Measurement of proliferation activity in human melanoma xenografts by magnetic resonance imaging

Tumor proliferation may be predictive for malignant progression and response to fractionated therapy of cancer. The purpose of the present work was to investigate whether the proliferation activity of solid tumors can be assessed in vivo from the proton relaxation times, T1 and T2. Tumors of four amelanotic human melanoma xenograft lines were studied. Three parameters were used to represent tumor proliferation activity; the volume doubling time, Tvol, the potential doubling time, Tpot, and the fraction of cells in S-phase. Tvol was determined from volumetric growth data. Tpot and S-phase fraction were determined by flow cytometric analysis of tumor cells after bromodeoxyuridine (BrdU) incorporation in vivo. T1 and T2 were measured by 1H-MRI in vivo, using spin-echo pulse sequences. The proliferation parameters and relaxation times differed considerably among the tumor lines. Significant correlations were found between the proliferation parameters and the relaxation times, regardless of whether Tvol, Tpot, or S-phase fraction was considered. Tumors with short Tvol and Tpot and high S-phase fraction had long T1 and T2 compared to tumors with long Tvol and Tpot and low S-phase fraction. The elongated T1 and T2 of fast growing tumors were probably due to increased interstitial and/or intravascular water content. The present results suggest that in vivo spin-echo 1H-MRI can be used to discriminate between tumors of high and low proliferation activity.     

Intratumor heterogeneity in perfusion in human melanoma xenografts measured by contrast-enhanced magnetic resonance imaging

The perfusion in tumors shows substantial spatial heterogeneity compared to that in normal tissues. The aim of the present study was to evaluate the intratumor heterogeneity in perfusion in tumors of two amelanotic human melanoma xenograft lines, A-07 and R-18, grown intradermally in Balb/c nu/nu mice. A non-invasive contrast-enhanced magnetic resonance imaging method yielding results in absolute values was applied. The perfusion was determined in manually defined regions of interest, corresponding to a whole tumor or to subregions of a tumor. The mean perfusion and the intertumor heterogeneity in perfusion were similar for the two tumor lines. For whole A-07 tumors, the perfusion ranged from 0.089 mL/(g . min) to 0.20 mL/(g . min) [mean: 0.15 mL/(g . min)], and for whole R-18 tumors, from 0.030 mL/(g . min) to 0.17 mL/(g . min) [mean: 0.13 mL/(g . min)]. The intratumor heterogeneity, on the other hand, was estimated to be 6.4 times larger in A-07 tumors than in R-18 tumors. The highest perfusion values, up to 0.69 mL/(g . min), were found in subregions of A-07 tumors. The intratumor heterogeneity was substantially larger than the intertumor heterogeneity in A-07 tumors, whereas in R-18 tumors, the intratumor heterogeneity was similar to the intertumor heterogeneity. These observations imply that measurements of mean tumor perfusion may have limited value as a predictive assay for outcome of treatment.     

Reconstruction of dynamic contrast enhanced magnetic resonance imaging of the breast with temporal constraints

A number of methods using temporal and spatial constraints have been proposed for reconstruction of undersampled dynamic magnetic resonance imaging (MRI) data. The complex data can be constrained or regularized in a number of different ways, for example, the time derivative of the magnitude and phase image voxels can be constrained separately or jointly. Intuitively, the performance of different regularizations will depend on both the data and the chosen temporal constraints. Here, a complex temporal total variation (TV) constraint was compared to the use of separate real and imaginary constraints, and to a magnitude constraint alone. Projection onto Convex Sets (POCS) with a gradient descent method was used to implement the diverse temporal constraints in reconstructions of DCE MRI data. For breast DCE data, serial POCS with separate real and imaginary TV constraints was found to give relatively poor results while serial/parallel POCS with a complex temporal TV constraint and serial POCS with a magnitude-only temporal TV constraint performed well with an acceleration factor as large as R=6. In the tumor area, the best method was found to be parallel POCS with complex temporal TV constraint. This method resulted in estimates for the pharmacokinetic parameters that were linearly correlated to those estimated from the fully-sampled data, with K^trans,R=6=0.97 K^trans,R=1+0.00 with correlation coefficient r=0.98, k_ep,R=6=0.95 k_ep,R=1+0.00 (r=0.85). These results suggest that it is possible to acquire highly undersampled breast DCE-MRI data with improved spatial and/or temporal resolution with minimal loss of image quality.     

Measurement of thermal diffusivity by magnetic resonance imaging

Nuclear magnetic resonance (NMR) may be used for monitoring temperature changes within samples based on measurements of relaxation times, the diffusion coefficient of liquids, proton resonance frequency or phase shifts. Such methods may be extended to the explicit measurement of the thermal diffusivity of materials by NMR imaging. A method based on measuring nuclear spin phase shifts or changes in the equilibrium nuclear magnetization has been developed for measuring transient thermal diffusion effects and thermal diffusivity with potential applications in NMR thermotherapy and materials science. In this method, a thermal pulse is applied to a medium, and the resultant temporal variations of the nuclear spin phase or of the magnitude of the nuclear magnetization produced by the thermal pulse are monitored at a spatial distance. The results obtained on common fluids agree well with the data from other methods.     

Potential contrast agents for magnetic resonance imaging

The development ofmagneto-pharmaceuticals plays an important role in the extension of nuclear magnetic resonance into diagnostic medicine. That is the reason why fundamental investigations leading to new insights into NMR contrast agents are presently being considered. The synthesis and the proton relaxation rates of some new contrast agents are presented. The high values ofR ₁, andR ₂ relaxivities of the compounds studied by us are promising for various and novel applications.     

Optimizing tissue contrast in magnetic resonance imaging

Magnetic resonance imaging demands that tissue contrast and signal-to-noise advantages be sought in each component of the imaging system. One component of magnetic resonance imaging in which contrast and signal-to-noise ratios are easily manipulated is in the choice of pulse sequences and interpulse delay times. This article provides a general method for determining the best choices of interpulse delay times in pulse sequences and applies that method to saturation recovery, inversion recovery, and spin-echo sequences. Saturation recovery and inversion recovery sequences with rephasing pulses, and tissues with unequal hydrogen densities are considered. Optimization of pulse sequences is carried out for the two distinct cases of (a) a fixed number of sequence repetitions and (b) a fixed total imaging time. Analytic expressions are derived or approximate expressions are provided for the interpulse delay times that optimize contrast-to-noise ratios in each pulse sequence. The acceptable range of interpulse delay times to obtain reasonable contrast using each pulse sequence is discussed.     

Macroscopic tumor volume of malignant glioma determined by contrast-enhanced magnetic resonance imaging with and without magnetization transfer contrast

The purposes of this study were to compare the conspicuity and lesion volume of contrast-enhancing macroscopic malignant glioma determined by postcontrast magnetic resonance (MR) imaging with and without magnetization transfer (MT) saturation, and to discuss possible implications for radiotherapy planning. Nineteen patients (age 24–60 years) with histologically proven malignant glioma were prospectively examined by MR imaging. After the administration of gadolinium dimeglumine (0.1 mmol/kg body weight), the lesions were imaged with an MT-weighted FLASH (fast, low-angle shot) pulse sequence and with a conventional T₁-weighted spin-echo (SE) sequence without MT saturation. The mean tumor volumes of gliomas measured on MT-weighted FLASH images were significantly (p < .01) larger than those obtained from T₁-weighted SE images (45 ± 15 cm³ vs. 33 ± 10 cm³). The mean contrast-to-noise ratio of enhancing lesions on MT-weighted FLASH was 48 ± 14 compared with 30 ± 14 on SE images, representing a significant (p < .01) improvement. We conclude that the volume of contrast enhancement of malignant glioma identified on MT-weighted FLASH images represents the area of disrupted blood-brain barrier. If this volume of subtle contrast enhancement is caused by tumor infiltration and represents the boost target volume for stereotactic radiosurgery or brachytherapy, MT-weighted FLASH images would be better than T₁-weighted SE images to define these volumes. These improved delineation of areas at highest risk for recurrence following radiation therapy should enhance the efficacy of treatment planning for high-boost therapy.     

Measurement of BAT activity by targeted molecular magnetic resonance imaging

ObjectiveThe aim of this study was to measure brown adipose tissue (BAT) activity by targeted peptide (CKGGRAKDC-NH2)-coupled, polyethylene glycol (PEG)-coated ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles with magnetic resonance imaging (MRI).MethodsThe peptide was conjugated with PEG-coated USPIO to obtain targeted probes. Male C57BL/6 J mice were randomly divided into cold exposing and control group (n = 5 per group). T2*-weighted images were obtained pre- and post-contrast probes. Histological and gene expression analyses were carried out.ResultsT2* relaxation time of BAT in the cold exposing group decreased more significantly compared to the control group. The calculated R2* increased with the reduction of T2* value. The ΔR2* (26.68 s⁻¹) of BAT in the cold exposing group was significantly higher (P < 0.05) than the control group. Iron particle sediments in BAT of the cold exposing group were revealed more than the control group with Prussian blue staining. The UCP1 expression level was up-regulated after cold activation.ConclusionsBAT activity could be measured in vivo by the targeted peptide-coupled, PEG-coated USPIOs with MRI.     

Assessment of extravascular extracellular space fraction in human melanoma xenografts by DCE-MRI and kinetic modeling

Tumor aggressiveness and response to therapy are influenced by the extravascular extracellular space fraction (EESF) of the malignant tissue. The EESF may, therefore, be an important prognostic parameter for cancer patients. The aim of this study was to investigate whether gadopentetate dimeglumine (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can be used to assess the EESF of tumors. Amelanotic human melanoma xenografts (A-07, R-18) were used as preclinical models of human cancer. Images of E.F (E is the initial extraction fraction of Gd-DTPA and F is perfusion) and lambda (the partition coefficient of Gd-DTPA) were obtained by Kety analysis of DCE-MRI data. Our study was based on the hypothesis that lambda is governed by the EESF and is not influenced significantly by microvascular density (MVD) or blood perfusion. To test this hypothesis, we searched for correlations between lambda and E.F, MVD or EESF by comparing lambda images with E.F images, histological preparations from the imaged tissue and the radial heterogeneity in EESF obtained by invasive imaging. Positive correlations were found between lambda and EESF. Thus, median lambda was larger in A-07 tumors than in R-18 tumors by a factor of 4.2 (P<.00001), consistent with the histological observation that EESF is approximately fourfold larger in A-07 tumors than in R-18 tumors. The radial heterogeneity in lambda in A-07 and R-18 tumors was almost identical to the radial heterogeneity in EESF. Moreover, lambda was larger in tissue regions with high EESF than in tissue regions with low EESF in A-07 tumors (P=.048). On the other hand, significant correlations between lambda and MVD or E.F could not be detected. Consequently, Kety analysis of Gd-DTPA-based DCE-MRI series of xenografted tumors provides lambda images that primarily reflect the EESF of the tissue.     

Gadolinium oxide: a protoype agent for contrast enhanced imaging of the liver and spleen with magnetic resonance

Gd2O3 particles (less than 2 microns) in suspension were evaluated as a potential contrast agent for liver-spleen imaging with magnetic resonance. The agent was administered IV to rabbits in doses ranging from 10 to 120 mumol/kg and the tissues removed after sacrifice for in vitro T1 and T2 analysis. The temporal response was determined in liver and spleen samples of rabbits given a fixed dose (60 mumol/kg) and sacrificed at intervals from 15 min to 60 hr later. Documentation of the subanatomic location of Gd2O3 particles in tissue was accomplished by electron microscopy and x-ray dispersion microanalysis. T1 weighted images were obtained at 0.12T on a prototype resistive scanner. The liver, spleen, and lung relaxation times are very responsive to Gd2O3 IV and the effect is dose related. A peak effect is observed between 3-7 hr after injection and relaxation times may normalize by 60 hr. By electron microscopic and x-ray analysis, Gd2O3 is most prominently found in the hepatic and splenic sinusoids. The images show marked enhancement of liver and splenic tissues, aiding in the clear delineation of these tissues from neighboring structures.     

Phase detection and contrast loss in magnetic resonance imaging

Several recent articles have assessed the relative efficiency of nuclear magnetic resonance (NMR) pulse sequences. One consideration that has received little attention is the effect on image contrast of displaying images without information on the sign of the reconstructed signals. The radiofrequency receivers currently used on most NMR imaging systems are quadrature detectors that preserve both the magnitude and sign of the NMR signal. Usually, however, sign or phase information is not used in the final image presentation. We point out that in imaging sequences that may have negative signals, such as inversion recovery, this loss of sign information produces a reduction in contrast between some tissues in an NMR image. We discuss the tissue parameters and interpulse delay times that result in contrast loss in inversion recovery and indicate the extent of contrast loss. We point out that for some tissues with unequal hydrogen spin densities, the region of contrast loss coincides with the region where maximum contrast would occur if sign information were preserved.     

Measurement of regional cerebral glucose uptake by magnetic resonance spin-lock imaging

Purpose

The regional uptake of glucose in rat brain in vivo was measured at high resolution using spin-lock magnetic resonance imaging after infusion of the glucose analogue 2-deoxy-d-glucose (2DG). Previous studies of glucose metabolism have used ¹³C-labeled 2DG and NMR spectroscopy, ¹⁸F-labeled fluorodeoxyglucose (FDG) and PET, or chemical exchange saturation transfer (CEST) MRI, all of which have practical limitations. Our goal was to explore the ability of spin-lock sequences to detect specific chemically-exchanging species in vivo and to compare the effects of 2DG in brain tissue on CEST images.

Methods

Numerical simulations of R_1p and CEST contrasts for a variety of sample parameters were performed to evaluate the potential specificity of each method for detecting the exchange contributions of 2DG. Experimental measurements were made in tissue phantoms and in rat brain in vivo which demonstrated the ability of spin-lock sequences for detecting 2DG.

Results

R_1p contrast acquired with appropriate spin-lock sequences can isolate the contribution of exchanging protons in 2DG in vivo and appears to have better sensitivity and more specificity to 2DG–water exchange effects than CEST.

Conclusion

Spin-lock imaging provides a novel approach to the detection and measurement of glucose uptake in brain in vivo.     

Virtual non-contrast enhanced magnetic resonance imaging (VNC-MRI)

PurposeApplication of contrast agents (CA) is widely used in various clinical fields like oncology. Similar to approaches used in computed tomography, virtual non-contrast enhanced (VNC) images can be generated with the goal to supersede true non-contrast enhanced (TNC) images.MethodsIn MRI a T1-mapping sequence with variable flip angle (VFA) was used to acquire two images with different image contrast at the same time. To generate VNC images postprocessing based on this technique, an image-space based material decomposition algorithm was used. The inverse of a sensitivity matrix, consisting of intensity values for both VFA images and every material respectively, was used to determine the three material fractions and to calculate the final VNC images. The technique was tested on a 3 T scanner using a phantom and two in-vivo scans of patients with glioma and glioblastoma respectively. In all these cases the required six values were manually derived from the respective material or the background from both VFA images.ResultsPostprocessing results of the phantom show that the chosen materials can be separated and visualized individually and unwanted materials can be suppressed. In the VNC images of in-vivo scans the signal of the CA is removed successfully.ConclusionIt was shown that VNC images that match the visual impression of the TNC images can be generated, resulting in possibly reduced scan times and avoided mismatches due to movement of the patient.     

New image contrast method in magnetic resonance imaging via ultrasound

When applied to a sample, ultrasound (US) gives rise to a displacement of tissue and a flow in a liquid due to the acoustic radiation pressure. These movements depend on the viscoelastic properties of the sample and can be visualized precisely with an MRI scanner using diffusion- sensitive pulse sequences. In this paper, measurements will be presented, which show the visualization of the US under variation of its parameters in different liquids and in tissue.     

Paramagnetic oil emulsions as oral magnetic resonance imaging contrast agents

The combination of a paramagnetic agent with an oil emulsion can uniformly enhance the small bowel. We discovered that the entire small bowel becomes homogeneously brighter than its surroundings when imaged with all commonly utilized pulse sequences. We have tried various combinations of ferric ammonium citrate, ferrous sulfate, gadolinium-DPTA and corn oil, olive oil and peanut oil. All paramagnetic oil emulsions tested were uniformly distributed throughout the small bowel, but the enhancement effect is much stronger with the ferric ammonium citrate and gadolinium-DPTA oil emulsions. We have also developed a mixture of Geritol, corn oil, ice cream and milk, which uniformly coats the small bowel wall, has good enhancement effect, tastes good, and is nutritious. With this dietary contrast, retroperitoneal structures including the pancreas can be well delineated. We conclude that the combination of a paramagnetic agent with an oil emulsion can work as a safe and effective magnetic resonance imaging (MRI) oral contrast agent with high patient acceptance.