John L. Robertson

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.

Non-thermal irreversible electroporation (N-TIRE) has shown promise as an ablative therapy for a variety of soft-tissue neoplasms. Here we describe the therapeutic planning aspects and first clinical application of N-TIRE for the treatment of an inoperable, spontaneous malignant intracranial glioma in a canine patient. The N-TIRE ablation was performed safely, effectively reduced the tumor volume and associated intracranial hypertension, and provided sufficient improvement in neurological function of the patient to safely undergo adjunctive fractionated radiotherapy (RT) according to current standards of care. Complete remission was achieved based on serial magnetic resonance imaging examinations of the brain, although progressive radiation encephalopathy resulted in the death of the dog 149 days after N-TIRE therapy. The length of survival of this patient was comparable to dogs with intracranial tumors treated via standard excisional surgery and adjunctive fractionated external beam RT. Our results illustrate the potential benefits of N-TIRE for in vivo ablation of undesirable brain tissue, especially when traditional methods of cytoreductive surgery are not possible or ideal, and highlight the potential radiosensitizing effects of N-TIRE on the brain.

Arsenic is a recognized reproductive toxicant in humans and induces malformations, especially neural tube defects, in laboratory animals. Early studies showed that murine malformations occurred only when a high dose of inorganic arsenic was given by intravenous or intraperitoneal injection in early gestation. Oral gavage of inorganic arsenic at maternally toxic doses caused reduced fetal body weight and increased resorptions. Recently, arsenic reproductive and developmental toxicity has been studied in situations more similar to human exposures and using broader endpoints, such as behavioral changes and gene expression. For the general population, exposure to arsenic is mostly oral, particularly via drinking water, repeated and prolonged over time. In mice and rats, methylated or inorganic arsenic via drinking water or by repeated oral gavage induced male and female reproductive and developmental toxicities. Furthermore, at nonmaternally toxic levels, inorganic arsenic given to pregnant dams via drinking water affected fetal brain development and postnatal behaviors. However, arsenic given by repeated oral gavage to pregnant mice and rats was not morphologically teratogenic. In this review of arsenic reproductive and developmental toxicity in rats and mice, the authors summarize recent in vivo studies and discuss possible underlying mechanisms. The influences of folate, selenium, zinc, and arsenic methylation on arsenic reproductive and developmental toxicity are also discussed.