Nanosecond pulsed electric field is a recently developed interventional radiology modality that can be used to treat a wide range of solid tumours. It does not cause direct Joule heating in the targeted region, thus spares vascular structures including veins, arteries and bile ducts, and avoids temperature-related problems such as vascular rupture and adhesion.
nsPEF has been shown to be an effective local ablative therapy for HCC treatment. Although the ablation effect of nsPEF on tumour cell death has been confirmed to occur through nano-pulse stimulation, the underlying mechanism is still unclear. The induction of tumour cell apoptosis [21–24] and anti-angiogenic effects [25] has been reported in previous studies. In 2011, Beebe et al. investigated the effect of nanosecond pulses on hepatocellular carcinoma [20]. The authors found that nsPEF could effectively treat ectopic hepatocellular carcinoma, and that the therapeutic effect was associated with changes in caspase-3 activity in tumour cells, which provides a theoretical basis for the preclinical application of orthotopic hepatocellular carcinoma. Chen et al. [14] studied the long-term survival of mice after nanosecond pulse ablation of hepatocellular carcinoma, and the mechanism by which this treatment modality exerts its effects. nsPEF ablation was shown to eliminate hepatocellular carcinoma by inducing apoptosis and inhibiting angiogenesis. These findings provide a further theoretical basis for the clinical application of nanosecond pulse ablation in hepatocellular carcinoma.
In addition, previous studies have shown that nsPEF has extensive biological effects in colon cancer [26–27], ovarian cancer [28–29], oral cancer [30–32], pancreatic cancer [33], and fibrosarcoma [34]. In addition to inducing tumour cell apoptosis, nsPEF modulates tumour cell proliferation, invasion and metastasis, the tumour microenvironment, angiogenesis, and other tumour characteristics[35–40].
The current study systemically followed up the ablation outcomes, and identified several advantages of applying nsPEF ablation: (1) The red blood cell count remained consistent, proving that massive haemorrhage did not occur during treatment. There was no significant difference between the pretreatment and post-treatment white blood cell counts, suggesting that strict asepsis during the ultrasound-guided puncture operations and nsPEF ablation could effectively prevent infection, which ensures further human-trial safety. (2) Liver enzyme levels can be used to assess the damage to liver function caused by ablation. Aminotransferase (ALT and AST) levels were temporarily elevated, which was assumed to result from hepatocytes death within the ablation area. Their subsequent recovery confirmed that the remaining liver volume is enough to compensate the damaged liver tissues, proving the safety of nsPEF. (3) In this study, we employed a synchronous cardiac pulse generation system that automatically stopped when the ECG detected irregular cardiac activity, effectively protecting the cardiac muscles from electrical injury. The slight changes in cardiac enzymes CK and CK-MB were not induced by myocardial injury but by muscle puncture. The cardiac troponin I levels and the return of CK and CK-MB to baseline after 14 days confirmed this hypothesis. In HCC patients, muscle injury-induced CK-MB release and the mild elevation of LDH are tolerant under Child-A or -B score situation. (4) Thermal ablation reportedly increases the risk of thrombogenicity, which can lead to the administration of heparin [41]. Our results showed that the blood platelet levels were reduced post treatment, and returned to baseline after 14 days. Coagulation indexes also underwent a temporary change, and their subsequent recovery indicated that nsPEF does not result in a procoagulant effect. In addition, the histopathologic results did not indicate thrombosis. Therefore, no anticoagulant therapy is required after nsPEF treatment. These findings provide a foundation for the future clinical application of nsPEF to treat tumours.
The current study sought to elucidate the effect of this technique on blood vessels in the ablation range of the tumour and the resistance of blood vessels of different diameters to this ablation. We investigated the effect of nsPEF on hepatic veins of different diameters and evaluated the feasibility and safety of nsPEF on porcine livers. The pathological follow-up showed that the hepatic veins in the ablated area were maintained along with the complete vascular structure, while the targeted perivascular tissues were accurately ablated with no sparing. Furthermore, we found that compared with the major hepatic veins (DIA > 6 mm), the smaller hepatic veins (DIA < 4 mm and DIA 4–6 mm) were more strongly affected by nsPEF treatment. However, after 14 days, the areas of traversing hepatic vein congestion had resolved in the ablated area, and the smaller hepatic veins had recovered. The flow velocity of the target hepatic veins before and after treatment was the same, and there was no obvious evidence of aneurysm or thrombus formation. Taken together, the above results indicate that nsPEF does not have a deleterious effect on hepatic veins.
There were several limitations to this study. Although the distance between the probe and vessels and their orientation to each other were taken into account, the vessels were not targeted directly in all cases. In addition, although our study mainly focused on the influence of nsPEF on hepatic veins with different diameters, there may additionally be portal veins, bile duct, and/or arteries close to the HCC tumour mass. The safety of this technique in these veszoneareasel types is also an important consideration that requires further investigation.