Purpose: To determine the safety and feasibility of percutaneous high-frequency irreversible electroporation (HFIRE) for primary liver cancer and evaluate the HFIRE-induced local immune response. Materials and Methods: HFIRE therapy was delivered percutaneously in 3 canine patients with resectable hepatocellular carcinoma (HCC) in the absence of intraoperative paralytic agents or cardiac synchronization. Pre-and post-HFIRE biopsy samples were processed with histopathology and immunohistochemistry for CD3, CD4, CD8, and CD79a. Blood was collected on days 0, 2, and 4 for complete blood count and chemistry. Numeric models were developed to determine the treatment-specific lethal thresholds for malignant canine liver tissue and healthy porcine liver tissue. Results: HFIRE resulted in predictable ablation volumes as assessed by posttreatment CT. No detectable cardiac interference and minimal muscle contraction occurred during HFIRE. No clinically significant adverse events occurred secondary to HFIRE. Microscopically, a well-defined ablation zone surrounded by a reactive zone was evident in the majority of samples. This zone was composed primarily of maturing collagen interspersed with CD3 þ /CD4 À /CD8 À lymphocytes in a proinflammatory microenvironment. The average ablation volumes for the canine HCC patients and the healthy porcine tissue were 3.89 cm 3 ± 0.74 and 1.56 cm 3 ± 0.16, respectively (P ¼ .03), and the respective average lethal thresholds were 710 V/cm ± 28.2 and 957 V/cm ± 24.4 V/cm (P ¼ .0004). Conclusions: HFIRE can safely and effectively be delivered percutaneously, results in a predictable ablation volume, and is associated with lymphocytic tumor infiltration. This is the first step toward the use of HFIRE for treatment of unresectable liver tumors.

Glioblastoma is the deadliest malignant brain tumor. Its location behind the blood–brain barrier (BBB) presents a therapeutic challenge by preventing effective delivery of most chemotherapeutics. H-FIRE is a novel tumor ablation method that transiently disrupts the BBB through currently unknown mechanisms. We hypothesized that H-FIRE mediated BBB disruption (BBBD) occurs via cytoskeletal remodeling and alterations in tight junction (TJ) protein regulation. Intracranial H-FIRE was delivered to Fischer rats prior to sacrifice at 1-, 24-, 48-, 72-, and 96 h post-treatment. Cytoskeletal proteins and native and ubiquitinated TJ proteins (TJP) were evaluated using immunoprecipitation, Western blotting, and gene-expression arrays on treated and sham control brain lysates. Cytoskeletal and TJ protein expression were further evaluated with immunofluorescent microscopy. A decrease in the F/G-actin ratio, decreased TJP concentrations, and increased ubiquitination of TJP were observed 1–48 h post-H-FIRE compared to sham controls. By 72–96 h, cytoskeletal and TJP expression recovered to pretreatment levels, temporally corresponding with increased claudin-5 and zonula occludens-1 gene expression. Ingenuity pathway analysis revealed significant dysregulation of claudin genes, centered around claudin-6 in H-FIRE treated rats. In conclusion, H-FIRE is capable of permeating the BBB in a spatiotemporal manner via cytoskeletal-mediated TJP modulation. This minimally invasive technology presents with applications for localized and long-lived enhanced intracranial drug delivery.

Clinical translation of novel therapeutics that improve the survival and quality of life of patients with neurological disease remains a challenge, with many investigational drug and device candidates failing in advanced stage clinical trials. Naturally occurring inherited and acquired neurological diseases, such as epilepsy, inborn errors of metabolism, brain tumors, spinal cord injury, and stroke occur frequently in companion animals, and many of these share epidemiologic, pathophysiologic and clinical features with their human counterparts. As companion animals have a relatively abbreviated lifespan and genetic background, are immunocompetent, share their environment with human caregivers, and can be clinically managed using techniques and tools similar to those used in humans, they have tremendous potential for increasing the predictive value of preclinical drug and device studies. Here, we review comparative features of spontaneous neurological diseases in companion animals with an emphasis on neuroimaging methods and features, illustrate their historical use in translational studies, and discuss inherent limitations associated with each disease model. Integration of companion animals with naturally occurring disease into preclinical studies can complement and expand the knowledge gained from studies in other animal models, accelerate or improve the manner in which research is translated to the human clinic, and ultimately generate discoveries that will benefit the health of humans and animals.

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