Body surface area and baseline blood pressure predict subclinical anthracycline cardiotoxicity in women treated for early breast cancer.

BACKGROUND AND AIMS: Anthracyclines are highly effective chemotherapeutic agents which may cause long-term cardiac damage (chronic anthracycline cardiotoxicity) and heart failure. The pathogenesis of anthracycline cardiotoxicity remains incompletely understood and individual susceptibility difficult to predict. We sought clinical features which might contribute to improved risk assessment. METHODS: Subjects were women with early breast cancer, free of pre-existing cardiac disease. Left ventricular ejection fraction was measured using cardiovascular magnetic resonance before and >12 months after anthracycline-based chemotherapy (>3 months post-Trastuzumab). Variables associated with subclinical cardiotoxicity (defined as a fall in left ventricular ejection fraction of ≥5%) were identified by logistic regression. RESULTS: One hundred and sixty-five women (mean age 48.3 years at enrollment) completed the study 21.7 months [IQR 18.0-26.8] after starting chemotherapy. All received anthracyclines (98.8% epirubicin, cumulative dose 400 [300-450] mg/m2); 18% Trastuzumab. Baseline blood pressure was elevated (≥140/90mmHg, mean 147.3/86.1mmHg) in 18 subjects. Thirty-four subjects (20.7%) were identified with subclinical cardiotoxicity, independent predictors of which were the number of anthracycline cycles (odds ratio, OR 1.64 [1.17-2.30] per cycle), blood pressure ≥140/90mmHg (OR 5.36 [1.73-17.61]), body surface area (OR 2.08 [1.36-3.20] per standard deviation (0.16m2) increase), and Trastuzumab therapy (OR 3.35 [1.18-9.51]). The resultant predictive-model had an area under the receiver operating characteristics curve of 0.78 [0.70-0.86]. CONCLUSIONS: We found subclinical cardiotoxicity to be common even within this low risk cohort. Risk of cardiotoxicity was associated with modestly elevated baseline blood pressure-indicating that close attention should be paid to blood pressure in patients considered for anthracycline based chemotherapy. The association with higher body surface area suggests that indexing of anthracycline doses to surface area may not be appropriate for all, and points to the need for additional research in this area

Barriers to adequate follow-up during adjuvant therapy may be important factors in the worse outcome for Black women after breast cancer treatment

<p>Abstract</p> <p>Introduction</p> <p>Black women appear to have worse outcome after diagnosis and treatment of breast cancer. It is still unclear if this is because Black race is more often associated with known negative prognostic indicators or if it is an independent prognostic factor. To study this, we analyzed a patient cohort from an urban university medical center where these women made up the majority of the patient population.</p> <p>Methods</p> <p>We used retrospective analysis of a prospectively collected database of breast cancer patients seen from May 1999 to June 2006. Time to recurrence and survival were analyzed using the Kaplan-Meier method, with statistical analysis by chi-square, log rank testing, and the Cox regression model.</p> <p>Results</p> <p>265 female patients were diagnosed with breast cancer during the time period. Fifty patients (19%) had pure DCIS and 215 patients (81%) had invasive disease. Racial and ethnic composition of the entire cohort was as follows: Black (N = 150, 56.6%), Hispanic (N = 83, 31.3%), Caucasian (N = 26, 9.8%), Asian (N = 4, 1.5%), and Arabic (N = 2, 0.8%). For patients with invasive disease, independent predictors of poor disease-free survival included tumor size, node-positivity, incompletion of adjuvant therapy, and Black race. Tumor size, node-positivity, and Black race were independently associated with disease-specific overall survival.</p> <p>Conclusion</p> <p>Worse outcome among Black women appears to be independent of the usual predictors of survival. Further investigation is necessary to identify the cause of this survival disparity. Barriers to completion of standard post-operative treatment regimens may be especially important in this regard.</p

The RUDY study platform – a novel approach to patient driven research in rare musculoskeletal diseases

Background: Research into rare diseases is becoming more common, with recognition of the significant diagnostic and therapeutic care gaps. Registries are considered a key research methodology to address rare diseases. This report describes the structure of the Rare UK Diseases Study (RUDY) platform that aims to improve research processes and address many of the challenges of carrying out rare musculoskeletal disease research. RUDY is an internet-based platform with online registration, initial verbal consent, online capture of patient reported outcome measures and events within a dynamic consent framework. The database structure, security and governance framework are described. Results: There have been 380 participants recruited into RUDY with completed questionnaire rates in excess of 50 %. There has been one withdrawal and two participants have amended their consent options. Conclusions: The strengths of RUDY include low burden for the clinical team, low research administration costs with high participant recruitment and ease of data collection and access. This platform has the potential to be used as the model for other rare diseases globally

Key Role of Mfd in the Development of Fluoroquinolone Resistance in Campylobacter jejuni

Campylobacter jejuni is a major food-borne pathogen and a common causative agent of human enterocolitis. Fluoroquinolones are a key class of antibiotics prescribed for clinical treatment of enteric infections including campylobacteriosis, but fluoroquinolone-resistant Campylobacter readily emerges under the antibiotic selection pressure. To understand the mechanisms involved in the development of fluoroquinolone-resistant Campylobacter, we compared the gene expression profiles of C. jejuni in the presence and absence of ciprofloxacin using DNA microarray. Our analysis revealed that multiple genes showed significant changes in expression in the presence of a suprainhibitory concentration of ciprofloxacin. Most importantly, ciprofloxacin induced the expression of mfd, which encodes a transcription-repair coupling factor involved in strand-specific DNA repair. Mutation of the mfd gene resulted in an approximately 100-fold reduction in the rate of spontaneous mutation to ciprofloxacin resistance, while overexpression of mfd elevated the mutation frequency. In addition, loss of mfd in C. jejuni significantly reduced the development of fluoroquinolone-resistant Campylobacter in culture media or chickens treated with fluoroquinolones. These findings indicate that Mfd is important for the development of fluoroquinolone resistance in Campylobacter, reveal a previously unrecognized function of Mfd in promoting mutation frequencies, and identify a potential molecular target for reducing the emergence of fluoroquinolone-resistant Campylobacter

Linking formal child care characteristics to children's socioemotional well-being: A comparative perspective

Most research on formal child care and children’s outcomes has focused on single countries. We, however, contend that policy context may moderate the association between formal child care characteristics and children’s socioemotional well-being. We examined this by comparing the Netherlands, Finland and the UK; three countries that differ regarding family policies. Of these three countries, Finland was recently ranked highest (ranked 1st) with regards to quality of child care in a recent analysis by the Economist ,followed by the UK (ranked 3rd) and then the Netherlands (ranked 7th) .We hypothesized that children who attend child - care settings in countries with higher- uality formal child- are provision would generally show better socioemotional outcomes. Data from the comparative ‘F amilies 24/7’ survey were used, including 990 parents with children aged 0–12. We distinguished between two age groups in our analysis. Results indicated that, compared to the UK, longer hours in formal care were less beneficial in the Netherlands. Furthermore, spen ding time in formal care during nonstandard hours was more harmful for children in Finland compared to the UK. Lastly, receiving care from multiple caregivers was more disruptive for British children than for Dutch children. No differences were found between Finland and the Netherlands

Variability in chemotherapy delivery for elderly women with advanced stage ovarian cancer and its impact on survival

Given the survival benefits of adjuvant chemotherapy for advanced ovarian cancer (OC), we examined the associations of survival with the time interval from debulking surgery to initiation of chemotherapy and with the duration of chemotherapy. Among patients ⩾65 years with stages III/IV OC diagnosed between 1991 and 2002 in the Surveillance, Epidemiology, and End Results-Medicare database, we developed regression models of predictors of the time interval from surgery to initiation of chemotherapy and of the total duration of chemotherapy. Survival was examined with Cox proportional hazards models. Among 2558 patients, 1712 (67%) initiated chemotherapy within 6 weeks of debulking surgery, while 846 (33%) began treatment >6 weeks. Older age, black race, being unmarried, and increased comorbidities were associated with delayed initiation of chemotherapy. Delay of chemotherapy was associated with an increase in mortality (hazard ratio (HR)=1.11; 95% CI, 1.0–1.2). Among 1932 patients in the duration of treatment analysis, the 1218 (63%) treated for 3–7 months had better survival than the 714 (37%) treated for ⩽3 months (HR=0.84; 95% CI, 0.75–0.94). This analysis represents one of the few studies describing treatment delivery and outcome in women with advanced OC. Delayed initiation and early discontinuation of chemotherapy were common and associated with increased mortality

Sustainable Urban Systems: Co-design and Framing for Transformation

Rapid urbanisation generates risks and opportunities for sustainable development. Urban policy and decision makers are challenged by the complexity of cities as social–ecological–technical systems. Consequently there is an increasing need for collaborative knowledge development that supports a whole-of-system view, and transformational change at multiple scales. Such holistic urban approaches are rare in practice. A co-design process involving researchers, practitioners and other stakeholders, has progressed such an approach in the Australian context, aiming to also contribute to international knowledge development and sharing. This process has generated three outputs: (1) a shared framework to support more systematic knowledge development and use, (2) identification of barriers that create a gap between stated urban goals and actual practice, and (3) identification of strategic focal areas to address this gap. Developing integrated strategies at broader urban scales is seen as the most pressing need. The knowledge framework adopts a systems perspective that incorporates the many urban trade-offs and synergies revealed by a systems view. Broader implications are drawn for policy and decision makers, for researchers and for a shared forward agenda