Evaluation of CH3-DTPA-Gd (NMS60) as a new MR contrast agent: early phase II study in brain tumors and dual dynamic contrast-enhanced imaging

PURPOSE: A newly developed contrast material, CH3-DTPA-Gd (NMS60), a trimer containing 3 Gd(3+) atoms per molecule, has been shown to offer greater enhancement and longer vascular retention than gadopentetate dimeglumine (Gd-DTPA) in animals. We report on our early phase II study on NMS60 in brain tumor patients together with supplementary investigations. METHODS AND MATERIALS: The longitudinal relaxation rate (R(1)=1/T(1)) and the transverse relaxation rate (R(2)*=1/T(2)*) of NMS60 and Gd-DTPA were determined at 20 degrees C in water at 1.5 T. An NMS60 dose of 0.1 or 0.2 mmol (Gd)/kg was randomly assigned and administered to 10 patients (five women, five men; mean age: 49 years) with brain tumors. Safety and contrast-enhancing ability of NMS60 were evaluated. Dual dynamic contrast-enhanced T(1) and R(2)* studies (DUCE imaging) were also carried out in two patients. RESULTS: Regarding the relaxivity per Gd, R(1) and R(2)* of NMS60 were 9.5 and 11.0 (mmol/L x s)(-1), respectively, compared to 4.8 and 7.2 (mmol/L x s)(-1) for Gd-DTPA. Although a transient slight increase of alanine aminotransferase was observed in one case, no other adverse reactions were observed after administration of NMS60. Contrast enhancement by NMS60 was excellent at both concentrations, and when tumor detectability was assessed with a five-point scale, the diagnostic usefulness was 4 or higher in all cases. In DUCE imaging, NMS60 appeared to show high signal intensity, when compared with the data obtained separately for Gd-DTPA. CONCLUSION: NMS60 had a high contrasting effect and little toxicity, and is expected to be clinically useful.     

Characterizing blood volume fraction (BVF) in a VX2 tumor

OBJECTIVES: Neovascular proliferation of a tumor's blood supply is an important precursor of malignant growth. Evaluation of blood volume may provide useful information for the characterization, prognosis and response of tumors to therapy. The purpose of this study was to determine and compare the blood volume of tumor tissue measured noninvasively by MRI and microbubble contrast ultrasound imaging. MATERIALS AND METHODS: Twenty-two rabbits injected with VX2 tumors were studied. The blood volume fraction in tumor and muscle tissue was obtained from MRI T(1)-weighted images using a blood-pool agent, Clariscan, and by ultrasound using Definity and pulse inversion imaging. RESULTS AND CONCLUSIONS: Similar results were obtained from MRI and ultrasound. Estimation of the blood volume in tissue in the rim of a VX2 tumor 1.5 to 5.0 cm in diameter relative to that in the surrounding muscle was (mean+/-S.D.) 3.31+/-1.43 by MRI and 2.99+/-1.83 by ultrasound. The blood volume in the tissue relative to the total tissue volume (relative blood volume fraction) measured by MRI was 13+/-4.1% in tumor versus 4+/-1.4% in muscle (P<.01). Our data also suggested that, compared to the distribution volume of an extracellular contrast agent, Gd-DTPA, Clariscan as an intravascular agent demonstrated high-quality depictions of vascular structure of the tumor.     

An MRA study of vascular stenosis in a pig model using CH3-DTPA-Gd (NMS60) and Gd-DTPA

PURPOSE: This study used an experimental arterial stenosis model in pigs to evaluate the utility of a new medium-weight MRI contrast agent, NMS60 (a synthetic oligomeric Gd complex containing three Gd(3+) atoms, molecular weight of 2158 Da) compared to Gd-DTPA for contrast-enhanced MRA. MATERIALS AND METHODS: We used six male white hybrid pigs. Under anesthesia, one femoral artery was exposed and an inflatable cuff placed around it. The cuff was tightened around the vessel until 80-90% stenosis was achieved using digital subtraction angiography as a guide. Animals were then immediately transferred to the MRI scanner and images acquired pre- and postcontrast injection (0.1 or 0.2 mmol Gd/kg Gd-DTPA or NMS60, as a rapid bolus) using high-resolution and dynamic MRA. RESULTS: The dynamic MRA scans acquired during contrast bolus injection clearly showed the stenosed femoral artery as a segment of close to zero enhancement during the arterial phase of the bolus transit, while on the high-resolution scans the stenosis was difficult to detect due to venous signal contamination. The signal-to-noise at peak enhancement on the dynamic scans was significantly greater with 0.1 mmol Gd/kg NMS60 compared to 0.1 mmol Gd/kg Gd-DTPA (14.6 vs. 9.9, P < .05) and not significantly greater than 0.2 mmol Gd/kg (14.6 vs. 12.8). DISCUSSION AND CONCLUSION: This new medium-weight contrast agent demonstrated significantly greater enhancement than Gd-DTPA and may be valuable to aid detection of vascular stenosis in humans.     

Gadolinium-DTPA-enhanced and digitally subtracted magnetic resonance imaging of estrogen-induced pituitary lesions in rats: correlation with pituitary anatomy

Pituitary hypertrophy and tumors were induced in male Sprague Dawley rats using estradiol-17 beta. This tumor model generates a variety of pituitary lesions which are relevant to human pituitary disease. In order to characterize these lesions, gadolinium DTPA was injected intravenously into the tail vein of estrogen treated and control rats. High resolution T1-weighted MR images, pre- and postenhancement, were obtained at 8 different time points spanning 300 days following the subcutaneous implantation of the estrogen pellets. Images with 2-mm slice thickness were made with a 2 Telsa small-bore MR imaging system. Both normal and tumorous pituitaries were found to enhance with contrast agent, but contrast uptake was not uniform. Gd-DTPA distribution was sensitive to the different types of lesions generated in the course of this study. Digital subtraction of congruent images, pre- and postcontrast, provided difference images reflecting contrast concentration and allowed identification of subtle enhancement effects. Hypertrophic pituitaries displayed uptake of contrast, but the distribution of contrast agent was nonuniform and appeared mottled. A bright rim enhancement was often seen anterior to the pituitary gland, most likely arising from the oculomotor nerves and arachnoid. Histological slices in the same anatomical plane as the MR images were obtained on the animals allowing identification of individual lesions. Cystic areas within tumors were found to give strong contrast enhancement in less than five min postinjection. Solid and hemorrhagic areas of the pituitary tumor were hypo- to isointense relative to surrounding brain and did not take up contrast agent. Significant perfusion in these areas apparently does not occur.(ABSTRACT TRUNCATED AT 250 WORDS)     

A comparative evaluation of CH3-DTPA-Gd (NMS60) for contrast-enhanced magnetic resonance angiography

In a canine model the signal dynamics of a new oligomer-based MR contrast agent (NMS60, 2158 Da) were compared to Gd-DTPA to investigate the agents' potential for magnetic resonance angiography (MRA). Twelve male mongrel dogs were imaged sequentially under anesthesia with two different MRA sequences (Tlw 3DSPGR). Initial enhancement was measured every 9 s for eight points in time. Thereafter, spatial highly resolved MRAs were obtained at 5, 10, 15, 20, 30, 45, and 60 min post-injection of two different dosages. Over the first 20 s following bolus administration the average arterial enhancement of 0.1 mmol(Gd)kg NMS60 was 44% greater than Gd-DTPA. Twenty minutes post-injection the relative signal intensity of NMS60 was as high as the peak signal intensity with Gd-DTPA at the same dosage level (0.1 mmol(Gd)/kg). In the animals that received NMS60 injections the vascular conspicuity was overly superior to those who received Gd-DTPA. No significant toxicity effects were noted for either dosage level. The intermediate weight contrast agent NMS60 offers greater vascular enhancement and retention time than Gd-DTPA. For a given set of optimized imaging parameters this offers improved spatial details, less arterial/venous overlap, and better vascular contrast.     

MR imaging of liver abscesses; application of Gd-DTPA

The potential utility of Gd-DTPA contrast enhancement of MR images in the evaluation of liver abscesses was assessed in rodents. Twelve rats with surgically implanted sterile liver abscesses were imaged at various stages of focal hepatic inflammation, 48 hours, 4 days, 7 days, 14 days and 21 days after lesion induction. Spin echo images, acquired before and repeatedly after intravenous injection of 0.2 mmol/kg Gd-DTPA, demonstrated improvement of the lesion-to-background contrast ranging from 2% to 40% depending on the stage of the disease. The enhancement pattern also varied with abscess evolution. Two, four and seven-day-old abscesses typically showed a ring enhancement, whereas two- and three-week-old abscesses presented largely homogeneously enhancing lesions. In the earlier lesions, contrast enhanced rim surrounding the low intensity center corresponded histologically to the formation of a capsule consisting of fibrous tissue and inflammatory cells. The center was necrotic. Data show that abscesses can be detected on images acquired with long repetition and echo times without injection of Gd-DTPA. The administration of Gd-DTPA, however, improved the lesion-to-background contrast and helped to define the abscess capsule evolution.     

The use of Gd-DOTA in magnetic resonance imaging of experimentally induced mammary tumors

Gd-DOTA contrast enhancement of MR images was evaluated on induced mammary tumors in female rats. A single intravenous injection of the carcinogenic N-nitrosourea ENU was administered to Wistar rats; this simple treatment led to a high percentage of mammary tumors without causing death. All the induced tumors were adenocarcinoma and their heterogeneousness depended on their size. The induced tumors did not have intra- or extravascular inflammatory spaces caused by heterotopic lesions, as is the case with implanted tumors. Before injection of Gd-DOTA, appearance of the patchy internal structure was clearly demonstrated on spin-echo images performed with long repetition times. Three doses of the paramagnetic contrast agent (0.1, 0.2, and 0.5 mmol/kg) were evaluated on two different T1-weighted MR sequences. Images were recorded before and repeatedly after intravenous injection of Gd-DOTA, and signal intensities and relaxation times were measured. On images acquired with the spin-echo 500/28 as well as the inversion-recovery 928/26/300 sequences, the results showed that 0.2 mmol/kg Gd-DOTA was the optimal dose for contrast enhancement and for clear visualization of the heterogeneousness of the mammary tumor.     

Recurrent hepatocellular carcinoma versus radiation-induced hepatic injury: differential diagnosis with MR imaging

The objective of this study was to assess the value of MR imaging in the differentiation between a recurrent hepatocellular carcinoma (HCC) and a radiation-induced hepatic injury. Nine male patients with suspected recurrence after radiotherapy for HCC underwent T(2)-, T(1)-weighted imaging and Gd-DTPA enhanced dynamic studies. T(2) relaxation times, signal intensity ratios in T(1)-weighted images (WI) and the relative enhancement of the dynamic study were calculated. Recurrent tumors and the irradiated area showed similar image characteristics: hypointense in T(1)-WI and hyperintense in T(2)-WI. T(2) values and signal intensity ratios in the T(1)-WI were not significantly different. In the gadolinium-enhanced dynamic study, a recurrent HCC showed early enhancement, followed by a rapid washout. However, the irradiated liver parenchyma showed hyperintensity from an early phase, and contrast enhancement tended to be more prominent and prolonged at the end of the dynamic studies. The characteristic findings of the dynamic MR study enable us to distinguish between a recurrent HCC and a radiation-induced hepatic injury.     

3D spin-lock imaging of human gliomas

We investigated whether the simultaneous use of paramagnetic contrast medium and 3D on-resonance spin lock (SL) imaging could improve the contrast of enhancing brain tumors at 0.1 T. A phantom containing serial concentrations of gadopentetate dimeglumine (Gd-DTPA) in cross-linked bovine serum albumin (BSA) was imaged. Eleven patients with histologically verified glioma were also studied. T₁-weighted 3D gradient echo images with and without SL pulse were acquired before and after a Gd-DTPA injection. SL effect, contrast, and contrast-to-noise ratio (CNR) were calculated for each patient. In the glioma patients, the SL effect was significantly smaller in the tumor than in the white and gray matter both before (p = 0.001, p = 0.025, respectively), and after contrast medium injection (p < 0.001, p < 0.001, respectively). On post-contrast images, SL imaging significantly improved tumor contrast (p = 0.001) whereas tumor CNR decreased slightly (p = 0.024). The combined use of SL imaging and paramagnetic Gd-DTPA contrast agent offers a modality for improving tumor contrast in magnetic resonance imaging (MRI) of enhancing brain tumors. 3D gradient echo SL imaging has also shown potential to increase tissue characterization properties of MR imaging of human gliomas.     

Comparison of T2 and LASER T2dagger image contrast in a rat model of acute cerebral ischemia

Previous studies have shown that T2(dagger)-weighted magnetic resonance images acquired using localization by adiabatic selective refocusing (LASER) can provide early tissue contrast following ischemia, possibly due to alterations in microscopic susceptibility within the tissue. The purpose of this study was to make a direct in vivo comparison of T2-, T2(dagger)- and diffusion-weighted image contrast during acute ischemia. Acute middle cerebral artery (MCA) occlusion was attempted in 14 rats using a modified Tamura approach incorporating electrocoagulation of the left MCA. T2(dagger)-weighted LASER images (Echo Time [TE]=108 ms), T2-weighted Carr-Purcell-Meiboom-Gill (CPMG) images (TE=110 ms) and diffusion-weighted images (b value=105 s/mm(2)) were acquired at 4 T within 1.5 h of ischemia onset. Tissue contrast in the MCA territory was quantified for histologically verified ischemic tissue (n=6) and in sham controls (n=4). T2(dagger)-weighted LASER images demonstrated greater contrast compared to the T2-weighted CPMG images, and more focal contrast compared to the diffusion-weighted images, suggesting different contrast mechanisms were involved.     

Gd-DTPA adrenal gland enhancement at 1.5 T

The change in relative signal intensity of normal adrenal glands in 31 patients was evaluated following bolus administration of 0.1 mmol/kg of gadolinium diethylenetriamine pentacetic acid (Gd-DTPA). A marked increase in relative intensity of greater than 300% was observed within 2.5 min following contrast administration upon comparison of pre- and postcontrast T1-weighted gradient-echo images (TR = 47 msec, TE = 13 msec, pulse angle 80 degrees). Significantly elevated relative intensities of 55% and 44% persisted on postcontrast T1-weighted spin-echo images obtained at further delay times averaging 8 and 20 min, respectively, when compared to the identical precontrast sequence.     

Gadolinium-DTPA enhanced MR imaging of intramuscular abscesses

Sterile, chemical and bacterial abscesses were induced in the paraspinal muscles of 16 rats before obtaining magnetic resonance (MR) images using a 0.35-T resistive system. Abscess intensity, T1 and T2 values were recorded before and after the intravenous administration of Gd-DTPA (0.2 mmol/kg). The MR appearances of the abscesses were correlated with histologic sections. Both sterile and bacterial abscess were detected on MR images without the use of contrast medium, particularly on the T2-weighted spin echo sequence (TE/TR 56/2000 ms). However, the inflammatory zones of abscesses markedly enhanced in intensity with a corresponding decrease in T1 values after the administration of Gd-DTPA (TE/TR 28/500 ms). A clear distinction between the necrotic center and the cellular periphery of each abscesses was evident only after contrast enhancement (TE/TR 28/500 ms). Thus paramagnetic Gadolinium-DTPA was beneficial for defining the histologic components of abscesses on spin echo MR images.     

Oxygen-induced MR signal changes in murine tumors

Breathing of 100% oxygen was used to challenge vascular autoregulation in 14 mice with either osteosarcomas (n = 6) or mammary carcinomas (n = 8). Reproducible and statistically significant signal intensity changes of –29 ± 6% to +35 ± 3% were observed on heavily T₂1-weighted images in the tumors during the oxygen challenge. No significant changes were observed in muscle. For the mammary carcinomas a higher percentage of tumor voxels showed significant signal-intensity decrease (31 ± 8%) compared to the percentage of voxels showing a signal-intensity increase (22 ± 3%). In contrast, for the osteosarcomas, a higher percentage of tumor voxels showed signal-intensity increase (52 ± 9%) compared to the percentage of voxels showing signal-intensity decrease (27 ± 9%). The regional distribution of these signal intensity changes did not correlate with the signal pattern on T₁-, T₂-,and T₂1-weighted and Gd-DTPA enhanced images acquired without breathing 100% oxygen. Most likely, the signal intensity changes represented the inability of the tumor’s neovascularization for autoregulation during the oxygen challenge, particularly in hypoxic regions. Although further investigation is needed, the findings that malignant tumor tissue showed signal intensity changes, whereas normal muscle tissue did not, suggests that this technique may prove useful in distinguishing benign from malignant tissue.     

Quantification of dynamic contrast-enhanced MR imaging of the knee in children with juvenile rheumatoid arthritis based on pharmacokinetic modeling

Improved management of arthritis requires a reliable, quantifiable, noninvasive method to monitor the degree of inflammation and therapeutic response during the early phase of the disease. For this purpose, the uptake of Gd-DTPA in the distal femoral physis and synovium in children with juvenile rheumatoid arthritis (JRA) was evaluated with a two-compartment pharmacokinetic model and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Employing a two-compartment pharmacokinetic model, the theoretical signal enhancement from Gd-DTPA enhanced dynamic 3D gradient-recalled echo (GRE) images was shown to have a simple linear relationship with tissue concentration independent of flip angle. The signal-enhancement patterns for each individual knee were found to be characterized by three pharmacokinetic parameters: k(ep) (min(-1)), the rate constant; k(el) (min(-1)), the elimination rate constant; and E(R) (min(-1)), the initial enhancement rate, which is proportional to the transfer constant K(trans) (min(-1)). Characteristic patterns were observed in the image signal intensity-time course. The initial enhancement rate, E(R), in regions of interest (ROIs) was found to have a wide range of variation: 5 to 38 min(-1) over the distal femoral physis and 1 to 10 min(-1) in the synovium. The E(R) of the synovium was correlated with the E(R) of the distal femoral physis (P<.05). In addition, the E(R) of the synovium was correlated to the clinical outcome measures of knee swelling. Further investigation is needed to determine whether wide variations in the pharmacokinetic parameters reflect the degree of disease activity, and whether there are changes in response to therapy. This method can also be applied in adults with rheumatoid arthritis (RA) and other disorders where T(1)-weighted contrast is used (breast cancer, brain tumors).     

Liposomal Gd-DTPA: effect of encapsulation on enhancement of hepatoma model by MRI

Liposomes entrapping gadolinium-DTPA (Gd-DTPA) were synthesized from 60 mole percent egg phosphatidylcholine (EPC) and 40 mole percent cholesterol or EPC alone entrapping Gd-DTPA in diameters of 100 and 200 nm. Rats bearing Morris hepatoma in their flanks were imaged by MR pre- and post-contrast with free Gd-DTPA and liposomal Gd-DTPA for up to four hours after IV contrast. Comparison of images after free and liposomal Gd-DTPA showed dramatic differences in tumor and organ enhancement. Liposomal Gd-DTPA enhancement of tumor corresponded more closely to histologically proven vascularized portions of tumor than free Gd-DTPA. Hepatic enhancement was greater with liposomal than free Gd-DTPA and time course of liver, kidney and tumor enhancement was prolonged. The 100-nm EPC Gd-DTPA liposomes caused the greatest enhancement. Gd-DTPA liposomes may be useful as liver and blood pool contrast agents. By varying lipid composition and vesicle size, patterns of enhancement may be selectively modified.     

MRI with superparamagnetic iron oxide: efficacy in the detection and characterization of focal hepatic lesions

The purpose of this study was to evaluate the potential of superparamagnetic iron oxide particles (SPIO) as tissue specific contrast agent in magnetic resonance (MR) imaging in detection and characterization of focal hepatic lesions. We investigated 45 patients with focal hepatic lesions. T1-weighted SE (TR 650/TE 15 ms) and T2-weighted SE (TR 2015-2030/TE 45 and 90 ms) unenhanced images were obtained. After SPIO application we performed T1-weighted images with and T2-weighted images with and without fat suppression using the same image parameters. Liver signal intensity decreased by 74% (min 47%, max 83%) on T2-weighted images after application of the contrast agent. Benign lesions (FNH, adenoma) showed an average signal drop of 40% (min 20%, max 47%) whereas malignant lesions showed no significant change of signal intensity on post-contrast images. The mean tumor-to-liver contrast-to-noise ratio (C/N) was improved in all post-contrast sequences irrespective of the lesion type. An additional increase of tumor-to-liver contrast by use of fat suppression technique could be established in the slightly T2-weighted sequence (TE 45 ms). In metastases, divided in different size groups, we could determine a significant size relation of tumor-to-liver C/N. After SPIO application the number of detected lesions increased distinctly, especially small foci are more easily demonstrated. SPIO particles are a efficacious contrast agent for MR examinations of the liver. For tumor characterization T1- and T2-weighted pre- and post-contrast images are necessary. The T1-weighted sequences are helpful to differentiate benign lesions such as cysts and hemangiomas from malignant lesions. Detection and differential diagnoses of hepatic lesions are improved by use of the SPIO-particles.     

MRI characterization of 9L-glioma in rat brain at 4.7 Tesla

In vivo estimation of intracranial tumor progression is important in tumor treatment response studies in animal models. High resolution MR images at 4.7 T of 9L-gliomas stereotactically implanted in Fisher-344 rat brains were obtained. Due to elongation of T1 at higher fields, tissue contrast is diminished in T1-weighted images. However, normal anatomy and vasogenic edema are clearly discerned in T2-weighted images (echo times of greater than 50 ms and recycle times of greater than 2 sec). Tumor tissue is not always clearly delineated. Images obtained after administration of contrast agents (Gadolinium DTPA), with short TR (0.6 sec) selectively enhanced the tumorous tissue, with little effect upon normal tissue and edema. Good correlation of enhanced tumor lesions has been observed with histological examination of formalin fixed brains. Relaxation times (T1 and T2) of tumor and normal tissues were measured using stimulated-echo and multi-echo sequences, respectively. Serial images corresponding to tumor growth were recorded, from which tumor volume progression was monitored.     

The effect of Gd-DTPA on T(1)-weighted choline signal in human brain tumours

The influence of Gd-DTPA on T(1)-weighted (T(1)W) proton MR spectra has been investigated in 19 patients with histologically verified low (n = 13) or high-grade (n = 6) gliomas. Repeat measurements were performed on 9 patients (7 low-grade and 2 high-grade), with 28 examinations performed in total. Comparison of spectra obtained before and after 0.2 mmol/kg Gd-DTPA showed contrast agent induced broadening of the choline signal without significant signal area change. Lack of enhancement of the choline signal with the T(1)-weighted acquisitions implies that the contrast agent and the trimethylamine-containing species do not undergo significant direct interaction. Contrast agent induced changes in the choline signal observed in this and previous studies may, therefore, be attributable to T2*/susceptibility-based effects.     

Magnetic resonance imaging of spinal intradural granulocytic sarcoma

We report the case of a young black male with a spinal intradural granulocytic sarcoma proved by needle aspiration. The tumor was evaluated by myelography, computed tomography, and magnetic resonance imaging (MRI). Other than its rarity, the "dripping candle wax" appearance on MR T1-weighted images and the lack of enhancement with Gd-DTPA makes this case unique. Progressive changes of the tumor following chemo- and radiotherapy were successfully demonstrated by MR.     

Renal-related perinephric fluid collections: MRI findings

We retrospectively reviewed MR studies on 10 patients with renal-related perinephric fluid collections who underwent MRI in three institutions between January 2001 and August 2004. All patients underwent MRI of the abdomen and T1-weighted, T2-weighted and serial contrast-enhanced images, including delayed-phase contrast-enhanced images 10-12 min after contrast injection, were obtained. Perinephric fluid collections in 5 patients revealed MRI findings of simple fluid content (i.e., hypointense on T1-weighted images and hyperintense on T2-weighted images). In another 5 patients, a complex perinephric fluid content (i.e., mixed hyper/hypointense on T1-weighted images and mixed hypo/hyperintense on T2-weighted images compatible with blood breakdown products and pus) was observed. In 5 patients, contrast extravasation on late-phase images that was compatible with urine leak was demonstrated. Our results suggest that MRI may determine the content of perinephric fluid collections on noncontrast T1-weighted and T2-weighted images and that contrast extravasation on late-phase images is associated with urine extravasation from renal collecting systems.