Sublethal heat stress-induced O-GlcNAcylation coordinates the Warburg effect to promote hepatocellular carcinoma recurrence and metastasis after thermal ablation.

The malignant transformation of residual hepatocellular carcinoma (HCC) cells after thermal ablation is considered as the main factor promoting postoperative HCC progression, which greatly limits the improvement of long-term survival, and at present there is no effective targeted therapeutic strategies. The Warburg effect is a metabolic feature correlated highly with malignant transformation (e.g. epithelial-to-mesenchymal transition [EMT]). Here, we showed that sublethal heat stress triggered a stronger Warburg effect of HCC cells, which contributed to the thermotolerance and invasion of HCC cells. Sublethal heat stress-induced O-GlcNAcylation was involved in this process. Such enhanced Warburg effect in HCC cells may be eliminated through O-GlcNAcylation inhibition, resulting in impaired thermotolerance and EMT, and thereby preventing tumor recurrence and metastasis of HCC-bearing mice after insufficient thermal ablation. Finally, we present evidence that sublethal heat stress-induced O-GlcNAcylation regulates the Warburg effect in HCC cells by promoting hypoxia-inducible factor 1α (HIF-1α) stability. In conclusion, the present study suggests that O-GlcNAcylation coordinates the Warburg effect to promote HCC progression after thermal ablation, which may serve as a novel potential target for controlling postoperative HCC recurrence and metastasis.

Medium or Large Hepatocellular Carcinoma: Sorafenib Combined with Transarterial Chemoembolization and Radiofrequency Ablation.

Purpose To determine the safety and efficacy of sorafenib combined with transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) (hereafter, S-TACE-RFA) in patients with medium or large (range, 3.1-7.0 cm in diameter) hepatocellular carcinoma (HCC). Materials and Methods This retrospective study evaluated the medical records of consecutive patients with medium or large HCC who underwent S-TACE-RFA or combined TACE and RFA (hereafter, TACE-RFA) from January 2010 to December 2014. Sorafenib was started 3-5 days after TACE, and RFA was performed 1-2 weeks after TACE. Treatment complications, recurrence-free survival (RFS), and overall survival (OS) in patients who underwent S-TACE-RFA were compared with those in patients who underwent TACE-RFA. Results Of the 174 patients who underwent S-TACE-RFA or TACE-RFA, 106 who met the eligibility criteria were included in this study. Among them, 40 underwent S-TACE-RFA and 66 underwent TACE-RFA. The patients who underwent S-TACE-RFA had longer RFS (median, 24.0 vs 10.0 months; P = .04) and better OS (median, 63.0 vs 36.0 months, P = .048) than those who underwent TACE-RFA. S-TACE-RFA and α-fetoprotein level were independent prognostic factors for survival in uni- and multivariable analyses. The rate of complications in patients who underwent S-TACE-RFA was similar to that in patients who underwent TACE-RFA (22.5% vs 18.2%, P = .59). Conclusion S-TACE-RFA resulted in longer RFS and better OS than did TACE-RFA in patients with medium or large HCC. © RSNA, 2018 Online supplemental material is available for this article.

Early prediction of survival in hepatocellular carcinoma patients treated with transarterial chemoembolization plus sorafenib.

AIM: To identify clinical biomarkers that could early predict improved survival in patients with advanced-stage hepatocellular carcinoma (HCC) treated with transarterial chemoembolization combined with sorafenib (TACE-S). METHODS: We retrospectively evaluated the medical records of consecutive patients with advanced-stage HCC who underwent TACE-S from January 2012 to December 2015. At the first follow-up 4-6 wk after TACE-S (median, 38 d; range, 33-45 d), patients exhibiting the modified Response Evaluation Criteria in Solid Tumors (mRECIST)-evaluated complete response, partial response, and stable disease were categorized as early disease control. At this time point, multiple variables were analyzed to identify the related factors affecting survival. RESULTS: Ninety-five patients were included in this study, and 60 of these patients achieved early disease control, with an overall disease control rate (DCR) of 63.2%. Patients who got sorafenib at the first TACE (no previous TACE) and patients without portal vein tumor thrombus (PVTT) had a higher DCR than those who underwent previous TACE before TACE-S (72.4% vs 48.6%, P = 0.019) and those with PVTT (75.5% vs 50.0%, P = 0.010). Early disease control after TACE-S, no previous TACE, and no PVTT were the independent prognostic factors for survival in the uni- and multivariate analyses. CONCLUSION: The first follow-up 4-6 wk after TACE-S can be used as the earliest time point to assess the response to TACE-S, and patients with mRECIST-evaluated early disease control, no previous TACE, and no PVTT had better survival.

Safety and Efficacy of Transarterial Chemoembolization Combined with CT-Guided Radiofrequency Ablation for Hepatocellular Carcinoma Adjacent to the Hepatic Hilum within Milan Criteria.

PURPOSE: To retrospectively evaluate safety and efficacy of conventional transarterial chemoembolization with ethiodized oil (Lipiodol) combined with CT-guided radiofrequency (RF) ablation for hepatocellular carcinoma (HCC) adjacent to the hepatic hilum. MATERIALS AND METHODS: Between January 2007 and December 2010, conventional transarterial chemoembolization combined with CT-guided RF ablation was performed in 40 patients with HCC adjacent to the hepatic hilum within Milan criteria (group A). Major complications, complete tumor ablation rate, local tumor progression rate, and overall survival were compared with 107 patients with HCC nonadjacent to the hepatic hilum (group B) treated by conventional transarterial chemoembolization combined with CT-guided RF ablation during the same period. RESULTS: Major complications included one case of large hepatic artery-portal vein fistula in group A (2.5%; 1/40) and one case of acute portal vein thrombosis, left heart failure, and tumor seeding in group B (2.8%; 3/107); the difference was not significant between the two groups (P = 1.000). There were no significant differences between the two groups in complete tumor ablation rate (80.0% vs 86.0%; P = .374), local tumor progression rates (1-year, 12.5% vs 14.1%; 2-year, 28.2% vs 24.2%; 3-year, 32.0% vs 27.6%; P = .723), and overall survival (1-year, 92.3% vs 91.8%; 3-year, 79.1% vs 79.3%; 5-year, 59.5% vs 58.4%; P = .555). CONCLUSIONS: Conventional transarterial chemoembolization combined with CT-guided RF ablation was safe and effective in selected patients with HCC adjacent to the hepatic hilum within Milan criteria.