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      Tumor Ablation with Irreversible Electroporation

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          Abstract

          We report the first successful use of irreversible electroporation for the minimally invasive treatment of aggressive cutaneous tumors implanted in mice. Irreversible electroporation is a newly developed non-thermal tissue ablation technique in which certain short duration electrical fields are used to permanently permeabilize the cell membrane, presumably through the formation of nanoscale defects in the cell membrane. Mathematical models of the electrical and thermal fields that develop during the application of the pulses were used to design an efficient treatment protocol with minimal heating of the tissue. Tumor regression was confirmed by histological studies which also revealed that it occurred as a direct result of irreversible cell membrane permeabilization. Parametric studies show that the successful outcome of the procedure is related to the applied electric field strength, the total pulse duration as well as the temporal mode of delivery of the pulses. Our best results were obtained using plate electrodes to deliver across the tumor 80 pulses of 100 µs at 0.3 Hz with an electrical field magnitude of 2500 V/cm. These conditions induced complete regression in 12 out of 13 treated tumors, (92%), in the absence of tissue heating. Irreversible electroporation is thus a new effective modality for non-thermal tumor ablation.

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          Nanosecond pulsed electric fields cause melanomas to self-destruct.

          We have discovered a new, drug-free therapy for treating solid skin tumors. Pulsed electric fields greater than 20 kV/cm with rise times of 30 ns and durations of 300 ns penetrate into the interior of tumor cells and cause tumor cell nuclei to rapidly shrink and tumor blood flow to stop. Melanomas shrink by 90% within two weeks following a cumulative field exposure time of 120 micros. A second treatment at this time can result in complete remission. This new technique provides a highly localized targeting of tumor cells with only minor effects on overlying skin. Each pulse deposits 0.2 J and 100 pulses increase the temperature of the treated region by only 3 degrees C, ten degrees lower than the minimum temperature for hyperthermia effects.
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            Electrochemotherapy: results of cancer treatment using enhanced delivery of bleomycin by electroporation.

            Over the last decade a new cancer treatment modality, electrochemotherapy, has emerged. By using short, intense electric pulses that surpass the capacitance of the cell membrane, permeabilization can occur (electroporation). Thus, molecules that are otherwise non-permeant can gain direct access to the cytosol of cells in the treated area.A highly toxic molecule that does not usually pass the membrane barrier is the hydrophilic drug bleomycin. Once inside the cell, bleomycin acts as an enzyme creating single- and double-strand DMA-breaks. The cytotoxicity of bleomycin can be augmented several 100-fold by electroporation. Drug delivery by electroporation has been in experimental use for cancer treatment since 1991. This article reviews 11 studies of electrochemotherapy of malignant cutaneous or subcutaneous lesions, e.g., metastases from melanoma, breast or head- and neck cancer. These studies encompass 96 patients with altogether 411 malignant tumours. Electroporation was performed using plate or needle electrodes under local or general anaesthesia. Bleomycin was administered intratumourally or intravenously prior to delivery of electric pulses. The rates of complete response (CR) after once-only treatments were between 9 and 100% depending on the technique used. The treatment was well tolerated and could be performed on an out-patient basis.
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              Effective treatment of cutaneous and subcutaneous malignant tumours by electrochemotherapy.

              Electrochemotherapy (ECT) enhances the effectiveness of chemotherapeutic agents by administering the drug in combination with short intense electric pulses. ECT is effective because electric pulses permeabilize tumour cell membranes and allow non-permeant drugs, such as bleomycin, to enter the cells. The aim of this study was to demonstrate the anti-tumour effectiveness of ECT with bleomycin on cutaneous and subcutaneous tumours. This article summarizes results obtained in independent clinical trials performed by five cancer centres. A total of 291 cutaneous or subcutaneous tumours of basal cell carcinoma (32), malignant melanoma (142), adenocarcinoma (30) and head and neck squamous cell carcinoma (87) were treated in 50 patients. Short and intense electric pulses were applied to tumours percutaneously after intravenous or intratumour administration of bleomycin. The tumours were measured and the response to the treatment evaluated 30 days after the treatment. Objective responses were obtained in 233 (85.3%) of the 273 evaluable tumours that were treated with ECT. Clinical complete responses were achieved in 154 (56.4%) tumours, and partial responses were observed in 79 (28.9%) tumours. The application of electric pulses to the patients was safe and well tolerated. An instantaneous contraction of the underlying muscles was noticed. Minimal adverse side-effects were observed. ECT was shown to be an effective local treatment. ECT was effective regardless of the histological type of the tumour. Therefore, ECT offers an approach to the treatment of cutaneous and subcutaneous tumours in patients with minimal adverse side-effects and with a high response rate.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS ONE
                plos
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2007
                7 November 2007
                : 2
                : 11
                : e1135
                Affiliations
                [1 ]CNRS UMR 8121, Institut Gustave-Roussy, Villejuif, France
                [2 ]University Paris-Sud, UMR 8121, Villejuif, France
                [3 ]School of Biomedical Engineering and Sciences, Virginia Tech-Wake Forest University, Blacksburg, Virginia, United States of America
                [4 ]Department of Bioengineering, University of California at Berkeley, Berkeley, California, United States of America
                [5 ]Department of Mechanical Engineering and Graduate Program in Biophysics, University of California at Berkeley, Berkeley, California, United States of America
                [6 ]Center for Bioengineering in the Service of Humanity and Society, School of Computer Science and Engineering, Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel
                Center for Genomic Regulation, Spain
                Author notes
                * To whom correspondence should be addressed. E-mail: luismir@ 123456igr.fr

                Conceived and designed the experiments: BR LM RD. Performed the experiments: PO BA FA CB EC. Analyzed the data: PO BR LM BA FA RD. Contributed reagents/materials/analysis tools: PO. Wrote the paper: BR LM RD.

                Article
                07-PONE-RA-02150R1
                10.1371/journal.pone.0001135
                2065844
                17989772
                e2c753b9-60c9-430d-8d06-2d734aa2a8ba
                Al-Sakere et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 4 September 2007
                : 9 October 2007
                Page count
                Pages: 8
                Categories
                Research Article
                Biophysics
                Oncology
                Biotechnology/Bioengineering
                Cell Biology/Cellular Death and Stress Responses

                Uncategorized
                Uncategorized

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