Rudy Meijer

Targeting of liver tumour in rats by selective delivery of holmium-166 loaded microspheres: a biodistribution study

Abstract. Intra-arterial administration of beta-emitting particles that become trapped in the vascular bed of a tumour and remain there while delivering high doses, represents a unique approach in the treatment of both primary and metastatic liver tumours. Studies on selective internal radiation therapy of colorectal liver metastases using yttrium-90 glass microspheres have shown encouraging results. This study describes the biodistribution of 40-µm poly lactic acid microspheres loaded with radioactive holmium-166, after intra-arterial administration into the hepatic artery of rats with implanted liver tumours. Radioactivity measurements showed >95% retention of injected activity in the liver and its resident tumour. The average activity detected in other tissues was ≤0.1%ID/g, with incidental exceptions in the lungs and stomach. Very little 166Ho activity was detected in kidneys (<0.1%ID/g), thereby indicating the stability of the microspheres in vivo. Tumour targeting was very effective, with a mean tumour to liver ratio of 6.1±2.9 for rats with tumour (n=15) versus 0.7±0.5 for control rats (n=6; P<0.001). These ratios were not significantly affected by the use of adrenaline. Histological analysis showed that five times as many large (>10) and medium-sized (4–9) clusters of microspheres were present within tumour and peritumoural tissue, compared with normal liver. Single microspheres were equally dispersed throughout the tumour, as well as normal liver parenchyma.

The Osteoporosis Prevention and Arterial effects of tiboLone (OPAL) study: design and baseline characteristics

The Osteoporosis Prevention and Arterial effects of tiboLone (OPAL) trial is a three-arm, randomized, placebo-controlled, double-blind study to determine the effect of tibolone 2.5 mg (Org OD 14) and continuous combined conjugated equine estrogens plus medroxyprogesterone acetate (0.625 mg/2.5 mg respectively) on progression of intima-media thickness of the carotid arteries and bone mineral density of the lumbar vertebrae and proximal femur in postmenopausal women. A total of 866 healthy postmenopausal women were recruited in six U.S. centers and five European centers. Duplicate carotid ultrasound examinations of the common carotid artery, the carotid bifurcation, and the internal carotid artery were performed at baseline. Single measurements of bone mineral density of the lumbar vertebrae and proximal femur were obtained at baseline. After randomization, ultrasound examinations were repeated every 6 months for 36 months following baseline, with a duplicate examination at the end of the study. Bone mineral density was measured every 12 months throughout the trial. The primary outcome is change in mean common carotid intima-media thickness (CIMT), defined as the average of the intima-media thickness measurements performed circumferentially at predefined angles for the near and far wall of 10-mm segments of the right and left distal common carotid arteries. Unique new features of the OPAL study are the specifically developed OPAL ultrasound protocol, yielding highly reproducible CIMT measurements, and the use of two experienced core laboratories for CIMT readings (one in the United States and one in Europe) with one common quality assurance and control program. The OPAL study is a large, placebo-controlled trial evaluating the effects of tibolone, as well as one of the first large randomized studies to determine the effects of continuous combined estrogen-progestin therapy on carotid atherosclerosis in healthy postmenopausal women. The OPAL study results are expected to complement other studies on atherosclerosis progression in healthy postmenopausal women.

Mannheim Consensus on Carotid Intima-Media Thickness: Opposite and Complementary Points of View

Arguments to restrict CIMT measurements in areas free of plaques given in the consensus were that such measurements are ‘easier, more accurate, reproducible and can be analyzed by automated edge detection reading software’. Although true, several multicenter studies with CIMT measurements done in various carotid segments (common, bifurcation, internal), the near and far walls, and that included lesions when these were present, showed that between-visit reproducibility of these CIMT measurements was very high (intraclass correlation coeffi cients 1 0.90, small absolute differences), both with manual tracing [5–8] and with automated edge detection programs [9] .

Asymmetrical distribution of atherosclerosis in the carotid artery: identical patterns across age, race, and gender

Background: Small autopsy studies and clinical practice indicated that carotid atherosclerosis develops in an asymmetrical helical pattern coinciding with regions of low shear stress. We investigated the distribution of carotid atherosclerosis as determined by maximum carotid intima-⊟media thickness (CIMT), to assess if we could confirm this atherosclerotic configuration across various populations with different cardiovascular risk. Methods and results: We used the individual baseline CIMT data from 3364 subjects from four recent international multicentre randomized controlled trials in which the carotid artery was systematically examined using the same ultrasound protocol and method to quantify CIMT. For each subject, circumferential information on the maximum CIMT of the left and right carotid arteries was obtained for the common carotid, bifurcation, and internal carotid artery segments. In each segment (common, bifurcation, internal), mixed modelling was used to study the differences in CIMT between angles, sides, gender, age, race, and studies. Each segment showed a different circumferential CIMT pattern. In all segments there were statistically significant differences between maximum CIMT across circumferential angles (p < 0.001); on average CIMT was highest in the posteromedial wall of the bifurcation and internal carotid segments and in the anterolateral wall of the common carotid segment. This asymmetric circumferential pattern was found to be identical in men and women, in young and old age, in different race groups, and across the studies. Conclusions: We confirmed the asymmetrical helix-like distribution of atherosclerosis in the carotid arteries and expand the evidence by showing that the atherosclerotic configuration is similar across populations with different vascular risks and across gender, age, and race. This has implications for future design of carotid ultrasound studies, as the angle of insonation is an important predictor of maximum CIMT.

Effect of carotid angioplasty and stenting on duplex velocity measurements in a porcine model.

Purpose: To evaluate if there are any differences in duplex ultrasound velocity measurements between native and stented carotid arteries using duplex ultrasound in an animal model. Methods: The common carotid artery of 5 pigs was exposed bilaterally (10 arteries). Diameters and velocities were measured by ultrasound in the proximal, mid, and distal native artery at the intended site of stent implantation. Measurements were repeated after bilateral stent placement (Wallstent versus Precise) under angiographic control. Outcomes of native versus stented arteries and Wallstent versus Precise were statistically compared. Results: Angiographic measurements matched well with duplex-measured diameters. The mean proximal stent diameter (3.5±0.5 mm) was significantly smaller than the native proximal artery diameter (4.2±0.4 mm, p=0.004), mostly due to narrowing of the Wallstent diameter to 3.2±0.5 mm (p=0.009). Proximal, mid, and distal segments of the Wallstents were narrower than those of the Precise stent, and associated peak systolic velocities (PSV) were higher at the 3 locations versus the Precise stent, although the differences were not statistically significant. Wallstent PSVs were higher than in the native artery at the proximal, mid, and distal segments, respectively; again, the differences were not statistically significant. Conclusion: Stent placement caused anatomical and hemodynamic alterations. Narrowings and associated increased velocities were noted. Such alterations, however, were stent-type dependent and did not justify a general approach to new velocity criteria indiscriminately applied to all stents.

CT attenuation measurements are valuable to discriminate pledgets used in prosthetic heart valve implantation from paravalvular leakage

OBJECTIVES Sutures with polytetrafluorethylene (PTFE) felt pledgets are commonly used in prosthetic heart valve (PHV) implantation. Paravalvular leakage can be difficult to distinguish from PTFE felt pledgets on multislice CT because both present as hyperdense structures. We assessed whether pledgets can be discriminated from contrast-enhanced solutions (blood/saline) on CT images based on attenuation difference in an ex vivo experiment and under in vivo conditions. METHODS PTFE felt pledgets were sutured to the suture ring of a mechanical PHV and porcine aortic annulus, and immersed and scanned in four different contrast-enhanced (Ultravist®; 300 mg jopromide ml(-1)) saline concentrations (10.0, 12.0, 13.6 and 15.0 mg ml(-1)). Scanning was performed on a 256-slice scanner with eight different scan protocols with various tube voltage (100 kV, 120 kV) and tube current (400 mAs, 600 mAs, 800 mAs, 1000 mAs) settings. Attenuation of the pledgets and surrounding contrast-enhanced saline were measured. Additionally, the attenuation of pledgets and contrast-enhanced blood was measured on electrocardiography (ECG)-gated CTA scans of 19 patients with 22 PHVs. RESULTS Ex vivo CT attenuation differences between the pledgets and contrast-enhanced solutions were larger by using higher tube voltages. CT attenuation values of the pledgets were higher than contrast-enhanced blood in patients: 420±26 Hounsfield units (mean±SD, range 383-494) and 288±41 Hounsfield units (range 202-367), respectively. CONCLUSIONS PTFE felt pledgets have consistently higher attenuation than surrounding contrast-enhanced blood. CT attenuation measurements therefore may help to differentiate pledgets from paravalvular leakage, and detect paravalvular leakage in patients with suspected PHV dysfunction.

Epicardial ultrasound in off-pump coronary artery bypass grafting: potential aid in intraoperative coronary diagnostics

BACKGROUND In off-pump coronary artery bypass surgery (OPCAB), epicardial ultrasound may aid in several intraoperative dilemmas. The aim of this study was to test a new mini-transducer for intraoperative coronary diagnostics. METHODS A 10 MHz mini-transducer (15 x 6 x 9 mm) was applied epicardially in eight open chest and two closed chest porcine OPCAB procedures (using robotics) and on four postmortem human hearts. The transducer fitted in between the suction pods of the cardiac stabilizer and passed an 11-mm port. RESULTS In the open chest cases the internal mammary arteries (including the side branches) could be visualized totally (n = 12). The left anterior descending coronary artery could be located over its entire course. Vascular anatomy, side branches, and septal perforators (diameter > or = 0.2 mm) could easily be discerned. In the closed chest cases the left anterior descending coronary artery, its side branches, and septal perforators could be visualized in both cases. In the postmortem human hearts the left anterior descending coronary artery could be visualized totally under the thick epicardial fibro-fatty layer and pathologic conditions could be identified. CONCLUSIONS The 10 MHz ultrasound mini-transducer showed promise as a diagnostic tool in both open and closed chest coronary procedures on the beating heart.

Lumen Reduction Measurements of the Internal Carotid Artery Before and After Levovist Enhancement: Reproducibility and Agreement with Angiography

Our aim was to assess reproducibility of three different lumen reduction measuring methods‐‐North American Symptomatic Carotid Endarterectomy Trial, European Carotid Surgery Trial, and common carotid‐‐using power Doppler and color Doppler sonography before and after Levovist enhancement. We included 20 symptomatic patients with mild or severe carotid disease. North American Symptomatic Carotid Endarterectomy Trial, European Carotid Surgery Trial, and common carotid measurements on longitudinal views and European Carotid Surgery Trial measurements on transverse views were performed. Examinations were repeated and the results compared to assess reproducibility of measurements. Correlation with angiography was obtained by calculating Pearson correlation coefficients. Reproducibility was significantly better (P < 0.05) for European Carotid Surgery Trial and common carotid measurements (95% limits of agreement between ‐10% to 10% and ‐19% to 17%) as compared to North American Symptomatic Carotid Endarterectomy Trial measurements (95% limits of agreement between ‐11% to 21% and ‐21% to 23%). Variability of measurements after enhancement increased slightly (not significant) for both power and color Doppler sonography. Additionally, European Carotid Surgery Trial measurements, using nonenhanced power Doppler or color Doppler sonography, did not correlate significantly with angiography, whereas North American Symptomatic Carotid Endarterectomy Trial and common carotid measurements correlated well with angiography, particularly in power Doppler mode after enhancement (r = 0.88 and r = 0.82, respectively). We conclude that for lumen reduction measurements of the internal carotid artery with power and color Doppler sonography, the common carotid method is the only method that is reproducible and has good correlation with angiography, which slightly improves after Levovist enhancement.

Carotid Intima-media Thickness Measurements: Relations with Atherosclerosis, Risk of Cardiovascular Disease and Application in Randomized Controlled Trials

Advances in the field of carotid ultrasound have been incremental, resulting in a steady decrease in measurement variability. Improvements in edge detection algorithms point toward increasing automation of CIMT measurements. The major advantage of CIMT is that it is completely noninvasive and can be repeated as often as required. It provides a continuous measure since all subjects have a measurable carotid wall. It is also relatively inexpensive to perform, and the technology is widely available. A graded relation between raising LDL cholesterol and increased CIMT is apparent. Increased CIMT has been shown consistently to relate the atherosclerotic abnormalities elsewhere in the arterial system. Moreover, increased CIMT predicts future vascular events in both populations from Caucasian ancestry and those from Asian ancestry. Furthermore, lipid‑lowering therapy has been shown to affect CIMT progression within 12–18 months in properly designed trials with results congruent with clinical events trials. In conclusion, when one wants to evaluate the effect of a pharmaceutical intervention that is to be expected to beneficially affect atherosclerosis progression and to reduce CV event risk, the use of CIMT measurements over time is a valid, suitable, and evidence‑based choice.

Striking Increases in Carotid Artery Wall Thickness in Healthy Subjects

Background: Atherosclerosis has long been thought to develop over time in a linear manner from gradual wall thickening to advanced thick lesions. However, evidence has emerged indicating a phasic rather than linear progression with time. A major reason for this non-linear pattern appears to be the occurrence of hemorrhages in the arterial wall, although data on this issue are still scarce. We studied the occurrence of temporarily impressive thickenings of the carotid arterial wall in a cohort of healthy postmenopausal women who were followed up for 3 years with regular carotid ultrasound examinations. Methods: The women were the European participants of a randomized placebo-controlled trial into the effect of hormone replacement therapy on progression of carotid intima-media thickness (CIMT). For a period of 3 years, the women underwent a standardized carotid ultrasound protocol every 6 months. Common, bifurcation and internal carotid segments were scanned on both sides, stored on videotape, and the near and far wall CIMT was measured on defined angles and segments, also in areas of plaque. Adverse events were routinely recorded. At the completion of the study, all segment-specific measurements were evaluated for outliers. Images were retrieved from videotape and evaluated whether the outlier resulted from a real morphological change or ‘measurement error’. Results: The 509 healthy postmenopausal women, free from previous symptomatic cardiovascular disease, underwent 3,812 carotid ultrasound scans during the study, and 44,924 carotid segments were evaluated. In 203 segments of 188 participants outliers were observed. True morphological changes were found in 12 participants, equivalent to a 3-year risk of 2.4%. These changes did not give rise to clinical symptoms. In the 6 women of whom we had follow-up measurements, the changes were reversed within 6–12 months. Conclusion: We observed acute increases in CIMT among 2.4% of healthy postmenopausal European women followed for 3 years. When assuming these were the result of vessel wall hemorrhages, our findings add to the body of evidence suggesting that vessel wall hemorrhages contribute to atherosclerosis development and also appear to occur clinically silent.