Induced abortion and the risk of breast cancer.
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Abortion, Induced↗
Biomedical subjects
V M Chinchilli
Publications and source records attributed to V M Chinchilli.
Re: Induced abortion and risk for breast cancer: reporting (recall) bias in a Dutch case-control study.
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Abortion, Induced↗
Enhanced anti-proliferative activity of the combination of tamoxifen plus HER-2-neu antibody.
HER-2/neu overexpression has been associated with poor prognosis in human breast cancer. Many of these cancers are also ER-positive. A logical therapeutic approach for patients who are ER-positive and overexpress HER-2/neu may be to block both the ER and the HER-2/neu pathways. In our study, we used both the MTT tetrazolium dye assay and 3H-thymidine incorporation to measure the effects of the anti-estrogen Tamoxifen or the 4D5 anti-HER-2/neu antibody alone or in combination on the growth of BT474 human breast cancer cells which express ER and overexpress HER-2/neu. We found an enhanced inhibitory effect on cell proliferation with the combination of Tamoxifen and the antibody compared to that seen by either agent alone. This simultaneous interruption of both the ER and the HER-2/neu pathways may be relevant in the clinical treatment of patients who are both ER-positive and overexpress HER-2/neu.
Antibodies, Monoclonal↗
The multivariate assessment of bioequivalence.
We propose an approach for comparing directly the reference and test blood concentration x time profiles of subjects in a bioequivalence trial under a crossover design. We compare the test and reference profiles via the construction of two regions, namely, an acceptable region based on the reference profile and another region based on reflecting the test profile about the reference profile. Also, we describe how to construct these regions if the assay for measuring the concentration has a lower limit of detection and how to adjust the reference and test concentrations of the n subjects participating in a bioequivalence trial. If the test and reference formulations are bioequivalent, then the area displaced by the latter region should be less than the area displaced by the acceptable region. Therefore, we construct a ratio of these areas for each subject. Then we calculate upper confidence limits for quantiles, either under theassumption of lognormality or based on a bootstrapping algorithm, to investigate population and/or individual bioequivalence.
Cross-Over Studies↗
Dietary assessment using a picture-sort approach.
Food-frequency questionnaires are usually administered as a list of foods to be checked off by the respondent or interviewer. Techniques in which participants sort into categories cards on which names or pictures of foods are printed can also be used to assess food intake. Food-frequency scores were obtained from a five-category picture sort administered to 4643 men and women aged > or = 65 y in the Cardiovascular Health Study (CHS). This one-step (qualitative) assessment yielded significant associations in expected directions between frequency scores and sex, age, race or ethnicity, body mass index, and use of a special diet. In the two-step (semiquantitative) version of this instrument, an interviewer documented specific frequencies and portion-size information for the foods in each sorting category. A substudy of the two-step version with 96 CHS participants indicated relative validity similar to that of conventionally administered food-frequency questionnaires. The one-step version may be broadly applicable to situations in which general food-pattern data can be informative and cost and time limitations are great. When it is feasible, the two-step picture sort may offer certain methodologic advantages because respondents have a chance to change their responses and the format may simplify the cognitive-response task. Sorting or picture-sort procedures deserve systematic attention in research on dietary assessment methods.
Aged↗
Dietary caffeine intake and bone status of postmenopausal women.
Dietary caffeine intake has been suggested as a risk factor for bone loss in postmenopausal women. We measured the bone density of both hips and the total body in 138 healthy, postmenopausal women aged 55-70 y who had either never used hormone replacement therapy (HRT) or had used HRT for < 1 y. In this cross-sectional study, participants were stratified according to their reported current and long-time caffeinated beverage use into one of three groups: low [0-2 cups (180 mL, or 6 oz per cup) caffeinated coffee per day], moderate (3-4 cups caffeinated coffee per day), or high (> or = 5 cups caffeinated coffee per day). Caffeine intake was measured from diet records and by gas chromatography of each subject's brewed, caffeinated beverages. No association between caffeine intake and any bone measurement was observed. The anthropometric and nutrient intakes of the three groups were similar. Compared with caffeine intake based on chemical analysis of brewed beverages, 3-d prospective food records and computer-assisted analysis overestimated caffeine intake by nearly two-thirds. In conclusion, the habitual dietary caffeine intake of this cohort of 138 postmenopausal women ranged from 0-1400 mg/d and was not associated with total body or hip bone mineral density measurements. This study does not support the notion that caffeine is a risk factor for bone loss in healthy postmenopausal women.
Absorptiometry, Photon↗
Simulated Bennett fracture treated with closed reduction and percutaneous pinning. A biomechanical analysis of residual incongruity of the joint.
UNLABELLED: Contact area and contact pressure within the trapeziometacarpal joint were measured during static and dynamic loading in a cadaver model. The measurements were repeated after a Bennett fracture had been simulated with use of an osteotomy of the metacarpal base. The beak fragment was recessed two millimeters and was fixed in close apposition to maintain the integrity of the palmar beak ligament, and contact area and contact pressure were measured during lateral pinch. Despite the resulting articular incongruity, the mean total contact area of the joint surface increased from 15.8 to 25.8 square millimeters (63 per cent) in all specimens after simulation of the Bennett fracture (p = 0.02), and it shifted dorsally in moderately osteoarthrotic and non-osteoarthrotic specimens. The mean contact area in the palmar region of the joint surface decreased, from 58 to 25 per cent of the total area (p = 0.04); that in the central region increased, from 28 to 52 per cent (p = 0.05); and that in the dorsal region increased, but not significantly with the numbers available, from 14 to 24 per cent (p = 0.18). No pathological concentration of contact pressure was seen at the margin of the articular step-off. The changes in area and pressure reflect an unloading of the metacarpal beak, where osteoarthrotic degeneration most commonly occurs. CLINICAL RELEVANCE: There is no biomechanical basis for predisposition to post-traumatic osteoarthrosis after a Bennett fracture with a small palmar-beak component and a residual two-millimeter articular step-off, provided that the fragments of the shaft and the beak heal in close apposition. This suggests that reduction of the metacarpal shaft relative to the trapezium and the beak fragment, rather than strict anatomical restoration of the joint surface, should be the priority of treatment. Bennett fractures that can be reduced with articular incongruity of no more than two millimeters may be treated satisfactorily with closed reduction and percutaneous pinning without the need for open anatomical reduction and internal fixation of the joint surface.
Carpal Bones↗
Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. Asthma Clinical Research Network.
BACKGROUND: Inhaled beta-agonists are the most commonly used treatment for asthma, but data suggest that regularly scheduled use of these agents may have deleterious effect on the control of asthma. We compared the effects of regularly scheduled use of inhaled albuterol with those of albuterol used only as needed in patients with mild chronic, stable asthma. METHODS: In a multicenter, double-blind study, we randomly assigned 255 patients with mild asthma to inhale albuterol either on a regular schedule (126 patients) or only as needed (129 patients). The patients were followed for 16 weeks. RESULTS: The primary outcome indicator, peak expiratory air flow measured in the morning, did not change significantly during the treatment period in the scheduled (416 liters per minute after the run-in period and 414 liters per minute after the treatment period) or the as-needed (424 liters per minute at both times) treatment groups (P=0.71). There were no significant differences between the two groups in peak flow variability, forced expiratory volume in one second, the number of puffs of supplemental albuterol needed, asthma symptoms, asthma quality-of-life score, or airway responsiveness to methacholine. The statistically significant differences between the groups in evening peak flow and in the short-term bronchodilator response to inhaled albuterol were small and judged to be clinically unimportant. CONCLUSIONS: In patients with mild asthma, neither deleterious nor beneficial effects derived from the regular use of inhaled albuterol beyond those derived from use of the drug as needed. Inhaled albuterol should be prescribed for patients with mild asthma on an as-needed basis.
Administration, Inhalation↗
Design and analysis of intra-subject variability in cross-over experiments.
Recently, interest has grown in the development of inferential techniques to compare treatment variabilities in the setting of a cross-over experiment. In particular, comparison of treatments with respect to intra-subject variability has greater interest than has inter-subject variability. We begin with a presentation of a general approach for statistical inference within a cross-over design. We discuss three different statistical models where model choice depends on the design and assumptions about carry-over effects. Each model incorporates t-variate random subject effects, where t is the number of treatments. We develop maximum likelihood (ML) and restricted maximum likelihood (REML) approaches to derive parameter estimators and we consider a special case in which closed-form expressions for the variance component estimators are available. Finally, we illustrate the methodologies with the analysis of data from three examples.
Area Under Curve↗
The effect of calcium supplementation and Tanner stage on bone density, content and area in teenage women.
One hundred and twelve Caucasian girls, 11.9 +/- 0.5 years of age at entry, were randomized into a 24-month, double-masked, placebo-controlled trial to determine the effect of calcium supplementation on bone mineral content, bone area and bone density. Supplementation was 500 mg calcium as calcium citrate malate (CCM) per day. Controls received placebo pills, and compliance of both groups averaged 72%. Bone mineral content, bone mineral area and bone mineral density of the lumbar spine and total body were measured by dual energy X-ray absorptiometry (DXA). Calcium intake from dietary sources averaged 983 mg/day for the entire study group. The supplemented group received, on average, an additional 360 mg calcium/day from CCM. At baseline and after 24 months, the two groups did not differ with respect to anthropometric measurements, urinary reproductive hormone levels or any measurement of pubertal progression. The supplemented group had greater increases of total body bone measures: content 39.9% versus 35.7% (p = 0.01), area 24.2% versus 22.5% (p = 0.15) and density 12.2% versus 10.1% (p = 0.005). Region-of-interest analyses showed that the supplemented group had greater gains compared with the control group for bone mineral density, content and area. In particular, in the lumbar spine and pelvis, the gains made by the supplemented group were 12%-24% greater than the increases made by the control group. Bone acquisition rates in the two study groups were further compared by subdividing the groups into those with below- or above-median values for Tanner score and dietary calcium intake. In subjects with below-median Tanner scores, bone acquisition was not affected by calcium supplementation or dietary calcium level. However, the calcium supplemented subjects with above-median Tanner had higher bone acquisition rates than the placebo group with above-median Tanner scores. Relative to the placebo group, the supplemented group had increased yearly gains of bone content, area and density which represented about 1.5% of adult female values. Such increases, if held to adult skeletal maturity, could provide protection against future risk of osteoporotic fractures.
Absorptiometry, Photon↗
Picture-sort method for administering a food frequency questionnaire to older adults.
OBJECTIVE: To assess the validity of a picture-sort approach to administering the National Cancer Institute food frequency questionnaire to older adults. DESIGN: A picture-sort interview was conducted in each respondent's home. After the picture sort, a 24-hour recall interview was administered on the same occasion. Five additional in-home recall interviews were subsequently conducted at approximately 1-month intervals. SUBJECTS/SETTING: Forty-seven female and 49 male volunteers aged 66 to 100 years were recruited from among Cardiovascular Health Study participants from Maryland and North Carolina. MAIN OUTCOME MEASURES: Estimates from the picture sort and the recall for intakes of macronutrients, cholesterol, fiber, and selected vitamins and minerals exclusive of supplements. STATISTICAL ANALYSES: Comparison of means estimated by the two methods and correlation analyses were used. Correlations were adjusted under varied assumptions about the nature of the information contained in the six 24-hour recalls relative to respondents' usual intakes. RESULTS: After correction for attenuation, Pearson correlation coefficients for macronutrients ranged from .41 for protein to .74 for saturated fat and cholesterol. For vitamins and minerals, correlations ranged from .26 for beta carotene to .62 for calcium. APPLICATIONS: Picture-sort estimates of mean nutrient intakes were comparable with estimates based on 24-hour recalls, and correlations with reference data were similar to those reported in the literature for conventionally administered food frequency questionnaires. This dietary assessment method may, therefore, offer a way to simplify or structure responses to improve ease of administration and increase respondents' liking for the interview without loss of data quality.
Aged↗
The assessment of individual and population bioequivalence.
We develop a statistical methodology for the assessment of individual bioequivalence when a crossover design is invoked. The location parameters for our model consist of population-averaged parameters for formulation, population-averaged parameters for nuisance effects (sequence, period, carryover, etc.), and subject-specific parameters for formulation. We do not impose any distributional assumptions other than the existence of first- and second-order moments. We derive unbiased estimators for all of the parameters in the model and construct subject-specific bioequivalence scores which exclude the effects of the nuisance parameters. We assess individual bioequivalence by constructing distribution-free tolerance intervals based on the sample of bioequivalence scores.
Calcium Channel Blockers↗
Induced abortion as an independent risk factor for breast cancer: a comprehensive review and meta-analysis.
STUDY OBJECTIVE: To ascertain, from the published reports to date, whether or not a significantly increased risk of breast cancer is specifically attributable to a history of induced abortion, independent of spontaneous abortion and age at first full term pregnancy (or first live birth); to establish the relative magnitude of such risk increase as may be found, and to ascertain and quantify such risk increases as may pertain to particular subpopulations of women exposed to induced abortion; in particular, nulliparous women and parous women exposed before compared with after the first full term pregnancy. INCLUDED STUDIES: The meta-analysis includes all 28 published reports which include specific data on induced abortion and breast cancer incidence. Since some study data are presented in more than one report, the 28 reports were determined to constitute 23 independent studies. Overall induced abortion odds ratios and odds ratios for the different subpopulations were calculated using an average weighted according to the inverse of the variance. An overall unweighted average was also computed for comparison. No quality criteria were imposed, but a narrative review of all included studies is presented for the reader's use in assessing the quality of individual studies. EXCLUDED STUDIES: All 33 published reports including data on abortion and breast cancer incidence but either pertaining only to spontaneous abortion or to abortion without specification as to whether it was induced or spontaneous. These studies are listed for the reader's information. RESULTS: The overall odds ratio (for any induced abortion exposure; n = 21 studies) was 1.3 (95% confidence interval of 1.2, 1.4). For comparison, the unweighted overall odds ratio was 1.4 (1.3,1.6). The odds ratio for nulliparous women was 1.3 (1.0,1.6), that for abortion before the first term pregnancy in parous women was 1.5 (1.2,1.8), and that for abortion after the first term pregnancy was 1.3 (1.1,1.5). CONCLUSIONS: The results support the inclusion of induced abortion among significant independent risk factors for breast cancer, regardless of parity or timing of abortion relative to the first term pregnancy. Although the increase in risk was relatively low, the high incidence of both breast cancer and induced abortion suggest a substantial impact of thousands of excess cases per year currently, and a potentially much greater impact in the next century, as the first cohort of women exposed to legal induced abortion continues to age.
Abortion, Induced↗
Issues in the use of inhaled glucocorticoids. The Asthma Clinical Research Network.
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Administration, Inhalation↗
A weighted concordance correlation coefficient for repeated measurement designs.
The need to quantify agreement between two raters or two methods of measuring a response often arises in research. Kappa statistics (unweighted and weighted) are appropriate when the data are nominal or ordinal, whereas the concordance correlation coefficient is more appropriate when the data are measured on a continuous scale. We develop weighted product-moment and concordance correlation coefficients which are applicable for repeated measurements study designs. We consider two distinct situations in which the repeated measurements are paired or unpaired over time. We illustrate the methodology with examples comparing (1) two assays for measuring serum cholesterol, (2) two estimates of dietary intake, from a food frequency questionnaire and dietary recalls, and (3) two measurements of percentage body fat, from skinfold calipers and dual energy x-ray absorptiometry.
Absorptiometry, Photon↗
The correlation coefficient in the interpretation of laboratory data.
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Chemistry, Clinical↗
Nonadditive developmental toxicity in mixtures of trichloroethylene, Di(2-ethylhexyl) phthalate, and heptachlor in a 5 x 5 x 5 design.
In order to identify nonadditive effects on development, three compounds were combined using five dosages of each agent (a 5 x 5 x 5 full-bacterial design). Trichloroethylene (TCE), di(2-ethylhexyl) phthalate (DEHP), and heptachlor (HEPT), in corn oil, were administered by gavage to Fischer-344 rats on Gestation Days 6-15. Dose levels were 0, 10.1, 32, 101, and 320 mg/kg/day for TCE; 0, 24.7, 78, 247, and 780 mg/kg/day for DEHP; and 0, 0.25, 0.8, 2.5, and 8 mg/kg/day for HEPT. The dams were allowed to deliver and their pups were weighed and examined postnatally. Maternal death showed no main effects but DEHP and HEPT were synergistic. For maternal weight gain on Gestational Days 6-8, main effects for all three agents were observed, as well as 6-8 main effects for all three agents were observed, as well as TCE-DEHP synergism, and DEHP-HEPT antagonism. Maternal weight gain on Gestational Days 6-20 adjusted for litter weight showed main effects for TCE and HEPT, but no interactions. Main effects for all three agents were evident for full-litter resorptions and prenatal loss. The HEPT main effects were unexpected and were interpreted as reflecting potentiation by HEPT of the other agents. For full-litter loss, the TCE-HEPT and DEHP-HEPT interactions were antagonistic, perhaps due to a "ceiling" effect. For prenatal loss, the TCE-DEHP interaction was synergistic. Postnatal loss showed DEHP and HEPT main effects but no interaction. Analysis of pup weights on Day 1 revealed TCE and DEHP main effects and DEHP-HEPT antagonism; on Day 6, DEHP and HEPT main effects, DEHP-HEPT antagonism, and TCE-DEHP synergism were evident. Microphthalmia and anophthalmia incidences revealed TCE and DEHP main effects but no interactions. This extensive examination of a full-factorial design elucidates the complexities of studying and interpreting mixture toxicity. The data are available for further analysis.
Abnormalities, Drug-Induced↗
Elevated serum c-erbB-2 antigen levels and decreased response to hormone therapy of breast cancer.
PURPOSE: Decisions concerning the use of hormone therapy to treat metastatic breast cancer are made on the basis of the presence of estrogen receptor (ER). Despite the presence of ER, half of patients will not respond to hormone treatment. The purpose of this study was to determine the effect of overexpression of HER-2/neu on the response to hormone therapy. PATIENTS AND METHODS: Sera from 300 metastatic breast cancer patients with ER-positive (ER+), ER status unknown, or ER-/progesterone receptor-positive (PR+) randomized to receive second-line hormone therapy with either megestrol acetate or fadrozole were evaluated. An enzyme immunoassay (EIA) specific for the extracellular domain of the c-erbB-2 (HER-2/neu) oncogene product was used to detect serum levels. RESULTS: Fifty-eight patients (19.3%) had elevated serum c-erbB-2 protein levels, using a selected cut-point of 30 U/mL. The response rate (complete responses [CRs] plus partial responses [PRs] plus stable disease [S]) to endocrine therapy was 40.9% in 242 patients with low serum c-erbB-2 levels and only 20.7% in 58 patients with elevated serum c-erbB-2 levels (P = .004). The median duration of treatment response was longer in the group with low serum c-erbB-2 levels (15.5 months) compared with the group with elevated serum c-erbB-2 levels (11.6 months). Survival was also significantly shorter in patients with elevated serum c-erbB-2 levels (P < .0001). CONCLUSION: Patients with ER+/c-erbB-2+ metastatic breast cancer are less likely to respond to hormone treatment than ER+/c-erbB-2- patients. Their survival duration is also shorter.
Adult↗