Silica dust, radon and death from non-malignant respiratory diseases in German uranium miners.

OBJECTIVE: To quantify the relationship between death from non-malignant respiratory diseases (NMRD) and exposure to silica dust or radon in a cohort of 58,690 former German uranium miners. METHODS: In the follow-up period from 1946 to 2008, a total of 2336 underlying deaths from NMRDs occurred, including 715 deaths from chronic obstructive pulmonary diseases (COPD) and 975 deaths from silicosis or other pneumoconiosis. Exposure to respirable crystalline silica and radon was individually assessed by means of a comprehensive job-exposure matrix. Risk analyses were based on a linear Poisson regression model with the baseline stratified by age, calendar year and duration of employment. RESULTS: There was no increase in risk of death from COPDs or any other NMRDs in relation to cumulative exposure to silica (mean=5.9, max=56 mg/m(3)-years), except in the group of deaths from silicosis or other pneumoconiosis. Here, a strong non-linear increase in risk was observed. Cumulative radon exposure (mean=280; max=3224 Working Level Months) was not related to death from COPDs or any other NMRDs. CONCLUSIONS: The present findings do not indicate a relationship between mortality from COPD with silica dust or radon. However, validity of cause of death and lack of control for smoking remain potential sources of bias.

Increase in testicular cancer incidence in six European countries: a birth cohort phenomenon.

BACKGROUND: For unknown reasons, the age-standardized incidence of testicular cancer has shown a rapid increase in virtually all countries (mostly Western) studied. For populations with a sufficiently long period of cancer registration, this development can be traced back to the first half of this century. PURPOSE: By evaluating data from six countries with long periods of cancer registration (Denmark, Norway, Sweden, the former German Democratic Republic [East Germany], Finland, and Poland), we sought to determine whether the increase in testicular cancer risk follows a birth cohort pattern and, if so, to quantify and compare any birth cohort effects. METHODS: A total of 30,908 incident cases of testicular cancer, diagnosed from 1945 through 1989 in men who were 20-84 years of age, were identified in population-based cancer registries in the six countries. In addition to performing simple trend analyses, we fitted several Poisson regression models (with the explanatory variables age, time period [calendar time], and birth cohort) to the data. Individual models were estimated by the maximum likelihood method. RESULTS: The age-standardized incidence of testicular cancer was found to vary among the six populations and, on the basis of total registration data, increased annually at rates ranging from 2.3% (in Sweden) to 5.2% (in East Germany). A comparison of several regression models indicated that birth cohort was a stronger determinant of testicular cancer risk than was calendar time for all six populations. Within each population, little variation in testicular cancer risk was observed for men born between 1880 and 1920; thereafter, the risk began to increase. Among men born in Denmark, Norway, and Sweden between 1930 and 1945 (the period encompassing the Second World War), the increasing trend in risk was interrupted (i.e., a leveling in risk occurred). After 1945, an uninterrupted increase in risk was observed for all six populations. With men born around 1905 as the reference group, the relative risk of testicular cancer for those born around 1965 varied from 3.9 (95% confidence interval [CI] = 2.7-5.6) in Sweden to 11.4 (95% CI = 8.3-15.5) in East Germany. CONCLUSIONS AND IMPLICATIONS: The increasing trend in testicular cancer risk observed for these six populations follows a birth cohort pattern. This distinct risk pattern provides a framework for the identification of specific etiologic factors.

Prognostic value of proliferating cell nuclear antigen and c-erbB-2 compared with conventional histopathological factors in breast cancer.

Expression of proliferating cell nuclear antigen (PCNA) and c-erbB-2 oncoprotein has been assessed in 471 women with breast cancer to evaluate their prognostic value as compared to conventional histopathological factors. In univariate analysis, high PCNA expression (> or = 20%) predicted a significantly worse survival in lymph-node-negative tumors (univariate P = 0.031). However, the effect disappeared in multivariate analysis and the histological grade remained the only independent factor for this group. Despite its close correlation to histological grade (P < 0.001), PCNA expression discriminated subsets with different survival within the heterogeneous group of moderately differentiated tumors (univariate P = 0.073, multivariate P = 0.075). PCNA expression was not found to be a significant prognostic factor in lymph-node-positive tumors, thus it was of limited value for breast cancer patients as a whole. c-erbB-2 protein overexpression was associated with a worse survival (univariate P = 0.019, multivariate P = 0.057) for the entire group of patients. The effect was mainly attributed to the significance of c-erbB-2 as an independent factor in lymph-node-positive (up to three nodes, multivariate P = 0.04; four or more nodes: multivariate P = 0.017) and large tumors (> 2 cm: multivariate P = 0.002). c-erbB-2 was without significance in lymph-node-negative patients. Though both factors might amplify the prognostic information for distinct patient subsets they do not achieve the strong prognostic value of conventional histopathological features in breast cancer.

On the background of differences in survival of female breast cancer patients in the German Democratic Republic and the Estonian SSR.

The aim of this study was to describe the age-specific survival patterns and to analyse the differences between the survival rates of female breast cancer patients in the German Democratic Republic in 1976-1977 and the Estonian SSR in 1968-1981. The estimated 5-year relative survival rate (RSR) was 64.1% in the GDR and 55.9% in Estonia. Patients aged 55 years or older at diagnosis had higher survival in the GDR (5-year RSR 62.6%) than in Estonia (49.5%). That result was clearly connected with higher proportion of advanced tumors among older patients in Estonia. For patients younger than 55 years the difference of the 5-year RSR between the both countries was not statistically significant (GDR 65.3%, Estonia 63.4%). The standardization of overall 5-year RSR by stage and age, but also only by stage of the disease produced virtually equal results for the GDR and Estonia. It means that the main source of the differences in overall breast cancer survival rates between the GDR and Estonia are the discrepancies in stage distribution, particularly in older age groups.

Predicted number of lung cancer cases in Germany among former uranium miners of the Wismut.

Between 1946-1990, the Wismut-Company in the former German Democratic Republic was the leading producer of uranium for the Soviet union. After the German reunification, a central welfare system for uranium miners of the Wismut Zentrale Betreuung Wismut (ZeBWiS) was initiated by the Hauptverband der Berufsgenossenschaften in 1992, and a data base of exposed employees was established. In spring 1993, data regarding 95,000 exposed persons were available from Saxony, but none from Thuringia. A sample of 3,654 persons was drawn. For 3,128 of them the working history at the Wismut could be reconstructed. Having established the age distribution and taking into account mortality of other causes, the expected age-specific mortality rates of lung cancer were calculated. Statistical risk models were applied. Assuming that for Saxony about 156,000 workers were exposed in underground mining and/or uranium processing, a total (past and future) of about 7,000-25,000 excess lung cancer cases are estimated to be due to exposure to radon and its progeny. From 1995 onwards about 1,300-4,800 additional cases are predicted in the population of exposed former Wismut workers in Saxony. The peak incidence was reached between 1985-1991. No prognosis for Thuringia can be given so far.

[The metastasis of rectal cancer]. / Metastazirovanie raka priamoi kishki.

Eight hundred and eighty-six cases of rectal cancer diagnosed and reported to the National Cancer Registry in 1980 were submitted to obduction. Metastases were identified in 46.8%. Liver, lung and bones were affected in 38.7%, 16.1 and 3.5% of cases, respectively. Pattern of metastatic spread was determined by histology, with adenocarcinoma giving rise to blood-borne metastases, mucinous adenocarcinoma producing mostly lymphogenic metastases and signet-ring cell carcinoma spreading in either way. Isolated liver involvement was established in 9% of patients showing liver metastases at radical surgery. The parameter reached 22% when cases of presacral recurrence were excluded. A histologically oriented scheme is suggested to assure complete diagnostic coverage of metastases and to develop a concept for the treatment of liver secondaries. Targeted intraperitoneal and endolymphatic application of cytotoxic agents for the treatment of liver metastases aimed at reduction of extrahepatic dissemination is discussed.

Ionizing radiation and risk of laryngeal cancer among German uranium miners.

Today it is uncontested that uranium miners are at increased risk of lung cancer, primarily owing to their exposure to radon. Whether they are also at an increased risk of cancer at other sites, especially in the respiratory tract, remains under discussion. The aim of the present study was to examine the laryngeal cancer risk among uranium miners. An individually matched case-control study of former uranium miners in East Germany was conducted, including 554 cases and 929 controls. Using conditional logistic regression models, a dose-response relationship between the risk of developing a laryngeal cancer and exposure to radon progeny could not be confirmed. Even in miners with a cumulative exposure of at least 1,000 WLM, only a slightly elevated risk could be observed of OR = 1.13 (0.75-1.70)95%. The study does not support the hypothesis of an association between exposure to short-lived radon progeny and laryngeal cancer risk. Moreover, signs are emerging that smoking could explain the moderate excess in laryngeal cancer cases observed in some miner cohorts.

[Analysis of the geographic distribution of cancer incidence exemplified by lung tumors in East Germany for the period 1978-1982]. / Analyse der geographischen Verteilung von Krebsinzidenzen am Beispiel der Lungentumoren in der DDR für den Zeitraum 1978-1982.

Analysing the regional distribution of cancer incidence a graphic presentation of the data in form of cancer maps often give a clear idea of the underlying distribution. Nevertheless, if the cancer map is variegated, an answer to the question of regional dependence of the incidence is difficult to find. Statistical methods as the test of Kemp et al. (3), which is based on the mean absolute difference in rank between all possible pairs of adjacent regions with a common border, or outlier tests can be helpful in such cases. An easy calculable approximation of Kemp's method will be presented and demonstrated on lung cancer incidence in districts of the GDR over the five-year period 1978-1982. Moreover statistical methods of generating new hypotheses about possible risk factors will be discussed.

[Methods of standardizing relative survival rates using rectal cancer in East Germany as an example]. / Methoden zur Standardisierung von relativen Uberlebensraten am Beispiel des Rektumkarzinoms in der DDR.

Statistical analyses concerning survival of cancer patients are mostly based on the concept of relative survival rates, which besides the crude survival rates, calculated by the life-table-method, take into account the influence of other (competing) causes of death. But the use of relative survival rates by no means a full reduction of the influence of age. Methods for standardization of such rates will be presented and demonstrated on the data of the National Cancer Registry in GDR for rectum cancer in 1980.

[Effect of regional centralized treatment on chances of survival in rectal cancer in East Germany]. / Untersuchung zum Einfluss der regional zentralisierten Behandlung auf die Uberlebenschancen beim Rektumkarzinom in der DDR.

Based on cases of rectum-carcinoma reported to the National Cancer Registry a population based method is demonstrated to measure the influence of a regional-centralized treatment on the relative survival rates for cancer patients. This new approach use a centralization-index, characterizing the centralization of treatment activities in single countries. It is shown, that the end results in regions with a high index are much better than that in other regions.

[Incidence of isolated metastatic organ involvement in rectal cancer in an autopsy sample]. / Zur Häufigkeit des isolierten metastatischen Organbefalls beim Rektumkarzinom im Obduktionsgut.

From the rectum carcinoma cases diagnosed and reported to the National Cancer Registry in 1980, 886 were submitted to obduction. Metastases were detected in 46.8% of the autopsy material. Affected were the liver in 38.7%, the lung in 16.1%, and the skeleton in 3.5% of the obducted cases. The pattern of metastases depended on the histological picture of the carcinoma: with adenocarcinomas, haematogenic metastases, and with mucigenic adenocarcinomas, lymphogenic metastases were predominant; the signet-ring-cell carcinomas develop their pronounced metastatic potency in either way. The isolated liver affection could be established in 9% of all liver metastatic patients who underwent radical operation, and in 22% following exclusion of a presacral recurrence, respectively. A histologically oriented scheme is proposed to complete the spreading diagnostics and to establish a therapeutic concept for liver metastases, and an additional, targeted, systematic intraperitoneal and endolymphatic application of cytostatic substances in the treatment of liver metastases to reduce the extrahepatic metastatic rate is discussed.

[Effect of oral contraceptives on the proliferative activity of breast cancer]. / Der Einfluss oraler Kontrazeptiva auf die Proliferationsaktivität des Mammakarzinoms.

In 471 breast cancer patients the possible influence of an antecedent oral contraceptive (OC) use on proliferative activity (PCNA-expression) of mammary carcinomas was investigated. PCNA-expression (Proliferating Cell Nuclear Antigen) was immunohistochemically assessed using formalin-fixed, paraffin-embedded tissue. PCNA-expression discriminated tumors of low (< 20%) and increased (> or = 20%) proliferative fractions. 297 (63%) patients had ever used OCs and 202 (43%) of them were long-term users (> or = 49 months). Age adjusted proliferative fractions showed no statistically significant differences dependent on duration of OC use (never, 1-48 months, > or = 49 months), despite a slightly higher frequency of tumors with an increased PCNA-expression in ever users of OCs (p = 0.125).

[The effect of air pollutants on the incidence of lung tumors in the GDR]. / Zum Einfluss von Luftschadstoffen auf die Inzidenz von Lungentumoren in der DDR.

On the basis of the data from the National Cancer Registry in the GDR an investigation was made, concerning the relationship between exposure to different levels of air pollution and lung cancer incidence. Estimates for the exposure to major factors of air pollution as sulfur dioxide, sedimentation dust and a global air index were calculated for each county of the GDR. The statistical comparison of these data with respect to the age-adjusted incidence rates of the corresponding counties for the time period 1978 to 1982 have not shown any differences neither in man nor in woman. On the other side a positive correlation to the per caput consumption of cigarettes was found.

Multicentre international liver tumour study protocol of the case-control study on hepatocellular cancer.

Toxicological evidence has recently shown that cyproterone acetate (CPA) is associated with increased adduct formation in liver cell cultures that was interpreted as a possible sign for genotoxicity. Likewise, a few spontaneous reports of liver cancer associated to CPA were published. This led to an alert announced by the German Drug Regulators. One reason to design a case-control study on hepatocellular cancer (HCC) and oral contraceptives (OC's) use (and specific subtypes such as CPA-containing ones) was that other clinical or pharmacoepidemiological studies were not available which dealt with this suspicion. This idea got support from the fact that most of the earlier case-control studies on HCC and OC were small, did not sufficiently control for confounding by: hepatitis B and C, exposure at work, use of other potentially hepatotoxic drugs and also did not distinguish between different types of OC's. Objectives, hypotheses, methods used and subjects studied are described in this paper. The study began in six countries (Germany, United Kingdom, France, Italy, Spain, Greece) on 1 July 1994. It will be finished by the end of June 1996, and first results can be expected by the end of 1996 or early 1997.

[The diagnostic and therapeutic status of cancer of the bile ducts and liver]. / Zur diagnostischen und therapeutischen Situation der Karzinome der Gallenwege und der Leber.

In 1980 in the GDR 641 primary liver carcinomas (380 male, incidence 3.8, 261 female, 1.4) and 1834 biliary tract carcinomas (414 male, 3.7 and 1420 female, 7.0) had been registered by the National Cancer Registry. An analysis of stage, age-distribution. Operability and resectability had been performed. For all stages of liver carcinomas the 5-year-survival-rate was 3.5% (male) and 1.0% (female), for the biliary tract carcinomas 3.4 and 4.9% respectively. At present a significant improvement of treatment results cannot be expected.

C-erbB-2 overexpression in primary breast cancer: independent prognostic factor in patients at high risk.

The prognostic value of c-erbB-2 protein overexpression has been evaluated in 463 patients with operable breast cancer after a median follow-up of 66 months. Overexpression was observed in 99/463 (21%) of the breast tumors. It showed significant positive correlation to histological grade (p < 0.0001) and tumor size (p < 0.02). A relationship of borderline significance was observed between c-erbB-2 protein overexpression and negative or low estrogen receptor (ER) content. No significant correlation was found to lymph node involvement or proliferating tumor cell fraction as determined by the proliferating cell nuclear antigen (PCNA). After a median follow-up of 66 months (range 6 to 109 months), the overall survival of all patients amounted to 63%. Multivariate analysis revealed lymph node involvement, tumor size, histological grade, histological type, c-erbB-2 protein overexpression, progesterone receptor (PR) content, and oral contraceptive use as independent prognostic factors. In an univariate analysis, the overall survival amounted to 72% and 38% of tumor patients with negative and positive c-erbB-2 protein overexpression, respectively. The most significant finding is that c-erbB-2 overexpression has been recognized as an independent predictive factor in subsets of tumor patients who would be expected to have a generally poor prognosis, such as those indicating axillary lymph node involvement, large tumor size (> 2 cm), and PR negativity.

[C-erbB-2, PCNA and histomorphologic factors in breast carcinoma after oral contraceptive use]. / C-erbB-2, PCNA und histomorphologische Faktoren beim Mammakarzinom nach Einnahme oraler Kontrazeptiva.

The influence of oral contraceptives (OC) on histomorphological and molecular biological prognostic factors was studied in 471 breast cancer patients. Differences in histological tumor type, histological grade, tumor size, lymph node status, hormonal receptor status, PCNA expression and c-erbB-2 protein overexpression were investigated in relation to the duration of OC use (< 5 years/ > or = 5 years) and the time since last use. A total of 297 (63%) patients had used oral contraceptives at some time in their life; 186 patients (39.5%) had used OC's for 5 years or more. There were no significant differences in the tumor characteristics investigated with respect to OC use in general. Neither long-term use at some time in their life nor long-term use until breast cancer diagnosis had an effect on histomorphological and molecular biological factors. Thus, steroid hormones contained in OC's had no direct effect on prognostic factors in breast cancer.

A case-control study of leukaemia as a second primary malignancy following ovarian and breast neoplasms.

The National Cancer Registry of the German Democratic Republic identified 105 leukaemias which had developed during 1968-1980 as second primary malignancies in women previously registered with a tumour of the breast or ovary. Matched controls were selected who had been diagnosed with the same first tumour, but had survived without further malignancy as long as the corresponding case. Treatment records were abstracted for leukaemia cases and controls, and a comparison made of the therapy received. There was a ten-fold increase in the risk of leukaemia following ovarian cancer among those treated with chemotherapy, which was almost exclusively cyclophosphamide. Among the breast cancer survivors, the relative risk of acute leukaemia associated with cyclophosphamide was 2.7.

Risk of leukaemia in ovarian tumour and breast cancer patients following treatment by cyclophosphamide.

A case-control study was conducted to determine whether the development of leukaemia was associated with chemotherapy for neoplasms of the ovary or breast, in a population where most such chemotherapy consisted of cyclophosphamide alone. Cases and controls were identified from the National Cancer Registry of the German Democratic Republic. Cases were women who had developed leukaemia as a second primary after an initial diagnosis, at least one year before, of an ovarian or breast tumour. Controls were patients with an ovarian tumour or breast cancer who had survived to the year when the case developed a leukaemia but who had not themselves developed a second malignancy. Controls were matched to cases by the site of the first primary and its year of diagnosis, as well as year of birth. The relative risk for acute leukaemia following treatment with cyclophosphamide alone was significantly elevated (P less than 0.05), at 14.6 for ovarian tumour patients and 2.7 for breast cancer patients. Among breast cancer patients the increased risk of leukaemia associated with chemotherapy was confined to women who had been under 50 years of age at the time of diagnosis of the breast cancer (for whom the relative risk was 13.1). No excess risk of leukaemia was observed in association with radiotherapy for either ovarian or breast cancer patients. The present findings strongly suggest that cyclophosphamide as a single chemotherapeutic agent is capable of inducing leukaemia in humans.

Occupational exposure and liver cancer in women: results of the Multicentre International Liver Tumour Study (MILTS).

The association of occupational variables and hepatocellular cancer (HCC) is discussed with particular reference to women, as little research has been undertaken on their behalf. This paper reports the results of an international case-control study concerning women and involves 317 cases of HCC and 1789 controls. Working in the chemical industry was shown to have only a marginally significant risk associated with HCC: adjusted odds ratio (OR) and 95% confidence interval 2.37 (1.04-5.41). Other non-significantly elevated ORs were observed in the pharmaceutical, plastics, PVC-producing, farming and butchery industries. Little consistency was found among the risk estimates for HCC, based on three different analytical approaches. None of the analyses showed a linear trend of risk with increasing duration of exposure. However, the numbers of exposed cases and controls were small for many of the occupations and therefore the study power and precision were low. We failed to find important and consistent evidence for a relationship between HCC in women and occupational variables. However, even weak evidence of occupational risk warrants careful consideration in future studies.