Neoadjuvant chemo-immunotherapy is improved with a novel pulsed electric field technology in an immune-cold murine model.

Chemo-immunotherapy uses combined systemic therapies for resectable and unresectable tumors. This approach is gaining clinical momentum, but survival increases leave considerable room for improvement. A novel form of Pulsed Electric Field (PEF) ablation combines focal tissue destruction with immune activation in preclinical settings. The PEFs induce lethal cell damage without requiring thermal processes, leaving cellular proteins intact. This affords PEF a favorable safety profile, improved antigenicity, and significant immunostimulatory damage-associated molecular pattern release compared to other focal therapies. Preclinical investigations demonstrate a combinatorial benefit of PEF with immunostimulation. This study evaluates whether this proprietary PEF therapy induces an immunostimulatory effect sufficient to augment systemic neoadjuvant chemotherapy and immunotherapy to reverse metastatic disease in an immune-cold murine tumor model. To determine whether PEF improves a neoadjuvant chemo-immunotherapy standard-of-care, partial PEF ablation was delivered to orthotopically inoculated 4T1 metastatic tumors in addition to combinations of cisplatin chemotherapy and/or αPD-1 immunotherapy, followed by resection. In addition, to determine whether PEF combined with chemo-immunotherapy improves local and metastatic response in unresectable populations, partial PEF ablation was added to chemo-immunotherapy in mice that did not receive resection. Blood cytokines and flow cytometry evaluated immune response. Partial PEF ablation generates an immunostimulatory tumor microenvironment, increases systemic immune cell populations, slows tumor growth, and prolongs survival relative to neoadjuvant systemic therapies-alone. These data suggest the addition of this proprietary PEF locoregional therapy may synergize with systemic standard-of-care paradigms to improve outcomes with potential or demonstrated metastatic disease in both resectable and unresectable patient cohorts.

Absence of Arrhythmogenicity with Biphasic Pulsed Electric Fields Delivered to Porcine Airways.

Pulsed electric field (PEF) technologies treat many types of tissue. Many systems mandate synchronization to the cardiac cycle to avoid the induction of cardiac arrhythmias. Significant differences between PEF systems make the assessment of cardiac safety from one technology to another challenging. A growing body of evidence suggests that shorter duration biphasic pulses obviate the need for cardiac synchronization, even when delivered in a monopolar fashion. This study theoretically evaluates the risk profile of different PEF parameters. It then tests a monopolar, biphasic, microsecond-scale PEF technology for arrhythmogenic potential. PEF applications of increasing likelihood to induce an arrhythmia were delivered. The energy was delivered throughout the cardiac cycle, including both single and multiple packets, and then with concentrated delivery on the t-wave. There were no sustained changes to the electrocardiogram waveform or to the cardiac rhythm, despite delivering energy during the most vulnerable phase of the cardiac cycle, and delivery of multiple packets of PEF energy across the cardiac cycle. Only isolated premature-atrial contractions (PAC) were observed. This study provides evidence that certain varieties of biphasic, monopolar PEF delivery do not require synchronized energy delivery to prevent harmful arrhythmias.

Pulsed Electric Field Ablation versus Radiofrequency Thermal Ablation in Murine Breast Cancer Models: Anticancer Immune Stimulation, Tumor Response, and Abscopal Effects.

PURPOSE: To compare the immune response and survival after size-matched radiofrequency (RF) ablation and a proprietary form of pulsed electric field (PEF) ablation in murine tumors. MATERIAL AND METHODS: Orthotopically inoculated EMT6 or 4T1 murine tumors received sham, RF ablation, or PEF ablation. 4T1 tumor ablations included subgroups with intraperitoneal checkpoint inhibition immunotherapy (αPD-1). Blood was collected for cytokine profiling and flow cytometry. Tumor size was measured and survival was monitored. Tumor samples were processed for histology, immunohistochemistry, flow cytometry, and cytokine profiling. Lungs were collected from 4T1-bearing mice for hematoxylin and eosin histology to assess metastatic spread and abscopal effect induced by ablation. RESULTS: PEF elicited distinct immunomodulatory effects, with clear differences in serum and tumor cytokine profiles compared with RF ablation, including intratumoral downregulation of vascular endothelial growth factor, hypoxia-inducible factor 1α, c-MET, interleukin-10, Ki67, and tumor necrosis factor-α (all P < .05). PEF increased innate immune activation, with enhanced recruitment of dendritic cells, M1 macrophages, and natural killer cells coupled with a reduction in M2 macrophages and myeloid-derived suppressor cells (all P < .05). Concurrently, PEF strengthened adaptive immunity compared with RF ablation, characterized by increased antigen-specific T cells and decreased regulatory T cells (all P < .05). PEF stalled tumor growth and increased survival at the end of the study (≥4× versus RFA). Finally, PEF promoted an abscopal effect of clearing metastases in the lungs, which was stronger in combination with αPD-1 than with PEF alone. CONCLUSIONS: The proprietary form of PEF used in this study evoked a preferential immunostimulatory profile versus RF ablation thermal ablation in mice, with implications for enhancing the therapeutic effectiveness of checkpoint inhibition immunotherapy for immunotherapy-unresponsive tumors.

Thermal Profiles for Focal Pulsed Electric Field Ablation.

BACKGROUND: Pulsed electrical field (PEF) ablation may cause tissue heating. These changes are reportedly small, but each PEF system and waveform will have a different behavior, and data are lacking. OBJECTIVES: This study sought to compare the temperature profile of focal point, monopolar biphasic PEF ablation versus radiofrequency (RF). METHODS: Ablation lesions were performed on perfused thigh muscle of swine. PEF lesions were performed with 3 compatible ablation catheters at the highest (25 amp) energy, and 1 catheter (Tacticath SE) was also used at the 22- and 19-amp levels. Temperature changes in the tissue were measured using fluoroptic temperature probes inserted at the muscle surface, as well as 3 mm and 7 mm below the surface. Temperatures were recorded continuously at baseline, during delivery, and after ablation. Muscle temperatures were compared with those of RF lesions performed with 1 catheter (Tacticath SE) at 30 W for 30 seconds. RESULTS: PEF ablation with 3energy settings produced small temperature changes. Maximum average temperature rise for PEF for the maximum (25-amp) energy setting (32 lesions) was 7.6 °C, 2.8 °C, and 0.9 °C at the surface, 3-mm depth, and 7-mm depth, respectively. The temperature rise was dose dependent, with lower energy settings yielding less temperature rise. RF ablations (10 lesions) produced temperature increases of 16.6 °C, 39.8 °C, and 9.5 °C at the surface, 3-mm depth, and 7-mm depth, respectively. CONCLUSIONS: PEF caused detectable temperature changes in muscle tissue, which never exceeded 2.8 °C at the 3-mm depth versus baseline. By contrast, RF produced substantial temperature rises. These data support that focal monopolar biphasic energy delivered by this PEF technology retains a favorable thermal safety profile.

Primer on Pulsed Electrical Field Ablation: Understanding the Benefits and Limitations.

Pulsed electrical field (PEF) energy is a promising technique for catheter ablation of cardiac arrhythmias. In this article, the key aspects that need to be considered for safe and effective PEF delivery are reviewed, and their impact on clinical feasibility is discussed. The most important benefit of PEF appears to be the ability to kill cells through mechanisms that do not alter stromal proteins, sparing sensitive structures to improve safety, without sacrificing cardiomyocyte ablation efficacy. Many parameters affect PEF treatment outcomes, including pulse intensity, waveform shape, and number of pulses, as well as electrode configuration and geometry. These physical and electrical characteristics must be titrated carefully to balance target tissue effects with collateral implications (muscle contraction, temperature rise, risk of electrical arcing events). It is important to note that any combination of parameters affecting PEF needs to be tested for clinical efficacy and safety. Applying PEF clinically requires knowledge of the fundamentals of this technology to exploit its opportunities and generate viable, durable health improvements for patients.

Numerical simulation modeling of the irreversible electroporation treatment zone for focal therapy of prostate cancer, correlation with whole-mount pathology and T2-weighted MRI sequences.

BACKGROUND: At present, it is not possible to predict the ablation zone volume following irreversible electroporation (IRE) for prostate cancer (PCa). This study aimed to determine the necessary electrical field threshold to ablate human prostate tissue in vivo with IRE. METHODS: In this prospective multicenter trial, patients with localized PCa were treated with IRE 4 weeks before their scheduled radical prostatectomy. In 13 patients, numerical models of the electrical field were generated and compared with the ablation zone volume on whole-mount pathology and T2-weighted magnetic resonance imaging (MRI) sequences. Volume-generating software was used to calculate the ablation zone volumes on histology and MRI. The electric field threshold to ablate prostate tissue was determined for each patient. RESULTS: A total of 13 patients were included for histological and simulation analysis. The median electrical field threshold was 550 V/cm (interquartile range 383-750 V/cm) for the software-generated histology volumes. The median electrical field threshold was 500 V/cm (interquartile range 386-580 V/cm) when the ablation zone volumes were used from the follow-up MRI. CONCLUSIONS: The electrical field threshold to ablate human prostate tissue in vivo was determined using whole-mount pathology and MRI. These thresholds may be used to develop treatment planning or monitoring software for IRE prostate ablation; however, further optimization of simulation methods are required to decrease the variance that was observed between patients.

Effects of internal electrode cooling on irreversible electroporation using a perfused organ model.

PURPOSE: This study evaluates the effects of active electrode cooling, via internal fluid circulation, on the irreversible electroporation (IRE) lesion, deployed electric current and temperature changes using a perfused porcine liver model. MATERIALS AND METHODS: A bipolar electrode delivered IRE electric pulses with or without activation of internal cooling to nine porcine mechanically perfused livers. Pulse schemes included a constant voltage, and a preconditioned delivery combined with an arc-mitigation algorithm. After treatment, organs were dissected, and treatment zones were stained using triphenyl-tetrazolium chloride (TTC) to demonstrate viability. RESULTS: Thirty-nine treatments were performed with an internally cooled applicator and 21 with a non-cooled applicator. For the constant voltage scenario, the average final electrical current measured was 26.37 and 29.20 A for the cooled and uncooled electrodes respectively ([Formula: see text]). The average final temperature measured was 33.01 and 42.43 °C for the cooled and uncooled electrodes respectively ([Formula: see text]). The average measured ablations (fixed lesion) were 3.88-by-2.08 cm and 3.86-by-2.12 cm for the cooled and uncooled electrode respectively ([Formula: see text], [Formula: see text]). Similarly, the preconditioned/arc-mitigation scenario yielded an average final electrical current measurement of a 41.07 and 47.20 A for the cooled and uncooled electrodes respectively ([Formula: see text]). The average final temperature measured was 34.93 and 44.90 °C for the cooled and uncooled electrodes respectively ([Formula: see text]). The average measured ablations (fixed lesion) were 3.67-by-2.27 cm and 3.58-by-2.09 cm for the cooled and uncooled applicators ([Formula: see text]). CONCLUSIONS: The internally-cooled bipolar applicator offers advantages that could improve clinical outcomes. Thermally mitigating internal perfusion technology reduced tissue temperatures and electric current while maintaining similar lesion sizes.

An evaluation of irreversible electroporation thresholds in human prostate cancer and potential correlations to physiological measurements.

Irreversible electroporation (IRE) is an emerging cancer treatment that utilizes non-thermal electric pulses for tumor ablation. The pulses are delivered through minimally invasive needle electrodes inserted into the target tissue and lead to cell death through the creation of nanoscale membrane defects. IRE has been shown to be safe and effective when performed on tumors in the brain, liver, kidneys, pancreas, and prostate that are located near critical blood vessels and nerves. Accurate treatment planning and prediction of the ablation volume require a priori knowledge of the tissue-specific electric field threshold for cell death. This study addresses the challenge of defining an electric field threshold for human prostate cancer tissue. Three-dimensional reconstructions of the ablation volumes were created from one week post-treatment magnetic resonance imaging (MRIs) of ten patients who completed a clinical trial. The ablation volumes were incorporated into a finite element modeling software that was used to simulate patient-specific treatments, and the electric field threshold was calculated by matching the ablation volume to the field contour encompassing the equivalent volume. Solutions were obtained for static tissue electrical properties and dynamic properties that accounted for electroporation. According to the dynamic model, the electric field threshold was 506 ± 66 V/cm. Additionally, a potentially strong correlation (r = -0.624) was discovered between the electric field threshold and pre-treatment prostate-specific antigen levels, which needs to be validated in higher enrollment studies. Taken together, these findings can be used to guide the development of future IRE protocols.

Characterization of Irreversible Electroporation Ablation with a Validated Perfused Organ Model.

PURPOSE: To develop and validate a perfused organ model for characterizing ablations for irreversible electroporation (IRE)-based therapies. MATERIALS AND METHODS: Eight excised porcine livers were mechanically perfused with a modified phosphate-buffered saline solution to maintain viability during IRE ablation. IRE pulses were delivered using 2 monopolar electrodes over a range of parameters, including voltage (1,875-3,000 V), pulse length (70-100 µsec), number of pulses (50-600), electrode exposure (1.0-2.0 cm), and electrode spacing (1.5-2.0 cm). Organs were dissected, and treatment zones were stained with triphenyl tetrazolium chloride to demonstrate viability and highlight the area of ablation. Results were compared with 17 in vivo ablations performed in canine livers and 35 previously published ablations performed in porcine livers. RESULTS: Ablation dimensions in the perfused model correlated well with corresponding in vivo ablations (R2 = 0.9098) with a 95% confidence interval of < 2.2 mm. Additionally, the validated perfused model showed that the IRE ablation zone grew logarithmically with increasing pulse numbers, showing small difference in ablation size over 200-600 pulses (3.2 mm ± 3.8 width and 5.2 mm ± 3.9 height). CONCLUSIONS: The perfused organ model provides an alternative to animal trials for investigation of IRE treatments. It may have an important role in the future development of new devices, algorithms, and techniques for this therapy.

The Influence of a Metal Stent on the Distribution of Thermal Energy during Irreversible Electroporation.

PURPOSE: Irreversible electroporation (IRE) uses short duration, high-voltage electrical pulses to induce cell death via nanoscale defects resulting from altered transmembrane potential. The technique is gaining interest for ablations in unresectable pancreatic and hepatobiliary cancer. Metal stents are often used for palliative biliary drainage in these patients, but are currently seen as an absolute contraindication for IRE due to the perceived risk of direct heating of the metal and its surroundings. This study investigates the thermal and tissue viability changes due to a metal stent during IRE. METHODS: IRE was performed in a homogeneous tissue model (polyacrylamide gel), without and with a metal stent placed perpendicular and parallel to the electrodes, delivering 90 and 270 pulses (15-35 A, 90 µsec, 1.5 cm active tip exposure, 1.5 cm interelectrode distance, 1000-1500 V/cm, 90 pulses/min), and in-vivo in a porcine liver (4 ablations). Temperature changes were measured with an infrared thermal camera and with fiber-optic probes. Tissue viability after in-vivo IRE was investigated macroscopically using 5-triphenyltetrazolium chloride (TTC) vitality staining. RESULTS: In the gel, direct stent-heating was not observed. Contrarily, the presence of a stent between the electrodes caused a higher increase in median temperature near the electrodes (23.2 vs 13.3°C [90 pulses]; p = 0.021, and 33.1 vs 24.8°C [270 pulses]; p = 0.242). In-vivo, no temperature difference was observed for ablations with and without a stent. Tissue examination showed white coagulation 1mm around the electrodes only. A rim of vital tissue remained around the stent, whereas ablation without stent resulted in complete tissue avitality. CONCLUSION: IRE in the vicinity of a metal stent does not cause notable direct heating of the metal, but results in higher temperatures around the electrodes and remnant viable tissue. Future studies should determine for which clinical indications IRE in the presence of metal stents is safe and effective.

Introduction to Irreversible Electroporation--Principles and Techniques.

Irreversible electroporation (IRE) is a novel nonthermal focal ablation technique that uses a series of brief but intense electric pulses delivered by paired electrodes into a targeted region of tissue, killing the cells by irreversibly disrupting cellular membrane integrity. Unlike other ablation methods, IRE has relatively little effect on connective tissues and nerves and has a low patient effect. The ability of IRE to achieve cell death immediately adjacent to large vessels without effect on the vessels themselves has raised the possibility of better treatment of advanced pancreatic cancer. Because of the low effect on the patient, IRE is well suited for use in conjunction with chemotherapeutic agents. The IRE effect is not uniform and is dependent on the intrinsic conductivity of the tissue, the number of pulses delivered, the current flow achieved, and the total time for the treatment. It is currently under investigation for a wide range of solid tumors and prostate cancer in humans and in animals in the breast, brain, and spinal cord. In clinical practice, IRE can be administered either percutaneously under imaging guidance or at open operation under direct vision. In animals there is some evidence of an immune response presumably due to exposure of the intracellular target material, resulting in a greater therapeutic effect. Unlike many other cancer treatments, IRE has been introduced for human clinical use at a very early stage of development of the technique and much of the basic understanding of how and when to use IRE is still under investigation.

Safety and feasibility of the NanoKnife system for irreversible electroporation ablative treatment of canine spontaneous intracranial gliomas.

OBJECT: Irreversible electroporation (IRE) is a novel nonthermal ablation technique that has been used for the treatment of solid cancers. However, it has not been evaluated for use in brain tumors. Here, the authors report on the safety and feasibility of using the NanoKnife IRE system for the treatment of spontaneous intracranial gliomas in dogs. METHODS: Client-owned dogs with a telencephalic glioma shown on MRI were eligible. Dog-specific treatment plans were generated by using MRI-based tissue segmentation, volumetric meshing, and finite element modeling. After biopsy confirmation of glioma, IRE treatment was delivered stereotactically with the NanoKnife system using pulse parameters and electrode configurations derived from therapeutic plans. The primary end point was an evaluation of safety over the 14 days immediately after treatment. Follow-up was continued for 12 months or until death with serial physical, neurological, laboratory, and MRI examinations. RESULTS: Seven dogs with glioma were treated. The mean age of the dogs was 9.3 ± 1.6 years, and the mean pretreatment tumor volume was 1.9 ± 1.4 cm(3). The median preoperative Karnofsky Performance Scale score was 70 (range 30-75). Severe posttreatment toxicity was observed in 2 of the 7 dogs; one developed fatal (Grade 5) aspiration pneumonia, and the other developed treatment-associated cerebral edema, which resulted in transient neurological deterioration. Results of posttreatment diagnostic imaging, tumor biopsies, and neurological examinations indicated that tumor ablation was achieved without significant direct neurotoxicity in 6 of the 7 dogs. The median 14-day post-IRE Karnofsky Performance Scale score of the 6 dogs that survived to discharge was 80 (range 60-90), and this score was improved over the pretreatment value in every case. Objective tumor responses were seen in 4 (80%) of 5 dogs with quantifiable target lesions. The median survival was 119 days (range 1 to > 940 days). CONCLUSION: With the incorporation of additional therapeutic planning procedures, the NanoKnife system is a novel technology capable of controlled IRE ablation of telencephalic gliomas.

Implications and considerations of thermal effects when applying irreversible electroporation tissue ablation therapy.

Irreversible electroporation (IRE) describes a cellular response to electric field exposure, resulting in the formation of nanoscale defects that can lead to cell death. While this behavior occurs independently of thermally-induced processes, therapeutic ablation of targeted tissues with IRE uses a series of brief electric pulses, whose parameters result in secondary Joule heating of the tissue. Where contemporary clinical pulse protocols use aggressive energy regimes, additional evidence is supplementing original studies that assert care must be taken in clinical ablation protocols to ensure the cumulative thermal effects do not induce damage that will alter outcomes for therapies using the IRE non-thermal cell death process for tissue ablation. In this letter, we seek to clarify the nomenclature regarding IRE as a non-thermal ablation technique, as well as identify existing literature that uses experimental, clinical, and numerical results to discretely address and evaluate the thermal considerations relevant when applying IRE in clinical scenarios, including several approaches for reducing these effects. Existing evidence in the literature describes cell response to electric fields, suggesting cell death from IRE is a unique process, independent from traditional thermal damage. Numerical simulations, as well as preclinical and clinical findings demonstrate the ability to deliver therapeutic IRE ablation without occurrence of morbidity associated with thermal therapies. Clinical IRE therapy generates thermal effects, which may moderate the non-thermal aspects of IRE ablation. Appropriate protocol development, utilization, and pulse delivery devices may be implemented to restrain these effects and maintain IRE as the vastly predominant tissue death modality, reducing therapy-mitigating thermal damage. Clinical applications of IRE should consider thermal effects and employ protocols to ensure safe and effective therapy delivery.

In vivo irreversible electroporation kidney ablation: experimentally correlated numerical models.

Irreversible electroporation (IRE) ablation uses brief electric pulses to kill a volume of tissue without damaging the structures contraindicated for surgical resection or thermal ablation, including blood vessels and ureters. IRE offers a targeted nephron-sparing approach for treating kidney tumors, but the relevant organ-specific electrical properties and cellular susceptibility to IRE electric pulses remain to be characterized. Here, a pulse protocol of 100 electric pulses, each 100 µs long, is delivered at 1 pulse/s to canine kidneys at three different voltage-to-distance ratios while measuring intrapulse current, completed 6 h before humane euthanasia. Numerical models were correlated with lesions and electrical measurements to determine electrical conductivity behavior and lethal electric field threshold. Three methods for modeling tissue response to the pulses were investigated (static, linear dynamic, and asymmetrical sigmoid dynamic), where the asymmetrical sigmoid dynamic conductivity function most accurately and precisely matched lesion dimensions, with a lethal electric field threshold of 575 ± 67 V/cm for the protocols used. The linear dynamic model also attains accurate predictions with a simpler function. These findings can aid renal IRE treatment planning under varying electrode geometries and pulse strengths. Histology showed a wholly necrotic core lesion at the highest electric fields, surrounded by a transitional perimeter of differential tissue viability dependent on renal structure.

An "Off-the-Shelf" System for Intraprocedural Electrical Current Evaluation and Monitoring of Irreversible Electroporation Therapy.

INTRODUCTION: Irreversible electroporation (IRE) ablation uses a series of brief electric pulses to create nanoscale defects in cell membranes, killing the cells. It has shown promise in numerous soft-tissue tumor applications. Larger voltages between electrodes will increase ablation volume, but exceeding electrical limits may risk damage to the patient, cause ineffective therapy delivery, or require generator restart. Monitoring electrical current for these conditions in real-time enables managing these risks. This capacity is not presently available in clinical IRE generators. METHODS: We describe a system using a Tektronix TCP305 AC/DC Current Probe connected to a TCPA300 AC/DC Current Probe Amplifier, which is read on a computer using a Protek DSO-2090 USB computer-interfacing oscilloscope. Accuracy of the system was tested with a resistor circuit and by comparing measured currents with final outputs from the NanoKnife clinical electroporation pulse generator. RESULTS: Accuracy of measured currents was 1.64 ± 2.4 % relative to calculations for the resistor circuit and averaged 0.371 ± 0.977 % deviation from the NanoKnife. During clinical pulse delivery, the system offers real-time evaluation of IRE procedure progress and enables a number of methods for identifying approaching issues from electrical behavior of therapy delivery, facilitating protocol changes before encountering therapy delivery issues. CONCLUSIONS: This system can monitor electrical currents in real-time without altering the electric pulses or modifying the pulse generator. This facilitates delivering electric pulse protocols that remain within the optimal range of electrical currents-sufficient strength for clinically relevant ablation volumes, without the risk of exceeding safe electric currents or causing inadequate ablation.

In vivo characterization and numerical simulation of prostate properties for non-thermal irreversible electroporation ablation.

BACKGROUND: Irreversible electroporation (IRE) delivers brief electric pulses to attain non-thermal focal ablation that spares vasculature and other sensitive systems. It is a promising prostate cancer treatment due to sparing of the tissues associated with morbidity risk from conventional therapies. IRE effects depend on electric field strength and tissue properties. These characteristics are organ-dependent, affecting IRE treatment outcomes. This study characterizes the relevant properties to improve treatment planning and outcome predictions for IRE prostate cancer treatment. METHODS: Clinically relevant IRE pulse protocols were delivered to a healthy canine and two human cancerous prostates while measuring electrical parameters to determine tissue characteristics for predictive treatment simulations. Prostates were resected 5 hr, 3 weeks, and 4 weeks post-IRE. Lesions were correlated with numerical simulations to determine an effective prostate lethal IRE electric field threshold. RESULTS: Lesions were produced in all subjects. Tissue electrical conductivity increased from 0.284 to 0.927 S/m due to IRE pulses. Numerical simulations show an average effective prostate electric field threshold of 1072 ± 119 V/cm, significantly higher than previously characterized tissues. Histological findings in the human cases show instances of complete tissue necrosis centrally with variable tissue effects beyond the margin. CONCLUSIONS: Preliminary experimental IRE trials safely ablated healthy canine and cancerous human prostates, as examined in the short- and medium-term. IRE-relevant prostate properties are now experimentally and numerically defined. Importantly, the electric field required to kill healthy prostate tissue is substantially higher than previously characterized tissues. These findings can be applied to optimize IRE prostate cancer treatment protocols.

The effects of metallic implants on electroporation therapies: feasibility of irreversible electroporation for brachytherapy salvage.

PURPOSE: Electroporation-based therapies deliver brief electric pulses into a targeted volume to destabilize cellular membranes. Nonthermal irreversible electroporation (IRE) provides focal ablation with effects dependent on the electric field distribution, which changes in heterogeneous environments. It should be determined if highly conductive metallic implants in targeted regions, such as radiotherapy brachytherapy seeds in prostate tissue, will alter treatment outcomes. Theoretical and experimental models determine the impact of prostate brachytherapy seeds on IRE treatments. MATERIALS AND METHODS: This study delivered IRE pulses in nonanimal, as well as in ex vivo and in vivo tissue, with and in the absence of expired radiotherapy seeds. Electrical current was measured and lesion dimensions were examined macroscopically and with magnetic resonance imaging. Finite-element treatment simulations predicted the effects of brachytherapy seeds in the targeted region on electrical current, electric field, and temperature distributions. RESULTS: There was no significant difference in electrical behavior in tissue containing a grid of expired radiotherapy seeds relative to those without seeds for nonanimal, ex vivo, and in vivo experiments (all p > 0.1). Numerical simulations predict no significant alteration of electric field or thermal effects (all p > 0.1). Histology showed cellular necrosis in the region near the electrodes and seeds within the ablation region; however, there were no seeds beyond the ablation margins. CONCLUSION: This study suggests that electroporation therapies can be implemented in regions containing small metallic implants without significant changes to electrical and thermal effects relative to use in tissue without the implants. This supports the ability to use IRE as a salvage therapy option for brachytherapy.

Improved local and systemic anti-tumor efficacy for irreversible electroporation in immunocompetent versus immunodeficient mice.

Irreversible electroporation (IRE) is a non-thermal focal ablation technique that uses a series of brief but intense electric pulses delivered into a targeted region of tissue, killing the cells by irrecoverably disrupting cellular membrane integrity. This study investigates if there is an improved local anti-tumor response in immunocompetent (IC) BALB/c versus immunodeficient (ID) nude mice, including the potential for a systemic protective effect against rechallenge. Subcutaneous murine renal carcinoma tumors were treated with an IRE pulsing protocol that used 60% of the predicted voltage required to invoke complete regressions in the ID mice. Tumors were followed for 34 days following treatment for 11 treated mice from each strain, and 7 controls from each strain. Mouse survival based on tumor burden and the progression-free disease period was substantially longer in the treated IC mice relative to the treated ID mice and sham controls for both strains. Treated IC mice were rechallenged with the same cell line 18 days after treatment, where growth of the second tumors was shown to be significantly reduced or prevented entirely. There was robust CD3+ cell infiltration in some treated BALB/C mice, with immunocytes focused at the transition between viable and dead tumor. There was no difference in the low immunocyte presence for untreated tumors, nude mice, and matrigel-only injections in both strains. These findings suggest IRE therapy may have greater therapeutic efficacy in immunocompetent patients than what has been suggested by immunodeficient models, and that IRE may invoke a systemic response beyond the targeted ablation region.

Experimental characterization and numerical modeling of tissue electrical conductivity during pulsed electric fields for irreversible electroporation treatment planning.

Irreversible electroporation is a new technique to kill cells in targeted tissue, such as tumors, through a nonthermal mechanism using electric pulses to irrecoverably disrupt the cell membrane. Treatment effects relate to the tissue electric field distribution, which can be predicted with numerical modeling for therapy planning. Pulse effects will change the cell and tissue properties through thermal and electroporation (EP)-based processes. This investigation characterizes these changes by measuring the electrical conductivity and temperature of ex vivo renal porcine tissue within a single pulse and for a 200 pulse protocol. These changes are incorporated into an equivalent circuit model for cells and tissue with a variable EP-based resistance, providing a potential method to estimate conductivity as a function of electric field and pulse length for other tissues. Finally, a numerical model using a human kidney volumetric mesh evaluated how treatment predictions vary when EP- and temperature-based electrical conductivity changes are incorporated. We conclude that significant changes in predicted outcomes will occur when the experimental results are applied to the numerical model, where the direction and degree of change varies with the electric field considered.