External beam irradiation for inhibition of intimal hyperplasia following prosthetic bypass: preliminary results.

To determine whether external beam irradiation delivered immediately after graft implantation can inhibit anastomotic intimal hyperplasia (IH) 1 month following polytetrafluoroethylene (PTFE) bypass in a sheep carotid artery model, 23 sheep underwent bilateral bypass of the ligated common carotid artery with 8-mm PTFE immediately followed by a single dose of irradiation (15, 21, or 30 Gy) to one side. The 15 animals with bilaterally patent grafts were euthanized at 1 month and graft-arterial anastomoses harvested. Using computer-aided image analysis, IH areas and thicknesses were measured. Graft patency in this model was 83% at 1 month and did not differ according to treatment administered. In the control animals, IH was greatest at mid-anastomosis, but minimal within the native vessel. All three radiation doses markedly inhibited mid-anastomotic IH area and thickness. At the proximal anastomosis, 30 Gy reduced the IH area 20-fold, from 2.06 to 0.14 mm2 (p < 0.0001 by ANOVA), and IH thickness 70-fold, from 29.0 to 0.4 micron (p < 0.0002); similar effects were seen at the distal anastomosis. No adverse effects of radiation treatment were observed. External beam irradiation in doses of 15 to 30 Gy delivered in a single fraction immediately after operation markedly inhibits development of intimal hyperplasia 1 month following end-to-side anastomosis with PTFE in sheep.

Circulating IL-6 as a predictor of radiation pneumonitis.

PURPOSE: We report results from a clinical research protocol investigating circulating pro-inflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor alpha [TNFalpha]) in relation to radiation pulmonary injury. METHODS AND MATERIALS: In a protocol for cytokine measurement, 25 patients had clinical follow-up longer than 12 months, and 24 had serial cytokine data. Serial plasma specimens before, during, and after thoracic radiotherapy were analyzed for IL-6 and TNFalpha using enzyme-linked immunosorbent assay (ELISA). Radiation pulmonary injury was defined using National Cancer Institute Common Toxicity Criteria. RESULTS: Of the 24 patients, 6 had Grade 1 pneumonitis, and 13 had Grade 2 pneumonitis. There was no Grade 3/4 pneumonitis. Median time of radiation pneumonitis was between 8 and 12 weeks post-therapy. IL-6 levels before, during, and after thoracic radiation therapy were significantly higher in those who developed pneumonitis. In contrast, we did not detect a significant correlation between plasma TNFalpha and radiation pneumonitis. CONCLUSIONS: High pretreatment plasma levels of IL-6 predisposed patients to the risk of radiation pneumonitis. Pretreatment IL-6 level may serve as a predictor for radiation pneumonitis. Serial plasma IL-6 was consistently higher for the pneumonitis group. The role of IL-6 in the cytokine cascades that promote radiation pulmonary injury deserves further investigation.

Comparability of the external vs internal location of radiation in inhibiting neointimal hyperplasia.

PURPOSE: One of the most controversial issues in utilizing radiation to inhibit restenosis is the importance of the location of the radiation source. The experimental results from using external forms of radiation have been contradictory and conflicting. In this study, we undertook to externally place a brachytherapy catheter source and to determine if a dose-response effect could be observed, as has been demonstrated with endovascular locations. MATERIALS AND METHODS: Neointimal hyperplasia was created in a rat carotid artery model by a balloon catheter technique. Immediately following injury, treatment groups received irradiation via an externally located high-dose rate (HDR) 192Ir brachytherapy catheter. This system allows for a more uniform dose delivery compared with endovascular radiation sources. Radiation was delivered to a 2-cm length of the injured vessel at doses of 5, 10, or 15 Gy and the animals were sacrificed at various time points following treatment (24 h to 6 months). Serial sections of tissue were stained immunohistochemically with primary antibodies for CD11b, platelet-derived growth factor (PDGF), and alpha-smooth muscle actin. RESULTS: Radiation doses of 5, 10, and 15 Gy inhibited the appearance of neointimal hyperplasia in a dose- and time-dependent manner. That is, doses of 5-15 Gy allowed for varying degrees of neointimal hyperplasia at 3 weeks posttreatment, with a greater resurgence of monocyte/macrophage activity at 5 Gy than at 10 or 15 Gy, where an absence of macrophage activity and PDGF expression was noted. From 2 to 6 months, the 10 and 15 Gy doses were again more suppressive of neointimal hyperplasia than 5 Gy, and at 6 months posttreatment the doses were approximately 25% and 50% effective, respectively. CONCLUSIONS: The demonstrated effectiveness of external brachytherapy provides "proof of principle," that it is the radiation dose delivered to the arterial wall, and not the location of the source, which is critical to a successful outcome. Ablation of the resident monocyte/macrophage population (or prevention of their activation) occurs with low to moderate doses of irradiation, leading to the absence of a cytokine cascade as evi denced by a lack of PDGF expression. A favorable therapeutic ratio exists, therefore, for radiation treatment of the arterial vasculature to prevent neointimal hyperplasia postangioplasty.

Effectiveness of fractionated external beam radiation in the inhibition of vascular restenosis.

BACKGROUND: From the clinical oncologic experience, fractionation of the radiation dose offers a better therapeutic window, both with respect to effectiveness and unwanted side effects. Thus, we undertook a pilot study in a rodent model, using a single dose of 15 Gy compared with fractionation schedules of 5 or 10 daily applications of 3 Gy. MATERIALS AND METHODS: Using a previously described rat angioplasty model, animals were randomly assigned to one of four groups: unilateral balloon injury, sham irradiation; unilateral balloon injury, bilateral 15 Gy single dose irradiation; unilateral balloon injury, bilateral 3 Gy x 5 daily fractions; or unilateral balloon injury, bilateral 3 Gy x 10 daily fractions. RESULTS AND CONCLUSIONS: All three radiation groups demonstrated a clear inhibition of neointimal hyperplasia. We therefore offer evidence for the effectiveness of fractionated radiation as a means to inhibit vascular restenosis in a rat carotid model. However, the 3 Gy x 5 schedule was less effective than either the 3 Gy x 10 schedule or the 15 Gy single dose. This study must be repeated using longer time points to provide proof of principle.

Tolerance of normal rabbit femoral arteries to single high dose external beam irradiation.

PURPOSE: We gave high single doses of external radiation to normal vessels to produce vascular injury and establish the dose tolerance in an animal model. We also performed immunohistochemical staining for macrophages and smooth muscle cells to assess qualitative changes in their populations. METHODS: Following direct bilateral inguinal cutdown in New Zealand white rabbits, single doses of 15, 20 and 30 Gy were delivered to one vessel. At predetermined time intervals following treatment, the animals underwent angiography and were sacrificed. Both systems were harvested and analyzed, and their luminal and medial areas compared. RESULTS: No statistically significant differences were found between any treatment vessel and its contralateral control at any time point. In addition, no alterations in subintimal or medial content of macrophages or smooth muscle cells were observed. CONCLUSIONS: Our data suggest that single radiation doses as high as 30 Gy appear to be well tolerated in the normal, uninjured rabbit vessel over a 6-month follow-up. However, the use of a diseased vessel model and longer follow-up times need to be studied to provide a better clinical understanding of the basic radiobiology of this technique.