A mechanistic model for medulloblastoma induction in mice.

Medulloblastomas in Patched heterozygous mice (Ptc1(+/-) mice) are induced with high probability by ionizing radiation applied in the immediate post-natal period. A mathematical model is described here that accommodates the dependence of the medulloblastoma incidence on dose, age at exposure and age. The model assumes that the first step in the development of the cancer is already present in all cells of the patched mouse due to germ-line inactivation of one allele of the patched tumor suppressor gene. The subsequent rate-limiting step is dependent linearly on dose at least up to 3 Gy. The observed strong decrease in carcinogenic effect of radiation between exposure on day 1 and day 10 is described by a physiological elimination of target cells during post-natal maturation of the brain. A single malignant cell develops into a tumor following a gamma-distribution with mean of about 160 days. The multiplicity of medulloblastomas is predicted.

Lung cancer mortality in the European uranium miners cohorts analyzed with a biologically based model taking into account radon measurement error.

The biologically based two-stage clonal expansion (TSCE) model is used to analyze lung cancer mortality of European miners from the Czech Republic, France, and Germany. All three cohorts indicate a highly significant action of exposure to radon and its progeny on promotion. The action on initiation is not significant in the French cohort. An action on transformation was tested but not found significant. In a pooled analysis, the results based on the French and German datasets do not differ significantly in any of the used parameters. For the Czech dataset, only lag time and two parameters that determine the clonal expansion without exposure and with low exposure rates (promotion) are consistent with the other studies. For low exposure rates, the resulting relative risks are quite similar. Exposure estimates for each calendar year are used. A model for random errors in each of these yearly exposures is presented. Depending on the used technique of exposure estimate, Berkson and classical errors are used. The consequences for the model parameters are calculated and found to be mostly of minor importance, except that the large difference in the exposure-induced initiation between the studies is decreased substantially.

Genetic background and 227Thorium as risk factors in biologically based models for induction of bone cancer in mice.

We explore the potential for the biologically based two-stage clonal expansion model to make statements about the influence of genetic factors on the steps in the model. We find evidence that the different susceptibility of BALB/C and CBA/Ca mice to bone cancer after (227)Thorium injection may be mostly due to different promotional responses to radiation. In BALB/C × CBA/Ca back-crossed mice, we analyzed the specific contribution of two individual loci in the carcinogenic process. This analysis suggests that the two high- or low-risk alleles are acting on promotion or on the background parameters, but not on radiation-induced initiation. Taken together with the comparison of CBA/Ca and BALB/C mice, this hints at the possibility that the two loci are candidates for modifying radiation-induced promotion.

Promotion of initiated cells by radiation-induced cell inactivation.

Cells on the way to carcinogenesis can have a growth advantage relative to normal cells. It has been hypothesized that a radiation-induced growth advantage of these initiated cells might be induced by an increased cell replacement probability of initiated cells after inactivation of neighboring cells by radiation. Here Monte Carlo simulations extend this hypothesis for larger clones: The effective clonal expansion rate decreases with clone size. This effect is stronger for the two-dimensional than for the three-dimensional situation. The clones are irregular, far from a circular shape. An exposure-rate dependence of the effective clonal expansion rate could come in part from a minimal recovery time of the initiated cells for symmetric cell division.

Systems biological and mechanistic modelling of radiation-induced cancer.

This paper summarises the five presentations at the First International Workshop on Systems Radiation Biology that were concerned with mechanistic models for carcinogenesis. The mathematical description of various hypotheses about the carcinogenic process, and its comparison with available data is an example of systems biology. It promises better understanding of effects at the whole body level based on properties of cells and signalling mechanisms between them. Of these five presentations, three dealt with multistage carcinogenesis within the framework of stochastic multistage clonal expansion models, another presented a deterministic multistage model incorporating chromosomal aberrations and neoplastic transformation, and the last presented a model of DNA double-strand break repair pathways for second breast cancers following radiation therapy.

Promoting action of radiation in the atomic bomb survivor carcinogenesis data?

The age-time patterns of risk in the atomic bomb survivor data on incidence of solid cancers suggest an action of low-LET radiation not only on the initiating event but also on promotion in a biologically motivated model that allows for both actions. The favored model indicates a decrease of radiation risks with age at exposure due to the initiating effect and with time since exposure due to the promoting effect. These result in a relative risk that depends mostly on attained age for ages at exposure above 20 years. According to the model, a dose of 100 mGy is inducing about the same number of initiating events that occur spontaneously in 1 year. Assuming that several mutations are needed to obtain intermediate cells with growth advantage does not improve the quality of fit. The estimated promoting effect could be explained if the number of intermediate cells increases by 80% at 1 Gy, e.g. due to stimulated cell repopulation.

[Outcome of pregnancy in patients with haemophilia B--two case reports]. / Schwangerschaft bei Hämophilie B--Zwei Fallberichte.

BACKGROUND: Haemophilia B is a congenital coagulation disorder with a low activity of the coagulation factor IX. The means of transmission is recessively gender dependent. Usually the female carrier of the haemophilia B has normal activity of the coagulation factor. However, in very rare cases the factor-IX-activity may be reduced considerably, even in a female carrier (Lyon-hypothesis). Both for mother and the child, who has potentially inherited the disorder, there is a dramatically increased tendency for bleeding with the potential for developing further complications. PATIENTS: The deliveries of two conductors with a low activity of coagulation factor IX are presented. With a monitored substitution of factor-IX-concentrate it was possible to prolong the pregnancies nearly before the date of birth. In one case ended the pregnancy in a caesarean section, the second patient had a normal delivery. CONCLUSION: Today interdisciplinary treatment and exactly planning of the birth may led even high risk pregnancies to a successful end.

Lung cancer risk in mice: analysis of fractionation effects and neutron RBE with a biologically motivated model.

Data from Argonne National Laboratory on lung cancer in 15,975 mice with acute and fractionated exposures to gamma rays and neutrons are analyzed with a biologically motivated model with two rate-limiting steps and clonal expansion. Fractionation effects and effects of radiation quality can be explained well by the estimated kinetic parameters. Both an initiating and a promoting action of neutrons and gamma rays are suggested. While for gamma rays the initiating event is described well with a linear dose-rate dependence, for neutrons a nonlinear term is needed, with less effectiveness at higher dose rates. For the initiating event, the neutron RBE compared to gamma rays is about 10 when the dose rate during each fraction is low. For higher dose rates this RBE decreases strongly. The estimated lifetime relative risk for radiation-induced lung cancers from 1 Gy of acute gamma-ray exposure at an age of 110 days is 1.27 for male mice and 1.53 for female mice. For doses less than 1 Gy, the effectiveness of fractionated exposure to gamma rays compared to acute exposure is between 0.4 and 0.7 in both sexes. For lifetime relative risk, the RBE from acute neutrons at low doses is estimated at about 10 relative to acute gamma-ray exposure. It decreases strongly with dose. For fractionated neutrons, it is lower, down to about 4 for male mice.

Interaction of smoking and radon in rats: a biologically based mechanistic model.

Data on rats exposed to cigarette smoke before or after exposure to radon are used to estimate smoke-dependent parameters of the biologically based two-stage clonal expansion model. The baseline parameters and the action of radon acting on initiation and promotion were fixed based on earlier work. Cigarette smoke acting on transformation and inducing a reduction of the radon dose to the target cells after a smoking period gives an acceptable description of the data.

Bone cancer risk in mice exposed to 224Ra: protraction effects from promotion.

This paper analyzes data for the osteosarcoma incidence in life-time experiments of (224)Ra injected mice with respect to the importance of initiating and promoting action of ionizing high LET-radiation. This was done with the biologically motivated two step clonal expansion (TSCE) model of tumor induction. Experimentally derived osteosarcoma incidence in 1,194 mice following exposure to (224)Ra with different total radiation doses and different fractionation patterns were analyzed together with incidence data from 1,710 unirradiated control animals. Effects of radiation on the initiating event and on the clonal expansion rate, i.e. on promotion were found to be necessary to explain the observed patterns with this model. The data show a distinct inverse protraction effect at high doses, whereas at lower doses this effect becomes insignificant. Such a behavior is well reproduced in the proposed model: At dose rates above 6 mGy/day a longer exposure produces higher ERR per dose, while for lower rates the reverse is the case. The TSCE model permits the deduction of several kinetic parameters of a postulated two-step bone tumorigenesis process. Mean exposure rates of 0.13 mGy/day are found to double the baseline initiation rate. At rates above 100 mGy/day, the initiation rate decreases. The clonal expansion rate is doubled at 8 mGy/day, and it levels out at rates beyond 100 mGy/day.

[Progressive systemic sclerosis and pregnancy]. / Progressive systemische Sklerodermie und Schwangerschaft.

Progressive systemic sclerosis is a connective tissue disease with inflammation and fibrosis. Pregnant women with progressive systemic sclerosis have an increased risk for preterm births and probably for small-for-date babies. We report the case of a 28-year-old II G O P suffering from progressive systemic sclerosis with severe pulmonary fibrosis and affection of the oesophagus. She was admitted to hospital at 32 weeks of gestation with premature labour and cervical incompetence. At 34 weeks of gestation she was delivered by Caesarean section with spinal anaesthesia because of foetal growth arrest and decreased pulmonary function. The operation and the postoperative course were without any complications. Pregnant women with progressive systemic sclerosis have an increased risk for renal and pulmonary complications (hypertension, hypoxia). Therefore careful interdisciplinary obstetric monitoring is very important.

Interpretation by modelling of observations in radon radiation carcinogenesis.

Biophysical models for radon-related induction of lung cancer are developed with the aim of reducing the uncertainties in current risk estimates at low doses by a better understanding of the relevant mechanisms. These models can make use of the full dosimetric information when extracting information on, say, age-at-exposure, protraction or fractionation effects. It is found that irradiation by radon and its progeny does act on the initiating event of carcinogenesis (e.g. mutation), but its dominating effect is via promoting the division of already initiated cells. Data show that the concept of a unit of exposure giving, in an additive way, a unit of lung cancer risk is too limited, while relatively simple mechanistic assumptions described in this article do yield an adequate description of observations. Exposures in epidemiological data sets are measured with error. For various error models it has been shown that likelihood-based techniques of correction work reliably; likewise for biologically based cancer models. When several parameters are allowed to be exposure dependent, for example, initiation and promotion, then their relative importance is influenced.

Time trends of thyroid cancer incidence in Ukraine after the Chernobyl accident.

The rate of childhood thyroid cancer incidence observed in northern Ukraine during the period 1986-1998 is described as a function of time-since-exposure, age-at-exposure, and sex. Conclusions are drawn for the excess absolute risk per dose: after a minimal latency period of about three years it shows a linear increase with time-since-exposure for at least nine years. It is roughly constant in age-at-exposure, up to 15 years. For girls exposed very young it is about a factor 2 larger than for boys. For children exposed at age 16-18 this ratio increases to about 5. The thyroids of young children are not more sensitive to radiation dose than those of older ones in absolute risk in northern Ukraine in the currently used data set. As the background is increasing with age, a constant absolute risk gives a decreasing relative risk.

Comparing regression methods for the two-stage clonal expansion model of carcinogenesis.

In the statistical analysis of cohort data with risk estimation models, both Poisson and individual likelihood regressions are widely used methods of parameter estimation. In this paper, their performance has been tested with the biologically motivated two-stage clonal expansion (TSCE) model of carcinogenesis. To exclude inevitable uncertainties of existing data, cohorts with simple individual exposure history have been created by Monte Carlo simulation. To generate some similar properties of atomic bomb survivors and radon-exposed mine workers, both acute and protracted exposure patterns have been generated. Then the capacity of the two regression methods has been compared to retrieve a priori known model parameters from the simulated cohort data. For simple models with smooth hazard functions, the parameter estimates from both methods come close to their true values. However, for models with strongly discontinuous functions which are generated by the cell mutation process of transformation, the Poisson regression method fails to produce reliable estimates. This behaviour is explained by the construction of class averages during data stratification. Thereby, some indispensable information on the individual exposure history was destroyed. It could not be repaired by countermeasures such as the refinement of Poisson classes or a more adequate choice of Poisson groups. Although this choice might still exist we were unable to discover it. In contrast to this, the individual likelihood regression technique was found to work reliably for all considered versions of the TSCE model.

Age-adjustment in experimental animal data and its application to lung cancer in radon-exposed rats.

Procedures for age-adjustment of cancer fractions are proposed which do not require fixed age intervals. The full available information on survival times can then be used, which is especially important in small treatment groups. For incidental cancers a non-decreasing prevalence function and for fatal cancers the Kaplan-Meier estimator is used. In the latter case, the estimated competing risk of the control population is standardized, not its true survival. This makes the technique also applicable to treatment groups with high incidence, which otherwise may give adjusted rates above 100%. In the application part these age-adjustment techniques are used here to study lung cancer in radon-exposed Wistar and Sprague-Dawley rats. The data include a classification in fatal and incidental lung cancers. For fatal lung cancer, the lifetime excess absolute risk (LEAR) at 1 WLM averaged over all exposed groups is 0.67x10(-4) for the Wistar rats, while for the Sprague-Dawley rats it is 0.40x10(-4). For the Sprague-Dawley rats, there are several groups exposed later in life. When the averaging is restricted to animals with start of exposure prior to 150 days of age, the weighted average risk among the Sprague-Dawley rats is 0.79x10(-4). Compared to groups with similar exposures as young adults (up to about 150 days), animals exposed later in life have substantially lower lifetime risks. The Wistar rats include groups with roughly equal exposure rates and ages at start of exposure, but with increasing exposure duration. Within these groupings the LEAR at 1 WLM does not decrease with additional exposure at higher age, as would be expected if the risk from exposures at different ages would be additive.

Lung tumour risk in radon-exposed rats from different experiments: comparative analysis with biologically based models.

Data sets of radon-exposed male rats from Wistar and Sprague-Dawley strains have been investigated with two different versions of the two-step clonal expansion (TSCE) model of carcinogenesis. These so-called initiation-promotion (IP) and initiation-transformation (IT) models are named after the cell-based processes that are assumed to be induced by radiation. The analysis was done with all malignant lung tumours taken to be incidental and with fatal tumours alone. For all tumours treated as incidental, both models could explain the tumour incidence data equally well. Owing to its better fit, only the IP model was applied in the analysis of fatal tumours that carry additional information on the time when they cause death. A statistical test rejected the hypothesis that a joint cohort of Wistar and Sprague-Dawley rats can be described with the same set of model parameters. Thus, the risk analysis has been carried out for the Wistar rats and the Sprague-Dawley rats separately and has been restricted to fatal tumours alone because of their similar effect in humans. Using a refined technique of age-adjustment, the lifetime excess absolute risk has been standardised with the survival function from competing risks in the control population. The age-adjusted excess risks for both strains of rats were of similar size, for animals with first exposure later in life they decreased markedly. For high cumulative exposure the excess risk increased with longer exposure duration, for low cumulative exposure it showed the opposite trend. In addition, high cumulative exposure exerted lethal effects other than lung cancer on the rats.

Studies of radon-exposed miner cohorts using a biologically based model: comparison of current Czech and French data with historic data from China and Colorado.

The biologically based two-stage clonal expansion (TSCE) model is used to analyze lung cancer in several miners studies, two new ones (Czech, French) and two historic ones (Chinese, Colorado). In all cases, the model assumptions are identical. An action of radiation on initiation, promotion, and transformation is allowed. While all four studies indicate a highly significant action of radiation on promotion, the action on initiation is not significant in the French cohort, and barely significant in the Colorado miners cohort. No action on transformation is found in the Colorado miners, while the other data sets indicate a borderline significance. The model can describe all the data sets adequately, with different model parameters. The observed patterns in exposure, time since beginning of exposure, birth year, age and calendar year are reproduced well. The doubling exposure rate for initiation is about 3.5 WLM/year in the new data sets, while it is higher in the historic data sets. For transformation the doubling rate is about 20 WLM/year for the new data sets, while again the historic data give higher estimates. The action of radiation on promotion is quite different in the four data sets. These differences also induce different risk estimates at low exposures. The larger power of the new studies at these low exposures, compared to the historic data requires less extrapolation when the risk at very low exposures is estimated.

A biologically based model for liver cancer risk in the Swedish thorotrast patients.

Data on liver tumors among 416 Swedish patients who were exposed to Thorotrast between 1930 and 1950 were analyzed with the biologically based two-step clonal expansion (TSCE) model. For background data, the Swedish Cancer Register for the follow-up period 1958 to 1997 was used. Effects of radiation on the initiating mutation and on the clonal expansion rate explained the observed patterns well. The TSCE model permits the deduction of several kinetic parameters of the postulated tumorigenesis process. Dose rates of 5 mGy/year double the spontaneous initiation rate. The clonal expansion rate is doubled by 80 mGy/year, and for females it reaches a plateau at dose rates beyond 240 mGy/year. For males the plateau is not significant. The magnitude of the estimated promoting effect of radiation can be explained with a moderate increase in the cell replacement probability for the intermediate cells in the liver, which is strikingly similar to the situation in lung tumorigenesis.

Mechanistic modelling in large case-control studies of lung cancer risk from smoking.

The two-step clonal expansion (TSCE) model is applied to large case-control studies, frequency matched for age, which allow estimation of the RR of lung tumour risk caused by smoking. For estimating background hazard rates, mortality data from the study areas are used to supplement the case-control data. Two approaches are used to analyse the data, based on the unconditional and the conditional likelihoods. They are demonstrated to give nearly identical results. Some model diagnostics are performed and demonstrate a good model fit. Our results indicate that smoking acts on the promotion and transformation parameters, but not on the initiation parameter of the TSCE model. The fitted relative risk of current smokers peaks between ages 50 and 60 years. The relative risk of male ex-smokers decreases strongly with time since end of exposure, but does not reach the risk of non-smokers, and does not decrease as much as for female ex-smokers.

Identifying dose dependences of the two-stage clonal expansion model with simulated cohorts.

The two-stage clonal expansion model of cancer induction is tested on recorded and simulated cohort data of radon-exposed rats. Unfortunately, different versions of the model, for which radiation acts on different biological processes, can provide a good description of the data. This is the case for an initiation-transformation and an initiation-promotion model when they are applied to lung tumour data of radon-exposed rats and all malignant tumours are assumed to be incidental. However, if one were able to use information on fatal tumours as well, the two models could be separated by their deviances.