CONCLUSION: A nationwide long‐term cohort study in Taiwan showed that nucleos(t)ide analogue therapy for chronic HBV infection is significantly associated with a reduced ICC risk.

Development of a scoring system to predict hepatocellular carcinoma in Asians on antivirals for chronic hepatitis B

BACKGROUND & AIMS The risk of hepatocellular carcinoma (HCC) during antiviral therapy in patients with chronic hepatitis B (CHB) is inadequately predicted by the scores built from untreated patients. We aimed at developing and validating a risk score to predict HCC in patients with CHB on entecavir or tenofovir treatment. METHODS This study analysed population-wide data from the healthcare databases in Taiwan and Hong Kong to identify patients with CHB continuously receiving entecavir or tenofovir. The development cohort included 23,851 patients from Taiwan; 596 (2.50%) of them developed HCC with a three-year cumulative incidence of 3.56% (95% CI 3.26-3.86%). The multivariable Cox proportional hazards model found that cirrhosis, age (cirrhosis and age interacted with each other), male sex, and diabetes mellitus were the risk determinants. These variables were weighted to develop the cirrhosis, age, male sex, and diabetes mellitus (CAMD) score ranging from 0 to 19 points. The score was externally validated in 19,321 patients from Hong Kong. RESULTS The c indices for HCC in the development cohort were 0.83 (95% CI 0.81-0.84), 0.82 (95% CI 0.81-0.84), and 0.82 (95% CI 0.80-0.83) at the first, second, and third years of therapy, respectively. In the validation cohort, the c indices were 0.74 (95% CI 0.71-0.77), 0.75 (95% CI 0.73-0.78), and 0.75 (95% CI 0.72-0.77) during the first three years, and 0.76 (95% CI 0.74-0.78) and 0.76 (95% CI 0.74-0.77) in the extrapolated fourth and fifth years, respectively. The predicted and observed probabilities of HCC were calibrated in both cohorts. A score <8 and >13 points identified patients at distinctly low and high risks. CONCLUSIONS The easily calculable CAMD score can predict HCC and may inform surveillance policy in patients with CHB during oral antiviral therapy. LAY SUMMARY This study analyses population-wide data from the healthcare systems in Taiwan and Hong Kong to develop and validate a risk score that predicts hepatocellular carcinoma during oral antiviral therapy in patients with chronic hepatitis B. The easily calculable CAMD score requires only simple information (i.e. cirrhosis, age, male sex, and diabetes mellitus) at the baseline of treatment initiation. With a scoring range from 0 to 19 points, the CAMD score discriminates the risk of hepatocellular carcinoma with a concordance rate of around 75-80% during the first three years on therapy. The risk prediction can be extrapolated to five years on treatment with similar accuracy. Patients with a score <8 and >13 points were exposed to distinctly lower and higher risks, respectively.