Contrast-enhanced MR imaging of liver and spleen: First experience in humans with a new superparamagnetic iron oxide

The aim of this prospective study was to obtain the first human safety and magnetic resonance (MR) imaging results with a new formulation of superparamagnetic iron oxide (SPIO) (SHU 555 A). The SPIO was tested at four iron doses, from 5 to 40 μmol/kg. Laboratory tests and clinical measurements were done in 32 healthy volunteers for up to 3 weeks after administration. MR imaging at 1.5 T was performed before and 8 hours to 14 days after fast intravenous injection (500 μmol Fe/min) of the SPIO (six subjects per dose). Results of this phase I study demonstrate that SHU 555 A at a concentration of 0.5 mol Fe/L was well tolerated. A dose-dependent minor increase in activated partial thromboplastin time, which remained within the normal range, was seen. All doses of SPIO caused a signal loss in both liver and spleen (P <.05) with a spin-echo sequence (TR = 2,300 msec, TE = 45 msec). The signal losses in the liver 8 hours after contrast agent injection were 58%, 79%, 82%, and 87% for the 5, 10, 20, and 40 μmol Fe/kg doses, respectively. The corresponding signal losses in the spleen were 23%, 45%, 65%, and 78%, respectively. The doses that reduced signal intensity by half were 3.1 μmol Fe/kg for the liver and 12.8 μmol Fe/kg for the spleen. The results suggest that the new SPIO formulation is a safe and efficient MR contrast agent.     

Enhancement effects of a hepatocyte receptor—specific MR contrast agent in an animal model

The enhancement characteristics of the liver and spleen produced by a hepatocyte-specific magnetic resonance imaging agent, an arabinogalactan-coated ultrasmall superparamagnetic iron oxide derivative, BMS 180550, were evaluated. Both heavily T1- and T2-weighted sequences were used. Imaging was performed in the farm pig model, as a function of contrast agent concentration (5, 10, and 20 μmol of iron per kilogram) and delay (immediate, 0.5, 2.5, 5.0, 7.5, and 9.0 hours) after bolus injection of BMS 180550. BMS 180550 provided excellent contrast enhancement characteristics by producing marked positive enhancement with T1-weighted sequences and marked negative enhancement with T2-weighted sequences. The T1-weighted enhancement immediately after contrast agent injection was of greater magnitude in the spleen (329% ± 83) than in the liver (66% ± 16). Postcontrast negative enhancement with T2-weighted sequences was largely hepatocyte specific at 5 and 10 μmol/kg but was also seen within the spleen at 20 μmol/kg. The authors discuss the possible mechanisms that produce these changes and conclude that 10 μmol/kg BMS 180550 is near the optimum dose for maximizing the enhancement properties of this agent with all sequences in the farm pig.     

Gadoteridol dose dependence in MR imaging of a liver abscess model

A necrotic liver abscess model was studied with magnetic resonance (MR) imaging at 1.5 T before and after intravenous administration of gadoteridol at doses of 0.1, 0.25, and 0.5 mmol/kg in 24 rabbits. Enhancement characteristics and lesion delineation were assessed with both breath-hold and non-breath-hold imaging techniques. Lesion delineation, as assessed both by signal intensity measurements and evaluations by two image readers blinded to imaging technique, was greatest on high-dose (0.5 mmol/kg) breath-hold images. Lesion rim enhancement was seen consistently only on postcontrast images obtained at a dose of 0.5 mmol/kg and progressed with time after injection of contrast material.     

Malignant lesions of the liver identified on T1- but not T2-weighted MR images at 1.5 T

The authors reviewed their 21/2-year experience with a magnetic resonance (MR) imaging protocol for a 1.5-T MR imager that included T2-weighted fat-suppressed spin-echo, T1-weighted breath-hold gradient-echo, and serial dynamic gadolinium-enhanced T1-weighted gradient-echo imaging to identify histologic types of malignant liver lesions more apparent on T1- than on T2-weighted images. MR images of 212 consecutive patients with malignant liver lesions were reviewed. T2-weighted, T1-weighted, and dynamic contrast-enhanced T1-weighted images were examined separately in a blinded fashion. Seven patients demonstrated liver lesions (lymphoma [two patients] and carcinoid, hepatocellular carcinoma, colon adenocarcinoma, transitional cell carcinoma, and melanoma [one patient each]) on T1-weighted images that were inconspicuous on T2-weighted images. In all cases, the lesions were most conspicuous on T1-weighted images obtained immediately after administration of contrast agent. Histologic confirmation was present for all seven patients. The consistent feature among these lesions was that they were hypovascular, due either to a fibrous stroma or to dense monoclonal cellularity. These results suggest that in some patients with hypovascular primary neoplasms, the lesions may be identified only on T1-weighted images, and that immediate postcontrast T1-weighted images are of particular value in demonstrating lesions.     

Dynamic gadolinium-enhanced echo-planar MR imaging of the liver: Effect of pulse sequence and dose on enhancement

To develop guidelines for clinical magnetic resonance imaging of the liver, the authors undertook an animal study to investigate the effect of dose and pulse sequence on liver signal intensity in gadopentetate dimeglumine—enhanced echo-planar imaging. Serial imaging of the liver was performed in anesthetized rats after intravenous administration of five different doses (0.01, 0.05, 0.1, 0.2, and 0.5 mmol/kg) of contrast agent, with six different pulse sequences. The results show that gadopentetate dimeglumine—enhanced echo-planar images obtained during the perfusion phase can yield either positive (due to increased T1 relaxation rates) or negative (due to susceptibility-induced increased T2 relaxation rates) liver enhancement depending on choice of pulse sequence and dose. At the current clinically recommended dose of 0.1 mmol/kg, maximal liver signal enhancement was seen with a T1-weighted inversion-recovery sequence, while maximal liver signal diminution was seen with a T2*-weighted gradient-echo sequence. The authors conclude that gadopentetate dimeglumine—enhanced echo-planar imaging can provide T1, T2, and T2* contrast that may be exploited for both lesion detection and lesion characterization.     

Gd-EOB-DTPA enhancement pattern of hepatocellular carcinomas in rats: Comparison with Tc-99m-IDA uptake

The enhancement pattern of chemically induced hepatocellular carcinomas (HCCs) after intravenous administration of the hepatobiliary magnetic resonance (MR) contrast agent gadolinium-EOB-DTPA (ethoxybenzyl-diethylenetriaminepentaacetic acid) was compared with the uptake pattern of technetium-99m-labeled iminodiacetic acid (IDA), a hepatobiliary radioactive tracer. The hepatocyte uptake of both the contrast agent and the scintigraphic agent has been shown to be driven by the organic anion transporter. The tumors enhanced less than the liver after Gd-EOB-DTPA administration, whereas the Tc-99m-IDA uptake of differentiated HCCs exceeded that of the liver at 30 minutes and 3 hours after administration. The enhancement pattern of a differentiated HCC with Gd-EOB-DTPA does not mirror that seen with Tc-99m-IDA.     

Signal changes in liver and spleen after Endorem administration in patients with and without liver cirrhosis

The goal of this study was to compare the effect of Endorem on the signal intensity of the spleen in patients with normal liver tissue and in patients with liver cirrhosis. Thirty patients with normal liver tissue and 47 with liver cirrhosis were examined before and after i. v. Endorem administration. The patients were examined with a 1.5-T magnet system (Magnetom Vision) using a semiflexible cp-array coil. Three different pulse sequences were used: a T1-weighted gradient-echo sequence, a T2-weighted fast spin-echo sequence with spectral fat suppression, and a T2^*-weighted gradient-echo sequence. The signal-to-noise ratios (SNRs) of two areas of the liver and spleen were determined. The mean SNRs of the liver and spleen in patients with and without liver cirrhosis were compared. For assessment of statistical significance, the t-test at a level of P < 0.05 was applied. After i. v. administration of Endorem, no differences were seen with the T1-weighted gradient-echo sequence for the liver and spleen and, with the T2-weighted fast spin-echo sequence, no differences were found for the spleen. Significant differences between both groups were seen for the liver with the T2-weighted fast spin-echo sequence. The SNR in the noncirrhotic liver group was 57.4 % lower than the SNR in the cirrhotic liver group. With the T2^*-weighted gradient-echo sequence, the SNRs of the liver and spleen in the noncirrhotic liver group, compared with the cirrhotic liver group, were 126.8 % and 45.6 % less, respectively. The effect of Endorem on the liver in patients with Child C-stage liver cirrhosis was 32.1 % less than in patients with Child B-stage liver cirrhosis. Likewise, the Endorem effect on the spleen was 27.1 % less in patients with Child C-stage compared with Child B-stage liver cirrhosis. Hepatic and splenic uptake of Endorem is significantly decreased in patients with liver cirrhosis. Received: 3 February 1999; Revision received: 21 October 1999; Accepted: 27 October 1999     

Superparamagnetic iron oxide: Detection of focal liver lesions at high-field-strength MR imaging

AMI-25 was evaluated at 1.5 T as a superparamagnetic iron oxide contrast agent for the liver. Sixteen patients with up to five suspected focal liver lesions were examined with T1-, proton-density—, and T2-weighted spin-echo sequences before and after intravenous administration of AMI-25 (15 μmol/kg iron). The contrast-to-noise ratio (C/N) increased from 1.8 to 3.5 on 600/15 (TR msec/TE msec) images and from 1.7 to 7.9 on 2,500/15 images after AMI-25 administration (P <.01). C/N did not change significantly on 2,500/90 images. Two blinded readers counted the number of lesions visible on unenhanced and contrast-enhanced images, with the 32 sets of images of the 16 patients presented in random order. Both readers identified more lesions on AMI-25–enhanced images, but the difference was not statistically significant (P >.05). Two patients reported minor side effects (flushing, sensation of heat, lower back pain). On the basis of the results obtained in a limited number of patients, the authors conclude that at 1.5 T, AMI-25 does not significantly improve the detection of focal liver lesions on conventional spin-echo images.     

Contrast-enhanced MR imaging of diffuse and focal splenic disease with use of magnetic starch microspheres

The diagnostic value of magnetic starch microspheres (MSM), a new superparamagnetic contrast agent, was studied in experimental models of diffuse and focal splenic disease in rats by means of ex vivo relaxometry and in vivo magnetic resonance (MR) imaging. Owing to small differences in unenhanced T1 and T2 values between diffuse lymphoma and normal spleen, MR imaging failed to distinguish tumor-bearing animals from control animals by signal-to-noise ratios (SNRs) obtained with T1- and T2-weighted spin-echo sequences. One hour after injection of 20 μmol/kg MSM, lymphomatous spleen showed significantly (P <.001) reduced enhancement relative to normal splenic tissue. As a result, animals with diffuse lymphoma (SNR: 10.3 ± 1.7) could be easily differentiated from control animals (SNR: 5.5 ± 0.6) on T2-weighted (TR msec/TE msec = 2,000/45) images. In focal splenic disease, MSM produced normal enhancement of nontumorous splenic tissue, whereas relaxation times of tumors were not different before and after contrast agent injection. On T2-weighted images (2,000/45), the tumor-spleen contrast-to-noise ratio increased from (4.8 ± 1.6 to 21.8 ± 1.9 +354%), improving conspicuity of splenic tumors. The results show that MSM-enhanced MR imaging improves the detection of diffuse and focal splenic disease.     

Solitary hepatic metastasis: Comparison of dynamic contrast-enhanced CT and MR imaging with fat-suppressed T2-weighted,Breath-hold T1-weighted FLASH,and dynamic gadolinium-enhanced FLASH sequences

Twenty consecutive cancer patients with a solitary hepatic metastasis detected with dynamic contrast-material—enhanced computed tomography (CT) who were considered for hepatic resection underwent magnetic resonance (MR) imaging within 18 days after CT. Histologic confirmation was obtained in all lesions. CT depicted 20 solitary lesions. MR imaging showed a solitary lesion in 14 patients, two lesions in three patients, and more than two lesions in three patients, for a total of 37 lesions. Twenty-three lesions less than 2 cm in diameter were missed with CT, and six lesions less than 1.3 cm in diameter were missed with MR imaging. MR imaging was superior to CT in the detection of hepatic metastases on a patient-by-patient basis (P <.01). The results suggest that MR imaging is superior to dynamic contrast-enhanced CT for the detection of hepatic metastases.     

Detection of acute and treated lesions of hepatosplenic candidiasis: comparison of dynamic contrast-enhanced CT and MR imaging.

Dynamic contrast-enhanced computed tomography (CT) was compared with 1.5-T magnetic resonance (MR) imaging with FLASH (fast low-angle shot), gadolinium-enhanced FLASH (Gd-FLASH), and T2-weighted fat-suppression (T2FS) sequences in 11 patients with hematologic malignancies, five with biopsy-confirmed hepatosplenic candidiasis treated with antifungal chemotherapy and six with a clinical history suggestive of acute hepatosplenic candidiasis. CT and MR images were separately interpreted in a prospective fashion. MR imaging showed lesions compatible with candidiasis in the liver in six patients, the spleen in five, and the kidneys in one. CT showed candidiasis-compatible lesions in the liver in three patients and the spleen in one; no renal lesions were shown. Differences between acute and treated candidal lesions were observed. Gd-FLASH images showed the most liver lesions (n = 106), followed by FLASH (n = 85), T2FS (n = 20), and CT (n = 18). MR imaging performed better than CT in distinguishing candidal hepatic lesions from recurrent lymphoblastic lymphoma in one patient and from hepatic infarcts in another. The results suggest that MR imaging may be superior to CT in detecting lesions of hepatosplenic candidiasis.     

Prolonged positive contrast enhancement with Gd-EOB-DTPA in experimental liver tumors: Potential value in tissue characterization

To evaluate the potential of the hepatobiliary magnetic resonance (MR) imaging contrast agent gadolinium EOB-DTPA (ethoxybenzyl diethylenetria-minepentaacetic acid) for the characterization of hepatic tumors, 79 primary and six implanted hepatomas in 38 rats were studied. MR imaging findings after administration of Gd-DTPA (0.3 mmol/kg) and Gd-EOB-DTPA (30 μmol/kg) were correlated with microangiographic and histologic findings. Gd-EOB-DTPA produced a strong liver enhancement, which caused prompt negative contrast enhancement (CE) in all implanted hepatomas and in 77 of 79 primary hepatomas. A positive CE that lasted up to 2 hours was found in two of 79 primary hepatomas, both of which were highly differentiated (grade I) hepatocellular carcinomas (HCCs). The rest were moderately differentiated to undifferentiated HCCs (grades II-IV). Rim enhancement, which corresponded histologically to peritumoral malignant infiltration sequestering normal hepatocytes, was seen around all implanted and some primary hepatomas. Positive tumor CE after administration of Gd-EOB-DTPA in this study is much less frequent but much more specific in comparison with the results of previous studies with manganese-DPDP (N, N′-dipyridoxylethylenediamine-N,N′-diacetate 5,5′-bis[phosphate]). These findings may help further discriminate hepatic tumors.     

Spin-echo and dynamic gadoliniumenhanced flash MR imaging of hepatocellular carcinoma: Correlation with histopathologic findings

Evaluation of histologic subtype and degree of differentiation in hepatocellular carcinoma (HCC) is essential because it affects patient prognosis and treatment planning. To evaluate the histologic subtype of HCC with magnetic resonance (MR) imaging, conventional spin-echo and dynamic studies were correlated with histopathologic and angiographic findings in 72 HCCs. Dynamic MR imaging was performed with the fast low-angle shot (FLASH) technique after administration of gadopentetate dimeglumine. There was considerable overlap in signal intensity between various tumor grades on both T1- and T2-weighted images. On dynamic MR images, the peak contrast enhancement ratio correlated with tumor grade (well-differentiated, 29.5 ± 24.7; moderately differentiated, 63.5 ± 24.1; poorly differentiated, 86.9 ± 26.4) or degree of dilatation of the sinusoidlike vascular space between tumor cells. The maximum contrast-to-noise ratio in tumor (relative to surrounding liver) was achieved within 60 seconds in 45 HCCs (mostly of the trabecular or pseudoglandular type). Enhancement was slight or minimal in 17 tumors (mostly small, well-differentiated tumors). In 10 tumors, the degree of enhancement increased with time, with maximum enhancement in the delayed phase (most frequently in scirrhous HCC). These dynamic patterns correlated with angiographic findings. These data indicate that the degree and pattern of enhancement on dynamic MR images reflect tumor differentiation and architecture of HCC.     

MR portography: Preliminary comparison with CT portography and conventional MR imaging

Magnetic resonance (MR) imaging with arterial portography (MRAP) was compared with computed tomography with arterial portography (CTAP) and conventional MR imaging for preoperative evaluation of hepatic masses in eight patients (nine studies). Twenty contiguous, 10-mm-thick-section CTAP images were obtained. MR imaging included T1- and T2-weighted spin-echo and fast multiplanar SPGR (spoiled gradient-recalled acquisition in the steady state) techniques. For MRAP, 0.1 mmol/kg gadopentetate dimeglumine was injected into the superior mesenteric artery. Portographic-phase, 8-mm-thick-section, axial SPGR images were first obtained, followed by “systemic phase” SPGR images. Lesions were seen best on the portographic-phase MRAP images and were less conspicuous on the systemic-phase MRAP, CTAP and conventional MR images. Of 19 visualized lesions, 18 were seen with MRAP; however; five subcentimeter lesions seen with MRAP were not seen with conventional MR imaging or CTAP. Systemic recirculation of iodinated contrast material from the bolus and from previous angiography is a potential limitation of CTAP. For both CTAP and MRAP, optimal results are expected if all images are obtained during a single breath hold, within seconds of the onset of contrast agent administration.     

Contrast-enhanced MR imaging of the liver: Comparison between Gd-BOPTA and mangafodipir

The purpose of the study was to evaluate the MR contrast agents gadolinium benzyloxypropionictetro-acetate (Gd-BOPTA) and Mangafodipir for liver enhancement and the lesion-liver contrast on T1W spin-echo (SE) and gradient-recalled-echo (GRE) images. Fifty-one patients (three groups of 17 patients each) with known or suspected liver lesions were evaluated with T1W SE (300/12) and GRE (77-80/2.3-2.5/80°) images before and after intravenous (IV) Gd-BOPTA (0.1 or 0.05 mmol/kg) or Mangafodipir (5 μmol/kg) in phase II to III clinical trials. Quantitative analysis by calculating liver signal-to-noise ratio (SNR), lesion-liver contrast-to-noise ratio (CNR), and spleen-liver CNR was performed. Liver SNR and spleen-liver CNR were always significantly increased postcontrast. SNR was highest after application of 0.1 mmol/kg Gd-BOPTA (51.3 ± 3.6, P < .05). CNR was highest after Mangafodipir (?22.6 ± 2.7), but this was not significantly different from others (P = .07). Overall, GRE images were superior to SE images for SNR and CNR. Mangafodipir and Gd-BOPTA (0.1 mmol/kg) provide equal liver enhancement and lesion conspicuity postcontrast. By all criteria, contrast-enhanced T1-weighted GRE were comparable to SE images.     

Sclerosed liver hemangioma mimicking malignant tumor at MR imaging: Pathologic correlation

This case report illustrates atypical magnetic resonance (MR) imaging findings in a liver hemangioma mimicking a malignant lesion—lower signal intensity than cerebrospinal fluid on T2-weighted spin-echo images and lack of early enhancement on dynamic contrast material—enhanced gradient-echo images. Pathologic analysis demonstrated nearly total replacement of the vascular cavities by dense fibrous tissue. In this rare, sclerosed form, this lesion could not be defined as a hemangioma with MR imaging.     

Hepatic parenchymal hyperperfusion abnormalities detected with multisection dynamic MR imaging: Appearance and interpretation

On arterial-dominant-phase images in multisection dynamic MR imaging, early-enhancing areas that are perfusion abnormalities rather than tumor deposit are sometimes encountered. The purpose of this article was to determine the frequency, location, and appearance of these hepatic parenchymal hyperperfusion abnormalities and to discuss possible causes of these abnormalities. Multisection dynamic MR images obtained in 415 patients with suspected hepatobiliary diseases were reviewed for the presence of hyperperfusion abnormalities. A total of 96 hyperperfusion abnormalities were identified in 88 (21%) of 415 patients. They were characterized from their shape, distribution, or location as lobar or segmental (n = 36 [38%]), subsegmental (n = 32 [33%]), or subcapsular (n = 28 [29%]) hyperperfusion abnormalities. Presumable etiologies were considered as follows: (a) compression, obstruction, or ligation of the portal vein; (b) siphoning effect by tumor; (c) aberrent cystic venous drainage; (d) percutaneous ethanol injection; (e) percutaneous needle biopsy; (f) rapid drainage by the subcapsular vein; or (g) cirrhosis or unknown. A significant percentage of patients had hepatic hyperperfusion abnormalities. Familiarity with these hyperperfusion abnormalities on multisection dynamic MR images is important to prevent false-positive diagnoses.     

Diagnosis of fatty liver with MR imaging.

The diagnosis of fatty liver with magnetic resonance (MR) imaging was evaluated in experimental rat models of simple fatty infiltration and fatty liver with hepatocellular injury. T1 and T2 were measured ex vivo and correlated with the histologic degree of fatty infiltration. Enhancement of fatty liver with four different cells-specific contrast agents was studied with ex vivo relaxometry and in vivo MR imaging. Quantitative analysis of conventional and chemical shift MR images was correlated with biochemically determined fat content of the liver. Diet-induced simple fatty infiltration of the liver caused a decrease in T1 of 15%, whereas the T1 of L-ethionine-induced fatty liver with hepatocellular injury increased by 12%. T2 showed a positive correlation with the degree of fatty infiltration in both models. Cell-specific hepatobiliary contrast agents showed the same liver uptake and relaxation enhancement in fatty livers as in normal livers. Conventional T1-weighted images and chemical shift images showed good correlation (r = .83 and .80, respectively) between signal intensity and the degree of fatty infiltration. However, only chemical shift imaging was reliable in the diagnosis of fatty liver.     

MR imaging of myositis ossificans: Variable patterns at different stages

Five patients with a palpable mass at presentation underwent magnetic resonance (MR) imaging. The final diagnosis was myositis ossificans (MO). MR imaging features, particularly after injection of gadopentetate dimeglumine, mimicked those of an inflammatory mass or neoplasm. The lesions were excised in three patients, and the Images were correlated with histologic findings. Three different appearances were noted on MR images, corresponding to the stages of maturation of MO. Two cases Involved early-stage lesions, and Tl-weighted MR images showed a mass with homogeneous intermediate signal intensity. Both lesions showed rim enhancement after contrast agent injection and high signal intensity on T2-weighted images. Pathologic specimens demonstrated stroma with masses of spindle cells in which osteoid production was interspersed. The enhanced rim of the lesion mimicked the expected MR appearance of an abscess or necrotic tumor. Areas of enhancement in adjacent muscle were also seen on postcontrast T1-weighted images. Intermediate-stage MO was present in one case; there was evidence of a thin rim of calcification on plain radiographs and fatty changes in the lesion on T1-weighted Images, corresponding with histologic findings. One case of a mature lesion showed a considerable degree of peripheral calcification both on MR images and at histology. MR imaging is nonspecific in the diagnosis of early-stage MO.