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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.

For nearly 40 years, there was no generally accepted staging system for malignant pleural mesothelioma. In 1994, members of the International Mesothelioma Interest Group, in collaboration with the International Association for the Study of Lung Cancer, proposed a TNM staging system based on analyses of outcomes in retrospective surgical series and small clinical trials. Subsequently accepted by the American Joint Commission on Cancer and the Union for International Cancer Control for the sixth editions of their staging manuals, this system has since been the international staging standard. However, it has significant limitations, particularly with respect to clinical staging and to the categories for lymph node staging. Here we provide an overview of the development of the International Association for the Study of Lung Cancer malignant pleural mesothelioma staging database, which was designed to address these limitations through the development of a large international data set. Analyses of this database, described in papers linked to this overview, are being used to inform revisions in the eighth editions of the American Joint Commission on Cancer and Union for International Cancer Control staging systems. ispartof: Journal of Thoracic Oncology vol:11 issue:12 pages:2082-2088 ispartof: location:United States status: published

‘ 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.

Chronic activation of the gastric mucosal adaptive immune response is a characteristic trait of gastric cancer. It has recently emerged that a new class of T helper (Th) cells, defined by their ability to produce interleukin (IL)-17A (Th17), is associated with a host of inflammatory responses, including gastritis. However, the role of these Th17 cells in the pathogenesis of gastric cancer is less clear. To formally address this, we employed gp130F/F mice, which spontaneously develop gastric inflammation-associated tumours akin to human intestinal-type gastric cancer. At the molecular level, these tumours demonstrate hyper-activation of the latent transcription factor signal transducer and activator of transcription (STAT)3 via the IL-6 cytokine family member, IL-11. In gp130F/F mice, the generation of Th17 cells, as well as the gastric expression of IL-17a and other Th17-related factors (Rort, IL-23), were augmented compared to wild-type gp130+/+ mice. Consistent with a role for IL-6 and STAT3 in regulating IL-17A, increased Th17 generation and gastric expression of Th17-related factors in gp130F/F mice were reduced to wild-type levels in gp130F/F:Stat3−/+ mice displaying normalized STAT3 activity, and also in gp130F/F:IL-6−/− mice. Importantly, genetic ablation of IL-17A in gp130F/F:IL-17a−/− mice did not suppress the initiation and growth of gastric tumours. Furthermore, IL-17A and RORC gene expression was strongly increased in human gastric biopsies from patients with gastritis, but not gastric cancer. Collectively, our data suggest that increased expression of Th17-related factors does not correlate with the molecular pathogenesis of gastric tumourigenesis.

This paper reviews what is known about the challenges of implementing quality improvement programs and draws on data from a systematic continuous quality improvement (CQI) project in remote communities in Australia and Fiji, known as Audit and Best practice for Chronic Disease, to synthesise lessons and discuss the potential for broader application in low and middle income countries, including Pacific Island countries and territories. Although a number of systematic reviews have indicated that quality improvement programs can be effective in changing professional practice and improving the quality of care and patient outcomes, little is known about the key ingredients for change or how services use and implement different strategies to achieve improvements. We identify key features of an innovative CQI model and factors related to implementation that support improvement in diabetes service delivery and intermediate outcomes. Requirements for supporting CQI are identified and the potential for wider application discussed. It is argued that the participatory action research approach supports innovation and broad-based change and the evidence it has produced extends the current knowledge base and facilitates the translation of knowledge into action, for both policy and practice.

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.

Low-grade serous ovarian cancer (LGSC) responds poorly to platinum based chemotherapy and is characterized by activating RAS-MAPK pathway mutations, including oncogenic BRAF. Drugs that target this pathway are effective in BRAF-mutant melanoma but other cancer types, such as colorectal cancers, are less sensitive. Early phase trials report a 15% response rate to MEK inhibitors in LGSC patients, however it is not known which features may predict response. We aimed to determine clinical characteristics and treatment response in women with LGSC and to determine whether response to targeted pathway inhibition is associated with specific mutation profiles in LGSC cell lines. Tumor samples from a cohort of grade 1 and 2 serous ovarian cancer patients were analyzed using targeted, exome or whole genome sequencing. Patient characteristics, treatment and clinical outcome were assessed. Cell lines derived from patients with LGSC with known mutation profiles, AOCS2 (KRAS/BRAF/NRAS wild-type), MPSC1 (BRAFV600L, NRASQ16R), VOA1056 (NRASQ16R) and HCC5075 (KRASG12V), were treated with BRAF (dabrafenib) or MEK inhibitors (trametinib, pimasertib and binimetinib) and response was compared to cell lines derived from high-grade serous cancer (HGSC) and BRAF-mutant melanoma. Women diagnosed with grade 1 or 2 serous carcinoma between 1994-2015 were identified from 1654 invasive ovarian serous cancer cases in the Australian Ovarian Cancer Study and the GynBiobank. HGSC cases were excluded following histopathology review and TP53 mutation screening. Amongst 65 confirmed LGSC patients, 18 (27.7%) had a KRAS mutation, 9 (13.8%) had a BRAF mutation and 7 (10.8%) had a NRAS mutation. Women with advanced stage LGSC and residual disease following debulking surgery had a similarly poor progression-free and overall-survival compared with HGSC patients. We saw a dramatic response to BRAF inhibition in a patient with BRAFV600E-positive LGSC, however, the LGSC cell lines did not respond to dabrafenib. This is not surprising as the cell lines did not harbour the hot-spot BRAFV600E mutation. MPSC1 has a BRAFV600L and a NRASQ16R mutation, but dabrafenib did not inhibit growth. HCC5075 (KRASG12V) was sensitive to all three MEK inhibitors, but response to MEK inhibition in the other LGSC cell lines was modest. In conclusion, LGSC are generally chemotherapy resistant and molecular analyses can identify targetable mutations. However, LGSC are heterogenous with respect to underlying mutations and response to pathway inhibitors is likely to depend on which mutations and pathways are activated. BRAF mutations are not uncommon in patients with LGSC and should be routinely tested as BRAF inhibitors can be an effective treatment for these patients. MEK inhibitors may also be effective in a subset of cases. The results highlight the need for novel clinical trial design, as traditional clinical trials are unlikely to be effective in rare ovarian cancer sub-types. Citation Format: Tania Moujaber, Dariush Etemadmoghadam, Cristina Mapagu, Catherine Kennedy, Yoke-Eng Chiew, Casina Kan, Nikilyn Nevins, Sivatharsny Srirangan, Sian Fereday, Nadia Traficante, Australian Ovarian Cancer Study group, David Bowtell, Rosemary Balleine, Paul Harnett, Anna deFazio. Mutations in low-grade serous ovarian cancer and response to BRAF and MEK inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2584.

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.

Epithelial cell adhesion molecule (EpCAM)-targeted capture remains the most common isolation strategy for circulating tumor cells (CTCs). However, epithelial-to-mesenchymal transition (EMT) leads to decreased epithelial EpCAM expression affecting the optimal CTC capture. In this study, we tested a cohort of ovarian cancer cell lines using flow cytometry to identify N-cadherin as the additional immunomagnetic cell surface target for ovarian cancer cell isolation. Combined immunomagnetic targeting of mesenchymal N-cadherin and epithelial EpCAM enriched CTCs from advanced ovarian cancer patient blood approximately three times more efficiently than targeting of EpCAM alone. We also show that more EMT-phenotype CTCs are captured by including N-cadherin targeting into CTC isolation protocols. However, after N-cadherin-based CTC isolation, in some blood samples of healthy individuals, we also observed the presence of cells expressing markers common to CTCs. Our data show that these “false positives” can be largely distinguished from CTCs as circulating endothelial cells (CECs) by vascular endothelial–cadherin co-staining. CEC counts are highly variable in patients and healthy controls. Our data demonstrate that a combination of EpCAM with N-cadherin-targeted isolation can improve CTC detection and widen the EMT-phenotype spectrum of captured CTCs.

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

Gastric cancer is the third most common cancer and the fourth most common cause of death due to cancer worldwide. There is a large potential for reducing the burden of this disease by early detection. We examined the protein factors involved in the early stages of gastric cancer development; Porcupine (Porc), Wntless (Wls) and Wnt. The Wnt proteins have important functions in stem cell biology, cardiac development and differentiation, angiogenesis, cardiac hypertrophy, cardiac failure, cancer, and aging. This study aimed to understand how modifications Porc and Wls control Wnt secretion from cells under physiological and chemical stresses (hypoxia, oxidative stress and endoplasmic reticulum (ER) stress (or the unfolded protein response)). Porc glycosylates and palmitoylates Wnt proteins in the ER, while Wntless transfers the modified Wnts from the Golgi to secretory vesicles for extracellular secretion. We found that both porc and wls mRNA expressions were significantly increased with antimycin A treatment and proteasome inhibition in Human Colon Cancer (HCT116) cells. Treatment with ER stressors (thapsigargin, tunicamycin, dithiolthreitol) significantly increased porc expression. With the exception of tunicamycin, the same treatments significantly increased wls expression. Porc and Wls protein expression increased with ER stressor and hypoxic mimetic treatment in both HCT116 and Human Embryonic Kidney (HEK293T) cells. From immunoblotting results, HIF was found to potentially play a role in porc and wls expression. We hypothesize that these stressors can alter Porc and Wls expression and function, leading to altered Wnt secretion and the development of gastric cancer.

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

As obesity rates in young children continue to rise, the need for innovative nutrition- and physical activity-focused programs is apparent. With limited preschool obesity prevention efforts, a physical activity program, Food Friends Get Movin' with Mighty Moves™, has been developed to compliment a successful nutrition social marketing campaign, Food Friends®. Building off formative research findings, this article focuses on two other stages of the social marketing process – the strategy development and program development – and how elements of the marketing framework were integrated into the design of Mighty Moves. Input from children, teachers, and early childhood specialists greatly contributed to strategy refinement, solidification of the exchange principle, and program development. This information increased the likelihood that the intervention would affect the desired behavior change or product. Superhero graphics were developed for the program as well as creative and engaging program concepts and materials.

Clostridium septicum alpha-toxin is a β-barrel pore-forming cytolysin that is functionally similar to aerolysin. Residues important in receptor binding, oligomerization, and pore formation have been identified; however, little is known about the activity of the toxin in an infection, although it is essential for disease. We have now shown that deletion of a small portion of the transmembrane domain, so that the toxin is no longer able to form pores, completely abrogates its ability to contribute to disease, as does replacement of the sole cysteine residue with leucine. However, although previous biochemical and cytotoxicity assays clearly indicated that mutations in residues important in oligomerization, binding, and prepore conversion greatly reduced activity or rendered the toxin inactive, once the mutated toxins were overexpressed by the natural host in the context of an infection it was found they were able to cause disease in a mouse model of myonecrosis. These results highlight the importance of testing the activity of virulence determinants in the normal host background and in an infectious disease context and provide unequivocal evidence that it is the ability of alpha-toxin to form a pore that confers its toxicity in vivo.

Clostridium perfringens and Clostridium septicum are the most common causes of clostridial myonecrosis or gas gangrene. Although they mediate a similar disease pathology, they elaborate functionally very different alpha-toxins. We used a reciprocal complementation approach to assess the contribution of the primary toxin of each species to disease and found that C. perfringens alpha-toxin (PLC) was able to mediate the gross pathology of myonecrosis even in a C. septicum background, although it could not induce vascular leukostasis. Conversely, while C. septicum alpha-toxin restored some virulence to a C. perfringens plc mutant, it was less active than in its native background.

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.

Clostridium septicum is the causative agent of spontaneous gas gangrene or atraumatic myonecrosis, a sudden and frequently fatal infection that is increasingly associated with malignancy of the colon. Little is known about the disease process although the focus of virulence studies has been the alpha-toxin, a pore-forming cytolysin that is encoded by the csa gene and secreted as an inactive protoxin. Until now a lack of techniques for the genetic manipulation of C. septicum has hindered the use of molecular approaches to understand pathogenesis. By introducing plasmids by conjugation from Escherichia coli, we have developed methods for the genetic manipulation of C. septicum and constructed a chromosomal csa mutant by allelic exchange. Virulence testing of an isogenic series of strains consisting of the wild type, the csa mutant, and a csa mutant complemented with the wild-type csa gene revealed that the development of fulminant myonecrosis in mice was dependent on the ability to produce a functional haemolytic alpha-toxin. Furthermore, the inhibition of leukocyte influx into the lesion, which is very typical of clostridial myonecrosis, was also dependent on the ability to produce alpha-toxin. This study represents the first definitive identification of a virulence factor in this organism and opens the way for further studies that will delineate the role of other putative virulence factors in this significant pathogen.

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.

Evidence of large numbers of people who are both homeless and drug dependent, the complexity of their needs, and the many difficulties which they can encounter when trying to access assistance highlight the importance of basic standards of good practice in working with homeless drug users. This is particularly relevant given the growth of new managerialism and the expansion of social care markets occurring within the UK public sector since the 1980s. Within this context, the aim of the present paper is to further understanding of how best to provide support to homeless drug users by examining good practice from the perspectives of both service providers and service users. Data were collected from 48 semi-structured interviews (12 with staff and 36 with clients) conducted in six case study agencies (three homelessness agencies and three drug agencies). Interviews were audio-recorded and the data were analysed using Framework. Findings from the study revealed that good practice related to five broad areas. These were: (1) staffing; (2) agency environment; (3) support provided; (4) service delivery; and (5) agency aims and objectives. Similarities between the views of service providers and users were evident. However, differences of opinion suggested that the best definitions of good practice are achieved by consultation with a range of stakeholders (including staff and clients). Data also showed that good practice is fundamentally related to the qualitative and intangible aspects of service provision, and not just to more easily quantifiable inputs, processes, outputs and outcomes. The paper concludes by arguing that the challenge for new managerialism is to build evaluation frameworks which can accommodate this complexity, and thus, begin to portray good practice in a more accurate and meaningful light.

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.

Objective Interleukin (IL)-6 is a key modulator of the acute phase response (APR), and while both are implicated in atherosclerosis, the pathological role of specific IL-6 signalling cascades is ill-defined. Since IL-6 employs the cytokine receptor gp130 to primarily activate the STAT3 pathway, here we evaluate whether gp130-dependent STAT3 activation modulates atherosclerosis. Methods High-fat diet-induced atherosclerosis was established in ApoE −/− mice crossed with gp130 F/F knock-in mice displaying elevated gp130-dependent STAT3 activation and production of the APR protein, serum amyloid A (SAA). Also generated were gp130 F/F : Stat3 −/+ : ApoE −/− mice displaying genetically-normalised STAT3 activation and SAA levels, and bone marrow chimeras involving ApoE −/− and gp130 F/F : ApoE −/− mice. At 10 weeks post high-fat diet, aortic atherosclerotic lesions, including the presence of CD68 + macrophages, and plasma lipid and SAA profiles, were assessed. Results Aortic plaque development and plasma triglyceride levels in gp130 F/F : ApoE −/− mice were significantly reduced (3-fold, P ApoE −/− littermates. By contrast, in gp130 F/F : ApoE −/− mice, atherosclerotic plaques contained augmented CD68 + macrophage infiltrates, and plasma SAA levels were elevated, compared to ApoE −/− mice. Atherosclerotic lesion development and plasma triglyceride levels in gp130 F/F : ApoE −/− and gp130 F/F : Stat3 −/+ : ApoE −/− mice were comparable, despite a significant ( P gp130 F/F : Stat3 −/+ : ApoE −/− mice. Aortic plaque development and plasma triglyceride levels were comparable in ApoE −/− mice reconstituted with gp130 F/F : ApoE −/− (ApoE F/F:ApoE ) or ApoE −/− (ApoE ApoE ) bone marrow cells. Conclusions Deregulation of gp130/STAT3 signalling augments the APR and macrophage infiltration during atherosclerosis without impacting on the development of aortic plaques.

Begging has become highly visible in the urban centres of Britain in recent years, yet the experiences and motivations of people involved in this activity have remained underresearched. This paper explores the implications for social policy arising from a detailed study of begging in Glasgow and Edinburgh. It reassesses the common understanding of begging as a 'homelessness issue' and demonstrates that, while rough sleeping was almost invariably implicated in people's routes into begging in these cities, securing accommodation was far from a guaranteed 'route out'. It emphasises the need for holistic services and effective policy co-ordination in responding to the wide-ranging social exclusion of people who beg. It also explores the importance, and difficulties, of securing their active involvement in policy and service development.

Begging is one of the most potent, and controversial, symbols of social exclusion in modern British society. This paper concentrates on the relationship between begging and rough sleeping. This focus was selected because moral debates concerning the 'legitimacy' of begging now seem inextricably bound up with the perceived accommo dation status of people begging as either 'roofless' or 'housed'. The paper draws upon a recent qualitative study in Glasgow and Edinburgh city centres which demonstrated a close relationship between begging and rough sleeping, and the complex needs and desperate circumstances of the people engaged in these activities. It challenges prevailing assumptions regarding the 'legitimacy' of begging arguing that, while begging appears to be largely confined to street homeless people in Glasgow and Edinburgh city centres, this does not undermine the moral imperative to meet the needs of the 'housed poor' who may beg elsewhere.

Background: Mammographic screening has been shown to reduce mortality from breast cancer and to offer more opportunity for breast conservation surgery (BCS). The minimum standards (or surrogate end-points) that need to be achieved by a screening programme if it is to reduce mortality have been derived from the Two County Study. Three surrogate end-points that can be used to gauge the quality of the screening service are that 50% of the identified infiltrating cancers should be < 15 mm; at least 30% of grade 3 cancers should be < 15 mm; and 70% of screen-detected cancers should have a negative axillary dissection. The present study assesses these end-points of effective screening in an urban population referred to The Strathfield Breast Centre (TSBC). The screening end-points and surgical treatment of one group of women referred with a BreastScreen New South Wales (NSW)-detected breast cancer (screen group) were compared to all the other, mostly symptomatic, breast cancer referrals (symptom group). The problems with the current pattern of acceptance of mammographic screening in TSBC’s referral area are discussed. Methods: A prospective non-randomized study was done via analysis of the prospective database at The Strathfield Breast Centre (TSBC). Results: There were 224 women in the screen group and 657 women in the symptom group. The mean tumour size was 18.1 mm in the screen group and 22.1 mm in the symptom group. There were significantly more small invasive cancers (< 15 mm) in the screen group (58%) compared with the symptom group (33%; P < 0.001). In the screen group there were more low-grade tumours but 30% of grade 3 tumours were < 15 mm compared with 16% in the symptom group (P = 0.009). In patients with invasive cancers who underwent axillary dissection, there was a significant difference in axillary node negativity, being 72% in the screen group and 59% in the symptom group (P = 0.003). In the screen group 64% of women had BCS compared with 51% in the symptom group (P = 0.002). Conclusions: These end-points of effective mammographic screening were met in the BreastScreen NSW group of women who were referred to TSBC despite the biases involved which could lessen the effectiveness of the screening programme. This crudely translated into a significant reduction in breast cancer mortality but selection and lead time bias has to be taken into account in evaluation of these data. There was a significantly greater chance of BCS in the screen group.

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.

Background: Male breast cancer is rare and experience of it in any single institution is limited. The aim of this study was to evaluate the presentation, management and outcome of male patients with breast cancer treated at Concord Repatriation General Hospital hospital over a 38-year period and to determine a best-practice protocol based on the results and a review of the literature. Methods: A total of 42 patients were retrospectively reviewed, pathology slides were re-examined and reclassified where necessary. Outcome was assessed and compared with results obtained from a literature review. Results: A trend towards less radical surgery has emerged. Overall 5-year survival was 50%, but, due to the late age at presentation, more than half the deaths were non-breast cancer related. One quarter of the patients presented with locally advanced or metastatic disease. Conclusions: The presentation, diagnosis pathology and outcome of breast cancer are similar in men and women, although the disease occurs at a later age in men. Radical surgery is not required in order to gain local control, but knowledge of axillary node status is important in determining prognosis and the need for adjuvant therapy.

Background: Breast cancer is the most commonly diagnosed cancer and the most common cause of cancer death in women. This report presents outcomes from a multidisciplinary breast clinic established in 1989 with the specific aim of providing a rapid, integrated assessment service for patients with breast disease. Methods: A prospective data collection and analysis using a Microsoft AccessTM (Microsoft Corp., North Ryde, NSW, Australia) database was established and has collected information on all patients presenting for diagnosis or ongoing management of breast cancer. Data on survival were obtained by routine follow-up visits or contact with the patient'general practitioner. Results: Patient age, mode of presentation and histopathology were similar to other population-based studies in Australia. Ninety-three per cent of the patients had a diagnosis confirmed on the day of consultation. The average time between diagnosis and surgery was 11.9 days. Breast preserving surgery was attempted in 68% and achieved in 50% of cases, 67% of patients had one stage surgery. Five-year disease-free survival was 74% and is comparable with other reports. Conclusions: The centralization of services and expertise has enabled us to provide efficient service and achieve internationally comparable outcomes.