Determination of lethal electric field threshold for pulsed field ablation in ex vivo perfused porcine and human hearts.

Introduction: Pulsed field ablation is an emerging modality for catheter-based cardiac ablation. The main mechanism of action is irreversible electroporation (IRE), a threshold-based phenomenon in which cells die after exposure to intense pulsed electric fields. Lethal electric field threshold for IRE is a tissue property that determines treatment feasibility and enables the development of new devices and therapeutic applications, but it is greatly dependent on the number of pulses and their duration. Methods: In the study, lesions were generated by applying IRE in porcine and human left ventricles using a pair of parallel needle electrodes at different voltages (500-1500 V) and two different pulse waveforms: a proprietary biphasic waveform (Medtronic) and monophasic 48 × 100 µs pulses. The lethal electric field threshold, anisotropy ratio, and conductivity increase by electroporation were determined by numerical modeling, comparing the model outputs with segmented lesion images. Results: The median threshold was 535 V/cm in porcine ((N = 51 lesions in n = 6 hearts) and 416 V/cm in the human donor hearts ((N = 21 lesions in n = 3 hearts) for the biphasic waveform. The median threshold value was 368 V/cm in porcine hearts ((N = 35 lesions in n = 9 hearts) cm for 48 × 100 µs pulses. Discussion: The values obtained are compared with an extensive literature review of published lethal electric field thresholds in other tissues and were found to be lower than most other tissues, except for skeletal muscle. These findings, albeit preliminary, from a limited number of hearts suggest that treatments in humans with parameters optimized in pigs should result in equal or greater lesions.

Optimization of Transpedicular Electrode Insertion for Electroporation-Based Treatments of Vertebral Tumors.

Electroporation-based treatments such as electrochemotherapy and irreversible electroporation ablation have sparked interest with respect to their use in medicine. Treatment planning involves determining the best possible electrode positions and voltage amplitudes to ensure treatment of the entire clinical target volume (CTV). This process is mainly performed manually or with computationally intensive genetic algorithms. In this study, an algorithm was developed to optimize electrode positions for the electrochemotherapy of vertebral tumors without using computationally intensive methods. The algorithm considers the electric field distribution in the CTV, identifies undertreated areas, and uses this information to iteratively shift the electrodes from their initial positions to cover the entire CTV. The algorithm performs successfully for different spinal segments, tumor sizes, and positions within the vertebra. The average optimization time was 71 s with an average of 4.9 iterations performed. The algorithm significantly reduces the time and expertise required to create a treatment plan for vertebral tumors. This study serves as a proof of concept that electrode positions can be determined (semi-)automatically based on the spatial information of the electric field distribution in the target tissue. The algorithm is currently designed for the electrochemotherapy of vertebral tumors via a transpedicular approach but could be adapted for other anatomic sites in the future.

Numerical mesoscale tissue model of electrochemotherapy in liver based on histological findings.

Electrochemotherapy (ECT) and irreversible electroporation (IRE) are being investigated for treatment of hepatic tumours. The liver is a highly heterogeneous organ, permeated with a network of macro- and microvasculature, biliary tracts and connective tissue. The success of ECT and IRE depends on sufficient electric field established in whole target tissue; therefore, tissue heterogeneity may affect the treatment outcome. In this study, we investigate electroporation in the liver using a numerical mesoscale tissue model. We numerically reconstructed four ECT experiments in healthy porcine liver and computed the electric field distribution using our treatment planning framework. We compared the computed results with histopathological changes identified on microscopic images after treatment. The mean electric field threshold that best fitted the zone of coagulation necrosis was 1225 V/cm, while the mean threshold that best fitted the zone of partially damaged liver parenchyma attributed to IRE was 805 V/cm. We evaluated how the liver macro- and microstructures affect the electric field distribution. Our results show that the liver microstructure does not significantly affect the electric field distribution on the level needed for treatment planning. However, major hepatic vessels and portal spaces significantly affect the electric field distribution, and should be considered when planning treatments.

Retrospective Study for Validation and Improvement of Numerical Treatment Planning of Irreversible Electroporation Ablation for Treatment of Liver Tumors.

OBJECTIVE: The aims of this study were to determine the electric field threshold that best fits the local response to irreversible electroporation (IRE) ablation of hepatic tumors as seen in follow-up MRI; to numerically evaluate the heat generating effect of IRE; and to demonstrate the utility of treatment planning to improve procedures in the future. METHODS: 18 cases of hepatic tumors treated with IRE ablation were numerically reconstructed and treatment outcome was computed with a numerical treatment planning framework. Simulated ablation volumes were compared to ablation volumes segmented from 6-week follow-up MRI. Two cases with a high thermal component were selected for numerical optimization. RESULTS: The best fit between segmented and simulated ablation zones was obtained at 900 V/cm threshold with the average absolute error of 5.6 ± 1.5 mm. Considerable heating was observed in 7/18 cases, where >50% of tumor volume experienced heating likely to cause thermal damage. In the selected two cases, thermal damage was eliminated with adjustment of applied voltages. CONCLUSION: Lesions visible on MRI 6 weeks post IRE represent areas that experienced an electric field of 900 V/cm or higher. This threshold is higher than previously reported for IRE of hepatic tumors. It is likely the 6-week follow-up period was too long and the ablation zone has already shrunk considerably, resulting in overestimation of the threshold. SIGNIFICANCE: We developed a sophisticated method for validation of the numerical treatment planning framework. A future prospective study can be effectively designed based on the findings of this study.

Investigation of safety for electrochemotherapy and irreversible electroporation ablation therapies in patients with cardiac pacemakers.

BACKGROUND: The effectiveness of electrochemotherapy of tumors (ECT) and of irreversible electroporation ablation (IRE) depends on different mechanisms and delivery protocols. Both therapies exploit the phenomenon of electroporation of the cell membrane achieved by the exposure of the cells to a series of high-voltage electric pulses. Electroporation can be fine-tuned to be either reversible or irreversible, causing the cells to either survive the exposure (in ECT) or not (in IRE), respectively. For treatment of tissues located close to the heart (e.g., in the liver), the safety of electroporation-based therapies is ensured by synchronizing the electric pulses with the electrocardiogram. However, the use of ECT and IRE remains contraindicated for patients with implanted cardiac pacemakers if the treated tissues are located close to the heart or the pacemaker. In this study, two questions are addressed: can the electroporation pulses interfere with the pacemaker; and, can the metallic housing of the pacemaker modify the distribution of electric field in the tissue sufficiently to affect the effectiveness and safety of the therapy? RESULTS: The electroporation pulses induced significant changes in the pacemaker ventricular pacing pulse only for the electroporation pulses delivered during the pacing pulse itself. No residual effects were observed on the pacing pulses following the electroporation pulses for all tested experimental conditions. The results of numerical modeling indicate that the presence of metal-encased pacemaker in immediate vicinity of the treatment zone should not impair the intended effectiveness of ECT or IRE even when the casing is in direct contact with one of the active electrodes. Nevertheless, the contact between the casing and the active electrode should be avoided due to significant tissue heating at the site of the other active electrode for the IRE protocol and may cause the pulse generator to fail to deliver the pulses due to excessive current draw. CONCLUSIONS: The observed effects of electroporation pulses delivered in close vicinity of the pacemaker or its electrodes do not indicate adverse consequences for either the function of the pacemaker or the treatment outcome. These findings should contribute to making electroporation-based treatments accessible also to patients with implanted cardiac pacemakers.

Peri-tumoral Metallic Implants Reduce the Efficacy of Irreversible Electroporation for the Ablation of Colorectal Liver Metastases.

PURPOSE: To evaluate the effect of peri-tumoral metallic implants (MI) on the safety and efficacy of percutaneous irreversible electroporation (IRE) of colorectal liver metastasis (CRLM). MATERIALS AND METHODS: In this retrospective study, 25 patients (12 women, 13 men; MI: 13, no MI: 12) were treated for 29 CRLM. Patient characteristics, tumor location and size, treatment parameters and the presence of MI were evaluated as determinants of local tumor progression (LTP) with the competing risks model (univariate and multivariate analyses). Patient-specific computer models were created to examine the effect of the MI on the electric field used to induce IRE, probability of cell kill and potential thermal effects. RESULTS: Patients had a median follow-up of 25 months, during which no IRE-related major complications were reported. Univariate analysis showed that tumor size (> 2 cm), probe spacing (> 20 mm) and the presence of MI (p < 0.05) were significant predictors of time to LTP, but only the latter was found to be an independent predictor on multivariate analysis (sub-hazard ratio = 6.5; [95% CI 1.99, 21.4]; p = 0.002). The absence of peri-tumoral MI was associated with higher progression-free survival at 12 months (92.3% [56.6, 98.9] vs 12.5% [2.1, 32.8]). Computer simulations indicated significant distortions and reduction in electric field strength near MI, which could have contributed to under-treatment of the tumor. CONCLUSIONS: Peri-tumoral MI increases the risk of treatment failure following IRE of CRLM.

Electrochemotherapy of Spinal Metastases Using Transpedicular Approach-A Numerical Feasibility Study.

Vertebral column is the most frequent site for bone metastases. It has been demonstrated in previous studies that bone metastases can be efficiently treated by electrochemotherapy. We developed a novel approach to treat spinal metastases, that is, transpedicular approach that combines electrochemotherapy with already established technologies for insertion of fixation screws in spinal surgery. In the transpedicular approach, needle electrodes are inserted into the vertebral body through pedicles and placed around the tumor. The main goal of our study was to numerically investigate the feasibility of the proposed treatment approach. Three clinical cases were used in this study-1 with a tumor completely contained within the vertebral body and 2 with tumors spread also to the pedicles and spinal canal. Anatomically accurate numerical models were built for all 3 cases, and numerical computations of electric field distribution in tumor and surrounding tissue were performed to determine the treatment outcome. Complete coverage of tumor volume with sufficiently high electric field is a prerequisite for successful electrochemotherapy. Close to 100% tumor coverage was obtained in all 3 cases studied. Two cases exhibited tumor coverage of >99%, while the coverage in the third case was 98.88%. Tumor tissue that remained untreated was positioned on the margin of the tumor volume. We also evaluated hypothetical damage to spinal cord and nerves. Only 1 case, which featured a tumor grown into the spinal canal, exhibited potential risk of neural damage. Our study shows that the proposed transpedicular approach to treat spinal metastases is feasible and safe if the majority of tumor volume is contained within the vertebral body. In cases where the spinal cord and nerves are contained within the margin of the tumor volume, a successful and safe treatment is still possible, but special attention needs to be given to evaluation of potential neural damage.