Abstract
Hepatic radiofrequency ablation (RFA) induces a drastic alteration of the biomechanical environment in the peritumoral liver tissue. The resulting increase in matrix stiffness has been shown to significantly influence carcinogenesis and cancer progression after focal RF ablation. To investigate the potential of an elastin-specific MR agent (ESMA) for the assessment of extracellular matrix (ECM) remodeling in the periablational rim following RFA in a VX2 rabbit liver tumor-model, twelve New-Zealand-White-rabbits were implanted in the left liver lobe with VX2 tumor chunks from donor animals. RFA of tumors was performed using a perfused RF needle-applicator with a mean tip temperature of 70 °C. Animals were randomized into four groups for MR imaging and scanned at four different time points following RFA (week 0 [baseline], week 1, week 2 and week 3 after RFA), followed by sacrifice and histopathological analysis. ESMA-enhanced MR imaging was used to assess ECM remodeling. Gadobutrol was used as a third-space control agent. Molecular MR imaging using an elastin-specific probe demonstrated a progressive increase in contrast-to-noise ratio (CNR) (week 3: ESMA: 28.1 ± 6.0; gadobutrol: 3.5 ± 2.0), enabling non-invasive imaging of the peritumoral zone with high spatial-resolution, and accurate assessment of elastin deposition in the periablational rim. In vivo CNR correlated with ex vivo histomorphometry (ElasticaVanGiesson-stain, y = 1.2x − 1.8, R2 = 0.89, p < 0.05) and gadolinium concentrations at inductively coupled mass spectroscopy (ICP-MS, y = 0.04x + 1.2, R2 = 0.95, p < 0.05). Laser-ICP-MS confirmed colocalization of elastin-specific probe with elastic fibers. Following thermal ablation, molecular imaging using an elastin-specific MR probe is feasible and provides a quantifiable biomarker for the assessment of the ablation-induced remodeling of the ECM in the periablational rim.
Highlights
Radiofrequency ablation (RFA) represents a well-established and guideline-approved minimally-invasive therapy for patients with very early and early stage hepatocellular carcinoma (HCC)[1,2,3]
The wound healing process implemented by the liver parenchyma in response to focal thermal ablation is characterized by an intense perifocal inflammation and a progressive deposition of structural proteins in the periablational rim resulting in a profound remodeling of the extracellular matrix with dramatic changes in the mechanical properties of the tumor microenvironment[6,16,29]
Both in vitro and in vivo studies have shown that increased tissue stiffness significantly promotes the proliferation, motility and progression of heat-exposed residual HCC cells and that stiffness-dependent upregulation of the pro-proliferative extracellular signal-regulated kinase (ERK) signaling cascade can be opposed by adjuvant therapies including Vitamin K1 and sorafenib[6,17,18,19,29,30,31]
Summary
Radiofrequency ablation (RFA) represents a well-established and guideline-approved minimally-invasive therapy for patients with very early and early stage hepatocellular carcinoma (HCC)[1,2,3]. Several studies have challenged the sufficiency of merely local considerations for focal ablation by demonstrating that focal tumor destruction may have widespread effects extending far beyond the zone of ablation In this regard, there is ever increasing experimental evidence suggesting that focal thermal ablation may provoke a host of secondary tissue reactions resulting in both anti-oncogenic (e.g. abscopal) as well as pro-oncogenic e ffects[4]. The purpose of our study was to translate the previously established techniques to the oncologic scenario and evaluate the use of ESMA for the non-invasive monitoring and quantification of ECM remodeling in the periablational rim following focal RFA in a VX2 rabbit liver tumor model
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