Visco-Elastic Parameters at Three-Dimensional MR Elastography for Diagnosing Non-Alcoholic Steatohepatitis and Substantial Fibrosis in Mice.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is increasing worldwide and is a growing cause of liver cirrhosis and cancer. The performance of the magnetic resonance elastography (MRE) visco-elastic parameters in diagnosing progressive forms of NAFLD, including nonalcoholic steatohepatitis (NASH) and substantial fibrosis (F ≥ 2), needs to be clarified. PURPOSE: To assess the value of three-dimensional MRE visco-elastic parameters as markers of NASH and substantial fibrosis in mice with NAFLD. STUDY TYPE: Prospective. ANIMAL MODEL: Two mouse models of NAFLD were induced by feeding with high fat diet or high fat, choline-deficient, amino acid-defined diet. FIELD STRENGTH/SEQUENCE: 7T/multi-slice multi-echo spin-echo MRE at 400 Hz with motion encoding in the three spatial directions. ASSESSMENT: Hepatic storage and loss moduli were calculated. Histological analysis was based on the NASH Clinical Research Network criteria. STATISTICAL TESTS: Mann-Whitney, Kruskal-Wallis tests, Spearman rank correlations and multiple regressions were used. Diagnostic performance was assessed with areas under the receiver operating characteristic curves (AUCs). P value <0.05 was considered significant. RESULTS: Among the 59 mice with NAFLD, 21 had NASH and 20 had substantial fibrosis (including 8 mice without and 12 mice with NASH). The storage and loss moduli had similar moderate accuracy for diagnosing NASH with AUCs of 0.67 and 0.66, respectively. For diagnosing substantial fibrosis, the AUC of the storage modulus was 0.73 and the AUC of the loss modulus was 0.81, indicating good diagnostic performance. Using Spearman correlations, histological fibrosis, inflammation and steatosis, but not ballooning, were significantly correlated with the visco-elastic parameters. Using multiple regression, fibrosis was the only histological feature independently associated with the visco-elastic parameters. CONCLUSION: MRE in mice with NAFLD suggests that the storage and loss moduli have good diagnostic performance for detecting progressive NAFLD defined as substantial fibrosis rather than NASH. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY STAGE: 2.

A Preclinical Validation of Iron Oxide Nanoparticles for Treatment of Perianal Fistulizing Crohn's Disease.

Fistulizing anoperineal lesions are severe complications of Crohn's disease (CD) that affect quality of life with a long-term risk of anal sphincter destruction, incontinence, permanent stoma, and anal cancer. Despite several surgical procedures, they relapse in about two-thirds of patients, mandating innovative treatments. Ultrasmall particles of iron oxide (USPIO) have been described to achieve in vivo rapid healing of deep wounds in the skin and liver of rats thanks to their nanobridging capability that could be adapted to fistula treatment. Our main purpose was to highlight preclinical data with USPIO for the treatment of perianal fistulizing CD. Twenty male Sprague Dawley rats with severe 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced proctitis were operated to generate two perianal fistulas per rat. At day 35, two inflammatory fistulas were obtained per rat and perineal magnetic resonance imaging (MRI) was performed. After a baseline MRI, a fistula tract was randomly drawn and topically treated either with saline or with USPIO for 1 min (n = 17 for each). The rats underwent a perineal MRI on postoperative days (POD) 1, 4, and 7 and were sacrificed for pathological examination. The primary outcome was the filling or closure of the fistula tract, including the external or internal openings. USPIO treatment allowed the closure and/or filling of all the treated fistulas from its application until POD 7 in comparison with the control fistulas (23%). The treatment with USPIO was safe, permanently closed the fistula along its entire length, including internal and external orifices, and paved new avenues for the treatment of perianal fistulizing Crohn's disease.

Prospective comparison of transient elastography, MRI and serum scores for grading steatosis and detecting non-alcoholic steatohepatitis in bariatric surgery candidates.

BACKGROUND & AIMS: Tools for the non-invasive diagnosis of non-alcoholic steatohepatitis (NASH) in morbidly obese patients with suspected non-alcoholic fatty liver disease (NAFLD) are an unmet clinical need. We prospectively compared the performance of transient elastography, MRI, and 3 serum scores for the diagnosis of NAFLD, grading of steatosis and detection of NASH in bariatric surgery candidates. METHODS: Of 186 patients screened, 152 underwent liver biopsy, which was used as a reference for NAFLD (steatosis [S]>5%), steatosis grading and NASH diagnosis. Biopsies were read by a single expert pathologist. MRI-based proton density fat fraction (MRI-PDFF) was measured in an open-bore, vertical field 1.0T scanner and controlled attenuation parameter (CAP) was measured by transient elastography, using the XL probe. Serum scores (SteatoTest, hepatic steatosis index and fatty liver index) were also calculated. RESULTS: The applicability of MRI was better than that of FibroScan (98% vs. 79%; p <0.0001). CAP had AUROCs of 0.83, 0.79, 0.73 and 0.69 for S>5%, S>33%, S>66% and NASH, respectively. Transient elastography had an AUROC of 0.80 for significant fibrosis (F0-F1 vs. F2-F3). MRI-PDFF had AUROCs of 0.97, 0.95, 0.92 and 0.84 for S>5%, S>33%, S>66% and NASH, respectively. When compared head-to-head in the 97 patients with all valid tests available, MRI-PDFF outperformed CAP for grading steatosis (S>33%, AUROC 0.97 vs. 0.78; p <0.0003 and S>66%, AUROC 0.93 vs. 0.75; p = 0.0015) and diagnosing NASH (AUROC 0.82 vs. 0.68; p = 0.0056). When compared in "intention to diagnose" analysis, MRI-PDFF outperformed CAP, hepatic steatosis index and fatty liver index for grading steatosis (S>5%, S>33% and S>66%). CONCLUSION: MRI-PDFF outperforms CAP for diagnosing NAFLD, grading steatosis and excluding NASH in morbidly obese patients undergoing bariatric surgery. LAY SUMMARY: Non-invasive tests for detecting fatty liver and steatohepatitis, the active form of the disease, have not been well studied in obese patients who are candidates for bariatric surgery. The most popular tests for this purpose are Fibroscan, which can be used to measure the controlled attenuation parameter (CAP), and magnetic resonance imaging, which can be used to measure the proton density fat fraction (MRI-PDFF). We found that, when taking liver biopsy as a reference, MRI-PDFF performed better than CAP for detecting and grading fatty liver as well as excluding steatohepatitis in morbidly obese patients undergoing bariatric surgery.

MRI Mapping of Renal T1: Basic Concept.

In renal MRI, measurement of the T1 relaxation time of water molecules may provide a valuable biomarker for a variety of pathological conditions. Due to its sensitivity to the tissue microenvironment, T1 has gained substantial interest for noninvasive imaging of renal pathology, including inflammation and fibrosis. In this chapter, we will discuss the basic concept of T1 mapping and different T1 measurement techniques and we will provide an overview of emerging preclinical applications of T1 for imaging of kidney disease.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This introduction chapter is complemented by two separate chapters describing the experimental procedure and data analysis.

Experimental Protocols for MRI Mapping of Renal T1.

The water proton longitudinal relaxation time, T1, is a common and useful MR parameter in nephrology research. Here we provide three step-by-step T1-mapping protocols suitable for different types of nephrology research. Firstly, we provide a single-slice 2D saturation recovery protocol suitable for studies of global pathology, where whole-kidney coverage is unnecessary. Secondly, we provide an inversion recovery type imaging protocol that may be optimized for specific kidney disease applications. Finally, we also provide imaging protocol for small animal kidney imaging in a clinical scanner.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This analysis protocol chapter is complemented by two separate chapters describing the basic concept and experimental procedure.

Analysis Protocols for MRI Mapping of Renal T1.

The computation of T1 maps from MR datasets represents an important step toward the precise characterization of kidney disease models in small animals. Here the main strategies to analyze renal T1 mapping datasets derived from small rodents are presented. Suggestions are provided with respect to essential software requirements, and advice is provided as to how dataset completeness and quality may be evaluated. The various fitting models applicable to T1 mapping are presented and discussed. Finally, some methods are proposed for validating the obtained results.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This analysis protocol chapter is complemented by two separate chapters describing the basic concept and experimental procedure.

Comparison of pulsed and oscillating gradient diffusion-weighted MRI for characterizing hepatocellular nodules in liver cirrhosis: ex vivo study in a rat model.

BACKGROUND: In contrast to classical pulsed gradient diffusion-weighted MRI, oscillating gradient diffusion-weighted MR imaging (DWI) is sensitive to short distance diffusion changes at the intracellular level. PURPOSE: To compare the diagnostic performance of pulsed and oscillating DWI for characterizing hepatocellular nodules in a rat model of hepatic cirrhosis. STUDY TYPE: Prospective, experimental study. ANIMAL MODEL: Cirrhosis was induced by weekly intraperitoneal injection of diethylnitrosamine in Wistar rats. FIELD STRENGTH/SEQUENCE: Ex vivo liver MRI was performed at 7T with T1 -weighted, T2 -weighted, pulsed, and oscillating gradient diffusion-weighted sequences. ASSESSMENT: Apparent diffusion coefficient from pulsed (ADCpulsed ) and oscillating gradient (ADCoscillating ) sequences was calculated in 82 nodules identified on the T1 /T2 -weighted images and on pathological examination. Two pathologists classified the nodules in three categories: benign (regenerative and low-grade dysplastic nodules), with intermediate malignancy (high-grade dysplastic nodules and early hepatocellular carcinomas) and overtly malignant (progressed hepatocellular carcinomas). STATISTICAL TESTS: Differences between groups were assessed with Kruskal-Wallis and Mann-Whitney tests. RESULTS: ADC, mainly ADCoscillating , increased in the group of nodules with intermediate malignancy (ADCpulsed : 0.75 ± 0.25 × 10-3 mm2 /s vs. 0.64 ± 0.07 × 10-3 mm2 /s in benign nodules, P = 0.025; ADCoscillating : 0.81 ± 0.20 × 10-3 mm2 /s vs. 0.65 ± 0.13 × 10-3 mm2 /s, P = 0.0008) and ADCpulsed decreased in the group of progressed hepatocellular carcinomas (ADCpulsed : 0.60 ± 0.08 × 10-3 mm2 /s, P = 0.042; ADCoscillating : 0.68 ± 0.08 × 10-3 mm2 /s, P = 0.1). DATA CONCLUSION: ADC during hepatocarcinogenesis in rats increased in nodules with intermediate malignancy and decreased in progressed hepatocellular carcinomas. Our results suggest that oscillating gradient DWI is more sensitive to the early steps of hepatocarcinogenesis and might be useful for differentiating between high-grade dysplastic nodules / early hepatocellular carcinomas and regenerating nodules / low-grade dysplastic nodules. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:1065-1074.

Preclinical Model of Perianal Fistulizing Crohn's Disease.

BACKGROUND: Fistulizing anoperineal lesions (FAPLs) are common and severe complications of Crohn's disease (CD), exposing patients to the risk of anal sphincter alteration and permanent stoma. Due to the limited efficacy of current treatments, identifying new local therapies is mandatory. However, testing new treatments is currently limited because no relevant preclinical model of Crohn's-like FAPL is available. Thus, a reliable and reproducible experimental model of FAPLs is needed to assess new therapeutic strategies. METHODS: Twenty-one rats received a rectal enema of 2,4,6-trinitrobenzensulfonic acid (TNBS) to induce proctitis. Seven days later, a transsphincteric fistula tract was created with a surgical thread, instilled with TNBS twice a week until its removal at day 7 (group 1), day 14 (group 2), or day 28 (group 3). In each rat, pelvic MRI was performed just before and 7 days after thread removal. Rats were sacrificed 7 days after thread removal for pathological assessment of the fistula tract. RESULTS: The optimal preclinical model was obtained in group 3. In this group, 7 days after thread removal, all animals (9 of 9) had a persistent fistula tract visible on MRI with T2-hypersignal (normalized T2 signal intensity: 2.36 ± 0.39 arbitrary units [a.u.] [2.08-2.81]) and elevation of the apparent diffusion coefficient (1.33 ± 0.16 10-3 millimeter squared per seconds [1.18-1.49]). The pathological examination of the fistula tract revealed acute and chronic inflammation, granulations, fibrosis, epithelialization, and proctitis in the adjacent rectum. CONCLUSIONS: This reproducible preclinical model could be used to assess the effectiveness of innovative treatments in perianal fistulizing CD.

Endothelial fatty liver binding protein 4: a new targetable mediator in hepatocellular carcinoma related to metabolic syndrome.

Metabolic syndrome (MS) is becoming the leading risk factor for hepatocellular carcinoma (HCC). HCC development related to MS may occur in advanced or non-advanced liver fibrosis, suggesting specific molecular pathways. Among these pathways, basal inflammatory state and adipokines production are involved. The aim of this study was to evaluate the role of fatty acid-binding protein 4 (FABP4). In this study, we demonstrate the specific overexpression of FABP4 in human HCC samples from patients with MS compared to other risk factors for chronic liver disease with FABP4 expression restricted to peritumoral endothelial cells. In vitro, glucose, insulin, VEGFA and hypoxia upregulated endothelial FABP4, which was reversed by metformin through mTOR pathway inhibition. FABP4 exerts oncogenic effects on hepatoma cell lines by upregulating the angiogenesis gene signature and pathways involved in the cell cycle, leading to increased cell proliferation and migration, and downregulating HIF1 pathway; effects were reversed in the presence of a specific FABP4 inhibitor (BMS309403). We showed the role of microvesicles as FABP4 vectors between endothelial and tumor cells. In vivo, BMS309403 significantly reduces tumor growth in heterotopic and orthotopic xenografted mice model. In conclusion, this study demonstrates the emerging oncogenic role of liver endothelial cells through FABP4 in HCC related to MS, and highlights new anti-neoplastic mechanism of metformin.

Obesity-induced pancreatopathy in rats is reversible after bariatric surgery.

Obesity is a risk factor for pancreatic diseases. Bariatric surgery is one of the most efficient treatments of morbid obesity. The aims were to assess pancreatic endocrine and exocrine lesions in obese rats, to analyze effects of bariatric surgery. Sixty-three male Wistar rats were included in five groups: 2 fed with high fat diet (HFD) or normal diet for 3 months, 2 fed with HFD or normal diet for 6 months; 1 group fed with HFD and undergoing bariatric surgery (n = 30). Quantitative MR imaging was performed in HFD6, ND6 and HFD3-BS. Pancreas specimens were analyzed after sacrifice for adipocyte infiltration, fibrosis, acinar-ductal metaplasia, abnormality of Langerhans islets (HHF: hypertrophy, hypervascularisation, fibrosis), and hemosiderin deposits in acinar or endocrine locations. We found that HFD6 rats had more fibro-inflammatory islets (P = 0.0139) and acinar-ducal metaplasia (P = 0.0843) than HFD3 rats. Rats with HFD3+6 had more fibro-inflammatory islets (P < 0.0001), hemosiderin deposits (p < 0.0001), fat infiltration (P = 0.0008) and acinar-ductal metaplasia lesions (P = 0.0424). Weight increase was associated with glycoregulation abnormalities (r = 0.44, P = 0.08) and adipocyte infiltrations (P = 0.009). After surgery, less fibro-inflammatory islets (P = 0.0004), fat and iron infiltrates (P = 0.005 and P = 0.06), and acino-ductal metaplasia (P = 0.05) were observed compared to HFD6 rats. MR image quantifications revealed increased elasticity, fat fraction, and R2 and a decreased elasticity wave dispersion coefficient in the high fat groups that reversed after surgery. MRI parameters were in strong correlation with respective histological counterparts. In conclusion, obese rats develop pancreatic inflammatory lesions with acinar-ductal metaplasia in acinar location and the endocrine-exocrine interface. These changes can be prevented by bariatric surgery. Quantitative MR imaging is accurate in identifying early pancreatic lesions.

Thymidine Metabolism as a Confounding Factor for 3'-Deoxy-3'-18F-Fluorothymidine Uptake After Therapy in a Colorectal Cancer Model.

Noninvasive monitoring of tumor therapy response helps in developing personalized treatment strategies. Here, we performed sequential PET and diffusion-weighted MRI to evaluate changes induced by a FOLFOX-like combination chemotherapy in colorectal cancer xenografts, to identify the cellular and molecular determinants of these imaging biomarkers. Methods: Tumor-bearing CD1 nude mice, engrafted with FOLFOX-sensitive Colo205 colorectal cancer xenografts, were treated with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) weekly. On days 1, 2, 6, 9, and 13 of therapy, tumors were assessed by in vivo imaging and ex vivo analyses. In addition, HCT116 xenografts, which did not respond to the FOLFOX treatment, were imaged on day 1 of therapy. Results: In Colo205 xenografts, FOLFOX induced a profound increase in uptake of the proliferation PET tracer 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) accompanied by increases in markers for proliferation (Ki-67, thymidine kinase 1) and for activated DNA damage response (γH2AX), whereas the effect on cell death was minimal. Because tracer uptake was unaltered in the HCT116 model, these changes appear to be specific for tumor response. Conclusion: We demonstrated that 18F-FLT PET can noninvasively monitor cancer treatment-induced molecular alterations, including thymidine metabolism and DNA damage response. The cellular or imaging changes may not, however, be directly related to therapy response as assessed by volumetric measurements.

Quantitative MRI in murine radiation-induced rectocolitis: comparison with histopathological inflammation score.

Murine radiation-induced rectocolitis is considered to be a relevant animal model of gastrointestinal inflammation. The purpose of our study was to compare quantitative MRI and histopathological features in this gastrointestinal inflammation model. Radiation rectocolitis was induced by localized single-dose radiation (27 Gy) in Sprague-Dawley rats. T2 -weighted, T1 -weighted and diffusion-weighted MRI was performed at 7 T in 16 rats between 2 and 4 weeks after irradiation and in 10 control rats. Rats were sacrificed and the histopathological inflammation score of the colorectal samples was assessed. The irradiated rats showed significant increase in colorectal wall thickness (2.1 ± 0.3 mm versus 0.8 ± 0.3 mm in control rats, P < 0.0001), normalized T2 signal intensity (4 ± 0.8 versus 2 ± 0.4 AU, P < 0.0001), normalized T1 signal intensity (1.4 ± 0.1 versus 1.1 ± 0.2 AU, P = 0.0009) and apparent and pure diffusion coefficients (ADC and D) (2.06 × 10-3 ± 0.34 versus 1.51 × 10-3 ± 0.23 mm2 /s, P = 0.0004, and 1.97 × 10-3 ± 0.43 mm2 /s versus 1.48 × 10-3 ± 0.29 mm2 /s, P = 0.008, respectively). Colorectal wall thickness (r = 0.84, P < 0.0001), normalized T2 signal intensity (r = 0.85, P < 0.0001) and ADC (r = 0.80, P < 0.0001) were strongly correlated with the histopathological inflammation score, whereas normalized T1 signal intensity and D were moderately correlated (r = 0.64, P = 0.0006, and r = 0.65, P = 0.0003, respectively). High-field MRI features of single-dose radiation-induced rectocolitis in rats differ significantly from those of control rats. Quantitative MRI characteristics, especially wall thickness, normalized T2 signal intensity, ADC and D, are potential markers of the histopathological inflammation score.

Magnetic resonance elastography of liver and spleen: Methods and applications.

The viscoelastic properties of the liver and spleen can be assessed with magnetic resonance elastography (MRE). Several actuators, MRI acquisition sequences and reconstruction algorithms have been proposed for this purpose. Reproducible results are obtained, especially when the examination is performed in standard conditions with the patient fasting. Accurate staging of liver fibrosis can be obtained by measuring liver stiffness or elasticity with MRE. Moreover, emerging evidence shows that assessing the tissue viscous parameters with MRE is useful for characterizing liver inflammation, non-alcoholic steatohepatitis, hepatic congestion, portal hypertension, and hepatic tumors. Further advances such as multifrequency acquisitions and compression-sensitive MRE may provide novel quantitative markers of hepatic and splenic mechanical properties that may improve the diagnosis of hepatic and splenic diseases.

3'-Deoxy-3'-[18F]Fluorothymidine Uptake Is Related to Thymidine Phosphorylase Expression in Various Experimental Tumor Models.

PURPOSE: We recently reported that high thymidine phosphorylase (TP) expression is accompanied by low tumor thymidine concentration and high 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) uptake in four untreated lung cancer xenografts. Here, we investigated whether this relationship also holds true for a broader range of tumor models. PROCEDURES: Lysates from n = 15 different tumor models originating from n = 6 institutions were tested for TP and thymidylate synthase (TS) expression using western blots. Results were correlated to [18F]FLT accumulation in the tumors as determined by positron emission tomography (PET) measurements in the different institutions and to previously published thymidine concentrations. RESULTS: Expression of TP correlated positively with [18F]FLT SUVmax (ρ = 0.549, P < 0.05). Furthermore, tumors with high TP levels possessed lower levels of thymidine (ρ = - 0.939, P < 0.001). CONCLUSIONS: In a broad range of tumors, [18F]FLT uptake as measured by PET is substantially influenced by TP expression and tumor thymidine concentrations. These data strengthen the role of TP as factor confounding [18F]FLT uptake.

Gadoxetate-enhanced MR imaging and compartmental modelling to assess hepatocyte bidirectional transport function in rats with advanced liver fibrosis.

OBJECTIVES: Changes in the expression of hepatocyte membrane transporters in advanced fibrosis decrease the hepatic transport function of organic anions. The aim of our study was to assess if these changes can be evaluated with pharmacokinetic analysis of the hepatobiliary transport of the MR contrast agent gadoxetate. METHODS: Dynamic gadoxetate-enhanced MRI was performed in 17 rats with advanced fibrosis and 8 normal rats. After deconvolution, hepatocyte three-compartmental analysis was performed to calculate the hepatocyte influx, biliary efflux and sinusoidal backflux rates. The expression of Oatp1a1, Mrp2 and Mrp3 organic anion membrane transporters was assessed with reverse transcription polymerase chain reaction. RESULTS: In the rats with advanced fibrosis, the influx and efflux rates of gadoxetate decreased and the backflux rate increased significantly (p = 0.003, 0.041 and 0.010, respectively). Significant correlations were found between influx and Oatp1a1 expression (r = 0.78, p < 0.001), biliary efflux and Mrp2 (r = 0.50, p = 0.016) and sinusoidal backflux and Mrp3 (r = 0.61, p = 0.002). CONCLUSION: These results show that changes in the bidirectional organic anion hepatocyte transport function in rats with advanced liver fibrosis can be assessed with compartmental analysis of gadoxetate-enhanced MRI. KEY POINTS: • Expression of hepatocyte transporters is modified in rats with advanced liver fibrosis. • Kinetic parameters at gadoxetate-enhanced MRI are correlated with hepatocyte transporter expression. • Hepatocyte transport function can be assessed with compartmental analysis of gadoxetate-enhanced MRI. • Compartmental analysis of gadoxetate-enhanced MRI might provide biomarkers in advanced liver fibrosis.

Response Monitoring with [18F]FLT PET and Diffusion-Weighted MRI After Cytotoxic 5-FU Treatment in an Experimental Rat Model for Colorectal Liver Metastases.

PURPOSE: The aim of the study was to investigate the potential of diffusion-weighted magnetic resonance imaging (DW-MRI) and 3'-dexoy-3'-[18F]fluorothymidine ([18F]FLT) positron emission tomography (PET) as early biomarkers of treatment response of 5-fluorouracil (5-FU) in a syngeneic rat model of colorectal cancer liver metastases. PROCEDURES: Wag/Rij rats with intrahepatic syngeneic CC531 tumors were treated with 5-FU (15, 30, or 60 mg/kg in weekly intervals). Before treatment and at days 1, 3, 7, and 14 after treatment rats underwent DW-MRI and [18F]FLT PET. Tumors were analyzed immunohistochemically for Ki67, TK1, and ENT1 expression. RESULTS: 5-FU inhibited the growth of CC531 tumors in a dose-dependent manner. Immunohistochemical analysis did not show significant changes in Ki67, TK1, and ENT1 expression. However, [18F]FLT SUVmean and SUVmax were significantly increased at days 4 and 7 after treatment with 5-FU (60 mg/kg) and returned to baseline at day 14 (SUVmax at days -1, 4, 7, and 14 was 1.1 ± 0.1, 2.3 ± 0.5, 2.3 ± 0.6, and 1.5 ± 0.4, respectively). No changes in [18F]FLT uptake were observed in the nontreated animals. Furthermore, the apparent diffusion coefficient (ADCmean) did not change in 5-FU-treated rats compared to untreated rats. CONCLUSION: This study suggests that 5-FU treatment induces a flare in [18F]FLT uptake of responsive CC531 tumors in the liver, while the ADCmean did not change significantly. Future studies in larger groups are warranted to further investigate whether [18F]FLT PET can discriminate between disease progression and treatment response.

Hepatic Fibrosis, Inflammation, and Steatosis: Influence on the MR Viscoelastic and Diffusion Parameters in Patients with Chronic Liver Disease.

Purpose To determine the relationship of liver fibrosis, inflammation, and steatosis with the magnetic resonance (MR) viscoelastic and diffusion parameters in patients with chronic liver disease and to compare the diagnostic accuracy of the imaging parameters in staging liver fibrosis. Materials and Methods Consecutive patients with chronic liver disease scheduled for liver biopsy were prospectively recruited from November 2010 to October 2012 for this institutional review board-approved study after they provided written informed consent. Sixty-eight patients underwent three-dimensional MR elastography and intravoxel incoherent motion diffusion-weighted MR imaging with a 1.5-T MR system. Fibrosis, inflammation, and steatosis were assessed with the METAVIR and steatosis, activity, and fibrosis (or SAF) scoring systems. Spearman correlation and multiple regression analyses were performed to determine the relationship between liver fibrosis, inflammation, steatosis, and alanine aminotransferase (ALT) levels and viscoelastic and diffusion parameters. The accuracy of three-dimensional MR elastography and diffusion-weighted MR imaging in the determination of fibrosis stage was assessed with Obuchowski measures. Results At multiple regression analysis, fibrosis was the only variable associated with viscoelastic parameters (ß = 0.6, P < .001, R2 = 0.33 for shear modulus; ß = 0.6, P < .001, R2 = 0.32 for elasticity). Fibrosis had a weaker independent association with the apparent diffusion coefficient (ß = -0.3, P = .02, R2 = 0.33) than did steatosis (ß = -0.5, P < .001, R2 = 0.33). Steatosis was the only factor independently associated with the pure diffusion coefficient (ß = -0.4, P = .002, R2 = 0.22). Inflammation and ALT level were not associated with the viscoelastic or diffusion parameters. The diagnostic accuracy of fibrosis staging was significantly higher when measuring the shear modulus rather than the apparent diffusion coefficient (Obuchowski measures, 0.82 ± 0.04 vs 0.30 ± 0.06; P < .001). Conclusion Fibrosis is independently associated with the MR viscoelastic parameters and is less associated with the diffusion parameters than is steatosis. These results and those of diagnostic accuracy suggest that MR elastography should be preferred over diffusion-weighted MR imaging in the staging of liver fibrosis. © RSNA, 2016.

Assessment of the residual tumour of colorectal liver metastases after chemotherapy: diffusion-weighted MR magnetic resonance imaging in the peripheral and entire tumour.

OBJECTIVES: To evaluate the value of diffusion-weighted imaging (DWI) in detecting residual tumours (RTs) in colorectal liver metastases (CLMs) following chemotherapy, with a focus on tumour periphery. METHODS: From January 2009-January 2012, 57 patients who underwent liver resection for CLMs with preoperative MRI (<3 months) including DWI were retrospectively included. CLMs were classified into three response groups on pathology: (1) major histological (MHR, RTs ≤ 10 %), (2) partial histological (PHR, RT = 10-49 %), and (3) no histological (NHR, RT ≥ 50 %). On DWI, regions of interest (ROIs) were drawn around the entire tumour and tumour periphery. Apparent diffusion (ADC) and pure diffusion (D) coefficients were calculated using a monoexponential fit, and compared using Kruskal-Wallis test on a lesion-per-lesion analysis. RESULTS: 111 CLMs were included. Fourteen (12.5 %), 42 (38 %) and 55 (49.5 %) CLMs presented a MHR, PHR and NHR, respectively. ADC and D of the peripheral ROIs were significantly higher in the MHR group (P = 0.013/P = 0.013). ADC and D from the entire tumour were not significantly different among the groups (P = 0.220/P = 0.103). CONCLUSION: In CLM treated with chemotherapy, ADC and D values from the entire tumour are not related to the degree of RT, while peripheral zone diffusion parameters could help identify metastases with MHR. KEY POINTS: Peripheral ADC and D of CLMs were higher with major pathological responses. Global ADC and D of CLMs were not different according to residual tumour. Diffusion-weighted images of CLM periphery could be an interesting biomarker of MHR. Diffusion-weighted images could be used to help tailor treatment.

Apparent diffusion coefficient is highly reproducible on preclinical imaging systems: Evidence from a seven-center multivendor study.

PURPOSE: To evaluate between-site agreement of apparent diffusion coefficient (ADC) measurements in preclinical magnetic resonance imaging (MRI) systems. MATERIALS AND METHODS: A miniaturized thermally stable ice-water phantom was devised. ADC (mean and interquartile range) was measured over several days, on 4.7T, 7T, and 9.4T Bruker, Agilent, and Magnex small-animal MRI systems using a common protocol across seven sites. Day-to-day repeatability was expressed as percent variation of mean ADC between acquisitions. Cross-site reproducibility was expressed as 1.96 × standard deviation of percent deviation of ADC values. RESULTS: ADC measurements were equivalent across all seven sites with a cross-site ADC reproducibility of 6.3%. Mean day-to-day repeatability of ADC measurements was 2.3%, and no site was identified as presenting different measurements than others (analysis of variance [ANOVA] P = 0.02, post-hoc test n.s.). Between-slice ADC variability was negligible and similar between sites (P = 0.15). Mean within-region-of-interest ADC variability was 5.5%, with one site presenting a significantly greater variation than the others (P = 0.0013). CONCLUSION: Absolute ADC values in preclinical studies are comparable between sites and equipment, provided standardized protocols are employed.