Electrochemotherapy of Tumours

Electrochemotherapy is a combined use of certain chemotherapeutic drugs and electric pulses applied to the treated tumour nodule. Local application of electric pulses to the tumour increases drug delivery into cells, specifically at the site of electric pulse application. Drug uptake by delivery of electric pulses is increased for only those chemotherapeutic drugs whose transport through the plasma membrane is impeded. Among many drugs that have been tested so far, bleomycin and cisplatin found their way from preclinical testing to clinical use. Clinical data collected within a number of clinical studies indicate that approximately 80% of the treated cutaneous and subcutaneous tumour nodules of different malignancies are in an objective response, from these, approximately 70% in complete response after a single application of electrochemotherapy. Usually only one treatment is needed, however, electrochemotherapy can be repeated several times every few weeks with equal effectiveness each time. The treatment results in an effective eradication of the treated nodules, with a good cosmetic effect without tissue scarring

Numerical optimization of gene electrotransfer into muscle tissue

<p>Abstract</p> <p>Background</p> <p>Electroporation-based gene therapy and DNA vaccination are promising medical applications that depend on transfer of pDNA into target tissues with use of electric pulses. Gene electrotransfer efficiency depends on electrode configuration and electric pulse parameters, which determine the electric field distribution. Numerical modeling represents a fast and convenient method for optimization of gene electrotransfer parameters. We used numerical modeling, parameterization and numerical optimization to determine the optimum parameters for gene electrotransfer in muscle tissue.</p> <p>Methods</p> <p>We built a 3D geometry of muscle tissue with two or six needle electrodes (two rows of three needle electrodes) inserted. We performed a parametric study and optimization based on a genetic algorithm to analyze the effects of distances between the electrodes, depth of insertion, orientation of electrodes with respect to muscle fibers and applied voltage on the electric field distribution. The quality of solutions were evaluated in terms of volumes of reversibly (desired) and irreversibly (undesired) electroporated muscle tissue and total electric current through the tissue.</p> <p>Results</p> <p>Large volumes of reversibly electroporated muscle with relatively little damage can be achieved by using large distances between electrodes and large electrode insertion depths. Orienting the electrodes perpendicular to muscle fibers is significantly better than the parallel orientation for six needle electrodes, while for two electrodes the effect of orientation is not so pronounced. For each set of geometrical parameters, the window of optimal voltages is quite narrow, with lower voltages resulting in low volumes of reversibly electroporated tissue and higher voltages in high volumes of irreversibly electroporated tissue. Furthermore, we determined which applied voltages are needed to achieve the optimal field distribution for different distances between electrodes.</p> <p>Conclusion</p> <p>The presented numerical study of gene electrotransfer is the first that demonstrates optimization of parameters for gene electrotransfer on tissue level. Our method of modeling and optimization is generic and can be applied to different electrode configurations, pulsing protocols and different tissues. Such numerical models, together with knowledge of tissue properties can provide useful guidelines for researchers and physicians in selecting optimal parameters for <it>in vivo </it>gene electrotransfer, thus reducing the number of animals used in studies of gene therapy and DNA vaccination.</p

Modeling electroporation of the non-treated and vacuum impregnated heterogeneous tissue of spinach leaves

Uniform electroporation of the heterogeneous structure of spinach leaf cross section is a technological challenge that is addressed in this investigation. Three dimensional models were created with cells arranged in specific tissue types, considering a leaf with its air fraction and a leaf where the air fraction was replaced by a solution of known properties using vacuum impregnation. The models were validated before electroporation, in the frequency domain, where alternating voltage and current signal at frequencies from 20 Hz to I MHz were used to measure conductivity of the tissue. They were also validated through measurements of current during electroporation when a single 250 mu s rectangular pulse with amplitudes ranging from 50 to 500 V was applied. Model validations show that both the frequency dependent conductivity and electroporation are well predicted. The importance of the wax layer and stomata in the model is thoroughly discussed. Industrial relevance: Our aim was to investigate electroporation of the spinach leaf by developing a model which would enable us to meet the technological challenge of achieving uniform electroporation in a highly heterogeneous structure in the context of a process aimed at improving freezing stability of plant foods. Pulsed electric field treatment may be used to introduce the cryoprotectant molecules into the cells, and hence improve the structure and properties of frozen food plants. (C) 2014 Elsevier Ltd. All rights reserved

Impact of ohmic heating on mass transfer in electroporated plant tissue-insights from numerical modelling

Electroporation, electropermeabilization or pulsed electric field treatment is the application of electric pulses of sufficient amplitude to target tissue, which entails not only permeabilization of cell membranes, but also heat generation and dissipation, i.e. ohmic heating. Noticeable rise in temperature has been observed in a number of electroporation applications. The temperature rise is a potential source of alteration of thermodynamic properties of tissue wherein mass transport is occurring. In example, transport parameters such as liquid viscosity and solute diffusivity are temperature-dependent, as they relate to thermodynamic processes. There is a need to evaluate whether the rate of mass transport is altered significantly by the elevated temperature in plant tissue electroporation. The goal is to advance the basic knowledge of the phenomenon, as well as to optimize further treatment protocols for industrial purposes. This work presents a theoretical study of thermal relations in tissue immediately following electroporation and begins with a hypothetical spatio-temporal distribution of temperature in a sample of plant tissue as calculated during the course of a simulated electroporation experiment. This step is followed by a mass transfer analysis, where two mathematical models of mass transport in electroporated tissue are used to study the impact of transiently elevated temperature to i) kinetics of diffusion of a test solute, and ii) kinetics of liquid redistribution in tissue and its flow to sample exterior caused by an externally applied pressure. The main result of the study is a detailed theoretical analysis on the potential influence of heat generated due to the application of electroporation on kinetics of mass transport in tissue. Preliminary theoretical findings of this mass transport study coupled to the heat transfer model indicate that, provided the initial temperature increase in tissue is within reasonable bounds and heat is rapidly conducted away from tissue (i.e. tissue is not thermally insulated), influence of the temperature rise to mass transport in treated tissue is negligible.Papers presented at the 13th International Conference on Heat Transfer, Fluid Mechanics and Thermodynamics, Portoroz, Slovenia on 17-19 July 2017 .International centre for heat and mass transfer.American society of thermal and fluids engineers

Energy-efficient biomass processing with pulsed electric fields for bioeconomy and sustainable development

Fossil resources-free sustainable development can be achieved through a transition to bioeconomy, an economy based on sustainable biomass-derived food, feed, chemicals, materials, and fuels. However, the transition to bioeconomy requires development of new energy-efficient technologies and processes to manipulate biomass feed stocks and their conversion into useful products, a collective term for which is biorefinery. One of the technological platforms that will enable various pathways of biomass conversion is based on pulsed electric fields applications (PEF). Energy efficiency of PEF treatment is achieved by specific increase of cell membrane permeability, a phenomenon known as membrane electroporation. Here, we review the opportunities that PEF and electroporation provide for the development of sustainable biorefineries. We describe the use of PEF treatment in biomass engineering, drying, deconstruction, extraction of phytochemicals, improvement of fermentations, and biogas production. These applications show the potential of PEF and consequent membrane electroporation to enable the bioeconomy and sustainable development

Towards treatment planning and treatment of deep-seated solid tumors by electrochemotherapy

<p>Abstract</p> <p>Background</p> <p>Electrochemotherapy treats tumors by combining specific chemotherapeutic drugs with an intracellular target and electric pulses, which increases drug uptake into the tumor cells. Electrochemotherapy has been successfully used for treatment of easily accessible superficial tumor nodules. In this paper, we present the first case of deep-seated tumor electrochemotherapy based on numerical treatment planning.</p> <p>Methods</p> <p>The aim of our study was to treat a melanoma metastasis in the thigh of a patient. Treatment planning for electrode positioning and electrical pulse parameters was performed for two different electrode configurations: one with four and another with five long needle electrodes. During the procedure, the four electrode treatment plan was adopted and the patient was treated accordingly by electrochemotherapy with bleomycin. The response to treatment was clinically and radiographically evaluated. Due to a partial response of the treated tumor, the metastasis was surgically removed after 2 months and pathological analysis was performed.</p> <p>Results</p> <p>A partial response of the tumor to electrochemotherapy was obtained. Histologically, the metastasis showed partial necrosis due to electrochemotherapy, estimated to represent 40-50% of the tumor. Based on the data obtained, we re-evaluated the electrical treatment parameters in order to correlate the treatment plan with the clinical response. Electrode positions in the numerical model were updated according to the actual positions during treatment. We compared the maximum value of the measured electric current with the current predicted by the model and good agreement was obtained. Finally, tumor coverage with an electric field above the reversible threshold was recalculated and determined to be approximately 94%. Therefore, according to the calculations, a small volume of tumor cells remained viable after electrochemotherapy, and these were sufficient for tumor regrowth.</p> <p>Conclusions</p> <p>In this, the first reported clinical case, deep-seated melanoma metastasis in the thigh of the patient was treated by electrochemotherapy, according to a treatment plan obtained by numerical modeling and optimization. Although only a partial response was obtained, the presented work demonstrates that treatment of deep-seated tumor nodules by electrochemotherapy is feasible and sets the ground for numerical treatment planning-based electrochemotherapy.</p> <p>Trial registration</p> <p>EudraCT:2008-008290-54</p

Recommendations for improving the quality of reporting clinical electrochemotherapy studies based on qualitative systematic review

Background: Electrochemotherapy is becoming a well-established treatment for malignancies of skin and non-skin origin and its use is widening across Europe. The technique was developed and optimized from solid experimental and clinical evidence. A consensus document is now warranted to formalize reporting results, which should strengthen evidence-based practice recommendations. This consensus should be derived from high quality clinical data collection, clinical expertise and summarizing patient feedback. The first step, which is addressed in this paper, aims to critically analyze the quality of published studies and to provide the recommendations for reporting clinical trials on electrochemotherapy. Methods: The quality of reporting in published studies on electrochemotherapy was analyzed in order to produce procedure specific reporting recommendations. A comprehensive literature search of studies published from 2006 to 2015 was performed followed by qualitative analysis of manuscripts assessing for 47 quality criteria grouped into four major clusters: (1) trial design, (2) description of patient population, (3) description of treatment delivery and patient outcome, (4) analysis of results and their interpretation. The summary measure during literature assessment was the proportion of studies fulfilling each manuscript quality criteria. Results: A total of 56 studies were screened, from the period 2006 to 2015, of which 33 were included in the qualitative analysis, with a total of 1215 patients. Overall, the quality of reporting was highly variable. Twenty-four reports (73%) were single-center, non-comparative studies, and only 15 (45%) were prospective in nature (only 2 of them were entered into a clinical trials registry). Electrochemotherapy technique was consistently reported, with most studies (31/33) adhering closely to published standard operating procedures. The quality of reporting the patient population was variable among the analyzed studies, with only between 45% and 100% achieving dedicated quality criteria. Reporting of treatment delivery and patient outcome was also highly variable with studies only fulfilling between 3% and 100%. Finally, reporting study results critically varied, fulfilling from 27% to 100% of the quality criteria. Based on the critical issues emerging from this analysis, recommendations and minimal requirements for reporting clinical data on electrochemotherapy were prepared and summarized into a checklist. Conclusions: There is an increasing body of published clinical data on electrochemotherapy, but more high quality clinical data are needed. Published papers often lack accurate description of study population, treatment delivery as well as patient outcome. Our recommendations, provided in the form of a summary checklist, are intended to ameliorate data reporting in future studies on electrochemotherapy and help researchers to provide a solid evidence basis for clinical practice