Stefanie J. C. G. Hectors

Dual-targeting of αvβ3 and galectin-1 improves the specificity of paramagnetic/fluorescent liposomes to tumor endothelium in vivo.

Molecular imaging of angiogenesis requires a highly specific and efficient contrast agent for targeting activated endothelium. We have previously demonstrated that paramagnetic and fluorescent liposomes functionalized with two angiogenesis-specific ligands, the galectin-1-specific anginex (Anx) and the α(v)β(3) integrin-specific RGD, produce synergistic targeting effect in vitro. In the current study, we applied Anx and RGD dual-conjugated liposomes (Anx/RGD-L) for angiogenesis-specific MRI in vivo, focusing on the specificity and efficacy of liposome association with tumor endothelium. The targeting properties, clearance kinetics and biodistribution of Anx/RGD-L were investigated in B16F10 melanoma-bearing mice, and compared to liposomes functionalized with either Anx (Anx-L) or RGD (RGD-L). The contrast enhancement produced by dual- and single-targeted nanoparticles in the tumor was measured using in vivo T(1)-weighted MRI, complemented by ex vivo immunohistochemical evaluation of tumor tissues. Blood clearance kinetics of Anx/RGD-L was three-fold more rapid than for RGD-L, but comparable to Anx-L. Both dual- and single-targeted liposomes produced similar changes in MRI contrast parameters in tumors with high inter-tumor variability (ΔR(1)=0.04±0.03s(-1), 24h post-contrast). Importantly, however, the specificity of Anx/RGD-L association with tumor endothelium of 53±6%, assessed by fluorescence microscopy, was significantly higher compared to 43±9% (P=0.043) and 28±8% (P=0.0001) of Anx-L and RGD-L, respectively. In contrast, long-circulating RGD-L were on average 16% more efficient in targeting tumor endothelium compared to Anx/RGD-L. Significant differences were also found in the biodistribution of investigated contrast agents. In conclusion, synergistic targeting of α(v)β(3) and galectin-1 improved the specificity of the association of the liposomal contrast agent to tumor endothelium in vivo, providing therefore a more reliable MRI readout of the angiogenic activity.

MRI methods for the evaluation of high intensity focused ultrasound tumor treatment: Current status and future needs

Thermal ablation with high intensity focused ultrasound (HIFU) is an emerging noninvasive technique for the treatment of solid tumors. HIFU treatment of malignant tumors requires accurate treatment planning, monitoring and evaluation, which can be facilitated by performing the procedure in an MR‐guided HIFU system. The MR‐based evaluation of HIFU treatment is most often restricted to contrast‐enhanced T1‐weighted imaging, while it has been shown that the non‐perfused volume may not reflect the extent of nonviable tumor tissue after HIFU treatment. There are multiple studies in which more advanced MRI methods were assessed for their suitability for the evaluation of HIFU treatment. While several of these methods seem promising regarding their sensitivity to HIFU‐induced tissue changes, there is still ample room for improvement of MRI protocols for HIFU treatment evaluation. In this review article, we describe the major acute and delayed effects of HIFU treatment. For each effect, the MRI methods that have been—or could be—used to detect the associated tissue changes are described. In addition, the potential value of multiparametric MRI for the evaluation of HIFU treatment is discussed. The review ends with a discussion on future directions for the MRI‐based evaluation of HIFU treatment. Magn Reson Med 75:302–317, 2016.

Intravoxel incoherent motion diffusion-weighted imaging of hepatocellular carcinoma: Is there a correlation with flow and perfusion metrics obtained with dynamic contrast-enhanced MRI?

To assess the correlation between intravoxel incoherent motion diffusion‐weighted imaging (IVIM‐DWI) and dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) metrics in hepatocellular carcinoma (HCC) and liver parenchyma.

Multiparametric MRI Analysis for the Identification of High Intensity Focused Ultrasound-Treated Tumor Tissue

Purpose In this study endogenous magnetic resonance imaging (MRI) biomarkers for accurate segmentation of High Intensity Focused Ultrasound (HIFU)-treated tumor tissue and residual or recurring non-treated tumor tissue were identified. Methods Multiparametric MRI, consisting of quantitative T1, T2, Apparent Diffusion Coefficient (ADC) and Magnetization Transfer Ratio (MTR) mapping, was performed in tumor-bearing mice before (n = 14), 1 h after (n = 14) and 72 h (n = 7) after HIFU treatment. A non-treated control group was included (n = 7). Cluster analysis using the Iterative Self Organizing Data Analysis (ISODATA) technique was performed on subsets of MRI parameters (feature vectors). The clusters resulting from the ISODATA segmentation were divided into a viable and non-viable class based on the fraction of pixels assigned to the clusters at the different experimental time points. ISODATA-derived non-viable tumor fractions were quantitatively compared to histology-derived non-viable tumor volume fractions. Results The highest agreement between the ISODATA-derived and histology-derived non-viable tumor fractions was observed for feature vector {T1, T2, ADC}. R1 (1/T1), R2 (1/T2), ADC and MTR each were significantly increased in the ISODATA-defined non-viable tumor tissue at 1 h after HIFU treatment compared to viable, non-treated tumor tissue. R1, ADC and MTR were also significantly increased at 72 h after HIFU. Conclusions This study demonstrates that non-viable, HIFU-treated tumor tissue can be distinguished from viable, non-treated tumor tissue using multiparametric MRI analysis. Clinical application of the presented methodology may allow for automated, accurate and objective evaluation of HIFU treatment.

Amide proton transfer imaging of high intensity focused ultrasound-treated tumor tissue.

In this study, the suitability of amide proton transfer (APT) imaging as a biomarker for the characterization of high intensity focused ultrasound (HIFU)‐treated tumor tissue was assessed.

Quantification of hepatocellular carcinoma heterogeneity with multiparametric magnetic resonance imaging

Tumour heterogeneity poses a significant challenge for treatment stratification. The goals of this study were to quantify heterogeneity in hepatocellular carcinoma (HCC) using multiparametric magnetic resonance imaging (mpMRI), and to report preliminary data correlating quantitative MRI parameters with advanced histopathology and gene expression in a patient subset. Thirty-two HCC patients with 39 HCC lesions underwent mpMRI including diffusion-weighted imaging (DWI), blood-oxygenation-level-dependent (BOLD), tissue-oxygenation-level-dependent (TOLD) and dynamic contrast-enhanced (DCE)-MRI. Histogram characteristics [central tendency (mean, median) and heterogeneity (standard deviation, kurtosis, skewness) MRI parameters] in HCC and liver parenchyma were compared using Wilcoxon signed-rank tests. Histogram data was correlated between MRI methods in all patients and with histopathology and gene expression in 14 patients. HCCs exhibited significantly higher intra-tissue heterogeneity vs. liver with all MRI methods (P < 0.030). Although central tendency parameters showed significant correlations between MRI methods and with each of histopathology and gene expression, heterogeneity parameters exhibited additional complementary correlations between BOLD and DCE-MRI and with histopathologic hypoxia marker HIF1α and gene expression of Wnt target GLUL, pharmacological target FGFR4, stemness markers EPCAM and KRT19 and immune checkpoint PDCD1. Histogram analysis combining central tendency and heterogeneity mpMRI features is promising for non-invasive HCC characterization on the imaging, histologic and genomics levels.

Multiparametric MRI analysis for the evaluation of MR-guided high intensity focused ultrasound tumor treatment

For the clinical application of high intensity focused ultrasound (HIFU) for thermal ablation of malignant tumors, accurate treatment evaluation is of key importance. In this study, we have employed a multiparametric MRI protocol, consisting of quantitative T1, T2, ADC, amide proton transfer (APT), T1ρ and DCE‐MRI measurements, to evaluate MR‐guided HIFU treatment of subcutaneous tumors in rats. K‐means clustering using all different combinations of the endogenous contrast MRI parameters (feature vectors) was performed to segment the multiparametric data into tissue populations with similar MR parameter values. The optimal feature vector for identification of the extent of non‐viable tumor tissue after HIFU treatment was determined by quantitative comparison between clustering‐derived and histology‐derived non‐viable tumor fractions. The highest one‐to‐one correspondence between these clustering‐based and histology‐based non‐viable tumor fractions was observed for the feature vector {ADC, APT‐weighted signal} (R2 to line of identity (R2y=x) = 0.92) and the strongest agreement was seen 3 days after HIFU (R2y=x = 0.97). To compare the multiparametric MRI analysis results with conventional HIFU monitoring and evaluation methods, the histology‐derived non‐viable tumor fractions were also quantitatively compared with non‐perfused tumor fractions (derived from the level of contrast enhancement in the DCE‐MRI measurements) and 240 CEM tumor fractions (i.e. thermal dose > 240 cumulative equivalent minutes at 43 °C). The correlation between histology‐derived non‐viable tumor fractions directly after HIFU and the 240 CEM fractions was high, but not significant. The non‐perfused fractions overestimated the extent of non‐viable tumor tissue directly after HIFU, whereas an underestimation was observed 3 days after HIFU.

Magnetic Resonance Imaging Predicts Histopathological Composition of Ileal Crohn’s Disease

Background and Aims Recently, smooth muscle hypertrophy has been suggested to be a contributor to small bowel lesions secondary to Crohns disease [CD], in addition to inflammation and fibrosis. Here, we assess the value of magnetic resonance imaging [MRI] for the characterisation of histopathological tissue composition of small bowel CD, including inflammation, fibrosis, and smooth muscle hypertrophy. Methods A total of 35 consecutive patients [male/female 17/18, mean age 33 years] with ileal CD, who underwent small bowel resection and a preoperative contrast-enhanced MRI examination within 1 month before surgery, were retrospectively included. Image assessment included qualitative [pattern/degree of enhancement, presence of ulcerations/fistulas/abscesses] and quantitative parameters [wall thickness on T2/T1-weighted images [WI], enhancement ratios, apparent diffusion coefficient [ADC], Clermont and Magnetic Resonance Index of Activity [MaRIA] scores). MRI parameters were compared with histopathological findings including active inflammation, collagen deposition, and muscle hypertrophy using chi square/Fisher or Mann-Whitney tests and univariate/multivariate logistic/linear regression analyses. Results Forty ileal segments were analysed in 35 patients. Layered pattern at early-post-contrast phase was more prevalent (odds ratio [OR] = 8; p = 0.008), ADC was significantly lower [OR = 0.005; p = 0.022], and MaRIA score was significantly higher [OR = 1.125; p = 0.022] in inflammation grades 2-3 compared with grade 1. Wall thickness on T2WI was significantly increased [OR = 1.688; p = 0.043], and fistulas [OR = 14.5; p = 0.017] were more prevalent in segments with disproportionately increased muscle hypertrophy versus those with disproportionately increased fibrosis. MaRIA/Clermont scores, wall thickness on T1WI and T2WI, and ADC were all significantly correlated with degree of muscular hypertrophy. Conclusions MRI predicts the degree of inflammation, and can distinguish prominent muscle hypertrophy from prominent fibrosis in ileal CD with reasonable accuracy (area under receiver operating characteristic curve [AUROC] > 0.7).

Cluster analysis of DCE-MRI data identifies regional tracer-kinetic changes after tumor treatment with high intensity focused ultrasound

Evaluation of high intensity focused ultrasound (HIFU) treatment with MRI is generally based on assessment of the non‐perfused volume from contrast‐enhanced T1‐weighted images. However, the vascular status of tissue surrounding the non‐perfused volume has not been extensively investigated with MRI. In this study, cluster analysis of the transfer constant Ktrans and extravascular extracellular volume fraction ve, derived from dynamic contrast‐enhanced MRI (DCE‐MRI) data, was performed in tumor tissue surrounding the non‐perfused volume to identify tumor subregions with distinct contrast agent uptake kinetics.

DCE-MRI of the prostate using shutter-speed vs. Tofts model for tumor characterization and assessment of aggressiveness

To quantify Tofts model (TM) and shutter‐speed model (SSM) perfusion parameters in prostate cancer (PCa) and noncancerous peripheral zone (PZ) and to compare the diagnostic performance of dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) to Prostate Imaging and Reporting and Data System (PI‐RADS) classification for the assessment of PCa aggressiveness.