Familial clustering of breast and prostate cancers and risk of postmenopausal breast cancer.

BACKGROUND: Previous studies have suggested that cancers of the breast and prostate cluster in families and that the presence of both diseases in a family may be associated with increased risk of breast cancer. PURPOSE: Our purpose was to evaluate whether 1) prostate cancer aggregates in families with postmenopausal breast cancer, 2) families with cancers of the breast and prostate are the same ones as families with cancers of the breast and ovary, and 3) a family history of prostate cancer is associated with increased risk of postmenopausal breast cancer. METHODS: We analyzed data from a large prospective cohort study of Iowa women that were (at baseline) aged 55-69 years in 1986. At the third follow-up survey in 1992, self-reported data on family history of breast, ovarian, and prostate cancers in parents and siblings were provided by 30,883 women. Additional information was collected to ascertain whether the age-of-onset of breast cancer in mothers or sisters was before or after the age of 45 years. Cancer occurrence was documented using the State Health Registry of Iowa. RESULTS: History of prostate cancer in their father or a brother was reported by 3384 (11.0%) of the women, and a total of 4090 women (13.2%) reported breast cancer in their mother or a sister. A positive family history of both cancers was reported by 556 women, significantly (two-sided P < .001) greater than the 457 women expected if the family histories were independent. The aggregation of breast, prostate, and ovarian cancers was reported by 22 participants, greater than the 2.7 expected (two-sided P < .0001). During 6 years of follow-up, 578 breast cancers were identified in the cohort at risk. Compared with women without a family history of either cancer, women with a family history of breast cancer had a relative risk (RR) of 1.37 (95% confidence interval [CI] = 1.06-1.79) if the affected relative had onset after the age of 45 years, and an RR of 1.71 (95% CI = 1.13-2.61) if the affected relative had onset at or before the age of 45. A family history of prostate cancer in the absence of a family history of breast cancer was associated with an RR of 1.19 (95% CI = .90-1.56). However, a family history of both breast and prostate cancers was associated with RRs of 2.06 (95% CI = 1.23-3.45) and 2.35 (95% CI = .97-5.67) for breast cancer onset in relatives of greater than 45 and less than or equal to 45 years, respectively. CONCLUSIONS: These observations are concordant with recent reports that suggest a shared familial risk (inherited or environmental) for these hormone-dependent malignancies.

Synergistic effect between alcohol and estrogen replacement therapy on risk of breast cancer differs by estrogen/progesterone receptor status in the Iowa Women's Health Study.

Two cohort studies have reported that alcohol and estrogen replacement therapy (ERT) act synergistically to increase the incidence of breast cancer. Possible interactions between alcohol consumption and family history of breast cancer or body mass index were also reported in the Iowa Women's Health Study data. In the Iowa Women's Health Study cohort, alcohol appears to be associated only with estrogen receptor-negative (ER-)/progesterone receptor-negative (PR-) breast cancers. Therefore, we investigated whether the interactions between alcohol and other risk factors differ according to ER/PR status. In January 1986, participants completed a questionnaire that included alcohol intake and other information. Through 1992, 939 breast cancer cases occurred among 37,105 postmenopausal women at risk. Cox proportional hazards regression was used to compute adjusted relative risks and to test for multiplicative interactions. Relative risks of ER+/PR+, ER+/PR-, and ER-/PR- breast cancer for women who consumed > or = 4.0 g of ethanol/day and reported ever using ERT compared to abstainers who never used ERT were 1.8, 1.3, and 2.6, respectively. Relative risks of ER+/PR+, ER+/PR-, and ER-/PR- breast cancer associated with any alcohol intake and a positive family history of breast cancer compared to abstainers with no family history of breast cancer were 1.7, 0.8, and 3.1, respectively. Relative risks of ER+/PR+, ER+/PR-, and ER-/PR- breast cancer associated with the highest quintile of body mass index and drinking > or = 4.0 g of ethanol/day compared to abstainers in the lower four-fifths of body mass index were 0.9, 1.8, and 2.0, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary fat and risk of breast cancer according to hormone receptor status.

The association of dietary fat with breast cancer in prospective cohort studies has generally been weak and not statistically significant. However, these studies have not considered whether the risk related to fat intake may differ according to estrogen or progesterone receptor status. Dietary habits and other breast cancer risk factors were assessed by mailed questionnaire in January 1986 in 34,388 postmenopausal Iowa women. Through 1991, 724 incident breast cancer cases were ascertained in this cohort using the Iowa cancer registry. Joint estrogen and progesterone receptor status was determined for 479 (66%) breast cancers. For tumors that were positive for both estrogen and progesterone receptors (ER+/PR+) (n = 329), age- and energy-adjusted relative risks for breast cancer adjusted from lowest to highest third of fat intake were 1.0, 1.05, and 1.22 (P trend = 0.14). Corresponding risks for ER+/PR- tumors (n = 75) were 1.0, 0.85, and 1.05 (P trend = 0.86) and for ER-/PR- tumors (n = 61) were 1.0, 1.06, and 0.73 (P trend = 0.68). Only 14 cases were classified as having ER-/PR+ tumors. Adjustment for other breast cancer risk factors did not appreciably alter these findings. There was a suggestion that dietary fat may be associated with ER+/PR+ breast cancers and not other breast cancers. These results are also consistent with an interpretation of no association between dietary fat with breast cancer, regardless of hormone receptor status. It has been suggested that etiological studies of breast cancer should investigate associations according to receptor status. This study provides evidence of a subset of breast cancers that may be related to dietary factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Progesterone and estrogen receptors and mammary neoplasia in the Iowa Women's Health Study: how many kinds of breast cancer are there?

Characterization of breast tumors on both estrogen receptor (ER) and progesterone receptor (PR) status suggests distinct biological and clinical profiles. We hypothesized that these tumor subtypes might also show specific differences in their relations with epidemiologic risk factors. Risk factors were assessed via a questionnaire mailed in January 1986 to 37,105 cancer-free women, ages 55-69 years: the Iowa Women's Health Study. To the end of 1992 (241,627 person-years of follow-up), 939 incident breast cancers were ascertained by the Iowa population-based Surveillance, Epidemiology, and End Results Cancer Registry. Joint ER and PR status was determined on a total of 610 (65%) tumors. Three patterns of association were seen in relation to epidemiologic risk factors. Endogenous hormone exposure variables--parity, age at first birth, age at menarche, body mass index, and body fat distribution as defined by waist-to-hip ratio--showed their expected pattern of associations only with PR+ breast cancers. In age- adjusted and polychotomous logistic regression analyses, both ER-PR- and ER+PR- breast cancers showed evidence of an inverted pattern of associations with several risk factors compared with that seen for ER+PR+ cancers [including parity (ER-PR-), waist-to-hip ratio (ER-PR-), body mass index (both), body mass index at age 18 years (ER-PR-), history of bilateral oophorectomy (ER+PR-), and oral contraceptive use (ER+PR-)]. Family history was not associated with ER+PR- cancers; only 8 (8%) of 99 patients with this subtype had a family history of breast cancer compared with 16% of all other types combined.(ABSTRACT TRUNCATED AT 250 WORDS)

Enamel fluoride in nursing rats with mothers drinking water with high fluoride concentrations.

The purpose of this study was to determine the F levels in plasma and molar enamel from rat pups whose mothers had received various levels of F during pregnancy and/or lactation. Rats were started on water containing 0 (Group I), 50 (Group II), or 100 (Group III) ppm F at the beginning of pregnancy or on the day of delivery. The mothers and pups were killed 13 days after delivery, and plasma F levels, milk F levels, and pup molar enamel F levels were determined. The mean maternal plasma F concentrations were 0.02 +/- 0.005 ppm in Group I, 0.10 +/- 0.031 ppm in Group II, and 0.21 +/- 0.057 ppm in Group III. The milk F values were about twice as high as the respective plasma concentrations. The plasma F concentration in control pups was 0.003 +/- 0.0002 ppm, and there was a rise to 0.006 +/- 0.0002 ppm in Group III. Enamel F concentrations were 0.62 +/- 0.13 ppm, 4.72 +/- 0.79 ppm, and 8.80 +/- 1.74 ppm, respectively. The plasma and enamel F values obtained from pups were not significantly different between the pre-natal/post-natal, and the post-natal-only groups. It was concluded that: fluoride levels in the plasma and enamel of control rat pups were much lower than those found in adult rats, such values could be increased only slightly when high doses of F were given to the mother, and unlike values reported for other species, rat milk fluoride concentrations were higher than the respective plasma values.

A comparison of the effects of continuous and periodic fluoride delivery on fluoride levels in plasma, enamel, and bones of nursing rats.

The purpose of this study was to determine and compare the F levels in plasma, enamel, and bones of nursing rat pups that received the same daily dose of F by continuous or periodic delivery during enamel development. The hypothesis was that F delivered continuously would result in enamel F levels higher than those attained when F was delivered periodically. For continuous delivery, copolymer devices (Southern Research Institute) that provide slow release of F were implanted in the backs of four-day-old rat pups. For periodic delivery, rat pups received F by intraperitoneal injection or gastric intubation. The doses were 0.01, 0.02, or 0.04 mg F/day. The rats were killed at 13 days of age, 24 hours after the last periodic delivery. Plasma was collected, femur and calvaria bones were removed, and enamel was scraped from developing first molars. Fluoride assay was by the microdiffusion method of Taves, with a F electrode. For the 0.02 mg F/day dose, plasma levels in control, implanted, injected, and gastric-intubated rats were 0.004, 0.020, 0.011, and 0.009 ppm, respectively. Enamel F levels were 1.1, 61.9, 54.0, and 42.3 ppm, respectively. Femur F levels were 2.2, 81.2, 84.8, and 68.1 ppm, respectively. Calvaria F levels were 2.5, 79.3, 80.1, and 67.9 ppm, respectively. The results showed that there was no significant difference in the enamel F levels or in the bone F levels in rat pups that received continuous or periodic, by injection, delivery of F at the same daily dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Tramadol and seizures: a surveillance study in a managed care population.

STUDY OBJECTIVE: To investigate the occurrence of tramadol-associated seizures. DESIGN: Retrospective cohort and case-control studies. SETTING: UnitedHealth Group-affiliated independent practice model health plans, from different regions of the United States, contracting with large networks of physicians. INTERVENTION: Analysis of administrative data from a large U.S. managed care population. PATIENTS: A cohort of 9218 adult tramadol users and 37,232 concurrent nonusers. MEASUREMENTS AND MAIN RESULTS: Fewer than 1% of users (80) had a presumed incident seizure claim after the first tramadol prescription. Risk of seizure claim was increased 2- to 6-fold among users adjusted for selected comorbidities and concomitant drugs. Risk was highest among those aged 25-54 years, those with more than four tramadol prescriptions, and those with history of alcohol abuse, stroke, or head injury. A case-control study among users was conducted to validate incident seizure outcomes from medical records. Only eight cases were confirmed, and all had cofactors associated with increased seizure risk. CONCLUSION: In a general population, risk of seizure may be associated with long-term therapy with tramadol or the presence of cofactors, or confined to a small sensitive population subset.

Medical records and privacy: empirical effects of legislation.

OBJECTIVE: To determine the effects of state legislation requiring patient informed consent prior to medical record abstraction by external researchers for a specific study. DATA SOURCES/STUDY SETTING: Informed consent responses obtained from November 1997 through April 1998 from members of a Minnesota-based IPA model health plan. STUDY DESIGN: Descriptive case study of consent to gain access to medical records for a pharmaco-epidemiologic study of seizures associated with use of a pain medication that was conducted as part of the FDA's post-marketing safety surveillance program to evaluate adverse events associated with approved drugs. DATA COLLECTION: The informed consent process approved by an institutional review board consisted of three phases: (1) a letter from the health plan's medical director requesting participation, (2) a second mailing to nonrespondents, and (3) a follow-up telephone call to nonrespondents. PRINCIPAL FINDINGS: Of 140 Minnesota health plan members asked to participate in the medical records study, 52 percent (73) responded and 19 percent (26) returned a signed consent form authorizing access to their records for the study. For 132 study subjects enrolled in five other health plans in states where study-specific consent was not required, health care providers granted access to patient medical records for 93 percent (123) of the members. CONCLUSION: Legislation requiring patient informed consent to gain access to medical records for a specific research study was associated with low participation and increased time to complete that observational study. Efforts to protect patient privacy may come into conflict with the ability to produce timely and valid research to safeguard and improve public health.

Healthy pregnancy program in a national managed care organization: evaluation of satisfaction and health behavior outcomes.

OBJECTIVE: To evaluate satisfaction with the Healthy Pregnancy Program (HPP), which was developed to educate and coordinate the care of pregnant women in a managed care setting. STUDY DESIGN: Telephone survey. PATIENTS AND METHODS: A random sample of program participants at 3 large health plans were contacted by telephone to evaluate their satisfaction with the program overall and with its components, including an educational booklet and telephone contact with a HPP nurse as needed. Women also were asked about changes in health behaviors (smoking, alcohol use, diet, and stress) resulting directly from participation in the HPP. Of 1155 eligible women participating in HPP who delivered a baby from April 1997 through March 1998, 684 completed the survey. The response rate was 59%. RESULTS: Overall satisfaction with the HPP was reported by 96% of the women, and 76% reported the 2 highest ratings of satisfaction (completely or very satisfied). Reports of satisfaction were more likely for women who entered the program early in pregnancy, who read the booklet, and who had more telephone contacts. In general, at least half of the women in each behavior category reported improving their behavior, especially if they were younger, identified as high risk, or having their first child. Verbatim comments supported the high satisfaction levels. CONCLUSIONS: The HPP is an example of a program that was developed to improve healthcare delivery in a managed care setting and, when evaluated, was found to result in highly satisfied mothers likely to improve their health behaviors.

The effect of fluoride on the electrophoretic patterns of developing rat molar enamel.

Rat pups were given 4 micrograms F/g X day from 3-7 days of age by intraperitoneal injection of NaF. Demineralized enamel matrix from 8- to 15-day-old rats was subjected to SDS-polyacrylamide gel electrophoresis. The results showed that there was a decrease in the relative proportion of high molecular-weight proteins with maturation. Enamel formed in the presence of F showed more abundant low molecular-weight proteins in the secretory stage and a delay in the decrease of high molecular-weight proteins with maturation. These observations indicate that F may influence the assembly or dis-assembly of early enamel proteins.

Periodontal status of individuals in early stages of human immunodeficiency virus infection.

The purpose of this study was to evaluate the association of periodontal health and human immunodeficiency virus infection among individuals in the early stages of disease who were participating in randomized placebo-controlled clinical trials of zidovudine. Previous reports have described a rapidly progressive periodontitis and atypical gigivitis associated with late stages of infection by the human immunodeficiency virus. A health history was completed by each subject. Baseline oral examinations were completed on 97 asymptomatic patients and nine with AIDS-related complex (ARC) during their regular clinic visit. Follow-up examinations were conducted at 3-month intervals throughout the 48 weeks of the oral study. Evaluations of plaque, calculus, gingival abnormalities, caries, and periodontal disease were conducted. Periodontal measurements included plaque index (PI), gingival index (GI), bleeding index (BI), probing depth (PD), and observation for cratering, necrosis, and tooth mobility on six teeth in each patient. More than half of the subjects had visited their dentist during the previous year and had had an oral prophylaxis; less than 25% of them had had either restorative work or extractions. The mean scores for periodontal indices averaged over the course of the study in asymptomatic and ARC respectively were: PI: 0.9 (SE 0.04) and 0.9 (SE 0.08), 0.818; GI: 1.0 (SE 0.04) and 0.9 (SE 0.07), P = 0.412; BI: 0.6 (SE 0.04) and 0.4 (SE 0.07), P = 0.278; PD: 2.9 (SE 0.05) and 2.6 (SE 0.10), P = 0.140. There was no evidence of cratering, necrosis, or tooth mobility in either group. Few had calculus or dental caries. There were no clinically significant differences detected between ARC versus asymptomatic patients. Dental histories and oral examinations showed that two groups of patients in early stages of HIV-disease were in good periodontal health.

Postmarketing surveillance of medications and pregnancy outcomes: clarithromycin and birth malformations.

PURPOSE: This retrospective surveillance study used linked administrative claims data and medical records to determine the rate and types of birth malformations in infants born to women exposed to the antibiotic, clarithromycin (Biaxin), during the first trimester of pregnancy. METHODS: Pharmacy and hospital claims from eight geographically diverse health plans were used to identify women who had a delivery claim within 270 days of a clarithromycin prescription over a 5-year period (1991-1995). Hospital delivery admission medical records for 143 mothers and their 149 infants were abstracted to identify birth malformations. RESULTS: Five infants were identified with major malformations, three with minor malformations, and four with undescended testicles likely to resolve with time. The observed rate of 3.4% (95% CI, 0.5, 6.3) for major malformations was not statistically significantly different compared to an expected rate of 2.8% based on earlier national data. There was no consistency across types of major malformations. CONCLUSIONS: These results provide no evidence that clarithromycin is a likely major teratogen in humans. Use of claims data is one way to evaluate quickly and efficiently the safety of prescription medications in humans during pregnancy, especially when both exposure and outcome are rare.

Liver enzyme monitoring in patients treated with troglitazone.

CONTEXT: Soon after initial marketing in March 1997, troglitazone, the first thiazolidinedione antidiabetic agent, was found to cause life-threatening acute liver failure. The drug was removed from the market in March 2000. OBJECTIVE: To evaluate the effect of US Food and Drug Administration (FDA) risk management efforts, including repeated labeling changes and "Dear Healthcare Professional" letters, on periodic liver enzyme monitoring of patients taking troglitazone. DESIGN, SETTING, AND PARTICIPANTS: Claims data from a large, multistate managed care organization were used to establish 4 cohorts of patients (N = 7603) with at least 90 days of health plan enrollment before first troglitazone prescription during 4 consecutive periods spanning April 1997 to September 1999 and representing 4 progressively stringent liver monitoring recommendations. MAIN OUTCOME MEASURES: Percentage of eligible troglitazone users in each cohort with baseline, monthly (for up to 6 months of continuous use), and complete (baseline and monthly) enzyme monitoring, based on computerized records of laboratory claims. RESULTS: Baseline testing increased from 15% before any FDA monitoring recommendations (cohort 1) to 44.6% following 4 separate FDA interventions (cohort 4; P<.001). In cohort 4, 33.4% of users had follow-up testing after 1 month of therapy, falling to 13% after 5 months of continuous use. In all cohorts, less than 5% received all recommended liver enzyme tests by the third month of continuous use. CONCLUSIONS: The FDA risk management efforts did not achieve meaningful or sustained improvement in liver enzyme testing. Evaluation of the impact of regulatory actions is needed before such actions can be regarded as effective or sufficient.

Association between family history of cancer and breast cancer defined by estrogen and progesterone receptor status.

There are recent data to suggest that risk factors for breast cancer may differ according to whether the tumor expresses detectable levels of the estrogen receptor (ER) and progesterone receptor (PR). While a family history of breast cancer is one of the most consistent predictors of the disease, we recently reported a modest inverse association with ER+PR- tumors. However, the definition of a family history of cancer did not consider second-degree relatives or cancer sites that may be etiologically related. The current report presents additional data analysis from the Iowa Women's Health Study, a prospective population-based cohort study conducted among 41,837 postmenopausal women. At baseline in 1986, respondents provided information on family history of cancers of the breast, ovaries, or uterus/endometrium in their mothers, sisters, daughters, maternal and paternal grandmothers, and maternal and paternal aunts. Data on family history of prostate cancer in fathers and brothers and age at onset of breast cancer in mothers and sisters were collected in 1992. Cohort members were followed for cancer incidence through the statewide tumor registry. After 7 years and more than 235,000 person-years of follow-up, 939 incident cases of breast cancer were identified. Information was obtained from the tumor registry on ER (+/-) and PR (+/-) status for 610 cases (65.0%). A family history of breast cancer in first-degree relatives was associated with increased risk (relative risk [PR] = 1.4; 95% confidence interval [CI]: 1.1-1.6) for all receptor-defined subtypes of breast cancer except ER+PR- tumors (RR = 0.7; 95% CI: 0.3-1.4). These results were unchanged when data on second-degree relatives were included. When the onset of breast cancer in relatives occurred at or before the age of 45 years, increased risks were evident only for ER-PR+ and ER-PR- tumors (RR = 2.3 and 3.3, respectively). Conversely, when relatives were affected with breast cancer after the age of 45 years, increased risks were most apparent for ER+PR+ and ER-PR+ tumors (RR = 1.3 and 3.2, respectively). A family history of prostate cancer in first-degree relatives was associated with a 1.2-fold increased risk of breast cancer (95% CI: 0.98-1.50), largely a reflection of the association with ER-PR- tumors (RR = 1.5; 95% CI: 0.8-3.0). The small numbers of cases in some categories and the corresponding wide CIs preclude definitive conclusions, but these data are at least suggestive that joint stratification of breast tumors on ER and PR status may be useful in partitioning breast cancer families into more homogeneous subsets.

Familial aggregation and heritability of waist-to-hip ratio in adult women: the Iowa Women's Health Study.

The aim of this study was to assess evidence that genetic factors influence body fat distribution. First-degree relatives of 324 cancer-free females in a population-based prospective study of 41,837 women (99% white) between the ages of 55 and 69 at baseline in 1986 were studied. A total of 396 living sisters (mean age 65.7 years) and 446 living daughters (mean age 41.2 years) were identified through a mailed 'family tree' questionnaire sent to each participant. Family members were mailed a questionnaire to obtain self-reported measures of current height and weight. A paper tape measure and written instructions were enclosed to obtain waist and hip circumferences. The age-adjusted mother-daughters correlations for waist-to-hip ratio and body mass index (kg/m2) were 0.19 and 0.23, respectively (P < 0.05 using Fisher's z-transformation). The corresponding sister-sister correlations were 0.23 and 0.19, respectively (P < 0.05). The sister-sister correlations were not significantly different from the mother-daughter correlations. After adjustment for body mass index the mother-daughter correlation for waist-to-hip ratio increased to 0.20 and the sister-sister correlation increased to 0.26. These familial correlations suggest that genes and common environment may contribute 40 to 50% of the total variance of waist-to-hip ratio in white women in the Midwest.

Association of body mass index and body fat distribution with risk of lung cancer in older women.

Obesity has been associated with an increased risk of cancer at a number of sites. A notable exception appears to be lung cancer, for which several studies suggest a modest inverse association. However, cigarette smoking is directly associated with lung cancer and inversely associated with body mass index. To investigate the hypothesis that body mass index is associated with lung cancer independent of cigarette smoking, the authors analyzed data from a prospective cohort study of 41,837 Iowa women aged 55-69 years at baseline in 1986. In addition, they examined whether central adiposity (high waist/hip ratio) was associated with lung cancer incidence. Through 1992 (6 years of follow-up), 233 cases of lung cancer were identified through the State Health Registry of Iowa. The body mass index at several ages was calculated from self-reports of height at baseline and weights at ages 18, 30, 40, and 50 years and at baseline. Current and former smokers generally had lower mean body mass indices than did nonsmokers at all ages except 18 years. Cases generally had lower body mass indices than did noncases at all ages except 18 and 30 years but, among current smokers, cases had higher mean body mass indices than did noncases at all ages except baseline, although the differences were not statistically significant. An apparent positive association of a high waist/hip ratio with lung cancer in the total cohort was found to be primarily accounted for by a higher waist/hip ratio in current and former smokers. When stratified by smoking status and adjusted for other risk factors, including age and pack-years of smoking, the body mass index at baseline, body mass index at age 50 years, and waist/hip ratio were not associated with lung cancer. The results of multivariate analyses suggest that the inverse association of body mass index with lung cancer can be explained by smoking status and that the positive association of waist/hip ratio with lung cancer can be explained by pack-years of smoking.