Low-energy gamma-emitting stents inhibit intimal hyperplasia with minimal "edge effects" in a pig coronary artery model.

PURPOSE: The objective of this study was to determine the effects of different doses of gamma-emitting radioactive stents on intimal hyperplasia in a porcine coronary stent model at 28 days. METHODS: Sixty-four bare stents and those coated with palladium-103 [activities of 0 (control), 0.5, 1.0, 2.0, and 4.0 mCi] were implanted in the coronary arteries of 32 pigs. Stented segments were evaluated by histomorphometry at 28 days. RESULTS: There was significantly more intima in the 0.5- and 1-mCi stents than in controls (4.27+/-0.52 and 4.71+/-1.13 vs. 1.71+/-0.61 mm(2); P<.0001). Neointimal formation in 2-mCi stents was similar to that in controls, while that in 4-mCi stents was reduced compared to that in controls (2.34+/-1.61 and 0.82+/-0.25 vs. 1.71+/-0.61 mm(2); P=NS and P<.05, respectively). Stent margin neointimal response was representative of that within the stent body, with nonsignficant modest increases in intimal area at adjacent nonstented segments in radioactive stent groups. There was a dose-dependent increase in inflammation scores. Radioactive stents had lower intimal smooth muscle and higher fibrin scores. There was an increase in adventitial fibrosis in 1- and 2-mCi stents versus controls (1.26+/-0.99, and 2.25+/-1.27 vs. 0.21+/-0.31; P<.001). CONCLUSION: Dose-response inhibition of in-stent hyperplasia with minimal "edge effects" occurs with low-energy gamma-emitting stents. An increased inflammatory response at higher doses in palladium-103 stents indicates that later follow-up studies are necessary.

Safety and effectiveness of radioactive coil embolization of aneurysms: effects of radiation on recanalization, clot organization, neointima formation, and surrounding nerves in experimental models.

BACKGROUND AND PURPOSE: Recanalization after coil embolization can be prevented by radiation emitted from 32P coils. We wanted to determine the upper limits of 32P activities that could be implanted onto coils with respect to the potential injury to nearby nerves, delay in organization of the clot, and effects on neointima formation and recanalization. METHODS: We studied the effects of various 32P activities on recanalization and organization of thrombus after coil occlusion of canine arteries and on neointima formation at the neck of canine carotid bifurcation aneurysms. We also tested potential injury to nerves in the vicinity of radioactive or nonradioactive coils in 3 models: the brachial plexus (near proximal vertebral arteries) and the lingual nerve in a lingual artery bifurcation aneurysm model, both models being treated by radioactive or standard coil occlusion. Finally, we wrapped lingual nerves with nonradioactive or high-activity coils and studied their effects on lingual nerves and tongues. Results were assessed with a pathological scoring system and compared with Mann-Whitney and Kruskal-Wallis tests. RESULTS: No deleterious effect of radiation on nerves could be detected. Neointima formation was not hampered, scores of aneurysms treated with 32P-coils being significantly better when compared with treatments with standard coils (P=0.002). Arteries treated with high-activity coils (>3.39 microCi) showed absent recanalization but delayed organization of the clot at 3 months compared with low-activity or nonradioactive coils (P<0.05). CONCLUSIONS: beta-Radiation can prevent recanalization after coil occlusion. We could not demonstrate any deleterious effects of radioactivity on nervous structure or on neointima formation. Delayed organization of thrombus provides a rational basis to establish an upper limit for 32P activities to be implanted onto coils.

In situ beta-irradiation of a brain arteriovenous malformation model.

BACKGROUND AND PURPOSE: The treatment of large brain arteriovenous malformations (BAVMs) is challenging, and embolization alone is seldom curative. The study goal is to enhance the efficacy of arteriovenous malformation embolization by adding a beta-emitting isotope to the embolic agent. METHODS: The pig rete mirabile was used as a BAVM model. The body distribution of radioactivity was evaluated after selective rete injection of N-butyl,2-cyanoacrylate mixed with (131)I-lipiodol in 8 animals using immediate whole body gamma-scintigraphy. Activities within the whole rete mirabile and selected tissue samples were quantified with a gamma counter immediately after sacrifice. Two pigs were submitted to serial gamma-scintigraphies for 6 weeks to detect delayed isotope leaching. Long-term effects of in situ irradiation were evaluated using a mixture of 188Re/N-butyl,2-cyanoacrylate in 8 pigs. In 1 animal, autoradiography was performed to evaluate local rete mirabile distribution of the radioactivity. Seven pigs were injected with 188Re/glue in 1 rete mirabile and with glue only on the opposite side, and the degree of vascular occlusion of both sides was compared on histology at 2 (n=2) or 6 months (n=5). RESULTS: There was negligible activity outside the target. Radiation caused occlusion of vessels unreached by the glue itself but in the vicinity of the radioactive source in 5 of 7 rete mirabile. CONCLUSIONS: Selective deposition of a beta-emitter inside a BAVM model may be achieved by current embolization techniques. The adjunct use of an isotope may increase the efficacy of embolization.

Accurate determination of dose-point-kernel functions close to the origin using Monte Carlo simulations.

Dose-point-kernel (DPK) functions are used extensively for the dosimetry of gamma and beta emitters in many physical problems. These functions are usually obtained from Monte Carlo simulations where the energy deposited in concentric spherical shells around a point source is tallied. The energy scored in a spherical shell divided by the shell mass is taken as the dose at some effective radius R(eff) of the shell. The effective radius R(eff), defined as the distance of a hypothetical zero-thickness scoring region from the source, can be evaluated in different ways for a finite thickness scoring region. For a shell thickness that is very small compared to the distance from the origin, this exact evaluation method becomes unimportant and the arithmetic mean is usually an accurate estimator for R(eff). However, accurately determining R(eff) can be problematic for the innermost regions when the radial dose function D(r) varies considerably over the finite spherical shell thickness. In this work, a new method for determining R(eff) is introduced which yields consistent results for any shell thickness, thus improving on previous Monte Carlo calculations for DPKs at or near the origin. Dimensionless DPK functions for monoenergetic electrons were reevaluated using EGSnrc with an emphasis on accuracy and consistency near the origin using our new method for determining R(eff). These improved functions were implemented in a software code to calculate the DPKs for an exhaustive list of 546 beta emitters, thus extending the compilation from previous works.

Endovascular treatment of intracranial aneurysms with radioactive coils: initial clinical experience.

BACKGROUND AND PURPOSE: Endovascular treatment of intracranial aneurysms is safe and effective but is associated with angiographic recurrences. Beta radiation prevents recanalization after coil embolization in experimental models. We wanted to assess the feasibility of using radioactive coil embolization to improve long-term results of endovascular treatment. METHODS: Platinum coils were ion-implanted with 0.13 to 0.26 microCi/cm of 32P. Forty-one patients aged 34 to 84 years with 44 aneurysms with a high propensity for recurrences were included. Radioactive coils were introduced into aneurysms to reach a target volumetric activity of 0.018 microCi/mm3. Nonradioactive coils were also used to ensure the same safety and the same angiographic results as the standard procedure. Angiographic results, procedure-related complications, and neurological events during follow-up were recorded. Angiographic follow-up data are available in 36 lesions 6 months after treatment. RESULTS: Forty of 44 aneurysms (91%) could be treated with radioactive coils. Target activities could be reached in 88% of lesions that could actually be coiled (35/40). Total activities ranged from 1.72 to 80.9 microCi, for a mean of 20.13+/-20.80 microCi. Procedure-related complications occurred in 7% of patients. Initial angiographic results were satisfactory (complete occlusions or residual necks) in 75% of lesions. Angiographic recurrences occurred in 11 (31%) of patients followed, within the expected range for standard coils. There was no complication from beta radiation during a mean follow-up period of 10 months. CONCLUSIONS: Radioactive coil embolization is feasible; target volumetric activities can be reached in most aneurysms considered for endovascular treatment.

Dose model for stent-based delivery of a radioactive compound for the treatment of restenosis in coronary arteries.

Radiolabeled drug-eluting stents have been proposed recently as a novel method to potentially reduce restenosis in coronary arteries. A P-32 labeled oligonucleotide (ODN) loaded on a polymer coated stent is slowly released in the arterial wall to deliver a therapeutic dose to the target tissue. However, the relatively low proportion of drugs transferred to the arterial wall (<2%-5% typically) raises questions about the degree to which radiolabeled drugs eluted from the stent can contribute to the total radiation dose delivered to tissues. A three-dimensional diffusion-convection transport model is used to model the transport of a hydrophilic drug released from the surface of a stent to the arterial media. Large drug concentration gradients are observed near the stent struts giving rise to a nonuniform radiation activity distribution for the drug in the tissues as a function of time. A voxel-based kernel convolution method is used to calculate the radiation dose rate resulting from this activity build-up in the arterial wall based on the medical internal radiation dose formalism. Measured residence time for the P-32 ODN in the arterial wall and at the stent surface obtained from animal studies are used to normalize the results in terms of absolute dose to tissue. The results indicate that radiation due to drug eluted from the stent contributes only a small fraction of the total radiation delivered to the arterial wall, the main contribution coming from the activity that remains embedded in the stent coating. For hydrophilic compounds with rapid transit times in arterial tissue and minimal binding interactions, the activity build-up in the arterial wall contributes only a small fraction to the total dose delivered by the P-32 ODN stent. For these compounds, it is concluded that radiolabeled drug-eluting stent will not likely improve the performance of radioactive stents for the treatment of restenosis. Also, variability in the delivery efficacy of drug delivery devices makes accurate dosimetry difficult and the drug washout in the systemic circulatory system may yield an unnecessary activity build-up and dose to healthy organs.

Feasibility study and dosimetric assessment of radiolabeled drugs injected to the coronary arterial wall to prevent restenosis.

PURPOSE: Intramural delivery of a P-32 radiolabeled oligonucleotide (ODN) using an infiltrating catheter has been proposed recently to potentially reduce restenosis in coronary arteries and tested on a limited number of human subjects. However, because of the low efficiency of drug retention (approximately 2-5%) after the initial washout period from this technique, the dose levels to nontarget organs may be significant and thus may require a detailed investigation. The radiation dose distributions resulting from this technique is investigated using the MIRD formalism and Monte Carlo calculations. MATERIALS AND METHODS: The total activity of the P-32 ODN to be injected during treatment to deliver a therapeutic dose of approximately 30 Gy to the arterial wall is estimated taking into account the drug delivery efficacy of the infiltrating device (approximately 2-5% typical). Using pharmacokinetic data for P-32 ODN, we estimate the dose to healthy organs resulting from the systemic fraction that is released into the circulatory system during washout (>95% typical). Variabilities in the biological parameters are also identified as important sources of error in the prescribed dose. RESULTS: A limitation to this technique is the poor accuracy in delivering the prescribed dose due to variability in the amount of drug delivered. Dose to organs is also an important limitation. For example, our calculation indicate that approximately 37 MBq (1 mCi) of P-32 labeled ODN are needed to deliver 30 Gy to the arterial wall assuming a delivery efficiency of 2-5% and a 24-h residence time. This may result in doses of approximately 1 Gy to the spleen and 0.2-0.4 Gy to the liver, kidneys and lungs (95% confidence interval). CONCLUSION: This novel therapy suffers from serious limitations. It is doubtful that a therapeutic dose can be delivered accurately, safely and effectively to the arterial wall because of the poor delivery efficacy and extreme variability found in drug delivery experiments. Also, dose levels to healthy organs appears to be too high to recommend the use of this technique in human experiments.

Re-evaluation of the dose to the cyst wall in P-32 radiocolloid treatments of cystic brain tumors using the dose-point-kernel and Monte Carlo methods.

Intracavity instillation of beta-emitting colloid pharmaceuticals is a common technique used to treat cystic brain tumors. Most of the dosimetric calculations that have been reported in the literature for this problem are based on empirical formulas derived by Loevinger. Concentration of P-32 radiolabeled solution for the delivery of a prescribed dose (200 Gy to the cyst wall) has been published previously using this formalism in what we refer to as a standard nomogram. The calculations using the Loevinger formulas for calculating the P-32 activity necessary to achieve 200 Gy at the cyst wall is re-evaluated and compared to numerically computed results based on full Monte Carlo simulations (EGSnrc) and the dose-point-kernel (DPK) integration method. For cyst diameters greater than 1 cm, the new calculations agree well with previously published results (the standard nomogram) to within a few percents. However, for cyst diameters of less than 1 cm, it is shown that the standard nomogram results underestimate the therapeutic activity by a factor of approximately 3 for very small diameters (approximately 0.2 cm). New tables based on our calculations are presented and the sources of discrepancies are identified. It is concluded that the new set of data based on our calculations should replace the standard nomogram to administer accurately the target dose to the cyst wall for the smaller diameter cysts (< 1 cm).

Feasibility of radioactive embolization of intracranial aneurysms using 32P-implanted coils.

BACKGROUND AND PURPOSE: Beta radiation can prevent recanalization after embolization. Our goal was to assess the feasibility of endovascular treatment of intracranial aneurysms using coils of a predetermined activity of 32P per centimeter. METHODS: We studied the total length of coils deployed into 357 intracranial aneurysms. Aneurysmal volumes were estimated using 3 mathematical models. We simulated that coils were implanted with 0.26 microCi/cm of 32P, calculated resulting volumetric activities, and compared them with "effective" levels derived from experimental data and "safe" levels prescribed for the clinical use of 32P in cystic craniopharyngiomas. RESULTS: Effective activities would have been reached in 92% to 98% of lesions had the coils been radioactive at the time of treatment. CONCLUSIONS: Radioactive coil embolization of aneurysms is feasible in most patients.

Late effects of low-energy gamma-emitting stents in a rabbit iliac artery model.

PURPOSE: To determine the long-term dose response of novel low-dose gamma-emitting stents in a rabbit iliac artery model. METHODS AND MATERIALS: Control stents (n=24) and 103Pd stents 1.0 to 4.0 mCi (n=36) were implanted in the iliac arteries of 30 New Zealand rabbits. Stents were evaluated by intravascular ultrasound (immediately post procedure and before killing) and by histomorphometry. RESULTS: At 26 weeks, 28 rabbits were killed, with no evidence of stent thrombosis. In the body of the stent there was a dose-response relationship with 50% inhibition of intimal hyperplasia at the highest activity compared to control stents (p=0.07) and a significant increase in intimal hyperplasia at the lowest activity (p < 0.01). At the stent edges, there was a significant reduction of lumen area at all activity levels compared to control stents, which was most prominent at the proximal stent edge. Higher-activity stents demonstrated incomplete endothelialization and immature neointimal formation. CONCLUSIONS: Continuous low-dose-rate irradiation by gamma-emitting 103Pd stents is feasible with reduction of in-stent hyperplasia in a dose-related manner. However, significant narrowing at the stent edges, increased in-stent hyperplasia at lower activities, and incomplete vascular healing with persistence of immature neointima at higher activities are significant limitations.

In situ beta radiation to prevent recanalization after coil embolization of cerebral aneurysms.

BACKGROUND AND PURPOSE: Endovascular treatment of cerebral aneurysms, a minimally invasive alternative to surgery, is too often followed by recanalization and recurrences. The purpose of this work was to assess if in situ beta radiation can inhibit recanalization after coil embolization. METHODS: Radioactive platinum coils (32P-coils) were produced by ion implantation of 32P. A single-coil arterial occlusion model was used to compare angiographic and pathological results at 1 to 12 weeks after nonradioactive and 32P-coil embolization of maxillary, cervical, and vertebral arteries in 26 dogs. Coils of varying activities were used and results compared to define the minimal activity required to inhibit recanalization. Similar experiments were performed in 16 porcine maxillary and lingual and 8 rabbit axillary arteries. Results of 32P-coil embolization of bifurcation aneurysms were then compared with embolization with nonradioactive coils in 12 dogs at 3 months. RESULTS: Nonradioactive coil embolization of canine arteries led to occlusion at 1 week, followed by recanalization at 2 weeks, which persisted at 3 months in all cases. 32P-coils, ion-implanted with activities above 0.13 microCi/cm, led to persistent occlusion at 3 months in 80% of arteries. 32P-coils ion-implanted with the same activity inhibited recanalization in porcine and rabbit arteries. Bifurcation aneurysms treated with 32P-coils had better angiographic results at 3 months (P=0.006) than aneurysms treated with nonradioactive coils. Arteries occluded were filled with fibrous tissue at 3 months. Aneurysms embolized with 32P-coils showed more complete neointimal coverage of the neck, without recanalization, as compared with aneurysms treated with nonradioactive coils. CONCLUSION: In situ low-dose beta radiation inhibits recanalization after coil embolization and may improve long-term results of endovascular treatment of aneurysms.