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Optimal TE for SPIO-Enhanced Gradient-Recalled Echo MRI for the Detection of Focal Hepatic Lesions

¹ Department of Diagnostic Radiology, Yonsei University College of Medicine, Seodaemun-ku Shinchon-dong 134, Seoul 120-752, Republic of Korea.
² Brain Korea 21 Project for Medical Science and Institute of Gastroenterology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
³ Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
⁴ Department of Diagnostic Radiology, NHIC Ilsan Hospital, Gyonggi-do, Korea.
⁵ Department of Radiology, Thomas Jefferson University Hospital, Philadelphia, PA.

Received April 26, 2005; accepted after revision July 10, 2005.

 
Address correspondence to M.-J. Kim (kimnex{at}yumc.yonsei.ac.kr).

Supported by Yonsei University Research Fund of 2006.

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Abstract

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OBJECTIVE. The objective of our study was to determine the optimal TE for superparamagnetic iron oxide (SPIO)-enhanced gradient-recalled echo (GRE) MRI for the detection of focal hepatic lesions.

MATERIALS AND METHODS. Ferucarbotran-enhanced GRE sequences, performed on a 1.5-T MR system, were used to evaluate 131 lesions (38 hepatocellular carcinomas, 37 metastases, 21 hemangiomas, 7 cholangiocarcinomas, 15 cysts, and 13 miscellaneous lesions) at four different TEs: 9, 13.5, 18, and 22.5 milliseconds. The lesion-to-liver signal difference-to-noise ratio (SDNR) was compared among the four GRE sequences by paired Student's t tests and among lesion types by an independent samples Student's t test. The McNemar test was used to compare the sensitivity for the detection of focal hepatic lesions. Wilcoxon's signed rank test was used to compare the subjective lesion conspicuity.

RESULTS. The SDNRs of lesions on GRE images obtained at a TE of 13.5 milliseconds (mean ± SD, 60 ± 24) were significantly (p < 0.001) higher than those at TEs of 9 (55 ± 23), 18 (55 ± 22), and 22.5 milliseconds (47 ± 19). The SDNR was highest at a TE of 13.5 milliseconds for SPIO-uptake lesions and was comparable on images obtained with TEs of 18 and 13.5 milliseconds for non-SPIO-uptake lesions. The non-SPIO-uptake lesions showed a significantly higher SDNR than the SPIO-uptake lesions at a TE of 22.5 milliseconds (p = 0.007). The overall sensitivity for lesion detection was not significantly different among the four GRE sequences, and the subjective ratings of lesion conspicuity were comparable for images obtained using TEs of 8, 13.5, and 18 milliseconds, but the ratings of lesion conspicuity were significantly lower for images obtained using a TE of 22.5 milliseconds (p < 0.001).

CONCLUSION. For ferucarbotran-enhanced MRI, lesion SDNR was highest on images obtained using a TE of 13.5 milliseconds, but the sensitivity and lesion conspicuity were comparable at TEs of 9 and 18 milliseconds. The SDNR of liver lesions varied according to the lesion's potential capability of taking up SPIO agents.

Keywords: contrast media • liver • liver disease • MR contrast agents • MR technique

Introduction

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Superparamagnetic iron oxide (SPIO) agents are being used for hepatic MRI examination to improve the detection and characterization of focal hepatic lesions: The use of ferumoxides has gained worldwide approval, and ferucarbotran has been approved for use in Europe and Asia [1-3]. Although various pulse sequences, including fast spin-echo and gradient-recalled echo (GRE) images, are adapted by many investigators for SPIO-enhanced MRI, T2^*-weighted GRE sequences are regarded as an essential technique for the detection of focal hepatic lesions [4-7]. However, scanning parameters have usually been determined empirically [1]. Among the various scanning parameters, the contrast enhancement effect of SPIO is most dependent on the TE because the magnetic susceptibility increases as the TE is increased.

In prior reports, SPIO-enhanced GRE images were obtained at TE values that varied from 2.1 to 22.5 milliseconds, depending on the investigation [6-11]. To define the optimal TE values for ferumoxides-enhanced GRE images, Matsuo et al. [12] recently compared GRE images obtained at five different TEs: 1.4, 4.2, 6, 8, and 10 milliseconds. In that study, GRE images obtained at a TE of 8 milliseconds performed better in terms of enabling detection of malignant lesions than those obtained at shorter TEs and a TE of 10 milliseconds. In a study by Ward et al. [13], GRE images obtained using ferumoxides at a TE of 15 milliseconds were more sensitive for the detection of colorectal metastasis than GRE images obtained at a TE of 11 milliseconds and fast spin-echo images. However, the two studies compared different ranges of TE values, and it is still not known whether GRE images obtained with a TE of longer than 15 milliseconds will allow improved lesion detection. Furthermore, whether lesion conspicuity on GRE images depends on the lesion character has not been fully evaluated. We conducted this study to determine the optimal TE values in SPIO-enhanced GRE MRI for the depiction of various focal hepatic lesions on a 1.5-T system.

Materials and Methods

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Patient Population
Between December 2003 and August 2004, contrast-enhanced GRE images were obtained using four different TEs (9, 13.5, 18, and 22.5 milliseconds) in 71 consecutive patients (44 men and 27 women; age range, 28-75 years [mean, 56 years]; body weight range, 48-100 kg [mean, 65 kg]) who underwent SPIO-enhanced hepatic MRI examinations. These examinations were performed because the findings of prior sonography, helical CT, or gadolinium-enhanced MRI were inconclusive or because further clarification about the number of lesions seen was needed. This study followed the guidelines of the institutional review board at our hospital, and informed written consent was obtained from all of the patients.

One hundred thirty-one focal hepatic lesions were confirmed either histologically or clinically. There were 38 hepatocellular carcinomas (HCCs) in 25 patients, 37 metastases in 17 patients, 21 hemangiomas in 16 patients, 15 cysts in 12 patients, 8 focal eosinophilic infiltrations in 3 patients, 7 intrahepatic cholangiocarcinomas in 5 patients, and 5 epithelioid hemangioendotheliomas in 1 patient. Eight patients had two types of lesion: 4 patients had HCC and cysts, 1 patient had a metastasis and 2 cysts, 1 patient had a metastasis and a hemangioma, and 2 patients had hemangiomas and cysts.

Liver metastases arose from the following primary tumors: colorectal carcinoma (15 lesions in 7 patients), gastric carcinoma (7 lesions in 3 patients), bronchogenic carcinoma (3 lesions in 2 patients), bile duct carcinoma (6 lesions in 2 patients), duodenal gastrointestinal stromal tumor (5 lesions in 1 patient), and breast carcinoma (1 lesion in 1 patient). The diameters of all the lesions ranged from 0.4 to 10.7 cm (mean, 2.5 cm). Specifically, the diameters of intrahepatic cholangiocarcinomas ranged from 1.0 to 10.7 cm (mean, 5.7 cm); cysts, from 0.8 to 1.8 cm (mean, 1.3 cm); epithelioid hemangioendotheliomas, from 1.6 to 2.4 cm (mean, 2.0 cm); focal eosinophilic infiltrations, from 1.1 to 2.9 cm (mean, 2.1 cm); HCCs, from 0.4 to 12.0 cm (mean, 2.5 cm); hemangiomas, from 0.4 to 4.1 cm (mean, 1.4 cm); and metastases, from 0.5 to 5.2 cm (mean, 2.1 cm).

Diagnosis was established as follows: A diagnosis of HCC was based on the findings of a percutaneous biopsy (2 lesions in 2 patients); on findings in a surgical specimen (7 lesions in 5 patients); or on typical clinical and laboratory findings in combination with the progression of the disease, as depicted on follow-up CT or MR images (29 lesions in 18 patients). In patients with metastasis to the liver, diagnosis was based on histologic findings of the primary tumor and rapid disease progression as depicted by serial follow-up images (27 lesions in 9 patients) or on surgery (10 lesions in 8 patients). Hemangiomas were diagnosed on the basis of their typical appearance on either sonography or CT and the absence of growth during a follow-up period of at least 6 months (19 lesions in 14 patients), on gross examination during surgery (1 lesion in 1 patient), or by surgical resection (1 lesion in 1 patient). Cysts were confirmed by typical findings on unenhanced T1- and T2-weighted MR images, and the MRI findings were correlated with either sonography or CT findings. Focal eosinophilic infiltrations were confirmed on the basis of biopsy results and the appropriate clinical findings. Intrahepatic cholangiocarcinomas were diagnosed on the basis of findings at surgery (n = 1) or biopsy (n = 4). Finally, diagnosis of epithelioid hemangioendothelioma was based on biopsy results.

Liver cirrhosis was diagnosed in 24 patients on the basis of clinical findings (n = 19) or surgery or biopsy findings (n = 5). The causes of liver cirrhosis were chronic hepatitis B virus in 20 patients, hepatitis C virus in 2, alcoholism in 1, and cryptogenic in 1. Three patients had hepatitis B virus without cirrhosis and 1 had hepatitis C virus without cirrhosis. Among the 38 HCCs, 29 (76%) were found in patients with hepatitis B virus; 4, in patients with hepatitis C virus; 1, in a patient with alcoholic cirrhosis; and 1 in a patient with cryptogenic cirrhosis. Seventeen hemangiomas (81%) were found in noncirrhotic patients and 4 in cirrhotic patients. Nine cysts (60%) were found in noncirrhotic patients. All other lesions were found in noncirrhotic patients.

MRI
MRI was performed on 1.5-T units (Signa Horizon, GE Healthcare). All images were obtained in the transverse plane using a phased-array multicoil. A rectangular field of view was adjusted for each patient in the range of 22-24 x 29-34 cm and was held constant for all sequences for each patient.

Unenhanced MRI was performed using four sequences. One was a respiratory-triggered T2-weighted fast spin-echo sequence with a TR range of 3,500-10,900 milliseconds and effective TE range of 96-105 milliseconds, echo-train length of 16, 2 signals acquired, a matrix of 256 x 256, superior and inferior spatial presaturation and chemically selective fat saturation, and a 7-to 8-mm slice thickness with a 1- to 2-mm gap. Two additional sequences were a breath-hold T1-weighted fast multiplanar spoiled GRE in-phase sequence (TR range/TE range, 150-200/4.2-4.6) followed by an out-of-phase sequence (120-180/1.5-2.3) with a flip angle of 90°, 1 signal acquired, a matrix of 256128, a 7- to 8-mm section thickness, and zero gap in 1 or 2 acquisitions. Breath-hold T2-weighted single-shot half-Fourier images were obtained with an effective TE of 180 milliseconds, a matrix of 256 x 160, and a 7- to 8-mm section thickness with a 1- to 2-mm gap for the fourth sequence.

For SPIO-enhanced MRI, a fixed volume of 1.4 mL (7.0-14.5 µmol of iron per kilogram of body weight) of ferucarbotran (Resovist, Schering) was administered as a rapid bolus by the hand injection method and was immediately followed by a saline solution flush of 15-20 mL at a rate of approximately 2-3 mL/s. Dynamic MRI was performed using a chemically selective fat-suppressed spoiled GRE sequence in the transverse plane during suspended respiration immediately after the IV injection of the ferucarbotran. Additional images were obtained at 30-35 seconds, 65-70 seconds, and 5 minutes after the injection. The imaging parameters included TR range/TE range, 180-200/1.5-2.2; 90° flip angle; 256 x 128 matrix with a three quarters rectangular field of view; 1 signal acquired; and 8- to 10-mm-thick sections with a zero intersection gap.

After the ferucarbotran-enhanced dynamic and 5-min delayed images were obtained, accumulation phase images were obtained 10 minutes after the administration of the contrast agent. Four sets of the breath-hold T2^*-weighted unspoiled steady-state GRE images were obtained with a TR of 200 milliseconds, flip angle of 30°, slice thickness of 7-8 mm with zero gap, receiver bandwidth of 32 kHz, and matrix of 256 x 160 at different TEs in the following order: 22.5, 18, 13.5, and 9 milliseconds. Each TE value was chosen to obtain the images in phase and to encompass the range of TEs used in previous studies but that had not been directly compared [5, 7, 12-14]. Each GRE sequence was designated as GRE_22.5, GRE₁₈, GRE_13.5, and GRE₉, respectively. In most patients, the time for a single breath-hold was 27 seconds. Using that breath-holding time, the number of slices per acquisition was 6, 7, 9, and 11 slices, respectively. Therefore, to overlap the end slice of each acquisition, 5, 4, 3, and 2 acquisitions were needed in each sequence. All the SPIO-enhanced GRE images were obtained between 10 and 30 minutes after the injection of the SPIO agent.

Image Analysis
For this study, the four sets of ferucarbotran-enhanced GRE images, but not the dynamic images, were evaluated. One observer drew a region of interest (ROI) in the focal lesion and hepatic parenchyma to measure the signal intensity (SI) of the focal lesions, hepatic parenchyma, and background noise at a workstation (Centricity, GE Healthcare) using standard software. To minimize the effects of partial volume averaging, only 106 lesions with diameters greater than 1 cm were included in this analysis: 35 HCCs, 27 metastases, 19 hemangiomas, 13 cysts, 3 focal eosinophilic infiltrations, 6 intrahepatic cholangiocarcinomas, and 3 epithelioid hemangioendotheliomas. The area of the ROI in the tumor was set to measure the homogeneous area of the lesion while avoiding areas of necrosis, hemorrhage, or fibrosis and attempting to maintain at least a 20-mm² ROI when possible. The ROI of the liver was drawn in the hepatic parenchyma near the tumor, to exclude a vessel and ghosting artifacts, and was at least 80 mm² in all cases.

The SI of the background noise was measured in a circular area that was ventral to the liver and outside the patient along the phase-encoding direction. The circular area also included ghosting artifacts. In some cases, respiratory ghosting artifacts were seen only at one or two particular sequences because the patients failed to hold their breath during these breath-hold sequences. In these cases, the most prominent respiratory ghosting areas were not included in the ROI. The area of background was maintained larger than 400 mm². The lesion-to-liver signal difference-to-noise ratio (SDNR) was calculated from the following equation:

where SI_lesion is the SI of the lesion, SI_liver is the SI of the liver, and SD_noise is the SD of the background noise. The signal-to-noise ratio (SNR) was also calculated from the following equation:

To eliminate the bias from clustered data, the SDNRs of lesions of the same pathology in each patient were averaged.

Two experienced gastrointestinal radiologists who had 5 and 2 years of experience in MRI of the abdomen and were not involved in the initial interpretation of the examinations jointly reviewed the four sets of MR images in random order and drew consensus results for all the MRI studies. The observers recorded the presence and anatomic segment of each lesion on standardized data sheets to compare the results of the four image sets. The observers recorded the conspicuity of the lesion in each image set based on a 4-point rating scale. A score of 1 indicated that the lesion was invisible; 2, poorly visible; 3, fairly visible; and 4, clearly visible. All the images were reviewed at a 1.5 x 1.5 K full PACS workstation (Centricity, GE Healthcare).

Statistical Analysis
Paired-samples two-tailed Student's t tests were used to compare the SDNR of every pair of each SPIO-enhanced GRE sequence. For statistical analysis, all lesions were classified into either of the two groups according to the potential capability of SPIO uptake by the lesions. HCCs, hemangiomas, and focal eosinophilic infiltration were classified as SPIO-uptake lesions, whereas all other lesions, including metastases and cysts, were classified as non-SPIO-uptake lesions. In each group, a paired-samples Student's t test was again performed to compare the SDNR of every pair of each SPIO-enhanced GRE sequence. An independent sample Student's t test was also performed to compare the SDNR between the SPIO-uptake and non-SPIO-uptake lesions. The McNemar test was used to compare the sensitivity between each pair of GRE sequences for the detection of focal hepatic lesions. The Wilcoxon's signed rank test was used to compare the subjective lesion conspicuity for depicted lesions. If a lesion was not seen on one sequence, the conspicuity was recorded as 1, retrospectively, in that sequence. When a lesion was not seen on all sequences, the conspicuity was regarded as 1 on all sequences, retrospectively.

The SNRs of each group were compared by a paired-samples Student's t test. Because we used a fixed dose of 1.4 mL of contrast material for all patients, the total dose was inversely correlated with the total body weight of the patients. To determine the effect of the variation of total dose, patients' body weights were compared with liver SNR and lesion SDNR using the Pearson's correlation coefficient. For all tests, a p value of < 0.05 was considered to indicate a statistically significant difference. Statistical analyses were performed with version 11 of SPSS software (Statistical Package for the Social Sciences) for Microsoft Windows.

Results

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The mean SDNR was highest at a TE of 13.5 milliseconds (mean ± SD = 60 ± 24 milliseconds) and was significantly higher (p < 0.001) than those at TEs of 9 (55 ± 23), 18 (55 ± 22), and 22.5 (47 ± 19) milliseconds (Table 1). The SDNRs at TEs of 9 and 18 milliseconds were comparable (p = 0.938) and were significantly higher than that at a TE of 22.5 milliseconds (p = 0.001). When the lesions were grouped into SPIO-uptake or non-SPIO-uptake lesions, the SDNRs of the non-SPIO-uptake lesions were higher than those of the SPIO-uptake lesions at TEs of 22.5 (p = 0.007) and 18 (p = 0.092) milliseconds. However, the SDNRs were comparable between the non-SPIO-uptake and SPIO-uptake lesions at TEs of 13.5 (p = 0.880) and 9 (p = 0.781) milliseconds.

The mean SDNR of cholangiocarcinomas was highest at a TE of 18 milliseconds and that of cysts was highest at a TE of 22.5 milliseconds (Fig. 1). The mean SDNRs of epithelioid hemangioendotheliomas, focal eosinophilic infiltrations, HCCs, hemangiomas, and metastases were highest at a TE of 13.5 milliseconds. For cysts, SDNRs at TEs of 18 (p = 0.009) and 22.5 (p = 0.014) milliseconds were significantly higher than that at a TE of 9 milliseconds. For HCCs, the SDNR at a TE of 13.5 milliseconds was significantly higher than those at TEs of 9 (p = 0.007), 18 (p < 0.001), and 22.5 (p < 0.001) milliseconds, and the SDNR on images obtained using a TE of 22.5 milliseconds was significantly lower than those obtained using TEs of 9 (p < 0.001), 13.5 (p < 0.001), and 18 (p < 0.001) milliseconds. For hemangiomas, the SDNR at a TE of 13.5 milliseconds was significantly higher than those at TEs of 18 (p = 0.002) and 22.5 (p < 0.001) milliseconds. The SDNR at a TE of 22.5 milliseconds was significantly lower than those at TEs of 9 (p = 0.018), 13.5 (p < 0.001), and 18 (p < 0.001) milliseconds. For metastases, the SDNR at a TE of 22.5 milliseconds was significantly lower than those at TEs of 9 (p = 0.002), 13.5 (p = 0.001), and 18 (p = 0.017) milliseconds, and there was no significant difference in the SDNR for images obtained using TEs of 9, 13.5, and 22.5 (p > 0.3) milliseconds.

View larger version (34K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1 —Bar graph shows mean signal difference-to-noise ratios (SDNR) of lesions on gradient-recalled MRI by lesion type. Mean SDNR of cholangiocarcinomas (CCC) was highest at TE of 18 milliseconds and that of cysts was highest at TE of 22.5 milliseconds. Mean SDNR of epithelioid hemangioendotheliomas (EHE), focal eosinophilic infiltrations (FEI), hepatocellular carcinomas (HCC), hemangiomas (HMG), and metastases (Mets) was highest at TE of 13.5 milliseconds.

For SPIO-uptake lesions, the SDNR at a TE of 13.5 milliseconds was significantly higher than those at TEs of 9 (p = 0.003), 18 (p < 0.001), and 22.5 (p < 0.001) milliseconds (Table 2 and Figs. 2A, 2B, 2C, 2D, 3A, 3B, 3C, and 3D). The SDNRs of SPIO-uptake lesions at TEs of 9 and 18 milliseconds were comparable (p = 0.196) and higher than that at a TE of 22.5 milliseconds (p < 0.001). For non-SPIO-uptake lesions, the SDNR was highest at a TE of 18 milliseconds but was comparable with that at a TE of 13.5 milliseconds (p = 0.647), and both were significantly higher than that at a TE of 22.5 milliseconds (p = 0.007 and 0.015, respectively). The SDNR at a TE of 9 milliseconds was comparable with those at TEs of 13.5, 18, and 22.5 milliseconds (Figs. 4A, 4B, 4C, and 4D).

View larger version (181K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2A —68-year-old man with hepatocellular carcinoma (HCC) and cirrhosis. Superparamagnetic iron oxide (SPIO)-enhanced gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds. Signal intensities of both HCC (arrow) and liver gradually decreased as TE was lengthened, but signal decrease of liver was more prominent between images obtained with TEs of 9 and 13.5 milliseconds. Signal difference-to-noise ratio was highest at TE of 13.5 milliseconds.

View larger version (177K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2B —68-year-old man with hepatocellular carcinoma (HCC) and cirrhosis. Superparamagnetic iron oxide (SPIO)-enhanced gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds. Signal intensities of both HCC (arrow) and liver gradually decreased as TE was lengthened, but signal decrease of liver was more prominent between images obtained with TEs of 9 and 13.5 milliseconds. Signal difference-to-noise ratio was highest at TE of 13.5 milliseconds.

View larger version (165K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2C —68-year-old man with hepatocellular carcinoma (HCC) and cirrhosis. Superparamagnetic iron oxide (SPIO)-enhanced gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds. Signal intensities of both HCC (arrow) and liver gradually decreased as TE was lengthened, but signal decrease of liver was more prominent between images obtained with TEs of 9 and 13.5 milliseconds. Signal difference-to-noise ratio was highest at TE of 13.5 milliseconds.

View larger version (155K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2D —68-year-old man with hepatocellular carcinoma (HCC) and cirrhosis. Superparamagnetic iron oxide (SPIO)-enhanced gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds. Signal intensities of both HCC (arrow) and liver gradually decreased as TE was lengthened, but signal decrease of liver was more prominent between images obtained with TEs of 9 and 13.5 milliseconds. Signal difference-to-noise ratio was highest at TE of 13.5 milliseconds.

View larger version (155K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3A —40-year-old woman with hemangioma. Superparamagnetic iron oxide (SPIO)-enhanced gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds. Signal intensity (SI) of both hemangioma (arrow) and liver decreased as TE was lengthened, but loss of SI of lesion is more prominent because contrast agent is pooling in lesion; hence, lesion conspicuity is decreased on images obtained with longer TEs.

View larger version (155K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3B —40-year-old woman with hemangioma. Superparamagnetic iron oxide (SPIO)-enhanced gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds. Signal intensity (SI) of both hemangioma (arrow) and liver decreased as TE was lengthened, but loss of SI of lesion is more prominent because contrast agent is pooling in lesion; hence, lesion conspicuity is decreased on images obtained with longer TEs.

View larger version (140K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3C —40-year-old woman with hemangioma. Superparamagnetic iron oxide (SPIO)-enhanced gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds. Signal intensity (SI) of both hemangioma (arrow) and liver decreased as TE was lengthened, but loss of SI of lesion is more prominent because contrast agent is pooling in lesion; hence, lesion conspicuity is decreased on images obtained with longer TEs.

View larger version (115K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3D —40-year-old woman with hemangioma. Superparamagnetic iron oxide (SPIO)-enhanced gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds. Signal intensity (SI) of both hemangioma (arrow) and liver decreased as TE was lengthened, but loss of SI of lesion is more prominent because contrast agent is pooling in lesion; hence, lesion conspicuity is decreased on images obtained with longer TEs.

View larger version (172K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4A —51-year-old man with metastasis from rectal carcinoma. Superparamagnetic iron oxide (SPIO)-enhanced gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds. There is no remarkable signal loss in small metastasis (arrow) on images obtained with longer TEs, and lesion conspicuity is comparable in all images; however, lesion looks smaller as TEs are increased.

View larger version (163K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4B —51-year-old man with metastasis from rectal carcinoma. Superparamagnetic iron oxide (SPIO)-enhanced gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds. There is no remarkable signal loss in small metastasis (arrow) on images obtained with longer TEs, and lesion conspicuity is comparable in all images; however, lesion looks smaller as TEs are increased.

View larger version (157K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4C —51-year-old man with metastasis from rectal carcinoma. Superparamagnetic iron oxide (SPIO)-enhanced gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds. There is no remarkable signal loss in small metastasis (arrow) on images obtained with longer TEs, and lesion conspicuity is comparable in all images; however, lesion looks smaller as TEs are increased.

View larger version (147K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4D —51-year-old man with metastasis from rectal carcinoma. Superparamagnetic iron oxide (SPIO)-enhanced gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds. There is no remarkable signal loss in small metastasis (arrow) on images obtained with longer TEs, and lesion conspicuity is comparable in all images; however, lesion looks smaller as TEs are increased.

In terms of detection sensitivity, 124 lesions (95%) were detected on images obtained at a TE of 9, 125 (95%) at a TE of 13.5, 122 (93%) at a TE of 18, and 120 (92%) at a TE of 22.5 milliseconds. The difference did not reach statistical significance in any comparison. Among the 11 lesions that were not detected on images at a TE of 22.5 milliseconds, 1 HCC, 1 metastasis, and 2 hemangiomas were seen on images at TEs of 18, 13.5, and 9 milliseconds. One HCC was detected at TEs of 18 and 13.5 milliseconds (Figs. 5A, 5B, 5C, and 5D). One metastasis and two hemangiomas were not detected on images obtained using a TE of 18 milliseconds, but these lesions were detected on the other images. Of the lesions that were not detected on the images obtained at a TE of 13 milliseconds, none was detected on the other images. One small metastasis that was not detected on images at a TE of 9 milliseconds was detected on the other GRE images, but this lesion was seen retrospectively. One well-differentiated HCC of 1.5 cm was not seen on any GRE image, but it was seen on an unenhanced T2-weighted fast spin-echo image (Figs. 6A, 6B, 6C, 6D, and 6E). An HCC of 1.7 cm and a hemangioma of 1.5 cm were not detected on GRE images obtained using a TE of 22.5 milliseconds. All other lesions not detected on any images were 1 cm or smaller in diameter.

View larger version (135K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 5A —46-year-old man with hepatocellular carcinoma (HCC). Superparamagnetic iron oxide (SPIO)-enhanced steady-state gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds. Signal intensity of small HCC is markedly decreased as TE increases due to contrast uptake within lesion and prominent susceptibility effect; hence, lesion is poorly shown on images obtained with longer TE.

View larger version (112K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 5B —46-year-old man with hepatocellular carcinoma (HCC). Superparamagnetic iron oxide (SPIO)-enhanced steady-state gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds. Signal intensity of small HCC is markedly decreased as TE increases due to contrast uptake within lesion and prominent susceptibility effect; hence, lesion is poorly shown on images obtained with longer TE.

View larger version (105K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 5C —46-year-old man with hepatocellular carcinoma (HCC). Superparamagnetic iron oxide (SPIO)-enhanced steady-state gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds. Signal intensity of small HCC is markedly decreased as TE increases due to contrast uptake within lesion and prominent susceptibility effect; hence, lesion is poorly shown on images obtained with longer TE.

View larger version (129K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 5D —46-year-old man with hepatocellular carcinoma (HCC). Superparamagnetic iron oxide (SPIO)-enhanced steady-state gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds. Signal intensity of small HCC is markedly decreased as TE increases due to contrast uptake within lesion and prominent susceptibility effect; hence, lesion is poorly shown on images obtained with longer TE.

View larger version (154K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 6A —68-year-old man with two hepatocellular carcinomas (HCCs) (Edmondson grade 2) and cirrhosis. Superparamagnetic iron oxide (SPIO)-enhanced gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds and unenhanced T2-weighted fast spin-echo image (TR/TE, 6,000/105) (E). Nodular HCC at lateral segment of liver (arrows) shows gradual signal decrease as TE increases. Another small HCC (Edmondson grade 1-2) at medial segment (arrowhead, E) was depicted on unenhanced T2-weighted fast spin-echo image only.

View larger version (166K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 6B —68-year-old man with two hepatocellular carcinomas (HCCs) (Edmondson grade 2) and cirrhosis. Superparamagnetic iron oxide (SPIO)-enhanced gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds and unenhanced T2-weighted fast spin-echo image (TR/TE, 6,000/105) (E). Nodular HCC at lateral segment of liver (arrows) shows gradual signal decrease as TE increases. Another small HCC (Edmondson grade 1-2) at medial segment (arrowhead, E) was depicted on unenhanced T2-weighted fast spin-echo image only.

View larger version (154K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 6C —68-year-old man with two hepatocellular carcinomas (HCCs) (Edmondson grade 2) and cirrhosis. Superparamagnetic iron oxide (SPIO)-enhanced gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds and unenhanced T2-weighted fast spin-echo image (TR/TE, 6,000/105) (E). Nodular HCC at lateral segment of liver (arrows) shows gradual signal decrease as TE increases. Another small HCC (Edmondson grade 1-2) at medial segment (arrowhead, E) was depicted on unenhanced T2-weighted fast spin-echo image only.

View larger version (146K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 6D —68-year-old man with two hepatocellular carcinomas (HCCs) (Edmondson grade 2) and cirrhosis. Superparamagnetic iron oxide (SPIO)-enhanced gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds and unenhanced T2-weighted fast spin-echo image (TR/TE, 6,000/105) (E). Nodular HCC at lateral segment of liver (arrows) shows gradual signal decrease as TE increases. Another small HCC (Edmondson grade 1-2) at medial segment (arrowhead, E) was depicted on unenhanced T2-weighted fast spin-echo image only.

View larger version (130K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 6E —68-year-old man with two hepatocellular carcinomas (HCCs) (Edmondson grade 2) and cirrhosis. Superparamagnetic iron oxide (SPIO)-enhanced gradient-recalled echo images obtained with TEs of 9 (A), 13.5 (B), 18 (C), and 22.5 (D) milliseconds and unenhanced T2-weighted fast spin-echo image (TR/TE, 6,000/105) (E). Nodular HCC at lateral segment of liver (arrows) shows gradual signal decrease as TE increases. Another small HCC (Edmondson grade 1-2) at medial segment (arrowhead, E) was depicted on unenhanced T2-weighted fast spin-echo image only.

The mean SNR of the liver was highest at a TE of 9 milliseconds (14.7 ± 6.5) and was significantly higher than those at TEs of 13.5 (8.6 ± 3.2, p < 0.001), 18 (5.9 ± 1.8, p < 0.001), and 22.5 (4.9 ± 1.3, p < 0.001) milliseconds. The mean SNR at a TE of 13.5 milliseconds was significantly higher (p <0.001) than those at TEs of 18 and 22.5 milliseconds. The mean SNR at a TE of 18 milliseconds was significantly higher (p < 0.001) than that at a TE of 22.5 milliseconds. There was no significant correlation between the liver SNR and patient body weight or total dose of ferucarbotran in all GRE sequences (R = -0.105 to -0.021, p >0.05).

Discussion

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The results of this study showed that the SDNR was significantly higher overall at a TE of 13.5 milliseconds for lesions. In addition, the subjective lesion conspicuity was comparable between TEs of 9 and 13.5 milliseconds, and the overall lesion sensitivity was not significantly different among the four image sets. However, the SDNR and lesion conspicuity were significantly lower and the largest number of lesions were not detected on images obtained with a TE of 22.5 milliseconds. Most lesions looked smaller as the TE increased and the magnetic susceptibility effect became more prominent, especially at the dome of the liver and the margin of the liver abutting the gastric or colonic air. For the lesions that were not seen only at a TE of 22.5 milliseconds, the detection failure was attributed to the prominent signal decrease and susceptibility effect, whereas failure in the detection of the remaining lesions was attributed to the inherent poor contrast of very small lesions and the substantial SPIO uptake in some of the lesions, including HCCs, hemangiomas, and focal eosinophilic infiltrations. The numbers of acquisitions for imaging the entire liver needed to be increased as TE was increased—from 2 acquisitions at a TE of 9 milliseconds to 5 acquisitions at a TE of 22.5 milliseconds. Therefore, we suggest that SPIO-enhanced GRE images should not be obtained at a TE of 22.5 milliseconds or longer for the detection of focal SPIO lesions.

Our results also showed that the SDNR of the focal liver lesions varied according to the lesion's capability for SPIO uptake. Although the lesions that may take up SPIO agents (e.g., hemangiomas and HCCs) showed the highest SDNR at a TE of 13.5 milliseconds, the lesions that may not take up SPIO agents (metastases and cysts) showed a comparably higher SDNR at TEs of 18 and 13.5 milliseconds. This was because the signal decrease was more pronounced in SPIO-uptake lesions than in non-SPIO-uptake lesions when the TE was increased to 18 milliseconds or more. Because hemangiomas and HCCs showed a more prominent signal drop on the images obtained using a very long TE (18 and 22.5 milliseconds), comparison of SPIO-enhanced GRE images obtained using a very long TE and those obtained using a moderately long TE (9 and 13.5 milliseconds) enables more accurate characterization of the lesions.

It is well known that benign hepatic lesions, including hemangiomas, focal nodular hyperplasia (FNH), and hepatic adenomas, can take up SPIO agents [15-19]. Previous studies have shown that SPIO-enhanced MRI reflects Kupffer cell count in HCCs and dysplastic nodules and is useful for estimation of histologic grading in HCC; and the conspicuity of well-differentiated HCC or dysplastic nodules is decreased on the SPIO-enhanced fast spin-echo or GRE images obtained using a TE of 8.4-10 milliseconds [20, 21]. In our study, one well-differentiated HCC that was well depicted on an unenhanced T2-weighted fast spin-echo image was not depicted on the contrast-enhanced GRE images because of SPIO uptake. However, even the HCC lesions that showed hyperintensity on the GRE images at TEs of 9 or 13.5 milliseconds showed a substantial decrease in SI on images obtained using a longer TE (18 and 22.5 milliseconds) in contrast with the non-HCC lesions such as metastases. The possibility of minimally retained Kupffer cell activity in the HCC or the increased vascularity of the tumor might have contributed to this finding.

The results of the present study deserve comparison with the results of the studies by Ward et al. [13] and Matsuo et al. [12]. Matsuo et al. compared GRE images at TEs of 1.4, 4.2, 6, 8, and 10 milliseconds for the detection of HCCs and metastases using ferumoxides at a dose of 10 µmol Fe/kg. In their study, GRE sequences at a TE of 8 milliseconds showed the highest sensitivity and liver-to-lesion contrast, but the difference was not significant when compared with GRE images obtained at a TE of 10 milliseconds. The flip angle used in their study was 70-90° and might have a higher T1 effect than the flip angle of 30° used in our study. In the study by Ward et al. [13], using ferumoxides at a dose of 7.5 µmol Fe/kg, SPIO-enhanced GRE images that were obtained at a TE of 15 milliseconds and at the flip angle of 30° showed significantly higher liver-to-lesion contrast than GRE images at a TE of 11 milliseconds, but the sensitivity was not significantly different for the detection of colorectal cancer metastases. These results are comparable to those of our study.

In the present study, we compared TEs of 9, 13.5, 18, and 22.5 milliseconds to encompass the TE range used in previous studies but not directly compared and to obtain in-phase images to reduce the ring cancellation artifacts from chemical shift effects along the liver surface [4-8, 10-14]. We used a flip angle of 30° to minimize the T1 effect and reduce pulsation artifact and to compare our data with the results of a previous study [13]. We also used a fixed bandwidth for all TE values. If we reduced the bandwidth as we increased TE, the SNR could be improved for images obtained with a long TE. However, if we did so, the disadvantages of increased artifact at the periphery of the liver and decreased slices per breath-hold might be more severe. We speculate that using a higher frequency encoding (e.g., 512 instead of 256) might reduce the apparent susceptibility at the periphery of the liver and improve the differentiation of a small lesion with a branch of a vessel by improving the spatial resolution. However, we maintained a constant frequency encoding in this study to directly compare the TE effect.

We used 1.4 mL (7.0-14.5 µmol Fe/kg) of ferucarbotran. A prior study showed that ferucarbotran, administered in a dose of 7.0-12.9 µmol of iron per kilogram of body weight, had similar T1 and T2 effects on the liver when compared with ferumoxides administered in a dose of 15 µmol/kg [22]. In this context, the dose used in our study might be somewhat higher than those used by Matsuo et al. [12] and Ward et al. [13]. Nonetheless, our results showed that lesion contrast can be increased until a TE of 18 milliseconds for metastases and until a TE of 13.5 milliseconds for HCCs and hemangiomas. This is also comparable with the findings of another study using a low dose (7.5 µmol Fe/kg) of ferumoxides and a 1.0-T system: Liver-to-lesion contrast-to-noise ratio was increased until a TE of 26 milliseconds [23].

Our results also showed that the patients' body weights were not correlated with the liver SNR or lesion SDNR on any GRE sequence. This suggests that the variation of dose range used in this study does not affect the liver SNR or lesion SDNR. These results are also similar to those of previous reports in which the efficacy of ferucarbotran was comparable for the doses of 8 and 16 µmol Fe/kg [24, 25].

A limitation of our study is that many lesions were not pathologically proven. Typical clinical and laboratory findings in combination with disease progression, as depicted on follow-up images, were used as the diagnostic criteria in these patients. Although we applied these diagnostic criteria as strictly as possible to exclude false-positive lesions, we might have missed small lesions. The relative high sensitivity of each GRE image set might be attributed to this lack of histologic confirmation. However, because we compared the SDNR and detection rate among the four image sets obtained under the same conditions only for the confirmed lesions, we believe that this limitation would not alter the validity of this study.

A second limitation is that we did not analyze observer variability but, rather, used consensus interpretation for lesion detection. A multiobserver analysis would have estimated better the sensitivity of each technique for depicting lesions and would have more accurately predicted differences between them in clinical practice. However, our consensus interpretation is still valid for evaluating the choice of optimal TE for SPIO-enhanced imaging.

A third limitation is that we did not randomize the order in which we obtained GRE images with a different TE; instead, we acquired the images with a TE of 22.5 milliseconds first and those with a TE of 9 milliseconds last. We chose this consistent order to avoid ambiguity between potential benefits to image contrast from more complete vascular clearance of contrast agent versus increased susceptibility artifacts from a longer TE; the signal drop was most profound on the images obtained with a TE of 22.5 milliseconds, even though vascular clearance might have been less. In addition, the time difference of 20 minutes between the first and the last image set probably had little effect on tissue contrast, particularly considering that a prior study using the same SPIO agent found no apparent differences between 10- and 40-minute contrast-enhanced MR images for evaluating focal lesions [25].

Because of the small number of histologically proven HCCs, we could not determine whether the decreased SI and SDNR of HCCs at very long TEs of 18 and 22.5 milliseconds might be related to the histologic grade or other microscopic characteristics. In many reports, researchers have shown that benign hepatocellular nodules, including FNH and hepatic adenomas, decrease in SI on SPIO-enhanced MR images [26-31]. Because none of these lesions were included in this study, we cannot state how the signal characteristics of those lesions might be changed on images obtained with the TE range used in our study.

We performed dynamic MRI as part of our post-ferucarbotran administration protocol, but we did not analyze these images for this study. On the T1-weighted SPIO-enhanced dynamic MR images, features that are useful for the characterization of focal lesions include peripheral globular enhancement of hemangiomas, rim enhancement of metastases, and early increased enhancement of HCCs [32-34]. We noted these findings in many lesions in our study, but this was not a purpose of this study.

A faster imaging sequence, such as diffusion-weighted echo-planar imaging [35], gradient and spin-echo [36], or balanced steady-state imaging (e.g., balanced fast-field echo, true fast imaging with steady-state free precession [FISP], or fast imaging employing steady-state acquisition [FIESTA]), might be useful as a faster method with fewer artifacts that has susceptibility contrast, but we have no data to address the potential utility of these techniques because they were not available at the time of this study.

In summary, our results showed that a TE of 13.5 milliseconds provided the highest SDNR for SPIO-enhanced GRE images, but the SDNR of liver lesions can vary according to the lesion's potential capacity for SPIO uptake. The subjective lesion conspicuity and sensitivity were comparable when the TE was in the range of 9-18 milliseconds, but the SDNR of the lesions that may take up SPIO agents substantially decreased on GRE images at TEs of 18 and 22.5 milliseconds.

In conclusion, we suggest that TE values can be chosen from 9 to 18 milliseconds for SPIO-enhanced MRI in consideration of scanning time and image quality. Our results also suggest that comparing the GRE images with a moderately long TE (9-13.5 milliseconds) and a very long TE (18-22.5 milliseconds) may be useful for characterization of focal hepatic lesions.

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