A family history of breast cancer will not predict female early onset breast cancer in a population-based setting

ABSTRACT: BACKGROUND: An increased risk of breast cancer for relatives of breast cancer patients has been demonstrated in many studies, and having a relative diagnosed with breast cancer at an early age is an indication for breast cancer screening. This indication has been derived from estimates based on data from cancer-prone families or from BRCA1/2 mutation families, and might be biased because BRCA1/2 mutations explain only a small proportion of the familial clustering of breast cancer. The aim of the current study was to determine the predictive value of a family history of cancer with regard to early onset of female breast cancer in a population based setting. METHODS: An unselected sample of 1,987 women with and without breast cancer was studied with regard to the age of diagnosis of breast cancer. RESULTS: The risk of early-onset breast cancer was increased when there were: (1) at least 2 cases of female breast cancer in first-degree relatives (yes/no; HR at age 30: 3.09; 95% CI: 128-7.44), (2) at least 2 cases of female breast cancer in first or second-degree relatives under the age of 50 (yes/no; HR at age 30: 3.36; 95% CI: 1.12-10.08), (3) at least 1 case of female breast cancer under the age of 40 in a first- or second-degree relative (yes/no; HR at age 30: 2.06; 95% CI: 0.83-5.12) and (4) any case of bilateral breast cancer (yes/no; HR at age 30: 3.47; 95%: 1.33-9.05). The positive predictive value of having 2 or more of these characteristics was 13% for breast cancer before the age of 70, 11% for breast cancer before the age of 50, and 1% for breast cancer before the age of 30. CONCLUSION: Applying family history related criteria in an unselected population could result in the screening of many women who will not develop breast cancer at an early age

Genomic instability and proliferative activity as risk factors for distant metastases in breast cancer

The role of genomic instability and proliferative activity for development of distant metastases in breast cancer was analysed, and the relative contribution of these two risk factors was quantified. A detailed quantitative comparison was performed between Ki67 and cyclin A as proliferative markers. The frequency of Ki67 and cyclin A-positive cells was scored in the same microscopic areas in 428 breast tumours. The frequency of Ki67-positive cells was found to be highly correlated with the frequency of cyclin A-positive cells, and both proliferation markers were equally good to predict risk of distant metastases. The relative contribution of degree of aneuploidy and proliferative activity as risk markers for developing distant metastases was studied independently. Although increased proliferative activity in general was associated with an increased risk of developing distant metastases, ploidy level was found to be an independent and even stronger marker when considering the group of small (T1) node negative tumours. By combining proliferative activity and ploidy level, a large group of low risk breast tumours (39%) could be identified in which only a few percentage of the tumours (5%) developed distant metastases during the 9-year follow-up time period

Gross genomic damage measured by DNA image cytometry independently predicts gastric cancer patient survival

BACKGROUND: DNA aneuploidy reflects gross genomic changes. It can be measured by flow cytometry (FCM-DNA) or image cytometry (ICM-DNA). In gastric cancer, the prevalence of DNA aneuploidy has been reported to range from 27 to 100%, with conflicting associations with clinicopathological variables. The aim of our study was to compare the DNA ploidy status measured using FCM-DNA and ICM-DNA in gastric cancer and to evaluate its association with clinicopathological variables. METHODS: Cell nuclei were isolated from 221 formalin-fixed, paraffin-embedded gastric cancer samples. DNA ploidy was assessed using FCM-DNA and ICM-DNA. RESULTS: A total of 178 (80.5%) gastric cancer samples were classified as DNA aneuploid using FCM-DNA, compared with 172 (77.8%) gastric cancer samples when using ICM-DNA. Results obtained from both methods were concordant in 183 (82.8%) cases (kappa = 0.48). Patients with ICM-DNA diploid gastric cancer survived significantly longer than those with ICM-DNA aneuploid gastric cancer (log rank 10.1, P = 0.001). For FCM-DNA data, this difference did not reach statistical significance. The multivariate Cox model showed that ICM-DNA ploidy status predicted patient survival independently of tumour-node-metastasis status. CONCLUSION: ICM-DNA ploidy status is an independent predictor of survival in gastric cancer patients and may therefore be a more clinically relevant read out of gross genomic damage than FCM-DNA. British Journal of Cancer (2009) 101, 1011-1018. doi:10.1038/sj.bjc.6605266 www.bjcancer.com (C) 2009 Cancer Research U

Increasing genome instability in adrenocortical carcinoma progression with involvement of chromosomes 3, 9 and X at the adenoma stage

The investigation of chromosomal aberrations in adrenocortical tumours has been limited by the difficulties of applying classical cytogenetics to tumours with low levels of proliferation. We have therefore applied the technique of interphase cytogenetics to paraffin-embedded archival specimens of 14 adrenocortical adenomas and 13 carcinomas. Hybridizations were performed using centromere-specific probes to chromosomes 3, 4, 9, 17, 18 and X, which have been shown to be altered in other types of tumours. Chromosomal imbalance was defined on the basis of changes in both chromosome index (CI) and signal distribution (SD). Where only one of these was altered, this was classified as a tendency to gain or loss. On the basis of the analysis of optimal hybridizations, carcinomas showed gains in all chromosomes studied, five of nine showing gains in multiple chromosomes. Gains were most common in chromosomes 3, 9 and, in particular X, eight of 11 showing gain, and one a tendency to gain. Chromosomal gain was seen less commonly in adenomas, but again chromosomes 3, 9 and X were involved. Losses were infrequent, only one carcinoma showing loss of chromosome 18, and adenomas showing a tendency to loss of chromosomes 4 (two cases), 17 (one case) and 18 (two cases). Our data suggest that changes in chromosomes 3, 9 and X are early events in adrenocortical tumorigenesis, and that there is increasing chromosomal instability with tumour progression. © 1999 Cancer Research Campaig

Social and cultural factors underlying generational differences in overweight: a cross-sectional study among ethnic minorities in the Netherlands

<p>Abstract</p> <p>Background</p> <p>The prevalence of overweight appears to vary in people of first and second generation ethnic minority groups. Insight into the factors that underlie these weight differences might help in understanding the health transition that is taking place across generations following migration. We studied the role of social and cultural factors associated with generational differences in overweight among young Turkish and Moroccan men and women in the Netherlands.</p> <p>Methods</p> <p>Cross-sectional data were derived from the LASER-study in which information on health-related behaviour and socio-demographic factors, level of education, occupational status, acculturation (cultural orientation and social contacts), religious and migration-related factors was gathered among Turkish and Moroccan men (n = 334) and women (n = 339) aged 15-30 years. Participants were interviewed during a home visit. Overweight was defined as a Body Mass Index ≥ 25 kg/m². Using logistic regression analyses, we tested whether the measured social and cultural factors could explain differences in overweight between first and second generation ethnic groups.</p> <p>Results</p> <p>Second generation women were less often overweight than first generation women (21.8% and 45.0% respectively), but this association was no longer significant when adjusting for the socioeconomic position (i.e. higher level of education) of second generation women (Odds Ratio (OR) = 0.77, 95%, Confidence Interval (CI) 0.40-1.46). In men, we observed a reversed pattern: second generation men were more often overweight than first generation men (32.7% and 27.8%). This association (OR = 1.89, 95% CI 1.09-3.24) could not be explained by the social and cultural factors because none of these factors were associated with overweight among men.</p> <p>Conclusions</p> <p>The higher socio-economic position of second generation Turkish and Moroccan women may partly account for the lower prevalence of overweight in this group compared to first generation women. Further research is necessary to elucidate whether any postulated socio-biological or other processes are relevant to the opposite pattern of overweight among men.</p

A molecular analysis by gene expression profiling reveals Bik/NBK overexpression in sporadic breast tumor samples of Mexican females

BACKGROUND: Breast cancer is one of the most frequent causes of death in Mexican women over 35 years of age. At molecular level, changes in many genetic networks have been reported as associated with this neoplasia. To analyze these changes, we determined gene expression profiles of tumors from Mexican women with breast cancer at different stages and compared these with those of normal breast tissue samples. METHODS: (32)P-radiolabeled cDNA was synthesized by reverse transcription of mRNA from fresh sporadic breast tumor biopsies, as well as normal breast tissue. cDNA probes were hybridized to microarrays and expression levels registered using a phosphorimager. Expression levels of some genes were validated by real time RT-PCR and immunohistochemical assays. RESULTS: We identified two subgroups of tumors according to their expression profiles, probably related with cancer progression. Ten genes, unexpressed in normal tissue, were turned on in some tumors. We found consistent high expression of Bik gene in 14/15 tumors with predominant cytoplasmic distribution. CONCLUSION: Recently, the product of the Bik gene has been associated with tumoral reversion in different neoplasic cell lines, and was proposed as therapy to induce apoptosis in cancers, including breast tumors. Even though a relationship among genes, for example those from a particular pathway, can be observed through microarrays, this relationship might not be sufficient to assign a definitive role to Bik in development and progression of the neoplasia. The findings herein reported deserve further investigation

Spectral morphometric characterization of breast carcinoma cells

The spectral morphometric characteristics of standard haematoxylin and eosin breast carcinoma specimens were evaluated by light microscopy combined with a spectral imaging system. Light intensity at each wavelength in the range of 450–800 nm was recorded for 104 pixels from each field and represented as transmitted light spectra. A library of six characteristic spectra served to scan the cells and reconstruct new images depicting the nuclear area occupied by each spectrum. Fifteen cases of infiltrating ductal carcinoma and six cases of lobular carcinoma were examined; nine of the infiltrating ductal carcinoma and three of the lobular carcinoma showed an in situ component. The spectral morphometric analysis revealed a correlation between specific patterns of spectra and different groups of breast carcinoma cells. The most consistent result was that lobular carcinoma cells of in situ and infiltrating components from all patients showed a similar spectral pattern, whereas ductal carcinoma cells displayed spectral variety. Comparison of the in situ and the infiltrating ductal solid, cribriform and comedo carcinoma cells from the same patient revealed a strong similarity of the spectral elements and their relative distribution in the nucleus. The spectrum designated as number 5 in the library incorporated more than 40% of the nuclear area in 74.08% of the infiltrating lobular cells and in 13.64% of the infiltrating ductal carcinoma cells (P < 0.001). Spectrum number 2 appeared in all infiltrating ductal cells examined and in none of the lobular cells. These results indicate that spectrum number 5 is related to infiltrating lobular carcinoma, whereas spectrum number 2 is characteristic for infiltrating ductal carcinoma cells. Spectral similarity mapping of central necrotic regions of comedo type in situ carcinoma revealed nuclear fragmentation into defined segments composed of highly condensed chromatin. We conclude that the spectral morphometric features found for lobular and ductal cell populations may serve future automated histological diagnostics. © 1999 Cancer Research Campaig

Dose-Dependent Effects of Endotoxin on Neurobehavioral Functions in Humans

Clinical and experimental evidence document that inflammation and increased peripheral cytokine levels are associated with depression-like symptoms and neuropsychological disturbances in humans. However, it remains unclear whether and to what extent cognitive functions like memory and attention are affected by and related to the dose of the inflammatory stimulus. Thus, in a cross-over, double-blind, experimental approach, healthy male volunteers were administered with either placebo or bacterial lipopolysaccharide (LPS) at doses of 0.4 (n = 18) or 0.8 ng/kg of body weight (n = 16). Pro- and anti-inflammatory cytokines, norephinephrine and cortisol concentrations were analyzed before and 1, 1.75, 3, 4, 6, and 24 h after injection. In addition, changes in mood and anxiety levels were determined together with working memory (n-back task) and long term memory performance (recall of emotional and neutral pictures of the International Affective Picture System). Endotoxin administration caused a profound transient physiological response with dose-related elevations in body temperature and heart rate, increases in plasma interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α and IL-1 receptor antagonist (IL-1ra), salivary and plasma cortisol, and plasma norepinephrine. These changes were accompanied by dose-related decreased mood and increased anxiety levels. LPS administration did not affect accuracy in working memory performance but improved reaction time in the high-dose LPS condition compared to the control conditon. In contrast, long-term memory performance was impaired selectively for emotional stimuli after administration of the lower but not of the higher dose of LPS. These data suggest the existence of at least two counter-acting mechanisms, one promoting and one inhibiting cognitive performance during acute systemic inflammation

Vascular Dysfunction in Horses with Endocrinopathic Laminitis

Endocrinopathic laminitis (EL) is a vascular condition of the equine hoof resulting in severe lameness with both welfare and economic implications. EL occurs in association with equine metabolic syndrome and equine Cushing's disease. Vascular dysfunction, most commonly due to endothelial dysfunction, is associated with cardiovascular risk in people with metabolic syndrome and Cushing's syndrome. We tested the hypothesis that horses with EL have vascular, specifically endothelial, dysfunction. Healthy horses (n = 6) and horses with EL (n = 6) destined for euthanasia were recruited. We studied vessels from the hooves (laminar artery, laminar vein) and the facial skin (facial skin arteries) by small vessel wire myography. The response to vasoconstrictors phenylephrine (10-9-10-5M) and 5-hydroxytryptamine (5HT; 10-9-10-5M) and the vasodilator acetylcholine (10-9-10-5M) was determined. In comparison with healthy controls, acetylcholine-induced relaxation was dramatically reduced in all intact vessels from horses with EL (% relaxation of healthy laminar arteries 323.5 ± 94.1% v EL 90.8 ± 4.4%, P = 0.01, laminar veins 129.4 ± 14.8% v EL 71.2 ± 4.1%, P = 0.005 and facial skin arteries 182.0 ± 40.7% v EL 91.4 ± 4.5%, P = 0.01). In addition, contractile responses to phenylephrine and 5HT were increased in intact laminar veins from horses with EL compared with healthy horses; these differences were endothelium-independent. Sensitivity to phenylephrine was reduced in intact laminar arteries (P = 0.006) and veins (P = 0.009) from horses with EL. Horses with EL exhibit significant vascular dysfunction in laminar vessels and in facial skin arteries. The systemic nature of the abnormalities suggest this dysfunction is associated with the underlying endocrinopathy and not local changes to the hoof