Contrast Agent Kinetics Research Articles

Prediction of Clinicopathologic Response of Breast Cancer to Primary Chemotherapy at Contrast-enhanced MR Imaging: Initial Clinical Results

To prospectively document changes in contrast agent kinetics in patients with primary breast cancer treated with systemic chemotherapy after one or two cycles and to determine whether kinetic measures can be used to predict final clinicopathologic response. Institutional committees on clinical research and ethics approval and patient consent were obtained. Dynamic magnetic resonance (MR) examinations were performed in 25 women with primary breast cancer before treatment and after the first (n = 21) and second (n = 15) cycle of neoadjuvant chemotherapy. Kinetic parameters (transfer constant, leakage space, and rate constant) were derived for whole tumor regions of interest. Changes in histogram distributions of pixel data (median value and range) and MR imaging-derived size were correlated with final clinical and histologic response by using nonparametric methods. Receiver operating characteristic (ROC) analysis of tumor size and transfer constant changes were used to identify patients in whom no benefit was gained from chemotherapy. After the first cycle of treatment, 12 of 14 clinical responders showed decreases in tumor size, and six of seven nonresponders showed increases or no change in tumor size (P < .001). Transfer constant changes did not differ between responders and nonresponders for either clinical or pathologic assessments. After two cycles of treatment, there were tumor size increases in five of six nonresponders compared with decreases in eight of nine responders (P < .001). Reductions in transfer constant range were also observed in responders for both clinical and pathologic assessments (P = .008 and .02, respectively). No other kinetic parameter change predicted response. Size and transfer constant range were equally accurate for predicting the absence of pathologic response after two cycles of treatment (sensitivity, specificity, and area under ROC curve were 100%, 90%, and 0.93, respectively, for size and 100%, 75%, and 0.94, respectively, for transfer constant range). Reductions in MR imaging-determined size of the primary tumor best predict clinicopathologic response of breast cancer after one cycle of neoadjuvant chemotherapy. Transfer constant and size changes are equally sensitive in the identification of patients who would gain no clinical or pathologic benefit after two cycles of treatment.

Magnetic Resonance Imaging Workbench: Analysis and Visualization of Dynamic Contrast-enhanced MR Imaging Data

Magnetic Resonance Imaging Workbench (MRIW) allows analysis of T1- and T2*-weighted dynamic contrast-enhanced magnetic resonance imaging data sets to extract tissue permeability and perfusion characteristics by using standard pharmacokinetic models. Parametric maps are calculated from individual pixel enhancement curves in regions of interest (ROIs) and displayed as color overlays on the anatomic images. User-defined ROIs can be saved to ensure consistency of later reanalysis. Individual parametric maps are visualized together with user-selected parameter time-series plots. The following selections are available: overall ROI enhancement curve and fit, histogram, and individual pixel enhancement curve and fit. Summary data (transfer constant, leakage space, rate constant, integrated area under the gadolinium curve after 60 seconds, relative blood volume, relative blood flow, and mean transit time) may be exported to permanent storage along with per-pixel results for statistical analysis. Numerical values for parameters are displayed below the plot for easy reference. The dynamic range of plots and parametric map overlays is interactively adjustable. Viewing individual enhancement curves and parametric maps allows radiologists to investigate the heterogeneity of contrast agent kinetics for lesion characterization and to scrutinize serial changes in response to therapy. MRIW is written in IDL, enabling it to be used on a variety of computer systems.

The quantification of absolute myocardial perfusion in humans by contrast echocardiography: Algorithm and validation

We sought to test whether myocardial blood flow (MBF) can be quantified by myocardial contrast echocardiography (MCE) using a volumetric model of ultrasound contrast agent (UCA) kinetics for the description of refill curves after ultrasound-induced microsphere destruction. Absolute myocardial perfusion or MBF (ml.min(-1).g(-1)) is the gold standard to assess myocardial blood supply, and so far it could not be obtained by ultrasound. The volumetric model yielded MBF = rBV.beta/rho(T), where rho(T) equals tissue density. The relative myocardial blood volume rBV and its exchange frequency beta were derived from UCA refill sequences. Healthy volunteers underwent MCE and positron emission tomography (PET) at rest (group I: n = 15; group II: n = 5) and during adenosine-induced hyperemia (group II). Fifteen patients with coronary artery disease underwent simultaneous MCE and intracoronary Doppler measurements before and during intracoronary adenosine injection. In vitro experiments confirmed the volumetric model and the reliable determination of rBV and beta for physiologic flow velocities. In group I, 187 of 240 segments were analyzable by MCE, and a linear relation was found between MCE and PET perfusion data (y = 0.899x + 0.079; r(2) = 0.88). In group II, resting and hyperemic perfusion data showed good agreement between MCE and PET (y = 1.011x + 0.124; r(2) = 0.92). In patients, coronary stenosis varied between 0% to 89%, and myocardial perfusion reserve was in good agreement with coronary flow velocity reserve (y = 0.92x + 0.14; r(2) = 0.73). The volumetric model of UCA kinetics allows the quantification of MBF in humans using MCE and provides the basis for the noninvasive and quantitative assessment of coronary artery disease.

Quantification of perfusion of liver tissue and metastases using a multivessel model for replenishment kinetics of ultrasound contrast agents

Low-MI (mechanical index) ultrasound allows real-time observation of replenishment kinetics after destruction (“flash”) of ultrasound contrast agents (USCA). We developed an examination protocol and a mathematical model to quantify perfusion of liver tissue and hepatic metastases. Using a modified multivessel model, we attempted a consistent, physiological description of microbubble replenishment in liver tissue. Perfusion parameters were calculated, separately for the arterial and portal venous phase of liver perfusion, using an i.v. bolus injection of 2 × 2.4 mL SonoVue®. The model was evaluated for 10 examinations of liver metastases using flash/low-MI imaging. In contrast to the established, exponential model, the new model consistently describes the sigmoid replenishment of USCA measured in vivo, using flash/low-MI imaging. Parameters for blood volume, blood velocity and blood flow in liver tissue and metastases can be calculated during the arterial and the portal venous phase after a CA bolus injection. The median arterial perfusion in the examined liver metastases was more than 2.5 times higher than in normal liver tissue, whereas the median perfusion during the portal venous phase was more than five times higher in the liver tissue than that in metastases. Microbubble replenishment measured with flash/low-MI US techniques can be consistently analyzed using the multivessel model, even after a bolus injection of USCA. This allows for the quantification of perfusion of liver tissue and hepatic metastases and provides promising parameters of tissue viability and tumor characterization. (E-mail: m.krix@dkfz.de)

A multivessel model describing replenishment kinetics of ultrasound contrast agent for quantification of tissue perfusion

To improve the quantification of tissue perfusion using intermittent sonography, a new model describing replenishment kinetics of microbubbles is proposed. The new approach takes into account the variability of blood flow velocities found in vivo, especially in tumors, and consistently describes the refilling process of microbubbles. Based upon this model, blood volume, blood velocity, blood flow and perfusion in 17 experimental tumors were calculated, and compared with the results obtained with the established, phenomenologically derived exponential kinetic model. In contrast to the existing model, our approach describes tissue vascularization more physiologically and allows deduction of a consistent new hyperbolic model for quantification of intermittent sonography. Blood volume and mean blood velocity did significantly correlate between both the new and the established model (k = 0.99; k = 0.94, both p < 0.001). However, mean tumor blood velocity was lower (−19%, p < 0.01) with the established model compared to the newly developed model. In addition, the range and distribution of blood flow velocities found in vivo can be estimated with the new model. Furthermore, it uses simpler mathematical fitting routines and allows easier data acquisition, which may allow a more practicable clinical application of intermittent sonography. In conclusion, a more valid, detailed and accurate calculation of perfusion parameters, especially of tumors, can be derived in vivo with the new multivessel model of intermittent sonography. (E-mail: m.krix@dkfz.de)

Hepatic Kinetics of MRI Contrast Agents in the Isolated Perfused Rat Liver

Most findings concerning the hepatic kinetics of the extracellular contrast agent Gd-DTPA/Dimeg have been obtained in vivo following a systemic injection. Moreover, the hepatic transport of another contrast agent Gd-BOPTA/Dimeg which enters into hepatocytes has only been studied in isolated hepatocytes, hepatic canalicular membrane vesicles, or oocytes transfected with the cRNA of the transporter. No study clearly defined the transport of Gd-BOPTA/Dimeg in the entire liver. The aim of our study was then to compare the hepatic kinetics of Gd-BOPTA/Dimeg and Gd-DTPA/Dimeg in the isolated perfused rat liver and to evidence the hepatic transport of Gd-BOPTA/Dimeg.

Assessment of tumor oxygenation in human cervical carcinoma by use of dynamic Gd-DTPA-enhanced MR imaging.

Increased knowledge of the physiological basis behind the signal enhancement in tumors during dynamic contrast-enhanced magnetic resonance (MR) imaging may be useful in development of predictive assays based on this technique. In the present work, the relative signal intensity (RSI) increase in gadopentetate dimeglumine (Gd-DTPA)-enhanced MR images of patients with cervical carcinoma was related to tumor perfusion, vascular density, cell density, and oxygen tension (pO(2)). The patients were subjected to MR imaging before the start of treatment (N = 12) and after two weeks of radiotherapy (N = 8). Perfusion was determined from the kinetics of contrast agent in tumors and arteries, vascular density and cell density were determined from tumor biopsies, and pO(2) was determined by polarographic needle electrodes. The maximal RSI was correlated to perfusion (P = 0.002) and cell density (P = 0.004), but was not related to vascular density. There was also a correlation between pO(2) and perfusion (P < 0.001). Moreover, pO(2) tended to be correlated to cell density (P = 0.1), but was not related to vascular density. There was a significant correlation between RSI and pO(2), regardless of whether the median pO(2) (P < 0.001) or the fraction of pO(2) readings below 2.5 mmHg (P < 0.001), 5 mmHg (P < 0.0001), or 10 mmHg (P < 0.001) was considered. Our results suggest that the Gd-DTPA-induced signal enhancement in MR images of cervical tumors is influenced by both perfusion and cell density. These parameters are also of major importance for tumor oxygenation, leading to a correlation between signal enhancement and oxygenation. Dynamic contrast-enhanced MR imaging may therefore possibly be useful in prediction of treatment outcome.

The influence of Doppler system settings on the clearance kinetics of different ultrasound contrast agents

Objective: To evaluate the influence of different Doppler system settings on time–intensity curves after ultrasound contrast agent (UCA) bolus injection. This is important for the comparison of different UCAs. Methods: Six sedated dogs were investigated with a transcranial Doppler system and Doppler power, sample volume size and high pass filter settings were modified during the procedure. Mean time intensity curves were determined and peak values of mean intensity as well as the decrease in Doppler intensity were compared for the different system settings. Three different UCAs were used (SonoVue™, BY963 and Levovist™). Results: The Doppler time intensity curves showed a typical two phase decrease with a distribution phase α and an elimination phase β with all three UCAs. Altering the system settings had a significant effect on the mean peak Doppler intensity for SonoVue™ ( P=0.02) but not for BY963 or Levovist™ ( P=0.07 and P=0.39, respectively), due to high variation of the Levovist™ and BY963 intensity values. There were no significant differences between the α slopes of BY963 and Levovist™ ( P=0.96), or the β slope of Levovist™ and SonoVue™ ( P=0.62), when the results of all system settings were combined. Conclusion: Different Doppler system settings show no significant influence on the decrease of mean Doppler intensity, but have a significant effect on peak intensity.

Simultaneous assessment of cerebral hemodynamics and contrast agent uptake in lesions with disrupted blood-brain-barrier.

The purpose of this study was to develop a method that eliminates the influence of the T1 relaxation time upon the signal-time course in perfusion-weighted imaging of cerebral lesions with blood-brain-barrier (BBB) disruption. On a 1.5 T whole body clinical magnetic resonance (MR) imager, we implemented a dual-echo RF-spoiled FLASH sequence (TE=6/23.6 ms). We developed a postprocessing routine that allowed to calculate a signal-time course representing only the change in T2* and another one representing only the change in T1. Using this method, we examined 7 patients with various brain lesions showing evidence of BBB disruption. In the signal-time-curves obtained from the early echo we found a distinct signal drop due to the T2* effect. These effects could be eliminated by the correction algorithm yielding a 67% higher signal increase. Correction of the signal-time curve of the late echo yielded a more pronounced maximum signal drop and a decrease in postcontrast signal intensity. We found that without this correction the relative regional cerebral blood volume and the first moment of the concentration-time curve were underestimated by 72% and 22%, respectively. The dual echo-sequence combined with the postprocessing algorithm separates T1 and T2* effects and thus allows to assess cerebral hemodynamics and contrast agent kinetics simultaneously. This method may be a useful tool for characterizing, staging, and therapy monitoring of brain tumors.

Magnetic resonance imaging of anatomic and vascular characteristics in a canine model of human aging

Dogs exhibit both neuroanatomical and cognitive changes as a function of age that parallel those seen in aging humans. This study describes in vivo changes in neuroanatomical and cerebrovascular characteristics of the canine brain as a function of age in a group of dogs ranging from 4 to 15 years old. Dynamic contrast-enhanced magnetic resonance imaging (MRI) was used to measure the kinetics of contrast agents in the brain. Measures of vascular volume and blood-brain barrier (BBB) permeability were derived from a pharmacokinetic analysis. Cortical atrophy and ventricular enlargement were characteristic features of the aged canine brain. Vascular volume did not vary as a function of age and BBB permeability exhibited a nonsignificant increasing trend with age. However, BBB dysfunction was detected in one middle-aged dog that in addition to having unusually large ventricles, demonstrated an early onset of diffuse senile plaques at postmortem. These findings indicate that BBB dysfunction detected by magnetic resonance imaging may be useful for predicting and potentially diagnosing early pathological conditions.

Dynamic MR imaging of the breast combined with analysis of contrast agent kinetics in the differentiation of primary breast tumours

To assess dynamic Gd-DTPA-enhanced magnetic resonance (MR) imaging in the diagnosis of primary breast pathology, and to test the hypothesis that analysis of contrast agent kinetics increases specificity. Forty-seven women underwent breast MR imaging using three-dimensional and dynamic spoiled gradient-recalled sequences. Image interpretation was based on the evaluation of lesion conspicuity, signal intensity, contour and enhancement pattern from the static acquisitions. Assessment of contrast kinetics was based on pixel-by-pixel analysis of the dynamic data. A two-compartment model described by three parameters (amplitude of uptake, exchange rate and washout rate), and a three-compartment model described by two parameters (permeability and exchange rate) were used. Regions of interest were drawn for all lesions found in the dynamic sections. Mean regional pixel values were calculated for each parameter and tested for diagnostic efficacy. Twenty-two malignant and 36 benign lesions were examined. Fibroadenomas accounted for 86% of the benign tumours. Image interpretation had a sensitivity of 0.95 and specificity of 0.86. The fat-suppressed post-contrast images permitted good visualization of the contour and matrix characteristics of fibroadenomas, but all non-fibroadenomatous benign lesions were classified as indeterminate or suspicious. Significant differences were found between benign and malignant lesions in the amplitude of uptake (P = 0.0008) and exchange rate (P < 0.00005) of the two-compartment model, and permeability (P=0.0001) and exchange rate (P < 0.00005) of the three-compartment model. However, image interpretation was superior to the isolated use of quantitative indices (P=0.02). The most discriminating parameters were the exchange rates of both models, with no significant difference between them. Assessment of lesion morphology is essential and probably sufficient for the differentiation of fibroadenomas from malignant tumours. However, specificity of conventional MR imaging may be much lower for other types of primary benign breast pathology. Analysis of Gd-DTPA kinetics improves the specificity obtained using simple enhancement measurements and can be used to produce parametric images that provide information about lesion heterogeneity, permeability and vascularity.

Differentiation of Spontaneous Canine Breast Tumors Using Dynamic Magnetic Resonance Imaging with 24-Gadolinium-DTPA-Cascade-Polymer, A New Blood-Pool Agent

The author assess the enhancement characteristics over time of spontaneous breast tumors in dogs comparing gadopentetate dimeglumine with a new blood-pool agent (24-gadolinium [Gd]-DTPA-cascade polymer). Eighteen dogs with spontaneous breast tumors (5 carcinomas, 4 adenomas, and 9 benign mixed-tissue tumors) underwent dynamic magnetic resonance imaging after intravenous injection of gadopentetate dimeglumine and the blood-pool agent. Signal intensity time curves were followed up to 30 minutes after injection of both agents in the same animal. A nonlinear fitting routine enabled calculation of the delivery and clearance half lives of the contrast agent kinetics in each tumor. For gadopentetate dimeglumine, a fast signal increase was found immediately after intravenous injection, with a subsequent signal decay in all tumors. No difference was observed between the enhancement kinetics of different tumor types after gadopentetate dimeglumine application. Similar kinetics were found in benign lesions after injection of the blood-pool agent. However, in carcinomas the blood-pool agent displayed a slower delivery, delayed peak enhancement, and slower tumor tissue clearance or even a signal plateau of more than 30 minutes. Dynamic magnetic resonance imaging of breast neoplasms using a blood-pool agent may help to better differentiate between benign and malignant lesions because it demonstrates the enlarged interstitial space and increased capillary permeability in carcinomas.

The Doppler kinetics of microbubble echo contrast

The right and left heart kinetics of a saccharide-based microbubble echo contrast agent were measured in 11 anesthetized dogs using Doppler intensity as a measure of microbubble concentration while controlling for the dose administered, weight of the subject and cardiac output. A two-phase Doppler time-intensity curve was noted in all vascular regions. A brief first pass effect (phase 1) was found to depend on the contrast dose, cardiac output and subject size. This was followed by a much longer nearly steady-state elevation in the Doppler intensity compared with baseline (phase 2). The kinetics of phase 2 were found to be the same in all vascular distributions and independent of cardiac output. The phase 2 kinetics depend on the contrast dose, subject size and elimination characteristics of the contrast agent. The clinically important conclusions are: (1) the magnitude of Doppler enhancement and duration of the contrast effect can be predicted using the simple formulas presented; (2) the flow-dependent portion of the arterial contrast effect is effectively over only a few seconds after intravenous injection; and (3) the kinetics of phase 2 are the same throughout the body.

Quantitative analysis of GD-DTPA enhanced dynamic MR images by simplex minimization

The introduction of fast clinical imaging techniques enables the dynamic sampling of contrast agent kinetics. The quantity of data generated by such techniques demands the application of automated analysis tools to provide objective assessments of contrast washin/washout characteristics across an entire image. Using a simple compartmental model, the washin/washout characteristics may be defined in terms of a biexponential function. Curve fitting to this nonlinear function may be approached using a nonlinear least squares technique. We demonstrate an alternative technique, simplex minimization, to be more robust in a comparative study using Monte Carlo simulation. The application of the technique is illustrated by pixel-by-pixel analysis of dynamic data obtained from a patient with primary carcinoma of the breast.

Recent advances in MR imaging/spectroscopy of cerebral ischemia.

Recent advances in high-resolution MR imaging and multinuclear spectroscopy have stimulated studies of the functional relationships between tissue hypoperfusion, cellular energy depletion, and brain edema associated with cerebral ischemia. The very slow (microns/sec) random translational motion of water protons in various brain tissues and intracranial fluid compartments can now be assessed with MR diffusion imaging. More slowly diffusing protons in ischemic tissues can be differentiated from normal parenchyma, CSF, and flowing blood, enabling the detection and localization of ischemic regions within minutes of the onset of stroke. Perfusion imaging "snapshots," obtained in as little as 25 msec with echoplanar MR methods, permit the evaluation of tissue washin/washout kinetics of contrast agents in the microvasculature, and thus the quantification of brain perfusion on a regional basis. Also, delineation of major intra- and extracranial arterial and venous structures with MR angiography, acquired with two- or three-dimensional Fourier transformation techniques, has enabled accurate noninvasive assessments of vascular occlusive disease. Finally, improvements in MR spectroscopic techniques have facilitated investigations of metabolic regulation and bioenergetics in experimental animal models of cerebral ischemia, as well as in stroke patients. Combined MR imaging and spectroscopy will likely play an important role in differentiating reversibly from irreversibly ischemic brain tissues and in the investigation of various neuroprotective pharmaceuticals.