Molecular characterization of Gleason patterns 3 and 4 prostate cancer using reverse Warburg effect-associated genes.

BACKGROUND: Gleason scores (GS) 3+3 and 3+4 prostate cancers (PCa) differ greatly in their clinical courses, with Gleason pattern (GP) 4 representing a major independent risk factor for cancer progression. However, Gleason grade is not reliably ascertained by diagnostic biopsy, largely due to sampling inadequacies, subjectivity in the Gleason grading procedure, and a lack of more objective biomarker assays to stratify prostate cancer aggressiveness. In most aggressive cancer types, the tumor microenvironment exhibits a reciprocal pro-tumorigenic metabolic phenotype consistent with the reverse Warburg effect (RWE). The RWE can be viewed as a physiologic response to the epithelial phenotype that is independent of both the epithelial genotype and of direct tumor sampling. We hypothesize that differential expression of RWE-associated genes can be used to classify Gleason pattern, distinguishing GP3 from GP4 PCa foci. METHODS: Gene expression profiling was conducted on RNA extracted from laser-capture microdissected stromal tissue surrounding 20 GP3 and 21 GP4 cancer foci from PCa patients with GS 3+3 and GS ≥4+3, respectively. Genes were probed using a 102-gene NanoString probe set targeted towards biological processes associated with the RWE. Differentially expressed genes were identified from normalized data by univariate analysis. A top-scoring pair (TSP) analysis was completed on raw gene expression values. Genes were analyzed for enriched Gene Ontology (GO) biological processes and protein-protein interactions using STRING and GeneMANIA. RESULTS: Univariate analysis identified nine genes (FOXO1 (AUC: 0.884), GPD2, SPARC, HK2, COL1A2, ALDOA, MCT4, NRF2, and ATG5) that were differentially expressed between GP3 and GP4 stroma (p<0.05). However, following correction for false discovery, only FOXO1 retained statistical significance at q<0.05. The TSP analysis identified a significant gene pair, namely ATG5/GLUT1. Greater expression of ATG5 relative to GLUT1 correctly classified 77.4 % of GP3/GP4 samples. Enrichment for GO-biological processes revealed that catabolic glucose processes and oxidative stress response pathways were strongly associated with GP3 foci but not GP4. FOXO1 was identified as being a primary nodal protein. CONCLUSIONS: We report that RWE-associated genes can be used to distinguish between GP3 and GP4 prostate cancers. Moreover, we find that the RWE response is downregulated in the stroma surrounding GP4, possibly via modulation of FOXO1.

Enumerating pelvic recurrence following radical cystectomy for bladder cancer: A Canadian multi-institutional study.

INTRODUCTION: We aimed to enumerate the rate of pelvic recurrence following radical cystectomy at university-affiliated hospitals in Canada. METHODS: Canadian, university-affiliated hospitals were invited to participate. They were asked to identify the first 10 consecutive patients undergoing radical cystectomy starting January 1, 2005, who had urothelial carcinoma stages pT3/T4 N0-2 M0. The first 10 consecutive cases starting January 1, 2005 who met these criteria were the patients submitted by that institution with information regarding tumour stage, age, number of nodes removed, and last known clinical status in regard to recurrence and patterns of failure. RESULTS: Of the 111 patients, 80% had pT3 and 20% pT4 disease, with 62% being node-negative, 14% pN1, and 27% pN2; 57% had 10 or more nodes removed. Cumulative incidence of pelvic relapse was 40% among the entire group. CONCLUSIONS: This review demonstrates a high rate of pelvic tumour recurrence following radical cystectomy for pT3/T4 urothelial cancer.

Establishing a professional profile of community health workers: results from a national study of roles, activities and training.

Community Health Workers (CHWs) have gained national recognition for their role in addressing health disparities and are increasingly integrated into the health care delivery system. There is a lack of consensus, however, regarding empirical evidence on the impact of CHW interventions on health outcomes. In this paper, we present results from the 2010 National Community Health Worker Advocacy Survey (NCHWAS) in an effort to strengthen a generalized understanding of the CHW profession that can be integrated into ongoing efforts to improve the health care delivery system. Results indicate that regardless of geographical location, work setting, and demographic characteristics, CHWs generally share similar professional characteristics, training preparation, and job activities. CHWs are likely to be female, representative of the community they serve, and to work in community health centers, clinics, community-based organizations, and health departments. The most common type of training is on-the-job and conference training. Most CHWs work with clients, groups, other CHWs and less frequently community leaders to address health issues, the most common of which are chronic disease, prevention and health care access. Descriptions of CHW activities documented in the survey demonstrate that CHWs apply core competencies in a synergistic manner in an effort to assure that their clients get the services they need. NCHWAS findings suggest that over the past 50 years, the CHW field has become standardized in response to the unmet needs of their communities. In research and practice, the field would benefit from being considered a health profession rather than an intervention.

High-throughput detection of prostate cancer in histological sections using probabilistic pairwise Markov models.

In this paper we present a high-throughput system for detecting regions of carcinoma of the prostate (CaP) in HSs from radical prostatectomies (RPs) using probabilistic pairwise Markov models (PPMMs), a novel type of Markov random field (MRF). At diagnostic resolution a digitized HS can contain 80Kx70K pixels - far too many for current automated Gleason grading algorithms to process. However, grading can be separated into two distinct steps: (1) detecting cancerous regions and (2) then grading these regions. The detection step does not require diagnostic resolution and can be performed much more quickly. Thus, we introduce a CaP detection system capable of analyzing an entire digitized whole-mount HS (2x1.75cm(2)) in under three minutes (on a desktop computer) while achieving a CaP detection sensitivity and specificity of 0.87 and 0.90, respectively. We obtain this high-throughput by tailoring the system to analyze the HSs at low resolution (8microm per pixel). This motivates the following algorithm: (Step 1) glands are segmented, (Step 2) the segmented glands are classified as malignant or benign, and (Step 3) the malignant glands are consolidated into continuous regions. The classification of individual glands leverages two features: gland size and the tendency for proximate glands to share the same class. The latter feature describes a spatial dependency which we model using a Markov prior. Typically, Markov priors are expressed as the product of potential functions. Unfortunately, potential functions are mathematical abstractions, and constructing priors through their selection becomes an ad hoc procedure, resulting in simplistic models such as the Potts. Addressing this problem, we introduce PPMMs which formulate priors in terms of probability density functions, allowing the creation of more sophisticated models. To demonstrate the efficacy of our CaP detection system and assess the advantages of using a PPMM prior instead of the Potts, we alternately incorporate both priors into our algorithm and rigorously evaluate system performance, extracting statistics from over 6000 simulations run across 40 RP specimens. Perhaps the most indicative result is as follows: at a CaP sensitivity of 0.87 the accompanying false positive rates of the system when alternately employing the PPMM and Potts priors are 0.10 and 0.20, respectively.

European School of Internal Medicine: a window of opportunity for RCP activities in Europe.

The Royal College of Physicians (RCP) is to host the European School of Internal Medicine for two years from 2009-10. This affords a unique opportunity for specialist registrars to exchange ideas about professional development and training and to make contacts with young internists from across Europe. Such links should prove useful for future RCP initiatives in European medicine.

Trends in heart failure mortality in England and Wales since 1950.

BACKGROUND: This study aims to analyse trends in heart failure mortality for England and Wales from 1950 to 2003. METHODS: A retrospective observational study was conducted using death certificate and population data from the Office for National Statistics. RESULTS: Unadjusted heart failure deaths rose by a factor of more than four between 1950 and 1974 and then fell by a quarter by 2003. When standardised for changes in the age, sex and size of the population, there was a tripling in mortality rate from 1950 to the mid-1970s and since then, a sustained decline in mortality rate of 50% by 2003. The unadjusted female heart failure death rate has been between 1.5-2 times that of males since the early 1970s, but this is much less marked when the differences in the age distribution and sizes of the male and female populations are taken into account. Heart failure mortality trends are similar to those of coronary heart disease (CHD), but the peak is about 10 years earlier, and the male/female ratios are reversed. There is a continuing rise in deaths from both heart failure and CHD in the very elderly (>85 years). CONCLUSION: Unlike hospital trends, deaths from heart failure in the community in England and Wales show a decline since the early 1970s, in spite of an ageing population. This may reflect genuine changes in heart failure incidence, or parallel changes in CHD.