Fibrotic Burden in the Liver Differs Across Metabolic Dysfunction-Associated Fatty Liver Disease Subtypes.

Background/Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is categorized into three subtypes: overweight/obese (OW), lean/normal weight with metabolic abnormalities, and diabetes mellitus (DM). We investigated whether fibrotic burden in liver differs across subtypes of MAFLD patients. Methods: This cross-sectional multicenter study was done in cohorts of subjects who underwent a comprehensive medical health checkup between January 2014 and December 2020. A total of 42,651 patients with ultrasound-diagnosed fatty liver were included. Patients were classified as no MAFLD, OW-MAFLD, lean-MAFLD, and DM-MAFLD. Advanced liver fibrosis was defined based on the nonalcoholic fatty liver disease fibrosis score (NFS) or fibrosis-4 (FIB-4) index. Results: The mean age of the patients was 50.0 years, and 74.1% were male. The proportion of patients with NFS-defined advanced liver fibrosis was the highest in DM-MAFLD (6.6%), followed by OW-MAFLD (2.0%), lean-MAFLD (1.3%), and no MAFLD (0.2%). The proportion of patients with FIB-4-defined advanced liver fibrosis was the highest in DM-MAFLD (8.6%), followed by lean-MAFLD (3.9%), OW-MAFLD (3.0%), and no MAFLD (2.0%). With the no MAFLD group as reference, the adjusted odds ratios (95% confidence intervals) for NFS-defined advanced liver fibrosis were 4.46 (2.09 to 9.51), 2.81 (1.12 to 6.39), and 9.52 (4.46 to 20.36) in OW-MAFLD, lean-MAFLD, and DM-MAFLD, respectively, and the adjusted odds ratios for FIB-4-defined advanced liver fibrosis were 1.03 (0.78 to 1.36), 1.14 (0.82 to 1.57), and 1.97 (1.48 to 2.62) in OW-MAFLD, lean-MAFLD, and DM-MAFLD. Conclusions: Fibrotic burden in the liver differs across MAFLD subtypes. Optimized surveillance strategies and therapeutic options might be needed for different MAFLD subtypes.

Outcome of untreated low-level viremia versus antiviral therapy-induced or spontaneous undetectable HBV-DNA in compensated cirrhosis.

BACKGROUND: Comparative outcomes of HBV-infected compensated cirrhosis with low-level viremia (LLV) versus maintained virological response (MVR) are unclear. We conducted a large, multiethnic, multicenter study to examine the natural history of LLV versus MVR in compensated cirrhosis. PATIENTS AND METHODS: We enrolled patients with HBV-infected compensated cirrhosis (n=2316) from 19 hospitals in South Korea, Singapore, and Japan. We defined the LLV group as untreated patients with ≥1 detectable serum HBV-DNA (20-2000 IU/mL), Spontaneous-MVR group as untreated patients with spontaneously achieved MVR, and antiviral therapy (AVT)-MVR group as patients achieving AVT-induced MVR. Study end points were HCC or hepatic decompensation. RESULTS: The annual HCC incidence was 2.7/100 person-years (PYs), 2.6/100 PYs, and 3.3/100 PYs for LLV (n=742), Spontaneous-MVR (n=333), and AVT-MVR (n=1241) groups, respectively ( p = 0.81 between LLV vs. Spontaneous-MVR groups and p = 0.37 between LLV vs. AVT-MVR groups). Similarly, the annual decompensation incidence was 1.6/100 PYs, 1.9/100 PYs, and 1.6/100 PYs for LLV, Spontaneous-MVR, and AVT-MVR groups, respectively ( p = 0.40 between LLV vs. Spontaneous-MVR groups and p = 0.83 between LLV vs. AVT-MVR groups). Multivariable analyses determined that HCC and decompensation risks in the LLV group were comparable to those with Spontaneous-MVR and AVT-MVR groups (all p >0.05). Propensity score matching also reproduced similar results for HCC and decompensation risks (all p >0.05 between LLV vs. Spontaneous-MVR groups and between LLV vs. AVT-MVR groups). CONCLUSIONS: Untreated LLV in HBV-infected compensated cirrhosis is not associated with increased risk of disease progression compared with Spontaneous-MVR and AVT-MVR. These data have important implications for practice and further research.

Long-term cardiovascular outcomes differ across metabolic dysfunction-associated fatty liver disease subtypes among middle-aged population.

BACKGROUND AND AIMS: The new metabolic dysfunction-associated fatty liver disease (MAFLD) criteria include the following three distinct subtypes: MAFLD with diabetes mellitus (DM), overweight/obese (OW), or lean/normal weight with metabolic dysfunction. We investigated whether long-term cardiovascular disease outcomes differ across the MAFLD subtypes. METHODS: From a nationwide health screening database, we included 8,412,730 participants (48.6% males) aged 40-64 years, free of cardiovascular disease history, between 2009 and 2010. Participants were categorized into non-MAFLD, OW-MAFLD, lean-MAFLD, and DM-MAFLD. The primary outcome was a composite cardiovascular disease event, including myocardial infarction, ischemic stroke, heart failure, or cardiovascular disease-related death. The presence of advanced liver fibrosis was estimated using a BARD score ≥ 2. RESULTS: Among the study participants, 3,087,640 (36.7%) had MAFLD, among which 2,424,086 (78.5%), 170,761 (5.5%), and 492,793 (16.0%) had OW-MAFLD, lean-MAFLD, and DM-MAFLD, respectively. Over a median follow-up period of 10.0 years, 169,433 new cardiovascular disease events occurred. With the non-MAFLD group as reference, multivariable-adjusted hazard ratios (95% confidence intervals) for cardiovascular disease events were 1.16 (1.15-1.18), 1.23 (1.20-1.27), and 1.82 (1.80-1.85) in the OW-MAFLD, lean-MAFLD, and DM-MAFLD groups, respectively. Participants with lean-MAFLD or DM-MAFLD had a higher cardiovascular disease risk than those with OW-MAFLD, irrespective of metabolic abnormalities or comorbidities. The presence of advanced liver fibrosis was significantly associated with a higher cardiovascular disease risk in each MAFLD subtype. CONCLUSION: Long-term cardiovascular disease outcomes differed across the MAFLD subtypes. Further studies are required to investigate whether preventive or therapeutic interventions should be optimized according to the MAFLD subtypes.

External Validation of the FSAC Model Using On-Therapy Changes in Noninvasive Fibrosis Markers in Patients with Chronic Hepatitis B: A Multicenter Study.

Antiviral therapy (AVT) induces the regression of non-invasive fibrosis markers (NFMs) and reduces hepatocellular carcinoma (HCC) risk among chronic hepatitis B (CHB) patients. We externally validated the predictive performance of the FSAC prediction model for HCC using on-therapy NFM responses. Our multicenter study consecutively recruited treatment-naïve CHB patients (n = 3026; median age, 50.0 years; male predominant (61.3%); cirrhosis in 1391 (46.0%) patients) receiving potent AVTs for >18 months between 2007 and 2018. During follow-up (median 64.0 months), HCC developed in 303 (10.0%) patients. Patients with low FIB-4 or APRI levels at 12 months showed significantly lower HCC risk than those with high NFM levels at 12 months (all p < 0.05). Cumulative 3-, 5-, and 8-year HCC probabilities were 0.0%, 0.3% and 1.2% in the low-risk group (FSAC ≤ 2); 2.1%, 5.2%, and 11.1% in the intermediate-risk group (FSAC 3-8); and 5.2%, 15.5%, and 29.8% in the high-risk group (FSAC ≥ 9) (both p < 0.001 between each adjacent pair). Harrell's c-index value for FSAC score (0.770) was higher than those for PAGE-B (0.725), modified PAGE-B (0.738), modified REACH-B (0.737), LSM-HCC (0.734), and CAMD (0.742). Our study showed that the FSAC model, which incorporates on-therapy changes in NFMs, had better predictive performance than other models using only baseline parameters.

Suboptimal Performance of Hepatocellular Carcinoma Prediction Models in Patients with Hepatitis B Virus-Related Cirrhosis.

This study aimed to evaluate the predictive performance of pre-existing well-validated hepatocellular carcinoma (HCC) prediction models, established in patients with HBV-related cirrhosis who started potent antiviral therapy (AVT). We retrospectively reviewed the cases of 1339 treatment-naïve patients with HBV-related cirrhosis who started AVT (median period, 56.8 months). The scores of the pre-existing HCC risk prediction models were calculated at the time of AVT initiation. HCC developed in 211 patients (15.1%), and the cumulative probability of HCC development at 5 years was 14.6%. Multivariate Cox regression analysis revealed that older age (adjusted hazard ratio [aHR], 1.023), lower platelet count (aHR, 0.997), lower serum albumin level (aHR, 0.578), and greater LS value (aHR, 1.012) were associated with HCC development. Harrell's c-indices of the PAGE-B, modified PAGE-B, modified REACH-B, CAMD, aMAP, HCC-RESCUE, AASL-HCC, Toronto HCC Risk Index, PLAN-B, APA-B, CAGE-B, and SAGE-B models were suboptimal in patients with HBV-related cirrhosis, ranging from 0.565 to 0.667. Nevertheless, almost all patients were well stratified into low-, intermediate-, or high-risk groups according to each model (all log-rank p < 0.05), except for HCC-RESCUE (p = 0.080). Since all low-risk patients had cirrhosis at baseline, they had unneglectable cumulative incidence of HCC development (5-year incidence, 4.9−7.5%). Pre-existing risk prediction models for patients with chronic hepatitis B showed suboptimal predictive performances for the assessment of HCC development in patients with HBV-related cirrhosis.

Novel Liver Stiffness-Based Nomogram for Predicting Hepatocellular Carcinoma Risk in Patients with Chronic Hepatitis B Virus Infection Initiating Antiviral Therapy.

Hepatocellular carcinoma (HCC) risk prediction is important to developing individualized surveillance approaches. We designed a novel HCC prediction model using liver stiffness on transient elastography for patients receiving antiviral therapy against hepatitis B virus (HBV) infection. We recruited 2037 patients receiving entecavir or tenofovir as first-line antivirals and used the Cox regression analysis to determine key variables for model construction. Within 58.1 months (median), HCC developed in 182 (8.9%) patients. Patients with HCC showed a higher prevalence of cirrhosis (90.7% vs. 45.9%) and higher liver stiffness values (median 13.9 vs. 7.2 kPa) than those without. A novel nomogram (score 0-304) was established using age, platelet count, cirrhosis development, and liver stiffness values, which were independently associated with increased HCC risk, along with hepatitis B e antigen positivity and serum albumin and total bilirubin levels. Cumulative HCC probabilities were 0.7%, 5.0%, and 22.7% in the low- (score ≤87), intermediate- (88-222), and high-risk (≥223) groups, respectively. The c-index value was 0.799 (internal validity: 0.805), higher than that of the PAGE-B (0.726), modified PAGE-B (0.756), and modified REACH-B (0.761) models (all p < 0.05). Our nomogram showed acceptable performance in predicting HCC in Asian HBV-infected patients receiving potent antiviral therapy.

Risk assessment of hepatocellular carcinoma and liver-related events using ultrasonography and transient elastography in patients with chronic hepatitis B.

Cirrhosis has prognostic value. We investigated whether the combined use of ultrasonography (US) and transient elastography (TE) to diagnose cirrhosis is beneficial for the risk assessment of hepatocellular carcinoma (HCC) and liver-related events in patients with chronic hepatitis B (CHB). A total of 9300 patients with CHB who underwent US and TE in two institutions between 2006 and 2018 were enrolled. TE value ≥13 kPa was set to indicate cirrhosis. Patients were divided into four groups: US(+)TE(+) (cirrhosis by US and TE), US(+)TE(-) (cirrhosis by US, but not by TE), US(-)TE(+) (cirrhosis by TE, but not by US) and US(-)TE(-) (non-cirrhosis by US and TE).The patients were predominantly male (n = 5474, 58.9%) with a mean age of 47.5 years. The proportions of patients with cirrhosis diagnosed by US and TE were 17.2% (n = 1595) and 13.2% (n = 1225), respectively. The proportion of patients with discordant results in diagnosing cirrhosis by US and TE was 18.7% (n = 1740). During follow-up (median: 60.0 months), HCC and liver-related events developed in 481 (5.2%) and 759 (8.2%) patients, respectively. The cumulative incidence rates of HCC and liver-related events were highest in the US(+)TE(+) group, intermediate-high in the US(-)TE(+) group, intermediate-low in the US(+)TE(-) group and lowest in the US(-)TE(-) group (overall p < .001). Cirrhosis assessed using US and TE was a major predictor of HCC and liver-related event development in patients with CHB. Cirrhosis assessed using TE seemed better in predicting HCC or liver-related events than using US, when cirrhosis diagnosis was discordant by US and TE.

Predictive score for hepatocellular carcinoma after hepatitis B e antigen loss in patients treated with entecavir or tenofovir.

The risk of developing hepatocellular carcinoma (HCC) after hepatitis B e antigen seroclearance (ESC) remains unclear. We established and validated a new risk prediction model for HCC development after ESC in patients with chronic hepatitis B (CHB) receiving antiviral therapy (AVT). Between 2006 and 2016, 769 patients (training cohort) and 1,061 patients (validation cohort) with CHB who experienced ESC during AVT using entecavir (ETV) or tenofovir disoproxil fumarate (TDF) were recruited. In the multivariate analysis, male sex (hazard ratio [HR] = 2.092; 95% confidence interval [CI] = 1.152-3.800), cirrhosis (HR = 5.141; 95% CI = 2.367-11.167) and fibrosis-4 index (FIB-4) of >3.25 (HR = 2.070; 95% CI = 1.184-3.620) were the independent risk factors for HCC development (all P < .05). Accordingly, a novel HCC-ESCAVT model was developed (1x[sex: male = 1, female = 0] + 3x(cirrhosis = 1, noncirrhosis = 0) + 1x(FIB-4: >3.25 = 1, ≤3.25 = 0). The cumulative risk for HCC development was significantly different among the risk groups based on the HCC-ESCAVT category (0-1, 2-4 and 5 for the low-, intermediate- and high-risk groups, respectively) (overall P < .001, log-rank test). The area under the receiver operating characteristic curve (AUC) for predicting HCC development 3, 5 and 10 years after ESC was 0.791, 0.771 and 0.790, respectively (all P < .05). The predictive value of the HCC-ESCAVT model was similar in the validation cohort (AUC = 0.802, 0.774 and 0.776 at 3, 5 and 10 years, respectively; all P < .05). Hence, we have developed and validated a new HCC-ESCAVT model for HCC development, which includes male sex, cirrhosis and FIB-4 of >3.25 as constituent variables.

Sarcopenia Is Independently Associated with the Degree of Liver Fibrosis in Patients with Type 2 Diabetes Mellitus.

Background/Aims: Sarcopenia is associated with liver fibrosis in patients with nonalcoholic fatty liver disease and chronic hepatitis B. We investigated the association between sarcopenia and hepatic fibrotic burden in patients with type 2 diabetes mellitus (T2DM). Methods: Patients with T2DM who had received a comprehensive medical health checkup were recruited. Muscle mass was assessed using computed tomography. Fibrotic burden was assessed using the fibrosis-4 index (FIB-4). The study population was divided by quartile stratification of the lumbar skeletal muscle index (LSMI). Results: Among 309 patients with T2DM, 75 (24.3%) had sarcopenia. These patients were significantly older and had higher FIB-4, whereas they had significantly lower body mass index (BMI) and LSMI than patients without sarcopenia (all p<0.05). The LSMI showed a significant negative correlation with the FIB-4 when analyzed in terms of quartile stratification (p=0.003). Multivariate analysis showed that female sex and higher BMI were independently associated with a reduced risk of sarcopenia (odds ratio [OR], 0.388; 95% confidence interval [CI], 0.199 to 0.755 and OR, 0.704; 95% CI, 0.618 to 0.801; all p<0.05), whereas a higher FIB- 4 was independently associated with an increased risk of sarcopenia (OR, 1.817; 95% CI, 1.180 to 2.797; p=0.007). Among patients with a BMI <25 kg/m2 (n=165), those with sarcopenia (n=54, 32.7%) had a significantly higher FIB-4 than those without (n=111, 67.3%; 1.66 vs 1.38, p=0.004). Conclusions: Sarcopenia is independently associated with fibrotic burden in patients with T2DM. Further studies should investigate whether the improvement of sarcopenia can ameliorate liver fibrosis in patients with T2DM.

An observational study on long-term renal outcome in patients with chronic hepatitis B treated with tenofovir disoproxil fumarate.

In patients with chronic hepatitis B (CHB), long-term effects of tenofovir disoproxil fumarate (TDF) on renal function have been controversial. This study aimed to analyse the real-world long-term effects of TDF on renal function in Korean patients with CHB. We analysed a cohort of 640 treatment-naïve patients with CHB who were treated with TDF between May 2012 and December 2015 at Severance Hospital, Seoul, Republic of Korea. The mean age was 48.3 years old, and 59.5% were male. The proportions of hypertension and diabetes mellitus (DM) were 11.6% and 14.2%, respectively, and that of liver cirrhosis was 20.8%. During the 5-year follow-up, using a linear mixed model, serum creatinine increased from 0.77 ± 0.01 mg/dL to 0.85 ± 0.02 mg/dL (P < .001), and eGFR decreased from 102.6 ± 0.6 mL/min/1.73 m2 to 93.4 ± 1.4 mL/min/1.73 m2 (P < .001). In subgroup analysis, eGFR was statistically more decreased in patients with age > 60 than ≦60 years old (P = .027), and in patients with diuretic use than without diuretic use (P = .008). In multivariate analysis, the independent risk factors for eGFR decrease > 20% were baseline eGFR < 60mL/min/1.73 m2 (P = .034) and the use of diuretics (P < .001). CHB patients on TDF experienced greater reduction in renal function with age > 60 and with diuretic use compared to those without these characteristics. Baseline eGFR < 60 mL/min/1.73 m2 and use of diuretics were independent risk factors of eGFR decline of more than 20% on TDF therapy.

Establishment and validation of a risk prediction model in patients with hepatocellular carcinoma treated with transarterial radioembolization.

BACKGROUND/AIMS: Few studies have reported the treatment outcomes of transarterial radioembolization (TARE) using yttrium-90 (Y) for hepatocellular carcinoma (HCC). We established and validated a new risk prediction model for patients with HCC treated with TARE. METHODS: Between 2010 and 2017, 113 and 35 patients with intrahepatic HCC treated with TARE were selected for the training and validation cohorts, respectively. The modified response evaluation criteria in solid tumors (mRECIST) were used for response evaluation. RESULTS: In the training cohort, the median age was 64.1 years (92 males and 21 females) and the mean survival after TARE was 50.3 months. The cumulative survival rates at six and 12 months were 92.0 and 84.0%, respectively. A new risk prediction model for patients with HCC treated with TARE (Y-scoring system) was established from the training cohort using five independent baseline variables [serum albumin < 3.5 g/dL, hazard ratio = 5.446; alpha-fetoprotein > 200 ng/mL (hazard ratio = 5.071); tumor number ≥ 3 (hazard ratio = 2.933); portal vein thrombosis (hazard ratio = 4.915); and hepatic vein invasion (hazard ratio = 8.500)] and two on-treatment variables [no des-gamma-carboxy prothrombin response (hazard ratio = 15.346) and progressive disease at three months (hazard ratio = 4.154)] for mortality (all P < 0.05). The predictive accuracy of the Y-scoring system was acceptable to predict six [area under the curve (AUC) = 0.845], nine (AUC = 0.868), and 12-month mortality (AUC = 0.886) (all P < 0.05). The predictive accuracy of the system was similarly maintained in the validation cohort (AUC 0.737-0.901 at 6-12 months). CONCLUSION: Our new risk prediction model can be used to stratify different prognoses in patients with HCC treated with TARE. Validation studies are required.

Diagnostic Performance of Serum Asialo-α1-acid Glycoprotein for Advanced Liver Fibrosis or Cirrhosis in Patients with Chronic Hepatitis B or Nonalcoholic Fatty Liver Disease.

BACKGROUND/AIMS: The utility of asialo-α1-acid glycoprotein (AsAGP) for assessing the fibrotic burden is unknown. This study examined the diagnostic performance of the AsAGP level for advanced liver fibrosis or cirrhosis in patients with chronic hepatitis B (CHB) or nonalcoholic fatty liver disease (NAFLD). METHODS: From July to December 2018, 48 patients with CHB and 75 with NAFLD were recruited prospectively. Transient elastography was used as the reference standard for liver fibrosis, and the cutoff liver stiffness values were defined as 10.0 kilopascal (kPa) for ≥F3 and 12.0 kPa for F4 in CHB patients, and 9.0 kPa for ≥F3 and 11.8 kPa for F4 in NAFLD patients. RESULTS: To predict stage ≥F3 and F4 fibrosis, the areas under the receiver operating characteristic curves of the AsAGP level in patients with CHB were 0.788 (95% CI 0.647-0.930; p=0.005) and 0.825 (95% CI 0.674-0.976; p=0.004), respectively. The cutoff AsAGP levels in patients with CHB that maximized the sum of the sensitivity and specificity values were 1.31 (sensitivity 100.0%, specificity 52.6%) and 1.55 (sensitivity 75.0%, specificity 80.0%), respectively. In contrast, the AsAGP level was similar regardless of the fibrosis stage in patients with NAFLD (all p>0.05 between the stages). CONCLUSIONS: The AsAGP level showed acceptable diagnostic accuracy in predicting advanced liver fibrosis and cirrhosis in patients with CHB but not in those with NAFLD. Further studies will be needed to validate the diagnostic performance of the AsAGP level in patients with NALFD.

Alpha-Fetoprotein, Des-Gamma-Carboxy Prothrombin, and Modified RECIST Response as Predictors of Survival after Transarterial Radioembolization for Hepatocellular Carcinoma.

PURPOSE: To evaluate the prognostic role of alpha-fetoprotein (AFP), des-gamma-carboxy protein (DCP), and modified Response Evaluation Criteria in Solid Tumors (mRECIST) in patients with hepatocellular carcinoma after transarterial radioembolization (TARE). MATERIALS AND METHODS: During 2009-2016, 63 patients with AFP >20 ng/mL, DCP >20 mAU/mL, and Child-Pugh class A who were treated with TARE were evaluated using landmark and risk-of-death method after TARE. Both resin microspheres (n = 46) and glass microspheres (n = 17) were used. AFP or DCP response was defined as more than 50% decrease from baseline. mRECIST response was defined as complete or partial response. Median age was 60 years, and the proportion of male sex was 77.8% (n = 49). The proportions of patients with Barcelona Clinic Liver Cancer stages A, B, and C were 7.9% (n = 5), 46.0% (n = 29), and 46.0% (n = 29), respectively. RESULTS: At the 3-month landmark, AFP, DCP, and mRECIST responders lived longer than nonresponders (median overall survival, 75.8 vs 7.6 months for AFP; 75.8 vs 7.1 months for DCP; and 75.8 vs 10.0 months for mRECIST; all P < .05). The 6-month risk of death at the 3-month landmark was statistically different only between DCP responders and nonresponders (P = .002). In multivariate analysis, age less than 70 years (P = .024), absence of distant metastasis (P = .049), DCP response (P = .003), and mRECIST response (P = .003) were independent predictors for overall survival at the 3-month landmark after TARE. CONCLUSIONS: AFP, DCP, and mRECIST responders showed better prognosis than nonresponders after TARE, and DCP response was a more potent predictor than AFP response. Tumor marker response, as well as radiologic response, may be useful to predict post-TARE survival.

Transarterial Chemoembolization in Treatment-Naïve and Recurrent Hepatocellular Carcinoma: A Propensity-Matched Outcome Analysis.

OBJECTIVES: Transarterial chemoembolization (TACE) improves the survival of patients with hepatocellular carcinoma (HCC); however, TACE treatment outcomes of patients with treatment-naïve HCC (TN-HCC) and those with recurrent HCC after curative resection (R-HCC) have not yet been compared. METHODS: We recruited 448 patients with TN-HCC, and 275 patients with R-HCC treated with TACE as first-line anti-cancer treatment. RESULTS: At first TACE, patients with TN-HCC showed a significantly lower proportion of male gender (74.9% vs. 84.3%), higher proportion of liver cirrhosis (61.9% vs. 49.3%), higher aspartate aminotransferase (median 48 vs. 31 IU/L), alanine aminotransferase (median 38 vs. 26 IU/L), alpha-fetoprotein (AFP) (median 96.6 vs. 7.7 ng/mL), and total bilirubin (mean 1.0 vs. 0.8 mg/dL) levels, longer prothrombin time (median 1.05 vs. 1.01 international normalized ratio), higher tumor number (mean 2.1 vs. 1.7), larger tumor size (median 3.1 vs. 1.6 cm), and lower proportion of Barcelona Clinic Liver Cancer stage 0-A (55.6% vs. 71.9%) than patients with R-HCC (all P < 0.05). Multivariate analysis showed that TACE for TN-HCC (vs. R-HCC) was an independent predictor of mortality (hazard ratio, 1.328; P = 0.024) with AFP level and tumor number (all P < 0.05). However, treatment outcomes between TN-HCC and R-HCC became statistically similar after propensity score-matched (PSM) analysis using liver cirrhosis, tumor size, and multiple tumors (P < 0.05). CONCLUSIONS: Based on the similar TACE treatment outcomes observed with the PSM analysis, the current TACE treatment guideline for patients with TN-HCC might similarly be applied for patients with R-HCC.

Refractoriness to transarterial chemoembolization in patients with recurrent hepatocellular carcinoma after curative resection.

BACKGROUND/AIMS: It is important to identify patients who are refractory to transarterial chemoembolization (TACE), which is performed for the treatment of hepatocellular carcinoma (HCC). We investigated the predictors of poor treatment outcomes in patients with recurrent HCC treated who were treated with TACE after curative resection. METHODS: 428 patients with recurrent HCC after curative resection who were treated with TACE were enrolled. RESULTS: The median age of the study population was 59.2 years. On multivariate analysis, ≥2 TACE procedures within 6 months (hazard ratio [HR] = 1.898), and the des-gamma carboxyprothrombin level (HR = 1.000) independently predicted the progression to Barcelona Clinic Liver Cancer (BCLC) stage C in patients with BCLC stage 0-B HCC (both P<0.05). In addition, ≥2 and ≥3 TACE procedures within 6 months independently predicted mortality in the entire study population (HR = 1.863 and 1.620, respectively). The probability of progression to BCLC stage C in patients with BCLC stage 0-B HCC and the mortality rate in the entire study population were significantly higher in patients treated with ≥2 TACE within 6 months than in those who underwent fewer procedures (P = 0.002 and P<0.001, respectively). CONCLUSIONS: More than 2 TACE procedures within 6 months might be associated with the refractoriness to TACE in patients with recurrent HCC after curative resection.

Predictors of Discordance in the Assessment of Skeletal Muscle Mass between Computed Tomography and Bioimpedance Analysis.

Computed tomography (CT) and bioimpedance analysis (BIA) can assess skeletal muscle mass (SMM). Our objective was to identify the predictors of discordance between CT and BIA in assessing SMM. Participants who received a comprehensive medical health check-up between 2010 and 2018 were recruited. The CT and BIA-based diagnostic criteria for low SMM are as follows: Defined CT cutoff values (lumbar skeletal muscle index (LSMI) <1 standard deviation (SD) and means of 46.12 cm²/m² for men and 34.18 cm²/m² for women) and defined BIA cutoff values (appendicular skeletal muscle/height² <7.0 kg/m² for men and <5.7 kg/m² for women). A total of 1163 subjects were selected. The crude and body mass index (BMI)-adjusted SMM assessed by CT were significantly associated with those assessed by BIA (correlation coefficient = 0.78 and 0.68, respectively; p < 0.001). The prevalence of low SMM was 15.1% by CT and 16.4% by BIA. Low SMM diagnosed by CT was significantly associated with advanced age, female gender, and lower serum albumin level, whereas low SMM diagnosed by BIA was significantly associated with advanced age, female gender, and lower BMI (all p < 0.05). Upon multivariate analysis, age >65 years, female and BMI <25 kg/m² had significantly higher risks of discordance than their counterparts (all p < 0.05). We found a significant association between SMM assessed by CT and BIA. SMM assessment using CT and BIA should be interpreted cautiously in older adults (>65 years of age), female and BMI <25 kg/m².

Conditional Survival Estimates Improve Over Time for Patients with Hepatocellular Carcinoma: An Analysis for Nationwide Korea Cancer Registry Database.

PURPOSE: Conditional survival estimates (CSE) can provide additional useful prognostic information on the period of survival after diagnosis, which helps in counseling patients with cancer on their individual prognoses. This study aimed to analyze conditional survival (CS) for hepatocellular carcinoma (HCC) using a Korean national registry. MATERIALS AND METHODS: Patients with HCC, registered in the Korean cancer registry database, were retrospectively reviewed. Overall survival (OS) was calculated using the Kaplan-Meier method. The 1-year CS at X year or month after diagnosis were calculated as CS1=OS(X+1)/OS(X). CS calculations were performed in each Barcelona Clinic Liver Cancer stage, after which patients at stage 0, A, and B underwent subgroup analysis using initial treatment methods. RESULTS: A total of 4,063 patients diagnosed with HCC from January 2008 to December 2010, and 2,721 who were diagnosed from January 2011 to December 2012, were separately reviewed. In 2008-2010, the 1-year CS of 1, 2, 3, 4, and 5-year survivors was 82.9%, 85.1%, 88.3%, 88.0%, and 88.6%, respectively. Patients demonstrated an increase in CSE over time in subgroup analysis, especially in the advanced stages. In 2011-2012, the 1-year CS of 6, 12, 18, 24, 30, and 36 months was 81.5%, 83.8%, 85.3%, 85.5%, 86.5%, and 88.8%, respectively. The subgroup analysis showed the same tendency towards increased CSE in the advanced stages. CONCLUSION: Overall, the CS improved with each additional year after diagnosis in both groups. CSE may therefore provide a more accurate prognosis and hopeful message to patients who are surviving with or after treatment.

Multicenter retrospective analysis of the safety and efficacy of regorafenib after progression on sorafenib in Korean patients with hepatocellular carcinoma.

Background The pivotal RESORCE trial showed that regorafenib was effective as second-line therapy for patients with advanced HCC who progressed on first-line sorafenib. Real-world data are needed to assess clinical outcomes and adverse events in the setting of daily practice. Methods Between April 2017 and August 2017, the Named Patient Program (NPP) was activated to provide controlled, pre-approval access of regorafenib in Korea. This analysis is a multicenter retrospective study of patients who received regorafenib under the NPP. Results A total of 49 patients entered into this NPP, and 40 patients received regorafenib in five Korean institutions. All but one patient received regorafenib as second-line therapy after progression on sorafenib, and 36 (90%) and 34 (85%) patients were classified as Child-Pugh A and BCLC stage C, respectively. The response rate was 10% (n = 4). The median progression-free survival (PFS) was 3.7 months (95% CI, 2.5-4.9 months), and the median overall survival (OS) was not reached. The 1 year OS rate was 54.6%. The time-to-progression (TTP) on prior sorafenib was significantly associated with PFS and OS. The most common grade 3-4 toxicities were hand-foot skin reaction (n = 3, 8%), hypertension (n = 2, 5%), and increased aspartate aminotransferase (n = 2, 5%). Conclusion Regorafenib was well-tolerated and effective in patients with advanced HCC who progressed on first-line sorafenib, with efficacy and safety outcomes consistent with those of the previous RESORCE trial. TTP on first-line sorafenib may predict the efficacy of subsequent regorafenib.