Increased risk of second malignancies after in situ breast carcinoma in a population-based registry

Among 1276 primary breast carcinoma in situ (BCIS) patients diagnosed in 1972–2002 in the Southern Netherlands, 11% developed a second cancer. Breast carcinoma in situ patients exhibited a two-fold increased risk of second cancer (standardised incidence ratios (SIR): 2.1, 95% confidence interval (CI): 1.7–2.5). The risk was highest for a second breast cancer (SIR: 3.4, 95% CI: 2.6–4.3; AER: 66 patients per 10 000 per year) followed by skin cancer (SIR: 1.7, 95% CI: 1.1–2.6; AER: 17 patients per 10 000 per year). The increased risk of second breast cancer was similar for the ipsilateral (SIR: 1.9, 95% CI: 1.3–2.7) and contralateral (SIR: 2.0, 95% CI: 1.4–2.8) breast. Risk of second cancer was independent of age at diagnosis, type of initial therapy, histologic type of BCIS and period of diagnosis. Standardised incidence ratios of second cancer after BCIS (SIR: 2.3, 95% CI: 1.8–2.8) resembled that after invasive breast cancer (SIR: 2.2, 95% CI: 2.1–2.4). Surveillance should be directed towards second (ipsi- and contra-lateral) breast cancer

Changes in plasma fatty acid composition are associated with improvements in obesity and related metabolic disorders: A therapeutic approach to overweight adolescents

Background & aims: In recent years, obesity has reached alarming levels among children and adolescents. The study of plasma fatty acid (FA) composition, as a reflection of diet, and its associations with other parameters, that are closely linked to obesity and the cardiometabolic profile, may be useful for setting nutritional goals for obesity treatment and prevention. This study explored the relationship between plasma FA levels and body fat and cardiometabolic risk markers, in overweight adolescents. Methods: A multidisciplinary weight loss program was followed by 127 overweight and obese adolescents aged 12-17 years old. Plasma FA composition, anthropometric indicators of adiposity and biochemical parameters were analyzed at baseline, two months (the end of the intensive intervention phase) and six months (the end of the extensive phase). Results: While saturated fatty acid (SFA) and n-6 polyunsaturated fatty acid (PUFA) levels decreased significantly during the intervention, monounsaturated fatty acid (MUFA) and n-3 PUFA showed the opposite trend. The decrease in SFA C14:0 was associated with a reduction in total and LDL cholesterol, apolipoprotein B and insulin. The increase in MUFAs, especially C18:1n-9, was related to a reduction in weight, fat mass, fat mass index and glucose. Regarding PUFAs, changes in the n-3 series were not associated with any of the parameters studied, whereas the reduction in n-6 PUFA5 was directly related to weight, fat mass, total and HDL cholesterol, apolipoprotein Al, glucose and insulin, and inversely associated with diastolic blood pressure. The adolescents with greater weight loss presented significant changes in MUFAs, n-6 PUFA5 and C14:0. Conclusions: Modifications in plasma FA composition were associated with adiposity reduction and cardiometabolic profile improvement in an anti-obesity program aimed at adolescents. The changes observed in FA composition were related to the success of the treatment, since the individuals most affected by these variations were those who presented the greatest weight loss

Risk of subsequent invasive breast carcinoma after in situ breast carcinoma in a population covered by national mammographic screening

Sweden was the first country to establish a nationwide breast cancer screening service. We used the Swedish Family-Cancer Database to evaluate the risk of invasive carcinoma after in situ carcinoma of the breast. Risk estimates for contralateral and ipsilateral invasive malignancies following age and histology specific in situ breast carcinomas were calculated using Poisson's regression analysis. The agreement between concordant and discordant morphologies of invasive and in situ breast cancer was measured using the kappa statistic. Women with in situ breast cancer showed a relative risk of 2.03 for contralateral and 3.94 for ipsilateral invasive breast cancer. The risk was higher for in situ carcinomas diagnosed before the age of 50 years and after lobular in situ breast cancers. A comparison of the risks during the past decades suggested that the risk of ipsilateral breast cancer has increased in Sweden but that of contralateral breast cancer has remained unchanged. In situ and the subsequent invasive breast cancers did not seem to share their morphologies

Relationship of Adiposity and Insulin Resistance Mediated by Inflammation in a Group of Overweight and Obese Chilean Adolescents

The mild chronic inflammatory state associated with obesity may be an important link between adiposity and insulin resistance (IR). In a sample of 137 overweight and obese Chilean adolescents, we assessed associations between high-sensitivity C-reactive protein (hs-CRP), IR and adiposity; explored sex differences; and evaluated whether hs-CRP mediated the relationship between adiposity and IR. Positive relationships between hs-CRP, IR and 2 measures of adiposity were found. Hs-CRP was associated with waist circumference (WC) in boys and fat mass index (FMI) in girls. Using path analysis, we found that hs-CRP mediated the relationship between adiposity (WC and FMI) and the homeostatic model assessment of insulin resistance (HOMA-IR) (p < 0.05) in both sexes. Our novel finding is that inflammation statistically mediated the well described link between increased adiposity and IR

Mediterranean Diet Reduces the Adverse Effect of the TCF7L2-rs7903146 Polymorphism on Cardiovascular Risk Factors and Stroke Incidence

OBJECTIVE Transcription factor 7-like 2 (TCF7L2) polymorphisms are strongly associated with type 2 diabetes, but controversially with plasma lipids and cardiovascular disease. Interactions of the Mediterranean diet (MedDiet) on these associations are unknown. We investigated whether the TCF7L2-rs7903146 (C>T) polymorphism associations with type 2 diabetes, glucose, lipids, and cardiovascular disease incidence were modulated by MedDiet. RESEARCH DESIGN AND METHODS A randomized trial (two MedDiet intervention groups and a control group) with 7,018 participants in the PREvención con DIetaMEDiterránea study was undertaken and major cardiovascular events assessed. Data were analyzed at baseline and after a median follow-up of 4.8 years. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) for cardiovascular events. RESULTS The TCF7L2-rs7903146 polymorphism was associated with type 2 diabetes (odds ratio 1.87 [95% CI 1.62–2.17] for TT compared with CC). MedDiet interacted significantly with rs7903146 on fasting glucose at baseline (P interaction = 0.004). When adherence to the MedDiet was low, TT had higher fasting glucose concentrations (132.3 ± 3.5 mg/dL) than CC+CT (127.3 ± 3.2 mg/dL) individuals (P = 0.001). Nevertheless, when adherence was high, this increase was not observed (P = 0.605). This modulation was also detected for total cholesterol, LDL cholesterol, and triglycerides (P interaction < 0.05 for all). Likewise, in the randomized trial, TT subjects had a higher stroke incidence in the control group (adjusted HR 2.91 [95% CI 1.36–6.19]; P = 0.006 compared with CC), whereas dietary intervention with MedDiet reduced stroke incidence in TT homozygotes (adjusted HR 0.96 [95% CI 0.49–1.87]; P = 0.892 for TT compared with CC). CONCLUSIONS Our novel results suggest that MedDiet may not only reduce increased fasting glucose and lipids in TT individuals, but also stroke incidence

Effect of a farnesyl transferase inhibitor (R115777) on ductal carcinoma in situ of the breast in a human xenograft model and on breast and ovarian cancer cell growth in vitro and in vivo

INTRODUCTION: The ras pathway is essential for cell growth and proliferation. The effects of R115777, a farnesyl transferase inhibitor, were investigated in cancer cell lines expressing varying levels of growth factor receptors and with differing ras status. Effects on tumour xenografts and human ductal carcinoma in situ (DCIS) of the breast in a xenograft mouse model were also tested. METHOD: In vitro, the concentrations required to reduce cell numbers by 50% (50% inhibitory concentration) were established (MDA-MB231, MCF-7, MCF-7/HER2-18, BT-474, SK-BR3 and SKOV3). Human DCIS was implanted in nude mice or, in separate experiments, cultured cells were injected (MDA-MB231, MCF-7/HER2-18, SKOV3) and allowed to form tumours. Proliferation and apoptosis were determined by immunohistochemistry in xenografts and cell tumours. RESULTS: The 50% inhibitory concentrations varied a hundred-fold, from 39 nmol/l (± 26 nmol/l) for SKBR3 to 5.9 μmol/l(± 0.8 μmol/l) for MDA-MB231. In MCF-7/HER2-18 and SKOV3 cells the levels of tumour growth inhibition were approximately 85% and 40%, respectively. There was a significant decrease in the cell turnover index (CTI; proliferation/apoptosis). In MDA-MB 231 with activated k-ras no inhibition was observed. In treated DCIS xenografts proliferation decreased and apoptosis increased. The CTI ratio between the start and 1 and 2 weeks of treatment were 1.99 and 1.50, respectively, for controls and 0.85 (P = 0.005) and 0.75 (P = 0.08) for treated xenografts. CONCLUSION: Treatment with the farnesyl transferase inhibitor reduced cell growth in vitro and cell tumour growth in vivo. In DCIS treatment resulted in a reduced CTI. R115777 is a promising treatment for breast cancer but the relation between effect and growth factor receptor and ras status has to be established

C-reactive protein reference percentiles among pre-adolescent children in Europe based on the IDEFICS study population

OBJECTIVES: C-reactive protein (CRP) is involved in a wide range of diseases. It is a powerful marker for inflammatory processes used for diagnostic and monitoring purposes. We aimed to establish reference values as data on the distribution of serum CRP levels in young European children are scarce. SUBJECTS: Reference values of high-sensitivity CRP concentrations were calculated for 9855 children aged 2.0-10.9 years, stratified by age and sex. The children were recruited during the population-based European IDEFICS study (Identification and prevention of Dietary-and lifestyle-induced health Effects in Children and infantS) with 18 745 participants recruited from 2007 to 2010. RESULTS: In 44.1 % of the children, CRP values were below or equal the detection limit of 0.2 mg/l. Median CRP concentrations showed a slight negative age trend in boys and girls, whereas serum CRP values were slightly higher in girls than in boys across all age groups. CONCLUSIONS: Our population-based reference values of CRP may guide paediatric practice as elevated values may require further investigation or treatment. Therefore, the presented reference values represent a basis for clinical evaluation and for future research on risk assessment of diseases associated with increased CRP levels among children

Integrated molecular profiles of invasive breast tumors and ductal carcinoma in situ (DCIS) reveal differential vascular and interleukin signaling

We use an integrated approach to understand breast cancer heterogeneity by modeling mRNA, copy number alterations, microRNAs, and methylation in a pathway context utilizing the pathway recognition algorithm using data integration on genomic models (PARADIGM). We demonstrate that combining mRNA expression and DNA copy number classified the patients in groups that provide the best predictive value with respect to prognosis and identified key molecular and stromal signatures. A chronic inflammatory signature, which promotes the development and/or progression of various epithelial tumors, is uniformly present in all breast cancers. We further demonstrate that within the adaptive immune lineage, the strongest predictor of good outcome is the acquisition of a gene signature that favors a high T-helper 1 (Th1)/cytotoxic T-lymphocyte response at the expense of Th2-driven humoral immunity. Patients who have breast cancer with a basal HER2-negative molecular profile (PDGM2) are characterized by high expression of protumorigenic Th2/humoral-related genes (24–38%) and a low Th1/Th2 ratio. The luminal molecular subtypes are again differentiated by low or high FOXM1 and ERBB4 signaling. We show that the interleukin signaling profiles observed in invasive cancers are absent or weakly expressed in healthy tissue but already prominent in ductal carcinoma in situ, together with ECM and cell-cell adhesion regulating pathways. The most prominent difference between low and high mammographic density in healthy breast tissue by PARADIGM was that of STAT4 signaling. In conclusion, by means of a pathway-based modeling methodology (PARADIGM) integrating different layers of molecular data from whole-tumor samples, we demonstrate that we can stratify immune signatures that predict patient survival