Magnetic Resonance Imaging and Molecular Characterization of a Hormone-Mediated Murine Model of Prostate Enlargement and Bladder Outlet Obstruction.

Urinary complications resulting from benign prostatic hyperplasia and bladder outlet obstruction continue to be a serious health problem. Novel animal model systems and imaging approaches are needed to understand the mechanisms of disease initiation, and to develop novel therapies for benign prostatic hyperplasia. Long-term administration of both estradiol and testosterone in mice can result in prostatic enlargement and recapitulate several clinical components of lower urinary tract symptoms. Herein, we use longitudinal magnetic resonance imaging and histological analyses to quantify changes in prostatic volume, urethral volume, and genitourinary vascularization over time in response to estradiol-induced prostatic enlargement. Our data demonstrate significant prostatic enlargement by 12 weeks after treatment, with no detectable immune infiltration by macrophages or T- or B-cell populations. Importantly, the percentage of cell death, as measured by terminal deoxynucleotidyl transferase dUTP nick-end labeling, was significantly decreased in the prostatic epithelium of treated animals as compared to controls. We found no significant change in prostate cell proliferation in treated mice when compared to controls. These studies highlight the utility of magnetic resonance imaging to quantify changes in prostatic and urethral volumes over time. In conjunction with histological analyses, this approach has the high potential to enable mechanistic studies of initiation and progression of clinically relevant lower urinary tract symptoms. In addition, this model is tractable for investigation and testing of therapeutic interventions to ameliorate or potentially reverse prostatic enlargement.

Potential of computer-aided diagnosis of high spectral and spatial resolution (HiSS) MRI in the classification of breast lesions.

PURPOSE: To compare the performance of computer-aided diagnosis (CADx) analysis of precontrast high spectral and spatial resolution (HiSS) MRI to that of clinical dynamic contrast-enhanced MRI (DCE-MRI) in the diagnostic classification of breast lesions. MATERIALS AND METHODS: Thirty-four malignant and seven benign lesions were scanned using two-dimensional (2D) HiSS and clinical 4D DCE-MRI protocols. Lesions were automatically segmented. Morphological features were calculated for HiSS, whereas both morphological and kinetic features were calculated for DCE-MRI. After stepwise feature selection, Bayesian artificial neural networks merged selected features, and receiver operating characteristic (ROC) analysis evaluated the performance with leave-one-lesion-out validation. RESULTS: AUC (area under the ROC curve) values of 0.92 ± 0.06 and 0.90 ± 0.05 were obtained using CADx on HiSS and DCE-MRI, respectively, in the task of classifying benign and malignant lesions. While we failed to show that the higher HiSS performance was significantly better than DCE-MRI, noninferiority testing confirmed that HiSS was not worse than DCE-MRI. CONCLUSION: CADx of HiSS (without contrast) performed similarly to CADx on clinical DCE-MRI; thus, computerized analysis of HiSS may provide sufficient information for diagnostic classification. The results are clinically important for patients in whom contrast agent is contra-indicated. Even in the limited acquisition mode of 2D single slice HiSS, by using quantitative image analysis to extract characteristics from the HiSS images, similar performance levels were obtained as compared with those from current clinical 4D DCE-MRI. As HiSS acquisitions become possible in 3D, CADx methods can also be applied. Because HiSS and DCE-MRI are based on different contrast mechanisms, the use of the two protocols in combination may increase diagnostic accuracy.

Classification of breast lesions pre-contrast injection using water resonance lineshape analysis.

Inhomogeneously broadened, non-Lorentzian water resonances have been observed in small image voxels of breast tissue. The non-Lorentzian components of the water resonance are probably produced by bulk magnetic susceptibility shifts caused by dense, deoxygenated tumor blood vessels (the 'blood oxygenation level-dependent' effect), but can also be produced by other characteristics of local anatomy and physiology, including calcifications and interfaces between different types of tissue. Here, we tested the hypothesis that the detection of non-Lorentzian components of the water resonance with high spectral and spatial resolution (HiSS) MRI allows the classification of breast lesions without the need to inject contrast agent. Eighteen malignant lesions and nine benign lesions were imaged with HiSS MRI at 1.5 T. A new algorithm was developed to detect non-Lorentzian (or off-peak) components of the water resonance. After a Lorentzian fit had been subtracted from the data, the largest peak in the residual spectrum in each voxel was identified as the major off-peak component of the water resonance. The difference in frequency between these off-peak components and the main water peaks, and their amplitudes, were measured in malignant lesions, benign lesions and breast fibroglandular tissue. Off-peak component frequencies were significantly different between malignant and benign lesions (p < 0.001). Receiver operating characteristic (ROC) analysis was used to assess the diagnostic performance of HiSS off-peak component analysis compared with dynamic contrast-enhanced (DCE) MRI parameters. The areas under the ROC curves for the 'DCE rapid uptake fraction', 'DCE washout fraction', 'off-peak component amplitude' and 'off-peak component frequency' were 0.75, 0.83, 0.50 and 0.86, respectively. These results suggest that water resonance lineshape analysis performs well in the classification of breast lesions without contrast injection and could improve the diagnostic accuracy of clinical breast MR examinations. In addition, this approach may provide an alternative to DCE MRI in women who are at risk for adverse reactions to contrast media.

A selective small molecule inhibitor of c-Met, PHA665752, inhibits tumorigenicity and angiogenesis in mouse lung cancer xenografts.

The c-Met receptor tyrosine kinase is emerging as a novel target in many solid tumors, including lung cancer. PHA-665752 was identified as a small molecule, ATP competitive inhibitor of the catalytic activity of the c-Met kinase. Here, we show that treatment with PHA665752 reduced NCI-H69 (small cell lung cancer) and NCI-H441 (non-small cell lung cancer) tumorigenicity in mouse xenografts by 99% and 75%, respectively. Reduction in tumor size was also observed by magnetic resonance imaging of tumors in mice. PHA665752 inhibited c-Met phosphorylation at the autophosphorylation and c-Cbl binding sites in mouse xenografts derived from non-small cell lung cancer cell lines (NCI-H441 and A549) and small cell lung cancer cell line (NCI-H69). PHA665752 also inhibited angiogenesis by >85% in all the abovementioned cell lines and caused an angiogenic switch which resulted in a decreased production of vascular endothelial growth factor and an increase in the production of the angiogenesis inhibitor thrombospondin-1. These studies show the feasibility of selectively targeting c-Met with ATP competitive small molecule inhibitors and suggest that PHA665752 may provide a novel therapeutic approach to lung cancer.

Three-dimensional shear in granular flow.

The evolution of granular shear flow is investigated as a function of height in a split-bottom Couette cell. Using particle tracking, magnetic-resonance imaging, and large-scale simulations, we find a transition in the nature of the shear as a characteristic height H* is exceeded. Below H* there is a central stationary core; above H* we observe the onset of additional axial shear associated with torsional failure. Radial and axial shear profiles are qualitatively different: the radial extent is wide and increases with height, while the axial width remains narrow and fixed.

Effect of air on granular size separation in a vibrated granular bed.

Using high-speed video and magnetic resonance imaging (MRI) we study the motion of a large sphere in a vertically vibrated bed of smaller grains. As previously reported we find a nonmonotonic density dependence of the rise and sink time of the large sphere. We show that air drag causes relative motion between the intruder and the bed during the shaking cycle and is ultimately responsible for the observed density dependence of the risetime. We investigate in detail how the motion of the intruder sphere is influenced by size of the background particles, initial vertical position in the bed, ambient pressure, and convection. We explain our results in the framework of a simple model and find quantitative agreement in key aspects with numerical simulations to the model equations.

Magnetic resonance imaging of changes in muscle tissues after membrane trauma.

A pure electroporation injury leads to cell membrane disruption and subsequent osmotic swelling of the tissue. The state of water in the injured area of a tissue is changed and differs from a healthy tissue. Magnetic resonance imaging (MRI), which is very sensitive to the quality of the interaction between mobile (water) protons and a restricted (protein) proton pool, is therefore a useful tool to characterize this injury. Here, we present a protocol designed to measure the difference between the values of the transverse magnetic relaxation time (T2) in MRIs of healthy and electrically injured tissue. In addition, we present a method to evaluate the two main contributions to the MRI contrast, the degree of structural alteration of the cellular components (including a major contribution from membrane pores), and edema. The approach is useful in assessing the level of damage that electric shocks produce in muscle tissues, in that edema will resolve in time whereas structural changes require active repair mechanisms.

Intruders in the dust: air-driven granular size separation.

Using MRI and high-speed video we investigate the motion of a large intruder particle inside a vertically shaken bed of smaller particles. We find a pronounced, nonmonotonic density dependence, with both light and heavy intruders moving faster than those whose density is approximately that of the granular bed. For light intruders, we furthermore observe either rising or sinking behavior, depending on intruder starting height, boundary condition, and interstitial gas pressure. We map out the phase boundary delineating the rising and sinking regimes. A simple model can account for much of the observed behavior and shows how the two regimes are connected by considering pressure gradients across the granular bed during a shaking cycle.

Semiquantitative analysis of dynamic contrast enhanced MRI in cancer patients: Variability and changes in tumor tissue over time.

PURPOSE: To evaluate variability of a simplified method for measuring semiquantitative DCE-MRI parameters in patients with cancer and to explore effects of treatment with a putative anti-angiogenic compound. MATERIALS AND METHODS: A total of 19 patients enrolled on treatment trials with the putative anti-angiogenic agent SU5416 underwent contrast enhanced examinations, and 11 had a second examination eight weeks post therapy. Contrast media concentration as a function of time was calculated using changes in signal and literature baseline T(1) values in normal muscle or liver reference tissue. Semiquantitative DCE-MRI parameters, including the area under the contrast concentration vs. time curve (AUC), were calculated for regions-of-interest in normal liver and muscle, and in tumors. RESULTS: The coefficients of variation for pretherapy parameters in normal tissue were 11% to 37%. No significant changes were detected in normal liver over two months of therapy. In tumors and muscle, a significant decrease in the AUC and maximum contrast concentration was observed. CONCLUSION: Variability of semiquantitative DCE-MRI parameters utilizing a method based on known T(1) values in a reference tissue is low enough to detect changes in tumors during therapy. Use of this method as a pharmacodynamic marker should be further investigated.

Phase II study of the Flk-1 tyrosine kinase inhibitor SU5416 in advanced melanoma.

PURPOSE: Vascular endothelial growth factor (VEGF) expression is prognostic in melanoma, and the activity of VEGF is mediated in part through the receptor tyrosine kinase Flk-1. A Phase II study of SU5416, a preferential inhibitor of Flk-1, was carried out in patients with metastatic melanoma to determine clinical response, tolerability, and changes in tumor vascular perfusion. EXPERIMENTAL DESIGN: Patients with documented progressive disease and