Pharmacokinetic parameters as a potential predictor of response to pharmacotherapy in benign prostatic hyperplasia: a preclinical trial using dynamic contrast-enhanced MRI

We sought to assess the possibility of using pharmacokinetic parameters as a predictor of response to benign prostatic hyperplasia (BPH) pharmacotherapy via a randomized, placebo-controlled, animal preclinical trial using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Twelve male beagles with BPH were enrolled in a preclinical experimental drug trial and divided into two randomized groups with six beagles each: one drug (finasteride) group and one placebo (control) group. Two baseline MRI examinations and three follow-ups during treatment were performed on a clinical 1.5-T MRI system using axial T1- and T2-weighted magnetic resonance images for prostate volume measurement and DCE-MRI for the assessment of prostate microcirculation. A total of 0.2 mmol/kg body weight of the Gd-based contrast agent was administered with an injection rate of 0.2 ml/s. The pharmacokinetic parameters, maximum enhancement ratio (MER), transfer constant and rate constant, were assessed to characterize the microcirculation in the parenchymal zone. The time-signal intensity curve from the external iliac artery was used as the arterial input function. The correlation between baseline evaluations (prostate volume and pharmacokinetic parameters) and therapy-induced prostate volume changes under finasteride treatment were assessed. The changes in prostate volume at the end of the trial exhibited a significant linear correlation to the initial parenchymal MER (P < .02) in the finasteride group. Larger prostate volume reductions coincided with smaller initial parenchymal MER. These findings show considerable promise of using parenchymal MER as a predictor of response to BPH pharmacotherapy with finasteride.     

Superior diagnostic strength of combined contrast enhanced MR-angiography and MR-imaging compared to intra-arterial DSA in liver transplantation candidates.

To evaluate the diagnostic value of combined contrast enhanced MRA (ce-MRA) and MRI compared to that of intra-arterial DSA (i.a.DSA) in liver transplantation, transjugular porto-systemic (TIPSS) and spleno-renal shunt candidates. 50 patients in the workup for liver transplantation underwent ce-MRA/MRI and i.a.DSA within a three days interval. Both examinations were assessed with respect to vessel anatomy and patency of the arterial, portal venous, porto-systemic collateral and systemic venous system. The results were compared with the intra-operative findings when available. Malignancy detection in ce-MRA/MRI and i.a.DSA were compared. There are no significant differences for the arterial part of the vascular supply to the liver that is important for transplantation. Although the differences for the portal system are not significant, the difference between the two techniques is of clinical importance because i.a.DSA failed to detect portal vein occlusion in 4 patients. Ce-MRA is significantly better for the detection of collaterals (p < 0.001) and the assessment of the inferior vena cava, the hepatic and the renal veins (p < 0.001). Although the detection of liver malignancy is poor in both techniques, ce-MRA/MRI is superior to i.a.DSA. This study shows that a one step diagnostic approach with a combination of ce-MRA and MRI is a valuable radiological tool with a superior diagnostic strength compared to i.a.DSA in the liver transplantation and shunt candidate. Therefore, ce-MRA/MRI should replace i.a.DSA in these patients groups.     

Dual-mode registration of dynamic contrast-enhanced ultrasound combining tissue and contrast sequences

This study proposes a new method for automatic, iterative image registration in the context of dynamic contrast-enhanced ultrasound (DCE-US) imaging. By constructing a cost function of image registration using a combination of the tissue and contrast-microbubble responses, this new method, referred to as dual-mode registration, performs alignment based on both tissue and vascular structures. Data from five focal liver lesions (FLLs) were used for the evaluation. Automatic registration based on the dual-mode registration technique and tissue-mode registration obtained using the linear response image sequence alone were compared to manual alignment of the sequence by an expert. Comparison of the maximum distance between the transformations applied by the automatic registration techniques and those from expert manual registration reference showed that the dual-mode registration provided better precision than the tissue-mode registration for all cases. The reduction of maximum distance ranged from 0.25 to 9.3 mm. Dual-mode registration is also significantly better than tissue-mode registration for the five sequences with p  -values lower than 0.03$0.03$. The improved sequence alignment is also demonstrated visually by comparison of images from the sequences and the video playbacks of the motion-corrected sequences. This new registration technique better maintains a selected region of interest (ROI) within a fixed position of the image plane throughout the DCE-US sequence. This should reduce motion-related variability of the echo-power estimations and, thus, contribute to more robust perfusion quantification with DCE-US.     

Three-dimensional contrast-enhanced ultrasound of the liver: Experience of 92 cases

Three-dimensional contrast-enhanced ultrasound (3D-CEUS) is a combination of three-dimensional ultrasound (3DUS) and contrast-enhanced ultrasound (CEUS). To evaluate the feasibility of 3D-CEUS in liver imaging, investigate possible influencing factors to its image quality, and evaluate the influence of 3D-CEUS to clinical outcome, low acoustic power (mechanical index, 0.08-0.13) 3D-CEUS was carried out in 102 focal liver lesions in 92 patients by using the LOGIQ 9 ultrasound scanner and a volume transducer (frequency range, 2-5 MHz; focusing ability, 2-25 cm in depth; azimuth aperture 5.9 cm). The lesions were classified into two groups: group 1 (n = 51) for characterization and group 2 (n = 51) for local treatment response evaluation. The factors that influenced the image quality of 3D-CEUS were analyzed. The image quality and usefulness of 3D-CEUS between the two groups were compared by using the χ²-test. The results showed that the lesion diameter, location, and scanning route had no significant influence on the image quality in both groups, whereas interfering factors damaged the image quality in group 1. In group 1, during arterial phase, high image quality was more frequently found in hyperenhanced and hypo- or non-enhanced lesions compared with isoenhanced lesions. In group 2, interfering factor and local treatment response had no obvious influence on the image quality. The visualization rate of high image quality was 94.1% (48/51) in group 2 vs. 72.6% (37/51) in group 1 (P = 0.012). The investigators found that 3D-CEUS improved confidence but made no change in diagnosis in 19 (37.3%) of 51 lesions in group 1, whereas 41 (80.4%) of 51 lesions in group 2 (P = 0.000). 3D-CEUS tends to obtain better image quality and lead to higher diagnostic confidence in the lesions for local treatment response evaluation, and perhaps is more useful in this aspect in future clinical settings.     

Depth profiling of porcine adipose tissue by Raman spectroscopy

Raman spectroscopy was applied on a depth profile of porcine adipose tissue (from skin to meat) with the purpose of (1) discriminating between fat layers and (2) estimating the variation in fatty acid composition as a function of fat depth and fat layer: total degree of unsaturation (iodine value), fractions of saturated, and monounsaturated and polyunsaturated fatty acids. The thickness and composition of the outer layer of porcine adipose tissue influences the final quality of backfat. A too‐thick outer layer is associated with problems such as oily appearance, rancidity development, and difficulties in separating muscle and adipose tissue when cutting. From principal component analysis on standard normal variate preprocessed Raman spectra (1800–800 cm^–1), it was possible to discriminate between the outer and the inner backfat layer. Principal component analysis loadings showed that the separation of layer was mainly explained by variation in the bands originating from vibration of double bond C = C stretching plus = C–H twisting and rocking. In the prediction of iodine value a three‐component partial least squares regression model based on full range Raman spectra showed a root mean square error of cross validation of 2.00 and R² = 0.69. Applying Cauchy–Lorentz band fitting proved that information regarding fat unsaturation was found not only in band intensity, but also in band parameters such as location and width. The results suggest Raman spectroscopy as a potential measurement technique for rapid grading of pork carcasses. Copyright © 2011 John Wiley & Sons, Ltd.     

Deep learning based classification of focal liver lesions with contrast-enhanced ultrasound

Classification of liver masses is important to early diagnosis of patients. In this paper, a diagnostic system of liver disease classification based on contrast enhanced ultrasound (CEUS) imaging is proposed. In the proposed system, the dynamic CEUS videos of hepatic perfusion are firstly retrieved. Secondly, time intensity curves (TICs) are extracted from the dynamic CEUS videos using sparse non-negative matrix factorizations. Finally, deep learning is employed to classify benign and malignant focal liver lesions based on these TICs. Quantitative comparisons demonstrate that the proposed method outperforms the compared classification methods in accuracy, sensitivity and specificity.     

Dynamic contrast-enhanced MR imaging of the liver: Parenchymal enhancement patterns

A retrospective study of 164 patients undergoing dynamic contrast-enhanced magnetic resonance (MR) imaging was performed to assess hepatic parenchymal enhancement patterns and to correlate these patterns with hepatic function and disease. Rapid T₁-weighted images were acquired before and after gadolinium administration. Hepatic enhancement patterns were analyzed blindly by two observers. Medical records were reviewed to document known liver pathology and liver function test results. A total of 72% of patients had homogeneous enhancement of the liver parenchyma; 28% had heterogeneous enhancement. Of the latter group, 61% of patients had enhancement conforming to segmental or lobar boundaries. Patients with heterogeneous enhancement patterns were more likely to have abnormal liver function test results and hepatic morphological abnormalities on their MR examinations than patients with homogeneous enhancement patterns. Heterogeneous hepatic enhancement on dynamic MR images is associated with a higher likelihood of liver disease and biochemical evidence of hepatic dysfunction than homogeneous enhancement.     

Measurement of K,Fe, Cu and Zn levels in secondary colorectal liver cancer and surrounding normal liver tissue,and their potential as a tissue classifier

An x‐ray fluorescence (XRF) system utilising a synchrotron radiation source was used to quantify the levels of Fe, Cu, Zn and K in colorectal liver metastases and surrounding normal liver tissue as a possible mechanism for detecting cancer in a tissue biopsy. Sixty samples were measured and a lower level of all four elements was found in the cancer samples compared with that of the normal liver. The difference in levels of Zn, Fe, Cu and K between cancer and normal tissue was significant with p values of < 0.01 for Zn, Fe and K, and 0.033 for Cu. The precision was estimated by repeated measurements yielding a precision of 96, 91, 95 and 86% for Zn, Cu, Fe and K, respectively. The homogeneity of the distribution of elemental concentrations was assessed by measuring eight normal liver and eight cancer samples from the same patient. The variation of Zn, Cu, Fe and K levels between normal liver samples was 10.4, 15.4, 15.85 and 29.1%, respectively, and in the colorectal metastases was 10.18, 15.92, 8.44 and 22.35%, respectively. Receiver operator characteristic (ROC) analysis was performed for all elements and showed that Zn could be a reliable indicator of tissue classification with an ROC area under the curve of 0.998 and a resulting sensitivity and specificity of 100 and 96.67%, respectively. Fe had an ROC area under the curve of 0.856 and sensitivity and specificity of 83.3 and 76.67%, respectively. Cu and K did not perform as well with areas under the curve of 0.75 and 0.706, respectively. Copyright © 2008 John Wiley & Sons, Ltd.     

Assessment of peripheral tissue perfusion disorder in streptozotocin-induced diabetic rats using dynamic contrast-enhanced MRI

Purpose

To assess peripheral tissue perfusion disorder in streptozotocin (STZ)-induced diabetic rats by using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).

Materials and Methods

A rat diabetes model was produced by intravenous injection of STZ. Diabetic rats were sustainably treated with either saline or insulin using an Alzet osmotic pump. Hind paw tissue perfusion was measured by signal intensity (SI) enhancement after gadolinium diethylenetriaminepentaacetic acid injection in DCE-MRI study and quantified using the initial area under the SI-time curve (IAUC). Peripheral tissue uptake of [¹⁴C]iodoantipyrine (IAP) was also determined as a marker of tissue blood flow for comparison with the IAUC value indicating tissue perfusion.

Results

STZ caused hyperglycemia at 1 and 2 weeks after injection. Treatment with insulin significantly alleviated hyperglycemia. At 2 weeks after STZ injection, peripheral tissue perfusion was clearly reduced in the diabetic rats and its reduction was significantly improved in the insulin-treated diabetic rats. Tissue perfusion evaluated by DCE-MRI was similar to the tissue blood flow measured by [¹⁴C]IAP uptake.

Conclusion

Our findings demonstrated that DCE-MRI can assess peripheral tissue perfusion disorder in diabetes. DCE-MRI could be suitable for noninvasive evaluation of peripheral tissue perfusion in both preclinical and clinical studies. It may also be useful for developing novel drugs to protect against diabetic vascular complications.     

Visualization of liver uptake function using the uptake contrast-enhanced ratio in hepatobiliary phase imaging

Purpose

To visualize liver uptake function using the uptake contrast-enhanced ratio in hepatobiliary phase (uptake CERH) magnetic resonance imaging.

Materials and methods

Thirty-seven patients with hepatocellular carcinoma (HCC) and 23 with metastatic liver cancer were evaluated. Hepatobiliary phase images were acquired 20 min after an intravenous bolus injection of gadoxetic acid disodium. We assumed that the contrast-enhanced ratio in the hepatobiliary phase (CERH) in the spleen was similar to the contrast-enhanced ratio in the extracellular matrix (CEREM). The Uptake CERH value was defined as the percentage signal gain between the precontrast and hepatobiliary phase images (without CEREM). The Uptake CERH value measured the tumor-free liver parenchyma. The association of the uptake CERH value with the biochemical liver function test results, and hepatocellular density in the liver parenchyma was assessed. Correlations were examined using Pearson correlation coefficient and the Mann–Whitney test.

Results

The uptake CERH value was correlated with albumin, bilirubin, indocyanine green retention rate at 15 min, prothrombin activity(%), platelet count, and cellular density in the liver parenchyma (p < 0.01).

Conclusions

Uptake CERH images are useful for visualizing liver uptake function.     

Validating fin tissue as a non-lethal proxy to liver and muscle tissue for stable isotope analysis of yellow perch (Perca flavescens)

Stable isotope ecology typically involves sacrificing the animal to obtain tissues. However, with threatened species or in long-term longitudinal studies, non-lethal sampling techniques should be used. The objectives of this study were to (1) determine if caudal fin tissue could be used as a non-lethal proxy to liver and muscle for stable isotope analysis, and (2) assess the effects of ethanol preservation on δ¹⁵N and δ¹³C in fin tissue of juvenile yellow perch Perca flavescens. The δ¹³C of caudal fin was not significantly different from liver (t₂₃?=??0.58; p?=?0.57), and was more correlated with δ¹⁵N in liver (r²?=?0.78) than muscle (r²?=?0.56). Ethanol preservation enriched ¹⁵N and ¹³C for caudal fins, but by using our developed regression models, these changes in δ¹⁵N and δ¹³C can now be corrected. Overall, caudal fin tissue is a more reliable proxy to liver than muscle for δ¹⁵N and δ¹³C in yellow perch.     

Assessment of the link between quantitative biexponential diffusion-weighted imaging and contrast-enhanced MRI in the liver

PurposeTo investigate if intravoxel incoherent motion (IVIM) modeled diffusion-weighted imaging (DWI) can be linked to contrast-enhanced (CE-)MRI in liver parenchyma and liver lesions.MethodsTwenty-five patients underwent IVIM-DWI followed by multiphase CE-MRI using Gd-EOB-DTPA (n = 20) or Gd-DOTA (n = 5) concluded with IVIM-DWI. Diffusion (D_slow), microperfusion (D_fast), its fraction (f_fast), wash-in-rate (R_early) and late-enhancement-rate (R_late) of Gd-EOB-DTPA were calculated voxel-wise for the liver. Parenchyma and lesions were segmented. Pre-contrast IVIM was compared 1) between low, medium and high R_early for parenchyma 2) to post-contrast IVIM substantiated with simulations 3) between low and high R_late per lesion type.ResultsD_fast and f_fast increased (P < 0.001) with 25.6% and 33.8% between low and high R_early of Gd-EOB-DTPA. D_slow decreased (− 15.0%; P < 0.001) with increasing R_early. Gd-DOTA demonstrated similar observations. f_fast (+ 10%; P < 0.001) and D_fast (+ 6.6%; P < 0.001) increased after Gd-EOB-DTPA, while decreasing after Gd-DOTA (− 4.2% and − 5.7%, P < 0.001) and were confirmed by simulations. For focal nodular hyperplasia lesions (n = 5) D_fast and f_fast increased (P < 0.001) with increasing R_late, whereas for hepatocellular carcinoma (n = 4) and adenoma (n = 7) no differences were found.ConclusionMicroperfusion measured by IVIM reflects perfusion in a way resembling CE-MRI. Also IVIM separated intra- and extracellular MR contrast media. This underlines the potential of IVIM in quantitative liver imaging.     

Step-down infusions of Gd-DTPA yield greater contrast-enhanced magnetic resonance images of BBB damage in acute stroke than bolus injections

A rat model of transient suture occlusion of one middle cerebral artery (MCA) was used to create a unilateral reperfused cerebral ischemic infarct with blood-brain barrier (BBB) opening. Opening of the BBB was visualized and quantitated by magnetic resonance (MR) contrast enhancement with a Look-Locker T(1)-weighted sequence either following an intravenous bolus injection (n=7) or during a step-down infusion (n=7) of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA). Blood levels of Gd-DTPA after either input were monitored via changes in sagittal sinus relaxation rate. Blood-to-brain influx constants (K(i)) were calculated by Patlak plots. On the basis of the MRI parameters and lesion size, the ischemic injury was determined to be similar in the two groups. The bolus injection input produced a sharp rise in blood levels of Gd-DTPA that declined quickly, whereas the step-down infusion led to a sharp rise that was maintained relatively constant for the period of imaging. Visual contrast enhancement and signal-to-noise (S/N) ratios were better with the step-down method (S/N=1.8) than with bolus injection (S/N=1.3). The K(i) values were not significantly different between the two groups (P>.05) and were around 0.005 ml/(g min). The major reason for the better imaging of BBB opening by the step-down infusion was the higher amounts of Gd-DTPA in plasma and tissue during most of the experimental period. These results suggest that step-down MR contrast agent (MRCA) administration schedule may be more advantageous for detection and delineation of acute BBB injury than the usually used bolus injections.     

Surface damage as a result of cavitation erosion

Erosion is regarded as a result of the periodic loading of a surface with spherical waves generated at the sites of the collapse of cavitation bubbles. One feature of cavitation loading is the formation of a zone of intense failure at the center of the contact surface. Damage appears a consequence of the formation of longitudinal cleavage cracks under the contact zone, which comprise a system of small annular cracks coaxial to a deep channel crack. The damage zone (blister) occupies a small fraction of the crater surface (the contact zone with the shock wave). The depth of the longitudinal cracks is an order of magnitude smaller than the thickness of the hardened layer. The hardening and erosion processes occur simultaneously. Zh. Tekh. Fiz. 68, 110–114 (September 1998)     

Contribution of intercellular links to ultrasonic absorption of liver tissue

The method discussed aims to characterize the ultrasonic absorption of liver tissues between 3 and 8.75 MHz by the slope of its linear variation with frequency. A transmission measuring device has been used and a data processing system has directly calculated this slope, which is reduced when the strength of intercellular links are lessened by mild treatment with trypsin, although the cells are left intact. This was performed on three batches of Wistar rats and the effect is explained mainly by reduction of the amplitude of relaxation processes dissipating energy in the cells.     

Nucleation of damage centres during ion implantation of silicon

Nucleation of damage centres in single crystal silicon held at room temperature and bombarded in a “random” direction with light ions is not at all times heterogeneous, as has sometimes been assumed. Homogeneous nucleation of interstitial clusters occurs at low ion fluences and this is characterized, for an extremely short period, by a linear dependence of the state of disorder on ion fluence, followed by a longer period during which disorder a (fluence)^1/2. During these periods of ‘nucleation’ and ‘primary growth’ small interstitial clusters behave as unsaturable traps. For higher fluences there is a smooth transfer to a form of damage increase which is not of displacement cascade origin. In this period of ‘secondary growth’ the state of disorder varies linearly with ion fluence, and interstitial clusters behave as nucleation traps.

It is shown how marked effects on the state of disorder due to changes in the mass of the bombarding ion, in the flux of the impinging beam, or in the temperature and impurity content of the bombarded crystal, can be simply traced to an early assistance for or a resistance to the onset of hetero- over homogeneous nucleation.     

Nuclear magnetic resonance study of iron overload in liver tissue

Whole-tissue and homogenized samples of human liver were studied in a NMR spectrometer, T1 and T2 relaxation times were measured as a function of added inorganic or organic iron. When inorganic iron (Fe+3) was added, pronounced T1 and T2 shortening was noted. However, when organic iron, in the form of ferritin, was added, the amount of T1 and T2 relaxation enhancement was much reduced for the same amount of added iron. The in vitro ferritin results model the situation found in clinical studies of hemochromatosis. Only in cases of severe iron overload were significant decreases in relaxation times observed. The T2 relaxation time was the more reliable indicator of excessive levels of iron in the liver. The large range of T1 and T2 values encountered in normal volunteers precludes the use of MR to quantitatively measure iron levels in the liver. The T1 and T2 relaxation times measured at intervals for one individual tend to fluctuate as well, making the use of MR to follow the course of treatment of iron overload disorders unreliable.     

Effect of mechanical tissue properties on thermal damage in skin after IR-laser ablation

The damage created instantaneously in dorsal skin and in the subjacent skeletal muscle layer after CO₂ and Er³⁺ laser incisions is histologically and ultrastructurally investigated. Light microscopical examinations show an up to three times larger damage zone in the subcutaneous layer of skeletal muscle than in the connective tissue above. The extent of thermally altered muscle tissue is classified by different zones and characterized by comparison to long time heating injuries. The unexpectedly large damage is a result of the change of elastic properties occurring abruptly at the transition between different materials. This leads to a discontinuity of the cutting dynamics that reduces the ejection of tissue material. We show that the degree of thermal damage originates from the amount of hot material that is not ejected out of the crater acting as a secondary heat source.     

Quantitative assessment of macromolecular concentration during direct infusion into an agarose hydrogel phantom using contrast-enhanced MRI

Convection-enhanced delivery (CED), that is, direct tissue infusion, has emerged as a promising local drug delivery method for treating diseases of the nervous system. Determination of the spatial distribution of therapeutic agents after infusion is important in evaluating the efficacy of treatment, optimizing infusion protocols and improving the understanding of drug pharmacokinetics. In this study, we provide a methodology to determine the concentration distribution of Gd-labeled tracers during infusion using contrast-enhanced magnetic resonance imaging (MRI). To the best of our knowledge, MR studies that quantify concentration profiles for CED have not been previously reported. The methodology utilizes intrinsic material properties (T₁ and R₁) and reduces the effect of instrumental factors (e.g., inhomogeneity of MR detection field). As a methodology investigation, this study used an agarose hydrogel phantom as a tissue substitute for infusion. An 11.1-T magnet system was used to image infusion of Gd-DTPA-labeled albumin (Gd-albumin) into the hydrogel. By using data from preliminary scans, Gd-albumin distribution was determined from the signal intensity of the MR images. As a validation test, MR-derived concentration profiles were found comparable to both results measured directly using quantitative optical imaging and results from a computational transport model in porous media. In future studies, the developed methodology will be used to quantitatively monitor the distribution of Gd tracer following infusion directly into tissues.