RESUMEN
AIM: To demonstrate changes in gastric mucosal blood flow caused by intraoperative radiotherapy of the celiac artery combined with external radiotherapy of the upper abdomen in a rabbit model. The study was designed to identify a possible correlation between a radiation-induced reduction in mucosal blood flow and the induction of gastric ulcer. MATERIAL AND METHOD: Intraoperative radiation doses of 0 or 30 Gy were given to the celiac artery in rabbits. After a delay of 14 days external radiotherapy of the upper abdomen with 3 x 4 Gy/week to a maximum total dose of 40 Gy was initiated. Gastric mucosal blood flow was assessed by intraventricular injection of radioactively-labelled microspheres (15 microns) followed by measurement of radioactivity in the mucosa. The injections were performed at various time intervals between 2 and 63 days after intraoperative radiation. RESULTS: Intraoperative radiotherapy, including sham-intraoperative radiation, resulted in a transitory reduction of mucosal blood flow by about 50% of the control value on day 7 (Figure 3). After a temporary recovery by day 14, a marked and permanent reduction in blood flow was assessed after week 6. This time corresponds to the time of development of gastric ulcer. CONCLUSIONS: A relationship between the time of ulcer development and of reduced gastric mucosal blood flow was observed after combined intraoperative and external radiotherapy. The mechanical component of intraoperative treatment has to be emphasized. Reduced blood flow was also seen after intraoperative radiotherapy alone, without an induction of ulcer by this treatment. Hence additional mucosal damage by external radiation must be present for the induction of gastric ulcer.
Asunto(s)
Arteria Celíaca/efectos de la radiación , Mucosa Gástrica/irrigación sanguínea , Cuidados Intraoperatorios , Abdomen/efectos de la radiación , Animales , Radioisótopos de Cerio , Relación Dosis-Respuesta en la Radiación , Femenino , Microesferas , Conejos , Flujo Sanguíneo Regional/efectos de la radiación , Úlcera Gástrica/etiología , Úlcera Gástrica/fisiopatología , Factores de TiempoRESUMEN
The present immunohistochemical study of radiation-induced damage in major blood vessels is based on a multidisciplinary study (Schultz-Hector et al., Radiother. Oncol., 38: 205-214, 1996) investigating the combined effect of IORT of the coeliac axis and upper abdominal ERT. The paper describes the sequential changes occurring in the coeliac artery after IORT with 30 Gy, i.e. during and after combined IORT and fractionated ERT (total dose 40 Gy). Within 24 h after IORT, the arterial wall was found to be invaded by TNF-alpha positive macrophages, which later on disappeared within 7-14 days. At 2 days post-IORT, the medical smooth muscle cells were strongly positive for TNF-alpha and remained positive throughout the observation period of 63 days. At 80 days, a comparison of different IORT dose groups showed that TNF-alpha expression after 20 and 30 Gy IORT plus 40 Gy ERT had subsided, while it was still strongly evident after 40 Gy IORT. Negative reactions in sham irradiated animals or animals treated with ERT alone indicate that TNF-alpha expression was caused by IORT. After > 30 days post-IORT, there was increased collagen type I deposition in the adventitia. In two animals receiving the full ERT course, intimal proliferations involving mainly smooth muscle cells were observed. Our findings indicate that some features typical of radiation induced arteriosclerosis such as periarterial fibrosis and intimal proliferations can occur as early as < 60 days postirradiation. Macrophage invasion as well as TNF-alpha expression in medial smooth muscle cells are known to be important steps in the development of spontaneous atherosclerotic lesions. Therefore, early TNF-alpha induction in the arterial wall by a high local dose of X-irradiation may be regarded as one initiating factor of chronic radiation-induced arteriosclerosis.
Asunto(s)
Arteria Celíaca/efectos de la radiación , Músculo Liso Vascular/efectos de la radiación , Traumatismos Experimentales por Radiación/etiología , Vasculitis/etiología , Animales , Arteriosclerosis/etiología , Arteriosclerosis/metabolismo , Arteriosclerosis/patología , Arteria Celíaca/metabolismo , Arteria Celíaca/patología , División Celular/efectos de la radiación , Colágeno/metabolismo , Colágeno/efectos de la radiación , Densitometría , Femenino , Inmunohistoquímica , Cuidados Intraoperatorios/efectos adversos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Conejos , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/patología , Dosificación Radioterapéutica , Radioterapia de Alta Energía/efectos adversos , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/efectos de la radiación , Vasculitis/metabolismo , Vasculitis/patología , Rayos X/efectos adversosRESUMEN
An experimental model in the rabbit is presented which is suitable for analysis of clinically relevant, early side-effects of combined upper abdominal IORT and ERT. Fractionated ERT alone given through an upper abdominal a.-p. field including the entire stomach caused gastric ulcerations within < or = 58 days. Latent times decreased with increasing dose and the ED50 for occurrence of ulcers was 39 +/- 3.3 Gy. Single doses of IORT of 20-40 Gy alone administered through a 2-cm diameter field localized on the coeliac axis and carefully excluding any intestinal mucosa caused neither gastric ulcerations nor other clinical symptoms. When ERT with 40 Gy was preceded by IORT with 20-40 Gy or by sham IORT, 13 out of 15 animals developed ulcers after latent times which in a life-table analysis were shown to be significantly shorter than after ERT alone. However, a statistically significant IORT dose-dependence of latent time or incidence of ulcers could not be demonstrated in the present experiment. The most significant histological changes were observed in the areas of gastric ulcers. Already during ERT, the mucosal epithelium was depleted and regenerative activity was evident in spite of ongoing fractionated irradiation. However, profound irregularities in glandular structure and distribution, as well as number of proliferating epithelial cells were still present in healed ulcers at 80 days. In summary, IORT to the coeliac artery did precipitate the development of gastric ulcers induced by subsequent ERT. On the one hand, the data indicate that the surgical procedure of IORT did contribute to this effect. On the other hand, IORT to the coeliac artery could cause transient, functional alterations in blood supply to the depending organs, i.e. the stomach, and could thus precipitate the development of radiation-induced ulcers.
Asunto(s)
Cuidados Intraoperatorios/efectos adversos , Traumatismos Experimentales por Radiación/patología , Úlcera Gástrica/etiología , Animales , Arteria Celíaca/efectos de la radiación , Modelos Animales de Enfermedad , Femenino , Mucosa Gástrica/efectos de la radiación , Conejos , Dosis de Radiación , Radioterapia de Alta Energía/efectos adversos , Úlcera Gástrica/patología , Factores de TiempoRESUMEN
BACKGROUND: In the course of radiation therapy of malignant tumors, inclusion of major arteries into the radiation field is often inevitable. PATIENTS AND METHODS: Clinical case reports and studies were compiled and analyzed with respect to the effect of irradiation on the risk of arteriosclerotic changes within the radiation field. The study concentrates on those anatomic locations which are involved frequently enough in order to allow a quantitative analysis. RESULTS: In a series of clinical studies, a consistent 3- to 4-fold increase in carotis stenoses is observed following radiation therapy of head and neck tumors. The majority of clinically symptomatic stenoses, however, is not observed earlier than 8 years post irradiation. Although observations in other peripheral arteries do not allow to estimate incidences, they do confirm, however, the finding of a very long latent time. Following mediastinal or thoracic wall irradiation, the risk of coronary artery disease is significantly increased after follow-up times of > or = 10 years. Radiation related arterial injury is sharply limited to arterial segments included in the treatment field and is often observed in unusual locations. The histological appearance and development however, is not fundamentally different from lesions observed in cases of generalized arteriosclerosis. Experimental observations indicate that patients with general arteriosclerosis risk factors might have a particularly increased risk of developing arterial injury following therapeutic irradiation. CONCLUSION: Irradiation of large blood vessels in the course of tumor therapy represents a long-term local risk factor for development of arteriosclerosis.