RESUMO
Background: Randomized controlled trials (RCTs) testing the combination therapy of transarterial chemoembolization (TACE) plus multikinase inhibitor (MKI) in patients with unresectable hepatocellular carcinoma (HCC) have yielded inconsistent results. Methods: In this work, a systematic review and meta-analysis was performed to compare the TACE+MKI combination therapy versus TACE monotherapy in HCC patients with time to progression (TTP) adopted as primary outcome. Results: A total of 10 RCTs comprising 2837 patients receiving combination therapy (TACE plus sorafenib, brivanib, orantinib or apatinib) were included. TACE+MKI significantly prolonged TTP (hazard ratio [HR] 0.74, 95% CI 0.62-0.89, p=0.001) versus TACE monotherapy. Subgroup analysis suggested MKI administration before TACE might be preferable to post-TACE MKI for TTP. TACE+MKI also increased objective response rate (ORR) (risk ratio [RR] 1.17, 95% CI 1.03-1.32, p=0.01), but failed to improve overall survival (OS) (HR 0.98, 95% CI 0.86-1.13, p=0.82) and progression-free survival (PFS) (HR 0.75, 95% CI 0.50-1.12, p=0.16). The incidence of any adverse event (AE) did not significantly differ between TACE+MKI and TACE groups (RR 1.17, 95% CI 0.96-1.42, p=0.01), while serious AEs showed significant difference (RR 1.41, 95% CI 1.26-1.59, p<0.0001). Nevertheless, these AEs showing significant difference were mainly associated with MKI toxicities rather than TACE. Conclusions: TACE+MKI combination therapy improved TTP and ORR but not OS and PFS in patients with unresectable HCC. Further high-quality trials are needed to verify these clinical benefits, and our findings could be very informative for future trial design.
RESUMO
Gastric cancer, is the fourth most common tumour type yet, ranks second in terms of the prevalence of cancer-related deaths worldwide. CXXC finger protein 4 (CXXC4) has been considered as a novel cancer suppressive factor, including gastric cancer. This study attempted to investigate the possible function of CXXC4 in gastric cancer and the underlying mechanism. The binding of the ETS domain-containing protein-1 (ELK1) to the long non-coding RNA MIR100HG promoter region was identified. Then, their expression patterns in gastric cancer tissues and cells (SGC7901) were detected. A CCK-8 assay was used to detect SGC7901 cell proliferation. Subsequently, SGC7901 cells were co-cultured with CD3+ T cells, followed by measurement of CD3+ T cell proliferation, magnitude of IFN-γ+ T cell population and IFN-γ secretion. A nude mouse model was subsequently developed for in vivo validation of the in vitro results. Low CXXC4 expression was found in SGC7901 cells. Nuclear entry of ELK1 can be inhibited by suppression of the extent of ELK1 phosphorylation. Furthermore, ELK1 is able to bind the MIR100HG promoter. Overexpression of CXXC4 resulted in weakened binding of ELK1 to the MIR100HG promoter, leading to a reduced proliferative potential of SGC7901 cells, and an increase in IFN-γ secretion from CD3+ T cells. Moreover, in vivo experiments revealed that CXXC4 inhibited immune escape of gastric cancer cells through the ERK1/2 axis. Inhibition of the CXXC4/ELK1/MIR100HG pathway suppressed the immune escape of gastric cancer cells, highlighting a possible therapeutic target for the treatment of gastric cancer.
