Search

Detection of gadolinium deposits in patients who have repeatedly been administered intravenous gadolinium chelates have given rise to concern regarding the long-term safety of magnetic resonance imaging (MRI) contrast media. Nevertheless, negative long-term clinical effects have not yet been observed. In some publications parallels have been drawn to the sequelae of thorotrast that was formerly used for arterial angiography. In this article the history of thorotrast use is briefly described and in particular why, despite warnings, this substance was used frequently and worldwide. A brief summary of the results of the German Thorotrast Study revealed that high excess rates were only observed for primary malignant liver tumors after a 15-year or longer latency period and to a lesser degree of leukemias, as well as for severe local complications due to paravascular injections, particularly in the neck region. Based on this historical review, we will venture to take stock of the outcome from the "success story" of this contrast agent.

A 69-year-old man presented with sudden onset of pain in the right upper abdomen. An enlarged liver and jaundice were found by his family physician and he was referred to our University Hospital. In 1936, 49 years previously, he underwent angiography of the left forearm with a contrast medium of undocumented type for evaluation of fracture in a hospital of the Imperial Army. Laboratory data revealed elevated bilirubin (total 3.8 mg/dl, direct 2.7 mg/dl), elevated liver enzyme (AST 215KU, ALT 93 KU), anemia (RBC 332 × 10, Hb 11.0 g/dl, WBC 8600), platelet count 23.6 × 10, negative AFP, negative HBsAg and HBsAb, total protein 5.7 g/dl, erythrocyte sedimentation rate 22/h, and serum creatinine 1.6 mg/ml. On physical examination a small amount of ascites was noted. The liver was enlarged and palpated 3 finger-breadths below his right costal margin. The patient expired soon after radiography and CT with no further examinations. Radiography of the abdomen revealed enlarged liver and atrophic spleen containing radiopaque material (Fig. 1). Non-enhanced CT of the upper abdomen showed a large low-density mass in the liver, containing irregular streaky densities. Reticular high densities were also seen in the other areas of liver parenchyma. There were spotty increased densities at the hepatic port and around the pancreas. The spleen was markedly dense and atrophic, consistent with Thorotrast deposition (Fig. 2a–c). CT of the abdomen after administration of contrast medium showed irregularly enhanced areas in the round low-density mass in the right lobe of the liver, consistent with a solid neoplasm (Fig. 3d, e). There was also a moderate amount of ascites around the liver (Fig. 3f). Introduction

Background: Autoradiography of tissue with radioactive substance such as Thorotrast by Fuji Computed Radiography (FCR) has been available. We obtained autoradiographs from Thorotrast-deposited tissue by FCR. However, the nature of radiation from tissue with Thorotrast was not certain, because alpha particles are shielded by the plastic front of the FCR cassette. Therefore, we undertook investigation to clearly explain the nature of radiation from Thorotrast in case of autoradiography.Materials and Methods: Tissue blocks of liver and spleen with Thorotrast deposition were imaged by autoradiography using FCR, and radioactivity of tissue blocks was measured by a GM survey meter. Measurement was carried out by both with and without an aluminum plate between the tissue and the surface of GM survey meter to shield beta-rays.Results: Autoradiographs of the liver and spleen with Thorotrast were successful. It took only one day to obtain autoradiograph of the spleen, and 14 days for the liver. The radioactivity count decreased dramatically when an aluminum plate was inserted between the specimen and GM survey meter, but some radiation remained. The tissue blocks were contained in a plastic bag and the front of the Cassette of Imaging Plate is covered by a thin plastic board, so alpha-rays from Thorium dioxide in Thorotrast had been shielded from the beginning.Conclusion: We concluded that the radiation from the tissue blocks with Thorotrast in a plastic bag was mostly from beta-rays and less than 5% of radiation was from gamma-rays from the daughter nuclei of Thorium dioxide.

The main objectives of this chapter are to review the wide array of toxicologic insults that may result in bone marrow damage and subsequent development of bone marrow fibrosis (myelofibrosis) in humans and animals. Etiologic and morphologic features of primary myelofibrosis (a clonally derived myeloproliferative neoplastic disease) are compared to more common, secondary myelofibrotic disease including various modalities of toxicologic-induced damage of bone marrow hematopoietic structures, and subsequent development of bone marrow fibroplasia.

Background: Angiosarcomas may develop as primary tumours of unknown cause or as secondary tumours, most commonly following radiotherapy to the involved field. The different causative agents may be linked to alternate tumorigenesis, which led us to investigate the genetic profiles of morphologically indistinguishable primary and secondary angiosarcomas.Methods: Whole-genome (18k) c-DNA-mediated annealing, selection, extension and ligation analysis was used to genetically profile 26 primary and 29 secondary angiosarcomas. Key findings were thereafter validated using RT-qPCR, immunohistochemistry and validation of the gene signature to an external data set.Results: In total, 103 genes were significantly deregulated between primary and secondary angiosarcomas. Secondary angiosarcomas showed upregulation of MYC, KIT and RET and downregulation of CDKN2C. Functional annotation analysis identified multiple target genes in the receptor protein tyrosine kinase pathway. The results were validated using RT-qPCR and immunohistochemistry. Further, the gene signature was applied to an external data set and, herein, distinguished primary from secondary angiosarcomas.Conclusions: Upregulation of MYC, KIT and RET and downregulation of CDKN2C characterise secondary angiosarcoma, which implies possibilities for diagnostic application and a mechanistic basis for therapeutic evaluation of RET-kinase-inhibitors in these highly aggressive tumours.

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.

Angiosarcoma is a rare type of soft tissue sarcoma that accounts for less than 1% of all sarcomas and only 2% of all primary hepatic tumours. Thorotrast, arsenic, and vinyl chloride monomer are frequently listed as occupational exposure risks. The estimated latency is long (10-40 years) in occupational cases and very long (60 years or more) in non-occupational cases. The symptoms and CT-scan appearance of hepatic angiosarcoma (HAS) are non-specific. We present a case of a 65-year-old Caucasian male with history of cryptogenic cirrhosis, low alpha-foetoprotein levels and a single, 4-cm nodule of potential atypical hepatocellular carcinoma (no washout at MRI and CT-scan) in segment VIII. Laparoscopic radiofrequency ablation (a biopsy of the neoplastic lesion was technically impossible) was performed, followed by liver transplantation (LT) 6 months later. High-grade multifocal HAS was found in the explanted liver, with extensive involvement of the venous portal structures. No complications were observed during the postoperative course, and initial immunosuppression included tacrolimus, mycophenolate mofetil and corticosteroids. Because of the histological findings, tacrolimus was switched to everolimus as the main immunosuppressive drug one month after LT. Despite this conversion, the patient developed bone metastases 3 months after LT and peritoneal carcinosis one month later. This case report suggests that everolimus conversion does not inhibit the development of tumour metastases. Consequently, HAS remains an absolute contraindication to LT because of the poor outcome. If LT has been performed for incidental HAS, new molecular therapies (e.g. vascular endothelial growth factor antagonists) should be considered immediately after LT to improve the outcome.

Results are presented of chromosome studies of bone marrow cells from a 62-year-old woman. The patient had been given 40 ml of Thorotrast in connection with a neuro-radiological examination 34 years earlier. Clinically, the patient was now considered to be in an incipient myeloid leucaemic phase. Ninety-seven per cent of the bone marrow cells belonged to a clone with characteristic marker chromosomes induced by radiation. Few data are available on chromosome analysis of bone marrow cells from Thorotrast patients. Therefore, the results of the present study are compared with data from chromosome analyses of 32P-treated patients with polycythaemia vera, in whom large clones were found in the bone marrow. The results of chromosome analysis of bone marrow cells from the Thorotrast patient support previous hypotheses concerning the carcinogenesis in radiation-induced leucaemia in patients with polycythaemia vera, treated with 32P. In the latter patients, the clone cells are pressumed to represent cell populations with selective qualities, originating from radiation-damaged cells, which possibly possess an increased tendency to malignant transformation because of a more pronounced sensitivity to carcinogenic agents. The cells might also be potentially malignant and manifest themselves as leucaemic cells, if the patient's immunological defence mechanism is broken.

Rabbits were injected with platelet antiserum to investigate whether antibody-induced injury of platelets triggers intravascular clotting. More than 97 % of the circulating platelets were acutely removed, and profound thrombocytopenia persisted during an observation period of 6 hrs. The thrombocytopenic effect of platelet antiserum was associated with moderately increased consumption of 125I-fibrinogen and significant decreases in factors V and VIII, while the level of antigen reacting like fibrinogen (FR-antigen) in serum did not increase. The antiserum produced a transient leucopenia, and the effects of platelet antiserum were therefore also evaluated in rabbits made severely leucopenic, but not thrombocytopenic, with nitrogen mustard. Similar results were obtained, indicating that the consumption of clotting factors did not result from leucocyte injury. Pretreatment with Thorotrast reduced rather than enhanced the clotting changes after platelet antiserum. In these animals non-clottable degradation products of fibrinogen were found in serum. In neither group were fibrin thrombi observed in glomerular capillaries at autopsy. Our findings support the concept that antibody-induced injury of the platelet membrane triggered moderate intravascular clotting in normal animals. Thorotrast modified the response probably in multiple ways.

Twenty-two years after an injection of thorotrast, myelofibrosis with extramedullary metaplasia of the spleen and lymph nodes developed in a man aged 50 years. Pancytopenia with erythroblasts and poikilocytes in the blood was present. The clinical picture was characterized by anaemia, infections and haemorrhages, which ultimately led to death. The case is remarkable owing to the absence of splenomegaly. Both the spleen and the lymph nodes were the site of marked follicular atrophy, presumably evoked by radiation from the deposited thorium dioxide, which was also present in the liver and bone marrow. This radioactive material, which is assumed to have induced the myeloproliferative disorder, is also likely to have accentuated the pancytopenia. It is pointed out that some of the cases which are described in the literature as aplastic anaemia after thorotrast injection had morphological changes in the red blood picture of the same type as in myelofibrosis. This diagnosis may be overlooked if the thorium radiation induces splenic atrophy instead of the splenomegaly which is otherwise a characteristic feature.

Fifteen years after an injection of thorotrast a typical acute Di Guglielmo erythraemia developed in a man aged 65 years. Death occurred a few months after the onset of the initial symptoms. Autoradiography revealed signs of alpha radiation in the liver and spleen. The role of thorium dioxide in the aetiology of the disease is discussed.

Five autopsy cases of peliosis hepatis occurring as a late complication of thorotrast (ThO2) liver disease are described. The liver contained many blood-filled cystic spaces of various sizes. Marked sinusoidal dilatation, disruption of cell cords and reticulin fiber framework, and cystic dilatation of sinusoids seem to represent the developmental stages of peliosis hepatis in sequence. Of the five cases, two had no other liver disease except for hepatic fibrosis, and the other three had associated neoplasms, such as angiosarcoma, hepatocellular carcinoma, cholangiocarcinoma, benign hemangioma, and their combinations. Peliosis hepatis seemed to have directly contributed to the patient's death in four cases. The most characteristic clinical feature was the fulminant terminal course with massive ascites, deep jaundice, and hepatic failure, often accompanied by hepatorenal syndrome and tendency to hemorrhage. Liver function study suggested progressive hepatic insufficiency with reduction in serum albumin, prothrombin and the clearance rate for test dyes, and increase in bilirubin. Clinical diagnosis was almost impossible without biopsy.

Ionizing radiation induces DNA double strand breaks followed by cell death. As a therapeutic modality, radiotherapy is an effective method for the cases surgically inoperable or ones with conservative treatment. However, recurrence and second cancer induction are major obstacles to radiotherapy. Our main goal is to establish more effective radiotherapy by elucidating whether recurrent cancers after radiotherapy are radioresistant or not, and molecular mechanisms of cancer induction by radiation exposure. We ultimately aim to establish therapeutical pathology. Therefore, we are concurrently trying to develop devices by which we can quantify histological images and support pathological diagnosis.

Malignant epithelioid hemangioendothelioma is a rare hepatic tumor of vascular origin. It is most commonly found in young to middle aged women, and the tumors vary in reported malignant potential. Compounds such as oral contraceptive pills, poly vinyl chloride, and Thorotrast have been identified as risk factors for subsequent disease development. Radiologic (“lollipop” sign, capsular flattening) and pathologic (Factor-VIII antigen staining positive) evaluation aids in the diagnosis. As with most mesenchymal tumors, surgical resection is the most effective means of controlling local disease and preventing distant metastasis, though adjuvant therapies have been offered for those that are unresectable or not transplant candidates. We present our case of a hepatic malignant epithelioid hemangioendothelioma and a review of the English-language literature.

It is well known that exposures like those from 226Ra, 224Ra and Thorotrast® injections increase the risk of neoplasia in bone marrow and liver. The thorium-based radioactive contrast agent Thorotrast® was introduced in 1929 and applied worldwide until the 1950s, especially in angiography and arteriography. Due to the extremely long half-life of several hundred years and the life-long retention of the thorium dioxide particles in the human body, patients suffer lifetime internal exposure. The health effects from the incorporated thorium were investigated in a few cohort studies with a German study being the largest among them. This retrospective cohort study was set up in 1968 with a follow-up until 2004. The study comprises 2326 Thorotrast patients and 1890 patients of a matched control group. For those being alive at the start of the study in 1968 follow-up was done by clinical examinations on a biannual basis. For the others, causes of death were collected in various ways. Additionally, clinical, radiological and biophysical studies of patients were conducted and large efforts were made to best estimate the radiation doses associated with incorporation of the Thorotrast. The aim of this paper is to describe the cohort, important results and some open questions. The data from the German Thorotrast Study are available to other interested researchers. Information can be found at http://storedb.org .

For radiation protection purposes, the relative contributions of bronchial (BB), bronchiolar (bb) and alveolar-interstitial (AI) doses to lung cancer risk are represented by their corresponding apportionment factors. The current assumption of equal apportionment factors can be tested by comparing different radon and thoron progeny exposures, which produce different regional dose distributions, with the pathologically observed regional cancer distributions: (1) radon progeny inhalation, (2) thoron progeny inhalation, (3) thoron and thoron progeny exhalation (Thorotrast patients) and (4) RP inhalation in rats, and cigarette smoke inhalation as smoking is the dominant cause of lung cancer. Comparison with the pathologically observed regional cancer distributions suggests (1) a smaller apportionment factor for the AI region as compared with BB and bb regions and (2) a higher value for the BB region relative to that for the bb region.

For the successful space traveling, the possibility for the detrimental effects on health including cancer caused by exposure to cosmic rays is a major concern. Thorotrast is a 25% colloidal solution of natural α -emitter, thorium dioxide used as a radiological contrast medium during World War II. It caused hepatic malignant tumors by the local exposure to α -particles decades after administration. Thorotrast-induced liver tumors consist of hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and angiosarcoma (AS) at nearly the same instance. We analyzed mutations of the p53 and the K-ras genes, microsatellite instability (MSI), and loss of heterozygosity (LOH) in Thorotrast ICC. The major p53 mutation observed in Thorotrast ICC was the transition type, suggesting that reactive oxygen species are not likely involved in gene mutations of Thorotrast cancers. MSI frequency in Thorotrast ICC was significantly higher than that in non-Thorotrast ICC. MSI was partly attributed to the inactivation of the hMLH1 mismatch repair gene via methylation of the promoter region and to monoclonal expansion of cells with mutations. Thorotrast ICC shared LOH pattern with non-Thorotrast HCC and ICC. Furthermore, we could assess the distribution and the quantity of deposited thorium using an imaging plate and a BAS image analyzer. The distribution of thorium deposits was not always consistent with that of apoptotic cells. We conclude that Thorotrast ICC is developed through complex carcinogenic steps including genomic instability and mutations of crucial genes during remodeling of the liver architecture. We emphasize how pathological specimens from Thorotrast patients are valuable for assessing the relevance of long-term exposure to low dose α -particles to radiation carcinogenesis.

In space research, estimates of health risks from high-LET radiation, as well as from mixed fields are needed. Features of several applications of the biologically based two step clonal expansion (TSCE) model on data with high-LET radiation, normally α-particles from radon and from Thorotrast, are reviewed. One conclusion is that radiation might not only influence the initiating event in carcinogenesis, but may also act as a promoter. A possible mechanism which gives a promoting action from cell inactivation is presented for the organs “lung”, with a two-dimensional arrangement of the cells at risk, and for “liver” where the sensitive cells are distributed in all three dimensions. Inferences for dose–response curves at low doses and dose rates are drawn. For liver, the number and size of premalignant clones is estimated from the cancer data.