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Fluorescence imaging using indocyanine green in thoracic and esophageal surgery is gaining popularity because of the potential to facilitate surgical planning, to stage disease, and to reduce postoperative complications. To optimize use of fluorescence imaging in thoracic and esophageal surgery, an expert panel sought to establish a set of recommendations at a consensus meeting.The panel included 12 experts in thoracic and upper gastrointestinal surgery from Asia-Pacific countries. Before meeting, 7 focus areas were defined: intersegmental plane identification for sublobar resections; pulmonary nodule localization; lung tumor detection; bullous lesion detection; lymphatic mapping of lung tumors; evaluation of gastric conduit perfusion; and lymphatic mapping in esophageal surgical procedures. A literature search of the PubMed database was conducted using keywords indocyanine green, fluorescence, thoracic, surgery, and esophagectomy. At the meeting, panelists addressed each focus area by discussing the most relevant evidence and their clinical experiences. Consensus statements were derived from the proceedings, followed by further discussions, revisions, finalization, and unanimous agreement. Each statement was assigned a level of evidence and a grade of recommendation.A total of 9 consensus recommendations were established. Identification of the intersegmental plane for sublobar resections, localization of pulmonary nodules, lymphatic mapping in lung tumors, and assessment of gastric conduit perfusion were applications of fluorescence imaging that have the most robust current evidence.Based on best available evidence and expert opinions, these consensus recommendations may facilitate thoracic and esophageal surgery using fluorescence imaging.

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

Supplementary Fig. S1. Generation of patient-derived xenografts from surgery and biopsy specimens of non small cell lung cancer Supplementary Fig. S2. Squamous cell carcinoma patient-derived xenografts recapitulate the genomic phenotype of patients'' tumors Supplementary Fig. S3. Analysis of biomarkers of response to FGFR inhibition Supplementary Fig. S4. High FGFR1 RNA expression does not predict patient outcome Supplementary Fig. S5. PIK3CA amplification does not predict response to PI3K inhibitors Supplementary Fig. S6. FGFR targeted therapy in FGFR inhibitor resistant tumors does not increase cisplatin sensitivity

Supplementary Table S2: GO term enrichment analysis of differentially expressed genes between t1 and t0, overlapping in PDX 788, 926, 792

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

Supplementary Table 1. Engraftment rates of lung cancer patient-derived xenografts vary according to histology and specimen type; Supplementary Table 3. TP53 mutations in primary lung cancer and corresponding PDX, as detected by exome sequencing; Supplementary Table 4. FGFR1 FISH scores are conserved for successive passages of squamous cell carcinoma PDXs 792, 406, 788, and 926; Supplementary Table 5. FGFR1 gene amplification does not always correlate with FGFR1 RNA expression in a tissue microarray patient cohort; Supplementary Table 6. FGFR1 gene amplification does not always correlate with FGFR1 RNA expression in squamous cell carcinoma patients from a tissue microarray cohort; Supplementary Table 7. FGFR1 gene amplification does not always correlate with RNA expression in a squamous cell carcinoma PDX cohort; Supplementary Material and Methods, and Supplementary Figure Legends

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

Cancer-Testis antigens (CTA) are immunogenic molecules with normal tissue expression restricted to testes but with aberrant expression in up to 30% of non-small cell lung cancers (NSCLCs). Regulation of CTA expression is mediated in part through promoter DNA methylation. Recently, immunotherapy has altered treatment paradigms in NSCLC. Given its immunogenicity and ability to be re-expressed through demethylation, NY-ESO-1 promoter methylation, protein expression and its association with programmed death receptor ligand-1 (PD-L1) expression and clinicopathological features were investigated. Lung cancer cell line demethylation resulting from 5-Aza-2'-deoxycytidine treatment was associated with both NY-ESO-1 and PD-L1 re-expression in vitro but not increased chemosensitivity. NY-ESO-1 hypomethylation was observed in 15/94 (16%) of patient samples and associated with positive protein expression (P < 0.0001). In contrast, PD-L1 expression was observed in 50/91 (55%) but strong expression in only 12/91 (13%) cases. There was no association between NY-ESO-1 and PD-L1 expression, despite resultant re-expression of both by 5-Aza-2'-deoxycytidine. Importantly, NY-ESO-1 hypomethylation was found to be an independent marker of poor prognosis in patients not treated with chemotherapy (HR 3.59, P = 0.003) in multivariate analysis. In patients treated with chemotherapy there were no differences in survival associated with NY-ESO-1 hypomethylation. Collectively, these results provided supporting evidence for the potential use of NY-ESO-1 hypomethylation as a prognostic biomarker in stage 3 NSCLCs. In addition, these data highlight the potential to incorporate demethylating agents to enhance immune activation, in tumours currently devoid of immune infiltrates and expression of immune checkpoint genes.

Backgrounds Victoria (Australia) and Denmark have comparable population sizes and high-quality healthcare systems. Lung cancer surgery, however, is performed in more than 20 Victorian hospitals compared to four in Denmark. Such differences in centralization may influence outcomes. We engaged clinical quality registries to enable international benchmarking by exploring patterns of lung cancer surgery including mortality and survival. Methods All patients undergoing lung cancer surgery between 2015 and 2018 registered in the Victorian Lung Cancer Registry and the Danish Lung Cancer Registry were included. Analyses on stage concordance, 30 and 90-day mortality, and overall survival were restricted to a selected subgroup with NSCLC and no neo-adjuvant therapy or metastatic disease and only one operation. Results We included 1554 Victorian and 4319 Danish patients. The resection rate was 26.3% in Victoria and 28% in Denmark, but a higher proportion of Victorian patients underwent wedge resection (19.1% versus 8.8%). Stage concordance was 59.6% and 54.9% in Victoria and Denmark, respectively. The 30- and 90-day mortality was 1.3% and 2.6% in Victoria, compared to 1.4% and 2.8% in Denmark with no difference in overall survival (p = 0.28) or risk-adjusted survival (HR: 1.10 (95% CI: 0.89-1.37); p = 0.38). Conclusion High-quality surgical lung cancer care was confirmed by similar high resection and low mortality rates including no overall survival difference. The drivers and consequences of stage discordance and differences in patterns of resection deserve further exploration. This study provides a model for international benchmarking using clinical quality registries, although caution remains in the interpretation given disparities in data completeness.

Introduction Marked variations in survival rates have brought into question whether standard clinicopathologic classification should be applied to patients presenting with multiple primary lung cancers (MPLCs). This study investigated the genetic profiles of MPLCs in a cohort of patients using next-generation sequencing and correlated results to clinicopathologic data and patient outcome. Methods Patients treated surgically with curative intent for two putative primaries of similar histopathology from January 2000 to December 2019 at St Vincent’s Hospital Melbourne. DNA and RNA was extracted from formalin-fixed, paraffin-embedded tumor tissue and sequenced on an Ion Torrent Personal Genome Machine system. Patient outcome was determined by overall survival and disease-free survival. Results A total of 40 cases fulfilled the inclusion criteria. Mutational profiling was concordant with clinicopathologic diagnosis in most cases; however, seven cases (17.5%) revealed shared mutations suggesting metastatic disease and this was associated with a substantial reduction in overall survival (p Conclusions Our results suggest that gene sequencing technologies are potentially a more accurate diagnostic and prognostic tool compared with traditional histopathologic evaluation in patients presenting with suspected MPLCs, which could better guide management and predict outcomes.

BACKGROUND: Many extrapulmonary neoplasms metastasize to the lungs. We conducted a retrospective review of all patients who underwent pulmonary metastasectomy for oligometastatic disease at two centres in order to determine long-term outcomes. METHODS: The study institutions' thoracic surgery databases were searched for all patients who underwent pulmonary metastasectomy from 2000 to 2017. RESULTS: There were a total of 476 patients who underwent pulmonary metastasectomy. Mean age at time of surgery was 57.2 ± 15.9 years. Mean number of pulmonary lesions was 1.9 ± 1.6. Mean disease-free interval (DFI) was 3.6 ± 4.3 years. The most common primary neoplasms were colorectal cancer (CRC) in 35.1% (167/476), sarcoma in 23.9% (114/476), melanoma in 16.2% (77/478), renal cell carcinoma (RCC) in 7.3% (35/476) and germ cell tumour (GCT) in 4.4% (21/476). Hospital mortality was 0.4% (2/476). Mean follow-up time was 3.8 ± 2.9 years. Survival was 88.9% (95% confidence interval 85.77-91.5) at 1 year and 49.6% (95% confidence interval 44.4-54.6) at 5 years. On multivariate Cox-regression analysis GCT (P = 0.004), CRC (P = 0.03), DFI of 36+ months (P = 0.007), R0 resection (P = 0.002) and non-anatomical, sub-lobar (wedge) resection (P = 0.002) were protective against mortality. CONCLUSION: Pulmonary metastasectomy is associated with survival of 50% at 5-year follow-up. DFI of over 36 months, R0 resections, lesions resectable by wedge resection rather than anatomic resection and GCT and CRC primary cancers were associated with improved survival.

Background Pulmonary carcinoids are rare neoplasms, accounting for approximately 1%–2% of all lung malignancies. A retrospective analysis was undertaken of all patients who underwent surgical resection of pulmonary carcinoid tumours across multiple institutions in Melbourne, Australia. Methods From May 2000 through April 2020, 241 patients who underwent surgical resection of pulmonary carcinoid tumours were retrospectively reviewed. Patient demographics, pathologic data, and long-term outcomes were recorded. Results Median age was 57.7 years and the majority of patients were female (58.9% vs. 41.1%). Typical carcinoid was present in 77.1%. Histological subtype was associated with several factors. Atypical carcinoid was more likely to have larger tumour size and nodal involvement. Overall survival for typical carcinoid at 5, 10, and 15 years was 98%, 95%, and 84%, and for atypical carcinoid was 88%, 82%, and 62%, respectively. Histological subtype and age were found to be independent predictors of overall survival, with worse outcomes for atypical and those above 60 years of age. Disease-free survival was related to sublobar resection (p Conclusion Excellent long-term outcomes can be achieved following surgical resection of pulmonary carcinoids. Atypical histology and lymph node involvement are significant prognostic factors, and sublobar resection should not be considered in patients with either of the above features. Typical carcinoid tumour without nodal involvement may be appropriate for sublobar resection. Typical and atypical carcinoid tumours should be considered distinct disease entities, and as such treated accordingly.

Treatment of elderly patients with lung cancer is significantly hindered by concerns about treatment tolerability, toxicity and limited clinical trial data in the elderly; potentially giving rise to treatment nihilism amongst clinicians. This study aims to describe survival in elderly patients with lung cancer and explore potential causes for excess mortality. Patients diagnosed with lung cancer in the Victorian Lung Cancer Registry between 2011–2018 were analysed (n=3481). Patients were age-categorised and compared using Cox-regression modelling to determine mortality risk, after adjusting for confounding. Probability of being offered cancer treatments was also determined, further stratified by disease stage. The eldest patients (≥80 years old) had significantly shorter median survival compared with younger age groups (, Treatment strongly determines lung cancer survival, yet nihilism may threaten treatment provision and survival outcomes. Older patients in this cohort had reduced multidisciplinary presentation, less treatment (OR 0.24) and 28% increased mortality risk. https://bit.ly/2ZGotj0

Background The COVID-19 pandemic has had a vast impact on cancer service delivery around the world. Previously reported results from our international survey of oncology clinicians, conducted through March-April 2020, found that clinicians reported altering management in both the curative and palliative settings and not in proportion to the COVID-19 case burden in their region of practice. This follow-up survey, conducted from 27th September to 7th November 2020, aimed to explore how attitudes and practices evolved over the 2020 pandemic period. Participants and methods Participants were medical, radiation and surgical oncologist and trainees. Surveys were distributed electronically via ESMO and other collaborating professional societies. Participants were asked to compare their practice prior to the pandemic to both the period of March-April 2020, referred to as the ‘early’ period, and the current survey period, referred to as the ‘later’ period. Results One hundred and seventy-two oncology clinicians completed the survey. The majority of respondents were medical oncologists (n = 136, 79%) and many were from Europe (n = 82, 48%). In the ‘early’ period, 88% (n = 133) of clinicians reported altering their practice compared to 63% (n = 96) in the ‘later’ period. Compared to prior to the pandemic, clinicians reported fewer new patient presentations in the ‘early’ period and a trend towards more patients presenting with advanced disease in the ‘later’ period. Conclusions Results indicate a swing back towards pre-COVID-19 practices despite an increase in the rate of cumulative COVID-19 cases across 2020. The impact of these changes on cancer associated morbidity and mortality remains to be measured over the months and years to come., Highlights • This collaborative international survey of oncology clinicians was conducted in October/November of 2020. • Findings indicate a swing back towards ‘pre-coronavirus disease’ practice. • Fewer clinicians altered practice compared to the ‘early’ period of the pandemic in 2020 (63% versus 88%). • Clinicians reported seeing more new patients and a greater proportion of patients presenting with advanced disease.

Advanced-stage hepatocellular carcinoma presenting with endobronchial metastases is an extremely rare phenomenon, with only a few cases reported to date. Despite endobronchial metastases being a rare occurrence, the clinically significant sequelae require prompt diagnosis and management. Therapeutic bronchoscopy represents an effective palliative treatment for malignant airway obstruction. This case report describes a 62-year-old man who presented with bilateral endobronchial metastases from advanced-stage hepatocellular carcinoma, requiring symptom palliation with laser bronchoscopy.

Author(s): Rivalland, Gareth; Mitchell, Paul; Murone, Carmel; Asadi, Khashayer; Morey, Adrienne L; Starmans, Maud; Boutros, Paul C; Walkiewicz, Marzena; Solomon, Benjamin; Wright, Gavin; Knight, Simon; John, Thomas | Abstract: BackgroundIn non-small cell lung cancer (NSCLC), mesenchyme to epithelial transition (MET) protein abundance increases with disease stage and is implicated in resistance to tyrosine kinase inhibitors. To better clarify the impact of MET overexpression on tumor behavior, we investigated a large cohort of patients who underwent curative surgical resection to determine whether MET gene amplification or protein abundance was prognostic.MethodsTissue microarrays (TMAs) were constructed using triplicate 1 mm cores of FFPE primary NSCLC specimens. TMAs underwent immunohistochemical (IHC) staining with the SP44 clone (Ventana) and cores were considered positive if g50% of tumor exhibited 2+ staining. The highest of triplicate values was used. MET gene amplification was detected using either SISH using Ventana's MET DNP probe or FISH using the D7S486/CEP 7 Abbott Probe. DNA was subjected to mutational profiling using Sequenom's LungCarta panel.ResultsData from two institutions comprising 763 patients (516; 68%) male were generated, including 360 stage I, 226 stage II, 160 stage III and 18 resected stage IV. High MET protein expression was detected in 25% (193/763), and was significantly more common in adenocarcinomas than squamous cell carcinoma (Pl0.01). MET gene copy number (GCN) correlated with high MET protein expression by IHC (P=0.01). Increased MET protein expression was associated with EGFR and KRAS mutations (Pl0.01 for both). Once polysomy was excluded, true MET gene amplification was detected in only 8/763 (1%) of samples. In multivariate analysis, neither MET protein abundance nor GCN were correlated to overall patient survival.ConclusionsMET expression by IHC and GCN amplification was not prognostic in this large Caucasian surgical series. MET's primary role remains as a therapeutic target.

Background Epidermal growth factor receptor gene (EGFR) exon 20 insertion (ex20-ins) mutations are an uncommon and heterogeneous group of non–small cell lung cancers (NSCLCs), resistant to conventional EGFR tyrosine kinase inhibitors (TKIs). Characteristics and outcomes of patients with EGFR ex20-ins have not been fully established; we sought to clarify them using a multinational patient database. Patients and Methods Patients with NSCLC from six Australian institutions with EGFR exon 20 mutations (ex20-mut), excluding T790M, were retrospectively reviewed. Clinical characteristics and outcomes with systemic treatments were collected and analyzed using comparative statistics. Results Among 109 patients with ex20-mut, 61% were females and 75% were Caucasians. More males presented with de novo metastatic disease (84% vs. 51%; P = .002). Central nervous system (48%) and liver (24%) metastases were common within metastatic patients (n = 86). Thirty-nine patients received platinum-based chemotherapy (PBC) and achieved a 43% objective response rate (ORR), median progression-free survival (mPFS) of 6.9 months, and median overall survival (mOS) of 31.0 months. Twenty-three of the patients with ex20-ins received conventional TKIs, resulting in an ORR of 13%, mPFS of 3.4 months (95% confidence interval [CI], 1.91-6.25), and mOS of 31.0 months (95% CI, 15.09-not reached). Nine patients with S786I mutations received TKIs, resulting in an ORR of 50%, mPFS of 18.2 months (2.79-not reached), and mOS of 33.4 months (95% CI, 16.14-not reached). Twenty-three patients received immune checkpoint inhibitor monotherapy (ICIm), resulting in an ORR of 4%, mPFS of 2.6 months (95% CI, 1.91-4.83), and mOS of 30.8 months (95% CI, 17.62-41.62). Conclusion Although phenotypically similar to patients with common EGFR mutations, patients with EGFR ex20-mut had worse survival, perhaps due to the lack of targeted therapies. Chemotherapy was superior to conventional EGFR TKIs in patients with EGFR ex20-ins, although there was moderate activity of TKIs in S768I mutations. ICIm was ineffective.

Background The decision for administering adjuvant chemotherapy (AC) in completely resected node-negative non-small cell lung cancer (NSCLC) is guided by likelihood of disease recurrence or death based on tumor, node, metastasis (TNM) stage. However, within each TNM stage are sub-groups of patients that are more or less likely to relapse than stage alone predicts. Methods In this retrospective cohort study, prospective data from 394 consecutive patients who underwent complete resection of node-negative NSCLC without adjuvant therapies, between 2002 and 2019 was retrospectively analyzed. Independent tumor and host risk factors for recurrence were subjected to multivariate analysis to develop a predictive risk model distributing patients into low-risk or high-risk categories. Results Recurrence risk was independently predicted by a neutrophil:lymphocyte ratio (NLR) of ≥3.5 [hazard ratio (HR), 1.9; 95% confidence interval (CI), 1.1-3.5], visceral pleural invasion (HR, 2.2; 95% CI, 1.3-3.8), histopathology other than adenocarcinoma or squamous cell (HR, 2.6; 95% CI, 1.2-5.5) and tumor size >33 mm (HR, 3.9; 95% CI, 2.3-6.7). The specific combination of risk factors contributed to a score for a risk model which classified 9% of Stage I and 69% of Stage ≥II patients as high-risk. The predicted 5-year disease-free survival (DFS) for high-risk and low-risk patients as scored by the predictive model was 30% and 85%, respectively. Conclusions Our readily reproducible, low-technology model, developed from individually validated tumor/host risk factors, identified sub-groups of resected node-negative NSCLC patients at significantly discordant risk of recurrence to their TNM stage category.

Blood-based liquid biopsies are considered a new and promising diagnostic and monitoring tool for cancer. As liquid biopsies only require a blood draw, they are non-invasive, potentially more rapid and assumed to be a less costly alternative to genomic analysis of tissue biopsies. A multi-disciplinary workshop (n = 98 registrations) was organized to discuss routine implementation of liquid biopsies in cancer management. Real-time polls were used to engage with experts&rsquo, about the current evidence of clinical utility and the barriers to implementation of liquid biopsies. Clinical, laboratory and health economics presentations were given to illustrate the opportunities and current levels of evidence, followed by three moderated break-out sessions to discuss applications. The workshop concluded that tumor-informed assays using next-generation sequencing (NGS) or PCR-based genotyping assays will most likely provide better clinical utility than tumor-agnostic assays, yet at a higher cost. For routine application, it will be essential to determine clinical utility, to define the minimum quality standards and performance of testing platforms and to ensure their use is integrated into current clinical workflows including how they complement tissue biopsies and imaging. Early health economic models may help identifying the most viable application of liquid biopsies. Alternative funding models for the translation of complex molecular diagnostics, such as liquid biopsies, may also be explored if clinical utility has been demonstrated and when their use is recommended in multi-disciplinary consensus guidelines.

Sarcomas, despite being a disparate group of malignant diseases, share a common propensity to metastasise to the lungs, regardless of origin of the primary. This risk correlates with location, size, grade and histological subtype [1]. Often this is the only clinical evidence of disease in patients after appropriate complete resection of their primary sarcoma. They may appear at the time of local recurrence in an incompletely resected or inappropriately treated primary sarcoma.

Objectives: To report clinician-perceived changes to cancer service delivery in response to COVID-19. Design: Multidisciplinary Australasian cancer clinician survey in collaboration with the European Society of Medical Oncology. Setting: Between May and June 2020 clinicians from 70 countries were surveyed; majority from Europe (n=196; 39%) with 1846 COVID-19 cases per million people, Australia (AUS)/New Zealand (NZ) (n=188; 38%) with 267/236 per million and Asia (n=75; 15%) with 121 per million at time of survey distribution. Participants Medical oncologists (n=372; 74%), radiation oncologists (n=91; 18%) and surgical oncologists (n=38; 8%). Results: Eighty-nine per cent of clinicians reported altering clinical practices; more commonly among those with versus without patients diagnosed with COVID-19 (n=142; 93% vs n=225; 86%, p=0.03) but regardless of community transmission levels (p=0.26). More European clinicians (n=111; 66.1%) had treated patients diagnosed with COVID-19 compared with Asia (n=20; 27.8%) and AUS/NZ (n=8; 4.8%), pConclusion: Clinicians reported widespread changes to oncology services, in regions of both high and low COVID-19 case numbers. Clinician concerns of potential negative impacts on patient outcomes warrant objective assessment, with system and policy implications for healthcare delivery at large.

One reason that lung cancer is the leading cause of cancer mortality worldwide, is that surgical intervention is highly dependent on earlier tumor stage and good patient condition. As large proportion of cases are already metastatic at presentation and many are locally advanced, curative surgery is only possible in a minority of fit patients. Increasing the number of patients achieving complete resection is one of the avenues to increase overall survival using our existing technology. In the past, complex cases may have been sporadically discussed between various specialists in order to achieve better outcomes. More recently, the idea of discussing those cases on a routine basis, rather than an accident of geography or referral pattern, gave rise to the multidisciplinary team. Lung cancer management is now increasingly complex, especially with novel modalities such as targeted therapies, immune checkpoint inhibitors and stereotactic body radiotherapy delivery. Likewise, in thoracic surgery, minimally invasive techniques, early recovery after surgery protocols and complex techniques for resecting locally advanced tumours or preserving lung parenchyma must all be deployed appropriately to continue our incremental gains in survival and quality of life. To highlight the role of specialist thoracic surgeon in the multidisciplinary care of locally advanced non-small cell lung cancer, we conducted a search of English language publications for its multidisciplinary-based surgical management. We limited our search to the last decade, then hand-searched relevant references. In addition, we used our large prospective database as a team-oriented specialized thoracic surgical service to benchmark and demonstrate the benefits of specialist surgeons in the modern multidisciplinary team. In conclusion, patients with locally advanced non-small cell lung cancer should have any surgical option withheld without a specialist thoracic surgical opinion as part of the multidisciplinary team discussion.

Lung cancer poses the greatest cancer-related death risk and males have poorer outcomes than females, for unknown reasons. Patient sex is not a biological variable considered in lung cancer standard of care. Correlating patient genetics with outcomes is predicted to open avenues for improved management. Using a bioinformatics approach across non-small cell lung cancer (NSCLC) subtypes, we identified where patient sex, mutation of the major tumor suppressor gene, Tumour protein P53 (TP53), and immune signatures stratified outcomes in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), among datasets of The Cancer Genome Atlas (TCGA). We exposed sex and TP53 gene mutations as prognostic for LUAD survival. Longest survival in LUAD occurred among females with wild-type (wt) TP53 genes, high levels of immune infiltration and enrichment for pathway signatures of Interferon Gamma (INF-&gamma, ), Tumour Necrosis Factor (TNF) and macrophages-monocytes. In contrast, poor survival in men with LUAD and wt TP53 genes corresponded with enrichment of Transforming Growth Factor Beta 1 (TGFB1, hereafter TGF-&beta, ) and wound healing signatures. In LUAD with wt TP53 genes, elevated gene expression of immune checkpoint CD274 (hereafter: PD-L1) and also protein 53 (p53) negative-regulators of the Mouse Double Minute (MDM)-family predict novel avenues for combined immunotherapies. LUSC is dominated by male smokers with TP53 gene mutations, while a minor population of TCGA LC patients with wt TP53 genes unexpectedly had the poorest survival, suggestive of a separate etiology. We conclude that advanced approaches to LUAD and LUSC therapy lie in the consideration of patient sex, TP53 gene mutation status and immune signatures.

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

BACKGROUND Pulmonary metastases are a sign of advanced malignant disease. Interdisciplinary management of metastatic cancer mandates the consideration of all treatment options, and in selected patients pulmonary metastasectomy can be performed with curative intent. This study aims to analyze the prognostic factors associated with survival and optimize the selection of surgical candidates. The sarcoma subset analysis aims to examine the role of multiple repeat resections for pulmonary metastatic recurrence. METHODS A total of 243 patients were analyzed in this retrospective cohort study. Overall survival was estimated using Kaplan-Meier analysis. Univariate analyses with log-rank tests and multivariate analysis with Cox proportional hazards model were undertaken to determine the independent prognostic factors for survival. RESULTS Multivariate analyses identified germ cell cancer (P = 0.01) and a disease-free interval of >36 months (P = 0.006) as significant independent prognostic factors for improved survival, whilst synchronous metastases (P = 0.04), multiple metastases (P = 0.005) and incomplete resection (P

Introduction Four different programmed death ligand 1 immunohistochemical assays are approved or in development as companion or complementary diagnostics to different immunotherapeutic agents in lung carcinoma. We sought to determine whether these assays are technically equivalent and whether one antibody can be used on an alternate staining platform. Methods Serial sections of tissue microarrays constructed from 368 cases of resected lung cancer were stained for 22C3 and 28-8 on the Dako Link 48 platform (Dako, Carpinteria, Ca) and for SP142 and SP263 on the Ventana Benchmark Ultra platform (Ventana Medical Systems, Tucson, AZ) strictly as per product insert. A protocol was developed to use the 22C3 antibody on the Ventana Benchmark Ultra platform. Results Differences in mean tumor cell and immune cell staining were observed between the four assays ( p Conclusions Concordance between the four programmed death ligand 1 immunohistochemical assays when performed and scored as intended show that apart from 28-8 and 22C3, they cannot be used interchangeably in clinical practice. A protocol was successfully developed to use 22C3 on an alternate platform, which may help to overcome some barriers to implementation.

We investigated correlations between diagnosis according to the 2015 World Health Organization (WHO) classification of unresected lung tumours, molecular analysis and TTF1 expression in small biopsy and cytology specimens from 344 non-small cell lung carcinoma (NSCLC) patients. One case failed testing for EGFR, KRAS and ALK abnormalities and six had insufficient tumour for ALK testing. Overall mutation rate in 343 cases was 48% for the genes tested, with 19% EGFR, 33% KRAS and 4% BRAF mutations, and 5% ALK rearrangements detected. More EGFR-mutant (78%) and ALK-rearranged (75%) tumours had morphologic adenocarcinoma than KRAS-mutant (56%) tumours. Despite no significant difference in the overall rate of any molecular abnormality between morphologic adenocarcinoma (52%) and NSCLC, favour adenocarcinoma (47%) (p = 0.18), KRAS mutations were detected more frequently in the latter group. No significant difference in the overall rate of any molecular abnormality between TTF1 positive (49%) and TTF1 negative tumours (44%) (p = 0.92) was detected, but more EGFR-mutant (97%) and ALK-rearranged tumours (92%) were TTF1 positive than KRAS-mutant tumours (68%). Rates of EGFR, KRAS and BRAF mutations and ALK rearrangements in this Australian NSCLC patient population are consistent with the published international literature. Our findings suggest that 2015 WHO classification of unresected tumours may assist in identifying molecular subsets of advanced NSCLC.

Background The association between socioeconomic status (SES) and lung cancer is internationally established but in Australia this relationship remains ill defined. Aims To examine the association between SES, place of residence and lung cancer outcomes in a large Australian cohort. Methods 2369 consecutive lung cancer patients managed by St Vincent's Hospital lung multidisciplinary meeting between 2001–2014 were included. Postcode data stratified participants by Socio-Economic Indexes for Areas, a validated measure of SES, and by geographical location, an important socioeconomic factor in Australia. Results There was no difference between socioeconomic groups in age (68 years), sex (63% males) or presentation (75% symptomatic). Low socioeconomic patients had increased smoking rates and a trend towards less adenocarcinoma. More low SES patients were from rural locations, had a greater frequency of earlier stage disease and curative treatment with higher overall survival even after multivariate analysis. When stratified for socioeconomic status, overall 5-year survival was significantly better in the low SES group (33% vs 24%, n = 2275, p = 0.02), although stage-stratified survival was similar in all socioeconomic groups. Conclusions Low SES patients were more frequently from rural locations and unexpectedly had earlier stage disease and higher overall survival. The excellent outcomes in rural and lower SES patients is reassuring but suggests that there is a population of these patients with advanced lung cancer who are not referred for multidisciplinary care. Further studies are required to better define this group and determine the barriers to referral to improve overall lung cancer outcomes.

SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor protein that has roles in key cellular processes including apoptosis and cellular proliferation. As these cellular processes are frequently disrupted in human tumours and little is known about the role of SASH1 in the pathogenesis of the disease, we analysed the prognostic value of SASH1 in non-small cell lung cancers using publicly available datasets. Here, we show that low SASH1 mRNA expression is associated with poor survival in adenocarcinoma. Supporting this, modulation of SASH1 levels in a panel of lung cancer cell lines mediated changes in cellular proliferation and sensitivity to cisplatin. The treatment of lung cancer cells with chloropyramine, a compound that increases SASH1 protein concentrations, reduced cellular proliferation and increased sensitivity to cisplatin in a SASH1-dependent manner. In summary, compounds that increase SASH1 protein levels could represent a novel approach to treat NSCLC and warrant further study.

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms., The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Here, Alcala and colleagues present a multi-omics analysis of these tumours, revealing distinct molecular and prognostic subgroups.

The KRAS oncoprotein, a critical driver in 33% of lung adenocarcinoma (LUAD), has remained an elusive clinical target due to its perceived undruggable nature. The identification of dependencies borne through common co-occurring mutations are sought to more effectively target KRAS-mutant lung cancer. Approximately 20% of KRAS-mutant LUAD carry loss-of-function mutations in KEAP1, a negative regulator of the antioxidant response transcription factor NFE2L2/NRF2. We demonstrate that Keap1-deficient KrasG12D lung tumors arise from a bronchiolar cell-of-origin, lacking pro-tumorigenic macrophages observed in tumors originating from alveolar cells. Keap1 loss activates the pentose phosphate pathway, inhibition of which, using 6-AN, abrogated tumor growth. These studies highlight alternative therapeutic approaches to specifically target this unique subset of KRAS-mutant LUAD cancers., Lung adenocarcinomas frequently harbour KRAS mutations, of which a subset are characterized by co-mutation of KEAP1. Here the authors show, in mice, that KrasG12D mutant tumours are metabolically distinct, with a bronchiolar cell-of-origin.

Pulmonary metastases are a sign of advanced malignancy and an omen of poor prognosis. Once primary tumors metastasize, they become notoriously difficult to treat and interdisciplinary management often involves a combination of chemotherapy, radiotherapy, and surgery. Over the last 25 years, the emerging body of evidence has recognized the curative potential of pulmonary metastasectomy. Surgical resection of pulmonary metastases is now commonly considered for patients with controlled primary disease, absence of widely disseminated extrapulmonary disease, completely resectable lung metastases, sufficient cardiopulmonary reserve, and lack of a better alternative systemic therapy. Since the development of these selection criteria, other prognostic factors have been proposed to better predict survival and optimize the selection of surgical candidates. Disease-free interval (DFI), completeness of resection, surgical approach, number and laterality of lung metastases, and lymph node metastases all play a dynamic role in determining patient outcomes. There is a definite need to continue reviewing these prognosticators to identify patients who will benefit most from pulmonary metastasectomy and those who should avoid unnecessary loss of lung parenchyma. This literature review aims to explore and synthesize the last 25 years of evidence on the long-term survival, prognostic factors, and patient selection process for pulmonary metastasectomy.

Thoracotomy is acknowledged as one of the most painful procedures in surgical practice, with the potential to result in significant acute and chronic sequelae, which become especially relevant in high-risk patient populations. Certain pathologies necessitate this surgical approach, and in those circumstances we must aim to mitigate postoperative complications by employing surgical techniques that decrease the risk of nerve injury, rib fracture, and unnecessary soft tissue trauma. We describe an approach to thoracotomy that incorporates evidence-based strategies to lessen the risk of these potential complications, which resulted in rapid postoperative recovery in a nonagenarian.

The advent of massively parallel sequencing has caused a paradigm shift in the ways cancer is treated, as personalised therapy becomes a reality. More and more laboratories are looking to introduce next generation sequencing (NGS) as a tool for mutational analysis, as this technology has many advantages compared to conventional platforms like Sanger sequencing. In Australia all massively parallel sequencing platforms are still considered in-house in vitro diagnostic tools by the National Association of Testing Authorities (NATA) and a comprehensive analytical validation of all assays, and not just mere verification, is a strict requirement before accreditation can be granted for clinical testing on these platforms. Analytical validation of assays on NGS platforms can prove to be extremely challenging for pathology laboratories. Although there are many affordable and easily accessible NGS instruments available, there are no standardised guidelines as yet for clinical validation of NGS assays. We present an accreditation development procedure that was both comprehensive and applicable in a setting of hospital laboratory for NGS services. This approach may also be applied to other NGS applications in service laboratories.

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 =

BACKGROUND/OBJECTIVE: Given the poor overall survival (OR) and progression-free survival (PFS) rates for lung cancers managed with surgical resection, there is a need to identify the prognostic markers that would improve the risk stratification of patients with operable lung cancer to inform treatment decisions. We investigate the prognostic utility of two established inflammation-based scores, the neutrophil–lymphocyte ratio (NLR) and the change in neutrophil–lymphocyte ratio (ΔNLR), throughout the operative period in a prospective cohort of patients with lung cancer who underwent surgical resection. METHODS: Demographic, clinical, and treatment details for 345 patients with lung cancer who underwent surgical resection between 2000 and 2019 at multiple centers across Melbourne, Victoria (Australia), were prospectively collected. Preoperative NLR and ΔNLR were calculated after which Cox univariate and multivariate analyses were conducted for OS and PFS against the known prognostic factors. RESULTS: Both univariate and multivariate analyses showed that preoperative NLR >4.54, as well as day 1 and day 2 postoperative NLR (P < 0.01), was associated with increased risk for postoperative mortality (hazard ratio 1.8; P < 0.01) and PFS (P < 0.05), whereas ΔNLR was not a significant predictor of OS or PFS. CONCLUSION: Elevated NLR among patients with lung cancer who underwent surgical resection was prognostic for poor OS and PFS, whereas ΔNLR was not found to be prognostic for either OS or PFS. Further research may yet reveal a prognostic value for ΔNLR when compared across a greater time period.

We describe a novel technique for the creation of a pleural tent and pleurectomy via the use of a laparoscopic hernia balloon. In this method a Spacemaker™ Structural Balloon Trocar (Covidien, USA) is tunnelled under the pleura at the site of thoracotomy or video assisted thoracoscopic surgery port and incrementally inflated under vision. This method is less traumatic than traditional methods, is more likely to provide an intact pleural tent, and allows the surgeon to operate in a near bloodless operative field.

Summary Background Increased detection of small-sized, peripheral, non-small-cell lung cancer has renewed interest in sublobar resection instead of lobectomy, the traditional standard of care for early-stage lung cancer. We aimed to assess morbidity and mortality associated with lobar and sublobar resection for early-stage lung cancer. Methods CALGB/Alliance 140503 is a multicentre, international, non-inferiority, phase 3 trial in patients with peripheral non-small-cell lung cancer clinically staged as T1aN0. Patients were recruited from 69 academic and community-based institutions in Australia, Canada, and the USA. Patients were randomly assigned intraoperatively to either lobar or sublobar resection. The random assignment was based on permuted block randomisation without concealment and was stratified according to radiographic tumour size, histology, and smoking status. The primary endpoint of the trial is disease-free survival; here, we report a post-hoc, exploratory, comparative analysis of perioperative mortality and morbidity associated with lobar and sublobar resection. Perioperative mortality was defined as death from any cause within 30 days and 90 days of surgical intervention and was calculated for all randomised patients. Morbidity was graded using Common Terminology Criteria for Adverse Events version 4.0. All analyses were done on an intention-to-treat basis for randomised patients with data available. This trial is registered with ClinicalTrials.gov, number NCT00499330. Findings Between June 15, 2007, and March 13, 2017, 697 patients were randomly allocated to either lobar resection (n=357) or sublobar resection (n=340; 59% wedge resection). Six (0·9%) patients died by 30 days, four (1·1%) after lobar resection and two (0·6%) after sublobar resection; by 90 days, ten (1·4%) patients had died, six (1·7%) after lobar resection and four (1·2%) after sublobar resection (difference at 30 days, 0·5%, 95% CI −1·1 to 2·3; difference at 90 days, 0·5%, 95% CI −1·5 to 2·6). An adverse event of any grade occurred in 193 (54%) of 355 patients after lobar resection and 172 (51%) of 337 patients after sublobar resection. Adverse events of grade 3 or worse occurred in 54 (15%) patients assigned lobar resection and in 48 (14%) patients assigned sublobar resection. No differences between surgical approaches were noted in cardiac or pulmonary complications. Grade 3 haemorrhage (requiring transfusion) occurred in six (2%) patients assigned lobar resection and eight (2%) patients assigned sublobar resection. Prolonged air leak occurred in nine (3%) patients after lobar resection and two (1%) patients after sublobar resection. Interpretation Our post-hoc analysis showed that perioperative mortality and morbidity did not seem to differ between lobar and sublobar resection in physically and functionally fit patients with clinical T1aN0 non-small-cell lung cancer. These data may affect the daily choices made by patients and their doctors in establishing the best treatment approach for stage I lung cancer. Funding National Cancer Institute.