Irreversible Electroporation (IRE)

Irreversible Electroporation (IRE)

By Mohammed Ezz El-dinAssistant Lecturer of Tropical Medicine & Gastroenterology Faculty of Medicine, Assiut UniversityEmail: squint_2008@yahoo.com

Irreversible Electroporation, what does it mean???

Irreversible ElectroporationIrreversible electroporation (IRE) is a new ablative technology that uses high-voltage, low-energy direct current to create nanopores in the cell membrane, disrupting the homeostasis mechanism and inducing cell death by initiating apoptosis. It is a minimally invasive procedure that uses electrical probes to permeate through the cell membrane of a tumor and kill the cancer cells inside it.It is just beginning to be used in the medical field as a possible replacement for chemotherapy, radiation treatment, as well as electro chemotherapy.

Electroporation

ReversibleElectric pulses create tiny holes in the cell Temporary as long as the energy is low (360 V/cm)Chemotherapy and Genetic therapy delivery

IrreversibleHigher energy (680 V/cm)Create permanent holes in the cellCell loses essential molecules and internal signals tell the cell to dieAblative therapy for tumors

The Origins of ElectroporationElectroporation originated with two men, Okino and Mohri in 1987 who independently discovered that the permeability of cell membrane can be increased by the use of reversible electric pulses, combined with anticancer drugs.This process is referred to as reversible electroporation or electro chemotherapy.The problem with this particular procedure is that it combines the use of an electric field along with combinations of chemical agents.

Ultimately , irreversible electroporation was derived from reversible electroporation.This discussion of this new method was described by Davalos et al. in 2005.This group of engineers discovered that electrical pulse treatment can be applied to a tumor without the use of cytotoxic cancer drugs.They conducted tests with models of the liver and found that the tumor size is greatly reduced due to the applied electric field. They also stated in their research that a unique aspect of irreversible electroporation is that the affected area can be controlled and monitored with electrical impedance tomography.

Safety and Efficacy in Animal ModelsThe safety of IRE has been evaluated in several animal models.Bile ducts and vessels integrity was completely preserved. The treatment areas were sharply demarcated.The vessel-preserving effect of IRE is believed to be due to the fact that the vessel wall contains a higher proportion of collagenous connective tissue and elastic fiber, and it lacks a normal cellular membrane. This belief was supported by the finding of mild inflammatory changes that were seen in vessels in the IRE-treated zone. This finding could be seen due to the fact that the inner most layer of the vessels lacks collagenous and elastic fibrous tissue.

Another explanation for preservation of the blood vessels following IRE is the presence of gap junctions in the smooth muscle cells of the blood vessels that may facilitate the passage of the electrical pulses of IRE without damaging the cell membrane, thereby preserving the integrity of the smooth muscle cell membrane.

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Safety and Efficacy in Human Subjects

The first human experience of IRE was published by Thomson et al. in 2011which described a single-center prospective non randomized cohort study performed to investigate the safety of IRE. Thirty-eight volunteers with advanced malignancy of the liver, kidney, or lung (69 separate tumors) unresponsive to standard treatment underwent IRE under general anesthesia.No mortalities occurred at 30 days. Transient ventricular arrhythmia occurred in four patients; electrocardiographically (ECG) synchronized delivery was used subsequently in the remaining 30 patients.

The authors concluded that IRE appeared to be safe for human clinical use, provided EKG synchronized delivery is used. When energy is applied, the ECG trigger monitor automatically detects the rising slope of the R wave and sends a signal to the NanoKnife generator, which delivers an energy pulse after a 50 ms (0.05 second) delay. The energy pulse is delivered during (or just before) the ventricular refractory period.

Irreversible Electroporation: How It WorksIn IRE it begins with the electric probes that are used as needles in the procedure. These electrical probes emit electrical pulses across the membrane of a tumor. The electrical pulses create an electric field across the membrane.The voltage generated from this electric field targets the cancer cells and destroys them.

NanoKnife SystemThe Nanoknife system created by Angiodynamics was granted approval by the FDA for surgical ablation of soft tissue in 2009.The Nanoknife system applies the methods of irreversible electroporation to permanently open cell membranes of tumors.Healthy tissue then has the opportunity to grow and populate the area where the dead tissue now lies.

A treatment procedure with the NanoKnife device requires the use of monopolar or bipolar probes. Monopolar probes are currently available in 15- and 20-cm lengths. When using the monopolar probes, a minimum of two probes are required to create an appropriate treatment zone. A maximum of six probes can be used for a single treatment, and the treatment zone at any given time is the tissue between two probes.

The NanoKnife generator has a treatment planning algorithm software that enables the user to evaluate different combinations with the number of needles required to create an adequate treatment zone.The only limitation is that the machine does not actually know precisely where the lesion is in relation to the needle placements, a factor that the operator must determine. The ideal spacing between two monopolar electrodes should be between 1.5 and 2 cm.

The exposure length of the active tip is determined by the depth of the lesion and by the type of the tissue treated, and treatments in the liver can be safely performed with an exposure between 1.5 and 3 cm.If the depth of the tumor is greater than the exposure (i.e., 4 cm), when the needle exposure is 2 cm then a pull back of the probes followed by a second treatment will be required to cover the depth of 4 cm while obtaining an appropriate treatment margin.

Bipolar electrodes have the two poles on the same needle separated by an insulated region, and they can ablate larger areas up to 2.0 x 2.0 x 2.5 cm.Typically, 90 high-voltage (1500 to 3000 V) direct current (25 to 45 A) electrical pulses are delivered between paired unipolar electrodes or a single bipolar electrode. With the revision of the treatment guidelines, the number of pulses for a successful treatment between a pair of monopolar electrodes has been reduced from 90 to 70.The voltage setting is determined by the distance between each pair of electrodes with the intent to generate at least 1000 V between the electrodes.

The generator is programmed to stop delivery and recharge if the current flow exceeded 48 A. The electrodes are placed percutaneously under imaging (computed tomography [CT] or ultrasound) guidance, with the maximum separation between the electrodes 2.2 cm.

Summary of the procedureMinimum of two electrodes:Direct current90 pulses of 1500 V/cm70 Nano seconds per pulse

Field generates pores

Up to 6 electrodes can be connected:19 gauge needleMax. distance between two needle is 2 Cm

Ablation time for 4 electrodes is 9 minutes

Primary tissue sites for uses of IREIrreversible electroporation will mainly be applied to areas of soft tissue.These areas include the pancreas, liver, kidneys, prostate and lungs.These areas are the main target areas of irreversible electroporation because these areas are located near blood vessels.

Precautions before IRE procedureA detailed cardiac history is crucial for IRE because patients with a known history of cardiac arrhythmias are not ideal candidates due to the risk of inducing dangerous rhythms during the procedure. IRE is approved by the FDA in the United States under a 510 (k) for surgical ablation of soft tissue; use of the technology in the liver is considered off label and should be discussed with the patient. Consultation with anesthesia is required because all IRE procedures are performed under general anesthesia.

Precautions during the procedureDuring treatment, a neuromuscular blockade is necessary to counteract the high electrical voltage generated during treatment. The patients electrocardiograph tracing, heart rate, oxygen saturation, respiratory rate, blood pressure, bispectral index, end tidal carbon dioxide, temperature, and urine output is continuously monitored by an anesthesiologist. The number of electrodes used in treatment and the number of treatment sessions are both based on tumor size.

Follow up after the procedureFollowing completion of the IRE treatment, we perform a post procedure CT scan the same day or the following day to evaluate for any immediate complications and to evaluate if the lesion has been entirely treated. Contrast is administered if renal function permits. Successful treatment is signified by a lack of contrast enhancement in the ablation zone and complete coverage of the lesion by the ablation zone.

Follow up after the procedureFollowing ablation, patients are transferred to recovery room and, if stable and/or not scheduled to receive additional therapies, discharged home the following day.Follow-up contrast-enhanced CT scans and/or magnetic resonance imaging are generally obtained 1, 3, and 6 months, and 1 year after treatment.

Advantages and Disadvantages of Irreversible Electroporation

Advantages

It is minimally invasive surgery that allows for quicker recovery time.The destruction of the tumor is monitored throughout the procedure to assure the target area is being tended to.IRE does substantial less harm to the body than chemotherapy or radiation.

Disadvantages

Nanoknife system costs $300,000, and each electric probe costs $2,000 making for expensive treatment.The Nanoknife system is designed mainly for small tumors, and would be rather ineffective with larger tumors.

Contraindications of IREInability to tolerate general anesthesia via neuromuscular blockadeImplanted pacemaker or cardiac defibrillator Symptomatic heart artery disease, cardiac arrhythmia or cardiac failurePresence of metal in vicinity of tumorCoagulopathyRecent seizures

Adverse Effects of Irreversible ElectroporationLike any other local ablative therapy, IRE is also associated with a few other adverse effects, be they general or procedure-related.

General intra-operative complicationsAs with all operations, IRE carries the risk of general anesthesia and positional neuropraxia. In two retrospective studies, such effects occurred in an isolated number of patients but were transient and self-limiting, and resolved without any long-term disability.

Specific intra-operative complications: Unintended injury to other organs and structures during manipulation of the electrodes Pneumothorax Cardiac arrhythmia Muscle contraction Hyperkalemia

Postoperative complicationsPostoperative pain

SummaryIrreversible electroporation is a tremendous step for the treatment of cancer.It is far less painful that the current treatments that are employed now, and is quite effective in eliminating the cell membrane of the cancer cells.t is a very benign procedure because it only destroys the bad tissue, leaving healthy tissue unharmed.Patients can have quick recovery times with little scarring or pain following the surgery.Treatment of tumors greater than 34 cm in maximal diameter with IRE results in decreased rates of complete ablation and higher likelihood of recurrence.With further research the Nanoknife system will be able to destroy larger tumors on a wider variety of areas on the body.

Waiting for Egyptian ExperienceNational Hepatology & Tropical Medicine Research Institute (NHTMRI), Cairo, Interventional ultrasonography Unit.

National Cancer Institute (NCI), Cairo, Interventional Radiology Unit.

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