BackgroundHepatocellular carcinoma (HCC) is a highly aggressive malignancy. Irreversible electroporation (IRE) is an ablative modality that uses high-voltage electrical pulses to permeabilize the cell membrane leading to cell necrosis. Unlike traditional thermal ablation, IRE is hardly affected by the “heat-sink” effect and can prevent damage of the adjacent vital structures. Nanosecond pulsed electric field (nsPEF) is a new IRE technique using ultra-short pulses (nanosecond duration), can not only penetrate the cell membranes, but also act on the organelles. Sufficient preclinical researches have shown that nsPEF can eliminate HCC without damaging vital organs, and elicit potent anti-tumor immune response.ObjectiveThis is the first clinical study to evaluate feasibility, efficacy, and safety of nsPEF for the treatment of HCC, where thermal ablation is unsuitable due to proximity to critical structures.Methods and analysisWe will conduct an open-labeled, single-arm, prospective, multicenter, and objective performance criteria trial. One hundred and ninety-two patients with HCC, in which the tumor is located immediately (<0.5 cm) adjacent to the portal vein, hepatic veins, bile duct, gastrointestinal tract, or diaphragm, will be enrolled among 4 academic medical centers. The primary outcomes are the rate of complete ablation at 1 month and adverse events. Secondary outcomes include technical success, technique efficacy, nsPEF procedural characteristics, local tumor progression, and local progression-free survival.Ethics and disseminationThe trial will be conducted according to the ethical principles of the Declaration of Helsinki and has been approved by the ethics committee of all participating centers. The results of this study will be published in peer-reviewed scientific journals and presented at relevant academic conferences.ConclusionsThis study is the Phase 1 clinical trial to evaluate the efficacy and safety of nsPEF in patients with HCC at high-risk locations where thermal ablation is contra-indicated. The results may expand the options and offer an alternative therapy for HCC.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT04309747.
Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death in the world. Nanosecond pulsed electric fields (nsPEFs) have emerged as a new treatment for cancer. This study aims to identify the effectiveness of nsPEFs in the treatment of HCC and analyze the alterations in the gut microbiome and serum metabonomics after ablation.Methods: C57BL/6 mice were randomly divided into three groups: healthy control mice (n = 10), HCC mice (n = 10), and nsPEF-treated HCC mice (n = 23). Hep1-6 cell lines were used to establish the HCC model in situ. Histopathological staining was performed on tumor tissues. The gut microbiome was analyzed by 16S rRNA sequencing. Serum metabolites were analyzed by liquid chromatography–mass spectrometry (LC-MS) metabolomic analysis. Spearman’s correlation analysis was carried out to analyze the correlation between the gut microbiome and serum metabonomics.Results: The fluorescence image showed that nsPEFs were significantly effective. Histopathological staining identified nuclear pyknosis and cell necrosis in the nsPEF group. The expression of CD34, PCNA, and VEGF decreased significantly in the nsPEF group. Compared with normal mice, the gut microbiome diversity of HCC mice was increased. Eight genera including Alistipes and Muribaculaceae were enriched in the HCC group. Inversely, these genera decreased in the nsPEF group. LC-MS analysis confirmed that there were significant differences in serum metabolism among the three groups. Correlation analysis showed crucial relationships between the gut microbiome and serum metabolites that are involved in nsPEF ablation of HCC.Conclusion: As a new minimally invasive treatment for tumor ablation, nsPEFs have an excellent ablation effect. The alterations in the gut microbiome and serum metabolites may participate in the prognosis of HCC ablation.
Background Liver tumor remains an important cause of cancer-related death. Nanosecond pulsed electric fields (nsPEFs) are advantageous in the treatment of melanoma and pancreatic cancer, but their therapeutic application on liver tumors need to be further studied. Methods Hep3B cells were treated with nsPEFs. The biological behaviors of cells were detected by Cell Counting Kit-8, 5-ethynyl-20-deoxyuridine, and transmission electron microscopy (TEM) assays. In vivo, rabbit VX2 liver tumor models were ablated by ultrasound-guided nsPEFs and radiofrequency ablation (RFA). Contrast-enhanced ultrasound (CEUS) was used to evaluate the ablation effect. HE staining and Masson staining were used to evaluate the tissue morphology after ablation. Immunohistochemistry was performed to determine the expression of Ki67, proliferating cell nuclear antigen, and α-smooth muscle actin at different time points after ablation. Results The cell viability of Hep3B cells was continuously lower than that of the control group within 3 days after pulse treatment. The proliferation of Hep3B cells was significantly affected by nsPEFs. TEM showed that Hep3B cells underwent significant morphological changes after pulse treatment. In vivo, CEUS imaging showed that nsPEFs could completely ablate model rabbit VX2 liver tumors. After nsPEFs ablation, the area of tumor fibrosis and the expression of Ki67, proliferating cell nuclear antigen, and α-smooth muscle actin were decreased. However, after RFA, rabbit VX2 liver tumor tissue showed complete necrosis, but the expression of PCNA and α-smooth muscle actin did not decrease compared to the tumor group. Conclusions nsPEFs can induce Hep3B cells apoptosis and ablate rabbit VX2 liver tumors in a non-thermal manner versus RFA. The ultrasound contrast agent can monitor immediate effect of nsPEF ablation. This study provides a basis for the clinical study of nsPEFs ablation of liver cancer.
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