Published online before print May 27, 2004, 10.1148/radiol.2321030876
(Radiology 2004;232:160-163.)
© RSNA, 2004
MR Imaging of the Stomach: Potential Use for Mangafodipir Trisodium— A Study in Swine1
Chun S. Zuo, PhD,
Peter R. Seoane, PhD,
Jiani Hu, PhD,
Philip P. Harnish, PhD and
Neil M. Rofsky, MD
1 From the Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (C.S.Z., N.M.R.); Eagle Vision Pharmaceutical, Exton, Pa (P.R.S., P.P.H.); and Department of Radiology, Wayne State University, Detroit, Mich (J.H.). Received May 29, 2003; revision requested August 12; final revision received November 12; accepted November 24. Supported in part by grant DK 58420–1 from the NIH to Eagle Vision Pharmaceutical. Address correspondence to C.S.Z., Brain Imaging Center, McLean Hospital, 115 Mill St, Belmont, MA 02215 (e-mail: czuo@mclean.harvard.edu).
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ABSTRACT
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PURPOSE: To evaluate mangafodipir trisodium as a potential contrast agent at magnetic resonance (MR) imaging of the stomach.
MATERIALS AND METHODS: Mangafodipir trisodium was injected intravenously into three swine at a dose of 5 µmol per kilogram of body weight. For comparison, gadopentetate dimeglumine was injected into three other swine at a dose of 0.1 mmol per kilogram of body weight. T1-weighted three-dimensional MR images were acquired in all six swine at 1.5 T before and approximately 10, 15, 20, 25, 30, and 40 minutes after contrast material administration. Extracted stomach specimens were imaged at 3.0 T. In vivo and ex vivo images were evaluated visually and quantitatively for contrast enhancement of the stomach, and in vivo images were evaluated for the presence of reflux from the duodenum.
RESULTS: Mangafodipir trisodium produced prolonged and selective enhancement of the inner surface of the stomach, in contrast to the more general enhancement seen with gadopentetate dimeglumine, and reflux from the duodenum could not account for this selective enhancement. Ex vivo images confirmed that T1 enhancement in the stomach wall with mangafodipir trisodium was limited to the inner surface. Gadopentetate dimeglumine did not produce selective enhancement of the inner surface of the stomach.
CONCLUSION: Mangafodipir trisodium preferentially enhances the inner surface of the stomach on MR images acquired in swine and, therefore, may have potential for use as a contrast agent at MR imaging of the human stomach.
© RSNA, 2004
Index terms: Animals • Experimental study • Magnetic resonance (MR), contrast media • Stomach, MR, 72.12143, 72.121412, 72.121415 • Stomach, mucosa
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INTRODUCTION
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Magnetic resonance (MR) imaging has been performed in patients with gastric diseases by using intravenous gadopentetate dimeglumine in conjunction with optional oral ferric ammonium citrate as negative contrast material (1). The use of intravenous gadopentetate dimeglumine, however, is limited because of the diffusion of the agent in extracellular fluid: The first pass provides a relatively short temporal window for MR imaging at high spatial resolution, typically only a few minutes (2,3). In addition, in many diseases it may be difficult to recognize or localize small lesions because of the distribution of gadopentetate dimeglumine to all layers of the stomach wall (eg, mucosa, submucosa). Although the degree of gadolinium-based contrast enhancement varies among diseases, a nonspecific extracellular agent that is distributed by diffusion cannot demonstrate selective uptake. Contrast agents that are subject to selective uptake by the inner surface of the stomach may facilitate the assessment of lesions in the interior stomach wall for tumor staging, as well as the early detection and diagnosis of gastric diseases (4).
Mangafodipir trisodium is an MR contrast agent approved for imaging of liver tissue (5–8). It is widely known that mangafodipir trisodium has a relatively high uptake in the liver, kidney cortex, and adrenal and salivary glands, as well as the pancreas (9–13). However, to our knowledge, there have been no prior studies of gastric contrast enhancement at MR imaging with mangafodipir trisodium.
We recently observed that mangafodipir trisodium exhibited preferential uptake in the inner surface of the stomach and produced prolonged contrast enhancement after intravenous administration. This observation suggested to us that mangafodipir trisodium may have potential utility for contrast-enhanced MR imaging of the stomach. Thus, the purpose of our study was to evaluate mangafodipir trisodium as a potential MR contrast agent for imaging of the stomach.
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MATERIALS AND METHODS
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Animals and Contrast Material
The study was performed according to an animal protocol approved by the Institutional Animal Care and Use Committee at Beth Israel Deaconess Medical Center. Six Yorkshire pigs with a mean body weight (± SD) of 36.5 kg ± 8.1 (range, 26–46 kg) were used for the evaluation. Mangafodipir trisodium (Teslascan; Nycomed, Princeton, NJ) was injected intravenously at a rate of 0.33 mL (± 0.05) per second at the recommended clinical dose of 5 µmol per kilogram of body weight into three pigs. For comparison, gadopentetate dimeglumine (Magnevist; Berlex Laboratories, Wayne, NJ) was injected intravenously at a dose of 0.1 mmol per kilogram of body weight into the other three swine at a rate of 0.45 mL (± 0.05) per second. Both contrast agents were delivered as a 15-second bolus by using a power injector (Spectris; Medrad, Indianola, Pa).
In Vivo MR Imaging
In vivo imaging was performed by one of the authors (C.S.Z.) using a 1.5-T whole-body MR imager (Magnetom Quantum; Siemens Medical Systems, Erlangen, Germany), a body coil to transmit, and a body phased-array coil to receive. Before and approximately 10, 15, 20, 25, 30, and 40 minutes after the contrast material injection, the animals were examined with a T1-weighted three-dimensional volumetric interpolated breath-hold examination sequence (repetition time msec/echo time msec, 3.8/1.6; flip angle, 25°; field of view, 300 x 300 mm; section thickness, 2 mm [postinterpolation slab thickness, 128 mm]; number of partitions, 64; imaging matrix, 228 x 256). The animals were imaged during suspended respiration (with a breath hold of approximately 28 seconds) controlled with a mechanical ventilator.
Ex Vivo MR Imaging
After in vivo MR imaging, the animals were sacrificed and prepared for ex vivo imaging by the same author who performed in vivo imaging (C.S.Z.). Their stomachs were extracted, washed with water, inflated with approximately 400 mL barium sulfate suspension (Readi-Cat 2, E-Z-Em, Westbury, NY) for negative contrast enhancement, and stored in an ice-water bath (temperature, approximately 4°C). Stomach specimens were then imaged ex vivo, about 12 hours after in vivo contrast material–enhanced imaging, with use of a 3.0-T whole-body system (Signa Excite; GE Medical Systems, Milwaukee, Wis) and a head transmit-and-receive coil to achieve high spatial resolution. Higher field strength at ex vivo imaging, compared with that at in vivo imaging, was used solely to achieve better spatial resolution. An increase of field strength from 1.5 T to 3.0 T would not, to our knowledge, be expected to increase the contrast enhancement produced by mangafodipir trisodium. A T1-weighted three-dimensional gradient-recalled-echo sequence was used with fat saturation, 6.2/2.2, a flip angle of 45°, section thickness of 1.2 mm (with no interpolation), matrix of 216 x 512, and field of view of 195 x 260 mm (ie, in-plane resolution of 900 x 500 µm).
Data Analysis
In vivo images before and during contrast enhancement were examined by a physicist and a radiologist (C.S.Z., N.M.R.) to evaluate the enhancement effect. To quantify the signal intensity enhancement, regions of interest (ROIs) in the wall of the stomach—approximately 30 pixels in each ROI—were selected by the radiologist who performed in vivo imaging. User-defined freehand ROIs limited to the interior wall of the stomach were placed in similar locations on the contrast-enhanced and nonenhanced images. The mean signal intensities of the stomach wall on each image were calculated from at least three ROIs, and at least three noncontiguous sections were used to determine the signal intensities of each stomach before and at each time point after contrast material injection. A radiologist (N.M.R.) visually evaluated each in vivo image obtained prior to and at various intervals after mangafodipir trisodium injection for the presence of reflux (areas of high signal intensity) from the duodenum into the stomach.
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RESULTS
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After the administration of mangafodipir trisodium, the inner surface of the stomach was preferentially contrast enhanced (Fig 1), although the precise layer in which enhancement occurred could not be determined with certainty. The liver was intensely enhanced approximately 20 minutes after mangafodipir trisodium administration. Contrast material was excreted from the liver through the common bile duct (11,14) approximately 15 minutes after mangafodipir administration, and sustained biliary enhancement was subsequently observed. In addition to the enhancement of the interior surface of the stomach wall, there was partial enhancement in the gallbladder lumen and the second portion of the duodenum.
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Figure 1. Coronal in vivo MR images obtained in swine stomach, A, before and, B, approximately 30 minutes after administration of mangafodipir trisodium with an intravenous bolus injection at a dose of 5 µmol per kilogram of body weight and with a T1-weighted three-dimensional volumetric interpolated breath-hold examination sequence (3.8/1.6, 25° flip angle, 300 x 300-mm field of view, 2-mm section thickness [128-mm postinterpolation slab thickness], 64 partitions, 228 x 256 matrix). In the contrast-enhanced image, note that the enhancing layer (arrow) is limited to the inner surface of the stomach wall.
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A plot of signal intensity values in the stomach wall against the time interval after contrast material administration (Fig 2) indicated that a 30% increase in signal intensity (versus nonenhanced signal intensity) occurred approximately 25–30 minutes after mangafodipir trisodium injection and remained relatively stable for at least 40 minutes. In comparison, gadopentetate dimeglumine reached its peak enhancement within minutes after its administration, and the enhancement was found to be nonspecific (2,3,15). Note that the imaging protocol used in this study has been used previously to evaluate kinetic enhancement in liver (15). The results of the previous study indicated that the gadopentetate dimeglumine enhancement peak in extracellular fluid, including that in the stomach, is achieved less than 2 minutes after contrast material administration. Gadopentetate dimeglumine achieved a higher level of enhancement than did mangafodipir trisodium, but this level was not sustained over time. Mangafodipir trisodium produced prolonged contrast enhancement that was subjectively judged to be confined to an inner layer of the stomach, compared with the nonspecific enhancement produced by gadopentetate dimeglumine.
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Figure 2. Graph shows contrast enhancement in the swine stomach wall at various intervals after administration of gadopentetate dimeglumine (Gd) and mangafodipir trisodium (Mn). The key parameter for comparison of these two contrast agents is not the peak level of enhancement but rather the selectivity and duration of enhancement: A 30% enhancement occurred approximately 30 minutes after mangafodipir trisodium injection and remained relatively constant for at least 40 minutes, compared with the early and abrupt decline in contrast enhancement with gadopentetate dimeglumine. S = MR imaging signal intensity at time t before and after contrast material injection, S0 = MR imaging signal intensity before contrast material injection.
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Evaluation of the in vivo images acquired before and at various intervals after mangafodipir trisodium administration indicated that one pig had no reflux throughout the MR imaging experiment, one did not have reflux until 1 hour after mangafodipir trisodium injection, and one had reflux approximately 16 minutes after the mangafodipir trisodium administration.
Figure 3 shows typical ex vivo images of the stomach in swine that had or had not received mangafodipir trisodium. The appearance on the control image of the nonenhanced stomach (Fig 3, A) was consistent with previously reported findings (16–18), and the contrast-enhanced image (Fig 3, B) clearly confirms that the inner surface of the stomach was enhanced with mangafodipir trisodium.
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Figure 3. Coronal ex vivo MR images of swine stomach obtained, A, without, and, B, with mangafodipir trisodium injection and a T1-weighted three-dimensional gradient-recalled-echo sequence with fat saturation (6.2/2.2, 45° flip angle, 1.2-mm section thickness [no interpolation], 216 x 512 matrix, and 195 x 260-mm field of view). In B, note the thin and well-defined enhancing layer (arrow) that is confined to the inner portion of the gastric wall and follows the contour of the gastric folds. The image in A appears to be in the transverse plane because the specimen was in a smaller container than that in B.
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DISCUSSION
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Blood supply and duodenal-gastric reflux are two possible mechanisms by which nonoral contrast agents may reach the interior surface of the stomach wall. The fact that mangafodipir trisodium was administered intravenously indicates that blood flow to the gastric vasculature was at least one of the channels that delivered the contrast material to the stomach wall. The stomach mucosa is known to have many highly active cells (4) that may contain many mitochondria. These mitochondria may be responsible for the selective uptake of manganese in the interior surface of the stomach wall (19,20).
It is conceivable that manganese might enter the stomach through reflux from the duodenum, as well as through blood flow. Liver is the major organ for uptake of manganese from mangafodipir trisodium in the blood circulation. We observed manganese excretion into the biliary system and duodenum, as has been shown previously (21). Since the animals in our study had empty stomachs a few hours before the experiments, it is possible that some of the manganese entered the stomach through duodenal reflux (22). Our visual examination of the images at various time points indicated that reflux partially contributed to the enhancement observed on the in vivo images in one of the pigs approximately 16 minutes after contrast material administration. However, the reflux mechanism could not account for the enhancement that occurred on images obtained in the other two pigs approximately 20 minutes after contrast material injection.
The relatively uniform enhancement of the interior surface of the stomach wall on the ex vivo images after internal rinsing, and the enhancement of the interior surface of the stomach wall prior to reflux observed on the contrast-enhanced in vivo images, leads us to believe that the selective enhancement of the interior surface of the stomach wall resulted from uptake of mangafodipir trisodium or manganese through the gastric blood supply.
The results of previous studies with radioisotopes (23–25) showed manganese uptake in the alimentary tract, including the stomach, duodenum, and rectum. The identification of the exact location of manganese uptake was beyond the scope of our study; at autoradiography of intestinal villi, however, manganese 52 (52Mn) was conspicuous in the epithelium and in the mucus that cohered to its free surface but was only slightly evident in the lamina propria. Moreover, 52Mn appeared to have accumulated in the distal part of the epithelial cells, a finding that is consistent with mitochondrial uptake.
Studies with radioisotopes (23–25) also indicated that the gastrointestinal tract was the major channel for manganese excretion. The selective enhancement observed in the inner surface of the stomach in our study seems consistent with findings in the aforementioned studies, which indicate that this enhancement was due to manganese that was either excreted into mucus or concentrated within the mucosa. These data also suggest that mangafodipir trisodium may enhance other areas of the gastrointestinal tract, a possibility that requires further study.
The conspicuity and detail of enhancement in the inner gastric layer of the specimen likely had several sources. The increased signal-to-noise ratio with 3.0 T likely supported the higher-resolution imaging technique employed at ex vivo imaging, compared with those at in vivo imaging with 1.5 T. Furthermore, motion does not occur at imaging in the ex vivo specimen. It is recognized that the sequence parameters were not identical for 1.5-T and 3.0-T imaging. While the longer T1 relaxation times at imaging with 3.0 T (26) may have necessitated some parameter adjustments, our 3.0-T strategy was empiric and influenced by system constraints. The minimum repetition time achievable is inversely related to the resolution and specific absorption rate calculations. We elected to accept the internal control of these features by the imaging system.
A limitation of our study is the lack of direct histologic identification of the exact location of manganese uptake at the cellular level. In addition, our study was restricted to normal animals, and the value of the technique for use in specific gastric disorders remains to be determined with further study.
In summary, the use of mangafodipir trisodium resulted in a prolonged and selective enhancement of the inner layer of the swine stomach, compared with the more broadly distributed enhancement seen with gadopentetate dimeglumine. Reflux from the duodenum could not account for this selective enhancement. This phenomenon is consistent with previous findings in radioisotope studies of manganese excretion routes, and it implies a potential role for mangafodipir trisodium in facilitating the MR assessment of gastric disorders.
Practical application: High-spatial-resolution MR images can depict multiple layers of the gastric tract (16–18). Studies of pathologic processes indicate that many disorders of the stomach originate in the mucosa and, in more advanced stages, extend to other layers (4). From this point of view, MR imaging with contrast agents that provide a prolonged enhancement window and selective enhancement of the inner surface of the stomach wall may enable earlier diagnosis of gastric disorders. Mangafodipir trisodium is commercially available for clinical use and possesses such potential. Further evaluations that include histologic correlation in surgical specimens are needed to determine the specific localization of this contrast agent.
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ACKNOWLEDGMENTS
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We thank Donna Helene Wolfe, MFA, for editorial assistance in preparation of the manuscript.
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FOOTNOTES
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Abbreviation: ROI = region of interest
Author contributions: Guarantor of integrity of entire study, C.S.Z.; study concepts, N.M.R.; study design, N.M.R., C.S.Z.; literature research, P.R.S., P.P.H., C.S.Z., N.M.R.; experimental studies, C.S.Z.; data acquisition, C.S.Z.; data analysis/interpretation, C.S.Z., J.H., N.M.R.; manuscript preparation, C.S.Z., N.M.R., P.R.S., P.P.H.; manuscript definition of intellectual content, P.R.S., P.P.H., C.S.Z.; manuscript editing and final version approval, N.M.R., C.S.Z.; manuscript revision/review, all authors
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REFERENCES
|
|---|
- D’Arienzo A, Scaglione G, Vicinanza G, et al. Magnetic resonance imaging with ferumoxil, a negative superparamagnetic oral contrast agent, in the evaluation of ulcerative colitis. Am J Gastroenterol 2000; 95:720-724.[CrossRef][Medline]
- Kang B, Kim J, Kim K, et al. Value of the dynamic and delayed MR sequence with Gd-DTPA in the T-staging of stomach cancer: correlation with the histopathology. Abdom Imaging 2000; 25:14-24.[CrossRef][Medline]
- Hamed M, Hamm B, Ibrahim M, Taupitz M, Mahfouz A. Dynamic MR imaging of the abdomen with gadopentetate dimeglumine: normal enhancement patterns of the liver, spleen, stomach, and pancreas. AJR Am J Roentgenol 1992; 158:303-307.[Abstract/Free Full Text]
- Cotran R, Kumar V, Collins T. Pathologic basis of disease Philadelphia, Pa: Saunders, 1999.
- Elizondo G, Fretz C, Stark D, et al. Preclinical evaluation of MnDPDP: new paramagnetic hepatobiliary contrast agent for MR imaging. Radiology 1991; 178:73-78.[Abstract/Free Full Text]
- Halavaara J, Lamminen A. MnDPDP as a negative hepatic contrast agent: evaluation of STIR imaging compared with T1-weighted SE and GE techniques. J Comput Assist Tomogr 1997; 21:94-99.[CrossRef][Medline]
- Rofsky N, Weinreb J, Bernardino M, Young S, Lee J, Noz M. Hepatocellular tumors: characterization with Mn-DPDP-enhanced MR imaging. Radiology 1993; 188:53-59.[Abstract/Free Full Text]
- Murakami T, Baron R, Peterson M. Hepatocellular carcinoma: MR imaging with mangafodipir trisodium (Mn-DPDP). Radiology 1996; 200:69-77.[Abstract/Free Full Text]
- Hustvedt S, Grant D, Southon T, Zech K. Plasma pharmacokinetics, tissue distribution and excretion of MnDPDP in the rat and dog after intravenous administration. Acta Radiol 1997; 38:690-699.[Medline]
- Rummeny E, Torres C, Kurdziel J, Nilsen G, Op de Beeck B, Lundby B. MnDPDP for MR imaging of the liver: results of an independent image evaluation of the European phase III studies. Acta Radiol 1997; 38:623-625.[Medline]
- Toft K, Hustvedt S, Grant D, et al. Metabolism and pharmacokinetics of MnDPDP in man. Acta Radiol 1997; 38:677-689.[Medline]
- Tirkkonen B, Aukrust A, Couture E, et al. Physicochemical characterisation of mangafodipir trisodium. Acta Radiol 1997; 38:780-789.[Medline]
- Wang C. Mangafodipir trisodium (MnDPDP)-enhanced magnetic resonance imaging of the liver and pancreas. Acta Radiol Suppl 1998; 415:1-31.[Medline]
- Thorstensen O, Isberg B, Jorulf H, Westman L, Svahn U, Venizelos N. MnDPDP enhancement in rabbit liver after intravenous bolus injection and slow infusion. Acta Radiol 1997; 38:717-723.[Medline]
- Zuo C, Seoane P, Lanigan T, et al. EVP-ABD: a potential manganese based MR contrast agent for hepatic vascular and tissue phase imaging. J Magn Reson Imaging 2002; 16:668-675.[CrossRef][Medline]
- Lubienski A, Grenacher L, Reith W, Schipp A, Mechtersheimer G, Dux M. MR imaging of gastric wall layers in vitro: correlation to the histologic wall structure. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 2002; 174:490-494.[Medline]
- Yamada I, Saito N, Takeshita K, et al. Early gastric carcinoma: evaluation with high-spatial-resolution MR imaging in vitro. Radiology 2001; 220:115-121.[Abstract/Free Full Text]
- Auh YH, Lim TH, Lee DH, et al. In vitro MR imaging of the resected stomach with a 4.7-T superconducting magnet. Radiology 1994; 191:129-134.[Abstract/Free Full Text]
- Case G. Magnetic resonance studies on the mitochondrial divalent cation carrier. Biochim Biophys Acta 1975; 375:69-86.[Medline]
- Bragadin M, Dell’antone P, Pozzan T, Volpato O, Azzone G. ESR determination of Mn++ uptake and binding in mitochondria. FEBS Lett 1975; 60:354-358.[CrossRef][Medline]
- Lee VS, Rofsky NM, Morgan GR, et al. Volumetric mangafodipir trisodium-enhanced cholangiography to define intrahepatic biliary anatomy. AJR Am J Roentgenol 2001; 176:906-908.[Free Full Text]
- Guyton A. Textbook of medical physiology Philadelphia, Pa: Saunders, 1976.
- Bertinchamps A, Miller S, Cotzias G. Interdependence of routes excreting manganese. Am J Physiol 1966; 211:217-224.[Free Full Text]
- Koshida Y, Kato M, Hara T. Autoradiographic observations of manganese in adult and embryo mice. Q J Exp Physiol Cogn Med Sci 1963; 48:370-378.[Abstract/Free Full Text]
- Maynard L, Cotzias G. The partition of manganese among organs and intracellular organelles of the rat. J Biol Chem 1955; 214:489-495.[Free Full Text]
- de Bazelaire CMJ, Duhamel GD, Rofsky NM, Alsop DC. MR imaging relaxation times of abdominal and pelvic tissues measured in vivo at 3.0 T: preliminary results. Radiology 2004; 230:652-659.[Abstract/Free Full Text]
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ABSTRACT
INTRODUCTION
