Alexandre Laurent

Embolization of hepatocellular carcinoma with drug-eluting beads: Doxorubicin tissue concentration and distribution in patient liver explants

BACKGROUND & AIMS To follow the local tissue delivery of doxorubicin in HCC explants from patients embolized with drug-eluting beads and to compare it with histologic modifications. METHODS Six patients with HCC underwent chemoembolization with doxorubicin-eluting beads (caliber 100-300 μm, dose 75-150 mg) followed by liver transplantation at different time points (8 h to 36 days). On sections of the explanted liver, the tissue concentration of doxorubicin was determined radially around bead-occluded vessels with microspectrofluorimetry. The intra/peritumoral location of the beads and the modifications of the surrounding tissue were determined on an adjacent hematein-eosin-saffron-stained section and compared to drug measurements. RESULTS Doxorubicin was detected in the tissue surrounding the beads at all times of explantation. The drug impregnates an area of at least 1.2 mm in diameter around the occluded vessel. The tissue concentration of drug ranges from 5 μM at 8 h to 0.65 μM at 1 month. In patient transplanted at 8 h, no major tissue modification was observed and we found 42% of the beads occluding intratumoral vessels. Drug concentration was not different around intratumoral and peritumoral occluded vessels. After 9-14 days, necrosis was present around 37% of vessels and at 32-36 days, around 40% of vessels. Necrotic tissue was associated with a deeper penetration and a higher concentration of the drug than non necrotized areas, though statistically significant only at 32-36 days. CONCLUSIONS Doxorubicin-eluting beads provide a sustained delivery of drug for a period of 1 month and local tissue concentrations above cytotoxic threshold in HCC-bearing livers.

Arterial distribution of calibrated tris-acryl gelatin and polyvinyl alcohol microspheres in a sheep kidney model.

Objective:The objective of this study was to compare the repartition in the renal arterial vasculature of tris-acryl gelatin microspheres (TGMS) and polyvinyl alcohol microspheres (PVAMS) of 3 calibers (500–700, 700–900, and 900–1200 μm). Materials and Methods:Twelve kidneys from 6 adult sheep were embolized and histologically analyzed. The number and size of microspheres and vessels were measured, as well as the deformation of TGMS and PVAMS, and the histologic location according to a classification in 5 zones of the kidney. Results:Two hundred eighty-four vessels were measured. The diameter of the occluded vessels increased when the caliber used for embolization was larger for TGMS and for PVAMS (P < 0.0001, each). The location of TGMS and PVAMS within the vasculature was different for each caliber, because PVAMS blocked significantly more distally than TGMS (P < 0.0001 each). The deformation within the tissue was greater for PVAMS (18.0 ± 12.3%) than for TGMS (9.0 ± 8.3%) in general (P < 0.001) and for each caliber of injected microspheres (P < 0.001 each). Conclusion:The repartition of a spherical embolic agent in a given vascular network can be influenced by its size and also by its deformation within the vascular bed.

Location of vessel occlusion of calibrated tris-acryl gelatin microspheres for tumor and arteriovenous malformation embolization.

PURPOSE To evaluate (i). the presence and number of calibrated tris-acryl gelatin microspheres (TGMS) in targeted organs after embolization of tumors or arteriovenous malformations (AVMs) and (ii). the possible correlations among the size of TGMS used for embolization, the size of TGMS found in specimens, and the size of the occluded vessels. MATERIALS AND METHODS Histologic slides were reviewed of 92 specimens from 80 patients with primarily head and neck tumors or AVMs operatively treated after embolization with TGMS of various sizes (40-120 microm, 100-300 microm, 300-500 microm, 500-700 microm, 700-900 microm, and 900-1200 microm). The diameters of the vessels containing TGMS, the size of TGMS, and the thickness of the inflammatory reactions developed around them were measured, and the location of the microspheres was recorded. RESULTS TGMS were found in 88% of the specimens; 1985 embolized vessels containing TGMS were analyzed. The median number of TGMS per vessel was one (mean +/- SD, 3.1 +/- 6.9). The diameter of the occluded vessels increased significantly (P <.0001) with increased size of TGMS used for embolization. In tumors, 92% of the occluded vessels were located inside the tumor. CONCLUSION There is an obvious correspondence between the size of the TGMS used for embolization and the diameter of the occluded vessels. This correlation confirms the possibility that the vessels to be occluded can be precisely targeted with the use of a proper TGMS size range.

MR temperature measurement in liver tissue at 0.23 T with a steady-state free precession sequence.

MRI can be used for monitoring temperature during a thermocoagulation treatment of tumors. The aim of this study was to demonstrate the suitability of a 3D steady‐state free precession sequence (3D Fast Imaging with Steady‐State Precession, 3D TrueFISP) for MR temperature measurement at 0.23 T, and to compare it to the spin‐echo (SE) and spoiled 3D gradient‐echo (3D GRE) sequences. The optimal flip angle for the TrueFISP sequence was calculated for the best temperature sensitivity in the image signal from liver tissue, and verified from the images acquired during the thermocoagulation of excised pig liver. Factors influencing the accuracy of the measured temperatures are discussed. The TrueFISP results are compared to the calculated values of optimized SE and 3D GRE sequences. The accuracy of TrueFISP in the liver at 0.23 T, in imaging conditions used during thermocoagulation procedures, is estimated to be ±3.3°C for a voxel of 2.5 × 2.5 × 6 mm3 and acquisition time of 18 s. For the SE and GRE sequences, with similar resolution and somewhat longer imaging time, the uncertainty in the temperature is estimated to be larger by a factor of 2 and 1.2, respectively. Magn Reson Med 47:940–947, 2002.

Fibrinogen binding and platelet retention: Relationship with the thrombogenicity of catheters

One of the major problems in the use of catheters is their thrombogenicity, since the embolization of clots near the central nervous system or the coronary arteries can cause permanent damage. In this work we have compared the in vivo thrombogenicity of four different angiography catheters and their in vitro activation of fibrinogen binding and platelet retention. The thrombogenicity of catheters has been evaluated in angiographic conditions by kinetic evaluation of the reduction of blood flow rate through the catheters. The binding of adhesive proteins (fibrinogen and von Willebrand factor [vWF] was studied in vitro using a direct-ELISA technique after circulation of anticoagulated whole blood through sections of catheters. The retention of platelets was studied in vitro using 111Indium-labelled platelets. Fibrinogen binding and platelet retention both seem to be good predictors of catheter thrombogenicity, fibrinogen being the better of the two. The most thrombogenic material has the highest fibrinogen and platelet retention rate. This study also confirms the inefficiency of albumin precoating for the prevention of fibrinogen deposition. The determination of fibrinogen deposition by direct-ELISA technique and platelet retention rate is very useful for preclinical testing of catheters.

Complement activation by substituted polyacrylamide hydrogels for embolisation and implantation

An inflammatory reaction has always been observed in vivo around particles used for therapeutic embolisation. Hydrogel microspheres based on Trisacryl, prepared by polymerisation of N-acryloyl-2-amino-2-(hydroxymethyl)-1,3-propanediol in the presence of a crosslinking agent, are amongst the best materials for such a purpose. The aim of this work was to evaluate in vitro the complement-activating capacity of the OH-bearing Trisacryl particles either microporous, or macroporous, or partially substituted with carboxylate, or diethylaminoethyl, or sulphonate groups, in order to be able to decrease the inflammatory reaction in vivo. Complement was activated in the presence of Trisacryl, but about seven times less than in the presence of Sephadex, despite a quasi-similar density in OH groups, and more than two times less than in the presence of hydroxymethylated polystyrene despite a higher OH density. This demonstrates that not only OH density, but also other features linked to the type of polymeric backbone, are involved in complement activation by OH-bearing polymeric surfaces. The microporous and macroporous particles activated complement at a similar level when crushed and a slight increase was observed on the rough surface of the macroporous microspheres, but the presence of the macropores did not increase complement activation. Concerning the effects of substituting groups on Trisacryl, a clear decrease in the complement activation has been found only in the presence of sulphonate groups.

MR monitoring of laser-induced lesions of the liver in vivo in a low-field open magnet: temperature mapping and lesion size prediction

The aims of this study were, firstly, to monitor temperature with magnetic resonance (MR) during laser ablations performed in pig livers in vivo in a low‐field open scanner (0.23T) and, secondly, to study the feasibility of lesion size prediction. Spin‐echo (SE) images of 29 sec acquired during laser applications allowed calculation of temperature maps using T1 and M0 temperature sensitivity. Temperature was also measured with thermocouples. Images of prediction of tissue damage were calculated using temperature maps and Arrhenius model. T2W sequences were acquired after the ablations. Animals were sacrificed immediately. Lesions were photographed macroscopically. Lesion surfaces were measured and compared in T2W images, temperature images, damage prediction images, and macroscopic pictures. A correlation exists between temperature measured with MR and with thermocouples (ρ = 0.878; P < 0.001, Spearman test). Mean surface of predicted damaged tissue is consistent with mean early necrosis measured in macroscopic pictures. Early T2W images underestimate mean necrosis size. J. Magn. Reson. Imaging 2001;13:42–49.

Elasticity and viscoelasticity of embolization microspheres.

The present study investigates the mechanical properties of three embolization microspheres (E-ms): tris-acryl gelatin microspheres (TG-ms), acrylamido polyvinyl alcohol microspheres (APVA-ms), and polyphosphazene-coated polymethylmethacrylate microspheres (PP-PMMA-ms). Compression and relaxation tests were performed on monolayers of particles and their Youngs moduli and relaxation half times (RHTs) were determined. The elasticity of E-ms was evaluated by applying Hertz theory with the assumptions of incompressibility and a Poissons ratio of 0.5. The Youngs moduli of TG-ms, APVA-ms, and PP-PMMA-ms were 39.6±5.05 kPa, 18.8±4.00 kPa, and 13.6±1.98 kPa, respectively. The RHTs of TG-ms, APVA-ms, and PP-PMMA-ms were 52.3±5.56 s, 59.1±8.16 s, and 31.0±7.01 s, respectively. TG-ms have a high rigidity and deform slightly under a sustained compression since they have a high elasticity. PP-PMMA-ms are soft and deform a lot under sustained compression. They are more viscous than the other two microspheres. APVA-ms have intermediate material properties, having the same low rigidity as PP-PMMA-ms and being more elastic than TG-ms.

Arterial blood supply to the uterus in nonpregnant sheep: a pertinent model for clinical practice?

Pelage J-P, Laurent A, Bonneau M, et al. Arterial blood supply to the uterus in nonpregnant sheep: A pertinent model for clinical practice? Invest Radiol 2001;36:721–725. rationale and objectives. Our goal was to study the arterial supply to the sheep uterus to compare its similarity with that of women and to evaluate the interest of this animal model for training in uterine artery embolization. methods. Ten nonpregnant sheep underwent aortography and selective study of the ovarian, internal iliac, uterine, and vaginal arteries. results. The uterus was supplied mainly by the uterine arteries in all sheep. The ovarian artery, which was identified in five sheep, had a thin anastomosis with the ipsilateral uterine artery at the tubal junction. The vaginal artery provided blood flow to the inferior part of the cervix and anastomosed with the ipsilateral uterine artery. conclusions. Because uterine vascularization of nonpregnant sheep is similar to that of women, the sheep represents an appropriate model for experimental uterine artery embolization. This model should be used for interventional radiologists in training not familiar with endovascular navigation inside pelvic arteries.

Poly(ethylene glycol) methacrylate hydrolyzable microspheres for transient vascular embolization.

Poly(ethylene glycol) methacrylate (PEGMA) hydrolyzable microspheres intended for biomedical applications were readily prepared from poly(lactide-co-glycolide) (PLGA)-poly(ethylene glycol) (PEG)-PLGA crosslinker and PEGMA as a monomer using a suspension polymerization process. Additional co-monomers, methacrylic acid and 2-methylene-1,3-dioxepane (MDO), were incorporated into the initial formulation to improve the properties of the microspheres. All synthesized microspheres were spherical in shape, calibrated in the 300-500 μm range, swelled in phosphate-buffered saline (PBS) and easily injectable through a microcatheter. Hydrolytic degradation experiments performed in PBS at 37 °C showed that all of the formulations tested were totally degraded in less than 2 days. The resulting degradation products were a mixture of low-molecular-weight compounds (PEG, lactic and glycolic acids) and water-soluble polymethacrylate chains having molecular weights below the threshold for renal filtration of 50 kg mol(-1) for the microspheres containing MDO. Both the microspheres and the degradation products were determined to exhibit minimal cytotoxicity against L929 fibroblasts. Additionally, in vivo implantation in a subcutaneous rabbit model supported the in vitro results of a rapid degradation rate of microspheres and provided only a mild and transient inflammatory reaction comparable to that of the control group.