(F-231) Comprehensive Investigation of INSPIRE Therapy: Mechanisms, Efficacy, and Treatment Optimization for Large Inoperable Tumors

Introduction:: Cancer continues to stand as a leading cause of death worldwide, presenting formidable challenges in managing inoperable solid tumors due to limited treatment efficacy and severe side effects. Among the most difficult types to treat are liver and pancreatic cancers, with low 5-year survival rates of 18% and 10%, respectively. Integrated Time Nanosecond Pulse Irreversible Electroporation (INSPIRE) is a promising emerging solution, utilizing ultrashort electrical pulses to selectively target malignant cells while sparing healthy tissues. This approach addresses a number of challenges associated with traditional electroporation treatments including the induction of intense muscle stimulation, the need for cardiac synchronization, and accidental induction of thermal damage to tissues adjacent to the applicators..

The present study aims to gain deeper insights into how electrical pulses interact with tissues in search of measurable clinical endpoints and to characterize how an array of treatment parameters affect the size and geometry of treatment zones following INSPIRE. This will provide a critical foundation for refining the INSPIRE approach and advancing its clinical applications. In this study, a porcine liver model was used. Treatments were administered percutaneously via a single needle and grounding pad approach. Treatment waveform, dose, target temperature and the use/omission of active electrode cooling were examined. CT scans were obtained one week post treatment at which time tissue samples were collected for histological analysis. Blood samples were additionally collected to assess cardiac safety.

Materials and Methods::

Pigs were placed under general anesthesia following typical protocols. An ultrasound guided percutaneous approach was used to place a single applicator into healthy liver parenchyma. The applicators consisted of a 1.2mm diameter internally cooled applicator with a 2 cm region of exposed electrode at the distal end of the applicator. INSPIRE treatments consisted of a bipolar waveform administered with an amplitude of +/- 6000V (12,000V peak-to-peak). The waveforms consisted of a single symmetric positive and negative pulse with a 5-microsecond delay between changes in polarity. Pulse widths of 0.5, 1.0, and 2.0 were investigated in this study. The delay between successive waveforms was adjusted via a temperature control algorithm with temperature set points of 45 and 65ºC. Each treatment administered a total dose of 0.02s. Treatments were administered without internal cooling or with active cooling via internal perfusion of the applicators with room temperature water at a rate of 10mL/min. Blood samples were collected pre-treatment, post-treatment, and at euthanasia to assess serum troponin levels, a marker for cardiac damage.   

One week post treatment, contrast enhanced  CTs were acquired. The liver was then collected for gross and histological analysis to assess ablative margins. Slicer 3D was used to conduct CT reconstructions to quantify treatment volumes and determine the geometry of liver ablation zone. Finally, through a parameter study, we identified the most effective and safe treatment settings, directly addressing treatment optimization.

Results, Conclusions, and Discussions:: The comparison between CT values and histological analysis in twelve pigs revealed a consistent positive correlation. The statistical analysis demonstrated a strong positive correlation (p < 0.05) between the CT values and histological measurements of lesion sizes. Specifically, higher CT volumes were consistently associated with larger lesion sizes observed in the histological analysis. These findings indicate that CT imaging serves as a reliable indicator of lesion dimensions and provides valuable information for treatment evaluation.

The significant positive correlation between CT values and histological measurements reinforces the clinical significance of CT imaging as a non-invasive and efficient tool for assessing treatment outcomes. With higher CT volumes consistently corresponding to larger lesion sizes, clinicians and researchers can confidently use CT imaging to monitor treatment progress and assess the effectiveness of interventions. Moreover, the ability to predict lesion sizes through CT imaging streamlines treatment evaluation, reducing the need for invasive procedures and associated risks. The results of this study provide valuable insights into the utility of CT imaging in pig research and its potential application in other animal models. However, it is important to acknowledge the limitation of the relatively small sample size in this study. While there is no significant difference between the CT reconstruction and histological analysis results, it allowed experiments with different parameters to determine which options are needed for ideal treatment.

The significance of the presented data extends beyond its immediate implications. Further studies are planned to investigate INSPIRE therapy in veterinary patients, which could pave the way for potential translational applications in veterinary medicine. Additionally, ongoing research will monitor tumor regression over the subjects' lifetimes, providing valuable insights into the long-term effectiveness of this treatment. Furthermore, the assessment of blood vessel patency in response to INSPIRE therapy will deepen our understanding of its impact on tumor vasculature. Such comprehensive investigations hold promise for advancing cancer treatment in both human and veterinary medicine, presenting opportunities for transformative therapies with improved patient outcomes and enhanced quality of life.

Acknowledgements (Optional): : Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers 1R01CA276232 and R01CA272550, by the North Carolina Biotechnology Center under award number 2021-TRG-6708, and by the Joint Biomedical Engineering Department of the University of North Carolina Chapel Hill and North Carolina State University

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