Radiologic-pathologic correlation of lesions in resected liver specimens with an ex vivo MRI-compatible localization device.

OBJECTIVE: Liver lesion characterization is limited by the lack of an established gold standard for precise correlation of radiologic characteristics with their histologic features. The objective of this study was to demonstrate the feasibility of using an ex vivo MRI-compatible sectioning device for radiologic-pathologic co-localization of lesions in resected liver specimens. METHODS: In this prospective feasibility study, adults undergoing curative partial hepatectomy from February 2018 to January 2019 were enrolled. Gadoxetic acid was administered intraoperatively prior to hepatic vascular inflow ligation. Liver specimens were stabilized in an MRI-compatible acrylic lesion localization device (27 × 14 × 14 cm3) featuring slicing channels and a silicone gel 3D matrix. High-resolution 3D T1-weighted fast spoiled gradient echo and 3D T2-weighted fast-spin-echo images were acquired using a single channel quadrature head coil. Radiologic lesion coordinates guided pathologic sectioning. A final histopathologic diagnosis was prepared for all lesions. The proportion of successfully co-localized lesions was determined. RESULTS: A total of 57 lesions were identified radiologically and sectioned in liver specimens from 10 participants with liver metastases (n = 8), primary biliary mucinous cystic neoplasm (n = 1), and hepatic adenomatosis (n = 1). Of these, 38 lesions (67%) were < 1 cm. Overall, 52/57 (91%) of radiologically identified lesions were identified pathologically using the device. Of these, 5 lesions (10%) were not initially identified on gross examination but were confirmed histologically using MRI-guided localization. One lesion was identified grossly but not on MRI. CONCLUSIONS: We successfully demonstrated the feasibility of a clinical method for image-guided co-localization and histological characterization of liver lesions using an ex vivo MRI-compatible sectioning device. KEY POINTS: • The ex vivo MRI-compatible sectioning device provides a reliable method for radiologic-pathologic correlation of small (< 1 cm) liver lesions in human liver specimens. • The sectioning method can be feasibly implemented within a clinical practice setting and used in future efforts to study liver lesion characterization. • Intraoperative administration of gadoxetic acid results in enhancement in ex vivo MRI images of liver specimens hours later with excellent image quality.

Improved free-breathing liver fat and iron quantification using a 2D chemical shift-encoded MRI with flip angle modulation and motion-corrected averaging.

OBJECTIVES: 3D chemical shift-encoded (CSE) MRI enables accurate and precise quantification of proton density fat fraction (PDFF) and R2*, biomarkers of hepatic fat and iron deposition. Unfortunately, 3D CSE-MRI requires reliable breath-holding. Free-breathing 2D CSE-MRI with sequential radiofrequency excitation is a motion-robust alternative but suffers from low signal-to-noise-ratio (SNR). To overcome this limitation, this work explores the combination of flip angle-modulated (FAM) 2D CSE imaging with a non-local means (NLM) motion-corrected averaging technique. METHODS: In this prospective study, 35 healthy subjects (27 children/8 adults) were imaged on a 3T MRI-system. Multi-echo 3D CSE ("3D") and 2D CSE FAM ("FAM") images were acquired during breath-hold and free-breathing, respectively, to obtain PDFF and R2* maps of the liver. Multi-repetition FAM was postprocessed with direct averaging (DA)- and NLM-based averaging and compared to 3D CSE using Bland-Altmann and regression analysis. Image qualities of PDFF and R2* maps were reviewed by two radiologists using a Likert-like scale (score 1-5, 5 = best). RESULTS: Compared to 3D CSE, multi-repetition FAM-NLM showed excellent agreement (regression slope = 1.0, R2 = 0.996) for PDFF and good agreement (regression slope 1.08-1.15, R2 ≥ 0.899) for R2*. Further, multi-repetition FAM-NLM PDFF and R2* maps had fewer artifacts (score 3.8 vs. 3.2, p < 0.0001 for PDFF; score 3.2 vs. 2.6, p < 0.001 for R2*) and better overall image quality (score 4.0 vs. 3.5, p < 0.0001 for PDFF; score 3.4 vs. 2.7, p < 0.0001 for R2*). CONCLUSIONS: Free-breathing FAM-NLM provides superior image quality of the liver compared to the conventional breath-hold 3D CSE-MRI, while minimizing bias for PDFF and R2* quantification. KEY POINTS: • 2D CSE FAM-NLM is a free-breathing method for liver fat and iron quantification and viable alternative for patients unable to hold their breath. • 2D CSE FAM-NLM is a feasible alternative to breath-hold 3D CSE methods, with low bias in proton density fat fraction (PDFF) and no clinically significant bias in R2*. • Quantitatively, multiple repetitions in 2D CSE FAM-NLM lead to improved SNR.

Loss of the long non-coding RNA OIP5-AS1 exacerbates heart failure in a sex-specific manner.

Long non-coding RNAs (lncRNAs) have been demonstrated to influence numerous biological processes, being strongly implicated in the maintenance and physiological function of various tissues including the heart. The lncRNA OIP5-AS1 (1700020I14Rik/Cyrano) has been studied in several settings; however its role in cardiac pathologies remains mostly uncharacterized. Using a series of in vitro and ex vivo methods, we demonstrate that OIP5-AS1 is regulated during cardiac development in rodent and human models and in disease settings in mice. Using CRISPR, we engineered a global OIP5-AS1 knockout (KO) mouse and demonstrated that female KO mice develop exacerbated heart failure following cardiac pressure overload (transverse aortic constriction [TAC]) but male mice do not. RNA-sequencing of wild-type and KO hearts suggest that OIP5-AS1 regulates pathways that impact mitochondrial function. Thus, these findings highlight OIP5-AS1 as a gene of interest in sex-specific differences in mitochondrial function and development of heart failure.

Limits of Fat Quantification in the Presence of Iron Overload.

BACKGROUND: Chemical shift encoded magnetic resonance imaging (CSE-MRI)-based tissue fat quantification is confounded by increased R2* signal decay rate caused by the presence of excess iron deposition. PURPOSE: To determine the upper limit of R2* above which it is no longer feasible to quantify proton density fat fraction (PDFF) reliably, using CSE-MRI. STUDY TYPE: Prospective. POPULATION: Cramér-Rao lower bound (CRLB) calculations, Monte Carlo simulations, phantom experiments, and a prospective study in 26 patients with known or suspected liver iron overload. FIELD STRENGTH/SEQUENCE: Multiecho gradient echo at 1.5 T and 3.0 T. ASSESSMENT: CRLB calculations were used to develop an empirical relationship between the maximum R2* value above which PDFF estimation will achieve a desired number of effective signal averages. A single voxel multi-TR, multi-TE stimulated echo acquisition mode magnetic resonance spectroscopy acquisition was used as a reference standard to estimate PDFF. Reconstructed PDFF and R2* maps were analyzed by one analyst using multiple regions of interest drawn in all nine Couinaud segments. STATISTICAL TESTS: None. RESULTS: Simulations, phantom experiments, and in vivo measurements demonstrated unreliable PDFF estimates with increased R2*, with PDFF errors as large as 20% at an R2* of 1000 s-1 . For typical optimized Cartesian acquisitions (TE1 = 0.75 msec, ΔTE = 0.67 msec at 1.5 T, TE1 = 0.65 msec, ΔTE = 0.58 msec at 3.0 T), an empirical relationship between PDFF estimation errors and acquisition parameters was developed that suggests PDFF estimates are unreliable above an R2* of ~538 s-1 and ~779 s-1 at 1.5 T and 3 T, respectively. This empirical relationship was further investigated with phantom experiments and in vivo measurements, with PDFF errors at an R2* of 1000 s-1 at 3.0 T as large as 10% with TE1 = 1.24 msec, ΔTE = 1.01 msec compared to 3% with TE1 = 0.65 msec, ΔTE = 0.58 msec. DATA CONCLUSION: We successfully developed a theoretically-based empirical formula that may provide an easily calculable guideline to identify R2* values above which PDFF is not reliable in research and clinical applications using CSE-MRI to quantify PDFF in the presence of iron overload. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1.

Temperature-corrected proton density fat fraction estimation using chemical shift-encoded MRI in phantoms.

PURPOSE: Chemical shift-encoded MRI (CSE-MRI) is well-established to quantify proton density fat fraction (PDFF) as a quantitative biomarker of hepatic steatosis. However, temperature is known to bias PDFF estimation in phantom studies. In this study, strategies were developed and evaluated to correct for the effects of temperature on PDFF estimation through simulations, temperature-controlled experiments, and a multi-center, multi-vendor phantom study. THEORY AND METHODS: A technical solution that assumes and automatically estimates a uniform, global temperature throughout the phantom is proposed. Computer simulations modeled the effect of temperature on PDFF estimation using magnitude-, complex-, and hybrid-based CSE-MRI methods. Phantom experiments were performed to assess the temperature correction on PDFF estimation at controlled phantom temperatures. To assess the temperature correction method on a larger scale, the proposed method was applied to data acquired as part of a nine-site multi-vendor phantom study and compared to temperature-corrected PDFF estimation using an a priori guess for ambient room temperature. RESULTS: Simulations and temperature-controlled experiments show that as temperature deviates further from the assumed temperature, PDFF bias increases. Using the proposed correction method and a reasonable a priori guess for ambient temperature, PDFF bias and variability were reduced using magnitude-based CSE-MRI, across MRI systems, field strengths, protocols, and varying phantom temperature. Complex and hybrid methods showed little PDFF bias and variability both before and after correction. CONCLUSION: Correction for temperature reduces temperature-related PDFF bias and variability in phantoms across MRI vendors, sites, field strengths, and protocols for magnitude-based CSE-MRI, even without a priori information about the temperature.

Free-breathing R2∗ mapping of hepatic iron overload in children using 3D multi-echo UTE cones MRI.

PURPOSE: To enable motion-robust, ungated, free-breathing R2∗ mapping of hepatic iron overload in children with 3D multi-echo UTE cones MRI. METHODS: A golden-ratio re-ordered 3D multi-echo UTE cones acquisition was developed with chemical-shift encoding (CSE). Multi-echo complex-valued source images were reconstructed via gridding and coil combination, followed by confounder-corrected R2∗ (=1/ T2∗ ) mapping. A phantom containing 15 different concentrations of gadolinium solution (0-300 mM) was imaged at 3T. 3D multi-echo UTE cones with an initial TE of 0.036 ms and Cartesian CSE-MRI (IDEAL-IQ) sequences were performed. With institutional review board approval, 85 subjects (81 pediatric patients with iron overload + 4 healthy volunteers) were imaged at 3T using 3D multi-echo UTE cones with free breathing (FB cones), IDEAL-IQ with breath holding (BH Cartesian), and free breathing (FB Cartesian). Overall image quality of R2∗ maps was scored by 2 blinded experts and compared by a Wilcoxon rank-sum test. For each pediatric subject, the paired R2∗ maps were assessed to determine if a corresponding artifact-free 15 mm region-of-interest (ROI) could be identified at a mid-liver level on both images. Agreement between resulting R2∗ quantification from FB cones and BH/FB Cartesian was assessed with Bland-Altman and linear correlation analyses. RESULTS: ROI-based regression analysis showed a linear relationship between gadolinium concentration and R2∗ in IDEAL-IQ (y = 8.83x - 52.10, R2 = 0.995) as well as in cones (y = 9.19x - 64.16, R2 = 0.992). ROI-based Bland-Altman analysis showed that the mean difference (MD) was 0.15% and the SD was 5.78%. However, IDEAL-IQ R2∗ measurements beyond 200 mM substantially deviated from a linear relationship for IDEAL-IQ (y = 5.85x + 127.61, R2 = 0.827), as opposed to cones (y = 10.87x - 166.96, R2 = 0.984). In vivo, FB cones R2∗ had similar image quality with BH and FB Cartesian in 15 and 42 cases, respectively. FB cones R2∗ had better image quality scores than BH and FB Cartesian in 3 and 21 cases, respectively, where BH/FB Cartesian exhibited severe ghosting artifacts. ROI-based Bland-Altman analyses were 2.23% (MD) and 6.59% (SD) between FB cones and BH Cartesian and were 0.21% (MD) and 7.02% (SD) between FB cones and FB Cartesian, suggesting a good agreement between FB cones and BH (FB) Cartesian R2∗ . Strong linear relationships were observed between BH Cartesian and FB cones (y = 1.00x + 1.07, R2 = 0.996) and FB Cartesian and FB cones (y = 0.98x + 1.68, R2 = 0.999). CONCLUSION: Golden-ratio re-ordered 3D multi-echo UTE Cones MRI enabled motion-robust, ungated, and free-breathing R2∗ mapping of hepatic iron overload, with comparable R2∗ measurements and image quality to BH Cartesian, and better image quality than FB Cartesian.

Feasibility and optimization of ultra-short echo time MRI for improved imaging of IVC-filters at 3.0 T.

PURPOSE: To determine the feasibility of ultra-short echo time (UTE) MRA for assessment of inferior vena cava (IVC) filters and evaluate the impact of different imaging protocols at 3.0 T, using conventional Cartesian MRA (cMRA) as the reference standard. METHODS: Patients with IVC-filters were recruited for this prospective IRB-approved, HIPAA-compliant study. Subjects underwent contrast-enhanced breath-held and a free-breathing 3D radial acquisition UTE-MRA (bhUTE, fbUTE) at three different flip angles (FA: 10°, 15°, 20°) to optimize T1-weighted image quality. Two radiologists performed a direct comparison consensus reading to assess the optimal FA. Image quality (IQ) of both UTE techniques at the best FA was rated independently on a 4-point Likert scale (0 = non-diagnostic, 3 = excellent) and compared to 3D T1-weighted breath-held cMRA. RESULTS: Nine subjects were recruited. Low FAs of 10° were rated best for both UTE techniques. fbUTE was excellent (3, IQR: 2; 3) and significantly better for IVC-filter depiction than cMRA (2, IQR: 0.75; 2, p = 0.001) and bhUTE (1.5, IQR: 0.75; 2, p < 0.001). Both UTE techniques showed significantly less filter-related artifacts (fbUTE: 28%, bhUTE: 33%) than cMRA (89%, p = 0.001 and p = 0.002, respectively). However, IQ of bhUTE was generally degraded due to high image noise and low image contrast. IQ of the IVC venogram was best with cMRA. Clinically relevant signal voids were only observed with the cage-shaped OptEase filter. CONCLUSION: UTE-MRA is feasible at 3.0 T for the assessment of IVC-filters, particularly using a free-breathing protocol. Larger studies are needed to investigate the clinical utility of free-breathing UTE-MRA for assessment of IVC-filter-related complications.

B0 and B1 inhomogeneities in the liver at 1.5 T and 3.0 T.

PURPOSE: The purpose of this work is to characterize the magnitude and variability of B0 and B1 inhomogeneities in the liver in large cohorts of patients at both 1.5 T and 3.0 T. METHODS: Volumetric B0 and B1 maps were acquired over the liver of patients presenting for routine abdominal MRI. Regions of interest were drawn in the nine Couinaud segments of the liver, and the average value was recorded. Magnitude and variation of measured averages in each segment were reported across all patients. RESULTS: A total of 316 B0 maps and 314 B1 maps, acquired at 1.5 T and 3.0 T on a variety of GE Healthcare MRI systems in 630 unique exams, were identified, analyzed, and, in the interest of reproducible research, de-identified and made public. Measured B0 inhomogeneities ranged (5th-95th percentiles) from -31.7 Hz to 164.0 Hz for 3.0 T (-14.5 Hz to 81.3 Hz at 1.5 T), while measured B1 inhomogeneities (ratio of actual over prescribed flip angle) ranged from 0.59 to 1.13 for 3.0 T (0.83 to 1.11 at 1.5 T). CONCLUSION: This study provides robust characterization of B0 and B1 inhomogeneities in the liver to guide the development of imaging applications and protocols. Field strength, bore diameter, and sex were determined to be statistically significant effects for both B0 and B1 uniformity. Typical clinical liver imaging at 3.0 T should expect B0 inhomogeneities ranging from approximately -100 Hz to 250 Hz (-50 Hz to 150 Hz at 1.5 T) and B1 inhomogeneities ranging from approximately 0.4 to 1.3 (0.7 to 1.2 at 1.5 T).

Motion-robust, high-SNR liver fat quantification using a 2D sequential acquisition with a variable flip angle approach.

PURPOSE: Chemical shift encoded (CSE)-MRI enables quantification of proton-density fat fraction (PDFF) as a biomarker of liver fat content. However, conventional 3D Cartesian CSE-MRI methods require breath-holding. A motion-robust 2D Cartesian sequential method addresses this limitation but suffers from low SNR. In this work, a novel free breathing 2D Cartesian sequential CSE-MRI method using a variable flip angle approach with centric phase encoding (VFA-centric) is developed to achieve fat quantification with low T1 bias, high SNR, and minimal blurring. METHODS: Numerical simulation was performed for variable flip angle schedule design and preliminary evaluation of VFA-centric method, along with several alternative flip angle designs. Phantom, adults (n = 8), and children (n = 27) were imaged at 3T. Multi-echo images were acquired and PDFF maps were estimated. PDFF standard deviation was used as a surrogate for SNR. RESULTS: In both simulation and phantom experiments, the VFA-centric method enabled higher SNR imaging with minimal T1 bias and blurring artifacts. High correlation (slope = 1.00, intercept = 0.04, R2 = 0.998) was observed in vivo between the proposed VFA-centric method obtained PDFF and reference PDFF (free breathing low-flip angle 2D sequential acquisition). Further, the proposed VFA-centric method (PDFF standard deviation = 1.5%) had a better SNR performance than the reference acquisition (PDFF standard deviation = 3.3%) with P < .001. CONCLUSIONS: The proposed free breathing 2D Cartesian sequential CSE-MRI method with variable flip angle approach and centric-ordered phase encoding achieved motion robustness, low T1 bias, high SNR compared to previous 2D sequential methods, and low blurring in liver fat quantification.

Diurnal Variation of Proton Density Fat Fraction in the Liver Using Quantitative Chemical Shift Encoded MRI.

BACKGROUND: Whole-organ, noninvasive techniques for the detection and quantification of nonalcoholic fatty liver disease features have clinical and research applications. However, the effect of time of day, hydration status, and meals are unknown factors with potential to impact bias, precision, reproducibility, and repeatability of chemical shift-encoded MRI (CSE-MRI) to quantify liver proton density fat fraction (PDFF). PURPOSE: To assess the effect of diurnal variation on PDFF using CSE-MRI, including the effect of time of day, the effect of meals and hydration status, as well as the day to day variability. STUDY TYPE: Prospective. SUBJECTS: Eleven healthy subjects and nine patients with observed hepatic steatosis. FIELD STRENGTH/SEQUENCES: A commercial quantitative confounder-corrected CSE-MRI sequence (IDEAL IQ) and an MR spectroscopy (MRS) sequence (multiecho STEAM) were acquired at 1.5T. ASSESSMENT: MRI-PDFF and MRS-PDFF estimates were compared across six visits (before and after a controlled breakfast, before and after an uncontrolled lunch, at approximately 4 pm, and then before breakfast on the following day) with three repeated measures for a total of 360 MRI-PDFF and MRS-PDFF measurements. STATISTICAL TESTS: Linear regression, Bland-Altman analysis, and mixed effect models were used to determine the bias, precision, and repeatability of PDFF measurements. RESULTS: No statistically significant linear trend was observed across visits for either MRI-PDFF or MRS-PDFF (P = 0.31 and 0.37, respectively). The repeatability was measured to be 0.86% for MRI-PDFF and 1.1% for MRS-PDFF over all six visits. For MRI-PDFF, the variability between all six visits (0.94%) was only slightly higher than within each visit (0.66%), with P < 0.001. For MRS-PDFF, the variability between all six visits was 1.29%, compared with 0.87% within each visit (P < 0.001). DATA CONCLUSION: Our results may indicate that it is not necessary to control for the time of day or the fasting/fed state of the patient when measuring PDFF using CSE-MRI. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:407-414.

Sensitivity of quantitative relaxometry and susceptibility mapping to microscopic iron distribution.

PURPOSE: Determine the impact of the microscopic spatial distribution of iron on relaxometry and susceptibility-based estimates of iron concentration. METHODS: Monte Carlo simulations and in vitro experiments of erythrocytes were used to create different microscopic distributions of iron. Measuring iron with intact erythrocyte cells created a heterogeneous distribution of iron, whereas lysing erythrocytes was used to create a homogeneous distribution of iron. Multi-echo spin echo and spoiled gradient echo acquisitions were then used to estimate relaxation parameters ( R2 and R2* ) and susceptibility. RESULTS: Simulations demonstrate that R2 and R2* measurements depend on the spatial distribution of iron even for the same iron concentration and volume susceptibility. Similarly, in vitro experiments demonstrate that R2 and R2* measurements depend on the microscopic spatial distribution of iron whereas the quantitative susceptibility mapping (QSM) susceptibility estimates reflect iron concentration without sensitivity to spatial distribution. CONCLUSIONS: R2 and R2* for iron quantification depend on the spatial distribution or iron. QSM-based estimation of iron concentration is insensitive to the microscopic spatial distribution of iron, potentially providing a distribution independent measure of iron concentration.

Combined gadoxetic acid and gadobenate dimeglumine enhanced liver MRI: a parameter optimization study.

PURPOSE: To demonstrate the feasibility of combined delayed-phase gadoxetic acid (GA) and gadobenate dimeglumine (GD) enhanced liver MRI for improved detection of liver metastases, and to optimize contrast agent dose, timing, and flip angle (FA). METHODS: Fourteen healthy volunteers underwent liver MRI at 3.0T at two visits during which they received two consecutive injections: 1. GA (Visit 1 = 0.025 mmol/kg; Visit 2 = 0.05 mmol/kg) and 2. GD (both visits = 0.1 mmol/kg) 20 min after GA administration. Two sub-studies were performed: Experiment-1 Eight subjects underwent multi-phase breath-held 3D-fat-saturated T1-weighted spoiled gradient echo (SGRE) imaging to determine the optimal imaging window for the combined GA + GD protocol to create a homogeneously hyperintense liver and vasculature ("plain-white-liver") with maximum contrast to muscle which served as a surrogate for metastatic lesions in both experiments. Experiment-2 Six subjects underwent breath-held 3D-fat-saturated T1-weighted SGRE imaging at three different FA to determine the optimal FA for best image contrast. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were evaluated. RESULTS: Experiment-1 The combined GA + GD protocol created a homogeneously hyperintense liver and vasculature with maximum CNR liver/muscle at approximately 60-120 s after automatic GD-bolus detection. Experiment-2 Flip angles between 25° and 35° at a dose of 0.025 mmol/kg GA provided the best combination that minimized liver/vasculature CNR, while maximizing liver/muscle CNR. CNR performance to achieve a "plain-white-liver" was superior with 0.025 mmol/kg GA compared to 0.05 mmol/kg. CONCLUSION: Combined GA + GD enhanced T1-weighted MRI is feasible to achieve a homogeneously "plain-white-liver". Future studies need to confirm that this protocol can improve sensitivity of liver lesion detection in patients with metastatic liver disease.

T1 -corrected quantitative chemical shift-encoded MRI.

PURPOSE: To develop and validate a T1 -corrected chemical-shift encoded MRI (CSE-MRI) method to improve noise performance and reduce bias for quantification of tissue proton density fat-fraction (PDFF). METHODS: A variable flip angle (VFA)-CSE-MRI method using joint-fit reconstruction was developed and implemented. In computer simulations and phantom experiments, sources of bias measured using VFA-CSE-MRI were investigated. The effect of tissue T1 on bias using low flip angle (LFA)-CSE-MRI was also evaluated. The noise performance of VFA-CSE-MRI was compared to LFA-CSE-MRI for liver fat quantification. Finally, a prospective pilot study in patients undergoing gadoxetic acid-enhanced MRI of the liver to evaluate the ability of the proposed method to quantify liver PDFF before and after contrast. RESULTS: VFA-CSE-MRI was accurate and insensitive to transmit B1 inhomogeneities in phantom experiments and computer simulations. With high flip angles, phase errors because of RF spoiling required modification of the CSE signal model. For relaxation parameters commonly observed in liver, the joint-fit reconstruction improved the noise performance marginally, compared to LFA-CSE-MRI, but eliminated T1 -related bias. A total of 25 patients were successfully recruited and analyzed for the pilot study. Strong correlation and good agreement between PDFF measured with VFA-CSE-MRI and LFA-CSE-MRI (pre-contrast) was observed before (R2 = 0.97; slope = 0.88, 0.81-0.94 95% confidence interval [CI]; intercept = 1.34, -0.77-1.92 95% CI) and after (R2 = 0.93; slope = 0.88, 0.78-0.98 95% CI; intercept = 1.90, 1.01-2.79 95% CI) contrast. CONCLUSION: Joint-fit VFA-CSE-MRI is feasible for T1 -corrected PDFF quantification in liver, is insensitive to B1 inhomogeneities, and can eliminate T1 bias, but with only marginal SNR advantage for T1 values observed in the liver.

Activin A-Induced Cachectic Wasting Is Attenuated by Systemic Delivery of Its Cognate Propeptide in Male Mice.

In cancer, elevated activin levels promote cachectic wasting of muscle, irrespective of tumor progression. In excess, activins A and B use the myostatin signaling pathway in muscle, triggering a decrease in protein synthesis and an increase in protein degradation, which ultimately leads to atrophy. Recently, we demonstrated that local delivery of engineered activin and myostatin propeptides (natural inhibitors of these growth factors) could induce profound muscle hypertrophy in healthy mice. Additionally, the expression of these propeptides effectively attenuated localized muscle wasting in models of dystrophy and cancer cachexia. In this study, we examined whether a systemically administered recombinant propeptide could reverse activin A-induced cachectic wasting in mice. Chinese hamster ovary cells stably expressing activin A were transplanted into the quadriceps of nude mice and caused an 85-fold increase in circulating activin A levels within 12 days. Elevated activin A induced a rapid reduction in body mass (-16%) and lean mass (-10%). In agreement with previous findings, we demonstrated that adeno-associated virus-mediated delivery of activin propeptide to the tibialis anterior muscle blocked activin-induced wasting. In addition, despite massively elevated levels of activin A in this model, systemic delivery of the propeptide significantly reduced activin-induced changes in lean and body mass. Specifically, recombinant propeptide reversed activin-induced wasting of skeletal muscle, heart, liver, and kidneys. This is the first study to demonstrate that systemic administration of recombinant propeptide therapy effectively attenuates tumor-derived activin A insult in multiple tissues.

Comparison of gadolinium-enhanced and ferumoxytol-enhanced conventional and UTE-MRA for the depiction of the pulmonary vasculature.

PURPOSE: To evaluate the feasibility of ferumoxytol (FE)-enhanced UTE-MRA for depiction of the pulmonary vascular and nonvascular structures. METHODS: Twenty healthy volunteers underwent contrast-enhanced pulmonary MRA at 3 T during 2 visits, separated by at least 4 weeks. Visit 1: The MRA started with a conventional multiphase 3D T1 -weighted breath-held spoiled gradient-echo MRA before and after the injection of 0.1 mmol/kg gadobenate dimeglumine (GD). Subsequently, free-breathing GD-UTE-MRA was acquired as a series of 3 flip angles (FAs) (6°, 12°, 18°) to optimize T1 weighting. Visit 2: After the injection of 4 mg/kg FE, MRA was performed during the steady state, starting with a conventional 3D T1 -weighted breath-held spoiled gradient-echo MRA and followed by free-breathing FE-UTE-MRA, both at 4 different FAs (6°, 12°, 18°, 24°). The optimal FA for best T1 contrast was evaluated. Image quality at the optimal FA was compared between methods on a 4-point ordinal scale, using multiphase GD conventional pulmonary MRA (cMRA) as standard of reference. RESULTS: Flip angle in the range of 18°-24° resulted in best T1 contrast for FE cMRA and both UTE-MRA techniques (p > .05). At optimized FA, image quality of the vasculature was good/excellent with both FE-UTE-MRA and GD cMRA (98% versus 97%; p = .51). Both UTE techniques provided superior depiction of nonvascular structures compared with either GD-enhanced or FE-enhanced cMRA (p < .001). However, GD-UTE-MRA showed the lowest image quality of the angiogram due to low image contrast. CONCLUSION: Free-breathing UTE-MRA using FE is feasible for simultaneous assessment of the pulmonary vasculature and nonvascular structures. Patient studies should investigate the clinical utility of free-breathing UTE-MRA for assessment of pulmonary emboli.

Relaxivity of Ferumoxytol at 1.5 T and 3.0 T.

OBJECTIVES: The aim of this study was to determine the relaxation properties of ferumoxytol, an off-label alternative to gadolinium-based contrast agents, under physiological conditions at 1.5 T and 3.0 T. MATERIALS AND METHODS: Ferumoxytol was diluted in gradually increasing concentrations (0.26-4.2 mM) in saline, human plasma, and human whole blood. Magnetic resonance relaxometry was performed at 37°C at 1.5 T and 3.0 T. Longitudinal and transverse relaxation rate constants (R1, R2, R2*) were measured as a function of ferumoxytol concentration, and relaxivities (r1, r2, r2*) were calculated. RESULTS: A linear dependence of R1, R2, and R2* on ferumoxytol concentration was found in saline and plasma with lower R1 values at 3.0 T and similar R2 and R2* values at 1.5 T and 3.0 T (1.5 T: r1saline = 19.9 ± 2.3 smM; r1plasma = 19.0 ± 1.7 smM; r2saline = 60.8 ± 3.8 smM; r2plasma = 64.9 ± 1.8 smM; r2*saline = 60.4 ± 4.7 smM; r2*plasma = 64.4 ± 2.5 smM; 3.0 T: r1saline = 10.0 ± 0.3 smM; r1plasma = 9.5 ± 0.2 smM; r2saline = 62.3 ± 3.7 smM; r2plasma = 65.2 ± 1.8 smM; r2*saline = 57.0 ± 4.7 smM; r2*plasma = 55.7 ± 4.4 smM). The dependence of relaxation rates on concentration in blood was nonlinear. Formulas from second-order polynomial fittings of the relaxation rates were calculated to characterize the relationship between R1blood and R2 blood with ferumoxytol. CONCLUSIONS: Ferumoxytol demonstrates strong longitudinal and transverse relaxivities. Awareness of the nonlinear relaxation behavior of ferumoxytol in blood is important for ferumoxytol-enhanced magnetic resonance imaging applications and for protocol optimization.

Specific targeting of TGF-ß family ligands demonstrates distinct roles in the regulation of muscle mass in health and disease.

The transforming growth factor-ß (TGF-ß) network of ligands and intracellular signaling proteins is a subject of intense interest within the field of skeletal muscle biology. To define the relative contribution of endogenous TGF-ß proteins to the negative regulation of muscle mass via their activation of the Smad2/3 signaling axis, we used local injection of adeno-associated viral vectors (AAVs) encoding ligand-specific antagonists into the tibialis anterior (TA) muscles of C57BL/6 mice. Eight weeks after AAV injection, inhibition of activin A and activin B signaling produced moderate (∼20%), but significant, increases in TA mass, indicating that endogenous activins repress muscle growth. Inhibiting myostatin induced a more profound increase in muscle mass (∼45%), demonstrating a more prominent role for this ligand as a negative regulator of adult muscle mass. Remarkably, codelivery of activin and myostatin inhibitors induced a synergistic response, resulting in muscle mass increasing by as much as 150%. Transcription and protein analysis indicated that this substantial hypertrophy was associated with both the complete inhibition of the Smad2/3 pathway and activation of the parallel bone morphogenetic protein (BMP)/Smad1/5 axis (recently identified as a positive regulator of muscle mass). Analyses indicated that hypertrophy was primarily driven by an increase in protein synthesis, but a reduction in ubiquitin-dependent protein degradation pathways was also observed. In models of muscular dystrophy and cancer cachexia, combined inhibition of activins and myostatin increased mass or prevented muscle wasting, respectively, highlighting the potential therapeutic advantages of specifically targeting multiple Smad2/3-activating ligands in skeletal muscle.

The effects of concomitant gradients on chemical shift encoded MRI.

PURPOSE: The purpose of this work was to characterize the effects of concomitant gradients (CGs) on chemical shift encoded (CSE)-based estimation of B0 field map, proton density fat fraction (PDFF), and R2*. THEORY: A theoretical framework was used to determine the effects of CG-induced phase errors on CSE-MRI data. METHODS: Simulations, phantom experiments, and in vivo experiments were conducted at 3 Tesla to assess the effects of CGs on quantitative CSE-MRI techniques. Correction of phase errors attributable to CGs was also investigated to determine whether these effects could be removed. RESULTS: Phase errors attributed to CGs introduce errors in the estimation of B0 field map, PDFF, and R2*. Phantom and in vivo experiments demonstrated that CGs can introduce estimation errors greater than 30 Hz in the B0 field map, 10% in PDFF, and 16 s-1 in R2*, 16 cm off isocenter. However, CG phase correction before parameter estimation was able to reduce estimation errors to less than 10 Hz in the B0 field map, 1% in PDFF, and 2 s-1 in R2*. CONCLUSION: CG effects can impact CSE-MRI, leading to inaccurate estimation of B0 field map, PDFF, and R2*. However, correction for phase errors caused by CGs improve the accuracy of quantitative parameters estimated from CSE-MRI acquisitions. Magn Reson Med 78:730-738, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

MR visible localization device for radiographic-pathologic correlation of surgical specimens.

PURPOSE: The detection of small parenchymal hepatic lesions identified by preoperative imaging remains a challenge for traditional pathologic methods in large specimens. We developed a magnetic resonance imaging (MRI) compatible localization device for imaging of surgical specimens aimed to improve identification and localization of hepatic lesions ex vivo. MATERIALS AND METHODS: The device consists of two stationary and one removable MR-visible grids lined with silicone gel, creating an orthogonal 3D matrix for lesion localization. To test the device, five specimens of swine liver with a random number of lesions created by microwave ablation were imaged on a 3T MR scanner. Two readers independently evaluated lesion coordinates and size, which were then correlated with sectioning guided by MR imaging. RESULTS: All lesions (n=38) were detected at/very close to the expected localization. Inter-reader agreement of lesion localization was almost perfect (0.92). The lesion size estimated by MRI matched macroscopic lesion size in cut specimen (±2mm) in 34 and 35, respectively, out of 38 lesions. CONCLUSION: Use of this MR compatible device for ex vivo imaging proved feasible for detection and three-dimensional localization of liver lesions, and has potential to play an important role in the ex vivo examination of surgical specimens in which pathologic correlation is clinically important.