BACKGROUND.Beige adipose tissue is associated with improved glucose homeostasis in mice. Adipose tissue contains β3adrenergic receptors (β3-ARs), and this study was intended to determine whether the treatment of obese, insulin-resistant humans with the β3-AR agonist mirabegron, which stimulates beige adipose formation in subcutaneous white adipose tissue (SC WAT), would induce other beneficial changes in fat and muscle and improve metabolic homeostasis. METHODS.Before and after β3-AR agonist treatment, oral glucose tolerance tests and euglycemic clamps were performed, and histochemical analysis and gene expression profiling were performed on fat and muscle biopsies. PET-CT scans quantified brown adipose tissue volume and activity, and we conducted in vitro studies with primary cultures of differentiated human adipocytes and muscle. RESULTS.The clinical effects of mirabegron treatment included improved oral glucose tolerance (P < 0.01), reduced hemoglobin A1c levels (P = 0.01), and improved insulin sensitivity (P = 0.03) and β cell function (P = 0.01). In SC WAT, mirabegron treatment stimulated lipolysis, reduced fibrotic gene expression, and increased alternatively activated macrophages. Subjects with the most SC WAT beiging showed the greatest improvement in β cell function. In skeletal muscle, mirabegron reduced triglycerides, increased the expression of PPARγ coactivator 1 α (PGC1A) (P < 0.05), and increased type I fibers (P < 0.01). Conditioned media from adipocytes treated with mirabegron stimulated muscle fiber PGC1A expression in vitro (P < 0.001). CONCLUSION.Mirabegron treatment substantially improved multiple measures of glucose homeostasis in obese, insulinresistant humans. Since β cells and skeletal muscle do not express β3-ARs, these data suggest that the beiging of SC WAT by mirabegron reduces adipose tissue dysfunction, which enhances muscle oxidative capacity and improves β cell function.TRIAL REGISTRATION. Clinicaltrials.gov NCT02919176.

Diffusion-weighted imaging relies on the detection of the random microscopic motion of free water molecules known as Brownian movement. With the development of new magnetic resonance (MR) imaging technologies and stronger diffusion gradients, recent applications of diffusion-weighted imaging in whole-body imaging have attracted considerable attention, especially in the field of oncology. Diffusion-weighted imaging is being established as a pivotal aspect of MR imaging in the evaluation of specific organs, including the breast, liver, kidney, and those in the pelvis. When used in conjunction with apparent diffusion coefficient mapping, diffusion-weighted imaging provides information about the functional environment of water in tissues, thereby augmenting the morphologic information provided by conventional MR imaging. Detected changes include shifts of water from extracellular to intracellular spaces, restriction of cellular membrane permeability, increased cellular density, and disruption of cellular membrane depolarization. These findings are commonly associated with malignancies; therefore, diffusion-weighted imaging has many applications in oncologic imaging and can aid in tumor detection and characterization and in the prediction and assessment of response to therapy.

Purpose: To investigate the relationship between temporal resolution of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and classification of breast lesions as benign versus malignant. Materials and Methods:Patients underwent T 1 -weighted DCE MRI with 15 s/acquisition temporal resolution using 1.5 Tesla (n ¼ 48) and 3.0T (n ¼ 33) MRI scanners. Seventy-nine patients had pathologically proven diagnosis and 2 had 2 years follow-up showing no change in lesion size. The temporal resolution of DCE MRI was systematically reduced as a postprocessing step from 15 to 30, 45, and 60 s/acquisition by eliminating intermediate time points. Average wash-in and wash-out slopes, wash-out percentage changes, and kinetic curve shape (persistently enhancing, plateau, or wash-out) were compared for each temporal resolution. Logistic regression and receiver operating characteristic (ROC) curve analysis were used to compare kinetic parameters and diagnostic accuracy.Results: Sixty patients (74%) had malignant lesions and 21 patients (26%) had benign lesions. All temporal-resolution parameters significantly predicted benign versus malignant diagnosis (P < 0.05). However, 45 s/acquisition and higher temporal-resolution datasets showed higher accuracy than the 60 s/acquisition dataset by ROC curve analysis (0.72 versus 0.69 for average wash-in slope; 0.85 versus 0.82, for average wash-out slope; and 0.88 versus 0.80 for kinetic curve shape assessment, for 45 s/acquisition versus 60 s/acquisition temporal-resolution datasets, respectively (P ¼ 0.027).Conclusion: DCE MRI data with at least 45-s temporal resolution maximized the agreement between the kinetic parameters and correct classification of benign versus malignant diagnosis. CONTRAST-ENHANCED (CE) MRI has proven to be an important tool in detecting and characterizing breast lesions with a sensitivity greater than 90% but widely varying specificity ranging from 30 to 84% (1-4). Dynamic contrast-enhanced (DCE) MRI has been shown to improve the specificity of MRI in the diagnosis of breast cancer (5). The most widely described features of the DCE MRI analysis is the uptake and wash-out patterns of the gadolinium contrast agent in regions of suspected abnormalities. These patterns are typically qualitatively classified as: (i) persistently enhancing type suggestive of benignity, (ii) wash-out type suggestive of malignancy, and (iii) plateau type representing an intermediate probability. Wash-in characteristics have also been related to malignant versus benign histology, depending on the slope of the uptake curve (6). However, DCE MRI breast protocols can vary in temporal resolution, and there is a need to define the optimal limit that is required for correct classification and diagnosis of lesions.Current MRI scanners and newest pulse sequences can rapidly image the entire breast in 15 s or less. However, this high temporal resolution is at the expense of reduced spatial resolution and/or signalto-noise (SNR) ratio that are important for morphologic assessment of the s...

OBJECTIVE-The type of contrast enhancement kinetic curve (i.e., persistently enhancing, plateau, or washout) seen on dynamic contrast-enhanced MRI (DCE-MRI) of the breast is predictive of malignancy. Qualitative estimates of the type of curve are most commonly used for interpretation of DCE-MRI. The purpose of this study was to compare qualitative and quantitative methods for determining the type of contrast enhancement kinetic curve on DCE-MRI.MATERIALS AND METHODS-Ninety-six patients underwent breast DCE-MRI. The type of DCE-MRI kinetic curve was assessed qualitatively by three radiologists on two occasions. For quantitative assessment, the slope of the washout curve was calculated. Kappa statistics were used to determine inter-and intraobserver agreement for the qualitative method. Matched sample tables, the McNemar test, and receiver operating characteristic (ROC) curve statistics were used to compare quantitative versus qualitative methods for establishing or excluding malignancy.RESULTS-Seventy-eight lesions (77.2%) were malignant and 23 (22.8%) were benign. For the qualitative assessment, the intra-and interobserver agreement was good (κ = 0.76-0.88), with an area under the ROC curve (AUC) of 0.73-0.77. For the quantitative method, the highest AUC was 0.87, reflecting significantly higher diagnostic accuracies compared with qualitative assessment (p < 0.01 for the difference between the two methods).CONCLUSION-Quantitative assessment of the type of contrast enhancement kinetic curve on breast DCE-MRI resulted in significantly higher diagnostic performance for establishing or excluding malignancy compared with assessment based on the standard qualitative method. Keywords breast cancer; breast imaging; contrast-enhanced MRI; dynamic MRI; kinetic curve; washout Contrast-enhanced MRI carries very high sensitivity but moderate specificity for the diagnosis of breast cancer [1,2]. Dynamic contrast-enhanced MRI (DCE-MRI) has been widely used to improve the specificity of MRI in characterizing breast lesions [3][4][5][6][7]. The NIH Public Access Materials and Methods Clinical SubjectsMRI scans of 300 consecutive patients who presented to our facility for bilateral breast MRI from January 2007 to February 2008 were retrospectively reviewed. Patients were included in the study if they had a breast lesion or lesions at least 1 cm in diameter that had a pathologically proven diagnosis or 2 years of imaging follow-up accepted as a proof of benignity. This study was approved by our institutional review board and was compliant with HIPAA.Ninety-one patients met the inclusion criteria of the study. Patients were scanned on either a 1.5-T (48 patients) or a 3-T (48 patients) clinical MRI system (1.5-T Intera and 3-T Achieva, Philips Healthcare) using a bilateral dedicated phased-array breast coil (4-channel breast array coil, Invivo). The MRI protocol included 2 minutes of high-temporal-resolution imaging (15 seconds per acquisition) to capture the wash-in phase of contrast enhancement, high-spatial-resolution ...