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Metabolic syndrome (MS) is becoming the leading risk factor for hepatocellular carcinoma (HCC). HCC development related to MS may occur in advanced or non-advanced liver fibrosis, suggesting specific molecular pathways. Among these pathways, basal inflammatory state and adipokines production are involved. The aim of this study was to evaluate the role of fatty acid-binding protein 4 (FABP4). In this study, we demonstrate the specific overexpression of FABP4 in human HCC samples from patients with MS compared to other risk factors for chronic liver disease with FABP4 expression restricted to peritumoral endothelial cells. In vitro, glucose, insulin, VEGFA and hypoxia upregulated endothelial FABP4, which was reversed by metformin through mTOR pathway inhibition. FABP4 exerts oncogenic effects on hepatoma cell lines by upregulating the angiogenesis gene signature and pathways involved in the cell cycle, leading to increased cell proliferation and migration, and downregulating HIF1 pathway; effects were reversed in the presence of a specific FABP4 inhibitor (BMS309403). We showed the role of microvesicles as FABP4 vectors between endothelial and tumor cells. In vivo, BMS309403 significantly reduces tumor growth in heterotopic and orthotopic xenografted mice model. In conclusion, this study demonstrates the emerging oncogenic role of liver endothelial cells through FABP4 in HCC related to MS, and highlights new anti-neoplastic mechanism of metformin.

Pancreaticopleural fistula secondary to chronic pancreatitis is a rare cause of recurrent pleural effusion. The demonstration of the fistula with endoscopic retrograde pancreatography and CT is invasive or limited. We [...]

MR imaging findings in patients with chronic liver diseases show that liver fibrosis is independently associated with shear modulus and elasticity, while liver steatosis has a stronger association with diffusion coefficients.

Interstitial collagen formation and transformation of the fenestrated hepatic sinusoids into continuous capillaries are major ultrastructural changes that occur in liver cirrhosis and fibrosis. These modifications lead to progressive restriction of blood–liver exchanges. The purpose of our study was to evaluate the permeability changes in a model of hepatic fibrosis by using dynamic computed tomography (CT) enhanced with contrast agents of different molecular masses. Dynamic single-section CT of the liver was performed after intravenous bolus administration of a low-molecular-mass contrast agent (iobitridol) and an experimental high-molecular-mass agent (P840) in normal control rabbits and in rabbits with hepatic fibrosis. Hepatic, aortic and portal venous time–density curves were fitted with a dual-input one-compartmental model to calculate the hepatic mean transit time and distribution volume of the contrast agents. In the rabbits with liver fibrosis, the mean transit time of the high-molecular-mass agent was shorter than that of the low-molecular-mass agent (10.0±1.8s and 12.0±1.2s respectively; P<0.05). The distribution volume accessible to the high-molecular-mass agent was also smaller (22.2±4.8% compared with 32.0±6.7%; P<0.01). In the normal rabbits, the mean transit times of the high- and low-molecular-mass agents did not differ significantly, and nor did their distribution volumes. Our results demonstrate decreased sinusoidal permeability for the high-molecular-mass agent P840 in a model of hepatic fibrosis. Non-invasive assessment of permeability changes in liver fibrosis can be performed with dynamic CT and contrast agents of different molecular masses.

Ferumoxtran, an ultrasmall superparamagnetic iron oxide particle, can be located in several tissue compartments in the liver, namely the extracellular space (blood and interstitium), reticuloendothelial cells, and possibly hepatocytes. To better understand the compartmental distribution of ferumoxtran in the liver, we performed a longitudinal study in the rat using microscopy and magnetic resonance imaging. At light microscopy, no substantial cellular uptake of ferumoxtran was observed before one hour after injection. With a dose of 15 μmol Fe/kg, the number of ferumoxtran particles in the reticuloendothelial cells peaked between one and four hours and with a 150 μmol Fe/kg dose, it peaked between eight and 24 hours. Within hepatocytes, only sparse particles were observed with electron microscopy, at a dose of 150 μmol Fe/kg. Imaging performed up until one hour after ferumoxtran injection showed a significant increase in liver signal intensity on T1‐weighted images. These results suggest that ferumoxtran mainly acts as an extracellular agent for at least one hour in the rat and that reticuloendothelial accumulation peaks at later time points. Substantial uptake within hepatocytes did not occur. J. Magn. Reson. Imaging 2001;13:594–599. © 2001 Wiley‐Liss, Inc.

Various liver diseases lead to significant alterations of the hepatic microcirculation. Therefore, quantification of hepatic perfusion has the potential to improve the assessment and management of liver diseases. Most methods used to quantify liver perfusion are invasive or controversial. This paper describes and validates a non-invasive method for the quantification of liver perfusion using computed tomography (CT). Dynamic single-section CT of the liver was performed after intravenous bolus administration of a low-molecular-mass iodinated contrast agent. Hepatic, aortic and portal-venous time—density curves were fitted with a dual-input one-compartmental model to calculate liver perfusion. Validation studies consisted of simultaneous measurements of hepatic perfusion with CT and with radiolabelled microspheres in rabbits at rest and after adenosine infusion. The feasibility and reproducibility of the CT method in humans was assessed by three observers in 10 patients without liver disease. In rabbits, significant correlations were observed between perfusion measurements obtained with CT and with microspheres (r = 0.92 for total liver perfusion, r = 0.81 for arterial perfusion and r = 0.85 for portal perfusion). In patients, total liver plasma perfusion measured with CT was 112±28 ml·min-1·100 ml-1, arterial plasma perfusion was 18±12 ml·min-1·100 ml-1 and portal plasma perfusion was 93±31 ml·min-1·100 ml-1. The measurements obtained by the three observers were not significantly different from each other (P > 0.1). Our results indicate that dynamic CT combined with a dual-input one-compartmental model provides a valid and reliable method for the non-invasive quantification of perfusion in the normal liver.

The purpose of this study was to compare in the same patients tailored and fixed scanning delays during gadolinium‐enhanced arterial‐phase magnetic resonance imaging of hypervascular liver tumors. Tailored scanning delays were obtained with automated region of interest threshold triggering. A delay of 23 seconds between the start of contrast material injection and imaging was used for fixed delay examinations. Quantitative and qualitative evaluation was performed in 21 patients with normal cardiac function referred for MR assessment of hypervascular liver tumors. In the tailored examinations, the median time delay between the start of contrast material injection and the start of magnetic resonance imaging was 21 seconds (range, 18–34 seconds). The median tumor‐to‐liver contrast during tailored examinations was 19.1 versus 14.7 during fixed delay examinations. This difference, however, was not significant. Similarly, the enhancement in the aorta, the portal vein, the liver, and the tumor did not differ significantly between examinations performed with tailored and fixed delays. It is concluded that in our group of patients with hypervascular liver tumors and normal cardiac function, no significant improvement in tumor‐to‐liver contrast and enhancement during the arterial phase was found when gadolinium‐enhanced magnetic resonance imaging was performed with a tailored scanning delay rather than with a fixed delay. J. Magn. Reson. Imaging 2000;11:244–249. © 2000 Wiley‐Liss, Inc.

To analyze the optimal timing strategy for the detection of hypervascular liver tumors during the arterial phase of magnetic resonance (MR) imaging, a test examination after injection of 2 mL of gadopentetate dimeglumine was performed in 47 patients. The time course of the tumor‐to‐liver contrast‐to‐noise ratio (CNR) for all studies together was determined relative to the start of injection, the time of peak aortic enhancement, and the time of peak enhancement in the tumor. All studies were grouped together and the highest CNR was transiently observed at the time of peak tumor enhancement. This CNR was significantly higher than those observed at fixed delays after peak aortic enhancement. However, the CNRs at peak tumor enhancement ±1.5 seconds did not differ significantly from those obtained after peak aortic enhancement. Finally, the CNRs obtained at fixed delays after the start of injection remained significantly lower. In hypervascular liver tumors, a higher CNR can be obtained during the arterial phase when the MR imaging delay is determined relative to the time of peak enhancement in the tumor or the aorta rather than being fixed after the start of contrast material injection. Timing based on the enhancement profile in the tumor rather than in the aorta should be performed only if rapid MR imaging is available with a time resolution of about 1.5 seconds to image the whole liver.J. Magn. Reson. Imaging 1999;9:562–567. © 1999 Wiley‐Liss, Inc.

The tumor‐to‐liver uptake of two reticuloendothelial agents, namely ferumoxides and technetium‐99m (Tc‐99m) sulfur colloid, was compared in focal nodular hyperplasia (FNH). Twelve patients with FNH who had undergone ferumoxides‐enhanced MR imaging and planar Tc‐99m sulfur colloid scintigraphy within 1 year were included from the study. Fourteen patients with FNH with a diameter larger than 3 cm were selected for the comparison. The tumor‐to‐liver ferumoxides uptake was calculated and the Tc‐99m sulfur colloid uptake was assessed visually. Ferumoxides uptake was observed in all but one patient with FNH (mean tumor‐to‐liver ratio = .36). The six tumors showing normal (n= 5) or increased (n= 1) radiocolloid uptake when compared to the liver accumulated more ferumoxides than the eight tumors showing decreased radiocolloid uptake (P< .01). However, in some tumors, no direct relation was observed between ferumoxides and Tc‐99m sulfur colloid uptake. Our observations suggest that ferumoxides uptake might not exactly mimic Tc‐99m sulfur colloid uptake in FNH.

Purpose: To compare the small bowel distribution and safety of a fast ingestion procedure of ferristene to those of the standard ingestion procedure.Material and Methods: Sixty-four patients received 0.5 gl ferristene in 800 ml water. Thirty-four patients of the fast ingestion group ingested ferristene with 20 mg of oral metoclopramide during the course of 30 min before MR imaging and received an i.v. injection of an antiperistaltic agent during the MR study. Thirty patients of the standard group ingested ferristene during the course of 2 h, without additional drugs. Ferristene distribution was assessed by 2 reviewers and adverse events were recorded.Results: More than 50 of the small bowel segments analyzed were filled with ferristene in 30 patients in the fast ingestion group and in 28 patients in the standard ingestion group. One patient in each group experienced nausea andor vomiting. Some bloating or sensation of fullness was reported by 2 patients in the fast ingestion group and by 3 patients in the standard ingestion group.Conclusion: The distribution of ferristene in the small bowel and the safety of the procedure were thus similar in the 2 groups using either a fast ingestion procedure with oral metoclopramide or the more time-consuming standard ingestion procedure.