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We discovered a novel somatic gene fusion, CD74–NRG1, by transcriptome sequencing of 25 lung adenocarcinomas of never smokers. By screening 102 lung adenocarcinomas negative for known oncogenic alterations, we found four additional fusion-positive tumors, all of which were of the invasive mucinous subtype. Mechanistically, CD74–NRG1 leads to extracellular expression of the EGF-like domain of NRG1 III-β3, thereby providing the ligand for ERBB2–ERBB3 receptor complexes. Accordingly, ERBB2 and ERBB3 expression was high in the index case, and expression of phospho-ERBB3 was specifically found in tumors bearing the fusion (P < 0.0001). Ectopic expression of CD74–NRG1 in lung cancer cell lines expressing ERBB2 and ERBB3 activated ERBB3 and the PI3K–AKT pathway, and led to increased colony formation in soft agar. Thus, CD74–NRG1 gene fusions are activating genomic alterations in invasive mucinous adenocarcinomas and may offer a therapeutic opportunity for a lung tumor subtype with, so far, no effective treatment.Significance: CD74–NRG1 fusions may represent a therapeutic opportunity for invasive mucinous lung adenocarcinomas, a tumor with no effective treatment that frequently presents with multifocal unresectable disease. Cancer Discov; 4(4); 415–22. ©2014 AACR.This article is highlighted in the In This Issue feature, p. 377

XLSX file 75K, This is an excel file containing 9 sheets, one for each of the 9 supplementary tables (S1 to S9) mentioned in the main text

PDF file 234K, This is a file containing the list of supplementary tables, the list of supplementary figures, as well as the 7 supplementary figures (S1 to S7) and their correspondent legends, mentioned in the main text

The time is now to catalyze a Grand Strategy. Brain Capital can be a key component in shaping economic resilience?linked to our digitalized, globalized, complex, and interconnected yet fragile global economy. Brain Capital resonates with existing efforts and helps build long-term globaleconomic recovery that promotes brain health and brain skills helping address urgent challenges caused and exacerbated by COVID. Current policies, concepts and economic measures neither account for the neuroscientific drivers of productivity nor the increasingly brain skills focused workforce demands of the twenty-first century.Furthermore, current approaches are insufficient to combat the rising complexity of challenges brought about by COVID. The preservation and development of Brain Capital positively impacts educational, social, health, institutional, and economic dimensions at the individual andcollective level. Hence, it should be considered a strategic resource for a country, corporations, and public policies in a brain-based world. Fil: Smith, Erin. University of Stanford; Estados Unidos Fil: Ali, Diab. Ochsner Clinical School; Estados Unidos. University of Queensland; Australia Fil: Wilkerson, Bill. Mental Health International; Canadá Fil: Dawson, Walter D.. Oregon Health and Science University; Estados Unidos. Portland State University; Estados Unidos. Trinity College Dublin; Irlanda. University of California; Estados Unidos Fil: Sobowale, Kunmi. University of California; Estados Unidos Fil: Reynolds, Charles. Univeristy of Pittsburgh. School of Medicine; Estados Unidos Fil: Berk, Michael. Deakin University; Australia. University of Melbourne; Australia Fil: Lavretsky, Helen. University of California; Estados Unidos Fil: Jeste, Dilip. University of California at San Diego; Estados Unidos Fil: Ng, Chee H.. University of Melbourne; Australia Fil: Soares, Jair C.. University of Texas Health Science Center at Houston; Estados Unidos Fil: Aragam, Gowri. University of Stanford; Estados Unidos Fil: Wainer, Zoe. University of Melbourne; Australia Fil: Manji, Husseini K.. Johnson & Johnson; Estados Unidos. University of Duke; Estados Unidos Fil: Licinio, Julio. SUNY Upstate Medical University; Estados Unidos Fil: Lo, Andrew W.. Massachusetts Institute of Technology; Estados Unidos Fil: Storch, Eric. Baylor College of Medicine; Fil: Fu, Ernestine. University of Stanford; Estados Unidos Fil: Leboyer, Marion. University Paris Est Créteil; Francia Fil: Tarnanas, Ioannis. Trinity College Dublin; Irlanda. University of California; Estados Unidos Fil: Ibañez, Agustin Mariano. Trinity College Dublin; Irlanda. Universidad Autónoma del Caribe; Colombia. University of California; Estados Unidos. Universidad Adolfo Ibañez; Chile. Universidad de San Andrés. Departamento de Matemáticas y Ciencias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Manes, Facundo Francisco. Universidad Favaloro; Argentina. Instituto de Neurología Cognitiva; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Caddick, Sarah. Thalamic; Reino Unido Fil: Fillit, Howard. The Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Abbott, Ryan. University of California; Estados Unidos. University of Surrey; Reino Unido Fil: Robertson, Ian H.. University of Texas; Estados Unidos. Trinity College Dublin; Irlanda. University of California; Estados Unidos Fil: Chapman, Sandra B.. University of Texas; Estados Unidos Fil: Au, Rhoda. University of Boston. School of Medicine; Estados Unidos Fil: Altimus, Cara M.. Milken Institute; Estados Unidos Fil: Hynes, William. Organisation for Economic Cooperation and Development. New Approaches to Economic Challenges Unit; Francia Fil: Brannelly, Patrick. Rainwater Charitable Foundation; Estados Unidos Fil: Cummings, Jeffrey. Cleveland Clinic Lou Ruvo Center for Brain Health; Estados Unidos. University Of Nevada, Las Vegas; Estados Unidos Fil: Eyre, Harris A.. Deakin University; Australia. University of Melbourne; Australia. University of Stanford; Estados Unidos. University of Adelaide; Australia

This lunchtime workshop aims to build on the opening plenary debate to examine the role and impact that integrated care can make in helping to re-orient health and care systems so that they enable better care experiences and care outcomes for people in financially sustainable ways. The workshop will examine the role of public policy to enable innovations in value-based care in Australia and beyond.The workshop will be led by Annette Schmiede, BUPA Health Foundation, and Zoe Wainer, BUPA ANZ with support from Professor Nick Goodwin, Director, Central Coast Research Institute and Alison Verhoeven, Chief Executive of AHHA.

Introduction: Non–small-cell lung cancer (NSCLC) has disproportionately negative outcomes in men compared with women. The importance of the relationship between sex and tumor, node, metastases (TNM) staging system remains unknown. The objective of this study was to investigate the effect of sex on NSCLC survival for each stage in the eighth edition of the TNM staging system in NSCLC. Patients and Methods: Two cohorts treated surgically with curative intent between 2000 and 2010 were analyzed. The primary cohort was from Australia with a second population set from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate analyses of putative and validated prognostic factors were undertaken to investigate sex-dependent prognostication with detailed analyses of sex differences in each TNM stage. The primary outcome was disease-specific survival (DSS) at 5 years. Results: Inclusion criteria were met by 555 patients in the Australian cohort, 335 men (60.4%) and 220 (39.6%) women; and 47,706 patients from the SEER cohort, 24,671 men (51.7%) and 23,035 women (48.3%). Five-year DSS was significantly worse for men in multivariate analyses for the Australian (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.04-1.98; P =.026) and SEER (HR, 1.24; 95% CI, 1.20-1.28; P

The field of personalized psychiatry focuses on an individual’s unique attributes to improve risk assessment, diagnosis, treatment, and prevention of psychiatric disorders. It is a broad, interdisciplinary field that focuses on a patient’s biology, lifestyle, and environment. Consumer participation is critical, and relevant to a number of facets of personalized psychiatry, including research, novel solution development, clinical care, and policy. This chapter outlines the rationale for consumer participation in the aforementioned areas, as well as models and mechanisms that facilitate this participation. Personalized psychiatry is a promising approach to improve patient outcomes in mental health, and ongoing consumer participation is a vital driver to its ongoing development.

BackgroundLung cancer has markedly poorer survival in men. Recognized important prognostic factors are divided into host, tumour and environmental factors. Traditional staging systems that use only tumour factors to predict prognosis are of limited accuracy. By examining sex-based patterns of disease-specific survival in non-small cell lung cancer patients, we determined the effect of sex on the prognostic value of additional host factors.

Background Lung cancer accounts for significant morbidity and mortality worldwide. The effect of recent changes in demographics and management on outcomes in Australia has not been clearly defined. Aims To compare three consecutive lung cancer cohorts to evaluate emergent differences in diagnosis, management and mortality. Methods For comparative analysis, 2119 lung cancer patients were divided into three successive cohorts. Current death data were sought from the Victorian Cancer Registry. Results Age at diagnosis, mode of presentation and pathology did not significantly differ between the groups. Significantly more females were diagnosed with lung cancer in the most recent cohort (P = 0.04). Amongst non-small-cell lung cancer patients, there were more adenocarcinomas and less large cell carcinomas in the latest cohort (P =

The delivery of healthcare that meets the requirements for quality, safety and cost-effectiveness relies on a well-trained medical workforce, including clinical academics whose career includes a specific commitment to research, education and/or leadership. In 2011, the Medical Deans of Australia and New Zealand published a review on the clinical academic workforce and recommended the development of an integrated training pathway for clinical academics. A bi-national Summit on Clinical Academic Training was recently convened to bring together all relevant stakeholders to determine how best to do this. An important part understood the lessons learnt from the UK experience after 10 years since the introduction of an integrated training pathway. The outcome of the summit was to endorse strongly the recommendations of the medical deans. A steering committee has been established to identify further stakeholders, solicit more information from stakeholder organisations, convene a follow-up summit meeting in late 2015, recruit pilot host institutions and engage the government and future funders.

Introduction The use of targeted therapies toward specific oncogenic driver mutations has become a critical factor in the treatment of patients with lung cancer. It is therefore essential to utilize tests with high performance characteristics. Fluorescence in situ hybridization (FISH) is the standard method for detecting anaplastic lymphoma kinase (ALK ) and ROS1 rearrangements in non–small-cell lung cancer but the utility of other methods such as immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) is unclear. Methods Three hundred and sixty-two lung cancer patients were tested with FISH, CISH, and IHC using three ALK antibodies (ALK1, 5A4, D5F3) and one ROS1 antibody in the detection of ALK and ROS1 rearrangements. Results There was a 97.4% concordance (298 of 306) between FISH and CISH for detection of ALK rearrangements. The ROS1 rearrangement status had a 97% (291 of 300) concordance between CISH and FISH. ALK protein expression was observed in 6 of 341 samples with the ALK1 and 5A4 antibodies and 5 of 341 samples with D5F3. All three antibodies stained each of the ALK FISH-positive samples (100% sensitivity). ROS1 protein expression was observed in 2 of 322 samples. One of three samples with a ROS1 rearrangement by FISH showed ROS1 protein expression (33.3% sensitivity). Conclusion Our findings show good correlation between FISH versus CISH in the detection of ALK and ROS1 rearrangements. FISH versus IHC showed good correlation in the detection of ALK rearrangements but showed weak correlation in the detection of ROS1 rearrangements. These results suggest CISH and IHC could be complimentary detection methods to FISH in the detection of ALK and ROS1 rearrangements.

The aim of this study was to investigate the prevalence of fibroblast growth factor receptor 1 (FGFR1) amplification by fluorescence in situ hybridization (FISH) in a lung cancer patient cohort and to correlate results with morphology, silver in situ hybridization (SISH), and patient outcome. FGFR1 FISH and SISH were performed in 406 and 385 lung cancer cases, respectively, and the results were compared. High-level FGFR1 amplification was defined as the ratio of FGFR1/centromere 8 ≥2, or tumor cell percentage with ≥15 signals ≥10%, or average number of signals/tumor cell nucleus ≥6. Low-level amplification was defined as tumor cell percentage with ≥5 signals ≥50%. Of 406 tumors tested, there were 191 squamous cell carcinomas, 28 carcinomas with focal squamous morphology, 24 large cell carcinomas with squamous immunoprofile, 115 adenocarcinomas, 17 neuroendocrine tumors, and 31 carcinomas without squamous morphology or immunoprofile. FGFR1 FISH was assessable in 368 tumors, with FGFR1 amplification identified in 50, including 48 tumors with either squamous morphology or immunoprofile (48 of 225, 21.3%), and two 'marker-null' tumors without squamous or glandular morphology or immunoprofile (2 of 143, 1.4%; P

We discovered a novel somatic gene fusion, CD74–NRG1, by transcriptome sequencing of 25 lung adenocarcinomas of never smokers. By screening 102 lung adenocarcinomas negative for known oncogenic alterations, we found four additional fusion-positive tumors, all of which were of the invasive mucinous subtype. Mechanistically, CD74–NRG1 leads to extracellular expression of the EGF-like domain of NRG1 III-β3, thereby providing the ligand for ERBB2–ERBB3 receptor complexes. Accordingly, ERBB2 and ERBB3 expression was high in the index case, and expression of phospho-ERBB3 was specifically found in tumors bearing the fusion (P < 0.0001). Ectopic expression of CD74–NRG1 in lung cancer cell lines expressing ERBB2 and ERBB3 activated ERBB3 and the PI3K–AKT pathway, and led to increased colony formation in soft agar. Thus, CD74–NRG1 gene fusions are activating genomic alterations in invasive mucinous adenocarcinomas and may offer a therapeutic opportunity for a lung tumor subtype with, so far, no effective treatment. Significance: CD74–NRG1 fusions may represent a therapeutic opportunity for invasive mucinous lung adenocarcinomas, a tumor with no effective treatment that frequently presents with multifocal unresectable disease. Cancer Discov; 4(4); 415–22. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 377

We investigated if gene copy number (GCN) alterations of the epidermal growth factor receptor (EGFR), as detected by silver enhanced in situ hybridisation (SISH), could be used to select patients for EGFR mutation testing. Resected lung adenocarcinoma specimens with adequate tumour were identified. EGFR SISH was performed using the Ventana Benchmark Ultra platform. EGFR GCN was classified according to the Colorado Classification System. EGFR mutations were scanned by high resolution melting and confirmed by Sanger sequencing. Thirty-four of 96 tumours were EGFR SISH positive (35%), and 31 of 96 tumours harboured one or more EGFR mutations (32%). Of 31 EGFR-mutant tumours, 18 were EGFR SISH positive (58%). There was a statistically significant relationship between the presence of an EGFR mutation and EGFR GCN (p = 0.003). Thirteen of 31 EGFR-mutant tumours were EGFR SISH negative (42%), and 16 of 65 EGFR-wild type tumours were EGFR SISH positive (24%). The sensitivity, specificity, positive predictive value and negative predictive value were 58%, 75%, 52.9% and 79%, respectively. Despite a significant relationship between EGFR GCN alterations and EGFR mutations, our results indicate that EGFR GCN as detected by SISH is not a suitable way to select patients for EGFR mutation testing.

Background Expression of aldehyde dehydrogenase 1A1 (ALDH1A1) and CD133 has been functionally associated with a stem cell phenotype in normal and malignant cells. The prevalence of such cells in solid tumours should therefore correlate with recurrence and/or metastasis following definitive surgical resection. The aim of this study was to evaluate the prognostic significance of ALDH1A1 and CD133 in surgically resected, early stage non-small cell lung cancer (NSCLC). Methods A retrospective analysis of ALDH1A1 and CD133 expression in 205 patients with pathologic stage I NSCLC was performed using immunohistochemistry. The association between the expression of both markers and survival was determined. Results We identified 62 relapses and 58 cancer-related deaths in 144 stage 1A and 61 stage 1B patients, analysed at a median of 5-years follow-up. Overexpression of ALDH1A1 and CD133, detected in 68.7% and 50.7% of primary tumours, respectively, was an independent prognostic indicator for overall survival by multivariable Cox proportional hazard model (p=0.017 and 0.039, respectively). Overexpression of ALDH1A1, but not of CD133, predicted poor recurrence-free survival (p=0.025). When categorised into three groups according to expression of ALDH1A1/CD133, patients with overexpression of both ALDH1A1 and CD133 belonged to the group with the shortest recurrence-free and overall survival (p=0.015 and 0.017, respectively). Conclusions Expression of ALDH1A1 and CD133, and coexpression of ALDH1A1 and CD133, is strongly associated with poor survival in early-stage NSCLC following surgical resection. These data are consistent with the hypothesis that expression of stem cell markers correlates with recurrence as an indirect measure of self-renewal capacity.

Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis(1-3). We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4 +/- 1 protein-changing mutations per million base pairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases, we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in the CREBBP, EP300 and MLL genes that encode histone modifiers. Furthermore, we observed mutations in PTEN, SLIT2 and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from Tp53 and Rb1 double knockout mice(4). Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background.

Background: Rheumatic heart disease constitutes a significant disease burden in under-resourced communities. Recognition of the devastating impact of rheumatic heart disease has resulted in volunteer cardiac teams from Australasia providing surgical services to regions of need. The primary objective of this study was to compare New Zealand hospitals' volunteer cardiac surgical operative results in Samoa and Fiji with the accepted surgical mortality and morbidity rates for Australasia. Methods: A retrospective review from seven volunteer cardiac surgical trips to Samoa and Fiji from 2003 to 2009 was conducted. Patient data were retrospectively and prospectively collected. Preoperative morbidity and mortality risk were calculated using the European System for Cardiac Operative Risk Evaluation (euroSCORE). Audit data were collated in line with the Australasian Society of Cardiac and Thoracic Surgeons guidelines. Results: One hundred and three operations were performed over 6 years. EuroSCORE predicted an operative mortality of 3.32%. In-hospital mortality was 0.97% and post-discharge mortality was 2.91%, resulting in a 30-day mortality of 3.88%. Conclusion: This study demonstrated that performing cardiac surgery in Fiji and Samoa is viable and safe. However, the mortality was slightly higher than predicted by euroSCORE. Difficulties exist in predicting mortality rates in patients with rheumatic heart disease from Pacific Island nations as known risk scoring models fail to be disease, ethnically or culturally inclusive. Audit processes and risk model development and assessment are an essential part of this complex surgical charity work and will result in improved patient selection and outcomes.

Lung cancer has markedly poorer survival in men. Recognized important prognostic factors are divided into host, tumour and environmental factors. Traditional staging systems that use only tumour factors to predict prognosis are of limited accuracy. By examining sex-based patterns of disease-specific survival in non-small cell lung cancer patients, we determined the effect of sex on the prognostic value of additional host factors.Two cohorts of patients treated surgically with curative intent between 2000 and 2009 were utilized. The primary cohort was from Melbourne, Australia, with an independent validation set from the American Surveillance, Epidemiology and End Results (SEER) database. Univariate and multivariate analyses of validated host-related prognostic factors were performed in both cohorts to investigate the differences in survival between men and women.The Melbourne cohort had 605 patients (61% men) and SEER cohort comprised 55 681 patients (51% men). Disease-specific 5-year survival showed men had statistically significant poorer survival in both cohorts (P 0.001); Melbourne men at 53.2% compared with women at 68.3%, and SEER 53.3% men and 62.0% women were alive at 5 years. Being male was independently prognostic for disease-specific mortality in the Melbourne cohort after adjustment for ethnicity, smoking history, performance status, age, pathological stage and histology (hazard ratio = 1.54, 95% confidence interval: 1.10-2.16, P = 0.012).Sex differences in non-small cell lung cancer are important irrespective of age, ethnicity, smoking, performance status and tumour, node and metastasis stage. Epidemiological findings such as these should be translated into research and clinical paradigms to determine the factors that influence the survival disadvantage experienced by men.

Genomic translocation events frequently underlie cancer development through generation of gene fusions with oncogenic properties. Identification of such fusion transcripts by transcriptome sequencing might help to discover new potential therapeutic targets. We developed TRUP (Tumor-specimen suited RNA-seq Unified Pipeline) (https://github.com/ruping/TRUP), a computational approach that combines split-read and read-pair analysis with de novo assembly for the identification of chimeric transcripts in cancer specimens. We apply TRUP to RNA-seq data of different tumor types, and find it to be more sensitive than alternative tools in detecting chimeric transcripts, such as secondary rearrangements in EML4-ALK-positive lung tumors, or recurrent inactivating rearrangements affecting RASSF8. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0558-0) contains supplementary material, which is available to authorized users.

Pulmonary carcinoids are rare neuroendocrine tumours of the lung. The molecular alterations underlying the pathogenesis of these tumours have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodelling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40 and 22.2% of the cases, respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine lung tumours, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumours but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin-remodelling genes is sufficient to drive transformation in pulmonary carcinoids.

Global health (GH) training is well established overseas (particularly in North America) and reflects an increasing focus on social accountability in medical education. Despite significant interest among trainees, GH is poorly integrated with specialty training programs in Australia. While there are numerous benefits from international rotations in resource-poor settings, there are also risks to the host community, trainee and training provider. Safe and effective placements rely on firm ethical foundations as well as strong and durable partnerships between Australian and overseas health services, educational institutions and GH agencies. More formal systems of GH training in Australia have the potential to produce fellows with the skills and knowledge necessary to engage in regional health challenges in a global context.

Rearrangements of anaplastic lymphoma kinase (ALK) gene in non-small cell lung cancer (NSCLC) define a molecular subgroup of tumors characterized clinically by sensitivity to ALK tyrosine kinase inhibitors such as crizotinib. Although ALK rearrangements may be detected by reverse transcriptase-PCR, immunohistochemistry or fluorescence in situ hybridization (FISH), the optimal clinical strategy for identifying ALK rearrangements in clinical samples remains to be determined. We evaluated immunohistochemistry using three different antibodies (ALK1, 5A4 and D5F3 clones) to detect ALK rearrangements and compared those with FISH. We report the frequency and clinicopathologic features of lung cancers harboring ALK translocations in 594 resected NSCLCs (470 adenocarcinomas; 83 squamous carcinomas, 26 large cell carcinomas and 15 other histological subtypes) using a tissue microarray approach. We identified an ALK gene rearrangement in 7/594 cases (1%) by FISH and all anti-ALK antibodies correctly identified the seven ALK-positive cases (100% sensitivity), although the intensity of staining was weak in some cases. These data indicate that the use of antibodies with high sensitivity and avidity to ALK may provide an effective pre-screening technique to complement the more expensive and labor-intensive approach of ALK FISH testing.

We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome-based diagnosis of lung cancer.

The identification of robust prognostic factors for patients with early-stage non–small cell lung cancer (NSCLC) is clinically important. The International Association for the Study of Lung Cancer has identified both sex and the maximum standardized uptake value (SUVmax) of 18 F-FDG in the primary tumor as measured by PET as potential prognostic variables. We examined the prognostic value of SUVmax in a surgical cohort of patients with NSCLC and disaggregated the findings by sex. Methods: Patients who had undergone a preoperative PET/CT scan and surgical resection with curative intent from 2001 to 2009 were identified from a prospective database. An SUVmax cutoff was calculated using receiver-operating-characteristic curves. Overall survival was correlated with SUVmax for the whole cohort and disaggregated by sex. Results: Inclusion criteria were met by 189 patients: 127 (67%) men and 62 (33%) women. Five-year survival was 54.6% for the whole cohort, 47.7% for men, and 68.2% for women. SUVmax correlated negatively with survival in a univariate analysis for the whole cohort (hazard ratio [HR], 2.51; 95% confidence interval [CI], 1.54–4.09; P , 0.001) and men (HR, 3.42; 95% CI, 1.94–6.05; P , 0.001) but not for women (HR, 1.61; 95% CI, 0.43–3.12; P 5 0.77), using 8 as a cutoff. In multivariate analysis, SUVmax correlated with overall survival for the whole cohort (HR, 1.70; 95% CI, 1.05–2.99; P 5 0.05) and men (HR, 2.40; 95% CI, 1.32–4.37; P 5 0.004) but not for women (HR, 0.80; 95% CI, 0.15–4.47; P 5 0.80). Conclusion: SUVmax independently predicted overall survival for men but not for women in this surgical cohort. Our results suggest that SUVmax is an independent prognostic variable in men with surgically

Rheumatic heart disease constitutes a significant disease burden in under-resourced communities. Recognition of the devastating impact of rheumatic heart disease has resulted in volunteer cardiac teams from Australasia providing surgical services to regions of need. The primary objective of this study was to compare New Zealand hospitals' volunteer cardiac surgical operative results in Samoa and Fiji with the accepted surgical mortality and morbidity rates for Australasia.A retrospective review from seven volunteer cardiac surgical trips to Samoa and Fiji from 2003 to 2009 was conducted. Patient data were retrospectively and prospectively collected. Preoperative morbidity and mortality risk were calculated using the European System for Cardiac Operative Risk Evaluation (euroSCORE). Audit data were collated in line with the Australasian Society of Cardiac and Thoracic Surgeons guidelines.One hundred and three operations were performed over 6 years. EuroSCORE predicted an operative mortality of 3.32%. In-hospital mortality was 0.97% and post-discharge mortality was 2.91%, resulting in a 30-day mortality of 3.88%.This study demonstrated that performing cardiac surgery in Fiji and Samoa is viable and safe. However, the mortality was slightly higher than predicted by euroSCORE. Difficulties exist in predicting mortality rates in patients with rheumatic heart disease from Pacific Island nations as known risk scoring models fail to be disease, ethnically or culturally inclusive. Audit processes and risk model development and assessment are an essential part of this complex surgical charity work and will result in improved patient selection and outcomes.

Introduction Lung adenocarcinoma is a heterogeneous group of tumors with a highly variable prognosis, not well predicted by the current pathologic classification system. The 2004 World Health Organization classification results in virtually all tumors encountered in clinical practice being allocated to the adenocarcinoma of mixed subtype category. A new classification developed by an international multidisciplinary expert panel sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society, is based on histomorphologic subtype and has recently been validated in a North American series of 514 stage I lung adenocarcinomas. We investigated the relationship between the new classification and patient survival in a series of Australian patients with stages I, II, and III lung adenocarcinoma. Methods We identified 210 patients from a surgical database who underwent resection of lung adenocarcinoma from 1996 to 2009. Two pathologists, blinded to patient outcome, independently performed histopathologic subtyping according to the new classification. Kaplan-Meier curves were used to calculate 5-year survival for each separate histopathologic subtype/variant. Univariate and multivariate analyses were undertaken to control for validated prognostic factors. Results We confirmed that the new subtypes of adenocarcinoma in situ, minimally invasive adenocarcinoma and lepidic-predominant adenocarcinoma had a 5-year survival approaching 100%, whereas micropapillary-predominant and solid with mucin-predominant adenocarcinomas were associated with particularly poor survival. Papillary-predominant and acinar-predominant adenocarcinomas had an intermediate prognosis. This effect persisted after controlling for stage. Conclusions Classification of lung adenocarcinoma according to the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification correlated with 5-year survival. These relationships persisted after controlling for known prognostic patient and tumor characteristics. The new classification has advantages not only for individual patient care but also for better selection and stratification for clinical trials and molecular studies.

Lung cancer remains one of the leading causes of cancer-related death in developed countries. Although lung adenocarcinomas with EGFR mutations or EML4-ALK fusions respond to treatment by epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibition, respectively, squamous cell lung cancer currently lacks therapeutically exploitable genetic alterations. We conducted a systematic search in a set of 232 lung cancer specimens for genetic alterations that were therapeutically amenable and then performed high-resolution gene copy number analyses. We identified frequent and focal fibroblast growth factor receptor 1 (FGFR1) amplification in squamous cell lung cancer (n = 155), but not in other lung cancer subtypes, and, by fluorescence in situ hybridization, confirmed the presence of FGFR1 amplifications in an independent cohort of squamous cell lung cancer samples (22% of cases). Using cell-based screening with the FGFR inhibitor PD173074 in a large (n = 83) panel of lung cancer cell lines, we demonstrated that this compound inhibited growth and induced apoptosis specifically in those lung cancer cells carrying amplified FGFR1. We validated the FGFR1 dependence of FGFR1-amplified cell lines by FGFR1 knockdown and by ectopic expression of an FGFR1-resistant allele (FGFR1(V561M)), which rescued FGFR1-amplified cells from PD173074-mediated cytotoxicity. Finally, we showed that inhibition of FGFR1 with a small molecule led to significant tumor shrinkage in vivo. Thus, focal FGFR1 amplification is common in squamous cell lung cancer and associated with tumor growth and survival, suggesting that FGFR inhibitors may be a viable therapeutic option in this cohort of patients.

Junior doctors face specific pressures related to their professional stage and development and can be at risk of poor health. A confidential survey conducted in 2008 by the Australian Medical Association Council of Doctors in Training investigated the health and wellbeing of junior doctors. There were 914 completed surveys: 71% of junior doctors were concerned about their own health, and 63% about the health of a colleague. A majority of junior doctors met well established criteria for low job satisfaction (71%), burnout (69%) and compassion fatigue (54%). The early stages of a medical career are demanding, and the health and wellbeing of junior doctors must be a personal priority, as well as the responsibility of the medical profession in general, to ensure a healthy medical workforce in the future.

Cancer incidence in the Australian Aboriginal and Torres Strait Islander population is higher and survival lower compared with non-Indigenous Australians. A proportion of these cancers are potentially preventable if factors associated with carcinogenesis are known and successfully avoided. We conducted a systematic review of the published literature to examine risk factors for cancer in the Australian Aboriginal and Torres Strait Islander population. Electronic databases Medline, Web of Science and the Australian Aboriginal and Torres Strait Islander Health Bibliographic Index were searched through August 2014 using broad search terms. Studies reporting a measure of association between a risk factor and any cancer site in the Australian Aboriginal and Torres Strait Islander population were eligible for inclusion. Ten studies (1991–2014) were identified, mostly with small sample sizes, showing marked heterogeneity in terms of methods used to assess exposure and capture outcomes, and often using descriptive comparative analyses. Relatively young (as opposed to elderly) and geographically remote Aboriginal and Torres Strait Islanders were found to be at increased risk for selected cancers while most modifiable lifestyle and behavioural risk factors were rarely assessed. Further studies examining associations between potential risk factors and cancer will help define public health policy for cancer prevention in the Australian Aboriginal and Torres Strait Islander population.

Horner syndrome is an uncommon but important clinical entity, representing interruption of the sympathetic pathway to the eye and face. Horner syndrome is almost always diagnosed clinically, though pharmacological testing can be used to confirm the diagnosis. Imaging modalities such as PET, CT and MRI are important components of work-up for patients presenting with acquired Horner syndrome. Our patient’s presentation with Horner syndrome unmasked the causative superior sulcus squamous cell carcinoma and a coincidental lower lobe adenocarcinoma. Successful radical treatment of these cancers resulted in complete resolution of the syndrome and disease-free survival at 18 months. We review the anatomy and pathophysiology underlying this and other causes of Horner syndrome.

Background Surgical resection (usually lobectomy) is considered the treatment of choice for individuals with stage I and II non-small cell lung cancer (NSCLC) and for some patients with resectable stage IIIA NSCLC. However much of the evidence supporting surgery is observational. Objectives To determine whether, in patients with early stage non-small cell lung cancer, surgical resection of cancer improves disease-specific and all-cause mortality compared with no treatment, radiotherapy or chemotherapy. To compare the effectiveness of different surgical approaches (e.g. lobectomy versus limited resection) in improving disease-specific or all-cause mortality in patients with early stage lung cancer. Search strategy Electronic databases (the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE (1966 to December 2003)), bibliographies, handsearching of a journal and discussion with experts were used to identify published and unpublished trials. Selection criteria Randomised controlled trials comparing surgery alone (or in combination with other therapy) with non-surgical therapy and randomised trials comparing different surgical approaches. Data collection and analysis A pooled hazard ratio was calculated where possible. Tests for statistical heterogeneity were performed. Main results Eleven trials were included with a total of 1910 subjects. There were no studies with an untreated control group. In a pooled analysis of three trials, four-year survival was superior in patients with resectable stage I to IIIA NSCLC who underwent resection and complete mediastinal lymph node dissection compared with those undergoing resection and lymph node sampling, the hazard ratio was estimated to be 0.78 (95% CI 0.65-0.93, P = 0.005). A further trial found an increased rate of local recurrence in patients with stage I NSCLC treated with limited resection compared with lobectomy. One small trial found a survival advantage in favour of chemotherapy followed by surgery compared to chemotherapy followed by radiotherapy in patients with stage IIIA NSCLC. However none of the other trials included in the review demonstrated a significant improvement in survival in patients treated with surgery compared with non surgical therapy. Several of the included trials had potential methodological weaknesses. Authors' conclusions Conclusions about the efficacy of surgery for local and loco-regional NSCLC are limited by the small number of participants studied to date and potential methodological weaknesses of trials. Current evidence suggests that lung cancer resection combined with complete mediastinal lymph node dissection is associated with a small to modest improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal nodes in patients with stage I to IIIA NSCLC.

e17539 Background: Cancer-testis antigens (CTAgs) have previously been shown to be markers of poor prognosis and to be associated with chemoresistance in short interference RNA screens. In contradistinction, we recently reported the CTAg NY-ESO-1 predicted improved responses to neoadjuvant chemotherapy in pathological stage IIIA NSCLC. Despite this, no significant survival benefit was seen in NY-ESO-1 positive (NY-ESO-1+) patients. Given that tissues available for staining in the neoadjuvant setting were limited, we investigated a retrospective cohort of patients who underwent curative surgery for pathological N2 disease. As some of these patients were operated on prior to the broad acceptance of adjuvant chemotherapy (ACT), half did not receive chemotherapy. We investigated NY-ESO-1 as a prognostic and/or predictive marker in these patients. Methods: Formalin fixed paraffin embedded tissues were reviewed and stained using standard methods for a panel of CTAgs including NY-ESO-1 by immunohistochemistry. Tumors were categorized as NY-ESO-1+ or NY-ESO-1-. Isolated DNA was subjected to mutation profiling using Sequenom’s MassArray platform. Molecular markers were correlated with clinicopathological features and survival. Results: NY-ESO-1 stained 26/104 (25%) samples, including 15 cases that received ACT and 11 that did not. NY-ESO-1+ tumors were enriched for squamous cell carcinomas over adenocarcinomas (12/29 vs. 8/57; p = 0.01). They also lacked EGFR mutants and were enriched for KRAS mutants amongst adenocarcinomas relative to NY-ESO-1- tumors (5/8 vs. 9/49; p=0.02). NY-ESO-1+ patients who did not receive ACT had significantly worse outcome than NY-ESO-1- patients who did not receive ACT (HR 2.66 1.2-5.86, p=0.01). Median survival favored NY-ESO-1+ patients who received chemotherapy (37.7 months) compared to NY-ESO-1- patients regardless of chemotherapy (28.2 ACT vs 15.7 No ACT; p= 0.25) and NY-ESO-1+ patients who did not receive ACT (7.75). Conclusions: In this dataset, NY-ESO-1 was poorly prognostic but also predictive for more favorable outcomes with chemotherapy. These data support our previous observation of increased responses to chemotherapy in NY-ESO-1+ N2 patients and warrant further study.

atypical subgroupwere found tobe significantlyolder, and presented with higher stage disease. Discussion: It is clear from the current study and previous reports that patients with atypical histopathology have different baseline characteristics, disease behavior and prognosis compared to patients with typical disease. The proposed TNM staging system appears to be applicable to patients in our surgical experience, and may offer more accurate prognostic information and assist in the management plans for individuals. doi:10.1016/j.hlc.2010.11.042 Comprehensive Adenocarcinoma Sub-typing Predicts Outcome After Lung Cancer Resection M. Daniels a,∗, G. Wrightb, P. Russell b, R. Williamsb, M. Conronb, Z. Wainer c a Alfred Health, Melbourne, Australia b St Vincent’s Hospital, Melbourne, Australia c University of Melbourne, Department of Surgery, St Vincent’s Hospital, Melbourne, Australia Background: Current lung adenocarcinoma pathological classification, published in 2004 by the World Health Organisation, has limited clinical utility. A new multidisciplinary classification has been proposed by the European Respiratory Society, the American Thoracic S o p c

Sex Differences in Outcomes Following Isolated CABG Surgery in Australian Patients: Analysis of the Australasian Society of Cardiac and Thoracic Surgeons Cardiac Surgery Database A. Saxena1,∗, D. Dinh2, Z. Wainer 3, M. Daniels 4, JA Smith5, G. Shardey6, A. Newcomb1 1Department of Cardiothoracic Surgery, St Vincent’s Hospital, Melbourne, Australia 2Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia 3University of Melbourne, Department of Surgery, St Vincent’s Hospital, Melbourne, Australia 4 Department of Cardiothoracic Surgery, Alfred Health, Melbourne, Australia 5Department ofCardiothoracic Surgery,MalvernMedicalCentre, Melbourne, Australia 6Department of Cardiothoracic Surgery,MonashMedical Centre, Melbourne, Australia

Background: Radical lobectomy for early-stage Non-Small Cell Lung Cancer (NSCLC) by way of Video-assisted Thoracic Surgery (VATS) is a safe procedure with reduced post-operative morbidity. It has yet to gain world wide acceptance due to a perceived oncological inadequacy. Mediastinal Lymph Node Dissection (MLND) has a confirmed 4-year survival advantage over lymph node (LN) sampling (HR 0.78; 95% CI: 0.63–0.93). We aim to compare the quality of MLND samples from VATS and Open lobectomies. Methods: VATS lobectomies were compared with open lobectomy controls from 2000 to 2008. Retrospective pathology reviews were performed on all MLND samples. LN was counted according to each IASLC nodal zones. The number of LN per zone and in total was compared. Anatomical location of the lobectomy and the 7th ed. cTNM stage was recorded. Results: We included 132 VATS and 157 Ospen lobectomies (132:157). Stage distribution for VATS and Open were: Stage IA (64:55), State IB (64:68), Stage IIA (3:17), Stage IIB (1:14), Stage IIIA (0:3). Mean tumour diameter was 26 mm and 37 mm for VATS and Open respectively. Anatomical location of lobectomies for VATS and Open were: Right (91:100), Left (49:64). The mean number of LN dissected by VATS was higher in the upper mediastinal (Mean 7.2 vs. 4.0; p < 0.05), aorto-pulmonary (Mean 3.0 vs. 2.6), subcarinal (3.0 vs. 2.4), and hilar/interlobar zones (2.0 vs. 1.8). In total, VATS averaged 23 LN per case compared with 18 for Open (p < 0.05). Open lobe MLND performed better for the lower mediastinal zone. Conclusion: The quality of VATS MLND is often better than that of a thoracotomy, and therefore an adequate oncological procedure for early-stage NSCLC with reduced post-operative morbidity.

Introduction We investigated the relationship between predominant subtype, according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Lung Adenocarcinoma Classification; mutation status; and patient outcome in stage III (N2) lung adenocarcinoma. Methods We identified 69 patients with stage III (N2) lung adenocarcinoma operated on with curative intent between 1993 and 2011 who had adequate tumor tissue for molecular analysis and adequate follow-up time for survival analysis. DNA was isolated and tested for mutations using Sequenom's OncoCarta Panel (v1.0; Sequenom, San Diego, CA). Results The majority of tumors were acinar (26 of 69 tumors; 38%), solid (24 of 69 tumors; 35%), and micropapillary predominant (13 of 69 tumors; 19%) subtypes. EGFR and KRAS mutations were identified in 17 of 59 tumors (29%) and 13 of 59 tumors (22%), respectively. EGFR mutations occurred most often in acinar (11 of 25 tumors; 44%) and micropapillary predominant tumors (five of 13 tumors; 38%) ( p = 0.009), whereas KRAS mutations occurred most often in solid predominant tumors (nine of 21 tumors; 43%) ( p = 0.016). Patients with acinar predominant tumors had significantly improved overall survival compared with those with non-acinar predominant tumors (hazard ratio: 0.45; 95% confidence interval: 0.22–0.91; p = 0.026), which remained significant after adjustment for EGFR status, T-stage, sex, and age. Patients with EGFR -mutant micropapillary predominant tumors had similar survival to those with EGFR -mutant acinar predominant tumors. The predominant subtype in the primary tumor was most often seen in the N2 node in micropapillary and solid predominant tumors but not in acinar predominant tumors. Conclusions The predominant subtype in the primary tumor was associated with overall survival in resected stage III (N2) lung adenocarcinoma and was independent of mutation status. Histologic subtyping provides important prognostic information and potentially molecular correlates.