Irreversible Electroporation Therapy Research Articles

Reduction of Muscle Contractions during Irreversible Electroporation Therapy Using High-Frequency Bursts of Alternating Polarity Pulses: A Laboratory Investigation in an Ex Vivo Swine Model

PurposeTo compare the intensity of muscle contractions in irreversible electroporation (IRE) treatments when traditional IRE and high-frequency IRE (H-FIRE) waveforms are used in combination with a single applicator and distal grounding pad (A+GP) configuration. Materials and MethodsAn ex vivo in situ porcine model was used to compare muscle contractions induced by traditional monopolar IRE waveforms vs high-frequency bipolar IRE waveforms. Pulses with voltages between 200 and 5,000 V were investigated, and muscle contractions were recorded by using accelerometers placed on or near the applicators. ResultsH-FIRE waveforms reduced the intensity of muscle contractions in comparison with traditional monopolar IRE pulses. A high-energy burst of 2-μs alternating-polarity pulses energized for 200 μs at 4,500 V produced less intense muscle contractions than traditional IRE pulses, which were 25–100 μs in duration at 3,000 V. ConclusionsH-FIRE appears to be an effective technique to mitigate the muscle contractions associated with traditional IRE pulses. This may enable the use of voltages greater than 3,000 V necessary for the creation of large ablations in vivo.

Induction of PD-L1 expression in pancreatic tumor microenvironment by IFN-y: rationale for PD-L1 therapy combination with irreversible electroporation therapy

Induction of PD-L1 expression in pancreatic tumor microenvironment by IFN-y: rationale for PD-L1 therapy combination with irreversible electroporation therapy

The use of IRE in multi-modality treatment for oligometastatic pancreatic cancer

IntroductionPancreatic ductal adenocarcinoma (PDAC) often presents late with only 20% of patients being candidates for resection while majority already have advanced metastases with median overall survival of 3–6 months. Currently, the role of oligometastasectomy and local therapy options in PDAC is unknown in patients who have favorable response to systemic chemotherapy. The aim of this study is to analyze the survival outcome of oligometastasectomy and local IRE therapy in select patients who are treated with systemic chemotherapy for PDAC metastases. MethodsWe utilized a prospective database from 2010 to 2016 to identify patients with local surgical therapy after induction systemic chemotherapy for oligometastatic PDAC (Stage 4). The initial local therapy treatment of distant metastatic lesions was followed by adjuvant chemotherapy. Subsequently, resection of the primary PDAC in conjunction with irreversible electroporation (IRE) was performed after favorable response by RECIST criteria. ResultsSeven patients were identified with metastatic PDAC treated with oligometastasectomy and/or local therapy. There was single metastatic lesion in 43% (3/7) of which 57% (4/7) were localized in the liver. The treatment of the primary pancreatic cancer was performed utilizing IRE in situ in 6/7 (86%) of patients in our study with resection or radiation of oligometastasis. The median survival in our study group was 16 months with 28% (2/7) patients who remain NED (range 16–41 months). ConclusionCombination of systemic chemotherapy and oligometastasectomy with adjunctive local IRE therapy is a feasible treatment strategy in highly select patients with oligometastatic PDAC that demonstrate favorable tumor biology with objective response to systemic therapy.

Irreversible Electroporation in Patients with Pancreatic Cancer: How Important Is the New Weapon?

Background Pancreatic cancer (PC) is a deadly disease with poor prognosis in the general population. We aimed to quantitate overall survival of patients with PC after irreversible electroporation (IRE) and the incidence of relevant complications. Methods We performed a literature search via five electronic databases (PubMed, Embase, Web of Science, Scopus, and Cochrane Library databases) up to August 2017. The primary outcomes were overall survival and prognosis. Secondary outcomes included the response of post-IRE complications. Fixed-effects or random-effects meta-analysis was conducted to pool these data. Results A total of 15 eligible articles involving 535 patients were included. The primary outcomes showed that the pooled prevalence estimates of overall survival were 94.1% (95% CI: 90.7–97.5), 80.9% (95% CI: 72.5–89.4), 54.5% (95% CI: 38.3–70.6), and 33.8% (95% CI: 14.2–53.5) at 3, 6, 12, and 24 months, and the pooled prevalence data of complete response (CR) at 2 months, partial response (PR) at 3 months, and progression at 3 months were 12.5% (95% CI: 2.9–22.2), 48.5% (95% CI: 39.4–57.6), and 19.7% (95% CI: 7.3–32.2), respectively. The secondary outcomes showed that the pooled prevalence values of post-IRE complications were abscess 6.6% (95% CI: 0.2–13), fistula 10.6% (95% CI: 2.5–18.7), pain 33.5% (95% CI: 14.5–52.5), infection 16.1% (95% CI: 3.9–28.4), thrombosis 4.9% (95% CI: 1.2–8.5), pancreatitis 7.2% (95% CI: 3.1–11.2), bleeding 4.2% (95% CI: −0.5–8.9), cholangitis 4.2% (95% CI: −0.5–8.9), nausea 9.6% (95% CI: 4.4–14.8), biliary obstruction 13.8% (95% CI: 4.2–23.3), chest tightness 7.6% (95% CI: 0.5–14.6), and hypoglycemia 5.9% (95% CI: −0.4–12.2). Conclusions This meta-analysis indicated a clear survival benefit for PC patients who received irreversible electroporation therapy, although future safety and effectivity monitoring from more large-scale studies will be needed.

The Feasibility of Enhancing Susceptibility of Glioblastoma Cells to IRE Using a Calcium Adjuvant.

Irreversible electroporation (IRE) is a cellular ablation method used to treat a variety of cancers. IRE works by exposing tissues to pulsed electric fields which cause cell membrane disruption. Cells exposed to lower energies become temporarily permeable while greater energy exposure results in cell death. For IRE to be used safely in the brain, methods are needed to extend the area of ablation without increasing applied voltage, and thus, thermal damage. We present evidence that IRE used with adjuvant calcium (5mM CaCl2) results in a nearly twofold increase in ablation area in vitro compared to IRE alone. Adjuvant 5mM CaCl2 induces death in cells reversibly electroporated by IRE, thereby lowering the electric field thresholds required for cell death to nearly half that of IRE alone. The calcium-induced death response of reversibly electroporated cells is confirmed by electrochemotherapy pulses which also induced cell death with calcium but not without. These findings, combined with our numerical modeling, suggest the ability to ablate up to 3.2× larger volumes of tissue in vivo when combining IRE and calcium. The ability to ablate a larger volume with lowered energies would improve the efficacy and safety of IRE therapy.

Portal Venous Stenting in Locally Advanced Pancreatic Cancer to Decrease Risk of Thrombosis Before Irreversible Electroporation: A Case Report and Review of the Literature

Background: For patients with locally advanced pancreatic cancer, irreversible electroporation (IRE) is a fairly novel treatment tool that has shown promise in improving survival. However, many patients being considered for IRE have tumors adjacent to and/or encasing portal vasculature, increasing risk of postoperative portal vein thrombosis and associated complications. This report describes a successful new approach of portal venous stenting preoperatively to decrease this risk.Case Presentation: A 64-year-old female with locally advanced pancreatic cancer, initially deemed too high risk for IRE therapy because of portal vein–superior mesenteric vein confluence encasement and compression, was offered and underwent venous stenting to decrease the chance of postoperative thrombosis and related complications. Stenting improved portal venous flow, decreased collateralization, and allowed for successful IRE. At 61 days post-IRE, there was no significant tumor growth and the stent remained patent.Conclusion: Preoperative portomesenteric stenting could expand the population eligible for IRE therapy, allowing for this treatment in patients without other options. To the authors' knowledge, this is the first reported case of portal venous stenting for this purpose.

Irreversible electroporation therapy improved progression free survival for locally advanced pancreatic adenocarcinoma in Taiwan

Irreversible electroporation therapy improved progression free survival for locally advanced pancreatic adenocarcinoma in Taiwan

Focal vs extended ablation in localized prostate cancer with irreversible electroporation; a multi-center randomized controlled trial.

BackgroundCurrent surgical and ablative treatment options for prostate cancer (PCa) may result in a high incidence of (temporary) incontinence, erectile dysfunction and/or bowel damage. These side effects are due to procedure related effects on adjacent structures including blood vessels, bowel, urethra and/or neurovascular bundle. Ablation with irreversible electroporation (IRE) has shown to be effective and safe in destroying PCa cells and also has the potential advantage of sparing surrounding tissue and vital structures, resulting in less impaired functional outcomes and maintaining men’s quality of life.Methods/DesignIn this randomized controlled trial (RCT) on IRE in localized PCa, 200 patients with organ-confined, unilateral (T1c-T2b) low- to intermediate-risk PCa (Gleason sum score 6 and 7) on transperineal template-mapping biopsies (TTMB) will be included. Patients will be randomized into focal or extended ablation of cancer foci with IRE. Oncological efficacy will be determined by multiparametric Magnetic Resonance Imaging, Contrast-Enhanced Ultrasound imaging if available, TTMP and Prostate Specific Antigen (PSA) follow-up. Patients will be evaluated up to 5 years on functional outcomes and quality of life with the use of standardized questionnaires.DiscussionThere is critical need of larger, standardized RCTs evaluating long-term oncological and functional outcomes before introducing IRE and other focal therapy modalities as an accepted and safe therapeutic option for PCa. This RCT will provide important short- and long-term data and elucidates the differences between focal or extended ablation of localized, unilateral low- to intermediate-risk PCa with IRE.Trial registrationClinicaltrials.gov database registration number NCT01835977. The Dutch Central Committee on Research Involving Human Subjects registration number NL50791.018.14.

Intra - operative Anesthesia Management in Patients Undergoing Surgical Irreversible Electroporation of the Pancreas, Liver, Kidney, and Retroperitoneal Tumors.

Background:Irreversible electroporation (IRE) is a relatively new approach to the management of multiple types of locally advanced soft tissue tumors. Unique peri-procedural anesthetic management is needed in the safe and effective delivery of this therapy.Objectives:This study analyzed IRE therapy in relation to anesthetic management for our initial cohort and then established and validated a set of best practical guidelines for general anesthesia in patients undergoing IRE for abdominal tumors.Patients and Methods:An IRB-approved prospective data collection outcome protocol was utilized. This study was broken up into two cohorts as follows: the initial 38 patients (pts) undergoing IRE in which anesthetic management was not defined or optimized and then a 40-pt validation cohort to establish the most efficacious anesthetic protocols.Results:During IRE delivery, a deeper neuromuscular blockade is required to ensure that all retroperitoneal muscle excitation was minimized. In the initial 38-pt cohort, attempts to treat hypertension (median SBP 190, range 185–215 and median diastolic 98, range 91–115) were made with various types of anti-hypertensives with minimal-to-insufficient effects. The established inhalation was sevoflurane with an approximate median dose of 8.0 volume percentage. Analgesic management of continuous remifentanil was utilized with epidural management, which optimized HTN and tolerance to IRE therapy.Conclusions:Anesthetic management for IRE of soft tissue deviates from standard anesthetic medical therapy in regards to depth of neuromuscular blockade and analgesic management during IRE energy delivery. However, minor modifications in anesthesia management allow for a safe and efficient patient procedure.

A review of basic to clinical studies of irreversible electroporation therapy.

The use of irreversible electroporation (IRE) for cancer treatment has increased sharply over the past decade. As a nonthermal therapy, IRE offers several potential benefits over other focal therapies, which include 1) short treatment delivery time, 2) reduced collateral thermal injury, and 3) the ability to treat tumors adjacent to major blood vessels. These advantages have stimulated widespread interest in basic through clinical studies of IRE. For instance, many in vitro and in vivo studies now identify treatment planning protocols (IRE threshold, pulse parameters, etc.), electrode delivery (electrode design, placement, intraoperative imaging methods, etc.), injury evaluation (methods and timing), and treatment efficacy in different cancer models. Therefore, this study reviews the in vitro, translational, and clinical studies of IRE cancer therapy based on major experimental studies particularly within the past decade. Further, this study provides organized data and facts to assist further research, optimization, and clinical applications of IRE.

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

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. 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. 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. 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.

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.

Artifact-reduced simultaneous MRI of multiple rats with liver cancer using PROPELLER

To explore simultaneous magnetic resonance imaging (MRI) for multiple hepatoma-bearing rats in a single session suppressing motion- and flow-related artifacts to conduct preclinical cancer research efficiently. Our institutional Animal Experimental Committee approved this study. We acquired PROPELLER (periodically rotated overlapping parallel lines with enhanced reconstruction) T2 - and diffusion-weighted images of the liver in one healthy and 11 N1-S1 hepatoma-bearing rats in three sessions using a 3-T clinical scanner and dedicated multiarray coil. We compared tumor volumes on MR images and those on specimens, evaluated apparent diffusion coefficients (ADC) of the tumor, and compared them to previously reported values. Each MRI session took 39-50 minutes from anesthesia induction to the end of scans for four rats (10-13 minutes per rat). PROPELLER provided artifact-reduced T2 - and diffusion-weighted images of the rat livers. Tumor volumes on MR images ranged from 0.04-1.81 cm(3) and were highly correlated with those on specimens. The ADC was 1.57 ± 0.37 × 10(-3) mm(2) /s (average ± SD), comparable to previously reported values. PROPELLER allowed simultaneous acquisition of artifact-reduced T2 - and diffusion-weighted images of multiple hepatoma-bearing rats. This technique can promote high-throughput preclinical MR research for liver cancer.

Irreversible Electroporation Therapy in the Management of Locally Advanced Pancreatic Adenocarcinoma

Locally advanced pancreatic cancer patients have limited options for disease control. Local ablation technologies based on thermal damage have been used but are associated with major complications in this region of the pancreas. Irreversible electroporation (IRE) is a nonthermal ablation technology that we have shown is safe near vital vascular and ductal structures. The aim of this study was to evaluate the safety and efficacy of IRE as a therapy in the treatment of locally advanced pancreatic cancer. We performed a prospective multi-institutional pilot evaluation of patients undergoing IRE for locally advanced pancreatic cancer from December 2009 to March 2011. These patients were evaluated for 90-day morbidity, mortality, and local disease control. Twenty-seven patients (13 women and 14 men) underwent IRE, with median age of 61 years (range 45 to 80 years). Eight patients underwent margin accentuation with IRE in combination with left-sided resection (n = 4) or pancreatic head resection (n = 4). Nineteen patients had in situ IRE. All patients underwent successful IRE, with intraoperative imaging confirming effective delivery of therapy. All 27 patients demonstrated nonclinically relevant elevation of their amylase and lipase, which peaked at 48 hours and returned to normal at 72 hour postprocedure. There has been one 90-day mortality. No patient has shown evidence of clinical pancreatitis or fistula formation. After all patients have completed 90-day follow-up, there has been 100% ablation success. IRE ablation of locally advanced pancreatic cancer tumors is a safe and feasible primary local treatment in unresectable, locally advanced disease. Confirming these early results must occur in a planned phase II investigational device exemption (IDE) study to be initiated in 2012.

The Improvement of Irreversible Electroporation Therapy Using Saline-Irrigated Electrodes: A Theoretical Study

Irreversible electroporation (IRE) is a novel therapy used to ablate tumors with high-field electric pulses applied in short durations. It is important to reduce the generation of heat in IRE to avoid the harmful effects of thermal damage. The objective of this simulation study was to examine the effects of saline irrigation in the reduction of heat upon electrodes used in IRE treatment of hepatocellular carcinoma. We used a two dimensional Finite Element Model of a tumor in a liver with electrodes placed at the center of the tumor. We simulated a typical electroporation protocol with varying thicknesses and conductivities of the saline layer, and we observed the maximum temperature and the distribution of the electric field and temperature in the tissue. Our results showed that the maximum temperature in the tissue decreases with the use of saline, but the surface area of the tumor that could potentially be thermally damaged may increase with the thickness and conductivity of the saline. With the use of saline, one can achieve upwards of a 17% reduction of the maximum temperature at the electrodes. Also, the distribution of temperature and the electric field becomes more homogenous between the electrodes as the conductivity of the saline layer increases for all thicknesses of saline. We conclude that irrigating electrodes with saline may be an effective measure to enhance the efficacy of irreversible electroporation by reducing the maximum temperature at the electrodes and also improving the extent and distribution of the electric field in the tissue. However, the properties of the saline should be adjusted so as to limit the increase of thermal damage propagated in the tissue.

Irreversible Electroporation of Renal Cell Carcinoma: A First-in-Man Phase I Clinical Study

Irreversible electroporation (IRE) is a newly developed nonthermal tissue-ablation technique in which high-voltage electrical pulses of microsecond duration are applied to induce irreversible permeabilisation of the cell membrane, presumably through nanoscale defects in the lipid bilayer, leading to apoptosis. The purpose of this study was to assess the feasibility and safety of ablating renal cell carcinoma (RCC) tissue by IRE. Six patients scheduled for curative resection of RCC were included. IRE was performed during anaesthesia immediately before the resection with electrographic synchronisation. Central haemodynamics were recorded before and 5min after electroporation. Five-channel electrocardiography (ECG) was used for detailed analysis of ST waveforms. Blood sampling and 12-lead ECG were performed before, during, and at scheduled intervals after the intervention. Analysis of ST waveforms and axis deviations showed no relevant changes during the entire study period. No changes in central haemodynamics were seen 5min after IRE. Similarly, haematological, serum biochemical, and ECG variables showed no relevant differences during the investigation period. No changes in cardiac function after IRE therapy were found. One case of supraventricular extrasystole was encountered. Initial histopathologic examination showed no immediate adverse effects of IRE (observation of delayed effects will require a different study design). IRE seems to offer a feasible and safe technique by which to treat patients with kidney tumours and could offer some potential advantages over current thermal ablative techniques.

Abstract No. 103: Liver-directed irreversible electroporation therapy: Longitudinal efficacy studies in a rat model of hepatocellular carcinoma

Irreversible electroporation (IRE) is an innovative loco-regional therapy recently introduced as a potential tissue ablation technique. Previous studies have demonstrated that IRE can ablate substantial volumes of tissue without inducing thermal effects. The purpose of our study was to investigate the efficacy of IRE for targeted ablation of HCC. We tested the hypothesis that IRE procedures would lead to tumor necrosis in a transplanted HCC rodent model.