Biomedical subjects
Publications and source records attributed to A B Miller.
Breast cancer, a significant cause of mortality, can often be tackled effectively if detected at an early stage. This may be achieved by mammography, physical examination by skilled practitioners, or self-examination of the breasts. However, the value and feasibility of these methods vary with the age of the subject and with economic and cultural circumstances.
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Between 1982 and 1987, 519 newly incident, histologically confirmed cases of breast cancer were identified in a cohort of 56,837 women enrolled in the Canadian National Breast Screening Study. These women had completed a dietary questionnaire before the occurrence of their breast cancer, and this has been used to estimate their intake of dietary fat and several other nutrients. There is evidence of a positive association between breast cancer and total fat intake, with a relative risk of 1.35 (95% confidence interval, 1.00-1.82) per 77 g per day, and some evidence of a dose-response relationship (P = .052).
Results are reported with respect to smoking data from a population-based case-control study of pancreatic cancer conducted in Toronto, Canada, between 1983 and 1986. Lifetime smoking histories were obtained for 249 cases and 505 controls. A statistically highly significant positive association was observed between lifetime cigarette consumption and risk of pancreatic cancer. There was a rapid decrease in risk with time for those who quit cigarette smoking, the risk for ex-smokers being the same as for lifetime non-smokers between 10 and 15 years after quitting. Limiting exposure to the 15 years prior to diagnosis considerably strengthens the association and leads to a much more clearly defined dose-response relationship with relative risks of 1.88, 4.61, and 6.52 for tertiles of consumption for current cigarette smokers compared with lifetime non-smokers (p trend less than 10(-5)). We conclude that the current data, together with those from previous studies, strongly support a causal relationship between cigarette smoking and risk of pancreatic cancer, and indicate that cessation of smoking is likely to prove a rapidly effective preventive measure for this major type of cancer.
Results are reported from a population-based study of 249 cases of pancreas cancer and 505 controls carried out in Toronto, Canada, between 1983 and 1986. Lifetime consumption of coffee and alcohol and medical histories were assessed by personal interviews. No evidence of any association was found with different types of coffee or alcohol after adjusting for smoking, calories and fibre intake. There was a significant increased risk associated with a history of diabetes mellitus within 5 years of cancer development. A protective effect of a history of some allergic conditions, hay fever, eczema and asthma, was observed, although the relative risks were not significant (p value greater than 0.10).
Primary prevention of cancer requires control of both involuntary and voluntary exposures. Involuntary exposures include carcinogens in air and water, and various forms of radiation. Often these exposures are difficult to characterise individually and difficult to study epidemiologically. Although it is unlikely that they account for more than a small proportion of cancers, it is important that we refine our techniques of study to facilitate their control. Voluntary (lifestyle) exposures are responsible for the majority of cancers. In many developed countries, tobacco accounts for approximately 30% of cancer deaths, and major public health endeavours are justified to reduce this toll. Dietary factors may be as important, with dietary fat the most important risk factor, vegetables and fruits being protective. In several studies, including a cohort study in Canada, dietary fat increases breast cancer risk, though other studies have been negative. The evidence for fat increasing the risk of colorectal is more consistent. Epidemiology has shown that secondary prevention of cancer is applicable by screening for breast cancer with mammography with or without physical examination in women age 50-69, and screening for cervix cancer in women age 25-60 with cervical cytology. Organised screening programmes are essential to ensure that a high proportion of women are screened, and that the tests are high quality with adequate quality control. Under these circumstances screening every 2 years for breast cancer and every 3 years for cervix cancer is cost-effective. Screening for other cancers cannot be recommended currently. There is a time to effect that must be recognised in planning primary or secondary prevention. Full effect of most primary activities will not be achieved for decades, screening may require a decade. Available knowledge must be applied now, however, to ensure the effect will eventually be seen, as is now occurring in some countries with the downturn in lung cancer mortality following smoking reduction in men.
alpha 2u-Globulin (alpha 2u) has been shown to accumulate in the kidneys of male rats treated with 2,2,4-trimethylpentane (TMP). 2,4,4-Trimethyl-2-pentanol (TMP-2-OH), a metabolite of TMP, is found reversibly bound to alpha 2u isolated from the kidneys of these treated rats. The objectives of the following study were to characterize the ability of [3H]TMP-2-OH to bind to alpha 2u in vitro and to determine whether other compounds that cause this protein to accumulate have the same binding characteristics. Although compounds that have been shown to cause the accumulation of alpha 2u in male rat kidneys compete in vitro with [3H]TMP-2-OH for binding to alpha 2u, they do so to varying degrees. The binding affinity (Kd) of the [3H]TMP-2-OH-alpha 2u complex was calculated to be on the order of 10(-7) M. The inhibition constant values (Ki) determined for d-limonene, 1,4-dichlorobenzene, and 2,5-dichlorophenol were all in the range 10(-4) M, whereas the Ki values for isophorone, 2,4,4- or 2,2,4-trimethyl-1-pentanol, and d-limonene oxide were determined to be in the range 10(-6) and 10(-7) M, respectively. TMP and 2,4,4- and 2,2,4-trimethylpentanoic acid did not compete for binding. This suggests that other factors, besides binding, are involved in the accumulation of alpha 2u. In this study the ability of a chemical to bind to alpha 2u was used as a measure of biological activity to assess structure-activity relationships among the chemicals tested and known to cause the accumulation of alpha 2u. The results so far suggest that binding is dependent on both hydrophobic interactions and hydrogen bonding.
Using data on potential years of life lost to ages 75 and 85, the potential effect of antiestrogens and estrogens on various competing causes of death is explored. Although for antiestrogens the beneficial effect sought is a reduction in breast cancer mortality, this could be largely eliminated by a small detrimental effect on cardiovascular disease mortality. Other competing causes of death, such as endometrial, ovarian, and liver cancer, and fractured neck of femur (as an indicator of osteoporosis), are of far less import. For estrogen use at the time of the menopause, no effect on mortality is sought. However, an adverse effect on breast cancer mortality would be of far greater significance than an effect on endometrial cancer. Indeed, the present endeavor to counter an adverse effect of estrogens on endometrial cancer by adding progestogens could be counterproductive. These competing causes of mortality have to be borne in mind in designing intervention trials.
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A sample of 176,808 Pap smears, taken from 70,236 women, was constructed from the records of a large cytopathology laboratory between 1962 and 1981. The prevalence of cervical dysplasia, based on the distribution of initial smear results, rose from 42.7 to 94.9 per 1000 during the study period. The relative risks (RR) for the manifestation of a malignancy (carcinoma in situ or worse) in a subsequent cervical smear were 1.48, 3.42, 20.9 and 71.5 for women with minimal, mild, moderate and severe dysplasia, respectively, compared with the entire cohort. The initial degree of dysplasia for women developing a malignancy was much more likely to be interpreted as moderate (RR = 5.0) or severe (RR = 42.3) than were those for controls. These results are strongly supportive of the hypothesis that the degree of dysplasia is related to the risk of development of cancer of the cervix.
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A nested case-control study was conducted within the Canadian National Breast Screening Study to examine whether there was evidence for biased reporting of past food intake. A total of 325 case patients with breast cancer and 628 matched control subjects completed a self-administered food frequency questionnaire in 1988, recalling their diets originally reported on enrollment into the National Breast Screening Study between 1982 and 1985. Recall of food items was very similar for case patients and control subjects. The magnitude of the odds ratios for the association between these food groups and breast cancer from the prospectively and retrospectively collected data was not systematically different. There was little evidence for recall bias in the reporting of past food intake from these data.
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Recent studies confirm that the only effective strategy for control of lung cancer is prevention, with abolition of smoking as the preliminary strategy. Lung cancer is beginning to decline in men, but is still rising in women, whose risk from cigarette smoking per amount smoked is now recognized to be similar to that of men. Passive smoke exposure increases risk in nonsmokers and probably smokers as well. Radon exposure increases risk but the effects in the general population are not quantified. Occupational factors continue to be evaluated while some dietary factors, especially from plant foods, are protective. There is probably a genetic contribution, but its nature is still under investigation. Prognostic factors are being evaluated with increased sophistication, with potential for contribution to stratification in clinical trials.
This nested case-control study conducted within a large dietary cohort study examined whether recall bias could explain the inconsistent results obtained in case-control and cohort studies of the association between dietary fat and breast cancer. Cases were defined as women diagnosed with breast cancer between 1982 and 1987 who had completed a self-administered food frequency questionnaire on enrollment in the cohort study between 1982 and 1985. They were matched to two controls each, and the study subjects were asked in 1988 to complete a second diet questionnaire addressing their diets at the time of enrollment. The mean nutrient intakes for 325 cases who completed the first diet questionnaire six months or more before breast cancer diagnosis and their 628 matched controls were very similar for the prospectively and retrospectively collected diet questionnaires. There was little difference in the magnitude of the odds ratios estimated from the two questionnaires for the association between breast cancer risk and these nutrients. These data do not provide evidence for recall bias in retrospectively collected nutrient data from breast cancer cases compared with their matched controls.
A nested case-control study within the Beaverlodge Uranium Miners Cohort was undertaken to assess any possible contribution of confounding by smoking and other mining experience to the risk estimate derived from the original cohort study. Next of kin have been interviewed for 46 lung cancer cases and 95 controls enrolled in the Beaverlodge Uranium Miners Cohort Study who died between 1950 and 1980. Confounding by cigarette smoking and other mining experience appears unlikely to have contributed to the relative risk coefficient for exposure to Rn decay products derived in the parent study. Data for smoking and exposure to Rn decay products are consistent with a multiplicative model, although considerable caution must be applied to this interpretation.
A retrospective questionnaire was conducted as to the risk factors for facial skin cancer with emphasis on acne and past treatments for acne, in particular use of benzoyl peroxide preparations. The response rate was 90.9% for 964 cases and 79.9% for 3856 controls. There was no association between acne and the use of any acne medication for the risk of facial skin cancer. Cases of skin cancer were significantly more likely to have used phototherapy or sunbeds than the controls (P = 0.024), and more likely to have had radiotherapy prior to diagnosis (P = 0.001). The major risk factors as determined by generalized linear interactive modelling were family history of skin cancer (odds ratio 2.68; 95% confidence interval 2.15, 3.34), light skin (1.54; 1.25, 1.89), sunburning easily (1.43; 1.16, 1.76) and Irish, Scottish, Scandinavian or German mothers (1.33; 1.11, 1.59).