Disease relevance of Thorotrast

• Survey of thorotrast-associated liver cancers in Japan [1].
• RESULTS: The cumulative risk for cancer at all sites (excluding brain tumors where the standardized incidence ratio [SIR] was 28) reached 86% 50 years after Thorotrast injection [2].
• A retrospective epidemiological study of deaths from hepatic angiosarcoma (HAS) in the U.S. showed that during 1964--74 there were 168 such cases, of which 37 (22%) were associated with previously known causes (vinyl chloride, 'Thorotrast', and inorganic arsenic) and 4 (3.1%) of the remaining 131 cases with the use of androgenic-anabolic steroids [3].
• Our results suggest that the increased risk for cancers of the liver and biliary tract among Danish epileptic patients is likely to be due to Thorotrast administration and factors associated with cirrhosis of the liver rather than to anticonvulsive treatment [4].
• A human hepatoma cell line, associated with thorotrast exposure, from an hepatitis B marker-negative patient was established as a permanent cell line (Mz-Hep-1) in tissue culture [5].

Psychiatry related information on Thorotrast

• In addition, the MSI(+) phenotype was not associated with the quantity of Thorotrast deposited or the latency period of ICC induction [6].

High impact information on Thorotrast

• Among 7,864 patients with epilepsy not known to have received radioactive Thorotrast, record linkage with national cancer incidence files identified 789 cancers, compared to 664 expected [relative risk (RR) = 1.19; 95% confidence interval = 1.11-1.27] [7].
• When yearly distribution, age, and time after thorotrast injection of patients with HPC were correlated with those of patients with other liver cancers, the only statistically significant difference between patients with HPC and patients with CLC (P less than 0.02) was in the years after thorotrast administration [1].
• The lack of fusion was evident in both fluorescence and electron micrographic studies which followed the transfer of acridine orange or Thorotrast from 2 degrees lysosomes to phagosomes [8].
• Experiments with cationized ferritin and Thorotrast provide evidence that internalization of these macromolecules takes place through the pits by pinocytosis [9].
• By the use of Thorotrast, we were able to demonstrate that the cell surface is deeply infolded, extending all the way to the hip joint [10].

Chemical compound and disease context of Thorotrast

• After exclusion of study subjects exposed to Thorotrast, no association was seen between treatment with phenobarbital and cancer of the liver (odds ratio, 1.0; 95% confidence interval, 0.1-8.0) or biliary tract (odds ratio, 0.8; 95% confidence interval, 0.1-4.2) [4].
• Autopsy findings and autoradiographs in 1 patient strongly suggest that persisting thorotrast deposits in the infantile vertebrae and pelvis have produced a chronic radiation osteitis and dense thickened bone trabeculae, which are more radiopaque than the surrounding adult bone [11].
• Therefore, we collected paraffin-embedded, formalin-fixed archival tissues from 18 hepatocellular carcinomas, 9 cholangiocarcinomas, and 9 hepatic angiosarcomas from Thorotrast-exposed patients [12].
• (2) Liver cancer and leukaemia in patients given intravascular injections of Thorotrast, a thorium-232 oxide preparation that concentrates in liver, spleen and bone marrow [13].
• A 72-year-old woman was found at autopsy to have hepatic angiosarcoma approximately 30 years after systemic thorium oxide (Thorotrast) injection [14].

Biological context of Thorotrast

• 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 [15].
• Since radiation induces genomic instability, we analyzed MSI in Thorotrast-induced ICC [6].
• Lung carcinoma and malignant mesothelioma in patients exposed to Thorotrast: incidence, histology and p53 status [16].
• 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 [15].
• However, frameshift mutations of mononucleotide repeats were not observed in Thorotrast ICC [6].

Anatomical context of Thorotrast

• Intravenously administered Thorotrast was observed in endothelial cells and in the extravascular spaces within 3 min after injection into thrombocytopenic animals, while it was seen only intravascularly in control rabbits [17].
• Use of electron-dense thoria particles to mark donor cells demonstrated the presence of injected cytoplasm in the vacuoles [18].
• In previous studies, this structure has often been described merely as "fibrin". After i.v. injection of Thorotrast, sterile vegetations showed remarkable accumulations of mononuclear phagocytes containing this substance, on surfaces projecting into the bloodstream [19].
• Minimal Thorotrast deposition in parapancreatic lymph nodes [20].
• The evidence from Thorotrast transfer and assessment of yeast viability indicates that C. albicans largely resists intracellular killing by resident macrophages in the face of entirely uninhibited P-LF [21].

Associations of Thorotrast with other chemical compounds

• Plain abdominal radiography demonstrated calcification in three patients and evidence of Thorotrast (thorium dioxide) deposition in one [22].
• In 2 adults who had received thorotrast intravenously at ages 2 and 3 years, respectively, radiopaque outlines of their infantile vertebrae were seen in the adult vertebrae [11].
• After ingestion of viable C. albicans by labeled cells, delivery of AO to phagosomes was highly suppressed (90%), and yet Thorotrast delivery was almost universal [21].
• Mouse peritoneal macrophages from glucocorticosteroid-treated animals fromed phagolysosomes just as effectively as macrophages from untreated animals (72% thorotrast-positive vacuoles in hydrocortisone-treated animals; 78% in controls) [23].
• These features are typical of "Thorotrastoma." Thorotrast stains greenish-brown with hematoxylin and eosin and appears as refractile granular particles of relatively uniform size either within histiocytes or as free material [24].

Gene context of Thorotrast

• We investigated mutations of the RAS and the TP53 genes in archival sections of ICC induced by Thorotrast [25].
• Compared to ICC that was not associated with Thorotrast, the frequency of mutation of the KRAS gene was lower, while that of the TP53 gene was more than two times higher [25].
• Methylation of the hMLH1 promoter was associated with the MSI(+) phenotype in Thorotrast ICC [6].
• Promoter regions of both the hMLH1 and the hMSH2 MMR genes tended to be hypermethylated in the tumor part compared to the adjacent nontumor part in Thorotrast ICC [6].
• The CAA-->CTA mutation, previously found at codon 61 of the Ha-ras gene in rat HCC, was observed in 5 further VC-induced HCC but was not detected in the Thorotrast-induced HCC, suggesting carcinogen-specificity [26].

Analytical, diagnostic and therapeutic context of Thorotrast

• PURPOSE: We re-established a formerly identified cohort of neurological patients receiving injections of Thorotrast for cerebral arteriography and assessed their incidence of cancer [2].
• A patient underwent cerebral angiography with thorium dioxide (Thorotrast) [27].
• Thorotrast was demonstrated in tissue sections by transmission and scanning electron microscopy, radioautography, and x-ray spectrometry [28].
• We report a case of recurrent Thorotrast into a liver allograft 10 years post-transplant [29].
• Adhesive arachnoiditis, a meningioma and a schwannoma were found at autopsy in a 56 year old man who had undergone Thorotrast myelography 33 years previously [28].

References