Long-term incidence in hepatocellular carcinoma and intrahepatic bile duct cancer in Denmark, Finland, Norway and Sweden, role of Thorotrast?

We analyzed long-term incidence trends in liver cancer (including hepatocellular carcinoma and intrahepatic cholangiocarcinoma) with an aim to interpret the changes in terms of known risk factors and hypothesize that historical exposure to Thorotrast, a radiographic contrast medium emitting alpha particles, has changed population rates. The NORDCAN database was used to collect cancer registry data from Denmark (DK), Finland (FI), Norway (NO) and Sweden (SE), which we used from 1953 (DK, FI and NO) and 1960 (SE) through 2019. Thorotrast, which caused a 100-fold risk of liver cancer was used in DK and SE, and probably also in FI between 1930 and 1950, but not in NO. The incidence trend for liver cancer showed a broad maximum at around 1980, most prominent and statistically significant in SE and DK men and women, and in all countries, a steadily increasing trend towards the end of follow-up. Incidence for NO was lower than for the other countries and the rates showed no peaking at around 1980. Birth cohort analysis identified a transient risk which could be dated to a period between 1930 and 1950 in countries other than NO. Considering a lag time between Thorotrast use and liver cancer appearance, the large incidence peak around 1980 in DK and DE was probably contributed by Thorotrast but considering the ecological nature of the findings, the association should be considered cautiously as hypothesis generating. The late increase in liver cancer risk is most likely lifestyle related and largely preventable.

Radiation databases and archives - examples and comparisons.

Studies of ionizing radiation effects through the archiving of data began with standardizing medical treatments in the early 1900s shortly after the discovery of X-rays. Once the breadth of the delayed effects of ionizing radiation was recognized, the need for long-term follow up became apparent. There are now many human archives of data from nuclear disasters and accidents, occupational exposures, and medical procedures. Planned animal irradiation experiments began around the time of the Cold War and included a variety of doses, fractions, dose rates, and types of ionizing radiation. The goal of most of these studies was to supplement information coming from human data through carefully planned experimental conditions and immediate and uninterrupted data collection. This review aims to highlight major archives and databases that have shaped the field of radiation biology and provide a broad range of the types of datasets currently available. By preserving all of these data and tissue sets, radiation biologists can combine databases and conduct large-scale analyses of detailed existing data and perform new assays with cutting edge scientific approaches.

Radiation pathology: from thorotrast to the future beyond radioresistance.

The effects of radiation on human health have been a major concern, especially after the Fukushima Daiichi Nuclear Power Plant (FNPP) accident. We can determine these effects only from radiological disasters. The radiological contrast medium Thorotrast is known to induce hepatic cancers decades after injection. Using archival materials from Thorotrast patients, we performed molecular pathological studies to elucidate carcinogenic mechanisms of internal radiation exposure. It is emphasized here that radiation-induced cancers are a complex consequence of biological response to radiation and ingested radionuclides. We further expanded the study to establish clinically relevant radioresistant cancer cells in order to develop more effective and less harmful radiation therapy. We also found that cancer cells can acquire radioresistance by low-dose fractionated radiation within one month. The FNPP accidents prompted us to collect tissue samples from animals in and around the evacuation zone in order to construct a tissue bank. The final goal of the bank is to enable research that will contribute to the common understanding of radioprotection.

Hepatic angiosarcoma occurring 65 years after thorium dioxide (Thorotrast) exposure: imaging, surgical and histo- pathologic findings of a historical case.

We report the CT, surgical and histopathologic findings of a rare case of Hepatic Angiosarcoma (HAS) diagnosed in a 85-year old women 65 years afterThorotrast (Th232) exposure for angiography. At the early arterial phase of dynamic MDCT, peripheral curvilinear and central nodular puddling of contrast produced in the 8 cm tumor.Then progressive contrast filling of the tumor was observed on the delayed scans. Associated pathognomonic signs related to previous Th232 exposure were also found comprising diffuse intrahepatic reticular bands of calcifications, numerous calcified epigastric lymph nodes and a calcified shrunken spleen. Emergency laparotomy was performed because of associated hemoperitoneum. With a delay of 65 years afterThorotrast exposure, this historical case probably represents, to our knowledge, the most delayed presentation of Th232 related HAS ever published.

Incidental hyperdensities within the reticuloendothelial system.

This is a case report of a 79-year-old woman who was found to have numerous hyperdense nodular lesions in the upper abdomen, which were incidentally discovered during routine follow-up of a lung nodule. These hyperdense lesions included a lace-like reticular distribution within the liver, multiple extremely dense lymph nodes, and a shrunken hyperdense spleen. We discuss differential considerations for such a constellation of findings and explain why we believe the findings in this case are consistent with prior thorium dioxide exposure. We conclude with a discussion of the pathophysiology and important complications of thorium dioxide exposure and the best imaging modalities for its detection. We believe that this is an important entity that all physicians should be aware of because even though it is seldom seen today, it has characteristic imaging findings and the correct diagnosis is critical given the increased risk of malignancy for which such patients should be screened for.

[The medical management of high risk individuals. Experiences with persons exposed to chronic internal irradiation]. / Über den ärztlichen Umgang mit Hochrisikopersonen. Erfahrungen bei Personen mit chronischer interner Strahlenexposition.

The medical management and counseling of persons at high risk due to exposure to chemicals or radiation or due to personal disposition, present an additional challenge for physicians and especially radiologists involved. This article is based on own experiences with patients who had been exposed to Thorotrast. They had been injected with the contrast medium Thorotrast, which was in use world-wide until around 1950. Thorotrast caused a chronic alpha irradiation mainly of the liver (up to 0.4 Gy/a), spleen (1.2 Gy/a) and bone marrow (0.1 Gy/a). For the Thorotrast patients and their physicians the most worrying problem was the risk of primary malignant liver tumors which occurred in more than 20% of the exposed persons, i.e. 100 times more frequently than in a non-exposed control group. The medical and especially radiological experiences with the management of these patients summarize a general aspect of the problem and can be referred to when managing other high risk groups.

Histological type of Thorotrast-induced liver tumors associated with the translocation of deposited radionuclides.

Exposure to internally deposited radionuclides is known to induce malignant tumors of various histological types. Thorotrast, a colloidal suspension of radioactive Thorium dioxide ((232)ThO(2)) that emits alpha-particles, was used as a radiographic contrast during World War II. Thorotrast is known to induce liver tumors, particularly intrahepatic cholangiocarcinoma (ICC) and angiosarcoma (AS), decades after injection. Therefore, patients injected with Thorotrast comprise a suitable study group to understand biological effects of internal ionizing radiation injury. Autoradiography and X-ray fluorescence spectrometry (XRF) were carried out on non-tumorous liver sections from Thorotrast-induced ICC (T-ICC) and Thorotrast-induced AS (T-AS). Autoradiography revealed that the slope of the regression line of the number of alpha tracks for the amount of deposited Thorium ((232)Th) was higher in non-tumorous parts of the liver with T-ICC than those with T-AS. XRF showed that the intensity ratio of Radium (Ra) to Thorium (Th) in non-tumorous liver tissue with T-ICC was significantly higher than that with T-AS. Furthermore, the mean (228)Ra/(232)Th radioactivity ratio at the time of death calculated was also significantly higher in T-ICC cases than in T-AS cases. These suggest that the metabolic behavior of radionuclides such as relocation and excretion, as well as the content of deposited radionuclides, is a major factor in determining the histological type of Thorotrast-induced liver tumors.

Ionizing radiation: a risk factor for mesothelioma.

In the majority of mesothelioma cases worldwide, asbestos is a likely causal factor, but several alternative factors, such as ionizing radiation, have been recognized. We reviewed ionizing-radiation evidence from epidemiology studies of (1) patients exposed to the diagnostic X-ray contrast medium "Thorotrast," (2) patients undergoing radiation therapy (i.e., to treat cancer), and (3) atomic energy workers chronically exposed to lower levels of radiation. The results from these populations are also supported by case reports of mesothelioma following therapeutic radiation. Statistically significant associations were found in many, but not all, epidemiology studies (particularly those of Thorotrast- and radiation-treated patients). Given the low mesothelioma rate in the general population, the consistently increased risk among these radiation-exposed individuals is noteworthy. Many studies were limited by the lack of a uniform manner in which mesothelioma was reported prior to introduction of a uniform classification system (ICD-10). Future studies that rely on ICD-10 should have greater power to detect an association. While the evidence falls short of a definitive causal link, considering studies in which statistical significance was achieved, the case reports, and the plausible mode of action, we conclude that the evidence is supportive of a causal link between ionizing radiation exposure and mesothelioma risk.

Long incubation period for the induction of cancer by thorotrast is attributed to the uneven irradiation of liver cells at the microscopic level.

Irradiation from internally deposited radionuclides induces malignant tumors. Ingested long-lived radionuclides accumulate in specific organs that are irradiated throughout life. To elucidate why the development of malignant tumors requires long-term internal exposure, of the order of decades, despite the fact that irradiation is continuous over this period, we analyzed intrahepatic cholangiocarcinoma in Thorotrast patients (Th-ICC). Autoradiography showed that the density of alpha-particle tracks was 50 times more concentrated than would be expected if Thorotrast were evenly distributed throughout the liver. The age-incidence curves revealed that while the incidence of hepatobiliary cancer in Japan increased in proportion to the 7th power of age, that of Th-ICC increased to the 6th power. Internal radiation significantly increased the randomness of hepatocyte distribution but not the density. Three major factors are considered to be responsible for the long incubation time: the uneven distribution of radionuclides, the limited range of radiation, and the movement of tumor precursor cells. Target cells susceptible to malignant transformation may undergo one event and may then migrate outside of the range of alpha particles, thereby avoiding immediate induction of successive additional events that would lead to cell death or neoplastic changes.

Mortality among Thorotrast-exposed patients and an unexposed comparison group in the German Thorotrast study.

Thorotrast was the brand name of a stabilised colloidal solution of thorium dioxide which was used preferentially as an X-ray contrast medium for arteriography between 1930 and 1950. The administration of the medium led to lifelong chronic alpha-particle irradiation by thorium decay products, mainly in the organs of deposition. Several epidemiological follow-up studies were set up after recognition of these side-effects among which the German study was the largest. After an extended follow-up, by 2004 only nine out of 2326 originally exposed subjects were still alive (while 151 of the comparison group, which originally numbered 1890 subjects, survived) and partially more than 70 years observation and chronic exposure time could be studied allowing for further observations to be made about long-term mortality effects of Thorotrast exposure. Median life-expectancy was shortened by 14 years and mortality increased, affecting total mortality SMR=287 for males, SMR=387 for females) as well as cause-specific, especially liver cancer (SMR=16,695 and SMR=12,680, respectively), and the haematopoietic system (SMR=556 and SMR=504, respectively), but not lung cancer. Mortality (total and selected cause-specific) increased with cumulative time since first exposure.

Thorium dioxide-related haemangiosarcoma of the liver.

Rare tumours of the liver are occasionally seen; thorium dioxide-related haemangiosarcoma of the liver, with an estimated frequency of 0.14 to 0.25 per million in the normal population, is one of these. Causes, epidemiology and pathobiology are described related to a clinical case of angiosarcoma. A differentiation of hepatic tumours with imaging techniques is presented. Last, a short review on up-to-date treatment of haemangiosarcoma is discussed. Lessons can always be learned from history: will the contrast agent gadolinium be the Th232 of this era?

[Electrophoretic and immunochemical research of rat urine proteins in dynamics after intravenous injection of thorium dioxide (thorotrast)].

Rats were treated with a single intravenous injection of thorotrast (thorium dioxide)--the source of alpha-rays. Dynamic investigation of urine protens of rats by methods of electrophoresis and immunoelectrophoresis was carried out during 22 months after thorotrast injection. Already the month after drug injection the selectivity of tubular reabsorbtion was disturbed. Three months after thorotrast injection the content of urinal proteins of tissue (in particular renal) origin was decreased. Finally the selectivity of renal filtration of proteins was damaged 4-6 months after thorotrast introduction. Serum proteins which were absent in normal urine (for example transferrin and lipoproteins) appeared in urine of affected rats. The urine proteins of serum origin were less degraded than those in normal urine. The alterations of glomerular filtration was increased up to 20-22 months when the spectrum of urine proteins became similar to the spectrum of serum proteins. The death of treated rats was occurred in this period. Thus the monitoring of urine proteins of rats treated with alpha-ray producing preparation throtrast allows to register the successive alterations of reabsorbtion, excretion and filtration functions of kidney.

Cholangiocarcinoma in association with Thorotrast exposure.

Thorotrast is a colloidal suspension of thorium dioxide that was used as an intravascular contrast agent until the 1950's. It is retained by the reticuloendothelial system, and because it emits densely ionizing radioactivity thorium dioxide it is carcinogenic. Two patients with prior thorium dioxide exposure diagnosed with cholangiocarcinoma and recently treated at the Massachusetts General Hospital are presented. Radiology, treatment, pathologic findings, and relevant literature are discussed.