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.

Hepatic resection after transarterial chemoembolization increases overall survival in large/multifocal hepatocellular carcinoma: a retrospective cohort study.

To investigate the prognosis of transarterial chemoembolization (TACE) followed by hepatic resection (HR) in large/multifocal hepatocellular carcinoma (HCC), the medical records of consecutive HCC patients who underwent TACE between January 2006 and December 2010 were retrospectively analyzed. Patients who received TACE alone comprised the T group (61 patients), while those who received HR after TACE comprised the T+R group (49 patients). All the resections were successfully performed, and only one class V complication occurred. While liver function was altered from baseline within 1 week after HR, it recovered within 1 month. Overall survival (OS) of the T+R and T groups were compared, and sub-group analyses were performed based on baseline α-fetoprotein (AFP) levels, the reduction of AFP, and tumor response before HR. Overall survival (OS) in the T+R group was longer than in the T group (47.00 ± 2.87 vs. 20.00 ± 1.85 months, P < 0.001). OS in the T+R group with AFP reduction was less than 50%, and OS among those with a poor tumor response before HR did not differ from the T group (P > 0.05). These patients may not benefit from the combined treatment. Our findings suggest HR after TACE is safe and effective for large/multifocal HCC, and prolongs OS when compared to TACE alone.

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.

Hepatocellular carcinoma with portal vein tumor thrombus: treatment with transarterial chemoembolization combined with sorafenib--a retrospective controlled study.

PURPOSE: To determine the safety and efficacy of transarterial chemoembolization (TACE) combined with sorafenib (hereafter, TACE-sorafenib) in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). MATERIALS AND METHODS: This study was approved by the institutional review board, and the requirement for informed consent was waived. The medical records of consecutive patients with HCC and PVTT who underwent TACE-sorafenib or TACE alone from January 2010 to December 2012 were retrospectively evaluated. Sorafenib (400 mg) was administered twice daily. Outcomes of patients who underwent TACE-sorafenib were compared with outcomes of patients who underwent TACE by using the Kaplan-Meier method according to types of PVTT: PVTT in the main portal vein (type A), PVTT in the first-order portal vein branch (type B), and PVTT in second- or lower-order portal vein branches (type C). RESULTS: Ninety-one patients were included in the analysis; 46 patients underwent TACE-sorafenib and 45 underwent TACE. TACE-sorafenib showed significant survival benefits compared with TACE in patients with type B (median survival, 13 months vs 6 months; P = .002) or type C (median survival, 15 months vs 10 months; P = .003) PVTT. TACE-sorafenib and main PVTT were the independent prognostic factors for survival at uni- and multivariate analysis. Liver function after TACE-sorafenib worsened only in patients with main PVTT. Sorafenib-related adverse events of grade 3 or higher occurred in 16 patients (35%). CONCLUSION: TACE-sorafenib side effects were acceptable, and this treatment may improve overall survival in patients with HCC with first-order or lower-branch PVTT when compared with patients who underwent TACE alone.

[Clinical observation of transcatheter arterial chemoembolization plus sorafenib in the treatment of advanced hepatocellular carcinoma with different types of portal vein tumor thrombosis].

OBJECTIVE: To explore the efficacy and safety of transcatheter arterial chemoembolization (TACE) plus sorafenib in the treatment of advanced hepatocellular carcinoma with different types of portal vein tumor thrombosis. METHODS: A total of 32 patients of advanced hepatocellular carcinoma with tumor thrombosis in portal vein were retrospectively analyzed. All of them took oral sorafenib after TACE. They were divided into 3 groups according to imaging examinations of tumor thrombosis in portal vein. Tumor thrombosis in main portal vein was group A, tumor thrombosis in right/left portal branch group B and tumor thrombosis in the second branch of portal vein group C. Tumor response rate, disease control rate (DCR), overall survival (OS) and time to tumor progression (TTP) was followed up. Liver functions were compared with the pre-treatment level. The occurrences of adverse events were recorded. RESULTS: DCR was 20.0% (Group A), 70.0% (Group B) and 91.7 % (Group C) at 2 months post-treatment. DCR in groups B and C had significant differences with group A (P < 0.05). The median OS was 3 (Group A), 9 (Group B) and 14 months (Group C) and the median TTP 0 (Group A), 3 (Group B) and 6 months (Group C) respectively. The median OS and median TTP were significantly longer in Groups B and C than those in Group A (P < 0.05). Liver function at 2 months post-treatment had no statistical difference with the baseline. The most common adverse effects included hand foot skin reaction (n = 23, 3 cases of grade 3), hypertension (n = 3), diarrhea (n = 25, 3 cases of grade 3), hair loss (n = 12), oral ulcers (n = 1) and gastrointestinal bleeding (n = 2). CONCLUSION: The combined use of TACE and sorafenib is both safe and efficacious in the treatment of advanced hepatocellular carcinoma with tumor thrombosis in portal vein. And it may prolong OS and TTP in hepatocellular carcinoma with tumor thrombosis in right/left portal vein and second branch of portal vein.