Hypoxia increases the metastatic ability of breast cancer cells via upregulation of CXCR4

<p>Abstract</p> <p>Background</p> <p>Chemokine SDF1α and its unique receptor CXCR4 have been implicated in organ-specific metastases of many cancers including breast cancer. Hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. We hypothesized that hypoxia would upregulate CXCR4 expression and lead to increased chemotactic responsiveness to its specific ligand SDF1α.</p> <p>Methods</p> <p>Three breast cancer cell lines MDA-MB-231, MCF7 and 4T1 were subjected to 48 hrs of hypoxia or normoxia. Cell surface receptor expression was evaluated using flow cytometry. An extracellular matrix invasion assay and microporous migration assay was used to assess chemotactic response and metastatic ability.</p> <p>Results</p> <p>CXCR4 surface expression was significantly increased in the two human breast cancer cell lines, MDA-MB-231 and MCF7, following exposure to hypoxia. This upregulation of CXCR4 cell surface expression corresponded to a significant increase in migration and invasion in response to SDF1-α <it>in vitro</it>. The increase in metastatic potential of both the normoxic and the hypoxic treated breast cancer cell lines was attenuated by neutralization of CXCR4 with a CXCR4 neutralizing mAb, MAB172 or a CXCR4 antagonist, AMD3100, showing the relationship between CXCR4 overexpression and increased chemotactic responsiveness.</p> <p>Conclusions</p> <p>CXCR4 expression can be modulated by the tissue microenvironment such as hypoxia. Upregulation of CXCR4 is associated with increased migratory and invasive potential and this effect can be abrogated by CXCR4 inhibition. Chemokine receptor CXCR4 is a potential therapeutic target in the adjuvant treatment of breast cancer.</p

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Design of the Balance@Work project: systematic development, evaluation and implementation of an occupational health guideline aimed at the prevention of weight gain among employees

<p>Abstract</p> <p>Background</p> <p>Occupational health professionals may play an important role in preventive health promotion activities for employees. However, due to a lack of knowledge and evidence- and practice based methods and strategies, interventions are hardly being implemented by occupational physicians to date. The aim of the Balance@Work project is to develop, evaluate, and implement an occupational health guideline aimed at the prevention of weight gain among employees.</p> <p>Methods</p> <p>Following the guideline development protocol of the Netherlands Society of Occupational Medicine and the Intervention Mapping protocol, the guideline was developed based on literature, interviews with relevant stakeholders, and consensus among an expert group. The guideline consists of an individual and an environmental component. The individual component includes recommendations for occupational physicians on how to promote physical activity and healthy dietary behavior based on principles of motivational interviewing. The environmental component contains an obesogenic environment assessment tool. The guideline is evaluated in a randomised controlled trial among 20 occupational physicians. Occupational physicians in the intervention group apply the guideline to eligible workers during 6 months. Occupational physicians in the control group provide care as usual. Measurements take place at baseline and 6, 12, and 18 months thereafter. Primary outcome measures include waist circumference, daily physical activity and dietary behavior. Secondary outcome measures include sedentary behavior, determinants of behavior change, body weight and body mass index, cardiovascular disease risk profile, and quality of life. Additionally, productivity, absenteeism, and cost-effectiveness are assessed.</p> <p>Discussion</p> <p>Improving workers' daily physical activity and dietary behavior may prevent weight gain and subsequently improve workers' health, increase productivity, and reduce absenteeism. After an effect- and process evaluation the guideline will be adjusted and, after authorisation, published. Together with several implementation aids, the published guideline will be disseminated broadly by the Netherlands Society of Occupational Medicine.</p> <p>Trial Registration</p> <p>ISRCTN73545254/NTR1190</p

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Predicting Lung Cancer Survival Using Probabilistic Reclassification of TNM Editions With a Bayesian Network

PURPOSE The TNM classification system is used for prognosis, treatment, and research. Regular updates potentially break backward compatibility. Reclassification is not always possible, is labor intensive, or requires additional data. We developed a Bayesian network (BN) for reclassifying the 5th, 6th, and 7th editions of the TNM and predicting survival for non-small-cell lung cancer (NSCLC) without training data with known classifications in multiple editions. METHODS Data were obtained from the Netherlands Cancer Registry (n = 146,084). A BN was designed with nodes for TNM edition and survival, and a group of nodes was designed for all TNM editions, with a group for edition 7 only. Before learning conditional probabilities, priors for relations between the groups were manually specified after analysis of changes between editions. For performance evaluation only, part of the 7th edition test data were manually reclassified. Performance was evaluated using sensitivity, specificity, and accuracy. Twoyear survival was evaluated with the receiver operating characteristic area under the curve (AUC), and model calibration was visualized. RESULTS Manual reclassification of 7th to 6th edition stage group as ground truth for testing was impossible in 5.6% of the patients. Predicting 6th edition stage grouping using 7th edition data and vice versa resulted in average accuracies, sensitivities, and specificities between 0.85 and 0.99. The AUC for 2-year survival was 0.81. CONCLUSION We have successfully created a BN for reclassifying TNM stage grouping across TNM editions and predicting survival in NSCLC without knowing the true TNM classification in various editions in the training set. We suggest binary prediction of survival is less relevant than predicted probability and model calibration. For research, probabilities can be used for weighted reclassification. (C) 2020 by American Society of Clinical Oncology

Predicting Lung Cancer Survival Using Probabilistic Reclassification of TNM Editions With a Bayesian Network

PURPOSE The TNM classification system is used for prognosis, treatment, and research. Regular updates potentially break backward compatibility. Reclassification is not always possible, is labor intensive, or requires additional data. We developed a Bayesian network (BN) for reclassifying the 5th, 6th, and 7th editions of the TNM and predicting survival for non-small-cell lung cancer (NSCLC) without training data with known classifications in multiple editions. METHODS Data were obtained from the Netherlands Cancer Registry (n = 146,084). A BN was designed with nodes for TNM edition and survival, and a group of nodes was designed for all TNM editions, with a group for edition 7 only. Before learning conditional probabilities, priors for relations between the groups were manually specified after analysis of changes between editions. For performance evaluation only, part of the 7th edition test data were manually reclassified. Performance was evaluated using sensitivity, specificity, and accuracy. Twoyear survival was evaluated with the receiver operating characteristic area under the curve (AUC), and model calibration was visualized. RESULTS Manual reclassification of 7th to 6th edition stage group as ground truth for testing was impossible in 5.6% of the patients. Predicting 6th edition stage grouping using 7th edition data and vice versa resulted in average accuracies, sensitivities, and specificities between 0.85 and 0.99. The AUC for 2-year survival was 0.81. CONCLUSION We have successfully created a BN for reclassifying TNM stage grouping across TNM editions and predicting survival in NSCLC without knowing the true TNM classification in various editions in the training set. We suggest binary prediction of survival is less relevant than predicted probability and model calibration. For research, probabilities can be used for weighted reclassification. (C) 2020 by American Society of Clinical Oncology

Geographic variation in volumetric breast density between screening regions in the Netherlands

Differences in breast density between populations may explain part of the variation in regional breast cancer screening performance. This study aimed to determine whether regional differences in breast density distribution are present in the Dutch screening population. As part of the DENSE trial, mammographic density was measured using a fully-automated volumetric method. The regions in our study were based on the geographic coverage of 14 reading units representing a large part of the Netherlands. General linear models were used. Four hundred eighty-five thousand and twenty-one screening participants with a median age of 60 years were included (2013-2014). The proportion of women with heterogeneously or extremely dense breasts ranged from 32.5 % to 45.7 % between regions. Mean percent dense volume varied between 6.51 % (95 % confidence interval [CI]: 6.46-6.55) and 7.68 % (95 % CI: 7.66-7.71). Age differences could not explain the variation. Socio-economic status (SES) was positively associated with volumetric density in all analyses (low SES: 6.95 % vs. high SES: 7.63 %; p (trend) <0.0001), whereas a potential association between urbanisation and breast density only became apparent after SES adjustment. There appears to be geographic variation in mammographic density in the Netherlands, emphasizing the importance of including breast density as parameter in the evaluation of screening performance. aEuro cent Mammographic density may affect regional breast cancer screening performance. aEuro cent Volumetric breast density varies across screening areas. aEuro cent SES is positively associated with breast density. aEuro cent Implications of volumetric breast density differences need to be studied further

Design of COSMIC:a randomized, multi-centre controlled trial comparing conservative or early surgical management of incomplete cervical cord syndrome without spinal instability

<p>Background: Incomplete cervical cord syndrome without spinal instability is a very devastating event for the patient and the family. It is estimated that up to 25% of all traumatic spinal cord lesions belong to this category. The treatment for this type of spinal cord lesion is still subject of discussion. From a biological point of view early surgery could prevent secondary damage due to ongoing compression of the already damaged spinal cord. Historically, however, conservative treatment was propagated with good clinical results. Proponents for early surgery as well those favoring conservative treatment are still in debate. The proposed trial will contribute to the discussion and hopefully also to a decrease in the variability of clinical practice.</p><p>Methods/Design: A randomized controlled trial is designed to compare the clinical outcome of early surgical strategy versus a conservative approach. The primary outcome is clinical outcome according to mJOA. This also measured by ASIA score, DASH score and SCIM III score. Other endpoints are duration of the stay at a high care department (medium care, intensive care), duration of the stay at the hospital, complication rate, mortality rate, sort of rehabilitation, and quality of life. A sample size of 36 patients per group was calculated to reach a power of 95%. The data will be analyzed as intention-to-treat at regular intervals, but the end evaluation will take place at two years post-injury.</p><p>Discussion: At the end of the study, clinical outcomes between treatments attitudes can be compared. Efficacy, but also efficiency can be determined. A goal of the study is to determine which treatment will result in the best quality of life for the patients. This study will certainly contribute to more uniformity of treatment offered to patients with a special sort of spinal cord injury.</p>