Research ArticleValidation of preclinical multiparametric imaging for prediction of necrosis in hepatocellular carcinoma after embolization
Introduction
Hepatocellular Carcinoma (HCC) ranks among the top six cancer moieties. Fewer than 15% of HCC patients can be cured by liver transplantation, surgical resection, or tumor ablation [1], [2], [3]. The majority of HCC are highly vascularized by arterioles only, which provides the rationale for the transcatheter arterial embolization (TAE) and chemoembolization (TACE) in cases of unresectable HCC that are not suitable for curative treatments, and more recently also the application of systemic angiogenesis inhibitors in HCC patients [4], [5], [6], [7]. Reliable quantification of residual vital tumor tissue after TAE could serve as an invaluable tool in the testing and implementation of novel combinatorial treatment regimens. Change in tumor volume is a standard therapy response marker according to the Response Evaluation Criteria In Solid Tumors (RECIST). However, measurements of changes in tumor volume often lack sufficient sensitivity for early detection of therapy response, requiring more sophisticated imaging methodologies [8], [9]. Nevertheless, in pre-clinical studies, where tumor growth rates commonly exceed those observed in humans, tumor size can serve as a marker of therapy response [10], [11].
Multiple imaging modalities, including magnetic resonance imaging (MRI) and positron emission tomography (PET), are available for the assessment of residual vital tumor tissue after TAE intervention. T2-weighted (T2w-) MRI can be used to evaluate tumor volume and heterogeneity, i.e., increased signal intensity in areas of necrosis. Dynamic contrast enhanced (DCE)-MRI allows the extraction of parameters, such as Ktrans and ve, considered to represent either tissue perfusion and/or capillary permeability (Ktrans) and extravascular extracellular distribution space (ve), respectively [12]. The predominantly arterial blood supply in HCC, in contrast to the portal vein blood supply of normal liver tissue, is used for tumor identification and in addition holds the potential to be used for treatment monitoring [13], [14]. Diffusion weighted MRI (DWI) allows the calculation of the apparent diffusion coefficient (ADC) which is proportional to and inversely correlated with restricted tissue diffusion, e.g., due to cell membranes or macromolecules. Compared to normal liver ADC values, lower values are found in areas of high cellularity such as HCC, whereas higher ADC values are characteristic of cysts [15], [16], [17]. [18F]-fluordeoxyglucose ([18F]-FDG) PET allows the imaging of glucose transport and metabolism which is significantly elevated in many tumor entities. However, underlying cirrhosis resulting in high liver uptake and a high level of differentiation resulting in low tumor uptake reduce the sensitivity of [18F]-FDG PET in human HCC. In small rodent tumor models, the lack of cirrhosis and the clonal character of the tumor population favor high sensitivity of [18F]-FDG, resulting in overestimation of its clinical use.
The value of T2w-MRI, DCE-MRI, DWI, and [18F]-FDG PET for prediction of residual vital tumor tissue after TAE is ideally analyzed and compared by the combined application of these techniques within the same animal. The aim of this study was to validate multimodality multiparametric imaging for response monitoring of orthotopic rat HCC after TAE, by testing the value of the different imaging parameters as individual or combined predictors for residual vital tumor tissue. To this end, the tumor volume (V), the relative [18F]-FDG uptake (FDG), the plasma-tissue transfer constant (Ktrans), the extravascular extracellular volume fraction (ve) and the apparent diffusion coefficient (ADC) were monitored before and after TAE treatment and correlated by histopathology as standard of reference.
Section snippets
Animal model and study protocol
All animal experiments and treatments were approved by the local ethics committee. Orthotopic tumor transplants were generated as previously described [18]. In brief, HCC was established in 25 six-week old male Buffalo rats (Harlan Winkelmann, Borchen, Germany) by injection of 106 syngeneic McA-RH7777 rat HCC cells in 20 μl suspension of serum-free Dulbecco’s Modified Eagle Medium into the right lateral liver lobe. 12–14 days after cell implantation, animals were screened for HCC nodules by MRI
Results
T2w-MRI, DCE-MRI and DWI image data allowed the robust identification of tumor nodules, located caudally in the right lateral lobe of the liver at all imaging time points (Fig. 2A–C). Untreated tumors appeared hyperintense on T2w images, exhibited longer pre-contrast T1 relaxation times and lower ADC values compared to adjacent normal liver tissue. In 50% (n = 8) of the animals [18F]-FDG PET images showed similar tracer uptake in tumor and liver tissues (0.65 <meanisocontou50/meanliver <1.35),
Discussion
A multiparametric imaging platform was validated in a clinically relevant rat HCC tumor model. The value of the different imaging parameters, as individual or combined early predictors of residual vital tissue after TAE, was quantified. Thus, a preclinical platform was established allowing for improved tumor stratification and testing of novel drug regimen in combinatorial therapy approaches.
As intended by the applied TAE intervention (PBS or EmboCept® treatment), a wide range of tumor necrosis
Conflict of interest
The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Financial support
This work was supported by the German Research Foundation (D.F.G.) within the SFB Initiative 824 (collaborative research center) “Imaging for Selection, Monitoring and Individualization of Cancer Therapies” (SFB 824, project C6) to R.B.
Acknowledgments
The authors thank Iryna Skuratovska, Yvonne Kosanke and Sybille Reder for excellent technical assistance, and Drs. Ambros Beer and Ken Herrmann for helpful discussion of the manuscript.
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