Radiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Published online before print May 9, 2006, 10.1148/radiol.2393040884
This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
2393040884v1
240/1/90    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Schnorr, J.
Right arrow Articles by Taupitz, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schnorr, J.
Right arrow Articles by Taupitz, M.
(Radiology 2006;240:90-100.)
© RSNA, 2006

Experimental Studies

Focal Liver Lesions: SPIO-, Gadolinium-, and Ferucarbotran-enhanced Dynamic T1-weighted and Delayed T2-weighted MR Imaging in Rabbits1

Jörg Schnorr, DVM, Susanne Wagner, DVM, Claudia Abramjuk, DVM, Randi Drees, DVM, Tania Schink, MSc, Eyk A. Schellenberger, MD, Herbert Pilgrimm, PhD, Bernd Hamm, MD and Matthias Taupitz, MD

1 From the Departments of Radiology (J.S., S.W., C.A., R.D., E.A.S., B.H., M.T.) and Medical Biometry (T.S.), Charité-Universitätsmedizin Berlin, Schumannstrasse 20/21, 10098 Berlin, Germany; and Ferropharm, Forschungslabor, Teltow, Brandenburg, Germany (J.S., S.W., H.P.). Received May 17, 2004; revision requested August 3; revision received May 9, 2005; accepted June 20; final version accepted September 1. Supported by Investitionsbank des Landes Brandenburg, program Produkt- und Verfahrensinnovation im Land Brandenburg, reference 80100562. Address correspondence to J.S. (e-mail: joerg.schnorr{at}charite.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To compare a superparamagnetic iron oxide (SPIO), VSOP-C184, with a gadopentetate dimeglumine with regard to signal-enhancing effects on T1-weighted dynamic magnetic resonance (MR) images and with another SPIO contrast medium with regard to signal-reducing effects on delayed T2-weighted MR images.

Materials and Methods: All experiments were approved by the responsible Animal Care Committee. Twenty rabbits (five for each contrast agent and dose) implanted with VX-2 carcinoma were imaged at 1.5 T. VSOP-C184 at 0.015 and 0.025 mmol Fe/kg was compared with gadopentetate dimeglumine at 0.15 mmol Gd/kg and ferucarbotran at 0.015 mmol Fe/kg. The imaging protocol comprised a T1-weighted dynamic gradient-echo (GRE) MR before injection and at 6-second intervals for up to 42 seconds after injection and a T2-weighted turbo spin-echo MR before and 5 minutes after injection. Images were evaluated quantitatively, and contrast media were compared by using nonparametric analysis of variance.

Results: At dynamic T1-weighted GRE MR imaging with 0.015-mmol Fe/kg VSOP-C184, 0.025-mmol Fe/kg VSOP-C184, gadopentetate dimeglumine, and ferucarbotran, the median peak contrast-to-noise ratio (CNR) was 20.7 (25th percentile, 16.3; 75th percentile, 22.6), 24.2 (25th percentile, 19.3; 75th percentile, 28.5), 16.4 (25th percentile, 13.7; 75th percentile, 20.3), and 14.0 (25th percentile, 11.4; 75th percentile, 16.8), respectively. Both doses of VSOP-C184 yielded significantly higher CNR (P < .05) than the other two agents. At T2-weighted turbo spin-echo imaging with 0.015-mmol Fe/kg VSOP-C184, 0.025-mmol Fe/kg VSOP-C184, gadopentetate dimeglumine, and ferucarbotran, the median CNR was 15.0 (25th percentile, 13.4; 75th percentile, 21.3), 15.7 (25th percentile, 14.5; 75th percentile, 19.8), 11.3 (25th percentile, 8.2; 75th percentile, 12.2), and 15.7 (25th percentile, 12.5; 75th percentile, 22.4), respectively. There was no significant difference between VSOP-C184 and ferucarbotran; both had a significantly higher CNR than did gadopentetate dimeglumine.

Conclusion: VSOP-C184 produces higher liver-to-tumor contrast at dynamic T1-weighted imaging than does gadopentetate dimeglumine; at delayed T2-weighted imaging, the contrast is comparable to that achieved with ferucarbotran.

© RSNA, 2006


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Superparamagnetic iron oxide (SPIO) particles were originally developed as contrast medium for magnetic resonance (MR) imaging of the liver, where they are administered to improve tumor detection at T2-weighted imaging. The particles improve contrast by being taken up by the Kupffer cells of normal liver tissue but not by metastases or poorly differentiated primary liver tumors. The contrast is made visible through the T2-shortening effect of the particles. The amount of SPIO necessary for good enhancement will accumulate in normal liver tissue about 5–10 minutes after intravenous injection (1–7). In addition, SPIO particles to some extent enable the differentiation of liver tumors, in particular, primary liver tumors or benign tumors, from liver metastases (8–10).

Intravenously injected SPIO particles also shorten the T1 relaxation time. The T1-shortening effect is particularly pronounced for ultrasmall SPIO (USPIO) particles (11–14). In liver MR imaging, the T1-shortening effect of SPIO and USPIO in combination with their blood pool properties can be used to obtain additional diagnostic information. Thus, vascularized structures show signal enhancement on T1-weighted images after intravenous injection, which, in particular, improves characterization of liver hemangiomas (11,12).

However, the SPIO or USPIO particles that have been investigated so far at liver MR imaging in experimental or clinical studies also have disadvantages. SPIO particles that can be administered as a bolus, such as ferucarbotran, produce only moderate signal enhancement, in particular in the early phase of a dynamic T1-weighted MR study. On the other hand, USPIO preparations with pronounced signal–enhancing properties, such as ferumoxtran-10, can be administered intravenously only as an infusion or slow injection. Hence, currently available SPIO or USPIO contrast media are of limited benefit compared with low-molecular-weight gadolinium-based contrast media in the early phase of a T1-weighted dynamic MR study of the liver (15).

The SPIO contrast medium VSOP-C184 is characterized by a higher ratio of T1 shortening to T2 shortening, compared with SPIO or USPIO preparations that have been studied so far at liver MR imaging (16). Moreover, with an overall diameter of about 7 nm, the VSOP-C184 particles are much smaller than SPIO and USPIO particles. The small size of VSOP-C184 particles is achieved by coating them with monomer citrate (17). In terms of its pharmacokinetic properties, VSOP-C184 is a blood pool contrast medium just as are other USPIO particles (18). VSOP-C184 was primarily developed for MR angiography and can be injected intravenously as a bolus. Results of preclinical investigations and phase I trials have shown VSOP-C184 to be well tolerated and safe (17,18). Most of the intravenously injected VSOP-C184 is ultimately cleared by the Kupffer cells of the liver (18). On the basis of these observations, we hypothesized that VSOP-C184 has a pronounced signal-enhancing effect on dynamic T1-weighted images of the liver and an effect comparable to that of conventional SPIO particles on delayed T2-weighted images. To test this hypothesis, we performed our study to compare VSOP-C184 with a low-molecular-weight gadolinium-based contrast medium with regard to the signal-enhancing effects on T1-weighted dynamic images and with another SPIO contrast agent with regard to the signal-reducing effects on delayed T2-weighted images.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
H.P., S.W., and J.S. are partners of Ferropharm. All other authors employed by the Charité Universitätsmedizin Berlin had control of the data. Ferropharm did not support the study; the study was supported by a public grant.

Animals and Procedures
A total of 20 rabbits (Charles River, Sulzfeld, Germany) with a body weight of 3.5 kg ± 0.45 (standard deviation) were investigated (five animals for each contrast medium and dose). All experiments performed in this study had been approved by the responsible Animal Care Committee (Landesamt für Gesundheitsschutz und technische Sicherheit Berlin).

For tumor implantation, the rabbits were anesthetized with an intramuscular injection of 50 mg of ketamine hydrochloride per kilogram of body weight (Ketavet; Parke-Davis, Berlin, Germany) and 5 mg/kg xylazine (Rompun; Bayer, Leverkusen, Germany). After the anesthetics took effect, the area below the xiphoid process was shaved and disinfected and a minimally invasive laparotomy was performed. The left liver lobe was pulled out for injection of 0.3–0.5 mL of a VX-2 tumor cell suspension containing 2 x 106 living cells. The VX-2 tumor is a squamous cell carcinoma of the rabbit. After injection of the tumor cells and a brief compression of the injection site, the liver lobe was repositioned and the abdominal wall was closed in two layers (C.A., J.S.).

The rabbits were imaged 14–18 days after tumor implantation. MR imaging was performed with the rabbits anesthetized in the same way as for tumor implantation. After the anesthetics took effect, a 2.5–3.0-mm endotracheal tube (Mallinckrodt Laboratories, Athlon, Ireland) was inserted into the trachea to maintain anesthesia with a mixture of 2%–3% isoflurane (Forene; Abbott, Wiesbaden, Germany) and medical oxygen. For controlling ventilation and anesthesia, an electronic system (ADS 1000; Engler Engineering, Hialeah, Fla) was used. For the administration of muscle relaxant, contrast medium, and other drugs, an indwelling 22-gauge catheter (Optiva 2; Ethicon, Pomezia, Italy) was placed into a marginal ear vein.

Contrast Media and Doses
VSOP-C184 (very small SPIO particle, citrate coating, 184th formulation; Ferropharm, Teltow, Germany) consists of an aqueous solution of SPIO particles coated with a citrate layer (17). The study was conducted in the setting of a scientific cooperative effort between the Department of Radiology at Charité-Universitätsmedizin Berlin and Ferropharm.

The concentration of the active substance is 27.9 g of iron per liter (0.50 mol/L). The particles have a core diameter of 4 nm, as determined with transmission electron microscopy, and a hydrodynamic diameter of 7.0 nm ± 0.15, as determined with photon correlation spectroscopy (BIC multiangle laser light scattering system; Brookhaven Instruments Corporation, Holtsville, NY). The T1 and T2 relaxivities (r1 and r2, respectively) of VSOP-C184, as determined in demineralized water at 40°C and 60 MHz by using an MR spectrometer (Minispec mq 60; Bruker, Karlsruhe, Germany), are 13.97 and 33.45 L · mmol–1 · sec–1, respectively. This results in a high r1/r2 ratio, which is why VSOP-C184, unlike conventional SPIO, is expected to produce pronounced signal enhancement at T1-weighted imaging.

The study drug was compared with two other contrast media: low-molecular-weight gadopentetate dimeglumine (Magnevist; Schering, Berlin, Germany) and the SPIO preparation ferucarbotran (Resovist; Schering). The relaxivities at 1.5 T (measured in demineralized water at 37° C) are 3.3 (r1) and 3.9 (r2) L · mmol–1 · sec–1 for gadopentetate dimeglumine and 8.7 (r1) and 61 (r2) L · mmol–1 · sec–1 for ferucarbotran (19).

VSOP-C184 was administered at doses of 0.015 and 0.025 mmol of iron per kilogram of body weight (hereafter, Fe/kg). The lower dose corresponds to the clinical dose of ferucarbotran administered for liver MR imaging. The higher dose was chosen because it is the dose for which experimental investigations have demonstrated an intravascular signal enhancement at first-pass MR angiography comparable to that achieved with a standard dose of gadopentetate dimeglumine (20). VSOP-C184 was diluted with 6% mannitol solution to yield a dilution of 0.075 mmol of iron per milliliter. The resultant amount enables good bolus injection. The corresponding injection volume of VSOP-C184 was 0.61 mL ± 0.02 for the 0.015-mmol Fe/kg dose and 1.11 mL ± 0.12 for the 0.025-mmol Fe/kg dose, depending on the body weight of the rabbits.

Gadopentetate dimeglumine was investigated at a dose of 0.15 mmol of gadolinium per kilogram of body weight (hereafter, Gd/kg), which is between the dose frequently used for liver MR imaging (0.1 mmol Gd/kg) and for first-pass MR angiography (0.2 mmol Gd/kg). Gadopentetate dimeglumine was administered as an undiluted 0.5-mol/L solution. The corresponding injection volume of gadopentetate dimeglumine was 0.89 mL ± 0.04.

Ferucarbotran was administered at a dose of 0.015 mmol Fe/kg, which is the mean of the doses used in the clinical setting. Two different amounts of ferucarbotran are administered in the clinical setting, and the dose is only roughly adjusted to the patient's body weight. Ferucarbotran was diluted in the same way as VSOP-C184. The corresponding injection volume of ferucarbotran was 0.55 mL ± 0.03. Each of the three contrast agents was injected as a bolus at a rate of 0.5 mL/sec, followed by a 5-mL saline flush. Five animals were examined with each contrast agent and dose.

MR Imaging Protocol
The rabbits were examined with a 1.5-T whole-body MR imager (Magnetom Vision, Siemens, Erlangen, Germany) by using the system's standard extremity coil. Transverse T1-weighted images were acquired with a two-dimensional gradient-echo (GRE) sequence and fast low-angle shot technique (repetition time msec/echo time msec, 35/4.1; flip angle, 60°; section thickness, 3 mm; section gap, 0.6 mm; four sections; matrix, 87 x 256; field of view, 150 x 300 mm; acquisition time, 6 seconds). Transverse T2-weighted images were acquired with a turbo spin-echo sequence (1800/85; turbo factor, five; section thickness, 3 mm; section gap, 0.6 mm; 18 sections; matrix, 120 x 256; field of view, 110 x 220 mm; acquisition time, 4 minutes 42 seconds). Both acquisitions were performed with phase encoding in the lateral direction to prevent pulsation artifacts of the large vessels from projecting onto the liver.

The animals were placed in the extremity coil in the supine position, and a scout view was obtained. Next, a total of 10 image data sets were acquired with the aforementioned sequences by using the following protocol: Precontrast T2-weighted turbo spin-echo sequence and dynamic T1-weighted GRE sequence with eight consecutive acquisitions and contrast medium injection in a 5-second interval immediately after the first acquisition, followed by seven additional T1-weighted GRE acquisitions without breaks. With this imaging series, the contrast medium dynamics for up to 42 seconds after injection were acquired. The T1-weighted GRE sequences of this dynamic series were performed with identical receiver-adjustment values. Finally, the T2-weighted turbo spin-echo sequence was repeated at 5 minutes after injection. All examinations were technically successful.

All rabbits were killed under deep anesthesia with intravenous injection of 1.5 mL of a commercially available mixture of tetracainhydrochloride (5 mg/mL), mebezoniumiodid (50 mg/mL), and embutramid (200 mg/mL) (T61; Intervet Deutschland, Unterschleissheim, Germany) immediately after MR imaging. The livers were removed, lamellated, and macroscopically inspected for the presence of liver tumors. The findings were recorded.

Analysis
From each data set, one slice that showed the liver tumor and a larger portion of normal liver tissue without partial volume effects was selected for determining the signal intensity of liver (SIliver), tumor (SItumor), and noise (SInoise) by means of standard region-of-interest measurements. The size of the region of interest for liver and tumor was 39.6 pixels ± 27.6 and that for noise was about 100 pixels. The measurements were performed by two experienced investigators (S.W. with 10 and C.A. with 3 years of experience) in consensus with regard to the location and size of the region of interest. For the measurements of SIliver, larger blood vessels were avoided. Moreover, larger necrotic areas were likewise excluded from the SItumor region of interest on T2-weighted turbo spin-echo images. SInoise was determined anterior to the rabbit in the frequency-encoding direction to exclude motion artifacts induced by respiration or vessel pulsation. SInoise in phase-encoding direction was not included in the analysis since the aim of our study was not to compare pulse sequences but to evaluate the signal intensity changes induced by the various contrast media. The measured signal intensity values were used to calculate signal-to-noise ratio (SNR) for the liver as SNRliver = SIliver/SInoise and for the tumor as SNRtumor = SItumor/SInoise for each animal and time point. The contrast between liver and tumor was determined by calculating the contrast-to-noise ratio (CNR) as CNR = (SIliver – SItumor)/SInoise. From these parameters, medians and quartiles were calculated for the five rabbits investigated per contrast medium and dose.

Statistical Analysis
For comparison of SNR and CNR values of the contrast media and the two doses of VSOP-C184, a two-factorial nonparametric analysis of variance was performed for the different image acquisition time points and contrast medium groups (21,22) to take into account the correlated nature of the repeated measurements. Peak values were compared by using the Mann-Whitney U test. The analysis was performed with SAS 8.1 (SAS Institute, Cary, NC) and SPSS 11.5 (SPSS, Chicago, Ill) software. Significance was assumed at P < .05. The study was planned as a pilot study to examine feasibility and get a first impression of the magnitude and variance of the differences between the four contrast media doses. Thus, no sample size estimation was performed.

The liver specimens of all animals showed one or more liver tumors. We ensured that the corresponding MR acquisitions and the quantitative analysis comprised one liver tumor per animal.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
T1-weighted Dynamic MR Imaging
Unenhanced T1-weighted GRE images depicted liver tumors with low signal intensity compared with that of normal liver tissue. After injection of VSOP-C184, there was an increase in SNR for the liver on dynamic T1-weighted GRE images, which was more pronounced with the higher dose (0.025 mmol Fe/kg) than the lower dose (0.015 mmol Fe/kg), but the difference was not significant (P = .254, Fig 1). Neither of the two VSOP-C184 doses produced a relevant change in SNR for the tumor (Fig 1). The resultant CNR increased significantly (P < .001) on T1-weighted GRE images during the acquisition period of up to 42 seconds after the injection of both doses of VSOP-C184, without a significant (P = .282) difference between the two doses. The CNR was highest between 24 and 42 seconds after injection (Figs 1, 2).


Figure 1
View larger version (28K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1a: Graphs depict SNRs of (a) liver and (b) tumor and (c) CNR after intravenous bolus injection of VSOP-C184 (0.015 and 0.025 mmol Fe/kg), gadopentetate dimeglumine, and ferucarbotran. VSOP-C184 produces a higher contrast between liver and tumor on dynamic T1-weighted GRE images than do gadopentetate dimeglumine and ferucarbotran. Symbols defined in a are also applicable to b and c.

 

Figure 1
View larger version (17K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1b: Graphs depict SNRs of (a) liver and (b) tumor and (c) CNR after intravenous bolus injection of VSOP-C184 (0.015 and 0.025 mmol Fe/kg), gadopentetate dimeglumine, and ferucarbotran. VSOP-C184 produces a higher contrast between liver and tumor on dynamic T1-weighted GRE images than do gadopentetate dimeglumine and ferucarbotran. Symbols defined in a are also applicable to b and c.

 

Figure 1
View larger version (17K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1c: Graphs depict SNRs of (a) liver and (b) tumor and (c) CNR after intravenous bolus injection of VSOP-C184 (0.015 and 0.025 mmol Fe/kg), gadopentetate dimeglumine, and ferucarbotran. VSOP-C184 produces a higher contrast between liver and tumor on dynamic T1-weighted GRE images than do gadopentetate dimeglumine and ferucarbotran. Symbols defined in a are also applicable to b and c.

 

Figure 2
View larger version (93K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2a: Transverse T1-weighted GRE MR images (35/4.1, 60° flip angle) through the upper abdomen of rabbits (a, c, e, g) before and (b, d, f, h) 24 seconds after intravenous bolus injection of (a, b) 0.015-mmol Fe/kg VSOP-C184, (c, d) 0.025-mmol Fe/kg VSOP-C184, (e, f) gadopentetate dimeglumine, and (g, h) ferucarbotran. All three agents produce an increase in contrast between liver and tumor (arrow), which is most pronounced after injection of both doses of VSOP-C184.

 

Figure 2
View larger version (115K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2b: Transverse T1-weighted GRE MR images (35/4.1, 60° flip angle) through the upper abdomen of rabbits (a, c, e, g) before and (b, d, f, h) 24 seconds after intravenous bolus injection of (a, b) 0.015-mmol Fe/kg VSOP-C184, (c, d) 0.025-mmol Fe/kg VSOP-C184, (e, f) gadopentetate dimeglumine, and (g, h) ferucarbotran. All three agents produce an increase in contrast between liver and tumor (arrow), which is most pronounced after injection of both doses of VSOP-C184.

 

Figure 2
View larger version (111K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2c: Transverse T1-weighted GRE MR images (35/4.1, 60° flip angle) through the upper abdomen of rabbits (a, c, e, g) before and (b, d, f, h) 24 seconds after intravenous bolus injection of (a, b) 0.015-mmol Fe/kg VSOP-C184, (c, d) 0.025-mmol Fe/kg VSOP-C184, (e, f) gadopentetate dimeglumine, and (g, h) ferucarbotran. All three agents produce an increase in contrast between liver and tumor (arrow), which is most pronounced after injection of both doses of VSOP-C184.

 

Figure 2
View larger version (120K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2d: Transverse T1-weighted GRE MR images (35/4.1, 60° flip angle) through the upper abdomen of rabbits (a, c, e, g) before and (b, d, f, h) 24 seconds after intravenous bolus injection of (a, b) 0.015-mmol Fe/kg VSOP-C184, (c, d) 0.025-mmol Fe/kg VSOP-C184, (e, f) gadopentetate dimeglumine, and (g, h) ferucarbotran. All three agents produce an increase in contrast between liver and tumor (arrow), which is most pronounced after injection of both doses of VSOP-C184.

 

Figure 2
View larger version (93K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2e: Transverse T1-weighted GRE MR images (35/4.1, 60° flip angle) through the upper abdomen of rabbits (a, c, e, g) before and (b, d, f, h) 24 seconds after intravenous bolus injection of (a, b) 0.015-mmol Fe/kg VSOP-C184, (c, d) 0.025-mmol Fe/kg VSOP-C184, (e, f) gadopentetate dimeglumine, and (g, h) ferucarbotran. All three agents produce an increase in contrast between liver and tumor (arrow), which is most pronounced after injection of both doses of VSOP-C184.

 

Figure 2
View larger version (105K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2f: Transverse T1-weighted GRE MR images (35/4.1, 60° flip angle) through the upper abdomen of rabbits (a, c, e, g) before and (b, d, f, h) 24 seconds after intravenous bolus injection of (a, b) 0.015-mmol Fe/kg VSOP-C184, (c, d) 0.025-mmol Fe/kg VSOP-C184, (e, f) gadopentetate dimeglumine, and (g, h) ferucarbotran. All three agents produce an increase in contrast between liver and tumor (arrow), which is most pronounced after injection of both doses of VSOP-C184.

 

Figure 2
View larger version (97K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2g: Transverse T1-weighted GRE MR images (35/4.1, 60° flip angle) through the upper abdomen of rabbits (a, c, e, g) before and (b, d, f, h) 24 seconds after intravenous bolus injection of (a, b) 0.015-mmol Fe/kg VSOP-C184, (c, d) 0.025-mmol Fe/kg VSOP-C184, (e, f) gadopentetate dimeglumine, and (g, h) ferucarbotran. All three agents produce an increase in contrast between liver and tumor (arrow), which is most pronounced after injection of both doses of VSOP-C184.

 

Figure 2
View larger version (106K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2h: Transverse T1-weighted GRE MR images (35/4.1, 60° flip angle) through the upper abdomen of rabbits (a, c, e, g) before and (b, d, f, h) 24 seconds after intravenous bolus injection of (a, b) 0.015-mmol Fe/kg VSOP-C184, (c, d) 0.025-mmol Fe/kg VSOP-C184, (e, f) gadopentetate dimeglumine, and (g, h) ferucarbotran. All three agents produce an increase in contrast between liver and tumor (arrow), which is most pronounced after injection of both doses of VSOP-C184.

 
Gadopentetate dimeglumine likewise produced an increase in SNR for the liver, which was comparable to that seen with both doses of VSOP-C184 for up to 24 seconds after injection (Fig 1). Gadopentetate dimeglumine also resulted in an increase in SNR for the tumor, but the increase was less pronounced than that for the liver (Fig 1). The resultant increase in CNR with use of gadopentetate dimeglumine peaked at 18 seconds after injection. The CNR was significantly inferior with use of gadopentetate dimeglumine than with use of both doses of VSOP-C184 (P < .001 for both).

Ferucarbotran produced an increase in SNR for the liver at all time points of dynamic T1-weighted GRE imaging, but no relevant change was seen in SNR for the tumor. This resulted in a significant (P = .031) increase in CNR, which peaked at 12 seconds after injection. The peak CNR seen with ferucarbotran did not differ significantly (P = .251) from the peak CNR achieved with gadopentetate dimeglumine but was significantly less than the peak produced with both doses of VSOP-C184 (P = .047 and .028).

At dynamic T1-weighted MR imaging, the median peak CNR for 0.015-mmol Fe/kg VSOP-C184, 0.025-mmol Fe/kg VSOP-C184, gadopentetate dimeglumine, and ferucarbotran was 20.7 (25th percentile, 16.3; 75th percentile, 22.6), 24.2 (25th percentile, 19.3; 75th percentile, 28.5), 16.4 (25th percentile, 13.7; 75th percentile, 20.3), and 14.0 (25th percentile, 11.4; 75th percentile, 16.8), respectively.

T2-weighted MR Imaging
Unenhanced T2-weighted turbo spin-echo images depicted liver tumors with signal intensity moderately higher than that of normal liver tissue. After injection of VSOP-C184, there was a significant decrease in SNR for the liver with use of both doses (0.015 and 0.025 mmol Fe/kg, P < .001 for both), without a significant (P = .257) difference between both doses (Fig 3), while neither dose affected the SNR for the tumor relevantly (Fig 3). This resulted in a significant (P < .001) increase in the absolute value of CNR with both doses of VSOP-C184, without a significant (P = .899) difference between the two doses (Figs 3, 4).


Figure 3
View larger version (20K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3a: Graphs depict SNRs of (a) liver and (b) tumor and (c) CNR before and after intravenous bolus injection of VSOP-C184, gadopentetate dimeglumine, and ferucarbotran. On delayed T2-weighted turbo spin-echo (T2-TSE) MR images (1800/85), the contrast between liver and tumor is comparable to that achieved with ferucarbotran and higher than that achieved with gadopentetate dimeglumine. Symbols defined in a are also applicable to b and c.

 

Figure 3
View larger version (9K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3b: Graphs depict SNRs of (a) liver and (b) tumor and (c) CNR before and after intravenous bolus injection of VSOP-C184, gadopentetate dimeglumine, and ferucarbotran. On delayed T2-weighted turbo spin-echo (T2-TSE) MR images (1800/85), the contrast between liver and tumor is comparable to that achieved with ferucarbotran and higher than that achieved with gadopentetate dimeglumine. Symbols defined in a are also applicable to b and c.

 

Figure 3
View larger version (8K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3c: Graphs depict SNRs of (a) liver and (b) tumor and (c) CNR before and after intravenous bolus injection of VSOP-C184, gadopentetate dimeglumine, and ferucarbotran. On delayed T2-weighted turbo spin-echo (T2-TSE) MR images (1800/85), the contrast between liver and tumor is comparable to that achieved with ferucarbotran and higher than that achieved with gadopentetate dimeglumine. Symbols defined in a are also applicable to b and c.

 

Figure 4
View larger version (141K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4a: Transverse T2-weighted turbo spin-echo MR images (1800/85) through the upper abdomen of rabbits (a, c, e, g) before and (b, d, f, h) 5 minutes after intravenous bolus injection of (a, b) 0.015-mmol Fe/kg VSOP-C184, (c, d) 0.025-mmol Fe/kg VSOP-C184, (e, f) gadopentetate dimeglumine, and (g, h) ferucarbotran. VSOP-C184 and ferucarbotran produce an increase in contrast between liver and tumor (arrow) with no difference between the two agents, whereas gadopentetate dimeglumine does not change the contrast.

 

Figure 4
View larger version (139K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4b: Transverse T2-weighted turbo spin-echo MR images (1800/85) through the upper abdomen of rabbits (a, c, e, g) before and (b, d, f, h) 5 minutes after intravenous bolus injection of (a, b) 0.015-mmol Fe/kg VSOP-C184, (c, d) 0.025-mmol Fe/kg VSOP-C184, (e, f) gadopentetate dimeglumine, and (g, h) ferucarbotran. VSOP-C184 and ferucarbotran produce an increase in contrast between liver and tumor (arrow) with no difference between the two agents, whereas gadopentetate dimeglumine does not change the contrast.

 

Figure 4
View larger version (142K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4c: Transverse T2-weighted turbo spin-echo MR images (1800/85) through the upper abdomen of rabbits (a, c, e, g) before and (b, d, f, h) 5 minutes after intravenous bolus injection of (a, b) 0.015-mmol Fe/kg VSOP-C184, (c, d) 0.025-mmol Fe/kg VSOP-C184, (e, f) gadopentetate dimeglumine, and (g, h) ferucarbotran. VSOP-C184 and ferucarbotran produce an increase in contrast between liver and tumor (arrow) with no difference between the two agents, whereas gadopentetate dimeglumine does not change the contrast.

 

Figure 4
View larger version (147K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4d: Transverse T2-weighted turbo spin-echo MR images (1800/85) through the upper abdomen of rabbits (a, c, e, g) before and (b, d, f, h) 5 minutes after intravenous bolus injection of (a, b) 0.015-mmol Fe/kg VSOP-C184, (c, d) 0.025-mmol Fe/kg VSOP-C184, (e, f) gadopentetate dimeglumine, and (g, h) ferucarbotran. VSOP-C184 and ferucarbotran produce an increase in contrast between liver and tumor (arrow) with no difference between the two agents, whereas gadopentetate dimeglumine does not change the contrast.

 

Figure 4
View larger version (142K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4e: Transverse T2-weighted turbo spin-echo MR images (1800/85) through the upper abdomen of rabbits (a, c, e, g) before and (b, d, f, h) 5 minutes after intravenous bolus injection of (a, b) 0.015-mmol Fe/kg VSOP-C184, (c, d) 0.025-mmol Fe/kg VSOP-C184, (e, f) gadopentetate dimeglumine, and (g, h) ferucarbotran. VSOP-C184 and ferucarbotran produce an increase in contrast between liver and tumor (arrow) with no difference between the two agents, whereas gadopentetate dimeglumine does not change the contrast.

 

Figure 4
View larger version (150K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4f: Transverse T2-weighted turbo spin-echo MR images (1800/85) through the upper abdomen of rabbits (a, c, e, g) before and (b, d, f, h) 5 minutes after intravenous bolus injection of (a, b) 0.015-mmol Fe/kg VSOP-C184, (c, d) 0.025-mmol Fe/kg VSOP-C184, (e, f) gadopentetate dimeglumine, and (g, h) ferucarbotran. VSOP-C184 and ferucarbotran produce an increase in contrast between liver and tumor (arrow) with no difference between the two agents, whereas gadopentetate dimeglumine does not change the contrast.

 

Figure 4
View larger version (124K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4g: Transverse T2-weighted turbo spin-echo MR images (1800/85) through the upper abdomen of rabbits (a, c, e, g) before and (b, d, f, h) 5 minutes after intravenous bolus injection of (a, b) 0.015-mmol Fe/kg VSOP-C184, (c, d) 0.025-mmol Fe/kg VSOP-C184, (e, f) gadopentetate dimeglumine, and (g, h) ferucarbotran. VSOP-C184 and ferucarbotran produce an increase in contrast between liver and tumor (arrow) with no difference between the two agents, whereas gadopentetate dimeglumine does not change the contrast.

 

Figure 4
View larger version (135K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4h: Transverse T2-weighted turbo spin-echo MR images (1800/85) through the upper abdomen of rabbits (a, c, e, g) before and (b, d, f, h) 5 minutes after intravenous bolus injection of (a, b) 0.015-mmol Fe/kg VSOP-C184, (c, d) 0.025-mmol Fe/kg VSOP-C184, (e, f) gadopentetate dimeglumine, and (g, h) ferucarbotran. VSOP-C184 and ferucarbotran produce an increase in contrast between liver and tumor (arrow) with no difference between the two agents, whereas gadopentetate dimeglumine does not change the contrast.

 
No relevant change in the absolute values of SNR for the liver and for the tumor was measured after intravenous injection of gadopentetate dimeglumine (Fig 3). The resultant absolute value of CNR did not change relevantly and was significantly (P = .032 and .022) below the values for VSOP-C184 (Figs 3, 4).

After injection of ferucarbotran, the SNR for the liver decreased significantly (P < .001) to the same level as that with use of both doses of VSOP-C184 (Fig 3a), while the SNR for the tumor did not change significantly (Fig 3, P = .255). This resulted in a significant (P < .001) increase in the absolute value of CNR, which did not differ significantly (P = .221 and .176) from the values calculated with use of both doses of VSOP-C184 (Figs 3, 4).

At delayed T2-weighted MR imaging with 0.015-mmol Fe/kg VSOP-C184, 0.025-mmol Fe/kg VSOP-C184, gadopentetate dimeglumine, and ferucarbotran, the median CNR was 15.0 (25th percentile, 13.4; 75th percentile, 21.3), 15.7 (25th percentile, 14.5; 75th percentile, 19.8), 11.3 (25th percentile, 8.2; 75th percentile, 12.2), and 15.7 (25th percentile, 12.5; 75th percentile, 22.4), respectively.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
Different types of contrast media are available for improving the detection and characterization of liver tumors compared with unenhanced MR imaging. Low-molecular-weight gadolinium chelates such as gadopentetate dimeglumine are used for dynamic T1-weighted MR studies. These contrast media improve the detection of hypervascularized liver tumors such as hepatocellular carcinoma or hypervascularized metastases, compared with unenhanced imaging, by depicting their hyperintensity during the arterial phase of dynamic MR imaging (23,24). The demonstration of characteristic enhancement patterns during dynamic T1-weighted MR imaging improves tumor characterization compared with unenhanced MR imaging. Typical patterns are the fill-in phenomenon in liver hemangiomas and ring enhancement or peripheral washout in metastases (25,26). However, the detection of hypovascularized metastases, for instance, from colorectal cancer, which account for the majority of liver metastases, is not improved in all cases by dynamic MR imaging with low-molecular-weight contrast media (27,28).

At delayed T2-weighted imaging, the detection of all liver metastases irrespective of their vascularization is improved after intravenous injection of SPIO particles (2,4–7). When liver imaging is performed by using an SPIO preparation that can be administered as an intravenous bolus, for which only ferucarbotran has been approved so far (in several European countries but not in the United States), a T1-weighted dynamic MR sequence can be performed immediately after injection. Hence, it is possible to exploit the blood pool properties and T1-shortening effect of this contrast medium to differentiate liver tumors on the basis of their enhancement patterns in a dynamic study. This is analogous to liver tumor differentiation with low-molecular-weight contrast media and works especially well for liver hemangiomas (29,30). Nevertheless, tumor characterization with ferucarbotran has only a limited role compared with low-molecular-weight contrast media, since the signal enhancement on T1-weighted images is much less pronounced (31).

The contrast medium VSOP-C184 investigated in this study was originally developed as a T1-shortening blood pool contrast medium for equilibrium MR angiography. Findings of animal experiments and initial clinical studies show that VSOP-C184 or similar precursors of this agent have a pronounced T1-shortening effect in blood and a long blood half-life, making it an effective contrast medium for equilibrium MR angiography of the arteries of the body trunk (18,32,33) and coronary arteries (33). Moreover, findings of an experimental study (20) have shown that VSOP-C184 produces a similar intravascular signal enhancement at first-pass MR angiography of the abdominal arteries as does gadopentetate dimeglumine. On the other hand, determination of its organ distribution performed as part of the preclinical characterization of VSOP-C184 has shown that a considerable proportion of the substance ultimately accumulates in the liver, thereby producing the signal loss (18) typical of SPIO or USPIO preparations such as ferucarbotran (34).

The results of our study show that VSOP-C184 administered at a dose of 0.015 mmol Fe/kg produces high contrast between liver and tumor at delayed MR imaging, the classic field of application of SPIO particles, and is comparable in this respect to ferucarbotran at an identical dose. This result is not surprising because VSOP-C184, just like ferucarbotran, is taken up by the Kupffer cells of the liver after intravenous injection (18,34), thereby shortening the T2 relaxation time of liver tissue, while that of tumors remains unaffected. Ferucarbotran has a short blood half-life of about 5 minutes after intravenous injection in humans (4) and rapidly accumulates in the liver (34). In comparison, VSOP-C184 has a rather long blood half-life of about 35 minutes in humans after intravenous injection of 0.015 mmol Fe/kg (17). For this reason, it is surprising that the findings of the present experimental study show that VSOP-C184, similar to ferucarbotran, produces a signal decrease that nearly reaches the level of noise as early as 5 minutes after intravenous injection when used in combination with a moderately T2-weighted sequence. This observation suggests that the portion of VSOP-C184 having accumulated in the liver at that time develops a pronounced T2-shortening effect after having been phagocytosed.

So far, no data are available about the precise time of phagocytosis of VSOP-C184 and the onset of the resulting T2-shortening effect in the liver during early phase after intravenous injection. However, the properties of the particles provide an explanation for their rather fast uptake in the liver. The VSOP-C184 particles have a negatively charged surface, and such particles are known to be rapidly phagocytosed and thus also undergo rapid uptake by the Kupffer cells of the liver (35). As expected, gadopentetate dimeglumine does not significantly alter the contrast between liver and tumor on delayed T2-weighted images.

At T1-weighted dynamic MR imaging, VSOP-C184 produced a marked signal intensity increase of the liver parenchyma, which was comparable to that seen after gadopentetate dimeglumine for up to 24 seconds after injection and then surpassed the latter. This increase and the fact that there is only little or no extravasation of VSOP-C184 in the tumor results in a high contrast between liver and tumor on T1-weighted GRE images. In contrast, gadopentetate dimeglumine produces a significant signal intensity increase on T1-weighted images that results from extravasation not only in the liver but also inside the tumor. As a result, the contrast between liver and tumor at dynamic T1-weighted MR imaging for up to 42 seconds after intravenous injection is significantly higher for VSOP-C184 at both doses investigated than it is for gadopentetate dimeglumine. Of the three contrast media investigated, ferucarbotran showed the lowest increase in contrast between liver and tumor at dynamic T1-weighted MR imaging, but the increase was significant compared with that at unenhanced MR imaging.

Overall, the results of our experimental study show that the contrast-enhancing effect on T2-weighted images of VSOP-C184 is comparable to an equivalent dose of the SPIO preparation ferucarbotran, which has been optimized for liver imaging. This observation suggests that VSOP-C184 in future clinical use might improve tumor detection to the same extent as does ferucarbotran. Moreover, our experimental findings demonstrate that VSOP-C184 has a considerable signal-enhancing effect immediately after injection at dynamic T1-weighted MR imaging. In the hypovascularized liver tumor model investigated in this study, this effect produces a significantly higher contrast between liver and tumor than does a low-molecular-weight gadolinium-based contrast medium optimized for T1-weighted imaging. It may thus be speculated that VSOP-C184 not only has the typical properties of a conventional SPIO but, in addition, also improves the detection and characterization of focal liver lesions at T1-weighted dynamic imaging.

Our experimental study had some limitations. We investigated only the VX-2 liver tumor model in rabbits, which is a markedly hypovascularized tumor (36). Hence, our data provide no information about the enhancement of hypervascularized liver tumors at dynamic T1-weighted MR imaging. However, models of clearly hypervascularized liver tumors, such as malignant metastases from neuroendocrine tumors or benign focal nodular hyperplasia, are not readily available for experimental investigation. Another possible limitation of our study was that we used only one dose of the low-molecular-weight contrast medium for comparison. Moreover, dynamic T1-weighted imaging was only performed up to 42 seconds after contrast medium injection. However, with the short circulation time of about 12 seconds in rabbits, this acquisition period comprises both arterial and portal venous phases, which are important for T1-weighted dynamic assessment of the liver.

In summary, the results obtained in experimental liver tumors presented here show that the use of VSOP-C184 as an SPIO contrast medium in liver MR imaging produces higher contrast between liver and tumor at dynamic T1-weighted imaging than does a low-molecular-weight contrast medium. On delayed T2-weighted images, the contrast between liver and tumor is comparable to that achieved with a SPIO preparation optimized for liver MR imaging. The SPIO contrast medium VSOP-C184 has the potential to overcome the disadvantage of the available bolus-applicable SPIO preparations in liver MR imaging, namely, their poor T1 effect in the early phase, without compromising T2-weighted imaging.

Practical application: For the possible clinical use of VSOP-C184 as an SPIO preparation for bolus administration in liver MR imaging, the results of the present study would have the following hypothetical consequences: VSOP-C184 can be used for dynamic T1-weighted MR imaging of the liver, where the high contrast in the early phase after injection may help in detection of liver tumors. Moreover, with the pronounced signal intensity increase, evaluation of enhancement patterns of different liver tumors on dynamic T1-weighted images may provide additional information for the characterization of liver tumors. This may be done by using the well-established signal enhancement patterns of liver tumors seen with low-molecular-weight contrast agents. The latter would be a new use of VSOP-C184, compared with conventional SPIO or USPIO preparations in the diagnostic evaluation of liver tumors at MR imaging. Finally, VSOP-C184 also has the known properties of SPIO contrast agents for liver MR imaging: mainly, pronounced contrast enhancement on delayed T2-weighted images with improved detection of liver tumors, compared with unenhanced imaging.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   ACKNOWLEDGMENTS
 
The authors thank Robert N. Muller, PhD, Mons, Belgium, and his study group for determining the particle size and relaxivities of VSOP-C184 and for letting us use the results in this publication. Thanks also go to Bettina Herwig for translating the manuscript.


   FOOTNOTES
 

Abbreviations: CNR = contrast-to-noise ratio • GRE = gradient echo • SNR = signal-to-noise ratio • SPIO = superparamagnetic iron oxide • USPIO = ultrasmall SPIO

See Materials and Methods for pertinent disclosures.

Author contributions: Guarantors of integrity of entire study, J.S., M.T.; study concepts, J.S., S.W., T.S.; study design, J.S., C.A.; literature research, R.D., H.P.; experimental studies, R.D., S.W., C.A., J.S.; data acquisition, S.W., C.A., J.S., M.T.; data analysis/interpretation, S.W., J.S., M.T., R.D.; statistical analysis, T.S., J.S., R.D.; manuscript preparation and definition of intellectual content, J.S., S.W., M.T.; manuscript editing, E.A.S., B.H.; manuscript revision/review, B.H., H.P., M.T.; manuscript final version approval, J.S., M.T., B.H.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

  1. Saini S, Stark DD, Hahn PF, Wittenberg J, Brady TJ, Ferrucci JT. Ferrite particles: a superparamagnetic MR contrast agent for the reticuloendothelial system. Radiology 1987;162:211–216.[Abstract/Free Full Text]
  2. Stark DD, Weissleder R, Elizondo G, et al. Superparamagnetic iron oxide: clinical application as a contrast agent for MR imaging of the liver. Radiology 1988;168:297–301.[Abstract/Free Full Text]
  3. Saini S, Stark DD, Hahn PF, et al. Ferrite particles: a superparamagnetic MR contrast agent for enhanced detection of liver carcinoma. Radiology 1987;162:217–222.[Abstract/Free Full Text]
  4. Hamm B, Staks T, Taupitz M, et al. Contrast-enhanced MR imaging of liver and spleen: first experience in humans with a new superparamagnetic iron oxide. J Magn Reson Imaging 1994;4:659–668.[Medline]
  5. Ba-Ssalamah A, Heinz-Peer G, Schima W, et al. Detection of focal hepatic lesions: comparison of unenhanced and SHU 555 A-enhanced MR imaging versus biphasic helical CTAP. J Magn Reson Imaging 2000;11:665–672.[CrossRef][Medline]
  6. del Frate C, Bazzocchi M, Mortele KJ, et al. Detection of liver metastases: comparison of gadobenate dimeglumine-enhanced and ferumoxides-enhanced MR imaging examinations. Radiology 2002;225:766–772.[Abstract/Free Full Text]
  7. Bluemke DA, Weber TM, Rubin D, et al. Hepatic MR imaging with ferumoxides: multicenter study of safety and effectiveness of direct injection protocol. Radiology 2003;228:457–464.[Abstract/Free Full Text]
  8. Grandin C, Van Beers BE, Robert A, Gigot JF, Geubel A, Pringot J. Benign hepatocellular tumors: MRI after superparamagnetic iron oxide administration. J Comput Assist Tomogr 1995;19:412–418.[Medline]
  9. Vogl TJ, Hammerstingl R, Pegios W, et al. The value of the liver-specific superparamagnetic contrast medium AMI-25 for the detection and differential diagnosis of primary liver tumors versus metastases. Rofo 1994;160:319–328.[Medline]
  10. Stroszczynski C, Gaffke G, Gretschel S, et al. Use of SPIO-enhanced T1- and T2-weighted images for the differentiation of liver lesions: an ROC analysis. Rofo 2003;175:1368–1375.[Medline]
  11. Saini S, Edelman RR, Sharma P, et al. Blood-pool MR contrast material for detection and characterization of focal hepatic lesions: initial clinical experience with ultrasmall superparamagnetic iron oxide (AMI-227). AJR Am J Roentgenol 1995;164:1147–1152.[Abstract/Free Full Text]
  12. Saini S, Sharma R, Baron RL, et al. Multicentre dose-ranging study on the efficacy of USPIO ferumoxtran-10 for liver MR imaging. Clin Radiol 2000;55:690–695.[CrossRef][Medline]
  13. Sahani D, Saini S, Sharma R, O'Malley M, Hahn P. Dynamic T1-weighted ferumoxides enhanced MRI for imaging liver hemangiomas: preliminary observations. Abdom Imaging 2001;26:166–170.[CrossRef][Medline]
  14. Müller M, Reimer P, Wiedermann D, et al. T1-weighted dynamic MRI with new superparamagnetic iron oxide particles (Resovist): results of a phantom study as well as 25 patients. Rofo 1998;168:228–236.[Medline]
  15. Takahama K, Amano Y, Hayashi H, Ishihara M, Kumazaki T. Detection and characterization of focal liver lesions using superparamagnetic iron oxide-enhanced magnetic resonance imaging: comparison between ferumoxides-enhanced T1-weighted imaging and delayed-phase gadolinium-enhanced T1-weighted imaging. Abdom Imaging 2003;28:525–530.[CrossRef][Medline]
  16. Taupitz M, Schmitz S, Hamm B. Superparamagnetic iron oxide particles: current state and future development. Rofo 2003;175:752–765.[Medline]
  17. Taupitz M, Wagner S, Schnorr J, et al. Phase I clinical evaluation of citrate-coated monocrystalline very small superparamagnetic iron oxide particles as a new contrast medium for MRI. Invest Radiol 2004;39:394–405.[CrossRef][Medline]
  18. Wagner S, Schnorr J, Pilgrimm H, Hamm B, Taupitz M. Monomer-coated very small superparamagnetic iron oxide particles as contrast medium for magnetic resonance imaging: preclinical in vivo characterization. Invest Radiol 2002;37:167–177.[CrossRef][Medline]
  19. 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.[CrossRef][Medline]
  20. Schnorr J, Wagner S, Abramjuk C, et al. Comparison of the iron-oxide-based blood-pool contrast medium VSOP-C184 with gadopentetate dimeglumine for first-pass MRA of the aorta and renal arteries in pigs. Invest Radiol 2004;39:546–553.[CrossRef][Medline]
  21. Akritas MG, Arnold SF, Brunner E. Nonparametric hypothesis and rank statistics for unbalanced factorial designs. J Am Stat Assoc 1997;92:258–265.[Medline]
  22. Brunner E, Langer F. Nonparametric analysis of longitudinal data. Munich, Germany: Oldenbourg, 1999.
  23. Noguchi Y, Murakami T, Kim T, et al. Detection of hepatocellular carcinoma: comparison of dynamic MR imaging with dynamic double arterial phase helical CT. AJR Am J Roentgenol 2003;180:455–460.[Abstract/Free Full Text]
  24. Dromain C, de Baere T, Baudin E, et al. MR imaging of hepatic metastases caused by neuroendocrine tumors: comparing four techniques. AJR Am J Roentgenol 2003;180:121–128.[Abstract/Free Full Text]
  25. Semelka RC, Martin DR, Balci C, Lance T. Focal liver lesions: comparison of dual-phase CT and multisequence multiplanar MR imaging including dynamic gadolinium enhancement. J Magn Reson Imaging 2001;13:397–401.[CrossRef][Medline]
  26. Hamm B, Thoeni RF, Gould RG, et al. Focal liver lesions: characterization with nonenhanced and dynamic contrast material-enhanced MR imaging. Radiology 1994;190:417–423.[Abstract/Free Full Text]
  27. Hamm B, Mahfouz AE, Taupitz M, et al. Liver metastases: improved detection with dynamic gadolinium-enhanced MR imaging? Radiology 1997;202:677–682.[Abstract/Free Full Text]
  28. Semelka RC, Cance WG, Marcos HB, Mauro MA. Liver metastases: comparison of current MR techniques and spiral CT during arterial portography for detection in 20 surgically staged cases. Radiology 1999;213:86–91.[Abstract/Free Full Text]
  29. Reimer P, Jahnke N, Fiebich M, et al. Hepatic lesion detection and characterization: value of nonenhanced MR imaging, superparamagnetic iron oxide-enhanced MR imaging, and spiral CT—ROC analysis. Radiology 2000;217:152–158.[Abstract/Free Full Text]
  30. Reimer P, Muller M, Marx C, et al. T1 effects of a bolus-injectable superparamagnetic iron oxide, SH U 555 A: dependence on field strength and plasma concentration—preliminary clinical experience with dynamic T1-weighted MR imaging. Radiology 1998;209:831–836.[Abstract/Free Full Text]
  31. Reimer P, Balzer T. Ferucarbotran (Resovist): a new clinically approved RES-specific contrast agent for contrast-enhanced MRI of the liver—properties, clinical development, and applications. Eur Radiol 2003;13:1266–1276.[Medline]
  32. Taupitz M, Schnorr J, Abramiuk C, et al. New generation of monomer-stabilized very small superparamagnetic iron oxide particles (VSOP) as contrast medium for MR angiography: preclinical results in rats and rabbits. J Magn Reson Imaging 2000;12:905–911.[CrossRef][Medline]
  33. Taupitz M, Wagner S, Schnorr J, et al. MR angiography of the entire coronary system with a very small iron oxide blood-pool contrast medium: results of a phase IB clinical trial (abstr). In: Proceedings of the Eleventh Meeting of the International Society for Magnetic Resonance in Medicine. Berkeley, Calif: International Society for Magnetic Resonance in Medicine, 2003; 725.
  34. Lawaczeck R, Bauer H, Frenzel T, et al. Magnetic iron oxide particles coated with carboxydextran for parenteral administration and liver contrasting: pre-clinical profile of SH U555A. Acta Radiol 1997;38:584–597.[Medline]
  35. Wilhelm C, Billotey C, Roger J, Pons JN, Bacri JC, Gazeau F. Intracellular uptake of anionic superparamagnetic nanoparticles as a function of their surface coating. Biomaterials 2003;24:1001–1011.[CrossRef][Medline]
  36. Tacke J, Adam G, Classen H, Muhler A, Prescher A, Gunther RW. Dynamic MRI of a hypovascularized liver tumor model: comparison of a new blood pool contrast agent (24-gadolinium-DTPA-cascade-polymer) with gadopentetate dimeglumine. J Magn Reson Imaging 1997;7:678–682.[Medline]




This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
2393040884v1
240/1/90    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager