Frank J. Londy

Anti-P-selectin antibody decreases inflammation and thrombus formation in venous thrombosis

PURPOSE Venous thrombosis and inflammation are interrelated. P-selectin contributes to activation of leukocyte-mediated inflammation. Therefore, we hypothesized that the neutralization of P-selectin would decrease vein wall inflammation and thrombosis. METHODS Twelve baboons underwent infrarenal inferior vena caval balloon occlusion to induce thrombosis. Two groups of four baboons received neutralizing intravenous anti-P-selectin antibody (PSab) GA6 or CY1748 before occlusion and at days 2 and 4. Four baboons received saline control injections. One baboon per group was killed at days 2, 6, and 13, and at 2 months. Analysis included phlebography, ultrasound, gadolinium (Gd)-enhanced magnetic resonance venography (reflecting vein wall inflammation), and histologic, morphometric, and protein evaluation of the vein wall. Thrombus presence or absence was assessed. RESULTS By day 2 in PSab baboons, vein wall Gd enhancement was decreased in the mid-inferior vena cava and the right iliac vein (p < 0.05; GA6 vs control baboons), normalizing by 2 months. The mid-inferior vena cava revealed fewer neutrophils and total leukocytes in PSab baboons; however, for GA6 in the right iliac vein these decreases were not present despite the absence of Gd enhancement; they were decreased with CY1748. PSab baboons demonstrated significantly less thrombus than control baboons (p < 0.01, GA6 and CY1748 vs control baboons). CONCLUSIONS Anti-P-selectin antibody decreases vein wall inflammation and thrombus formation. Inhibition of P-selectin may be useful in venous thrombosis prophylaxis.

Multi-system repeatability and reproducibility of apparent diffusion coefficient measurement using an ice-water phantom

To determine quantitative quality control procedures to evaluate technical variability in multi‐center measurements of the diffusion coefficient of water as a prerequisite to use of the biomarker apparent diffusion coefficient (ADC) in multi‐center clinical trials.

Diffusion Coefficient Measurement Using a Temperature-Controlled Fluid for Quality Control in Multicenter Studies

To present the use of a quality control ice‐water phantom for diffusion‐weighted magnetic resonance imaging (DW‐MRI). DW‐MRI has emerged as an important cancer imaging biomarker candidate for diagnosis and early treatment response assessment. Validating imaging biomarkers through multicenter trials requires calibration and performance testing across sites.

Venous thrombosis prophylaxis by inflammatory inhibition without anticoagulation therapy

OBJECTIVE This study was performed to determine the effectiveness of recombinant P-selectin glycoprotein ligand Ig (rPSGL-Ig) pretreatment to decrease thrombosis and inflammation in experimental venous thrombosis. rPSGL-Ig, a unique mucin-like glycoprotein, has a high affinity for P-selectin. METHODS Twelve juvenile baboons underwent inferior vena cava (IVC) thrombosis with temporary 6-hour IVC balloon occlusion. Before balloon placement, the animals received rPSGL-Ig (4 mg/kg; n = 8) or saline solution for control (n = 4). The animals underwent evaluation with duplex ultrasound scan imaging, magnetic resonance venography (MRV), phlebography, coagulation profile, and tissue analysis at death for cytokines and vein wall leukocyte morphometrics. With the MRV results, thrombus development, thrombus resolution, and inflammation (gadolinium; square millimeters of enhancement) were assessed. RESULTS Each animal provided two time points for evaluation (days 2 and 6 after balloon occlusion). A significant decrease in IVC thrombosis between balloons was found in the rPSGL-Ig animals (1 of 16) versus the control animals (5 of 8; P <.01). The MRV results showed significantly less enhancement in the rPSGL-Ig animals at days 2 and 6 (P <.05). Spontaneous thrombus resolution (including balloon sites) was significantly greater from day 2 to day 6 in the rPSGL-Ig animals versus the control animals (23% vs 2%; P <.001), without pulmonary embolism. Lower interleukin-8, platelet factor IV, and monocyte chemotactic protein-1 levels were found in rPSGL-Ig vein walls without significant differences in vein wall leukocyte morphometrics. There were significantly lower D-dimer levels in the rPSGL-Ig-treated animals (P <.05), but there were no differences in measurements of coagulation. Adequate circulating rPSGL-Ig levels were documented. CONCLUSION Pretreatment with rPSGL-Ig results in: (1) a significant inhibition of thrombosis and vein wall inflammation; (2) a decrease in vein wall cytokine expression; and (3) a promotion of thrombus resolution. Inflammatory inhibition by rPSGL-Ig without anticoagulation therapy provides effective venous thrombosis prophylaxis in experimental venous thrombosis.

Viral IL-10 Gene Transfer Decreases Inflammation and Cell Adhesion Molecule Expression in a Rat Model of Venous Thrombosis

Post-thrombotic inflammation probably contributes to chronic venous insufficiency, and little effective treatment exists. IL-10 is an anti-inflammatory cytokine that previously has been shown to decrease perithrombotic inflammation and thrombosis. We investigated in a rat model whether local expression of viral IL-10 (vIL-10) in a segment of vein that undergoes thrombosis would confer an anti-inflammatory effect and how this effect might be mediated. Rats underwent inferior vena cava isolation, cannulation, and instillation of saline or adenovirus encoding either β-galactosidase or vIL-10. Two days after transfection, thrombosis was induced, 2 days after this the rats underwent gadolinium (Gd)-enhanced magnetic resonance venography exam, and the vein segments were harvested. Tissue transfection was confirmed by either RT-PCR of vIL-10 or positive 5-bromo-4-chloro-3-indolyl β-d-galactopyranoside (X-Gal) staining. vIL-10 significantly decreased both leukocyte vein wall extravasation and area of Gd enhancement compared with those in controls, suggesting decreased inflammation. Immunohistochemistry demonstrated decreased endothelial border staining of P- and E-selectin, while ELISA of vein tissue homogenates revealed significantly decreased P- and E-selectin and ICAM-1 levels in the vIL-10 group compared with those in controls. Importantly, native cellular IL-10 was not significantly different between the groups. However, neither clot weight nor coagulation indexes, including tissue factor activity, tissue factor Ag, or von Willebrand factor levels, were significantly affected by local vIL-10 expression. These data suggest that local transfection of vIL-10 decreases venous thrombosis-associated inflammation and cell adhesion molecule expression, but does not directly affect local procoagulant activity.

Prophylactic P-selectin inhibition with PSI-421 promotes resolution of venous thrombosis without anticoagulation

P-selectin inhibition has been evaluated as a therapeutic for prevention and treatment of venous thrombosis. In this study, a novel oral small-molecule inhibitor of P-selectin, PSI-421, was evaluated in a baboon model of stasis induced deep vein thrombosis (DVT). Experimental groups included i) primates receiving a single oral dose of 1 mg/kg PSI-421 two days prior and continued six days after thrombosis (n = 3); ii) primates receiving a single daily subcutaneous dose of 0.57 mg/kg enoxaparin sodium two days prior and continued six days post thrombosis (n = 3); and iii) primates receiving no treatment (n = 3). PSI-421 treated primates had greater percent vein reopening and less vein wall inflammation than the enoxaparin and controls at day 6. Microparticle tissue factor activity (MPTFA) was significantly lower in the animals receiving PSI-421 immediately after thrombosis (T+6 hours day 0) suggesting lower potential for thrombogenesis in these animals. PSI-421 also reduced soluble P-selectin levels versus controls at T+6 hours day 0, day 2 and 6. Experimental animals in any group showed no adverse effects on coagulation. This study is the first to demonstrate a reduction in MPTFA associated with vein reopening and reduced vein inflammation due to oral P-selectin inhibition in a baboon model of DVT.

Multiphase-multistep gadolinium-enhanced MR angiography of the abdominal aorta and runoff vessels.

Schoenberg SO, Londy FJ, Licato P, et al. Multiphase-multistep gadolinium-enhanced MR angiography of the abdominal aorta and runoff vessels. Invest Radiol 2001;36:283–291. rationale and objectives. To optimize three-dimensional gadolinium magnetic resonance angiography (3D-Gd-MRA) of the aorta and runoff vessels by addressing fundamentally different requirements for temporal and spatial resolution in a single semiautomated examination. methods.The technique was designed to obtain pure arterial-phase 3D-Gd-MR angiograms with adequate spatial resolution for each station while avoiding incomplete enhancement due to delayed filling vessels as well as venous overlay. During gadolinium-chelate infusion, a breath-held multiphase 3D-Gd-MRA scan was initiated in the aorta by automatic triggering, followed by automatic table movement. The acquisition was tailored to the vessels of interest by tilting of the 3D volumes. A spatial resolution of 1.7 × 1.2 × 0.8 mm in the calves was achieved by use of elliptical-centric k-space reordering. Signal-to-noise ratio was maximized with a 12-element peripheral vascular coil. Twelve patients with peripheral vascular disease were studied. results.In cases of aortic occlusive disease (n = 2), dissections (n = 3), or aneurysms (n = 4), substantially delayed fill-in of reconstituted arteries, false lumens, or aneurysmal segments occurred, which was detected only on the later 3D-Gd-MRA phase. High-resolution arterial-phase scans in the calves were obtained, with only one case of substantial venous overlay. Correlation to digital subtraction angiography revealed excellent agreement of pathological findings. conclusions.Multiphase-multistep 3D-Gd-MRA reduces the limitations of standard 3D-Gd-MRA techniques with respect to anatomic coverage, spatial resolution, and nonuniform arterial vessel enhancement.

Arterial-phase three-dimensional gadolinium magnetic resonance angiography of the renal arteries. Strategies for timing and contrast media injection: original investigation.

RATIONALE AND OBJECTIVES The authors review different imaging and contrast-media infusion strategies for arterial-phase three-dimensional (3D) gadolinium-enhanced magnetic resonance angiography (Gd-MRA). METHODS The influence of physicochemical factors on the infusion of contrast media, including viscosity, flow rate, inline pressure, and cannula size, is assessed. The combination of manual or automated contrast-media administration with timing-dependent or -independent 3D Gd-MRA techniques is reviewed regarding the aspects of effectiveness, robustness, image quality, and costs. RESULTS For effective bolus delivery with high flow rates, the type and temperature of the contrast media, the size of the cannula, and an immediate saline flush must be considered. Timing-dependent techniques based on a test bolus and using automated contrast-media infusion as well as timing independent techniques such as MR SmartPrep or multiphase 3D Gd-MRA by using a manual injection with a SmartSet tubing set, are all effective procedures for arterial phase 3D Gd-MRA. CONCLUSIONS Manual contrast-media injection with a tubing set can be used for timing-independent MRA techniques. The multiphase 3D Gd-MRA approach seems to be favorable for different MR systems, robustness, and speed.

Preoperative MR Angiography in Free Fibula Flap Transfer for Head and Neck Cancer: Clinical Application and Influence on Surgical Decision Making

OBJECTIVE We review the fibular free flap surgical procedure to illustrate the usefulness of preoperative lower limb MR angiography and to show how calf vascular anatomy on MR angiography affects patient surgical management. CONCLUSION With its high positive predictive value and sensitivity, preoperative MR angiography can improve the chances of a successful outcome at the recipient mandibular site. It provides the reconstructive surgeon with a road map, revealing vascular anomalies or disease that could alter or contraindicate surgery.

Resolution of venous thrombosis using a novel oral small-molecule inhibitor of P-selectin (PSI-697) without anticoagulation

P-selectin inhibition has been shown to decrease thrombogenesis in multiple animal species. In this study, we show that a novel oral small-molecule inhibitor of P-selectin, PSI-697, promotes thrombus resolution and decreases inflammation in a baboon model of venous thrombosis. Experimental groups consisted of the following: 1) primates receiving a single oral dose of PSI-697 (30 mg/kg) daily starting three days pre-iliac vein balloon occlusion, and continued for six days; 2) primates receiving a single treatment dose of a low-molecular-weight-heparin (LMWH) (1.5 mg/kg) daily starting one day pre-iliac balloon occlusion, and continued for six days; and 3) primates receiving a single oral dose of a vehicle control daily starting three days pre-iliac vein balloon occlusion, and continued for six days. Animals receiving PSI-697, although thrombosed after balloon deflation, demonstrated greater than 80% vein lumen opening over time, with no opening (0%) for vehicle control (p < 0.01). LMWH opening evident after balloon deflation slightly deteriorated over time compared to PSI-697. PSI-697 therapy also significantly decreased vein wall inflammation determined by magnetic resonance venography (MRV). Importantly, this beneficial opening occurred without measured anticoagulation. Animals receiving PSI-697 demonstrated significantly increased plasma D-dimer levels versus LMWH and control animals six hours post thrombus induction (p < 0.01). This study is the first to demonstrate the effectiveness of oral P-selectin inhibition to modify venous thrombogenesis, increase vein lumen opening, and decrease inflammation in a large animal model.