Irreversible Electroporation Treatment Research Articles

Real-World Safety of Prostate Cancer Focal Therapy: MAUDE Database Analysis.

Objective: The aim of this study was to assess the real-world safety profile of medical devices used in focal prostate cancer treatment utilizing the Manufacturer and User Facility Device Experience (MAUDE) database. Methods: The MAUDE database was searched for reports on high-intensity focused ultrasound (HIFU), cryoablation, laser ablation, and irreversible electroporation (IRE) devices used in prostate cancer treatment from 1993 to 2023. Adverse events were identified and categorized. Results: We identified 175 reports for HIFU, 1362 for cryoablation, 615 for laser ablation, and 135 for IRE devices, with 28, 284, 126, and 2 respective reports, directly related to prostate cancer treatment. The aggregated data revealed the majority of complications were minor, with 82.5% (n = 363 out of 440 total complications) classified as Clavien-Dindo grade 1 or 2. Common minor complications included erectile dysfunction and urinary retention. Severe complications such as rectal fistulas were noted in HIFU and IRE treatments, along with singular mortality due to pulmonary embolism in cryoablation. Conclusions: Our analyses from MAUDE reveal that devices used in focal therapy for prostate cancer are predominantly associated with minor complications, underscoring their overall real-world safety profile. However, the occurrence of severe adverse events emphasizes the critical importance of rigorous patient selection and meticulous procedural planning. These findings provide valuable insights into the safety profile of focal therapy devices and contribute to the growing body of evidence on their use in prostate cancer treatment.

Computer modelling and vegetable bench test of a bipolar electrode array intended for use in high frequency irreversible electroporation treatment of skin cancer

Computer modelling and vegetable bench test of a bipolar electrode array intended for use in high frequency irreversible electroporation treatment of skin cancer

Targeted Ablation Using Ultrasound-Guided Irreversible Electroporation of Index Tumors (TARGET Study): Prospective Development Study Evaluating Safety, Patient-Reported Outcomes, and Oncologic Efficacy.

We studied patient-reported functional outcomes, safety, and oncologic efficacy of focal irreversible electroporation as a primary treatment for intermediate-risk prostate cancer. Between February 2015 and April 2017, 20 consecutive patients elected irreversible electroporation and underwent 22 treatments. All underwent MRI-targeted and systematic transrectal biopsies. Eligibility criteria were grade group 2/3 prostate cancer in a maximum of 2 adjacent sextant prostate sectors in 1 hemigland without extraprostatic extension on MRI. Ablation was performed with a 5-mm cancer margin. Any grade group 1 cancer outside mapped index lesion was untreated. Outcome measures were based on the Prostate Quality of Life Survey, Male Sexual Health Questionnaire, and MRI-targeted and systematic biopsies at 3 and 12 months. Nineteen patients completed irreversible electroporation. One had electrocardiographic changes, and irreversible electroporation was aborted. No deterioration was detected in urinary or sexual domains (-0.2, 95% CI -1.4, 0.9, P = .7, and -1.9, 95% CI -10.1, 6.4, P = .6, respectively) or health-related quality of life (-0.2, 95% CI -1.4, 1.0, P = .7) at 6 months post ablation. Ejaculation volume decreased at 12 months (-1.5 points, 95% CI -2.4, -0.5, P = .003). At 12 months of follow-up, 14/19 patients (74%, 95% CI 49%, 91%) had no clinically significant cancer anywhere in the prostate. Radical treatment-free survival was 79% at 2 years (95% CI 53%, 92%) and 73% at 4 years (95% CI 47%, 88%). Our data show promising oncologic and functional outcomes following focal irreversible electroporation treatment for carefully selected patients with intermediate-risk prostate cancer. Further research should compare irreversible electroporation with active surveillance.

IRE made easy: introducing the robotic grid system for multiple parallel needle insertion in irreversible electroporation treatment

PurposeAccurate needle placement is crucial for successful tumor treatment using the irreversible electroporation (IRE) method. Multiple needles are inserted around the tumor, ideally in parallel, to achieve uniform electric field distribution. This paper presents a robot utilizing a grid system to enable multiple needles insertion while maintaining parallelism between them.MethodsThe robotic system has two degrees of freedom, which allow for the adjustment of the grid system to accommodate targeting lesions in various positions. The robot’s performance was evaluated by testing its accuracy across various configurations and target depth locations, as well as its ability to maintain the needle parallelism.ResultsThe robot has dimensions of ϕ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\\phi }$$\\end{document} 134 mm and a height of 46 mm, with a total weight of 295 g. The system accuracy test showed that the robot can precisely target points across different target depths and needle orientations, with an average error of 2.71±0.68\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$2.71\\pm 0.68$$\\end{document} mm. Moreover, multiple insertions at different grid locations reveal needle orientation deviations typically below 1∘\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$1^{\\circ }$$\\end{document}.ConclusionThis study presented the design and validation of a robotic grid system. The robot is capable of maintaining insertion accuracy and needle parallelism during multiple needle insertions at various robot configurations. The robot showed promising results with limited needle deviation, making it suitable for IRE procedures.

Effectiveness and safety of irreversible electroporation when used for the ablation of stage 3 pancreatic adenocarcinoma: A registry study (DIRECT).

e16301 Background: Outcomes for patients with Stage 3 pancreatic ductal adenocarcinoma (PDAC) remain poor with a mean overall survival (OS) of 11 months. Irreversible electroporation (IRE) is a method of local tumor ablation that causes cell death by disrupting homeostasis in the cell membrane. Previous research suggests IRE can be useful in the multi-disciplinary treatment of Stage 3 PDAC. The present study was designed to assess the effectiveness and safety of IRE for Stage 3 PDAC in a real-world setting after induction chemotherapy. Methods: Patients with Stage 3 PDAC treated with IRE were prospectively enrolled in a multicenter registry study. Enrollment required 3 months of active multi-agent chemotherapy, with no progression before IRE treatment. Endpoints were 30- and 90-day mortality from enrollment and the new onset of an adverse event (AE). Results: 87 patients were enrolled in the registry between May 2019 and May 2023. Mean age was 64.0 ± 8.4 years, 57.5% were female and mean tumor diameter was 2.2 ± 0.7 cm. Mean time from diagnosis to IRE treatment was 8.9 ± 4.9 months. All subjects underwent induction chemotherapy with the most common being FOLFIRINOX alone, gemcitabine with albumin-bound paclitaxel, or a combination of both in 47 (54.0%) patients. Thirty-seven (42.5%) patients had prior radiation therapy. All procedures were performed using an open approach with 50 (57.5%) for in-situ tumor ablation and 37 (42.5%) with the intent of margin accentuation in combination with resection. Major adjunctive procedures were performed for 70 (80.5%) patients. Common adjunctive surgeries were cholecystectomy (33.3%), Whipple procedure (28.7%) and either distal or subtotal pancreatectomy (11.4%). Mean IRE delivery time was 55.7 ± 54.5 minutes with an average of 3.1 probes (range 2 to 6) used per procedure. There was a mean of 1031.1 ± 882.1 pulses delivered per procedure. The 30- and 90-day mortality was 3/87 (3.4%) and 4/82 (4.9%) respectively. There were 21 (24.1%) patients who developed AEs related to IRE treatment during the 90-day post-procedure period (9 patients had AEs that were definitely related to IRE, 5 probably and 7 possibly). Of these related events, only three were Grade 4 or higher (arterial hemorrhage, cardiac arrest, and septic shock). Overall, gastrointestinal related AEs were the most common representing 16 of the 28 (57.1%) of all AEs associated with the IRE procedure. One patient died within 30 days of the procedure due to an intraperitoneal arterial hemorrhage that was deemed to be definitely related to the IRE treatment. Conclusions: The use of IRE for curative intent tumor ablation alone or in combination with resection following induction chemotherapy in patients with locally advanced Stage 3 PDAC has acceptable safety and is associated with acceptable morbidity and mortality rates in appropriately selected patients. Clinical trial information: NCT03899649 .

Irreversible electroporation promotes a pro-inflammatory tumor microenvironment and anti-tumor immunity in a mouse pancreatic cancer model.

Pancreatic cancer is a significant cause of cancer-related mortality and often presents with limited treatment options. Pancreatic tumors are also notorious for their immunosuppressive microenvironment. Irreversible electroporation (IRE) is a non-thermal tumor ablation modality that employs high-voltage microsecond pulses to transiently permeabilize cell membranes, ultimately inducing cell death. However, the understanding of IRE's impact beyond the initiation of focal cell death in tumor tissue remains limited. In this study, we demonstrate that IRE triggers a unique mix of cell death pathways and orchestrates a shift in the local tumor microenvironment driven, in part, by reducing the myeloid-derived suppressor cell (MDSC) and regulatory T cell populations and increasing cytotoxic T lymphocytes and neutrophils. We further show that IRE drives induce cell cycle arrest at the G0/G1 phase in vitro and promote inflammatory cell death pathways consistent with pyroptosis and programmed necrosis in vivo. IRE-treated mice exhibited a substantial extension in progression-free survival. However, within a span of 14 days, the tumor immune cell populations reverted to their pre-treatment composition, which resulted in an attenuation of the systemic immune response targeting contralateral tumors and ultimately resulting in tumor regrowth. Mechanistically, we show that IRE augments IFN-γ signaling, resulting in the up-regulation of the PD-L1 checkpoint in pancreatic cancer cells. Together, these findings shed light on potential mechanisms of tumor regrowth following IRE treatment and offer insights into co-therapeutic targets to improve treatment strategies.

The Induction of Combined Hyperthermal Ablation Effect of Irreversible Electroporation with Polydopamine Nanoparticle-Coated Electrodes.

Irreversible electroporation (IRE) is a prominent non-thermal ablation method widely employed in clinical settings for the focal ablation therapy of solid tumors. Utilizing high-voltage, short-duration electric pulses, IRE induces perforation defects in the cell membrane, leading to apoptotic cell death. Despite the promise of irreversible electroporation (IRE) in clinical applications, it faces challenges concerning the coverage of target tissues for ablation, particularly when compared to other thermal ablation therapies such as radiofrequency ablation, microwave ablation, and cryoablation. This study aims to investigate the induced hyperthermal effect of IRE by applying a polydopamine nanoparticle (Dopa NP) coating on the electrode. We hypothesize that the induced hyperthermal effect enhances the therapeutic efficacy of IRE for cancer ablation. First, we observed the hyperthermal effect of IRE using Dopa NP-coated electrodes in hydrogel phantom models and then moved to in vivo models. In particular, in in vivo animal studies, the IRE treatment of rabbit hepatic lobes with Dopa NP-coated electrodes exhibited a two-fold higher increase in temperature (ΔT) compared to non-coated electrodes. Through a comprehensive analysis, we found that IRE treatment with Dopa NP-coated electrodes displayed the typical histological signatures of hyperthermal ablation, including the disruption of the hepatic cord and lobular structure, as well as the infiltration of erythrocytes. These findings unequivocally highlight the combined efficacy of IRE with Dopa NPs for electroporation and the hyperthermal ablation of target cancer tissues.

Consensus Guidelines of Irreversible Electroporation for Pancreatic Tumors: Protocol Standardization Using the Modified Delphi Technique.

Since no uniform treatment protocol for pancreatic irreversible electroporation (IRE) exists, the heterogeneity throughout literature complicates the comparison of results. To reach agreement among experts, a consensus study was performed. Eleven experts, recruited according to predefined criteria regarding previous IRE publications, participated anonymously in three rounds of questionnaires according to a modified Delphi technique. Consensus was defined as having reached ≥80% agreement. Response rates were 100, 64, and 64% in rounds 1 to 3, respectively; consensus was reached in 93%. Pancreatic IRE should be considered for stage III pancreatic cancer and inoperable recurrent disease after previous local treatment. Absolute contraindications are ventricular arrhythmias, implantable stimulation devices, congestive heart failure NYHA class 4, and severe ascites. The inter-electrode distance should be 10 to 20 mm and the exposure length should be 15 mm. After 10 test pulses, 90 treatment pulses of 1,500 V/cm should be delivered continuously, with a 90-µs pulse length. The first postprocedural contrast-enhanced computed tomography should take place 1 month post-IRE, and then every 3 months. This article provides expert recommendations regarding patient selection, procedure, and follow-up for IRE treatment in pancreatic malignancies through a modified Delphi consensus study. Future studies should define the maximum tumor diameter, response evaluation criteria, and the optimal number of preoperative FOLFIRINOX cycles.

Temperature Distribution on Classical Two Needles IRE Setup Versus a Single Needle Prototype.

Irreversible Electroporation (IRE) is a non-thermal minimally invasive cancer therapy used in the treatment of liver tumors. However, the therapy entails an electrical current flux which can be high enough to cause a noticeable temperature increase. Therefore, the analysis of the heat distribution is important: during any IRE treatment, the target area is intended to be treated with non-thermal effects, where existing thermal effects should not damage nearby sensitive structures. This article aims to compare the established two parallel needles electrode setup, used by FDA-approved electroporation delivering devices, to a single needle, multiple electrode prototype design. Levels and distributions of the temperature at different distances from the applicators during an IRE liver treatment were investigated. The prototype results were collated with already published in-vivo data. All electrode configurations were analyzed numerically in COMSOL Multiphysics for different pulse protocols. The extension of coagulation necrosis predicted by the model matched available in-vivo data. While the maximum average temperature during pulsation was higher for the prototype (74 °C) than for the two-needle IRE setup (57 °C), the thickness of the coagulation necrosis around the conductive electrodes was in the same range for both configurations. However, the location differed completely: the necrosis engendered by the prototype was located inside the tumor, while the two-needle IRE setup created necrosis outside the tumor, potentially closer to sensitive structures. The results highlighted the importance of heat distribution analysis for the design of new IRE needles as well as for IRE treatment planning. Proper analysis ensures that the non-thermal effects are maximized while minimizing any potential thermal damage to surrounding sensitive structures.

One-year Follow-up Results of Transperineal Biopsy For Patients Undergoing Irreversible Electroporation Treatment in Localized Prostate Cancer.

This article reports on the early results of a 1-year follow-up study investigating the efficacy of irreversible electroporation in the treatment of localized prostate cancer. The study included 18 out of 40 patients diagnosed with low- and intermediate-risk prostate cancer who underwent irreversible electroporation. Treatment results were evaluated through confirmation biopsies, comparing prostate-specific antigen levels, international prostate symptom scoring, and international index of erectile dysfunction scores before irreversible electroporation and at the 12-month mark. The mean age of the patients was 61.1 years (SD ±6.5). Out of the 18 patients, 16 were tumor free (88.8%), while 2 experienced recurrences, one within the treatment field and the other outside of it (P < .001). Irreversible electroporation significantly reduced mean prostate-specific antigen levels (6.73 ng/mL vs. 2.05 ng/mL, P < .001), indicating a 69.5% reduction within 12 months. Furthermore, there was a significant improvement in mean international prostate symptom scores at the 12-month followup (10.05 vs. 7.52, P=.003). The mean international index of erectile dysfunction scores before treatment was 19.17 (SD ±5.85), and after irreversible electroporation, it was 18.67 (SD ±6.34), with no statistically significant change (P=.065). The short-term oncological results of irreversible electroporation treatment are promising, particularly for patients in the low- and intermediate-risk groups. Additionally, irreversible electroporation does not negatively impact the international index of erectile dysfunction; however, it may lead to a decrease in international prostate symptom scores.

Effect of Near-Infrared Pre-Irradiation on Irreversible Electroporation Treatment of Rat Gastric Tissues

Irreversible electroporation (IRE) is a recognized ablation technique that induces apoptosis via potent electric fields. Nonetheless, the heterogeneity of biological tissues often results in inconsistent treatment outcomes, leaving residual viable cells and leading to potential relapse. To address this, previous strategies incorporated chemical enhancers to IRE, but these faced limitations such as limited tissue diffusion and hyperpigmentation. In this study, we explore the synergistic application of near-infrared (NIR) irradiation with IRE. Using an in vivo rat gastric tissue model, we pre-irradiated samples with NIR at 3 J/cm2 prior to IRE. The combined treatment, termed NIRE, produced a change in tissue impedance of 13.5 Ohm compared to IRE alone, indicating NIR’s potential in modulating tissue electrical properties. Subsequent histopathological and molecular assessments revealed a 1.12-fold increase in apoptosis for NIRE over IRE. Notably, the apoptosis-related proteins BCL and p21 exhibited a 1.24-fold and 1.29-fold overexpression following NIRE treatment, respectively, emphasizing NIRE’s enhanced apoptotic activation. In essence, our findings underscore the augmented therapeutic efficacy of IRE when complemented with NIR, presenting a promising avenue for bolstering treatment outcomes in tissue ablation.

New Surgical Approach to Treat Fibroids and Solid Tumors - Thermal and Nonthermal Ablation.

There is a trend toward more minimally invasive treatment for symptomatic uterine fibroids. They are image-guided ablation surgery with focused ultrasound, microwave, and radiofrequency ablations that are becoming tested and used in some medical centers or hospitals. Nevertheless, these image-guided ablation surgeries involve thermal ablation to the fibroids, which might lead to thermal injury to the surrounding tissues, for example, nerve injury, vessel injury, and skin burn due to heat diffusion. A new technology - irreversible electroporation (IRE) - is a new paradigm for treating solid tumors. This nonthermal ablation process does not induce high temperatures when treating cancers or solid tumors. The IRE treatment may soon be used for treating fibroids or other solid tumors. In a few clinical trials, IRE is currently used in experimental studies for treating gynecological cancers. This paper will present the minimally invasive thermal ablation treatments for fibroids, introduce this new nonthermal IRE ablation in treating gynecological cancer, and propose its future uses in uterine fibroids.

The Effect of Partial Electrical Insulation of the Tip and Active Needle Length of Monopolar Irreversible Electroporation Electrodes on the Electric Field Line Pattern and Temperature Gradient to Improve Treatment Control.

Unintentional local temperature effects can occur during irreversible electroporation (IRE) treatment, especially near the electrodes, and most frequently near the tip. Partial electrical insulation of the IRE electrodes could possibly control these temperature effects. This study investigated and visualized the effect of partial electrical insulation applied to the IRE electrodes on the electric field line pattern and temperature gradient. Six designs of (partial) electrical insulation of the electrode tip and/or active needle length (ANL) of the original monopolar 19G IRE electrodes were investigated. A semolina in castor oil model was used to visualize the electric field line pattern in a high-voltage static electric field. An optical method to visualize a change in temperature gradient (color Schlieren) was used to image the temperature development in a polyacrylamide gel. Computational models were used to support the experimental findings. Around the electrode tip, the highest electric field line density and temperature gradient were present. The more insulation was applied to the electrodes, the higher the resistance. Tip and ANL insulation together reduced the active area of and around the electrodes, resulting in a visually enlarged area that showed a change in temperature gradient. Electrically insulating the electrode tip together with an adjustment in IRE parameter settings could potentially reduce the uncontrollable influence of the tip and may improve the predictability of the current pathway development.

Irreversible electroporation for prostate cancer using PSMA PET-CT.

To demonstrate the clinical usefulness of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) computerized tomography (CT) for irreversible electroporation (IRE) in prostate cancer patients. From January to May 2021, 17 men were diagnosed with localized prostate cancer through preoperative mpMRI and [18F] florastamin PSMA PET-CT imaging, followed by transperineal MRI-ultrasound fusion-guided biopsy. The patients underwent IRE focal therapy at the target lesions under general anesthesia. To evaluate the treatment outcome, serum prostate-specific antigen (PSA) levels were followed up in the 1st, 3rd, 6th, 9th, 12th months, and mpMRI was taken in the 1st and 12th months, followed by MR fusion biopsy in the 12th month post-IRE. The mean age of the patients was 66.1±9.3 with a median PSA of 7.5ng/ml. After the treatment, PSA nadir was 4.06±3.4, and 11 (64.7%) achieved decline of PSA more than 50% from the baseline. Rate of negative biopsy for prostate cancer is 88% (15/17) at 12monthsMR fusion biopsy after the IRE treatment. Among the relapsed cases, 1 (6.9%) patient recurred at margin of treated area, and 1 (6.9%) patient was from outfield recurrence. When excluding initial four patients, none of the patients had cancer recur. When treating with IRE focal therapy, PSMA-PET CT is a potentially valuable diagnostic approach for localizing prostate cancer; it supports the detection of lesions with conventional mpMRI, enabling to perform the procedure more completely.

Abstract No. 158 Characterizing the Anti-Tumor Immune Response to IRE vs Thermal Ablation Therapy in an Immunocompetent Oncopig Model of Hepatocellular Carcinoma

Immunotherapies for cancer treatment are designed to mobilize a patient’s own immune system against their malignancy locally and systemically. Percutaneous ablation techniques have the potential to work in conjunction with modern immunotherapies by priming the patient’s own lymphocytes to attack previously untreated cancer cells. This phenomenon, known as the abscopal effect, has garnered interest because of the potential for locoregional therapies to induce local and systemic anti-tumor effects and shrinkage of distant tumors (Fionda, 2020). The goal of this study is to evaluate the anti-tumor immune response to irreversible electroporation (IRE) compared with microwave (MWA) and cryoablation in an immunocompetent Oncopig liver tumor model of hepatocellular carcinoma. In-situ liver tumors were induced in a transgenic immunocompetent porcine liver model (2-4 tumors in each liver) with Cre-recombinase induced TP53 and KRAS mutations (Oncopig). Oncopigs were separated into three treatment groups (n = 2), each undergoing either MWA, cryoablation or IRE treatment of a single liver tumor under US or CT guidance. Pre-, immediate post- and 1-week post ablation imaging was performed to evaluate treated and non-treated tumor growth. At each time point, venous blood was also drawn and assayed for critical cytokines related to anti- or pro-tumor immune response. Systemic cytokine levels were correlated to targeted and off-targeted tumor volumes after each time point. Liver tumors were induced at an 83.3% (20/24) success rate. Treated tumors decreased by an average 7% in volume across all treatment modalities on 1-week follow-up imaging. Off-target tumors increased by volume by 71.7% with IRE, 13.6% with MWA and 1.4% with cryoablation. On 1-week blood samples, IRE treated pigs demonstrated lower circulating concentrations of pro-inflammatory IL-2 cytokines when compared with cryoablation (10.9 vs 40.7 pg/mL; P = 0.051). There was no difference in IL-2 levels between MWA and cryoablation-treated pigs (40.7 vs 42.4 pg/mL; P = 0.97). The pro- and anti-tumor immune response is dependent on the type of ablation modality. IRE had the lowest levels of inflammatory marker IL-2 and the lowest degree of tumor control in off target tumors at the one-week time point. Modulating inflammatory pathways via these cytokines after IRE may potentially play a role in amplifying the abscopal effect in liver tumors.

Abstract No. 5 ▪ FEATURED ABSTRACT Adjuvant Macrophage Repolarization to M1 Phenotype Augments Post-Ablation Local Tumor Control and Improves Overall Survival in a Murine Model of Bladder Tumors

To investigate the impact of adjuvant macrophage repolarization to inflammatory M1 phenotype on local tumor control and overall survival following irreversible electroporation (IRE) of murine bladder tumors. Mouse bladder cancer cell line (MB49) was used to induce subcutaneous tumors in C57BL/6 (n = 8/group) or NOD-SCID (n = 10/group) mice. Animals were randomized to receive (i) IRE, (ii) supramolecular nanotherapeutic for M1 repolarization (SNT), (iii) IRE+SNT or (iv) sham control. Mice assigned to IRE treatment received electric pulses (875 or 1500V/cm for C57BL/6 mice and 875V/cm for NOD-SCID mice, 90 pulses, 100 us duration) with tweezer electrodes. SNT treatment was administered by intravenous injection (40 mg/kg, 1,3- and 5-days post treatment). Mice were sacrificed at Day 1 or 6 for flow cytometry following IRE or were kept under observation in a survival study. Flow cytometry for macrophage markers (M1: CD80, M2: CD206) and T Cell markers (CD8, CD4 and FoxP3) from tumor samples was performed. Tumor samples underwent immunohistochemistry for cell death, macrophages (F4/80) or T cell markers. Local tumor volume and overall survival were evaluated and compared between cohorts and mouse strains to understand cross-interactions with adaptive immunity. Ablation of subcutaneous tumor with IRE stimulated robust macrophage infiltration that uniformly exhibited an immunosuppressive M2 phenotype at Day 3 and 5. SNT effectively repolarized macrophages at the site of ablation to M1 phenotype, with corresponding change in gene expression of NOS2 and IL-6. There was significantly higher population of CD80+ cells and reduced CD206+ cells at Day 1. Adjuvant SNT did not alter CD4+ and CD8+ cells but greatly reduced FoxP3+ population in vivo. IRE+SNT treated mice had greater reduction in local tumor growth, reduced lung metastases and high overall survival. These findings were reduced in NOD-SCID mice, indicating contribution of adaptive immunity under conditions of M1 repolarization. Repolarization of macrophages attracted to the site of ablation to a M1 phenotype promotes local tumor control, reducing the development of metastatic disease and prolonging survival in a mouse model of bladder cancer.

Irreversible Electroporation in Pancreatic Cancer-An Evolving Experimental and Clinical Method.

Pancreatic cancer has no symptoms until the disease has advanced and is aggressive cancer with early metastasis. Up to now, the only curative treatment is surgical resection, which is possible in the early stages of the disease. Irreversible electroporation treatment offers new hope for patients with unresectable tumors. Irreversible electroporation (IRE) is a type of ablation therapy that has been explored as a potential treatment for pancreatic cancer. Ablation therapies involve the use of energy to destroy or damage cancer cells. IRE involves using high-voltage, low-energy electrical pulses to create resealing in the cell membrane, causing the cell to die. This review summarizes experiential and clinical findings in terms of the IRE applications. As was described, IRE can be a non-pharmacological approach (electroporation) or combined with anticancer drugs or standard treatment methods. The efficacy of irreversible electroporation (IRE) in eliminating pancreatic cancer cells has been demonstrated through both in vitro and in vivo studies, and it has been shown to induce an immune response. Nevertheless, further investigation is required to assess its effectiveness in human subjects and to comprehensively understand IRE's potential as a treatment option for pancreatic cancer.

Synergism between SUMO inhibition and irreversible electroporation for pancreatic cancer

Background: Irreversible electroporation (IRE) is being studied as a treatment option for patients with locally advanced pancreatic cancer (PC). Our laboratory has shown that combination of IRE with immunotherapy optimizes the local and distant effects of IRE treatment. Post-translational protein modification by small ubiquitin-like modifier (SUMO ) is upregulated in cancer and is important for the function of immune checkpoints. TAK-981 is a novel inhibitor of SUMO ylation that inhibits PC cell proliferation and also upregulates type I interferon responses, boosting anti-tumor immunity. We hypothesized that there would be synergistic effects of combining IRE with TAK-981 treatment.

Histological Response to 5 kHz Irreversible Electroporation in a Porcine Liver Model.

Unlike necrosis by thermal ablation, irreversible electroporation (IRE) is known to induce apoptosis by disrupting plasma membrane integrity with electric pulses while preserving the structure of blood vessels and bile ducts in liver tissue without a heat sink effect. This study aimed to investigate thermal damage and histopathological effects in the porcine liver by high-frequency electric pulses (5 kHz) which is much higher than the widely used 1 Hz. The electric field and thermal distributions of 5 kHz electric pulses were compared with those of 1 Hz in numerical simulations. 5 kHz-IRE was applied on pigs under ultrasound imaging to guide the electrode placement. The animals underwent computed tomography (CT) examination immediately and 1 day after IRE. After CT, IRE-treated tissues were taken and analyzed histologically. CT revealed that hepatic veins were intact for 1-day post-IRE. Histopathologically, the structure of the portal vein was intact, but endothelial cells were partially removed. In addition, the hepatic artery structure from which endothelial cells were removed were not damaged, while the bile duct structure and cholangiocytes were intact. The thermal injury was observed only in the vicinity of the electrodes as simulated in silico. 5 kHz-IRE generated high heat due to its short pulse interval, but the thermal damage was limited to the tissue around the electrodes. The histopathological damage caused by 5 kHz-IRE was close to that caused by 1 Hz-IRE. If a short-time treatment is required for reasons such as anesthesia, high-frequency IRE treatment is worth considering. Our observations will contribute to a better understanding of the IRE phenomena and search for advanced therapeutic conditions.

Enhanced Therapeutic Potential of Irreversible Electroporation under Combination with Gold-Doped Mesoporous Silica Nanoparticles against EMT-6 Breast Cancer Cells

Irreversible electroporation (IRE) is a non-thermal tumor ablation technique that delivers short pulses of strong electric fields to cancer tissues and induces cell death through the destruction of cell membranes. Here, we synthesized gold-doped mesoporous silica nanoparticles (Au-MSNs) via incipient wetness impregnation and evaluated the therapeutic potentials of combination therapy with IRE. The fabricated Au-MSNs had around 80-100 nm of particle size and were successfully end-doped with Au nanoparticles. Combination treatment of IRE (800 V/cm) and Au-MSNs (100 μg/mL) increased cell membrane permeability by 25-fold compared with single IRE treatment. Cellular reactive oxygen species (ROS) and lipid peroxidation of EMT-6 cells were significantly increased by 14- and 265-fold, respectively, under combination treatment of IRE (800 V/cm) and Au-MSNs (100 µg/mL). Cytotoxic cell death increased by 28% under a combination treatment of IRE (800 V/cm) and Au-MSNs (100 ug/mL) over single IRE. Our studies suggest that the combination treatment of IRE with Au-MSNs can enhance the therapeutic efficacy of IRE for breast cancer.