Author ORCID Identifier

0000-0003-0544-5677

Date of Graduation

5-2022

Document Type

Dissertation (PhD)

Program Affiliation

Medical Physics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Erik N. K. Cressman, Ph.D., M.D.

Committee Member

Mark D. Pagel, Ph.D.

Committee Member

James A. Bankson, Ph.D.

Committee Member

Michael C. Gustin, Ph.D.

Committee Member

Rick R. Layman, Ph.D.

Committee Member

R. Jason Stafford, Ph.D

Abstract

Thermochemical ablation (TCA) is a minimally invasive therapy under development for hepatocellular carcinoma, a leading cause of cancer death worldwide. TCA utilizes acid-base chemistry delivered simultaneously to induce local ablation when administered. When delivered via a mixing catheter placed directly into the tumor, acid (e.g., AcOH) and base (e.g., NaOH) react to completion at the catheter tip, producing the acetate salt, water, and releasing heat (Δ>50°C) in sufficient quantities to induce lethal osmotic and thermal stress in tumor cells. However, these two reagents are not distinguishable from tissues with noninvasive imaging modalities, which makes monitoring the delivery of TCA difficult. Image-guided delivery of TCA can help ensure complete ablation of the tumor and margins for assessment of therapeutic response. This research seeks to address these limitations in image guidance by developing novel theranostic agents that provide both imaging and therapeutic capabilities for image-guided TCA intervention.

Fluorine-19 magnetic resonance imaging (19F-MRI) is investigated as a potential method for image guidance in TCA, which is made possible with the inclusion of trifluoroacetic acid (TFA). TFA is an ideal theranostic agent for chemical ablation due to the strong acid properties capable of inducing severe tissue damage and enabling detection with 19F-MRI. In this study, 19F-MRI of TCA is established as a method for real-time injection tracking of chemical ablation and TFA is demonstrated as an effective, imageable therapeutic agent for the ablation of solid tissue. This approach was demonstrated in ex vivo porcine liver experiments where severe tissue damage was confirmed with histopathology. 19F-MRI pulse sequence optimization resulted in two sequences achieving reasonable SNR with relatively short scan times: rapid relaxation with relaxation enhancement (RARE) and balanced steady-state free precession (bSSFP). Optimization of the sequences enabled a cine approach for real-time image-guided delivery of TFA into tissue. In this application with TFA as the acid reagent in TCA, the fluorinated salt product can be used for 19F-MRI image guidance.

Quantitative dual-energy computed tomography (DECT) imaging with cationic cesium (Cs+) as a theranostic was also evaluated for TCA image guidance. DECT high- and low-energy data was acquired of Cs+ standards in a commercial phantom to determine the dual-energy ratio (DER) on two systems with different dual-energy technologies: a dual-source system and a split-filter system. A calibration curve defining the relationship between Cs+ concentration and CT signal showed excellent linear agreement for concentrations between 0 – 250 mM for both scanners. The limit-of-detection (LOD) was 1.36 mM and 6.11 mM cesium hydroxide (CsOH) for the dual-source and split-filter systems, respectively. This approach to quantitative assessment was tested and validated in a gelatin phantom with standards of known Cs+ concentration. Following establishing upper and lower detection limits in phantoms, an ex vivo model was applied to Cs+ based TCA with DECT image guidance for validation. 250 mM CsOH was mixed with the base reagent NaOH and directly injected into the ex vivo tissue model. A line profile was applied to the ablated area to quantify the Cs+ concentration at different locations in the ablation zone. These experiments demonstrate an alternative method for image-guided interventions for tracking the delivery of theranostic agent with DECT, along with a quantitative approach to ensure therapeutic effect.

The primary goal for this work was the development of imaging tools that enable in vivo characterization of TCA. The validated quantitative DECT method was selected for image-guided delivery of TCA in a rabbit VX2 tumor model. Three treatment groups included an untreated control, 5 M AcOH/NaOH, and 10 M AcOH/NaOH. All AcOH/NaOH solutions were spiked with 250 mM CsOH and injected directly into the flank tumor using ultrasound imaging. Following delivery, DECT was performed to confirm complete delivery of Cs+ to all tumors. Application of line profiles to the treated area confirmed delivery and quantification of the Cs+ concentration necessary for therapeutic ablation. Following euthanasia, tumors were excised and prepared for histopathology. Quantitative histopathology analysis showed that tissue sections from the 10 M treatment group exhibited significantly more damage than those from the 5 M treatment group (P = 0.0005, 95% CI: -23.43 to -6.053).

In summary, theranostic TFA or Cs+ in the acid or base reagent of TCA enabled successful image guidance with 19F-MRI and quantitative DECT, respectively.

Keywords

Image-Guidance, MRI, DECT, Cesium, Ablation, Hepatocellular Carcinoma (HCC), Thermochemical Ablation (TCA), Diagnostic Imaging, Interventional Radiology, Imaging Physics

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