Purpose: Brain metastases of breast cancer appear to be increasing in incidence, confer significant morbidity, and threaten to compromise gains made in systemic chemotherapy. The blood-tumor barrier (BTB) is compromised in many brain metastases; however, the extent to which this influences chemotherapeutic delivery and efficacy is unknown. Herein, we answer this question by measuring BTB passive integrity, chemotherapeutic drug uptake, and anticancer efficacy in vivo in two breast cancer models that metastasize preferentially to brain.Experimental Design: Experimental brain metastasis drug uptake and BTB permeability were simultaneously measured using novel fluorescent and phosphorescent imaging techniques in immune-compromised mice. Drug-induced apoptosis and vascular characteristics were assessed using immunofluorescent microscopy.Results: Analysis of over 2,000 brain metastases from two models (human 231-BR-Her2 and murine 4T1-BR5) showed partial BTB permeability compromise in greater than 89% of lesions, varying in magnitude within and between metastases. Brain metastasis uptake of 14 C-paclitaxel and 14 C-doxorubicin was generally greater than normal brain but less than 15% of that of other tissues or peripheral metastases, and only reached cytotoxic concentrations in a small subset ($10%) of the most permeable metastases. Neither drug significantly decreased the experimental brain metastatic ability of 231-BR-Her2 tumor cells. BTB permeability was associated with vascular remodeling and correlated with overexpression of the pericyte protein desmin.Conclusions: This work shows that the BTB remains a significant impediment to standard chemotherapeutic delivery and efficacy in experimental brain metastases of breast cancer. New brain permeable drugs will be needed. Evidence is presented for vascular remodeling in BTB permeability alterations. Clin Cancer Res; 16(23); 5664-78. Ó2010 AACR.Historically, brain metastases occurred in 10% to 20% of patients with disseminated breast cancer after the development of systemic lung, liver, and bone metastases. In such patients, treatment has been primarily palliative, with brain metastases rarely being the cause of death (1, 2). In recent years, however, the rate of brain metastasis has increased, approaching or exceeding 35% in subpopulations of metastatic breast cancer patients, particularly those with Her2 þ or "triple-negative" (estrogen and progesterone receptor negative, Her2 normal) tumors (3-5). The causes for this increase may be multiple, including improved systemic therapy, more frequent imaging, and the "sanctuary site" status of the brain. The net effect is that the patient experience is changing (6), with brain metastases more commonly presenting in patients who are responding to systemic therapy or have stable disease, and patients are succumbing to brain metastases (7). Clearly, a proportion of breast cancer patients are doing well systemically when brain metastases occur and need effective treatments for central nervous system (CNS) disease. Cur...

Clustering based on clinicophysiologic parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways.

No abstract

age, sex, general practice) of adults (18+ years) Major osteoporotic fracturesUsing anonymised electronic medical records from UK primary care (CPRD Gold 1998-2016 and hospital admissions 10% ↑ fracture risk people with atopic eczema compared to people without 10% ↑ hip fractures 10% ↑ pelvis fractures 18% ↑ spine fractures 7% ↑ wrist fractures without atopic eczema (n=2,569,030) with atopic eczema (n=526,808) Fractures ↑ in people with severe atopic eczema compared to people without: • over double spine fracture risk • 66% ↑ pelvis fractures • 50% ↑ hip fractures a Time From a

Background Atopic eczema is a common inflammatory skin disease. Various inflammatory conditions have been linked to cardiovascular disease, a major cause of global mortality and morbidity. Objective We sought to systematically review and meta-analyze population-based studies assessing associations between atopic eczema and specific cardiovascular outcomes. Methods MEDLINE, Embase, and Global Health were searched from inception to December 2017. We obtained pooled estimates using random-effects meta-analyses. We used a multivariate Bayesian meta-regression model to estimate the slope of effect of increasing atopic eczema severity on cardiovascular outcomes. Results Nineteen relevant studies were included. The effects of atopic eczema reported in cross-sectional studies were heterogeneous, with no evidence for pooled associations with angina, myocardial infarction, heart failure, or stroke. In cohort studies atopic eczema was associated with increased risk of myocardial infarction (n = 4; relative risk [RR], 1.12; 95% CI, 1.00-1.25), stroke (n = 4; RR, 1.10; 95% CI, 1.03-1.17), ischemic stroke n = 4; RR, 1.17; 95% CI, 1.14-1.20), angina (n = 2; RR, 1.18; 95% CI, 1.13-1.24), and heart failure (n = 2; RR, 1.26; 95% CI, 1.05-1.51). Prediction intervals were wide for myocardial infarction and stroke. The risk of cardiovascular outcomes appeared to increase with increasing severity (mean RR increase between severity categories, 1.15; 95% credibility interval, 1.09-1.21; uncertainty interval, 1.04-1.28). Conclusion Significant associations with cardiovascular outcomes were more common in cohort studies but with considerable between-study heterogeneity. Increasing atopic eczema severity was associated with increased risk of cardiovascular outcomes. Improved awareness among stakeholders regarding this small but significant association is warranted.

U-BIOPRED cohort n=91 epithelial brushings or biopsies IL-17 High Clinical phenotype Nasal polyps Smoking Antibiotic use Epithelial Gene Expression Profile Clinical phenotype FeNO Exacerbations Gene expression shared with psoriasis IDO1 IL1B DEFB4B S100A8, S100A9 PI3 CXCL3, CXCL8 CXCL10, CCL20 Gene signature SERPINB2 POSTN CLCA1 IL-13 High T cell infiltration Neutrophilia Eosinophilia IL-17-high asthma with features of a psoriasis immunophenotype From a the Respiratory,

Lack of training, access to plastic surgeons, and absence of appropriate reimbursement for these cases are significant barriers to the adoption of oncoplastic techniques.

K.A. reports and receives consulting fees from TARGET DERM, a company starting an atopic dermatitis disease registry, and receives grant funding (through her University) from Pfizer. L.S. is a trustee of the British Heart Foundation (BHF), and reports grants outside of the submitted work from Wellcome, the Medical Research Council, National Institute for Health Research, GSK, the BHF and Diabetes UK. S.M.L. reports grants from the Wellcome Trust, and received an Innovative Medicines Initiative BIOMAP Horizon 2020 grant during the conduct of the study. A.A., K.E.M., Y.S., A.M. and A.R. declare they have no conflicts of interest. A.A. and K.E.M. contributed equally to the study and are joint first authors. S.M.L. had the original idea for the study. All authors were involved in the study design. K.M. undertook initial data management. A.A. undertook subsequent SummaryBackground Atopic eczema is a common chronic inflammatory skin disease. Research suggests an association between atopic eczema and obesity, with inconsistent evidence from European populations. Objectives To explore the association between diagnosed atopic eczema and being overweight or obese, and whether increased atopic eczema severity was associated with higher body mass index. Methods We undertook a cross-sectional analysis within a cohort of adults (matched by age, sex and general practice) with and without a diagnosis of atopic eczema. We used primary care (Clinical Practice Research Datalink Gold) and linked hospital admissions data (1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016). We used conditional logistic regression to compare the odds of being overweight or obese (adjusting for confounders and potential mediators) in those with atopic eczema (mild, moderate and severe, and all eczema) vs. those without. Results We identified 441 746 people with atopic eczema, matched to 1 849 722 without. People with atopic eczema had slightly higher odds of being overweight or obese vs. those without [odds ratio (OR) 1Á08, 95% confidence interval (CI) 1Á07-1Á09] after adjusting for age, asthma and socioeconomic deprivation. Adjusting for potential mediators (high-dose glucocorticoids, harmful alcohol use, anxiety, depression, smoking) had a minimal impact on effect estimates (OR 1Á07, 95% CI 1Á06-1Á08). We saw no evidence that odds of being overweight or obese increased with increasing atopic eczema severity, and there was no association in people with severe eczema. Conclusions We found evidence of a small overall association between atopic eczema and being overweight or obese. However, there was no association with obesity among those with the most severe eczema. Our findings are largely reassuring for this prevalent patient group who may already have an increased risk of cardiovascular disease.