Freund's vaccine adjuvant promotes Her2/Neu breast cancer

<p>Abstract</p> <p>Background</p> <p>Inflammation has been linked to the etiology of many organ-specific cancers. Indirect evidence suggests a possible role for inflammation in breast cancer. We investigated whether the systemic inflammation induced by Freund's adjuvant (FA) promotes mammary carcinogenesis in a rat model in which cancer is induced by the <it>neu </it>oncogene.</p> <p>Methods</p> <p>The effects of FA on hyperplastic mammary lesions and mammary carcinomas were determined in a <it>neu</it>-induced rat model. The inflammatory response to FA treatment was gauged by measuring acute phase serum haptoglobin. In addition, changes in cell proliferation and apoptosis following FA treatment were assessed.</p> <p>Results</p> <p>Rats receiving FA developed twice the number of mammary carcinomas as controls. Systemic inflammation following FA treatment is chronic, as shown by a doubling of the levels of the serum biomarker, haptoglobin, 15 days following initial treatment. We also show that this systemic inflammation is associated with the increased growth of hyperplastic mammary lesions. This increased growth results from a higher rate of cellular proliferation in the absence of changes in apoptosis.</p> <p>Conclusion</p> <p>Our data suggests that systemic inflammation induced by Freund's adjuvant (FA) promotes mammary carcinogenesis. It will be important to determine whether adjuvants currently used in human vaccines also promote breast cancer.</p

Predicting early brain metastases based on clinicopathological factors and gene expression analysis in advanced HER2-positive breast cancer patients

The overexpression or amplification of the human epidermal growth factor receptor 2 gene (HER2/neu) is associated with high risk of brain metastasis (BM). The identification of patients at highest immediate risk of BM could optimize screening and facilitate interventional trials. We performed gene expression analysis using complementary deoxyribonucleic acid-mediated annealing, selection, extension and ligation and real-time quantitative reverse transcription PCR (qRT-PCR) in primary tumor samples from two independent cohorts of advanced HER2 positive breast cancer patients. Additionally, we analyzed predictive relevance of clinicopathological factors in this series. Study group included discovery Cohort A (84 patients) and validation Cohort B (75 patients). The only independent variables associated with the development of early BM in both cohorts were the visceral location of first distant relapse [Cohort A: hazard ratio (HR) 7.4, 95 % CI 2.4–22.3; p < 0.001; Cohort B: HR 6.1, 95 % CI 1.5–25.6; p = 0.01] and the lack of trastuzumab administration in the metastatic setting (Cohort A: HR 5.0, 95 % CI 1.4–10.0; p = 0.009; Cohort B: HR 10.0, 95 % CI 2.0–100.0; p = 0.008). A profile including 13 genes was associated with early (≤36 months) symptomatic BM in the discovery cohort. This was refined by qRT-PCR to a 3-gene classifier (RAD51, HDGF, TPR) highly predictive of early BM (HR 5.3, 95 % CI 1.6–16.7; p = 0.005; multivariate analysis). However, predictive value of the classifier was not confirmed in the independent validation Cohort B. The presence of visceral metastases and the lack of trastuzumab administration in the metastatic setting apparently increase the likelihood of early BM in advanced HER2-positive breast cancer

DNA Double-Strand Break Repair Genes and Oxidative Damage in Brain Metastasis of Breast Cancer

Background Breast cancer frequently metastasizes to the brain, colonizing a neuro-inflammatory microenvironment. The molecular pathways facilitating this colonization remain poorly understood. Methods Expression profiling of 23 matched sets of human resected brain metastases and primary breast tumors by two-sided paired t test was performed to identify brain metastasis–specific genes. The implicated DNA repair genes BARD1 and RAD51 were modulated in human (MDA-MB-231-BR) and murine (4T1-BR) brain-tropic breast cancer cell lines by lentiviral transduction of cDNA or short hairpin RNA (shRNA) coding sequences. Their functional contribution to brain metastasis development was evaluated in mouse xenograft models (n = 10 mice per group). Results Human brain metastases overexpressed BARD1 and RAD51 compared with either matched primary tumors (1.74-fold, P < .001; 1.46-fold, P < .001, respectively) or unlinked systemic metastases (1.49-fold, P = .01; 1.44-fold, P = .008, respectively). Overexpression of either gene in MDA-MB-231-BR cells increased brain metastases by threefold to fourfold after intracardiac injections, but not lung metastases upon tail-vein injections. In 4T1-BR cells, shRNA-mediated RAD51 knockdown reduced brain metastases by 2.5-fold without affecting lung metastasis development. In vitro, BARD1- and RAD51-overexpressing cells showed reduced genomic instability but only exhibited growth and colonization phenotypes upon DNA damage induction. Reactive oxygen species were present in tumor cells and elevated in the metastatic neuro-inflammatory microenvironment and could provide an endogenous source of genotoxic stress. Tempol, a brain-permeable oxygen radical scavenger suppressed brain metastasis promotion induced by BARD1 and RAD51 overexpression. Conclusions BARD1 and RAD51 are frequently overexpressed in brain metastases from breast cancer and may constitute a mechanism to overcome reactive oxygen species–mediated genotoxic stress in the metastatic brain

Overweight in children and its perception by parents: cross-sectional observation in a general pediatric outpatient clinic

Abstract Background Childhood overweight is a growing problem in industrialized countries. Parents play a major role in the development and the treatment of overweight in their children. A key factor here is the perception of their child’s weight status. As we know of other studies, parental perception of children’s weight status is very poor. This study aimed to determine factors associated with childhood overweight and parental misperception of weight status. The height and weight of children, as reported by parents were compared with measured data. Methods The study was conducted at a general pediatric outpatient clinic in Vienna, Austria. A total of 600 children (aged 0–14 years) participated in the study. Collection of data was performed by means of a questionnaire comprising items relating to parental weight and social demographics. The parents were also asked to indicate their children’s weight and height, as well as the estimated weight status. Children were weighed and measured and BMI was calculated, allowing a comparison of estimated values and weight categories with the measured data. Results Parental BMI, parental weight and a higher birth weight were identified as factors associated with childhood overweight. No association with the parents’ educational status or citizenship could be proven. We compared parents’ estimations of weight and height of their children with measured data. Here we found, that parental estimated values often differ from measured data. Using only parental estimated data to define weight status leads to misclassifications. It could be seen that parents of overweight children tend to underestimate the weight status of their children, compared to parents of children with normal weight. Conclusions Pediatricians should bear in mind that parental assessment often differs from the measured weight of their children. Hence children should be weighed and measured regularly to prevent them from becoming overweight. This is of particular importance in children with higher birth weight and children of overweight parents. Trial registration Study was not registered. The study was approved by the Ethic committee of the city of Vienna. (EK 13–146-VK)

Noise levels in general pediatric facilities: A health risk for the staff?

This study was initiated to investigate noise levels in general pediatric facilities. Although occupational noise limits of 85dBA for LAeq,8h (daily noise exposure) and 140dBC for LCpeak (peak sound level) have proven to prevent hearing loss, even low levels of continuous noise (45dBA and above) can cause adverse health effects (ISO = International Organization for Standardization, A = Austrian VOLV). The sound level measurements of LAeq (equivalent sound level) and LCpeak were conducted with a decibel meter in the examination rooms (EXR) and waiting rooms (WR) of 10 general pediatric practices and outpatient clinics in the city of Vienna, Austria. LAeq,8h was calculated from LAeq, and independent variables with a potential influence on noise levels were also examined. In EXR, the random sample consisted of 5 to 11 measuring periods per facility (mean: 7.1 ± 1.9) with a total duration between 43.85 and 98.45 min. (total: 10:19:04). With LAeq ranging from 67.2 to 80.2dBA, specific recommended limits were exceeded considerably (ISO: 45dBA; A: 50dBA). In WR, the random sample comprised 5 to 18 measurements per facility (mean: 13.7 ± 5.0) with a total duration ranging from 25 to 90 min. (total: 11:25:00). The values for LAeq were between 60.6dBA and 67.0dBA. All of these significantly exceeded recommended limits of 55dBA (ISO) and 5 out of 10 exceeded 65dBA (A). LCpeak reached 116.1dBC in WR and 114.1dBC in EXR. The highest calculated daily noise exposure of pediatricians (LAeq,8h) was 79dBA. Although no significantly increased risk for hearing loss can be concluded from our findings, it must be assumed that noise levels in general pediatrics have the potential to cause stress and associated health issues. Further research is necessary to foster the recognition of noise-related health impairments of pediatric staff as occupational diseases

Ultrasound of the infant hip: manual fixation is equivalent to Graf’s technique regarding image quality—a randomized trial

Abstract Background In Middle Europe ultrasonography is the standard method used to screen for developmental dysplasia of the hip in infants. Our aim was to determine whether manual fixation of the child is equivalent to Graf’s technique regarding image quality. Methods This randomized trial was conducted at a free-standing general pediatric outpatient clinic in Vienna, Austria. Healthy infants in the 1st and between the 6th and 8th week of life with no hip malalignment were included. After randomization, Group 1 was examined using Graf’s fixation device and participants in Group 2 were fixated on the examination couch by their parents. In a second step, all images underwent a blinded evaluation. Results A total of 117 babies (Group 1: n = 62, Group 2: n = 54, excluded: n = 1) were examined and 230 images (Group 1: n = 122, Group 2: n = 108) were evaluated, of which 225 were sonographically normal. Two images, showing a type IIa right hip and a type IIa + left hip respectively, were excluded. One participant had to be excluded as the respective images showed two pathologic hip joints. Two images in Group 1 and three in Group 2 were not evaluable. No statistical association between image quality (11 quality criteria and overall evaluability) and fixation technique (0.12 ≤ p ≤ 1.0 or constant) was found. Conclusions Considering sonographically normal hip joints, we found no evidence that manual fixation differed from Graf’s technique regarding image quality. In future studies, hip pathologies should be included and discomfort of infants and parents during the examination should be addressed. Trial registration German Clinical Trials Register, ID: DRKS00015694), registered retrospectively on October 7th, 2018