Evaluation of the safety and feasibility of electrochemotherapy with intravenous bleomycin as local treatment of bladder cancer in dogs.

Local treatment of canine urothelial carcinoma (UC) of the bladder is a challenge. More than 90% of the cases invade the muscular layer, more than 50% develop on bladder sites with a difficult surgical approach and often requiring radical surgical procedures. This study aims to evaluate the safety and feasibility of electrochemotherapy (ECT) with intravenous bleomycin (BLM) as a local therapy for bladder UC. This prospective study included 21 dogs with spontaneous bladder UC. Regional/distant metastases and neoplastic infiltration of the serosa was considered the main exclusion criteria. We had no deaths during ECT or in the immediate postoperative period, and no suture dehiscence. Most dogs (19/21) developed mild adverse effects, whereas two dogs developed ureteral stenosis. Complete response (CR) was achieved in 62% of the cases (13/21), while partial response (PR) was achieved in 24% (5/21). The median survival and disease-free survival times were 284 and 270 days, respectively. Overall survival was significantly better in the dogs who achieved a CR. In conclusion, ECT was well-tolerated in dogs with UC, demonstrating its safety and feasibility. These data pave the way for new studies aimed at evaluating the effectiveness of ECT in canine bladder UC as a translational model for human disease.

Computer optimization of conductive gels for electrochemotherapy.

Electrochemotherapy (ECT) requires covering the entire tumor and safe margins with a suitable pulsed electric field (PEF). The PEF distribution depends on the biological and electrical parameters. The biological tissue may have diffractive geometry with non-linear conductivity behavior due to electroporation. That characteristic may provoke ECT-insufficient electric field regions, also known as blind spots. The conductive gels can fill holes and bumps, being a tool to homogenize the electric field. We executed an in vitro vegetal tissue experiment to validate a numerical model under different gels conditions. We used a study case in silico experiment to investigate gel influence on PEF distribution and electrical current. We propose a case-oriented methodology to optimize the gel during the ECT pre-treatment. Results show that the optimized gel completely treats a region of interest while avoiding unnecessary current increase and damage to healthy tissue by over treatment. The optimized gel conductivity may be lower than the previously reported (0.5 to 1 S/m) and may be in the range of the commercially available gels. For a veterinary mastocytoma exophytic nodule ECT case study, using needles electrode, the 0.2 S/m gel is the optimum gel.

Electrochemotherapy Effectiveness Loss due to Electric Field Indentation between Needle Electrodes: A Numerical Study.

Electrochemotherapy is an anticancer treatment based on applying electric field pulses that reduce cell membrane selectivity, allowing chemotherapy drugs to enter the cells. In parallel to electrochemotherapy clinical tests, in silico experiments have helped scientists and clinicians to understand the electric field distribution through anatomically complex regions of the body. In particular, these in silico experiments allow clinicians to predict problems that may arise in treatment effectiveness. The current work presents a metastatic case of a mast cell tumor in a dog. In this specific treatment planning study, we show that using needle electrodes has a possible pitfall. The macroscopic consequence of the electroporation was assessed through a mathematical model of tissue electrical conductivity. Considering the electrical and geometrical characteristics of the case under study, we modeled an ellipsoidal tumor. Initial simulations were based on the European Standard Operating Procedures for electrochemotherapy suggestions, and then different electrodes' arrangements were evaluated. To avoid blind spots, multiple applications are usually required for large tumors, demanding electrode repositioning. An effective treatment electroporates all the tumor cells. Partially and slightly overlapping the areas increases the session's duration but also likely increases the treatment's effectiveness. It is worth noting that for a single application, the needles should not be placed close to the tumor's borders because effectiveness is highly likely to be lost.

Modeling environment for numerical simulation of applied electric fields on biological cells.

The application of electric pulses in cells increases membrane permeability. This phenomenon is called electroporation. Current electroporation models do not explain all experimental findings: part of this problem is due to the limitations of numerical methods. The Equivalent Circuit Method (ECM) was developed in an attempt to solve electromagnetic problems in inhomogeneous and anisotropic media. ECM is based on modeling of the electrical transport properties of the medium by lumped circuit elements as capacitance, conductance, and current sources, representing the displacement, drift, and diffusion current, respectively. The purpose of the present study was to implement a 2-D cell Model Development Environment (MDE) of ionic transport process, local anisotropy around cell membranes, biological interfaces, and the dispersive behaviour of tissues. We present simulations of a single cell, skeletal muscle, and polygonal cell arrangement. Simulation of polygonal form indicates that the potential distribution depends on the geometrical form of cell. The results demonstrate the importance of the potential distributions in biological cells to provide strong evidences for the understanding of electroporation.

Numerical simulation of electroporation in spherical cells.

This article presents a numerical study of the electroporation process of spherical cells suspended in an electrolyte solution, using the equivalent circuit method (ECM) for field calculation proposed by Ramos et al. A model for the electric conductance of the cell membrane derived from the analytical and experimental results obtained by Glaser et al. for planar lipidic membranes was applied. The influence of the cell concentration and membrane properties (described in the model) on the membrane current, membrane potential, and dependence of the electrolyte conductivity on the applied electric field was studied. These results clarify the electric events connected with the pore opening process and allow the planning of experimental approaches to study reversible membrane rupture in real cells.