IMAGING ECONOMICS : What ramifications do higherfield-strength (3T) magnets have for contrast use?
SAHANI : The distinct benefits offered by 3T MRI over 1.5T MRI include increased signal-to-noise ratio that can be used either to increase spatial resolution (for the detection and characterization of small tumors) or to reduce scanning time (to enable data acquisition during a short breath-hold). With high-field MRI, augmentation of the susceptibility effects is also seen, which has an impact on functional imaging. In addition, T1 relaxivity of the tissues is prolonged at the high magnetic field strength; this property can be exploited for time-of-flight MR angiography, as better background-tissue suppression is achieved.
High-field MRI is, however, also associated with a few disadvantages. The T1 and T2 relaxivity of the tissues is altered, and that can change the way that various tissues in the body look on T1-weighted and T2-weighted images. For example, the tissue contrast between gray and white matter is slightly reduced on T1-weighted images. Increased susceptibility effects on gradient echo images in regions where an alteration of local magnetic field is usually present (such as the skull base and paranasal sinuses) result in signal loss. In addition, the chemical-shift artifact at the fat-water interface becomes pronounced, along with increased flow-related artifacts.
For these reasons, the application of contrast agents in high-field MRI may be different. Functional studies for the assessment of tissue viability or tumor perfusion can now be performed with better time resolution. This may be further supported by the availability of macromolecular contrast agents such as feruglose and ultrasmall superparamagnetic iron oxide (USPIO), which permit the assessment of tissue permeability, for the study of characteristics such as tumor grade, tumor type, and response to drugs that target angiogenesis. Likewise, contrast agents influencing T2 properties of the tissue will be highly affected at high field strengths. For example, the increased susceptibility effects exacerbate the impact of superparamagnetic iron oxide (SPIO), and these contrast agents may find newer applications such as MR lymphangiography, in addition to existing liver and lymph-node imaging. MRI of the coronary arteries has now become a reality due to the enhanced speed and spatial resolution offered by high-field MRI. Blood-pool MRI contrast agents that have longer intravascular circulation may be best suited for this indication. Similarly, using contrast media that target necrotic myocardium, imaging to assess myocardial viability can be precisely performed. Tumor-directed MRI contrast media that may provide better delineation and progression information for various tumors are being developed.
IMAGING ECONOMICS : What are the implications for contrast in the rapidly growing field of MR angiography (MRA)?
SAHANI : The field of MRA is growing rapidly, and this is attributable mainly to advances in MRI hardware and software technology. Extracellular gadolinium-based contrast agents have been the backbone of MRA. Current MRI technology permits scanning one or two vascular territories within a single breath-hold to catch the optimal vascular phase of the gadolinium chelates, and evaluation of multiple regions without venous contamination can be difficult. In addition, the diffusion of gadolinium chelates into extravascular-extracellular space results in a decreased signal from the vessels. With high-field MRI, in combination with parallel imaging and multichannel phased-array coils, not only is faster imaging with better spatial resolution allowed, but scanning several vascular territories may be possible using a single bolus of extracellular contrast. On the other hand, blood-pool contrast agents that stay longer in the intravascular space are highly desirable for obtaining high-quality MRA even at low field strengths.
IMAGING ECONOMICS : What impact have organ-specific contrast agents had on the utility of MRI? What is under development in this category?
SAHANI : In liver imaging, tissue-specific contrast agents are useful in both detection and characterization of liver lesions. Due to the prolonged imaging window available with these liver-specific contrast agents, highspatial-resolution imaging of the liver can be performed in multiple short breath-holds. This may enhance the detection of small liver tumors. MRI enhanced using the hepatobiliary-specific contrast agent mangafodipir trisodium has increased sensitivity for detection of liver metastases, compared with gadolinium-enhanced MRI and spiral CT. Similar observations have been made for reticuloendothelial-cellspecific SPIO-enhanced MRI. It is conceivable that the susceptibility effect with iron oxide particles may be enhanced at a high field strength, thereby resulting in an increased signal-to-noise ratio. Prospective clinical studies should be undertaken to confirm these claims and to assess any impact on patient management.
Two new MRI contrast agents, gadobenate and gadoxetate, have reached the successful completion of phase III clinical trials in the United States. These agents have a dual mode of action: initial extracellular circulation and a delayed liver-specific uptake. Therefore, a single contrast agent can serve both for liver-lesion characterization and for lesion detection. Since a significant fraction of these two contrast agents is finally excreted in the bile, functional biliary imaging can be performed to evaluate biliary anomalies, postoperative bile leaks, and anastomotic strictures. Other agents, such as liposomal encapsulated gadolinium diethylenetriaminepentaacetic acid (DTPA) or tetraazacyclododecanetetraacidic (DOTA) acid complexes, have been investigated as liver-specific agents; however, tolerance and the stability of these compounds are still critical issues.
Blood-pool agents have a prolonged intravascular circulation, as opposed to the shorter circulating time of gadolinium-DTPA. Therefore, high-resolution MRA of several territories using respiratory or cardiac gated techniques can be undertaken using a single contrast bolus. By virtue of their blood property, these agents may have an important place in routine MRA, even using low-field scanners. The various blood-pool agents under development include feruglose, ferucarbotran, gadofosveset, gadofluorine-8(M), gadomer 17, gadomeritol, and ferumoxtran. These agents are macromolecules that do not cross the normal capillary endothelium, and this property can be exploited to estimate the permeability-surface area product of tumors. It may also help differentiate or grade the tumors based on the permeability-surface area product. In a recent study using feruglose to assess microvascular permeability in breast tumors, Daldrup-Link et al 1 found that an endothelial transfer coefficient of >0 has a sensitivity and specificity of 73% in differentiating malignant breast lesions from benign processes. Gadomer 17 has also been tried for quantitative perfusion of the myocardium. 2
Contrast agents with lymph-node specificity allow selective positive or negative enhancement of normal lymphoid tissue and thus may help characterize lymph nodes as benign or malignant. Use of gadofluorine-M, a lymph-nodespecific contrast agent, results in a positive enhancement of normal lymph nodes and lack of enhancement in the nodes harboring metastases. On the other hand, USPIO particles are taken up by the lymph nodes 24 to 36 hours following intravenous infusion. The normal lymph node demonstrates signal loss due to the susceptibility effect on T2-weighted images. This agent is highly effective and safe in differentiating benign and metastatic lymph nodes from prostate cancer. 3
IMAGING ECONOMICS : Looking ahead, what are some of the more promising ideas being researched in MRI contrast?
SAHANI : Several tissue-specific contrast agents are under development. Agents that specifically accumulate in atherosclerotic plaques include long-circulating USPIOs that accumulate in the monocytes and macrophages of atherosclerotic plaque and gadofluorines that accumulate in deep regions of intima that are probably rich in foam cells and cellular debris. 4 Similarly, monoclonal antibodies labeled with paramagnetic or superparamagnetic particles are being studied for targeting tumors. MRI contrast agents that specifically target glucose receptors on tumor cells are also in development; coupled with the high spatial resolution of high-field scanners, these agents may help detect small tumor foci. 5
IMAGING ECONOMICS : What progress has been made toward US Food and Drug Administration (FDA) approval for blood-pool agents?
SAHANI : At present, none of these agents has received formal approval from FDA for this indication. Phase III clinical trials for two blood-pool agents have been completed, and their manufacturers are currently awaiting FDA approval for them.
IMAGING ECONOMICS : What is the US status of feruglose and other contrast agents that might not leak out of normal capillaries?
SAHANI : Feruglose has completed phase II clinical trials and, for undisclosed reasons, the manufacturer has stopped further trials. New information about this agent is yet to come. All the macromolecular blood-pool agents have a similar property: leaking through defective capillaries, but not normal capillaries. These agents are still in development.
- Daldrup-Link HE, Rydland J, Helbich TH, et al. Quantification of breast tumor microvascular permeability with feruglose-enhanced MR imaging: initial phase II multicenter trial. Radiology. 2003;229:885-892.
- Gerber BL, Bluemke DA, Chin BB, et al. Single-vessel coronary artery stenosis: myocardial perfusion imaging with Gadomer-17 first-pass MR imaging in a swine model of comparison with gadopentetate dimeglumine. Radiology. 2002;225:104-112.
- Harisinghani MG, Barentsz J, Hahn PF, et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer [erratum appears in N Engl J Med. 2003;349:1010]. N Engl J Med. 2003;348:2491-2499.
- Weinmann HJ, Ebert W, Misselwitz B, Schmitt-Willich H. Tissue-specific MR contrast agents. Eur J Radiol. 2003;46:33-44.
- Luciani A, Olivier JC, Clement O, et al. Glucose-receptor MR imaging of tumors: study in mice with PEGylated paramagnetic niosomes. Radiology. 2004;231:135-142.