Effects of iodine-125 seed brachytherapy on patients with heterochronous pulmonary metastasis from hepatocellular carcinoma: A propensity score matching study.

Purpose: To investigate the effects of iodine-125 seed brachytherapy (ISB) on the overall survival (OS) of patients with heterochronous pulmonary metastasis (HPM) secondary to hepatocellular carcinoma (HCC). Materials and Methods: The clinical and imaging data of 123 patients with HPM secondary to HCC treated at a single center from July 2012 to July 2020 were analyzed retrospectively. The patients were divided into ISB and non-ISB groups based on ISB treatment. Propensity score matching yielded 46 pairs of patients. A total of 191 lesions were treated, and the data were evaluated for 6 months after ISB. The OS rates of the two groups were compared using the Kaplan-Meier method. Independent prognostic factors were determined using a Cox proportional hazards regression model. Results: The percentages of lung lesions in complete remission, partial remission, disease stable, and disease progression stages were 49.2%, 32.8%, 9.6%, and 8.4%, respectively. The disease control rate was 91.6%. The median follow-up time from the initial diagnosis was 47 months and 33 months for the ISB and non-ISB groups, respectively. Patients in the ISB group had a longer OS than those in the non-ISB group (1-year: 95.7% vs. 80.3%; 3-year: 62.9% vs. 45.7%; 5-year: 37% vs. 20.9%; P < 0.05). Multivariate analysis demonstrated that ISB treatment, tumor differentiation, vascular invasion, and Child - Pugh score were independent prognostic factors for survival. Conclusion: ISB improves local control and OS rates of HPM secondary to HCC; thus, it is an effective and feasible option for patients with HPM secondary to HCC.

125I Radioactive Particles Drive Protective Autophagy in Hepatocellular Carcinoma by Upregulating ATG9B.

Background and Aims: 125I radioactive particles implantation have demonstrated efficacy in eradicating hepatocellular carcinoma (HCC). However, progressive resistance of HCC to 125I radioactive particles has limited its wide clinical application. Methods: We investigated the cellular responses to 125I radioactive particles treatment and autophagy-related 9B (ATG9B) silencing in HCC cell lines and Hep3B xenografted tumor model using Cell Counting Kit-8 reagent, western blotting, immunofluorescence, flow cytometry, transmission electron microscopy and immunohistochemistry. Results: In this study, we demonstrated that 125I radioactive particles induced cell apoptosis and protective autophagy of HCC in vitro and in vivo. Inhibition of autophagy enhanced the radiosensitivity of HCC to 125I radioactive particles. Moreover, 125I radioactive particles induced autophagy by upregulating ATG9B, with increased expression level of LC3B and decreased expression level of p62. Furthermore, ATG9B silencing downregulated LC3B expression and upregulated p62 expression and enhanced radiosensitivity of HCC to 125I radioactive particles in vitro and in vivo. Conclusions: Inhibition of ATG9B enhanced the antitumor effects of 125I particle radiation against HCC in vitro and in vivo. Our findings suggest that 125I particle radiation plus chloroquine or/and the ATG9B inhibitor may be a novel therapeutic strategy for HCC.

Iodine-125 Seeds Inhibit Carcinogenesis of Hepatocellular Carcinoma Cells by Suppressing Epithelial-Mesenchymal Transition via TGF-ß1/Smad Signaling.

To investigate the radioactive iodine-125 (I-125) seed on migrating and invading of hepatocellular carcinoma (HCC) cells and its mechanism, the irradiation of PLC and Huh7 cells was carried out with I-125 seeds in vitro. Cell counting kit 8 assay was employed to measure cell viability. Cell migration was evaluated by using wound-healing assay. Cell invasion was detected by Transwell assay; RT-PCR and Western blot were used for the detection of the mRNA and proteins of TGF-ß1 signaling pathway-related genes. The viability of PLC and Huh7 cells declined in a dose-dependent manner with increasing irradiation from 0 Gy, 2 Gy, 4 Gy, and 6 Gy, to 8 Gy, respectively. The IC50 of PLC and Huh7 cells were 6.20 Gy and 5.39 Gy, respectively, after 24 h of irradiation. Migration and invasion abilities of I-125 group cells were greatly weakened (P < 0.05) comparing with the control group. According to the outcomes of RT-PCR and WB, I-125 seed irradiation significantly inhibited the mRNA and protein expression of N-cadherin, vimentin, TGF-ß1, p-Smad2/3, and Snail. But the mRNA and protein expressions of E-cadherin were enhanced. Rescue experiment demonstrates that TGF-ß1 activator could reverse the inhibitory effects of I-125 on invasion and migration of cells. The results of in vivo experiments further verified that the I-125 seeds can inhibit the proliferation and TGF-ß1 of xenographed PLC cells. In conclusion, I-125 seeds restrain the invasion and migration of HCC cells by suppressing epithelial to mesenchymal transition, which may associate with the inhibition of the TGF-ß1 signaling.

Clinical Outcome of CT-Guided Iodine-125 Radioactive Seed Implantation for Intrahepatic Recurrent Hepatocellular Carcinoma: A Retrospective, Multicenter Study.

The efficacy and safety of CT-Guided Iodine-125 Radioactive Seed Implantation (RSI) for the treatment of intrahepatic recurrent hepatocellular carcinoma (rHCC) were analyzed in this multicenter retrospective study. We reviewed the medical records of patients with rHCC treated with I-125 seed implantation at four different hospitals in China from December 2011 and January 2021. The local progression-free survival (LPFS),liver PFS, and overall survival (OS) were calculated, and the short-term efficacy and treatment-related toxicities were evaluated. A total of 82 patients were enrolled; the median follow-up time was 46 months (range, 3-80 months). The 1-, 3- and 5-year LPFS rates were 63.8%, 27.1%, and 7.9%, respectively, and the corresponding OS rates were 74.8%, 32.9%, and 12.6%, respectively. Univariate analysis showed that factors influencing LPFS included the maximum lesion diameter, Barcelona Clinic Liver Cancer (BCLC) stage, interval between treatment and recurrence, and D90. Multivariate analyses revealed that the BCLC stage, interval between treatment and recurrence, and D90 were independent factors influencing LPFS, whereas BCLC stage, D90, and short-term efficacy were independent factors influencing OS. In summary, I-125 seed implantation is a safe and effective treatment for rHCC. The BCLC stage, interval, and D90 were found to influence the local control. A larger, prospective study is required to confirm the dose-response curve for Iodine-125 RSI of rHCC.