Combined effects of endogenous sex hormone levels and mammographic density on postmenopausal breast cancer risk: results from the Breakthrough Generations Study.

BACKGROUND: Mammographic density and sex hormone levels are strong risk factors for breast cancer, but it is unclear whether they represent the same aetiological entity or are independent risk factors. METHODS: Within the Breakthrough Generations Study cohort, we conducted a case-control study of 265 postmenopausal breast cancer cases and 343 controls with prediagnostic mammograms and blood samples. Plasma was assayed for oestradiol, testosterone and sex hormone-binding globulin (SHBG) concentrations and mammographic density assessed by Cumulus. RESULTS: Oestradiol and testosterone were negatively and SHBG positively associated with percentage density and absolute dense area, but after adjusting for body mass index the associations remained significant only for SHBG. Breast cancer risk was independently and significantly positively associated with percentage density (P=0.002), oestradiol (P=0.002) and testosterone (P=0.007) levels. Women in the highest tertile of both density and sex hormone level were at greatest risk, with an odds ratio of 7.81 (95% confidence interval (CI): 2.89-21.1) for oestradiol and 4.57 (95% CI: 1.75-11.9) for testosterone and high density compared with those who were in the lowest tertiles. The cumulative risk of breast cancer in the highest oestradiol and density tertiles, representing 8% of controls, was estimated as 12.8% at ages 50-69 years and 19.4% at ages 20-79 years, and in the lowest tertiles was 1.7% and 4.3%, respectively. Associations of breast cancer risk with tertiles of mammographic dense area were less strong than for percentage density. CONCLUSIONS: Endogenous sex hormone levels and mammographic density are independent risk factors for postmenopausal breast cancer, which in combination can identify women who might benefit from increased frequency of screening and chemoprophylaxis.

Male breast cancer, age and sex chromosome aneuploidy.

BACKGROUND: In cultured, dividing transformed T lymphocytes and in dividing bone marrow cells from normal men and those with a haematological malignancy, sex chromosome aneuploidy has been found to increase in prevalence and degree with age. This has rarely been investigated in non-dividing uncultured blood samples. The loss and gain of the X chromosome in dividing transformed lymphocytes in women with age is much more frequent than that of the Y chromosome in males. However, paradoxically X chromosome aneuploidy is rarely seen in the dividing cells of bone marrow of females. METHODS: In blood samples from 565 men with breast cancer and 54 control men from the England and Wales general population, 80 cell nuclei per sample were scored for presence of X and Y chromosomes using fluorescent centromeric probes. RESULTS: Sex chromosome aneuploidy, largely Y chromosome loss, was present in 63% of cases and 57% of controls, with the prevalence and degree of aneuploidy increasingly sharply and highly significantly with age. At ages 65-80 years, 71% of cases and 85% of controls showed aneuploidy and 15% and 25%, respectively, had ≥ 10% of cells aneuploid. Allowing for age, aneuploidy was less prevalent (P=0.03) in cases than controls. CONCLUSION: Sex chromosome aneuploidy in non-dividing nuclei of peripheral blood cells is frequent in adult men, the prevalence and degree increasing sharply with age. The possible relation of sex chromosome aneuploidy to breast cancer risk in men, and to cancer risk generally, needs further investigation, ideally in cohort studies.

Breast cancer risk following Hodgkin lymphoma radiotherapy in relation to menstrual and reproductive factors.

BACKGROUND: Women treated with supradiaphragmatic radiotherapy (sRT) for Hodgkin lymphoma (HL) at young ages have a substantially increased breast cancer risk. Little is known about how menarcheal and reproductive factors modify this risk. METHODS: We examined the effects of menarcheal age, pregnancy, and menopausal age on breast cancer risk following sRT in case-control data from questionnaires completed by 2497 women from a cohort of 5002 treated with sRT for HL at ages <36 during 1956-2003. RESULTS: Two-hundred and sixty women had been diagnosed with breast cancer. Breast cancer risk was significantly increased in patients treated within 6 months of menarche (odds ratio (OR) 5.52, 95% confidence interval (CI) (1.97-15.46)), and increased significantly with proximity of sRT to menarche (Ptrend<0.001). It was greatest when sRT was close to a late menarche, but based on small numbers and needing reexamination elsewhere. Risk was not significantly affected by full-term pregnancies before or after treatment. Risk was significantly reduced by early menopause (OR 0.55, 95% CI (0.35-0.85)), and increased with number of premenopausal years after treatment (Ptrend=0.003). CONCLUSION: In summary, this paper shows for the first time that sRT close to menarche substantially increases breast cancer risk. Careful consideration should be given to follow-up of these women, and to measures that might reduce their future breast cancer risk.

The Breakthrough Generations Study: design of a long-term UK cohort study to investigate breast cancer aetiology.

BACKGROUND: The rationale, design, recruitment and follow-up methods are described for the Breakthrough Generations Study, a UK cohort study started in 2003, targeted at investigation of breast cancer aetiology. METHODS: Cohort members have been recruited by a participant referral method intended to assemble economically a large general population cohort from whom detailed questionnaire information and blood samples can be obtained repeatedly over decades, with high completeness of follow-up and inclusion of large numbers of related individuals. 'First-generation' recruits were women contacted directly, or who volunteered directly, to join the study. They nominated female friends and family, whom we contacted, and those who joined ('second generation') nominated others, reiterated for up to 28 generations. RESULTS: The method has successfully been used during 2003-2011 to recruit 112,049 motivated participants with a broad geographic and socioeconomic distribution, aged 16-102 years, who have completed detailed questionnaires; 92% of the participants gave blood samples at recruitment. When eligible, 2½ years after recruitment, >98% completed the first follow-up questionnaire. Thirty percent are first-degree relatives of other study members. CONCLUSION: The 'generational' recruitment method has enabled recruitment of a large cohort who appear to have the commitment to enable long-term continuing data and sample collection, to investigate the effects of changing endogenous and exogenous factors on cancer risk.

A case-control study of risk of leukaemia in relation to mobile phone use.

BACKGROUND: Mobile phone use is now ubiquitous, and scientific reviews have recommended research into its relation to leukaemia risk, but no large studies have been conducted. METHODS: In a case-control study in South East England to investigate the relation of acute and non-lymphocytic leukaemia risk to mobile phone use, 806 cases with leukaemia incident 2003-2009 at ages 18-59 years (50% of those identified as eligible) and 585 non-blood relatives as controls (provided by 392 cases) were interviewed about mobile phone use and other potentially aetiological variables. RESULTS: No association was found between regular mobile phone use and risk of leukaemia (odds ratio (OR)=1.06, 95% confidence interval (CI)=0.76, 1.46). Analyses of risk in relation to years since first use, lifetime years of use, cumulative number of calls and cumulative hours of use produced no significantly raised risks, and there was no evidence of any trends. A non-significantly raised risk was found in people who first used a phone 15 or more years ago (OR=1.87, 95% CI=0.96, 3.63). Separate analyses of analogue and digital phone use and leukaemia subtype produced similar results to those overall. CONCLUSION: This study suggests that use of mobile phones does not increase leukaemia risk, although the possibility of an effect after long-term use, while biologically unlikely, remains open.

Determinants of age at menarche in the UK: analyses from the Breakthrough Generations Study.

BACKGROUND: Early menarche increases breast cancer risk but, aside from weight, information on its determinants is limited. METHODS: Age at menarche data were collected retrospectively by questionnaire from 81,606 women aged 16-98, resident in the UK and participating in the Breakthrough Generations Study. RESULTS: Menarche occurred earlier in women who had a low birthweight (P(trend)<0.001), were singletons (P<0.001), had prenatal exposure to pre-eclampsia (P<0.001) or maternal smoking (P=0.01), were not breastfed (P(trend)=0.03), were non-white (P<0.001), were heavy (P(trend)<0.001) or tall (P(trend)<0.001) compared with their peers at age 7 and exercised little as a child (P(trend)<0.001). Menarcheal age increased with number of siblings (P<0.001) independently of birth order, and had an inverse association with birth order after adjustment for sibship size (P<0.001). In a multivariate model, birthweight, ethnicity, weight, height, exercise, sibship size and birth order remained significant, and maternal age at birth became significant (positive association, P<0.001). CONCLUSION: Age at menarche was influenced by both pre- and post-natal factors, and these factors may affect breast cancer risk through this route.

Risk of cervical abnormality after age 50 in women with previously negative smears.

There is discussion over the benefit of continuing cervical screening in women over the age of 50 with a history of negative cytology. We aimed to determine the risk of abnormal cytology in such women. Screening history data from 1985 to 2003 were obtained for a cohort of 2 million women from the NHS cervical screening programme from four Health Authorities in England. The 57,651 women in the cohort who reached age 40 between 1 January 1985 and 31 December 1990 and had at least one routine or opportunistic smear between ages 50 and 54 were included in the analysis. Exposure groups (negative cytology history, negative but including inadequate smears, and positive history) were defined on the basis of screening histories from ages 40 to 49. Sixty-four percent (134/206) (95% CI: 57-71%) of the moderate dyskaryosis or worse lesions at ages over 50 were detected from women in the negative smear history group. After allowance for time since last negative smear, the relative risk for the first primary smear over the age of 50 having moderate dyskaryosis or worse decreased from 0.60 (95% CI: 0.41-0.84) for two negative smear episodes to 0.25 (95% CI: 0.10-0.56) for four negative smear episodes, compared with the positive history group. If screening were discontinued for all women over 50 with a negative history, the majority of cytological abnormalities now being detected at these ages that lead directly to referral to colposcopy would be missed.

The use of screening episodes linked to CIN3 and invasive cancer registrations to study outcomes from the NHS Cervical Screening Programme.

UNLABELLED: The use of screening episodes linked to CIN3 and invasive cancer registrations to study outcomes from the NHS Cervical Screening ProgrammeObjective: To examine how NHS cervical screening data can be collected and analysed in order to evaluate women's screening histories as episodes rather than as individual smears. DESIGN: Analysis of routine cervical screening data grouped into screening episodes for a cohort of women regarding episodes starting in a given year. SETTING: NHS Cervical Screening Programme. POPULATION: Data from four Health Authorities (now eight Primary Care Trusts) from the NHS Cervical Screening Programme with primary smears (first in an episode) taken between 1 April 1999 and 31 March 2000. METHODS: Cytology information obtained from the call/recall ('Exeter') computer system was linked to cervical intraepithelial neoplasia (CIN) 3 and invasive cancer outcome information obtained from cancer registries. Screening histories were divided into episodes, each starting with a primary smear that was followed up to episode closure or, for episodes still open followed for an average 4.25 years, from the primary smear. The episode was divided into two parts (up to referral to colposcopy and following the referral). The outcomes of the episodes are described including referral rate to colposcopy and CIN3 and invasive cancer rates by factors such as age. MAIN OUTCOME MEASURES: Episode histories and rates of referral to colposcopy, CIN3 and invasive cancer. RESULTS: There were 176 923 episodes from 176 319 women (1.003 episodes per woman) followed up to March 2004, the date at which the first phase of information accrual ceased. Of these episodes, 172 100 (97.3%) were closed either by a negative smear referring the woman back to routine recall or by default (defined as no smear recorded within 21 months following a smear requiring an action of repeat or refer to colposcopy). The remaining 4823 (2.7%) of episodes were still open, of which in 3121 (1.8%) the woman had been referred to colposcopy and in 1702 (1.0%) no referral decision had been made. Referral rates to colposcopy varied by age from 5.7% in women aged 20-24 years down to 0.9% in women aged 60-64 years. The overall efficiency of screening was highest for woman aged about 30 years, with a CIN3 detection rate of eight per 1000 women and a positive predictive value (for CIN3 or worse) of referral to colposcopy of 21%. CONCLUSION: The study has shown that routinely collected NHS cervical screening data can be combined to give information on complete episodes, allowing important performance measures to be studied. We suggest that in future information in the NHS screening system should be structured to facilitate such analysis and to allow cytology and histology information to be readily linked.

Cancer risk in patients with constitutional chromosome deletions: a nationwide British cohort study.

The finding of increased risks of specific cancers in individuals with constitutional deletions of chromosomes 11p and 13q led to the discovery of cancer predisposition genes at these locations, but there have been no systematic studies of cancer risks in patients with constitutional deletions, across the chromosome complement. Therefore, we assessed cancer incidence in comparison with national cancer incidence rates in a follow-up of 2561 patients with constitutional autosomal chromosome deletions diagnosed by microscopy or fluorescence in situ hybridisation in Britain during the period 1965-2002. Thirty cancers other than non-melanoma skin cancer occurred in the cohort (standardised incidence ratio (SIR)=2.4, 95% confidence interval (CI) 1.6-3.5). There were significantly increased risks of renal cancer in persons with 11p deletions (SIR=1869, 95% CI 751-3850; P=4 x 10(-21)), eye cancer with 13q deletions (SIR=1084, 95% CI 295-2775; P=2 x 10(-11)), and anogenital cancer with 11q deletions (SIR=305, 95% CI 63-890; P=3 x 10(-7)); all the three latter cancers were in the 11 subjects with 11q24 deletions. The results strongly suggest that in addition to suppressor genes relating to Wilms' tumour risk on 11p and retinoblastoma on 13q, there are suppressor genes around 11q24 that greatly affect anogenital cancer risk.

An examination of the role of opportunistic smear taking in the NHS cervical screening programme using data from the CSEU cervical screening cohort study.

OBJECTIVE: The objective of this study was to study the prevalence of opportunistic smear taking in the NHS cervical screening programme between 1999 and 2003 and the relationship of this to screening interval policy. DESIGN: A cohort study of nearly 2 million women, with data on screening at ages 20-64 years from 1988 to 2003 has been constructed. Data from 1999 to 2003 have been used in this analysis. Screening episodes have been divided into those where the primary smear was initiated by the national call/recall system (invitational), normally at 3- or 5-yearly intervals, and those initiated by the GP or woman (opportunistic). Opportunistic smears were further classified as routine (occurring within 6 months of 3 or 5 years) or sporadic (occurring at other times). SETTING: NHS cervical screening programme. POPULATION: Four Health Authorities in England (now Primary Care Trusts) with supplementary studies on national data. METHODS: Screening episodes have been defined. All episodes start with a primary smear defined as being invitational or opportunistic in origin. MAIN OUTCOME MEASURE: Proportion of primary smear that were invitational or opportunistic. RESULTS: In total, 72% of incident screen primary smears were invitational and 28% were opportunistic. The proportion of opportunistic primary smears was 17 and 43% in 3- or 5-yearly screening policy areas, respectively, resulting in a considerably reduced average screening interval for women aged 20-64 years in 5-year policy areas. CONCLUSION: The NHS cervical screening programme is strongly influenced by opportunistic smear taking. In particular, nominally 5-year policy areas experienced much higher levels of opportunistic smear taking than those with a 3-year policy, causing the average interval in the 5-year areas to be much shorter than the policy would suggest. In future, with the change in national policy for inviting women aged 25-49 years every 3 years and those aged 50-64 years every 5 years, the level of opportunistic smear taking, particularly in the older group of women, needs to be carefully monitored. A lack of compliance may result in greater than predicted costs with little or no additional cancer prevention.

Trends in cancer mortality in 15 industrialized countries, 1969-1986.

BACKGROUND: Assessing trends in cancer provides a means for gauging progress against the disease, estimating future demands for care and treatment, and suggesting clues about shifting causal factors that may account for the more recent changes. PURPOSE: This study was designed to evaluate trends in the major sites of cancer associated with high mortality rates in 15 industrialized countries. To highlight differences among regions, we grouped these countries into six geographic areas: United States, Eastern Europe, Western Europe, East Asia, Oceania, and Nordic countries. In addition, cancer mortality trends in these regions were compared with incidence patterns in the United States. METHODS: Data provided by the World Health Organization were used to evaluate age-specific mortality trends from 1969 through 1986 for lung, breast, prostate, stomach, and colorectal cancers and for all other sites considered as a group. We also assembled and analyzed data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute for the same sites and age groups from 1973 through 1986. RESULTS: Over the period 1969 through 1986, recorded cancer mortality in persons aged 45 years and older in the six regions studied has increased for lung, breast, and prostate cancers in most age groups, while the decline in stomach cancer mortality is substantial. The increase in lung cancer deaths in men aged 45-54 years has slowed greatly or reversed in all areas except Eastern Europe and East Asia. Trends for intestinal cancer vary by age and region. For all other sites considered as a group, increases have occurred for persons older than 64 years in most regions. In Eastern Europe, there are disturbingly high rates and rapid increases for several of the major forms of cancer in persons aged 45-54 years. In general, trends for cancer incidence in the United States parallel those for mortality. For intestinal cancer, however, incidence has increased while mortality has declined. CONCLUSIONS: The trends we report cannot be explained solely by changes in cigarette smoking or aging. Other causes of changes in cancer incidence and mortality need to be determined. IMPLICATIONS: The increasing and decreasing trends in mortality from and incidence of cancer that we found are important for health care planning and may also suggest opportunities for research in cancer prevention.

Risk of second malignancy after Hodgkin's disease in a collaborative British cohort: the relation to age at treatment.

PURPOSE: To assess long-term site-specific risks of second malignancy after Hodgkin's disease in relation to age at treatment and other factors. PATIENTS AND METHODS: A cohort of 5,519 British patients with Hodgkin's disease treated during 1963 through 1993 was assembled and followed-up for second malignancy and mortality. Follow-up was 97% complete. RESULTS: Three hundred twenty-two second malignancies occurred. Relative risks of gastrointestinal, lung, breast, and bone and soft tissue cancers, and of leukemia, increased significantly with younger age at first treatment. Absolute excess risks and cumulative risks of solid cancers and leukemia, however, were greater at older ages than at younger ages. Gastrointestinal cancer risk was greatest after mixed-modality treatment (relative risk [RR] = 3.3; 95% confidence interval [CI], 2.1 to 4.8); lung cancer risks were significantly increased after chemotherapy (RR = 3. 3; 95% CI, 2.4 to 4.7), mixed-modality treatment (RR = 4.3; 95% CI, 2.9 to 6.2), and radiotherapy (RR = 2.9; 95% CI, 1.9 to 4.1); breast cancer risk was increased only after radiotherapy without chemotherapy (RR = 2.5; 95% CI, 1.4 to 4.0); and leukemia risk was significantly increased after chemotherapy (RR = 31.6; 95% CI, 19.7 to 47.6) and mixed-modality treatment (RR = 38.1; 95% CI, 24.6 to 55. 9). These risks were generally greater after treatment at younger ages: for patients treated at ages younger than 25 years, there were RRs of 18.7 (95% CI, 5.8 to 43.5) for gastrointestinal cancer after mixed-modality treatment, 14.4 (95% CI, 5.7 to 29.3) for breast cancer after radiotherapy, and 85.2 (95% CI, 45.3 to 145.7) for leukemia after chemotherapy (with or without radiotherapy). CONCLUSION: Age at treatment has a major effect on risk of second malignancy after Hodgkin's disease. Although absolute excess risks are greater for older patients, RRs of several important malignancies are much greater for patients who are treated when young. The increased risk of gastrointestinal cancers may relate particularly to mixed-modality treatment, and that of lung cancer to chemotherapy as well as radiotherapy; there are also well-known increased risks of breast cancer from radiotherapy and leukemia from chemotherapy. The roles of specific chemotherapeutic agents in the etiology of solid cancers after Hodgkin's disease require detailed investigation.

Lung cancer after Hodgkin's disease: a nested case-control study of the relation to treatment.

PURPOSE: To investigate the causes of the raised risk of lung cancer in patients who have had Hodgkin's disease, and in particular the relationship to treatment. PATIENTS AND METHODS: A nested case-control study was conducted within a cohort of 5,519 patients with Hodgkin's disease treated in Britain during 1963 through 1993. For 88 cases of lung cancer and 176 matched control subjects, information on treatment and other risk factors was extracted from hospital case-notes, and odds ratios for lung cancer in relation to these factors were calculated. RESULTS: Risk of lung cancer was borderline significantly greater in patients treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy than those who did not receive this treatment (relative risk [RR] = 1.66; 95% confidence interval [CI], 0.99 to 2.82), and increased with number of cycles of MOPP (P =.07). Exclusion of lung cancers for which histologic confirmation was not available strengthened these associations (RR = 2.41; 95% CI, 1.33 to 4.51; P =.004 for any MOPP and P =.007 for trend with number of cycles of MOPP). Risks were not raised, however, after chlorambucil, vinblastine, procarbazine, and prednisone treatment. There was evidence that the raised risk of lung cancer occurring in relation to radiotherapy was restricted to histologies other than adenocarcinoma. CONCLUSION: The results suggest that MOPP chemotherapy may lead to elevated risk of lung cancer, at least in certain subgroups of patients. The role of chemotherapy in the etiology of lung cancer after Hodgkin's disease deserves further investigation.

Growth hormone treatment of children with brain tumors and risk of tumor recurrence.

GH is increasingly used for treatment of children and adults. It is mitogenic, however, and there is therefore concern about its safety, especially when used to treat cancer patients who have become GH deficient after cranial radiotherapy. We followed 180 children with brain tumors attending three large hospitals in the United Kingdom and treated with GH during 1965-1996, and 891 children with brain tumors at these hospitals who received radiotherapy but not GH. Thirty-five first recurrences occurred in the GH-treated children and 434 in the untreated children. The relative risk of first recurrence in GH-treated compared with untreated patients, adjusted for potentially confounding prognostic variables, was decreased (0. 6; 95% confidence interval, 0.4-0.9) as was the relative risk of mortality (0.5; 95% confidence interval, 0.3-0.8). There was no significant trend in relative risk of recurrence with cumulative time for which GH treatment had been given or with time elapsed since this treatment started. The relative risk of mortality increased significantly with time since first GH treatment. The results, based on much larger numbers than previous studies, suggest that GH does not increase the risk of recurrence of childhood brain tumors, although the rising trend in mortality relative risks with longer follow-up indicates the need for continued surveillance.

Long-term survival in Hodgkin's disease patients. A comparison of relative survival in patients in trials and those recorded in population-based cancer registries.

The prognosis of Hodgkins disease (HD) has improved during the last 30 years. This study was planned to analyse long-term survival of LID patients and to compare survival rates estimated from clinical trials and population-based data. Individual data were analysed on 2,755 adult HD patients entering randomised clinical trials of the British National Lymphoma Investigation BN LI) between 1970 and 1987, and 5,064 patients with HD incident 1978-1984 recorded in the UK population-based cancer registries participating in the EUROCARE study. Relative survival of Hodgkins disease patients allowing for mortality expected from general population rates was analysed by a proportional hazards regression model including covariates. Although relative mortality decreased with longer follow-up, it was still significantly positive at 9-10 years after diagnosis in both the clinical trials and the population-based data sets. Relative mortality was worse for late stage than for early stage patients even at 10-15 years after first treatment (BNLI data). Whereas 10-year relative survival was identical in trials and population-based patients at ages under 45 years (> 69%), it was much higher in BNLI older patients than in the population-based patients. In the older age group (65-74 years) the BNLI patients had 39% relative survival whilst for the population-based patients it was only 27%, Generalisation of clinical trials results to the general population must be done with caution, especially for older patients.

Risk of lymphoid neoplasia after cardiothoracic transplantation. a cohort study of the relation to Epstein-Barr virus.

BACKGROUND: Organ transplantation is associated with a greatly increased risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disease (LPD), which is often fatal. There has been little epidemiological analysis, however, of the risk factors for LPD in transplant patients and none on whether the risks of non-EBV-associated lymphoid neoplasms are also increased. METHODS: The risk of lymphoid neoplasia was assessed in a cohort of 1563 patients who underwent cardiothoracic transplantation at Harefield Hospital, UK from 1980 to 1994 and were followed until December 1995. EBV antibody was assessed in the patients before transplantation, and lymphoid neoplasms were assessed for EBV RNA and latent EBV gene expression. RESULTS: Thirty cases of LPD occurred during follow-up. One lymphoma of unknown EBV status occurred. There were also six cases of EBV-negative non-Hodgkin's lymphoma (EBV-negative NHL), a highly significant excess over expectations from the general population rates of NHL (standardized incidence ratio 10.2 [95% confidence interval, 4.6-22.8]). The risk of LPD was significantly 10-fold raised in individuals who were EBV seronegative before transplantation; independently of this, it decreased steeply with age at transplantation and was greatest in the first year after transplantation. The risk was significantly raised in young seronegative recipients if the donor was older than the recipient. EBV-negative NHL occurred entirely in men 45 years old and older who were EBV seropositive before transplantation, and risk was not related to duration since transplantation. CONCLUSIONS: The risk factors found for LPD accord with EBV etiology and with greater hazard from primary infection than from reactivation. A second non-Hodgkin's lymphoid neoplasm, not related to EBV, seems also to be a consequence of transplantation and immunosuppression but is unlikely to be due to first infection by a ubiquitous agent. Its etiology and prevention need investigation separately from LPD.

Mortality and cancer incidence in Vietnamese refugees in England and Wales: a follow-up study.

Mortality and cancer incidence were analysed in follow-up of a cohort of 3327 Vietnamese refugees who came to Britain after the end of the Vietnam war. Overall mortality of the refugees was very low compared to expectations based on England and Wales national rates: the all-cause standardized mortality ratio for males was 64 (95% confidence interval 52-77) and for females was 56 (95% confidence interval 44-71). This resulted particularly from very low mortality from ischaemic heart disease and colorectal cancer in each sex, and breast cancer in women. Mortality in the refugees was greatly increased for tuberculosis, cancer of the stomach in both sexes, cancers of the nasopharynx and liver in males, and peptic ulcer in females. Cancer incidence data showed in addition an excess of cancer of the penis. Despite the great trauma and stress of their flight, the only indication of a possible effect of the migration on the mortality of the refugees who survived to reach Britain was the excess of peptic ulcer deaths in women.

Mortality during 25 years of follow-up of a cohort with diabetes.

BACKGROUND: Diabetes is one of the most common chronic diseases in Western populations. There have been few large published cohort studies of people with diabetes that have had more than 10 years of follow-up, and none other than the present one are in the UK. Such studies are important to understand the long-term fatal consequences of diabetes and their variation over time and between countries. METHODS: Cause-specific mortality was analysed in follow-up from 1966-1970 to December 1992 of 5783 members of the British Diabetic Association living in England and Wales during 1966-1970. Comparison was made with age-, sex- and calendar year-specific mortality by cause in the general population of England and Wales. RESULTS: During the follow-up 3399 (58.8%) subjects died. The relative risk of all-cause mortality in the cohort compared to the general population was 2.31 in women and 1.58 in men (both P < 0.001).Relative risks were greater for women than men at almost all ages and for each major diabetes-related cause of death. Absolute excess ('attributable') mortality rates were also greater in women than in men, except at ages < 50. Half the deaths in each sex were from circulatory diseases and only 3.4% were from renal disease. The relative risks of mortality for all-causes and circulatory diseases were particularly great at younger ages, but changed little with duration of follow-up. At ages < 40 the relative risks for all-causes were 3.75 in men and 5.51 in women and for ischaemic heart disease were 10.44 and 25.25 respectively (all P < 0.001). At these ages one-third of deaths were due to acute complications of diabetes, suicides and accidents, whereas at older ages these accounted for only 4% of deaths. CONCLUSIONS: The mortality rates at young ages in the cohort were around twice those in Sweden, Norway and Israel, suggesting that many of the deaths in England and Wales are preventable. The results also indicate a particular need for investigation and amelioration of cardiovascular risk factors in English and Welsh patients, especially women.

Risk of death from motor-vehicle injury in Brazilian steelworkers: a nested case-control study.

OBJECTIVES: In a cohort of 21,816 Brazilian steelworkers we found mortality from motor-vehicle injury was twice that in the State population. A nested case-control study was therefore undertaken to investigate possible socio-demographic, medical and occupational risk factors for this increased risk. METHODS: Cases were defined as all steelworkers in the cohort who died of motor-vehicle injury during employment in the period 1977-1992. For each case, four controls were selected at random from workers in the cohort who were employed at the time of death of the case, and who were born in the same year as the case. Data on socio-demographic factors, and medical and occupational histories were obtained from personnel, industrial hygiene and medical records, and the relation of these factors to risk of motor-vehicle injury was analysed using conditional logistic regression. RESULTS: In a multivariate analysis, the risk of death from motor-vehicle injury was independently associated with being unmarried (odds ratio [OR] compared to married = 3.21, 95% confidence interval [CI]: 1.84-5.59), having a hearing defect (OR = 2.28, 95% CI: 1.10-4.74) and exposure to moderate (OR = 1.71, 95% CI: 1.03-2.83) or high (OR = 2.00, 95% CI: 1.18-3.39) levels of noise at work. The risk of fatal motor-vehicle injury increased with intensity of occupational noise exposure (P = 0.004). CONCLUSIONS: The raised risk of motor-vehicle injury death associated with single marital status is likely to relate to selective factors in the types of individual who remain single, and behaviours associated with being unmarried. The raised risks in relation to hearing defects and exposure to occupational noise, factors that do not appear to have been examined previously, imply that occupational noise exposures might be a cause of fatal motor-vehicle accidents outside the workplace. This finding may have widespread public health consequences since high levels of noise in the workplace and occupationally acquired hearing deficits are prevalent in several occupations. Further investigation is needed to confirm the associated and its mechanisms and, if it is causal, to develop preventive strategies.

Pre-natal and early life risk factors for childhood onset diabetes mellitus: a record linkage study.

BACKGROUND: Using data from the Oxford Record Linkage Study (ORLS) we conducted a case-control study to examine pre-natal and early life risk factors for childhood and adolescent onset diabetes mellitus. METHODS: We identified 160 boys and 155 girls born 1965-1986 and admitted to hospital with a diagnosis of diabetes during 1965-1987 in the ORLS area. Up to eight controls were matched to each case on sex, year of birth and hospital or place of birth. We linked the hospital records for each child to all of that child's hospital records and to his or her mother's maternity record. RESULTS: There were no significant associations between subsequent diabetes and birthweight, gestational age, birthweight for gestational age, maternal age and parity. There were increased risks with not breastfeeding (relative risk [RR] = 1.33; 95% CI: 0.76-2.34), and with diabetes recorded in the mother during pregnancy (RR = 5.87; 95% CI : 0.90-38.3), but these were not statistically significant. There was a significantly raised risk with pre-eclampsia or eclampsia during pregnancy (RR = 1.48; 95% CI: 1.05-2.10). CONCLUSIONS: Pre-eclampsia may be the result of an immunogenetic incompatibility between mother and fetus, and this early immunological disturbance might be related to incidence of diabetes in later life.