Biomedical subjects
A B Miller
Publications and source records attributed to A B Miller.
Analysis of direct and inverted DJH rearrangements in a human Ig heavy chain transgenic minilocus.
D to JH rearrangement can occur either by a deletional or an inversional mechanism. In this study, we have analyzed deletional and inversional D to JH recombination in a human Ig heavy chain transgenic minilocus. The analysis of these events in a transgenic minilocus rather than in vivo in the human is simplified by the presence of a limited number of well defined VH, D, and JH gene segments in the minilocus. We show that in the transgenic minilocus, all D gene segments can be rearranged by deletion and virtually all can be rearranged by inversion. We also show that depending upon the D gene segment, rearrangement by deletion occurs approximately 1 to 1000 times more frequently than rearrangement by inversion. Our data suggest that in vivo, signal and coding end sequences are the major influences on the rearrangement frequency of a particular gene segment in a given orientation rather than its position within the transgenic locus. Additionally, our data indicate that intronic and recombination signal sequences are involved in the bias for deletion over inversion rather than the recombinase machinery itself.
Quantitative classification of mammographic densities and breast cancer risk: results from the Canadian National Breast Screening Study.
BACKGROUND: The radiographic appearance of the female breast varies from woman to woman depending on the relative amounts of fat and connective and epithelial tissues present. Variations in the mammographic density of breast tissue are referred to as the parenchymal pattern of the breast. Fat is radiologically translucent or clear (darker appearance), and both connective and epithelial tissues are radiologically dense (lighter appearance). Previous studies have generally supported an association between parenchymal patterns and breast cancer risk (greater risk with increasing densities), but there has been considerable heterogeneity in risk estimates reported. PURPOSE: Our objective was to determine the level of breast cancer risk associated with varying mammographic densities by quantitatively classifying breast density with conventional radiological methods and novel computer-assisted methods. METHODS: From the medical records of a cohort of 45,000 women assigned to mammography in the Canadian National Breast Cancer Screening Study (NBSS), a multicenter, randomized trial, mammograms from 354 case subjects and 354 control subjects were identified. Case subjects were selected from those women in whom histologically verified invasive breast cancer had developed 12 months or more after entering the trial. Control subjects were selected from those of similar age who, after a similar period of observation, had not developed breast cancer. The mammogram taken at the beginning of the NBSS was the image used for measurements. Mammograms were classified into six categories of density, either by radiologists or by computer-assisted measurements. All radiological classification and computer-assisted measurements were made using one craniocaudal view from the breast contralateral to the cancer site in case subjects and the corresponding breast of control subjects. All P values represent two-sided tests of statistical significance. RESULTS: For all subjects, there was a 43% increase in the relative risk (RR) between the lower and the next higher category of density, as determined by radiologists, and there was a 32% increase as determined by the computer-assisted method. For all subjects, the RR in the most extensive category relative to the least was 6.05 (95% confidence interval [CI] = 2.82-12.97) for radiologists and 4.04 (95% CI = 2.12-7.69) for computer-assisted methods. Statistically significant increases in breast cancer risk associated with increasing mammographic density were found by both radiologists and computer-assisted methods for women in the age category 40-49 years (P = .005 for radiologists and P = .003 for computer-assisted measurements) and the age category 50-59 years (P = .002 for radiologists and P = .001 for computer-assisted measurements). CONCLUSION: These results show that increases in the level of breast tissue density as assessed by mammography are associated with increases in risk for breast cancer.
Alan B. Miller, Chairman and CEO, Universal Health Services. Interview by Kevin Lumsdon.
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Strategies for global control of cervical cancer.
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An epidemiological perspective on cancer screening.
OBJECTIVE: To provide an epidemiological perspective on cancer screening. METHODS AND RESULTS: For screening to be applicable as public health policy, the disease has to be an important health problem, there has to be evidence that early detection results in improved outcome, that adequate facilities for diagnosis, therapy, and subsequent management of true and false positives are available, that screening is acceptable to the target groups, and that programs are cost effective in the population. Although it is relatively easy to demonstrate that screening results in earlier detection of cancer, survival is a biassed measure of its effectiveness. The only valid design to study the efficacy of screening is the randomized trial. Cervical cancer screening was introduced before these requirements were recognized. There is, however, good evidence of its effectiveness; the challenge is to make programs cost effective. For breast cancer, studies show little or no evidence of effectiveness of mammography screening in women age 40-49. For women age 50-69, there is good evidence of effectiveness in trials comparing screening with no screening. These support the introduction of population-based programs for this age group. The challenge is to put the research results into practice to ensure cost-effective programs. For colo-rectal cancer, there is some evidence that both screening sigmoidoscopy and the fecal occult blood test will reduce mortality. It is not clear, however, whether programs using either or both these tests will be cost effective. For lung cancer, there is good evidence of no benefit for screening. For ovarian, prostate, mouth, and skin cancer, although early detection has been demonstrated, there is no evidence of reduction in mortality in the target groups; indeed, prostate screening could result in lowering the overall quality of life. CONCLUSION: Screening, which offers a fairly rapid return from appropriate investment, should remain part of our armamentarium for cancer control.
Screening for gastrointestinal cancer.
No new sound evidence pointing to the effectiveness of screening for any gastrointestinal cancer has become available in the past year. Although recommended in Japan, screening for gastric cancer is expensive, and in a study in Venezuela it was found to be ineffective. The sensitivity of the standard hemoccult test for fecal occult blood is low; variants have improved sensitivity but relatively poor specificity remains. A major review of the evidence on colorectal cancer screening concluded that it was not recommended as part of the periodic health examination. Colorectal cancer mortality is falling in North America, possibly due to prevention (dietary modification) rather than screening. As dietary modification has benefits on other cancers and diseases, it is preferable as a colorectal cancer control strategy. Screening for other gastrointestinal cancers cannot be recommended.
Perspectives on cancer prevention.
Cancer prevention is a major component of cancer control, which also comprises screening, treatment, rehabilitation and palliative care. Preventive approaches need to be congruent with those adopted for other chronic diseases, with a major impact in reduction of incidence and mortality of many common cancers to be expected from smoking control and dietary modification. Increasing interest is now being paid to other environmental causes of cancer, and to gene-environment interactions. However, one of the major research needs remains the evaluation of better ways to convince people to make the necessary changes in their lifestyle that will reduce their risk of cancer.
Primary prevention of cancer: needs and opportunities for research.
Strategies for cancer prevention generally come from observational epidemiology and must include monitoring for the effects of the actions. The measurement-iterative loop allows us to refine our approach to cancer prevention. When available, clinical trials can also provide strategies for control. Exposure-specific strategies are described; these are such things as health promotion and behavior modification, legislative approaches, treatment for addiction, changes in the food supply, chemoprevention, occupational and environmental regulation, immunization, identification of persons with enhanced genetic susceptibility, and improved surveillance systems. For some exposures such as tobacco, zero exposure is the goal. For others, prudent avoidance or exposures as low as reasonably achievable are appropriate approaches. Research on how to impact deeply ingrained lifestyle and cultural factors has high priority.
Failures of cervical cancer screening.
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The Canadian Childhood Cancer Control Program.
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Re: May we agree to disagree, or how do we develop guidelines for breast cancer screening in women?
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Pre-morbid body size and the prognosis of women with breast cancer.
Obesity has been associated with poor prognosis of breast cancer, but studies investigating indicators of adiposity, independent of height, such as skinfold thickness and weight/height ratio, have been limited. From a cohort of 89,835 women in the National Breast Screening Study, data on histologically confirmed, incident cases of invasive carcinoma of breast, diagnosed between January 1981 to June 1992, were analyzed. Body measurements were taken at enrollment and other risk-factor information from a self-administered questionnaire completed prior to diagnosis of the breast cancer. Mortality data were obtained by linkage to Statistics Canada, provincial cancer registries, and annual follow-up of cases through physicians. Of the 5 measures of body size studied among cases, poor prognosis was associated with higher triceps skinfold thickness only. With every 5 mm increase in skinfold, the risk of dying increased approximately 12% (relative risk, 1.12; 95% confidence intervals, 1.01 to 1.24) in the 1033 cases examined and adjusted for age at diagnosis, number of positive axillary nodes involved, and body weight. Compared with women in the lowest quartile of skinfold thickness, women in the fourth quartile had a relative risk (RR) of 1.64 (95% CI, 0.99 to 2.73). None of the other measures--weight, height, body mass index or weight/height ratio--reached any statistical significance. Since the reliability and validity of skinfold measures used in our study were never established, and no data were available for changes in body size after diagnosis, the results of this study on skinfold thickness should be used only as indicative of a need for further studies.
Premorbid diet and the prognosis of women with breast cancer.
BACKGROUND: Consumption of a high-fat diet has been associated with poor survival in breast cancer patients. However, studies examining this association are limited and have not used adjustment of energy in their estimates. PURPOSE: The effect of usual diet before diagnosis of breast cancer on the risk of dying of breast cancer was examined in a cohort of women with breast cancer from the National Breast Screening Study (NBSS) in Canada. METHODS: From a cohort of 89,835 women in the NBSS, a total of 1270 histologically confirmed cases of invasive carcinoma of the breast were identified by active follow-up, supplemented by passive follow-up involving record linkage to provincial cancer registries. Of these, 678 case patients who had completed a diet history and were diagnosed from January 1982 up to June 1992 formed the cohort for this investigation. Diet was ascertained from a self-administered diet-history questionnaire. Mortality data were obtained by linkage to the Canadian Mortality Data Base of Statistics Canada, provincial cancer registries, and annual follow-up of cases through physicians. Risk of dying and survival probabilities were estimated by the Cox proportional hazards method and the actuarial life-table method. RESULTS: There were 83 deaths in this study cohort of 678 women; 76 deaths were due to breast cancer, and the remaining seven resulted from other causes. The 5-year survival rate was 90%. For every 5% increase in energy from saturated fat, the risk of dying of breast cancer increased by 50% (hazard ratio = 1.50; 95% confidence interval [CI]: 1.08-2.08). No significant increase in risk was seen with total fat intake (hazard ratio = 1.21; 95% CI = 0.91-1.61) or oleic acid intake (hazard ratio = 1.25; 95% CI = 0.90-1.74). There was a lower risk of dying of breast cancer in the highest quartiles of beta carotene intake (hazard ratio = 0.48; 95% CI = 0.23-0.99) and vitamin C intake (hazard ratio = 0.43; 95% CI: 0.21-0.86); both vitamins showed a significant dose-response relationship (P for trend, < or = .05). These effects varied with menopausal status at diagnosis and tumor characteristics. CONCLUSIONS: These results suggest an increased risk of dying of breast cancer with higher intakes of saturated fat before diagnosis and slightly reduced risk with higher intakes of beta carotene and vitamin C. IMPLICATIONS: More attention should be paid to premorbid dietary habits in relation to breast cancer prognosis. Further studies, however, need to be done with full ascertainment of dietary changes prior to and subsequent to diagnosis.
Re: "A comparison of prospective and retrospective assessments of diet in the study of breast cancer".
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Incidence and mortality from breast cancer in the Mama Program for Breast Screening in Finland, 1973-1986.
BACKGROUND: A cohort of women enrolled in the Mama breast self-examination-(BSE) containing breast screening program in Finland from 1973 through 1975 (with BSE used for screening and mammography for diagnosis) was studied. METHODS: Twenty-eight thousand seven hundred eighty-five women who returned calendars recording their practice of BSE over a 2-year period have been followed by linkage with the records of the Finnish Cancer Registry through 1986. The incidence of and mortality from breast cancer was compared with that expected in the Finnish population based on a model incorporating Finnish national data for breast cancer incidence and case fatality. RESULTS: Breast cancer incidence was higher than expected (a rate ratio of 1.19 over all ages). The stage distribution of cases was not different from that expected from Finnish cancer registry data for 1980, but the breast cancer mortality was lower than expected (a rate ratio of 0.75). The latter difference occurred mainly in Years 3-6 of the follow-up period. The effect seemed similar in women under and over the age of 50 years. The cohort was of higher educational status than the Finnish population, and the mortality from all causes was lower than the general Finnish population, an effect seen in previous studies of compliers with breast screening. CONCLUSIONS: The reduction in mortality from breast cancer in the study cohort is consistent with an effect of the BSE-containing Mama program, though selection bias, inherent in any observational study of screening, provided an alternative explanation for the findings.
Cancer risks associated with occupational exposure to magnetic fields among electric utility workers in Ontario and Quebec, Canada, and France: 1970-1989.
To determine whether occupational exposure to magnetic fields of 50-60 Hz was associated with cancer among electric utility workers, the authors used a case-control design nested within three cohorts of workers at electric utilities: Electricité de France--Gaz de France, 170,000 men; Ontario Hydro, 31,543 men; and Hydro-Québec, 21,749 men. During the observation period, 1970-1989, 4,151 new cases of cancer occurred. Each participant's cumulative exposure to magnetic fields was estimated based on measurements of current exposure of 2,066 workers performing tasks similar to those in the cohorts using personal dosimetry. Estimates were also made of past exposure based on knowledge of current loading, work practices, and usage. Workers who had more than the median cumulative exposure to magnetic fields (3.1 microtesla (microT)-years) had a higher risk for acute nonlymphoid leukemia (odds ratio (OR) = 2.41, 95% confidence interval (CI) 1.07-5.44). The same observation holds for acute myeloid leukemia (OR = 3.15, 95% CI 1.20-8.27). There was also an elevated risk for mean exposure above 0.2 microT (acute nonlymphoid leukemia, OR = 2.36, 95% CI 1.00-5.58; acute myeloid leukemia, OR = 2.25, 95% CI 0.79-6.46). However, there were no clear dose-response trends with increasing exposure and no consistency among the three utilities. Men whose cumulative exposure to magnetic fields was above the 90th percentile (15.7 microT-years) had an elevated risk for brain cancer (OR = 1.95, 95% CI 0.76-5.00) that was not statistically significant. No association with magnetic fields was observed for any of the other 29 types of cancer studied, including skin melanoma, male breast cancer, and prostate cancer. Controlling for potential confounding factors did not change the results.
Biased utilization of DHQ52 and JH4 gene segments in a human Ig transgenic minilocus is independent of antigenic selection.
We have assessed the effect of antigenic selection on human Ig heavy chain D and JH gene segment utilization in mice that contain transgenes composed of 2 VH (psi VH3-105 and VH5-251), 10 D, 6 JH, C mu, and C gamma 1 human gene segments. Human heavy chains using the functional VH5-251 gene segment are expressed in the serum and on the surface of murine B cells. The second VH gene segment (psi VH3-105) is not expressed as a protein but is rearranged and transcribed into mRNA. We previously reported that the functional VH5-251 mu transcripts preferentially used the DHQ52 and JH4 gene segments similar to their use in the human repertoire. Here, we demonstrate that the nonfunctional (psi VH3-105) gene segment shows the same bias in D and JH gene segment utilization. Because transcripts using the pseudo-VH gene segment cannot be subjected to antigenic selection, we conclude that the restricted repertoire observed is Ag independent. Analysis of pseudo VH gene segment recombination products reveals no bias in D gene segment reading frame utilization. Finally, we demonstrate that in the human transgene coding sequence complementarities can affect the recombination site and that D inversion is common.