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Currently, it is not entirely clear whether hypoxia-inducible factor-1α (HIF-1α) is involved in the regulation of COX-2 expression and epithelial-to-mesenchymal transition (EMT), and whether these events affect the prognosis of hepatocellular carcinoma (HCC) patients treated with transcatheter arterial chemoembolization (TACE). In this report the relationship between HIF-1α and COX-2 protein expression, EMT in tumor specimens from HCC patients after TACE surgery and the clinical significance of HIF-1α and COX-2 expression were analyzed using statistical approaches. HepG2 cells treated with CoCl2 was employed as a hypoxia cell model in vitro to study hypoxia-induced HIF-1α, COX-2 expression, and EMT alteration. The results showed that HIF-1α and COX-2 protein expression increased in HCC tissues after TACE surgery. Moreover, there was positive correlation between upregulation of HIF-1α and COX-2. Elevated expression of HIF-1α increased both Snail and Vimentin protein expression, while it reduced E-cadherin protein expression. It was further verified that hypoxia enhanced protein expression of HIF-1α and COX-2 in HepG2 cells treated with CoCl2. Upregulation of HIF-1α and COX-2, together with EMT alteration resulted in increased migration and invasion of HepG2 cells under hypoxia. In conclusion, TACE surgery results in aggravated hypoxia status, leading to increased HIF-1α protein expression in HCC tissue. To adapt to hypoxic environment, HIF-1α stimulates COX-2 protein expression and promotes EMT process in hepatocellular cancer cells, which enhances HCC invasion and metastasis, and might contribute to poor prognosis in HCC patients post TACE treatment.

There is considerable potential for integrating transarterial chemoembolization (TACE), programmed death-(ligand)1 (PD-[L]1) inhibitors, and molecular targeted treatments (MTT) in hepatocellular carcinoma (HCC). It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations. In this nationwide, retrospective, cohort study, 826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT (combination group, n = 376) or TACE monotherapy (monotherapy group, n = 450) were included from January 2018 to May 2021. The primary endpoint was progression-free survival (PFS) according to modified RECIST. The secondary outcomes included overall survival (OS), objective response rate (ORR), and safety. We performed propensity score matching approaches to reduce bias between two groups. After matching, 228 pairs were included with a predominantly advanced disease population. Median PFS in combination group was 9.5 months (95% confidence interval [CI], 8.4–11.0) versus 8.0 months (95% CI, 6.6–9.5) (adjusted hazard ratio [HR], 0.70, P = 0.002). OS and ORR were also significantly higher in combination group (median OS, 19.2 [16.1–27.3] vs. 15.7 months [13.0–20.2]; adjusted HR, 0.63, P = 0.001; ORR, 60.1% vs. 32.0%; P < 0.001). Grade 3/4 adverse events were observed at a rate of 15.8% and 7.5% in combination and monotherapy groups, respectively. Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS, OS, and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice, with an acceptable safety profile.

AIM:To evaluate long-term effect of ethanol embolization for the treatment of hepatocellular carcinoma (HCC) with severe hepatic arterioportal shunt (APS), compared with Gelfoam embolization. METHODS:Sixty-four patients (ethanol group) and 33 patients (Gelfoam group) with HCC and APS were respectively treated with ethanol and Gelfoam for APS before the routine interventional treatment for the tumor. Frequency of recanalization of shunt, complete occlusion of the shunt, side effects, complications, and survival rates were analyzed between the two groups. RESULTS:The occlusion rate of APS after initial treatment in ethanol group was 70.3%(45/64), and recanalization rate of 1 month after embolization was 17.8%(8/45), and complete occlusion rate was 82.8%(53/64). Those in Gelfoam group were 63.6%(21/33), 85.7%(18/21), and 18.2%(6/33). There were significant differences in recanalization rate and complete occlusion rate between the two groups (P<0.05). The survival rates in ethanol group were 78% at 6 months, 49% at 12 months, 25% at 24 months, whereas those in Gelfoam group were 58% at 6 months, 23% at 12 months, 15% at 24 months. The ethanol group showed significantly better survival than Gelfoam group (P<0.05). In the ethanol group, there was a significant prolongation of survival in patients with monofocal HCC (P<0.05) and Child class A (P<0.05). There were no significant differences in survival rate in the Gelfoam group with regard to the number of tumor and Child class (P>0.05). The incidence rate of abdominal pain during procedure in ethanol group was 82.8%. There was no significant difference in postembolization syndromes between two groups. Procedure-related hepatic failure did not occur in ethanol group. CONCLUSION:Ethanol embolization for patients with HCC and severe APS is efficacious and safe, and may contribute to prolongation of the life span versus Gelfoam embolization.Huang MS, Lin Q, Jiang ZB, Zhu KS, Guan SH, Li ZR, Shan H. Comparison of long-term effects between intra-arterially delivered ethanol and Gelfoam for the treatment of severe arterioportal shunt in patients with hepatocellular carcinoma.