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Abstract
Introduction Ipsos MORI were commissioned by the Global Lung Cancer Coalition to explore the prevalence of smoking within countries; and awareness of the symptoms of lung cancer. Two questions were asked: 1. Can I just check, do you consider yourself to be: a) A current smoker – i.e. someone who is a regular smoker at the present time; b) A former smoker – i.e. someone who used to smoke regularly but has quit; c) Someone who has never smoked – i.e. someone who has never smoked at all, or only very occasionally in the past (less than 100 cigarettes in your lifetime); d) Don’t know. 2. There are many warning signs and symptoms of lung cancer. Please name as many symptoms of lung cancer as you can think of.[1] A quantitative survey was conducted across: Argentina, Australia, Bulgaria, Canada, Denmark, Egypt, France, Germany, Great Britain, Ireland, Italy, Japan, Mexico, Norway, Portugal, Slovenia, Spain, Sweden, Switzerland, the Netherlands, and the USA. This abstract outlines the headline findings[2]. Methodology A nationally representative quota sample for each country of 500–1,204 adults was interviewed from 2 June – 16 August 2013[3], using Omnibus services (please note the lowest age varied slightly between countries)[4]. Face-to-face in-home interviewing was used in Bulgaria, France, Germany, Great Britain, Portugal and Spain, and telephone (CATI[5]) interviewing elsewhere (in Argentina, Australia, Canada, Denmark, Egypt, Ireland, Italy, Japan, Mexico, Norway, Slovenia, Sweden, Switzerland, the Netherlands, and the USA). Data have been weighted to the known adult population profile of each country. Please also note that booster surveys took place in Mexico, Norway, Sweden and Slovenia to boost the number of smokers in order to allow robust comparisons. In each country, data were weighted back to the original profile of smokers and non-smokers to ensure that smokers were not over-represented. Discussion of findings: where is smoking prevalence highest? Of all the 21 countries surveyed, people in Bulgaria are most likely to be current smokers (41%), followed by Spain (33%) and France (30%). The lowest proportions of current smokers are found in Sweden (12%) and Australia (13%). Egypt, however, has the highest proportion of people who have never smoked at all (70%). Figure 1 Spontaneous awareness of the symptoms of lung cancer The combined results from all countries show that breathlessness (40%) and coughing (39%) are the most frequently recognised symptoms of lung cancer. Other symptoms relating to coughing, as well as general or unspecified coughing, are also commonly mentioned: coughing blood (17%), a cough that doesn’t go away (14%), and a cough that gets worse (8%). Tiredness or a lack of energy (13%) and an ache or pain when coughing or breathing (11%), are spontaneously mentioned by more than one in ten people as well. It should also be recognised that approaching one in four could not name any symptoms, instead stating that they didn’t know (23%). Figure 2 Spontaneous awareness varies significantly by country. For example, fewer than one in four Japanese adults mention breathlessness (22%), compared to a high of 56% in Ireland. Likewise, whilst 27% state tiredness or a lack of energy to be a symptom of lung cancer in Bulgaria, only 5% of Australians do the same. The following table shows the most frequently mentioned symptoms in each country. Breathlessness is the symptom respondents are most commonly aware of in fifteen countries, with general or unspecified coughing emerging more frequently in the other six.

Country	Most frequently mentioned	Second most frequently mentioned	Third most frequently mentioned
Argentina	Breathlessness (31%)	A cough (26%)	Tiredness or lack of energy (12%)
Australia	Breathlessness (53%)	A cough (37%)	Coughing blood (32%)
Bulgaria	Breathlessness (50%)	Coughing blood (37%)	A cough that gets worse (30%)
Canada	Breathlessness (49%)	A cough (45%)	Coughing blood (20%)
Denmark	Breathlessness (51%)	A cough (48%)	An ache or pain when coughing or breathing (20%)
Egypt	Breathlessness (25%)	Persistent chest infections (23%)	A cough (15%)
France	A cough (54%)	Breathlessness (37%)	A cough that doesn't go away (25%)
Germany	Breathlessness (36%)	Coughing blood (34%)	A cough that doesn't go away (31%)
Great Britain	Breathlessness (46%)	A cough (43%)	Coughing blood (27%)
Ireland	Breathlessness (56%)	A cough (56%)	Coughing blood (27%)
Italy	Breathlessness (42%)	A cough that doesn't go away (32%)	A cough (29%)
Japan	A cough (50%)	Breathlessness (22%)	A cough that doesn't go away (21%)
Mexico	A cough (33%)	Breathlessness (27%)	An ache or pain when coughing or breathing (10%)
Netherlands	Breathlessness (45%)	A cough (45%)	Tiredness or lack of energy (13%)
Norway	Breathlessness (47%)	A cough (40%)	Chest and/or shoulder pains (9%)
Portugal	Breathlessness (35%)	A cough (33%)	Tiredness or lack of energy (18%)
Slovenia	A cough (52%)	Breathlessness (31%)	Coughing blood (10%)
Spain	A cough (29%)	Breathlessness (25%)	Tiredness or lack of energy (20%)
Sweden	A cough (46%)	Breathlessness (42%)	Tiredness or lack of energy (10%)
Switzerland	A cough (53%)	Breathlessness (43%)	An ache or pain when coughing or breathing (12%)
USA	Breathlessness (38%)	A cough (37%)	Coughing blood (14%)

When analysing the mean number of potential symptoms of lung cancer mentioned in each country depending on whether respondents are current smokers, former smokers, or have never smoked at all, awareness appears to be fairly consistent. Please note that people who said that they did not know any symptoms have been excluded from this analysis. The following table highlights within each country which of the three groups has the highest mean score (i.e. the most mentions of symptoms per respondent). The key finding from this is that current smokers often mention fewer symptoms of lung cancer than former smokers or people who have never smoked. In three countries (France, Ireland and Portugal), current smokers do appear to have a greater awareness of potential symptoms, whilst in Sweden, current and former smokers have the same mean score.

Mean number of mentions of symptoms of lung cancer per respondent (who named at least one symptom)
Country	Current smokers	Former smokers	Never smokers
Argentina	1.97	1.97	2.11
Australia	2.04	2.47	2.28
Bulgaria	3.63	4.18	3.97
Canada	2.57	2.53	2.77
Denmark	2.39	2.34	2.43
Egypt	3.09	3.32	3.32
France	2.54	2.53	2.40
Germany	3.02	3.66	3.69
Great Britain	2.77	2.89	2.75
Ireland	3.21	2.99	2.94
Italy	2.46	2.53	2.43
Japan	2.41	2.55	2.67
Mexico	1.98	1.84	2.00
Netherlands	1.99	2.19	2.24
Norway	1.86	2.14	2.18
Portugal	2.61	2.54	2.43
Slovenia	2.35	2.46	2.16
Spain	2.13	2.30	2.13
Sweden	1.98	1.98	1.89
Switzerland	1.94	2.31	2.23
USA	1.93	1.97	2.01

[1] A pre-coded list was provided for interviewers to code responses. Respondents were able to code multiple responses. [2] Please note that at this stage the findings are based on interim data. [3] The base sizes in each country were as follows: Argentina (500), Australia (1,000), Bulgaria (1,148), Canada (1,005), Denmark (650), Egypt (1,009), France (953), Germany (1,073), Great Britain (957), Ireland (1,000), Italy (510), Japan (1,204), Mexico (600), Norway (529), Portugal (1,203), Slovenia (580), Spain (500), Sweden (550), Switzerland (510), the Netherlands (1,004), and the USA (1,000) [4] The lowest age for each country is as follows: Germany: 14 years; Australia, Ireland, Mexico and Norway: 15 years; Sweden: 17 years; Egypt and Japan: 20 years; all other countries: 18 years. [5] Computer Assisted Telephone Interviewing

Abstract

Abstract
Lung Cancer Public Information Campaign – Striving to Ensure Earlier Lung Cancer Diagnosis Jesme Fox, Medical Director, Roy Castle Lung Cancer Foundation, UK. ________________________________________________________________________ Background Despite recent advances, lung cancer remains a disease characterized by late diagnosis and poor outcomes. Diagnosing more lung cancer patients, at an early stage, when curative treatments are an option, will save lives. In recent years, there has been a focus on lung cancer screening. In countries where lung cancer screening is available, high risk individuals are being directed to these services. In other counties, advocates are calling for further research to evaluate the benefit of screening tools. Raising general public awareness of the signs and symptoms associated with lung cancer is of importance in the pursuit of earlier diagnosis. It is a key function of many advocacy groups working in the lung cancer field. With the variety of associated signs and symptoms, this is a difficult area. Using nationally agreed guidelines, advocacy groups have produced information, such as the GLCC awareness raising leaflets, available for download, in 13 languages [1]. As noted in a 2013 survey, undertaken by Public Health England, [2], 40% of people surveyed were unaware that a persistent cough could be a symptom of lung cancer.. Challenges Much negativity surrounds lung cancer and impacts on effective campaigning. Lung cancer is seen as a ‘depressing story’ and it is often difficult to engage the media. The notion of ‘self infliction’ surrounding this disease, adds to this difficulty. Furthermore, the stigma and blame associated with lung cancer is in itself, a contributing factor to late presentation in this disease [3, 4, 5,]. Stigmatisation has a very negative impact on the disease and on advocacy initiatives. Central to the lung cancer advocacy community is its focus on reducing the stigma associated with this disease. Many diseases are life style related, yet are not impacted in this way. It is important that whilst undertaking awareness campaigns, the messages of ‘no one deserves lung cancer’ and ‘smoker, former smoker or never smoker – anyone can get lung cancer’ are distributed widely. Public awareness raising campaigns in lung cancer Much of the awareness campaigning to date has come from the emerging Lung Cancer Patient Advocacy movement. Sadly, with poor survival, the number of lung cancer advocates and advocacy groups is relatively small, as compared with other common cancers. However, a key focus has been the November, ‘Lung Cancer Awareness Month’ initiative, initially developed in the US, by the Alliance for Lung Cancer Advocacy, Support and Education (now the Lung Cancer Alliance) and adopted by the global community, through the Global Lung Cancer Coalition, in 2001. The campaign aims to raise awareness of the signs and symptoms associated with lung cancer, change public perceptions and help to de-stigmatize this disease. An early example of this was the 2002 general public and media campaign, organized in the UK by the Roy Castle Lung Cancer Foundation and Macmillan Cancer Relief [6]. In recent years, the cross country initiative, involving Australia, Egypt and the US, being the ‘Shine a Light on Lung Cancer’ campaign, originally developed by Lung Cancer Alliance [7]. Other campaigns, from across the globe, will be described. In the UK, we have seen a number of general public lung cancer awareness raising initiatives, through the National Awareness and Early Diagnosis Initiative (NAEDI). We have also seen local campaigns such as the ‘’Doncaster Cough Campaign’’ [8] – in the 11 GP surgeries studied, after its first year (2008), noted, 19% of lung cancers diagnosed in Stage I and II, an increase from 11% in the previous year. We have also seen centrally, government funded campaigns. In England, the Department of Health, in 2012, funded the national ‘Be Clear on Cancer – Lung Cancer’ campaign [9]. This campaign, focusing on ‘’persistent cough’’ and results from the pilot study noted a 22% increase in the number of patients who visited their General Practitioner with relevant symptoms and also noted an increase in Chest CTscans being performed. This campaign has been repeated in the summer of 2013. In Scotland, the ‘Detect Cancer Early’ campaign is developing a national lung cancer component. References GLCC website (lung cancer signs and symptoms awareness leaflets, for download) http://www.lungcancercoalition.org/en/download-our-awareness-leaflet Online omnibus survey for Public Health England, conducted with representative sample of 1045 adults, between 7 and 10 June 2013 by TNS BMRB. http://www.gov.uk/government/news/don’t-ignore-a-persistent-cough-warns-lung-cancer-campaign Corner, J., J. Hopkinson, and L. Roffe, Experience of health changes and reasons for delay in seeking care: A UK study of the months prior to the diagnosis of lung cancer. Social Science and Medicine, 2006. 62: p. 1381-1391. Tod, A.M., J. Craven, and P. Alllmark, Diagnostic delay in lung cancer: a qualitative study Journal of Advanced Nursing 2008. 61(3): p. 336-343. Corner, J., et al., Is late diagnosis of lung cancer inevitable? Interview study of patients recollections of symptoms before diagnosis. Thorax, 2005. 60: p. 314-319. Baird J. Raising the Public Profile of Lung Cancer – Report of a National Lung Cancer Awareness Campaign in the UK. Lung Cancer (2003) 42, 119-123. Lung Cancer Alliance – Shine a Light campaign http://www.lungcanceralliance.org/shinealightonlungcancer/ Athey, U.L., Suckling R.J, Tod, A.M, Walters, S.J, Rogers, T.K, Thorax, 2012. May: 67(5); 412-7. Early diagnosis of lung cancer : evaluation of a community based social marketing intervention. Be Clear on Cancer – Lung Cancer campaign http://www.campaigns.dh.gov.uk/category/beclearoncancer/

Abstract
Background: In Japan and Asian countries, patient advocacy has not been popular to citizens and government, especially in patients with lung cancer compared to USA and EU countries. Therefore, a few clinicians had played a role as advocate instead of cancer survivors group or governments. Clinicians as advocates have a certain advantage to give professional information by themselves, with trained communication skill about bad news, and to use medical resources which is involved to medical society for lung cancer or hospital. West Japan Oncology Group (WJOG), non-profit organization which was established in 2000 by volunteer oncologists, has the mission to conduct and support multi-center clinical co-operative study for cancer and to provide the information about lung cancer, the importance and necessity of clinical study for standard treatment widely, therefore to contribute improving social welfare. Methods: To achieve the mission of WJOG, we carried out open lecture in city hall in major city every year and published lecture recordings in newspaper as well DVD video distribution. In another way, we planed to publish the guideline book for the patients with lung cancer and revised in five years interval. The board of directors determined the plan and the guideline editors committee was organized by WJOG member in March, 2006. The committee edited constitution, drafting, plan, writing as an enterprise in 2006, and 2011. Questions and answers style was adopted in accordance to previous US guidebook . Results: In these 12 years, 27 times of open lecture were held and medical specialists for oncology, novelists with cancer, representative or president of organization for patients advocacy, and etc gave lecture and discussed with patients. Nearly two to eight hundred people had participated in each meeting, occupied by most women and senior citizens. The questionnaire survey to participant revealed satisfaction for lecture and expectation for next meeting. The contents of lecture appeared full page in the Asahi which has a large circulation of almost 8 million (the second position in the world) as well as DVD-video was distributed widely to institute participating to our study and patients for the purpose of providing larger citizens with useful information. Furthermore WJOG official web site show the detail of each lecture in Japanese because Japanese patients with lung cancer are old and difficult to read English web site. Last year, second edition guideline book for patients was edited which consists of 118 questions and answers with full color 200 pages, as well posted to the WJOG website. GLCC international quantitative survey in 2010 showed that Japan is one of the countries with the greatest proportion of adults who think lung cancer is the biggest killer Conclusions: It seems that patient advocacy is developed to be more popular through open lecture, newspaper, web site and guideline book even in Japan. This method may be one of the ways to raise public awareness of lung cancer in Asian countries.

Abstract
Working with survivors is the foundation for every one of our programs at Lung Cancer Alliance. We examined the past nine years and the varying degrees of success of each of our initiatives based on the engagement of survivors to accomplish our goals. We will discuss the ways in which survivors join our movement and the various ways in which advocacy can help them during their journey with lung cancer.

Abstract
Background There is evidence from a variety of sources that lung cancer outcomes in the UK are worse than in many other parts of the developed world [1,2]. Part of this ‘survival gap’ can be explained by late diagnosis as evidenced by an excess of deaths within the first few months of diagnosis [3] and a high rate of patients (~40%) being first diagnosed during emergency hospital admissions [4]. However stage-for-stage survival is also worse in the UK [2], surgical resection rates are [5] and there is a clear relationship between these rates and survival [6].Methods The National Lung Cancer Audit (NLCA) had its first full year of data collection in 2005. Its aim was to collect a core dataset of around 140 items on all patients newly diagnosed and with lung cancer and mesothelioma in all hospitals in England expanding to cover the entire UK from 2008. Data is collected by the Multi-disciplinary teams and entered onto a secure national database. As of May 2013 there are almost 220,000 patient records for England alone in the database and all hospitals in the UK regularly report data for their patients. Annual reports contain a wide range of indicators including: numbers of patients diagnosed; treatment rates for surgery, chemotherapy and radiotherapy, case mix factors such as age, stage, performance status, co-morbidity and socio-economic status. Median and one-year survival rates are also reported. Data are presented both in terms of crude percentages and case-mix adjusted odds ratios. These reports, including the identification of hospitals, are available to the public. The programme has been backed up by a series of meetings with hospital teams to identify their particular strengths and weaknesses, to support them in service improvement and to share examples of best practice.Results The table below shows some examples of data completeness and the ‘headline indicators’ from England and Wales between 2005 and 2011 (the latest period for which data are available). It will be seen that data quality and completeness has improved as have all the process and outcome indicators.Figure 1 We have demonstrated that there is wide variation in treatment and survival within the UK [7,8]. One of the most dramatic and important impacts of the audit has been the realisation of just how low surgical resection rates were in some parts of the UK and that this was related to a serious shortage of specialist thoracic surgeons in many areas [9]. The number of thoracic surgeons has almost doubled since the publication of the first audit report and the overall resection rate has increased by almost 50%. In addition, we have many examples of where local practice and service configuration have been significantly improved as a result of this process. We are now assessing the extent to which these changes have been translated into improvements in survival. The Roy Castle Lung Cancer Foundation has developed a web-based system called the ‘Lung Cancer Smart Map’ [10] which allows patients to search how treatment in their area compares both with other hospitals and against national standards. Patient empowerment of this sort is potentially one of the most effective ways to drive up standards of care.Conclusions In summary, we have demonstrated that population-based data collection is feasible and as a result, the NLCA database is one of the largest and most detailed lung cancer databases in the world. The regular feedback and support that we have given to clinical teams and to patients has had a significant impact on the quality of care for patients in the UK and is now incorporated into our Cancer registration systems, with its potential value being enhanced by linkage to a wide variety of other data sources.References 1. Lung cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the United Kingdom: a population-based study, 2004-2007. Walters S, Maringe C, Coleman MP, et al. Thorax, 2013;68:551-564 2. Coleman MP, Forman D, Bryant H, et al.; ICBP Module 1 Working Group. Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995-2007 (the International Cancer Benchmarking Partnership): an analysis of population-based cancer registry data. Lancet,2011;377:127–138 3. National comparisons of lung cancer survival in England, Norway and Sweden 2001- 2004: differences occur early in follow-up Holmberg L, Sandin F, Bray F, et al. Thorax, 2010;65:436-441. 4. Elliss-Brookes L, McPhail S, Ives A, et al. Routes to diagnosis for cancer – determining the patient journey using multiple routine data sets. Br J Cancer 2012;107(8):1220-6. 5. Recent trends in resection rates among non-small cell lung cancer patients in England. Riaz SP, Linklater KM, Page R, et al. Thorax, 2012;67(9):811-4. 6. Variation in radical resection for lung cancer in relation to survival: population-based study in England 2004-2006. Riaz SP, Lüchtenborg M, Jack R, et al.Eur J Cancer 2012;48:54-60 7. Exploring Variations in Lung Cancer Care Across the UK - The “Story So Far” for the National Lung Cancer Audit. P Beckett, I Woolhouse, R A Stanley, M D Peake. Clinical Medicine, 2012; 12:4-8 8. Health & Social Care Information Centre. The National Lung Cancer Audit Report 2012. Available at: https://catalogue.ic.nhs.uk/publications/clinical/lung/nati-clin-audi-supp-prog-lung-canc-coho-2011/clin-audi-supp-prog-lung-nlca-lap-2012-rep.pdf 9. The effects of increased provision of Thoracic Surgical Specialists on the variation in lung cancer resection rate in England. Lau KK, Rathinam S, Waller DA & Peake M.D. J Thoracic Oncology, 2013;8(1):68-72 10. Lung Cancer Smart Map, available at: www.roycastle.org/lungcancermap

Abstract
At its strategic review in September 2011 the IASLC undertook a thorough overall of its existing committee structure. As the membership of the organisation expanded and its influence globally was increasing it was felt that it was appropriate for the organisation to move beyond its traditional scientific and educational roles to embrace fundamentally important aspects of care such as advocacy, the involvement of nurses and allied professionals and tackling the scourge of tobacco dependency. There were already several established advocacy organisations, especially in North America, the UK and Australia. Our aim was not to compete but to network with these bodies to ensure that advocacy issues were included in the discussions of every one of our other committees and at every educational activity organised by the IASLC and its partners. We are thus delighted that at this World Conference, the first since our committee was established, we have high profile sessions such as this, in collaboration with the Global Lung Cancer Coalition, and those held yesterday, organised by the Australian Lung Foundation and other partners. From 2015 our World Conferences will be held annually and our programme of regional meetings in Europe, Asia, North and South America will continue. We hope that the IASLC meetings and our journal, the Journal of Thoracic Oncology, will be seen as the appropriate platform for issues such as patient advocacy, specialist nurse care, smoking cessation and tobacco control to be aired. The members of the IASLC are specialists in every research and clinical care aspect of thoracic oncology, working to improve the outcomes for lung cancer and other thoracic malignancies. You, the advocates, are our link to patients who need, deserve and demand better care. Let us work together to the benefit our patients.

Background
Integration of the proposed IASLC classification of adenocarcinomas (ACA) into TNM staging has been challenging for pathologists. Until recently, at Swedish, we staged patients per the AJCC staging and separately described lesions with a BAC component placing them into 3 groups based on the percent of ACA invasion. But, we found this was not a good predictor of survival. We aimed to more clearly define this population by comparing patients reclassified according to the proposed IASLC classification and the AJCC 7[th] edition staging to determine if they could be integrated as a single staging system.

Methods
We retrospectively reviewed patients with BAC from 2000-2012 and classified them according to the IASLC classification as ACA in situ (AIS), minimally invasive ACA (MIA) or lepidic predominant ACA (LPA) and according to the AJCC 7[th] edition staging (stage I, II or III). We then reclassified these patients separating AIS and MIA as stage 0 in the AJCC 7[th] edition staging.

Results
We evaluated 145 consecutive patients with a median follow-up of 30 months. Using IASLC [AIS (N=23), MIA (N=18), LPA (N=104)]; local recurrence rates were: AIS (4%), MIA (11%) and LPA (2%). Regional (8%) and distant (10%) recurrences were only with LPA. Disease-free survival in patients with AIS (96%) and MIA (89%) was higher versus patients with LPA (80%). Five year cancer-specific survival was 100% for patients with AIS and MIA while it was 84% for LPA patients. Using AJCC 7[th] edition [I (N=125), II (N=12), III (N=8)]; recurrence rates were local: stage I (3%), stage III (13%). Regional: stage I (5%), stage II (8%), stage III (13%); and distant: stage I (6%), stage II (17%), stage III (13%). Stage I disease-free survival was 86%, stage II 75% and stage III 61%. Five year cancer-specific survival was stage I 90%, stage II 81% and stage III 60%. Separating AIS and MIA as stage 0 [0 (N=42), I (N=84), II (N=11), III (N=8)]; local recurrence rates were: stage 0 (7%), stage I (1%), stage III (13%). Regional: stage I (7%), stage II (9%), stage III (13%); and distant: stage I (10%), stage II (18%), stage III (13%). Disease-free survival was higher in stage 0 (93%) compared to stage I (82%), stage II (73%) and stage III (61%). Five year cancer-specific survival was 100% for stage 0, while it was lower for stage I 84%, stage II 80%, and stage III 60%, p<0.05.

Conclusion
The IASLC/ATS/ESR classification system appears to better discriminate patients with BAC compared to current AJCC staging. The results also suggest that patients with AIS and MIA may be classified as stage 0 in the AJCC staging system based on favorable outcomes and survival.

Background
The purpose of this study is to validate the prognostic impact and the frequency of EGFR mutation in lung adenocarcinoma of Japanese patients based on new lung adenocarcinoma classification proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS).

Methods
We reclassified 486 adenocarcinomas according to the new classification. The percentage of each histopathological subtype and the predominant pattern were determined. EGFR mutation also was investigated 241 of 486 adenocarcinomas. The relationship between these results and clinicopathological backgrounds was investigated statistically.

Results
The histopathological assessment according to the IASLC/ATS/ERS classification showed that 8.4% (n = 41) of the cases were adenocarcinoma in situ (AIS) ; 9.2% (n = 45) were minimally invasive adenocarcinoma (MIA) ; 18.3% (n = 89) were lepidic predominant ; 20.4% (n = 99) were acinar predominant ; 28.0% (n = 136) were papillary predominant ; 10.5% (n = 51) were solid predominant ; 2.3% (n=11) were micropapillary (MP) predominant, and 2.9% (n=14) were invasive mucinous adenocarcinoma (IMA). In univariate analysis, the patients with AIS and MIA subtypes had neither recurrence nor death within the follow-up periods. This was followed by the patients with lepidic predominant. The patients with papillary predominant, those with acinar predominant and those with IMA showed almost similar disease-free survival. The patients with solid predominant and MP predominant showed worse disease-free survival (Figure). Multivariate analysis showed that the new classification was an independent predictor of disease-free survival (Hazards ratio: 2.59; 95% confidence interval: 1.69-3.96; p<0.001). EGFR mutation was detected in 131 of 241 adenocarcinomas (54.4%). The each prevalence of EGFR mutation of AIS/MIA/Lepidic/Papillary/Acinar/Solid/MP/IMA was 62.1%/60%/77.1%/50%/49%/27.8%/42.9%/0%.Figure 1

Conclusion
The new IASLC/ATS/ERS adenocarcinoma classification is very useful predictive marker to plan and determine a therapeutic strategy for lung adenocarcinoma.

Background
In 2011, the IASLC/ATS/ERS proposed a new classification for lung adenocarcinoma (ADC) that has powerful prognostic value. However, tumors in each subtype may still include heterogeneous prognostic subgroups - especially in the acinar, papillary, and solid subtypes, in which the majority of tumors are classified. Recently, immune markers such as CD markers and cytokines have been identified as prognostic factors in lung cancer. In this study, we investigate whether tumor budding further stratifies prognosis for stage I lung ADC, independent of the IASLC/ATS/ERS classification, and whether it correlates with prognostic immune markers.

Methods
All available tumor slides from patients with therapy-naive, surgically resected solitary stage I lung ADC (1995-2009) were reviewed (n=1038). Tumors were classified according to the IASLC/ATS/ERS classification. Mitoses were counted at 10 high-power fields (HPFs) (x400 magnification). Tumor budding (tumor nest composed of <5 cells) was assessed, at 10 HPFs (x200 magnification), in areas with the smallest tumor nests and was graded by the maximum number of budding : 0, 0/HPF; 1, 1-4/HPF; 2, 5-9/HPF, and 3, ≥10/HPF. Tissue microarrays were constructed from tumoral and stromal cores, and immunostaining for CD3, FoxP3, IL-7R, and IL-12Rβ2 was performed. Lymphocytes positive for CD3 and FoxP3 were scored in tumor and stroma, and tumors were classified using our recently reported FoxP3/CD3 risk index (JCO 2013). Tumoral expression of IL-7R and IL-12Rβ2 was dichotomized by the sum of intensity (0-3) and distribution (1, 1%-50%; 2, >50%) scores: negative (total score <1) and positive (≥1). Recurrence-free probability (RFP) was estimated using the Kaplan-Meier method; multivariate analyses were performed using the Cox proportional hazards model.

Results
RFP was lowest for patients with budding grade 3 (n=180; 5-year RFP, 69%; p<0.001), followed by grade 2 (n=139; 75%), 1 (n=189; 81%), and 0 (n=530; 89%). Budding grade was dichotomized into negative (grades 0-1) or positive (grades 2-3) using colorectal cancer criteria. The RFP for patients with positive budding (n=319; 5-year RFP, 72%) was significantly lower than that for patients with negative budding (n=719; 87%; p<0.001), which was confirmed in a subgroup analysis limited to stage IA (p=0.004) and IB (p<0.001) patients. Tumor budding further stratified RFP in patients with acinar (p<0.001), papillary (p=0.027), and solid (p=0.015) tumors. Budding was more frequently observed in tumors with high-grade histology (solid and micropapillary; p<0.001), lymphovascular invasion (p<0.001), and high mitotic count (p<0.001). Tumor budding was positively correlated with stromal CD3+ lymphocytes (p<0.001), stromal FoxP3+ (p<0.001), FoxP3/CD3 risk index (high FoxP3, low CD3) in stroma (p<0.001), and tumoral IL-7R expression (p<0.001). In multivariate analysis, tumor budding was an independent prognostic factor for recurrence (HR=1.13; p=0.002).

Conclusion
Tumor budding was a significant prognostic factor in stage I lung ADC, independent of IASLC/ATS/ERS classification, and it correlated with a protumor immune microenvironment (high FoxP3+ lymphocyte infiltration and high IL-7R expression). These findings may inform therapeutic decisions and stratify patients for additional therapy, including immunotherapy.

Background
Currently, non-small cell lung carcinomas (NSCLCs) are mainly classified by histologic analysis and mucin staining: (1) squamous cell carcinoma (SCC) shows keratinization and intercellular bridges; (2) adenocarcinoma shows lepidic, acinar, papillary, micropapillary, or solid pattern, with mucin production; and (3) large cell carcinoma lacks these findings. However, recent studies have shown promising improvements in the classification of NSCLC with immunostain-based markers, including p40 and thyroid transcription factor–1 (TTF-1). In this study, we investigate the use of immunohistochemical analysis in reclassifying NSCLCs originally diagnosed as SCCs.

Methods
All available tumor slides from patients with therapy-naive, surgically resected solitary NSCLCs originally diagnosed as SCC (1999-2009) were reviewed. Tissue microarrays were constructed with 3 cores (n=480), and immunostaining for p40, p63, TTF-1 (clone 8G7G3/1), TTF-1 (SPT24), napsin A, chromogranin A, synaptophysin, and CD56 was performed. Immunoreactivity was scored semiquantitatively by staining intensity (weak, moderate, or strong) and percentage of positive tumor cells (diffuse, ≥50%; focal, <50%). Tumors were first grouped by p40 and TTF-1 (8G7G3/1) status: (1) group A (favor SCC): p40 (+) and TTF-1 (8G7G3/1) (-); (2) group B (favor adenocarcinoma): p40 (- or +) and TTF-1 (8G7G3/1) (+); and (3) group C (favor large cell carcinoma): p40 (-) and TTF-1 (8G7G3/1) (-). Immunostain-based tumor classification was then confirmed with histologic findings and other markers.

Results
In group A (n=448), 1 tumor was reclassified as adenosquamous carcinoma by histologic findings and focal immunoreactivity for p40, p63, and TTF-1 (SPT24). In group B (n=15), 2 tumors were reclassified as large cell neuroendocrine carcinoma (LCNEC) by neuroendocrine morphologic findings and differentiation (1 as pure LCNEC and the other as combined LCNEC with SCC). In group C (n=17), 6 tumors were confirmed as large cell carcinoma because they lacked adenocarcinoma morphology and TTF-1 [SPT24] expression (2 of these showed focal p63 reactivity without keratinization); 4 were reclassified as large cell carcinoma (favor adenocarcinoma) because they were focally positive for TTF-1 (SPT24) but negative for TTF-1 (8G7G3/1) and napsin A; 2 were reclassified as adenocarcinoma because they were diffusely and strongly positive for TTF-1 (SPT24) but focally (<10%) positive for p63, without keratinization; 3 were reclassified as LCNEC by neuroendocrine morphologic findings and differentiation; and 2 were reclassified as small cell carcinoma by morphologic findings. All tumors finally diagnosed as SCC (n=447) using histologic findings and immunohistochemical analysis were positive for p40 and p63. Among them, 27 tumors were positive for TTF-1 (SPT24) (19 focally and 8 diffusely) but negative for TTF-1 (8G7G3/1), with all showing clear squamous morphologic pattern, thus verifying the greater specificity of the TTF-1 8G7G3/1 clone in SCC.

Conclusion
After immunohistochemical reevaluation of 480 NSCLCs originally diagnosed as SCC by classical morphologic analysis, 33 (7%) were reclassified as other histologic types. Immunohistochemical analysis may provide additional valuable information to achieve an accurate diagnosis, particularly in poorly differentiated NSCLCs and in tumors for which the diagnosis of nonkeratinizing SCC is considered.

Abstract not provided

Background
Rapid on site examination (ROSE) is encouraged at EBUS-TBNA to improve the yield of this procedure. However, many centres do not have the resources to meet this demand. Due to new therapeutic options in lung cancer, it is not sufficient to merely distinguish between non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC). Immunohistochemistry (IHC) distinction where possible is now standard practice, as well additional molecular testing where clinically indicated. We investigated the diagnostic yield of smears vs. cell block and the provision of cellular material for ancillary testing.

Methods
A retrospective audit of all EBUS-TBNA procedures performed until the end of July 2012 was undertaken. Diagnostic yield on smears versus cell block was recorded. Cell blocks were reviewed by an experienced pathologist to determine diagnostic accuracy and whether IHC and molecular testing were possible.

Results
208 procedures were recorded with 101(48.5%) malignant cases, 81(38.9%) benign cases and 26(12.5%) with insufficient sampling. The average number of passes was 4.5. For malignancies, smear diagnosis was possible in 95% of cases and cell block diagnosis in 93.5% (87/93) of cases. There was sufficient material for IHC in 97.7% (85/87) of malignant cases where required. In 79.3% (69/87) of NSCLCs molecular testing was theoretically possible based on the tumour load of samples obtained.

Conclusion
Cell blocks are not inferior to smears for diagnostic accuracy and provide sufficient samples for ancillary testing. However, ROSE assists the physician on how best to manage samples for ancillary testing.

Background
ALK gene rearrangement defines a new molecular subtype of NSCLC with response to Crizotinib, (Xalkori®) a dual MET and ALK inhibitor. To date, determination of ALK gene rearrangements has been performed in biopsies and/or surgical specimens. However, advanced lung cancer is often diagnosed by FNA cytology obtained through minimally invasive procedures, and frequently cytological specimens are the only samples available. We assessed the feasibility of determining ALK gene rearrangements in cytological samples.

Methods
We studied prospectively 53 cytological samples from 53 NSCLC patients (30 M/23 F) for ALK gene rearrangements by FISH (Abbot dual colour break apart probe). Tumour samples were obtained by bronchoscopy -FNA in 26 cases (49.1%), EBUS-FNA in 7 (13.2%), EUS-FNA in 3 cases (5.7%), CT-FNA in 3 (5.7%), and direct FNA in 6 cases (11.3%). Two cavity fluids (3.8%), 4 imprints from surgical specimens (7.5%), and 2 cellblocks received for consultation (3.8%) were also studied. FISH was performed on Papanicolau stained smears in 15 cases (28.3%), non-stained ThinPrep in 28 cases (52.8%), cell block in 9 cases (17%), and 1 stained ThinPrep. All cases were tested for EGFR and KRAS mutations.

Results
Thirty-seven samples (69.8%) were adequate for FISH analysis. Three cases (8.1%) had ALK gene rearrangements: positive cases were non-smoker women with adenocarcinoma, two of them with signet ring cells. One case had a concurrent EGFR mutation in exon 21. FISH study was unsuccessful in 16 cases (30.2%): 10 from Papanicolau stained smears (62.5%), 5 from unstained ThinPrep (31.3%), and 1 from a cell block. Nineteen ThinPrep slides were adequate for FISH analysis (86.4%) as well as 8 out of 9 cell blocks. Correlation cytological / paraffin embedded samples was performed in 4 cases with a concordance rate of 100%.

Conclusion
Determination of ALK gene rearrangements in cytological specimens is feasible. It is mandatory an exquisite management and care of the samples to preserve quality. ThinPrep and cell blocks are the most suitable samples for FISH analysis, while Papanicolau stained smears provide poor results. Coexistence of ALK gene rearrangements and EGFR mutations was observed in one case, indicating that such alterations are not necessarily mutually exclusive.

Background
Activating mutations in the epidermal growth factor receptor (EGFR) confer sensitivity to gefitinib and erlotinib in patients with NSCLC. However, response is often short-lived, and patients ultimately relapse, indicating that other concomitant actionable mutations could influence outcome in these patients. The EML4-ALK fusion gene has recently been identified in a subset of NSCLCs, but its specific role remains unclear. We have evaluated the frequency and impact of the concomitant presence of EML4-ALK in patients included in the randomized phase III EURTAC trial.

Methods
The EURTAC study enrolled 173 EGFR-mutant NSCLC patients who were randomized to receive erlotinib or standard chemotherapy with cisplatin or carboplatin plus docetaxel or gemcitabine. Tumor specimens were available from 95 of these patients for the analysis of EML4-ALK. EML4-ALK variants 1 and 3 (v1, v3) were analyzed by an independent single round of PCR followed by sequencing, using cDNA as a sample.

Results
EML4-ALK was detected in 15 samples (15.79%). Nine tumors contained v1 (E13;A20) and six v3 (E6;A20). No significant differences were found in baseline characteristics between patients with and without EML4-ALK. Progression-free survival was 10.4 months (m) for patients harboring the EML4-ALK fusion gene compared to 7.1 m for those without EML4-ALK. Overall survival (OS) was not reached in patients with EML4-ALK, compared to 22.9 m in those without. Complete data on outcome according to treatment arm will be presented.

Conclusion
Our findings indicate that the EML4-ALK rearrangement is concomitant with EGFR mutations in a considerable number of NSCLC patients and may affect outcome.

Background
Stromal cells, including macrophages, lymphocytes and fibroblasts, are known to interact with cancer cells and to produce a specific microenvironment capable of influencing tumor progression. Tumor-associated macrophages (TAMs) are recruited into cancer-induced stroma and produce a specific microenvironment for cancer progression. CD204 positive TAMs are reportedly related to tumor progression and clinical outcome in some tumors. The aim of this study was to clarify the correlation between CD204 positive TAMs and the clinicopathological features of lung squamous cell carcinoma.

Methods
We investigated the relationships between the numbers of CD204 positive TAMs and clinicopathological factors, microvessel density (MVD), and the numbers of Foxp3 positive lymphocytes in 208 consecutively resected cases. We also examined the relationships between the numbers of CD204 positive TAMs and the expression levels of cytokines involved in the migration and differentiation of CD204 positive TAMs.

Results
A high number of CD204 positive TAMs in the stroma was significantly correlated with an advanced p-stage, T factor, N factor, and the presence of vascular and pleural invasion. A high number of CD204 positive TAMs in the stroma was also a significant prognostic factor for all p-stages and p-stage I. Moreover, the numbers of CD204 positive TAMs were correlated with the MVD and the numbers of Foxp3 positive lymphocytes. A high number of CD204 positive TAMs was strongly correlated with the tissue expression level of MCP-1. CD204 positive TAMs were shown to be significant independent prognostic factors in a multivariate analysis.

Conclusion
CD204 positive TAMs were an independent prognostic factor in lung squamous cell carcinoma. CD204 positive TAMs, along with other tumor-promoting stromal cells such as regulatory T cells and endothelial cells, may create tumor-promoting microenvironments.

Abstract not provided

Background
We investigated blood vessel invasion (BVI) as a possible negative prognostic factor in patients with stage I non-small cell lung cancer (NSCLC) according to the 7[th] Edition of the TNM classification.

Methods
Between 1999 and 2007, a total of 694 consecutive patients with pathological stage I NSCLC underwent complete resection with systematic lymph node dissection at Tokyo Medical University Hospital. All sections of the specimens were stained by Elastica van Gieson to visualize elastic fibers and were examined to determine the prognostic symptoms of BVI. We statistically analyzed the association between BVI and clinicopathologic factors, as well as clinical outcomes.

Results
BVI was detected in 201 patients with stage I NSCLC (29.0%). The 5-year overall survival (OS) rates of the non-BVI and BVI patients were 90.5% and 66.0%, respectively (p < 0.0001). BVI was found to be a significant independent prognostic factor by multivariate survival analysis in stage IA and stage IB NSCLC (HR 2.591, p < 0.001; HR 2.347, p = 0.009, respectively). The 5-year OS rate of patients with BVI was significantly worse than that of patients without BVI in the T1a (94.5% vs 87.5%, p < 0.0001), T1b (82.7% vs 65.9%, p = 0.034), and T2a (90.9% vs 61.8%, p < 0.0001) subgroups.

Conclusion
We identified the presence of BVI as an independent poor prognostic factor in patients with stage I NSCLC. In the future revision of the TNM staging system, the routine use of elastic fiber stains in pathological evaluations of lung cancer for BVI determination might be recommended, and tumors with BVI should be upstaged to the higher current T staging.

Background
In non-small cell lung cancer (NSCLC), visceral pleural invasion (VPI) is incorporated as a staging factor in the current TNM classification. Microscopic vessel invasion (MVI: defined collectively as histological blood vessel invasion and lymphatic permeation) has been reported to be a strong independent predictor of poor prognosis, but it has not been incorporated in the TNM classification. We assessed the prognostic significance of MVI as well as VPI.

Methods
Between August 1992 to December 2009, 2657 consecutive patients with pathological T1-4N0-2M0 NSCLC underwent complete resection at our institution. We analyzed the prognostic significance of MVI for recurrence in addition to the conventional prognostic factors. The recurrence-free proportion was estimated using the Kaplan-Meier method and differences were analyzed by the log-rank test. Cox regression analyses were used to identify independent risk factors for recurrence.

Results
The 5-year recurrence-free proportion for patients with or without MVI was 52.6% and 87.5%, respectively (p < 0.001). On multivariate analysis, MVI, similarly to VPI, was found to be an independently significant predictor of recurrence (HR 2.78). In 1601 patients with pathological stage I disease without adjuvant chemotherapy, MVI and VPI were the two strongest independent predictors of recurrence on multivariate analysis (HR 2.74 and 1.84, respectively). Evident and significant separation of the recurrence-free proportion curves among the following 3 groups according to the number of the two risk factors (VPI and MVI) was observed; both VPI and MVI absent (0), either VPI or MVI present (1), and both VPI and MVI present (2). We compared the recurrence-free proportion of patients stratified by tumor size and the number of the risk factors (0/1/2) (Table 1). The groups of small tumor size without PL and MVI showed the best recurrence-free proportions (T1a_0, T1b_0, and T2a_0). The T1a_1, T1b_1, and T2a_1 subgroups showed poorer outcomes which were comparable with the T2b_0 subgroup. The groups with both PL and MVI, even in small tumor size groups, resulted in poor outcomes equivalent to that of T3_0/1 groups. The T3_2 group showed the poorest outcome equivalent to the T4 group.

Conclusion
This study demonstrated that MVI was a significantly independent risk factor for recurrence in resected T1-4N0-2M0 NSCLC patients. We propose the T-classification of tumors with either MVI or VPI (1) should be upgraded to the next T level and that with both MVI and VPI (2) to the second T level (Table 1).

Table 1. Incorporation of PL and MVI into T classification Current (7th) T Classification Tumor Size (cm) No. of VPI and MVI Risk Factors Recurrence-free Proportion at 5 Years (%) OurProposalT T1a ≤ 2 0 92.2 T1 ≤ 2 1 72.2 T2 ≤ 2 2 58.2 T3 T1b > 2, ≤ 3 0 89.6 T1 > 2, ≤ 3 1 64.8 T2 > 2, ≤ 3 2 50.9 T3 T2a > 3, ≤ 5 0 87.8 T1 > 3, ≤ 5 1 61.9 T2 > 3, ≤ 5 2 44.8 T3 T2b > 5, ≤ 7 0 75.9 T2 > 5, ≤ 7 1 49.4 T3 > 5, ≤ 7 2 47.5 T3 T3 > 7 0 58.2 T3 > 7 1 50.6 T3 > 7 2 38.8 T4

Background
The distinction of intrapulmonary metastases from multiple primary tumors is of great clinical importance as it influences staging, prognosis and therapeutic strategy. Although Comprehensive Histologic Assessment (CHA) was recommended by International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) to differentiate multiple lung primary non-small cell carcinomas from metastases, the limitations of CHA have been addressed. Lung adenocarcinoma in situ is characterized by noninvasive lepidic growth. Whether this histological characteristic could be served for assessing primary lung cancer has not been well determined. In this study we evaluated the application value of CHA and lepidic growth component (LGC) in distinguishing multiple primary lung cancers from intrapulmonary metastases.

Methods
We retrospectively analyzed a cohort of 23 patients with 50 multiple lung tumors. All of the patients have follow up data. The histological evaluation was performed according to 2011 IASLC/ATS/ERS Classification of Lung Adenocarcinoma. The percentage of each tumor subtype in each case was recorded. The intrapulmonary metastases and multiple primary tumors were differentiated based on CHA and LGC (if applicable).

Results
According to CHA alone, there were 11 and 12 cases diagnosed as multiple primary tumors and intrapulmonary metastases, respectively. Disease-free interval (DFI) of the 11 patients with multiple primary tumors was ranged from 11 to 110 months and DFI of the 12 patients with intrapulmonary metastases was ranged from 1 to 93 months. There was no statistically significant difference between these two types of patients (P=0.362). According to CHA with inclusion of LGC, 15 and 8 cases were diagnosed as multiple primary tumors and intrapulmonary metastases, respectively. DFI of the 15 and 8 cases were ranged from 11 to 110 months and from 1 to 34 months, respectively. Statistical significance was detected (P=0.034). These results suggested that CHA combining with LGC might have assessment advantage to distinguish multiple primary tumors from intrapulmonary metastases compared to use CHA alone. Figure 1

Conclusion
The appearance of adenocarcinoma with LGC might indicate lung primaries. Combining with CHA, LGC could potentially improve diagnosis to differentiate multiple primary tumors and intrapulmonary metastases.

Background
The current IASLC/ERS/ATS classification of pulmonary adenocarcinoma indicates that different patterns of growth in adenocarcinoma are associated with prognostic value. There is however, very little information concerning histological prognostic markers in squamous cell carcinomas of the lung. In contrast to adenocarcinoma, squamous cell carcinoma is more homogeneous histologically. However, the World Health Organization classification of lung tumors recognizes different patterns of growth in squamous cell carcinomas. In this study we evaluated several histological parameters including growth patterns and nuclear features and their association with prognosis in a population of stage 1 squamous cell carcinomas.

Methods
A cohort of 165 stage I squamous cell carcinomas of the lung were evaluated. The presence of different histological growth patterns such as papillary, infiltrative, pushing borders, intraalveolar, pseudo-glandular, basaloid, small nest and presence of infiltrating single cells, as well as the cell type (clear cell, transitional, syncytial, and glassy) were evaluated in a semi- quantitative manner by recording the percent of each histological pattern or cell type with 10% increments totaling 100% for tumor. In addition, the presence of peripheral palisading, nuclear features (nuclei size, chromatin patterns, nuclear contour, presence of nucleoli, and mitotic figures), and keratinization were also evaluated. The association of predominant pattern of growth, cell type, and nuclear features with recurrence free survival (RFS), characterized by time to recurrence or death of disease and overall survival (OS) were evaluated.

Results
There were 66 women and 97 men in this population with a mean age of 75±9 year old. All patients were smokers. The mean follow-up was of 47.8 months (4 years). Among histological growth patterns, tumors with predominant papillary and pushing borders appear to have a slightly better outcome compared to other predominant patterns of growth (RFS p=0.05 and OS 0.025). It is interesting to note that squamous cell carcinomas with a predominant basaloid growth pattern, which is considered to be a pattern of poor differentiation, did not have worse prognosis copared to other features. There was no association of cell type, nuclear features, presence of palisading or keratinization with prognosis. There was no difference of nuclear features among tumors with different growth patterns and cell types.

Conclusion
Squamous cell carcinomas appear to be more homogeneous than adenocarcinomas of the lung despite some histological variances. Evaluation of several histological parameters like growth pattern, cell type, and nuclear features failed to indicate a strong association of any of these parameters with prognosis, with exception of papillary and pushing border growth patterns that when present as predominant patterns of growth were associated with a better prognosis. This suggests that contrary to adenocarcinoma, a histological based grading system may not be easily established for squamous cell carcinomas of the lung.

Abstract not provided

Abstract
The IASLC Staging Projects The International Association for the Study of Lung Cancer (IASLC) now has four staging projects. The first one, for lung cancer, originated during an international workshop on intrathoracic staging organized at the Royal Brompton Hospital, London, UK, in 1996. (1) It is an ongoing project with two phases: a retrospective phase, during which 81,495 analyzable lung cancer patients diagnosed between 1990 and 2000 were registered: 68,463 non-small cell lung cancers (NSCLC) and 13,032 small cell lung cancers (SCLC) (2); and a prospective phase, that includes 78,640 analyzable cases of NSCLC and 5,912 cases of SCLC diagnosed between 1999 and 2010. The retrospective database was used to revise the 6[th] edition of the tumour, node and metastases (TNM) classification and prepare for the 7[th] edition; (3, 4, 5) the data of the prospective phase will be used to inform the 8[th] edition of the TNM classification due to be published in 2016. This writer chairs the Lung Cancer Domain. In 2008, mesothelioma was incorporated into the activities of the IASLC Staging Project lead by Dr. Valerie Rusch as chair of the Mesothelioma Domain. As with lung cancer, a call was made to collect retrospective series from around the world and, at the same time, an online registration system was created for prospective collection of data. The retrospective mesothelioma database contains 3,101 surgically treated patients. This population was first analysed to assess the existing TNM classification and staging system for mesothelioma. (6) These analyses showed that more data are needed to refine the classification beyond what the retrospective database can do. In essence, more detailed data on the T, N and M descritpors is needed. The prospective collection of data is an ongoing project that collects surgically and non-surgically treated patients and is intended to inform the 8[th] edition of the TNM classification. In 2009, thymic malignancies were incorporated into the IASLC Staging and Prognostic Factors Committee (SPFC). So far, more than 10,000 retrospective cases have been collected and are now being analysed by the statistitians at Cancer Research And Biostatistics (CRAB), in Seattle, WA, USA. The main objective of these analyses is to establish a TNM classification for thymomas and thymic carcinomas. The Thymic Domain of the Committee is chaired by Dr. Frank Detterbeck. (7) Finally, also in 2009, oesophageal cancer was incorporated into the activities of the IASLC SPFC under the leadership of Dr. Tom Rice, who is the chair of the Oesophageal Cancer Domain of the SPFC. More than 10,000 cases are registered in a database stored and analysed at the Cleveland Clinic, Cleveland, OH, USA. The surgical cases were used to inform the 7[th] edition. Plans are made to analyse the non-surgical series and validate data to inform the 8[th] edition of the TNM classification. How to contribute Individuals, institutions, cooperative groups and proprietors of registries can contribute by submitting their databases directly to CRAB, provided their databases include the information that is essential for the IASLC Staging Projects, i.e. clinical and pathological data on the different T, N and M descriptors, treatment modality and survival. CRAB statisticians have to be informed about the characteristics of the databases to assess if they are useful for the project prior to submission. This is, indeed, the easiest way to contribute: to submit your database. CRAB accepts databases on lung cancer and mesothelioma. Databases of thymic malignancies can be submitted either to CRAB or to the International Thymic Malignancies Interest Group (ITMIG). ITMIG will assess the data and will forward the specific staging data to CRAB for analysis. Those wishing to contribute oesophageal cancer cases should get in touch with the chair of the Oesophageal Cancer Domain of the SPFC, Dr. Tom Rice, at the Cleveland Clinic, Cleveland, OH, USA. Contribution is best through the Worldwide Esophageal Cancer Collaboration (WECC). Those who want to contribute prospective cases can use the on-line registration system that CRAB has established for lung cancer and mesothelioma. There also is an on-line registration system for thymic tumours provided by the ITMIG. Submitting retrospective databases and on-line registration of prospective cases take time and may cost money. In order to facilitate grant application to those who need the assistance of a data manager, CRAB has prepared a document describing the project that can be used to complete the grant application forms. This document can be accessed through the IASLC website at www.iaslc.org. Go to ‘Staging’ and there you will find all the necessary information about the IASLC Staging Projects. Those who cannot participate submitting cases can participate analysing data not directly related to the main staging projects. An outline of the research project has to be sent to the Chair of the IASLC SPFC stating the objectives and the variables needed for the study. Approval will be granted based on the availability of data, the relevance of the project and the willingness of the applicant to pay for the CRAB statisticians’ work required for the extraction and analysis of data. (9) References 1. Goldstraw P. Report on the international workshop on intrathoracic staging, London, October 1996. Lung Cancer 1997;18:107-111. 2. Goldstraw P, Crowley JJ. The International Association for the Study of Lung Cancer international staging project on lung cancer. J Thorac Oncol 2006;1:281-286 3. Goldstraw P, ed. Staging manual in thoracic oncology. Orange Park, FL: Editorial Rx Press; 2009. 4. Sobin L et al., eds. TNM classification of malignant tumours. 7[th] edition. Oxford: Wiley-Blackwell; 2009;138-146. 5. Edge SB et al., eds. Cancer staging manual. 7[th] edition. New York: Springer; 2010;253-270. 6. Rusch VW et al. Initial analysis of the International Association for the Study of Lung Cancer mesothelioma database. J Thorac Oncol 2012;7:1631-1639. 7. Detterbeck FC, Huang J. Overview. J Thorac Oncol 2011;6(Suppl 3):s1689-1690. 8. Rice TW et al. 7[th] edition of the AJCC Cancer Staging Manual: esophageal and esophagogastric junction. Ann Surg Oncol 2010;17:1721-1724. 9. Goldstraw P et al. We probably have the answer: now what is the question? J Thorac Oncol 2009:4:939-940.

Abstract
Clinical research in non-small-cell lung cancer is a rapidly evolving field. We conducted a survey of lung cancer surgical clinical trials listed on clinicaltrials.gov. 658 records were found, which were mainly consisted of trials studying the surgical procedure and (neo) adjuvant therapy. Phase III trials account for 15.5%. Only 34.9 %( 230 records) trials were completed, and 43 studies present results in clinicaltrials.gov. The median time to completion (MTC) of Ph III surgical procedure trials was 9.4 years. The MTC of Ph III neo-adjuvant and adjuvant trials had not been reached but are longer than 10 years. In comparison, the MTC of Ph III trials in first line setting were only 4.5 years. We summarized the characteristics of these trials with real-world case examples. Our analyses reveal that it is critically needed for regulatory authorities, clinical trial sponsors, collaborative research groups, and academic institutions to work together to build the infrastructure and research cooperation for clinical trials with surgical components. In 2007, a national collaborative clinical research group, Chinese Thoracic Oncology Group (CTONG), was established. CTONG is a network of researchers, physicians and healthcare professionals in public institutions across China. Currently, there are 22 member hospitals in the group. A CTONG-sponsored trial (CTONG1104) is discussed to illustrate our experience with surgical clinical trials. In summary, to expedite clinical research in early stage lung cancer, it is necessary for investigators to collaborate in cooperative clinical trials. As cancer treatment is multidisciplinary, while retaining a surgical focus, surgical trials require multidisciplinary collaboration.

Abstract
Background: Since video-assisted thoracoscopic surgery (VATS) was first reported in the 1990s, this approach has been rapidly gaining popularity worldwide because of its less morbidity and expedited patient recovery. As a milestone, VATS lobectomy was first introduced into NCCN Guidelines in 2006, and then has been recommended as a reasonable and acceptable alternative in the treatment of non-small cell lung cancer (NSCLC) since 2007. However, whether VATS’s superiority really exists in the domain of NSCLC has raised unprecedented dispute in the past two decades, especially when compared to other minimally invasive approaches like axillary thoracotomy. Major debates have involved surgical trauma, post-operative neuralgia, shoulder dysfunction, influence on respiratory function/quality of life (QOL), and finally oncologic outcomes. So far, strong evidence demonstrating decreased morbidity and equivalent long-term survival of the new technique is lacking. In an attempt to obtain a better answer, we designed and initiated this multicenter randomized controlled trial (RCT) in China, which compared VATS and axillary approaches in terms of various surgical and oncologic outcomes for early stage NSCLC. Methods: 400 patients were planned to be recruited in this study since 2008, and then randomized into VATS group (Experimental group) and axillary thoracotomy group (Control group). The Inclusion Criteria include: ①Clinical early stage NSCLC, no hilar and mediastinal lymphadenopathy (short diameter ≤ 1 cm assessed on computed tomography scan); ②No medical contraindications to lung resection; ③Age ≤ 75 years old and ≥18 years old; ④Ability to give informed consent. And the Exclusion Criteria are: ①Evidence of invasion into neighboring organs; ②Extensive pleura symphysis; ③Central tumors; ④Inability to tolerate single-lung ventilation; ⑤Previous thoracotomy or high-dose radiation on the chest ; ⑥Pregnant or lactating female patients; ⑦Inability to sign the informed consent form because of psychological, family and society factors; ⑧History of other malignancies in the past 5 years except for non-melanoma skin cancer, cervix cancer in situ or early-stage prostate cancer; ⑨Other uncontrolled factors (like intra-operative conversion to thoracotomy). Surgery criteria would be a radical lobectomy plus hilar and mediastinal lymph node dissection. Also, the VATS lobectomy was defined by the avoidance of rib-spreading and use of the thoracoscope for visualization. The total number of ports is not relevant in this definition, but is typically 3 and 4. Five-year overall survival (OS) and disease-free survival (DFS), as the primary endpoints will be evaluated. Peri-operative parameters, including post-operative chest pain, cytokines response, post-operative respiratory reserve, Karnofsky performance status and QOL would be explored. In addition, operation time, intra-operative blood loss, chest tube drainage, indwelling period of chest tube, etc. would be documented and compared between two groups. Lung Cancer Symptom Scale (LCSS) was adopted to estimate the QOL before operation and at post-operative standpoints of 1, 3, 6, 9 and 12 months. Post-operative respiratory function would be measured in first three months, while Karnofsky performance status and chest pain at the standpoint of 1 year after surgery. Cytokines response, to be exact, serum levels of IL-2, IL-4, IL-6, IL-10, TNF and IFN-r, would be analyzed in first 48 hours after surgery. Randomization was done via an interactive web response system with computer-generated randomization codes. This study has been registered in Clinicaltrials.gov (NCT01102517) and sponsored by Sun Yat-sen University Clinical Research 5010 plan as well as Guangdong provincial high-tech projects. Result: Five leading hospitals throughout China contributed to this RCT. 425 patients was recruited up to May 2013; nonetheless, 336 patients were finally analyzed in the study. The latest DMC review happened on May 2013 and our RCT was regarded to be strictly adhering to the protocol with good quality control. No surgery-related mortality was documented in both VATS and axillary thoracotomy groups. Unfortunately, four patients in the study group were excluded because of intra-operative conversion to axillary thoracotomy. The conversion rate was 0.94% (4/425) in our study. Another fact needs to be clarified that the remaining 85 patients were excluded due to a variety of reasons, which included extensive pleura symphysis (9 patients), benign pulmonary lesions (35 patients), small cell lung cancer (3 patients), accidental pleural metastasis (2 patients), Age > 75 years old (2 patients), invalid case report forms (13 patients), and inability to adhere to the randomized surgical approaches (21 patients). As a result, 175 patients in VATS group and 161 patients in axillary thoracotomy group were finalized and analyzed by the database. No significant difference between the two groups in terms of the anatomical location of the tumors, histological subtypes and clinical stages. Impressively, the operation time for the VATS lobectomy group was significantly shorter than that of the control group (150 min vs. 170 min, P<0.05). There was also remarkably less intra-operative blood loss in the study group (100 ml vs. 150 ml, P<0.001). Another important finding was that no significant differences were identified regarding the number of cleared lymph nodes and number of lymph node regions (10 vs 12; 5 vs 5, respectively). The peri-operative complication rates, once again, showed no significant difference between the two groups. Patients who undertook VATS lobectomy experienced significantly better post-operative QOL, and the superiority was showed in all the aspects of LCSS. When looking at cytokines response which may reflect the acute surgical injuries or trauma, IL-2, IL-4, IL-6, IL-10, TNF and IFN-r consistently demonstrated lower expression levels throughout the time in the VATS group. However, only the patients who recruited in Sun Yat-sen University Cancer Center underwent the evaluation of cytokines response (180 patients). Regarding the primary endpoints, although longer follow-up is still needed before drawing a clear conclusion, initial analyze did show no significant difference was seen between the two groups regarding OS and DFS. We considered these results were premature, but we also believed current data tended to demonstrate a statistical non-inferiority result. Conclusions: Our multicenter RCT has illustrated that VATS approach is a safe approach for the treatment of early stage NSCLC, and may be superior to axillary thoracotomy approach in terms of intra-operative blood loss, acute surgical injuries and post-operative QOL. However, we also realized that longer follow-up is necessary to determine its oncologic equivalency.

Abstract
Introduction Building translational research capacity is a daunting task if a thoracic surgeon has not inherited a fully set up laboratory. It is possible, however, for a thoracic surgeon to be involved in and even drive translational research. Given that surgeons are the major procurers of tissue and data in lung cancer, it should actually be more commonplace. It requires passion, organization, the understanding and assistance of colleagues, and the ability to seize what opportunities exist and create new ones with strategic collaboration. Creating this capacity also involves modifying surgical practice to facilitate research then building the relationships, funding and infrastructure. In this article, these building blocks are explored. A translational research project is presented as a successful application of this formula. Building Blocks As a principle, the pillars research capacity-building are: ~ Research-Based Surgical Practice ~ Relationships ~ Infrastructure ~ Funding Sources For individual surgeons and circumstances, these may differ. Some components may already exist and some may seem unattainable. It is often overlooked that simple changes to standard practice can make research a natural activity. For example, focusing audits on the procedures that are the subject of potential research, aligning timing of routine follow-up so that outcome assessment becomes automatic, or a policy that all tissue excess to diagnostic needs is routinely stored in a tissue bank. A research coordinator, at least part-time, is essential for any sustainable research activity. Beyond that, key relationships may differ. For me, the most important initial relationship is an anatomical pathologist with a keen interest in lung. Without such a person to review and precisely classify tumors, the power and applicability of any study is seriously diminished. However, a relationship with a laboratory-based clinician or scientist is necessary in order to have access, training and conduct of the benchtop component of research. The surgeon should be active in these endeavours (at least initially) to promote goodwill and a free-flowing exchange of ideas. Other clinicians or specialist scientists may then need to be involved depending on the scope of the potential research projects. Whatever infrastructure is available for research will often need to be augmented. Many useful research tests are already available in a diagnostic pathology laboratory (e.g. advanced immunohistochemistry, mutation screening, PCR). Some facilities may be shared with researchers in other specialties, resulting in synergies for both groups. This may be the way to acquire part time bench space, for example. After determining what capabilities are required to conduct the projected range of research, funding will be the next concern. It is not usually possible to get large project and infrastructure support without a track record and without the funds it is difficult to get a good track record. Therefore preliminary work needs to be funded from a range of more modest resources to pay for direct research costs and services outside any collaborative effort. Local organizations such as Rotary, Apex etc. are often keen to donate to research with a potential impact on their community. This could, for example, fund the construction of tissue microarrays or purchase of essential equipment. Anything that a name can be attached to is usually fair game for such donors. Hospital research foundations are the easiest target for competitive grants. Specialist societies commonly have foundations for distributing grants-in-aid. Participation in capitation-funded clinical trials may provide the salary for a research coordinator, allowing their spare time to be dedicated to translational projects. An Example of Surgeon Driven Translational Research After several years of building relationships, collaborations, infrastructure and funding, our group was able to assess our core research advantages. Figure 1 plots the gradual ascent to critical mass for research funding in our thoracic unit.Figure 1 Our example project investigated the genomic/transcriptomic landscape of the recently classified subtypes of lung adenocarcinoma.[1] Other than one gene expression study[2] using outdated array-based platforms and subtype classifications, no molecular signature has been reported to correlate to the morphology seen by the pathologist under the microscope. It is debated whether these subtypes are genetically different or just a spectrum of the same tumour. Inter-observer differences in classifying these subtypes are particularly problematic for the new micropapillary subtype; therefore a molecular marker is an important goal. To investigate these new subtypes (table 1), we carefully selected tumors with classical morphological regions of the differing subtypes. From this group, 29 tumours were selected with known mutations in one or more of EGFR, KRAS, BRAF and TP53. These would be the most likely cases to prove our hypothesis that there are differential genomic aberrations within subtypes of the same tumor.

Table 1. Subtypes of lung adenocarcinoma investigated, as classified in the 2011 IASLC/ATS/ERS pathological classification of lung adenocarcinoma.

Subtype	Description
Lepidic	Minimal metastatic potential. Malignant cells growing along but not invading airway walls
Acinar	Moderate metastatic potential. Glandular structures in invasive stroma
Papillary	Moderate metastatic potential. Branching structures with fibrovascular stromal cores covered by malignant cells.
Solid with/without mucin	High metastatic potential. Sheets or nests of malignant cells with or without intracellular mucin.
Micropapillary	High metastatic potential. Papillary tufts of tumor cells without fibrovascular cores either lying apparently free in alveolar spaces or surrounded by thin fibrous septa, often at a tumor’s edge.

After marking the subtypes in areas of tumor purity > 50%, punches of formalin-fixed paraffin embedded tumor were deparaffinized and DNA was extracted. High resolution melting was then used to screen for mutations in all selected subtypes of each tumor. In 3 out of 11 KRAS mutant tumors and 2 out of 4 BRAF mutant tumors, heterogeneity was found in mutation status between subtypes of lesser and higher metastatic potential. No differences were seen between subtypes for EGFR mutant tumors, however we did find a single case of very high copy number of the EGFR mutant allele mapping only to the micropapillary subtype in the tumor. The significance of this finding is far-reaching. It provides a genetic basis to support the new pathological classification and may inform its next revision. It also brings into question the accuracy of small biopsies in detecting mutations other than EGFR. It has the potential to unravel the biological evolution of lung adenocarcinoma, with EGFR apparently an early event, whereas KRAS and BRAF may be acquired later and result in a transition to a more malignant subtype phenotype within a given tumor. Conclusion This example demonstrates that surgeons can drive important translational research as well as advancing other researchers’ goals. Although it takes years to develop such programs, once critical mass is achieved the results create further opportunities to sustain future research and incorporate advances in sequencing platforms and knowledge in lung cancer biology. References

1	Travis, W. D. et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 6, 244–285 (2011).
2	Bryant, C. M. et al. Clinically relevant characterization of lung adenocarcinoma subtypes based on cellular pathways: an international validation study. PLoS One 5, e11712 (2010).

Abstract
For a long time, radiotherapy for lung cancer were considered in terms of being either curative, palliative or radical. Conventional radiotherapy for early stage NSCLC was general considered ‘ curative’, but the more modest expectation in patients with locally advanced NSCLC led to it being referred to as ‘radical’, as disease recurrences was considered very likely. In metastatic NSCLC, the role of radiotherapy was considered only in a palliative context, since it was generally accepted that in disseminated disease, local therapies could never be curative. These classifications have been reappraised in the light of recent data. In small cell lung cancer (SCLC), which has a very high risk of distant spread, recent studies have established that local treatments can extent survival and contribute to cure. This is not only the case for thoracic radiotherapy, but also for prophylactic radiotherapy to the brain (PCI; prophylactic cranial irradiation). Studies in patients with limited disease SCLC have shown a survival benefit of about 5% at 3 years,a benefit of similar magnitude to that for thoracic radiotherapy in this patient group. Even in patients with proven disseminated SCLC (extensive stage), the use of PCI has improved survival. In a randomized trial, patients who received PCI had a 1 year survival of 27% compared to 13% for patients who did not receive PCI [1]. A study on the use of thoracic radiotherapy after the completion of chemotherapy in patients with ES-SCLC has recently been closed and the results are awaited next year. With the advancements in radiotherapy techniques, we can now ablate tumors with very high doses, and with great precision using stereotactic techniques. Local control rates in excess of 90% are obtained and in fit, potentially operable patients, 5-year survival rates above 60 % are achieved [2,3]. These ablative radiation doses may also exert a benefical immunological effect both locally and systemically. The same principles of high-dose high-precision radiotherapy are being applied in patients with a limited number of metastases (oligometastases). This patient group is increasingly being identified due to improved imaging techniques, and interest is growing due to the availability of more effectivity of systemic therapy in subgroups of lung cancer. Aggressive treatment of metastases by surgery or ablative therapy, such as SBRT, might offer a real chance of cure for these patients. We have initiated a clinical study to evaluate the benefit of this approach [4]. References 1. Slotman BJ et al., New Engl J Med 357, 664-72, 2007. 2. Onishi H et al., Int J Radiat Oncol Biol Phys 75, 243-247, 2011. 3. Lagerwaard FJ et al., Int J Radiat Oncol Biol Phys 83, 348-53, 2012 [updated]. 4. Palma D et al., BMC Cancer 12, 305, 2012.

Abstract
Decision making in advanced NSCLC undoubtedly should primarily consider evidence based treatment standards recommended by international guidelines (1, 2) According to international guidelines, decision making in 2013 is characterized by customizing therapy in advanced non-small cell lung cancer, by selecting a specific therapeutic regimen based on tumor histology and molecular biology. This refers to first-line therapy in patients with good performance status, but also to subsequent lines of therapy since antineoplastic drugs and regimens used in induction therapy directly influence the selection of agents/regimens considered for second/third-line treatment. The availability of antineoplastic monoclonal antibodies, small molecules and newer cytotoxic such as pemetrexed, the antiangiogenic bevacizumab as well as the tyrosine kinase inhibitors erlotinib, gefitinib and crizotinib has recently changed the treatment algorithm of advanced NSCLC. Therapy optimization by modern medical therapy is characterized by treatment individualization based on predictive factors. This process seems to continue since other products holding considerable promise for the near future such as tumor vaccines and other immunotherapeutic approaches, anti-angeniogenic agents, and newer EGFR-targeting monoclonal antibodies have already reached the level of phase III-testing or the registration process. Today’s recommendation can be summarized as follows: First-line therapy: In patients with good performance status with non-squamous tumors haboring an activating EGFR-mutation, an EGFR tyrosine kinase inhibitor may be the leading option, not only because of being active but also because of its feasibility and improved toxicity profile (3-5). In patients with non-squamous cell tumors not expressing EGFR-mutations, combination therapy remains standard with pemetrexed as the preferred partner of cisplatin (6). Furthermore, it has been demonstrated that in non-squamous NSCLC the addition of bevacizumab to standard doublet therapy improves survival (7, 8). With regard to patients with squamous cell tumors gemcitabine, vinorelbine or taxanes in combination with platinum-based agents remain the chemotherapeutic standards. Bevacizumab and pemetrexed are not recommended in squamous cell tumors either because of the agents toxicity profile (bevacizumab) or because of being less effective in this particular histological subtype (pemetrexed). For elderly patients not being fit for standard doublet chemotherapy medical treatment requires modification. Here single agent therapy is widely considered to be the preferred option for maintaining quality of life, reducing tumor association symptoms and improving survival (9). Fit elderly patients benefit from combination chemotherapy as much as younger patients and platinum-based chemotherapy is recommended as well (10, 11). Combination therapy remains investigational in patients with poor performance status (≥ PS 2), and single agent chemotherapy is the preferred option (12). Second-line therapy: In patients with disease progression during or after completion of induction (first-line) chemotherapy second-line therapy is indicated if the patient remains in good clinical condition. Selection of drugs for second-line therapy is based on whether the drug has been used earlier, the toxicity profile or the patients wish. The approved options for second-line therapy are docetaxel and pemetrexed (in case of non-squamous histology), erlotinib and gefitinib (in tumors expressing activating EGFR-mutations) (13-16). Crizotinib has recently been registered for second-line therapy in ALK-positive tumors (17). Maintenance therapy: The prolongation of induction therapy represents an evidence based new option to improve outcome in advanced NSCLC, in general and with strong implications for second line therapy, in particular. Three randomized studies investigated pemetrexed and erlotinib as maintenance therapy following 4 cycles of chemotherapy (18-21). In these trials switch-early second-line- (pemetrexed, erlotinib) or continuation-true- (pemetrexed) maintenance therapy has significantly increased PFS and OS. Based on this given evidence these two compounds have been registered for maintenance therapy in patients with advanced NSCLC, not progressing following 4 cycles of first-line standard platinum-based therapy. According to the European Medicines Agency (EMA) pemetrexed is indicated as monotherapy for maintenance treatment of locally advanced or metastatic NSCLC other than predominantly squamous cell histology in patients who’s disease has not progressed immediately following platinum-based chemotherapy, including platinum-pemetrexed combinations, and erlotinib is indicated as monotherapy for maintenance treatment in patients with locally advanced or metastatic NSCLC with stable disease after 4 cycles of standard platinum-based first-line therapy. When prescribing erlotinib, clinical factors associate with prolonged survival should be taken into account. There is clearly more which must be considered and which would lead to stop or even not to initiate a modern medical therapy. Even if national and international treatment recommendations undoubtedly represent the backbone of the decision making process, the management of patients with advanced non-small cell lung cancer often clinically requires modification for a number of reasons not necessarily considered by guidelines.This refers to first and subsequent-line treatment as well. The majority of lung cancer patients are older patients and often express specific age related treatment expectations. Other relevant factors for decision making in a non-curative setting are patient social environment and patient psychological status, regulations of national health care providers and reimbursement systems, drug availability, diagnostic and health care infrastructure. These circumstances modify decision making and lead to the use of older agents and regimens, to changes in dosing and scheduling of newer agents and regimens, to single agent therapy, to a reduction of treatment cycles and to a more free indication of best supportive care measures. Our increased understanding of the molecular biology of lung cancer and the change of its epidemiology has opened up venues for more rational treatment strategies and at the same time has challenged the additional diagnostic algorithms, the established health care financing and the complex process of drug development. Customized therapy and therapeutic targeting were made possible through the identification of new treatment predictors and the development of a number of antineoplastic agents which have shown clinical evidence for being more beneficial then the treatment standard in selected patients. Consequently, therapy individualization by histology and molecular markers has significantly influence the work of pathologists around the globe and the process of obtaining a therapeutically relevant tumor diagnosis. Not only histological sub-typing becomes clinical relevant but molecular information is also of increasing importance for treatment selection. Routine molecular testing in certified laboratories must be established, and this diagnostic process should ideally performed under the guidance of evidence based recommendation such as the recently published guidelines from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology for the molecular testing to select patients for EGFR-ALK-thyrosine kinase inhibitors (22). This process requires advanced diagnostic techniques and expertise. Investigating and implementing medical targeting in lung cancer because of its large dimension is costly and characterize by the limitation of financial and clinical resources, and currently not every where available. Since the majority of large randomized phase III trials during the last decade turned out negative in their primary endpoints, the time of conducting trials on large unselected patient population seems definitely over and the classical investigational strategy must probably be replaced by smaller trials in selected patients, and trials using study endpoints which can function as substitutes for the traditional overall survival endpoints (23). This inevitable change in the altitude of conducting clinical trials will increase the need for patients treated in clinical trials and, therefore, has a significant impact in decision making in advanced NSCLC. Another hurdle for making promising therapies difficult to be generally prescribed are that clinical evidence of being beneficial and the scientific rational do not necessarily equal clinical practicability and reimbursement in a given cultural and economic system. For Europe and specifically Germany it is important that an agent has reached a positive vote by the registration agency EMA and that it find acceptance by the national health care providers responsible for reimbursement. For this reasons the clinical evidence of being beneficial must be well documented and strong. Information about treatment selection by predictive factors and treatment restriction to patients who benefit the most is very welcome. In addition, if the treatment selection requires advanced diagnostic testing generally accepted and validated methods should easy to be reached and should provide reliable and reproducible results by at the same time being cost effective. References: 1. Azzoli et al, J Clin Oncol 29, 3825-3831, 2011 2. Peters et al, Ann Oncol 23 (suppl. 7), 56-64, 2012 3. Mok et al et al, N Engl J Med 361, 947-957, 2009 4. Zhou et al, Lancet Oncol 12, 735-742, 2011 5. Rosell et al, Lancet Oncol 13, 329-346, 2012 6. Scagliotti et al, J Clin Oncol 26, 3543-3551, 2008 7. Sandler et al, N Engl J Med 355, 2542-2550, 2006 8. Reck et al, J Clin Oncol 27, 1227-1235, 2009 9. Gridell et al, J Natl Cancer Inst 95, 362-372, 2003 10. Langer et al, J Clin Oncol 22 (suppl), 639 (abstr. 2571), 2003 11. Quoix et al, Lancet 378, 1079-1088, 2011 12. Gridelli et al, Ann Oncol 15, 419-426, 2004 13. Shepherd et al, J Clin Oncol 18, 2095-2103, 2000 14. Hanna et al, J Clin Oncol 22, 1589-1597, 2004 15. Thatcher et al, Lancet 366, 1527-1537, 2005 16. Douillard et al, J Clin Oncol 28, 744-752, 2010 17. Shaw et al, N Engl J Med 368, 2385-2394, 2013 18. Capuzzo et al, Lancet Oncol 11, 521-529, 2010 19. Ciuleanu et al, Lancet 374, 1432-1400, 2009 20. Paz-Ares et al, Lancet Oncol 13, 247-255, 2012 21. Paz-Ares et al, J Clin Oncol 31, 2895-2902, 2013 22. Lindeman et al, J Thoracic Oncol 8, 823-859, 2013 23. Pilz and Manegold, Memo 6, 92-97, 2013

Abstract
Advance care planning refers to a “process of discussion, reflection, understanding and communication between a patient, their family and health providers for the purpose of clarifying values, treatment preferences and goals of end of life care” (1). Advance care planning provides a formal means of ensuring health professionals and family members are aware of the patient’s wishes for care if they were to become too unwell to speak for themselves in the future. This process may include the patient completing an Advance Care Directive, which documents their wishes and/or the appointment of a substitute decision maker. Advance care planning is a patient-centred initiative that promotes shared-decision making and supports substitute decision-making, where appropriate, and aims to achieve good end of life care. The potential benefits of advance care planning for patients with advanced lung cancer have been highlighted in recent literature and clinical practice guidelines (2-4). However, there are many barriers to implementing advance care planning in this setting including patient, family, health professional and system related factors. In particular doctors and nurses caring for patients with lung cancer may be reluctant to raise the topic of advance care planning for fear of upsetting patients or they may lack confidence in knowing how to discuss it. This talk will focus on evidence-based strategies and practical tips for health professionals when having advance care planning discussions with patients with advanced lung cancer and their families. Recommendations from Australian “Clinical practice guidelines for communicating prognosis and end-of-life issues with adults in the advanced stages of a life-limiting illness, and their caregivers” will be described (5). The key recommendations are for health professionals to: Prepare for the discussion, where possible; Relate to the person; Elicit patient/caregiver understanding and information preferences; Provide information, tailored to the individual needs of both patients and their families; Acknowledge emotions and concerns; (foster) Realistic hope; Encourage questions and further discussions; and Document what had been discussed. (PREPARED). Sample phrases and useful questions for facilitating advance care planning discussions will be presented. Further resources regarding advance care planning will be provided (6-9). References: (1) Royal Australasian College of General Practitioners Advance Care Planning Definition http://www.racgp.org.au/your-practice/business/tools/support/acp/ (2) Mack JW, Cronin A, Keating NL et al. Associations between end-of-life discussion characteristics and care received near death: a prospective cohort study. Journal of Clinical Oncology 2012; 35: 4387-4395 (3) (USA) National Comprehensive Cancer Network: Practice guidelines in oncology: Palliative care. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (4) Smith, T, Clayton, J, Michael, N. What is the role of advance care planning and timing of referral for patients with lung cancer? [Version URL: http://wiki.cancer.org.au/australiawiki/index.php?oldid=47787, cited 2013 Aug 26]. Available from http://wiki.cancer.org.au/australia/Clinical_question:What_is_the_role_of_advance_care_planning_and_timing_of_referral_for_patients_with_lung_cancer%3F. In: Cancer Council Australia Lung Cancer Guidelines Working Party. Clinical practice guidelines for the treatment of lung cancer. Sydney: Cancer Council Australia. Available from: http://wiki.cancer.org.au/australia/Guidelines:Lung_cancer (5) Clayton JM, Hancock KM, Butow PN, Tattersall MHN, Currow DC. Clinical practice guidelines for communicating prognosis and end-of-life issues with adults in the advanced stages of a life-limiting illness, and their caregivers. Medical Journal of Australia 2007; 186: S77- 108 https://www.mja.com.au/journal/2007/186/12/clinical-practice-guidelines-communicating-prognosis-and-end-life-issues-adults (6) The conversation project http://theconversationproject.org (7) Respecting Patient Choices http://www.respectingpatientchoices.org.au (8) Oncotalk http://www.oncotalk.info (9) Vital talk http://vitaltalk.blogspot.com.au

Abstract
Metastatic lung cancer remains an incurable condition despite recent advances in medical therapy. New treatments can prolong survival and enhance quality of life for patients. Lung cancers can shrink and impressive responses may divert attention from the inevitable reality that the cancer will eventually acquire resistance to therapy. In the current era, patients are guided through multiple lines of therapy; first line, maintenance, second-line and so on. Such ‘lines of therapy’ extend the time on active therapeutic measures designed to alter the biological behavior of advanced lung cancer. Cancer centres that conduct clinical trials may offer potential active intervention beyond the proven ‘lines of therapy’, thereby extending time on active therapy. This may delay the transition to end-of-life care, but the likelihood of benefit with therapies beyond 2[nd] line is low. Whilst oncologists have a greater armamentarium in the fight against lung cancer, there comes a time for every patient when the medical advice will be to stop ‘active therapy’ as there is no prospect of benefit. The focus of care will be on symptom control with acceptance of palliative care. This is the time when patients accept that medical intervention will not prolong survival time, cannot alter the growth and spread of the cancer and will not influence the harmful effect of the cancer on the body. The body will fail, and in the process a functional decline will become obvious. This transition to ‘end-of-life’ care is not a clearly defined time point. Complex decision-making and emotional discussions are usually required. Several issues should be taken into account in determining when anti-cancer therapies should continue to be utilised or when such measures should be abandoned. These issues include: The likelihood of a beneficial response to a proposed therapy The safety and toxicity of the proposed intervention The patient’s ‘performance status’ – an overall measure of functional capacity Comorbidity and organ dysfunction Patient preference There are validated measures of prognosis that may assist in determining when this transition to palliative care should commence, including extent of cancer, weight loss, serum albumin, white cell count, neutrophil to lymphocyte ratio, lactate dehydrogenase and measures of critical organ function (cerebral, pulmonary, liver and renal). The synthesis of all of this information, a global assessment of the patient and knowledge of all the available treatment options is required to determine the timing of transition to ‘end-of-life’ care. The transition is usually handled through a multidisciplinary approach, with potential involvement of multiple health care professionals including the general practitioner, palliative care physician, medical oncologist, radiation oncologist and surgeon. Additional input from health care professionals in the fields of psychology, psychiatry, dietetics, social work and physiotherapy can enhance the quality of care in this transition period, depending on the degrees of distress and disability. Expert counseling is required. Involvement of the primary carers and family in discussions and decision-making is also important. Optimising care for patients during the late stages of cancer should focus on alleviating symptoms, allow planning for death, facilitate arrangements and enable personal commitments before death, dealing with grief and supporting the caregivers. These measures can improve quality of life, reduce anxiety and permit a more peaceful death. Ongoing active cancer therapies may introduce adverse events, require additional hospital visits and expose patients to invasive procedures. This can delay the introduction and implementation of optimal palliative care in the ‘end-of life’ period. The transition to end of life care should also be an opportunity to consider advanced directives. This issue needs to be discussed in a sensitive manner. Decisions around intensive medical intervention and confirmation of ‘not-for-resuscitation’ status will allow for patient wishes to be respected and permit patient autonomy at this difficult stage. An appreciation and acceptance of ‘end’-of-life’ care, when the prognosis is clearly very poor and death from an advancing lung cancer inevitable, will improve the prospect of allowing a comfortable death, a ‘good death’. This should be a goal that every cancer specialist seeks for patients with incurable cancer.

Abstract
Symptom clusters is a relatively new field of study, recognizing that patients are often experience multiple concurrent symptoms and some of them may be interlinked. Understanding these clusters may improve the management of unrelieved symptoms in patients with lung cancer. A symptom cluster is defined as two or more symptoms that are related to each other and that occur together (Kim et al, 2005; Molassiotis et al, 2010). A small amount of research has highlighted over the past decade the different symptom clusters that are reported by patients with lung cancer. Brown et al (2011) have shown a five-symptom cluster that includes fatigue, breathlessness, cough, pain and anorexia, present in 64% of women with lung cancer. Henoch et al (2009) identified three clusters, including a pain cluster (pain, nausea, bowel issues, appetite loss, fatigue); a mood cluster (mood, outlook, concentration, insomnia), and a respiratory cluster (breathing, cough). The latter respiratory cluster has also been shown with our own work and it was stable at various assessments over the first 12 months from diagnosis (Molassiotis et al, 2010). Depression, fatigue and pain is another one (Fox & Lyon, 2006) as is pain, fatigue and insomnia (Hoffman et al, 2007). On the clinical level, it is suggested that physicians and oncology nurses should think in terms of these naturally clustering symptoms when recommending plans for symptom management, in order to be more effective in the overall management of a larger spectrum of symptoms. However, all these studies have some methodological shortcoming, as many of the identified clusters reflect the measurement symptom tool used each time, some have small sample sizes and are often secondary analyses. Patients who experience symptom clusters are more distressed and have more severe symptom-reporting than those who experience single symptoms, and they form a particular group of patients in need of more careful intervention. More recently we have carried out a qualitative study with 19 patients and their caregivers assessed at diagnosis, and 3, 6 and 12 months post-diagnosis. We have identified, for a first time using such methodology and the patients experience, a consistent and stable symptom cluster of fatigue, breathlessness and cough, which we called it ‘respiratory distress’ symptom cluster (Molassiotis et al, 2011). Two other messages came out clearly from this study: a) that the patients’ symptom experiences and coping efforts need to be understood within the context of a panorama of symptoms which frequently co-occur and which may interact in complex ways. This suggests that it may therefore be potentially problematic within the lung cancer population to determine a patient's experience of a single symptom in isolation given the complex array of symptoms that patients may experience. b) cough, which is under-represented in research within this population, may play an important role in shaping the patients' symptom experience, and may be linked with breathlessness more strongly than we currently think. Also both breathlessness and cough lead to anxiety and emotional distress. How do we improve the symptom cluster experience? We need to develop symptom interventions that are moving from a reductionist model of focusing on a single symptom to understanding the clinical usefulness and relationships of symptoms through symptom clusters and developing interventions that affect all symptoms in the cluster. This area is still in its infancy and there are only a couple of ongoing trials with such more ‘complex’ interventions. How do these broader interventions look like? Complementary therapies may be good ‘candidates’ for such an approach; indeed, we have carried out a trial using acupuncture to manage cancer-related fatigue in breast cancer patients, and we have seen that many patients reported also reductions in hot flushes and joint pains too. Mindfulness therapy may be a good option for the common mood-related symptom cluster. Educational interventions could also be appropriate approaches. However, how one structures and develops a new intervention to attend to clusters of symptoms needs significant thinking and energy. Our team is currently testing a new such intervention focusing on the respiratory distress symptom cluster. However, to ‘shape’ the intervention we followed several steps: Through patient and caregiver interviews (Ellis et al, 2012) important implications for patient participation and adherence to the intervention were identified, including the perceived relevance of potential techniques; appreciable benefits in the short-term; convenience; patient preferences; timing of the intervention; venue; caregiver involvement; the provider of the intervention, and contact with other patients. Through health care professionals’ focus group interviews (Wagland et al, 2012) it was clear that to have a successful intervention we had to consider also staffing time and space, and there was a recognition that the preference of most patients to make as few hospital visits as possible also complicated the teaching of such interventions. Moreover, it was recognized that there may only be a small window of opportunity in which to effectively teach lung cancer patients a novel non-pharmacological intervention as the period between diagnosis and the onset of severe symptoms is often short. Finally, we assessed patient preferences for the intervention components through a discrete choices experiment (Molassiotis et al, 2012). After this work, we developed the intervention that includes primarily diaphragmatic breathing exercises, cough suppression exercises, and acupressure (main intervention) together with anxiety management, vocal hygiene, and energy conservation techniques, delivered through two educational sessions as a self-management strategy that involves both patients and caregivers. Currently we are testing this intervention in a pilot trial aiming to explore the impact of this novel non-pharmacological supportive intervention on symptom distress, coping and service utilisation in patients with lung cancer and their caregivers, and to test the feasibility of carrying out a trial using this intervention, including practical and logistical issues of providing the intervention in practice. The trial has currently recruited 60/100 patients and is envisaged to complete recruitment by the end of 2013. Preliminary findings from the trial will be presented.

Abstract not provided

Abstract
An estimated 225,000 men and woman will be diagnosed with lung cancer in 2013 (NCI-SEER Data). Approximately 80% of lung cancer patients will be diagnosed with non-small cell lung cancer (NSCLC), and an estimated 25% will present with early-stage or operable disease (Jones 2009). The overall 5 year survival rate for lung cancer is 16%. However, if detected early the survival rate is 53% (ACS 2010). Improvements in surgical techniques, coupled with more effective chemotherapy regimens, have led to significant survival gains for patients with operable disease (Jones 2009). With improved survival rates, long-term treatment sequelae and quality of life (QOL) are gaining increasing attention in terms of post-treatment management of early stage patients. For patients with inoperable or more advanced disease, measures to improve symptoms and QOL are also being evaluated. An individual is considered a cancer survivor from the time of diagnosis, through the balance of his or her life (NCI- Survivorship Definitions 2004). Lung cancer survivors may experience a myriad of long-term and late effects related to their diagnosis and treatment exposures. Symptoms may include dyspnea, fatigue, decreased physical endurance, depression, inability to sleep and weight loss (Anderson 2011). Anticipated age-related losses in physical function and comorbidities such as chronic obstructive pulmonary disease (COPD), ischemic heart disease and hypertension can add to post treatment complications, long term effects and overall recovery. Exercise therapy continues to gain recognition as an effective intervention in cancer rehabilitation. While early studies mainly focused on breast cancer survivors, a growing number of studies have been conducted over the past several years evaluating exercise following a lung cancer diagnosis in the post treatment setting. A review of literature suggests lung cancer patients are good candidates for pulmonary rehabilitation following treatment. Peddle-McIntyre et al describe progressive resistance exercise training, or PRET, as an intervention that has been successful in improving muscular strength, body composition, physical fitness, physical function and QOL in some cancer survivor groups citing, however, that no studies have focused solely on lung cancer survivors. Their prospective study including early stage NSCLS survivors who had undergone surgical resection preliminarily revealed significant improvement in muscle strength, muscular endurance and peak inspiratory pressure. The 6-minute walk distance (6MWD), regarded as a prognostic indicator in certain chronic illnesses, also demonstrated improvements suspected to correlate with preserving body function and delaying onset of mobility limitations. Several studies have demonstrated the benefits of exercise in COPD patients, who are known to experience respiratory symptoms comparable to lung cancer patients. A prospective study conducted by Anderson et al utilized an established COPD rehabilitation program in lung cancer patients to evaluate impact on fitness and QOL. Patients who had undergone pulmonary surgery as well as those who were surgically ineligible (comprising the majority of participants) were included in the study. Interventions included supervised exercise in the clinic setting and instruction on home exercising. Walking was the main element. Results showed improved physical fitness and performance as measured by the Incremental Shuttle Walk Test (ISWT), Endurance Shuttle Walk Test (ESWT) and spirometry after the exercise intervention. Pulmonary function and self reported QOL, however, did not demonstrate improvement. Spruit et al (2006) conducted a non-randomized clinical trial in patients who had a history of surgery, chemotherapy and/or radiotherapy evaluating an inpatient rehabilitation program on pulmonary function, 6MWD and peak cycling load. Patients were trained in daily cycling, walking, weight training, and gymnastics (focusing on flexibility and mobility). No change was seen in pulmonary function post intervention. However, significant improvements were seen in the 6MWD and peak cycling load. Symptom scores for dyspnea and fatigue also improved significantly. In focusing on patients with newly diagnosed advanced NSCLC with good performance status, Temel et al conducted a study to determine feasibility of implementing a twice weekly physical therapy (PT) run program using aerobic exercise (bicycle and treadmill) and weight training. Functional capacity as measured by the 6-minute walk test (6MWT), muscle strength, QOL and lung cancer symptoms and fatigue were evaluated. Results included no significant post intervention improvement in QOL or fatigue. Lung cancer symptoms, though, were significantly improved. Additionally, no deterioration in the 6MWT or muscle strength were reported. Lastly, Jones et al (2008) studied the effects of aerobic cycle training on changes in VO2peak and QOL among post surgery NSCLC patients. Results included increased VO2peak, improved QOL and decreased fatigue. Exercise therapy is becoming increasingly acknowledged as an integral component of cancer rehabilitation. The limited literature focusing on lung cancer survivors at different stages post diagnosis support exercise training as safe and well tolerated (Jones 2009). Adherence and ability to complete prescribed programs remains an issue, not surprisingly, for this patient population. While studies thus far have other limitations, they illustrate the need for large randomized trials to better determine the timing, support and specific interventions that will optimally benefit lung cancer survivors. References Available as a separate document

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Abstract
The purpose of this session is to allow delegates to bring cases for discussion in relation to unusual thoracic tumours, primarily related to the pathology but also in relation to clinical management of complex pathological cases. Respiratory medicine does not provide a huge volume of material for the diagnostic pathologist, but much of this is related to thoracic cancers and their differential diagnoses. This sometimes leads to a lack of experience in managing rare and complex cases and most pathologists will have an, albeit informal, link for specialist opinion to help in this instance. Indeed, it is now a recommendation in the United Kingdom that a pathway of referral is part of the multidisciplinary management of lung cancer patients. In the speaker’s experience, around 60% of referrals for complex cases relate to tumour pathology, and this is perhaps increasing with the relative decrease in biopsy for non-neoplastic diseases and increased interest in the subtyping of more common tumours. Cases referred for specialist opinion tend to breakdown into small lung biopsies, in particular asking the question, "is there enough evidence to call the biopsy definitively malignant?" This is, in particular, in relation to adenocarcinoma. Another common area is the differential diagnosis of mesothelioma, in particular in relation to spindle cell rather than epithelioid proliferations in the pleura. The third common area for referral is the "rare" tumour, where cases will often be sent because the referring pathologist has been no previous experience of the particular neoplasm. This process is not only of benefit to the referrer but also for the specialist as it allows accrual of potential new entities, an example being primary pulmonary myxoid sarcomas with EWSR1-CREB1 fusion where cases were collected over a period of 12 years from first sighting. Even within these groups, the pattern of referral has changed over the last two decades. Between 1995 and 2000, there were frequent referrals in relation to the differential diagnosis of pulmonary marginal zone lymphoma of MALT origin and reactive pulmonary lymphoid hyperplasia. Now that distinguishing criteria are much more established, these referrals are much rarer. However the last two years has seen an increase in referrals of non-small cell carcinoma, in relation to the need for further subtyping, with many of the cases being those with diverging immunophenotype. Little has been done to assess the value of specialist referral. However a review of personal experience of 50 cases affirmed diagnoses in 26/50 (52%) cases, revised in 16/50 (32%) and favoured diagnoses in 8/50. 80% of reports were deemed to have major clinical significance. Average (laboratory and pathologist) coast was £130.47 respectively (in 2009), excluding lymphoma investigations and corporate costs and current charges in the UK vary between £150 and £250 per case for slide/block reviews. The author would argue that the cost of referral appears is offset by a high level of definitive diagnosis, negating further investigation. Average turnaround time was 5 days, excluding those over holidays, with 80% reported within 7 days. Prolonged reporting times were mainly due to those referring not sending blocks or unstained slides, necessitating further despatch of material. There is also additional delay when cases require molecular analysis. With the advance of digital pathology, this has potential to facilitate and speed up external opinions, although is still in its infancy. This is because referrals often comprise numerous slides which are still quicker to send and review via the microscope than scan and then go through remotely. However, for single or small numbers of slides, the technology has greater potential. Finally, the question is often asked what happens when the putative specialists are unable to make a diagnosis. In the author’s experience, some are undiagnosable for practical reasons, such as poor fixation, whilst some are sufficiently complex and unusual that a further collective opinion from fellow specialists is obtained and fed back to the referring pathologist. This is often after much emailing and debate!

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Abstract
A Practical Approach to the Incidental Pulmonary Nodule David Midthun, M.D. David Milne, M.D. The finding of a pulmonary nodule (or multiple nodules) on an imaging study presents a decision point for the patient and physician. In the absence of a completely sensitive and specific non-invasive test for malignancy, the physician and patient must weigh the options for management. The vast majority of such nodules are benign; however the detection of a nodule may be the first and only point in time of a chance of cure in the patient with lung cancer. Guidelines for nodule evaluation by the American college of Chest physicians (ACCP) and the Fleischner Society may help guide the decision making. Studies of lung cancer screening have shown high rates of nodule detection and that the rate is related to the CT slice thickness (collimation) used. Screening with 10 mm collimation results in detection of one or more nodules in approximately 20-25% of participants, 5 mm collimation increases this to 40-50% of participants, and 1.25 mm collimation raises detection to as high as 60%. A review of the data from 8 CT studies in high risk patients (current or former smokers, age 50 or above) reported that likelihood of malignancy was 0 to 1% for nodules < 5 mm, 6 to 28% for nodules 5 to 10 mm, 33 to 60% for nodules > 11-20 mm, and 64 to 82% for nodules > 20-30 mm. The finding of a nodule on CT should first prompt review of any available old images that might include the nodule for comparison. Review of old images may show that the nodule is growing or, alternatively, establish that it has been stable for 2 or more years. Stability in size over a two-year period has been established as an excellent indicator of benignancy for a solid nodule. If old images are not available, nodules < 8 mm may be observed with follow-up CT at an interval determined by the nodule size. Evidence for nodule growth is a hallmark of malignancy and should lead to a staging PET-CT scan (in those who are candidates for surgery) and consideration of prompt resection. Calcification in a benign pattern is an excellent indicator that a nodule is a granuloma and needs no further pursuit. Eccentric calcification should maintain concern for malignancy. Ground-glass nodules (GGN) are nodules of low density (attenuation) that are generally only visible by CT scan. They deserve special mention as they may represent low-grade adenocarcinomas which behave differently than most malignancies presenting as solid nodules. Malignant GGNs typically exhibit slow growth with doubling times on average over 400 days and, for this reason, the 2-year stability rule for solid nodules doesn’t apply and a longer period of follow-up is needed. PET scanning is not helpful to distinguish malignancy due to the low density of the lesions, and needle biopsy is often nondiagnostic. GGNs may show growth or stay the same size yet develop a solid component in the process of progression. PET scanning uses the injection of the glucose analog 18F-2-fluorodeoxyglucose (FDG) and identifies elevated metabolic activity. Nodule enhancement is an indication that a nodule is more likely malignant than benign, and absence of enhancement is a strong predictor that a nodule is benign. In a multicenter prospective study reported that FDG-PET had an overall sensitivity of 92% and a specificity of 90% for detecting malignant nodules, yet the sensitivity fell to only 80% when nodules of 15 mm or smaller were analyzed. A meta-analysis of pulmonary nodules showed that PET had a sensitivity of 94% and a specificity of 86%. The lower limit of solid nodule size for PET applicability using current techniques is about 8-10 mm. A growing nodule that shows no enhancement on PET should still be considered suspicious for malignancy and prompt needle biopsy or resection. If multiple nodules are present, then evaluation is dictated by the largest nodule. Observation may be appropriate for patients with nodules that are larger than 8-10 mm and have a low likelihood of malignancy based lack of enhancement. Whether or not an indeterminate nodule > 8-10 mm should be biopsied is the subject of considerable debate and practices vary. The two biopsy techniques for assessment of nodules are bronchoscopy and transthoracic needle aspiration (TTNA). Bronchoscopy with fluoroscopy alone has a yield of less than 20% in the setting of malignant nodules less than 2 centimeters and in the range of 40-60% when the nodule is 3-4 cm. Studies of guided bronchoscopy using endobronchial ultrasound and/or electromagnetic guidance have shown marked improvements in diagnostic yield over standard fluoroscopic guidance. Studies using one or more of these techniques have shown yields of 60 to 80% of peripheral nodules of a mean diameter of 2- to 25 mm. Yields remain highest with TTNA; multiple studies report yields of 90% and above for nodules < 2 cm and 95% for nodules > 2 cm. Pneumothorax is the most frequent complication of TTNA. Likelihood of obtaining a specific diagnosis in the setting of a benign lesion is problematic for both bronchoscopy and TTNA. Decision as to the method of biopsy involves lesion size, location, presence of a bronchus leading to the lesion, and comorbidities. Preoperative diagnosis may not be needed for lesions that show growth or are nearing 3cm and are PET avid due to the high likelihood of malignancy and low likelihood a biopsy is going to provide a specific benign diagnosis. An exception would be in countries where there is a high prevalence of tuberculosis where sampling may remain appropriate. Resection is the ultimate management for many lesions that remain indeterminate after imaging evaluation especially in a high risk individual. There are currently too many benign nodules removed surgically. Series of video assisted thoracic surgery (VATS) have reported benign nodules representing as high as 50-86% of nodules resected. Reduction in benign nodule resections may be achieved by observing smaller nodules, by utilizing PET-CT, and by performing biopsy by TTNA or bronchoscopy when information is discordant.

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Background
A new IASLC/ATS/ERS classification for lung adenocarcinoma has been proposed to classify invasive lung adenocarcinoma patients according to the predominant growth pattern present in the tumor: lepidic (LEP), papillary (PAP), acinar (ACN), micropapillary (MPP) and solid (SOL). Several studies have reported consistently that early stage resectable lung adenocarcinoma patients with LEP predominant pattern have a better prognosis, while MPP and SOL predominant patterns have a significantly poorer prognosis. However, the prognostic significance of these histological patterns has not been tested in clinical trials. Furthermore, the clinical utility of this new classification for predicting benefit from adjuvant chemotherapy is unknown.

Methods
The representative single H&E slide of 1766 non-small cell lung cancer patients from IALT, JBR.10, CALGB 9633 and ANITA adjuvant chemotherapy trials who participated in the LACE-Bio study were reviewed to confirm the histological diagnosis. These cases were independently assessed by two pathologists involved in the development of this new IASLC/ATS/ERS classification for subtyping. Discordant cases were resolved by consensus. Clinical outcomes were overall survival (OS, main outcome), disease-free survival (DFS) and specific disease-free survival (SDFS) (DFS with censoring deaths not related to cancer). Multivariable Cox models stratified by trial were used for prognostic analyses and the interaction between treatment (chemotherapy / control) and histology subtypes added for predictive analyses. The five histology subtypes were first analysed separately and 3 groups (LEP, PAP+ACN and MPP+SOL) were considered.

Results
573 patients were classified as 23 (4%) as LEP, 148 (26%) as ACN, 99 (17%) as PAP, 39 (7%) as MPP and 264 (46%) as SOL. The distribution of histology subtypes was different across trials (p=0.02) but not related with standard prognostic variables. The number of deaths, events and cancer-related events were 269, 320 and 292 respectively. No significant difference was observed between the survival curves of 5 subtypes whatever the endpoint. No prognostic value of 3 histological subtypes was observed for OS (p=0.21 in the control arm) contrary to DFS (p=0.04) and SDFS (p=0.03). These last 2 results were explained by the difference between PAP+ACN and MPP+SOL with hazard ratio (HR)~ACN+PAP vs. MPP+SOL~=0.66 95% confidence interval (CI)=[0.47-0.91] and HR~ACN+PAP vs. MPP+SOL~=0.67 [0.44-0.89] for DFS and SDFS, respectively. Due to the small number of patients with LEP predominant pattern, the predictive value was assessed after excluding this subtype. MPP+SOL patients reported significant DFS benefit from adjuvant chemotherapy (HR=0.58 [0.43-0.80], p<0.001) compared to ACN+PAP patients (HR=1.12 [0.79-1.59], p=0.53; p interaction < 0.01). A similar result was observed for SDFS with HR=0.58 [0.42-0.80], p<0.005 in MPP+SOL compared to HR=1.13 [0.78-1.63], p=0.52 in ACN+PAP (p interaction <0.01) while no predictive effect for OS.

Conclusion
Resectable lung adenocarcinoma patients with micropapillary and solid predominant patterns showed a trend for poorer DFS and SDFS compared to patients with the other subtypes, and they show a significantly higher benefit from adjuvant chemotherapy on these outcomes. Histological subtypes according to the IASLC/ATS/ERS classification may be proposed as a stratification factor in design of future adjuvant chemotherapy trials.

Background
The real prognosis of mucinous adenocarcinomas (MAs) diagnosed according to the current IASLC/ATS/ERS lung adenocarcinoma classification is controversial, and in particular, the prognostic value of MA and the relationship among pathologic features, clinicoradiologic presentation, and response to surgical treatment are still unclear. Therefore, the aim of this single-institution retrospective study is to analyze the prognostic role of clinicopathologic and radiologic features in surgically resected MA in a homogenous population of Asian patients.

Methods
Analyzed variables are clinicoradiologic presentations, operation type, histologic subtypes, and stage. Univariate and multivariate analyses of survival were performed.

Results
From 1994 through 2011, 161 resected lung carcinomas were diagnosed as MA in 158 patients, according to the IASLC/ATS/ERS classification. 158 patients included 114 in 1 stage (72%), 29 in 2 (18%), and 15 in 3 (10%). 117 tumors (73%) were nodular-type and 44 (27%) were consolidation-type. Among 117 nodular MAs, 6 were pure GGO nodules.7 tumors presented as multiple lesions. 4 were AIS (lepidic pattern), 1 was MIA (acinar), and 156 (97%) were invasive adenocarcinoma (147 with acinar and 9 with cribriform pattern). The 5-year recurrence rate was 22%, and the 5-year survival rate was 88%. Five-year OS for patients with nodular type compared with those with consolidation-type was 89 versus 57 % (P < 0.001). Based on the multivariate Cox-proportional analysis, consolidation-type on CT (HR 1.42), cribriform pattern (HR 10.35), higher stage (HR 1.51), and higher SUVmax (HR 1.27) were significant poor prognostic predictor for DFS. As for recurrence, SUV max was the only significant predictor in both multivariate Cox-proportional analysis (HR 1.16, P = 0.016) and the log-rank test (cut-off 4.4, P = 0.045). Figure 1 Figure 2

Conclusion
Consolidation-type on CT, cribriform pattern, higher stage, and higher SUVmax would be predictive for lower overall survival. Also, SUVmax would be predictive for higher recurrence and may necessitate more aggressive adjuvant treatment.

Background
Recent advantages of molecular study reveal several subsets of lung adenocarcinoma (AdCa) with specific genetic alterations of receptor tyrosine kinase (RTK), including EGFR, ALK, RET and ROS, which are dramatically responding to targeted inhibitors for activating RTK. The goal of this study is to evaluate the correlation between genetic alteration and histologic phenotype of lung AdCa, including cell type characteristics and mucin phenotype.

Methods
319 surgically resected lung Ad CA was examined genetic alterations of EGFR by Cycleave or direct sequencing, ALK by FISH and immunohistochemistry and KRAS by PCR-RFLP and direct sequencing methods. Resected materials were reviewed detail histologic findings, using HE-stained slides of whole tumor. A histologic predominant subtype of AdCa, based on a new IASLC/ATS/ERS classification, and nuclear grading were evaluated. The mucin phenotype of AdCa was evaluated by Immunohistochemical staining, including muc1, muc2, muc5ac and muc6. The correlation between genetic alteration and histologic phenotypes was examined.

Results
Genetic alterations of this study were 150 EGFR, 44 ALK, 9 KRAS and 116 wild-type. EGFR mutated AdCa had 55.4% lepidic- (lep), 40% papillary- (pap), 2.6% of acinar- (aci) and 2% of solid- (sol) predominant subtypes. ALK AdCa had 20.5% of lep, 36.4% pap, 18.2% aci, 22.7% sol and 2.3% micropapillary predominant subtypes. Kras mutated AdCa were 44.4% pap, 33.3% aci and 22.2% sol. All wild type AdCa were 35.3% of lep, 53.4% pap, 5.2% aci- and 6% sol. Presence of mucin producing cells was observed in 4.7, 90.9, 66.7, and 26.7% of EGFR, ALK, KRAS and wild type AdCa, respectively. EGFR and ALK showed lower nuclear grade compared to KRAS. IHC examination revealed ALK AdCa was positive for muc1, but negative for muc2, 5ac and 6, in contrast to wild type /EGFR AdCa which were positive for muc1, sometimes for muc2, muc 5ac and/or muc6.

Conclusion
In summary, the most common histologic phenotype of EGFR AdCa was lepidic-predominant, non-mucin producing with low nuclear grade; ALK AdCa was papillary, mucin producing with low nuclear grade, and KRAS was papillary, mucin producing with high nuclear grade. The predominant subtype-based classification of AdCa showed an incomplete correlation to a genetic abnormality. Cell type characteristics, including mucin phenotype, would be useful to predict the genetic alteration of lung AdCa, in addition to the predominant subtype which is architecture-based assessment.

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Background
The new IASLC/ATS/ERS classification of lung adenocarcinoma (ADC) histologic subtypes is now recommended for prognostic stratification. The ability to determine histologic subtype accurately by frozen section (FS) may help surgeons to choose limited resection versus anatomic resection in the management of lung ADC. The aim of this study is to investigate the accuracy and interobserver agreement of FS for predicting histologic subtype.

Methods
FS and permanent section slides from 361 surgically resected stage I lung ADCs ≤3 cm were reviewed for predominant histologic subtype and presence or absence of lepidic, acinar, papillary, micropapillary, and solid patterns. To determine interobserver agreement, 50 cases were additionally reviewed by 3 pathologists. To test the accuracy of FS in determining degree of invasion in cases with predominantly lepidic growth pattern, 5 pathologists reviewed FS slides from 35 patients and attempted to discriminate between adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic predominant adenocarcinoma (LPA).

Results

Parameter	Accuracy, % (95% CI)	Sensitivity, % (95% CI)	Specificity, % (95% CI)	κ
Predominant histologic subtype
Overall	68 (63–73)	Not applicable	Not applicable	0.565
Lepidic	90 (86–92)	75 (64–84)	93 (90–96)	0.681
Acinar	76 (71-80)	70 (61–77)	79 (73–84)	0.481
Papillary	85 (81-88)	62 (50–72)	91 (87–94)	0.527
Micropapillary	94 (91-96)	21 (9–40)	99 (97–100)	0.277
Solid	91 (88-94)	79 (67–87)	94 (90–96)	0.700
Presence or absence of each histologic pattern
Lepidic	80 (76–84)	75 (69–80)	91 (84–96)	0.588
Acinar	89 (85–92)	90 (86–93)	67 (35–90)	0.252
Papillary	72 (67–77)	70 (64–75)	79 (69–87)	0.397
Micropapillary	67 (62–72)	37 (30–45)	94 (89–97)	0.321
Solid	84 (80–88)	69 (61–76)	96 (92–98)	0.670

The accuracy of FS for predicting histologic subtype is shown in the Table. There was moderate agreement on the predominant histologic subtype between FS diagnosis and final diagnosis (κ=0.565). FS had high specificity for micropapillary and solid patterns (94% and 96%, respectively), but sensitivity was low (37% and 69%, respectively). The interobserver agreement was satisfactory (κ > 0.6, except for acinar pattern). All cases of AIS were correctly diagnosed using FS. For MIA, only 41.3% of FS diagnoses were correct, and 52% were overdiagnosed as LPA; for cases of LPA, 79% of FS diagnoses were correct.

Conclusion
FS can provide information on the presence of aggressive histologic patterns—micropapillary and solid—with high specificity but low sensitivity. FS is not suitable for determining the predominant pattern or degree of invasion. Although FS can be helpful in diagnosing AIS, it has poor accuracy in distinguishing MIA from LPA.

Background
The new IASLC/ATS/ERS lung adenocarcinoma classification, proposed in 2011, has significant prognostic value. For lung squamous cell carcinoma (SCC), however, no pathologic findings have been widely accepted to predict patient outcomes with the exception of TNM stage. Tumor budding has been recognized as a factor of poor prognosis in colorectal cancer, and nuclear grading has been widely accepted as a prognostic indicator in breast cancer. In this study, we determine whether histologic findings can independently predict prognosis in lung SCC.

Methods
All available tumor slides from patients with therapy-naive, surgically resected solitary lung SCC (1999-2009) were reviewed (n=485; stage I/II/III, 281/136/68). Tumors were graded by means of tumor differentiation. Tumors were classified as keratinizing, nonkeratinizing, and basaloid subtypes by presence (≥5%) or absence of keratinization and by predominant (≥50%) basaloid pattern. Tumor budding (tumor nests composed of <5 cells) and presence of single tumor-cell invasion were assessed using 10 high-power fields (HPFs) (x200 magnification) in the areas with the smallest tumor nests. Tumor budding was considered positive when the maximum number of budding was ≥10/HPF. Single tumor-cell invasion was considered positive when it was identified at 10 HPFs. Nuclear diameter was evaluated, at ≥3 HPFs in the largest nuclei, using nearby small lymphocytes as reference and was classified as either large (>4 small lymphocytes) or small (≤4). Overall survival (OS) was estimated using the Kaplan-Meier method, and multivariate analyses were performed using the Cox proportional hazards model.

Results
Basaloid subtype correlated with better OS than nonbasaloid subtype (p=0.046). Tumor budding (p<0.001), single tumor-cell invasion (p<0.001), and large nuclei (p=0.005) correlated with worse OS (Table). However, tumor differentiation and presence of keratinization did not correlate with prognosis. The prognostic significance of tumor budding was confirmed in a subgroup analysis limited to stage I (p=0.028) and stage II/III (p=0.008) patients. In addition, basaloid subtype correlated with favorable prognosis (p=0.042), and both single tumor-cell invasion (p=0.014) and large nuclei (p=0.021) were associated with poor prognosis in a subgroup analysis limited to stage I patients. In multivariate analysis, tumor budding (HR=1.04; p=0.024) and large nuclei (HR=1.09; p=0.035) were independent prognostic factors for survival.

Table. Overall survival by histologic findings

Histologic finding		5-year OS	p
Subtype	Basaloid	69% (n=33)	0.046
	Nonbasaloid	58% (n=452)
Tumor budding	+	39% (n=76)	<0.001
	-	62% (n=409)
Single cell invasion	+	47% (n=197)	<0.001
	-	67% (n=288)
Nuclei	Large	50% (n=153)	0.005
	Small	63% (n=332)

Conclusion
Tumor budding and large nuclei, but not histologic subtype, were significant prognostic factors, independent of TNM stage, for lung SCC. These findings may help to make therapeutic decisions and stratify patients for additional therapy.

Background
Fibroblast growth factor receptor 1 (FGFR1), which codes for a receptor tyrosine kinase, was recently reported to be amplified in 20% of lung squamous cell carcinoma (SqCC). In vitro and preclinical tests suggest that FGFR1 amplification is a therapeutic target. Our aims were to investigate the prevalence of FGFR1 amplification by fluorescence in situ hybridization (FISH) and determine correlation with outcome in an Australian cohort of resected lung cancer. We also correlated results of FGFR1 FISH with silver in situ hybridization (SISH).

Methods
A clinically-annotated tissue microarray was constructed from resected lung cancer tissue collected from 1996-2012. FGFR1 FISH and SISH were performed according to manufacturer’s protocols, with SISH performed on Ventana benchmark XT platform. FGFR1 FISH and SISH were scored by one pathologist, with high level amplification defined as ratio of FGFR1/centromere 8 ≥ 2, or tumor cell percentage with ≥ 15 signals ≥ 10%, or average number of FGFR1 signals/tumor cell nucleus ≥ 6, and low level amplification as tumor cell percentage with ≥ 5 signals ≥ 50%. Results of FGFR1 FISH and SISH were compared. Patient outcome related to FGFR1-amplified tumors was assessed and compared to patients with SqCC, or with a morphologic component of, or immunoprofile of SqCC, but normal FGFR1 copy number.

Results
Of 406 tumors tested, there were 191 pure SqCC, 28 carcinomas with a SqCC component, 24 large cell carcinomas with an immunoprofile of SqCC, 115 adenocarcinomas, 22 pulmonary neuroendocrine tumors, and 28 other carcinomas without a morphologic component or immunoprofile of SqCC. FGFR1 amplification was assessable in 368 tumors. FGFR1 amplification was identified with FISH in 50 tumors, 48 (48/225; 21.3%) of which were either pure SqCC or a carcinoma with morphologic component or immunoprofile of SqCC. Only two cases were completely of non-squamous origin (2/143; 1.4%, p<0.00001). FGFR1 SISH was performed in 385 tumors, with 347 tumors assessable. Of 46 FGFR1 FISH-amplified tumors assessed with FGFR1 SISH, all showed FGFR1 amplification with SISH, whilst all other tumors tested were negative. Survival from radically treated FGFR1-amplified tumors was similar to all others with a squamous component (73% versus 60% 5-yr survival, HR 0.68, p=0.25; Figure 1).Figure 1

Conclusion
FGFR1 amplification with FISH was identified in 21.3% of pure SqCC or carcinomas with a morphologic component or immunoprofile of SqCC, but only 1.4% of completely non-squamous tumors. All adenocarcinomas and neuroendocrine tumors were negative. FGFR1 SISH showed 1:1 correlation to FGFR1 FISH.

Abstract not provided