Overview: cancer, HIV and AIDS.
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Biomedical subjects
Publications and source records attributed to V Beral.
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The AIDS epidemic drew attention to KS, a previously rare and little studied condition. The epidemiological evidence summarized here strongly suggests that the disease is caused by a transmissible agent, in addition to HIV. Sexual contact is the most important mode of transmission of the agent, although transmission by blood and perinatally may also occur (Beral et al, 1990).
Nearly all studies have suggested that the use of oral contraceptives (OC) is not associated with the aggregate risk of breast cancer diagnosed in women aged 20-54. Because of age-specific differences in the breast cancer-parity relationship and because of age-specific differences in other breast cancer risk factors, the Centers for Disease Control reexamined data from the Cancer and Steroid Hormone Study to assess whether OC use has different effects on the risk of breast cancer at different ages of diagnosis. This was a population-based case-control study conducted in eight geographic areas in the United States during 1980-1982. In these data, the relationship between the risk of breast cancer and OC use appeared to vary by age at diagnosis. Among women aged 20-34 years at diagnosis or interview, those who had ever used OC had a slightly increased risk of breast cancer (odds ratio 1.4, 95% confidence interval 1.0-2.1) when compared with women of the same ages who had never used OC. Among these women, there were no trends of increasing or decreasing risk with any measure of OC use. Among women aged 35-44 years, there was no association between OC use and breast cancer. Among women aged 45-54 years, those who used OC had a slightly decreased risk of breast cancer (odds ratio 0.9, 95% confidence interval 0.8-1.0). Among these women, the risk estimates decreased significantly with increasing time since first and last use. Although the slightly increased risk estimates for the youngest women are compatible with findings by other investigators, the decreased risk estimates for the oldest women have not been described in as many studies. Available data provide no reasons for changes in prescribing practices or in the use of OC as related to breast cancer risk.
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In the United States Kaposi's sarcoma is at least 20,000 times more common in persons with acquired immunodeficiency syndrome (AIDS) than in the general population and 300 times more common than in other immunosuppressed groups. Among persons with the acquired immunodeficiency syndrome (AIDS) reported to Centers for Disease Control by March 31, 1989, 15% (13,616) had Kaposi's sarcoma. Kaposi's sarcoma was commoner among those who had acquired the human immunodeficiency virus (HIV) by sexual contact than parenterally, the percentage with Kaposi's sarcoma ranging from 1% in men with haemophilia to 21% in homosexual or bisexual men. Women were more likely to have Kaposi's sarcoma if their partners were bisexual men rather than intravenous drug users. Kaposi's sarcoma risk was not consistently related to age or race but varied across the United States, being greatest in the areas that were the initial foci of the AIDS epidemic. Thus Kaposi's sarcoma in persons with AIDS may be caused by an as yet unidentified infectious agent, transmitted mainly by sexual contact.
The association between time to conceive reported by 2817 fertile women who had recently had a liveborn child and consumption of coffee, tea, and "cola" drinks has been investigated. No evidence for an adverse effect of caffeine was found. For levels of consumption ranging from less than one cup of coffee per week (501 mg caffeine per month) to more than two cups of coffee per day (7000 mg per month), the average time to conceive was similar. The fecundability ratio adjusted for known risk factors for time to conceive was 1.03 (95% confidence interval 0.92-1.16) between those who consumed more than 7000 mg caffeine per month and those who consumed 500 mg or less per month. Furthermore caffeine consumption was not associated with infertility in 1818 infertile women and their primiparous controls.
Studies of the association of ectopic pregnancy with contraception have generated a conflicting array of results because of methodologic differences between studies. We estimated the absolute incidence rates of ectopic pregnancy for various contraceptives by multiplying the pregnancy rate by the proportion of pregnancies with ectopic implantation for each method. Our results indicated a more than 500-fold difference in ectopic pregnancy incidence, from a low of 0.005 ectopic pregnancies per 1000 women years of oral contraception or vasectomy to a high of 2.6 per 1000 women years of no contraception. These estimated incidence rates should be useful for clinicians and patients seeking to better understand the risks and benefits of contraceptives.
A cluster of childhood leukemia in a village near a nuclear plant in northern England prompted further studies of cancer in the vicinity of other nuclear plants in the United Kingdom. These studies demonstrated that the risk of childhood leukemia was increased near certain other nuclear plants. Although the reasons for the increase are still unclear, the scientific debate stimulated by these findings has clarified some of the special methodological problems encountered when studying rare diseases in small areas. Firstly, unless a specific hypothesis is defined in advance, the relevance of a single geographic cluster of disease can rarely be interpreted. Even when a prior hypothesis exists, the small number of cases which generally occur in a small area make the findings highly sensitive to reporting, diagnostic, or classification errors. The statistical power of such investigations is also usually low and only marked increases in risk can be detected. Furthermore, conventional statistical tests may be inappropriate if the underlying spatial distribution of the disease is not random; and little is known about the background distribution of disease in small areas. Investigations of specific hypotheses about defined sources of environmental contamination, especially if they can be replicated, are more likely to result in conclusive findings that are in-depth studies of individual clusters.
With the increasing practice of assisted conception, the health of the resulting children is becoming an increasingly important issue. Experience with four thousand children conceived by IVF or GIFT indicates that multiple pregnancy, which frequently results from assisted conception, is the main determinant of complications during pregnancy and of the health of the children at the time of birth. Overall malformation rates are similar to those in the country as a whole. There are, however, still insufficient numbers of children studied to draw firm conclusions about the risk of specific types of malformations. This will require the continued monitoring of children resulting from assisted conception, and the continued co-operation of many individuals and centres practising assisted conception.
Follow up data on 37,355 employees of the United Kingdom Atomic Energy Authority (UKAEA) for the period 1946-79 were analysed to investigate the extent to which selection for work on the basis of health affected subsequent death rates. Causes of death were grouped into two broad categories for analysis: all cancers and all other causes of death. Evidence for an effect of selection of healthy individuals into the workforce was sought primarily by examining standardised mortality ratios (SMRs) by period since recruitment. SMRs for both categories were particularly low during the first two years after recruitment (SMR = 69, 95% confidence interval (CI) 48-97 for all cancers; SMR = 55, 95% CI 44-69 for all other causes of death). SMRs for all cancers did not increase significantly with period since recruitment (chi 2 for trend = 0.4, p = 0.53) but did increase for causes of death other than cancer (chi 2 for trend = 11.1, p = 0.001). Although adjustment for social class strengthened the association between death from causes other than cancer and period since recruitment (chi 2 for trend = 18.8, p less than 0.001), simultaneous adjustment for all confounding factors considered (age at death, sex, calendar period of death, geographical location of the workforce, and social class) produced results broadly similar to those obtained from the unadjusted analyses for both cause of death categories. SMRs remained low even after 25 years of follow up (SMR = 84, 95% CI 69-101 for all cancers; SMR = 81, 95% CI 72-91 for all other causes of death). The persistently low SMRs observed in this workforce are unlikely to be due to the selection of healthy individuals at the time of recruitment but may be due to differences in sociodemographic and lifestyle characteristics. The effect on mortality of selection of individuals out of the workforce due to ill health was also examined. SMRs were particularly high for both categories in the first two years after termination of employment in individuals who left before normal retirement age (SMR = 167, 95% CI 131-211 for all cancers; SMR = 149, 95% CI 128-173 for all other causes of death). In comparison, death rates for the subsequent three years after termination of employment were lower (SMR = 89, 95% CI 67-115 for all cancers, SMR = 99, 95% CI 85-115 for all other causes of death). The persistently low SMRs observed in this workforce are unlikely to be due to the selection of healthy individuals at the time of recruitment but may be due to differences in sociodemographic and lifestyle characteristics. The effect on mortality of selection of individuals out of the workforce due to ill health was also examined. SMRs were particularly high for both categories in the first two years after termination of employment in individuals who left before normal retirement age (SMR = 167, 95% CI 131-211 for all cancers; SMR 149,95% CI 128-173 for all other causes of death). In comparison, death rates for the subsequent three years after termination of employment were lower (SMR = 89, 95% CI 67-115 for all cancers SMR = 99, 95% CI 85-115 for all other causes of death). Apart from this initial fall, there was little evidence of a systematic increase or decrease in mortality with increasing period was not significantly associated with durationof employment for either cause of death category either before or after adjustment for confounding factors. Whereas selection of individuals into or out of the workforce on the basis of health affects the way in which death rates change with time, other factors such as sociodemographic characteristics or health related behaviour determine the general level of mortality in the longer run. The persistently low SMRs observed in this workforce throughout the follow up period suggest that selection on the latter factors are likely to have had a considerable effect on death rates in the UKAEA workforce.
An analysis of the incidence of malignant melanoma according to occupation is presented using data from two national cancer registries. The data relate to 3991 cases of cutaneous malignant melanoma, 662 cases of ocular melanoma, and 179 cases of noncutaneous, non-ocular melanoma in subjects aged 15-64 in England and Wales diagnosed from 1971 to 1978 and to 5003 cases of cutaneous malignant melanoma diagnosed from 1961 to 1979 in Sweden in subjects born between 1896 and 1940. Professional workers of both sexes in both countries experienced an excess incidence of cutaneous malignant melanoma. An excess of ocular melanoma and of non-cutaneous, non-ocular melanoma also existed for this group in England and Wales. Pharmacists, medical doctors, and dentists had a high incidence of cutaneous melanoma in both countries and were represented three times when listing the top 20 occupations in both countries and both genders. Combining the data from cutaneous malignant melanoma over both sexes and both registries the occupations with the highest incidence ratios (expressed as a percentage) were: airline pilots, incidence ratio (IR) = 273, (95% confidence limits 118-538); finance and insurance brokers IR = 245 (140-398); professional accountants IR = 208 (134-307); dentists IR = 207 (133-309); inspectors and supervisors in transport IR = 206 (133-304); pharmacists IR = 198 (115-318); professionals not elsewhere classified IR = 196 (155-243); judges IR = 196 (126-289); doctors IR = 188 (140-248); university teachers IR = 188 (110-302); and chemists IR = 188 (111-296). No particular exposure in the workplace seemed to link these groups and only a few worked in high technology environments. Many of the highest risk groups have in common a high level of education. In England and Wales and in Sweden this might correlate particularly with foreign travel abroad was more unusual than it is now, but evidence on present and past exposure to sun by occupation is needed to clarify the reasons for the association.
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OBJECTIVE: To examine associations between reported respiratory symptoms (as elicited by questionnaire) and subsequent mortality. DESIGN: Prospective cohort study. SETTING: 92 General practices in Great Britain. PARTICIPANTS: A nationally representative sample of 1532 British men and women aged between 40 and 64. MAIN OUTCOME MEASURES: Mortality from all causes, cardiovascular disease, lung cancer, and chronic bronchitis. RESULTS: Subjects were interviewed in 1958 regarding various respiratory symptoms (including cough, phlegm, breathlessness, and wheeze) by using a questionnaire which formed the basis of the Medical Research Council's questionnaire on respiratory symptoms. By the end of 1985, 889 deaths had been reported, including 51 in men due to chronic bronchitis. After adjustment for differences in age and smoking habits death rates from chronic bronchitis in men who reported symptoms were greater than those in men who did not for each of the symptoms examined. The adjusted mortality ratios were 3.4 (95% confidence interval 1.8 to 6.5) for morning cough, 3.7 (2.0 to 6.9) for morning phlegm, 6.4 (3.0 to 13.8) for breathlessness when walking on the level, and 10.5 (4.4 to 24.6) for wheeze most days or nights. Mortality ratios were also significantly raised for four episodic symptoms not usually included in more recent respiratory symptom questionnaires--namely, occasional wheeze (mortality ratio 6.0; 95% confidence interval, 2.4 to 15.1), weather affects chest (5.7; 3.1 to 10.3), breathing different in summer (4.9; 2.8 to 8.6), and cold usually goes to chest (3.7; 2.0 to 6.8). The excess mortality associated with these symptoms remained significant after further adjustment for breathlessness or phlegm. Ratios for all cause mortality in men and women were also significantly raised for most respiratory symptoms, death rates being some 20-50% higher in people reporting symptoms after adjustment for age, sex, and smoking. Breathlessness was the only symptom significantly associated with excess mortality from cardiovascular disease (mortality ratio 1.4 (95% confidence interval 1.0 to 1.9) for breathlessness when walking on the level). Ratios were generally around unity and not significant for mortality due to lung cancer. CONCLUSIONS: The results suggest that episodic symptoms, which often do not appear in standard respiratory questionnaires, predict subsequent mortality from chronic obstructive airways disease. This supports the hypothesis that reversible airflow obstruction may be a precursor of progressive and irreversible decline in ventilatory function.
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A hospital-based case-control study of ovarian cancer was conducted in London and Oxford between October 1978 and February 1983. Menstrual characteristics, reproductive and contraceptive history and history of exposure to various environmental factors were compared between 235 women with histologically diagnosed epithelial ovarian cancer and 451 controls. High gravidity, hysterectomy, female sterilisation and oral contraceptive use were associated with a reduced risk of ovarian cancer. Infertility and late age at menopause were associated with an increase in risk. While these factors were related, they were each found to be independently associated with ovarian cancer risk after adjusting for the effect of the other factors.
Of 47,000 women followed since 1968, those who had used oral contraceptives (ever-users) had a significantly higher incidence rate of cervical cancer than never-users. After standardisation of rates by age, parity, smoking, social class, number of previously normal cervical smears, and history of sexually transmitted disease, the excess was 41 per 100,000 woman-years for carcinoma-in-situ and 8 per 100,000 woman-years for invasive cervical cancer. Incidence increased with increasing duration of use: the standardised incidence rate for cervical cancer in women who had taken the pill for more than 10 years was four times than in never-users. Ever-users had a lower incidence of other uterine cancers (deficit 5 per 100,000 woman-years); a lower incidence of ovarian cancer was also found (deficit 4 per 100,000), but was not statistically significant. Overall, ever-users had an excess incidence for genital tract cancers 37 per 100,000 woman-years. This excess was mainly from carcinoma-in-situ of the cervix; the excess incidence of invasive cervical cancer was offset by the deficits in other uterine and ovarian cancers. Standardised mortality rates from genital cancer were similar in ever-users and never-users. Of relevance to clinical practice is the substantially different distribution of primary cancer sites: cervical cancer accounted for 75% of the invasive genital cancers and 74% of deaths from genital cancer in ever-users, but only 31% of the invasive cancers and 30% of deaths in never-users.
A total of 22,552 workers employed by the Atomic Weapons Establishment between 1951 and 1982 were followed up for an average of 18.6 years. Of the 3115 who died, 865 (28%) died of cancer. Mortality was 23% lower than the national average for all causes of death and 18% lower for cancer. These low rates were consistent with the findings in other workforces in the nuclear industry and reflect, at least in part, the selection of healthy people to work in the industry and the disproportionate recruitment of people from the higher social classes. At some time during their employment 9389 (42%) of the workers were monitored for exposure to radiation, the average cumulative whole body exposure to external radiation being 7.8 mSv. Their mortality was generally similar to that of other employees, even when exposures were lagged by 10 years. The rate ratio after a 10 year lag in workers with a radiation record compared with other workers was 1.01 (95% confidence interval 0.92 to 1.10) for all causes of death and 1.06 (0.89 to 1.27) for all malignant neoplasms. The only significant differences were for prostatic cancer (rate ratio 2.23; 95% confidence interval 1.13 to 4.40) and for cancers of ill defined and secondary sites (rate ratio 2.37; 1.23 to 4.56). Cancers of lymphatic and haemopoietic tissues were notable for their low occurrence in the study population, with only four deaths from leukaemia and two from multiple myeloma in workers with a radiation record, 9.16 and 3.55 deaths respectively being expected on the basis of national rates. Among workers who had a radiation record 3742 (40%) were also monitored for possible internal exposure to plutonium, 3044 (32%) to uranium, 1562 (17%) to tritium, 638 (7%) to polonium, and 281 (3%) to actinium. In these workers mortality from malignant neoplasms as a whole was not increased, but after a 10 year lag death rates from prostatic and renal cancers were generally more than twice the national average, these excesses arising in a small group of workers monitored for exposure to multiple radionuclides. Though mortality from lung cancer in workers monitored for exposure to plutonium was below the national average, it was some two thirds higher than in other radiation workers, the excess being of borderline statistical significance. Mortality from malignant neoplasms as a whole showed a weak and non-significant increasing trend with increasing level of cumulative whole body exposure to external radiation. When the exposures were lagged by 10 years the trend became stronger and significant, the estimated increase in relative risk per 10 mSv being 7.6% (95% confidence interval 0.4% to 15.3%). This trend was confined almost entirely to workers who were also monitored for exposure to radionuclides (p<0.001), the main contributions coming from lung cancer and prostatic cancer. Exposures of the lung and prostate from internal sources of radiation were not quantified, except for the contribution from tritium. It was therefore not possible to assess the extent to which the associations were due to internally deposited radionuclides rather than external exposure. The finding for prostatic cancer taken in conjunction with the results of other studies suggest a specific occupational hazard in a small group of workers in the nuclear industry who had comparatively high exposures to external radiation and who were also monitored for internal exposure to multiple radionuclides. Research is needed to discover whether any of the radionuclides and other substances concerned are concentrated in the prostate. The occurrence of lung cancer in this workforce requires further investigation taking into account smoking habits and tissue doses from inhaled radionuclides.