Nonthermal irreversible electroporation (NTIRE) is a new minimally invasive technique to treat cancer. It is unique because of its nonthermal mechanism of tumor ablation. Intracranial NTIRE procedures involve placing electrodes into the targeted area of the brain and delivering a series of short but intense electric pulses. The electric pulses induce irreversible structural changes in cell membranes, leading to cell death. We correlated NTIRE lesion volumes in normal brain tissue with electric field distributions from comprehensive numerical models. The electrical conductivity of brain tissue was extrapolated from the measured in vivo data and the numerical models. Using this, we present results on the electric field threshold necessary to induce NTIRE lesions (495-510 V/cm) in canine brain tissue using 90 50-mus pulses at 4 Hz. Furthermore, this preliminary study provides some of the necessary numerical tools for using NTIRE as a brain cancer treatment. We also computed the electrical conductivity of brain tissue from the in vivo data (0.12-0.30 S/m) and provide guidelines for treatment planning and execution. Knowledge of the dynamic electrical conductivity of the tissue and electric field that correlates to lesion volume is crucial to ensure predictable complete NTIRE treatment while minimizing damage to surrounding healthy tissue.

Irreversible electroporation is a new technique to kill cells in targeted tissue, such as tumors, through a nonthermal mechanism using electric pulses to irrecoverably disrupt the cell membrane. Treatment effects relate to the tissue electric field distribution, which can be predicted with numerical modeling for therapy planning. Pulse effects will change the cell and tissue properties through thermal and electroporation (EP)-based processes. This investigation characterizes these changes by measuring the electrical conductivity and temperature of ex vivo renal porcine tissue within a single pulse and for a 200 pulse protocol. These changes are incorporated into an equivalent circuit model for cells and tissue with a variable EP-based resistance, providing a potential method to estimate conductivity as a function of electric field and pulse length for other tissues. Finally, a numerical model using a human kidney volumetric mesh evaluated how treatment predictions vary when EP- and temperature-based electrical conductivity changes are incorporated. We conclude that significant changes in predicted outcomes will occur when the experimental results are applied to the numerical model, where the direction and degree of change varies with the electric field considered.

BackgroundIrreversible electroporation (IRE) is a new minimally invasive technique to kill undesirable tissue in a non-thermal manner. In order to maximize the benefits from an IRE procedure, the pulse parameters and electrode configuration must be optimized to achieve complete coverage of the targeted tissue while preventing thermal damage due to excessive Joule heating.MethodsWe developed numerical simulations of typical protocols based on a previously published computed tomographic (CT) guided in vivo procedure. These models were adapted to assess the effects of temperature, electroporation, pulse duration, and repetition rate on the volumes of tissue undergoing IRE alone or in superposition with thermal damage.ResultsNine different combinations of voltage and pulse frequency were investigated, five of which resulted in IRE alone while four produced IRE in superposition with thermal damage.ConclusionsThe parametric study evaluated the influence of pulse frequency and applied voltage on treatment volumes, and refined a proposed method to delineate IRE from thermal damage. We confirm that determining an IRE treatment protocol requires incorporating all the physical effects of electroporation, and that these effects may have significant implications in treatment planning and outcome assessment. The goal of the manuscript is to provide the reader with the numerical methods to assess multiple-pulse electroporation treatment protocols in order to isolate IRE from thermal damage and capitalize on the benefits of a non-thermal mode of tissue ablation.

CpG oligodeoxynucleotides (ODNs) are synthetic DNA sequences containing unmethylated cytosine-guanine motifs with potent immunomodulatory effects. Via Toll-like receptor 9 agonism of dendritic cells and B cells, CpG ODNs induce cytokines, activate natural killer cells, and elicit vigorous T-cell responses that lead to significant antitumor effects, including improved efficacy of chemotherapeutic agents. On the basis of these properties of CpG ODNs, we tested whether they also could enhance tumor response to radiotherapy. Using an immunogenic mouse tumor, designated FSa, the response to radiotherapy was assayed by tumor growth delay and tumor cure rate (TCD 50 , radiation dose yielding 50% tumor cure rate). Treatments were initiated when established tumors were either 6 or 8 mm in diameter. CpG ODN as a single agent given s.c. peritumorally had little effect on tumor growth; however, it dramatically enhanced tumor growth delay in response to single-dose radiation by a factor of 2.58 -2.65. CpG ODN also dramatically improved tumor radiocurability, reducing the TCD 50 by a factor of 1.