Intraindividual comparison of gadobenate dimeglumine and Ferucarbotran-enhanced MR imaging of hepatocellular carcinoma Peter Fries1 Wolfgang Loytved1 Luigi Grazioli2 Richard Semelka3 Miles Kirchin4 Arno Bücker1 Günther Schneider1 1 Clinic of Diagn. and Interv. Radiology, Saarland University Hospital, Homburg / Germany 2 Radiological Department, University of Brescia, Brescia, Italy 3 Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, USA 4 World Wide Medical & Regulatory Affairs, Bracco Imaging SpA, Milan, Italy

Purpose Hepatocellular carcinoma (HCC) is the most frequent primary malignant liver tumor in adults. While in case of multifocal HCC the therapeutic options and the prognosis are limited, solitary HCC may potentially cured by surgical resection. In this context, an accurate imaging modality for the detection and characterization of focal liver lesions is crucial for successful patient treatment and care.

Purpose In general, magnetic resonance imaging (MRI) is considered the modality of choice for the detection and characterization of focal liver lesions (FLL). In particular, the use of MR contrast agents is essential for the evaluation of vascularization of the detected lesions. Besides conventional extracellular gadolinium-based contrast agents like Gd-DTPA or Gd-DTPA-BMA, liver-specific contrast agents offer significant advantages.

Purpose Liver-specific contrast agents fall into two broad categories: Gd-based Gd-BOPTA (MultiHance , Bracco, Italy) Gd-EOB-DTPA (Primovist , Schering, Germany) Superparamagnetic iron oxides (SPIO) Ferumoxides (SPIO) (Ferridex, Endorem, Guerbet) Ferucarbotran (USPIO) (Resovist, Schering, Germany)

Purpose Gd-based liver-specific agents: Targeted to hepatocytes Allow for conventional dynamic liver imaging acquiring T1w breath-hold sequences in the arterial, portalvenous and equilibrium phase In addition, imaging in the delayed hepatobiliary phase after CM uptake into functioning hepatocytes and excretion into bile ducts

Purpose SPIO based liver-specific agents: Targeted to Kupffer cells Ultrasmall paramagnetic iron oxides (USPIO, Ferucarbotran) may be used for dynamic liver imaging acquiring T1w sequences as with Gd-agents Delayed imaging will be performed acquiring T2w TSE sequences

Purpose The aim of the presented study was to intra-individually compare Gd-BOPTA (MultiHance) and Ferucarbotran (Resovist) for contrast enhanced MR imaging of the liver in patients with hepatocellular carcinoma.

Methods and Materials Fifteen patients with 59 confirmed (biopsy or follow up) lesions of HCC were included in the study. Each underwent two MRI examinations. The first study was performed with Gd-BOPTA and the second, after an interval of 3 to 7 days, with Ferucarbotran. It was necessary to perform Gd-BOPTA-enhanced imaging first in order to avoid adverse influences on the Gd-BOPTA-enhanced exam caused by the extended residence time of iron oxide particles in the liver.

Methods and Materials Imaging protocol: unenhanced T2w (TSE and HASTE) and T1w (GRE) dynamic T1w GRE sequences after bolus injection of either contrast agent Contrast media doses: Gd-BOPTA (0.05 mmol/kg BW) Ferucarbotran (< 60 kg BW: 486 mg / > 60 kg BW: 756 mg).

Methods and Materials Liver specific phase Gd-BOPTA 45 min - 2 hours p.i. T1w GRE, T1w fs GRE Ferucarbotran 20 min post-injection T2w TSE, T2w HASTE, T1w GRE

Methods and Materials All images were transferred to an external workstation and prepared for blinded off-site evaluation. Blinded evaluation was performed using a dedicated viewer on CD-ROM that automatically displayed images from each patient in a standard fashion. A total of four readings were performed for each patient.

Methods and Materials The order of patient presentation was randomized for each reading and the following image sets were evaluated: Reading 1: unenh. + dynamic after Gd-BOPTA. Reading 2: unenh. + dynamic after Ferucarbotran. Reading 3: unenh. + dynamic + hepatobil. phase after Gd-BOPTA. Reading 4: unenh. + dynamic + Kupffer cell phase after Ferucarbotran

Methods and Materials Evaluation of the data set included the assessment of the total number of lesions detected in each image set. In addition, the size, location and degree of vascularization of each lesion were recorded for subsequent lesion tracking. Finally a definite diagnosis for each lesion was assigned. An exact Fisher test was performed to analyze significant (p<0.05) differences between the two CE-MRI studies.

Results A significant difference was noted between Gd-BOPTA and Ferucarbotran for the detection of HCCs in the dynamic phase alone: Gd-BOPTA: 47/59 Ferucarbotran: 24/59 P = 0.01

Results A significant difference was noted between Gd-BOPTA and Ferucarbotran for the detection of HCCs in the dynamic phase + liver specific phase: Gd-BOPTA: 49/59 Ferucarbotran: 32/59 P = 0.01

Results In two patients HCC were not diagnosed with Ferucarbotran- enhanced but with Gd-BOPTA-enhanced MRI. In two patients HCC were misdiagnosed as metastases using Ferucarbotran. In two patients HCC were rated as metastases with either contrast agent.

Results Diffuse HCC: T2w HASTE T2w TSE T1w unenhanced Unenhanced images show multiple small lesions in both liver lobes.

Results Diffuse HCC: Dynamic Imaging Gd-BOPTA Ferucarbotran Lesions are hypervascular on arterial phase images post Gd-BOPTA, however, with Ferucarbotran vascularization of the lesions can not be evaluated sufficiently.

Results Diffuse HCC: Dynamic Imaging Gd-BOPTA T1w In the equilibrium phase the lesions show a wash-out of contrast medium, in some larger lesions in addition a pseudo-capsule can be seen, indicating HCC.

Results Diffuse HCC: Liver Specific Phase Ferucarbotran Gd-BOPTA T2w HASTE T1w Gd-BOPTA With both contrast agents miliar lesions can be detected, however Ferucarbotran due to missing dynamic information does not allow for a specific DDX. T2w TSE T1w

Results Solitary HCC: T2w HASTE T2w TSE T1w Opposed-phase This solitary HCC in liver segment 4 depicts with high signal intensity on T1w and low SI on T2w sequences due to hemosiderin depositions.

Results Solitary HCC: Dynamic Imaging Ferucarbotran Gd-BOPTA T1w T1w Gd-BOPTA Gd-BOPTA enhanced dynamic images demonstrate the typical findings in HCC, a hypervascular tumor with early CM wash-out and pseudocapsule; these important findings are not obvious with Ferucarbotran due to increased SI of the lesion in T1w images based on the hemosiderin deposition.

Results Solitary HCC: Liver Specific Phase Ferucarbotran Gd-BOPTA T2w HASTE T1w Gd-BOPTA T2w TSE Both the liver-specific phase images with Gd-BOPTA and Ferucarbotran do not allow for a specific diagnosis, since the contrast behavior on unenhanced images interferes with liver specific contrast medium uptake. T1w

Results Well-differentiated HCC: T2w TSE T2w HASTE Unenhanced images demonstrate a large tumor, almost replacing the complete right liver lobe. T1w

Results Well-differentiated HCC: Dynamic Imaging Ferucarbotran Gd-BOPTA The lesion is inhomogeneously hypervascular on arterial phase images post Gd-BOPTA, in distinction, with Ferucarbotran vascularization of the lesions can not be evaluated sufficiently.

Results Well-differentiated HCC: Liver Specific Phase Ferucarbotran T2w HASTE T2w TSE T1w Gd-BOPTA Liver specific images with Gd-BOPTA show contrast media uptake in part of the lesion, indicating well differentiated tumor areas, with Ferucarbotran part of the lesion behaves like normal liver tissue and the total extend of the lesion may be underestimated (arrow). T1w

Conclusion Gd-BOPTA permits detection of significantly more lesions of HCC for both, the dynamic phase imaging alone and the dynamic contrast enhanced imaging with delayed liver specific imaging as compared to Ferucarbotran. This is mainly due to greater sensitivity for the detection of hypervascular lesions during dynamic arterial phase imaging.