Detection of hepatic malignancies using Mn-DPDP (manganese dipyridoxal diphosphate) hepatobiliary MRI contrast agent

0730-725X/90%3.00 + .OO Copyright @ 1990 Pergamon Press plc

Magnelic Reson~nceImag;n~, Vol. 8, pp. 261-216, IWO Printed in the USA. All rights reserved.

0 Original Contribution DETECTION OF HEPATIC MALIGNANCIES USING MmDPDP (MANGANESE DIPYRIDOXAL DIPHOSPHATE) HEPATOBILIARY MRI CONTRAST AGENT STUART

W. YOUNG,

Department

BEVERLY

BRADLEY,

HOLDE

H.

MULLER,

AND DANIEL

L. RUBIN

of Diagnostic Radiology and Nuclear Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA

A new hepatobiliary contrast agent (Mn-DPDP) was used in the detection of liver metastases in six rabbits with seven hepatic V2 carcinomas. This contrast agent is derived from pyridoxyl+phosphate which is biomimetically designed to be secreted by the hepatocyte. After Mn-DPDP administration, a 105% increase in liver signal to noise was obtained using a 200120 (TRITE) pulsing sequence, and a 62% decrease in intensity was observed using a 1200/60 pulsing sequence. Liver V2 carcinoma contrast enhancement increased 427% using the 200120 pulsing sequence and 176% using the 1200/60 pulsing sequence. Four of seven V2 carcinomas were not detectable prior to the administration of Mn-DPDP (SO Ccmol/kg). Two neoplasms were only detectable in retrospect (after MnDPDP) on the 1200/60 sequence. The smallest neoplasms detected in this study were l-4 mm. Mn-DPDP appears to be a promising MRI contrast agent.

Keywords: Contrast agents; MRI; Liver; Cancer; V2 carcinoma; Mn-DPDP.

per paramagnetic’** and fluorinated’*” emulsions to label the reticuloendothelia1 system within the liver. Although these studies have been successful in labeling and enhancing the reticuloendothelial system, the Kupffer cells comprise only 2% of the liver volume,” and thus, these types of agents only label a small portion of the total volume of the liver. Nevertheless, ferrite particles have been shown to enable the detection of 2-mm liver metastases in rats.12 More recently hepatocellular MRI contrast agents have been developed to both label the hepatocyte volume (78%) of the liver and be rapidly secreted in the bile, and these agents appear to be promising MRI contrast agents. 13-16The paramagnetic contrast agent Mn-DPDP (S-095, Salutar Inc., Sunnyvale, CA) is a manganese chelate derived from pyridoxal-S-phosphate that is secreted by the liver.17-19 Mn-DPDP has recently been shown to produce sustained (60-90 min) contrast enhancement of the liver in vivo on both long and short TRITE pulsing sequences and to be useful in measuring hepatocyte function.‘4”’ An hepatobiliary MRI contrast agent might be able to detect metas-

INTRODUCTION

CT has been the procedure of choice for detecting liver malignancies,’ recently overall accuracy of T1-weighted pulse sequences has been found to be superior to contrast enhanced CT.2 Hepatic metastases are present in over one-third of patients dying with cancer,3 and although primary and metastatic malignancies of the liver have a dire prognosis, early detection and treatment could potentially improve survivaL4 MR contrast agents have been developed in an attempt to facilitate the early detection of small liver lesions and to improve MRI sensitivity and clinical efficacy.5 These efforts have led to the recent use of such wellknown MRI relaxation agents as Gd-DTPA or GdDOTA.6,7 These types of water-soluble agents have a distribution volume throughout the extracellular space, and thus, accumulate in both normal and abnormal tissue. One approach to selectively enhancing the difference between normal and abnormal liver tissue has been the utilization of particulate paramagnetic,7 suAlthough

RECEIVED 4/25/89; ACCEPTED l/5/90. AcknowledgmentsWe are grateful to Lisa Pettegrew for manuscript preparation. This study was supported in part by a grant from Salutar, Inc., Sunnyvale, CA.

Address correspondence and reprint requests to Stuart W. Young, M.D., Diagnostic Radiology, S-058, Stanford University Medical Center, Stanford, CA 94305, USA.

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tases within the liver that agents confined to the extracellular space or Kupffer cells might not be capable of detecting. This study was conducted to evaluate Mn-DPDP as a MRI contrast agent with potential use in the early detection of liver metastases. METHODS

Twelve New Zealand white rabbits (1.6-2.5 kg) were anesthetized using 35-mg/kg ketamine and Smg/kg rompun i.v. Rabbits were scanned (1.5 T GE Signa scanner) before and for 60 min after 50 pmol/kg body weight i.v. of Mn-DPDP, using pulsing sequences with TR intervals ranging from 100-2000 msec and TE intervals between 20 and 80 msec. A 200/20 and a 1200/60 pulsing sequences (NEX = 6, FOV = 16, 256 x 128 matrix, slice thickness: 10 mm, gap lo%, and a 90degree presaturation pulse) were selected because they visually appeared to produce best contrast enhancement of the images. Using these pulsing sequences, ROIs were obtained from the liver, gallbladder, and background regions in normal animals for 60 min after contrast administration. Subsequently, rabbits were injected percutaneously with a V2 carcinoma cell suspension containing approximately 1 x lo6 cells per ml using a previously described technique. 21 Transaxial Mn-DPDP enhanced MRI scans of the liver were obtained between 11 and 30 days following V2 carcinoma cell suspension injection. All animals with V2 carcinoma were scanned at 30 min after Mn-DPDP administration. Liver, V2 carcinoma, and background ROI data were used to calculate the percentage change in image intensity as an estimate of V2 carcinoma contrast enhancement. When neoplasms were first observed on the MRI scans, the animals were necropsied following an overdose of Nembutal i.v. The livers were removed at necropsy, fixed in 10% formalin, and sectioned in the axial plane with serial slices. The V2 carcinomas were measured in situ and no adjustments were made for the 5-10% shrinkage in overall liver size caused by the formalin fixation. Subsequently, histological slides were obtained for all liver sections. RESULTS

The time intensity studies in normal rabbits supported our previous experience that maximal liver contrast enhancement following Mn-DPDP injection occurs at approximately 20 min and persists for up to 90 min.14v’5 Changes in liver signal intensity were obtained with both pulsing sequences following Mn-DPDP administration (Figs. l-4, Table 1). A 105% increase in liver

Table 1. Change in signal intensity Mn-DPDP administration Organ

200/20*

Liver

79

% Change** 105

following

1200/60*

% Change**

-85

-62

*Mean of 12 livers (ROI post Mn-DPDP - background) - (ROI pre-Mn-DPDP - background). **[(ROI post Mn-DPDP - background) - (ROI pre-Mn-DPDP background)] x lOO/(ROI pre-Mn-DPDP - background).

intensity was observed using the 200/20 pulsing sequence following the administration of Mn-DPDP. Mn-DPDP in conjunction with the 1200/60 pulsing sequence produced a 62% decrease in liver intensity. The decreased signal intensity observed using the longer TR/TE sequence seemed to correlate with T2 shortening from 32 msec to 25 msec measured in a single animal using a 4-echo method and a TR of 2000. Bile within the gallbladder often had layers of differing intensity presumably related to bile concentration gradients. As a result, the standard deviations of the gallbladder data were quite large (200120 = -43.2 + 126; 1200/60 = -5.3 + 104; MEAN f SD). Hepatic Cancer Detection MRI scans were interpreted by two of us, and animals with scans judged to be positive were sacrificed for histological evaluation. A growing V2 carcinoma was diagnosed if abnormal signal intensity regions within the liver were noted. The MRI scans of six rabbits were interpreted as being positive for V2 carcinoma liver metastases. These animals were sacrificed and the presence of V2 carcinomas was confirmed by histological evaluation. The MRI scans from three other rabbits that had been injected with V2 carcinoma were considered to be normal, and necropsy of these rabbits revealed no V2 carcinomas within the liver parenchyma on histological sections. Three of the six V2 carcinoma animals had sequential (two to three) MRI scans, and in all cases, the first study did not reveal V2 carcinoma within the liver even with the use of Mn-DPDP (Figs. 1, 3, 4). Follow-up scans in all animals (mean follow-up interval of the 3 livers = 7.7 days), however, subsequently did reveal V2 carcinoma growing within the liver (Figs. 1, 3, 4). In the six animals with seven V2 carcinomas, four of the V2 carcinomas (three spherical tumors and a linear extension of the four) were not visible prior to the administration of Mn-DPDP. The V2 carcinomas, not detectable prior to Mn-DPDP administration, ranged from 1 mm to 4 mm in diameter (Figs. 2, 3). Another V2 carcinoma had a 3-mm spherical component and

Detection

of hepatic

malignancies

using Mn-DPDP

a 6-mm linear appendage which was i mm to 1 mm in cross section (Fig. 4). The 3-mm spherical component was detectable only on the precontrast 1200/60 (but not on the 200/20) pulsing sequence. The thin, linear appendage was not detectable on either pulsing sequence prior to Mn-DPDP administration, and in addition, the l-mm x 6-mm linear appendage was only detectable on the 1200/60 post-Mn-DPDP study. A second 3-mm x 17-mm V2, similar to the spherical V2 shown in Fig. 4, was also only detectable in retrospect (following Mn-DPDP) on the 1200/60, but not the 200/20 pulsing sequence. In two additional animals, a 4-mm and a 2.5-cm x 3-cm (Fig. 1) V2 tumor was visible before contrast media on both the 200/20 and 1200/60 pulsing sequence, but they were detectable following contrast media (Table 2). Conspicuity of V2 carcinomas on liver images appeared generally to be best on the 200120 sequence (Table 2); however, some V2 carcinomas were only detectable on the 1200/60 sequence either before (Fig. 2) or after (Fig. 4) Mn-DPDP. Following Mn-DPDP administration, liver cancers were seen as a low intensity lesion superimposed on a high intensity background of normal liver on the 200/20 sequence; however, a high intensity malignancy superimposed on a background of low intensity liver was noted on the 1200/60 sequence (Figs. 1-4, Table 2). One unexpected result of these studies was the finding that contrast enhancement secondary to MnDPDP was considerably greater in right lateral liver lobule than in the remainder of the liver. The right lateral liver lobule is a flattened lobule of liver projecting inferiorly over the right kidney (Figs. 1, 2). On the 200/20 images, liver intensity readings (mean of 3 studies) following Mn-DPDP were as follows: right lateral lobule = 304; remaining liver parenchyma =

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0 S.W. YOUNG ET AL.

273; intensity difference = 30%. This increased contrast enhancement effect greatly facilitated the detection of V2 carcinoma located in the right lateral lobule (Fig. 2(B)). The V2 carcinoma/liver intensity readings prior to Mn-DPDP administration were 214/214 and 191/197 on the 200/20 and 1200160 pulsing sequences, respectively; and 230/3 11 and 841155 following Mn-DPDP. A l-mm x l-mm x l-cm (slice thickness) ROI was used to obtain these data and some partial voluming effects were undoubtedly included in these data. DISCUSSION The results of this study have indicated that MnDPDP produces contrast enhancement of the liver on both short and long TR/TE sequences using protocols specifically designed to maximize paramagnetic effect of the contrast agent. Although no attempt was made to optimize noncontrast enhanced MRI scans for V2 carcinoma detection, four of the seven V2 carcinomas were not detected until Mn-DPDP was administered. Following Mn-DPDP, V2 carcinomas between one millimeter and several centimeters in diameter were detected. Detecting small hepatic carcinomas is probably facilitated because Mn-DPDP is distributed throughout the extracellular and intracellular (within the hepatocytes) space, and thus, produces a paramagnetic effect in over 90% of the liver volume.” Mn-DPDP has also been recently demonstrated to be safe in phase I clinical trials. I3 The use of targetable contrast agents with predictable physiological activity can potentially improve the MRI evaluation of the liver. Labeling of the reticuloendothelial system has been accomplished using 19F emulsions,‘,” paramagnetics such as gadolinium

Table 2. Contrast enhancement of V2 liver carcinomas following

Mn-DPDP

administration

200/20 Mn-DPDP

Organ

Pre

1200/60 Post

Pre

Post

V2 Carcinoma*

172 f 71

152 * 51

204 -t 39

215 -+ 58

Liver*

195 f 46

278 -t 40

153 + 41

75 2 23

-23

-126

51

140

V2-Liver V2 Contrast

*(ROI - background;

tlmprovement

427

Enhancementt mean +

176

SD; n = 5).

in V2 conspicuity due to the contrast [(Post difference

agent was calculated - Pre difference)/Pre

using the following difference]

formula:

x 100

Post [(Mean V2 Intensity - BKG) - (Mean Liver Intensity - BKG)] - Pre [(Mean V2 Intensity - BKG) - (Mean Liver Intensify - BKG)] x lOO/Pre [(Mean V2 Intensity - BKG) - (Mean Liver Intensity - BKG)]. BKG = background intensity reading measured in air.

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Detection of hepatic malignancies using Mn-DPDP 0 SW.

YOUNG

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ET AL.

Fig. 1. Axial MRI scans obtained through the liver of a rabbit bearing V2 carcinoma within the liver on day 15 [(A)-(D)] and day 22 [(E)-(H)] following V2 cell suspension injection [see table below for key to Fig. (A)-(H)]. Note that the V2 carcinoma (long arrow) is barely visible on the 200/20 sequence before the administration of Mn-DPDP. However, conspicuity increases greatly following Mn-DPDP on both sequences and conspicuity is greatest on the 1200/60 imaging sequence. The tumor has increased greatly in size between the two scans and has grown into both the right and left medial lobule of the liver and at autopsy on day 22 was found to be nearly completely replacing the medial halves of both of these lobes (size at autopsy 2.5 cm in diameter x 3 cm in length). Conspicuity of the V2 increases on the 200/20 sequence mainly because of an increase in the signal intensity of the liver, and the V2 is seen as a black neoplasm against a white background. Conspicuity increases on the 1200/60 sequence because of an increase in the intensity of the V2 (related to the longer TR/TE pulsing sequence) and a decrease in liver intensity due to the Mn-DPDP. The neoplasm is seen as an increased signal against a black background of the surrounding liver. [Gall bladder = curved arrow; right lateral lobule of the liver = open arrow in (B) and (D)].

Key to images in Fig. 1. 200/20

1200/60

TR/TE Date

Pre-Mn

Post-Mn

Pre-Mn

Post-Mn

15 days 22 days

A E

B F

C G

D H

hydroxy colloid,22 and superparamagnetic (predominately producing T2 shortening) agents such as ferrite.‘*12 Labeling of the Kupffer cells within the liver with ferrite particles has enabled the detection of 2-mm and smaller rat tumors.i3 One problem with agents that are phagocytosed by the reticuloendothelial system is that they tend to persist within tissues. This approach is also relatively nonselective in that phagocytic reticuloendothelial cells present within the lung, spleen, and bone marrow also accumulate considerable amounts of the injected contrast agent; this is an undesirable side effect if the primary organ system to be examined is the liver. Mn-DPDP is taken up by the hepatocytes and secreted in the bile1s-20and thus offers one additional approach to exploiting the intrinsic liver physiology. Mn-DPDP has been shown to produce a sustain-

able contrast enhancement of the liver between 20 and 90 min following intravenous administration.‘4,‘5 The pharmacokinetics were similar to those previously reported using rats. 19,24Signal-to-noise ratios of the liver were considerably increased and contrast enhancement of V2 carcinomas on liver images was improved using this contrast agent on both short and long TR/TE pulsing sequences. Contrast enhancement of V2 carcinomas on the longer TRITE sequence used in this study may be due in part to T2 shortening. These observations appear to confirm a preliminary report in which contrast-to-noise was reported to be increased in liver implants in rats.22 Although the 200/20 pulsing sequence often produced the maximum V2 conspicuity (Table 2, Fig. 2), comparison of both pulsing sequences was useful in overall MRI interpre-

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212

E

F

Fig. 2. Axial MRI scans obtained in a V2 carcinoma bearing rabbit on day 11 following V2 implantation using a 200/20 [(A) and (B), right lateral lobule of liver; (C) and (D) medial lobules of liver] and 1200/60 [(E) and (F), medial lobules of liver] pulsing sequence before [(A), (C), (E)] and after [(B), (D), (F)] the administration of Mn-DPDP. The V2 carcinoma within the liver in both the right medial lobule [long arrow, (D), (F)] and right lateral lobule [short arrow, (B)] were not visible prior to the administration of Mn-DPDP on the 200/20 sequence (C), however, the V2 on the 1200/60 sequence (E) is just visible, and when the position of the V2 is confirmed on the post-Mn-DPDP scan. The right medial lobule tumor measured 3 mm in diameter by 17 mm long, whereas the right lateral lobule tumor measured 1 mm by 2 mm. Note that there is increased contrast enhancement of the right lateral lobule due to the Mn-DPDP when compared to the effect of the contrast agent elsewhere in the liver. This increased signal intensity (also noted in Fig. 1) increased the conspicuity of the small tumor in the right lateral lobule and undoubtedly aided in its detection. The V2/liver intensity readings prior to Mn-DPDP administration were 214/214 and 191/197 on the 200/20 and 1200/60 pulsing sequences respectively; and 230/311 and 84/155 following Mn-DPDP. Note the zone of contrast enhancement transition anterior to the aorta.

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D Fig. 3. The first MRI scan obtained in this anima1 was on day 15 (following V2 carcinoma injection), and was negative both before and after the administration of Mn-DPDP. However, the right lung base metastasis was visible on the day 15 scan. The axial MRI scans obtained on day 20 at the level of the mid portion of the liver utilize the 200/20 [(A), (B)] and 1200/60 [(C), (D)] pulsing sequences. (A) and (C) were obtained before and (B) and (D) were obtained after Mn-DPDP administration. Although the liver V2 carcinoma is not visible prior to Mn-DPDP administration, a 4-mm right medial lobule V2 is noted following contrast media [long arrow, (B) and (D)]. At autopsy, the right medial lobule tumor had a dumbbell configuration and was 3 to 4 mm in diameter at each end, but considerably narrower (1 mm) in the waist between the two enlarged ends. Also, note the lung metastasis [short arrow, (B) and (D)].

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D

Fig. 4. Following injection of the V2 carcinoma cells, the first MRI scan obtained on day 12 was normal. However, this serial sequence obtained on day 23 [(A) and (B), 200/20] and day 30 [(C) and (D), 1200/60] reveals the development of a detectable V2 carcinoma on the day 23 MRI scan [long arrow, (A), (B)]. These neoplasms were visible on both the 200/20 and 1200/60 pulsing sequences although the V2 was only visible on the 200120 sequence following Mn-DPDP. An autopsy was performed on day 30, and it revealed a g-mm spherical tumor present in the tip of the right medial lobule of the liver; however, the cancer had grown linearly into the parenchyma of the interlobular fissure, and this was detectable only on the 1200/60 imaging sequence as a thin linear high intensity signal extending between the gall bladder (curved arrow) and the body of the tumor (long arrow). At autopsy this linear portion of the V2 carcinoma tumor was approximately $ mm to 1 mm in width.

Detection of hepatic malignancies using Mn-DPDP 0 S.W. YOUNGET

tation and only the 1200/60 sequence detected V2 cancers in some rabbits (Figs. 2, 4). The increased contrast enhancement observed in the right lateral lobule is interesting and was useful in detecting V2 carcinomas present in this lobule of the liver. Increased segmental intensity differences have been reported on 2000/75 (TR/TE) MRI scans obtained at 1.5 T from regions associated with segmental occlusion of the portal venous system.25 It is possible that the Mn-DPDP increased signal intensity from the right lateral lobule is related to the somewhat slower flow in this posteriorly placed liver lobule. Although we have never observed differentiation hepatic blood flow using microspheres, 26 Mn-DPDP has also been shown to be useful in measuring the metabolic status of the hepatocyte,‘4T’5 and this phenomenon may reflect some altered metabolic state or concentration of Mn-DPDP of this region of the rabbit liver. However, the explanation of this phenomenon is still uncertain. In conclusion, this preliminary study has demonstrated that Mn-DPDP is an excellent MRI contrast agent potentially useful in the detection of liver metastases.

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gelstad, B.; Quay, SC.; Ferruci, J.T. Hepatobiliary contrast agents: Pre-clinical efficacy studies. Society of Magnetic Resonance in Medicine Seventh Annual Meeting and Exhibition, August 20-26, 1988, San Francisco, CA. Book of Abstracts, 2:795. 21. Young, S.W.; Hollenberg, N.K.; Kazam, E.; Berkowitz, D.; Hainen, R.; Sandor, T.; Abrams, H.L. Resting host and tumor vascular responses to norepinephrine. Cuncer Res. 39(6):1898-1903; 1979. 22. Gadian, D.G.; Payne, J.A.; Bryant, D.J.; Young, 1.R.; Carr, D.H.; Bydder, G.M. Gadolinium-DTPA as a contrast agent in MR imaging: Theoretical projections and practical observations. J. Comput. Assist. Tomogr. 9:242-251; 1985. 23. Lui, A.; Lumeng, L.; Li, T.K. Metabolism

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