Usefulness of controlled attenuation parameter in monitoring clinically relevant decline of hepatic steatosis for non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) is the reference standard of hepatic steatosis assessment. This study evaluates usefulness of controlled attenuation parameter (CAP) in monitoring the clinically relevant outcome by MRI-PDFF for non-alcoholic fatty liver disease (NAFLD) patients. METHODS: NAFLD patients were enrolled prospectively. Instruction was given in lifestyle modifications with exercise and control of metabolic factors. MRI-PDFF and CAP were performed at enrollment and follow-up, with the diagnostic validity of CAP in monitoring clinically relevant outcome defined as a decline of ≥30% relative to baseline value by MRI-PDFF. RESULTS: A total of 75 patients (male/female: 49/26, mean age: 53.2) were enrolled. Baseline MRI-PDFF, CAP and liver stiffness was 14.4%, 300.2 dB/m and 6.5 kPa. In a median interval of 369 days, thirteen (17.3%) patients achieved clinically relevant outcome with decline of 46.7 dB/m by CAP, compared with increase of 5.1 in the other patients. In multivariate analysis, clinically relevant outcome was associated with changes (Δ) of CAP and glucose. Assessed by area under receiver operating curve, the performances of ΔCAP in predicting clinically relevant outcome were 0.815 and 0.808, and with the specificity of >90%, the ΔCAP cutoff was -46 dB/m and -15% relative to baseline value; sensitivity was 53.8% and 46.2% with negative predictive value of 90.3% and 88.9% respectively. CONCLUSIONS: For NAFLD patients, CAP exhibited good performance in monitoring clinically relevant decline of hepatic steatosis in MRI-PDFF. With the cutoffs of -46 dB/m or -15%, ΔCAP is useful in excluding clinical relevant outcome achievement.

Tumor Necrosis Is an Indicator of Poor Prognosis Among Hepatoma Patients Undergoing Resection.

INTRODUCTION: Tumor necrosis has been associated with poor prognosis in hepatocellular carcinoma (HCC) patients undergoing liver resection (LR). However, more evidence is needed to clarify this issue. METHODS: Patients who underwent upfront LR between 2010 and 2018 for newly diagnosed HCC without undergoing neoadjuvant therapy were enrolled in this retrospective study. Tumor necrosis was classified as present or absent according to retrospective examinations. The association between tumor necrosis, pathologic characteristics, overall survival (OS), and recurrence-free survival (RFS) were analyzed. RESULTS: Among 756 patients who underwent LR for HCC, tumor necrosis was present in 279 (36.9%) patients. Compared with patients without tumor necrosis, patients with tumor necrosis had higher proportions of tumors sized >5.0 cm (P < 0.001), multiple tumors (P < 0.001), microvascular or macrovascular invasion (P < 0.001), poorly differentiated or undifferentiated tumors (P < 0.001), and T stage 3 or 4 (P < 0.001) on pathological examination. The presence of tumor necrosis was associated with worse OS and RFS compared with the absence of tumor necrosis: 5-y OS was 56% versus 78% (P < 0.001); 5-y RFS was 42% versus 55% (P < 0.001). In multivariate analysis, the presence of tumor necrosis was an independent factor associated with worse OS (hazard ratio: 1.956; 95% confidence interval: 1.409-2.716; P < 0.001) and RFS (hazard ratio: 1.422; 95% confidence interval: 1.085-1.865; P = 0.011). CONCLUSIONS: Tumor necrosis was associated with worse OS and RFS among patients who underwent LR for HCC.

Overall survival among patients who undergo resection does not differ significantly between T1a and T1b hepatocellular carcinoma based on the 8th American Joint Commission on Cancer.

PURPOSE: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for hepatocellular carcinoma (HCC) has been used since 2018. However, whether any significant difference in overall survival (OS) exists between patients with T1a and T1b HCC who undergo resection has been controversial. We aim to clarify this issue. METHODS: We consecutively enrolled newly diagnosed HCC patients who underwent liver resection (LR) from 2010 to 2020 at our institution. OS was estimated using the Kaplan-Meier method and compared using log-rank tests. Prognostic factors for OS were identified by multivariate analysis. RESULTS: This study enrolled 1250 newly diagnosed HCC patients who underwent LR. No significant differences in OS were identified between patients with T1a and T1b tumors among all patients (p = 0.694), cirrhotic patients (p = 0.753), non-cirrhotic patients (p = 0.146), patients with alpha-fetoprotein (AFP) > 20 ng/ml (p = 0.562), patients with AFP ≤ 20 ng/ml (p = 0.967), patients with Edmondson grade 1 or 2 (p = 0.615), patients with Edmondson grade 3 or 4 (p = 0.825), patients positive for hepatitis B surface antigen (HBsAg; p = 0.308), in patients positive for anti-hepatitis C virus (HCV) antibody (p = 0.781), or patients negative for both HBsAg and anti-HCV antibody (p = 0.125). Using T1a as the reference, multivariate analysis showed that T1b is not a significant predictive factor for OS (hazard ratio (HR): 1.338; 95% confidence interval (CI):0.737-2.431; p = 0.339). CONCLUSION: No significant difference in OS was observed between patients who underwent LR to treat T1a and T1b HCC tumors.

Radiographic tumor burden score is useful for stratifying the overall survival of hepatocellular carcinoma patients undergoing resection at different Barcelona Clinic Liver Cancer stages.

PURPOSE: The Barcelona Clinic Liver Cancer (BCLC) staging system has been recommended for prognostic prediction. However, prognosis is variable at different BCLC stages. We aimed to evaluate whether the radiographic tumor burden score (TBS) could be used to stratify prognosis in different BCLC stages. METHODS: Hepatocellular carcinoma (HCC) patients undergoing liver resection (LR) at BCLC-0, -A, or -B stage in our institution in 2007-2018 were divided into derivation and validation cohorts. Overall survival (OS) was analyzed according to the TBS and BCLC stage. TBS cutoff values for OS were determined with X-tile. RESULTS: Of the 749 patients in the derivation cohort, 138 (18.4%) had BCLC-0, 542 (72.3%) BCLC-A, and 69 (9.2%) BCLC-B HCC; 76 (10.1%) had a high TBS (> 7.9), 477 (63.7%) a medium TBS (2.6-7.9), and 196 (26.2%) a low TBS (< 2.6). OS worsened progressively with increasing TBS in the cohort (p < 0.001) and in BCLC-A (p = 0.04) and BCLC-B (p = 0.002) stages. Multivariate analysis showed that the TBS was associated with OS of patients with BCLC-A (medium vs. low TBS: hazard ratio [HR] = 2.390, 95% CI = 1.024-5.581, p = 0.04; high vs. low TBS: HR = 3.885, 95% CI = 1.443-10.456, p = 0.007) and BCLC-B (high vs. medium TBS: HR = 2.542, 95% CI = 1.077-6.002, p = 0.033) HCC. The TBS could also be used to stratify the OS of patients in the validation cohort (p < 0.001). CONCLUSION: The TBS could be used to stratify the OS of the entire cohort and BCLC stages A and B of HCC patients undergoing LR.

Seven centimeters as an optimal cutoff value for prognosis stratification in large monofocal hepatocellular carcinoma.

PURPOSE: Barcelona Clinic Liver Cancer (BCLC) guidelines designate monofocal hepatocellular carcinoma (HCC) > 2 cm as BCLC A, and large monofocal HCC is defined at > 5 cm. We aimed to evaluate the optimal cutoff value for large monofocal HCC based on prognosis stratification. METHODS: From 2011 to 2018, 3055 patients with newly diagnosed HCC, who were managed in our institution, including 868 patients with monofocal HCC > 2 cm and 330 patients with BCLC B, were enrolled in this retrospective study. RESULTS: Monofocal HCC > 5 cm patients had worse overall survival (OS) than monofocal HCC 2-5 cm patients (5-year OS: 54% vs. 57%; p = 0.047), confirmed by multivariate analysis (hazard ratio (HR): 1.492, 95% confidence interval (CI): 1.055-2.110; p = 0.024). Monofocal HCC > 5 cm patients had better OS than BCLC B HCC patients (5-year OS: 54% vs. 25%; p < 0.001), confirmed by multivariate analysis (HR: 0.670, 95% CI: 0.481-0.934; p = 0.018). Using 7 cm as the monofocal HCC cutoff value resulted in worse OS than monofocal HCC 2-7 cm (5-year OS: 50% vs. 57%; p = 0.02), confirmed by multivariate analysis (HR: 1.625, 95% CI: 1.039-2.540; p = 0.033). Monofocal HCC > 7 cm patients had better OS than BCLC B patients (p = 0.006). However, no significant difference was identified in the multivariate analysis (HR: 0.726; 95% CI: 0.473-1.115; p = 0.144). CONCLUSIONS: The prognosis of monofocal HCC > 7 cm was similar to that of BCLC B, indicating that 7 cm represents an optimal cutoff value for prognosis stratification in large monofocal HCC.

A simple preoperative model to predict overall survival of patients undergoing liver resection for hepatocellular carcinoma ≥10 cm.

BACKGROUND: Studies have rarely reported on preoperative predictors of prognosis of patients undergoing liver resection (LR) for HCC ≥10 cm. We developed a simple model to predict overall survival (OS) of these patients. METHODS: We enrolled 305 patients with HCC ≥10 cm undergoing LR. Cirrhosis and imaging-defined AJCC stage were used to develop a preoperative model. Patients were divided into three groups based on the Kaplan-Meier estimator. RESULTS: Group 1 included patients with AJCC stage 1 and no cirrhosis (n = 86), group 2 those with AJCC stage 1 and cirrhosis plus those with AJCC stage 2 or 3 and no cirrhosis (n = 166), and group 3 those with AJCC stage 2 or 3 and cirrhosis (n = 51). The five-year OS of group 1, 2, and 3 was 55%, 32%, and 25%, respectively (p < 0.001). With group 1 as the reference, multivariate analysis of OS showed that group 2 (HR = 2.043; 95% CI = 1.332-3.134; p = 0.001) and group 3 (HR = 2.740; 95% CI = 1.645-4.564; p < 0.001) were independent predictors of OS. CONCLUSION: We developed a simple model to predict OS of patients undergoing LR for HCC ≥10 cm.

Predictors of Virological Suppression After Clinical Relapse in Patients Who Discontinued Entecavir or Tenofovir.

BACKGROUND: The predictors of persistent virological suppression after clinical relapse remain unclear. AIMS: To investigate the predictors of retreatment or persistent virological suppression after clinical relapse in chronic hepatitis B (CHB) patients who discontinued entecavir or tenofovir disoproxil fumarate (TDF). METHODS: A total of 243 hepatitis B e antigen-negative CHB patients without cirrhosis who experienced clinical relapse after entecavir or TDF cessation were enrolled. RESULTS: Of the 243 CHB patients, 192 received retreatment and 51 did not receive retreatment after clinical relapse. Of the 51 patients without retreatment, 23 achieved persistent virological suppression (persistent HBV DNA < 2000 IU/mL at least 2 years) and 10 experienced hepatitis B surface antigen (HBsAg) loss. The Cox regression analysis showed that short consolidation duration, short duration of the first clinical relapse from the end of treatment (EOT), and high bilirubin and HBV DNA levels at the first clinical relapse were independent predictors of retreatment. Long duration of the first clinical relapse from the EOT and low HBsAg levels at the first clinical relapse were independent factors of patients with persistent virological suppression. The rates of persistent virological suppression at the first clinical relapse among patients with HBsAg < 100 and ≥ 100 IU/mL were 44.4% (12/27) and 5.1% (11/216) (P < 0.001), respectively. Baseline HBsAg levels and no retreatment requirement were independent factors associated with HBsAg loss. CONCLUSIONS: The HBsAg of 100 IU/mL at the first clinical relapse could predict persistent virological suppression after clinical relapse in patients who discontinued entecavir or TDF therapy.

The characteristics of patients with macrovascular invasion in hepatocellular carcinoma: when East meets West.

PURPOSE: To evaluate the prevalence and extension of macrovascular invasion (MaVI) in a large cohort of hepatocellular carcinoma (HCC) patients and analyze the association between MaVI and overall survival (OS). METHODS: From 2011 to 2018, 2540 patients with newly diagnosed HCC who were managed in our institution were enrolled in this retrospective study. Tumor invasion of the intrahepatic branches of the portal or hepatic veins was defined as peripheral MaVI. Tumor invasion of the main portal vein or inferior vena cava was defined as central MaVI. RESULTS: MaVI prevalence was 16.2% (n = 411). Among patients with Barcelona Clinic Liver Cancer (BCLC) stage C and Child-Pugh class A, 165 patients presented with peripheral MaVI and 89 patients with central MaVI. The median OS was 13.2 months (95% confidence interval [CI]: 11.4-15.4) in the peripheral MaVI group and 6.6 months (95% CI: 3.6-9.5) in the central MaVI group (p < 0.001). In patients with BCLC stage C and Child-Pugh class B or BCLC stage D, 68 patients presented with peripheral MaVI and 89 patients with central MaVI. The median OS was 3.6 months (95% CI: 3.1-4.2) in the peripheral MaVI group and 2.8 months (95% CI: 2.1-3.4) in the central MaVI group (p = 0.674). CONCLUSION: The extension of MaVI significantly affected patient survival only in those with BCLC stage C and Child-Pugh class A. In patients with BCLC stage C and Child-Pugh class B or BCLC stage D, survival was poor irrespective of MaVI status.

Incorporating albumin-bilirubin grade and up-to-seven criteria to predict outcomes of patients with intermediate stage hepatocellular carcinoma after transarterial (chemo)embolization.

BACKGROUND/PURPOSE: This study is to use albumin-bilirubin (ALBI) grade and up-to-7 (UT7) criteria to assess outcomes of patients with intermediate stage hepatocellular carcinoma (HCC) after transarterial (chemo)embolization (TA(C)E). METHODS: Between January 2012 and January 2019, newly diagnosed intermediate HCC patients underwent TA(C)E were enrolled and analyzed. The demographics, clinical characteristics and survival were obtained from medical chart reviews. RESULTS: A total of 359 patients were enrolled and 30.4% of them were within UT7 criteria (UT7 (-)). There were 36.5%, 59.3%, and 4.2% of the patients with ALBI grade I, II, and III, respectively. Beyond UT7 (UT7 (+)) and ALBI grade II/III were associated with overall mortality in multivariate analysis. Based on ALBI grade I/II/III and UT7 -/+, patients were classified into six groups as ALBI grade I plus UT7 (-), II plus UT7 (-), III plus UT7 (-), I plus UT7 (+), II plus UT7 (+), and III plus UT7(+). Distributions of median survival were 47.5, 32.9, 15, 34.3, 16.7 and 14.3 months, respectively. Patients with statistically insignificant survivals were further combined. Patients with ALBI grade I plus UT7 (-) were reclassified as ALBI-U class I, whereas ALBI grade II plus UT7 (-) and I plus UT7 (+) were ALBI-U class II, and the others were ALBI-U class III. There were 8.4%, 48.7%, and 42.9% of patients in ALBI-U class I, II, and III, respectively. The 5-year survival rate was 48.8%, 22.5%, and 13.7% in ALBI-U class I, II, and III, respectively (p < 0.01). CONCLUSION: ALBI-U classification was useful in predicting outcomes of patient with intermediate stage HCC after TA(C)E.

Reappraisal of the roles of alpha-fetoprotein in hepatocellular carcinoma surveillance using large-scale nationwide database and hospital-based information.

BACKGROUND/PURPOSE: Controversies over the use of alpha-fetoprotein (AFP) for detection of hepatocellular carcinoma (HCC) existed from guidelines. Using large-scale database and hospital-based information, we aimed to reappraise the role of AFP in HCC surveillance, including proportion of AFP elevation by stage of HCC, additional benefit of AFP in combination of ultrasonography (US) in the detection of early HCC, and survival in early HCC with high AFP levels. METHODS: This retrospective study enrolled 43,437 patients from database of the Taiwan Cancer Registry (TCR) and 4250 patients from Kaohsiung Chang Gung Memorial Hospital (KCGMH) between January 2011 and December 2017. RESULTS: The HCC cases in KCGMH accounted for 9.8% of the total cases in the TCR. Among both nationwide database and hospital-based information, the proportion of early HCC patients with an AFP level of ≥20 ng/mL was approximately 40%. In KCGMH, the proportion of patients with an AFP level of ≥20 ng/mL and a virus-related (hepatitis B and C) etiology was around 41.7%; furthermore, among patients with early HCC, those with an AFP level of ≥20 ng/mL had 4.7 years of median survival and 48.3% of the 5-year overall survival rate. By hospital electronic medical records review of early HCC cohort in KCGMH, approximately 10.9% of patients with AFP levels ≥20 ng/mL had US-undetectable early HCC. CONCLUSION: This study suggested that AFP in combination with US would add an additional benefit as being a prompted role for detection of early HCC in patients with US-undetectable HCC.

Statin use is associated with a lower risk of recurrence after curative resection in BCLC stage 0-A hepatocellular carcinoma.

BACKGROUND: Use of statins is associated with a reduced risk of hepatocellular carcinoma (HCC). However, the effect of statin use on HCC recurrence is unclear. This study aimed to evaluate the effect of statin use on recurrence after curative resection among patients with HCC. METHODS: We retrospectively assessed 820 patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 or A HCC who underwent primary resection between January 2001 and June 2016 at Kaohsiung Chang Gung Memorial Hospital. Exposure to statins was defined as use of a statin for at least 3 months before HCC recurrence. Factors that influenced overall survival (OS) and recurrence-free survival (RFS) were analyzed using Cox proportional hazards models. RESULTS: Of the 820 patients, 46 (5.6%) used statins (statin group) and 774 (94.4%) did not (non-statin group). During the mean follow-up of 76.5 months, 440 (53.7%) patients experienced recurrence and 146 (17.8%) patients died. The cumulative incidence of HCC recurrence was significantly lower in the statin group than the non-statin group (p = 0.001); OS was not significantly different between groups. In multivariate analysis, age (hazard ratio [HR]: 1.291; p = 0.010), liver cirrhosis (HR: 1.743; p < 0.001), diabetes (HR:1.418; p = 0.001), number of tumors (HR: 1.750; p < 0.001), tumor size (HR: 1.406; p = 0.004) and vascular invasion (HR: 1.659; p < 0.001) were independent risk factors for HCC recurrence, whereas statin use (HR: 0.354; p < 0.001) and antiviral therapy (HR: 0.613; p < 0.001) significantly reduced the risk of HCC recurrence. The statin group still had lower RFS than the non-statin group after one-to-four propensity score matching. CONCLUSION: Statins may exert a chemo-preventive effect on HCC recurrence after curative resection.

Microscopic portal vein invasion is a powerful predictor of prognosis in patients with hepatocellular carcinoma who have undergone liver resection.

BACKGROUND AND OBJECTIVES: A recent study proposed simple classifications of microscopic vascular invasion (MVI): microscopic portal vein invasion (MPVI) and microvessel invasion (MI). We aim to validate these classifications of MVI. METHODS: This retrospective study consecutively enrolled 514 Barcelona Clinic Liver Cancer stage 0, A, and B naïve hepatocellular carcinoma patients who underwent liver resection in our institution from 2011 to 2017. RESULTS: Among these 514 patients, 240 patients were classified as having no MVI at all (designated as no vascular invasion, NVI), 157 patients were classified as having MI only, and 117 patients were classified as having MPVI. The 5-year overall survival (OS) rate in the MI-only group was 83.3%, which was not significantly different from that of the NVI group (87.2%), p = .20. Using NVI as a reference, multivariate analysis showed that MI-only is not an independent variable associated with OS. The 5-year OS in the MPVI group was 59.2%, which was significantly lower than those for MI-only (p < .001) and NVI groups (p < .001). Using NVI as a reference, multivariate analysis showed that MPVI is an independent variable associated with OS (HR, 3.12; 95% CI, 1.80-5.40; p < .001). CONCLUSIONS: The results of this study validate the simple MVI classifications to be clinically useful.

Clinical and novel application of FibroScan, FIB-4 and aspartate aminotransferase-to-platelet ratio index in liver fibrosis evaluation in patients with hepatocellular carcinoma and their roles in oesophageal variceal prediction.

BACKGROUND: Non-invasive techniques for liver fibrosis diagnosis are very important for clinician especially in high-risk patients for liver biopsy. We further explored the diagnostic accuracy of FibroScan, FIB-4 and aminotransferase-to-platelet ratio index (APRI) in identifying liver fibrosis and assess their predictive role for oesophageal varices in patients with hepatocellular carcinoma (HCC). METHODS: In total, 380 patients who underwent surgery for HCC were included based on retrospective study design. Liver fibrosis was pathologically diagnosed using the Ishak scoring system. Liver stiffness parameters were measured using FibroScan. APRI and FIB-4 were calculated. Among those, 121 patients who received oesophagogastroduodenoscopic examination underwent variceal evaluation. RESULTS: For liver cirrhosis diagnosis with FibroScan, the optimal cut-off values for the patients with HCC overall, left HCC and right HCC were 8.85, 11.75 and 8.70 kPa (the accuracy were 78.7%, 78.4% and 79.2%, respectively). They had high areas under the receiver operating characteristic curve of 0.84, 0.84 and 0.85. The combined FibroScan, APRI and FIB-4 had very high specificity (more than 92%) for cirrhosis diagnosis. The optimal cut-off liver stiffness values for the diagnosis of varices were all 11.2 kPa. For predicting varices, the optimal cut-off values of FIB-4 and APRI were 2.64 and 0.71, their accuracy were 64.3%-78.4%, 69.4% and 72.7%, respectively. CONCLUSIONS: FibroScan, FIB-4 and APRI have moderate accuracy for liver fibrosis diagnosis and oesophageal varices prediction in patients with hepatoma. This is a study of these non-invasive techniques applied in specific hepatoma patients and with inevitable limitations and need future more studies for validation.

Chronic hepatitis B exhibited higher rate of hepatocellular carcinoma occurrence than hepatitis C in cirrhotic patients after effective antiviral treatment.

BACKGROUND/PURPOSE: Effective antiviral-therapy can reduce the risk of liver cirrhosis related hepatocellular carcinoma in patients with chronic hepatitis B and hepatitis C. Yet, the difference of hepatocellular carcinoma development in chronic hepatitis B and hepatitis C patients with cirrhosis after effective antiviral therapy treatment is unknown. In this study, We comprehensive explored the difference among them. METHODS: 1363 patients with cirrhosis and hepatitis B virus treated with nucleos(t)ide analogues (NUCs) with completely suppressed virus, and patients with cirrhosis and hepatitis C virus treated with pegylated interferon (peg-IFN)/ribavirin (RBV) combination therapy who achieved sustained virologic response were enrolled. RESULTS: Total 261 developed hepatocellular carcinoma within a median follow-up of 4.25 years. Univariate analysis, patients developed hepatocellular carcinoma tended to be of older age, and had lower platelet counts, were chronic hepatitis B carriers, and had higher serum alfa-fetoprotein (AFP) (≥20 ng/mL), FIB-4 index and APRI scores. Subsequent multivariate analysis revealed older age, lower platelet counts, high AFP levels and chronic hepatitis B carriers were independent risk factors of hepatocellular carcinoma. CONCLUSION: Our findings identify that chronic hepatitis B patients were with a higher risk of hepatocellular carcinoma compared to chronic hepatitis C patients after achieving virological response. Special attention should be paid to those patients.

The Role of Protease-Activated Receptor 2 in Hepatocellular Carcinoma after Hepatectomy.

Background and Objectives: Protease activated receptor-2 (PAR2) is elevated in a variety of cancers and has been promoted as a potential therapeutic target. However, the clinical and prognostic values of PAR2 in hepatocellular carcinoma (HCC) are poorly characterized. This study aimed to evaluate the expression of PAR2 in HCC tissues and examine the prognostic value of PAR2 after resection in HCC. Materials and Methods: Two hundred and eight resected specimens were collected from HCC patients at Kaohsiung Chang Gung Memorial Hospital. PAR2 protein expression was assessed by western blotting in HCC tissues and matched normal tissues. The correlation between PAR2 expression and clinicopathological parameters was analyzed. Disease-free survival (DFS) and overall survival (OS) were compared using the log-rank test. A Cox regression model was used to identify independent prognostic factors. Results: PAR2 was expressed at higher levels in HCC tissues than the paired adjacent nontumor tissues. High expression of PAR2 was associated with advanced tumor, node, metastasis (TNM )stage and histological grade. Kaplan-Meier analysis indicated high PAR2 expression was associated with poorer DFS and OS compared to low PAR2 expression. Multivariate analyses indicated high PAR2 expression [hazard ratio (HR), 1.779, p = 0.006), α-fetoprotein (AFP) (HR, 1.696, p = 0.003), liver cirrhosis (HR, 1.735, p = 0.002), and advanced TNM stage (HR, 2.061, p < 0.001) were prognostic factors for DFS, and advanced TNM stage (HR, 2.741, p < 0.001) and histological grade (HR, 2.675, p = 0.002) and high PAR2 expression (HR, 1.832, p = 0.012) were significant risk factors for OS. In subgroup analyses, the combination of PAR2 expression and serum AFP provided improved prognostic ability for OS and DFS. Conclusion: Combination PAR2 and AFP predict HCC outcomes after resection. PAR2 represents a potentially clinically relevant biomarker for HCC.

The influence of direct-acting antivirals in hepatitis C virus related hepatocellular carcinoma after curative treatment.

This study was done to elucidate the influence of direct-acting antiviral (DAA) agents on the recurrence of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related HCC (HCV-HCC) after curative therapies. HCV-HCC patients who received curative therapies and obtained a complete response were analyzed. From January 2017 to September 2017, 112 HCV-HCC patients received DAA and obtained a sustained virological response (SVR). From January 2006 to December 2014, another 345 HCV-HCC patients received peg-interferon-based treatment and 118 obtained SVR. From January 2012 to December 2016, 248 HCV-HCC patients had complete HCC response and did not receive antiviral treatment. Patients were divided into DAA, IFN, and Untreated groups based on what antiviral treatment they received. There were 82 patients in the DAA group, 80 patients in the IFN group, and 160 patients in the Untreated group. During the follow-up period, the DAA group had 22 (26.8%) recurrent cases, whereas the IFN group had 46 (56.8%) cases after antiviral treatment. Among the 22 recurrent cases in the DAA group, 19 (86.9%) experienced HCC recurrence during 1 year after DAA initiation. Compared with the IFN group, the DAA group had poorer one-year recurrence-free survival (75.4% vs. 95%, p < 0.001), even after adjustment with propensity score matching (81.4% vs. 93.9%, p = 0.034). However, DAA was an improving factor for HCC recurrence compared with the Untreated group in the multivariate analysis. Among HCV-HCC patients with complete treatment, those with DAA-induced SVR had a higher one-year recurrence rate than those who received IFN-based antiviral therapy, but DAA did not seem to increase HCC recurrence compared to untreated patients.

Liver resection of hepatocellular carcinoma within and beyond the Barcelona Clinic Liver Cancer guideline recommendations: Results from a high-volume liver surgery center in East Asia.

BACKGROUND: The Barcelona Clinic Liver Cancer (BCLC) guidelines were updated in 2012, and a single large hepatocellular carcinoma (HCC) more than 5 cm was regarded as BCLC stage A rather than B in the updated version. In this study, we sought to re-evaluate the outcomes of patients with HCC who underwent liver resection (LR) within (stage 0 and A) and beyond (stage B and C) the BCLC guideline recommendations of the updated BCLC staging system. METHODS: This retrospective study enrolled 774 consecutive patients with naïve HCC who underwent LR from 2011 to 2018 at our institution. The overall survival (OS) and recurrence-free survival (RFS) of these patients were examined. RESULTS: Of the patients, 606 had BCLC stage 0 or A HCC, and 168 had BCLC stage B or C HCC. The 5-year OS and RFS among the patients within the BCLC criteria for LR were 75.2% and 56.1%, respectively, vs 54.9% and 34.0%, respectively, among the patients beyond the BCLC criteria (P < .001). Alpha-fetoprotein more than 400 ng/mL (hazard ratio = 2.06, 95% confidence interval, 1.31-3.26, P = .002) was the only independent variable associated with recurrence among the patients beyond the BCLC criteria. CONCLUSIONS: LR provided acceptable outcomes among selected patients with BCLC stage B and C HCC.

Usefulness of Controlled Attenuation Parameter in Detecting and Monitoring Hepatic Steatosis with MRI-PDFF as Reference.

BACKGROUND: Controlled attenuation parameter (CAP) has been developed to estimate the extent of hepatic steatosis. AIMS: The purpose was to evaluate the usefulness of CAP in assessing hepatic steatosis and its change using magnetic resonance imaging proton density fat fraction (MRI-PDFF) as reference standard. METHODS: Consecutive patients with liver steatosis were enrolled prospectively. We assessed hepatic steatosis with CAP and MRI-PDFF at enrollment and 12-month follow-up. The correlations between the two methods were analyzed. With MRI-PDFF as reference, the performance of CAP in diagnosis of steatosis severity and its changes was assessed. RESULTS: A total of 50 patients were enrolled, and 45 of them had follow-up MRI-PDFF and CAP at a median interval of 399 days. The mean hepatic steatosis was 13.4% by MRI-PDFF and 291.6 dB/m by CAP. There were positive correlations between CAP and MRI-PDFF in steatosis severity and its change. The median value of CAP was 254, 301.5, and 329.5 dB/m for steatosis < 10%, 10-20%, and > 20%, respectively. For CAP in detecting steatosis ≥ 10% and > 20%, the diagnostic performance was 0.821 and 0.814. With the cutoff of 275 dB/m for ≥ 10% steatosis, the positive predictive value was 84.8%. With the cutoff of 325 dB/m for > 20% steatosis, the negative predictive value was 91.9%. In multiple linear regression, one dB/m change by CAP was associated with 0.039% change by MRI-PDFF. CONCLUSIONS: In assessing liver fat content, CAP correlated with MRI-PDFF and was useful for detection and monitoring of hepatic steatosis.

Elevated levels of serum urokinase plasminogen activator predict poor prognosis in hepatocellular carcinoma after resection.

BACKGROUND: Urokinase plasminogen activator (uPA) is an extracellular matrix-degrading protease that is involved in the invasiveness and progression of cancer. There is good evidence that uPA expression is a clinically relevant biomarker in some solid tumors, but its role in hepatocellulcar carcinoma (HCC) is uncertain. We evaluated the prognostic value of serum uPA before surgery in HCC patients receiving curative resection. METHODS: Serum uPA levels were determined by enzyme-linked immunosorbent assay in 282 HCC patients who received complete liver resections at Kaohsiung Chang Gung Memorial Hospital. Overall survival (OS) curves were constructed using the Kaplan-Meier method and compared using the log-rank test. A Cox proportional -hazards regression model was used to identify independent prognostic factors. The median follow-up time was 52 months. RESULTS: Patients with higher pretreatment serum uPA (≥1 ng/ml) had significantly shorter OS (p = 0.002). Patients with liver cirrhosis, hypoalbuminemia, and thrombocytopenia were significantly more likely to present with elevated uPA levels. Multivariate Cox regression analyses indicated that high pretreatment serum uPA [hazard ratio (HR), 1.848, p = 0.006], vascular invasion (HR, 2.940, p < 0.001), and pathology stage III/IV (HR, 3.517, p < 0.001) were independent prognostic factors for OS. In further stratified analyses, the combination of serum uPA and AFP had more capacity to predict OS. CONCLUSIONS: We conclude that uPA is a clinically relevant biomarker in HCC patients receiving curative resection, with higher expression of uPA being associated with higher mortality. This also highlights the potential utility of uPA as a therapeutic target for improved treatment strategies.

Clinical characteristics and prognosis of HCC occurrence after antiviral therapy for HCV patients between sustained and non-sustained responders.

BACKGROUND: Hepatitis C virus (HCV)-infected patients who achieved sustained virologic response (SVR) may still develop hepatocellular carcinoma (HCC). The characteristic of HCC and the prognosis between SVR and non-SVR patients were not well known. METHODS: Among 1884 HCV-infected patients who were treated with pegylated IFN plus ribavirin therapies, 122 patients developed HCC during follow-up were enrolled in this study. Laboratory data were collected before and at least 1 year after IFN-based therapy, as well as the latest follow-up. RESULTS: Both SVR and non-SVR patients had similar risk factors to develop HCC, but with a little difference. Liver cirrhosis plays a key role in HCC occurrence in both groups. Among the patients who developed HCC, non-SVR patients had significantly higher total bilirubin, higher FIB-4, lower pre-treatment platelet count, higher pre-treatment AFP levels and higher proportion of cirrhosis than SVR patients before occurrence of HCC. After curative treatment, SVR patients had lower recurrence and longer overall survival than non-SVR patients by Kaplan-Meier analysis. Multivariate analysis revealed that APRI ≥0.7 was the independent risk factor for HCC recurrence; and AFP ≥20 ng/ml post IFN therapy, as well as HCC recurrence were the independent risk factors of mortality. CONCLUSION: Liver cirrhosis plays a key role in HCC occurrence after antiviral therapies. SVR patients may have lower HCC recurrence and longer survival rates than non-SVR patients. Only APRI was associated with HCC recurrence; and post-IFN AFP and HCC recurrence were predictive of subsequent mortality independently.