Intravoxel incoherent motion MRI for monitoring the therapeutic response of hepatocellular carcinoma to sorafenib treatment in mouse xenograft tumor models.

Background With the introduction of targeted therapies, there has been a growing need for non-invasive imaging methods which accurately evaluate therapeutic effects and overcome the limitations of tumor size-based therapeutic response assessments. Purpose To assess diagnostic values of intra-voxel incoherent motion (IVIM) imaging in evaluating therapeutic effects of sorafenib on hepatocellular carcinoma (HCC) using mouse xenograft model. Material and Methods Twenty-four mice bearing Huh-7 were divided into a control group and two treatment groups received sorafenib doses of 5 mg/kg (5 mg-Tx) or 30 mg/kg (30 mg-Tx). IVIM imaging was performed using 10 b-values (0-900 s/mm2). The apparent diffusion coefficient (ADC), diffusion coefficient ( D), and perfusion fraction ( f) were measured for whole tumors and tumor periphery. Changes between baseline and post-treatment parameters ( Δ ADC, Δ D, and Δ f) were calculated, and these parameters were compared with microvessel density (MVD) and area of tumor cell death. Results The post-treatment f and Δ f for tumor periphery were significantly higher in control group, followed by 5 mg-Tx and 30 mg-Tx ( P < 0.001). MVD showed significant positive correlation with post-treatment f ( r = 0.584, P = 0.003) and negative correlation with D ( r = -0.495, P = 0.014) for tumor periphery, while no parameter showed significant correlation with area of tumor cell death. Conclusion The f is significantly correlated with MVD of HCC, and could potentially be used to evaluate the anti-angiogenic effects of sorafenib.

Intravoxel incoherent motion diffusion-weighted imaging of the pancreas: Characterization of benign and malignant pancreatic pathologies.

PURPOSE: To evaluate the diagnostic value of apparent diffusion coefficient (ADC) and intravoxel incoherent motion (IVIM) parameters in differentiating patients with either a normal pancreas (NP), pancreatic ductal adenocarcinoma (PDAC), neuroendocrine tumor (NET), solid pseudopapillary tumor (SPT), acute pancreatitis (AcP), vs. autoimmune pancreatitis (AIP). MATERIALS AND METHODS: In all, 84 pathologically confirmed pancreatic tumors (60 PDACs, 15 NETs, 9 SPTs), 20 pancreatitis (13 AcPs, 7 AIPs), and 30 NP subjects underwent IVIM diffusion-weighted imaging using 10 b-values (0-900 sec/mm2 ) at 1.5T. The ADC, pure molecular diffusion coefficient (Dslow ), perfusion fraction (f), and perfusion-related diffusion coefficient (Dfast ) were calculated and compared using a Kruskal-Wallis test and post-hoc Dunn procedure. Receiver operating characteristic (ROC) analysis was performed to assess diagnostic performance. RESULTS: The f and Dfast of the PDAC were significantly lower than that of the NP (f = 0.10 vs. 0.24; Dfast = 42.21 vs. 71.74 × 10-3 mm2 /sec; P < 0.05). In ROC analysis, f showed the best diagnostic performance (area-under-the-curve, 0.919) among all parameters in differentiating PDAC from NP (P ≤ 0.001). The f values of AcP (0.11) and AIP (0.13) and the Dfast values of SPT (20.48 × 10-3 mm2 /sec) and AcP (24.49 × 10-3 mm2 /sec) were significantly lower compared with NP (f = 0.24; Dfast = 71.74 × 10-3 mm2 /sec; P < 0.05). For NET, the f (0.21) was significantly higher than that of PDAC (0.10, P < 0.01). CONCLUSION: Perfusion-related parameters f and Dfast are more helpful in characterizing pancreatic diseases than ADC or Dslow . The PDCA, SPT, AcP, and AIP were characterized by reduced f and Dfast values compared with normal pancreas. The f value might help in differentiating between PDAC and NET. LEVEL OF EVIDENCE: 3 J. Magn. Reson. Imaging 2017;45:260-269.

Intravoxel incoherent motion diffusion-weighted imaging for characterizing focal hepatic lesions: Correlation with lesion enhancement.

PURPOSE: To evaluate the value of intravoxel incoherent motion (IVIM) parameters for characterizing focal hepatic lesions, and to assess the correlation between IVIM parameters and arterial nodule enhancement. MATERIALS AND METHODS: We retrospectively evaluated 161 lesions (91 hepatocellular carcinomas [HCCs], 27 intrahepatic cholangiocarcinomas [IHCCs], 20 hemangiomas, 9 combined hepatocellular-cholangiocarcinomas, 9 metastases, and 5 other tumors) in 161 patients (105 men and 56 women; mean age, 56.4 years). Diffusion-weighted imaging was performed using nine b-values (0-900 s/mm2 ) at 1.5T. Apparent diffusion coefficient (ADC), molecular diffusion coefficient (Dslow ), perfusion fraction (f), and perfusion-related diffusion coefficient (Dfast ) were compared among the hepatic lesions using analysis of variance (ANOVA). Receiver-operating-characteristic analysis was performed to assess diagnostic performance. The enhancement fraction (EF) and the relative enhancement (RE) of the hepatic lesions on arterial phase gadoxetic acid-enhanced images were correlated with the IVIM parameters using Spearman's test. RESULTS: For the differentiation of hemangiomas from malignant tumors, Dslow showed the largest area under the curve (0.933) among all parameters. Although ADC did not show any difference among malignant lesions (P ≥ 0.28), HCCs showed a significantly lower Dslow than IHCC (P < 0.001) and a higher f than did IHCC (P < 0.001) and metastasis (P = 0.027); f had a significant positive correlation with EF (r = 0.420, P < 0.001) and RE (r = 0.264, P = 0.001). CONCLUSION: IVIM parameters are more helpful in characterizing malignant hepatic lesions than ADC; f may reflect the extent and degree of hepatic nodule enhancement in the arterial phase, and may allow for differentiation of HCC from IHCC and metastasis. LEVEL OF EVIDENCE: 3 J. MAGN. RESON. IMAGING 2017;45:1589-1598.

Intravoxel incoherent motion diffusion-weighted MRI of the abdomen: The effect of fitting algorithms on the accuracy and reliability of the parameters.

PURPOSE: To evaluate the influence of fitting methods on the accuracy and reliability of intravoxel incoherent motion (IVIM) parameters, with a particular emphasis on the constraint function. MATERIALS AND METHODS: Diffusion-weighted (DW) imaging data were analyzed using IVIM-based full-fitting (simultaneous fit of all parameters) and segmented-fitting (step-by-step fit of each parameter), each with and without the constraint function, to estimate the molecular diffusion coefficient (Dslow ), perfusion fraction (f), and flow-related diffusion coefficient (Dfast ). Computational simulations were performed at variable signal-to-noise ratios to evaluate the relative error (RE) and coefficient of variation (CV) of the estimated IVIM parameters. DW imaging of the abdomen was performed twice at 1.5 Tesla using nine b-values (0-900 s/mm2 ) in 12 health volunteers (6 men and 6 women; mean age: 30 years). The measurement repeatability of IVIM parameters in the liver and the pancreas was evaluated using the within-subject coefficient of variation (w CV). RESULTS: In simulations, full-fitting without the constraint function yielded the largest RE (P < 0.001 for Dslow and f; P ≤ 0.044 for Dfast ) and CV (P ≤ 0.033 for Dslow and f; P ≤ 0.473 for Dfast ) for IVIM parameters among all four algorithms. In volunteer imaging, full-fitting without the constraint function also resulted in the poorest repeatability for Dslow (w CV, 17.12%-65.45%) and f (w CV, 19.35%-42.84%) in the liver and pancreas, while the other algorithms had similar repeatability values (w CV, 4.05%-11.99% for Dslow and 9.65%-18.66% for f). Measurement repeatability of Dfast (w CV, 29.52%-85.01%) was the poorest among the IVIM parameters. CONCLUSION: For accurate and reliable measurement of IVIM parameters, segmented fitting or full-fitting with the constraint function should be used for IVIM-based analysis of DW imaging. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;45:1637-1647.

Perfusion Assessment Using Intravoxel Incoherent Motion-Based Analysis of Diffusion-Weighted Magnetic Resonance Imaging: Validation Through Phantom Experiments.

OBJECTIVES: The aims of this study were to demonstrate the theoretical meaning of intravoxel incoherent motion (IVIM) parameters and to compare the robustness of 2 biexponential fitting methods through magnetic resonance experiments using IVIM phantoms. MATERIALS AND METHODS: Intravoxel incoherent motion imaging was performed on a 3 T magnetic resonance imaging scanner using 15 b values (0-800 s/mm) for 4 phantoms with different area fractions of the flowing water compartment (FWC%), at the infusion flow rates of 0, 1, 2, and 3 mL/min. Images were quantitatively analyzed using monoexponential free biexponential, and segmented biexponential fitting models. RESULTS: There were some inconsistent variations in Dslow with changing flow rates. The perfusion fraction, f, showed a significant positive correlation with the flow rate for both the free and segmented fitting methods (ρ = 0.838 to 0.969; P < 0.001). The fast diffusion coefficient, Dfast, had a significant positive correlation with the flow rate for segmented fitting (ρ = 0.745 to 0.969; P < 0.001), although it showed an inverse correlation with the flow rate for free fitting (ρ = -0.527 to -0.791; P ≤ 0.017). Significant positive correlations with the FWC% of the phantoms were noted for f (P = 0.510 for free fitting and P = 0.545 for segmented fitting, P < 0.001). CONCLUSIONS: The IVIM model allows for an approximate segmentation of molecular diffusion and perfusion, with a minor contribution of the perfusion effect on Dslow. The f and Dfast can provide a rough estimation of the flow fraction and flow velocity. Segmented fitting may be a more robust method than free fitting for calculating the IVIM parameters, especially for Dfast.

Shear Wave Elastography for Assessment of Steatohepatitis and Hepatic Fibrosis in Rat Models of Non-Alcoholic Fatty Liver Disease.

The purpose of this study was to evaluate shear wave elastography (SWE) as a method for determining the severity of non-alcoholic fatty liver disease (NAFLD) and the stage of hepatic fibrosis, as well as the major determinants of liver elasticity among the various histologic and biomolecular changes associated with NAFLD. Rat NAFLD models with various degrees of NAFLD severity were created and imaged using SWE. The explanted livers were subjected to histopathologic evaluation and RNA expression analysis. Among the histologic and biomolecular findings, the fibrosis stage and the collagen RNA level were significant independent factors associated with liver elasticity (p < 0.001). Liver elasticity was effective in detecting non-alcoholic steatohepatitis (NASH) and in determining fibrosis stage, and the corresponding areas under the receiver operating characteristic curves were 0.963 and 0.927-0.997, respectively. In conclusion, SWE is a potential non-invasive method for the detection of NASH and staging of hepatic fibrosis in patients with NAFLD.

Phagocytic function of Kupffer cells in mouse nonalcoholic fatty liver disease models: Evaluation with superparamagnetic iron oxide.

PURPOSE: To evaluate the Kupffer cell (KC) phagocytic function using superparamagnetic iron oxide-enhanced magnetic resonance imaging (SPIO-MRI) in animal models with nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: Mouse NAFLD models with varying severity were created by feeding high-fat, high-cholesterol (HFHC) diets to ob/ob mice for 3, 6, or 12 weeks. SPIO-MRI was performed on a 4.7-T animal scanner in the mouse NAFLD models, in wildtype control mouse, and in the NAFLD mice (NAFLD treatment group) that received 6 weeks of pioglitazone treatment. The relative signal loss (RSL) of the liver was measured in each animal to represent the magnitude of SPIO-induced signal loss of the liver. Liver samples were analyzed for steatosis, inflammation, fibrosis, and the number of SPIO particles and KCs. RESULTS: RSL values of the NAFLD mice (range of RSL value, 26.3%-53.8%) seen on SPIO-MRI were significantly lower than those of the control mice (67.7%-74.8%, P ≤ 0.008) and decreased in proportion to the duration of their HFHC diet (mean ± SD, 53.7% ± 10.9, 44.7% ± 8.2, and 26.3% ± 12.6, after 3-, 6-, and 12-week HFHC diet, respectively, on 20-minute delayed images). For the NAFLD treatment group, the RSL values increased after 6 weeks of pioglitazone treatment, compared with the values before treatment (P ≤ 0.039). The RSL values had significant independent correlation with both hepatic steatosis (P = 0.007) and inflammation (P = 0.023). CONCLUSION: KC phagocytic dysfunction is aggravated in the progression of NAFLD and may be reversible with therapeutic intervention. SPIO-MRI may be useful for classifying the severity of NAFLD and monitoring the treatment response of NAFLD.