phosphorus-radioisotopes and Hyperplasia

We sought to assess the efficacy of vascular brachytherapy (VBT) combined with stenting for the primary prevention of restenosis.. Intravascular brachytherapy after stent implantation for de novo lesions has been abandoned for the present. We revisited this procedure by optimizing all procedural steps-the use of glycoprotein IIb/IIa blockers, direct stenting, adequate radiation coverage, avoidance of edge damage, source centering, intravascular ultrasound-guided dosimetry, and continuation of a dual anti-platelet regimen for one year.. The Beta-Radiation Investigation with Direct stenting and Galileo in Europe (BRIDGE) study is a multicenter, randomized controlled trial evaluating the long-term efficacy of VBT with P-32 (20 Gy at 1 mm in the coronary wall) after direct stenting. The primary end point was angiographic intra-stent late loss; secondary end points were six months binary restenosis and neo-intimal hyperplasia. Patients (n = 112) with de novo lesions (2.5 to 4.0 mm in diameter up to 15 mm long) were randomized to either VBT or no-VBT.. At six months, intra-stent loss was 0.43 and 0.84 mm (p < 0.001) in the irradiated and control groups, respectively. Intra-stent neo-intimal volume was reduced from 36 mm3 to 10 mm3. However, in the irradiated group there were six late occlusions as well as eight restenoses outside the stented and peri-stented area at the fall-off dose edges of the irradiated area. Accordingly, the target vessel revascularization and major adverse cardiac and cerebrovascular events rates at one year in the VBT group (20.4% and 25.9%, respectively) were higher than in the control group (12.1% and 17.2%, respectively).. Despite the optimization of pre-, peri-, and post-procedural factors and despite the relative efficacy of the brachytherapy for the prevention of the intra-stent neo-intimal hyperplasia, the clinical outcome of the irradiated group was less favorable than that of the control group.

Topics: Aged; Aspirin; Brachytherapy; Clopidogrel; Coronary Angiography; Coronary Restenosis; Europe; Female; Humans; Hyperplasia; Male; Middle Aged; Phosphorus Radioisotopes; Platelet Aggregation Inhibitors; Primary Prevention; Radiation Dosage; Stents; Ticlopidine; Tunica Intima; Ultrasonography, Interventional

Intracoronary radiation is a promising therapy to decrease restenosis after percutaneous intervention. The aim of this pilot study was to determine the mechanism of intracoronary beta-radiation after balloon angioplasty and stenting in a double-blind placebo-controlled randomized fashion. Twenty-six patients were randomized to either placebo (n = 6) or 3 doses (28, 35 and 42 Gy) of beta-radiation (n = 20) using the Guidant brachytherapy system (27 mm long 32P source wire). Of these, 21 patients underwent post-procedure and 6-month follow-up three-dimensional intravascular ultrasound (IVUS) assessment. Volumetric quantification was performed by means of a semi-automated contour detection system after an ECG-gated motorized pullback IVUS imaging and three-dimensional reconstruction. We compared the volumetric changes (Delta) of total vessel volume (TVV), plaque volume (PV) and lumen volume (LV) after 6 months between placebo (dummy wire) and irradiated patients. In addition, the volume of neointimal hyperplasia was quantified within the stented segments. There was an opposite behavior of TVV and LV change between placebo (DeltaTVV = -24 mm3 and DeltaLV = -42 mm3) and irradiated (DeltaTVV = +18 mm3 and (DeltaLV = +5 mm3) patients. The mean neointimal formation within the stented segment in the irradiated patients (n = 7) was 1.9 mm3 (1.5%). Our results suggest that beta-radiation affects vessel remodeling after percutaneous intervention and inhibit neointimal formation in stented patients.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Vessels; Double-Blind Method; Female; Humans; Hyperplasia; Male; Middle Aged; Phosphorus Radioisotopes; Pilot Projects; Radiography; Stents; Tunica Intima; Ultrasonography, Interventional

Topics: Angioplasty, Balloon, Coronary; Beta Particles; Brachytherapy; Cell Division; Coronary Disease; Coronary Vessels; Humans; Hyperplasia; Phosphorus Radioisotopes; Secondary Prevention; Stents; Tunica Intima

Edge restenosis is a major problem after radioactive stenting. The cold-end stent has a radioactive mid-segment (15.9 mm) and non-radioactive proximal and distal 5.7 mm segments. Conceptually this may negate the impact of negative vascular remodelling at the edge of the radiation.. ECG-gated intravascular ultrasound with three-dimensional reconstruction was performed post-stent implantation and at the 6-month follow-up to assess restenosis within the margins of the stent and at the stent edges in 16 patients. Angiographic restenosis was witnessed in four patients, all in the proximal in-stent position. By intravascular ultrasound in-stent neointimal hyperplasia, with a >50% stented cross-sectional area, was seen in eight patients. This was witnessed proximally (n=2), distally (n=2) and in both segments (n=4). Echolucent tissue, dubbed the 'black hole' was seen as a significant component of neointimal hyperplasia in six out of the eight cases of restenosis. Neointimal hyperplasia was inhibited in the area of radiation: Delta neointimal hyperplasia=3.72 mm3 (8.6%); in-stent at the edges of radiation proximally and distally Delta neointimal hyperplasia was 7.9 mm3 (19.0%) and 11.4 mm3 (25.6%), respectively (P=0.017). At the stent edges there was no significant change in lumen volume.. Cold-end stenting results in increased neointimal hyperplasia in in-stent non-radioactive segments.

Topics: Brachytherapy; Cell Division; Coronary Disease; Coronary Vessels; Humans; Hyperplasia; Phosphorus Radioisotopes; Secondary Prevention; Stents; Tunica Intima; Ultrasonography, Interventional

A recognized limitation of radioactive stents is the development of restenosis at the stent edges, known as the "candy-wrapper" effect. The mechanisms of this effect remain incompletely understood and controversial. The aim of this study is to assess the effect of endovascular irradiation on neointima formation and vascular remodeling. (32)P Palmaz-Schatz stents (1.5-4 microCi) were implanted in 11 patients with restenosis after previous percutaneous transluminal coronary angioplasty (PTCA). Intravascular ultrasound (IVUS) images of target sites and adjunct vessel segments were acquired both during intervention and after 6 months. The angiographic restenosis rate was 54%, and the MLD decreased from 2.21 +/- 0.6 mm to 1.38 +/- 0.4 mm at follow-up (P < 0.01). IVUS analysis demonstrated that late lumen loss was the result of neointimal tissue proliferation, which was nonuniformly distributed and exaggerated at both the central articulation and the distal stent edges. Negative remodeling did not contribute to restenosis. In contrast, we found a linear relationship between increase of area stenosis and a positive remodeling index (r = 0.84, P < 0.0001). Restenosis after implantation of (32)P Palmaz-Schatz stents was mainly the result of neointimal tissue proliferation which tended to be nonuniformly distributed in the stent articulation and edges. Negative remodeling or stent recoil was not observed. Cathet Cardiovasc Intervent 2001;54:41-48.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Disease; Endothelium, Vascular; Female; Graft Occlusion, Vascular; Humans; Hyperplasia; Male; Middle Aged; Phosphorus Radioisotopes; Stents; Ultrasonography, Interventional

We hypothesized that magnetic resonance imaging (MRI) scans taken prior to radiosynoviorthesis may be predictive of response to the procedure in persons with haemophilia. Specifically, response would be inversely related to the severity of synovial hyperplasia. Radiosynoviorthesis was administered to 21 joints with recurrent haemorrhage (target joints). A detailed self-report of haemorrhage history, joint evaluation with scoring according to the World Federation of Haemophilia orthopaedic joint and pain scales, plain radiographs, and MRI studies of the joints were performed pre- and post-radiosynoviorthesis. To augment comparison of the MRI findings to those assessed using the Arnold-Hilgartner and Pettersson scales, a provisional MRI scale for evaluation of haemophilic arthropathy was designed. We found the MRI findings prior to the procedure were not predictive of clinical response; independent of the severity of synovial hyperplasia, most joints bled less and showed improvement by the WFH orthopaedic score. There was generally no change in the severity of synovial hyperplasia after the procedure. We conclude that MRI evaluation is not routinely indicated prior to radiosynoviorthesis.

Topics: Adolescent; Adult; Ankle; Child; Elbow; Follow-Up Studies; Hemarthrosis; Hemophilia A; Hemophilia B; Humans; Hyperplasia; Knee; Magnetic Resonance Imaging; Phosphorus Radioisotopes; Radiography; Severity of Illness Index; Synovial Membrane

According to early clinical trials, vascular brachytherapy performed prior to or shortly after angioplasty is very effective in reducing restenosis rates. The purpose of this study was to investigate the effects of a novel radioactive catheter that allows simultaneous balloon angioplasty and beta-particle irradiation in the prevention of restenosis.. The balloon surface of an angioplasty catheter was impregnated with the radioisotope(32)P. Dosimetry calculations using a Monte Carlo method were performed at a radial distance of 0.2 mm from the balloon surface. Rabbit iliac arteries were dilated and simultaneously irradiated with a dose of 20 Gy delivered to the adventitia. Control arteries were only dilated and not irradiated. Neointimal areas, cell numbers and the perimeter of the arteries were measured by histomorphometry after 6 weeks.. Neointima formation was reduced after balloon dilatation and simultaneous beta-particle irradiation using the(32)P impregnated angioplasty catheter as compared to balloon dilatation alone with a non-impregnated catheter (0.09+/-0.06 vs 0.27+/-0.09 mm(2)neointimal area and 168+/-45 vs 360+/-133 cells/0.05 mm(2)neointima, P<0.001 vs control, respectively). In addition, balloon dilatation with the(32)P impregnated angioplasty catheter increased the vessel perimeter as compared to balloon dilatation with a non-impregnated catheter (4. 7+/-0.2 vs 3.9+/-0.3 mm, P<0.001 vs control).. Simultaneous balloon dilatation and vascular brachytherapy with a novel(32)P impregnated angioplasty catheter markedly reduces restenosis in vivo by preventing neointimal hyperplasia and constrictive vascular remodelling.

Topics: Angioplasty, Balloon; Animals; Arteriosclerosis; Beta Particles; Brachytherapy; Catheterization; Female; Hyperplasia; Iliac Artery; Models, Animal; Monte Carlo Method; Phosphorus Radioisotopes; Rabbits; Radiotherapy Dosage; Recurrence; Tunica Intima

Although endovascular radiotherapy inhibits neointimal hyperplasia, the exact cellular alterations induced by beta irradiation remain to be elucidated.. We investigated in vitro the ability of 32P-labeled oligonucleotides to alter (1) proliferation of human and porcine vascular smooth muscle cells (VSMCs) and human coronary artery endothelial cells (ECs), (2) cell cycle progression, (3) cell viability and apoptosis, (4) cell migration, and (5) cell phenotype and morphological features. beta radiation significantly reduced proliferation of VSMCs (ED50 1.10 Gy) and ECs (ED50 2.15 Gy) in a dose-dependent manner. Exposure to beta emission interfered with cell cycle progression, with induction of G0/G1 arrest in VSMCs, without evidence of cell viability alteration, apoptosis, or ultrastructural changes. This strategy also proved to efficiently inhibit VSMC migration by 80% and induce contractile phenotype appearance, as shown by the predominance of alpha-actin immunostaining in beta-irradiated cells compared with control cells.. 32P-labeled oligonucleotide was highly effective in inhibiting proliferation of both VSMCs and ECs in a dose-dependent fashion, with ECs showing a higher resistance to these effects. beta irradiation-induced G1 arrest was not associated with cytotoxicity and apoptosis, thus demonstrating a potent cytostatic effect of beta-based therapy. This effect, coupled to that on VSMC migration inhibition and the appearance of a contractile phenotype, reinforced the potential of ionizing radiation to prevent neointima formation after angioplasty.

Topics: Angioplasty, Balloon, Coronary; Animals; Apoptosis; Beta Particles; Cell Cycle; Cell Division; Cell Movement; Cells, Cultured; Coronary Vessels; Culture Media, Serum-Free; DNA Fragmentation; Dose-Response Relationship, Radiation; Endothelium, Vascular; Humans; Hyperplasia; Microscopy, Electron; Microscopy, Fluorescence; Muscle, Smooth, Vascular; Phosphorus Radioisotopes; Swine; Tunica Intima

To investigate the effects of the soft extravascular model (SEM) with 32P on intimal hyperplasia and smooth muscle cell preliferation in autogenous vein grafts.. We transplanted the femoral veins to the co-lateral femoral arteries in rabbits. The animals were divided into three groups of Aspirin group, 32P group and control group. We observed the expression density of endothelin type A receptor cDNA (ETAcDNA) and intimal relative thickness by using in situ molecular hybridization of ETAcDNA by computerized image analysis technology.. SEM with beta-ray obviously inhibited SMC preliferation from 1 W to 12 W postoperation, and notably restrained intimal hyperplasia at early to middle stage of graft. Aspirin could not inhibit SMC proliferation and intimal hyperplasia under the condition of this experiment.

Topics: Animals; Beta Particles; Endothelium, Vascular; Female; Femoral Artery; Femoral Vein; Hyperplasia; Male; Muscle, Smooth, Vascular; Phosphorus Radioisotopes; Prostheses and Implants; Rabbits; Silicone Elastomers

Considerable experimental evidence exists that neointimal hyperplasia after angioplasty is inhibited by gamma-irradiation of the treated arteries. A beta-particle radiation is absorbed in tissue within a shorter distance away from the source than gamma-radiation and may be more suitable for localized vessel irradiation. This study outlines a method to implant a beta-particle-emitting radioisotope (32P; half-life, 14.3 days) into metallic stents. The effects of these stents on the inhibition of neointimal hyperplasia was compared with conventional stents in a rabbit model.. 32P was produced by irradiation of red amorphous phophorus (31P) with neutrons and was implanted into Palmaz-Schatz stents (7.5 mm in length) after being kept apart from 31P in a mass separator. The radioisotope was tightly fixed to the stents, and the ion implantation process did not alter the surface texture. Stent activity levels of 4 and 13 microCi were chosen for the study. Four and 12 weeks after placement of conventional stents and 32P-implanted stents in rabbit iliac arteries, vascular injury and neointima formation were studied by histomorphometry. Immunostaining for smooth muscle cell (SMC) alpha-actin was performed to determine SMC cellularity in the neointima. SMCs were quantified by computer-assisted counting of alpha-actin immunoreactive cells. Endothelialization of the stents was evaluated by immunostaining for endothelial cell von Willebrand factor. No difference in vessel wall injury was found after placement of conventional and 32P-implanted stents. Neointima formation was potently inhibited by 32P-implanted stents only at an activity level of 13 microCi after 4 and 12 weeks. Neointimal SMC cellularity was reduced in 32P-implanted stents compared with conventional stents. Radioactive stents were endothelialized after 4 weeks, but endothelialization was less dense than in conventional stents.. Neointima formation in rabbits is markedly suppressed by a beta-particle-emitting stent incorporating the radioisotope 32P. In this model, a dose-response relation with this type of radioactive stent was observed, indicating that a threshold radiation dose must be delivered to inhibit neointima formation after stent placement over the long term.

Topics: Angioplasty, Balloon; Animals; Beta Particles; Brachytherapy; Endothelium, Vascular; Evaluation Studies as Topic; Hyperplasia; Iliac Artery; Muscle, Smooth, Vascular; Phosphorus Radioisotopes; Rabbits; Stents

Radiation delivered by intravascular stent is an appealing approach to prevent neointimal hyperplasia, since it nonselectively kills dividing cells. In particular, beta-particle-emitting radioisotope stents may prove to be an ideal means of local irradiation in that 95% of the dose is delivered within 4 mm of the stent edge and the dose drops off rapidly to < 1/1,000 of the original dose at 5 months postimplantation. In the in vitro smooth muscle cell model, one can observe a zone of growth inhibition around radioactive stent wires that averages about 6 mm at very-low-activity levels (0.006 microCi/cm of wire). In vivo studies in animal models, including porcine iliac and coronary arteries and rabbit iliac arteries, have shown the effectiveness of radioisotope stents in inhibiting neointimal proliferation. Proliferating endothelial cells appear to be relatively radioresistant. A computer model was employed to look at the radiation dose delivered as a function of distance from the stent. With very-low-activity stents, presumably, DNA of the smooth muscle cells is damaged as they migrate through the "electron fence" on the way to the neolumen, diminishing the population of myofibroblasts and reducing hyperplasia. Catheter-based radiation therapies may disable these cells before they migrate, although such an approach may not inhibit early recoil or late contraction. Based on the characteristics of beta emissions (i.e., rapid drop-off, minimal leaching), radioisotope stents containing phosphorus-32 appear to be safe. A randomized triple-blind clinical trial is planned to assess restenosis at 6 months in native coronary arteries treated with radioisotope stents.

Topics: Animals; Beta Particles; Computer Simulation; Equipment Design; Hyperplasia; Muscle, Smooth, Vascular; Phosphorus Radioisotopes; Radiation Dosage; Randomized Controlled Trials as Topic; Stents; Tunica Intima

Intimal thickening is a universal response to endothelial denudation and is also thought to be a precursor of atherosclerosis. We have demonstrated selective supersensitivity in arterial intimal hyperplasia to norepinephrine and we now report a possible mechanism for this. Binding studies in rabbit aorta with the selective alpha 1-adrenergic radioligand 125I-HEAT demonstrated that there was no change in receptor density (20 +/- 4 fmole/10(6) cells) in intact vascular smooth muscle cells at either 5 or 14 days after denudation. However, competition studies showed a 2.6-fold increase in alpha 1-adrenergic receptor affinity for norepinephrine in intimal hyperplastic tissue (P less than 0.05). This increased affinity for norepinephrine was associated with a greater increase in 32P-labeled phosphatidylinositol (148% intimal thickening versus 76% control) and phosphatidic acid (151% intimal thickening versus 56% control) following norepinephrine stimulation of free floating rings of intimal hyperplastic aorta. These data suggest that the catecholamine supersensitivity in rabbit aortic intimal hyperplasia is receptor mediated and may be linked to the phosphatidylinositol cycle.

Topics: Animals; Aorta; Cell Membrane; Hyperplasia; Muscle, Smooth, Vascular; Norepinephrine; Phospholipids; Phosphorus Radioisotopes; Rabbits; Receptors, Adrenergic; Receptors, Adrenergic, alpha

The composition of the hemopoiesis was determined in iliac crest biopsies of 51 patients with polycythaemia vera. There was a good correlation between thrombopoiesis and thrombocytes and, to a minor degree also between erythropoiesis and erythrocytes in untreated patients as well as between granulopoiesis and granulocytes in 32P-treated patients. In patients with normal blood counts there existed no correlation between the bone marrow and the blood counts within smaller limits of the cell count. Histomorphometric analysis shows no difference either between untreated and 32P-treated patients or between patients with and without splenomegaly. This is an argument against a significant intrasplenic hemopoiesis or an intrasplenic cell pooling, or destruction (hypersplenism), respectively. The blood sinusoids are hyperplastic and distended. With increasing hyperplasia of the hemopoiesis the sinusoids become relatively smaller. So changes in vascularisation may be of importance in the infrequent transitions into myelofibrosis and/or leukemia.

Topics: Biopsy; Blood Cell Count; Blood Platelets; Blood Vessels; Bone Marrow Examination; Erythrocyte Count; Erythropoiesis; Granulocytes; Hematopoiesis; Humans; Hyperplasia; Hypersplenism; Ilium; Phosphorus Radioisotopes; Polycythemia Vera; Splenomegaly