© 2013, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(13)60096-X

 

 

Acknowledgment: The authors thank Dr. Fiona Murray-Zmijewski, Medicus International for editorial support in preparing the manuscript.

Contributors: All authors contributed to the conceptual design, data analysis and preparation of this manuscript. All authors have read and approved the final manuscript for submission.

Funding: The study was supported by a grant from Bayer HealthCare/Bayer Schering Pharma AG.

Ethical approval: The study was conducted in compliance with ethical principles based on the Declaration of Helsinki, the International Conference on Harmonization Guidelines for Good Clinical Practice (GCP) and informed written consent was obtained from all participants.

Competing interest: The author or one or more of the authors have received benefits for personal or professional use from a commercial party related directly or indirectly to the subject of this article.

 

 

 

 

 

 

(Hepatobiliary Pancreat Dis Int 2013;12:607-616)

 

KEY WORDS:gadoxetate disodium; magnetic resonance imaging; liver; focal liver lesions

Liver-specific gadolinium-based contrast agents are helpful in magnetic resonance (MR) imaging for detecting and characterizing focal liver lesions.^{[1, 2]} The liver has a large interstitial space and, therefore, there is a reduction in the natural contrast gradient between lesions and healthy tissue. The use of a contrast agent helps to improve visibility in MR imaging. Gadoxetate disodium (Gd-EOB-DTPA) is a paramagnetic, hydrophilic, ionic, highly water-soluble, liver-specific and intravenous contrast agent in MR imaging. Due to its weak protein-binding capabilities,^[3] the T1 relaxivity of Gd-EOB-DTPA in human plasma at 37 �� is 6.9 L/mmol per second at 1.5T magnetic field, which is higher than that of most other gadolinium chelates, Gd-EOB-DTPA is available as a 0.25 mol/L solution, and its high relaxivity helps compensate for the lower gadolinium concentration (most gadolinium chelates are available as 0.5 mol/L solutions).^[2] The recommended dose is 0.025 mmol/kg body weight (BW), which is lower than that of the standard dose of 0.1 mmol/kg BW for most other gadolinium chelates.^[2]

 

The selective uptake of Gd-EOB-DTPA via the organic anionic transporter protein in hepatocytes increases liver-to-lesion contrast.^[4-7] Homogeneous enhancement of liver parenchyma by Gd-EOB-DTPA was observed with peak liver intensity between 10 and 20 minutes after injection.^[8-11] Gd-EOB-DTPA-enhanced imaging has been shown to be helpful in the detection and characterization of liver lesions.^{[1, 11-19]}

 

The present study is a multicenter, open-label, phase III clinical study, which aimed to evaluate the efficacy and safety of Gd-EOB-DTPA as a contrast agent for enhanced MR imaging of focal liver lesions in Chinese patients, and to demonstrate the sensitivity of Gd-EOB-DTPA-enhanced MR imaging in lesion detection.

 

 

This was a single-arm, open-label, multicenter study in Chinese patients with known or suspected focal liver lesions who were referred for contrast-enhanced MR imaging for further examination. Following enrollment, each patient was evaluated at baseline and on the day of the contrast-agent injection, with a full safety evaluation within 24 hours post-injection. An Independent Ethics Committee or Institutional Review Board at each study center approved the study protocol. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and all patients provided written informed consent.

 

Patients with age from 18 to 75 years old were recruited from seven centers in China. The focal liver lesion was identified or suspected by the examination of ultrasound, computed tomography (CT)/spiral-CT, conventional angiography, CT-angiography, CT-arterial photography or unenhanced/contrast-enhanced MR imaging within two months. Exclusion criteria included: administration of any contrast agent within 24 hours or scheduled to receive any contrast agent within 24 hours; breast feeding; patients who required emergency treatment; severely impaired hepatic or renal function; patients who were clinically unstable and whose clinical course during the observation period was unpredictable; patients who are unable to sign the informed consent; contraindication to MR imaging examination; history of severe allergy or anaphylactic reaction to any allergen including drugs and contrast agents; patients who were scheduled for liver biopsy/surgery or other surgeries within 24 hours, or had a biopsy within 24 hours before the planned contrast-agent injection; or those who were likely to have any therapy or change in therapy between the study of MR imaging and the procedures for the pre-defined standard of reference (SOR) required for endpoint verification.

 

Each patient received a single intravenous bolus injection of 0.25 mol/L Gd-EOB-DTPA at a dosage of 0.025 mmol/kg BW. Administration of the Gd-EOB-DTPA with a power injector was via a peripheral vein, preferably the forearm or the antecubital vein, at a rate of 1.0-2.0 mL/s, followed by a 20 mL of 0.9% saline flush.

 

A phased array coil covering the whole liver was used for imaging, and pre-contrast MR imaging was performed according to specified pulse sequences (Table 1). Patients then underwent dynamic T1-weighted (T1w) three-dimensional (3D) gradient-recalled echo imaging with fat suppression 18-23 seconds after the administration of Gd-EOB-DTPA. The pulse sequence was repeated at 45-60 seconds and at 120 seconds, with breaks between the dynamic sets to allow the patient to breathe. A T1w two-dimensional (2D) pulse sequence with fat suppression was performed 20 minutes after Gd-EOB-DTPA administration, and was followed immediately by a T2-weighted (T2w) pulse sequence with fat suppression or a half-Fourier acquisition single-shot turbo spin-echo sequence. The same imaging parameter settings were used both pre- and post-contrast for each pulse sequence in each patient (Table 1). All pre- and post-contrast MR images, including dynamic images, were verified for image quality control and blinded reading. Any deviation from the MR imaging or dynamic procedure was recorded.

 

The image analyses included: pre-contrast T1w-2D and T2w images (pre-contrast MR image); dynamic 3D plus post-contrast T1w-2D and T2w images (post-contrast MR image); combined pre- and post-contrast T1w and T2w images and dynamics (all per-protocol sequences). All images were assessed by seven clinical investigators, who were onsite readers, and by three blinded readers via an off-site imaging core laboratory. Radiologists were qualified, independent professionals not affiliated with the study centers. Radiologists were blinded to the patients' clinical and laboratory data. All blinded readers received training for completion of the electronic case report form, procedure of the imaging work station and definition of the scores. MR images (pre-, post- and combined pre- and post-contrast) were allocated to the blinded readers in a randomized order.

 

The diagnoses of MRI were confirmed using a pre-defined SOR which included: 1) surgery in combination with intra-operative ultrasound within 1 month after MR imaging; 2) interventional digital subtraction angiography within 1 month after MR imaging, in combination with multi-slice CT within 1 month before or after MR imaging; and 3) conventional ultrasound in combination with multi-slice CT within 1 month before or after MR imaging.

 

The SOR reports are as follows: number of lesions, location (drawing and numbering the lesions on segment maps according to the Couinaud system), and size. The total number of lesions was tracked by a central, independent radiologist, who compared the liver maps of each patient provided by the investigators for the defined SOR procedures, in order to assess the true number of lesions, and thus, identify the true disease state for a patient.

 

The final diagnosis was made within 1 month after MR imaging according to the image characterization. These findings were verified by the SOR and additional further clinical examinations, such as further diagnostic procedures, laboratory tests and biopsy.

 

The primary efficacy variable was the sensitivity of lesion detection, as assessed by the blinded readers based on the number of lesions detected in pre- and post-contrast MR imaging and verified by SOR.

 

The secondary variables pertaining liver lesions included: numbers, characterizations, diagnostic confidence, diagnostic confidence in characterizations, and accuracy of characterization and differentiation. The lesions were also assessed according to size (<1 cm; ≥1 to <3 cm; ≥3 cm) and location according to liver segment for both pre- and post-contrast images. Lesion characterization was assessed using morphologic features, and enhancement patterns detected in the pre- and post-contrast images. Lesions were classified as either "malignant" or "benign" according to the assessment given by the investigators and blinded readers. Diagnostic confidence was assessed according to the reader's confidence in liver lesion detection and characterization, recorded on separate 5-point scales ranging from 1=low to 5=high.

 

The adverse events were assessed by vital signs, physical examinations and clinical laboratory parameters at baseline within 24 hours before and after Gd-EOB-DTPA injection. Any clinically relevant changes in laboratory parameters and/or the patient's physical condition were recorded.

 

All patients who received any amount of contrast agent were included in the safety analysis; patients who received any amount of contrast agent, had a valid SOR and had data available from both pre- and post-contrast MR imaging but had a major deviation from the protocol, were included in the full-analysis set (FAS). Finally, patients who received a contrast-agent injection and had no major protocol deviation were included in the per-protocol set (PPS).^[20] Major protocol deviations included: missing image sets either pre- or post-contrast, scanner or patient-related problems including inadequate flow rate leading to inadequate images, or an incorrect dose of the contrast agent.

 

For lesion detection evaluations, "complete-case patients" were defined as those with pre- and post-contrast MR image sets evaluable for all three blinded readers and incomplete-case patients were defined as those with an image set that was not evaluable by at least one of the blinded readers. Similar rules were used for the analysis of lesion characterization and classification. The primary analysis was based on the PPS. When the number of lesions detected in the MR image exceeded those detected in the corresponding SOR, the lesion count from the SOR was used for the sensitivity calculation. Lesions detected in the MR images, but not in the SOR were considered to be "additional" or "false-positive" lesions. Sensitivity estimates for pre- and post-contrast image sets, together with 95%, two-sided, normal approximated confidence intervals (CIs), were derived from the average results from the blinded readers. The average sensitivity was the primary efficacy. The investigators' assessments were presented as a mean score. Lesion detection, size, characterization and diagnostic confidence were summarized with descriptive statistics for complete-case patients. The diagnostic accuracy was calculated according to the pre-contrast and combined pre- and post-contrast images. Differences were calculated as the number obtained from combined pre- and post-contrast minus that from pre-contrast image.^[21] Descriptive statistics were provided for the number of additional lesion characterizations detected in either MR image set, but not in the SOR. Safety parameters were also assessed.

 

 

Of the 247 patients, 234 were injected with Gd-EOB-DTPA. Thirteen patients failed the screening process: seven withdrew consent, three did not meet the inclusion criteria, and three failed because of "other" reasons: 1 was because of MR scanner error, 1 with psoriasis and 1 with a lumbar replacement. The FAS comprised 195 patients. The PPS comprised 178 patients (Fig. 1).

 

Among the 234 patients, the mean age was 50.28 years (range 19-79). Seventy-nine (33.8%) patients were female. The percentage of female patients was similar in the FAS and PPS (32.8% and 32.0%, respectively). Liver lesion types were classified as benign (94/234, 40.2%), malignant (112/234, 47.9%) and no detectable lesion (50/234, 21.4%); patients were counted more than once if multiple lesions were detected. A total of 63 patients had metastases in which the primary tumors were from the gastrointestine (60.3%), lung (6.3%), breast (4.8%), pancreas (6.3%), other (liver, esophagus, pharynx nasalis, left ankle, left side of back, mediastinum, bladder and testis, 14.3%) or unknown (7.9%) organs. In 34 patients with liver cirrhosis, 18 (52.9%) were classified into Child-Pugh A, 7 (20.6%) B and 2 (5.9%) C, but 7 could not be classified. The type of liver lesions in the PPS was comparable with the safety analysis set. Case studies exhibiting Gd-EOB-DTPA-enhanced imaging in focal liver lesions are shown in Figs. 2 and 3.

 

A total of 177/178 (99.4%) and 193/195 (99.0%) patients assigned as complete-case patients for the purposes of lesion detection were in the PPS and FAS, respectively. With respect to characterization, all 178 (100%) in the PPS were assessed as complete-case patients, whereas 194/195 (99.5%) in the FAS were assigned as complete-case patients.

 

The total number of liver lesions detected in the SOR was 613 (mean 3.5; range 0-24 lesions per patient) for the complete-case patients in the PPS, and 648 (mean 3.4; range 0-24 lesions per patient) for the complete-case patients in the FAS. In the PPS analysis, the sensitivity of liver lesion detection was significantly improved by Gd-EOB-DTPA (94.78%; 95% CI: 92.79, 96.77) compared with pre-contrast MR imaging (85.32%; 95% CI: 80.74, 89.90). Significant improvements in favor of Gd-EOB-DTPA were also found for each of the single-blinded readers with a difference of 8.65%, 12.23% and 7.50% for readers 1, 2 and 3, respectively, as well as the investigators' assessment (Table 2). Results were comparable for the FAS population: sensitivity of Gd-EOB-DTPA-enhanced MR imaging was 94.70% (95% CI: 92.75, 96.65) compared with that of 85.55% (95% CI: 81.19, 89.90) in pre-contrast MR imaging. The results of the FAS cohort were also significantly in favor of the Gd-EOB-DTPA-enhanced MR images compared with pre-contrast images (data not shown).

 

All three readers detected additional lesions (i.e. not detected in the SOR) in Gd-EOB-DTPA-enhanced MR and pre-contrast images, with a higher number detected in Gd-EOB-DTPA-enhanced MR images. Results were similar for both the PPS and the FAS. These additional lesions were consistently seen by the blinded readers in both the FAS and the PPS, six patients (3.4%) with more than 20 additional lesions. The lesion type was characterized as "metastasis" in the SOR in four patients; "hepatocellular carcinoma" and "liver cyst" in one patient and "liver cyst" and "hemangioma" in another patient.

 

For all lesion sizes evaluated in the PPS, the sensitivity estimates in lesion detection increased with Gd-EOB-DTPA-enhanced MR imaging compared with pre-contrast MR imaging. The best improvements were for small lesions (<1 cm) where the difference was statistically significant (20.63%) for the average reader, the sensitivity of Gd-EOB-DTPA-enhanced image was 86.00% (95% CI: 79.79, 92.22) while pre-contrast was 65.38% (95% CI: 55.25, 75.51) (Table 3). Significant differences were also observed with Gd-EOB-DTPA compared with pre-contrast images for each of the individual blinded readers and the investigators' assessment for the detection of the lesions bigger than 1 cm (Table 3).

 

The mean confidence rate for lesion detection in the PPS did not change between Gd-EOB-DTPA-enhanced MR and pre-contrast imaging (Table 4). However, Gd-EOB-DTPA-enhanced MR imaging showed "high" confidence (rating of 5). In the investigator analysis, the mean confidence rate was similar between Gd-EOB-DTPA-enhanced imaging and pre-contrast imaging (4.9 vs 4.7, Table 4).

 

Of the 178 complete-case patients in the PPS, 165 (92.7%) had at least one unique lesion characterized in the SOR. Twelve patients had liver lesions that were "not assessable" in the SOR and one patient had no lesions in the SOR; therefore, 165 patients were evaluated for the accuracy of lesion characterization. The total number of unique lesions characterized in the SOR was 220 and the mean number of unique lesions per patient was 1.2. "Additional" or "false-positive lesions" were not included in this part of the analysis.

 

In the PPS analysis for the average reader, the accuracy of lesion characterization was significantly greater in combined pre- and post-contrast imaging (66.97%; 95% CI: 62.24, 71.70) compared with pre-contrast MR imaging (55.61%; 95% CI: 50.80, 60.41) (Table 5). For each individual blinded reader, differences in pre- and post-contrast images for the accuracy of lesion characterization were also significantly greater in Gd-EOB-DTPA than in pre-contrast images (13.64%, 9.55% and 10.91% for readers 1, 2 and 3, respectively). Similar results were obtained for the investigator analysis (15.45%) (Table 5).

 

For the average reader, the combined imaging was more accurate than pre-contrast imaging for each of the five most frequent lesion types, 5.56% for hepatocellular carcinoma, 7.97% for liver cysts, 9.09% for focal nodular hyperplasia, 11.90% for metastasis and 24.03% for hemangioma (PPS analysis). Furthermore, Gd-EOB-DTPA-enhanced imaging increased the accuracy of the lesion characterization compared with pre-contrast imaging for the five most common lesion types. In the investigator's analysis, the accuracy was also higher in combined imaging than in pre-contrast imaging. The accuracy of lesion characterization by lesion type was 14.58% for hepatocellular carcinoma, 10.87% for liver cysts, 5.36% for metastasis, 9.30% for hemangioma and 72.73% for focal nodular hyperplasia.

 

The diagnostic confidence in lesion characterization (rated using a 5-point scale) also showed that combined pre- and post-contrast images increased the mean confidence score compared with pre-contrast imaging (Table 6). The confident rate of combined pre- and post-contrast MR was higher than that of pre-contrast imaging. The biggest difference was seen in reader 1, who rated 30.5% of the lesions with a characterization confidence rating >4 at pre-contrast MR imaging, and 97.0% of the lesions with the combined pre- and post-contrast MR imaging (Table 6). This was further pronounced when considering a rating of 5, with reader 1 rating only 8.6% of the lesions with a high characterization confidence rate at pre-contrast MR imaging, but 76.2% at the combined MR imaging.

 

The differentiation of benign and malignant lesions was improved with combined imaging compared with pre-contrast imaging for both the average reader (benign lesions: 65.77% [95% CI: 58.66, 72.89] vs 52.08% [95% CI: 45.33, 58.84]; malignant lesions: 68.21% [95% CI: 61.87, 74.55] vs 59.26% [95% CI: 52.38, 66.14]) and the investigators' assessment (Table 7).

 

Five (2.1%) of the 234 patients had treatment-related adverse events. These were nausea (2 patients), increased blood bilirubin (2) and decreased white blood cell count (1), all of which were mild or moderate. No deaths or serious adverse events were reported during the study. There was no delayed allergic reaction during the follow-up. Furthermore, no patients were withdrawn from the study because of adverse events.

 

 

This multicenter, open-label study with a corresponding blinded reading showed that a single bolus injection of 0.025 mmol/kg BW Gd-EOB-DTPA was well tolerated and improved the sensitivity in liver lesion detection in Chinese patients with known or suspected focal liver lesions. The strong safety profile of Gd-EOB-DTPA was confirmed by this study. Gd-EOB-DTPA-enhanced imaging significantly improved the sensitivity of liver lesion detection by 9.46% compared with pre-contrast imaging for the average reader (PPS analysis). A significant improvement in liver lesion detection was also observed with Gd-EOB-DTPA for each individual blinded reader, and the clinical investigators. Furthermore, the improvement in detection of liver lesions observed with Gd-EOB-DTPA-enhanced imaging was even more pronounced in detecting small lesions (<1 cm), with a difference of 20.63% compared with pre-contrast imaging. These results from a Chinese population are in line with previously published data predominantly in Caucasian patients^{[12, 15]} or Japanese patients.^[19]

 

The sensitivity of liver lesion detection, when compared with a SOR, is an objective and quantitative parameter. In clinical situations, it is relevant for the radiologist to determine the number of liver lesions, as this will influence the therapy decision, especially for patients with malignancies. Moreover, the confidence of the radiologist in the detection capability of the imaging procedure, and consequently, of the contrast-enhanced images, impacts on further patient management, e.g. investigation/diagnostic tests and therapy decisions. Correct and reliable detection of liver lesions as well as the type of lesion itself determine patient management.

 

The rate of false-positive lesions was also evaluated in order to provide a surrogate measure for the specificity of Gd-EOB-DTPA. Contrast-enhanced imaging procedures may result in an increase in false-positive rates; however, a weak SOR can result in false-positive lesions in test procedures known to have a higher performance; yet, a combination of pathologic and imaging procedures was selected to establish a strong SOR for this study. The number of patients with at least one false-positive lesion was higher for Gd-EOB-DTPA-enhanced imaging compared with pre-contrast imaging in 6/177 patients for all three blinded readers. Overall, this rate was relatively low compared with the result from the literature and studies previously performed with Gd-EOB-DTPA.^{[1, 15]} It is also possible that the additional lesions detected using Gd-EOB-DTPA were not false-positive, but simply had not been detected previously.

 

Diagnostic confidence in liver lesion detection was evaluated as a qualitative parameter. It is usual in clinical practice for radiologists to use clinical information when making assessments. In this study, a clear improvement in diagnostic confidence in lesion detection was seen for Gd-EOB-DTPA compared with pre-contrast imaging in the investigators' assessment for lesions with a score of at least 4, and also with a score of at least 5. Furthermore, the diagnostic confidence in lesion detection was higher for Gd-EOB-DTPA compared with pre-contrast images for two out of three blinded readers with a score of at least 5.

 

Diagnostic confidence in lesion characterization was significantly improved with combined pre- and post-contrast Gd-EOB-DTPA-enhanced imaging compared with pre-contrast imaging alone. Although not explicitly required, the patient population enrolled revealed a good balance between benign and malignant lesions and allowed for a reliable assessment of the characterization capabilities of Gd-EOB-DTPA. Precision in lesion characterization was improved overall and for the most frequent lesion types (focal nodular hyperplasia, metastasis, hepatocellular carcinoma, liver cyst and hemangioma) using combined pre- and post-contrast MR imaging compared with pre-contrast MR imaging for the average reader and the blinded readers. The improvement in lesion characterization with the Gd-EOB-DTPA-enhanced MR imaging examination suggests the potential for reducing the need for biopsies and decreasing biopsy false-negative rates.

 

The results presented here support previous studies showing that 0.025 mmol/kg Gd-EOB-DTPA is effective in the detection and classification of liver lesions.^{[12,13,15,16, 19, 22]} In particular, a previous study has shown that Gd-EOB-DTPA improves the detection of small lesions.^[19] Improvements in diagnostic imaging are likely to have a positive impact on patient treatment, especially as Gd-EOB-DTPA has a strong safety profile; previous phase I and II studies have shown doses of up to 0.1 mmol/kg to be well tolerated.^{[4, 17]} Further evidence suggests that Gd-EOB-DTPA is particularly useful for the detection of small lesions, including small hepatocellular carcinoma lesions (<1 cm).^[23] Gd-EOB-DTPA is also more effective than gadopentetate dimeglumine for detecting hepatic lesions.^{[10, 14]} Optimal hepatic imaging with Gd-EOB-DTPA is around 20 minutes post-injection, compared with 60-120 minutes post-injection for gadobenate dimeglumine, another hepatobiliary contrast agent.^[24] Gd-EOB-DTPA-enhanced MR imaging has also been shown to improve lesion classification accuracy compared with spiral-CT.^{[1, 13, 18]}

 

The multicenter design of this study minimized any potential bias that might have occurred if the study had been conducted at a single center. As no liver-specific contrast agent is approved for the use in China, it was not deemed appropriate to use a comparator contrast agent. However, this study did compare pre- and post-contrast images for analyses of lesion detection, and combined pre- and post-contrast images for analyses in characterization and lesion classification within the same patient.

 

In conclusion, this open-label study demonstrated that Gd-EOB-DTPA improves sensitivity in liver lesion detection, particularly for lesions smaller than 1 cm. Gd-EOB-DTPA was associated with significantly improved precision in lesion characterization and classification, and a high level of diagnostic confidence. The good safety profile of Gd-EOB-DTPA was confirmed in this study of Chinese patients with liver lesions.

 

 

1 Hammerstingl R, Huppertz A, Breuer J, Balzer T, Blakeborough A, Carter R, et al. Diagnostic efficacy of gadoxetic acid (Primovist)-enhanced MRI and spiral CT for a therapeutic strategy: comparison with intraoperative and histopathologic findings in focal liver lesions. Eur Radiol 2008;18:457-467. PMID: 18058107

2 Zech CJ, Herrmann KA, Reiser MF, Schoenberg SO. MR imaging in patients with suspected liver metastases: value of liver-specific contrast agent Gd-EOB-DTPA. Magn Reson Med Sci 2007;6:43-52. PMID: 17510541

3 Rohrer M, Bauer H, Mintorovitch J, Requardt M, Weinmann HJ. Comparison of magnetic properties of MRI contrast media solutions at different magnetic field strengths. Invest Radiol 2005;40:715-724. PMID: 16230904

4 Hamm B, Staks T, Mühler A, Bollow M, Taupitz M, Frenzel T, et al. Phase I clinical evaluation of Gd-EOB-DTPA as a hepatobiliary MR contrast agent: safety, pharmacokinetics, and MR imaging. Radiology 1995;195:785-792. PMID: 7754011

5 Weinmann HJ, Schuhmann-Giampieri G, Schmitt-Willich H, Vogler H, Frenzel T, Gries H. A new lipophilic gadolinium chelate as a tissue-specific contrast medium for MRI. Magn Reson Med 1991;22:233-237. PMID: 1812351

6 Schuhmann-Giampieri G, Schmitt-Willich H, Press WR, Negishi C, Weinmann HJ, Speck U. Preclinical evaluation of Gd-EOB-DTPA as a contrast agent in MR imaging of the hepatobiliary system. Radiology 1992;183:59-64. PMID: 1549695

7 van Montfoort JE, Stieger B, Meijer DK, Weinmann HJ, Meier PJ, Fattinger KE. Hepatic uptake of the magnetic resonance imaging contrast agent gadoxetate by the organic anion transporting polypeptide Oatp1. J Pharmacol Exp Ther 1999;290:153-157. PMID: 10381771

8 Hamm B, Thoeni RF, Gould RG, Bernardino ME, Lüning M, Saini S, et al. Focal liver lesions: characterization with nonenhanced and dynamic contrast material-enhanced MR imaging. Radiology 1994;190:417-423. PMID: 8284392

9 Reimer P, Rummeny EJ, Shamsi K, Balzer T, Daldrup HE, Tombach B, et al. Phase II clinical evaluation of Gd-EOB-DTPA: dose, safety aspects, and pulse sequence. Radiology 1996;199:177-183. PMID: 8633143

10 Vogl TJ, Kümmel S, Hammerstingl R, Schellenbeck M, Schumacher G, Balzer T, et al. Liver tumors: comparison of MR imaging with Gd-EOB-DTPA and Gd-DTPA. Radiology 1996;200:59-67. PMID: 8657946

11 Saito K, Kotake F, Ito N, Ozuki T, Mikami R, Abe K, et al. Gd-EOB-DTPA enhanced MRI for hepatocellular carcinoma: quantitative evaluation of tumor enhancement in hepatobiliary phase. Magn Reson Med Sci 2005;4:1-9. PMID: 16127248

12 Bluemke DA, Sahani D, Amendola M, Balzer T, Breuer J, Brown JJ, et al. Efficacy and safety of MR imaging with liver-specific contrast agent: U.S. multicenter phase III study. Radiology 2005;237:89-98. PMID: 16126918

13 Halavaara J, Breuer J, Ayuso C, Balzer T, Bellin MF, Blomqvist L, et al. Liver tumor characterization: comparison between liver-specific gadoxetic acid disodium-enhanced MRI and biphasic CT--a multicenter trial. J Comput Assist Tomogr 2006;30:345-354. PMID: 16778605

14 Hammerstingl R, Zangos S, Schwarz W, Rosen T, Bechstein WO, Balzer T, et al. Contrast-enhanced MRI of focal liver tumors using a hepatobiliary MR contrast agent: detection and differential diagnosis using Gd-EOB-DTPA-enhanced versus Gd-DTPA-enhanced MRI in the same patient. Acad Radiol 2002;9:S119-120. PMID: 12019845

15 Huppertz A, Balzer T, Blakeborough A, Breuer J, Giovagnoni A, Heinz-Peer G, et al. Improved detection of focal liver lesions at MR imaging: multicenter comparison of gadoxetic acid-enhanced MR images with intraoperative findings. Radiology 2004;230:266-275. PMID: 14695400

16 Kim YK, Kim CS, Han YM, Kwak HS, Jin GY, Hwang SB, et al. Detection of hepatocellular carcinoma: gadoxetic acid-enhanced 3-dimensional magnetic resonance imaging versus multi-detector row computed tomography. J Comput Assist Tomogr 2009;33:844-850. PMID: 19940648

17 Reimer P, Rummeny EJ, Daldrup HE, Hesse T, Balzer T, Tombach B, et al. Enhancement characteristics of liver metastases, hepatocellular carcinomas, and hemangiomas with Gd-EOB-DTPA: preliminary results with dynamic MR imaging. Eur Radiol 1997;7:275-280. PMID: 9038130

18 Zech CJ, Grazioli L, Breuer J, Reiser MF, Schoenberg SO. Diagnostic performance and description of morphological features of focal nodular hyperplasia in Gd-EOB-DTPA-enhanced liver magnetic resonance imaging: results of a multicenter trial. Invest Radiol 2008;43:504-511. PMID: 18580333

19 Ichikawa T, Saito K, Yoshioka N, Tanimoto A, Gokan T, Takehara Y, et al. Detection and characterization of focal liver lesions: a Japanese phase III, multicenter comparison between gadoxetic acid disodium-enhanced magnetic resonance imaging and contrast-enhanced computed tomography predominantly in patients with hepatocellular carcinoma and chronic liver disease. Invest Radiol 2010;45:133-141. PMID: 20098330

20 Miettinen OS. The matched pairs design in the case of all-or-none responses. Biometrics 1968;24:339-352. PMID: 5683874

21 Schwenke C, Busse R. Analysis of differences in proportions from clustered data with multiple measurements in diagnostic studies. Methods Inf Med 2007;46:548-552. PMID: 17938777

22 Stern W, Schick F, Kopp AF, Reimer P, Shamsi K, Claussen CD, et al. Dynamic MR imaging of liver metastases with Gd-EOB-DTPA. Acta Radiol 2000;41:255-262. PMID: 10866081

23 Kim SH, Kim SH, Lee J, Kim MJ, Jeon YH, Park Y, et al. Gadoxetic acid-enhanced MRI versus triple-phase MDCT for the preoperative detection of hepatocellular carcinoma. AJR Am J Roentgenol 2009;192:1675-1681. PMID: 19457834

24 Runge VM. A comparison of two MR hepatobiliary gadolinium chelates: Gd-BOPTA and Gd-EOB-DTPA. J Comput Assist Tomogr 1998;22:643-650. PMID: 9676461