Radiotherapy inhibits neointimal hyperplasia after artificial vascular replacement through Skp2/P27kip1.

We aimed to establish an animal model of abdominal aortic vascular replacement in mongrel dogs to investigate the effect of extracorporeal radiotherapy on the intima. Twenty healthy mongrel dogs were randomly divided into four groups: 5-week control group, 5-week radiotherapy group, 10-week control group and 10-week radiotherapy group. We first performed an artificial vascular replacement of the abdominal aortic segment. The radiotherapy group received external radiotherapy with a dose of 7 Gy for 4 days. The thickness of neointimal hyperplasia, immunoreactivity and expression of proliferation-related factors were detected by hematoxylin and eosin (HE) staining, immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR )and western blotting at 5 and 10 weeks after the reconstruction. The results showed that the intimal thickness of the artificial blood vessel in the 5- and 10-week radiotherapy groups was thinner than that in the control groups by HE staining. The immunoreactivity and expression levels of Skp2, c-Myc and CyclinE1 were significantly decreased in the radiotherapy groups than those in control groups by immunohistochemistry, qRT-PCR and western blotting. On the contrary, immunoreactivity and expression levels of P27kip1 were increased. In conclusion, we discovered that postoperative external radiotherapy significantly decreases the intimal hyperplasia of artificial blood vessels by regulating c-Myc-Skp2-P27-CyclinE1 network.

Endocervical gastric-type adenocarcinoma, an unrelated HPV tumour: difficulties in screening and diagnosis.

Gastric-type adenocarcinoma of the cervix (GAS) is an uncommon and aggressive tumour unrelated to human papillomavirus (HPV) infection with distinctive histological and immunohistochemical characteristics. GAS may be associated with lobular endocervical glandular hyperplasia (LEGH), another unusual lesion. We report a case of a 59-year-old woman with screening cytology 'AGC-Neo' and cervical conisation exhibiting cervical intraepithelial neoplasia grade 1, extensive LEGH and canal sampling with abundant mucinous cells. Based on the possible association between LEGH and GAS, a total hysterectomy was performed. The histological diagnosis revealed a morphological gradient of lesions: LEGH, minimal deviation adenocarcinoma and GAS with lymphatic invasion. Immunohistochemistry revealed strong MUC6 expression and no p16 staining. After pelvic radiotherapy, the patient continues follow-up evaluation. The diagnostic difficulties of GAS and its relationship with LEGH are discussed. This rare tumour is important because it is poorly symptomatic and potentially aggressive. In addition, the methods for cancer control related to HPV do not affect this tumour.

Autoimmune polyglandular syndrome in a woman of 51 years.

INTRODUCTION: Autoimmune polyglandular syndromes (APS) are constellations of symptoms and signs of multiple glandular insufficiencies. We report a rare case of type III APS in a female patient. CASE REPORT: A 51-year-old woman was treated with radiotherapy because of thymus hyperplasia when she was two years old; she was diagnosed with celiac disease and autoimmune hypothyroidism at 41 years old and with sicca syndrome and myasthenia gravis seronegative a few years later. CONCLUSIONS: Our patient demonstrates a previous constellation of diseases of APS, which may be a random association but may also indicate a common immunological and genetic disturbance. The APS is an expression of a system impairment of immune tolerance to autoreactive clones, and this is necessary because the phenomena can become aggressive and expressed clinically. We suppose that the development of thymic hyperplasia or its radiotherapy in childhood may have compromise the patient's immune system.

On the mechanism of cellular toxicity in breast cancer by ionizing radiation and chemotherapeutic drugs.

Breast cancer is the second leading cause of cancer mortality and the most frequent cancer found in women around the globe. The development of breast cancer is a multistep and complicated process that includes the development of ductal and lobular cells into atypical hyperplasia, carcinoma in situ, and invasive carcinoma, with an ability to metastasize. The efficacy of radiotherapy in breast cancer seems to be reduced because of a frequently observed lack of cellular sensitivity to apoptosis. Both Bcl-2 and p53 are linked to apoptosis pathways and are known to play a role in the outcome of radiotherapy. Resistance of tumor cells to therapeutic drugs and the undesirable cytotoxicity of normal cells are frequently observed in treatment outcomes in clinics. Research is, therefore, needed to develop strategies for improving the protocols of chemotherapy and radiotherapy in patients with breast cancer. This review focuses on understanding the molecular mechanisms of enhanced tumor cell killing by the combined action of certain anticancer drugs together with gamma radiation in vitro, with possible implications for practical applications in clinics.

Intraoperative use of a gamma probe for the treatment of condylar hyperplasia: description of a new technique.

PURPOSE: The purpose of this article is to describe a new technique to perform a high condylectomy using a γ-probe. MATERIALS AND METHODS: A 15-year-old female patient presented with right condylar hyperplasia. Because the condition was active, a high condylectomy was performed to stop the abnormal growth of the affected condyle. To resect an adequate amount of bone and prevent relapse, a γ-probe was used to guide bone removal. The patient was injected with technetium-99m methylene diphosphate 25 mCi 2 hours before she was brought to the operating room. Bone was removed from the superior aspect of the right condyle until the reading with the γ-probe was equivalent to normal bone. RESULTS: Seven millimeters of bone was removed from the top of the condyle before the γ-emission from the remaining condyle was equivalent to the mandibular parasymphysis used as a control. No relapse was noted 9 months after surgery. CONCLUSION: The γ-probe may help a surgeon remove the correct amount of bone when performing a high condylectomy, especially in type II (vertical pattern) condylar hyperplasia.

Radiation therapy for dialysis access stenosis: unfulfilled promise or false expectations.

Hemodialysis vascular access dysfunction is a major cause of morbidity and hospitalization in the hemodialysis population at a cost of well over $1 billion per annum. Venous stenosis (due to venous neointimal hyperplasia [VNH]) is the most common cause of polytetrafluroethylene PTFE) dialysis access graft and arteriovenous fistula (AVF) failure. Despite the magnitude of the clinical problem, however, there are currently no effective therapies for this condition. We and others have previously demonstrated that VNH in PTFE dialysis grafts and AVF is composed of smooth muscle cells/myofibroblasts, endothelial cells within neointimal microvessels, and peri-graft macrophages. Radiation therapy blocks the proliferation and activation of all these cell types. The current review will dissect out the available in vitro, experimental, and clinical data on the use of radiation therapy for vascular stenosis in general, and for dialysis access dysfunction in particular. It is important to try and identify whether there is still a role for radiation therapy in this specific clinical setting. We believe that this is a critically important question to answer in view of the huge unmet clinical need that is currently associated with hemodialysis vascular access dysfunction.

Phosphodiesterase inhibitors block the acceleration of skin permeability barrier repair by red light.

We previously demonstrated that exposure to red light (550-670 nm) accelerates epidermal permeability barrier recovery after barrier disruption. Furthermore, we showed that photosensitive proteins, originally found in retina, are also expressed in epidermis. In retina, transducin and phosphodiesterase 6 play key roles in signal transmission. In this study, we evaluate the role of phosphodiesterese 6 in the acceleration by red light of epidermal permeability barrier recovery. Immunohistochemical study and reverse transcription-PCR assays confirmed the expression of both transducin and phosphodiesterase 6 in epidermal keratinocytes. Topical application of 3-isobutyl-1-methylxanthine, a non-specific phosphodiesterase inhibitor, blocked the acceleration of the barrier recovery by red light. Topical application of zaprinast, a specific inhibitor of phosphodiesterases 5 and 6, also blocked the acceleration, whereas T0156, a specific inhibitor of phosphodiesterase 5, had no effect. Red light exposure reduced the epidermal hyperplasia induced by barrier disruption under low humidity, and the effect was blocked by pretreatment with zaprinast. Our results indicate phosphodiesterase 6 is involved in the recovery-accelerating effect of red light on the disrupted epidermal permeability barrier.

Vaporización fotoselectiva de la prostata (VFP) vs enucleación de la próstata con láser Holmio (HOLEP): resultados actuales y estrategias / PVP vs HOLEP current outcomes and future strategies

La vaporización foto selectiva de la próstata (VFP), con un láser de fosfato de titanio y potasio (KTP) y la enucleación de la próstata con láser Holmio (HoLEP) representan en la actualidad las técnicas más prometedoras en el tratamiento de la hiperplasia benigna de próstata (HBP) asociada con obstrucción benigna de próstata (OBP). Las características específicas del láser y las interacciones óptimas entre el láser y el tejido prostático resultan en una uniforme y eficiente ablación de la próstata con la consiguiente formación de una celda prostática claramente desobstruida. El KTP y el HoLEP pueden ser considerados procedimientos ambulatorios, ya que solo requieren unas pocas horas de cateterización y están asociados con mínimo discomfort postoperatorio, mientras que al mismo tiempo ofrecen resultados al menos equivalentes a los estándares de referencia de la resección transuretral de próstata y la prostatectomía abierta. No hay duda de que se necesitan grandes estudios con seguimiento más largo para definir con mayor precisión la duración de los resultados del KTP y el HoLEP en el manejo de la HBP. Esta revisión abordará cuestiones de actualidad acerca de cómo se llevan a cabo ambas técnicas, sus resultados y limitaciones, así como su papel en el manejo futuro de la HBP(AU)

Photoselective vaporization of the prostate (PVP) with a potassium titanyl phosphate (KTP) láser and Holmium láser enucleation of the prostate (HoLEP) currently represent the most promising new technologies applied to the treatment of benign prostatic hyperplasia (BPH) associated with benign prostatic obstruction (BPO). The specific láser-light characteristics and the optimal interactions between lásers and prostatic tissue result in an even and efficient ablation of the prostate resulting in the formation of a clearly de-obstructed prostate cavity. PVP and HoLEP can be considered day-case procedures, as they require only a few hours of catheterization and are associated with minimal postoperative discomfort, while at the same time they offer results at least equivalent to the reference standards transurethral resection of the prostate and open prostatectomy. There is no doubt that larger studies with longer follow-up are necessary to further define the durability of results of PVP and HoLEP in the management of BPH, this review will address current issues regarding how both techniques are performed, their results and limitations as well as their role in the future management of BPH(AU)

Recurrent intravascular papillary endothelial hyperplasia of the right middle finger treated with radiation therapy.

We describe a case of recurrent intravascular papillary endothelial hyperplasia involving the middle finger which was successfully-treated with photon and proton radiotherapy following two previous surgical excisions.

Increased expression of nuclear NF-kappaB after coronary artery balloon injury can be inhibited by intracoronary beta-irradiation.

PURPOSE: Molecular mechanisms by which balloon angioplasty injury-induced neointimal hyperplasia can be reduced by intravascular brachytherapy are unclear. We investigated the role of nuclear factor-kappaB (NF-kappaB) in neointimal hyperplasia following intracoronary irradiation. MATERIALS AND METHODS: Fifty-four coronary arteries from 30 pigs were divided into 6 groups: sham control, balloon angioplasty injury alone, beta-irradiation at doses of 14 or 20 Gy, and 14 or 20 Gy beta-irradiation immediately followed by balloon injury. Coronary arteries were injured by overstretch balloon angioplasty and then the arteries were irradiated using a Rhenium-188 ((188)Re) beta-emitting solution-filled balloon. Pigs were scarified one day or one week after coronary interventions for molecular detection and six weeks after the procedures for histological examination. RESULTS: Six weeks after coronary interventions, the histological results show that balloon angioplasty injury had induced intimal hyperplasia in coronary artery but the response was significantly reduced by 28% and 60% when the injury was immediately treated by 14 and 20 Gy (188)Re beta-irradiation, respectively. The expression of arterial NF-kappaB p65, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) were detected at one day and one week after the procedures. The treatment of balloon injury could significantly induce the NF-kappaB p65 expression in both gene and protein levels, and such induction could be significantly reduced by (188)Re beta-irradiation at dose of 20 Gy. However, the similar result on the regulation of gene expression affected by the beta-irradiation could not be observed in ICAM-1 and VCAM-1. CONCLUSION: The inhibitory effect of intracoronary brachytherapy on neointimal formation following overstretch balloon angioplasty could involve inhibition of NF-kappaB p65.

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.

Effects of irradiation using a radioisotope-filled balloon on tissue hyperplasia caused by stent placement in a canine urethral model.

PURPOSE: To evaluate 20 Gy and 40 Gy of intraluminal beta-irradiation using a 188Re-7mercaptoacetyltriglycine (MAG3)-filled balloon catheter to reduce tissue hyperplasia caused by covered stent placement for 12 weeks of follow-up in a canine urethral model. MATERIAL AND METHODS: Ten dogs underwent 188Re-MAG3-filled balloon dilatation immediately after stent placement; 20 Gy at 1-mm tissue depth in group I (n = 5) and 40 Gy in group II (n = 5), whereas 5 dogs (group III) underwent conventional balloon dilatation only. RESULTS: There were no significant differences among the three groups for percentage diameter of stenosis, although this was highest in group III. There was a tendency toward lower mean thickness of the epithelial layer and the papillary projection for out-stent area, and thickness of the papillary projection and degree of inflammatory cells for instent area in groups I and II compared with group III. Thickness of the papillary projection in out-stent area was significantly different among the three groups (P = 0.031). It was significantly less thick in group I than in group III (P < 0.05), whereas group II was not significantly different from group III. CONCLUSION: 188Re-MAG3-filled balloon dilatation has the potential to reduce tissue hyperplasia after 12 weeks of follow-up in a canine urethral model. The use of 20 Gy compared to 40 Gy did not show significant differences.

Ionizing radiation to prevent arterial intimal hyperplasia at the edges of the stent: induces necrosis and fibrosis.

BACKGROUND: Although ionizing radiation has been proposed for the prevention of intimal hyperplasia in coronary and peripheral arteries in multicenter clinical trials, information is lacking on how irradiation affects arterial histology after stenting and especially how it affects the edges of the stent. We investigated intimal hyperplasia recasting with histological changes in arterial wall at the edges of the stent after arterial stenting followed by adequate external radiation for the prevention of intimal hyperplasia in pigs. MATERIALS AND METHODS: The aorta was experimentally stented in 30 pigs who were then assigned to two groups: irradiation with 20 Gy and a control group with no irradiation. The aorta was resected for morphometric and histological studies 6 weeks after procedure. RESULTS: Intimal thickness was reduced and the intima/media ratio was significantly lower in irradiated groups than in control pigs. In the irradiated group histological examination at the edges of the stent showed thin neointimal proliferation with an intact endothelium. In all sections analyzed in the 20-Gy irradiated group the vascular media at 45 days contained necrotic areas and fibrosis with calcifications. CONCLUSIONS: After arterial injury, adequate ionizing radiation effectively reduces neointimal thickening. Irradiation-induced histological changes include previously undetected recasting with necrosis and fibrosis at the arterial edges of the stent. The parietal recasting we observed in animal arteries irradiated at high doses is unclear and a cause of concern especially after clinical spontaneous dissection was recently reported. The use of ionizing radiation for the prevention of arterial restenosis awaits confirmation with a long-term follow-up including specific experimental histological analyses.

External beam radiation therapy reduces the rate of re-stenosis in patients treated with femoral stenting: results of a randomised study.

BACKGROUND AND PURPOSE: To evaluate the feasibility and efficacy of external beam irradiation (EBI) for the prevention of re-stenosis due to neointimal hyperplasia, after percutaneous transluminal angioplasty (PTA) and stent placement of the superficial femoral artery. PATIENTS AND METHODS: A total of 60 patients with the diagnosis of superficial femoral artery stenoses or occlusions due to peripheral arterial obstructive disease underwent PTA and implantation of a self-expandable stent at their superficial femoral artery. After the procedure, patients were randomised and 30 of them received EBI (6 MV photons, total dose 24 Gy in six fractions in 2 weeks), while the rest 30 received no radiation therapy. RESULTS: EBI was technically feasible in all patients, without serious radiation related side effects. Overall, a statistically significant difference was observed in stenosis categories between the two groups at 6 months follow-up (P=0.04). More specifically, significantly more patients in the control group presented with stenosis greater or equal than 70% [EBI group 30% (9/30); control group 66.7% (20/30); P=0.009]. This difference in the percentage of re-stenosis had as a consequence significantly lower re-intervention rates among the patients of the irradiated group [17% (5/30) versus 47% (14/30); P=0.025] during the 6 months follow-up period. We also observed that the irradiated patients had re-stenosis at the stent ends, while the non-irradiated had re-stenosis at the stent ends and the lumen. Three of the irradiated patients, who discontinued the anti-platelet treatment, have shown thrombosis of the irradiated artery during the first month from the completion of the treatment. CONCLUSIONS: It is our belief that EBI is a feasible, safe and effective method for the prevention of neointimal hyperplasia at the superficial femoral artery. Further studies are deemed necessary to optimise the radiotherapy schedule.

Reduction of tissue hyperplasia with a rhenium-188 mercaptoacetyltriglycine-3-filled balloon: preliminary study in a canine urethral model.

PURPOSE: To evaluate the efficacy of beta-radiation therapy with rhenium-188 mercaptoacetyltriglycine-3 (MAG(3))-filled balloons to reduce tissue hyperplasia secondary to stent placement in 18 canine urethras. MATERIALS AND METHODS: Eight dogs were treated with 188-Re MAG(3)-filled balloon dilation immediately after stent placement and were killed 4 weeks later (group I, n = 4) or 8 weeks later (group II, n = 4). Five dogs were treated with 188-Re MAG(3)-filled balloon dilation 2 weeks after stent placement and were killed 4 weeks after stent placement (group III). The remaining five dogs were treated with conventional balloon dilation immediately after stent placement and were killed 4 weeks later; these animals formed the control group (group IV). Retrograde urethrography (RUG) was performed during follow-up and three histologic parameters were investigated: the number of epithelial layers, papillary projection thickness, and degree of submucosal inflammatory cell infiltration. The areas inside and outside the ends of the stents were evaluated in each case after animal sacrifice. After testing statistical significance of data for RUG and histologic findings in the four study groups, the Mann-Whitney U test was used to compare groups I and II to determine delayed effects of irradiation, groups I and III to determine benefits of delayed irradiation, groups I and IV to determine efficacy of immediate irradiation for reducing tissue hyperplasia, and groups III and IV to determine efficacy of delayed irradiation for reducing tissue hyperplasia. RESULTS: There were no significant differences in the four study groups on RUG before animal sacrifice. Between groups I and II, group II showed significantly lower mean values in five of six histologic comparisons. Between groups I and III, group III showed significantly lower mean values in only papillary projection thickness inside the stent ends. Between groups I and IV, group I showed significantly lower mean values in all three histologic parameters outside the stent ends. Between groups III and IV, group III showed significantly lower mean values in only two histologic parameters (papillary projection thickness in the in-stent area and inflammatory cell infiltration outside the stent edges). CONCLUSION: beta-Irradiation with use of a 188-Re MAG(3)-filled balloon shows the potential to reduce tissue hyperplasia secondary to stent placement in a canine urethral model. Treatment with 188-Re MAG(3)-filled balloons at the time of stent placement shows not only favorable outcomes for reducing tissue hyperplasia but also improved delayed effects until 8 weeks.

Post-dilatation intravascular brachytherapy trials on hypercholesterolemic rabbits using 32P-phosphate solutions in angioplasty balloons.

PURPOSE: Response of peripheral arteries to post-dilatation intravascular brachytherapy (IVBT) using 32P liquid sources was studied in a rabbit model. METHODS: The applied sources were angioplasty balloons filled with aqueous solutions of Na2H32PO4, NaCl and iodinated contrast. Dose distribution was calibrated by thermoluminescence dosimetry. The uncertainty of in vitro determinations of the activity-dose dependence was +/- 15-30%. The animal experiments were performed on rabbits with induced hypercholesterolemia. The 32P sources were introduced into a randomly chosen (left or right) iliac artery, immediately after balloon injury. Due to the low specific activity of the applied sources, the estimated 7-49 Gy doses on the internal artery surface required 30-100 min irradiations. A symmetric, balloon-occluded but non-irradiated artery of the same animal served as control. Radiation effects were evaluated by comparing the thicknesses of various components of irradiated versus untreated artery walls of each animal. RESULTS: The treatment was well tolerated by the animals. The effects of various dose ranges could be distinguished although differences in individual biological reactions were large. Only the 49 Gy dose at "zero" distance (16 Gy at 1.0 mm from the balloon surface) reduced hypertrophy in every active layer of the artery wall. The cross-sectional intimal thicknesses after 7, 12, 38 and 49 Gy doses were 0.277, 0.219, 0.357 and 0.196 mm2 respectively, versus 0.114, 0.155, 0.421 and 0.256 mm2 in controls (p < 0.05). The lowest radiation dose on the intima induced the opposite effect. Edge intimal hyperplasia was not avoided, which agrees with other reports. The edge restenosis and the variability of individual response to identical treatment conditions must be considered as limitations of the post-dilatation IVBT method. CONCLUSION: Only application of highest irradiation doses was effective. The irradiation dose should be planned and calculated for adventitia.

Sebaceous hyperplasia treated with a 1450-nm diode laser.

BACKGROUND: Sebaceous hyperplasia is a benign proliferation of the sebaceous gland. Previous treatment options have included isotretinoin, destructive modalities, and pulsed-dye laser. OBJECTIVE: To evaluate the efficacy of a 1450-nm diode laser for the treatment of sebaceous hyperplasia. METHODS: Ten patients with sebaceous hyperplasia were treated one to five times with a 1450-nm diode laser. Fluences of 16 to 17 J/cm2 were used, with cooling durations of 40 to 50 ms. Patients and physicians evaluated treated lesions for improvement. Measured areas of treated lesions were also recorded. RESULTS: In most cases, patients and physicians rated improvement as "very good" or better. After two to three treatments, 84% of lesions shrunk greater than 50%, and 70% shrunk greater than 75%. Adverse effects were unusual; one atrophic scar and one case of transient hyperpigmentation were observed. CONCLUSION: The 1450-nm diode laser is effective and safe for the treatment of sebaceous hyperplasia.

External beam ionizing radiation for inhibition of myointimal hyperplasia after dilatation and anastomoses: experimental models and results.

In recent years there has been intensive research on the use of ionizing radiation for inhibition of intimal hyperplasia (IH). Results have clearly established that beta ionizing radiation delivered from an endoluminal source after angioplasty inhibits intimal restenosis. This effect has been confirmed by recent multicenter clinical trials in patients undergoing coronary dilatation. The purpose of this study was to determine if gamma radiation therapy delivered superficially from an external source also reduced smooth muscle cell proliferation in two animals models-the first involving experimentally induced restenosis and the second involving anastomosis between a prosthesis and artery. Ultimately we hope to develop a therapeutic application for patients undergoing peripheral anastomoses, especially in the lower extremities. Two different animal models were used in this two-stage study. The first-stage rabbit model (model 1) involved balloon injury of the aorta to validate the dose effect of external beam irradiation. The second-stage porcine model (model 2) involved aortic bypass followed by external beam irradiation of the distal anastomosis site. In model 1 a total of 56 rabbits were studied. They were divided into five groups including one control group in which external radiation was not applied after balloon injury and four test groups in which external radiation was applied in a single fraction on day 0 at four different doses: 10 grays, 15 grays, 20 grays, and 25 grays. In model 2, a total of 24 pigs underwent aortic bypass with a 6-mm PTFE graft followed by irradiation of the distal end-to-side anastomosis at a dose of 20 grays on day 0. In both models specimens were harvested after 6 weeks and studied histologically after staining with HES and orcein, histomorphometrically by measuring intimal hyperplasia, and immunohistochemically using actin and factor VIII/von Willebrand factor (F VIII/vWF). The zones of study on the anastomosis were separated into base of the artery to the tip and heel of the anastomosis and the edge of the arteriotomy. Measurements were compared using the Mann Whitney test. In the first-stage model designed to study IH in rabbits, mean intimal and medial thickness values and the intima-to-media ratio showed no difference between the control group and the groups irradiated at doses of 10 grays and 15 grays (p = 0.111, p = 0.405, and p = 0.14); (p = 0.301, p = 0.206, and p = 0.199). Conversely, there was a significant difference between the control group and the groups irradiated at 20 grays and 25 grays (p < 0.0001, p = 0.107 and p = 0.008; p = 0.008, p = 0.155, and p = 0.008). Histological examination demonstrated extensive changes in the wall with high-grade fibrosis after application of ionizing radiation. In the second-stage swine model, irradiation significantly inhibited development of IH at the level of anastomosis both at the base of the artery (p < 0.01) (tip 0.06 vs. 0.27 mm and heel 0.04 vs. 0.36) and at the level of the arteriotomy at the suture site (p < 0.001) (0.13 vs. 0.86 mm). Immunochemical analysis of the thickened zones showed a positive reaction of endothelial cells to smooth muscle actin and F VII/vWF. Like irradiation applied using an endoluminal source, superficial gamma ionizing radiation from an external source inhibits IH. Analysis of the dose effect showed that the overall dose must be between 15 and 20 grays. External radiation also reduces overall IH at the anastomosis between a prosthesis and artery. Although these experimental data are promising, further study will probably be necessary before attempting to undertake clinical trials using external beam radiation therapy for patients undergoing peripheral anastomoses.