Thorotrast associated nodular regenerative hyperplasia of the liver.
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A case of nodular regenerative hyperplasia (NRH) of the liver is described in association with exposure to the radiographic contrast medium Thorotrast. This is the first case in which the pathological findings have been fully documented. It is suggested that NRH may have developed through Thorotrast induced damage to portal vein radicles. (+info)
p53 mutations in tumor and non-tumor tissues of thorotrast recipients: a model for cellular selection during radiation carcinogenesis in the liver.
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Concerns over cancer development from exposure to environmental sources of densely ionizing, high linear energy transfer (LET) radiation, such as alpha-particles from radon, is a current public health issue. The study of tumors attributable to high LET irradiation would greatly augment our insights into the biological mechanisms of carcinogenesis. Chronic low-dose-rate internal exposure to alpha-radiation from thorium dioxide deposits following intravascular administration of the radiographic contrast agent Thorotrast is known to markedly increase the risk of cancer development, especially that of hepatic angiosarcomas and cholangiocarcinomas. Although the mechanism is hypothesized to be via cellular damage, DNA being a major target, wrought by the high LET alpha-particles, the specific genes and the actual sequence of events involved in the process of transforming a normal cell into a malignant one are largely unknown. To shed some light on the molecular mechanisms of cancer development during a lifetime exposure to alpha-radiation, we analyzed the most commonly affected tumor suppressor gene in humans, p53, in 20 Thorotrast recipients who developed cancer, mostly of hepatic bile duct and blood vessel origin. Of the 20 cases, 19 were found to harbor p53 point mutations. Moreover, the accompanying non-tumor tissues from these patients also had p53 mutations, albeit at lower frequency. The distribution pattern of the point mutations was significantly different between the non-tumor and tumor tissues, with most mutations in malignant tissues located in the highly conserved domains of the p53 gene. Our results support the idea that p53 mutations are important in the genesis of Thorotrast-induced tumors but that these point mutations are a secondary outcome of genomic instability induced by the irradiation. Additionally, non-tumor cells harboring p53 mutations may gain some survival advantage in situ but mutations in the domains responsible for the formation of structural elements critical in binding DNA may be necessary for a cell to reach full malignancy. (+info)
Inhibition of intravascular fibrin deposition by dipyridamole in experimental animals.
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Intravascular fibrin deposition was induced in rabbits by endotoxin, the infusion of fibrin monomer (FM), and by the infusion of thrombin and EACA. A previously developed radioisotope technique was used to measure the fibrin deposits in various organs. Dipyridamole treatment of rabbits caused significant inhibition of fibrin deposition in all three experimental models. The drug also inhibited platelet consumption and, in the thrombin- and EACA-infused animals, fibrinogen consumption as well. The results obtained with dipyridamole were compared with the effect of thorotrast. It was concluded from this comparison that the effect of dipyridamole could not be attributed to inhibition of the reticuloendothelial system. It is postulated that dipyridamole inhibits the final step at which soluble FM is precipitated as fibrin in vivo. (+info)
Locoregional late effects of paravascular thorotrast deposits: results of the german thorotrast study.
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PURPOSE: The aim of this study was to assess late effects of long-term exposure to alpha irradiation caused by paravascular Thorotrast deposits. SUBJECTS AND METHODS: 899 patients, who had received the radioactive contrast medium Thorotrast for angiography in the 1930s and 1940s, and 662 controls were followed-up since 1968 every two years by standardized clinical and laboratory examinations. Initially, X-ray plain films of the thorax, upper abdomen and the former injection site were performed. In selected patients the sites of paravascular Thorotrast deposits were evaluated by ultrasonography, CT and MRI. RESULTS: Paravascular Thorotrast deposits were detected in 245 patients. Clinical symptoms related to deposits appeared 10 to 30 years after Thorotrast administration. The severity of symptoms depended on the location and extension of granulomas and were mainly caused by fibrosis, nerve paralysis and vascular changes. Four malignant tumors adjacent to granulomas were observed (one soft tissue sarcoma in the groin, two squamous cell carcinomas of the parotid gland and one lymphoepithelial carcinoma of the nasopharynx). MRI including MRA allowed an accurate determination of tissue damage, whereas the utility of US and CT was restricted due to strong sound attenuation and streak artefacts caused by the high X-ray absorption of Thorotrast. DISCUSSION AND CONCLUSION: Locoregional late effects of paravascular Thorotrast deposits mainly comprise radiation induced, fibrotic tissue destruction. The incidence of malignant tumors, in particular sarcomas, adjacent to deposits, however, is much lower than initially expected. (+info)
Implanted depleted uranium fragments cause soft tissue sarcomas in the muscles of rats.
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In this study, we determined the carcinogenicity of depleted uranium (DU) metal fragments containing 0.75% titanium in muscle tissues of rats. The results have important implications for the medical management of Gulf War veterans who were wounded with DU fragments and who retain fragments in their soft tissues. We compared the tissue reactions in rats to the carcinogenicity of a tantalum metal (Ta), as a negative foreign-body control, and to a colloidal suspension of radioactive thorium dioxide ((232)Th), Thorotrast, as a positive radioactive control. DU was surgically implanted in the thigh muscles of male Wistar rats as four squares (2.5 x 2.5 x 1.5 mm or 5.0 x 5.0 x 1.5 mm) or four pellets (2.0 x 1.0 mm diameter) per rat. Ta was similarly implanted as four squares (5.0 x 5.0 x 1.1 mm) per rat. Thorotrast was injected at two sites in the thigh muscles of each rat. Control rats had only a surgical implantation procedure. Each treatment group included 50 rats. A connective tissue capsule formed around the metal implants, but not around the Thorotrast. Radiographs demonstrated corrosion of the DU implants shortly after implantation. At later times, rarifactions in the radiographic profiles correlated with proliferative tissue responses. After lifetime observation, the incidence of soft tissue sarcomas increased significantly around the 5.0 x 5.0 mm squares of DU and the positive control, Thorotrast. A slightly increased incidence occurred in rats implanted with the 2.5 x 2.5 mm DU squares and with 5.0 x 5.0 mm squares of Ta. No tumors were seen in rats with 2.0 x 1.0 mm diameter DU pellets or in the surgical controls. These results indicate that DU fragments of sufficient size cause localized proliferative reactions and soft tissue sarcomas that can be detected with radiography in the muscles of rats. (+info)
The relationship between internally deposited alpha-particle radiation and subsite-specific liver cancer and liver cirrhosis: an analysis of published data.
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Chronic exposure to high LET radiation has been shown to cause liver cancer in humans based on studies of patients who received Thorotrast, a colloidal suspension of thorium dioxide formerly used as a radiological contrast agent, and on studies of Russian nuclear weapons workers exposed to internally ingested plutonium. Risk estimates for these exposures and specific subtypes of liver cancer have not been previously reported. Combining published data with tumor registry data pertinent to the Thorotrast cohorts in Germany, Denmark, Portugal, and Japan and to Russian workers, we generally found significantly elevated risks of three major histologic types of liver tumors: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), and hemangiosarcoma (HS) for Thorotrast exposures. In contrast, HS was the only liver tumor significantly associated with the lower alpha-particle doses experienced by the Russian workers. Excess cases per 1,000 persons exposed to Thorotrast were similar for the three liver cancer subtypes but lower for plutonium exposure. Odds ratios (OR) of HS and CC for Thorotrast were from 26 to 789 and from 1 to 31 times higher than those for HCC, respectively. ORs of liver cirrhosis for Thorotrast exposure ranged from 2.7 (95% confidence interval (CI): 2.2-3.4) to 6.7 (5.1-8.7). (+info)
Fatal abdominal thorotrast granuloma.
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We report a case of fatal abdominal thorotrast granuloma seen in a 65-year-old man who had undergone a femoral angiography of thorotrast with some accidental extravasation 49 years previously. As the thorotrast granuloma gradually increased in size, it caused ureteral obstruction, venous thrombosis, and perforation of the urinary bladder and rectum. Symptomatic abdominal thorotrast granuloma is quite rare and this is the first reported case of the granuloma associated with perforation through the urinary bladder and rectum. (+info)
STUDIES ON THE LYMPHOCYTOSIS INDUCED IN MICE BY BORDETELLA PERTUSSIS.
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1. Intravenous injection into mice of phase I Bordetella pertussis vaccine resulted in a striking hyperleucocytosis with a predominating lymphocytosis. Intraperitoneal inoculation was less effective, and subcutaneous administration was inactive. 2. Active immunization prevented the hyperleucocytosis; passive immunization was less effective. 3. Reticuloendothelial blockage reduced the effect of the vaccine. 4. Extirpation of the spleen or thymus did not alter the leucocyte response. 5. Histologic studies suggested that the increase in circulating lymphocytes resulted from release of cells from lymphoid organs, including the thymus. (+info)