The spatial distribution of radiodense breast tissue: a longitudinal study

Introduction Mammographic breast density is one of the strongest known markers of susceptibility to breast cancer. To date research into density has relied on a single measure ( for example, percent density (PD)) summarising the average level of density for the whole breast, with no consideration of how the radiodense tissue may be distributed. This study aims to investigate the spatial distribution of density within the breast using 493 mammographic images from a sample of 165 premenopausal women (similar to 3 medio-lateral oblique views per woman).Methods Each breast image was divided into 48 regions and the PD for the whole breast ( overall PD) and for each one of its regions ( regional PD) was estimated. The spatial autocorrelation ( Moran's I value) of regional PD for each image was calculated to investigate spatial clustering of density, whether the degree of clustering varied between a woman's two breasts and whether it was affected by age and other known density correlates.Results The median Moran's / value for 165 women was 0.31 (interquartile range: 0.26, 0.37), indicating a clustered pattern. High-density areas tended to cluster in the central regions of the breast, regardless of the level of overall PD, but with considerable between-woman variability in regional PD. The degree of clustering was similar between a woman's two breasts (mean within-woman difference in Moran's / values between left and right breasts = 0.00 (95% confidence interval (CI) = -0.01, 0.01); P = 0.76) and did not change with aging (mean within-woman difference in I values between screens taken on average 8 years apart = 0.01 (95% CI = -0.01, 0.02); P = 0.30). Neither parity nor age at first birth affected the level of spatial autocorrelation of density, but increasing body mass index (BMI) was associated with a decrease in the degree of spatial clustering.Conclusions This study is the first to demonstrate that the distribution of radiodense tissue within the breast is spatially autocorrelated, generally with the high-density areas clustering in the central regions of the breast. The degree of clustering was similar within a woman's two breasts and between women, and was little affected by age or reproductive factors although it declined with increasing BMI

Impact of non-axillary sentinel node biopsy on staging and treatment of breast cancer patients

The purpose of this study was to evaluate the occurrence of lymphatic drainage to non-axillary sentinel nodes and to determine the implications of this phenomenon. A total of 549 breast cancer patients underwent lymphoscintigraphy after intratumoural injection of 99mTc-nanocolloid. The sentinel node was intraoperatively identified with the aid of intratumoural administered patent blue dye and a gamma-ray detection probe. Histopathological examination of sentinel nodes included step-sectioning at six levels and immunohistochemical staining. A sentinel node outside level I or II of the axilla was found in 149 patients (27%): internal mammary sentinel nodes in 86 patients, other non-axillary sentinel nodes in 44 and both internal mammary and other non-axillary sentinel nodes in nineteen patients. The intra-operative identification rate was 80%. Internal mammary metastases were found in seventeen patients and metastases in other non-axillary sentinel nodes in ten patients. Staging improved in 13% of patients with non-axillary sentinel lymph nodes and their treatment strategy was changed in 17%. A small proportion of clinically node negative breast cancer patients can be staged more precisely by biopsy of sentinel nodes outside level I and II of the axilla, resulting in additional decision criteria for postoperative regional or systemic therapy

Exploration of Shared Genetic Architecture Between Subcortical Brain Volumes and Anorexia Nervosa

In MRI scans of patients with anorexia nervosa (AN), reductions in brain volume are often apparent. However, it is unknown whether such brain abnormalities are influenced by genetic determinants that partially overlap with those underlying AN. Here, we used a battery of methods (LD score regression, genetic risk scores, sign test, SNP effect concordance analysis, and Mendelian randomization) to investigate the genetic covariation between subcortical brain volumes and risk for AN based on summary measures retrieved from genome-wide association studies of regional brain volumes (ENIGMA consortium, n = 13,170) and genetic risk for AN (PGC-ED consortium, n = 14,477). Genetic correlations ranged from − 0.10 to 0.23 (all p > 0.05). There were some signs of an inverse concordance between greater thalamus volume and risk for AN (permuted p = 0.009, 95% CI: [0.005, 0.017]). A genetic variant in the vicinity of ZW10, a gene involved in cell division, and neurotransmitter and immune system relevant genes, in particular DRD2, was significantly associated with AN only after conditioning on its association with caudate volume (pFDR = 0.025). Another genetic variant linked to LRRC4C, important in axonal and synaptic development, reached significance after conditioning on hippocampal volume (pFDR = 0.021). In this comprehensive set of analyses and based on the largest available sample sizes to date, there was weak evidence for associations between risk for AN and risk for abnormal subcortical brain volumes at a global level (that is, common variant genetic architecture), but suggestive evidence for effects of single genetic markers. Highly powered multimodal brain- and disorder-related genome-wide studies are needed to further dissect the shared genetic influences on brain structure and risk for AN

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (?genetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits

Allergies are associated with arterial changes in young children

BACKGROUND: Inflammation is important in atherosclerosis development. Whether common causes of inflammation, such as allergies and infections, already exert this influence in early childhood is unknown. The objective of this study was to investigate the association between both allergies and infections with children's vasculature. DESIGN: This was a longitudinal study in a general population cohort. METHODS: In 390 five-year-olds of the WHISTLER (Wheezing-Illnesses-Study-LEidsche-Rijn) birth cohort, carotid intima-media thickness (CIMT) and arterial stiffness were obtained ultrasonographically. Physician-diagnosed allergies and infections and recent prescriptions of systemic antihistamines and antibiotics were obtained, as well as parental history of allergies. General linear regression was performed with vascular characteristics as dependent variables and measures of inflammation as independent variables. RESULTS: Having both a positive parental history of allergy and an allergy diagnosis showed 15.0 µm (95% confidence interval (CI): 2.3-27.8, p = 0.02) larger CIMT than not having such history and diagnosis. Having a positive parental history of allergy only showed 11.9 µm (0.87-23.0, p = 0.04) larger CIMT. Recent use of antihistamines and antibiotics showed 18.8 µm (1.6-35.9, p = 0.03) and 16.1 µm (4.5-27.7, p = 0.01) larger CIMT, respectively. Childhood infections were not clearly related to vascular parameters. Neither allergy nor infections were associated with arterial stiffness. CONCLUSION: An allergic predisposition is already associated with thicker arterial walls in early childhood

Adult derived genetic blood pressure scores and blood pressure measured in different body postures in young children

Aims: Several genes are related to blood pressure (BP) levels in adults, but it is largely unknown whether these genes also determine BP early in life. Methods: Systolic BP (SBP) and diastolic BP (DBP) were measured in 720 5-year-old children from the WHeezing-Illnesses-STudy-LEidsche-Rijn (WHISTLER) birth cohort in sitting and supine positions using a semi-automatic oscillometric device. Illumina chip technology was used to genotype 18, 19, 11 and 12 single nucleotide polymorphisms associated with adult SBP, DBP, mean arterial pressure (MAP) and hypertension, respectively, in the children's DNA and separate weighted genetic risk scores (GRSs) were constructed. The associations are reported as linear regression coefficients (mmHg BP in childhood/GRS score point) or odds ratios (highest childhood BP quintile/hypertension GRS score point). Results: A higher GRS for SBP was related to higher supine SBP (0.37, 95% CI 0.01 to 0.7), but not to supine DBP (-0.05, 95% CI-0.4 to 0.3) or supine MAP (0.19, 95% CI-0.1 to 0.5). A higher GRS for DBP was related to a higher supine SBP (0.66, 95% CI 0.1 to 1.2), but not to supine DBP (-0.07, 95% CI-0.6 to 0.4) or supine MAP (0.28, 95% CI-0.2 to 0.7). With the sitting BP measurements, the GRSs for SBP and DBP were related to neither SBP nor DBP. No association was found between GRS for MAP and SBP, DBP or MAP. Hypertension GRS was not associated with a higher BP in children. Conclusions: Higher scores for adult derived diastolic and systolic BP genes appear to be related to higher supine systolic BP at age 5 year