Computer-assisted severity of effect assessment of hematopoietic cell renewal after radiation exposure based on mathematical models.

After accidental radiation exposure, one of the most significant health impairments is the partial or complete failure of the blood forming systems. Depending on the degree of damage, a suitable therapy must be prepared in time. This requires the assessment of the degree of damage of the blood-forming system and, in particular, of the stem-cell pool. A new approach for assessing the degree of hematopoietic impairment based on dynamic reactions of blood counts immediately following radiation exposure is presented. Cell kinetic mathematical models of blood cell turnover, neural networks, and expert-assessed clinical data records of historical radiation accidents are combined to provide a method for automatic classification of patients and to assign them to clinically related categories of severity. Using this computer-assisted approach, it is possible to distinguish those patients that are likely to restore their blood-cell formation autochthonously from those that need stem-cell transplantation.

A multi-compartment cell repopulation model allowing for inter-compartmental migration following radiation exposure, applied to leukaemia.

There is much uncertainty about cancer risks at the high radiation doses used in radiotherapy (RT). It has generally been assumed that cancer induction decreases rapidly at high doses due to cell killing. However, this is not seen in all RT groups, and a model recently developed by Sachs and Brenner [2005. Solid tumor risks after high doses of ionizing radiation. Proc. Natl Acad. Sci. USA 102, 13040-13045] proposed a mechanism for repopulation of cells after radiation exposure that explained why this might happen, at least for solid tumours. In this paper, this model is generalized to allow for heterogeneity in the dose received, and various alternate patterns of repopulation are also considered. The model is fitted to the Japanese atomic bomb survivor leukaemia incidence data, and data for various therapeutically irradiated groups. Two sets of parameters from these model fits are used to assess the sensitivity of model predictions. It is shown that in general allowing for heterogeneity in dose distribution and haematopoietic stem cell migration results in lower risks than the same average dose administered uniformly and without such migration, although this does not hold in the limiting case of complete stem cell repopulation between radiation dose fractions. We also investigate the difference made by assuming a compartmental repopulation signal, and a global repopulation signal. In general we show that in the absence of stochastic extinction, compartmental repopulation always predicts a larger number of mutated cells than global repopulation. However, in certain dose regimes stochastic extinction cannot be ignored, and in these cases the numbers of mutated cells predicted with global repopulation can exceed that for compartmental repopulation. In general, mutant cell numbers are highly overdispersed, with variance much greater than the mean.

[Assessment of hematopoiesis regeneration in patients with solid tumors after radiotherapy]. / Ocena regeneracji ukladu krwiotwórczego u chorych na nowotwory lite leczonych promieniowaniem jonizujacym.

The myelotoxicity is one of the most severe adverse events of radiotherapy. Increase of CD34+ cells level in peripheral blood as result of raised output of granulocyte colony stimulating factor (G-CSF) can be result of hematopoiesis regeneration after radiotherapy. The aim of this study was to determine the hematopoiesis regeneration using analysis of CD34+ cells level in peripheral blood and serum concentration of G-CSF in patients treated with radiotherapy according to irradiated body region and irradiation field size. Two groups of irradiated patients were examined. Group I consisted of 11 patients (mean age 56) with gynecological malignancies (teletherapy dose 40-50 Gy for pelvic area and brachytherapy with Cs). Group II consisted of 10 patients (mean age 58) with head and neck malignancies (teletherapy only 50-70 Gy). Every patient was evaluated 3 times: before radiotherapy, in the day of ending and 14 days after therapy. 3 ml of blood for CD34 and serum for G-CSF estimation were collected. Blood cells were stained with monoclonal antibody specific for CD34 antigen and analysed by flow cytometry. G-CSF level was estimated by ELISA. After radiotherapy in both groups statistically significant leukopenia (p < 0.001) was observed. There was no difference between two groups in levels of CD34+ cells before and in the last day of therapy but there was significant increase of CD34+ cells in group I compared with group II 14 days after treatment (p < 0.01). Decrease of CD34+ cells during radiotherapy and after its ending in all patients was observed but only in group II was statistically significant. Positive correlation between amount of leukocytes and CD34+ cells percentage was stated. There were no statistically significant differences in serum G-CSF concentration within particular groups and between group I and II. Our results indicate that evaluation of CD34+ cells level in peripheral blood is useful in prediction of hematopoiesis regeneration after radiotherapy. G-CSF serum concentration is not prognostic factor in these groups of patients.

Monte Carlo determination of age-dependent steady-state dose to red bone marrow and bone from 14C exposure.

Monte Carlo simulations were carried out to calculate the age-dependent dose from the beta decay of 14C to marrow and bone on the basis of a steady-state specific-activity model. A model of the trabecular cavity containing spherical fat cells in a square lattice surrounded by haemopoietic tissue was employed. The age-dependent 14C dose to haemopoietic (red) marrow was estimated taking account of the change in the fat cell size with fat fraction. Allowances were made for the change in the percentage cellularity and distribution of active marrow in the whole skeleton as a function of age. Age-dependent changes in trabecular cavity size and bone composition were found to have only a small effect on dose. Dose rates were estimated under steady-state conditions, for food ingested with a 14C specific activity of 1 Bq g(-1) of C. The equivalent dose rate to the haemopoietic tissue of a 20 year-old adult is 77 microSv a(-1), and 39 microSv a(-1) for a 3-month-old infant. Similarly, the equivalent dose rate to the bone surfaces of an adult is 48 microSv a(-1), and 38 microSv a(-1) for an infant. Therefore, the equivalent dose rate to marrow and bone stem cells increases with age under steady state conditions.

Monte Carlo modeling of the effects of injected short-, medium- and longer-range alpha-particle emitters on human marrow at various ages.

The effects of injected short-, medium- and longer-range alpha-particle emitters ((149)Tb, (211)At/(211)Po and (213)Bi/(213)Po, respectively) on the total hemopoietic stem cell population of active normal bone marrow in humans of various ages has been estimated using Monte Carlo modeling. The fraction of the normal hemopoietic stem cells that are hit and survive has been calculated as a first step toward estimating the risk of development of therapy-induced leukemia. The fraction was lowest for the shorter-range alpha-particle emitter ((149)Tb) and highest for the longer-range alpha-particle emitter ((213)Bi/(213)Po), with the value for the medium-range alpha-particle emitter (211)At/(211)Po being intermediate between these. There was little variation in the data with the age of the subject within each alpha-particle emitter. This lack of age dependence provides reassurance that the fraction of cells hit in any subject of any age with normal marrow can be estimated by modeling newborn marrow (which requires little computing time) despite age-related differences in microarchitecture.

Radionuclide therapy with bone-seeking compounds: Monte Carlo calculations of dose-volume histograms for bone marrow in trabecular bone.

The purpose of the present work was to investigate how haematopoietic stem cell survival is affected by the differences in the dose distribution that arise from different radionuclides contained in bone-seeking radiopharmaceuticals. This was carried out in three steps: (a) calculations of representative dose distributions in individual bone marrow cavities that are irradiated by sources of 89Sr, 186Re, 117mSn or 153Sm, uniformly distributed on the bone surfaces; (b) assessment of the corresponding haematopoietic stem cell survival and (c) a comparison of these results with results obtained using the assumption of a uniform dose distribution. Two different idealized models of the geometry of trabecular bone were formulated, each consisting of an infinite array of identical elements. Monte Carlo simulations were used to generate dose-volume histograms that were used to assess haematopoietic stem cell survival with two different assumptions about spatial cell distributions. Compared with a homogeneous dose distribution, the estimated cell survival was markedly higher for 117mSn and 153Sm, and only slightly different for 89Sr and 186Re. The quantitative results differed between the two geometric models and the assumptions about spatial cell distribution, but the trends were the same. The results imply that it is necessary to include dose distributions for individual bone marrow cavities in considerations concerning bone marrow toxicity.