The European Radiobiology Archives (ERA)--content, structure and use illustrated by an example.

The European Radiobiology Archives (ERA), supported by the European Commission and the European Late Effect Project Group (EULEP), together with the US National Radiobiology Archives (NRA) and the Japanese Radiobiology Archives (JRA) have collected all information still available on long-term animal experiments, including some selected human studies. The archives consist of a database in Microsoft Access, a website, databases of references and information on the use of the database. At present, the archives contain a description of the exposure conditions, animal strains, etc. from approximately 350,000 individuals; data on survival and pathology are available from approximately 200,000 individuals. Care has been taken to render pathological diagnoses compatible among different studies and to allow the lumping of pathological diagnoses into more general classes. 'Forms' in Access with an underlying computer code facilitate the use of the database. This paper describes the structure and content of the archives and illustrates an example for a possible analysis of such data.

Target cells in internal dosimetry.

Data related to radium induced bone sarcomas in humans are used as a method of defining target cells on bone surfaces and in the bone marrow. The differential distribution of radiation induced bone sarcoma types, with a high ratio of non-bone producing, mainly fibroblastic tumours, challenges the ICRP concept that the bone lining cells are target cells. Multipotential mesenchymal stem cells are located within the range of alpha particles and are the most likely target cells for the fibroblastic type of bone sarcoma. The histogenesis of bone sarcomas after irradiation with alpha emitters shows that their final histopathology is not dependent on a single target cell. Each target cell has a microenvironment, which has to be regarded as a synergistic morpho-functional tissue unit. For this the concept of 'histion', a term used in general pathology, is proposed. Interactions between target cells that have been hit by alpha particles, leading to lethal, mutational or transformation events with all components of a 'histion', will prove critical to understanding the pathogenesis of both deterministic and stochastic late effects.

Induction of malignant bone tumors in radium-224 patients: risk estimates based on the improved dosimetry.

Mainly between 1945 and 1955, several thousand German patients with ankylosing spondylitis, tuberculosis, or--in a few cases--other diseases received multiple injections of the short-lived alpha-particle emitter radium-224. In the early 1950s, the follow-up of 899 patients was initiated, and the study has continued since then. It includes most of the high-dose patients and nearly all of those treated as children or juveniles, i.e. under the age of 21. In the study cohort, 56 malignant bone tumors occurred in a temporal wave that peaked 8 years after exposure, whereas less than one case would have been expected during the follow-up. Most of the malignant bone tumors were osteosarcomas and fibrous-histiocytic sarcomas. A new analysis has now been performed, primarily because an improved dosimetry resulted in modified bone surface doses, especially for those treated at younger ages. A significant increase in bone tumor risk with decreasing age at exposure is now demonstrated. The earlier finding of an inverse protraction factor is confirmed. In the new formulation, the dependence on dose rate or duration applies only at higher doses; i.e., the initial slope of the dose dependence is unrelated to dose rate or exposure duration, which is in contrast to earlier analyses but is in agreement with microdosimetric considerations and general radiobiological experience.

Late effects in ankylosing spondylitis patients treated with 224Ra.

This study is comprised of 1577 ankylosing spondylitis patients from 9 German hospitals who have been treated with multiple injections of (224)Ra. The majority of the patients, most of them treated in the years 1948-1975, received one series of 10 weekly intravenous injections of about 1 MBq of (224)Ra each. This dose leads to a mean absorbed dose due to alpha-particle radiation of 0.56 Gy to the marrow-free skeleton of a 70- kg man (mean bone surface dose of about 5 Gy). To provide comparative information on causes of death and on health effects possibly related to the basic disease itself, a control group of 1462 ankylosing spondylitis patients with roughly the same age distribution has been established. By the end of 1998, 649 patients in the exposed group and 762 control patients had died. Among other observations, it is of particular interest that 13 cases of leukemia in the exposed group have been observed. This is a highly significant excess (P < 0.001) compared to a standard population, but only a marginally significant excess in comparison to the seven cases observed in the control group. Subclassification of the leukemias shows a clear preponderance of the myeloid leukemias in the exposed group (8 cases observed compared to 1.7 cases expected, P < 0.001), whereas in the control group the observed cases are within the expected range for myeloid leukemia (3 cases observed compared to 2.2 cases expected, P = 0.3). The (224)Ra cohort of the earlier study (higher-dose group) has provided a risk coefficient that predicts about 8 excess malignant bone tumors for the irradiated cohort in this study. In actuality, 4 cases of malignant tumors in the skeleton have been observed so far. However, excess of breast cancer has not been observed in either the irradiated or the control group, which is in contrast to the findings in the earlier (224)Ra cohort of Study I.

Pathology of radium-induced bone tumors: new aspects of histopathology and histogenesis.

A revision of bone tumor pathology in patients treated with multiple injections of the short-lived alpha-particle emitter radium-224, predominantly for tuberculosis and ankylosing spondylitis, revealed an unexpectedly high proportion of bone sarcomas of the fibrous connective tissue type. This included the first case of malignant fibrous histiocytoma of bone described after internal irradiation. A comparison of bone tumor types in the radium-224 patients and bone sarcoma after incorporation of radium-226 and radium-228 and external irradiation and in tumors arising at sites of pre-existing bone lesions showed the same spectrum of tumors. The high incidence of bone tumors of the fibroblastic and fibrohistiocytic type was observed in all these "secondary" bone sarcomas. These results suggest that a close histogenetic relationship exists between disorder of the local milieu caused by deterministic radiation damage accompanied by disturbances of the remodeling process. The reactive proliferation of the predominantly fibroblastic tissue could be the presumptive origin of these special types of radiation-induced bone sarcomas.

International radiobiology archives of long-term animal studies: structure, possible uses and potential extension.

Animal experiments have contributed a great deal to our information on effects and risks arising from exposure to radionuclides. This applies, in particular, to alpha-emitting radionuclides where information from man is limited to thorotrast, 224Ra and 226Ra. The late C.W. Mays was the first to suggest that animal data in conjunction with epidemiological data could allow estimates of human risks for radionuclides - predominantly from actinides - where information in man is scarce. The 'International Radiobiology Archives of Long-term Animal Studies' were created through the combined efforts of European, American and Japanese scientists and aim to safeguard the large amount of existing data on long-term animal experiments and make them available for, among others, an improved assessment of risks from alpha-emitting radionuclides. This paper summarizes the structure of the archives and reviews their present status and future plans. It also demonstrates the extensive information available in these archives on alpha-emitting radionuclides which is suitable for further analysis. Also, the structure of the animal archives could - in a slightly modified form - accommodate the epidemiological data available on 224Ra and thorotrast and, thus, facilitate a direct comparison of data from man, dogs and rodents.

Suppression of T1-receptor expression by antisense RNA abrogates differentiation of osteogenic osteosarcoma cells.

Soluble and membrane-associated variants of the orphan T1-receptor, a homolog of interleukin-1 receptor type I, are expressed in proliferating preosteoblasts in differentiating bone. Recent evidence reveals that T1-receptor synthesis is retained in osteogenic osteosarcoma cells. Here we report that the suppression of T1-receptor expression by mouse osteosarcoma cells using a T1 -antisense expression vector results in the abrogation of the osteogenic potential of the tumor cells. T1-antisense-expressing tumor cells formed anaplastic tumors in vivo and failed to express the osteoblast-specific genes collagen type 1, alkaline phosphatase, and osteocalcin when cultured in a 3-dimensional collagen type I matrix in vitro. Suppression of T1-receptor synthesis did not affect the expression of the essential bone cell-specific transcription factor AML3/CBFA1 in the osteosarcoma cells. These data provide the first evidence that T1-receptor plays a key role in osteogenic differentiation.

Cytometry in histological sections of colon carcinoma.

A short description of a project of cytometry in histological sections of colon carcinoma is given with emphasis on the methodical aspects. Possible strategies of cytometric measurement and problems related to it (focus, overlap, segmentation of objects) are described. The main effort concerns interactive selection of tumor cells and the segmentation in cases of densely distributed and overlapping nuclei. All other succeeding processing steps are performed fully automatically. The resulting quantitative features are stored together with the original images on an optical disk for further examinations and reexaminations, allowing the direct relation of feature values to visual image content. The evaluation of the features as well as their interpretation is only at the beginning. Especially the problem of relating section information with true 3-dimensional information is not described here and necessitates further research. In a first investigation only a few tumors without and with metastases were analyzed. The preliminary results correspond with findings of Kunze et al.

Bone tumor induction after incorporation of short-lived radionuclides.

Temporally-limited internal irradiation after incorporation of short-lived bone-seeking radionuclides is a useful experimental tool for the investigation of extrinsic and intrinsic factors which modify the dose dependence of bone tumor risk. Here we describe some of the results obtained in experiments with female mice (mainly NMRI). The future aim of such experiments should be the prediction of risk of late effects using early molecular-biological changes. Molecular-biological descriptions in our model are at present very limited.

[Diagnostic and therapeutic considerations in aneurysmatic bone cysts of the jaws]. / Diagnostische und therapeutische Aspekte zur aneurysmatischen Knochenzyste des Kiefers.

A case of aneurysmatic bone cyst of the mandible is described. Following curettage the condition recurred twice and was then successfully treated with cross-section and primary reconstruction of the mandible. The pathogenesis of aneurysmatic bone cysts and the indications for radical surgical treatment are discussed.

[CT-guided biopsy: methods, results and complications]. / CT-gesteuerte Biopsie--Methoden, Resultate und Komplikationen.

Percutaneous CT-guided biopsies were carried out in 350 patients; on 291 occasions, 14- or 18-gauge and, on 59 occasions, an 0.95 mm cutting biopsy cannula was employed. Using the 14- and 18-gauge needles, a histological diagnosis was possible in 191 cases, a sensitivity of 82.7%. The 0.95 mm cannulas proved successful in 39 of the 59 punctures, producing a markedly lower sensitivity of 66.2%. The most common cause of an incorrect biopsy with large needles was bad position of the needle, whereas the small needles provided inadequate material. Complications which, however, did not require treatment, occurred in 5 patients (1.4%).

[Askin tumor. Rare neurogenic tumor with metastasis to mouth, jaw and face regions]. / Der Askin-Tumor. Ein seltener neurogener Tumor mit Beteiligung der Mund-Kiefer-Gesichtsregion.

One case of a malignant peripheral neuroectodermal tumor of the thoracopulmonary region (Askin-Tumor) is reported. The tumor represents a distinct pathologic entity of neuroectodermal origin. The patient developed a metastasis in the upper jaw and in a lumbar vertebra. Morphologic and immunocytochemical findings of this extremely rare tumor were described and differential diagnosis from other soft-tissue round-cell sarcomas, such as Ewing's sarcoma and neuroblastoma are discussed. Problems associated with the clinical behavior and treatment are outlined. The prognosis in most cases of Askin-tumor is poor. The recommended therapy is radical resection, irradiation and combination chemotherapy containing anthracyclines and a high dose of alkylating agents.

[Primary extranodal non-Hodgkin lymphoma of the stomach. Value of surgery within the scope of a multimodality treatment concept]. / Das primär extranodale Non-Hodgkin-Lymphom des Magens. Stellenwert der Operation im Rahmen eines multimodalen Behandlungskonzeptes.

The clinical course of 22 patients was analyzed in a retrospective study; all of these were suffering from malignant lymphoma of the stomach and most underwent radical resection as the only therapeutic measure. A unrelated effect on the survival rate was found in a high-grade malignancy metastatic disease of celiac lymph nodes (stage II2E) and tumor size. On the basis of the presented data we assume that low-grade malignant lymphomas stages IE can be cured by radical resection. In stage II1E and II2E we recommend multi-disciplinary treatment strategy with radical resection followed by radiation therapy in low-grade malignancy or chemotherapy in high-grade malignancy.

Preoperative staging of a distal common bile duct tumor by endoscopic ultrasound.

A 27-yr-old man with a long-standing history of primary sclerosing cholangitis presented with recurrent episodes of fever and progressive weight loss over 6 mo. The diagnosis of a distal cholangiocarcinoma was made by endoscopic retrograde cholangiography and transpapillary biopsy. The extent of the tumor could be reliably assessed by endoscopic ultrasound, whereas computed tomography scan, angiography, and transabdominal ultrasound failed to visualize the tumor. The intraoperative findings and histologic work-up of the resected specimen confirmed a T3N0M0 adenocarcinoma of the distal common bile duct.

Fibrin-fibronectin compounds in human ovarian tumor ascites and their possible relation to the tumor stroma.

Covalently linked heterogeneous fibrin-fibronectin compounds were detected in ascitic fluid of 31 patients with advanced ovarian cystadenocarcinoma by means of enzyme-linked immunosorbent assay techniques, immunoaffinity chromatography, and Western blot analysis. Deposition of fibrin and fibronectin could also be demonstrated immunohistochemically in Carnoy-fixed tissue sections. Fibrin and fibronectin were found in the tumor stroma within tumor nests and more prominently in stroma surrounding the tumor nests. The association of fibrin and fibronectin was especially pronounced in the stroma surrounding the tumor islands. Fibronectin was also found to be associated with stroma cells. Areas within the tumor stroma showed superimposed staining for both fibrin and fibronectin supporting the assumption that the covalently linked fibrin-fibronectin conjugates found in ascitic fluid may stem from the provisional tumor stroma by proteolytic release.

[First laser irradiation of a bile duct carcinoma under endoscopic control]. / Erste Laser-Bestrahlung eines Gallengangkarzinoms unter endoskopischer Sicht.

For the first time a hepatic-duct carcinoma was treated palliatively with percutaneous endoscopic Neodym-YAG laser irradiation. This enlarged the lumen of the bile duct encased by tumour. The method can be combined with prosthetic as well as radiotherapeutic procedures. The equipment consists of an ordinary choledochoscope and a laser apparatus. The choledochoscope merely needs minimal technical modification of the outer valve of its working channel. Biopsies under endoscopic control make it possible to obtain tissue samples adequate for histological examination before treatment is begun.

[Stomach cancer--the current situation from the surgical viewpoint]. / Magenkarzinom--Bestandsaufnahme aus chirurgischer Sicht.

From July 1st 1982 to December 31st 1986, 359 patients with a histologically confirmed gastric carcinoma were operated on. At the beginning of therapy, 44.3% were in the pathological anatomical stages I and II, 55.7% in stages III and IV (UICC 1987). 307 patients could be resected (resection rate 85.5%). The proportion of R0 resections (no residual tumor) was 61.9%, R1 resections (microscopically demonstrable tumor residues) 23.1% and R2 resections (macroscopical tumor residues) 15%. Overall, a curative resection could be carried out in 61.9% of the cases and a palliative resection in 38.1% of the cases. In 21.5%, a subtotal gastric resection, in 48.2% a total gastrectomy and in 30.3% an extended total gastrectomy was necessary in addition. The lethality was 3.0% for subtotal resection, 5.4% for the simple total gastrectomy and 9.6% for the extended total gastrectomy. The prognosis corresponds to the tumor stage at the beginning of therapy (three year actuarial survival: stage I 76%, stage II and III 26%, stage IV 7%).