Caroline Diorio

Genetic polymorphisms of the vitamin D binding protein and plasma concentrations of 25-hydroxyvitamin D in premenopausal women

BACKGROUND Vitamin D status, determined on the basis of 25-hydroxyvitamin D [25(OH)D] concentrations, is associated with the risk of several diseases. Vitamin D binding protein (DBP) is the major carrier of vitamin D and its metabolites, but the role of DBP single nucleotide polymorphisms (SNPs) on 25(OH)D concentrations is unclear. OBJECTIVE The objective was to evaluate the association of 2 DBP gene SNPs with 25(OH)D concentrations and explore whether such association varies according to the amount of vitamin D that needs to be transported. DESIGN This cross-sectional study included 741 premenopausal white women, mostly of French descent. Plasma 25(OH)D concentrations were measured by radioimmunoassay. DBP-1 (rs7041) and DBP-2 (rs4588) were genotyped with a Sequenom MassArray platform. Associations and interactions were modeled by using multivariate linear regression. RESULTS DBP-1 and DBP-2 SNPs were in strong linkage disequilibrium and were both associated with 25(OH)D concentrations. An additional copy of the rare allele of DBP-1 or DBP-2 was associated with lower 25(OH)D concentrations (beta = -3.29, P for trend = 0.0003; beta = -4.22, P for trend < 0.0001, respectively). These DBP polymorphisms explained as much of the variation in circulating 25(OH)D as did total vitamin D intake (r2 = 1.3% for DBP-1, r2 = 2.0% for DBP-2, and r2 < or = 1.2% for vitamin D intake). CONCLUSION Circulating 25(OH)D concentrations in premenopausal women are strongly related to DBP polymorphisms. Whether DBP rare allele carriers have a different risk of vitamin D-related diseases and whether such carriers can benefit more or less from dietary interventions, vitamin D supplementation, or sun exposure need to be clarified.

Insulin-Like Growth Factor-I, IGF-Binding Protein-3, and Mammographic Breast Density

Some studies have suggested that insulin-like growth factor (IGF) pathway is related to premenopausal breast density, one of the strongest known breast cancer risk factors. This study was designed specifically to test the hypothesis that higher levels of IGF-I and lower levels of IGF-binding protein (IGFBP)-3 are associated with high mammographic breast density among premenopausal but not among postmenopausal women. A total of 783 premenopausal and 791 postmenopausal healthy women were recruited during screening mammography examinations. Blood samples were collected at the time of mammography, and plasma IGF-I and IGFBP-3 levels were measured by ELISA. Mammographic breast density was estimated using a computer-assisted method. Spearmans partial correlation coefficients (rs) were used to evaluate the associations. Adjusted mean breast density was assessed by joint levels of IGF-I and IGFBP-3 using generalized linear models. Among premenopausal women, high levels of IGF-I and low levels of IGFBP-3 were independently correlated with high breast density (rs = 0.083; P = 0.021 and rs = −0.124; P = 0.0005, respectively). Correlation of IGF-I with breast density was stronger among women in the lowest tertile of IGFBP-3 than among those in the highest tertile of IGFBP-3 (rs = 0.138; P = 0.027 and rs = −0.039; P = 0.530, respectively). In contrast, the correlation of IGFBP-3 with breast density was stronger among women in the highest tertile of IGF-I than among those in the lowest tertile of IGF-I (rs = −0.150; P = 0.016 and rs = −0.008; P = 0.904, respectively). Women in the combined top tertile of IGF-I and bottom tertile of IGFBP-3 had higher mean breast density than those in the combined bottom tertile of IGF-I and top tertile of IGFBP-3 (53.8% versus 40.9%; P = 0.014). No significant association was observed among postmenopausal women. Our findings confirm that IGF-I and IGFBP-3 are associated with breast density among premenopausal women. They provide additional support for the idea that, among premenopausal women, these growth factors may affect breast cancer risk, at least in part, through their influence on breast tissue morphology as reflected on mammogram.

Vitamin D and Calcium Intakes from Food or Supplements and Mammographic Breast Density

Background: A better understanding of factors that affect breast density, one of the strongest breast cancer risk indicators, may provide important clues about breast cancer etiology and prevention. This study evaluates the association of vitamin D and calcium, from food and/or supplements, to breast density in premenopausal and postmenopausal women separately. Methods: A total of 777 premenopausal and 783 post-menopausal women recruited at two radiology clinics in Quebec City, Canada, in 2001 to 2002, completed a food frequency questionnaire to assess vitamin D and calcium. Breast density from screening mammograms was assessed using a computer-assisted method. Associations between vitamin D or calcium and breast density were evaluated using linear regression models. Adjusted means in breast density were assessed according to the combined daily intakes of the two nutrients using generalized linear models. Results: In premenopausal women, total intakes of vitamin D and calcium were inversely related to breast density (β = −1.4; P = 0.004 for vitamin D; β = −0.8; P = 0.0004 for calcium). In multivariate linear regression, simultaneous increments in daily total intakes of 400 IU vitamin D and 1,000 mg calcium were associated with an 8.5% (95% confidence interval, 1.8-15.1) lower mean breast density. The negative association between dietary vitamin D intake and breast density tended to be stronger at higher levels of calcium intake and vice versa. Among postmenopausal women, intakes of vitamin D and calcium were not associated with breast density. Conclusion: These findings show that higher intakes of vitamin D and calcium from food and supplements are related to lower levels of breast density among premenopausal women. They suggest that increasing intakes of vitamin D and calcium may represent a safe and inexpensive strategy for breast cancer prevention.

Effect of exercise on cancer-related fatigue: a meta-analysis.

ABSTRACT Numerous randomized controlled trials have been conducted to determine efficacy of exercise on cancer-related fatigue. However, many trials lacked sufficient power to demonstrate significant differences, and little is known about how the effect of exercise differs depending on patient- and intervention-level characteristics. A meta-analysis was performed to determine whether exercise reduces fatigue compared with usual care or nonexercise control intervention in patients with cancer. The authors searched Ovid MEDLINE, EMBASE, PsycINFO, The Cochrane Central Register of Controlled Trials, and CINAHL. Two authors independently extracted the data. Randomized controlled trials comparing exercise with control intervention in cancer patients in which fatigue was quantified were eligible. Seventy-two randomized controlled trials were identified, 71 in adults and 1 in children. Exercise had a moderate effect on reducing fatigue compared with control intervention. Exercise also improved depression and sleep disturbance. Type of exercise did not significantly influence the effect on fatigue, depression, or sleep disturbance. Exercise effect was larger in the studies published 2009 or later. There was only one pediatric study. The results of this study suggest that exercise is effective for the management of cancer-related fatigue.

Genetic Polymorphisms Involved in Insulin-like Growth Factor (IGF) Pathway in Relation to Mammographic Breast Density and IGF Levels

The insulin-like growth factor (IGF) pathway is believed to play a role in carcinogenesis of the mammary gland. Single nucleotide polymorphisms (SNPs) of IGF-I, IGF-binding protein-3 (IGFBP-3), IGF receptor 1, insulin receptor substrate 1, and phosphoinositide-3-kinase, catalytic, β polypeptide genes, which are members of the IGF pathway, have been associated with risk of common cancers, breast density, and/or IGF levels but results remain inconclusive. Thus, we evaluated the association of 11 targeted IGF pathway SNPs with circulating IGF levels and mammographic breast density. Among 741 white premenopausal women, blood samples were collected at time of screening mammography, and plasma IGF-I and IGFBP-3 levels were measured by ELISA. Percent and absolute breast density were estimated using a computer-assisted method. Multivariate linear models were used to examine the associations. Women carrying increasing number of copies of the rare allele of IGF-I rs1520220 and rs6220 SNPs had increased percent breast density (Ptrend = 0.04 and 0.06, respectively). Carriers of increasing number of copies of the rare allele of phosphoinositide-3-kinase, catalytic, β polypeptide rs361072 SNP had decreased percent (Ptrend = 0.04) and absolute (Ptrend = 0.02) breast density. An association of insulin receptor substrate 1 rs1801278 SNP with absolute density (Ptrend = 0.03) was also observed. All four IGFBP-3 SNPs (including rs2854744) were associated with IGF-I and IGFBP-3 levels. This study shows that several components of the IGF pathway are associated with breast density or IGF levels. Our findings provide additional support for the idea that several components of the IGF pathway may affect breast cancer risk and that this effect on breast cancer development may be mediated, at least in part, through its influence on the morphogenesis of breast tissue. (Cancer Epidemiol Biomarkers Prev 2008;17(4):880–8)

Influence of Insulin-like Growth Factors on the Strength of the Relation of Vitamin D and Calcium Intakes to Mammographic Breast Density

Diets with higher vitamin D and calcium contents were found associated with lower mammographic breast density and breast cancer risk in premenopausal women. Because laboratory studies suggest that the actions of vitamin D, calcium, insulin-like growth factor (IGF)-I, and IGF-binding protein-3 (IGFBP-3) on human breast cancer cells are interrelated, we examined whether IGF-I and IGFBP-3 levels could affect the strength of the association of vitamin D and calcium intakes with breast density. Among 771 premenopausal women, breast density was measured by a computer-assisted method, vitamin D and calcium intakes by a food frequency questionnaire, and levels of plasma IGF-I and IGFBP-3 by ELISA methods. Multivariate linear regression models were used to examine the associations and the interactions. The negative associations of vitamin D or calcium intakes with breast density were stronger among women with IGF-I levels above the median (beta = -2.8, P = 0.002 and beta = -2.5, P = 0.002, respectively) compared with those with IGF-I levels below or equal to the median (beta = -0.8, P = 0.38 and beta = -1.1, P = 0.21; P(interaction) = 0.09 and 0.16, respectively). Similar results were observed within levels of IGFBP-3 (P(interaction) = 0.06 and 0.03, respectively). This is the first study to report that the negative relation of vitamin D and calcium intakes with breast density may be seen primarily among women with high IGF-I or high IGFBP-3 levels. Our findings suggest that the IGF axis should be taken into account when the effects of vitamin D and calcium on breast density (and perhaps breast cancer risk) are examined at least among premenopausal women.

Synchronized Seasonal Variations of Mammographic Breast Density and Plasma 25-Hydroxyvitamin D

Background: Dietary vitamin D has been associated with lower mammographic breast density, a strong biomarker for breast cancer risk. Blood 25-hydroxyvitamin D [25(OH)D] is an integrated measure of vitamin D status (from food, supplements, and sun exposure) and varies with season. Our objective was to assess seasonal variations of breast density and compare such variations, if any, with that of 25(OH)D. Methods: This cross-sectional study includes 741 premenopausal women recruited at screening mammography. Plasma 25(OH)D at recruitment was measured by RIA. Breast density was evaluated using a computer-assisted method. Seasonal variations were modeled using multivariate linear regression and semi-parametric cubic smoothing splines. Results: Season was strongly associated with 25(OH)D (P < 0.0001). The highest smoothed mean 25(OH)D levels were seen at the end of July (81.5 nmol/L) and the lowest in mid-April (52.4 nmol/L). Breast density showed modest seasonal variations (P = 0.028). The lowest smoothed mean breast density was observed in early December (38.5%) and the highest at the beginning of April (44.3%). When a 4-month lag time was presumed, seasonal variations of breast density appeared to be a mirror image of those of 25(OH)D, and the correlation of daily smoothed estimates of mean breast density and 25(OH)D was negative and strong (r = −0.90). Conclusion: In premenopausal women, changes in blood vitamin D seem to be inversely related to changes in breast density with a lag time of about 4 months. This finding encourages further investigation of the possibility that vitamin D could reduce breast density and breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(5):929–33)

Vitamin D receptor polymorphisms (FokI, BsmI) and breast cancer risk: association replication in two case–control studies within French Canadian population

Vitamin D has been associated with reduced breast cancer risk. We studied the association of two vitamin D receptor (VDR) gene single nucleotide polymorphisms restriction enzyme detecting SNP of VDR (FokI and BsmI) with breast cancer risk in two independent case–control studies carried out in the same population. The modifying effect of family history of breast cancer on this relationship was also evaluated. The first and second studies included respectively 718 (255 cases/463 controls) and 1596 (622 cases/974 controls) women recruited in Quebec City, Canada. FokI and BsmI genotypes were assessed. Relative risks of breast cancer were estimated by multivariate logistic regression. Compared with homozygotes for the common F allele (FF genotype), FokI ff homozygotes had a higher breast cancer risk (study 1: odds ratio (OR)=1.22, 95% confidence interval (CI)=0.76–1.95; study 2: OR=1.44, 95% CI=1.05–1.99; and combined studies: OR=1.33, 95% CI=1.03–1.73). Significant interactions were observed between FokI and family history of breast cancer in the two studies as well as in the combined analysis (P interaction=0.031, 0.050 and 0.0059 respectively). Among women without family history, odds ratios were 1.00, 1.27 (95% CI=1.02–1.58) and 1.57 (95% CI=1.18–2.10) respectively for FF, Ff and ff carriers (Ptrend=0.0013). BsmI Bb+bb genotypes were associated with a weak non-significant increased risk in the two studies (combined OR=1.22, 95% CI=0.95–1.57) without interaction with family history. Results support the idea that vitamin D, through its signalling pathway, can affect breast cancer risk. They also suggest that variability in observed associations between VDR FokI and breast cancer from different studies may partly be explained by the proportion of study subjects with a family history of breast cancer.

Factors associated with upgrading to malignancy at surgery of atypical ductal hyperplasia diagnosed on core biopsy

Previous studies have shown that 4-54% of breast lesions reported on core biopsies as atypical ductal hyperplasia (ADH) are upgraded on further excision to ductal carcinoma in situ (DCIS) or invasive carcinoma. We evaluated the rate of upgrading ADH to carcinoma at surgery for ADH diagnosed by percutaneous biopsy, and examined characteristics associated with malignancy. We identified 13,488 consecutive biopsies conducted at one center over a nine-year period. A total of 422 biopsies with ADH in 415 patients were included. DCIS or invasive carcinoma was found in 132 cases (31.3% upgrading). Multivariate model revealed that ipsilateral breast symptoms, mammographic lesion other than microcalcifications alone, 14G core needle biopsy, papilloma co-diagnosis, severe ADH and pathologists with lower volume of ADH diagnosis were factors statistically associated with malignancy. However, no subgroups were identified for safe clinical-only follow-up. Surgery is recommended in all cases of ADH diagnosed by percutaneous breast biopsy.

Low Socioeconomic Status Is Associated with Prolonged Times to Assessment and Treatment, Sepsis and Infectious Death in Pediatric Fever in El Salvador

Background Infection remains the most common cause of death from toxicity in children with cancer in low- and middle-income countries. Rapid administration of antibiotics when fever develops can prevent progression to sepsis and shock, and serves as an important indicator of the quality of care in children with acute lymphoblastic leukemia and acute myeloid leukemia. We analyzed factors associated with (1) Longer times from fever onset to hospital presentation/antibiotic treatment and (2) Sepsis and infection-related mortality. Method This prospective cohort study included children aged 0–16 years with newly diagnosed acute leukemia treated at Benjamin Bloom Hospital, San Salvador. We interviewed parents/caregivers within one month of diagnosis and at the onset of each new febrile episode. Times from initial fever to first antibiotic administration and occurrence of sepsis and infection-related mortality were documented. Findings Of 251 children enrolled, 215 had acute lymphoblastic leukemia (85.7%). Among 269 outpatient febrile episodes, median times from fever to deciding to seek medical care was 10.0 hours (interquartile range [IQR] 5.0–20.0), and from decision to seek care to first hospital visit was 1.8 hours (IQR 1.0–3.0). Forty-seven (17.5%) patients developed sepsis and 7 (2.6%) died of infection. Maternal illiteracy was associated with longer time from fever to decision to seek care (P = 0.029) and sepsis (odds ratio [OR] 3.06, 95% confidence interval [CI] 1.09–8.63; P = 0.034). More infectious deaths occurred in those with longer travel time to hospital (OR 1.36, 95% CI 1.03–1.81; P = 0.031) and in families with an annual household income <US