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Narrative research approaches provide the opportunity for constructing a detailed understanding of lived experiences relevant to medical education, in areas such as illness narratives, explorations of doctor-patient relationships, and the development of professional identities in students and educators. The benefits of the depth of data gathered in narrative research are, however, counterbalanced by possible weaknesses relating to a focus on individual cases and the risk of identification of participants where subjects are sensitive or unique. To address these concerns, researchers from a variety of social science disciplines, carrying out research employing a range of methodological approaches, have begun to use ‘composite narratives’ in which the commonalities in the experiences of research participants are combined to create joint narrative or narratives which illustrate participants’ shared experiences. Composite narratives have been used both as a component of the methodological approach and as a method of presenting the results of research in a variety of methodologies. This A Qualitative Space paper explores the role, strengths, and weaknesses of narrative research, before outlining the ways in which composite narrative has been defined within existing research. Distinctions between the various approaches to creating composite narratives are discussed, highlighting the differences in the types of data utilised, and the approaches taken to data analysis and presentation. A key distinction is identified between the use of composite narratives as part of an integrated methodology and as an approach to the presentation of data. Finally, issues relating to trustworthiness, reflexivity, and implications for researchers are considered.

The incidence of adenocarcinoma of the distal oesophagus (DO) and gastro-oesophageal junction (GOJ) are increasing. They may represent differing disease processes. This study aimed to assess clinicopathological and survival differences between patients with DO and GOJ adenocarcinomas.Data were extracted from a prospective single-surgeon database of consecutive patients undergoing an open Ivor-Lewis oesophagectomy for oesophageal adenocarcinoma (distal oesophagus, Siewert type I and II). Differences in clinicopathological characteristics and survival were evaluated and prognostic factors examined using univariate and multivariate survival analyses.The data were available for 234 patients who underwent an oesophagectomy between 1992 and 2019. DO tumours had higher rates of Barrett's oesophagus (P 0.001), presented with lower tumour stage (P = 0.02) and were more likely to be associated with fewer lymph nodes resected (P = 0.003) than GOJ tumours. The median overall survival for distal oesophageal tumours was 29.2 months, while gastro-oesophageal tumours was 38.6 months. Kaplan Meier analysis did not show a difference in overall survival between the two groups (P = 0.08). However, when adjusted for potential confounders, GOJ tumours were associated with a reduced adjusted hazard of death (adjusted HR 0.58, 95% CI 0.36-0.92, P = 0.022) compared with DO tumours.This study suggests that GOJ cancers have different clinicopathological characteristics and improved survival compared to DO tumours.

Background Anesthetic induction and other procedures performed by anesthetists are potentially stressful for children. Pediatric anesthetists use communication to rapidly establish rapport and engagement with children and reduce anxiety and discomfort. Communication in pediatric anesthesia is increasingly topical, but there is limited discussion regarding which specific techniques should be taught to trainees. Aims The aim of this research was to identify which communication techniques used locally by pediatric anesthetic specialists, trainees, and nurses are viewed as the most effective and valuable to teach trainees. Methods Qualitative semi-structured focus groups (7) and in-depth interviews (7) were used to gather data from 30 specialist pediatric anesthetists, trainees, and assistants from a major tertiary pediatric anesthetic department. Inductive and deductive thematic data analysis explored communication techniques used locally. Results The research identified the range of communication techniques being utilized to establish rapport and engage with children, including methods for distraction and focusing attention such as storytelling, guided imagery, and positive suggestions. Thematic analysis revealed a series of core overarching principles for successful application, using social skills within an adaptable, competent, child-centered approach. Drawing on the experiences of specialist practitioners and trainees, teaching these communication techniques would ideally employ an interactive approach involving both modeling and specific communication education with focus on developing communication skills via experiential learning using self-reflection and feedback. Conclusions Within the range of communication techniques being utilized by pediatric anesthetists exist a series of core principles that are essential to engaging and building rapport with children. Focusing on the importance of these common core elements in trainee education, in addition to the range of techniques available, may provide a pragmatic framework for centers providing pediatric anesthesia to consider when designing their trainee curriculum.

The WNT (Wingless and Int-1) proteins play a role in stem cell development and cell differentiation. Mutations in the WNT proteins lead to the development of various tumours, including gastric tumours. Porcupine (PORCN) is a palmitoyltransferase and Wntless (WLS) is a dedicated WNT transport protein that modify and fold the WNT proteins respectively and are involved in their proper secretion and binding to the frizzled (FZD) receptor and the lipoprotein receptor-related protein 5 or 6 (LRP5/6). We investigated how modifications of PORCN and WLS result in changes in WNT expression and secretion from cells under stress conditions that occur in the tumour microenvironment (hypoxia, oxidative stress, endoplasmic reticulum (ER) stress). In the present study, we found the mRNA expression of both PORCN and WLS were significantly increased with treatments inducing oxidative stress (antimycin A) and proteasome inhibition (MG-132), in human colon cancer (HCT116) and human intestinal epithelial cell-6 (HIEC-6) cells. Treatment with ER stressors thapsigargin, tunicamycin, and dithiolthreitol significantly increased PORCN gene expression, while treatment with thapsigargin and dithiolthreitol increased WLS gene expression. The expression of PORCN and WLS proteins increased with hypoxia and ER stressor treatments in both HCT116 and HIEC-6 cells. All stressors used in this study increased beta-catenin (β-catenin) expression in HCT116 cells. Our results suggest that these stressors alter PORCN, WLS and β-catenin expression and function which may, in turn, alter WNT secretion. Silencing the expression of PORCN and WLS with siRNA expression reduced the expression of WLS and WNT3A in HCT116 cells. The possibility exists that PORCN specifically may be involved in a novel signaling pathway, independent of its palmitoleation of the WNT proteins and its role in their secretion, that is rate-limiting for cancer cell growth and tumorigenesis, within the tumour microenvironment.

Pragmatic measures of therapist delivery of evidence-based practice (EBP) are critical to assessing the impact of large-scale, multiple EBP implementation efforts. As an initial step in the development of pragmatic measurement, the current study examined the concordance between therapist and observer ratings of items assessing delivery of EBP strategies considered essential for common child EBP targets. Possible EBP-, session-, and therapist-levels factors associated with concordance were also explored. Therapists and independent observers rated the extensiveness of therapist (n = 103) EBP strategy delivery in 680 community psychotherapy sessions in which six EBPs were used. Concordance between therapist- and observer-report of the extensiveness of therapist EBP strategy use was at least fair (ICC ≥ .40) for approximately half of the items. Greater therapist-observer concordance was observed in sessions where a structured EBP was delivered and in sessions where therapists reported being able to carry out planned activities. Findings highlighted conditions that may improve or hinder therapists' ability to report on their own EBP strategy delivery in a way that is consistent with independent observers. These results can help inform the development of pragmatic therapist-report measures of EBP strategy delivery and implementation efforts more broadly.

At a time when UK general practice is facing significant challenges and departments of academic general practice in UK universities are in decline, this cross-sectional qualitative case study examines the experiences of general practitioner (GP) academics in a Scottish university department of general practice undergraduate education. The study explores GPs’ reasons for entering academic careers, their routes into academic careers and their experiences of balancing clinical and academic work through examining the individual narratives of GP academics. Data were gathered through autobiographical written narrative, individual interviews and an autoethnographic study, and were analysed using a thematic narrative approach. Findings are presented as composite narratives synthesising the predominant experiences of three distinct groups of GPs who entered academia at different stages of their careers. GP academics described limited understanding of academic general practice prior to taking up an academic post. Entry to academic general practice was associated with an interest in teaching and was often prompted by a dissatisfaction with clinical practice. Academic GPs described concerns about career prospects and changing professional identity but valued the scholarship and creativity associated with their academic roles. This study provides insights into the motivations of academic GPs and the factors influencing academic career progression.

BACKGROUND Curative oesophagectomy for oesophageal cancer is associated with considerable potential mortality. Surgeons are increasingly treating older patients presenting with oesophageal cancer as the population ages. The question remains as to the survival in an older population group, many of whom are not fit for combined multimodal therapy. This study aimed to assess the effect of age on overall survival and disease-free survival in patients undergoing curative oesophagectomy for cancer. METHODS Patient data were analysed from a prospectively maintained database. Demographic, surgical and survival outcomes were compared between groups according to age less than 75 years or 75 and older. RESULTS Oesophagectomy was performed in 351 patients between 1990 and 2019 (283 patients

Purpose: The majority of gastric cancer patients are diagnosed with late-stage disease, for which distinct molecular subtypes have been identified that are potentially amenable to targeted therapies. However, there exists no molecular classification system with prognostic power for early-stage gastric cancer (EGC) because the molecular events promoting gastric cancer initiation remain ill-defined. Experimental Design: miRNA microarrays were performed on gastric tissue from the gp130F/F preclinical EGC mouse model, prior to tumor initiation. Computation prediction algorithms were performed on multiple data sets and independent gastric cancer patient cohorts. Quantitative real-time PCR expression profiling was undertaken in gp130F/F-based mouse strains and human gastric cancer cells genetically engineered for suppressed activation of the oncogenic latent transcription factor STAT3. Human gastric cancer cells with modulated expression of the miR-200 family member miR-429 were also assessed for their proliferative response. Results: Increased expression of miR-200 family members is associated with both tumor initiation in a STAT3-dependent manner in gp130F/F mice and EGC (i.e., stage IA) in patient cohorts. Overexpression of miR-429 also elicited contrasting pro- and antiproliferative responses in human gastric cancer cells depending on their cellular histologic subtype. We also identified a miR-200 family–regulated 15-gene signature that integrates multiple key current indicators of EGC, namely tumor invasion depth, differentiation, histology, and stage, and provides superior predictive power for overall survival compared with each EGC indicator alone. Conclusions: Collectively, our discovery of a STAT3-regulated, miR-200 family–associated gene signature specific for EGC, with predictive power, provides a molecular rationale to classify and stratify EGC patients for endoscopic treatment. Clin Cancer Res; 24(6); 1459–72. ©2018 AACR.

The inhibition of host innate immunity pathways is essential for the persistence of attaching and effacing pathogens such as enteropathogenic Escherichia coli (EPEC) and Citrobacter rodentium during mammalian infections. To subvert these pathways and suppress the antimicrobial response, attaching and effacing pathogens use type III secretion systems to introduce effectors targeting key signaling pathways in host cells. One such effector is the arginine glycosyltransferase NleB1 (NleBCR in C. rodentium) that modifies conserved arginine residues in death domain-containing host proteins with N-acetylglucosamine (GlcNAc), thereby blocking extrinsic apoptosis signaling. Ectopically expressed NleB1 modifies the host proteins Fas-associated via death domain (FADD), TNFRSF1A-associated via death domain (TRADD), and receptor-interacting serine/threonine protein kinase 1 (RIPK1). However, the full repertoire of arginine GlcNAcylation induced by pathogen-delivered NleB1 is unknown. Using an affinity proteomic approach for measuring arginine-GlcNAcylated glycopeptides, we assessed the global profile of arginine GlcNAcylation during ectopic expression of NleB1, EPEC infection in vitro, or C. rodentium infection in vivo. NleB overexpression resulted in arginine GlcNAcylation of multiple host proteins. However, NleB delivery during EPEC and C. rodentium infection caused rapid and preferential modification of Arg117 in FADD. This FADD modification was extremely stable and insensitive to physiological temperatures, glycosidases, or host cell degradation. Despite its stability and effect on the inhibition of apoptosis, arginine GlcNAcylation did not elicit any proteomic changes, even in response to prolonged NleB1 expression. We conclude that, at normal levels of expression during bacterial infection, NleB1/NleBCR antagonizes death receptor-induced apoptosis of infected cells by modifying FADD in an irreversible manner.

A small proportion of patients with malignant pleural mesothelioma (MPM) achieve pathological complete response (CR) following treatment with current practice induction chemotherapy. Our analysis of 58 patients with MPM treated with platinum-based chemotherapy showed 4 patients (7%) attained pathological CR at subsequent extrapleural pneumonectomy (EPP). Patient and tumour factors such as age, gender, smoking habit, histological subtype, and clinical stage were not found to be associated with pathological CR. Patients with pathological CR had longer disease-free survival (29.2 vs. 13.8 months; p = 0.08) and overall survival (76.4 vs. 23.4 months; p = 0.06) but this did not reach statistical significance. Our study suggests that patients who achieve pathological CR after chemotherapy may have improved survival in MPM.

Context: There is a need to improve both primary palliative care (PPC) education and its assessment in graduate medical education (GME). We developed an instrument based on published palliative care (PC) competencies to assess resident competency and educational interventions. Objectives: To describe the development and psychometric properties of a novel, competency-based instrument to measure resident knowledge and self-efficacy in PPC. Methods: We created a 2-part instrument comprised of a knowledge test (KT) and a self-efficacy inventory (SEI) addressing 18 consensus, core PC resident competencies across 5 domains: pain and symptom management; communication; psychosocial, spiritual, and cultural aspects of care; terminal care and bereavement; and PC principles and practice. The instrument was distributed to 341 internal medicine residents during academic years 2015 to 2016 and 2016 to 2017. A standard item analysis was performed on the KT. Internal consistency (Cronbach α) and variable relationships (factor analysis) were measured for the SEI. Results: One hundred forty-four residents completed the survey (42% response). For 15 KT items, difficulty ranged from 0.17 to 0.98, with 7 items ranging 0.20 to 0.80 (typical optimum difficulty); discrimination ranged from 0.03 to 0.60 with 10 items ≥0.27 (good to very good discrimination). Cronbach α was 0.954 for 35 SEI items. Factor analysis of combined 2015 to 2016 items yielded 4 factors explaining the majority of variance for the entire set of variables. Conclusion: Our instrument demonstrates promising psychometric properties and reliability in probing the constructs of PC and can be further utilized in PC GME research to assess learners and evaluate PPC educational interventions.

Introduction Patients with lung cancer who harbor multiple pulmonary sites of disease have been challenging to classify; a subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee was charged with developing proposals for the eighth edition of the tumor, node, and metastasis (TNM) classification to address this issue. Methods A systematic literature review and analysis of the International Association for the Study of Lung Cancer database was performed to develop proposals for revision in an iterative process involving multispecialty international input and review. Results Details of the evidence base are summarized in other articles. Four patterns of disease are recognized; the clinical presentation, pathologic correlates, and biologic behavior of these suggest specific applications of the TNM classification rules. First, it is proposed that second primary lung cancers be designated with a T, N, and M category for each tumor. Second, tumors with a separate tumor nodule of the same histologic type (either suspected or proved) should be classified according to the location of the separate nodule relative to the index tumor—T3 for a same-lobe, T4 for a same-side (different lobe), and M1a for an other-side location—with a single N and M category. Third, multiple tumors with prominent ground glass (imaging) or lepidic (histologic) features should be designated by the T category of the highest T lesion, the number or m in parentheses (#/m) to indicate the multiplicity, and a collective N and M category for all. Finally, it is proposed that diffuse pneumonic-type lung cancers be designated by size (or T3) if in one lobe, T4 if involving multiple same-side lobes, and M1a if involving both lungs with a single N and M category for all areas of involvement. Conclusion We propose to tailor TNM classification of multiple pulmonary sites of lung cancer to reflect the unique aspects of four different patterns of presentation. We hope that this will lead to more consistent classification and clarity in communication and facilitate further research in the nature and optimal treatment of these entities.

Background: Development of targeted therapies for high-grade serous ovarian cancer (HGSC) remains challenging, as contributing molecular pathways are poorly defined or expressed heterogeneously. CUB-domain containing protein 1 (CDCP1) is a cell-surface protein elevated in lung, colorectal, pancreas, renal and clear cell ovarian cancer. Methods: CUB-domain containing protein 1 was examined by immunohistochemistry in HGSC and fallopian tube. The impact of targeting CDCP1 on cell growth and migration in vitro, and intraperitoneal xenograft growth in mice was examined. Three patient-derived xenograft (PDX) mouse models were developed and characterised for CDCP1 expression. The effect of a monoclonal anti-CDCP1 antibody on PDX growth was examined. Src activation was assessed by western blot analysis. Results: Elevated CDCP1 was observed in 77% of HGSC cases. Silencing of CDCP1 reduced migration and non-adherent cell growth in vitro and tumour burden in vivo. Expression of CDCP1 in patient samples was maintained in PDX models. Antibody blockade of CDCP1 significantly reduced growth of an HGSC PDX. The CDCP1-mediated activation of Src was observed in cultured cells and mouse xenografts. Conclusions: CUB-domain containing protein 1 is over-expressed by the majority of HGSCs. In vitro and mouse model data indicate that CDCP1 has a role in HGSC and that it can be targeted to inhibit progression of this cancer.

Purpose: Low-grade serous ovarian carcinomas (LGSC) are Ras pathway-mutated, TP53 wild-type, and frequently associated with borderline tumors. Patients with LGSCs respond poorly to platinum-based chemotherapy and may benefit from pathway-targeted agents. High-grade serous carcinomas (HGSC) are TP53-mutated and are thought to be rarely associated with borderline tumors. We sought to determine whether borderline histology associated with grade 2 or 3 carcinoma was an indicator of Ras mutation, and we explored the molecular relationship between coexisting invasive and borderline histologies. Experimental Design: We reviewed >1,200 patients and identified 102 serous carcinomas with adjacent borderline regions for analyses, including candidate mutation screening, copy number, and gene expression profiling. Results: We found a similar frequency of low, moderate, and high-grade carcinomas with coexisting borderline histology. BRAF/KRAS alterations were common in LGSC; however, we also found recurrent NRAS mutations. Whereas borderline tumors harbored BRAF/KRAS mutations, NRAS mutations were restricted to carcinomas, representing the first example of a Ras oncogene with an obligatory association with invasive serous cancer. Coexisting borderline and invasive components showed nearly identical genomic profiles. Grade 2 cases with coexisting borderline included tumors with molecular features of LGSC, whereas others were typical of HGSC. However, all grade 3 carcinomas with coexisting borderline histology were molecularly indistinguishable from typical HGSC. Conclusion: Our findings suggest that NRAS is an oncogenic driver in serous ovarian tumors. We demonstrate that borderline histology is an unreliable predictor of Ras pathway aberration and underscore an important role for molecular classification in identifying patients that may benefit from targeted agents. Clin Cancer Res; 20(24); 6618–30. ©2014 AACR.

INTRODUCTION: Revisions to the TNM stage classifications for lung cancer, informed by the international database (N = 94,708) of the International Association for the Study of Lung Cancer (IASLC) Staging and Prognostic Factors Committee, need external validation. The objective was to externally validate the revisions by using the National Cancer Data Base (NCDB) of the American College of Surgeons.METHODS: Cases presenting from 2000 through 2012 were drawn from the NCDB and reclassified according to the eighth edition stage classification. Clinically and pathologically staged subsets of NSCLC were analyzed separately. The T, N, and overall TNM classifications were evaluated according to clinical, pathologic, and "best" stage (N = 780,294). Multivariate analyses were carried out to adjust for various confounding factors. A combined analysis of the NSCLC cases from both databases was performed to explore differences in overall survival prognosis between the two databases.RESULTS: The databases differed in terms of key factors related to data source. Survival was greater in the IASLC database for all stage categories. However, the eighth edition TNM stage classification system demonstrated consistent ability to discriminate TNM categories and stage groups for clinical and pathologic stage.CONCLUSIONS: The IASLC revisions made for the eighth edition of lung cancer staging are validated by this analysis of the NCDB database by the ordering, statistical differences, and homogeneity within stage groups and by the consistency within analyses of specific cohorts.

Nodal categories for malignant pleural mesothelioma are derived from the lung cancer staging system and have not been adequately validated. The International Association for the Study of Lung Cancer developed a multinational database to generate evidence-based recommendations to inform the eighth edition of the TNM classification of malignant pleural mesothelioma.Data from 29 centers were entered prospectively (n = 1566) or by transfer of retrospective data (n = 1953). Survival according to the seventh edition N categories was evaluated using Kaplan-Meier survival curves and Cox proportional hazards regression analysis. Survival was measured from the date of diagnosis.There were 2432 analyzable cases: 1603 had clinical (c) staging, 1614 had pathologic (p) staging, and 785 had both. For clinically staged tumors there was no separation in Kaplan-Meier curves between cN0, cN1 or cN2 (cN1 versus cN0 hazard ratio [HR] = 1.06, p = 0.77 and cN2 versus cN1 HR = 1.04, p = 0.85). For pathologically staged tumors, patients with pN1 or pN2 tumors had worse survival than those with pN0 tumors (HR = 1.51, p 0.0001) but no survival difference was noted between those with pN1 and pN2 tumors (HR = 0.99, p = 0.99). Patients with both pN1 and pN2 nodal involvement had poorer survival than those with pN2 tumors only (HR = 1.60, p = 0.007) or pN0 tumors (HR = 1.62, p0.0001).A recommendation to collapse both clinical and pN1 and pN2 categories into a single N category comprising ipsilateral, intrathoracic nodal metastases (N1) will be made for the eighth edition staging system. Nodes previously categorized as N3 will be reclassified as N2.

Successful infection by enteric bacterial pathogens depends on the ability of the bacteria to colonize the gut, replicate in host tissues and disseminate to other hosts. Pathogens such as Salmonella, Shigella and enteropathogenic and enterohaemorrhagic (EPEC and EHEC, respectively) Escherichia coli use a type III secretion system (T3SS) to deliver virulence effector proteins into host cells during infection that promote colonization and interfere with antimicrobial host responses. Here we report that the T3SS effector NleB1 from EPEC binds to host cell death-domain-containing proteins and thereby inhibits death receptor signalling. Protein interaction studies identified FADD, TRADD and RIPK1 as binding partners of NleB1. NleB1 expressed ectopically or injected by the bacterial T3SS prevented Fas ligand or TNF-induced formation of the canonical death-inducing signalling complex (DISC) and proteolytic activation of caspase-8, an essential step in death-receptor-induced apoptosis. This inhibition depended on the N-acetylglucosamine transferase activity of NleB1, which specifically modified Arg 117 in the death domain of FADD. The importance of the death receptor apoptotic pathway to host defence was demonstrated using mice deficient in the FAS signalling pathway, which showed delayed clearance of the EPEC-like mouse pathogen Citrobacter rodentium and reversion to virulence of an nleB mutant. The activity of NleB suggests that EPEC and other attaching and effacing pathogens antagonize death-receptor-induced apoptosis of infected cells, thereby blocking a major antimicrobial host response.

Introduction: The M component and TNM stage groupings for malignant pleural mesothelioma (MPM) have been empirical. The International Association for the Study of Lung Cancer developed a multinational database to propose evidence-based revisions for the eighth edition of the TNM classification of MPM. Methods: Data from 29 centers were submitted either electronically or by transfer of existing institutional databases. The M component as it currently stands was validated by confirming sufficient discrimination (by Kaplan-Meier analysis) with respect to overall survival (OS) between the clinical MO (cM0) and cM1 categories. Candidate stage groups were developed by using a recursive partitioning and amalgamation algorithm applied to all cM0 cases. Results: Of 3519 submitted cases, 2414 were analyzable and 84 were cM1 cases. Median OS for cM1 cases was 9.7 months versus 13.4 months (p = 0.0013) for the locally advanced (T4 or N3) cM0 cases, supporting inclusion of only cM1 in the stage IV group. Exploratory analyses suggest a possible difference in OS for single- versus multiple-site cM1 cases. A recursive partitioning and amalgamation generated survival tree on the OS outcomes restricted to cM0 cases with the newly proposed (eighth edition) T and N components indicates that optimal stage groupings for the eighth edition will be as follows: stage IA (T1N0), stage IB (T2-3N0), stage II (T1-2N1), stage IIIA (T3N1), stage IIIB (T1-3N2 or any T4), and stage IV (any M1). Conclusions: This first evidence-based revision of the TNM classification for MPM leads to substantial changes in the T and N components and the stage groupings. (C) 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Background Addressing evidence-practice gaps in primary care remains a significant public health challenge and is likely to require action at different levels of the health system. Whilst Continuous Quality Improvement (CQI) is associated with improvements in overall delivery, little is known about delivery of different types of care processes, and their relative improvement during CQI. Methods We used data from over 15,000 clinical audit records of clients with Type 2 diabetes collected as part of a wide-scale CQI program implemented between 2005 and 2014 in 162 Aboriginal and Torres Strait Islander health centres. We abstracted data from clinical records on 15 service items recommended in clinical guidelines and categorised these items into five modes of care on the basis of the mechanism through which care is delivered: laboratory tests; generalist-delivered physical checks; specialist-delivered checks; education/counselling for nutrition and physical activity and education/counselling for high risk substance use. We calculated delivery for each patient for each of mode of care by determining the proportion of recommended services delivered for that mode. We used multilevel regression models to quantify variation attributable to health centre or client level factors and to identify factors associated with greater adherence to clinical guidelines for each mode of care. Results Clients on average received 43 to 60 % of recommended care in 2005/6. Different modes of care showed different patterns of improvement. Generalist-delivered physical checks (delivered by a non-specialist) showed a steady year on year increase, delivery of laboratory tests showed improvement only in the later years of the study, and delivery of counselling/education interventions showed early improvement which then plateaued. Health centres participating in CQI had increased odds of top quartile service delivery for all modes compared to baseline, but effects differed by mode. Health centre factors explained 20–52 % of the variation across jurisdictions and health centres for different modes of care. Conclusions Levels of adherence to clinical guidelines and patterns of improvement during participation in a CQI program differed for different modes of care. Policy and funding decisions may have had important effects on the level and nature of improvements achieved.

Introduction Stage classification provides a consistent language to describe the anatomic extent of disease and is therefore a critical tool in caring for patients. The Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer developed proposals for revision of the classification of lung cancer for the eighth edition of the tumor, node, and metastasis (TNM) classification, which takes effect in 2017. Methods An international database of 94,708 patients with lung cancer diagnosed in 1999–2010 was assembled. This article describes the process and statistical methods used to refine the lung cancer stage classification. Results Extensive analysis allowed definition of tumor, node, and metastasis categories and stage groupings that demonstrated consistent discrimination overall and within multiple different patient cohorts (e.g., clinical or pathologic stage, R0 or R-any resection status, geographic region). Additional analyses provided evidence of applicability over time, across a spectrum of geographic regions, histologic types, evaluative approaches, and follow-up intervals. Conclusions An extensive analysis has produced stage classification proposals for lung cancer with a robust degree of discriminatory consistency and general applicability. Nevertheless, external validation is encouraged to identify areas of strength and weakness; a sound validation should have discriminatory ability and be based on an independent data set of adequate size and sufficient follow-up with enough patients for each subgroup.

Introduction It can be difficult to distinguish between a second primary and a metastasis in patients with lung cancer who have more than one pulmonary site of cancer. Methods A systematic review of the literature was conducted by a subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee to develop recommendations to identify second primary lung cancers. The process entailed review of knowledge relating to the mechanism of metastasis, determination of clonality, and outcomes of patients with resected tumors. Results It is easier to determine that two tumors are different than that they are the same; finding similarities does not establish that they are the same. For example, most second primary lung cancers are of the same histotype. Few criteria are reliable by themselves; these include different histologic cancer types or matching DNA breakpoints by sequencing and a comprehensive histologic assessment of resected specimens. Characteristics that are suggestive but associated with potential misclassification include the presence or absence of biomarkers, imaging characteristics, and the presence or absence of nodal involvement. Conclusions Clinical and pathologic (i.e., after resection) criteria are presented to identify two foci as separate primary lung cancers versus a metastasis. Few features are definitive; many commonly used characteristics are suggestive but associated with a substantial rate of misclassification. Careful review by a multidisciplinary tumor board, considering all available information, is recommended.

Introduction Small cell lung cancer (SCLC) is commonly classified as either limited or extensive, but the Union for International Cancer Control TNM Classification of Malignant Tumours seventh edition (2009) recommended tumor, node, and metastasis (TNM) staging based on analysis of the International Association for the Study of Lung Cancer (IASLC) database. Methods Survival analyses were performed for clinically and pathologically staged patients presenting with SCLC from 1999 through 2010. Prognosis was compared in relation to the TNM seventh edition staging to serve as validation and analyzed in relation to proposed changes to the T descriptors found in the eighth edition. Results There were 5002 patients: 4848 patients with clinical and 582 with pathological stages. Among these, 428 had both. Survival differences were confirmed for T and N categories and maintained in relation to proposed revisions to T descriptors for seventh edition TNM categories and proposed changes in the eighth edition. There were also survival differences, notably at 12 months, in patients with brain-only single-site metastasis (SSM) compared to SSM at other sites, and SSM without a pleural effusion showed a better prognosis than other patients in the M1b category. Conclusion We confirm the prognostic value of clinical and pathological TNM staging in patients with SCLC, and recommend continued usage for SCLC in relation to proposed changes to T, N, and M descriptors for NSCLC in the eighth edition. However, for M descriptors, it remains uncertain whether survival differences in patients with SSM in the brain simply reflect better treatment options rather than better survival based on anatomic extent of disease.

Introduction: The current T component for malignant pleural mesothelioma (MPM) has been predominantly informed by surgical data sets and consensus. The International Association for the Study of Lung Cancer undertook revision of the seventh edition of the staging system for MPM with the goal of developing recommendations for the eighth edition. Methods: Data elements including detailed T descriptors were developed by consensus. Tumor thickness at three pleural levels was also recorded. An electronic data capture system was established to facilitate data submission. Results: A total of 3519 cases were submitted to the database. Of those eligible for T-component analysis, 509 cases had only clinical staging, 836 cases had only surgical staging, and 642 cases had both available. Survival was examined for T categories according to the current seventh edition staging system. There was clear separation between all clinically staged categories except T1a versus T1b (hazard ratio = 0.99, p = 0.95) and T3 versus T4 (hazard ratio = 1.22, p = 0.09), although the numbers of T4 cases were small. Pathological staging failed to demonstrate a survival difference between adjacent categories with the exception of T3 versus T4. Performance improved with collapse of T1a and T1b into a single T1 category; no current descriptors were shifted or eliminated. Tumor thickness and nodular or rindlike morphology were significantly associated with survival. Conclusions: A recommendation to collapse both clinical and pathological T1a and T1b into a T1 classification will be made for the eighth edition staging system. Simple measurement of pleural thickness has prognostic significance and should be examined further with a view to incorporation into future staging. (C) 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

The IASLC Staging and Prognostic Factors Committee has collected a new database of 94,708 cases donated from 35 sources in 16 countries around the globe. This has now been analysed by our statistical partners at Cancer Research And Biostatistics and, in close collaboration with the members of the committee proposals have been developed for the T, N, and M categories of the 8th edition of the TNM Classification for lung cancer due to be published late 2016. In this publication we describe the methods used to evaluate the resultant Stage groupings and the proposals put forward for the 8th edition.

‘ Mutated in Colorectal Cancer ' ( MCC ) is emerging as a multifunctional protein that affects several cellular processes and pathways. Although the MCC gene is rarely mutated in colorectal cancer, it is frequently silenced through promoter methylation. Previous studies have reported loss of heterozygosity (LOH) of the closely linked MCC and APC loci in both colorectal and lung cancers. APC promoter methylation is a marker of poor survival in non-small cell lung cancer (NSCLC). However, MCC methylation has not been previously studied in lung cancer. Therefore, we wanted to determine if MCC is silenced through promoter methylation in lung cancer and whether this methylation is associated with LOH of the MCC locus or methylation of the APC gene. Three polymorphic markers for the APC/MCC locus were analysed for LOH in 64 NSCLC specimens and matching normal tissues. Promoter methylation of both genes was determined using methylation specific PCR in primary tumours. LOH of the three markers was found in 41–49% of the specimens. LOH within the MCC locus was less common in adenocarcinoma (ADC) (29%) than in squamous cell carcinoma (SCC) (72%; P =0.006) or large cell carcinoma (LCC) (75%; P =0.014). However, this LOH was not accompanied by MCC promoter methylation, which was found in only two cancers (3%). In contrast, 39% of the specimens showed APC methylation, which was more common in ADC (58%) than in SCC (13%). Western blotting revealed that MCC was expressed in a subset of lung tissue specimens but there was marked variation between patients rather than between cancer and matching non-cancer tissue specimens. In conclusion, we have shown that promoter methylation of the APC gene does not extend to the neighbouring MCC gene in lung cancer, but LOH is found at both loci. The variable levels of MCC expression were not associated with promoter methylation and may be regulated through other cellular mechanisms.

OBJECTIVE: To study the effects of college students' physical activity and gender on depressive and suicidal symptoms. METHOD: The National College Health Assessment survey was administered to college students nationwide. Data were analyzed with 4x2 ANOVAs and Games-Howell post hoc tests when appropriate. RESULTS: More frequent physical activity related to less frequent depressive symptoms and consideration of suicide, but not with attempted suicide. Males reported depressive symptoms less frequently than did females. CONCLUSION: Depression research has implications for an increasingly sedentary college population. Institutions should provide increased access and knowledge pertaining to emotional health and psychological benefits through physical activity. Language: en

Introduction Separate tumor nodules with the same histologic appearance occur in the lungs in a small proportion of patients with primary lung cancer. This article addresses how such tumors can be classified to inform the eighth edition of the anatomic classification of lung cancer. Separate tumor nodules should be distinguished from second primary lung cancer, multifocal ground glass/lepidic tumors, and pneumonic-type lung cancer, which are addressed in separate analyses. Methods Survival of patients with separate tumor nodules in the International Association for the Study of Lung Cancer database were analyzed. This was compared with a systematic literature review. Results Survival of clinically staged patients decreased according to the location of the separate tumor nodule relative to the index tumor (same lobe > same side > other side) in N0 and N-any cohorts (all M0 except possible other-side nodules). However, there was also a decrease in the proportion of patients resected; among only surgically resected or among nonresected patients no survival differences were noted. There were no survival differences between patients with same-lobe nodules and those with other T3 tumors, between patients with same-side nodules and those with T4 tumors, and patients with other-side nodules and those with other M1a tumors. The data correlated with those identified in a literature review. Conclusions Tumors with same-lobe separate tumor nodules (with the same histologic appearance) are recommended to be classified as T3, same-side nodules as T4, and other-side nodules as M1a. Thus, there is no recommended change between the seventh and eighth edition of the TNM classification of lung cancer.

Local recurrence and distant failure after adjuvant radiation therapy for breast cancer remain significant clinical problems, incompletely predicted by conventional clinicopathologic markers. We had previously identified microRNA-139-5p and microRNA-1274a as key regulators of breast cancer radiation response in vitro. The purpose of this study was to investigate standard clinicopathologic markers of local recurrence in a contemporary series and to establish whether putative target genes of microRNAs involved in DNA repair and cell cycle control could better predict radiation therapy response in vivo.With institutional ethics board approval, local recurrence was measured in a contemporary, prospectively collected series of 458 patients treated with radiation therapy after breast-conserving surgery. Additionally, independent publicly available mRNA/microRNA microarray expression datasets totaling >1000 early-stage breast cancer patients, treated with adjuvant radiation therapy, with >10 years of follow-up, were analyzed. The expression of putative microRNA target biomarkers-TOP2A, POLQ, RAD54L, SKP2, PLK2, and RAG1-were correlated with standard clinicopathologic variables using 2-sided nonparametric tests, and to local/distant relapse and survival using Kaplan-Meier and Cox regression analysis.We found a low rate of isolated local recurrence (1.95%) in our modern series, and that few clinicopathologic variables (such as lymphovascular invasion) were significantly predictive. In multiple independent datasets (n>1000), however, high expression of RAD54L, TOP2A, POLQ, and SKP2 significantly correlated with local recurrence, survival, or both in univariate and multivariate analyses (P

IntroductionLung cancer is the leading cause of cancer-related mortality and requires more effective molecular markers of prognosis and therapeutic responsiveness. Special AT-rich binding protein 1 (SATB1) is a global genome organizer that recruits chromatin remodeling proteins to epigenetically regulate hundreds of genes in a tissue-specific manner. Initial studies suggest that SATB1 overexpression is a predictor of poor prognosis in breast cancer, but the prognostic significance of SATB1 expression has not been evaluated in lung cancer.MethodsA cohort of 257 lung cancers was evaluated by immunohistochemistry. Epigenetic silencing of SATB1 was examined in cell lines by 5-Aza 2-deoxycytidine and trichostatin A treatment, and chromatin immunoprecipitation.ResultsSignificant loss of SATB1 expression was found in squamous preinvasive lesions (p < 0.04) and in non-small cell lung cancers (p < 0.001) compared with matched normal bronchial epithelium. Loss of SATB1 independently predicted poor cancer-specific survival in squamous cell carcinomas (SCCs; hazard ratio: 2.06, 95% confidence interval: 1.2–3.7, p = 0.016). Treatment of lung cancer cell lines with the histone deacetylase inhibitor trichostatin A resulted in up-regulation of SATB1. SATB1 was associated with a decrease in the active chromatin mark acetylated histone H3K9 and an increase in the repressive polycomb mark trimethylated H3K27 in a SCC cell line relative to a normal bronchial epithelial cell line.ConclusionsThis is the first study showing that SATB1 expression is lost in early preinvasive squamous lesions and that loss of SATB1 is associated with poor prognosis in lung SCC. We hypothesize that the SATB1 gene is epigenetically silenced through histone modifications.

Extrapleural pneumonectomy (EPP) has been established as a viable surgical option in the treatment of malignant pleural mesothelioma (MPM) for selected patients. A number of pathological staging systems have been developed to prognosticate survival outcomes. We assessed 91 patients with MPM who underwent EPP in our institution and evaluated the applicability of the most updated staging systems in the current literature. After a mean follow-up of 20 months, the median overall survival was 27.6 months. Postoperative pathological staging according to the International Mesothelioma Interest Group criteria (P = 0.026) and the Brigham and Women's Hospital criteria (P = 0.039) were both found to be significant prognostic factors. Adjuvant chemotherapy (P = 0.022) and radiotherapy (P = 0.008) were associated with improved survival outcomes. These findings are consistent with previous reports that demonstrated the usefulness of pathological staging systems as a prognostic tool in patients with MPM after undergoing EPP. However, preoperative clinical staging systems need to be developed to facilitate the patient selection process prior to surgery.

Background: There has been an evolving role of surgery for malignant pleural mesothelioma (MPM) over the past 25 years. The objective of this study was to investigate whether the survival results for MPM patients after surgery have improved within this time period by an analysis of a prospective cohort of 540 patients.Methods: Five hundred and forty consecutive patients with MPM were treated by a thoracic surgical team. These patients were categorized into two groups: Group I (before September 1999, n = 270) and Group II (after September 1999, n = 270). The two groups were compared for clinicopathologic data and survival results. The statistical analyses of all prognostic parameters used overall survival as the endpoint.Results: Group II had higher proportions of epithelial tumors and patients who had preoperative PET scan, extrapleural pneumonectomy (EPP), postoperative radiotherapy and pemetrexed chemotherapy. The overall survival results were significantly better in Group II compared with Group I (p = 0.004). Four factors were found to be independently associated with an improved survival in multivariate analysis: epithelial subtype (p 100 cases (p = 0.006), patients who underwent EPP (p = 0.001) and those who received pemetrexed chemotherapy (p = 0.016). The median survival for patients selected for EPP was 20 months, as compared to 9 months for pleurodesis/decortication and pleurodesis.Conclusions: Significant improvement of overall survival results has been achieved in the more recent 270 MPM patients through accumulated experience in a specialist treatment center.

Introduction The role of the number of metastatic nodes in esophageal cancer surgery is of interest. We assess predictors of survival after oesophagectomy for esophageal and gastroesophageal junction malignancy. Methods Prospective data of consecutive patients undergoing oesophagectomy and systematic lymphadenectomy between 1991 and 2007. Results Of 224 patients, 148 patients (66%) had adenocarcinoma, 70 (31%) squamous cell carcinoma, and 6 (2.6%) were other tumor types. Five-year survival was 43% with hospital mortality of 3.5%. Locoregional recurrence occurred in 14%. The total number of affected nodes significantly reduced survival (four or more metastatic nodes). Further analysis of the ratio of nodes affected to the total number resected showed a significant decrease in survival as the percentage of positive nodes increased (p Conclusions Patients undergoing surgery for esophageal cancer should be staged according to a minimum total number of metastatic lymph nodes and ratios because this more accurately predicts survival than current staging systems.

Objective Back pain has consistently ranked among the top general health complaints among college students, but few studies have examined risk factors for back pain in this age group. This cross-sectional survey evaluated the association between the self-reported annual low back pain with the estimated usual backpack weight among college students. Methods Data were collected from health education students during the spring semester of 2007 at the Colorado State University using an online survey. Adjusted odds ratios were calculated using logistic regression. Results Four hundred sixty-five (94.6%) health education students completed the online survey. The annual prevalence of low back pain was 29.2% (n = 136). A 25% increase in the odds of annual low back pain for each 4-kg increase in the estimated usual backpack weight was observed after adjusting for sex, smoking, reporting frequently feeling overwhelmed, and body mass index (adjusted odds ratio per 4-kg increase, 1.25; 95% confidence interval, 1.17-1.32). There was no evidence of an increased association of annual low back pain with carrying a backpack weight greater than 10% of the students body weight compared with those carrying less (adjusted odds ratio, 1.02; 95% confidence interval, 0.63-1.65). Conclusions The results of this study suggest that increasing reported backpack weight is associated with increased prevalence of annual low back pain. However, these results do not provide evidence to support the recommendation that the backpack weight necessarily be less than 10% of body weight.

Background: Examining variation in diabetes care across regions/organizations provides insight into underlying factors related to quality of care. The aims of this study were to assess quality of diabetes care and its variation among Aboriginal community health centres in Australia, and to estimate partitioning of variation attributable to health centre and individual patient characteristics. Methods: During 2005–2009, clinical medical audits were conducted in 62 Aboriginal community health centres from four states/territories. Main outcome measures include adherence to guidelines‐scheduled processes of diabetes care, treatment and medication adjustment, and control of HbA1c, blood pressure, total cholesterol and albumin/creatinine ratio (ACR). Results: Wide variation was observed across different categories of diabetes care measures and across centres: (1) overall adherence to delivery of services averaged 57% (range 22–83% across centres); (2) medication adjustment rates after elevated HbA1c: 26% (0–72%); and (3) proportions of patients with HbA < 7% : 27% (0–55%); with blood pressure < 130/80 mmHg: 36%(0–59%). Health centre level characteristics accounted for 36% of the total variation in adherence to process measures, and 3–11% of the total variation in patient intermediate outcomes; the remaining, substantial amount of variation in each measure was attributable to patient level characteristics. Conclusions: Deficiencies in a range of quality of care measures provide multiple opportunities for improvement. The majority of variation in quality of diabetes care appears to be attributable to patient level characteristics. Further understanding of factors affecting variation in the care of individuals should assist clinicians, managers and policy makers to develop strategies to improve quality of diabetes care in Aboriginal communities. Refereed/Peer-reviewed

Objective This study aimed to evaluate the perioperative and long-term outcomes associated with extrapleural pneumonectomy for patients with malignant pleural mesothelioma. Methods From October 1994 to April 2008, 70 patients were selected for extrapleural pneumonectomy. Univariate analysis was performed using the Kaplan–Meier method and compared using the log-rank test. Multivariate analysis with entering and removing limits of P less than .10 and P greater than .05, respectively, was used. The prognostic factors included age, gender, side of disease, asbestos exposure, histology, positron emission tomography, date of surgery, neoadjuvant chemotherapy, completeness of cytoreduction, lymph node involvement, perioperative morbidity, adjuvant radiotherapy, and pemetrexed-based chemotherapy. Results The mean age of patients was 55 years (standard deviation=10). Fifty-eight patients had epithelial tumors. Six patients received neoadjuvant chemotherapy, 28 patients received adjuvant radiotherapy, and 16 patients received postoperative pemetrexed-based chemotherapy. Forty-four patients had no lymph node involvement. The perioperative morbidity and mortality were 37% and 5.7%, respectively. Complications included hemothorax (n = 7), atrial fibrillation (n = 6), empyema (n = 4), bronchopulmonary fistula (n = 3), right-sided heart failure (n = 2), pneumonia (n = 1), constrictive pericarditis (n = 1), acute pulmonary edema (n = 1), small bowel herniation (n = 1), and disseminated intravascular coagulopathy (n = 1). The median survival was 20 months, with a 3-year survival of 30%. Asbestos exposure, negative lymph node involvement, and receipt of adjuvant radiation or postoperative pemetrexed-based chemotherapy were associated with improved survival on both univariate and multivariate analyses. Conclusion The present study supports the use of extrapleural pneumonectomy-based multimodal therapy in carefully selected patients with malignant pleural mesothelioma.

Timeliness of immunisation is important in achieving a protective effect at the individual and population levels. Recent international research has highlighted the importance of organisational features of the health system in timely immunisation. This paper reports on an analysis of the availability of records of timely delivery of childhood immunisations in Indigenous primary care services and organisational features of vaccination programs in different jurisdictions in Australia. The findings demonstrate wide variation in recorded timely delivery of immunisations between health centres within and between jurisdictions. Significant deficiencies in the approach to delivery and recording of immunisations appear to be principally related to fragmented systems of delivery, recording and communication between child health and primary care services. Understanding these deficiencies presents opportunities for improving timely immunisation. Refereed/Peer-reviewed

International audience; OBJECTIVE: In the 2003 Supplement for tumor, node, metastasis (TNM) Staging classification it states that TNM staging "applies to all types of carcinoma including small cell carcinoma; however, it does not apply to carcinoids." Despite this caveat, most publications on typical and atypical carcinoids use the TNM staging system for nonsmall cell carcinoma and are able to demonstrate prognostic significance for the different stages. For this reason, as the next TNM Staging proposal is being considered, we sought to investigate the carcinoid cases submitted to the International Association for the Study of Lung Cancer (IASLC) database, as well as the National Cancer Institute Surveillance Epidemiology and End Results (SEER). MATERIALS AND METHODS: In the data collected for the IASLC Staging Project database over the time period 1990 to 2000, there were 513 broncho-pulmonary carcinoids. A total of 1619 broncho-pulmonary carcinoid cases diagnosed over the period 1990-2002 were analyzed from the SEER database, including 1437 surgical cases. Pathologic slides were not available for histologic review. RESULTS: Most of tumors in both the IASLC and SEER databases were Stage I (82% and 78%, respectively), as defined by the IASLC proposals for the 7th edition of TNM staging system. T status was a statistically significant predictor of survival for both the SEER data (p < 0.0001) and the IASLC database (p = 0.0156), though for different reasons. N status showed significant survival correlations in both data sets (p < 0.0001). The effect of M status was significant (p < 0.0001) within the SEER data and not studied in the IASLC cases, which were almost exclusively M0. We found that all three T, N, and M categories as defined for non-small cell lung cancer are generally useful for staging of pulmonary carcinoid tumors. Significant differences in survival for overall stages I versus II versus III/IV were identified in both data sets. Patients with multiple same lobe nodules had a 100% 5-year survival, which may be a reason to reevaluate their status in the IIB category in future analyses. CONCLUSIONS: In summary, the IASLC proposals for the 7th edition of TNM are helpful in predicting prognosis for broncho-pulmonary carcinoid tumors. It is the recommendation of the IASLC Staging project that TNM be applied to broncho-pulmonary carcinoid tumors. A prospective collection of data through an International Registry of Pulmonary Neuroendocrine Tumors planned by the IASLC will allow for further detailed analysis of staging data for broncho-pulmonary carcinoids.

Purpose: The standard of care for ovarian cancer includes platinum-based chemotherapy. It is not possible, however, to predict clinical platinum sensitivity or to design rational strategies to overcome resistance. We used a novel approach to identify altered gene expression associated with high sensitivity to cisplatin, to define novel targets to sensitize tumor cells to platins and ultimately improve the effectiveness of this widely used class of chemotherapeutics. Experimental Design: Using differential display PCR, we identified genes differentially expressed in a mutagenized cell line with unusual sensitivity to cisplatin. The most highly differentially expressed gene was selected, and its role in determining cisplatin sensitivity was validated by gene transfection and small interfering RNA (siRNA) approaches, by association of expression levels with cisplatin sensitivity in cell lines, and by association of tumor expression levels with survival in a retrospective cohort of 71 patients with serous ovarian adenocarcinoma. Results: The most highly differently expressed gene identified was ANKRD1, ankyrin repeat domain 1 (cardiac muscle). ANKRD1 mRNA levels were correlated with platinum sensitivity in cell lines, and most significantly, decreasing ANKRD1 using siRNA increased cisplatin sensitivity >2-fold. ANKRD1 was expressed in the majority of ovarian adenocarcinomas tested (62/71, 87%), and higher tumor levels of ANKRD1 were found in patients with worse outcome (overall survival, P = 0.013). Conclusions: These findings suggest that ANKRD1, a gene not previously associated with ovarian cancer or with response to chemotherapy, is associated with treatment outcome, and decreasing ANKRD1 expression, or function, is a potential strategy to sensitize tumors to platinum-based drugs.

More extensive resection for esophageal cancer has been reported to improve survival in several series. We compared results from an unselected consecutive cohort of patients undergoing radical esophagectomy, including removal of all periesophageal tissue with a 2-field abdominal and mediastinal lymphadenectomy for esophageal and gastroesophageal malignancy. A prospective electronic database was reviewed for patients with esophageal malignancy undergoing an open esophagectomy between 1991 and 2004. Data were analyzed on an SPSS file (version 12.0, Chicago, IL, USA) using chi(2) or Fisher's exact test; odds ratio and 95% confidence interval; and the Kaplan-Meier method, log-rank test and Cox's proportional hazards regression for survival analysis. There were 178 patients with a median age of 65 years and a 70/30 male to female ratio. Median follow-up was 20.4 months. Pathology comprised adenocarcinoma in 64% of patients, squamous cell carcinoma 30%, and other malignancies 6%. Seventeen patients had neoadjuvant therapy. Hospital mortality was 3.3%. Complete resection was achieved in 87%. Local recurrence occurred at a median of 13 months in 6.7% of patients. Overall 5-year survival was 42%. For patients with invasive squamous cell carcinoma and adenocarcinoma the 5-year survival was 47% and 40.3%, respectively, and for patients without nodal involvement it was 71.5%, with one to four nodes involved, 23.5% and with >4 nodes, 5% (P < 0.001). Survival decreased with increasing direct tumor spread (P < 0.001) and pathological stage (P < 0.001). Esophageal resection with systematic 2-field lymphadenectomy can be performed with acceptable operative mortality and favorable survival.

The authors evaluated psychosocial factors of stress and their effects on the prevalence of low back pain (LBP) among a population of college students in a major university in Colorado.This was a nested cross-sectional study of 973 respondents who completed the National College Health Assessment survey. The authors evaluated a subset of questions pertaining to psychosocial stressors against the presence of LBP.The annual prevalence of LBP among the population studied was 42.8%. The stressful psychosocial variables of feeling very sad, exhausted, and overwhelmed were associated with the prevalence of LBP.The prevalence of LBP among this younger population is significant and understudied.

Aims To investigate the role of DNA repair proteins and their prognostic significance in non-small-cell lung cancer (NSCLC). Methods and results A retrospective analysis of 108 cases of stage I–II NSCLC was undertaken. Immunohistochemical expression of DNA repair proteins MLH1, MSH2 and MGMT was assessed using tissue microarrays of paraffin-embedded samples of invasive carcinoma and precursor lesions. Results were analysed in relation to clinicopathological parameters and patient survival. Reduced expression of MLH1 was found in 58.5% of tumours and occurred less frequently in poorly differentiated tumours (P = 0.044) and large cell carcinomas (P = 0.004). MSH2 and MGMT expression was reduced in 18.1% and 77.8% of cases, respectively. There was an inverse relationship between MLH1 and MSH2 expression (P = 0.012). Normal expression of MLH1, MSH2 and MGMT was found in all cases of squamous metaplasia and squamous dysplasia. Only a single case of carcinoma in situ (12.5%) showed reduced MLH1, none showed reduced MSH2 and 25% showed reduced MGMT. Survival analyses showed no prognostic significance based on expression of MLH1 (P = 0.92), MSH2 (P = 0.78) or MGMT (P = 0.57). Conclusions Reduction in expression of DNA repair proteins MLH1, MSH2 and MGMT is relatively common in NSCLC, appears to be a late event in the development of invasive malignancy and does not influence survival in this patient cohort. Cooper W A, Kohonen-Corish M R J, Chan C, Kwun S Y, McCaughan B, Kennedy C, Sutherland R L & Lee C-S (2008) Histopathology52, 613–622 Prognostic significance of DNA repair proteins MLH1, MSH2 and MGMT expression in non-small-cell lung cancer and precursor lesions

Introduction Cripto is a founding member of the EGF-CFC family, and plays an important role in tumourigenesis, tumour cell proliferation and migration. We aimed to determine the significance of Cripto expression on the survival of patients with breast cancer. Methods Immunohistochemical detection of Cripto was performed by using mAb C13 on 120 formalin-fixed paraffin-embedded breast tumour specimens in tissue microarrays. This cohort comprises a series of 120 patients with primary operable breast cancer diagnosed between 1989 and 1995, retrieved from the Concord Repatriation General Hospital breast carcinoma database. Results Using a cutoff value of 80%, Cripto overexpressed in 57 of the 120 (47.5%) patients. We found significant associations between overexpression of Cripto and the Nottingham Prognostic Index (NPI, p p p = 0.04), PR ( p = 0.02) as well as Ki-67 ( p = 0.02). Univariate analysis reveals that there is a significant correlation between overexpression of Cripto and survival ( p = 0.0003). Cox regression analysis indicates that the overexpression of Cripto is an independent prognostic factor in breast cancer (HR 2.79, 95%CI 1.20–6.50). Conclusion The unique epitope recognized by mAb C13 is overexpressed on breast tumour tissues. In this series of invasive breast cancers, overexpression of Cripto was more often found in high grade and poor prognosis tumours compared to low grade and good prognosis breast cancers. Moreover, overexpression of Cripto was significantly associated with decreased patient survival.

Introduction Mesenchymal epithelial transition factor (MET) is a promising therapeutic target in non–small-cell lung cancer (NSCLC) but there are limited data about MET alterations in treatment-naive NSCLC and whether or not these changes are consistent between primary tumors and metastases. We aimed to investigate concordance, clinicopathological correlations, and prognostic value of MET alterations in primary NSCLC and corresponding nodal metastases. Materials and Methods MET gene copy number (GCN) status was evaluated using fluorescent in situ hybridization (FISH) and MET protein expression using immunohistochemistry (IHC) in tissue microarray sections from a retrospective cohort of 300 surgically resected NSCLCs including 93 cases with nodal metastases. Results Primary NSCLCs were MET IHC positive in 28 (10.3%) of cases and MET FISH positive (high polysomy or amplification) in 22 (8.1%) but only 1 (0.4%) showed amplification. In metastases, high MET GCN (18.3%) and protein expression (21.3%) was more frequent compared with primary tumors. The status of MET in lymph nodes significantly correlated with MET status in the corresponding primary tumors. Squamous cell carcinomas showed lower MET overexpression compared with nonsquamous tumors but there were no other associations with clinicopathological characteristics. Patients with tumors that were either MET FISH positive or IHC positive had a significantly better overall survival in univariate and multivariate analyses. Conclusion Alterations of MET are more commonly seen in nodal metastases than primary tumors and this might have implications for their utility as predictive biomarkers to select patients for MET inhibition. MET overexpression and MET high polysomy occur in a low proportion of primary NSCLCs and is associated with a good prognosis.

Although breast cancer is the major cause of cancer-related death in women, there is little comprehensive information on long-term outcomes, particularly pertaining to site of relapse. The Strathfield Breast Centre (TSBC) is a multidisciplinary breast clinic that has collected patient data prospectively over 14 years.All women with invasive, non-metastatic breast cancer, referred to TSBC from 1989 until 2002, were studied (n=2509). After initial treatment, patients were reviewed at 3-12-month intervals, including annual mammography and/or breast ultrasound. Information was collected on demographics, pre- and post-operative management and patient outcomes. Survival was analysed by the method of Kaplan and Meier.The mean age was 58 years and median follow-up 4 years (range1-14) with complete data for 81%. In total, 456 patients (18%) had a local, nodal or distant relapse. The most common site of first relapse was to bone (in 125 patients), followed by local recurrence (124), lung (73) and liver (57). The median interval from primary breast surgery until recurrence was 2.3 years and disease-free intervals correlated to survival (p0.0001). After local recurrence the 5-year survival was 41%, vs. 20% for nodal and 13% for distant recurrence (p0.0001). Following breast-conserving surgery, the 5-year disease-free survival after local recurrence was 49.4%, vs. 33.1% after chest wall recurrence (p=0.0361). Of distant relapses, bone metastases had the best prognosis, with median survival 2.4 years.These data provide information on treatment outcomes in a multidisciplinary setting and statistical information that will be useful when discussing the fears and expectations of patients after the diagnosis of breast cancer.

Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.

Background: It is generally recognised that continuous quality improvement (CQI) programs support development of high quality primary health care systems. However, there is limited evidence demonstrating their system-wide effectiveness. We examined variation in quality of Type 2 diabetes service delivery in over 100 Aboriginal and Torres Strait Islander primary health care centres participating in a wide-scale CQI project over the past decade, and determined the influence of health centre and patient level factors on quality of care, with specific attention to health centre duration of participation in a CQI program. Methods: We analysed over 10,000 clinical audit records to assess quality of Type 2 diabetes care of patients in 132 Aboriginal and Torres Strait Islander community health centres in five states/territories participating in the ABCD project for varying periods between 2005 and 2012. Process indicators of quality of care for each patient were calculated by determining the proportion of recommended guideline scheduled services that were documented as delivered. Multilevel regression models were used to quantify the amount of variation in Type 2 diabetes service delivery attributable to health centre or patient level factors and to identify those factors associated with greater adherence to best practice guidelines. Results: Health centre factors that were independently associated with adherence to best practice guidelines included longer participation in the CQI program, remoteness of health centres, and regularity of client attendance. Significantly associated patient level variables included greater age, and number of co-morbidities and disease complications. Health centre factors explained 37% of the differences in level of service delivery between jurisdictions with patient factors explaining only a further 1%. Conclusions: At the health centre level, Type 2 diabetes service delivery could be improved through long term commitment to CQI, encouraging regular attendance (for example, through patient reminder systems) and improved recording and coordination of patient care in the complex service provider environments that are characteristic of non-remote areas.

Healthcare workers who carry out exposure-prone procedures are theoretically at increased risk of acquiring blood-borne virus infections. GB virus C (GBV-C) is a recently described blood-borne virus that is related distantly to hepatitis C virus. The occupational risk of GBV-C infection to healthcare workers is unknown. This study collected detailed occupational and personal risk data in parallel with a blood specimen, to establish the prevalence and determinants of GBV-C infection among dental healthcare workers. The presence of GBV-C antibodies was detected using commercially available ELISA; GBV-C RNA was detected by nested PCR using primers from the conserved 5' noncoding region. The overall prevalence of GBV-C antibodies among the study population was 11.1% (98/880, 95% confidence interval [CI], 9.1-13.4%) and 4.6% were positive for GBV-C RNA (46/879, 95% CI, 2.5-5.1%), resulting in a cumulative prevalence of 15.7%. These figures are similar to those described in other populations. There was no significant difference in lifetime exposure to GBV-C between dentists (17.7%) and dental nurses/hygienists (14.3%). Significantly more dental nurses/hygienists aged 16-30 years had been exposed to GBV-C compared to dentists of the same age (chi(2) = 13.75; P < 0.001). Conversely, significantly more dentists 46 years or older had evidence of exposure to GBV-C compared to dental nurses/hygienists (chi(2) = 6.79; P = 0.009). The high prevalence of GBV-C infection did not seem to be related to past parenteral exposure, and the data suggest that sexual transmission, rather than occupational transmission, was a more important route for GBV-C infection among this population.

Intracellular nucleotide binding and oligomerization domain (NOD) receptors recognize antigens including bacterial peptidoglycans and initiate immune responses by triggering the production of pro-inflammatory cytokines through activating NF-κB and MAP kinases. Receptor interacting protein kinase 2 (RIPK2) is critical for NOD-mediated NF-κB activation and cytokine production. Here we develop and characterize a selective RIPK2 kinase inhibitor, WEHI-345, which delays RIPK2 ubiquitylation and NF-κB activation downstream of NOD engagement. Despite only delaying NF-κB activation on NOD stimulation, WEHI-345 prevents cytokine production in vitro and in vivo and ameliorates experimental autoimmune encephalomyelitis in mice. Our study highlights the importance of the kinase activity of RIPK2 for proper immune responses and demonstrates the therapeutic potential of inhibiting RIPK2 in NOD-driven inflammatory diseases.

AimsInsulin-like growth factor-1 receptor (IGF1R) is a tyrosine kinase membrane receptor involved in tumourigenesis that may be a potential therapeutic target. We aimed to investigate the incidence and prognostic significance of alterations in IGF1R copy number, and IGF1R protein expression in resected primary non-small cell lung cancer (NSCLC), and lymph node metastases.MethodsIGF1R gene copy number status was evaluated by chromogenic silver in situ hybridisation and IGF1R protein expression was evaluated by immunohistochemistry in tissue microarray sections from a retrospective cohort of 309 surgically resected NSCLCs and results were compared with clinicopathological features, including EGFR and KRAS mutational status and patient survival.ResultsIGF1R gene copy number status was positive (high polysomy or amplification) in 29.2% of NSCLC, and 12.1% exhibited IGF1R gene amplification. High IGF1R expression was found in 28.3%. There was a modest correlation between IGF1R gene copy number and protein expression (r=0.2, pIGF1R gene copy number and protein expression in primary tumours were significantly associated with alterations in lymph node metastases (pIGF1R gene copy number and protein expression was significantly higher in squamous cell carcinomas (SCC) compared with other subtypes of NSCLC (pEGFR or KRAS mutational status or overall survival.ConclusionsHigh IGF1R gene copy number and protein overexpression are frequent in NSCLC, particularly in SCCs, but they are not prognostically relevant.

The purpose of this study was to examine the influence of self-care education on illness behaviors and health locus of control of Mexican American women. Participants were randomly assigned to a control (n = 60) or experimental group (n = 60). Subjects completed the Multidimensional Health Locus of Control questionnaire and an Illness Behavior Assessment at pretest and 6-months. The experimental group received a self-care manual and participated in two 2-hour seminars on how to effectively use the textbook. The experimental group demonstrated a significant increase in self-care behaviors, and significant changes in Internal Health Locus of Control and Powerful Others Health Locus of Control. Chance Health Locus of Control was found to have a low, direct correlation with age, and a low, indirect correlation with education. The conclusion of this investigation is that self-care education can positively influence illness behaviors and Health Locus of Control in Mexican American women.