Activated Integrated Stress Response Induced by Salubrinal Promotes Cisplatin Resistance in Human Gastric Cancer Cells via Enhanced xCT Expression and Glutathione Biosynthesis.

The integrated stress response (ISR) pathway is essential for adaption of various stresses and is related to mitochondrion-to-nucleus communication. Mitochondrial dysfunction-induced reactive oxygen species (ROS) was demonstrated to activate general control nonderepressible 2 (GCN2)⁻eukaryotic translation initiation factor 2α (eIF2α)⁻activating transcription factor-4 (ATF4) pathway-mediated cisplatin resistance of human gastric cancer cells. However, whether or how ISR activation per se could enhance chemoresistance remains unclear. In this study, we used eIF2α phosphatase inhibitor salubrinal to activate the ISR pathway and found that salubrinal reduced susceptibility to cisplatin. Moreover, salubrinal up-regulated ATF4-modulated gene expression, and knockdown of ATF4 attenuated salubrinal-induced drug resistance, suggesting that ATF4-modulated genes contribute to the process. The ATF4-modulated genes, xCT (a cystine/glutamate anti-transporter), tribbles-related protein 3 (TRB3), heme oxygenase 1 (HO-1), and phosphoenolpyruvate carboxykinase 2 (PCK2), were associated with a poorer prognosis for gastric cancer patients. By silencing individual genes, we found that xCT, but not TRB3, HO-1, or PCK2, is responsible for salubrinal-induced cisplatin resistance. In addition, salubrinal increased intracellular glutathione (GSH) and decreased cisplatin-induced lipid peroxidation. Salubrinal-induced cisplatin resistance was attenuated by inhibition of xCT and GSH biosynthesis. In conclusion, our results suggest that ISR activation by salubrinal up-regulates ATF4-modulated gene expression, increases GSH synthesis, and decreases cisplatin-induced oxidative damage, which contribute to cisplatin resistance in gastric cancer cells.

Impact of Steatosis on Prognosis of Patients with Early-Stage Hepatocellular Carcinoma After Hepatic Resection.

BACKGROUND: It is still unclear whether steatosis determines the prognosis of patients with hepatocellular carcinoma (HCC). This study aimed to compare the clinical manifestations and outcomes between early-stage HCC patients with and without steatosis after hepatic resection. METHODS: We enrolled 188 patients who underwent hepatic resection for HCC within the Milan criteria. After surgery, fibrosis, steatosis, lobular inflammation, portal inflammation, and ballooning in the background liver were assessed. Factors related to prognosis after surgery were analyzed by multivariate analysis. RESULTS: Seventy-four patients (39.4 %) had steatosis. Patients with steatosis had larger body mass index, higher fasting glucose levels, and higher rates of ballooning than those without steatosis. After a median follow-up period of 69.8 months, 73 patients died. The cumulative survival rates at 5 years were 57.8 and 75.6 % for patients with and without steatosis, respectively (p = 0.008). Multivariate analysis disclosed that an age of > 65 years [hazard ratio (HR) 1.996, p = 0.009], platelet count of <10(5)/mm(3) (HR 2.198, p = 0.005), indocyanine green retention rate at 15 min of >10 % (HR 2.037, p = 0.022), multinodularity (HR 2.389, p = 0.004), and steatosis (HR 1.773, p = 0.023) were independent risk factors associated with poor overall survival after resection. The impact of steatosis on postsurgical prognosis was more apparent in patients without cirrhosis. CONCLUSIONS: The presence of steatosis in the background liver was associated with a poor prognosis in early-stage HCC patients after hepatic resection, especially for noncirrhotic patients.

Differential roles of serum hepatitis B virus DNA and hepatitis B surface antigen level in predicting virological breakthrough in patients receiving lamivudine therapy.

BACKGROUND AND AIM: The role of serum hepatitis B surface antigen (HBsAg) level in determining virological breakthrough (VB) for patients with hepatitis B virus (HBV) infection receiving lamivudine remains unclear. The study aimed to evaluate the impact of serum HBsAg levels on VB among patients receiving lamivudine therapy, especially in a setting of low HBV viral load. METHODS: Two hundred sixty-eight consecutive treatment-naïve patients who underwent lamivudine therapy for chronic hepatitis B were enrolled. Factors in terms of VB were analyzed by multivariate analysis. RESULTS: After a median treatment duration of 67.1 weeks, 102 patients had VB. Multivariate analysis showed that positive hepatitis B e antigen (HBeAg) (hazard ratio 2.165, P = 0.026) and HBV DNA levels ≥ 2000 IU/mL after 6 months of lamivudine therapy (hazard ratio 5.236, P = 0.001) were independent risk factors predicting VB. The cumulative VB rates stratified by HBeAg-positive and -negative at 3 years were 44.7% and 26.3%, respectively. At 3 years, the cumulative VB rates stratified by the HBV DNA < 2000 and ≥ 2000 IU/mL after 6 months of therapy were 25.5% and 79.4%, respectively. For HBeAg-positive patients with serum HBV DNA < 2000 IU/mL after 6 months of therapy, baseline HBsAg levels ≥ 20,000 IU/mL was the only risk factor associated with VB. CONCLUSIONS: For chronic hepatitis B patients treated with lamivudine, serum HBV DNA level > 2000 IU/mL after 6 months of therapy could predict subsequent VB. In patients with lower on-treatment viral load, baseline serum HBsAg level is associated with the emergence of VB, especially for those with serum positive HBeAg.

Comparison of prognosis by viral etiology in patients with hepatocellular carcinoma after radiofrequency ablation.

UNLABELLED: BACKGROUND; Radiofrequency ablation (RFA) has been performed as a first line curative treatment modality for patients with hepatocellular carcinoma (HCC) within the Milan criteria currently. However, prognosis of hepatitis B- and hepatitis C-related HCC after RFA remains debatable. This study aimed to assess the impact of viral etiology on the prognosis of HCC patients undergoing RFA. MATERIAL AND METHODS: One hundred and ninety-two patients with positive serum HBV surface antigen (HBsAg) and negative serum antibody against HCV (anti-HCV) were enrolled as the B-HCC group and 165 patients with negative serum HBsAg and positive anti-HCV as the C-HCC group. Post-RFA prognoses were compared between the two groups using multivariate and propensity score matching analyses. RESULTS: The B-HCC group had higher male-to-female ratio and better liver functional reserve than the C-HCC group. After a median follow-up of 23.0 ± 22.7 months, 55 patients died and 189 patients had tumor recurrence after RFA. The cumulative five-year survival rate was 75.9% and 69.5% in the B-HCC and C-HCC groups, respectively (p = 0.312), while the five-year recurrence-free survival rate was 19.0% and 26.6%, respectively (p = 0.490). After propensity-score matching, the B-HCC group still had comparable overall survival rate (p = 0.679) and recurrence-free survival rate (p = 0.689) to the C-HCC group. For 132 patients with Barcelona-Clinic Liver Cancer stage 0, the five-year overall survival and recurrence-free survival rates were also comparable between the two groups (p = 0.559 and p = 0.872, respectively). CONCLUSION: Viral etiology is not essential for determining outcome in HCC patients undergoing RFA.

Efficacy of non-selective ß-blockers as adjunct to endoscopic prophylactic treatment for gastric variceal bleeding: a randomized controlled trial.

BACKGROUND & AIMS: Gastric variceal obturation (GVO) therapy is the current treatment of choice for gastric variceal bleeding (GVB). However, the efficacy of non-selective ß-blockers (NSBB) in the secondary prevention of GVB is still debatable. This study aimed at evaluating the efficacy of additional NSBB to repeated GVO in the secondary prevention of GVB. METHODS: From April 2007 to March 2011, 95 patients with GVB after primary hemostasis using GVO were enrolled. Repeated GVO were performed until GV eradication. Forty-eight and 47 patients were randomized into the GVO alone group (Group A) and the GVO+NSBB group (Group B), respectively. Primary outcomes in terms of re-bleeding and overall survival were analyzed by multivariate analysis. RESULTS: After a mean follow-up of 18.10 months in group A, 26 patients bled and 20 died. In group B, 22 patients bled and 22 died after a mean follow-up of 20.29 months. The overall re-bleeding and survival rates analyzed by the Kaplan-Meier method were not different between the two groups (p=0.336 and 0.936, respectively). The model of end-stage liver disease (MELD) score and main portal vein thrombosis (MPT) were independent determinants of re-bleeding while MPT and re-bleeding were independent factors of mortality by time-dependent Cox-regression model. Asthenia was the most common adverse event and was higher in group B (p<0.001). CONCLUSIONS: Adding NSBB therapy to repeated GVO provides no benefit for the secondary prevention of bleeding and mortality in patients with GVB.

Younger hepatocellular carcinoma patients have better prognosis after percutaneous radiofrequency ablation therapy.

GOALS: To evaluate the impact of age on the prognosis of patients with hepatocellular carcinoma (HCC) undergoing percutaneous radiofrequency ablation (RFA). BACKGROUND: Whether age plays an important role in the outcomes of HCC after RFA remains controversial. STUDY: Two hundred fifty-eight consecutive treatment naive HCC patients who underwent RFA were enrolled. Patients aged ≤ 65 years (n = 100) were defined as the younger group and those aged > 65 years (n = 158) were the elderly group. Their clinicopathologic features and prognosis were compared. RESULTS: Younger patients had a higher male-to-female ratio, higher prevalence of hepatitis B virus, and smaller tumor size than elder patients. After median follow-up of 28.5 ± 18.7 months, 45 patients died. The cumulative 5-year survival rates were 81.3% and 65.4% in younger and elder HCC patients, respectively (P = 0.008). Multivariate analysis disclosed that age > 65 years, serum albumin level ≤ 3.7 g/dL, prothrombin time international normalized ratio > 1.1, α-fetoprotein (AFP) > 20 ng/mL, and no antiviral therapy after RFA were independent risk factors associated with poor overall survival. Besides, there were 163 patients with tumor recurrence after RFA. Multivariate analysis showed that age > 65 years, platelet count ≤ 10/mm, AFP > 20 ng/mL, multinodularity, and tumor size > 2 cm were the independent risk factors predicting recurrence. CONCLUSIONS: Both liver functional reserve (serum albumin level, prothrombin time international normalized ratio, platelet count, and antiviral therapy) and tumor factors (tumor size, number, and AFP level) were crucial in determining post-RFA prognosis in HCC patients. Moreover, younger HCC patients have better overall survival and lower recurrence rate after RFA compared with elder patients.

Prognostic significance of computed tomography scan-derived splenic volume in hepatocellular carcinoma treated with radiofrequency ablation.

GOALS: To evaluate the clinical implication of splenic volume measured by computed tomography (CT) scan in hepatocellular carcinoma (HCC) patients undergoing percutaneous radiofrequency ablation (RFA). BACKGROUND: Splenomegaly is an important sign of portal hypertension and poor liver function in patients with advanced liver disease. But whether it could predict the prognosis of patients with HCC is still obscure. STUDY: We enrolled 161 treatment-naive HCC patients. Splenomegaly was defined as splenic volume >300 mL by CT scan and its impact on prognosis was analyzed. Moreover, noninvasive serum markers were validated to predict splenomegaly. RESULTS: A total of 78 patients were with splenomegaly, while the remaining 83 patients had normal splenic volume at the time of receiving RFA. After a median follow-up of 38.1±20.8 months, 41 patients died. The cumulative 5-year survival rates were 54.8% and 77.8% in patients with splenomegaly and in those with normal splenic volume, respectively (P=0.003). By multivariate analysis, age 65 years and older, serum albumin levels ≤3.5 g/dL, and splenic volume >300 mL were independent risk factors associated with poor overall survival after RFA. For predicting splenomegaly by noninvasive serum markers, platelet count yielded the highest area under the curve from corresponding receiver operating curves with a level of 0.868 at a cut-off value of 11,7000/mm(3). CONCLUSIONS: HCC patients with splenomegaly measured by CT scan have relatively poorer liver functional reserve than those with normal splenic volume. Splenomegaly is an independent risk factor predicting overall survival for patients with small HCC undergoing RFA.

Survival rates are comparable after radiofrequency ablation or surgery in patients with small hepatocellular carcinomas.

BACKGROUND & AIMS: Differences in efficacy of radiofrequency ablation (RFA) and surgical resection (SR) are not clear for patients with hepatocellular carcinoma (HCC). METHODS: From 2002 to 2007, 419 patients with HCCs ≤5 cm were enrolled consecutively in the study. Among these patients, 190 and 229 patients received RFA and SR, respectively, as their first treatment. Factors were analyzed in terms of overall survival and recurrence by multivariate analysis and propensity score matching analysis. RESULTS: The SR group had younger age, a higher male-to-female ratio, higher prevalence of hepatitis B virus, lower prevalence of hepatitis C virus, better liver function reserve, and larger tumor size than the RFA group. The cumulative 5-year overall survival rates were 79.3% in the SR group and 67.4% in the RFA group. During the follow-up period, tumors recurred in 244 patients in a median time of 14.5 ± 15.7 months. Before propensity-score matching, the RFA group had shorter overall survival time (P = .009) and higher tumor recurrence rate (P < .001) than the SR group. After matching, RFA was comparable to SR in overall survival time (P = .519), but the RFA group still had a greater incidence of tumor recurrence (P < .001). In patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 HCC, RFA was as effective as SR for overall survival time and recurrence. CONCLUSIONS: Patients with small HCCs have a higher rate of tumor recurrence following RFA than surgery, but overall survival rates are comparable between therapies. RFA is as effective as surgery in patients with BCLC stage 0 HCC.

Comparative analysis of noninvasive models to predict early liver fibrosis in hepatitis B e Antigen-negative Chronic Hepatitis B.

BACKGROUND: Portal or bridging fibrosis is an indication for antiviral treatment in patients with chronic hepatitis B (CHB). An early marker predictive of liver fibrosis in hepatitis B e antigen (HBeAg)-negative CHB patients can alert clinicians to plan for treatment before disease progression. GOALS: To predict early and significant liver fibrosis (Ishak score ≥2) in HBeAg-negative CHB by validating several noninvasive markers derived from CHC. STUDY: One hundred seventy-seven consecutive treatment-naive HBeAg-negative CHB patients who underwent liver biopsy were divided into a training group (n=121) and a validation group (n=56). Factors associated with liver fibrosis were analyzed. RESULTS: Multivariate analysis identified Lok's model ≥0.87, cirrhosis discriminant score greater than 4, and positive alanine aminotransferase ratio platelet score as independent factors associated with liver fibrosis in the training group. The area under the receiver operating characteristic curve revealed that Lok's model was better than cirrhosis discriminant score in predicting liver fibrosis in both the training and the validation groups. In patients with hepatitis B virus DNA greater than 2000 IU/mL or greater than 20,000 IU/mL, Lok's model showed equal prediction value (area under the receiver operating characteristic curve 0.709 and 0.704, respectively). Lok's model could also discriminate high and low hepatitis B virus DNA loads. In general, liver biopsy can be avoided in one-third (58 of 177) of patients by Lok's model. CONCLUSIONS: Lok's model ≥0.87 can be an early marker of liver fibrosis in HBeAg-negative CHB patients. Lok's model has clinical applications not only for CHC, but also for HBeAg-negative CHB.

Correlation between clinical indication for treatment and liver histology in HBeAg-negative chronic hepatitis B: a novel role of alpha-fetoprotein.

BACKGROUND: It is unclear whether clinical indication for antiviral treatment is in agreement with histological indication in HBeAg-negative chronic hepatitis B (CHB). This study aimed to clarify this relationship and identify factors associated with liver histology. PATIENTS AND METHODS: We investigated 152 consecutive, treatment-naïve, HBeAg-negative CHB patients who had undergone liver biopsies at a tertiary medical centre in Taiwan. Clinical indications for treatment included a serum alanine aminotransferase level more than twice the upper limit of normal and an hepatitis B virus DNA level > 2000 IU/ml. Factors associated with the histological indication (Ishak's grade > or = 7 and/or stage > or = 2) were analysed. RESULTS: The association between the clinical and the histological indications was significant (P=0.011). However, the agreement was poor (kappa value=0.197). In patients satisfying the clinical indication, age > 52 years [odds ratio (OR)=2.669, P=0.042], serum alpha-fetoprotein (AFP) level > 7 ng/ml (OR=7.070, P<0.001) and platelet count < 130 x 10(9)/L (OR=11.720, P=0.025) were identified to be independent factors associated with histological indication. In patients who did not satisfy the clinical indication, multivariate analysis revealed that only an AFP level > 7 ng/ml (OR=10.345, P=0.021) was independently associated with histological indication. Combining the clinical indication and/or AFP level > 7 ng/ml to predict liver histology, the sensitivity and the negative predictive value could improve from 86 to 94.4% and 66.7 to 81% respectively. CONCLUSION: AFP level is associated with liver histology in HBeAg-negative CHB. Serum AFP level can serve as a surrogate indicator to identify patients who need antiviral treatment.

DNAJA3/Tid1 Is Required for Mitochondrial DNA Maintenance and Regulates Migration and Invasion of Human Gastric Cancer Cells.

BACKGROUND: Gastric cancer is a common health issue. Deregulated cellular energetics is regarded as a cancer hallmark and mitochondrial dysfunction might contribute to cancer progression. Tid1, a mitochondrial co-chaperone, may play a role as a tumor suppressor in various cancers, but the role of Tid1 in gastric cancers remains under investigated. METHODS: The clinical TCGA online database and immunohistochemical staining for Tid1 expression in tumor samples of gastric cancer patients were analyzed. Tid1 knockdown by siRNA was applied to investigate the role of Tid1 in gastric cancer cells. RESULTS: Low Tid1 protein-expressing gastric cancer patients had a poorer prognosis and higher lymph node invasion than high Tid1-expressing patients. Knockdown of Tid1 did not increase cell proliferation, colony/tumor sphere formation, or chemotherapy resistance in gastric cancer cells. However, Tid1 knockdown increased cell migration and invasion. Moreover, Tid1 knockdown reduced the mtDNA copy number of gastric cancer cells. In addition, the Tid1-galectin-7-MMP-9 axis might be associated with Tid1 knockdown-induced cell migration and invasion of gastric cancer cells. CONCLUSIONS: Tid1 is required for mtDNA maintenance and regulates migration and invasion of gastric cancer cells. Tid1 deletion may be a poor prognostic factor in gastric cancers and could be further investigated for development of gastric cancer treatments.

Predictive value of aspartate aminotransferase to alanine aminotransferase ratio for hepatic fibrosis and clinical adverse outcomes in patients with primary biliary cirrhosis.

BACKGROUND: The aspartate aminotransferase to alanine aminotransferase ratio (AAR) was seldom applied for fibrosis assessment in primary biliary cirrhosis (PBC) patients. GOALS: To validate the AAR for evaluating hepatic fibrosis, disease severity, and prognosis in patients with PBC. STUDY: Ninety-two consecutive PBC patients were retrospectively evaluated to validate the AAR for assessing the severity of liver function, the degrees of hepatic fibrosis, and predicting outcomes. RESULTS: AAR showed modest correlations to Mayo score, model for end-stage liver disease score, and Child-Pugh score (r2=0.156,P<0.001; r2=0.084, P=0.005; r2=0.142, P<0.001, respectively)in evaluating the severity of liver function. For 46 patients who underwent liver biopsy, 35 were in early stage fibrosis and the other 11 were in advanced fibrosis. AAR was significantly higher in patients with advanced fibrosis than those with early fibrosis (mean+/-standard deviation; 1.40+/-0.44 vs. 0.98+/-0.65,P=0.001). The AAR yielded the highest area under the receiver operating curve of 0.847 than Mayo score, model for end-stage liver disease score, and Child-Pugh score in predicting advanced fibrosis. During a median follow-up of 44.5 months, 24 patients expired and 68 patients were alive. Patients with an AAR of 1 or less had significantly better prognosis than their counterparts(P=0.043). CONCLUSIONS: AAR is a simple and reliable marker to assess liver function and hepatic fibrosis as well as to predict outcomes in PBC patients.

Natural history and prognostic factors of primary biliary cirrhosis in Taiwan: a follow-up study up to 18 years.

PURPOSE: The natural history of primary biliary cirrhosis (PBC) has been little studied in Asia. We conducted a Taiwanese cohort study on the natural history of PBC and analysed the prognostic factors. METHODS: This study enrolled 96 consecutive PBC patients between 1985 and 2006 to evaluate the baseline characteristics and outcomes. RESULTS: There were 74 females and 22 males. Eighty-five were positive for antimitochondrial antibodies in sera, and 11 were negative. The clinical manifestations and prognosis were similar between these two groups. In a median follow-up of 47.5+/-55.8 months, 27 patients died. Multivariate analysis indicated that the independent prognostic factors were serum albumin (P=0.021), creatinine (P=0.033) and ursodeoxycholic acid treatment (P=0.008). Besides, 42 patients developed adverse outcomes. Albumin (P<0.001), bilirubin (P=0.019) and prothrombin time (PT) (P=0.010) were significant factors. Moreover, a Mayo risk score <5, a Model for End-Stage Liver Disease (MELD) score <6, a Child-Pugh stage A and early liver histology were associated with favourable outcomes. CONCLUSION: Serum albumin, bilirubin and PT were independent prognostic factors of adverse outcomes for Taiwanese PBC patients. Besides, the Mayo risk score, the MELD score, the Child-Pugh stage and liver histology were also validated to predict survival.

Successful radiofrequency ablation therapy for hepatocellular carcinoma in a male patient with early stage primary biliary cirrhosis and positive serum hepatitis B core antibody.

Hepatocellular carcinoma (HCC) occurring in a 66-year-old male patient with early stage primary biliary cirrhosis (PBC) was successfully treated by radiofrequency ablation (RFA) therapy. He was diagnosed with PBC based on the findings of pruritus, elevated serum alkaline phosphate level and positive serum antimitochondrial antibody in 2005. The serologic tests for hepatitis B surface antigen, hepatitis B surface antibody and hepatitis C virus antibody were all negative. But antibody against hepatitis B core antigen was positive. Abdominal ultrasonography and dynamic computed tomography revealed 1 hypervascular tumor, 2.6 cm in diameter, in segment V of the liver in 2007. Liver biopsy showed a moderately differentiated HCC. Non-tumorous liver was compatible with Scheuer's classification of stage II PBC. The tumor was successfully treated by RFA. This case report demonstrates that HCC can arise from precirrhotic PBC and can be successfully treated by RFA. Regular surveillance for HCC is warranted for all patients with PBC, irrespective of stage.

A comparison of clinical manifestations and prognoses between patients with hepatocellular carcinoma and Child-Pugh scores of 5 or 6.

The objective of this work is to compare the outcomes between the Child-Pugh score 5 (A5 group) and Child-Pugh score 6 (A6 group) in patients with hepatocellular carcinoma (HCC). Whether HCC patients with A5 and A6 groups have different prognoses is still obscure. We enrolled 2462 consecutive treatment-naive HCC patients from 2007 to 2012. Among them, 1486 patients had Child-Pugh grade A, including 1016 in the A5 group and 470 in the A6 group. Factors in the prognoses were analyzed by multivariate analysis. Compared with those in the A6 group, patients in the A5 group were younger, had higher proportions of tumors within the Milan criteria, and more of them underwent curative therapies. The cumulative survival rates at 5 years were 51.3% and 37.1% for patients in the A5 and A6 groups, respectively (P < 0.001). Multivariate analysis showed that the independent risk factors associated with poor overall survival were nonhepatitis C virus carrier, serum albumin ≤ 4 g/dL, aspartate aminotransferase > 45 U/L, α-fetoprotein > 20 ng/mL, multinodularity, tumor size > 3 cm, vascular invasion, and noncurative therapies, but not the Child-Pugh numeric score. The Child-Pugh numeric score had a significant prognostic effect only in patients who had tumors beyond the Milan criteria and received noncurative therapies. HCC patients with A5 group had a better overall survival rate than those with A6 group due to the early tumor stage and higher rate of receiving curative treatments. Tumor factors and treatment modalities were more important than the Child-Pugh numeric score.

Milan criteria, multi-nodularity, and microvascular invasion predict the recurrence patterns of hepatocellular carcinoma after resection.

AIMS: This study aims to evaluate the risk factors for tumor recurrence beyond the Milan criteria (MC) for patients with hepatocellular carcinoma (HCC) after surgical resection (SR) in which salvage liver transplantation is relatively contraindicated. METHODS: A total of 447 patients who underwent SR for HCC were enrolled consecutively. Among them, 248 and 199 patients were within the Milan criteria and beyond the Milan criteria (BMC group), respectively. Overall survival, recurrence, and disease-free survival were analyzed by multivariate analysis. RESULTS: After a median follow-up of 34.4 months, 130 patients died. Microvascular invasion, higher Edmondson stage of tumor cell differentiation, BMC group, and no anti-viral therapy were associated with poor overall survival. Multi-nodularity, higher Edmondson stage, BMC group, and no anti-viral therapy were independent risk factors for tumor recurrence, while BMC group and no anti-viral therapy were independent risk factors for disease-free survival. The Milan criteria, multi-nodularity, and microvascular invasion were used to stratify the patients into low-, medium-, and high-risk groups for tumor recurrence outside the MC and showed statistical significance (low vs. medium, p = 0.011; low vs. high, p < 0.001; medium vs. high, p = 0.009). CONCLUSIONS: The combination of the MC, multi-nodularity, and microvascular invasion predict the post-operative recurrence of HCC and may provide a roadmap for further treatment.