Application Of Irreversible Electroporation Research Articles

EW-7197, transforming growth factor β inhibitor, combined with irreversible electroporation for improving skin wound in a rat excisional model

To evaluate the safety and efficacy of combining EW-7197 with irreversible electroporation (IRE) for improving wound healing, 16 male Sprague–Dawley rats were randomly divided into four groups of four rats each after dorsal excisional wound induction: sham control group; oral administration of EW-7197 for 7 days group; one-time application of IRE group; and one-time application of IRE followed by oral administration of EW-7197 for 7 days group. Measurement of wound closure rate, laser Doppler scanning, histological staining (hematoxylin and eosin and Masson’s trichrome), and immunohistochemical analyses (Ki-67 and α-SMA) were performed to evaluate the efficacy. Fifteen of 16 rats survived throughout the study. Statistically significant differences in wound closure rates were observed between the combination therapy group and the other three groups (all P < 0.05). The degrees of inflammation, α-SMA, and Ki-67 were reduced in the EW-7197 and IRE monotherapy groups; however, not statistically significant. The fibrosis score exhibited significant reduction in all three treatment groups, with the most prominent being in the combination therapy group. This study concludes that oral administration of EW-7197 combined with IRE demonstrated effectiveness in improving skin wound in a rat excisional model and may serve as a potential alternative for promoting healing outcomes.

Self-Expandable Electrode Based on Chemically Polished Nickel-Titanium Alloy Wire for Treating Endoluminal Tumors Using Bipolar Irreversible Electroporation.

The application of irreversible electroporation (IRE) to endoluminal organs is being investigated; however, the current preclinical evidence and optimized electrodes are insufficient for clinical translation. Here, a novel self-expandable electrode (SE) made of chemically polished nickel-titanium (Ni-Ti) alloy wire for endoluminal IRE is developed in this study. Chemically polished heat-treated Ni-Ti alloy wires demonstrate increased electrical conductivity, reduced carbon and oxygen levels, and good mechanical and self-expanding properties. Bipolar IRE using chemically polished Ni-Ti wires successfully induces cancer cell death. IRE-treated potato tissue shows irreversibly and reversibly electroporated areas containing dead cells in an electrical strength-dependent manner. In vivo study using an optimized electric field strength demonstrates that endobiliary IRE using the SE evenly induces well-distributed mucosal injuries in the common bile duct (CBD) with the overexpression of the TUNEL, HSP70, and inflammatory cells without ductal perforation or stricture formation. This study demonstrates the basic concept of the endobiliary IRE procedure, which is technically feasible and safe in a porcine CBD as a novel therapeutic strategy for malignant biliary obstruction. The SE is a promising electrical energy delivery platform for effectively treating endoluminal organs.

Benefitial role of electrochemotherapy in locally advanced pancreatic cancer - radiological perspective.

Irreversible electroporation (IRE) of locally advanced pancreatic cancer is an increasingly used method for unresectable pancreatic cancer that can be used in cytoreduction followed by surgical treatment and shows promising results in palliative care.IRE is an ablative technique where electric pulses cause damage to the cell membrane leading to apoptosis without the destruction of stroma. The application of IRE increases the concentration of hydrophobic regimens like bleomycin within the tumor, what could improve the effectiveness of treatment. This fusion of those two treatments is called electrochemotherapy. In this review, the authors will discuss the radiological perspective of possible beneficial role of irreversible electroporation in relation with chemotherapy in pancreatic cancer treatment.

The First Study of Irreversible Electroporation with Calcium Ions and Chemotherapy in Patients with Locally Advanced Pancreatic Adenocarcinoma

(1) Background: In the last two decades, anticancer treatment has been extensively developed based on various physical methods, including electroporation (EP). On the basis of many in vitro and in vivo studies, electroporation and further electrochemotherapy (ECT) have been established as a treatment method for cutaneous and subcutaneous lesions. In this procedure, after placing electrodes in the tumor mass and the generation of electrical pulses, a reversible or irreversible rearrangement of the cell membrane occurs. Calcium electroporation has already been applied to treat skin tumors and subcutaneous tissue tumors. Here, we demonstrate the first application of irreversible electroporation (IRE) in combination with calcium ions and chemotherapy for patients with cancer. (2) Methods: This study aimed to present and compare the findings and outcomes of patients with locally advanced pancreatic adenocarcinoma who were qualified for the procedure. Two patients were treated with IRE with calcium ions after chemotherapy (paclitaxel + Gemcitabine (GCB) or FOLOX) or only FOLFOX (folinic acid calcium folinate, fluorouracil, and oxaliplatin). The clinicopathological data, overall survival, and the safety of the procedure were analyzed. (3) Results: Two patients were treated with calcium electroporation. One of the patients developed pancreatitis and the second developed pancreatic fistula, but both of them continued standard systemic treatment. Overall survival was 9 months in the first case and 21 months in the second case (and the patient is still alive). Calcium electroporation had a good impact on QOL (Quality of Life). (4) Conclusions: IRE accompanied chemotherapy, and intratumoral calcium ions administration might represent an additional therapy to surgery and chemotherapy in patients with locally advanced pancreatic cancer (LAPC), particularly in unresectable cases. However, further studies of randomized trials should be undertaken to elucidate the role of chemotherapy in IRE protocols.

Optimizing Integrated Electrode Design for Irreversible Electroporation of Implanted Polymer Scaffolds.

Irreversible electroporation (IRE) is an emerging technology for non-thermal ablation of solid tumors. This study sought to integrate electrodes into microporous poly(caprolactone) (PCL) scaffolds previously shown to recruit metastasizing cancer cells in vivo in order to facilitate application of IRE to disseminating cancer cells. As the ideal parallel plate geometry would render much of the porous scaffold surface inaccessible to infiltrating cells, numerical modeling was utilized to predict the spatial profile of electric field strength within the scaffold for alternative electrode designs. Metal mesh electrodes with 0.35mm aperture and 0.16mm wire diameter established electric fields with similar spatial uniformity as the parallel plate geometry. Composite PCL-IRE scaffolds were fabricated by placing cylindrical porous PCL scaffolds between two PCL dip-coated stainless steel wire meshes. PCL-IRE scaffolds exhibited no difference in cell infiltration in vivo compared to PCL scaffolds. In addition, upon application of IRE in vivo, cells infiltrating the PCL-IRE scaffolds were successfully ablated, as determined by histological analysis 3 days post-treatment. The ability to establish homogeneous electric fields within a biomaterial that can recruit metastatic cancer cells, especially when combined with immunotherapy, may further advance IRE technology beyond solid tumors to the treatment of systemic cancer.

Cancer Treatments of the Irreversible Electroporation

Irreversible electroporation (IRE) is a kind of non-thermal tumor treatment strategy. Based on this, Nanoknife emerged, which is approved by FDA in 2011. From then on, clinical application of nanosecond electrical pulsed have showed an explosive growth. At the cell level, the biophysical mechanism of nonthermal irreversible electroporation of electrical pulsed was studied. At the animal level, it has studied the safety of irreversible electroporation and preclinical animal experiments, also the clinical application of irreversible electroporation. We reviewed Animal studies of IRE and Clinical application of IRE. Also traditional medical imaging methods such as CT, magnetic resonance imaging (MRI) and ultra-sound imaging can be used in the IRE therapy. The evidences can prove the beneficial effects and safety of IRE in tumor treatment and verify the potential of IRE in clinical treatment to some extent. However, larger clinical trials are still needed to confirm these conclusions. Hopefully, as we go deeper into IRE, we get a more thorough understanding of it and the application will appear in various fields.

Histological analysis of human pancreatic carcinoma following irreversible electroporation in a nude mouse model.

AIMTo determine changes in the morphology and function of pancreatic cancer cells after irreversible electroporation (IRE) treatment, and to explore the clinical significance of IRE treatment for pancreatic cancer providing an experimental basis for the clinical application of IRE treatment.METHODSIRE was carried out in an athymic nude mouse model of pancreatic carcinoma generated with human pancreatic cancer cells 1. In therapy groups, IRE electrodes were inserted with 90 pulses per second at 800 V/cm applied to ablate the targeted tumor tissues. Histological assessment of the affected tissue was performed by hematoxylin and eosin staining (HE). Quantification of cell proliferation and apoptosis was performed by evaluating Ki67 and caspase-3 levels, respectively. Flow cytometry was used to assess cell apoptosis. Ultrasound imaging was carried out to evaluate IRE treatment results. Pathological correlation studies showed IRE is effective for the targeted ablation of pancreatic tumors in an orthotopic mouse model.RESULTSIRE was efficacious in removing tumors in the orthotopic mouse model. The IRE-ablated zone displays characteristics of nude mouse models at different time-points as assessed by hematoxylin and eosin staining. Immunohistochemical analysis of samples from the pancreatic cancer models showed significantly enhanced caspase-3 cleavage and Ki67. Flow cytometry data corroborated the above findings that apoptosis in tumor cells was observed immediately on the first postoperative day, and with time the middle and late stages of apoptosis were observed. For ultrasound imaging studies, the IRE ablation zone became a hyperechoic area due to increasing inflammatory and immunologic cellular contents.CONCLUSIONIRE is a promising new approach for pancreatic cancer, with many potential advantages over conventional ablation techniques.

Combination therapy comprising irreversible electroporation and hydroxycamptothecin loaded electrospun membranes to treat rabbit VX2 subcutaneous cancer.

Irreversible electroporation (IRE) is a kind of promising cancer treatment technology. However, local recurrence still occurs because of incomplete ablation. The aim of this study was to investigate the combined therapy of IRE and a hydroxycamptothecin loaded electrospun membrane (EM/HCPT) to treat rabbit VX2 subcutaneous cancer. HCPT loaded membranes were developed by electrospinning. Mechanical test and in vitro drug release study of EM/HCPT were performed. 24 rabbits with subcutaneous VX2 tumor were randomly divided into four groups: the control group, the EM/HCPT group, the IRE ablation group, and the IRE + EM/HCPT group. The tumor cells were ablated by IRE first, followed by subcutaneous implantation of EM/HCPT to release HCPT constantly in order to damage the residual cancer cells. The tumor inhibition efficacy was assessed by the tumor real-time monitoring, histological and immunofluorescent analyses, and transmission electron microscopy (TEM) examination. Assessment of the release from EM/HCPT showed that HCPT release lasted for about 7days. The in vivo antitumor efficacy assessment, histological and immunofluorescent analyses, and TEM examination showed that IRE + EM/HCPT had the best tumor inhibition ability. In addition, the biochemical analyses and hematoxylin and eosin (H&E) staining of normal organs indicated that IRE + EM/HCPT treatment was safe. Our study provided a new concept in cancer treatment and might promote the application of IRE.

Comparative Study of the Biological Responses to Conventional Pulse and High-Frequency Monopolar Pulse Bursts

Given its nonthermal property and other advantages, irreversible electroporation (IRE) has quickly translated into clinical applications. An increasing number of clinical cases using IRE have also revealed crucial issues. The uneven distribution of the electric field caused by the heterogeneity of biological tissues has not been completely and effectively addressed to date. The use of high-frequency monopolar pulse bursts (HFMPBs) is expected to solve this problem. The high-frequency content of the HFMPB is used to ensure the uniform distribution of the electric field in the tissue. A temperature increase similar to that of the conventional pulse method does not cause thermal damage and results in a killing effect similar to that of the conventional technique. Meanwhile, the subpulse has a pulse duration of 1-100 μs, which remains unexplored and may induce new cell responses. This paper analyzes the HFMPB based on the frequency domain and infers that the cell death pathways under this pulse induce necrosis and other processes, such as apoptosis. The phosphatidylserine externalization rate had a peak value at a different inner frequency of HFMPB when the electric field was 1 kV/cm for melanoma cells. This new type of pulse is expected to solve the problem of the uneven distribution of the electric field without altering the cell killing effect. If this effect is also verified in tissue ablation, these new types of pulses will promote the clinical application of IRE.

Evaluation of the safety of irreversible electroporation on the stomach wall using a pig model.

The aim of the present study was to evaluate the effects of irreversible electroporation (IRE) on the stomach wall following the direct application of IRE onto the organ surface. IRE ablation was performed in 8 Tibetan mini-pigs, which were randomly assigned into two groups based on their ablated areas: Group A, gastric cardia, fundus of stomach, gastric body and group B, lesser gastric curvature, greater gastric curvature, stomach pylorus. Two IRE needles were placed in the space between the stomach wall and the liver (not inserted into the stomach tissue), and three lesions were created in each pig. Serum aminotransferase and white blood cell (WBC) levels were measured. Gastroscopy and endoscopic ultrasonography were performed. From each group, 2 pigs were sacrificed on day 7 post-IRE; the remaining pigs were sacrificed on day 28 post-IRE. There were no signs of perforation on the stomach wall. Serum aminotransferase and WBC levels increased in both groups on day 1 post-IRE and decreased gradually thereafter. The gastroscopy procedure revealed oval ulcers on day 7 post-IRE and smaller ulcers on day 28 post-IRE. Transmural necrosis, inflammation and fibrosis were observed at 7 days post-IRE. Healing ulcers were observed at 28 days post-IRE. In conclusion, IRE ablation caused damage to the stomach wall; however, IRE did not induce any perforation.

Irreversible electroporation of hepatocellular carcinoma: patient selection and perspectives.

Irreversible electroporation (IRE) is a novel form of tissue ablation that uses high-current electrical pulses to induce pore formation of the cell lipid bilayer, leading to cell death. The safety of IRE for ablation of hepatocellular carcinoma (HCC) has been established. Outcome data for ablation of HCC by IRE are limited, but early results are encouraging and suggest equivalency to the outcomes obtained for thermal ablation for appropriately selected, small (<3 cm) tumors. Long-term oncologic efficacy and histopathologic response data have not been published, and therefore, application of IRE for the treatment of HCC should still be viewed with caution.

Role of local ablative techniques (Radiofrequency ablation and Irreversible Electroporation) in the treatment of pancreatic cancer.

Thanks to continuous research and investment in technology, the ablation of tumors has become common. Through the application of different types of energy is possible to induce cellular injury of the neoplastic tissue, leading to cellular death. Radiofrequency ablation (RFA) and irreversible electroporation (IRE) represent the most applied ablative techniques on pancreatic cancer. RFA and IRE, causing necrosis and apoptosis of neoplastic cells, are able to destroy neoplastic tissue, to drastically modify the neoplastic microenvironment and, possibly, to stimulate both directly and indirectly the anti-tumor immune system. This article provides part of our experience with the application of RFA and IRE on pancreatic adenocarcinoma (PDAC).

The therapeutic effect of irreversible electroporation ablation in mouse model of gastrointestinal cancer.

62 Background: Irreversible electroporation (IRE) is a promising novel technique for the ablation of tumors. IRE has an advantage over other ablation technique in its mechanism to remove undesired cells by affecting the cell membrane without thermally destructing blood vessels, nerves and the surrounding tissues. Studies regarding the clinical application of IRE have been performed in humans, as well as in animals, for organs such as the liver, kidney, prostate, etc. and IRE is now accepted as a novel anti-cancer ablation modality. The aim of this study was to evaluate the therapeutic effect of IRE in mouse model of gastrointestinal cancer for the first time. Methods: The Caco2 cells (ATCC) were cultured in petri-dishes. Male nude mice (Immunodeficient (CAnN.Cg-Foxn1 nu/CrljBgi) 6 weeks old, Orient Inc., Korea) were introduced. Caco2 cells were each visually injected at 1.0 x 107cells/ml into both flakes (one for control, the other for IRE). We performed in vivo IRE procedures in the tumors of nude mouse model. Electrical pulses were applied to the tumor of nude mouse using a DC generator at 1~2kV/cm amplitude, 20~50 pulses, 100 µA length, with 1mm separation between two needle type electrodes. We analyzed the tissues with H&amp;E staining and TUNEL assay immediately afterwards, and then 10 hours, 24 hours. Results: All mice were preserved during the experiment without significant complications. There was complete cell death within the IRE lesions without intervening live cells in 2KV after 24 hours. H&amp; E statin and Tunnel stain at 10hr after 2KV IRE ablation revealed more severe apoptotic cell death comparing with control group. Apoptotic index peaks at 10 hours after IRE ablation, and decreases in 24hours. The framework of extracellular matrix and blood vessels were not affected by IRE. Conclusions: The present study demonstrated that IRE ablated colon cancer tissue very effectively through the induction of cellular apoptosis. This study suggests that IRE has the potentiality in treatment of gastrointestinal cancer patients.

Application of irreversible electroporation in the management of locally advanced pancreatic adenocarcinoma

Irreversible electroporation (IRE) is a non-temperature based novel ablation therapy in which short high-voltage pulses are applied to treat tissues to permeabilize the cell membrane irreversibly and thus lead to cell apoptosis. Because it is characterized as non-thermal, IRE can reduce the risk of thermal damage to vital organs and structures so that it is more feasible for the treatment of unresectable pancreatic cancer and thus provide an ideal alternative to other thermal treatment modalities. This review aims to analyze current literature of IRE and to discuss the new progress of the application of IRE in the ma-nagement of locally advanced pancreatic adenocarcinoma. Key words: Irreversible electroporation; Locally advanced pancreatic adenocarcinoma; Ablation

Evolving Techniques in Pancreatic Surgery.

Evolving Techniques in Pancreatic Surgery.

Local Ablative Strategies for Ductal Pancreatic Cancer (Radiofrequency Ablation, Irreversible Electroporation): A Review.

Pancreatic ductal adenocarcinoma (PDAC) has still a dismal prognosis. Locally advanced pancreatic cancer (LAPC) accounts for the 40% of the new diagnoses. Current treatment options are based on chemo- and radiotherapy regimens. Local ablative techniques seem to be the future therapeutic option for stage-III patients with PDAC. Radiofrequency Ablation (RFA) and Irreversible Electroporation (IRE) are actually the most emerging local ablative techniques used on LAPC. Initial clinical studies on the use of these techniques have already demonstrated encouraging results in terms of safety and feasibility. Unfortunately, few studies on their efficacy are currently available. Even though some reports on the overall survival are encouraging, randomized studies are still required to corroborate these findings. This study provides an up-to-date overview and a thematic summary of the current available evidence on the application of RFA and IRE on PDAC, together with a comparison of the two procedures.

Sa1596 The Therapeutic Effect of Irreversible Electroporation Ablation in Colon Cancer Animal Model

Irreversible electroporation (IRE) is a promising novel technique for the ablation of tumors. IRE has an advantage over other ablation technique in its mechanism to remove undesired cells by affecting the cell membrane without thermally destructing blood vessels, nerves and the surrounding tissues. Studies regarding the clinical application of IRE have been performed in humans, as well as in animals, for organs such as the liver, kidney, prostate, etc. and IRE is now accepted as a novel anti-cancer ablation modality.

Irreversible electroporation facilitates gene transfer of a GM-CSF plasmid with a local and systemic response

Electroporation uses an electric field to induce pores in the cell membrane that can transfer macromolecules into target cells. Modulation of electrical parameters leads to irreversible electroporation (IRE), which is being developed for tissue ablation. We sought to evaluate whether the application of IRE may induce a lesser electric field in the periphery where reversible electroporation may occur, facilitating gene transfer of a granulocyte macrophage colony-stimulating factor (GM-CSF) plasmid to produce its biologic response. Yorkshire pigs underwent laparotomy, and IRE of the liver was performed during hepatic arterial infusion of 1 or 7 mg of a naked human GM-CSF plasmid. The serum, liver, lymph nodes, and bone marrow were harvested for analysis. Human GM-CSF level rose from undetectable to 131 pg/mL in the serum at 24 hours after IRE and plasmid infusion. The liver demonstrated an ablation zone surrounded by an immune infiltrate that had greater macrophage intensity than when treated with IRE or plasmid infusion alone. This dominance of macrophages was dose dependent. Distant effects of GM-CSF were found in the bone marrow, where proliferating myeloid cells increased from 14% to 25%. IRE facilitated gene transfer of the GM-CSF plasmid and brought about a local and systemic biologic response. This technique holds potential for tumor eradication and immunotherapy of residual cancer.

Sa1417 The Effect of Irreversible Electroporation in Rat Stomach: According to Different Electric Energy

Irreversible electroporation (IRE) is a novel, non-thermal method of tissue ablation using short pulses of high-voltage pulse current. IRE induces the breakdown of cell homeostasis and thereby cell death. Studies regarding the clinical application of IRE have been performed in humans, as well as in animals, for organs such as the liver, kidney, pancreas, prostate, brain, etc. and IRE has been tried as a novel anti-cancer ablation modality. This is the first study about the effect of IRE on stomach.

Treatment planning considerations for IRE in the lung: placement of needle electrodes is critical

Purpose The poor electrical conductivity of the lung parenchyma, the difference in conductivity between tumor and healthy tissue and the absence of strong post-ablation imaging findings makes it difficult to plan and deliver irreversible electroporation (IRE) treatment in this organ. We use numerical modeling and simulations to arrive at guidelines for planning IRE ablations in the lung. Materials and Methods A numerical model of the Laplace equation for electric field distribution in biological tissue was constructed using Comsol Multiphysics as a 1.5 cm diameter spherical tumor surrounded by normal lung tissue. Simulations were performed considering use of two treatment needles. Two variables were given consideration for their effect on outcomes. First, the ratio of electrical conductivity between tumor and normal lung (conductivity:-0.1 S/m) tissue was varied between 3 and 10 times that of the latter. Second, the location of the two treatment needles were varied with respect to each other, where both were placed within the tumor, both were placed in healthy tissue but closely bracketing the tumor, and finally one needle was placed within the tumor while the other was located outside it. Treatments were simulated at field strength of 1500 V/cm. The critical ablation zone was considered to be 600 V/cm and used to demarcate the ablated zone. Concurrently, retrospective clinical cases were analyzed to determine similar needle placement conditions and the corresponding conductivity changes reported by the IRE console. Results Simulations indicate the strong role played by the conductivity ratio of tumor and surrounding healthy tissue on ablation outcome. This factor is normally not considered in the treatment planning software available on the clinically used IRE console. Second, the relative location of the needles played an important role in ablation outcomes, with needle electrodes placed in healthy tissue causing incomplete treatment in the surrounding region. Finally, it was found that the conductivity changes reported by the console are not an independent indicator of treatment success. Conclusion Simulation modeling can be used to assist treatment planning for application of IRE to ablate tumors in the lung.