Endoglin, VEGF, and its receptors in predicting metastases in endometrial carcinoma.

Preoperative evaluation of the risk for metastases in endometrial carcinoma is challenging. The growth of new vessels, angiogenesis, is important for tumor growth and purported to be involved in the metastatic process. The aim of this study was to evaluate the significance of preoperative serum levels and immunohistochemical expression of angiogenic markers in predicting a metastasized disease. Preoperative sera from 98 consecutive women presenting with endometrial carcinoma were collected. Serum concentrations of VEGF, sFLT1, and CD105 were assessed by enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry was used to assess the expression of CD105, VEGF, FLT1, and KDR. The results were correlated to the presence of metastases, presence of deep (≥50%) myometrial invasion, and the histological grade of the tumor. Tumors with other than endometrioid histology were excluded. Of the 80 evaluable patients, 11 had a metastasized disease. The serum concentration of VEGF was higher in the group with metastases than in the group without metastases (median [range], 743 pg/mL [546-1,183 pg/mL] vs. 383 pg/mL [31-1,524 pg/mL], p < 0.001, respectively). In the multivariable analysis, the concentration of VEGF was the sole independent, albeit weak predictive factor for the presence of metastases (odds ratio, 1.004, 95% confidence interval, 1.002-1.007; p = 0.001). The immunohistochemical expression of the markers was not associated with any of the clinicopathological features of the tumors. The results of the present study suggest that preoperative serum VEGF concentration correlates with the presence of metastases in endometrioid endometrial carcinoma.

Vascular cell adhesion molecule 1, soluble Fas and hepatocyte growth factor as predictors of mortality in nonagenarians: the Vitality 90+ study.

BACKGROUND: Ageing is characteristically accompanied by changes in vascular endothelial markers and growth factor as well as increased cellular death. We analysed the associations of the plasma levels of vascular cell adhesion molecule-1 (VCAM-1), hepatocyte growth factor (HGF) and soluble Fas (sFAS), and their combinations, with 4-year mortality to identify new biomarkers. METHODS: A total of 238 individuals, both community-dwelling and institutionalised, aged 89 91 years and participating in the Vitality 90+ study were included. Biomarkers of endothelial function (VCAM-1), growth factor (HGF) and a marker of apoptosis (sFAS) were determined from plasma using Luminex® technology. This newly-determined data was combined with earlier data, e.g., 4-year mortality and medical history. RESULTS: Subjects who died during the follow-up had higher baseline plasma levels of VCAM-1, sFas, and HGF. When other known risk factors were adjusted for, subjects in the highest concentration tertile for VCAM-1 (HR 1.85; 95% CI, 1.12-3.05) and HGF (HR 2.22; 95% CI, 1.33-3.71) had higher mortality compared to those in the lowest tertile. In the adjusted analyses, when compared to subjects with none of the biomarkers in the highest concentration tertile, mortality was also higher when sFas and VCAM-1 were simultaneously (HR 2.03; 95% CI, 1.13-3.64) or all three were simultaneously (HR 3.63; 95% CI, 1.65-7.97) in the highest concentration tertile. CONCLUSIONS: Our results suggest that increased concentrations of these biomarkers, separately and in combination, associate with mortality among the aged and are prognostic markers of death.

Predictive value of serum human epididymis protein 4 and cancer antigen 125 concentrations in endometrial carcinoma.

OBJECTIVE: The purpose of this study was to evaluate the performance of preoperative serum levels of human epididymis protein 4 (HE4) and cancer antigen 125 (CA125) in the prediction of the presence of metastases in endometrial carcinoma. STUDY DESIGN: Preoperative sera were collected from 98 women with a diagnosis of endometrial carcinoma. The concentrations of HE4 and CA125 were assessed by enzyme-linked immunosorbent assay and correlated with the results of the final histopathologic report. RESULTS: Fourteen patients had metastases (≥stage IIIA, International Federation of Gynecology and Obstetrics 2009 classification). The serum concentrations of HE4 and CA125 were higher in the group with metastases than in the group without metastases (median [interquartile range], 148.6 pmol/L [71.6-219.1 pmol/L] vs 77.2 pmol/L [52.9-99.3 pmol/L]; P = .001; and 20.0 U/mL [10.1-70.8 U/mL] vs 4.3 U/mL [2.9-10.4 U/mL]; P < .001, respectively). By a multivariate analysis, the combination of HE4 and CA125 (a risk score algorithm) was the only predictive factor for the presence of metastases (odds ratio, 21.562; 95% confidence interval, 5.472-84.963; P < .001), and the grade was the predictor for a deep (≥50%) myometrial invasion by the tumor (odds ratio, 2.005; 95% confidence interval, 1.123-3.581; P = .019). The sensitivity, specificity, positive predictive value, and negative predictive value for the combination of the markers to predict the presence of metastases were 71.4%, 89.5%, 55.6%, and 94.4%, respectively. CONCLUSION: A combination of preoperative HE4 and CA125 seems to be a better predictor of metastatic disease than either 1 alone in endometrial carcinoma.

Genetic variants and their interactions in the prediction of increased pre-clinical carotid atherosclerosis: the cardiovascular risk in young Finns study.

The relative contribution of genetic risk factors to the progression of subclinical atherosclerosis is poorly understood. It is likely that multiple variants are implicated in the development of atherosclerosis, but the subtle genotypic and phenotypic differences are beyond the reach of the conventional case-control designs and the statistical significance testing procedures being used in most association studies. Our objective here was to investigate whether an alternative approach--in which common disorders are treated as quantitative phenotypes that are continuously distributed over a population--can reveal predictive insights into the early atherosclerosis, as assessed using ultrasound imaging-based quantitative measurement of carotid artery intima-media thickness (IMT). Using our population-based follow-up study of atherosclerosis precursors as a basis for sampling subjects with gradually increasing IMT levels, we searched for such subsets of genetic variants and their interactions that are the most predictive of the various risk classes, rather than using exclusively those variants meeting a stringent level of statistical significance. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive value of the variants, and cross-validation was used to assess how well the predictive models will generalize to other subsets of subjects. By means of our predictive modeling framework with machine learning-based SNP selection, we could improve the prediction of the extreme classes of atherosclerosis risk and progression over a 6-year period (average AUC 0.844 and 0.761), compared to that of using conventional cardiovascular risk factors alone (average AUC 0.741 and 0.629), or when combined with the statistically significant variants (average AUC 0.762 and 0.651). The predictive accuracy remained relatively high in an independent validation set of subjects (average decrease of 0.043). These results demonstrate that the modeling framework can utilize the "gray zone" of genetic variation in the classification of subjects with different degrees of risk of developing atherosclerosis.

FTO genotype is associated with body mass index after the age of seven years but not with energy intake or leisure-time physical activity.

CONTEXT: A common variant in the FTO gene, rs9939609, associates with body mass index (BMI) in adults and in children aged 7 yr or older. OBJECTIVE: Our aim was to examine the associations of the FTO genotype with BMI, cardiovascular risk factors, energy intake, and leisure-time physical activity in children followed up since infancy. METHODS: Healthy participants of the STRIP Study, genotyped for rs9939609, were followed from age 7 months (n = 640) to 15 yr (n = 438). The children were randomly assigned to lifestyle intervention and control groups. Height, weight, blood pressure, and serum lipids were measured annually. Food records and physical activity index were obtained at age 15 yr. RESULTS: The FTO genotype did not associate with BMI in children younger than 7 yr of age. From age 7 yr onward, the children homozygous for the A allele had progressively higher BMI than the children with one or two T alleles (P = 0.029 for FTO by age interaction). Furthermore, in longitudinal, BMI Z-score-adjusted analysis, the AA genotype associated with higher systolic and diastolic blood pressure and with elevated serum total and low-density lipoprotein-cholesterol (P = 0.01, P < 0.001, P = 0.05, and P = 0.04 for main effect, respectively). The FTO genotype did not associate with energy intake or physical activity index at age 15. The FTO *Study group interactions were not significant. CONCLUSIONS: Our results suggest that the effect of the FTO genotype on BMI becomes evident only after age 7 yr. These results further suggest that the FTO gene is not directly associated with energy intake or physical activity.

Plasma-soluble CD40 is related to cholesterol metabolism in patients with moderate hypercholesterolemia.

OBJECTIVES: CD40 is a marker of immunological activation and is expressed in the atherosclerotic lesions. We studied whether CD40 and cholesterol synthesis pathways are associated with each other. DESIGN: Forty-three subjects were randomly assigned to receive either simvastatin (n = 14), atorvastatin (n = 15), or placebo (n = 14) for eight weeks. Plasma samples were obtained before and at the end of the follow-up. sCD40 levels were measured in duplicate using an enzyme-linked immunosorbent assay. Cholesterol, its precursor lathosterol, the plant sterols campesterol and sitosterol as well as 27-hydroxycholesterol were quantified by gas-liquid chromatography-mass spectrometry. RESULTS: sCD40 was inversely correlated with the lathosterol to cholesterol ratio (r = - 0.47, p = 0.002), an indicator of cholesterol synthesis rate, as well as apolipoprotein A-I (r = - 0.38, p = 0.01) in addition to being directly correlated with 27-hydroxycholesterol (r = 0.40, p = 0.008). In multivariate linear regression analysis these three predictors explained 37% of the total variability of sCD40 levels. Simvastatin or atorvastatin treatment had no significant effect on sCD40 levels. CONCLUSION: These results indirectly suggest that sCD40 concentrations are related to cellular cholesterol levels. This may be a novel indication for the relationship between immunological processes and cholesterol metabolism.