Nottingham Prognostic Index Plus (NPI+): a modern clinical decision making tool in breast cancer

Current management of breast cancer (BC) relies on risk stratification based on well-defined clinicopathologic factors. Global gene expression profiling studies have demonstrated that BC comprises distinct molecular classes with clinical relevance. In this study, we hypothesized that molecular features of BC are a key driver of tumour behaviour and when coupled with a novel and bespoke application of established clinicopathologic prognostic variables, can predict both clinical outcome and relevant therapeutic options more accurately than existing methods. In the current study, a comprehensive panel of biomarkers with relevance to BC was applied to a large and well-characterised series of BC, using immunohistochemistry and different multivariate clustering techniques, to identify the key molecular classes. Subsequently, each class was further stratified using a set of well-defined prognostic clinicopathologic variables. These variables were combined in formulae to prognostically stratify different molecular classes, collectively known as the Nottingham Prognostic Index Plus (NPI+). NPI+ was then used to predict outcome in the different molecular classes with.Seven core molecular classes were identified using a selective panel of 10 biomarkers. Incorporation of clinicopathologic variables in a second stage analysis resulted in identification of distinct prognostic groups within each molecular class (NPI+). Outcome analysis showed that using the bespoke NPI formulae for each biological breast cancer class provides improved patient outcome stratification superior to the traditional NPI. This study provides proof-of-principle evidence for the use of NPI+ in supporting improved individualised clinical decision making

Dietary acid load and chronic kidney disease among adults in the United States

Abstract Background Diet can markedly affect acid-base status and it significantly influences chronic kidney disease (CKD) and its progression. The relationship of dietary acid load (DAL) and CKD has not been assessed on a population level. We examined the association of estimated net acid excretion (NAEes) with CKD; and socio-demographic and clinical correlates of NAEes. Methods Among 12,293 U.S. adult participants aged >20 years in the National Health and Nutrition Examination Survey 1999–2004, we assessed dietary acid by estimating NAEes from nutrient intake and body surface area; kidney damage by albuminuria; and kidney dysfunction by eGFR < 60 ml/min/1.73m2 using the MDRD equation. We tested the association of NAEes with participant characteristics using median regression; while for albuminuria, eGFR, and stages of CKD we used logistic regression. Results Median regression results (β per quintile) indicated that adults aged 40–60 years (β [95% CI] = 3.1 [0.3–5.8]), poverty (β [95% CI] = 7.1 [4.01–10.22]), black race (β [95% CI] = 13.8 [10.8–16.8]), and male sex (β [95% CI] = 3.0 [0.7- 5.2]) were significantly associated with an increasing level of NAEes. Higher levels of NAEes compared with lower levels were associated with greater odds of albuminuria (OR [95% CI] = 1.57 [1.20–2.05]). We observed a trend toward greater NAEes being associated with higher risk of low eGFR, which persisted after adjustment for confounders. Conclusion Higher NAEes is associated with albuminuria and low eGFR, and socio-demographic risk factors for CKD are associated with higher levels of NAEes. DAL may be an important target for future interventions in populations at high risk for CKD.http://deepblue.lib.umich.edu/bitstream/2027.42/109474/1/12882_2014_Article_829.pd

Markers of mineral metabolism and vascular access complications: The Choices for Healthy Outcomes in Caring for ESRD (CHOICE) study

Introduction: Vascular access dysfunction is a major cause of morbidity in patients with end‐stage renal disease (ESRD) on chronic hemodialysis. The effects of abnormalities in mineral metabolism on vascular access are unclear. In this study, we evaluated the association of mineral metabolites, including 25‐hydroxy vitamin D (25(OH)D) and fibroblast growth factor‐23 (FGF‐23), with vascular access complications.Methods: We included participants from the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) Study who were using an arteriovenous fistula (AVF; n = 103) or arteriovenous graft (AVG; n = 116). Serum levels of 25(OH)D, FGF‐23, parathyroid hormone (PTH), calcium, phosphorus, C‐reactive protein (CRP) and interleukin‐6 (IL‐6) were assessed from stored samples. Participants were followed for up to 1 year or until a vascular access intervention or replacement.Findings: A total of 24 participants using an AVF and 43 participants using an AVG experienced access intervention. Those with 25(OH)D level in the lowest tertile (3750 RU/mL) was associated with greater risk of AVF intervention (aHR = 2.56; 95% CI: 1.06, 6.18). Higher PTH was associated with higher risk of AVF intervention (aHR = 1.64 per SD of log(PTH); 95% CI: 1.02, 2.62). These associations were not observed in participants using an AVG. None of the other analytes were significantly associated with AVF or AVG intervention.Discussion: Low levels of 25(OH)D and high levels of FGF‐23 and PTH are associated with increased risk of AVF intervention. Abnormalities in mineral metabolism are risk factors for vascular access dysfunction and potential therapeutic targets to improve outcomes.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153726/1/hdi12798_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153726/2/hdi12798.pd

First-Trimester Follistatin-Like-3 Levels in Pregnancies Complicated by Subsequent Gestational Diabetes Mellitus

Objective: To determine whether maternal levels of follistatin-like-3 (FSTL3), an inhibitor of activin and myostatin involved in glucose homeostasis, are altered in the first trimester of pregnancies complicated by subsequent gestational diabetes mellitus (GDM). Research Design and Methods: This was a nested case-control study of subjects enrolled in a prospective cohort of pregnant women with and without GDM ($\geq$2 abnormal values on a 100-g glucose tolerance test at ~28 weeks of gestation). We measured FSTL3 levels in serum collected during the first trimester of pregnancy. Logistic regression analyses were used to determine the risk of GDM. Results: Women who developed GDM (n = 37) had lower first-trimester serum levels of FSTL3 compared with women who did not (n = 127) (median 10,789 [interquartile range 7,013-18,939] vs. 30,670 [18,370-55,484] pg/ml, P < 0.001). When subjects were divided into tertiles based on FSTL3 levels, women with the lowest levels demonstrated a marked increase in risk for developing GDM in univariate (odds ratio 11.2 [95% CI 3.6-35.3]) and multivariate (14.0 [4.1-47.9]) analyses. There was a significant negative correlation between first-trimester FSTL3 levels and ~28-week nonfasting glucose levels (r = -0.30, P < 0.001). Conclusions: First-trimester FSTL3 levels are associated with glucose intolerance and GDM later in pregnancy

Cytoplasmic PML promotes TGF-β-associated epithelial–mesenchymal transition and invasion in prostate cancer

Epithelial–mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-β signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-β signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-β canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-β signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit

Challenging the perceptions of cancer service provision for the disadvantaged: evaluating utilisation of cancer support services in Western Australia

Purpose: The main aim of the study was to evaluate the distributive utilisation of services provided by the Cancer Council of Western Australia according to age, social disadvantage and geographic location. Results were used to determine if social justice principles in terms of service provision were upheld. Methods: Cross-sectional study design to evaluate utilisation of cancer support services over a 12-week period in 2007 using administrative records. Service utilisation incidence rates (population information obtained from de-identified cancer registry data) and incidence rate ratios were calculated by gender, age group, cancer type, socioeconomic status and location. Results: The Information services (52%, n = 4,932) were the most popular Cancer Council of Western Australia (CCWA) services followed by Emotional Support services (21%, n =  2,045). All CCWA services were more likely to be accessed by those with a lower socioeconomic status, except for Clinical Services. The rate of utilisation for patients with cancer in the 65+ years age group was found to be under-serviced relative to the 40–64 years age group. Conclusions: Overall, the study has shown that CCWA services are not provided uniformly (horizontal equity) across strata of socio-economic status. Given that the prevalence of cancer generally increases with socio-economic advantage, the findings were notable in regard to one particular outcome. Results for age indicate that there may be some underlying accessibility issues for the aged population. The findings are consistent with current literature highlighting issues of disadvantage in regard to the ability of elderly persons with cancer to access services and support

Attainment of clinical performance targets and improvement in clinical outcomes and resource use in hemodialysis care: a prospective cohort study

BACKGROUND: Clinical performance targets are intended to improve patient outcomes in chronic disease through quality improvement, but evidence of an association between multiple target attainment and patient outcomes in routine clinical practice is often lacking. METHODS: In a national prospective cohort study (ESRD Quality, or EQUAL), we examined whether attainment of multiple targets in 668 incident hemodialysis patients from 74 U.S. not-for-profit dialysis clinics was associated with better outcomes. We measured whether the following accepted clinical performance targets were met at 6 months after study enrollment: albumin (≥4.0 g/dl), hemoglobin (≥11 g/dl), calcium-phosphate product (<55 mg(2)/dl(2)), dialysis dose (Kt/V≥1.2), and vascular access type (fistula). Outcomes included mortality, hospital admissions, hospital days, and hospital costs. RESULTS: Attainment of each of the five targets was associated individually with better outcomes; e.g., patients who attained the albumin target had decreased mortality [relative hazard (RH) = 0.55, 95% confidence interval (CI), 0.41–0.75], hospital admissions [incidence rate ratio (IRR) = 0.67, 95% CI, 0.62–0.73], hospital days (IRR = 0.61, 95% CI, 0.58–0.63), and hospital costs (average annual cost reduction = $3,282, P = 0.002), relative to those who did not. Increasing numbers of targets attained were also associated, in a graded fashion, with decreased mortality (P = 0.030), fewer hospital admissions and days (P < 0.001 for both), and lower costs (P = 0.029); these trends remained statistically significant for all outcomes after adjustment (P < 0.001), except cost, which was marginally significant (P = 0.052). CONCLUSION: Attainment of more clinical performance targets, regardless of which targets, was strongly associated with decreased mortality, hospital admissions, and resource use in hemodialysis patients

Inequalities in colorectal cancer screening participation in the first round of the national screening programme in England

BACKGROUND: Introduction of organised, population-based, colorectal cancer screening in the United Kingdom using the faecal occult blood test (FOBT) has the potential to reduce overall colorectal cancer mortality. However, socio-economic variation in screening participation could exacerbate existing inequalities in mortality.METHODS: This study examined FOBT uptake rates in London, England in relation to area-level socio-economic deprivation over the first 30 months of the programme during which 401 197 individuals were sent an FOBT kit. Uptake was defined as return of a completed test kit within 3 months. Area-level deprivation in each postcode sector was indexed with the Townsend Material Deprivation Index. Analyses controlled for area-level household mobility, ethnic diversity and poor health, each of which was associated with lower return rates.RESULTS: The results showed a strong socio-economic gradient in FOBT uptake, which declined from 49% in the least deprived quintile of postcodes to 38% in the middle quintile and 32% in the most deprived quintile. Variation in socio-economic deprivation between sectors accounted for 62% of the variance in return rates, with little attenuation as a result of controlling for ethnic diversity, household mobility or health status.CONCLUSION: These results highlight the need to understand the causes of socio-economic gradients in screening participation and address barriers that could otherwise increase disparities in colorectal cancer survival