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Background: Dietary calcium and vitamin D intakes may be inversely associated with cardiovascular disease (CVD) risk, possibly because of their potential beneficial effects on circulating lipids. Clinical trials that have evaluated the effect of calcium supplementation on lipids are limited by a short follow-up, and data on vitamin D are scarce. Objective: The objective was to evaluate the effect of a longer-term effect (over 5 y) of calcium and vitamin D (CAD) supplementation on changes in the concentrations of several lipids: LDL, HDL, non-HDL, total cholesterol, triglycerides, and lipoprotein(a) [Lp(a)]. Design: The study was conducted in 1259 postmenopausal women in the Calcium plus Vitamin D Trial (1 g elemental Ca as carbonate plus 400 IU vitamin [D.sub.3]/d compared with placebo) of the Women's Health Initiative. Analyses were conducted by intention-to-treat. Repeated measurements on lipids during follow-up were analyzed by linear mixed-effects models. Results: Overall, the change in lipids was relatively small [[less than or equal to ]5% except for Lp(a), which was 20-25%], and there was no significant difference in the mean change of any lipid variable between the active and placebo groups. Conclusions: Our results indicate that CaD supplementation is not associated with lipid changes over 5 y. Existing and future CaD trials should consider evaluating this association for different doses of supplements. This study was registered at clinicaltrials.gov as NCT00000611. Am J Clin Nutr 2010;91:894-9. doi: 10.3945/ajcn.2009.28579.

The Aspirin/Folate Polyp Prevention Trial found that aspirin, but not folic acid, reduced recurrence of colorectal adenomas. This study examined whether treatment effects on inflammation markers explained the trial results. The trial had a factorial design with three aspirin (placebo, 81, and 325 mg/d) and two folic acid (placebo and 1 mg/d) groups. There were 884 subjects who had colonoscopic evaluation for adenomas at year 3 and plasma levels of C-reactive protein (CRP), interleukin 6 (IL-6), tumor necrosis factor [alpha] (TNF-[alpha]), soluble TNF receptor type II (sTNF-R2), and IL-1 receptor antagonist (IL-1Ra) measured at baseline and year 3. Among individuals not receiving folic acid, there was a 4% decrease (mean ratio of year 3 to baseline levels = 0.96, 95% confidence interval [CI] = 0.82 to 1.14) in CRP for a period of 3 years in the 325 mg of aspirin group vs a 20% increase (mean ratio = 1.20, 95% CI = 1.03 to 1.41) in the placebo group (P = .027). By contrast, the reverse was observed among individuals who also received folic acid ([P.sub.interaction] = .013). Changes in inflammation markers were not associated with adenoma recurrence. Low-dose aspirin (325 mg/d) is beneficial in stabilizing CRP levels, which may be abrogated by folate. Nevertheless, inflammation markers do not mediate the chemopreventive effect of aspirin on colorectal adenomas. J Natl Cancer Inst 2009;101:1650-1654 DOI: 10.1093/jnci/djp346

Background The positive association between obesity and postmenopausal breast cancer has been attributed, in part, to the fact that estrogen, a risk factor for breast cancer, is synthesized in adipose tissue. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed associations between circulating levels of insulin and/or insulin-like growth factor (IGF)-I, a related hormone, and the risk of breast cancer independent of estrogen level. Methods We conducted a case-cohort study of incident breast cancer among nondiabetic women who were enrolled in the Women's Health Initiative Observational Study (WHI-OS), a prospective cohort of 93676 postmenopausal women. Fasting serum samples obtained at study entry from 835 incident breast cancer case subjects and from a subcohort of 816 randomly chosen WHI-OS subjects were tested for levels of insulin, glucose, total IGF-I, free IGF-I, insulin-like growth factor binding protein-3, and estradiol. Multivariable Cox proportional hazards models were used to estimate associations between levels of the serologic factors and baseline characteristics (including body mass index [BMI]) and the risk of breast cancer. All statistical tests were two-sided. Results Insulin levels were positively associated with the risk of breast cancer (hazard ratio [HR] for highest vs lowest quartile of insulin level = 1.46, 95% confidence interval [CI] = 1.00 to 2.13, [P.sub.trend] = .02); however, the association with insulin level varied by hormone therapy (HT) use ([P.sub.interaction] = .01). In a model that controlled for multiple breast cancer risk factors including estradiol, insulin level was associated with breast cancer only among nonusers of HT (HR for highest vs lowest quartile of insulin level = 2.40, 95% CI = 1.30 to 4.41, [P.sub.trend] < .001). Obesity (BMI [greater than or equal to] 30 kg/[m.sup.2]) was also associated with the risk of breast cancer among nonusers of HT (HR for BMI [greater than or equal to] 30 kg/[m.sup.2] vs 18.5 to Conclusion These data suggest that hyperinsulinemia is an independent risk factor for breast cancer and may have a substantial role in explaining the obesity--breast cancer relationship.

Background: Infection with human papillomavirus (HPV) type 16 (HPV16) is a major cause of high-grade cervical intraepithelial neoplasia (CIN). Experiments were planned to evaluate the role of cell-mediated immunity (e.g., lymphocyte proliferation) against HPV in the natural history of HPV-associated neoplasia and to identify antigenic sequences of the HPV16 proteins E6 and E7 against which an immune response may confer protection. Methods: Forty-nine women with abnormal cervical cytology and biopsy-confirmed CIN were followed through one or more clinic visits. Lymphoproliferative responses of peripheral blood mononuclear cells to HPV16 E6 and E7 peptides were assessed in long-term (3-week) cultures. HPV DNA was detected in cervicovaginal lavage by means of polymerase chain reaction and Southern blotting. Disease status was determined by cervical cytologic examination and colposcopy. Reported P values are two-sided. Results: Subjects with positive lymphoproliferative responses to E6 and/or E7 peptides were more likely to be HPV negative at the same clinic visit than were nonresponders (P = .039). Subjects who were negative for HPV and those with a low viral load were more likely to be responders than were those with a high viral load (P for trend = .037). Responses to N-terminal E6 peptide 369 were associated with absence of HPV infection at the same clinic visit (P = .015). Subjects with positive responses to E6 or E7 peptides at one clinic visit were 4.4 times more likely to be HPV negative at the next visit than were nonresponders (P = .142). Responses to E6 peptide 369 and/or E7 C-terminal peptide 109 were associated with an absence of HPV infection (P = .02 for both) and an absence of CIN (P = .04 and .02, respectively) at the next visit. Conclusions: Lymphoproliferative responses to specific HPV16 E6 and E7 peptides appear to be associated with the clearance of HPV infection and the regression of CIN. [J Natl Cancer Inst] 1997;89:1285-93]

Background: Cervical dysplasia, also referred to as squamous intraepithelial lesion (SIL) in cytology or cervical intraepithelial neoplasia in histopathology, is thought to have the potential to advance in progressive stages to cervical cancer. However, not all cases of SIL progress, and most of the mild lesions spontaneously regress. Factors that govern regression, persistence, and progression of SIL are poorly understood. Purpose: Our analysis sought to identify factors that determined persistence or regression of SIL. Methods: Seventy subjects with histopathologically confirmed cervical dysplasia were followed at 3-month intervals for 15 months. At each visit, the cervix was evaluated by Pap smear and colposcopy, and exfoliated cervicovaginal cells were analyzed for human papillomavirus (HPV) DNA. For each subject, data from every two consecutive visits were grouped as a pair. Persistent SIL was considered present if a lesion was detected at a visit (t) as well as at the next visit (t + 1) and absent if a lesion was detected at visit t but not at visit t + 1. A statistical model for time-dependent data correlated persistent SIL with various risk factors. Results: Age, ethnicity, education, sexual behavior, smoking, and the use of oral contraceptives did not correlate with persistent SIL. The risk of persistent SIL was associated with continual HPV infection in visits t and t + 1 (HPV positive by Southern blot analysis: odds ratio [OR] = 3.91, and 95% confidence interval [CI] = 1.58-9.65; HPV positive by polymerase chain reaction [PCR]: OR = 2.42, and 95% CI = 1.03-5.67) and a persistent high viral load (OR = 4.07, and 95% CI = 1.35-12.30). When typed by PCR, individuals with type-specific persistent infection in visits t and t + 1, and particularly those with a continual high viral load (OR = 4.97; 95% CI = 1.45-17.02), had the highest risk for persistent SIL compared with those with a low level of type-specific persistent infection or non-type-specific persistent infection. The presence of persistent HPV infection in visits t - 1 and t (the preceding time interval) was also predictive of persistent SIL in visits t and t + 1, although the strength of association was weaker, suggesting that persistent HPV and SIL occur synchronously. Conclusion: HPV infection and its associated cervical lesions tend to occur concurrently, and type-specific persistent HPV infection, particularly with a high viral load, produces chronic cervical dysplasia. Implications: The natural history of genital HPV infection directly influences the prognosis of cervical dysplasia as measured by persistence of the lesion. Testing for HPV infection may be valuable in the clinical management of women with cervical dysplasia.