Serum insulin‐like growth factor (IGF)‐I and IGF binding protein‐3 in relation to terminal duct lobular unit involution of the normal breast in Caucasian and African American women: The Susan G. Komen Tissue Bank

Lesser degrees of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini/TDLU, are associated with elevated breast cancer risk. In rodent models, the insulin‐like growth factor (IGF) system regulates involution of the mammary gland. We examined associations of circulating IGF measures with TDLU involution in normal breast tissues among women without precancerous lesions. Among 715 Caucasian and 283 African American (AA) women who donated normal breast tissue samples to the Komen Tissue Bank between 2009 and 2012 (75% premenopausal), serum concentrations of IGF‐I and binding protein (IGFBP)‐3 were quantified using enzyme‐linked immunosorbent assay. Hematoxilyn and eosin‐stained tissue sections were assessed for numbers of TDLUs (“TDLU count”). Zero‐inflated Poisson regression models with a robust variance estimator were used to estimate relative risks (RRs) for association of IGF measures (tertiles) with TDLU count by race and menopausal status, adjusting for potential confounders. AA (vs. Caucasian) women had higher age‐adjusted mean levels of serum IGF‐I (137 vs. 131 ng/mL, p = 0.07) and lower levels of IGFBP‐3 (4165 vs. 4684 ng/mL, p < 0.0001). Postmenopausal IGFBP‐3 was inversely associated with TDLU count among AA (RR_T3vs.T1 = 0.49, 95% CI = 0.28–0.84, p‐trend = 0.04) and Caucasian (RR_T3vs.T1=0.64, 95% CI = 0.42–0.98, p‐trend = 0.04) women. In premenopausal women, higher IGF‐I:IGFBP‐3 ratios were associated with higher TDLU count in Caucasian (RR_T3vs.T1=1.33, 95% CI = 1.02–1.75, p‐trend = 0.04), but not in AA (RR_T3vs.T1=0.65, 95% CI = 0.42–1.00, p‐trend = 0.05), women. Our data suggest a role of the IGF system, particularly IGFBP‐3, in TDLU involution of the normal breast, a breast cancer risk factor, among Caucasian and AA women.     

The impact of delayed blood centrifuging,choice of collection tube,and type of assay on 25-hydroxyvitamin D concentrations

Studies have examined the associations between cancers and circulating 25-hydroxyvitamin D [25(OH)D], but little is known about the impact of different laboratory practices on 25(OH)D concentrations. We examined the potential impact of delayed blood centrifuging, choice of collection tube, and type of assay on 25(OH)D concentrations. Blood samples from 20 healthy volunteers underwent alternative laboratory procedures: four centrifuging times (2, 24, 72, and 96 h after blood draw); three types of collection tubes (red top serum tube, two different plasma anticoagulant tubes containing heparin or EDTA); and two types of assays (DiaSorin radioimmunoassay [RIA] and chemiluminescence immunoassay [CLIA/LIAISON^®]). Log-transformed 25(OH)D concentrations were analyzed using the generalized estimating equations (GEE) linear regression models. We found no difference in 25(OH)D concentrations by centrifuging times or type of assay. There was some indication of a difference in 25(OH)D concentrations by tube type in CLIA/LIAISON^®-assayed samples, with concentrations in heparinized plasma (geometric mean, 16.1 ng ml^?1) higher than those in serum (geometric mean, 15.3 ng ml^?1) (p = 0.01), but the difference was significant only after substantial centrifuging delays (96 h). Our study suggests no necessity for requiring immediate processing of blood samples after collection or for the choice of a tube type or assay.     

Estrogen metabolism in menopausal hormone users in the women's health initiative observational study: Does it differ between estrogen plus progestin and estrogen alone?

The WHI found an unexpected reduced breast cancer risk in women using CEE alone. We hypothesized CEE alone induces estrogen hydroxylation along the 2-pathway rather than the competing 16-pathway, a pattern linked to reduced postmenopausal breast cancer risk. One thousand eight hundred and sixty-four women in a WHIOS case–control study of estrogen metabolism and ovarian and endometrial cancer were studied of whom 609 were current E + P users (351 used CEE + MPA), while 272 used E alone (162 used CEE). Fifteen EM were measured, and analyses were conducted for each metabolite, hydroxylation pathway (2-, 4-, or 16-pathway) and ratios of pathway concentrations using inverse probability weighted linear regression. Compared to E + P users, all EM were higher in E alone users (significant for unconjugated estrone, total/conjugated estradiol, total/unconjugated 2-methoxyestrone, 4-methoxyestrone and unconjugated estriol). The relative concentrations of 2- and 4-pathway EM did not differ between the MHT users (2-pathway EM comprised 15% and 4-pathway EM <2% of the total), but 16-pathway EM were lower in E alone users (p = 0.036). Ratios of 2- and 4-pathway EM compared to 16-pathway EM were significantly higher in E alone compared to E + P users. Similar but not significant patterns were observed in CEE-alone and CEE + MPA users. Our data suggest that compared to E + P users, women using E alone have more extensive metabolism via the 2- vs. the competing 16-pathway. This is consistent with epidemiologic evidence of reduced postmenopausal breast cancer risk associated with this metabolic profile and may provide a clue to the breast cancer risk reduction in CEE alone users during the WHI.     

Evidence for a link between TNFRSF11A and risk of breast cancer

Intracellular signaling mediated by the receptor activator of nuclear factor-κB [Rank, encoded by the tumor necrosis factor receptor superfamily, member 11a (Tnfrsf11a) gene] is fundamental for mammary gland development in mice, regulating the expansion of stem and progenitor cell compartments. Conversely, Rank overexpression in mice promotes abnormal proliferation and impairs differentiation, leading to an increased incidence of tumorigenesis. Here, we show that a common genetic variant near the 5'-end of TNFRSF11A, rs7226991, is associated with breast cancer risk in the general population and among carriers of mutations in the breast cancer 2, early onset (BRCA2) gene. Akin to the results of the Cancer and Genetics Markers of Susceptibility initiative, combined analysis of rs7226991 in two Spanish case-control studies (1,365 controls and 1,323 cases in total) revealed a significant association with risk: odds ratio (OR) = 0.88, 95% confidence interval (CI) 0.78-0.98, P (trend) = 0.025. Subsequent examination of BRCA1 (n = 1,017) and BRCA2 (n = 885) mutation carriers revealed a consistent association in the latter group: weighted hazard ratio ((w)HR) = 0.70; 95% CI 0.55-0.88; and P (trend) = 0.003; compared to BRCA1 mutation carriers, (w)HR = 0.91; 95% CI 0.76-1.10; and P (trend) = 0.33. The results of this study need to be replicated in other populations and with larger numbers of BRCA1/2 mutation carriers.     

Sonographic Examination of the Fetal Vermis

Prenatal imaging of the fetal cerebellar vermis is challenging even for experienced examiners. We found that by aiming the ultrasound beam through the mastoid fontanel and then rotating the data set in a multiplanar reconstruction and applying volume contrast imaging in the C plane, we were consistently able to obtain images of the vermis in the standard midsagittal plane. Images of the fetal vermis suitable for morphologic evaluation were obtained in 408 of 414 cases (98.5%) at gestational ages of 18 weeks to 31 weeks 6 days; the examination time was only minimally increased.     

Occult hepatitis B in blood donors in Indonesia: altered antigenicity of the hepatitis B virus surface protein

Background and aims  

Occult hepatitis B virus infection (OBI) poses a challenge to the safety of blood donation. The prevalence of OBI is not well documented in Indonesia, although this information in such an endemic country is needed. This study was aimed to evaluate the prevalence of occult hepatitis B in blood donors from two cities of Indonesia, and to study the genetic variation and its effect on the predicted antigenicity of HBsAg.     

Pregnancy outcome of patients with known celiac disease

OBJECTIVE: Celiac disease is a permanent intolerance to gluten, probably induced by an autoimmune mechanism. Controversy exists regarding the association between celiac disease and infertility, abortions, intra-uterine growth restriction (IUGR) and stillbirths. The present study was designed to investigate pregnancy outcome of patients with celiac disease. METHODS: A retrospective comparison between all pregnancies of women with and without known celiac disease, delivered during the years 1988-2002, was conducted. RESULTS: During the study period there were 48 deliveries of patients with celiac disease and 143,663 pregnancies of patients without known celiac disease. No statistically significant differences were noted between the groups regarding maternal or perinatal outcomes, including fertility treatments (0% among patients with known celiac versus 2.5% among patients without known celiac sprue; p=0.267), recurrent abortions (0 versus 5.2%; p=0.103), perinatal mortality (2.1 versus 1.4%; p=0.668). However, higher rates of labor induction (29.2 versus 11.9%; p<0.001) and IUGR (6.3 versus 2.1%; p=0.042) were found among patients with celiac disease as compared to patients without known celiac disease. CONCLUSION: The course of pregnancy of patients with celiac disease including perinatal outcomes is favorable. Since we found higher rates of IUGR, careful surveillance should be performed for early detection of IUGR. Further, prospective studies should focus on screening for celiac disease among patients presenting with IUGR of an unknown etiology.