Over the last 50 years additional energy-based methods for cancer treatment have emerged, including focused ultrasound, thermal ablation, electroporation, targeted drug delivery and Tumor Treating electric Fields. These modes of treatment are being integrated into oncological practice. In this workshop leading researchers in industry and academia will provide an in-depth overview on the scientific and engineering basis of energy- based cancer therapies. The workshop will open with a basic overview of cancer biology, followed by presentations covering: low-intensity tumor treating electric fields; electroporation; thermal therapies and image-guided drug delivery; and therapeutic ultrasound.
Attendees of the workshop will gain: 1 an overview of the fundamentals of cancer biology; 2 an in-depth understanding of the biophysical principles underlying energy-based cancer interventions; 3 an appreciation of practical technologies for treating cancer based on these principles; 4 exposure to current research trends investigating synergism of energy-based treatment modalities with other techniques e.
His expertise is in minimally invasive techniques for the treatment of kidney, adrenal, and prostate cancers. Another method for avoiding excessive charge build up in tissues being treated by electroporation is to deliver counteracting pulses simultaneously from one or more pulse generator. In embodiments, the pulses delivered by the generators can overlap in time for some portion of the pulse and be offset from one another. In particular, a first pulse generator administers a first positive pulse for a desired amount of time. Here, the pulse has a duration in the 10 ns to 10 ms range.
At some time after the first pulse is generated, a second pulse from a second pulse generator is administered. In this example, the second pulse is of the same magnitude as the first pulse yet opposite in polarity.
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By overlapping the pulses, or simultaneously applying the pulses, the net effect during the overlap is that the tissue does not experience a charge. In effect the overlap of the pulses creates a delay and the charge delivered to the tissue is only the portion of each pulse that is outside of the overlap, i. As shown, a first positive electrical pulse is initiated by a first pulse generator. At a desired time following administration of the first pulse, a second pulse equal in magnitude to the first pulse but opposite in charge is initiated using a second pulse generator. It is noted that in this figure that although a summation of the two individual signals offset by a delay pulse duration is shown, one of skill in the art could easily incorporate additional signals in order to manipulate additional pulse parameters.
Further, and as with all embodiments described in this specification, the positive and negative applied voltages do not have to be of equal magnitude. In one such embodiment, electrical pulses are delivered in a series of two pulses of alternating polarity from millisecond to nanosecond range. Use of alternating polarities reduces or eliminates charge buildup on the electrode s. The net effect of the pulses in the tissue is a net charge of zero and an additional benefit is avoiding the need for complex circuitry as the need for abrupt switching of the polarity is obviated.
If monitored during the procedure and in real time, adjustments to the protocol, including adjustments to the type, length, number, and duration of the pulses, could then be made, if necessary, to avoid damage of the tissue being treated. It is important to note that bipolar pulses are only effective for electroporation if each pulse within the train is long enough in duration to charge the plasma membrane to a permeabilizing level. If this is not the case, the pulses offset each other from fully charging the plasma, and supra-poration effects dominate when the pulse amplitude is increased.
Additionally, a delay can be included between pulses within the train, or the total number of pulses within the train can be controlled, to limit the Joule heating in the tissue while still delivering a lethal dose of energy. Embodiments of the invention are equally applicable to any electroporation-based therapy EBT , including therapies employing reversible electroporation, such as gene delivery therapy and electrochemotherapy, to name a few. One of skill in the art is equipped with the skills to modify the protocols described herein to apply to certain uses. The repetition rate of pulse trains can also be controlled to minimize interference with, and allow treatment of vital organs that respond to electrical signals, such as the heart.
The concept of alternating polarity of pulses can be extended to the use of multiple electrodes. For example, a combination of three electrodes can be used to deliver three sequential sets of alternating polarity pulses to a target tissue. Of course, this concept can be applied using any numbers of electrodes and pulse times to achieve highly directed cell killing.
One of the main advantages of N-TIRE over other focal ablation techniques is that the pulses do not generate thermal damage due to resistive heating, thus major blood vessels, extracellular matrix and other tissue structures are spared. See B. Al-Sakere, F. Andre, C. Bernat, E. Connault, P. Opolon, R. Davalos, B. Rubinsky, and L.
Edd, L. Horowitz, R. Davalos, L. Mir, and B. The inventors have found that with real time temperature data measured at the electrode-tissue interface, the non-thermal aspect of the technique can be confirmed. One such way to measure temperature in-vivo during the pulse delivery is to use fiber optic probes. USA were placed at the electrode-tissue interface and 7.
The electrode exposure and separation distance were each 5 mm. The polarity of the electrodes was alternated between the sets to minimize charge build-up on the electrode surface. These parameters were determined from previous in-vivo N-TIRE procedures which showed sufficient ablation of tissue. For treatment planning purposes, in order to model accurate N-TIRE treatment, it is beneficial to incorporate changes in conductivity due to permeabilization of the tissue as described in detail in the treatment planning section of this specification , as well as incorporate information relating to temperature changes.
See P. Garcia, J. Rossmeisl, R. Neal, II, T. Ellis, J. Olson, N. Henao-Guerrero, J. Robertson, and R. Conductivity changes due to thermal effects could have important implications with a number of different treatment parameters, including electrode geometry and pulse parameters i. More particularly, what is shown is the temperature distribution measured by the probe located at the electrode-tissue interface and 7.
For the probe at the interface, four sets of mild increase in temperatures are seen. The probe in the insulation also shows some very mild increase in temperature that is probably due to heat conduction from the treatment region. This confirms that any cell death achieved by the procedure was a direct result of N-TIRE since at the electrode-tissue interface the highest thermal effects are expected to be achieved. It is also apparent from this data that it can be assumed in numerical modeling that electrical conductivity changes due to electroporation only and not temperature.
The present invention has been described with reference to particular embodiments having various features. It will be apparent to those skilled in the art that various modifications and variations can be made in the practice of the present invention without departing from the scope or spirit of the invention. One skilled in the art will recognize that these features may be used singularly or in any combination based on the requirements and specifications of a given application or design. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention.
It is intended that the specification and examples be considered as exemplary in nature and that variations that do not depart from the essence of the invention are intended to be within the scope of the invention. Effective date : Year of fee payment : 4. Embodiments provide patient-specific treatment protocols derived by the numerical modeling of 3D reconstructions of target tissue from images taken of the tissue, and optionally accounting for one or more of physical constraints or dynamic tissue properties.
The present invention further relates to systems, methods, and devices for delivering bipolar electric pulses for irreversible electroporation exhibiting reduced or no damage to tissue typically associated with an EBT-induced excessive charge delivered to the tissue. Field of the Invention The present invention provides systems, methods, and devices for electroporation-based therapies EBTs.
A review of basic to clinical studies of irreversible electroporation therapy.
Description of Related Art Irreversible electroporation IRE and other electroporation-based therapies EBTs , such as electrogenetransfer or electrochemotherapy, may often be administered in a minimally invasive fashion. Example I General Stages of Planning Electroporation-Based Treatments A canine patient with a cm 3 tumor in the left thigh was treated according to a treatment planning embodiment of the invention. This description is intended to provide guidance as to the formulation of a basic treatment planning system, which can be operably configured to include one or more of the following stages: Image Acquisition.
Visualizing and Reconstructing 3D Geometry. Geometry Modeling. Assign Model Properties. Evaluate any Physical Placement Constraints. Placement of Electrodes. Simulation of the Electric Field Distribution. Evaluate Success of Outcome. Example II Comprehensive Package System: Treatment Planning Software Due to the great complexity and time required to develop customized treatment protocols for each patient, it is desirable to automate one or more steps, or the entirety, of the treatment planning process.
Model Creation. Running the Program. Exemplary Optimization Quality Function. Therapy Application. Example IV Treatment Systems, Methods, and Devices Using Bipolar Electric Pulses It has been found that alternating polarity of adjacent electrodes minimizes charge build up and provides a more uniform treatment zone. Example V Monitoring Temperature During Electroporation Procedures One of the main advantages of N-TIRE over other focal ablation techniques is that the pulses do not generate thermal damage due to resistive heating, thus major blood vessels, extracellular matrix and other tissue structures are spared.
The invention claimed is: 1. A treatment planning system for determining a patient-specific electroporation-based treatment protocol comprising: a processing module operably configured for performing the following stages: receiving and processing information from medical images of a target structure and preparing a 3-D reconstruction model of the target structure;. The treatment planning system of claim 1 , wherein the processing module is capable of performing the stages in real time.
The treatment planning system of claim 2 , wherein the processing module further comprises functionality for monitoring electrode or tissue temperature in real time and for considering electrode or tissue temperature in the analysis. The treatment planning system of claim 1 , wherein the information from medical images is extracted from an array of images obtained from one or more imaging modalities chosen from radiographs, tomography, nuclear scintigraphy, CT, MRI, fMRI, PET, or US. The treatment planning system of claim 1 , wherein the numerical model analysis comprises finite element modeling FEM.
The treatment planning system of claim 5 , wherein the target structure is a targeted region or mass; or is a targeted region or mass with neighboring regions; or is a 3D map of voxels to be treated as independent elements in the finite modeling software. The treatment planning system of claim 1 , wherein the 3D reconstruction is a surface or a solid volume.
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The treatment planning system of claim 1 , wherein the numerical model analysis involves accounting for physical constraints, tissue heterogeneities, dynamic effects of electropermeabilization, dynamic thermal effects, and multiple-treatment effects. The treatment planning system of claim 1 , further comprising a self-optimization algorithm for constructing the protocols. The treatment planning system of claim 9 , wherein the self-optimization algorithm is capable of repeatedly evaluating one or more of physical constraints, placement of electrodes, electric field distribution simulations, and outcome success of the protocols, and evaluation of outcome success until one or more effective protocol is constructed.
The treatment planning system of claim 1 , wherein the treatment region and parameters for electroporating are determined automatically, interactively, or automatically and interactively with or without user input. The treatment planning system of claim 1 , capable of constructing protocols for an initial patient treatment or retreatment with or without additional medical images. The treatment planning system of claim 1 , further adapted for instructing an electrical waveform generator to perform the protocol.
The treatment planning system of claim 13 , further comprising an electrical waveform generator in operable communication with the processing module and capable of receiving and executing the treatment protocol. The treatment planning system of claim 14 , wherein the generator is operably configured for delivering a bipolar pulse train. The treatment planning system of claim 13 , wherein instructing comprises specifying a number of bipolar pulses to be delivered, a length of pulse duration at any pole, and a length of any delay between pulses.
The treatment planning system of claim 1 , wherein the electrical conductivity is provided as a conductivity map. A treatment planning method comprising: receiving and processing information from medical images of a target structure and preparing a 3-D reconstruction model of the target structure;. The treatment planning system of claim 18 , wherein the electrical conductivity is provided as a conductivity map.
The method of claim 18 , wherein the numerical model analysis comprises finite element modeling FEM. The method of claim 21 , wherein the target structure is a targeted region or mass; or is a targeted region or mass with neighboring regions; or is a 3D map of voxels to be treated as independent elements in the finite modeling software. The method of claim 18 , wherein the 3D reconstruction is a surface or a solid volume. The method of claim 18 , wherein the numerical model analysis involves accounting for physical constraints, tissue heterogeneities, dynamic effects of electropermeabilization, dynamic thermal effects, or multiple-treatment effects.
The method of claim 18 , wherein the electroporation protocol is determined automatically, interactively, or automatically and interactively with or without user input. The method of claim 18 , capable of constructing protocols for an initial patient treatment or retreatment with or without additional medical images.
The method of claim 18 , further comprising instructing an electrical waveform generator to perform the electroporation protocol. The method of claim 27 , wherein the instructing comprises specifying a number of bipolar pulses to be delivered, a length of pulse duration at any pole, and a length of any delay between pulses. The method of claim 27 , wherein the instructing comprises instructions for delivering a bipolar pulse train. The method of claim 18 , further comprising monitoring electrode or tissue temperature in real time and considering electrode or tissue temperature in the analyzing.
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US9198733B2 - Treatment planning for electroporation-based therapies - Google Patents
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Dev, et al. Inbunden Engelska, Spara som favorit. Skickas inom vardagar. Electroporation-Based Therapies for Cancer reviews electroporation-based clinical studies in hospitals for various cancer treatments, including melanomas, head and neck cancers, chest wall breast carcinomas, and colorectal cancers, as well as research studies in the lab using cell lines, primary cells, and animals. Cancer kills about one American per minute, amounting to over , deaths in the United States and millions, worldwide, each year.
There is a critical need for safe, effective, and affordable alternative treatment modalities, especially for inoperable, recurring, and chemo-resistant cancers, that do not respond well to current treatment regimen.