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M P Little

Publications and source records attributed to M P Little.

At least 19 recordsLinked to original sources
PubMed1999

Comparison of breast cancer incidence in the Massachusetts tuberculosis fluoroscopy cohort and in the Japanese atomic bomb survivors.

Breast cancer has occurred in excess among women exposed briefly to atomic bomb radiation and among those exposed repeatedly over many years to medical radiation for tuberculosis (TB). The excess relative risk of breast cancer incidence in the Japanese atomic bomb survivors, however, is significantly higher (two-sided P = 0.04) than that in the Massachusetts TB fluoroscopy patients. The best estimate of the ratio between the excess relative risk coefficients for the Japanese and Massachusetts cohorts is 2.11 (95% CI 1.05, 4.95). However, this higher relative excess risk is attributable to the lower baseline risk of breast cancer among Japanese women compared with the Massachusetts women, and the excess absolute breast cancer risks in the two data sets are statistically indistinguishable (two-sided P = 0.32). The best estimate of the ratio between the excess absolute risk coefficients among Japanese and Massachusetts women is 0.73 (95% CI 0.41, 1.44). After childhood exposures, an early onset of radiation-induced breast cancer was seen among Japanese atomic bomb survivors but not among the Massachusetts women. There are some indications (two-sided P = 0.04) of differences in the patterns of risk over time since exposure between these groups exposed in childhood. However, in general there are no marked differences between the Massachusetts and Japanese data sets in the age and time distribution of risk of radiation-induced breast cancer. These data provide little evidence for a reduction of breast cancer risk after fractionated irradiation.

Adolescent↗
PubMed1998

Risks of brain tumour following treatment for cancer in childhood: modification by genetic factors, radiotherapy and chemotherapy.

A cohort of 4,400 persons treated for various cancers of childhood in France and the UK was followed up over an extended period to assess risks of subsequent brain tumour in relation to the radiotherapy and chemotherapy that the children received for their first cancer. Elevated risks of subsequent brain tumours were associated with first central nervous system (CNS) tumour (two-sided p = 0.0002) and neurofibromatosis (two-sided p = 0.001). There was also elevated brain tumour risk (two-sided p = 0.003) associated with ionising radiation exposure, the risk being concentrated among benign and unspecified brain tumours. The radiation-related risk of benign and unspecified brain tumours was significantly higher than that of malignant brain tumours (two-sided p< or =0.05); there was no significant change of malignant brain tumour risk with ionising radiation dose (two-sided p > 0.2). In general, there were no strong associations between alkylating agent dose and brain tumour risk. The only significant association between brain tumour risk and alkylating agent dose was in relation to compounds used (bleomycin, chloraminophen) that are thought not to deliver substantial doses to the brain; the statistical significance of the trend with dose depended on a single case, and thus must be considered a weak result.

Adolescent↗
PubMed1998

Variations with time and age in the risks of solid cancer incidence after radiation exposure in childhood.

The Japanese atomic bomb survivor incidence data set and data on five other groups exposed to ionizing radiation in childhood are analysed and evidence found for a reduction in the radiation-induced relative risk of cancers other than leukaemia with increasing time since exposure. Overall, reductions of 5.7-6.1 per cent per year of time since exposure are indicated, depending on the time at which the reduction is presumed to start, and all the reductions are statistically significant at the 5 per cent level. There is no significant heterogeneity in the speed of the reductions in relative risk with time by cohort, by cancer type, sex, or age at exposure group. There is a significant reduction of relative risk with increasing age at exposure, but adjustment for age at exposure does not markedly affect the time trends of relative risk. For all of the groups considered, there is a statistically significant increase in the excess absolute risk with increasing time since exposure. However, by contrast with the relative homogeneity of the time trends of relative risk, there is statistically significant heterogeneity by cancer type within the Japanese cohort (P = 0.05) and between the cohorts (P < 0.0001) in the speed of increase of the excess absolute risk with time since exposure.

Age Factors↗
PubMed1998

Curvature in the cancer mortality dose response in Japanese atomic bomb survivors: absence of evidence of threshold.

PURPOSES: To investigate the evidence for a threshold in the cancer dose-response curve. MATERIALS AND METHODS: Japanese atomic bomb survivor cancer mortality data, based on follow-up to 1990, was used, taking account of random errors in DS86 dose estimates. RESULTS: For all solid cancers analysed together, there is a significant positive dose response (two-sided p<0.05) if all survivors who received <0.5 Sv are considered, but the significance vanishes if doses of <0.2 Sv are considered; the same is also true for leukaemia. For solid cancer mortality there is no indication of curvilinearity in the dose response: no statistically significant improvement in fit to a linear relative risk model is provided by addition of quadratic or threshold dose terms. If a relative risk model with a threshold (the dose response is assumed linear above the threshold) is fitted to solid cancer mortality data, the best estimate of the threshold is < 0.00 Sv (95% CI <0.00-0.13). If a linear-quadratic-threshold model is used the best estimate of the threshold is < 0.00 Sv (95% CI < 0.00-0.15). For leukaemia mortality there is highly statistically significant upward curvature in the dose response. In particular, if a relative risk model with a threshold (the dose response is assumed linear above the threshold) is fitted to the leukaemia data, the best estimate of the threshold is 0.16 Sv (95% CI 0.05-0.40) (two-sided p=0.001 for test of departure of threshold from 0). However, there is no evidence for a threshold effect (two-sided p = 0.16) when a quadratic term is included in the dose response: the best estimate of threshold in this case is 0.09Sv (95% CI <0.00-0.29). Moreover, addition of a quadratic term improves the fit of a linear-threshold model at borderline levels of statistical significance (two-sided p = 0.07). Therefore, the most parsimonious description of the leukaemia dose response is provided by a linear-quadratic function of dose. CONCLUSIONS: There is no evidence of threshold-type departures from the linear-quadratic dose response either for solid tumours or for leukaemia in the Japanese atomic bomb survivor mortality data.

Dose-Response Relationship, Radiation↗
PubMed1998

Cancer predisposition, radiosensitivity and the risk of radiation-induced cancers. IV. Prediction of risks in relatives of cancer-predisposed individuals.

Individuals carrying cancer-predisposing germline mutations are known to be at a higher risk for cancers than those who do not carry them. This is also true of their biological relatives because they have a higher probability of being carriers of such mutant genes than unrelated individuals in the population. Further, there are now sufficient grounds for assuming that cancer-predisposed individuals may also be at a higher risk for cancers induced by ionizing radiation. In our earlier work, we examined the impact of this heterogeneity (with respect to cancer predisposition and radiosensitivity differentials) on risks of radiation-induced cancer at the population level. This paper is focused on the question of risks of radiation-induced cancer in relatives of cancer-predisposed individuals. Using an autosomal dominant model of cancer predisposition and radiosensitivity developed earlier and applying it to breast cancer risks associated with mutations in the BRCA1 gene, we show that: (1) The risk ratio (i.e. the ratio of risk of radiation-induced cancer in relatives to that in unrelated individuals) in the population increases with the degree of biological relatedness of the relative, being higher for close than for distant relatives; incomplete penetrance of the mutant gene "dilutes" this risk ratio. (2) The proportion of excess radiation-induced cancers in relatives (i.e. the attributable fraction) is higher than in unrelated individuals. (3) In relatives, the proportion of excess cancers due to radiosensitivity differentials alone depends on the strength of predisposition, the radiosensitivity differentials assumed, the radiation dose, the proportion of cancers due to predisposition, the mutant gene frequency and the penetrance of the mutant gene. This is in contrast to the situation for unrelated individuals, for whom the above-mentioned proportion is dependent on the first three but not on the last three of these factors. Further, even when the proportion of excess cancers is small, most of it is due to radiosensitivity differential alone both in unrelated individuals and in relatives. (4) For values of predisposition strength and radiosensitivity differential <10, even when the estimated frequency of a mutant BRCA1 gene is 0.0047 and the proportion of breast cancers due to these mutations is 38% (as is the case for Ashkenazi Jewish women under age 30), the increase in breast cancer risks is only marginal even for first-degree relatives. (5) These findings support the conclusion that increases in radiation risks to relatives (compared to those in unrelated individuals), to be detectable epidemiologically, will occur only when the mutant alleles are common and the strength of predisposition and radiosensitivity differentials are conjointly dramatic.

Breast Neoplasms↗
PubMed1997

Cancer in the offspring of radiation workers: a record linkage study.

OBJECTIVES: To test the "Gardner hypothesis" that childhood leukaemia and non-Hodgkin lymphoma can be caused by fathers' exposure to ionising radiation before the conception of the child, and, more generally, to investigate whether such radiation exposure of either parent is a cause of childhood cancer. DESIGN: Case-control study. SETTING: Great Britain. SUBJECTS: 35,949 children diagnosed as having cancer, together with matched controls. MAIN OUTCOME MEASURES: Parental employment as radiation worker as defined by inclusion in the National Registry for Radiation Workers and being monitored for external radiation before conception of child; cumulative dose of external ionising radiation for various periods of employment before conception; dose during pregnancy. RESULTS: After cases studied by Gardner and colleagues were excluded, fathers of children with leukaemia or non-Hodgkin lymphoma were significantly more likely than fathers of controls to have been radiation workers (relative risk 1.77, 95% confidence interval 1.05 to 3.03) but there was no dose-response relation for any of the exposure periods studied; indeed, the association was greatest for those with doses below the level of detection. No increased risk was found for fathers with a lifetime preconception dose of 100 mSv or more, or with a dose in the 6 months before conception of 10 mSv or more. There was no increased risk for the group of other childhood cancers. Mothers' radiation work was associated with a significant increase of childhood cancer (relative risk 5.00, 1.42 to 26.94; based on 15 cases and 3 controls). Only four of the case mothers and no controls were radiation workers during pregnancy. CONCLUSIONS: These results do not support the hypothesis that paternal preconception irradiation is a cause of childhood leukaemia and non-Hodgkin lymphoma; the observed associations may be chance findings or results from exposure to infective or other agents. If there is any increased risk for the children of fathers who are radiation workers, it is small in absolute terms: in Britain the average risk by age 15 years is 6.5 per 10,000; our best estimate, using all available data, is that the increase is 5.4 per 10,000. For mothers, the numbers are too small for reliable estimates of the risk, if any, to be made.

Adolescent↗
PubMed1997

Estimates of neutron relative biological effectiveness derived from the Japanese atomic bomb survivors.

PURPOSE: To investigate neutron relative biological effectiveness. MATERIALS AND METHODS: The latest Japanese atomic bomb survivor cancer incidence and mortality datasets with the current (DS86) dosimetry system are analysed using generalized relative risk models and generalized absolute risk models, both with and without recently indicated adjustments to the Hiroshima DS86 neutron dose estimates. RESULTS: Without adjustments to the Hiroshima neutron doses, the best estimate of neutron relative biological effectiveness for all tumours in the incidence data is 63.3 (95% CI < 0-275.3) when a generalized relative risk model is used; when a generalized absolute risk model is used in the incidence data the best estimate is 53.5 (95% CI < 0-201.0); when a generalized relative risk model is used in the mortality data, the best estimate is 287.7 (95% CI 38.0- > 10[3]). When likely adjustments are made to the Hiroshima neutron doses the best estimate of neutron relative biological effectiveness in the incidence data using a generalized relative risk model is 15.1 (95% CI < 0-51.4); when a generalized absolute risk model is used in the incidence data the best estimate is 9.0 (95% CI < 0-32.9); when a generalized relative risk model is used in the mortality data the best estimate is 55.1 (95% CI 9.5-280.3). Although there are no significant differences between groupings of the solid tumour sites in their estimated neutron relative biological effectiveness, there are indications that the neutron relative biological effectiveness of solid tumours is lower than that of leukaemia, whether or not adjustments are made to the Hiroshima neutron dose estimates. Uncertainties in the likely adjustments to the DS86 Hiroshima neutron and gamma dose estimates as well as uncertainties in the modelling of excess risk in the two cities (Hiroshima and Nagasaki) imply that these findings should be treated with caution. CONCLUSIONS: Likely adjustments to the Hiroshima neutron dose estimates imply a substantial increase in information on neutron relative biological effectiveness. Whether or not adjustments are made to the Hiroshima neutron doses, there are indications of inconsistency between the estimates of neutron relative biological effectiveness for solid tumours and leukaemia. Dosimetric and modelling uncertainties mean that these findings should be treated with caution.

Humans↗
PubMed1997

The risk of non-melanoma skin cancer incidence in the Japanese atomic bomb survivors.

The latest Japanese atomic bomb survivor non-melanoma skin cancer incidence dataset is analysed and indicates substantial curvilinearity in the dose-response curve, consistent with a possible dose threshold of about 1 Sv, or with a dose-response in which the excess relative risk is proportional to the fourth power of dose, with a turning-over in the dose-response at high doses (> 3 Sv). The time distribution of the radiation-induced excess risk is best described by a model in which the relative excess risk is proportional to a product of powers of time since exposure and attained age. The fits of generalized relative risk models with exponential functions of time and age at exposure (and in particular of attained age) to adjust the relative risk are less satisfactory, as also are the fits of other models in which products of powers of time since exposure, age at exposure and attained age adjust the excess absolute risk. Sensitivity analyses indicate the importance of likely adjustments to the Hiroshima neutron doses for the optimal model parameters, particularly if values of the neutron relative biological effectiveness (RBE) of more than 5 are assumed. If adjustments recently proposed are made to the Hiroshima neutron doses, then using the optimal model (in which excess risk is proportional to the fourth power of dose) the best estimate of the neutron RBE is 1.3 (95% CI < 07.1). However, uncertainties in skin dose estimates for the atomic bomb survivors means that the findings with respect to the neutron RBE and the non-linearity in the dose-response curve should be treated with caution.

Dose-Response Relationship, Radiation↗
PubMed1997

Curvilinearity in the dose-response curve for cancer in Japanese atomic bomb survivors.

Recently released data on cancer incidence in Japanese atomic bomb survivors are analyzed using a variety of relative risk models that take account of errors in estimates of dose to assess the dose response at low doses. If a relative risk model with a threshold (the dose response is assumed linear above the threshold) is fitted to solid cancer data, a threshold of more than about 0.2 Sv is inconsistent with the data, whereas these data are consistent with there being no threshold. Among solid cancer subtypes there is strong evidence for a possible dose threshold only for nonmelanoma skin cancer. If a relative risk model with a threshold (the dose response is assumed linear above the threshold) is fitted to the leukemia data, a threshold of more than about 0.3 Sv is inconsistent with the data. In contrast to the estimates for the threshold level for solid cancer data, the best estimate for the threshold level in the leukemia data is significantly different from zero even when allowance is made for a possible quadratic term in the dose response, albeit at borderline levels of statistical significance (p = 0.04). There is little evidence for curvature in the leukemia dose response from 0.2 Sv upwards. However, possible underestimation of the errors in the estimates of the dose threshold as a result of confounding and uncertainties not taken into account in the analysis, together with the lack of biological plausibility of a threshold, makes interpretation of this finding questionable.

Dose-Response Relationship, Radiation↗
PubMed1997

Cancer predisposition, radiosensitivity and the risk of radiation-induced cancers. III. Effects of incomplete penetrance and dose-dependent radiosensitivity on cancer risks in populations.

Recent studies have identified a number of genes in the human genome at which germinal mutations predispose the individuals to one or another type of cancer. These studies also show that not all individuals carrying the mutant genes develop cancers (i.e., the mutant genes are not fully penetrant). At least some of these predisposed genotypes also have a higher sensitivity to cancers induced by ionizing radiation than those who are not so predisposed, which may be dependent on dose. This paper presents an analysis of the impact of such heterogeneity on estimates of cancer risks for an irradiated population. This is done by extending the Mendelian one-locus, two-allele model of cancer predisposition and radiosensitivity developed earlier to allow for incomplete penetrance and dose dependence of radiosensitivity differentials among genotypes. The model is applied to recently published data for breast cancer and hereditary non-polyposis colon cancer using a range of possible values for the strength of predisposition and radiosensitivity differentials. It is shown that, after radiation exposures, the ratio of cancer risks in a heterogeneous population relative to that in a homogeneous population increases with increasing dose, but that the dose dependence of the relative risk diminishes at higher doses. Likewise, the attributable risk (i.e. the proportion of the increase in risk that is due to both increased susceptibility and increased radiosensitivity) and the proportion of attributable risk due to increased radiosensitivity also increase with dose, and the dose dependence of each measurement also diminishes at higher doses. However, when the proportion of cancers due to the susceptible genotypes is small (<10%) (as is likely to be the case for breast cancer in non-Ashkenazi women), the increases in the relative risk and attributable risk are marked only when there are very large increases in cancer susceptibility (>1000-fold) and radiosensitivity (>100-fold) in the susceptible group. When the proportion of cancers due to the susceptible genotypes is appreciable (> or = 10%) (as may be the case for breast cancer in Ashkenazi Jewish women), there may be large increases in the relative risk and attributable risk for comparatively modest increases in cancer susceptibility (>10-fold) and radiosensitivity (>100-fold) in the susceptible subpopulation. For any given combination of strength of predisposition and radiosensitivity differential, incomplete penetrance dilutes the effect.

Breast Neoplasms↗
PubMed1997

Thyroid disease in the west of Ireland: an atypical incidence of neoplasia.

This study was established to review the spectrum of thyroid disease presenting to a regional centre in the West of Ireland. Over a ten year period 414 thyroidectomies were performed. The most common histological diagnosis was nodular goitre (238 patients). There were 134 thyroid neoplasms; 87 (65%) adenomas, 40 (30%) carcinomas and 7 (5%) lymphomas. A breakdown of the cancers revealed 17 (36%) papillary and 14 (30%) follicular carcinomas with 7 (15%) lymphomas. Six (13%) patients presented with anaplastic tumors. Solitary nodules had a high cancer risk (25%) in comparison with multinodular or diffuse goitres (5%). Thyroiditis accounted for 38 cases while only 10 thyroidectomies were performed for Graves' disease.

Adenocarcinoma, Follicular↗
PubMed1996

Modelling lymphocytic leukaemia incidence in England and Wales using generalizations of the two-mutation model of carcinogenesis of Moolgavkar, Venzon and Knudson.

Generalizations of the two-mutation carcinogenesis model of Moolgavkar, Venzon and Knudson (MVK) are fitted to England and Wales lymphocytic leukaemia incidence data covering the period 1971-1988. Both acute lymphocytic leukaemia (ALL) and chronic lymphocytic leukaemia (CLL) can be fitted by a model with two mutations. These two-mutation models are such that the first (but not the second) mutation rate and the susceptible stem cell population vary rapidly with age. CLL is also adequately fitted by a model with three mutations, and the mutation rates and the variation in the stem cell population numbers implied by the three-mutation model are more plausible than those of the two-mutation model. For CLL there are no significant differences between the sexes in either of the optimal models fitted, but this is not the case for ALL. Thus the original MVK model adequately describes population rates of lymphocytic leukaemia in England and Wales.

Adolescent↗
PubMed1996

Evidence for curvilinearity in the cancer incidence dose-response in the Japanese atomic bomb survivors.

The recently released data on cancer incidence in the Japanese atomic bomb survivors are analysed using a variety of relative risk models which take account of errors in estimates of dose to assess the dose-response at low doses. For all solid cancers analysed together there is a significant positive dose-response (at the one-sided 2.5% significance level) if all survivors who received < 0.5 Sv are considered, but the significance vanishes if doses of < 0.2 Sv are considered. If a relative risk model with a threshold (the dose-response being assumed linear above the threshold) is fitted to the solid cancer data, a threshold of more than about 0.2 Sv is inconsistent with the data, whereas these data are consistent with there being no threshold. Linear-quadratic models and linear-quadratic models with an exponential cell-sterilization term provide no better fit than the linear model. For the three main radiation-inducible leukaemia subtypes analysed together (acute lymphatic leukaemia, acute myeloid leukaemia and chronic myeloid leukaemia) there is a significant positive dose-response (at the one-sided 2.5% significance level) if all survivors who received < 0.5 Sv are considered, but the significance vanishes if doses of < 0.2 Sv are considered. If a relative risk model with a threshold (the dose-response being assumed linear above the threshold) is fitted to the leukaemia data, a thresh-old of more than about 0.3 Sv is inconsistent with the data. In contrast with the solid cancer data, the best estimate for the threshold level in the leukaemia data is significantly different from zero, even when allowance is made for a possible quadratic term in the dose-response, albeit at borderline levels of statistical significance (p = 0.04). There is little evidence for curvature in the leukaemia dose-response from 0.2 Sv upwards. However, the possible underestimation of the errors in the estimates of the dose threshold as a result of confounding and uncertainties not taken into account in the analysis, together with the lack of biological plausibility of a threshold, makes the interpretation of this finding questionable.

Humans↗
PubMed1995

A review of the risks of leukemia in relation to parental pre-conception exposure to radiation.

The apparent risk of childhood leukemia resulting from paternal pre-conception radiation exposure found among children of the Sellafield (West Cumbria, UK) workforce is compared with the apparent risk in a number of other epidemiological studies. In particular, the extent of the incompatibility of the leukemia pre-conception exposure risks in the offspring of the Sellafield workforce born in the village of Seascale with the risks for those born in the rest of west Cumbria, and with the risks in the offspring of the Japanese bomb survivors, the Ontario radiation workers, and the Scottish radiation workers is discussed. A variety of animal data relating to the possibility of leukemia arising as a result of parental pre-conception exposure is also considered. It is concluded that the extent of the inconsistency of the leukemia risks in the Seascale data with this body of epidemiological and experimental data makes it highly unlikely that the association observed in the West Cumbria dataset represents a causal relationship.

Animals↗