Magnetic resonance elastography (MRE) is a noninvasive phase-contrast technique for estimating the mechanical properties of tissues by imaging propagating mechanical waves within the tissue. In this study, we hypothesize that changes in arterial wall stiffness, experimentally induced by formalin fixation, can be measured using MRE in ex vivo porcine aortas. In agreement with our hypothesis, the significant stiffness increase after sample fixation were clearly demonstrated by MRE and confirmed by mechanical testing. The results indicate that MRE can be used to examine the stiffness changes of the aorta. This study has provided evidence of the effectiveness of using MRE to directly assess the stiffness change in aortic wall. The results offer motivation to pursue MRE as a noninvasive method for the evaluation of arterial wall mechanical properties.

Measurement of shear wave propagation speed has important clinical applications because it is related to tissue stiffness and health state. Shear waves can be generated in tissues by the radiation force of a focused ultrasound beam (push beam). Shear wave speed can be measured by tracking its propagation laterally from the push beam focus using the time-of-flight principle. This study shows that shear wave speed measurements with such methods can be transducer, depth, and lateral tracking range dependent. Three homogeneous phantoms with different stiffness were studied using curvilinear and linear array transducer. Shear wave speed measurements were made at different depths, using different aperture sizes for push, and at different lateral distance ranges from the push beam. The curvilinear transducer shows a relatively large measurement bias that is depth dependent. The possible causes of the bias and options for correction are discussed. These bias errors must be taken into account to provide accurate and precise time-of-flight shear wave speed measurements for clinical use.

Purpose

To conduct a rigorous evaluation of the repeatability of liver stiffness assessed by magnetic resonance elastography (MRE) in healthy and hepatitis-C infected subjects.

Materials and Methods

A biopsy-correlated repeatability study using 4-slice MRE was conducted in 5 healthy and 4 HCV-infected subjects. Subjects were scanned twice on day 1 and after 7 – 14 days. Each slice was acquired during a 14 second breath-hold with a commercially available acquisition technique (MR-Touch, GE Healthcare). Results were analyzed by two independent analysts.

Results

The intraclass correlation coefficient (ICC) was 0.85 (90% CI: 0.71 to 0.98) for the between-scan average of maximum stiffness within each slice and 0.88 (90% CI: 0.78 to 0.99) for the average of mean stiffness within each slice for the primary analyst. For both analysts, the average of the mean liver stiffness within each slice was highly reproducible with ICC of 0.93 and 0.94. Within-subject coefficients of variation ranged from 6.07% to 10.78% for HCV+ and healthy subjects.

Conclusion

MRE is a highly reproducible modality for assessing liver stiffness in HCV patients and healthy subjects and can discriminate between moderate fibrosis and healthy liver. MRE is a promising modality for non-invasive assessment of liver fibrosis. (Clinicaltrials.gov identifier: NCT00896233)

Objectives

Magnetic Resonance Elastography (MRE) allows noninvasive assessment of tissue stiffness in vivo. Renal arterial stenosis (RAS), a narrowing of the renal artery, promotes irreversible tissue fibrosis that threatens kidney viability and may elevate tissue stiffness. However, kidney stiffness may also be affected by hemodynamic factors. This study tested the hypothesis that renal blood flow (RBF) is an important determinant of renal stiffness as measured by MRE.

Material and Methods

In six anesthetized pigs MRE studies were performed to determine cortical and medullary elasticity during acute graded decreases in RBF (by 20, 40, 60, 80, and 100% of baseline) achieved by a vascular occluder. Three sham-operated swine served as time control. Additional pigs were studied with MRE six weeks after induction of chronic unilateral RAS (n=6) or control (n=3). Kidney fibrosis was subsequently evaluated histologically by trichrome staining.

Results

During acute RAS the stenotic cortex stiffness decreased (from 7.4 ± 0.3 to 4.8 ± 0.6 kPa, p=0.02 vs. baseline) as RBF decreased. Furthermore, in pigs with chronic RAS (80±5.4% stenosis) in which RBF was decreased by 60±14% compared to controls, cortical stiffness was not significantly different from normal (7.4 ± 0.3 vs. 7.6 ± 0.3 kPa, p=0.3), despite histological evidence of renal tissue fibrosis.

Conclusion

Hemodynamic variables modulate kidney stiffness measured by MRE and may mask the presence of fibrosis. These results suggest that kidney turgor should be considered during interpretation of elasticity assessments.

Purpose

To investigate the correlation between MRE assessed spleen stiffness and direct portal vein pressure gradient (D-HVPG) measurements in a large animal model of portal hypertension.

Materials and Methods

Cholestatic liver disease was established in adult canines by common bile duct ligation. A spin echo based EPI MRE sequence was used to acquire 3-D/3-axis abdominal MRE data at baseline, four weeks, and eight weeks. Liver biopsies, blood samples, and D-HVPG measurements were obtained simultaneously.

Results

Animals developed portal hypertension (D-HVPG: 11.0±5.1 mmHg) with only F1 fibrosis after four weeks. F3 fibrosis was confirmed after eight weeks despite no further rise in portal hypertension (D-HVPG: 11.3±3.2 mmHg). Mean stiffnesses of the spleen increased over two-fold from baseline (1.72±0.33 kPa) to four weeks (3.54±0.31 kPa), and stabilized at eight weeks (3.38±0.06 kPa) in a pattern consistent with changes in portal pressure. A positive correlation was observed between spleen stiffness and D-HVPG (r2 = 0.86, p<0.01).

Conclusion

These findings indicate a temporal relationship between portal hypertension and the development of liver fibrosis in a large animal model of cholestatic liver disease. The observed direct correlation between spleen stiffness and D-HVPG suggest a non-invasive MRE approach to diagnose and screen for portal hypertension.

Background

Polylactic-co-glycolic acid (PLGA) nanoparticles have been used to increase the relative oral bioavailability of hydrophobic compounds and polyphenols in recent years, but the effects of the molecular weight of PLGA on bioavailability are still unknown. This study investigated the influence of polymer molecular weight on the relative oral bioavailability of curcumin, and explored the possible mechanism accounting for the outcome.

Methods

Curcumin encapsulated in low (5000–15,000) and high (40,000–75,000) molecular weight PLGA (LMw-NPC and HMw-NPC, respectively) were prepared using an emulsification-solvent evaporation method. Curcumin alone and in the nanoformulations was administered orally to freely mobile rats, and blood samples were collected to evaluate the bioavailability of curcumin, LMw-NPC, and HMw-NPC. An ex vivo experimental gut absorption model was used to investigate the effects of different molecular weights of PLGA formulation on absorption of curcumin. High-performance liquid chromatography with diode array detection was used for quantification of curcumin in biosamples.

Results

There were no significant differences in particle properties between LMw-NPC and HMw-NPC, but the relative bioavailability of HMw-NPC was 1.67-fold and 40-fold higher than that of LMw-NPC and conventional curcumin, respectively. In addition, the mean peak concentration (Cmax) of conventional curcumin, LMw-NPC, and HMw-NPC was 0.028, 0.042, and 0.057 μg/mL, respectively. The gut absorption study further revealed that the HMw-PLGA formulation markedly increased the absorption rate of curcumin in the duodenum and resulted in excellent bioavailability compared with conventional curcumin and LMw-NPC.

Conclusion

Our findings demonstrate that different molecular weights of PLGA have varying bioavailability, contributing to changes in the absorption rate at the duodenum. The results of this study provide the rationale for design of a nanomedicine delivery system to enhance the bioavailability of water-insoluble pharmaceutical compounds and functional foods.

In the rapid development of nanoscience and nanotechnology, many researchers have discovered that metal oxide nanoparticles have very useful pharmacological effects. Cuprous oxide nanoparticles (CONPs) can selectively induce apoptosis and suppress the proliferation of tumor cells, showing great potential as a clinical cancer therapy. Treatment with CONPs caused a G1/G0 cell cycle arrest in tumor cells. Furthermore, CONPs enclosed in vesicles entered, or were taken up by mitochondria, which damaged their membranes, thereby inducing apoptosis. CONPs can also produce reactive oxygen species (ROS) and initiate lipid peroxidation of the liposomal membrane, thereby regulating many signaling pathways and influencing the vital movements of cells. Our results demonstrate that CONPs have selective cytotoxicity towards tumor cells, and indicate that CONPs might be a potential nanomedicine for cancer therapy.

Background

Liver stiffness assessed by transient elastography is described as a potential risk factor for hepatocellular carcinoma (HCC) in cirrhosis. However, the strict assessment of hepatic parenchymal areas uninvolved with HCC has not been investigated.

Aims

To determine if liver stiffness of non-malignant hepatic parenchyma by MR elastography (MRE) is higher in patients with HCC compared to controls.

Methods

Cases were defined by compensated cirrhosis with a Child-Turcotte-Pugh (CTP) score < 7 and HCC by radiological criteria or histology. Control subjects with compensated cirrhosis were frequency matched to cases by sex and disease etiology. Overt manifestations of portal hypertension and previous therapy for liver disease or HCC were exclusion criteria. Region of interest analyses were performed on hepatic parenchyma regions distant to HCC location among cases.

Results

30 patients with HCC and 60 matched controls comprised the study cohort. The mean age for cases was 64 ± 10 years (range, 45–85) with 70% men. Major disease etiologies were chronic viral hepatitis (57%), nonalcoholic fatty liver disease (33%), and alcohol (10%). Twenty-eight (93%) patients had solitary HCC lesions with a mean size of 5.2 cm (range, 2–14 cm). However, patients with HCC had similar liver stiffness among uninvolved areas distant to HCC lesions as compared to controls without HCC (mean, 6.1±2.0 kPa vs. mean, 6.3 ± 2.5 kPa, p=0.7).

Conclusion

In contrast to previous studies with transient elastography, we did not observe a systematic association between liver stiffness assessed by MRE and the presence of HCC in patients with compensated cirrhosis.

Objective

MR elastography (MRE) is an MRI-based technique for quantitatively assessing tissue stiffness by studying shear wave propagation through tissue. The goal of this study was to test the hypothesis that hepatic MRE performed before and after a meal will result in a postprandial increase in hepatic stiffness among patients with hepatic fibrosis because of transiently increased portal pressure.

Subjects and Methods

Twenty healthy volunteers and 25 patients with biopsy-proven hepatic fibrosis were evaluated. Preprandial MRE measurements were performed after overnight fasting. A liquid test meal was administered, and 30 minutes later a postprandial MRE acquisition was performed. Identical imaging parameters and analysis regions of interest were used for pre- and postprandial acquisitions.

Results

The results in the 20 subjects without liver disease showed a mean stiffness change of 0.16 ± 0.20 kPa (range, −0.12 to 0.78 kPa) or 8.08% ± 10.33% (range, −5.36% to 41.7%). The hepatic stiffness obtained in the 25 patients with hepatic fibrosis showed a statistically significant increase in postprandial liver stiffness, with mean augmentation of 0.89 ± 0.96 kPa (range, 0.17–4.15 kPa) or 21.24 ± 14.98% (range, 7.69%–63.3%).

Conclusion

MRE-assessed hepatic stiffness elevation in patients with chronic liver disease has two major components: a static component reflecting structural change or fibrosis and a dynamic component reflecting portal pressure that can increase after a meal. These findings will provide motivation for further studies to determine the potential value of assessing postprandial hepatic stiffness augmentation for predicting the progression of fibrotic disease and the development of portal hypertension. The technique may also provide new insights into the natural history and pathophysiology of chronic liver disease.

MR Elastography (MRE) is an MRI-based technique for quantitatively assessing the mechanical properties of tissues, based on the propagation of shear waves. Multiple studies have described many potential applications of MRE, from characterizing tumors to detecting diffuse disease processes. Studies have shown that MRE can be successfully implemented to assess abdominal organs. The first clinical application MRE to be well documented is the detection and characterization of hepatic fibrosis, which systematically increases the stiffness of liver tissue. In this diagnostic role, offers a safer, and less expensive, and potentially more accurate alternative to invasive liver biopsy. Emerging results suggest that measurements of liver and spleen stiffness may provide an indirect way to assess portal hypertension. Preliminary studies have demonstrated that is possible to use MRE to evaluate the mechanical properties of other abdominal structures, such as the pancreas and kidneys. Steady technical progress in developing practical protocols for applying MRE in the abdomen and pelvis provides opportunities to explore many other potential applications of this emerging technology.

A novel imaging technique is described in which the mode conversion of longitudinal waves is used for the qualitative detection of stiff lesions within soft tissue using Magnetic Resonance Elastography (MRE) methods. Due to the viscoelastic nature of tissue, high-frequency shear waves attenuate rapidly in soft tissues but much less in stiff tissues. By introducing minimally attenuating longitudinal waves at a significantly high frequency into tissue, shear waves produced at interfaces by mode conversion will be detectable in stiff regions, but will be significantly attenuated and thus not detectable in the surrounding soft tissue. This contrast can be used to detect the presence of stiff tissue. The proposed technique is shown to readily depict hard regions (mimicking tumors) present in tissue-simulating phantoms and ex vivo breast tissue. In vivo feasibility is demonstrated on a patient with liver metastases where the tumors are readily distinguished. Preliminary evidence also suggests that quantitative stiffness measurements of stiff regions obtained with this technique are more accurate than those from conventional MRE because of the short shear wavelengths. This rapid, qualitative technique may lend itself to applications in which the localization of stiff, suspicious neoplasms is coupled with more sensitive techniques for thorough characterization.

Aim

To evaluate the potential value of magnetic resonance elastography (MRE) for characterizing solid liver tumors.

Materials and Methods

Forty-four liver tumors (metastases-14, hepatocellular carcinoma- 12, hemangioma-9, cholangiocarcinoma-5, focal nodular hyperplasia-3, and hepatic adenoma-1) were evaluated with MRE. MRE was performed on a 1.5 T scanner with a modified phase-contrast, gradient echo sequence to collect axial wave images sensitized along the through-plane motion direction. The tumors were identified in T2-, T1-weighted and gadolinium enhanced T1-weighted images and the MRE images were obtained through the tumor. A stiffness map (elastogram) was generated by an automated process using an inversion algorithm. The mean shear stiffness of the tumor was calculated using a manually specified region of interest placed over the tumor in the stiffness map. The stiffness value of non-tumor bearing hepatic parenchyma was also calculated. Statistical analysis was performed on the stiffness values for differentiation between normal liver, fibrotic liver, benign tumors and malignant tumors.

Results

Malignant liver tumors had significantly higher mean shear stiffness than benign tumors, fibrotic liver and normal liver (10.1kPa vs. 2.7kpa (p<0.001), vs. 5.9kPa (p<0.001) and vs. 2.3kPa (p<0.001) respectively). Fibrotic livers had stiffness values overlapping both the benign and malignant tumors. Cut-off values of 5kPa accurately differentiate malignant tumors from benign tumors and normal liver parenchyma in this preliminary investigation.

Conclusions

MR elastography is a promising, non-invasive technique for assessing solid liver tumors. MRE may provide new, quantitative tissue characterization parameters for differentiating benign and malignant liver tumors.

Background

Liver stiffness measurement is associated with portal hypertension in patients with chronic liver disease. However, the relationship between spleen stiffness and clinically significant portal hypertension remains unknown.

Aims

To determine the feasibility of measuring spleen stiffness with magnetic resonance (MR) elastography and to prospectively test this technique in healthy volunteers and patients with liver fibrosis.

Methods

Following Institutional Review Board approval, spleen stiffness was measured with MR elastography in 12 healthy volunteers (mean age, 37 years; age range, 25-82 years) and 38 patients with various etiologies of chronic liver disease (mean age, 56 years; age range, 36–60 years). Various statistical analyses were performed to assess all measurements.

Results

MR elastography of the spleen was successfully performed in all volunteers and patients. The mean spleen stiffness was significantly lower in volunteers (mean, 3.6 kPa ± 0.3) than it was in patients with liver fibrosis (mean, 5.6 kPa ± 5.0, range, 2.7–19.2 kPa; p < .001). In addition, a significant correlation between liver and spleen stiffness was observed for the entire cohort (r2=.75, p<0.001). Predictors of spleen stiffness were splenomegaly, spleen volume, and platelet count. In the setting of cirrhosis, the presence of esophageal varices was observed in 100% of patients with mean spleen stiffness values ≥ 10.5 kPa.

Conclusion

MR elastography of the spleen is feasible and shows promise as a quantitative method for predicting the presence of esophageal varices in patients with advanced hepatic fibrosis.

Magnetic Resonance Elastography (MRE) is a technique for quantifying the acoustic response of biological tissues to propagating waves applied at low frequencies in order to evaluate mechanical properties. Application-specific MRE drivers are typically required to effectively deliver shear waves within the tissue of interest. Surface MRE drivers with transversely oriented vibrations have often been used to directly generate shear waves. These drivers may have disadvantages in certain applications, such as poor penetration depth and inflexible orientation. Therefore, surface MRE drivers with longitudinally oriented vibrations are used in some situations. The purpose of this work was to investigate and optimize a longitudinal driver system for MR elastography applications. It is shown that a cone-like hemispherical distribution of shear waves are generated by these drivers and the wave propagation is governed by diffraction in the near field. Using MRE visualization of the vector displacement field, the properties of the shear wave field created by longitudinal MRE drivers of various sizes were studied to identify optimum shear wave imaging planes. The results offer insights and improvements in both experimental design and imaging plane selection for 2-D MRE data acquisition.

Background & Aims

Accurate detection of hepatic fibrosis is crucial for assessing prognosis and candidacy for treatment in patients with chronic liver disease. Magnetic Resonance (MR) Elastography, a technique for quantitatively assessing the mechanical properties of soft tissues, has previously been shown to have potential for non-invasively detecting liver fibrosis. The goal of this work was to obtain preliminary estimates of the sensitivity and specificity of the technique in diagnosing liver fibrosis, and to assess its potential for identifying patients who can potentially avoid biopsy.

Methods

MR Elastography was performed in 35 normal volunteers and 50 patients with chronic liver disease. MRI measurements of hepatic fat/water ratios were obtained to assess the potential for fat infiltration to affect stiffness-based detection of fibrosis.

Results

Liver stiffness increased systematically with fibrosis stage. Receiver operating curve (ROC) analysis demonstrated that, with a shear stiffness cut off value of 2.93 kPa, the predicted sensitivity and specificity for detecting all grades of liver fibrosis is 98% and 99%. ROC analysis also provided evidence that MR Elastography can discriminate between patients with moderate and severe fibrosis (grades 2–4) and those with mild fibrosis (sensitivity 86%, specificity 85%). Hepatic stiffness does not appear to be influenced by the degree of steatosis.

Conclusions

MR Elastography is a safe, non-invasive technique with excellent diagnostic accuracy for assessing hepatic fibrosis. Based on the high negative predictive value of MR Elastography, an initial clinical application may be to triage patients who are under consideration for biopsy to assess possible hepatic fibrosis.