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Background. The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed about 90% of the worldwide epidemiological evidence on the relation between risk of breast cancer and use of hormone replacement therapy (HRT). Methods. Individual data on 52,705 women with breast cancer and 108,411 women without breast cancer from 51 studies in 21 countries were collected, checked, and analysed centrally. The main analyses are based on 53,865 postmenopausal women with a known age at menopause, of whom 17,830 (33%) had used HRT at some time. The median age at first use was 48 years, and 34% of ever-users had used HRT for 5 years or longer. Estimates of the relative risk of breast cancer associated with the use of HRT were obtained after stratification of all analyses by study, age at diagnosis, time since menopause, body-mass index, parity, and the age a woman was when her first child was born. Findings. Among current users of HRT or those who ceased use 1-4 years previously, the relative risk of having breast cancer diagnosed increased by a factor of 1.023 (95% CI 1.011-1.036; 2p = 0.0002) for each year of use; the relative risk was 1.35 (1.21-1.49; 2p = 0.00001) for women who had used HRT for 5 years or longer (average duration of use in this group 11 years). This increase is comparable with the effect on breast cancer of delaying menopause, since among never-users of HRT the relative risk of breast cancer increases by a factor of 1.028 (95% CI 1.021-1.034) for each year older at menopause. 5 or more years after cessation of HRT use, there was no significant excess of breast cancer overall or in relation to duration of use. These main findings did not vary between individual studies. Of the many factors examined that might affect the relation between breast cancer risk and use of HRT, only a woman's weight and body-mass index had a material effect: the increase in the relative risk of breast dancer associated with long durations of use in current and recent users was greater for women of lower than of higher weight or body-mass index. There was no marked variation in the results according to hormonal type or dose but little information was available about long durations of use of any specific preparation. Cancers diagnosed in women who had ever used HRT tended to be less advanced clinically than those diagnosed in never-users. In North America and Europe the cumulative incidence of breast cancer between the ages of 50 and 70 in never-users of HRT is about 45 per 1000 women. The cumulative excess numbers of breast cancers diagnosed between these ages per 1000 women who began use of HRT at age 50 and used it for 5, 10, and 15 years, respectively, are estimated to be 2 (95% CI 1-3), 6 (3-9), and 12 (5-20). Whether HRT affects mortality from breast cancer is not known. Interpretation. The risk of having breast cancer diagnosed is increased in women using HRT and increases with increasing duration of use. This effect is reduced after cessation of use of HRT and has largely, if not wholly, disappeared after about 5 years. These findings should be considered in the context of the benefits and other risks associated with the use of HRT.

Risk of Hodgkin's disease (HD) in young adults has frequently been associated with limited access to social contact in childhood and related correlates of childhood social class. In addition, case clustering has sometimes been associated with influxes of population into relatively isolated communities. To investigate this further, disease incidence rates for HD at ages 0 to 24 from a specialist tumour registry have been regressed against relevant electoral ward characteristics derived from routine census and Ordnance Survey data for England and Wales. Proximity to built-up areas and higher socio-economic status (SES) emerge as significant risk factors. The relative risks are 1.21 (95% Cl: 1.01-1.46) for high SES wards and 1.29 (1.05-1.58) for "inner zone" wards. No association of disease risk with distance travelled to work was apparent. Regions farther from built-up areas have a lower overall incidence and a shift, particularly for males, of the age distribution towards older ages. The distribution resembles the intermediate pattern for HD reported from European rural areas of low SES but never previously for high SES. Isolated areas also show an increased intensity of spatial clustering (29% of cases being classified as clustered). These findings have implications for the 'late host response' model which suggest a viral aetiology for Hodgkin's disease in young people and provide a basis for future analytical studies.

Maternal smoking during pregnancy inhibits fetal growth, and is a major cause of childhood and adult morbidity, including increased risks of cardiovascular disease and diabetes. However, the use of birthweight as a proxy for future smoking-related morbidity is hindered by its wide variability, suggesting a role for other birthweight-modifying factors. We report here, for the first time, that interactions between specific fetal HLA-DQA1 and DQB1 alleles and maternal smoking can influence birthweight. We compared mean birthweights of a series of term, HLA-DQ typed white UK newborns (n = 552) whose mothers had either smoked (n = 211) or not smoked (n = 341) during pregnancy. Maternal smoking during pregnancy resulted in an average birthweight reduction of 244 g, but the combined effects of maternal smoking and fetal DQA1*0101 or DQB1*0501 alleles resulted in a 230 and 240 g further reduction in mean birthweight, respectively, resulting from interactions between smoking and these DQ types. Other fetal DQ allele-specific interactions with maternal smoking are suggested by a "protective" effect on smoking-associated birthweight reduction in newborns typing for DQA1*0201 and DQB1*0201. Our results suggest biological interactions between maternal cigarette smoking during pregnancy and specific fetal DQ alleles that affect fetal growth. The precise nature of these interactions merits further investigation, as knowledge of fetal HLA-DQ type may be useful in refining risk estimates of severe fetal growth restriction because of maternal smoking during pregnancy.

The association between tumor Epstein-Barr virus (EBV) status and clinical outcome in Hodgkin lymphoma (HL) is controversial. This population-based study assessed the impact of EBV status on survival in age-stratified cohorts of adults with classic HL (cHL). Data from 437 cases were analyzed with a median follow-up of 93 months. Overall survival (OS) was significantly better for EBV-negative compared with EBV-positive patients (P < .001), with 5-year survival rates of 81% and 66%, respectively; disease-specific survival (DSS) was also greater for EBV-negative patients (P = .03). The impact of EBV status varied with age at diagnosis. In patients aged 16 to 34 years, EBV-associated cases had a survival advantage compared with EBV-negative cases, but differences were not statistically significant (P = .21). Among patients 50 years or older, EBV positivity was associated with a significantly poorer outcome (P = .003). Excess deaths occurred in EBV-positive patients with both early- and advanced-stage disease. In multivariate analysis of OS in the older patients, EBV status retained statistical significance after adjusting for the effects of sex, stage, and B symptoms (P = .01). Impaired immune status may contribute to the development of EBV-positive cHL in older patients, and strategies aimed at boosting the immune response should be investigated in the treatment of these patients. (Blood. 2005;106:2444-2451)

An epidemiologic study of index and family infectious mononucleosis and adult Hodgkin's disease (HD): Evidence for a specific association with EBV+ve HD in young adults. Infectious mononucleosis (IM) is an established risk factor for Hodgkin's disease (HD). A substantial minority (33%) of cases of HD have. Epstein-Barr virus (EBV) DNA within the malignant cells (are EBV+ve). It is unclear whether risk after IM applies specifically to EBV+ve HD. We report the results of a population-based case-control study of HD in adults (n = 408 cases of classical H D, 513 controls) aged 16-74 years; the case series included 113 EBV+ve and 243 EBV-ve HD. Analyses compared total HD, EBV+ve HD and EBV-ve HD with the controls and EBV+ve HD with EBV-ve HD cases using, mainly, logistic regression. Regression analyses were adjusted for gender, age-group and socioeconomic status, and were per formed for the whole age range and separately for young (< 35 years) and old adults ( greater than or equal to 35 years); formal tests of effect modification by age were included. For the young adults, reported 1M in index or relative was strongly and significantly associated with EBV+ve HD when compared to controls (odds ratio [OR] = 2.94, 95% confidence interval [Cl]: 1.08-7.98 and OR = 5.22, 95% Cl: 2.15-12.68, respectively). These results may be interpreted as indications that late first exposure to EBV increases risk of HD, especially in young adults; this applies primarily to EBV+ve HD. (C) 2003 Wiley-Liss, Inc.

From 1992-2001, 7 countries in Europe gradually recruited men for the European Randomised Screening for Prostate Cancer (ERSPC) trial. Centres recruit different age groups and have different designs for recruiting and countries have different underlying risks for prostate cancer. Recruitment has reached 163,126 men aged 55-69 at entry now. Our purpose was to calculate the power of the trial and at what point in time can statistically significant differences in prostate cancer mortality be expected. Recruitment data were collected from the screening centres. We calculated the expected number of prostate cancer deaths in each follow-up year, based on national statistics and expected rate in trial entrants. The power was calculated using different assumptions on intervention effect and contamination rate and also if the ERSPC trial would cooperate with other trials. With an assumed 25% intervention effect in men actually screened and a 20% contamination rate, the trial will reach a power of 0.86 in 2008. With an assumed intervention effect of 40%, the power reaches 0.90 in 2003-2004. Pooling data with those of the Prostate, Lung, Colorectal and Ovary (PLCO) trial early is expected to improve the power to 79% (20% intervention effect) to 92% (40% intervention effect PLCO). Adding more centres with compliance rates lower than 45% decreases the power of the trial. The ERSPC trial has sufficient power to detect a significant difference in prostate cancer mortality between the 2 arms if the true reduction in mortality by screening is 25% or more or if contamination remains limited to 10% if the true effect is 20% or more. If early detection and treatment turns out to have a stronger effect as may be suggested by observational data, the ERSPC trial is likely to conclusively show that within the next 5 years.

The ability of pathology characteristics to predict outcome was tested with the 1029 cancers accumulated in the Edinburgh Randomized Trial of breast screening after 14 years follow-up. The majority (55.7%) were in the screening arm, which also had more operable cases (81.3% vs 62.2%); the reduction in the proportion of inoperable breast cancers in a UK female population invited to mammographic screening is a notable effect of the trial. In the 691 operable invasive cases the size, histological type, grade, node status and node number group individually showed highly significant (P< 0.001) association with survival. In multivariate analysis the Nottingham Prognostic Index (NPI) derived from these features showed highly significant association with survival (P< 0.001). However, when first adjusted for NPI, combined addition of pathological size in 6 categories and histological type as special or not had an independent association with survival that was statistically firmly based (P< 0.001). For operable breast cancer the gains are in smaller sizes, better histological features, and higher proportion node negative. The weighting factors applied to pathology indicators of survival in the NPI are not optimal for a population included in a trial of screening. In particular, a linear trend of the index with pathological size is not appropriate. Inclusion of histological type as special or not improves the index further. © 2000 Cancer Research Campaign

Many different aetiologies for childhood cancer have been suggested, but few are well established. One is that parental autoimmune disease is linked with susceptibility for haematopoietic malignancies in their offspring during childhood. The present study is the first to investigate this hypothesis using a follow-up design. A cohort of 53 811 children of more than 36 000 patients diagnosed with a systemic, organ-specific or suspected autoimmune disease were followed up for cancer incidence in the Danish Cancer Registry during 1968–1993. The parents were identified through the National Registry of Patients, while their children were traced in the Central Population Register. Cancer incidence among the offspring was compared with that in the corresponding childhood population of Denmark. In total, 115 cancers were observed among children aged 0–19 years, yielding a non-significant standardized incidence ratio of 1.07. Lymphomas contributed 21 cases to the overall number of tumours, 60% more than expected (95% confidence interval (CI) 1.0–2.4); leukaemia contributed 37 cases representing an excess of 30% (95% CI 0.9–1.8). Our results give some support to the hypothesis that parental autoimmune disease is associated with childhood lymphoma and leukaemia. © 2000 Cancer Research Campaign

A UK population-based case–control study of Hodgkin's disease (HD) in young adults (16–24 years) included 118 cases and 237 controls matched on year of birth, gender and county of residence. The majority (103) of the cases were classified by Epstein–Barr virus (EBV) status (EBV present in Reed–Stenberg cells), with 19 being EBV-positive. Analyses using conditional logistic regression are presented of subject reports of prior infectious disease (infectious mononucleosis (IM), chicken pox, measles, mumps, pertussis and rubella). In these analyses HD cases are compared with matched controls, EBV-positive cases and EBV-negative cases are compared separately with their controls and formal tests of differences of association by EBV status are applied. A prior history of IM was positively associated with HD (odds ratio (OR) = 2.43, 95% confidence interval (CI) = 1.10–5.33) and with EBV-positive HD (OR = 9.16, 95% CI = 1.07–78.31) and the difference between EBV-positive and EBV-negative HD was statistically significant (P = 0.013). The remaining infectious illnesses (combined) were negatively associated with HD, EBV-positive HD and EBV-negative HD (in the total series, for ≥2 episodes compared with ≤1, OR = 0.45, 95% CI = 0.25–0.83). These results support previous evidence that early exposure to infection protects against HD and that IM increases subsequent risk; the comparisons of EBV-positive and EBV-negative HD are new and generate hypotheses for further study. © 2000 Cancer ResearchCampaign

Prostate cancer is an important and growing public health problem. PSA testing is able to lead to the identification of large numbers of cases of prostate cancer while still asymptomatic. This provides the potential for important reductions in prostate cancer mortality through the introduction of screening programs. The most reliable evidence that this potential can be realised can only come from randomised controlled trials (RCTs). Alternative sources of evidence are compared with that from RCTs; the costs of a wrong decision would be high and it is argued that the case for RCTs is clear.

Summary Background The Edinburgh randomised trial of breastcancer screening recruited women aged 45–64 years from 1978 to 1981 (cohort 1), and those aged 45–49 years during 1982–85 (cohorts 2 and 3). Results based on 14 years of follow-up and 270 000 woman-years of observation are reported. Methods Breast-cancer mortality rates in the intervention group (28 628 women offered screening) were compared with those in the control group (26 026) with adjustment for socioeconomic status (SES) of general medical practices. Rate ratios were derived by means of logistic regression for the total trial population and for women first offered screening while younger than 50 years. Analyses were by intention to treat. Findings Initial unadjusted results showed a difference of just 13% in breast-cancer mortality rates between the intervention and control groups (156 deaths [5·18 per 10 000] vs 167 [6·04 per 10 000]; rate ratio 0·87 [95% CI 0·70–1·06]), but the results were influenced by differences in SES by trial group. After adjustment for SES, the rate ratio was 0·79 (95% CI 0·60–1·02). When deaths after diagnosis more than 3 years after the end of the study were censored the rat ratio became 0·71 (0·53–0·95). There was no evidence of heterogeneity by age at entry and no evidence that younger entrants had smaller or delayed benefit (rate ratio 0·70 [0·41–1·20]). No breast-cancer mortality benefit was observed for women whose breast cancers were diagnosed when they were younger than 50 years. Othercause mortality rates did not differ by trial group when adjusted for SES. Interpretation Our findings confirm results from randomised trials in Sweden and the USA that screening for breast cancer lowers breast-cancer mortality. Similar results are reported by the UK geographical comparison, UK Trial of Early Detection of Breast Cancer. The results for younger women suggest benefit from introduction of screening before 50 years of age.

Methodological considerations in the study of clusters and clustering of childhood cancer are reviewed briefly. A selection of 11 studies of individual clusters of childhood leukaemia which are either particularly notable or recent and have been reported in peer review journals is then considered. Focus is placed on sources of alerts, descriptive studies, field-work studies, conclusions and communication management. Some of these studies are probably essential but they are unlikely to yield firm conclusions; studies of large data sets are recommended. No causal factor has been identified which can explain a single cluster of childhood leukaemia.

A total of 872 children aged up to 14 years, who were diagnosed withleukemia in Greece during the decade 1980-89, were allocated by place ofresidence to the 601 administrative districts of the country. Evaluation ofspatial clustering was done using the Potthoff-Whittinghill method, whichvalidly assesses heterogeneity of leukemia risk among districts with variableexpected numbers of cases. There was highly significant evidence for spatialclustering occurring particularly among children living in urban and, to alesser extent, semi-urban areas. The evidence was stronger for childrenyounger than 10 years old, applied also to children in different five-yearage groups, and persisted when cases of acute lymphoblastic leukemia wereanalyzed separately. These findings provide support to the hypothesis thatlocalized environmental exposures could contribute to the etiology ofchildhood leukemia, but they cannot distinguish between exposures of physicalor chemical nature, nor can they exclude socially conditioned patterns ofexposure to infectious agents.

Acute lymphoblastic leukemia (ALL) in the childhood peak may be arare response to delayed first exposure to one or more common infectiousagent(s). Mycoplasma Pneumonia has the appropriate socioeconomic correlatesand clinical symptoms and the hypothesis that delayed first exposure to itmay contribute to ALL is considered. Counts of positive reports of MPneumonia from disease surveillance data for England and Wales (UnitedKingdom) for 1975-92 have been taken as proxies for community burden ofinfection. Variation by months of birth (cohort) and diagnosis (period) ofincidence of ALL in children born and diagnosed 1975-92 are compared withpredictions. When periods were classified by mean M Pneumonia count rate inthe nine preceding months, standardized morbidity ratios (SMR) for thehighest and lowest 20 percent were 108 and 89 (rate ratio [RR] = 1.2, 95percent confidence interval [CI] = 1.1-1.4). SMRs for cohorts with highestand lowest predicted risk (i.e., lowest and hi ghest M Pneumonia count ratearound birth and during infancy) were 110 and 97 (RR = 1.1, CI = 1.0-1.3).The trend for period was most marked in the cohorts with low opportunity forexposure when young. This ecologic analysis provides preliminary support forthe hypothesis.

Evaluation of population screening must be based on a randomized clinical trial (RCT) with the study population randomized into two arms: an intervention group invited to screening and a control group not invited to screening. Reduced mortality in the intervention group is evidence of a benefit from screening. Individual randomization is the ideal, but cluster randomization is often used for logistical and ethical reasons. The use of volunteer subjects is methodologically acceptable, but results cannot be generalized. Seven RCTs of breast cancer screening by mammography have been carried out in the United States, Canada, Sweden, and Scotland. All the studies, except the Canadian, were designed to assess the effect of screening across a wide range of ages at entry. The question of the efficacy of breast cancer screening at younger ages (< 50 years) arose early, after the first results were reported. To address this question, basic elements of the screening protocol must be considered when interpreting the results; these are screening modality (e.g., mammography with or without physical examinations), interscreening interval, and number of screening rounds. This article examines the possible influence of these factors and reviews the design choices and the characteristics of the seven RCTs.

Objective: To determine any cardiac or vascular morbidity associated with long term treatment with tamoxifen given after mastectomy for primary breast cancer. Design: Cohort study using linkage between database of a randomised trial and statistics of Scottish hospital inpatients to identify episodes of cardiac and vascular morbidity. Setting: NHS hospitals in Scotland. Subjects: 1312 women who had undergone mastectomy for breast cancer and who were randomised either to a treatment group to receive adjuvant tamoxifen or to a control group to be given tamoxifen only on first relapse of disease. Maximum duration of tamoxifen treatment was 14 years. Total woman years of follow up were 9943. Main outcome measures: Randomised and observational comparisons of risk (expressed as hazard ratios) of myocardial infarction, other cardiac event, cerebrovascular disease, or thromboembolic event according to treatment allocated and between non-users, former users, and current users of tamoxifen. Results: Use of tamoxifen was associated with lower rates of myocardial infarction. Hazard ratio for women in control group was 1.92 (95% confidence interval 0.99 to 3.73) compared with women allocated to adjuvant treatment. The association was stronger for current use: hazard ratio for non-users was 3.49 (1.52 to 8.03) compared with current users. Current users of tamoxifen, however, had higher rates of thromboembolic events: hazard ratio for non-users was 0.40 (0.18 to 0.90) compared with current users. Conclusions: Our results provide further evidence that tamoxifen reduces the risk of myocardial infarction. Thromboembolic events should be carefully monitored in trials of tamoxifen, particularly those of prophylactic treatment, in which tamoxifen is given to healthy women.

Space-time clustering analyses of acute lymphoblastic leukaemia in children, by immunophenotype, were carried out using a population-based registry. Significant evidence was found of space-time clustering for cases of the precursor B-cell sub-type, in the childhood peak, based on time and location at birth. British Journal of Cancer (2002) 87, 513–515. doi:10.1038/sj.bjc.6600498 www.bjcancer.com © 2002 Cancer Research UK

Clusters of childhood leukaemia have, during a lengthy and controversial history, focussed attention on two alternative putative aetiological agents: infections and localised environmental pollution. In the United Kingdom emphasis is currently placed on the latter because of reports of localised clusters in the vicinity of two nuclear reprocessing plants. Now the most recent studies of spatial clustering in the United Kingdom also support the hypothesis that a substantial population of cases of childhood acute lymphoblastic leukaemia (ALL) arise as a rare host response to certain patterns of exposure to common infectious agents--the aberrant response model. Relevant aspects of the epidemiology of ALL are reviewed from this perspective and the hypothesis shown to be capable of unifying reported associations with different types of risk factor. It is probable that specific agent(s) are involved though none have been identified and these may share many epidemiological characteristics of herpes viruses. The possible relevance of these results to associations with prenatal parental occupational exposures to dusts and ionising radiation is explored.

This study relates to 1803 newly diagnosed cases of Hodgkin's Disease (HD) registered between 1984 and 1988 by a specialist leukaemia-lymphoma registry covering approximately half of England and Wales. In addition to registration data the analyses use routine census data. Rye classification is available for the majority of cases with only 7% being unclassified. The data confirm that the young adult peak in HD occurrence is attributable to the nodular sclerosing subtype (NS), and there is some evidence that NS has a different geographical distribution by county to the other Rye subtypes. Because of possible geographical biases in the classification, subsequent spatial analyses are disaggregated by age at diagnosis with particular emphasis being placed on the two age groups 0-34 and 50-79 years. For these, trends of risk by areal socioeconomic status are in opposite directions and the effects of urban-rural status while in the same direction also differ significantly. Allowance for these does not, however, explain the significant difference between the county distributions of the two groups. Patterns of spatial clustering are quite distinct with evidence for local spatial aggregation amongst younger cases.

STUDY OBJECTIVE--The aims of the study were (1) to test for uniformity of distribution of childhood leukaemias and other malignancies; and (2) to consider the aetiological implications of unusual distributions. DESIGN--A test for spacial clustering was applied using a method which allows for unequal distribution of the population at risk and avoids using census data to provide population denominators. When clustering was identified, four possible aetiological links which had already been suggested to the Leukaemia Research Fund Centre were examined in a local area. SETTING--The study was carried out in the Yorkshire Health Region in the north of England. PATIENTS--144 children under 15 years of age with a diagnosis of malignant disease known to the Yorkshire Regional Childhood Tumour Registry between 1974 and 1986 were included in the analysis. Of these 53 had leukaemias and nine had lymphomas. MEASUREMENTS AND RESULTS--Significant localised clustering was found in North Humberside, though not in the whole of the Yorkshire Health Region. A number of clustered cases were identified, some of whom were in a post code sector, Hull 10, to the west of Kingston-upon-Hull, about which concern had been expressed since 1985. There was however no evidence that disease clustering was confined to this area. Four previously suggested hypotheses about causation in this particular area were examined but the results were negative or inconclusive. CONCLUSIONS--The identification of spacial clustering must be seen as only the first step in a series of investigations; it can only rarely lead to aetiological conclusions by itself, but it can motivate and target other investigations.

Previous studies have provided evidence that infections may play a part in the aetiology of certain childhood cancers. The finding of space-time clustering indicates the presence of an environmental component to aetiology and is especially supportive of a role for infections. Space-time clustering occurs when excess numbers of cases of a disease are observed within small geographical locations at limited periods of time and this cannot be explained in terms of general excesses in those locations or at those times. To investigate whether infections may be involved in the aetiology of childhood cancer, we have analysed for space-time clustering using a large set of national population-based data from Great Britain for the period 1969-1993. Data were examined by a second-order procedure based on K-functions, with fixed thresholds of closeness in space (0.5-7.5 km) and closeness in time (0.1-1.5 years). Locations were addresses at diagnosis. Tests were repeated, replacing geographical distances with distances to the 19th-33rd nearest neighbours and this provided the primary result for each analysis. There were a total of 32,295 cases of childhood cancer. The analyses showed statistically significant evidence of space-time clustering for acute lymphoblastic leukaemia over the whole age range (p = 0.04), but especially for ages 1-4 years (p = 0.03). There was less statistically significant evidence for total leukaemia (p = 0.048). Significant space-time clustering was also evident for soft tissue sarcomas (p = 0.03) and osteosarcomas (p = 0.02). Results support other evidence suggesting a role for infections in the aetiology of these particular diagnostic groups.

Summary An accumulating body of data suggests that the Epstein–Barr virus (EBV), a lymphotropic herpesvirus, is involved in the pathogenesis of a proportion of cases of Hodgkin lymphoma (HL). In this study, we showed that the frequency of circulating EBV-infected cells was significantly higher (P

Objective To test the hypothesis that reduced exposure to common infections in the first year of life increases the risk of developing acute lymphoblastic leukaemia. Design and setting The United Kingdom childhood cancer study (UKCCS) is a large population based case-control study of childhood cancer across 10 regions of the UK. Participants 6305 children (aged 2-14 years) without cancer; 3140 children with cancer (diagnosed 1991-6), of whom 1286 had acute lymphoblastic leukaemia (ALL). Main outcome measure Day care and social activity during the first year of life were used as proxies for potential exposure to infection in infancy. Results Increasing levels of social activity were associated with consistent reductions in risk of ALL; a dose-response trend was seen. When children whose mothers reported no regular activity outside the family were used as the reference group, odds ratios for increasing levels of activity were 0.73 (95% confidence interval 0.62 to 0.87) for any social activity, 0.62 (0.51 to 0.75) for regular day care outside the home, and 0.48 (0.37 to 0.62) for formal day care (attendance at facility with at least four children at least twice a week) (P value for trend < 0.001). Although not as striking, results for non-ALL malignancies showed a similar pattern (P value for trend < 0.001). When children with non-ALL malignancies were taken as the reference group, a significant protective effect for ALL was seen only for formal day care (odds ratio = 0.69, 0.51 to 0.93; P = 0.02). Similar results were obtained for B cell precursor common ALL and other subgroups, as well as for cases diagnosed above and below age 5 years. Conclusion These results support the hypothesis that reduced exposure to infection in the first few months of life increases the risk of developing acute lymphoblastic leukaemia.

We previously demonstrated significant space-time clustering amongst cases of childhood leukaemia (in particular acute lymphoblastic leukaemia (ALL)), central nervous system (CNS) tumour (especially astrocytoma), soft tissue sarcoma and Wilms' tumour. We hypothesised that there may be common aetiological mechanisms between some of these diagnostic groups. To test this hypothesis we analysed for cross-space-time clustering between these diagnostic groups, using population-based data from north-west England. Data were examined by a second-order procedure based on K-functions. Reference points in time and space were dates and addresses at birth and diagnosis. The results showed statistically significant (P < 0.05) cross-clustering between cases of leukaemia and CNS tumour and between cases of ALL and astrocytoma. There was no statistically significant cross-clustering of Wilms' tumours and soft tissue sarcomas with any other malignancy. In conclusion, these findings are consistent with common, possibly infectious, aetiological mechanisms for childhood leukaemia (particularly ALL) and CNS tumours (particularly astrocytoma).

Is the timing of exposure to infection a major determinant of acute lymphoblastic leukaemia in Hong Kong? The hypothesis that protection of infants from exposure to infectious agents with delayed first exposure to one or more specific agents together contribute to the aetiology of childhood leukaemia, especially common acute lymphoblastic leukaemia (cALL), has substantial indirect support from descriptive epidemiology and case-control studies in developed Western countries. A case-control study of childhood leukaemia diagnosed at ages 2-14 years has now been conducted in Hong Kong. Cases (n = 98) formed a consecutive series of Chinese children diagnosed with acute leukaemia; controls (n = 228) were identified following a survey using random digit dialling and required to attend for medical examination by a paediatrician. Interviews with mothers were conducted in hospital by one trained interviewer using a structured questionnaire. Odds ratios (OR) and 95% confidence intervals (Cl) are reported for exposure variables capable of serving as proxies for exposure to infection in two critical time periods: first year of life, year before reference date (diagnosis for cases, corresponding date for controls). Analyses used logistic regression with adjustment for appropriate confounders. Change of area of residence reduced risk if during the first time period (OR = 0.47 [95% CI 0.23, 0.98]) and increased risk if during the second (OR = 3.92, [95% CI 1.47, 10.46]). Reported roseola and/or fever and rash in the first year of life reduced risk (OR = 0.33 [95% CI 0.16, 0.68]) whereas tonsillitis in the period 3-12 months before reference date increased risk (OR = 2.56 [95% Cl 1.22, 5.38]). Some other proxies for exposure to infection at the critical times were associated with predicted patterns of risk but day-care attendance failed to show predicted associations. These results provide support for the delayed exposure hypothesis in an affluent geographical setting in which population exposure to infectious agents is quite distinct from the settings of previous case-control studies.

BACKGROUND As part of a nested case-control study of benign proliferative breast disease (BPBD) conducted within the cohort of women participating in the Alberta breast screening programme, an analysis of all women who had a benign breast biopsy between 1990 and 1995 was undertaken to identify the epidemiological risk factors for BPBD. METHODS The breast biopsies of all eligible women were re-reviewed by a panel of four pathologists using Page's classification for benign breast disease. Cases were 165 women whose biopsies, upon review, showed benign breast tissue changes ranging from sclerosing adenosis to atypical ductal hyperplasia. Controls were 217 women whose biopsies showed no evidence of any proliferative or neoplastic changes. In-person interviews were conducted with all study subjects. RESULTS Women with >/=25% fibroglandular breast tissue density, as compared to women with

The epidemiology of Hodgkin’s disease suggests that it is a heterogeneous condition comprising more than one disease entity. The Epstein–Barr virus (EBV) is present in the Reed–Sternberg cells of a proportion of cases and is likely to play a role in the pathogenesis of these cases. In this study we show that EBV association rates vary with age at diagnosis. We suggest that Hodgkin’s disease can be divided into three disease entities on the basis of EBV association and age, thereby providing biological support for the multiple aetiology hypothesis proposed by MacMahon (Cancer Res 1966; 26: 1189–1290).

OBJECTIVE To improve understanding of the etiology of IDDM by analyzing spatial and space-time distribution of the incidence in children. RESEARCH DESIGN AND METHODS Statistical tests to detect clustering were applied to a population-based register of 1,490 children (aged 0–16 years) with IDDM in Yorkshire, northern England. The Knox test analyzed clustering in space and time, and the Potthoff-Whittinghill test quantified spatial differences in incidence between small-area census units (electoral wards). The Potthoff-Whittinghill test was conditioned for childhood population density and deprivation (Townsend index). RESULTS Both tests demonstrated clustering of IDDM in Yorkshire children. Space-time and spatial clustering is strongest in the younger children (0–4 and 5–9 years of age), even after conditioning for known associations. Clustering was more common in the county of Humberside during the years 1982–1985 and in wards of low population density (< 0.26 0- to 16 year-old subjects per hectare). CONCLUSIONS The study revealed a nonrandom space-time distribution of IDDM in children not accounted for by known covarying demographic factors. The Potthoff-Whittinghill test has not previously been applied to childhood IDDM. The new finding of strong clustering in young children is consistent with early exposure, possibly in utero, to infectious agents or localized environmental sources.

Background Various methods of analysis have been used to study age-period-cohort models. The main aim of this paper is to illustrate and compare three such methods. Those of Clayton and Schifflers, Robertson and Boyle, and De Carli and La Vecchia. The main differences between these methods lie in their approach to distinguish between linear-period and linear-cohort effects. Clayton and Schifflers do not attempt to solve this identification problem, whereas Robertson and Boyle, and De Carli and La Vecchia attempt to tackle this question. Methods In order to study the assumptions and problems of these methods, we analysed data from 2678 subjects aged 30-84 in Yorkshire, UK, who were diagnosed with non-Hodgkin's lymphoma (NHL) during the period 1978-1991. Loglinear Poisson models were used to examine the effects of age, period and cohort. Results All three methods of analysis agree that, after stratification for sex and county, the age-standardized rate has been increasing at about 5% per year. The Robertson-Boyle method differed from the Clayton-Schifflers method in showing a significant non-linear cohort effect, and a significant county-cohort interaction. The method of De Carli-La Vecchia agreed more closely with Clayton-Schifflers than with Robertson-Boyle. Conclusions The linear increase in incidence would lead to a doubling of the number of cases within 15 years. There is controversy over whether the identification problem can be solved and should be solved. Many authors would not rely on the results of the methods of Robertson and Boyle, or De Carli and La Vacchia.

This article presents additional follow-up analysis of women aged 45‐49 from the Edinburgh Randomized Trial of Breast Cancer Screening. The screening protocol included four mammographic examinations at two-year intervals and seven annual clinical examinations. Altogether, 21,774 women aged 45‐49 were recruited from 1978 to 1985 using cluster randomization. After 10‐14 years of follow-up, breast cancer mortality has been reduced by 12% to 18% (rate ratios, with and without adjustment for socio-economic status, are 0.88 and 0.82 respectively, with 95% confidence intervals [CIs] of 0.55‐1.41 and 0.51‐1.32). These benefits are smaller than that reported previously with shorter follow-up. This article also presents data from an observational study that compared survival beyond baseline (50‐52 years) of women first offered screening before and after age 50. Based on six-year data, the results suggest that earlier screening confers follow-up benefit (hazard ratio for later screening = 1.60; 95% CI: 0.96‐2.67), but these findings are not statistically significant. The trial is too small to yield statistically significant results by itself, but can make useful contributions to overview and meta-analyses. [Monogr Natl Cancer Inst 1997:22:31‐35]

Objective— To determine the pathological and biological characteristics of breast cancers diagnosed by screening and examined at the Edinburgh University pathology department. Methods— These cancers were classified by screening status: never screened (n=111), prevalence screen detected (n=105), and previously screened (n=74). The last category arose in women who had been regularly screened during the trial; the cancers were diagnosed as interval cases before the first invitation to service screening (n=33) or were incidence screen detected at that time (n=41). Results— Association (for operable invasive cancers, n=250) of cancer characteristics with screening status reflects influences of biology (aggressiveness) or chronology (time of diagnosis), or both. The prognostic indicators tumour grade, histological type, and oestrogen receptor status were found in a smaller percentage of the patients with poor prognosis among the prevalence screen detected cases (9%, 77%, 18%) than among those previously screened (29%, 84%, 35%). The chronological factors size and node status were found in a smaller percentage of patients with poor prognosis among women previously screened (31%, 24%) than among those never screened (62%, 39%)). Apart from these two, no other factors improved the diagnosis in the previously screened group compared with the never screened group. Conclusions— These results suggest that favourable characteristics of screen detected cases are often due to the effects of length bias on “biological factors” and fail to show that current local screening practice has succeeded in advancing the diagnosis of breast cancers to a less aggressive phase.

Summary. .To determine whether increased rates of childhood acute lymphoblastic leukaemia (ALL) which had been reported in isolated areas could be attributed to higher proportions of households owning cars, ecological analysis was performed with electoral wards as area units. Previous data were re-analysed using the proportion of households having no car, taken from the 1981 census of England and Wales, as an additional explanatory factor. A specialist registry of haematopoietic malignancies covering one-third of England and Wales (3270 electoral wards) recorded 438 cases of ALL in children diagnosed 1984-89, including 304 in the childhood peak (at ages 1–7 years). Relative risks were derived by Poisson regression of total childhood ALL and at ages 1–7 years for groups of electoral wards classified by isolation and car ownership. Multivariable analyses included adjustment for socio-economic status. No evidence of increased risk of childhood ALL in areas where more households own cars was found. ALL at ages 1–7 years was inversely associated with car ownership (risk in wards with least cars relative to those with most cars = 2.28,95% CI: 1.12-4.64). The associations with geographic isolation persisted after allowing for car ownership (risks for ALL in young children in isolated relative to built-up areas = 2.19,95% CI: 1.44-3.33). Levels of car ownership cannot explain the increased rates of childhood ALL which have been observed in isolated areas. No support has been found for a hypothesis relating these excesses to benzene exposure of children transported in cars. The previous explanation for the small area variation of childhood ALL in terms of geographical isolation and interpretation in terms of exposure to common infections continues to be justified.

Hodgkin’s disease (HD) may be the rare outcome of a common infection which is influenced by host genetic susceptibility. We have analysed this hypothesis by determining the frequency of HLA-DPB1 alleles in two series of HD patients using molecular typing methods. One series consisted of a retrospective/prospective group of 118 patients over the age of 15 years, and the other a prospective group of 45 patients between the ages of 16 and 24 years. In both series, the proportion of patients typing for HLA-DPB1 *0301 was greater than that for the controls, suggesting that this may be an HD-susceptibility allele. Analysis of DPB1 alleles in relation to HD subtype also showed that the increase in *0301 was present in nodular sclerosing HD (HDNS) patients, as well as in mixed cellularity HD (HDMC) and lymphocyte predominant HD (HDLP) patients. Preliminary evidence was obtained suggesting an increase in *0401, and possibly *0501, in HDMC and HDLP. Analysis of *0301-like hypervariable region (HVR) associations with HD subtypes indicated an increase in an *0301-like HVR-C motif in HDNS, but not in non-HDNS. The frequency of *0301- and *0401 -like HVR-C and HVR-F amino acid residues also differed in HDNS and non-HDNS patients. The frequency of the HVR-C amino acid residues Asp55, Glu56 (*0301) was increased in HDNS, but not in non-HDNS patients, whereas the frequency of Ala55, Ala56 (*0401) was increased in non-HDNS, but not in HDNS patients. In addition, the frequency of the HVR-F amino acid residues Asp84, Glu85 and Ala86 (*0301) was greater in the HDNS than non-HDNS patients, whereas there was no increase in Gly84, Gly85, Pro86 (*0401). Although these are preliminary findings, they suggest that genetic susceptibility to an infectious aetiology in HD may reside at the level of DPB peptide-binding residues rather than with a specific allele.

OBJECTIVE--To determine whether parental occupations and chemical and other specific exposures are risk factors for childhood leukaemia. DESIGN--Case-control study. Information on parents was obtained by home interview. SETTING--Three areas in north England: Copeland and South Lakeland (west Cumbria); Kingston upon Hull, Beverley, East Yorkshire, and Holderness (north Humberside), and Gateshead. SUBJECTS--109 children aged 0-14 born and diagnosed as having leukaemia or non-Hodgkin's lymphoma in study areas during 1974-88. Two controls matched for sex and date and district of birth were obtained for each child. MAIN OUTCOME MEASURES--Occupations of parents and specific exposure of parents before the children's conception, during gestation, and after birth. Other adults living with the children were included in the postnatal analysis. RESULTS--Few risk factors were identified for mothers, although preconceptional association with the food industry was significantly increased in case mothers (odds ratio 2.56; 95% confidence interval 1.32 to 5.00). Significant associations were found between childhood leukaemia and reported preconceptional exposure of fathers to wood dust (2.73, 1.44 to 5.16), radiation (3.23, 1.36 to 7.72), and benzene (5.81, 1.67 to 26.44); ionising radiation alone gave an odds ratio of 2.35 (0.92 to 6.22). Raised odds ratios were found for paternal exposure during gestation, but no independent postnatal effect was evident. CONCLUSION--These results should be interpreted cautiously because of the small numbers, overlap with another study, and multiple exposure of some parents. It is important to distinguish periods of parental exposures; identified risk factors were almost exclusively restricted to the time before the child's birth.

Mothers of 294 children aged 3-9 years were interviewed about their child's previous history of vaccinations and infections. The study group comprised healthy children selected at GP surgeries (n = 136) and those hospitalized for both minor and serious conditions (n = 168). The results evaluate the entire study group for the pattern of reporting vaccinations and infectious episodes under three years of age, comparing two different data sources-mothers' reports and GP records. Maternal recall accuracy is formally tested (Kappa statistic) for agreement with GP records. For vaccination history the results indicate that mothers and GPs are inadequate data sources, and suggest use of computerized health district records to improve data accuracy. Major differences on infectious history were evident for two types of questions-closed for specific infections and open-ended for 'other infections'. Specific infections (e.g. measles) were systematically over-reported by mothers compared with GP records, but mothers failed to 'time' the event. Concordance for 'other infections' was also poor, but, by contrast, GPs systematically over-recorded this range of infections, indicating substantial inaccuracy in mothers' recall. The authors suggest that GP records should be the preferred source of data for these 'other' infectious episodes, especially under one year of age. Improved questionnaire design would elicit more accurate maternal reports on specified infections for which a GP may well not be consulted and corroboration would be impossible.

Data from a specialist registry of haematopoietic malignancies in England and Wales (1984-1988) have been analysed to investigate variations of incidence by age and diagnostic subtype of lymphoid malignancies in young people (aged 0-24 years). Attention has been focussed on the role of community lifestyle indicators for small areas, derived from routine sources, in an ecological analysis. The predominant conditions were acute lymphoblastic leukaemia (ALL)--42.4%, and Hodgkin's disease (HD)--37.5%. Lowest overall incidence at approximately 8 years of age corresponded to the termination of the childhood peak for ALL. Opposite trends of incidence rates with distance from urban centres (urban distance) were observed for the two age groups: odds ratios (OR) for areas greater than 20 km from towns and cities were 1.46 (95% confidence interval 1.01-2.12) for ages 0-7 and 0.75 (95% confidence interval 0.56-0.99) for ages 8-24. For the younger group this was entirely attributable to ALL. HD, which was dominant in the older group, had highest incidence in connurbations but the gradient of risk for older onset ALL followed the overall pattern for this age group. A positive relationship with socioeconomic status was evident for both age groups but this was considerably stronger for the older cases (OR = 1.16, 95% confidence interval 1.01-1.33) than for the younger for whom it was not independent of urban distance. These results display an association between expression of lymphoid malignancies in young people and urban distance which is not attributable to socioeconomic status; for urban distances the distribution is shifted towards ALL and towards younger age at onset.