Relaxation effects of clustered particles.

Relations between spatial distribution of superparamagnetic iron oxide (SPIO) particles and the image contrast caused by SPIO were investigated. Actual clustering pattern of particles was measured in the liver and spleen of animals using intravital laser confocal microscopy. SPIO-doped phantoms with and without Sephadex beads were made to simulate these patterns, and relaxation parameters were measured using a 1.5-T clinical scanner. Finally, these results were compared to clinical image data using SPIO particulate agent. Intravital microscopy indicated that the clustering of latex beads was more predominant in hepatic Kupffer cells than in splenic macrophages (P < 0.001). Phantoms without Sephadex beads showed an approximately linear increase of 1/T1 (R1), 1/T2 (R2) and 1/T2* (R2*) values with increasing SPIO concentration. However, with Sephadex beads, R1 and R2 showed little change with increasing SPIO concentration, while R2* showed the same linear increase with SPIO. Also, the R2* values were higher with Sephadex beads. These results were consistent with the clinical imaging data, where signal reduction was significantly smaller in the spleen (-0.4% +/- 27.4%) than in the liver (50.4% +/- 16.8%, P < 0.00001) on T2*-weighted images, but the reduction in the spleen (47.2% +/- 16.1%) was equivalent to the liver (38.8% +/- 26.0%) on T2-weighted images.

Hepatic iron concentration: noninvasive estimation by means of MR imaging techniques.

PURPOSE: To identify a magnetic resonance (MR) imaging method sufficiently sensitive and specific in the estimation of hepatic iron content to obviate liver biopsy. MATERIALS AND METHODS: Thirty-eight patients underwent percutaneous needle biopsy of the liver with chemical measurement of the hepatic iron concentration and hepatic MR imaging with several spin-echo and gradient-recalled-echo (GRE) techniques. Correlations between MR imaging parameters and the hepatic iron concentration were determined. RESULTS: Inverse curvilinear relationships were noted between several MR parameters and hepatic iron concentrations. GRE sequences with short repetition and echo times were more accurate and precise than spin-echo sequences for the estimation of hepatic iron concentration. A GRE sequence with a repetition time of 18 msec, an echo time of 5 msec, and a flip angle of 10 degrees showed close correlation between the hepatic iron concentration and the natural logarithm of the ratio of the signal intensity of liver to the SD of background noise (r = -0.94) and low coefficient of variation (12%). CONCLUSION: MR imaging with these parameters is a rapid, noninvasive, and accurate modality for estimation of hepatic iron concentration; it is sufficiently accurate and precise to obviate liver biopsy for the purpose of measuring hepatic iron concentration.

Effects of spatial distribution on proton relaxation enhancement by particulate iron oxide.

The proton relaxation effect of superparamagnetic iron oxide (SPIO) particles under varying conditions of spatial distribution was investigated with use of phantoms. Agar phantoms containing various concentrations of SPIO or gadopentetate dimeglumine, with and without Sephadex beads, were studied. Phantoms with Sephadex had a heterogeneous spatial distribution of iron oxide, comparable to liver tissue in vivo. Relaxometry at 0.47 T showed decreased T2 relaxivity of SPIO in Sephadex phantoms compared with that in agar phantoms without Sephadex. On T2-weighted images obtained at 1.5 T, the signal intensity of Sephadex phantoms showed less SPIO relaxation effect than that of plain agar phantoms. Unlike SPIO, gadopentetate dimeglumine showed the same relaxivities and signal intensity in plain agar and Sephadex phantoms. The results show that the T2 relaxation effect of iron oxide depends on its spatial distribution. A heterogeneous spatial distribution, as in intact liver tissue, diminishes the T2 relaxivity of iron oxide particles.

Contrast-enhanced MR imaging of the liver.

Postcontrast images with a 0.1 mmol/kg dose of a gadolinium chelate with extracellular distribution, when acquired dynamically during breath holding, can improve both differential diagnosis and lesion recognition in liver MR imaging. Initial results at 0.3 mmol/kg, compared with 0.1 mmol/kg, suggest a substantial improvement in lesion identification at the high dose, as assessed by using signal intensity difference divided by noise. Of the gadolinium chelates with predominantly renal excretion, only gadoteridol is presently approved in the United States at the high dose, with limited clinical evaluation for liver imaging performed to date. For linear chelates, such as gadopentetate dimeglumine and gadodiamide injection, the degree to which release of free gadolinium ion occurs is a possible issue because of lower in vivo stability (42,43). Preliminary results with hepatobiliary gadolinium chelates and iron particulate agents are favorable with regard to efficacy, although these agents remain in clinical trials.

Enhanced tumor detection in the presence of fatty liver disease: cell-specific contrast agents.

It is assumed that hepatobiliary, cell-specific contrast agents will be adversely affected by the presence of diffuse liver disease. The diagnostic efficacy for tumor detection in the presence of fatty liver disease was experimentally studied at contrast-enhanced magnetic resonance (MR) imaging with manganese-DPDP (N,N'-dipyridoxylethylenediamine-N,N'-diacetate 5,5'-bis[phosphate]) and gadobenate dimeglumine (Gd-BOPTA/dimeg) and compared with conventional and chemical shift imaging. Carcinosarcoma was implanted into the liver of rats, and fatty liver was induced with L-ethionine. Without contrast agents, the tumor-fatty liver contrast-to-noise ratio (C/N) was increased on T1-weighted and decreased on T2-weighted MR images relative to tumor-bearing control rats without fatty liver. Chemical shift imaging (phase-contrast method) increased the tumor-fatty liver C/N from 2.3 +/- 1.0 to 6.1 +/- 1.7 (P < .001). Mn-DPDP and Gd-BOPTA/dimeg increased the tumor-fatty liver C/N from -5.4 +/- 1.6 to -11.0 +/- 1.9 and -9.8 +/- 3.4, respectively (P < .001). The hepatobiliary, cell-specific contrast agents were equally effective in both fatty and non-fatty liver and outperformed both chemical shift and conventional MR imaging in detecting liver tumors.

Contrast-enhanced MR imaging of diffuse and focal splenic disease with use of magnetic starch microspheres.

The diagnostic value of magnetic starch microspheres (MSM), a new superparamagnetic contrast agent, was studied in experimental models of diffuse and focal splenic disease in rats by means of ex vivo relaxometry and in vivo magnetic resonance (MR) imaging. Owing to small differences in unenhanced T1 and T2 values between diffuse lymphoma and normal spleen, MR imaging failed to distinguish tumor-bearing animals from control animals by signal-to-noise ratios (SNRs) obtained with T1- and T2-weighted spin-echo sequences. One hour after injection of 20 mumol/kg MSM, lymphomatous spleen showed significantly (P < .001) reduced enhancement relative to normal splenic tissue. As a result, animals with diffuse lymphoma (SNR: 10.3 +/- 1.7) could be easily differentiated from control animals (SNR: 5.5 +/- 0.6) on T2-weighted (TR msec/TE msec = 2,000/45) images. In focal splenic disease, MSM produced normal enhancement of nontumorous splenic tissue, whereas relaxation times of tumors were not different before and after contrast agent injection. On T2-weighted images (2,000/45), the tumor-spleen contrast-to-noise ratio increased from 4.8 +/- 1.6 to 21.8 +/- 1.9 (+354%), improving conspicuity of splenic tumors. The results show that MSM-enhanced MR imaging improves the detection of diffuse and focal splenic disease.

Orally administered manganese chloride: enhanced detection of hepatic tumors in rats.

To evaluate its potential as a tissue-specific hepatobiliary magnetic resonance (MR) contrast agent, manganese chloride was orally administered to rats in increasing doses of 100-1,500 mumol/kg MnCl2, and the relaxation times of liver, pancreas, kidney, and heart were measured with ex vivo relaxometry and in vivo MR imaging. Two hours after ingestion of 200 mumol/kg MnCl2, liver T1 was decreased by 48%, whereas tumor T1 decreased by only 9%. On spin-echo MR images, the signal-to-noise ratio in liver increased by 54%; the contrast-to-noise ratio in tumor, by 375%. The T1 of pancreas, kidney, and heart decreased by 8%, 23%, and 13%, respectively. At subjective assessment, the signal intensity of the upper gastrointestinal tract was reduced, likely because of the high concentration of manganese in the lumen, and delineation of the intestine from other abdominal structures was improved. These results indicate that orally administered MnCl2 causes substantial, reproducible, and tissue-specific enhancement of liver. Because enhancement of tumor was minimal, orally administered MnCl2 may potentially be used to improve detection of hepatic tumors.

Enhancement of tumor-liver contrast-to-noise ratio with gadobenate dimeglumine in MR imaging of rats.

The efficacy for tumor detection of the hepatocyte-specific contrast agent gadobenate dimeglumine (gadolinium-BOPTA/Dimeg) was evaluated in four different experimental tumor models in rats. Histologic findings were correlated with quantitative data derived from ex vivo relaxometry and in vivo magnetic resonance (MR) imaging. Noninfiltrating tumors showed maximal enhancement of liver parenchyma 5-10 minutes after contrast agent administration, with a plateau over the next 30 minutes. In contrast, infiltrating tumors, which caused hepatocellular injury and inflammatory changes, delayed maximal enhancement of tumor-free parenchyma by 15-20 minutes. Nonspecific tumor enhancement depended on tumor vascularity and occurred in the early phase after contrast agent administration. Despite differences in specific enhancement of tumor-free parenchyma and nonspecific tumor enhancement, tumor-liver contrast-to-noise ratios increased 96%-248% in all tumor models 30 minutes after intravenous administration of 75 mmol/kg Gd-BOPTA/Dimeg. Gd-BOPTA/Dimeg enhanced tumor conspicuity independently of the histologic characteristics of the tumor.

Accumulation of iron oxide particles around liver metastases during MR imaging.

The histologic nature of the bright ring ("peritumoral edema") around some liver metastases on T2-weighted magnetic resonance (MR) images is controversial. In the case reported, particles of the iron oxide contrast agent AMI-25 are retained in the peritumoral zone of a colon cancer metastasis, causing the bright ring to disappear. The location of iron particles in resected specimens could be used systematically to study peritumoral edema.

Preclinical evaluation of MnDPDP: new paramagnetic hepatobiliary contrast agent for MR imaging.

Manganese(II)-N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis (phosphate) (MnDPDP) is a paramagnetic complex designed for use as a hepatobiliary agent. The T1 relaxivity of MnDPDP (2.8 [mmol/L]-1.sec-1 in aqueous solution) was similar to that of gadolinium diethylenetriaminepentaacetic acid (DTPA) (4.5 [mmol/L]-1.sec-1) and gadolinium tetraazocyclodecanetetraacetic acid (DOTA) (3.8 [mmol/L]-1.sec-1). However, in liver tissue the T1 relaxivity of MnDPDP (21.7 [mmol/L]-1.sec-1) was threefold higher than that reported for Gd-DOTA (6.7 [mmol/L]-1.sec-1). Maximum liver T1 relaxation enhancement occurred 30 minutes after injection of MnDPDP, at which time 54MnDPDP biodistribution studies indicated that 13% of total body activity was in the liver. Enhanced (MnDPDP, 50 mumol/kg) MR images showed a fivefold increase in tumor-liver contrast-to-noise ratio over baseline unenhanced images. Results of the authors' acute and subchronic toxicity studies suggest that MnDPDP will be safe at the doses necessary for clinical imaging; at 10 mumol/kg, the safety factor (LD50/effective dose) for MnDPDP is 540, significantly greater than the safety factor of Gd-DTPA (ie, 60-100).

Iron oxide-enhanced MR imaging of the liver and spleen: review of the first 5 years.

Superparamagnetic iron oxide (SPIO) particles are a potent new class of MR contrast agents affording improved detection of hepatic and splenic neoplasms. In this report we review the development of this agent through preclinical studies and early clinical results at Massachusetts General Hospital during a 5-year investigation. SPIO particles are sequestered by normal phagocytic Kupffer cells of the reticuloendothelial system (RES) but are not retained in tumor tissue. Consequently, there is a fivefold increase in T2 relaxation between normal RES tissue and tumor, with a comparable advantage in quantitative signal-to-noise ratio, contrast-to-noise ratio, and lesion detectability in the liver and spleen on MR imaging. Increased lesion conspicuity can be exploited to decrease threshold size for lesion detection to less than 3 mm. Clinically beneficial effects occur with a variety of mildly T2-weighted spin-echo pulse sequences; gradient-echo techniques show even greater benefit after administration of SPIO. Metabolically, pharmaceutical-grade preparations are biodegradable and bioavailable, being rapidly turned over into body iron stores and incorporated into erythrocyte hemoglobin. Early dose-escalation clinical trials have identified a probable clinical dose range of 10-20 mumols Fe/kg body weight. In the United States, SPIO compounds evaluated to date are still approved for use in investigational studies only. Newer commercial formulations currently being evaluated may extend clinical safety margins.

Detection of hepatic metastases: comparison of contrast-enhanced CT, unenhanced MR imaging, and iron oxide-enhanced MR imaging.

Diagnostic accuracy of contrast-enhanced CT, unenhanced MR imaging, and MR images enhanced with superparamagnetic iron oxide was evaluated in 10 patients with histologically proved hepatic metastases. First, diagnostic performance of the imaging technique with respect to the ability of radiologists to recognize the presence or absence of a metastasis was measured by using receiver-operating-characteristic (ROC) analysis of single images. Second, the total number of lesions (N = 108) detected by "complete" CT and MR examinations was counted. Finally, lesion-liver contrast-to-noise ratios (CNR) were measured in all MR sequences. The area under the ROC curve was .67 +/- .03 for contrast-enhanced CT, .81 +/- .07 for the unenhanced SE 260/14 sequence, and .92 +/- .01 for the iron oxide-enhanced SE 1500/40 sequence. The enhanced SE 1500/40 sequence yielded significantly (p less than .005) greater accuracy than did contrast-enhanced CT. The same sequence detected significantly (p less than .05) more lesions than all other imaging techniques (19% more than the best unenhanced MR sequence and 36% more than contrast-enhanced CT). The enhanced SE 1500/40 sequence also yielded the highest CNR value (19.5 +/- 10.2) of all MR sequences. These results indicate that iron oxide-enhanced MR imaging is a superior imaging technique for the detection of hepatic lesions.

Localization of P-31 MR signal with use of superparamagnetic iron oxide particles.

Volume localization of magnetic resonance signals was achieved by using the regional susceptibility differences produced by superparamagnetic iron oxide particles. In vitro experiments demonstrated a direct linear relationship between the concentration of particulate iron and phosphorus-31 chemical shift or line broadening. In vivo experiments indicated that an intravenous dose of 5-10 mg of iron per kilogram of body weight suppressed P-31 signal from normal liver in healthy rats. In rats with hepatic implants of mammary adenocarcinoma, superparamagnetic iron oxide particles suppressed detectable P-31 or hydrogen-1 signal arising from healthy liver tissue, but not that from tumor. Signal due to surface tissues, which affect surface-coil spectra, could be selectively suppressed with a film-based application of particles to the abdominal wall. Thus, P-31 spectra from simulated or actual lesions could be selectively detected after chemically suppressing signals from neighboring or surrounding tissue.

Hepatic tumors: quantitative tissue characterization with MR imaging.

To determine which quantitative methods of image analysis are most suitable for the differential diagnosis of benign and malignant hepatic lesions, the authors analyzed magnetic resonance images obtained at 0.6 T in 42 patients with proved hepatic cavernous hemangioma and 63 patients with various hepatic malignancies. The lesion-liver signal-intensity ratio for images obtained with a repetition time of 2,350 msec and echo time of 180 msec was most helpful in distinguishing hemangiomas from cancer (area under the receiving operator characteristic curve [ROC] = 0.99 +/- 0.005). All 38 lesions with lesion-liver signal-intensity ratios greater than 3.5 were hemangiomas, whereas all 57 hepatic tumors with a ratio less than 2.5 were malignant neoplasms. A specificity of 93% and sensitivity of 89% can be achieved with use of quantitative signal-intensity data only. The authors conclude that in conjunction with heavily T2-weighted pulse sequences, signal-intensity ratios are an important adjunct to morphologic analysis in the differential diagnosis of hepatic neoplasms.

First clinical trial of a new superparamagnetic iron oxide for use as an oral gastrointestinal contrast agent in MR imaging.

The authors report the results of preclinical testing and initial clinical application of a superparamagnetic iron oxide specifically prepared as a contrast agent for magnetic resonance (MR) imaging of the gastrointestinal tract. MR imaging was performed at 0.6 and 1.5 T in 15 volunteers. Images of the upper abdomen and pelvis were obtained before and after ingestion of the contrast material at doses of 22.5-225.0 mg of iron in 600-900 L. Two readers scored the images. Delivery of contrast material into the proximal and distal small bowel, with obvious loss of signal intensity (T2 enhancement), was achieved in all subjects. Enhanced images showed improved delineation of the head and tail of the pancreas, anterior margins of the kidneys, and paraaortic region. The contrast agent did not generate artifacts, an improvement over prototype formulations evaluated previously in animals. Except for a brief episode of diarrhea in five subjects, the agent was well tolerated. Use of this contrast agent improved the diagnostic quality of abdominal MR images by enabling the distinction of the bowel from nonbowel structures at concentrations that did not produce image distortion.