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.

Morphology and in vivo growth characteristics of an atypical murine proliferative osseous lesion induced in vitro.

Mandibular condyles of late embryonic NMRI mice were used to study the effect of the FBR murine osteosarcoma virus in an in vitro tissue culture system. Chondroprogenitor cells and chondroblastic cells present in the condylar tissue normally undergo rapid differentiation in vitro which results in an advanced stage of bone formation. The infection of condyles with FBR murine osteosarcoma virus induced the transformation of bone progenitor cells and the formation of an atypical proliferative osseous lesion. In markedly disorganized tissue many spindle-like cells, giant cells, and pleomorphic cells were seen together with the formation of large bone spicules and the heavy mineralization of osteoid-like material and of the remaining cartilage. Fibroblast-like cells were found to penetrate from the perichondrial zone into the condylar mass and also into the underlying collagen sponge. The in vivo growth characteristics of FBR murine osteosarcoma virus-infected condyles after 3 days in culture were studied via s.c. transplantation into syngeneic mice. Control condyles developed normal trabecular bone, whereas the infected condyles induced a strong cellular response with the presence of atypical cells and newly formed connective tissue and bone in situ. These observations raise the possibility of a novel approach for further investigations related to numerous aspects of virus-induced osteosarcomagenesis.

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.

Alkyl-lysophospholipids lack influence on the occurrence of radiation-induced lymphomas and AKR-leukemia.

Oral application of 2 synthetic alkyl-lysophospholipids ET-18-OCH3 and ET-18-OH at 50 micrograms/mouse every second day during the time to detect the appearance of tumors did not prevent or delay the occurrence of radiation-induced lymphomas or AKR-leukemia in mice.

Pathology of radiation-induced bone tumors.

The object of this review is to present data on the pathology of radiation-induced bone tumors, which include the following topics. Incidence and latent periods of bone tumors in humans after external and internal irradiation. Histologic features of radiation-induced bone tumors. Experimental induction of bone tumors in animals. Pathogenesis of radiation-induced bone tumors.

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.

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.

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.

Experimental induction of bone tumors by short-lived bone-seeking radionuclides.

Single and repeated applications of 224Ra and single applications of 227Th to more than 600 female NMRI mice 3 - 4 weeks old, and to male NMRI mice have led to a high rate of osteosarcomas. Tumor incidence is dose-related. 227Th is more carcinogenic than 224Ra which induced the highest tumor incidence of 60% after a single injection of 5 muCi per Kg body weight or more. Repeated injections of 224Ra to female mice yielded a tumor incidence of up to 92%. Most of these osteosarcomas consist of well-differentiated bone-forming osteoplastic tissue. Half of the tumors occurred in the spine, particularly in the lumbar region. In protraction experiments, multifocal osteosarcomas have been observed. Less than 10% of the mice with osteosarcoma had developed metastases in lung, spleen, liver, and kidney. The possible mechanisms of the protraction effect are discussed.

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.

[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%).

A rare source of occult gastrointestinal bleeding: jejunal filiae secondary to metastatic lung carcinoma.

A case of occult gastrointestinal bleeding due to jejunal metastases of a primary lung carcinoma in a 53-year-old man is reported. When after healing of a large gastric ulcer melena persisted, a subsequently performed double contrast enema of the small bowel revealed evidence of several jejunal tumors. This was confirmed by angiography of the superior mesenteric artery and computed tomography of the abdomen. After resection of the tumor-bearing jejunal loop, histological evaluation revealed metastases secondary to a large-cell bronchogenic carcinoma which had been resected 1 year previously.

Follow-up study of late effects in 224Ra treated ankylosing spondylitis patients.

We are following 1531 patients treated with 224Ra from 14 hospitals in the F.R.G. and 267 control patients with ankylosing spondylitis not treated with any form of ionizing radiation. Since 1970 three cases of malignant tumour in the skeleton have been found among 224Ra-treated patients with skeletal doses below 90 rad compared with 0.4-0.6 expected. Two of these three cases were tumours of the bone marrow. An effect of 224Ra on the haematopoietic system cannot be excluded. Also, seven cases of cataract were found among 274 224Ra patients. The mean time since 224Ra treatment was 26 yr. The mean age at diagnosis was 66 yr. The cataract incidence was not unusual for people of this age.

The role of time-factor and RBE for the induction of osteosarcomas by incorporated short-lived bone-seekers.

In a large series of experiments, fractionated injections of short-lived bone-seekers have been shown in many cases to cause a remarkable increase of the osteosarcoma incidence compared with a single administration of the same total skeletal dose. This effect has been observed with both alpha- and beta-emitters. In addition the latency period was shortened by protracting the dose. The total skeletal doses investigated ranged between 0.9 and 20 Gy for alpha-emitters (224Ra and 227Th) and between 28 and 112 Gy for the beta-emitter (177Lu). In all cases the protracted dose had higher or at least equal effects when compared with a single application. Reference experiments with long-lived alpha- and beta-emitting bone-seeking nuclides (226Ra and 90Sr) showed that the incidence of osteosarcomas per Gy was sometimes lower than that observed when the same skeletal dose was applied by protraction of short-lived radionuclides. The dependence of osteosarcoma incidence on dose-time distribution, duration of internal irradiation, and radiation quality is discussed. In this context the possibility that the critical initial dose rate may be related to the initiating event within the multi-stage hypothesis of carcinogenesis is considered.

[Cardia cancer: attempt at a therapeutically relevant classification]. / Kardiacarcinom: Versuch einer therapeutisch relevanten Klassifikation.

On the basis of a prospective analysis of 107 adenocarcinomas of the gastro-esophageal junction we propose a differentiation into adenocarcinomas of Barrett's esophagus (endobrachyesophagus), "real" carcinoma of the cardia, and subcardial carcinoma of the fundus. This classification allows the determination of an adequate surgical resection. Therefore the operative risk can be kept low. Total esophagogastrectomy is reserved only for advanced "real" carcinomas of the cardia in this concept.

[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.

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.

Primary malignant fibrous histiocytoma of the left atrium. Surgical and chemotherapeutic management.

A primary malignant fibrous histiocytoma of the left atrium was diagnosed in a 27 year old woman. After surgical excision the tumour recurred together with enlargement of the right hilar lymph nodes. The patient was then treated with nine courses of chemotherapy using a combined drug regimen. During the first course the tumour regressed, and after nine courses almost complete remission was achieved. Subsequently, the residual tumour was removed by resection of the right lung, the right hilar, paratracheal, and paraeosophageal lymph nodes and by cardiotomy with partial resection of the right and left atria and atrial septum followed by a reconstruction of the atrias. To date, more than two years after initial presentation, the patient is alive and well.

[Unusual contrast medium distribution in the left ventricular myocardium in infants with a high degree of aortic valve stenosis and endocardial fibroelastosis. Pathologico-morphologic findings]. / Ungewöhnliche Kontrastmittelverteilung im linksventrikulären Myokard bei Säuglingen mit hochgradiger valvulärer Aortenstenose und Endokardfibroelastose. Pathologisch-morphologische Befunde.

In 5 newborn infants with severe valvular aortic stenosis, left ventricular angiocardiography revealed conspicuous pathologic-morphologic findings consisting of a fine network of contrast medium opacification in the region of the posterior wall. Subsequently performed histologic examination of tissue removed from the involved regions showed, in addition to endocardial fibroelastosis, two structures which were assumed to be the morphologic substrates for the unusual distribution of contrast medium. On the one hand, antler-like spaces with a well-demarcated lining of fibroelastic tissue, similar to the thickened endocardium, were found in the inner half of the left ventricular wall connected to the lumen of the left ventricle through bottle-necked communications. On the other hand, oval or oblong lumina, substantially larger in caliber than capillaries but showing only a single endothelial layer could be demonstrated. With the sectioning technique employed, anastomoses of the latter spaces with the left ventricle or the previously mentioned system of spaces could not be established. The cause of the development or maintenance of these sinusoidal spaces may be attributable to the elevated diastolic left ventricular pressure, while the elevated systolic pressure may have been a decisive etiologic factor for the endocardial fibroelastosis. Whether the intratrabecular spaces represent persistent embryonic myocardial sinusoids cannot be differentiated unequivocally. In support of the stated contentions, however, are other results indicating that the extent of structural changes in the ventricular wall increases proportionately with the duration of existence of the obstructive lesion in the embryonic period.