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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.

Geographical variation operates at a variety of scales. Methods of mapping variation in disease incidence between different countries or even counties are relatively well developed. When, however, the question relates to much smaller aggregations (that is, “clustering”), attention has mainly been restricted to areas near putative point hazards; the majority of cases are excluded from such an investigation. In this study we show how clustering may be investigated and displayed in such a way that it becomes a powerful tool in epidemiological research. As examples we use incidence data from the Yorkshire health region for selected childhood cancers and adult haematopoietic malignancies. The methods would readily extend to any small clusters of rare events.

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.

A proportion of Hodgkin lymphoma (HL) cases are causally associated with the Epstein-Barr virus (EBV) but the aetiology of the remaining cases remains obscure. Over the last 3 decades several studies have found an association between HL and measles virus (MV) including a recent cohort study describing the detection of MV antigens in Hodgkin and Reed-Sternberg cells, the tumour cells in HL. In the present study we looked at the relationship between history of MV infection and risk of developing HL in a population-based, case/control study of HL. In addition we used immunohistochemistry and RT-PCR to look for direct evidence of MV in HL biopsies. There was no significant difference in the proportion of cases reporting previous measles compared to controls in the entire data set or when young adults were considered separately. Using a robust immunohistochemical assay for MV infection, we failed to find evidence of MV in biopsies from 97 cases of HL and RT-PCR studies similarly gave negative results. This study therefore provides no evidence that MV is directly involved in the development of HL. However, when age at first reported MV infection was investigated, significant differences emerged with children infected before school-age having higher risk, especially of EBV-ve HL, when compared with children infected at older ages; the interpretation of these latter results is unclear.

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)

BACKGROUND Recent data has suggested that polymorphisms in the prostate specific antigen (PSA) may increase prostate cancer (PC) risk. The PSA gene contains a G/A substitution in the androgen response element (ARE) 1 region. The androgen receptor (AR) gene has polymorphic regions containing variable length glutamine and glycine repeats and these are believed to be associated with PC risk. The effect on PC risks from PSA polymorphisms alone and synergistically with the AR gene was examined in this report. METHODS One hundred PC patients and an age matched cohort of 79 benign prostate hyperplasia and 67 population controls were entered in this study. DNA was extracted from blood and PSA/ARE promoter region amplified by PCR. PCR products were cut with Nhe 1 restriction enzyme to distinguish G/A alleles. AR/CAG and GGC repeat length was detected by automated fluorescence from PCR products. RESULTS We found a significantly higher PSA/GG distribution in PC (30%) than either benign prostatic hyperplasia (BPH) (18%) or population controls (16%) (P = 0.025). Furthermore the GG distribution within cases was even greater in younger men (

Somatic inactivation of NFKBIA, the gene encoding IκBα, is a frequent occurrence in the malignant Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin lymphoma (HL). Impairment of IκBα function results in deregulated NF-κB activity, a characteristic of HRS cells. The molecular basis for familial HL, which accounts for approximately 4% of all HL cases, is unclear. To date, familial HL cases have not been evaluated for germline NFKBIA mutations. We screened the entire NFKBIA gene in 8 individuals with familial HL but found no mutations in the coding region or promoter sequences. We identified the first germline NFKBIA missense mutation in a patient with presumed sporadic HL. The frequency of 4 polymorphisms within the NFKBIA gene and promoter region was investigated in a series of HL and control samples; no significant differences emerged but a novel polymorphism was identified in the promoter region. Overall, our results suggest that germline mutations of NFKBIA are not a significant cause of familial aggregation of HL but may contribute to inherited susceptibility to HL. © 2005 Wiley-Liss, Inc.

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.

The aetiology of most childhood solid tumours (other than central nervous system [CNS] tumours) is unclear. To investigate whether certain environmental exposures may be involved, we have analysed for space-time clustering using population-based data from North West England for the period 1954-98. Knox tests for space-time interactions between cases were applied with fixed thresholds of close in space

In a previous study, we obtained preliminary evidence in a small series of patients (n = 63) suggesting that susceptibility to childhood common acute lymphoblastic leukaemia (c-ALL) was associated with an allele at the HLA-DPB1 locus, DPB1*0201. We have now tested this hypothesis by comparing the frequency of children with leukaemia (n = 982) who typed for specific DPB1 alleles and two groups of non-leukaemic children, one consisting of children with solid tumours, excluding lymphomas (n = 409), the other consisting of normal infants (n = 864). We found that significantly more children with c-ALL and T-ALL, but not pro-B ALL or acute non-ALL typed for DPB1*0201 as compared with children with solid tumours [odds ratio (OR), 95% confidence interval (CI) for c-ALL: 1.76, 1.20-2.56; T-ALL: 1.93, 1.01-3.80] and normal infants (OR, 95% CI for c-ALL: 1.83, 1.34-2.48; T-ALL: 2.00, 1.10-3.82). In childhood c-ALL, significantly more children than those with solid tumours or normal infants typed for DPB1 alleles coding specific polymorphic amino acids lining the antigen-binding site of the DPbeta1*0201 allotypic protein, suggesting that susceptibility to childhood c-ALL may be influenced by DPbeta ABS amino acid polymorphisms shared by DPbeta1*0201 and other DPbeta1 allotypes. These results point to a mechanism of c-ALL susceptibility that involves the presentation of specific antigenic peptides, possibly derived from infectious agents, by DPbeta1*0201-related allotypic proteins, leading to the activation of helper T cells mediating proliferative stress on preleukaemic cells.

To investigate whether infections or other environmental exposures may be involved in the aetiology of childhood central nervous system tumours, we have analysed for space–time clustering and seasonality using population-based data from the North West of England for the period 1954 to 1998. Knox tests for space–time interactions between cases were applied with fixed thresholds of close in space

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.

Low folate intake as well as alterations in folate metabolism as a result of polymorphisms in the enzyme methylenetetrahydrofolate reductase ( MTHFR ) have been associated with an increased incidence of neural tube defects, vascular disease, and some cancers. Polymorphic variants of MTHFR lead to enhanced thymidine pools and better quality DNA synthesis that could afford some protection from the development of leukemias, particularly those with translocations. We now report associations of MTHFR polymorphisms in three subgroups of pediatric leukemias: infant lymphoblastic or myeloblastic leukemias with MLL rearrangements and childhood lymphoblastic leukemias with either TEL - AML1 fusions or hyperdiploid karyotypes. Pediatric leukemia patients ( n = 253 total) and healthy newborn controls ( n = 200) were genotyped for MTHFR polymorphisms at nucleotides 677 (C→T) and 1,298 (A→C). A significant association for carriers of C677T was demonstrated for leukemias with MLL translocations ( MLL +, n = 37) when compared with controls [adjusted odd ratios (OR) = 0.36 with a 95% confidence interval (CI) of 0.15–0.85; P = 0.017]. This protective effect was not evident for A1298C alleles (OR = 1.14). In contrast, associations for A1298C homozygotes (CC; OR = 0.26 with a 95% CI of 0.07–0.81) and C677T homozygotes (TT; OR = 0.49 with a 95% CI of 0.20–1.17) were observed for hyperdiploid leukemias ( n = 138). No significant associations were evident for either polymorphism with TEL - AML1 + leukemias ( n = 78). These differences in allelic associations may point to discrete attributes of the two alleles in their ability to alter folate and one-carbon metabolite pools and impact after DNA synthesis and methylation pathways, but should be viewed cautiously pending larger follow-up studies. The data provide evidence that molecularly defined subgroups of pediatric leukemias have different etiologies and also suggest a role of folate in the development of childhood leukemia.

Summary The nearest neighbour analysis method has been developed to determine whether a disease case may be regarded as being unusually close to other neighbouring cases of the same disease. Using this method, each disease case is classified as spatially ‘clustered’ or ‘non-clustered’. The method is also used to provide a test for global clustering. ‘Clusters’ are constructed by amalgamating geographically neighbouring clustered cases into one contiguous ‘cluster area’. This paper describes a method for studying differences between clustered and non-clustered cases, in terms of case ‘attributes’. These attributes may be person related, such as age and sex, or area based, such as geographical isolation. The area-based variables are subject to geographical correlation. The comparison of clustered and non-clustered cases may reveal similarities or differences, which may, in turn, give clues to disease aetiology. A method for studying ‘linkage’ or similarities in attributes between cases that occur in the same clusters is also described. The methods are illustrated by application to incidence data for leukaemias and lymphomas.

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.

Previous studies of space-time clustering in childhood leukaemia have produced equivocal and inconsistent results. To address this issue we have used Manchester Children's Tumour Registry leukaemia data in space-time clustering analyses. Knox tests for space-time interactions between cases were applied with fixed thresholds of close in space

TEL-AML1 fusions are the most common chromosome translocations in childhood leukemia and often, if not always, occur in utero. We previously reported the genomic sequencing of nine TEL-AML1 translocations and showed unique structural features of a breakpoint cluster region in TEL intron 5. We now report data on sequencing and mapping of TEL-AML1 from an additional 11 patients and, using Monte Carlo statistical methods, have analyzed the intronic distribution of the 24 TEL-AML1 fusion junctions sequenced to date. Compared to a null hypothesis of random breakpoint allocation within TEL intron 5 and AML1 introns 1 and 2, significant microclustering was evident on both TEL and AML1. In contrast to previous reports, the two strongest microclusters on TEL were 3' to an unstable repeat region. AML1 demonstrated four highly significant microclusters, two of which were proximal to exons. We note the necessity of sequencing multiple breakpoints before the description of putative microcluster regions. TEL-AML1 breakpoints may be distributed into microclusters because of specific DNA sequence or chromatin features in susceptible cells. We also report on additional features of breakpoints, including a complex t(12;3;21) in one patient and an inverted sequence in another.

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.

There is good evidence for an association between Epstein-Barr virus (EBV) and Hodgkin's disease (HD). In approximately one-third of cases, the EBV genome is detectable in Reed-Sternberg (RS) cells and there is expression of the viral nuclear antigen EBNA-1 and the latent membrane protein LMP-1. Expression of LMP-2 has been demonstrated at the mRNA level, and it is presumed that the protein is expressed alongside LMP-1. The LMP-2 protein is known to contain an epitope presented to cytotoxic T-cells which is restricted through the HLA class I antigen A*0201 in healthy seropositive individuals. Since most HLA-A*02-positive Caucasians are HLA-A*0201-positive, it was hypothesized that HLA-A*02-positive individuals would be under-represented among Caucasians with EBV-associated HD. HLA-A*02 status was determined, using flow cytometry and/or the polymerase chain reaction, for 276 individuals including 176 cases of HD. There was no significant difference between the frequency of HLA-A*02 positivity in HD cases and controls, and between EBV-associated and non-associated cases of HD. The A*02 alleles of 14 cases of EBV-associated HD were further subtyped using nested PCR; all except one case were found to be A*0201-positive. We therefore investigated whether there was any evidence for mutation of the epitope representing amino acids 426-434 of LMP-2a which is restricted through HLA-A*0201. In 10/11 cases the nucleotide sequence encoding this epitope was identical to the published sequence; in the remaining case there was a mutation which would not be expected to alter the conformation of the epitope. Overall, our data suggest that other mechanisms of immune escape must be operative in EBV-associated HD.

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.

A single nucleotide polymorphism (SNP) is present at position -174 of the human interleukin-6 gene. The risk of developing Hodgkin's lymphoma (HL) in young adults decreases with an increasing number of C alleles at this position. We analysed the effect of this SNP on incidence and outcome in HL. DNA samples from 408 cases and 349 controls were screened and analysed following stratification by age, histological subtype and Epstein-Barr virus status. Although the risk of classical HL in young adults decreased with increasing C alleles, case-control differences were not significant. An excess of G alleles was observed for nodular lymphocyte predominant HL in young adults (n = 21), which was significant.

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

As part of a more comprehensive study, complete residential histories were collected from 109 cases of childhood leukaemia and non-Hodgkin's lymphoma who were diagnosed while resident in Gateshead, West Cumbria or North Humberside (1973-1987), and who were born in the same areas. Corresponding data were obtained from the same number of controls matched by date of birth, sex and area of residence at diagnosis and birth. Altogether, 1332 years of residential history were available for analysis and of these 131 (9.8 per cent) included a change of home. Moving house was much more frequent for both cases and controls in the first two years of life (69 out of 432 child-years, i.e. 16 per cent). The moves were mostly over short distances, with only 23 per cent being 5 km or more and only 9 per cent into another administrative district. Twenty-eight per cent of the children had moved house at least once by their second birthday and 48 per cent by the age of five years. Few case-control differences were apparent and none achieved statistical significance. There was a suggestion of more mobility for case children in the first few years of life, especially for cases diagnosed shortly after the removal. When the residence of mothers in the year preceding the childrens' birth was examined, there were relatively few removals in this period (26, i.e. 24 per cent, altogether, of which 14 were over 5 km and nine from another administrative district). Of these, 18 case mothers had moved (11 over 5 km) compared with eight control mothers (three over 5 km).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Udgivelsesdato: 2010-Apr-6 A proportion of classical Hodgkin lymphoma (HL) is believed to be causally related to infection with the ubiquitous lymphotropic EBV. The determining factors for development of EBV-related HL remain poorly understood, but likely involve immunological control of the viral infection. Accordingly, markers of the HLA class I region have been associated with risk of EBV-related HL. To study the host genetic component of EBV-related HL further, we investigated the lymphoma's association with HLA-A*01 and HLA-A*02 simultaneously in the setting of infectious mononucleosis (IM), a risk factor for EBV-related HL, in a case-series analysis including 278 EBV-related and 656 EBV-unrelated cases of HL. By logistic regression, HLA-A*01 alleles [odds ratio (OR) per allele, 2.15; 95% CI, 1.60-2.88] were associated with increased and HLA-A*02 alleles (OR per allele, 0.70; 95% CI, 0.51-0.97) with decreased risk of EBV-related HL. These allele-specific associations corresponded to nearly 10-fold variation in risk of EBV-related HL between HLA-A*01 and HLA-A*02 homozygotes. History of IM was also associated with risk of EBV-related HL (OR, 3.40; 95% CI, 1.74-6.66). The association between history of IM and EBV-related HL was not seen in the presence of HLA-A*02 because this allele appeared to neutralize the effect of IM on EBV-related HL risk. Our findings suggest that HLA class I-restricted EBV-specific cytotoxic T-cell responses and events in the early immune response to EBV infection in IM play critical roles in the pathogenesis of EBV-related HL.

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).

The Epstein-Barr virus (EBV) is associated with a proportion of Hodgkin lymphoma (HL) cases, and this association is believed to be causal. The aetiology of cases lacking EBV in the tumour cells (EBV HRS-ve), which make up the majority of cases in western countries, is obscure. It has been suggested that EBV may also cause these tumours by using a hit-and-run mechanism. Support for this idea comes from the finding that most young adult patients, who are likely to have a good immune response to EBV, have EBV HRS-ve HL. We investigated this possibility using a combined serologic and molecular approach. Analysis of EBV seroprevalence rates in an epidemiologic study of young adult HL revealed that cases with EBV HRS-ve HL were more likely to be EBV-seronegative than controls. Furthermore, additional studies clearly showed that some HL patients have never been infected by EBV. Quantitative PCR was used to look for the presence of deleted EBV genomes in a series of adult cases with both EBV HRS+ve and HRS-ve HL. Subgenomic fragments were detected in equimolar proportions. This study, therefore, found no evidence to support the idea that a hit-and-run mechanism involving EBV plays a role in the pathogenesis of HL.

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.

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.