Irreversible electroporation

from Wikipedia, the free encyclopedia

In the irreversible electroporation ( Engl. Irreversible electroporation , or IRE NTIRE for Non-Thermal Irreversible electroporation ) is one in 2006 by the Food and Drug Administration approved, minimally invasive, non-thermal Gewebeablationsverfahren .

Explanation of the procedure

Short-pulsed, strong electrical fields create nanometer-sized pores in the phospho-dilipid layers that form the cell membrane . Two forms of cell damage can occur as a result:

1) Reversible electroporation (RE): Cells can survive up to a certain degree of damage from nano-pores. One then speaks of reversible electroporation (RE). Possible medical use of RE is e.g. B. Application of locally acting cytotoxic drugs (such as bleomycin ). See electrochemotherapy .

2) Irreversible electroporation (IRE): If the cell membrane is damaged by nano-pores, both healthy and pathologically altered cells are no longer viable and die as a result of apoptosis . For comparison: All other minimally invasive ablation procedures cause necrotic cell death (mostly by thermal means).

Particular importance is attached to the IRE with regard to the curative treatment of complicated localized tumors . Although the IRE is a comparatively new procedure and there are no randomized multi-center studies or long-term experience, the procedure, thanks to its intrinsic tissue selectivity, allows the treatment of previously inoperable tumors in some areas, as well as better functional retention of the respective organ, shorter healing times and less pain. Areas of application researched so far include the prostate , kidneys and liver .

The short, strong electric fields are generated by long, precisely placed needles and with computer-controlled potential differences between these needles.

The procedure has had 510 (k) FDA approval for the ablation of soft tissue by the company AngioDynamics under the name NanoKnife since 2006.

Physical basics

The microscopic functionality of the IRE ablation has not been conclusively clarified. There are defects in the cell membrane due to changes in the transmembrane potential. The increase in cell membrane permeability is followed by the loss of homeostasis and ends with apoptosis of the cell.

A molecular electrodynamic simulation by Tarek shows the pore formation in two steps:

1) When the electric field is applied, water molecules line up and penetrate the hydrophobic center of the phosphodilipid membrane.

2) These water channels increase in diameter and length and expand into water-filled pores, which are stabilized by the lipid heads.

In an article by EW Lee 2011, the mechanism is discussed in more detail and the pores in the cell walls are shown and quantified using images from the scanning electron microscope .

properties

1) Tissue selectivity - preservation of vital structures also in the treatment field:
By ablating the cells by means of IRE, the cells die an apoptotic cell death. Structures that mainly consist of proteins such as connective tissue or epithelial tissue or generally pericellular matrix proteins are not affected by the IRE. This means that critical structures such as arteries , veins , bile ducts or the urethra are preserved. The electrically insulating myelin layer around nerves also protects nerves from IRE to a certain extent. The extent to which nerves damaged by IRE can regenerate has not been conclusively researched.

2) Sharp IRE margins - predictability:
In IRE there is no or only a very narrow transition zone between the cells that are recovering and those that are dying due to apoptosis. This zone is about one to two rows wide. There are no wide transition areas, as occur with all thermal or radiation-based methods. No heat sink effects have to be taken into account either (larger blood vessels quickly dissipate the heat introduced so that there is no sufficient cell damage). Thanks to this and the multi-electrode concept, even geometrically complex areas can usually be precisely planned.

3) No thermal damage - no necrosis:
Due to the long pauses between pulses in relation to the pulse lengths, there is no Joule heating of the tissue. The design means that there is no thermally induced necrotic cell damage (or only very locally at the needle tips). Accordingly, the necrosis-typical short- and long-term effects are absent.

4) Short treatment time:
An IRE treatment usually takes about five minutes. However, placing the IRE needles can be time-consuming.

5) Display of the treatment field:
The treatment volume can be displayed both during, shortly after and longer after a treatment using ultrasound , MRI or CT .

Current technical problems and limitations of the IRE are:

1) Strong muscle contractions due to direct stimulation of the motor endplate .

2) Planning and implementation in the case of inhomogeneous tissues (e.g. lungs) through jumps in the relative permittivity in the treatment area.

3) Due to the sensitivity of these organs to electrical currents, its use in the heart or brain is probably only possible and useful to a very limited extent.

execution

A number of probes in the form of long needles are placed around the target volume. The penetration location for the probes is selected on the basis of anatomical aspects. Imaging for correct placement is essential and can be done using sonography, magnetic resonance imaging, or computed tomography. The probes are connected to the IRE generator, which sequentially builds up potential differences between two needles. The geometry of the IRE field is calculated in real time and can be influenced by the operator. Depending on the size of the treatment area and the number of probes, the ablation takes between one and ten minutes. As a rule, muscle relaxants are necessary, as otherwise strong muscle contractions due to direct irritation of the motor endplate will occur despite general anesthesia .

Typical parameters:

  • Number of pulses per ablation sequence: 90
  • Pulse length: 100 μs
  • Pause between pulses: 100 to 1000 ms
  • Field strength: 1500 volts / cm
  • Amperage: approx. 50 A (depending on tissue and geometry)
  • Maximum ablation volume with two needles: 4 × 3 × 2 cm³

Application areas and research

prostate

Treatment of prostate cancer with IRE goes back to Gary Onik and Boris Rubinsky in 2007. Prostate carcinomas are often located at critical interfaces that could possibly be damaged by thermal or radiation therapy : for example urethra, bladder, rectum, neurovascular bundles or bladder sphincters . These critical border areas can potentially be included in the treatment field without leaving any lasting damage. The IRE can be used for prostate diseases in the sense of a focal therapy as well as complete ablation. Inoperable recurrences can be treated in many cases. Long-term studies on recurrence rates are not yet available. The first study on the use of IRE in prostate cancer patients in the focal sense was published in 2010 by Gary Onik und Boris Rubinsky. Post-treatment 3d mapping biopsies in all 16 patients showed no evidence of cancer cells in the treatment area. The patient's Gleason score ranged from 6 to 8. The potency was unchanged in all 16 patients. There were no complications. A study of early clinical experience from England is available. The results are positive and promising, but currently only relate to the safety of the procedure, so that the German Society for Urology warned in February 2015 against premature hopes regarding the effectiveness of the IRE. In Germany, IRE on the prostate has been carried out and further developed by Michael K. Stehling (VITUS Prostata Center Offenbach) since 2011. Other clinics in Germany are testing the NanoKnife .

Liver and kidneys

Due to the property of IRE to spare large vessels, epithelial units and nerves, some otherwise inoperable tumors of the liver, pancreas or kidneys can be treated with IRE. Various studies are in progress. In 2012, Wendler and Liehr angiographically demonstrated the preservation of renal vessels in the kidney during IRE therapy.

Other organs

Robert E. Nwal and Rafael V. Davalos reported in 2009 on the applicability of the IRE in breast cancer and other heterogeneous systems.

History and Development

IRE's first observations go back to 1898.

However, the modern scientific applicability of the IRE as an ablation method was derived much later from the development of electrochemotherapy and electrogen therapy. In these therapeutic methods, reversible electroporation (RE) was always the goal and IRE was an undesirable effect. The first analysis of a potential clinical benefit of IRE was by Davalos et al. created in 2005.

Due to the special properties of the IRE, it is currently being intensively researched in many medical centers around the world.

Future research and development should expand and refine the areas of application of IRE. The aim over the next few years will be to determine in which cases IRE is a superior treatment option and where problems arise. Long-term data in all areas of application are pending. With High Frequency Irreversible Electroporation (H-FIRE), the application-relevant problem of strong muscle contraction may be brought under control in the future.

literature

  • B. Rubinsky: Irreversible Electroporation Series in biomedical engineering. Springer, 2010, ISBN 3-642-05420-X , 312 pp.

Web links

Individual evidence

  1. ↑ Irreversible electroporation: implications for prostate ablation B Rubinsky - Technology in cancer research & treatment, 2007 - tcrt.org.
  2. ↑ Angiography in the isolated perfused kidney: radiological evaluation of vascular protection in tissue ablation by nonthermal irreversible electroporation JJ Wendler, M Pech, S Blaschke, M Porsch… -… interventional radiology, 2012 - Springer
  3. ↑ Irreversible electroporation in locally advanced pancreatic cancer: Potential improved overall survival RCG Martin II, K McFarland, SE OCN - Annals of Surgical Oncology , 2012 - Springer
  4. ↑ JF Edd, L. Horowitz, RV Davalos, LM Mir, B. Rubinsky: In vivo results of a new focal tissue ablation technique: irreversible electroporation. In: IEEE transactions on bio-medical engineering. Volume 53, Number 7, July 2006, pp. 1409-1415, ISSN  0018-9294 . doi : 10.1109 / TBME.2006.873745 . PMID 16830945 .
  5. ↑ M. Tarek: Membrane electroporation: a molecular dynamics simulation. In: Biophysical Journal. Volume 88, Number 6, June 2005, pp. 4045-4053, ISSN  0006-3495 . doi : 10.1529 / biophysj.104.050617 . PMID 15764667 . PMC 1305635 (free full text).
  6. ↑ EW Lee, D. Wong et al. a .: Electron microscopic demonstration and evaluation of irreversible electroporation-induced nanopores on hepatocyte membranes. In: Journal of vascular and interventional radiology: JVIR. Volume 23, Number 1, January 2012, pp. 107-113, ISSN  1535-7732 . doi : 10.1016 / j.jvir.2011.09.020 . PMID 22137466 .
  7. ↑ E. Maor, B. Rubinsky: Endovascular nonthermal irreversible electroporation: a finite element analysis. In: Journal of biomechanical engineering. Volume 132, Number 3, March 2010, p. 031008, ISSN  1528-8951 . doi : 10.1115 / 1.4001035 . PMID 20459196 .
  8. ↑ H. Schoellnast, S. Monette et al. a .: The delayed effects of irreversible electroporation ablation on nerves. In: European radiology. Volume 23, Number 2, February 2013, pp. 375-380, ISSN  1432-1084 . doi : 10.1007 / s00330-012-2610-3 . PMID 23011210 .
  9. ↑ a b c E. W. Lee, S. Thai, ST Kee: Irreversible electroporation: a novel image-guided cancer therapy. In: Gut and liver. Volume 4 Suppl 1, September 2010, pp. S99-S104, ISSN  1976-2283 . doi : 10.5009 / gnl.2010.4.S1.S99 . PMID 21103304 . PMC 2989557 (free full text).
  10. ↑ a b R. E. Neal, RV Davalos: The feasibility of irreversible electroporation for the treatment of breast cancer and other heterogeneous systems. In: Annals of biomedical engineering. Volume 37, Number 12, December 2009, pp. 2615-2625, ISSN  1521-6047 . doi : 10.1007 / s10439-009-9796-9 . PMID 19757056 .
  11. ↑ JF Edd, L. Horowitz et al. a .: In vivo results of a new focal tissue ablation technique: irreversible electroporation. In: IEEE transactions on bio-medical engineering. Volume 53, Number 7, July 2006, pp. 1409-1415, ISSN  0018-9294 . doi : 10.1109 / TBME.2006.873745 . PMID 16830945 .
  12. ↑ a b C. B. Arena, MB Sano u. a .: High-frequency irreversible electroporation (H-FIRE) for non-thermal ablation without muscle contraction. In: Biomedical engineering online. Volume 10, 2011, p. 102, ISSN  1475-925X . doi : 10.1186 / 1475-925X-10-102 . PMID 22104372 . PMC 3258292 (free full text).
  13. ↑ G. Onik, P. Mikus, as Rubinsky: Irreversible electroporation: ablation implications for prostate. In: Technology in cancer research & treatment. Volume 6, Number 4, August 2007, pp. 295-300, ISSN  1533-0346 . PMID 17668936 .
  14. ↑ Onik, Gary, and Boris Rubinsky. "Irreversible electroporation: first patient experience focal therapy of prostate cancer." Irreversible electroporation. Springer Berlin Heidelberg, 2010. 235-247.
  15. ↑ Dickinson, CL, et al. 584 Early clinical experience of focal therapy for localized prostate cancer using irreversible electroporation. In: European Urology Supplements 12.1 (2013): e584-e584.
  16. ↑ DGU / BDU press office: Urologists warn against false hopes: Unjustified advertising for outsider therapy "IRE" for prostate cancer ( memento of the original from November 24, 2015 in the Internet Archive ) Info: The archive link was inserted automatically and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. . At: dgu.de, February 4, 2015 (accessed February 18, 2015). @1@ 2Template: Webachiv / IABot / www.dgu.de
  17. ^ MK Stehling: Adjunct Associate Professor of Radiology. ( Memento of the original from April 21, 2013 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. Boston University School of Medicine; NanoKnife | Innovative prostate cancer treatment | Vitus Prostate Center @1@ 2Template: Webachiv / IABot / www.bilddiagnostik.de
  18. ↑ M. Bower, L. Sherwood et al. a .: Irreversible electroporation of the pancreas: definitive local therapy without systemic effects. In: Journal of Surgical Oncology . Volume 104, Number 1, July 2011, pp. 22-28, ISSN  1096-9098 . doi : 10.1002 / jso.21899 . PMID 21360714 .
  19. ^ UB Liehr, JJ Wendler u. a .: [Irreversible electroporation: the new generation of local ablation techniques for renal cell carcinoma]. In: The Urologist. Ed. A. Volume 51, Number 12, December 2012, pp. 1728–1734, ISSN  1433-0563 . doi : 10.1007 / s00120-012-3038-8 . PMID 23139026 .
  20. ^ GW Fuller: Louisville Water Company (Louisville Ky.). Report on the investigations into the purification of the Ohio River water: at Louisville, Kentucky, made to the president and directors of the Louisville Water Company. New York: D. Van Nostrand Company, 1898.
  21. ↑ E. Neumann, M. Schaefer-Ridder u. a .: Gene transfer into mouse lyoma cells by electroporation in high electric fields. In: The EMBO journal. Volume 1, Number 7, 1982, pp. 841-845, ISSN  0261-4189 . PMID 6329708 . PMC 553119 (free full text).
  22. ^ TK Wong, E. Neumann: Electric field mediated gene transfer. In: Biochemical and biophysical research communications. Volume 107, Number 2, July 1982, pp. 584-587, ISSN  0006-291X . PMID 7126230 .
  23. ^ RV Davalos, IL Mir, B. Rubinsky: Tissue ablation with irreversible electroporation. In: Annals of biomedical engineering. Volume 33, Number 2, February 2005, pp. 223-231, ISSN  0090-6964 . PMID 15771276 .