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  • WCLC 2015

    16th World Conference on Lung Cancer

    Access to all presentations that occur during the 16th World Conference on Lung Cancer in Denver, Colorado

    Presentation Date(s):
    • September 6 - 9, 2015
    • Total Presentations: 2499

    To review abstracts of the presentations below, narrow down your search by using the Filter options below, and then select the session listing of your choice. Click the "+" for a presentation to expand & view the corresponding Abstract details.

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    P1.05 - Poster Session/ Prevention and Tobacco Control (ID 215)

    • Type: Poster
    • Track: Prevention and Tobacco Control
    • Presentations: 8
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      P1.05-001 - Rural Tobacco Smoke Pollution: Preliminary Results of a Longitudinal Study (ID 124)

      K. Buettner-Schmidt, B. Boursaw, M.L. Lobo

      • Abstract
      • Slides

      Background:
      In 2012, North Dakota enacted a comprehensive smoke-free law. In 2014, the 3rd phase of a stratified random sample longitudinal study of tobacco smoke pollution in restaurants and bars was conducted (n = 107). Phase 1 was conducted prior to passage of the law, Phases 2 and 3 were conducted 3 and 21 months post-implementation respectively.

      Methods:
      Tobacco smoke pollution levels were assessed by collection of particulate matter 2.5 microns aerodynamic in diameter or smaller using SidePak [TM] AM510 Personal Aerosol Monitors.

      Results:
      The geometric mean PM~2.5 ~was 6.9 microns/m[3]. Statistically significant reduction in mean PM~2.5~ occurred from Phases 1 to 3 but not from Phases 2 to 3 in all venues and for bars alone. A significant increase in indoor PM~2.5~ occurred when there was outdoor smoking or ashtrays within 20 feet of the venue entrance, exit, or windows and when smoking was observed within designated outdoor smoking shelters. Multi-level linear models found that the presence of a local ordinance and venue type were predictors of PM~2.5~ in Phase 1 but not in Phases 2 or 3. Significant decreases in mean PM~2.5~ by rurality occurred between Phases 1 and Phase 3. In contrast with the Phase 1 study, there were no significant differences in PM~2.5~ by rurality in only Phase 3.

      Conclusion:
      This longitudinal study is the largest rural pre and post-law rural study known globally. Passage of the comprehensive statewide smoke-free law effectively reduced PM~2.5~ levels in restaurants and bars statewide.

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      P1.05-003 - Dutch Government Taken to Court by 2 Chest Physicians Because of Violation WHO FCTC 5.3 (ID 820)

      W.D. Kanter

      • Abstract
      • Slides

      Background:
      The Youth Smoking Prevention Foundation is taking the Kingdom of the Netherlands to court to end the structural and excessive influence exerted by the tobacco lobby on government anti-smoking policies. The Foundation is calling on the Dutch government to comply fully with the anti-smoking convention (WHO FCTC), which it signed and which is therefore legally binding. One of the most important articles in the convention states that every form of influence by the tobacco industry on policies to deter smoking must be avoided. In the court summons issued, the Foundation offers dozens of examples that show how the government has systematically violated this provision, and even invites the tobacco industry to clarify its position on matters of policy development. 19,000 tobacco-related deaths More than 19,000 Dutch people, half of them younger than 65, die each year as a result of smoking. In addition, an average of 120 children under the age of 18 start smoking every day. Some 60 of them will continue to smoke for the rest of their lives, and 30 of them will die prematurely from the effects of smoking. Smoking is by far the biggest cause of death that could be avoided through prevention. However, the marketing techniques deployed by the tobacco industry are so refined that many youths cannot resist the temptation to start smoking. Moreover, cigarettes are designed to be highly addictive. Children who start smoking end up addicted within weeks. For many of them, the question of ‘free will’ no longer applies: they are unable to stop smoking without help. Numerous national and international laws and conventions make it a duty of the Dutch government to protect the health of its citizens from a serious cause of illness like tobacco. With as many as 19,000 tobacco deaths every year, the government has an obligation to do all in its power to combat the massive scale of premature fatalities. And it should certainly prevent minors from starting to smoke, because almost nobody starts after they turn 18. Despite all this, the Dutch government has failed to implement measures that could be very effective in achieving results: imposing much higher taxes on tobacco and greatly reducing the current number of over 60,000 points of sale. Instead, the government listens to the tobacco industry, whose effective lobbying continues to successfully obstruct measures to discourage tobacco use.

      Methods:
      not applicable

      Results:
      ongoing lawsuit.

      Conclusion:
      The lawsuit is ongoing. Our foundation has had a lot publicity in all national media (television ,newspapers) As a chest physician working in an oncology center mainly treating patients with lungcancer it is very powerfull to start a lawsuit against the state to prevent lung cancer. We are making progress: we are at the table of several Ministries (finance, health department) to discuss the firewall protocol against the lobby of big tobacco. We use social media and patients advocates to make our message even stronger

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      P1.05-004 - Smoking Prevention Intervention with School Classes at a University Hospital by Thoracic Surgeon and Pulmonologist (ID 901)

      M. Schuurmans, S. Tomaszek, D. Schneiter, W. Weder, S. Hillinger

      • Abstract

      Background:
      Smoking prevention in schoolchildren with the aim to inform and prevent smoking initiation has been widely studied and has shown variable results. Interventions provided by physicians in a hospital setting have been rarely reported. Here we show the feasibility and gain of knowledge of our smoking prevention project in a hospital setting.

      Methods:
      Interventions performed from November 2009 - December 2014 were evaluated. Overall 790 children participated in our preventive intervention. A 7-item questionnaire was provided to the school classes (Grades 6 to 10) before and after a two-hour smoking prevention intervention consisting of anatomical models, oral presentations, videos, patient interviews and hands-on lung function tests. The goal was to show the anatomical and physiological basics as well as age-based information about the harms of smoking. During the intervention the children have been motivated to be actively involved. Class selection has been performed for groups of children in a highly vulnerable phase of age before smoking initiation.

      Results:
      The baseline questionnaire was completed by 768 children, the one after intervention by 719. The knowledge about which organs are affected by smoking increased from 7.1-99.3% to 64.5-99.5% (p<0.01). While only 58.9% knew that only a minority of people is able to quit smoking successfully, 96.3% answered the question correctly after intervention (p<0.001). Prior to the intervention only 75.6% believed that minor tobacco consumption is not damaging which increased to 87.8% after the teaching session (p<0.05). Smoking hookah was believed to be less harmful than cigarettes by 32.2% of children decreasing to 8.3% after the intervention (p<0.001).

      Conclusion:
      Information on health effects provided by lung specialists in the hospital leads to a statistically significant increase in knowledge as assessed by a short questionnaire. The intervention is feasible and well received. This kind of interventions might help to prevent schoolchildren from smoking in a highly vulnerable phase of age.

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      P1.05-005 - Italian Multicentric Survey on Smoking Cessation in Lung Disease Patients and the Role of Healthcare Workers in This Contest (ID 1343)

      S. Demichelis, S.G. Rapetti, D. Galetta, A. Bruno, E. Bria, S. Pilotto, G. Valmadre, A. Catino, M. Gianetta, S. Vallone, M.V. Pacchiana, S. Novello

      • Abstract
      • Slides

      Background:
      Smoking is a risk factor for several lung diseases. Quitting smoking provides positive outcomes and gives the best chance for the treatment in patients with pulmonary diseases, including lung cancer diagnoses. Currently few centers in Italy offer counseling for smoking cessation in cancer patients (and for patients with other lung diseases), despite the demonstrated efficacy of it.

      Methods:
      408 patients with pulmonary diseases (72% with lung cancer) were prospectively and sequentially evaluated from January 2013 to February 2015. An anonymous survey was developed with the aim to understand if current or former smoker patients received information by healthcare workers about smoking cessation before or after the diagnosis, their reaction and the actions adopted for quitting smoking. The survey included the Fagerström test for assessing the intensity of addiction to nicotine and it was conducted in several Italian Thoracic Oncology Units and Pulmonology Divisions.

      Results:
      After a pulmonary disease diagnosis, 72% of patients state to quit smoking, 20% to smoke less or not feel the same pleasure as before and only 8% confirms to continue to smoke or smoking even more. Among former smokers (298 people), 150 patients state how long they quitted smoking and in 45% of the cases was at the time of diagnosis or even later, about 35% 10 years before the diagnosis and 8% between 5 and 10 years earlier, while 12% more recently. Most of current smokers state that they continue because smoking helps them to control the stress, others because they like it or are not able to quit and very few because is a repetitive gesture. Data show that 39% of patients did not receive information about smoking cessation by health professionals, 26% received it before the diagnosis, 12% after it and 23% received it both before and after the diagnosis. Concerning the reaction to the counseling, 53% considers positively the health care provider action, even if 28% hoped they could have helped them more quit smoking and 19% reports a warning and paternalistic attitude of them. Only 23% of patients who attempted to quit smoking considers the gradual termination as the most effective measure, more than the sudden interruption. Regarding the smoking-cessation method or specific therapy adopted, 65% disclosed they simply quitted smoking overnight and 80% confirmed it as the most effective technique, while only 16% used electronic cigarettes, 8% a nicotine replacement treatment, 7% books and 4% attending a dedicated clinic. The Fagerström Test confirms that 50% has a low to moderate dependence to nicotine, while 50% has a high dependence.

      Conclusion:
      The survey was distributed to 293 lung cancer patients and 115 with pulmonary disease (mainly COPD patients). The result analysis underlines that the vast majority quitted smoking after having received their diagnosis. No main differences were seen evaluating the group with malignant and non-malignant diseases. Although many of them got advice by healthcare workers, the recourse to the use of techniques, drugs or access to specific clinic is still very low, especially considering that 50% of patients result highly dependent to nicotine.

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      P1.05-006 - One Cigarette Takes 12.6 Minutes of Your Life (ID 2560)

      E. Thunnissen

      • Abstract
      • Slides

      Background:
      Smoking is the largest cause of premature mortality. Smoking cessation is important, but is difficult to reach. A general underestimation of personal risk in smokers or a degree of misunderstanding around key risk factors for disease may be substantial. [1]The aim of this abstract is to calculate the reduction in average life expectancy per cigarette.

      Methods:
      Men born in 1900-1930 who smoked only cigarettes and continued smoking died on average about 10 years younger than lifelong non-smokers. Cessation at age 60, 50, 40, or 30 years gained, respectively, about 3, 6, 9, or 10 years of life expectancy.[2]Assuming that these men started at age 15 years and died at age of 72 this results on average in 57 years of smoking. Also assumed is that each day one pack of 20 cigarettes is smoked.

      Results:
      Smoking for 57 years 20 cigarettes per day results in a total of 416,100 cigarettes. The total number of minutes in 10 years is 5,256,000. The average decrease in life expectancy is 12.6 minutes/ cigarette or 4.2 hours /pack, equals more than a day/week. Discussion: If a smoker is aware of the reduced life expectancy then smoking of one cigarette may be looked-upon as a mini-suicide attempt. Taken also into account the passive smoking effect, the smoker may be seen as a mini-suicide-nano-terrorist.

      Conclusion:
      Conclusion The reduction in average life expectancy is 12.6 minutes per cigarette or 4 hours per pack. This knowledge may be of help to raise more awareness for the dangers of smoking. 1. Bethea J, Murtagh B, Wallace SE. “ I don ’ t mind damaging my own body ” A qualitative study of the factors that motivate smokers to quit. 2015;1–9. 2. Doll R, Peto R, Hall E, Wheatley K, Gray R. Mortality in relation to consumption of alcohol: 13 years’ observations on male British doctors. BMJ. 1994;309(6959):911–8.

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      P1.05-007 - One-Stop Counselling, Social Support & Stop Smoking Aids Helps Smokers Quit (ID 198)

      E. Odiase

      • Abstract
      • Slides

      Background:
      It has been a normal practice for governments, not-for-profits and other platforms to provide Quitlines to help smokers quit. There has been positive results, however a recent study shows that a one-stop platform can offer more desirable outcomes.

      Methods:
      We conducted a 6-month study through an online survey involving 1,200 smokers who visited a revolutionary one-stop smoking cessation online platform, www.quitgate.com. Figure 1After visitors ordered a product or called the Quitline, a questionaire was emailed to them. Questions asked included year of smoking initiation, number of cigarettes smoked per day and number of quit attempts and through what means.



      Results:
      Interestingly, 37% of the participants reported that they were motivated to quit because when they called the Quitline and received counselling from the Tobacco Treatment Specialist, they were immediately provided without obligation, the option of getting a smoking cessation product on same platform with either some of the product free or highly discounted. Another group, 11% said they prefered the platform to quit because it was social, friendly, professional, non-judgemental and yet non-clinical. Overall, most of the participants said it was a great idea to have a one-stop platform which provided free professional counselling, smoking cessation products, tools/apps like smoking calculator, DNA (Dependence on Nicotine Assessment) low prices, free shipping and premium customer service to highly motivate smokers quit for good.

      Conclusion:
      It is great to note that while Quitlines are provided by several institutions to help in smoking cessation, an important area of also making smoking cessation products availble either for free or a little amount will go a long way to motivate smokers. The Centers for Disease Control and Prevention-CDC cites evidence-based counseling, behavioral cessation therapies, medication, and social support as treatments that increase the chances of tobacco cessation

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      P1.05-008 - Big Tobacco and the Creation of an Epidemic of Smoking-Related Adenocarcinoma of the Lung: SEER-Based Analysis, 1973-2011 (ID 2479)

      G. Strauss, A. Moreno-Koehler, M. Finkelman

      • Abstract
      • Slides

      Background:
      When epidemiologic research first demonstrated an association between cigarette smoking and lung cancer in the early 1950s, adenocarcinoma comprised about 5% of lung cancers and appeared to be unrelated to smoking. In the 1960s and 1970s, adenocarcinoma increased sharply, and became strongly related to cigarette smoking. At the 2007 IASLC-sponsored 12th World Conference in Lung Cancer in Seoul, Korea, our group reported that by 2003, adenocarcinoma of the lung had risen to comprise 47% of all lung cancers in the US. The objective of this presentation is to update and expand upon our previous analysis.

      Methods:
      We analyzed time trends in lung cancer histology with changes in cigarette design and Tobacco Industry actions over six decades. We utilized Surveillance-Epidemiology and End Results (SEER) data on 419,941 lung cancers diagnosed between 1973 and 2011 to analyze time trends of age-standardized incidence rates of five histologic subtypes: adenocarcinoma, squamous cell, small cell, large cell, and adenosquamous carcinoma.

      Results:
      Over time, the percentage of lung cancers that were adenocarcinomas increased from 29% (in 1973-1974) to 55% (in 2010-2011). During this 38-year period, the percentage of lung cancers that were squamous cell carcinomas decreased from 41% to 26%. Among all patients, adenocarcinoma incidence surpassed squamous carcinoma by 1985-1989 to become the most common histologic subtype. Adenocarcinoma surpassed squamous cell in 1990-1994 in men, while it was already most common in women by 1973-1974. Adenocarcinoma rose 77% in men from 1973-1974 to 1990-1994, while it rose 197% in women between 1973-1974 and 2005-2006. Among whites, adenocarcinoma surpassed squamous carcinoma by 1985-1989, while this occurred among blacks by 1990-1994. It was already most common among other race individuals in 1973-1974. Adenocarcinoma was already most common among patients <50 years of age by 1973-1974, while adenocarcinoma rapidly increased and surpassed squamous carcinoma in all other age groups by 1990-1994.

      Conclusion:
      Incidence of adenocarcinoma of the lung has continued to increase to such an extent that it comprises a clear majority of all lung cancers in the US. Indeed, our analysis demonstrated that lung adenocarcinoma currently represents 55% of US lung cancers. It is the most common histology in men and women, in whites, blacks, and other-races, and in all age groups. The question of how the actions of Big Tobacco helped to create this epidemic will be addressed in a separate presentation at this meeting.

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      P1.05-009 - EGCG Regulated Ku70 Acetylation for Apoptosis in Human Lung Cancer A549 Cells (ID 194)

      M. Li, J.J. Li, Q.H. Gu, L.M. Cao, H.P. Yang, C.P. Hu

      • Abstract
      • Slides

      Background:
      Lung cancer is one of the malignant tumors whose global incidence and mortality are very high. The chemoprevention has become an important prevention and control means of lung cancer except for giving up smoking and early detection. Research has showed the main component in green tea (-)-epigallocatechin-3-gallate (EGCG) is a potential chemopreventive agent for various tumors, especially lung cancer.

      Methods:
      The cells in each group were treated with different concentrations of EGCG for a certain time in the experiment. Two gene point mutation plasmid were constructed and transfected in A549 cells. Induction of apoptosis was examined using AnnexinV/Pl double staining flow cytometry. Western Blot detected the protein expressions of Bax, Bcl-xl and Caspase-3. Co-immunoprecipitation was used to detect the interaction of Ku70-Bax and acetylation status of Ku70. P<0.05 showed the difference had statistical significance.

      Results:
      Treatment of A549 cells with EGCG induced apoptosis with increasing expression of Bax and Caspase-3, but decreasing expression of Bcl-xl. EGCG could up-regulate K70 acetylation status of A549 cells,then down-regulate the interaction of Bax-Ku70 in the manner of concentration and time dependent. The apoptosis-promoting effect of EGCG on A549 cells was obviously weakened with the interaction of Bax-Ku70 strengthened and Caspase-3 (17KDa) expression declining after pCDNA3.1(+)-Ku70 plasmid and pCDNA3.1(+) -Ku70[539/542R] plasmid transfection.

      Conclusion:
      The authors induced apoptosis in human lung adenocarcinoma A549 cells after treatment with EGCG, and it was realized by interfering the interaction between Ku70 and Bax through regulating K70 acetylation. It verified that two loci K539 and K542 of Ku70 acetylation might play a crucial role in EGCG inducing apoptosis of A549 cells.

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    P1.06 - Poster Session/ Screening and Early Detection (ID 218)

    • Type: Poster
    • Track: Screening and Early Detection
    • Presentations: 29
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      P1.06-001 - Ultra-Low Dose-CT Accurately Detects Significant Lung Nodules with a Fraction of the Radiation of Conventional Low Dose-CT (ID 2621)

      A. Miller, D. Jackson, S. Deshpande, C. Hui, G. Hamilton, K. Lau

      • Abstract

      Background:
      Indeterminate lung nodules are a common and increasing incidental finding on CT imaging and there are widely accepted surveillance protocols. However, even when using Low Dose (LD)-CT with a total effective dose of ~1mSv, concerns exist regarding the cumulative radiation exposure of subjects under surveillance, particularly in individuals not at high risk of lung cancer. By utilizing the Model Based Iterative Reconstruction (MBIR) technique, CT images can be obtained with a radiation dose comparable to chest x-ray (0.06-0.1 mSv). At this Ultra-Low Dose (ULD), MBIR images have generally less signal to noise ratio which may prevent small nodule detection. The aim of this prospective study was to assess the efficacy of ULD-CT in detecting clinically significant lung nodules (≥4mm) as compared to LD-CT.

      Methods:
      Following approval from the local Human Research Ethics Committee, adult subjects undergoing CT surveillance for incidental lung nodules were recruited from a tertiary hospital. Once informed consent was obtained, both standard LD- and a ULD-CT chest were performed. Scans were performed on the GE750HD Discovery scanner. Demographic information including lung cancer risk factor evaluation was obtained by questionnaire. Patients who withdrew consent or whose images were degraded by gross movement or metallic artefacts were excluded. Images from the ULD-CT were reconstructed with MBIR prior to reading. Each of LD/ULD-CT image sets was read blindly, randomly and independently by two experienced thoracic radiologists. The number, size and location of nodules was reported and subsequently compared.

      Results:
      100 subjects were recruited with a mean age of 65 years (range 32-87). Around 62% were ever smokers, with 30% smoking ≥30 pack years. Around 30% had risk factors other than smoking, but only ⅓ of these (9%) did not have a significant smoking history. Only a small proportion were high risk as evidenced by only 8 meeting Lung Cancer screening criteria (NLST criteria). A total of 200 nodules ≥4mm were detected, with all seen on both LD and ULD-CTs. In addition, there were 244 nodules <4mm seen on the LD-CT, with greater than 80% sensitivity for the ULD-CT, with minor variation between lobes. There were no false positive findings. There was a 10 fold reduction in effective radiation when comparing ULD-CT (0.09mSv) imaging with the standard LD-CT (1.11mSv). Lung nodules were subjectively better seen on the ULD-CT.

      Conclusion:
      ULD-CT with the advanced MBIR allows detection of all clinically significant lung nodules while achieving a radiation dose comparable to that of plain chest radiography. Particularly in low-risk populations, the use of ULD-CT for surveillance of lung nodules has the potential to significantly reduce cumulative radiation exposure.

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      P1.06-002 - Lung Cancer Screening Guidelines May Not Capture the Complete Population At-Risk (ID 525)

      A. Plank, W. Moore, B. Nemesure

      • Abstract
      • Slides

      Background:
      In December 2013, the United States Preventive Services Task Force (USPSTF) provided a level B recommendation for the use of low-dose computed tomography (LDCT) to screen high-risk patients for lung cancer. Most recently, in February 2015, the Centers for Medicare and Medicaid Services (CMS) likewise approved coverage for at-risk patients, defined as those 55 years of age or older with a strong (30 pack-year) smoking history. The current USPSTF and CMS specified eligibility criteria for lung cancer screening are similar to those implemented by the National Lung Screening Trial and other studies which provided the evidence base that precipitated the decision to screen high risk patients, however these criteria may not adequately capture all sub-groups that comprise the complete population at risk for developing lung cancer. For example, younger patients (50+ years) who have a moderate (20 pack-year) smoking history and at least one other known lung cancer-related risk factor are considered to be at high risk by the National Comprehensive Cancer Network (NCCN). The purpose of this investigation is to investigate the prevalence of lung cancer among younger and older age groups of screening patients nationwide and to begin to provide important data that may assist with evaluating the adequacy of the eligibility criteria currently being used to define the population at-risk for developing lung cancer.

      Methods:
      The Center for Lung Cancer Screening and Prevention at the Stony Brook Cancer Center, recently conducted an electronic survey of all Lung Cancer Alliance Centers of Excellence for Lung Cancer Screening nationwide. The survey collected information regarding numbers and age groups of patients screened, numbers and stages of lung cancers detected, smoking history and other demographic variables. Lung cancer status (cancer detected vs. no cancer detected), stratified by age group (50-54 years vs 55-80 years) are presented here. A total of 24 Centers (among 240) provided data for the survey. Many Centers did not have available data for the younger subgroup of patients likely due to the implementation of the USPSTF criteria rather than the NCCN guidelines that recommend screening this younger, at-risk subgroup.

      Results:
      The survey data were cumulated over all 24 participating Centers of Excellence nationwide and included 7,252 patients. Of these, n= 697 patients were 50-54 years of age and n=6,555 were 55 years or older. Among the younger cohort, 16 patients (2.3%) were found to have lung cancer. In the older age category, lung cancer was detected in 130 patients or 2.0%.

      Conclusion:
      These findings suggest that this younger subgroup of at-risk patients warrant further consideration for lung cancer screening. Additionally the data suggest that this well-defined subgroup of 50-54 year old patients who have a moderate smoking history and at least one other known lung cancer-related risk factor may be at even higher risk for developing the disease than those 55+ years with a 30 pack-year smoking history. These nationwide data highlight the urgent need to re-evaluate the eligibility criteria currently being used to define the population at risk for developing lung cancer.

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      P1.06-003 - Low-Dose CT Lung Cancer Screening in the Community: A Prospective Cohort Study Incorporating a Gene-Based Lung Cancer Risk Test (ID 879)

      R. Young, R.J. Hopkins, V.K. Lam, E. Cabebe, M. Miller, G.D. Gamble

      • Abstract
      • Slides

      Background:
      Following the publication of the National Lung Screening Trial (NLST) results in 2011, CT screening for lung cancer is now widely recommended in the US. However concerns remain with regards to patient selection according to risk level and overdiagnosis.Moreover adherence outside screening trials is typically about 50-60% and has been shown to be highly dependent on an individual's risk perception. This feasibility study explores the relevance of gene-based data on lung cancer risk assessment and adherence to screening, in a pilot screening program.

      Methods:
      This feasibility study was initiated in 2010 prior to NLST results being published. Following local media-based advertising, 157 current or former smokers (>50 years old with ≥20 pack year history), volunteered for lung cancer risk assessment and CT screening (using the IELCAP protocol). Participants were followed up for a mean of 2.4 years.At baseline CT screening, participants were assigned their lung cancer risk category according to a published and prospectively validated gene-based risk algorithm. This algorithm combines clinical risk variables with risk genotypes, derived from analysis of 20 risk single nucleotide polymorphisms (SNPS), to derive a composite lung cancer risk score categorised as moderate, high or very high.

      Results:
      SNP genotype results contributed to overall lung cancer risk in 88% of participants compared to the contribution from age = 68%, family history of lung cancer = 29% and self reported chronic obstructive pulmonary disease =15%. The SNP genotype results were the sole basis of risk in 18% of participants and contributed to risk in a further 70% of participants (total 88%). Adding SNP scores to the clinical risk score re-assigned screening participants into different risk categories in 28% (44/157) of participants (Figure 1). Importantly, timely adherence to the CT screening protocol was two-fold greater in those with a very high risk score compared to the high and moderate risk categories (71% vs 52% vs 52% respectively, OR =2.3, P<0.05). Figure 1



      Conclusion:
      In this feasibility study of a pilot community-based CT screening program we found gene-based risk assessment was of interest to all screening volunteers. As part of risk assessment, personalised SNP data made the greatest contribution to overall assignment of lung cancer risk in association with established clinical variables and significantly improved screening adherence. We conclude that gene-based risk stratification helps assign lung cancer risk and appears to improve adherence to screening.

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      P1.06-004 - Common Misconceptions About Lung Cancer Screening: A Nationwide Survey (ID 1755)

      A. Cortot, L. Greillier, C. Touboul, F. Eisinger, X. Pivot, J. Viguier, J. Blay, C. Lhomel, S. Couraud, J. Morere

      • Abstract
      • Slides

      Background:
      The National Lung Cancer Screening Trial has demonstrated the efficacy of lung cancer screening based on annual low-dose computed tomography (CT) scanning in both former and current smokers. Nationwide lung cancer screening programs are therefore expected to be implemented. Adhesion to these programs will depend largely on public information regarding lung cancer screening. Here, we report on widespread beliefs regarding lung cancer screening in the general population prior to any information campaigns on lung cancer screening.

      Methods:
      The EDIFICE French nationwide observational surveys, conducted every 3 years since 2005, set out to characterize behaviors related to cancer screening. The 4th edition, EDIFICE 4, was conducted by phone interviews of a representative sample of 1602 subjects aged between 40 and 75 years, using the quota method, from June 12 to July 10, 2014. Attitudes and opinions regarding colorectal, prostate, breast, cervical and lung cancer screening were assessed.

      Results:
      For 43% of the French population, lung cancer screening is more reassuring than distressing. This figure is lower than those reported for perceptions of other screening programs, including colorectal cancer screening (51%) and breast cancer screening (63% vs. 46.7% for lung cancer screening in the female population). Eleven percent of the respondents (N=162) declared having already undergone a lung cancer screening test. For the vast majority (87%, N=140), this comprised a chest X-ray and for 63%, (N=101) the chest X-ray was not associated with another type of examination. Respondent-declared reasons for not undergoing screening included absence of risk factors (36%), absence of respiratory symptoms (34%), absence of physician recommendations for screening (29%) and futility (11%). Seven percent of current smokers and 32% of former smokers did not undergo screening because they did not consider themselves at risk for lung cancer. Fear of the results pushed 9% of current smokers to avoid lung cancer screening. However, 22% of all respondents and 38% of current smokers declared their intention to undergo a lung cancer screening test in the future.

      Conclusion:
      The general population has many misconceptions of lung cancer screening. Implementation of nationwide lung cancer screening programs should include information for the general public regarding selection criteria, techniques used and the benefits of lung cancer screening using low-dose CT scanning.

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      P1.06-005 - The Correlation between Visceral Pleural Invasion in T1a Non-Small Lung Cancer and Lymph Node Metastasis (ID 2638)

      M. Tsuboi, H. Takizawa, D. Matsumoto, N. Kawakita, K. Kajiura, H. Toba, Y. Kawakami, S. Sakiyama, K. Kondo, A. Tangoku

      • Abstract
      • Slides

      Background:
      Visceral pleural invasion (VPI) of non-small cell lung cancer (NSCLC) has been recognized as a poor prognostic factor. Peripheral lung cancers often invade visceral pleura, and positive VPI upstages the T category of tumors from T1a to T2a. In addition, it is possible that peripheral lung cancers with positive VPI causes lymph nodes metastasis because of subpleural lymphovascular invasion. In this study, we statistically analyzed the correlation between VPI and lymph node metastasis.

      Methods:
      129 patients with NSCLC and a tumor diameter of ≤ 2cm underwent lobectomy or segmentectomy with systematic lymph node dissection in Tokushima University Hospital between January 2008 to December 2013. Excluding 11 patients who were not examined by FDG-PET before the surgery, we reviewed the medical records of 118 patients to obtain information on age, sex, CEA, SUVmax, CT findings, pathological VPI and lymph node metastasis.

      Results:
      Patient characteristics were as follows: median age of 66.5 (range: 41-86); male/female: 52/66; histologic type adenocarcinoma/squamous cell carcinoma/other: 103/12/3. 13(36.1%) of 36 patients who were suspected to be with visceral pleural invasion by preoperative CT findings were diagnosed with pathological visceral pleural invasion. The mean SUVmax on FDG-PET in patients with VPI was significantly higher than that of patients without VPI(p=0.01). Pathological visceral pleural invasion was identified in 19(16.1%) of 118 patients and associated with high incidence of lymph node metastasis significantly on multivariable analyses (p=0.00).

      Conclusion:
      VPI is important factors of lymph node involvement in small peripheral lung cancers. It is difficult to identify VPI of peripheral lung cancers by preoperative CT findings. FDG-PET may be useful for diagnose VPI.

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      P1.06-006 - Metabolomics by NMR Facilitates the Non-Invasive Diagnosis and Staging of NSCLC (ID 1374)

      C. Pérez-Rambla, L. Puchades-Carrasco, E. Jantus-Lewintre, F. García-García, R. Lucas, S. Calabuig, A. Blasco, J. Dopazo, C. Camps, A. Pineda-Lucena

      • Abstract
      • Slides

      Background:
      Lung cancer (LC) is the most common cause of cancer death worldwide. At present, the diagnosis is primarily based on symptoms and detection occurs at late stages, thus resulting in a very poor prognosis. If the diagnosis could be shifted to early stages, then the overall morbidity for this disease could be dramatically altered. Metabolomics, an analytical platform used in combination with statistical techniques, has been shown to be a very powerful approach for the understanding of biological pathways involved in the onset and progression of diseases. The objective of this study was to identify, using metabolomics by NMR, a set of specific metabolites that could be used for LC screening in the clinical context.

      Methods:
      Metabolic profiles corresponding to a training set of serum samples from early-stage (n = 66) and advanced-stage (n = 69) NSCLC patients were obtained using [1]H-NMR spectroscopy. A matched control set of 71 serum samples from healthy subjects was also included. Furthermore, NMR experiments were also performed for an external validation set consisting of 20 early-stage and 20 advanced-stage NSCLC patients, 13 healthy individuals, and 27 benign pulmonary disease patients (BPD).

      Results:
      Multivariate statistical modeling of the data revealed that the serum of NSCLC patients, when compared with healthy individuals, exhibit a specific serum metabolic profile (R[2 ]= 0.931; Q[2 ]= 0.873) characterized by statistically significant differences in the concentrations of a number of lipids, organic acids and amino acids. The metabolic profiles obtained for NSCLC patients and healthy individuals were also different to that obtained for BPD patients. A similar analysis performed to compare the serum metabolomic profile of NSCLC patients at early and advanced stages of the disease (R[2 ]= 0.779; Q[2 ]= 0.592) showed that disease evolution has also a reflection in the metabolic profile of patients. Furthermore, a logistic regression analysis allowed the identification of a specific combination of five metabolites (threonine, glutamine, lactate, choline and methanol) that enables the discrimination between healthy individuals and NSCLC patients with a 77,5% sensitivity and a 76,9% specificity (70% for all non-cancer samples).

      Conclusion:
      Our results highlight the potential of metabolomics by [1]H-NMR for identifying biological pathways involved in the onset and progression of NSCLC, thus providing a sensitive, specific, minimally invasive and easily implementable method in clinical practice for the early diagnosis of NSCLC and for the optimization of risk profile models. Acknowledgements: Spanish Ministerio de Economía y Competitividad (MINECO, SAF2011-28350), Centro de Investigación Príncipe Felipe and Fundación Mutua Madrileña for their economic support and Red de Biobancos de Valencia and Bruker BioSpin for technical contributions. This study was also supported by the ISCIII (RTICC, RD12/0036/0025).

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      P1.06-007 - Plasma Circulating MicroRNA-944 and MicroRNA-3662 as Novel Histologic Type-Specific Lung Cancer Biomarkers (ID 521)

      T. Powrózek, P. Krawczyk, D. Kowalski, K. Winiarczyk, M. Olszyna-Serementa, M. Nicoś, M. Krzakowski, J. Milanowski

      • Abstract
      • Slides

      Background:
      Altered expression of microRNAs is associated with development and invasion of cancers by regulating post-transcriptionally gene function. Possibility of detection of circulating miRNAs expression in patients’ plasma or serum make them valuable biomarkers of different neoplasms, such as lung cancer.

      Methods:
      We investigated potential role of miR-944 and miR-3662 expression analysis as a novel lung cancer biomarkers and their lung tumor specificity in plasma samples of 90 lung cancer patients (40 NSCLC patients in stage IA-IIIA and 20 NSCLC patients in stage IIIB-IV; 8 SCLC patients with limited and 22 SCLC patients with extensive disease) and 85 healthy individuals using qRT-PCR analysis.

      Results:
      Expression of miR-944 and miR-3662 was significantly upregulated in lung cancer patients in comparison to healthy individuals. Higher stage of lung cancer correlated with higher miRNAs expression (Figure 1). Receiver operating curves (ROC) analysis have presented diagnostic power of analysis of both miRNAs expression for detection of patients with I and II stage of NSCLC with area under curve (AUC) of 0.881. Moreover, miR-944 has shown diagnostic accuracy for operable squamous cell carcinoma detection (AUC=0.982) whereas miR-3662 - for operable adenocarcinoma (AUC=0.926) (Figure 2).Figure 1Figure 2





      Conclusion:
      Our research is a first study investigating the plasma expression of miR-944 and miR-3662 in patients with neoplasms and in healthy individuals. Moreover, this is a first study that described a miR-3662 expression. We have shown that examination of these two miRNAs may be considered as a tool for NSCLC early diagnosis as well as for non-invasive diagnosis of lung cancer late stages. Studied miRNAs have also shown high utility in detection of histological type-specific NSCLC subtypes, such as adenocarcinoma and squamous-cell carcinoma.

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      P1.06-008 - Functional Polymorphisms in PD-L1 Gene Are Associated with the Prognosis of Patients with Early Stage Non-Small Cell Lung Cancer (ID 1124)

      D.K. Jung, C.C. Jin, M.J. Hong, S.K. Do, J.Y. Park

      • Abstract
      • Slides

      Background:
      This study was conducted to investigate whether polymorphisms of genes involved in immune checkpoints can predict the prognosis of patients with early stage non-small cell lung cancer (NSCLC) after surgical resection.

      Methods:
      Twelve single nucleotide polymorphisms (SNPs) of PD-1, PD-L1, and CTLA-4 genes were selected and genotyped. A total of 354 patients with early stage NSCLC who underwent curative surgical resection were enrolled. The association of the SNPs with overall survival (OS) was analyzed.Twelve single nucleotide polymorphisms (SNPs) of PD-1, PD-L1, and CTLA-4 genes were selected and genotyped. A total of 354 patients with early stage NSCLC who underwent curative surgical resection were enrolled. The association of the SNPs with overall survival (OS) was analyzed.

      Results:
      Among the 12 SNPs investigated, PD-L1 SNP1C>G, SNP2G>C, and SNP3T>A were significantly associated with worse survival outcomes in multivariate analyses. When the three SNPs were combined, OS decreased in a dose-dependent manner as the number of bad genotypes increased (Ptrend = 0.0003). A higher expression of the reporter gene for the SNP2G- SNP3T haplotype was observed compared with the SNP2C- SNP3A haplotype by luciferase assay (P = 0.004). Patients with higher expression of PD-L1 mRNA had a better survival compared with lower expression (P = 0.03).

      Conclusion:
      PD-L1 SNP1C>G, SNP2G>C, and SNP3T>A polymorphisms may be useful for the prediction of prognosis in patients with surgically resected NSCLC. Further studies are needed to confirm our findings and to understand the role of PD-L1 in the antitumor immunity.

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      P1.06-009 - Volatolomic Signatures to Assess Sensitivity to FGFR Tyrosine Kinase Inhibitors (ID 1711)

      R. Kwon, O. Barash, H. Kayal, L. Rozeboom, G. Courthod, A.A. Kowalewski, C.J. Rivard, B. Rikke, N. Peled, H. Haick, F.R. Hirsch

      • Abstract
      • Slides

      Background:
      Targeted therapy is transforming the treatment of lung cancer. Such therapies are critically dependent on companion diagnostics that can predict the response to therapy. An ideal test is one that is quick, inexpensive, and non-invasive. In this regard, artificial intelligence nanosensor-based devices that profile volatolomic signatures (through volatile organic compounds (VOCs) analysis) have shown exciting potential. Numerous studies have shown cancer cells produce characteristic patterns of VOCs as a byproduct of their metabolism. These patterns can be used to diagnose patients with cancer using exhaled-breath samples. Here we asked whether the VOC patterns emanating from cancer cells could also be used to guide targeted therapy. In particular, we investigated whether lung cancer cell lines known to be sensitive to FGFR tyrosine kinase inhibitors (TKIs) can be distinguished from cell lines known to be resistant using an array of cross reactive, highly sensitive chemiresistors composed of gold nanoparticles (GNP) and carbon nanotubes (CNTs) coated with various recognition layers previously shown to be highly effective at profiling VOCs.

      Methods:
      Fourteen sensitive cell lines having an IC~50~ ≤ 50 nM for Ponatinib and AZD4547 (nonspecific and specific FGFR TKIs, respectively) and 21 resistant cell lines representing small cell and non-small cell lung cancers were cultured in complete media (RPMI 1640, 10% fetal bovine serum, and penicillin/streptomycin) under standard conditions to 50% to 75% confluency. SKC Tenax® TA Adsorbent resin was used to collect the VOCs from the head space of each cell line over a period of 60 to 72 hours. Triplicate measures were collected on each sample along with biological replicates. VOCs were also collected at the same time from control plates containing media only. After thermal desorption, the VOC pattern of each sample was characterized using a chemiresistor array of 36 sensors and 4 features per sensor. A statistical pattern recognition analysis was then conducted using a discriminant function analysis (DFA) algorithm to identify the most informative sensors and features.

      Results:
      We found that sensitive cell lines could be distinguished from resistant cell lines using only 4 sensors and one feature from each (GNP+dodecanethiol, CNT+PAH, GNP+thiol and CNT+β dextrin). Leave-one-out cross validation indicated a sensitivity of 88% for the FGFR TKI-sensitive cell lines with 100% specificity and 92% accuracy. The area under the receiver-operating characteristic curve was 70% and Wilcoxon p-value of 0.06.

      Conclusion:
      Profiling the VOCs emanating from lung cancer cells shows excellent diagnostic potential as a means of gauging initial sensitivity to FGFR1 TKIs. Consequently, this study suggests that the electronic nose devices currently being developed to profile exhaled breath for cancer detection could also play an important role in predicting responses to targeted therapies. Although cell lines are useful for identifying the VOC pattern that predicts the cancer cell response to therapy, they do not necessarily reflect the complexity that occurs in vivo due to interactions with the microenvironment. Therefore, future studies are needed to confirm if these results can be extended to project efficacy in patients assigned to FGFR TKI therapy.

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      P1.06-010 - Allelic Heterogeneity and Its Role in Identifying Non-Small Cell Lung Cancer Phenotypes (ID 2180)

      L.M. Alley, R.B. Penney, K. Arnaoutakis, M. Steliga, S.K. Jeffus, M.S. Orloff

      • Abstract
      • Slides

      Background:
      More people die of lung cancer (LC) annually than of prostate, colon, and breast cancers combined, making it the leading cause of cancer-related mortality in the United States. LC can be divided into two main categories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC is the predominant LC category accounting for roughly 85% to 90% of all diagnosed LCs. NSCLC can be further subdivided into three main histological subtypes including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Phenotypic characterization (i.e. histological features and LC subtypes) for NSCLC tissues remains a difficult task. Many studies have revealed certain genes that are associated with NSCLC; however, these genes cannot completely decipher between its varying phenotypes. CD36 is a biologically plausible candidate gene that is significantly under-expressed in NSCLC tissues compared to normal tissues. This differential expression is not observed in NSCLC tissue subtypes; however, significant differences in CD36 expression have been observed in NSCLC subtype-derived cell lines. Based on this previous expression data, we hypothesized that allelic heterogeneity within CD36 exons could disparately contribute to the development of NSCLC subtypes.

      Methods:
      To test this hypothesis, we obtained fresh-frozen LC tissues from the UAMS tissue bank and performed mutation screenings using Sanger sequencing methods and Mutation Surveyor software. Quantitative RT-PCR was performed on tissue mRNA and CD36 mRNA expression was normalized to HPRT1 (a housekeeping gene that is more stable in lung tissues) expression in the same samples. Genotype-specific CD36 expressions profiles were then identified and analyzed.

      Results:
      Several previously undiscovered variants were identified in Exon 4 of the CD36 gene. Two of these variants are associated with mRNA expression differences between the variant and wild-type genotypes that identify phenotypic heterogeneity. Adenocarcinoma samples with transcript harboring the first variant genotype overexpressed CD36 mRNA as compared to adenocarcinoma samples containing the wild-type genotype (p=0.013; N=37). In squamous cell carcinoma samples, there was no significant difference between samples with the first variant and wild-type (p=0.74; N=26). Squamous cell carcinoma samples with CD36 transcript harboring the second variant genotype was relatively under-expressed when compared to the squamous cell carcinoma samples with the wild-type genotype, though the comparison only approached significance at p=0.053 (N=37). A similar comparison in adenocarcinoma samples yielded non-significant results (p=0.59; N=25).

      Conclusion:
      Identification of NSCLC phenotypes is critical to treatment, but remains difficult with current histopathological methods. Our analysis of publicly available expression data has shown that probes used in global expression microarrays cannot completely and reliably distinguish between NSCLC phenotypes at the CD36 locus. We propose that allelic heterogeneity at the CD36 locus may alter array probe binding properties leading to inconsistent expression results. Our data has identified two previously undiscovered CD36 variants that may uniquely lead to altered CD36 mRNA expressions correlating to specific NSCLC subtypes. Hence, these results suggest that we may be able to accurately quantify transcripts associated with NSCLC subtypes using allele-specific probes.

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      P1.06-011 - miR-126 Is a Potential Diagnostic Marker for Malignant Pulmonary Nodules in Endobronchial Epithelial Lining Fluid (ID 1712)

      N. Kahn, S. Kaduthanam, U. Schirmer, T. Muley, R. Kuner, F. Herth, M. Meister, H. Sültmann

      • Abstract
      • Slides

      Background:
      Early detection and diagnostic clarification of indeterminate pulmonary nodules by less invasive methods could contribute to better intervention strategies and to the reduction of the high mortality in lung cancer patients. Endobronchial epithelial lining fluid (EELF) might contains molecular markers with diagnostic potential. With the bronchoscopic microsampling (BMS) technique, it is possible to collect EELF in close proximity to the suspected lesion without the risk of biopsy-associated complications. We investigated whether microRNA (miRNA) in EELF collected by BMS may be useful to facilitate preoperative diagnosis of indeterminate pulmonary nodules.

      Methods:
      The study included 24 non–small-cell lung cancer patients with 48 EELF samples. From each patient, EELF was collected from subsegmental bronchi close to the indeterminate pulmonary nodule, which was detected by computed tomography, and from the contralateral healthy lung. Diagnosis was confirmed by transbronchial biopsy or surgery. Global miRNA expression profile analysis (754 miRNAs) was performed using quantitative real-time polymerase chain reaction (qRT-PCR) with eight sample pairs. miRNAs potentially associated with a malignant phenotype were selected for further qRT-PCR analysis in an independent validation cohort (16 sample pairs).

      Results:
      All patients underwent BMS without complications. miRNA profiling by qRT-PCR could be reliably applied to EELF samples and resulted in potential miRNA markers for malignant pulmonary nodules. In particular, the miRNA pair miR-126/miR-126* significantly differentiated between EELF close to the indeterminate pulmonary nodules and the sample taken from the healthy contralateral lung (p<0.0001).

      Conclusion:
      Our study suggests that the analysis of miR-126/miR-126* in EELF collected by BMS could be a potentially useful adjunct to other diagnostic techniques aiming at the preoperative diagnosis of indeterminate pulmonary nodules.

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      P1.06-012 - Components of Serum Peptidome Can Differentiate between Healthy Controls and Patients with Early Stage Lung Cancer (ID 915)

      P. Widlak, M. Pietrowska, J. Polanska, M. Marczyk, R. Dziadziuszko, W. Rzyman

      • Abstract
      • Slides

      Background:
      Screening with low-dose computed tomography of high-risk group for lung cancer development allows for early detection of malignancy in a minor proportion of subjects and leads to improved outcomes. Implementation of complementary minimally-invasive molecular markers for more efficient pre-selection of candidates for imaging tests or help to further define detected changes is a rational way to further improve efficacy of such screening. Here we aimed to identify features of serum peptidome that could be used for differentiation of individuals with early lung cancer from other participants of lung cancer screening program.

      Methods:
      Blood samples were collected during lung cancer screening program performed in Pomerania district (Poland). MALDI-ToF mass spectrometry was used to characterize the low-molecular-weight fraction of serum proteome in the 800-14,000 Da range (i.e. endogenous serum peptidome). The analysis was performed in a group of 100 lung cancer patients (with early stage lung cancer diagnosed without clinical symptoms during the screening program or through routine diagnostic procedures) and a matched group of 300 controls (participants of the screening without malignancy).

      Results:
      Components of mass spectra were detected and specific features allowing differentiation of cancer cases were identified. The first group of 50 cancer cases and 150 matched controls was used to built and test multi-component peptide signature for cancer classification; obtained classifier showed about 70% specificity and sensitivity. The signature was validated in the second group of independently analyzed samples (50 cancer cases and 150 matched controls); the classifier performed well and the total number of misclassifications was below 25%.

      Conclusion:
      MALDI-based profiling of serum peptidome allowed identification of components differentiating patients with early stage lung cancer from healthy individuals. Hence, biomarker based on serum peptide signature has a potential applicability for early detection of lung cancer.

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      P1.06-013 - Delays of Diagnosis and Treatment of Lung Cancer in a Populous Region of Brazil (ID 2849)

      F.C. Abrão, I.R.L.B.D. Abreu, A.R. Silva, J.H.G. Rodrigues, L.T.C. Correa

      • Abstract
      • Slides

      Background:
      This study was undertaken to measure delays of diagnosis and treatment of lung cancer in a poor region of São Paulo, Brazil, where there are four million people. In addition, the relation of delay times and survival was analyzed

      Methods:
      We retrospectively reviewed 509 patients with lung cancer between July 2008 and December 2014. All patients admitted with lung cancer in our institution, which is the only reference for patients with cancer in this region, were considered eligible for this study once they had not undergone any previous oncology treatment. Dates for symptoms, visits to doctors, treatment and death were recorded. The delays in the diagnosis and treatment of lung cancer were arranged in the following time intervals: -Time (months) from the first symptoms experienced by the patient (history patients - HP) to the date on which the patient was diagnosed with cancer (DX); -Time (months) from initial presentation to the first appointment (first app) with a specialist in our institution to the date on which the patient was diagnosed with cancer (DX); -Time (months) from date on which the patient was diagnosed with cancer (DX) to the starting date of treatment (TTO). Descriptive analysis of data was carried out using measures of central tendency (median). Kaplan-Meier survival estimates were used to determine 5-year lung cancer specific survival for all patient and Log-rank (Mantel-cox) and Breslow (Generalized Wilcoxon) analyses were used to compare differences between factors. Survival was calculated from the date of patient admission at our institution to the date of last follow-up or until death from any cause. Statistical analyses were performed using SPSS v 17.0 for Windows.

      Results:
      Demographic characteristics of the 509 lung cancer patients were analyzed. The median age of these patients was 62 years (range 26 -96 years) and more than 75 percent of these patients were smokers. For all patients, median overall survival was 7 months (95% CI: 5.7 to 8.2) with 34.5% of these patients surviving one year and 8.1% surviving five years. Patients have spent a relevant time waiting in each interval period. For instance, the median time from the history patient (HP) to the diagnosis (DX) was 3 months. From the first appointment (first app) to diagnosis (DX) was 1 month, however, 79% of patients were diagnosed up to 2 months. Finally, the median time from the diagnosis (DX) to the starting date of treatment (TTO) was 1 month, but the majority of patients (82.5%) started the treatment up to 2 months. There was no statistical relationship between the delays and the mortality of patients. The time gap between the development of the first symptoms and the beginning of treatment was not relevant to the mortality rate of lung cancer, as shown in the survival data of the Kaplan-Meier graph.

      Conclusion:
      We have a relatively long time for confirmation of lung cancer and also to start treatment. Despite these data were not an independent significant factor for survival, this type of study is important to alert medical societies and government health agencies.

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      P1.06-014 - Impact of Surgery for Stage I Non-Small Cell Lung Cancer on Quality of Life (ID 1586)

      R. Schwartz, R. Yip, I. Olkin, E. Taioli, C.I. Henschke

      • Abstract
      • Slides

      Background:
      The literature is mixed regarding the impact of lung cancer surgery on physical and mental health quality of life (QoL)[1-4]. Some studies have found an improvement in QoL post surgery[1] while others have indicated a decrease in various aspects of QoL[2,3]. Further, the impact on QoL is often dependent on numerous factors such as type of surgery. The current study aims to assess the impact of surgery on both physical and mental health QoL in screening-diagnosed patients with early stage lung cancer, an under-studied population.

      Methods:
      SF-12 QoL indicators were collected from 86 participants (40 women, 46 men) at baseline CT screening and one-year follow up post-surgery for clinical stage IA non-small cell lung cancer. 69 had lobectomy and 17 had sublobar resection. Average time of follow up was 12 months since surgery (SD: 1.5 months; range: 9-15 months post surgery). Univariate and multivariate analyses were performed to examine the difference in physical (PHC) and mental (MHC) health component scores of the SF-12 before and after surgery using the Wilcoxon signed rank and Mann Whitney tests.

      Results:

      SF-12 Quality of Life Scores Pre and Post Surgery
      ALL M(SD) MALE M(SD) FEMALE M(SD) LIMITED RESECTION M(SD) LOBECTOMY M(SD)
      PHC Baseline (Pre-Surgery) 49.4(6.8) 49.8(5.8) 49.0(7.8) 47.8 (7.8) 49.8(6.5)
      Post-Surgery 48.7(7.1) 48.5(7.7) 49.0(6.4) 50.3(6.3) 48.3(7.2)
      Difference (Post-Pre) -0.7(7.6) -1.3(7.5) 0.0(7.6) 2.5*(6.0) -1.5(7.7)
      MHC Baseline (Pre-Surgery) 53.7(8.6) 55.5(7.6) 51.7(9.3) 52.3(13.4) 54.0(7.1)
      Post-SurgerY 55.8(8.2) 57.3(8.1) 54.1(8.2) 55.7(6.3) 55.8(8.7)
      Difference (Post-Pre) 2.0*(9.6) 1.7*(8.5) 2.4*(10.9) 2.9(10.7) 1.8(9.4)
      *p<.05
      There was no significant change in PHC post-surgery (Wilcoxon signed rank test, S=-216, p=0.32), but MHC significantly improved from baseline to post-surgery (S=527, P=0.01). Mean MHC was significantly higher among males as compared to females at both baseline (Chi-square=3.95, p=.047) and post-surgery (Chi-square=4.23, p=.039) and after controlling for age, ethnicity, and education, while no differences in PHC was observed. Further, there was an improvement in PCS score post-surgery among participants who underwent limited resection while a decrease in PCS score was observed among those who underwent lobectomy. The change in PCS score was significantly different between type of surgery (t=-2.01, p=0.048). After controlling for demographics, the difference was borderline significant (F=3.62, p=0.06).

      Conclusion:
      Surgery for early stage lung cancer was associated with an increase in mental health QoL one year after surgery, however, physical health QoL was not affected by surgery overall, but it did marginally improve among participants who underwent limited resection as compared to lobectomy. Further, although mental health QoL improved for both males and females, females had lower mental health QoL as compared to males at both time points. Current study findings have implications for lung cancer health professionals regarding how to most effectively present the possible impacts of surgery on the QoL of this subset of patients in which disease has not yet significantly progressed.

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      P1.06-015 - A Population Based Study on Pulmonary Carcinoids in Iceland: Epidemiology, Diagnosis and Survival Over Sixty Years (ID 2158)

      A. Petursdottir, B.M. Fridriksson, J. Sigurdardottir, H. Isaksson, S. Jonsson, T. Gudbjartsson

      • Abstract
      • Slides

      Background:
      Pulmonary carcinoids are usually localized to the lungs but can also metastasize to mediastinal lymph nodes or to other organs. We studied the incidence and patient outcome in a well-defined population over a 60 year period.

      Methods:
      A nationwide study, including all pulmonary carcinoids diagnosed in Iceland from 1955 to 2014. Histologic specimens were re-evaluated and information retrieved from medical records. The tumors were staged according to the TNM staging system (6[th] edition). Survival was estimated using the Kaplan-Meier method, with end of follow-up on January 1[st] 2015. Mean follow-up was 186 months.

      Results:
      93 patients (62 females, average age of 52 years) were diagnosed during the 60 year period. Incidence increased from 0,2/100.000/year between 1955-1964 to 0,7 2005-2014. A total of 26 out of 85 patients (31%) were asymptomatic upon diagnosis and the rate of incidental detection increased from 17% in the first 30 years to 33% in the later 30 years. The most common symptoms were cough (56%), pneumonia (28%) and chest pain (11%). Mean tumor diameter was 2,7 cm (range: 0,3-6,3), 71 (84%) patients were diagnosed with typical carcinoid tumors and 14(16%) with atypical carcinoid tumors. Out of 77(91%) patients who had surgery, 65(84%) underwent a lobectomy. One patient died within 30 days of surgery. Most patients(n=67, 79%) were on stage I upon diagnosis and 4(5%) on stage II. Another 4 patients were on stage III with mediastinal lymph node metastases, all with typical histology. Out of six patients(7%) with distal metastases (stage IV), two had typical histology. Five patients(6%) had died from pulmonary carcinoids upon follow-up, but total 5-year survival was 92% for all patients and 87% for patients with typical carcinoids.

      Conclusion:
      The incidence of pulmonary carcinoids in Iceland has tripled over the last 6 decades, mostly due to steep increase in incidental detection on chest imaging. Most patients (>84%) are diagnosed with a localized disease, where long-term outcome is excellent.

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      P1.06-016 - A Novel Functional Polymorphism in CIR1 Gene Is Associated with the Risk of Lung Cancer (ID 1131)

      C. Jin, D.K. Jung, J.Y. Park

      • Abstract
      • Slides

      Background:
      We evaluated the associations between potentially functional variants in cancer-related genes and the risk of lung cancer to identify genetic factors responsible for lung cancer susceptibility in a Korean population.

      Methods:
      A total of 1,969 potentially functional single nucleotide polymorphisms (SNPs) of 1,151 genes involved in carcinogenesis were evaluated using the Affymetrix custom-made GeneChip in 610 NSCLC patients and 610 healthy controls. A replication study was performed on an independent set of 490 cases and 486 controls.

      Results:
      Eighty two SNPs with P < 0.05 for genotype distribution in the discovery set were tested in the replication study. Among the 82 SNPs, three SNPs (corepressor interacting with RBPJ 1 [CIR1] SNP1T>C, solute carrier family 38, member 4 [SLC38A4] SNP2C>T, ribonucleotide reductase M1 [RRM1] SNP3T>C) constantly showed significant associations with lung cancer (adjusted odds ratio [aOR] = 0.68, 95% CI = 0.59-0.84, P < 0.0001; aOR = 0.74, 95% CI = 0.63-0.88, P = 0.001; aOR = 0.72, 95% CI = 0.56-0.93, P = 0.01, respectively, under dominant model). Promoter assay demonstrated a decreased reporter gene expression for CIR1 SNP1 C allele was observed compared with T allele (P = 0.02).

      Conclusion:
      Our results suggest that the three SNPs, particularly CIR1 SNP1T>C, may contribute to lung cancer susceptibility in Koreans.

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      P1.06-017 - Small Cell Lung Cancer in Lung Cancer Screening: Frequency and Outcome (ID 2476)

      M. Silva, C. Galeone, A. Marchianò, G. Calareso, S. Sestini, C. La Vecchia, G. Sozzi, N. Sverzellati, G. Pelosi, U. Pastorino

      • Abstract
      • Slides

      Background:
      Only 30% of small cell lung cancers (SCLC) are diagnosed as limited stage (LS-SCLC), whereas the majority of cases show extensive stage disease (ES-SCLC). Specific frequency and outcome of SCLC within lung cancer screening trials have not been described. The purpose of this study was to describe the frequency and outcome of SCLC in lung cancer screening trials with annual or biennial LDCT controls.

      Methods:
      The population was selected from two lung cancer screening trials (one pilot study and one randomized controlled study) based on serial low-dose computed tomography (LDCT). Subjects with diagnosis of SCLC were selected and the stage of the disease was assessed at the time of diagnosis, as follows: a) TNM staging system; b) 2-stage staging system (e.g. LS-SCLC or ES-SCLC). Survival curves were estimated using Kaplan-Meier method and were compared by log-rank test.

      Results:
      5,134 subjects were recruited and, thereafter, followed up for a median time of 8.3 years, with 45,141 person-year of clinical follow up. Ten SCLC were reported with incidence of SCLC 22/100,000 person-year, notably, 8 in the LDCT arms with incidence of 24/100,000. SCLC was diagnosed in 3/1643 women and 7/3385 men, age at diagnosis 65 years (range 53-73), and cumulative tobacco consumption of 82 pack-years (range 30-113). The proportion of SCLC among all lung cancers diagnosed in the screening was 10/164. Six out of the 8 SCLC reported in LDCT arms were screen-detected, whereas 2 SCLC were non-screen-detected. Median standard uptake value (SUV) by [18]F-Fluorodeoxyglucose Positron Emission Tomography was 10 (range 5.5-14.4). According to TNM classification, all but 1 SCLC were advanced stage at the time of diagnosis, whereas according to the 2-stage system 5 LS-SCLC and 5 ES-SCLC were observed. The prevalence of LS-SCLC was 62.5% in LDCT arm, in particular, 66.7% among screen-detected and 50% non-screen-detected. The 2 SCLC reported in control group were both ES-SCLC. Six of the 10 subjects died from SCLC, with median overall survival of 21.2 months (95% CI 7.4 – nc months; Figure). Median overall survival was 12-month longer for LS-SCLC (p = 0.02). Survival at 5 years was 0%. Figure 1.



      Conclusion:
      SCLC was diagnosed with higher proportion of LS-SCLC in LDCT-based screening trials, as compared to data from the literature. Median overall survival of LS-SCLC was slightly longer than ES-SCLC, allegedly related to diagnosis anticipation. None of these patients was alive at 5 years.

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      P1.06-018 - Can 30-Mortality after Lung Cancer Resection Be Used as an Individual Surgeon Quality Outcome Internationally? National Data from the UK (ID 2866)

      C. Proli, M.E. Cufari, H. Raubenheimer, M. Al Sahaf, L. Shedden, G. Luciano, P. Perikleous, N. Asadi, H. Chavan, M. Meza Guzman, M. Dusmet, E. Lim

      • Abstract
      • Slides

      Background:
      Internationally, one of the most commonly reported quality outcome in surgery for lung cancer is 30 day mortality. However, is difficult to know what constitutes unacceptably high mortality or unacceptable variation between surgeons. In October 2014 national data was released from the Society for Cardiothoracic Surgery (SCTS) in the United Kingdom (UK) on hospital and individual surgeon volume performance for lung cancer resection in the UK. The implicit assumption is benchmarking of the performance. The aim of this study is to report on the impact of individual surgeon volume in relation to each death associated with the an average 30-day mortality rate of 2.2% using national data driven performance control limits (i.e. funnel plots), and determine the applicability on surgeon performance internationally.

      Methods:
      Data released by the SCTS were downloaded, complied and analysed. Each step change for individual mortality was calculated, and alert limits modelled using current UK national standard of the upper 99% binomial confidence limit.

      Results:
      Data from 29 units were published with the annual volume of 125 surgeons for 2012. Data from 6 surgeons were excluded for no lung resections performed. In the remaining 118 surgeons, the mean (SD) annual lung resection volume for cancer was 42 (27). A total of 25% of surgeons performed 18 resections (or less) per year. For 50% of surgeons undertaking 40 resections (or less) each death represents at least 2.5% (0 to 13%) of their annual work load. Using a 99% binomial confidence limit at 50 cases, the upper alert is 16%. Therefore for the majority of surgeons, a mortality rate of 15% which is 7.5 fold higher than average would not trigger the conventional national alert limits.

      Conclusion:
      Based on UK national data, lung cancer resection volumes for individual surgeons are low and for the majority even a single death (which could be due to chance), affects the overall mortality rate much more, carries a disproportionately high weighting and may encourage risk adverse behaviour whilst simultaneously failing to detect 7.5 fold increased mortality rates using conventional national limits. Such data driven limits would also not be applicable on an international level basis unless individual surgeon volume is higher than 100 resections per year, a level that was not achieved by most UK surgeons.

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      P1.06-019 - A Comparison of Demographic Risk Variables for Lung Cancer in New Zealand Europeans and Maori: Are Maori More Susceptible to the Effects of Smoking? (ID 867)

      R.J. Hopkins, C. Kendall, G.D. Gamble, R. Young

      • Abstract
      • Slides

      Background:
      Lung Cancer is the leading cause of cancer death among New Zealand (NZ) Maori. Over the past twenty years lung cancer incidence has decreased in New Zealand for non-Maori but has increased for Maori, and is recognised to be the highest in the world of any ethnic group. Nationally, the incidence of lung cancer in Maori is 3.5 times higher than that in New Zealand Europeans, and lung cancer mortality in Maori males and females respectively, is 2.4 and 4.2 times higher than NZ Europeans. Maori have a higher incidence of lung cancer than countries with similar smoking rates. This suggests that there are additional factors other than smoking that predispose Maori to this disease. In the current study demographic and the well-established clinical risk variables for lung cancer were compared between New Zealand Maori and Europeans residing in the greater Auckland region and who were diagnosed between January 2004-January 2015.

      Methods:
      A retrospective review of patient clinical notes for those identified as being of NZ Maori ethnicity who were diagnosed with lung cancer (n=473) between January 2004 and January 2015 and treated within the greater Auckland region. Data extracted included histological type, smoking history, spirometry and basic demographics. This data was then compared with an established cohort of NZ European patients n= 417, with similar recruitment criteria over the period 2004-2008.

      Results:
      Despite comparable smoking exposure histories, NZ Maori patients were diagnosed on average 6 years younger than NZ European lung cancer patients (P<0.0001). At diagnosis, current smoking rate was 2 fold greater in NZ Maori compared to NZ Europeans (69% vs 36%, P<0.0001). Although NZ Maori patients had similar rates of COPD (≈64%), they had a trend towards less GOLD 1 (mild stage disease, P=0.08) and significantly greater airflow obstruction (worse COPD, FEV~1~%predicted 64% vs 73% in NZ Europeans, P<0.001). At lower smoking exposure (≤10 pk yrs), COPD rates in Maori with lung cancer were 2 fold greater than in NZ Europeans (64% vs 32% respectively, P<0.05). NZ Maori lung cancer patients had a lower prevalence of adenocarcinoma than in NZ Europeans (32% vs 43%, P=0.002) and a higher proportion of more aggressive lung cancer subtypes (squamous, non-small cell and small cell cancers) than NZ Europeans (61% vs 52%, P<0.0007).

      Conclusion:
      These results show that lung cancer in NZ Maori is associated with younger age at diagnosis, worse lung function and more aggressive histological subtypes compared to NZ Europeans. These results suggest that NZ Maori may have a greater inherent susceptibility to lung cancer compared to NZ Europeans. This greater susceptibility to lung cancer in Maori, along with socio-cultural factors, may contribute to their considerably greater mortality. These results suggest that for the future management of lung cancer, prevention measures (such as smoking cessation and tobacco control), risk assessment (such as lung function testing) and early diagnostic approaches (such as computed tomography screening) should be prioritised in high risk groups, particularly those with NZ Maori ancestry.

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      P1.06-020 - Detection of Aberrant ALK Expression from Circulating Tumor Cells for Accurate Monitoring of ALK Driven NSCLC (ID 3277)

      K.D. Lawrence, P. Tsinberg, B.L. Schweitzer, L.W. Abad, L. Arnold, D. Hout

      • Abstract
      • Slides

      Background:
      Insight Genetics Inc. and Biocept, Inc. have established a collaboration to develop a non-invasive work flow to enhance detection of the oncogenic Anaplastic Lymphoma Kinase (ALK) status in NSCLC patients. A barrier to detection of oncogenic transcripts in circulating tumor cells (CTCs) has been purification methods that are incompatible with downstream qPCR detection technologies. In contrast, Biocept's proprietary CTC capture technology has been shown to be benign for follow up qPCR detection using Insight Genetics proprietary qPCR-based oncogenic ALK detection assay.

      Methods:
      Initial studies were conducted to demonstrate cell capture on the Biocept platform with spiked ALK fusion positive H3122 cells. These studies show this to be a feasible option for non-invasive detection of ALK mRNA. A pre-amplification allele-specific approach including reference controls was incorporated. H3122 cells spiked into peripheral blood also demonstrated feasibility of the accurate detection of aberrant ALK expression using the Biocept CTC extraction methodology and Insight Genetics’ qPCR detection strategy.

      Results:
      Results from these studies and the detection of aberrant ALK expression from a cohort of ALK positive patients will be presented along with the potential to use CTCs to monitor ALK inhibitor resistant mutation profiles.

      Conclusion:
      Together, Biocept’s proprietary CTC capture technology coupled to Insight Genetics qPCR ALK detection assay appears to be a viable strategy to accurately monitor ALK status in NSCLC patient populations using a liquid biopsy.

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      P1.06-021 - Is Safe to Follow High-Risk Patients with Suspicious Lung Nodules without Invasive Tests? (ID 3182)

      R.S. Santos, J.P. Franceschini, M.C. Ghefter, A.L.C. Trajano, R.C. Chate, V.M. Boaventura, R. Saad Junior

      • Abstract

      Background:
      Low dose computed tomography (LDCT) screening for lung cancer (LC) provides reduction in mortality rates among individuals at high risk. Pre-Test Probability of Malignancy (PTPM) is a common tool used during the decision process: when the probability of malignancy is moderate or high, patients should be referred for further testing or tissue sampling. However, in some cases, these statistic models may give an overestimated value, especially in countries with a high incidence of granulomatous diseases. We have calculated the PTPM in our LDCT screening program and this work explores its main results.

      Methods:
      Prospective cohort of current or former smokers, with a heavy smoking history. Data of the first LDCT were analyzed to calculate the PTPM. The inclusion criteria were similar to NLST. LDCT scans with indeterminate pulmonary nodules above 4mm in size were considered positive and were evaluated by a multidisciplinary team. The PTPM model used in this study was designed by Swensen et al and included patient’s age, smoking history, diameter of the nodule, spiculation and upper lobe location. A PTPM > 60% was considered high and between 6 and 60% was considered moderate.

      Results:
      From January 2013 to July 2014, 790 were included in the protocol. We found 310 positive LDCT at baseline (39%), 34 (11%) with high PTPM. Among them, 16 were followed with LDCT in 3 (56.2%), 6 (37.5%) or 12 (6.3%) months and the remaining were investigated with PET-CT and/or lung biopsy. From the patients followed by LDCT, one case showed an increase in nodule size and was investigated with lung biopsy; all others were stable in one-year follow up. LC was diagnosed in 7 patients and benign diseases in 5 patients with high PTPM, including 1 case of tuberculosis. Other 4 cases of NSCLC were found in the moderate PTPM group (n=272). Therefore, malignancy rate was 20.6% for high PTPM and 1.5% for moderate PTPM nodules.

      Conclusion:
      The Swensen’s PTPM model overestimates the prevalence of LC in both groups of moderate and high-calculated values of PTPM. The decision making process should include other variables discussed in a multidisciplinary board, been safe to follow patients with further image tests.

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      P1.06-022 - The British Thoracic Society Guideline on the Investigation and Management of Pulmonary Nodules (2015) (ID 2328)

      D.R. Baldwin, M.C. Callister

      • Abstract
      • Slides

      Background:
      British Thoracic Society (BTS) Guidelines are aimed primarily at practitioners within the UK. They are National Health Service Evidence accredited which means they must adhere to robust guideline development methodology. The evidence base for this guideline comes mostly from countries outside the UK so the recommendations will have relevance to other countries healthcare systems.

      Methods:
      The recommendations are based on a comprehensive review of the literature on pulmonary nodules and expert opinion. A third of the 360 references cited were from 2012 onwards, reflecting the rapid expansion of the evidence base. The new evidence has resulted in important differences from guidelines previously published by the American College of Chest Physicians and the Fleischner Society.

      Results:
      There are four algorithms: initial approach to solid nodules; surveillance of solid nodules; management of sub-sold nodules; and pulmonary nodule treatment. Two malignancy prediction calculators are recommended to assess the risk of malignancy; one (the Brock University model) that performs best for smaller nodules and one that has the better accuracy for larger nodules following PET-CT (the Herder model). There are recommendations based on recent evidence from screening studies, for a higher nodule size threshold for follow up (≥5mm or ≥80mm[3]). This will reduce the number of follow up CTs which, in the UK at least, are not cost effective. Surveillance recommendations are also different from previous guidelines: people can be discharged after 1 year of stability if measured by semi-automated volumetry. Management is also dependent on the volume doubling time (VDT) with immediate further assessment for nodules that show a VDT of ≤400 days and either biopsy or further observation for nodules with VDTs of >400 to ≤600 days. People with nodules with a VDT >600 days have the option of discharge, if VDT is measured by volumetry. As in previous guidelines, a 3 month repaet CT is recommended for sub-solid nodules.After that, management is governed by risk assessment by the Brock tool (with the proviso that it may underestimate risk after the initial CT) and according to specific features that predict malignancy. Acknowledging the good prognosis of sub-solid nodules, there are recommendations for less aggressive options in their management. The guidelines provide more clarity in the use of further imaging, with ordinal scale reporting for PET-CT recommended to facilitate incorporation into the Herder risk model and more clarity about the place of biopsy and its influence on pre-test probability. Segmentectomy can be considered for primary diagnosis and treatment for nodules smaller than 2cm, and sub-lobar resection is recommended for pure ground glass nodules. Where fitness levels preclude surgery, non-surgical treatment with stereotactic ablative radiotherapy or radiofrequency ablation is recommended, even where biopsy is not possible, provided the probability of malignancy is high. Finally, there are evidence based recommendations about the information that people need that should be provided for them.

      Conclusion:
      The BTS guideline is intended to be used both as a summary in the day to day management of the person with a pulmonary nodule as well as a comprehensive reference text.

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      P1.06-023 - Addition of Low Dose Computed Tomography Image-Features Improves Diagnostic Accuracy for Indeterminate Pulmonary Nodules (ID 1019)

      R. Bhagalia, X. Huang, K. Desai, R. Walker, P.P. Massion

      • Abstract
      • Slides

      Background:
      Lung cancer is the leading cause of cancer related deaths world-wide. While low dose computed tomography (LDCT) screening of the high risk patient population was recently shown to decrease deaths from lung cancer by 20%, LDCT also resulted in 18% over-diagnosis [c.f. Patz-E.-F.-JAMA-2003] with a positive predictive value of only 52.9% when a suspicious LDCT finding led to a biopsy [c.f. Church-T.-NEJM-368-2003]. We tested whether combining novel image-features (IF) with routinely collected baseline-features (BF) can improve the accuracy of diagnosing suspicious findings on baseline LDCT.

      Methods:
      This exploratory case-control study included N=123 (66-cancer, 57-no-cancer) high risk subjects with at least one suspicious finding (nodule >= 8mm [c.f. Lung-RADS-ACR-2014]) on baseline LDCT screening at Vanderbilt University on a VCT Discovery (GE-Healthcare, UK) or a Brilliance iCT 128 SP (Philips, Amsterdam) system. The cohort was randomly divided into a separate training-set (N=55, 32-cancer, 23-no-cancer) and a test-set (N=68, 34-cancer, 34-no-cancer). All model training and leave-one-out cross-validation were strictly restricted to the training-set. Performance was evaluated on the unseen test-set. Definitive lung cancer or no-cancer diagnosis, smoking history and at least 6 baseline-features (BF6) viz. age, family-history, pack-smoking-years, body-mass-index, nodule-location, nodule-size were recorded for all subjects. Baseline lung cancer predictions were generated by (a) using the Gould-model [c.f. Gould,M.-Chest-2007] and (b) fitting an Elastic-Net Regularized Generalized Linear Model (GLMnet [c.f. Zou-H.-Journ-Royal-Stats-Soc-B-2005]) to BF6. The final baseline model (“GLMnet:BF”) effectively utilized 4 baseline-features with the coefficients for age and body-mass-index shrunk to zero. New LDCT specific information was extracted by computing 589 intensity, shape, surface and texture features (IF589) [c.f. Aerts-H.-Nat-Comm-S2014, Way-T.-Med-Phys-2009] from a 3D volume-of-interest (VOI) encompassing a rough Graph-cuts [c.f. Li-K.-IEEE-PAMI-2006] segmentation for each suspicious nodule. A GLMnet was fit to all 595 features (BF6 and IF589) yielding a final enhanced model (“GLMnet:BF+IF”), which contained 12 features after GLMnet shrinkage : 10 IF related to VOI energy, nodule shape and surface statistics and image intensity variability and 2 BF (family-history, nodule-location).

      Results:
      Baseline AUC increase by 7.4% from 0.81 (Gould-model) and 0.80 (GLMnet:BF) to 0.87 (GLMnet:BF+IF). At 88% sensitivity, false positive rate reduced by 60% from 56% (Gould-model) and 44% (GLMnet:BF) to 18% (GLMnet:BF+IF); accuracy improved from 65% (Gould-model) and 71% (GLMnet:BF) to 84% (GLMnet:BF+IF). Fig.1 below shows more details: Figure 1



      Conclusion:
      This initial exploratory analysis showed that image-features extracted from suspicious LDCT findings may help reduce the number of unnecessary biopsies. Additional validation studies are warranted to determine the value of this structural imaging-based approach.

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      P1.06-024 - Patterns of <sup>18</sup>F FDG-PET/CT Studies in Patients with Suspected or Confirmed Lung Cancer - A Johannesburg Academic Hospital Perspective (ID 527)

      O.A. Ayeni, O. Evbuomwan, K. Purbhoo, M.D.T. Vangu

      • Abstract

      Background:
      Lung cancer incidence has increased rapidly in developing countries over the last few decades. It is estimated to account for nearly one-fifth of cancer-related deaths in South Africa. Imaging plays an integral role in the evaluation of patients with lung cancer. 2-[[18]F] fluoro-2-deoxy-d- positron emission tomography ([18]F FDG-PET) is now an accepted part of the imaging assessment. Integrated FDG-PET/ CT imaging is recognised as being superior to PET alone and CT alone in the imaging of lung cancer especially for staging of untreated non-small cell lung cancer (NSCLC). An audit was conducted to describe the patterns of disease in our centre.

      Methods:
      Retrospective audit which included 89 studies performed for patients with suspected or histologically confirmed lung cancer referred to us for PET/CT from September 2008 to March 2015. PET/CT reports of the patients were retrieved together with relevant clinical information from the case files whenever necessary. Over two-third (71%) of patients were referred for diagnosis/staging, others for re-staging (19%) and response to therapy (10%). All of the studies were reported by qualified and experienced Nuclear Medicine Physicians and the CT components of these studies were also read in conjunction with qualified Radiologists.

      Results:
      There were 89 scans from 87 patients. Majority of the patients were males (60%) and the mean age was 61.0 ± 9.4 years. About 42% (n=37) of the studies were performed on patients with histologically confirmed lung cancer; of the remaining indications, 15% (n=13) were referred for solitary pulmonary nodule and 43% (n=39) for multiple pulmonary nodules and masses. More than two-thirds (71%) were referred for staging, about one fifth (19%) for re-staging and 10% to assess response to treatment. The vast majority (94%) of known lung cancer were NSCLC that included adenocarcinoma (40%), squamous cancer (29%) and NSCLC not otherwise specified [NOS] (26%). F-18 FDG PET/CT showed almost an equal number in the presence (37%) or absence of metastases (36%). No significant differences were noted on FDG PET uptake between the three subtypes mentioned above (p > 0.05, Chi square). However, there was a tendency for a difference between these histological subtypes [squamous, adenocarcinoma and NSCLC NOS] for the presence of metastases (p<0.09) and the sites of metastatic predilection (p<0.08). Just more than half (53%) of patients showed evidence of positive regional nodal involvement on PET. All SPN were visualised on PET (sensitivity 100%) with about 57% with high FDG uptake (mean SUV=7.71) and about 43% with low FDG uptake (mean SUV=1.05). Correlation with histology was available for 38% of all SPNs and FDG PET correctly identified all of them as malignant or benign (100% specificity).

      Conclusion:
      [18]F FDG-PET/CT is useful in characterising solitary pulmonary nodules (SPNs) and staging as well as monitoring treatment response in lung cancer. Although it cannot replace histological confirmation of nodal and metastatic involvement, it serves as a roadmap to identify areas for tissue diagnosis. The detection of metastases may alter the therapeutic decision of NSCLC.

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      P1.06-025 - Statistical Analysis of 18F-FDG-PET/CT Findings of Ground Glass Nodule (GGN) (ID 1689)

      A. Bessho, K. Nishii, N. Fukamatsu, Y. Ogata, S. Hosokawa, M. Sakugawa, M. Kaji

      • Abstract
      • Slides

      Background:
      18F-FDG-PET/CT (PET/CT) is one of the most important image inspections for the diagnosis of lung cancer. However, there are often false negatives caused by small lesions such as Ground Glass Nodule (GGN). Whether PET/CT is useful for the diagnosis of GGN is unknown. Therefore, we analyzed the relationship of computed tomography (CT) findings (size, properties) and maximum standardized up-take values (SUV-max) of GGN.

      Methods:
      We had 69 patients with pathological-Stage IA-IB lung adenocarcinoma who underwent surgical resection and PET/CT from January 2010 to December 2014. We retrospectively examined their clinical characteristics, CT findings, and PET/CT findings.

      Results:
      Characteristics of 69 patients were as follows, 47 - 86 years old (median 70 years old), female/male: 39/30, pathological-Stage IA/IB: 59/10. GGN diameter: 1.1 - 41.13mm (median 19.43mm), Solid-part diameter: 0.0 - 23.23mm (median 4.55mm), Solid-part-ratio (solid-part diameter / GGN diameter): 0 - 77% (median 20%). SUV-max was insignificant to 6.8 (median 1.0). Correlation coefficient of each factor and SUV-max were as follows, GGN diameter: 0.49, Solid-part diameter: 0.54, Solid-part-ratio: 0.41 (Pearson’s product-moment correlation). All pure-GGN show no significant SUV-max (<2.5), even though there are some large GGN included (max 40.0mm). GGN diameter >20mm or solid-part diameter >5mm were significant factor of FDG-uptake (Fisher’s exact test). In this study, SUV-max was lower than significant level with solid-part diameter <4.55mm.

      Conclusion:
      There was no significant SUV-max with diagnostic value in pure-GGN. PET/CT is not useful for pure-GGN or small part-solid nodule (solid-part diameter <4.55mm). There is higher correlation in the solid-part diameter and SUV-max. We should keep in mind the limitation of PET/CT for GGN diagnosis.

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      P1.06-026 - 18F-FDG PET/CT Evaluation of Non-Small Cell Lung Cancer - Initial Experience from Johannesburg (ID 63)

      O. Evbuomwan, O.A. Ayeni, K. Purbhoo, M.D.T. Vangu

      • Abstract
      • Slides

      Background:
      Lung cancer is the most common cause of cancer-related mortality, with an overall five year survival of 16.6%. It is most likely to recur in the first four years after therapy. The overall five year survival for newly diagnosed lung cancer is poor in both developed and developing countries. In South Africa, statistics show that lung cancer caused 52,217 deaths between 1995 and 2006. The 2009 data from South Africa showed that the number of male and female cases of lung cancer was 1440 and 685, respectively. [18]F-FDG PET/CT allows non-invasive imaging of non-small cell lung cancer (NSCLC) based on the increased glucose metabolism by the cancer cells. [18]F-FDG PET/CT imaging of NSCLC has been found to be useful in staging, early detection of recurrence, detection of residual disease and monitoring of treatment response. Our study was carried out to evaluate its role in histologically proven NSCLC in our center.

      Methods:
      We retrospectively reviewed data of 34 patients with histologically confirmed NSCLC. A total of 51 scans were reviewed, of which 17 were follow-up PET/CT scans. Eleven patients had 1 follow up (FU) scan, 5 patients had 2 FU scans and one patient had 3 FU scans. FDG-PET/CT findings were reported as positive or negative for disease. Sites for distant and nodal metastases were noted. Follow up scans were also compared with previous or base line scans to assess for treatment response, early detection of recurrence and detection of residual disease. Of the total number of patients, only 24 patients have had follow up to see how PET/CT influenced their management.

      Results:
      Data were analysed from 20 males (59%) and 14 females (41%) of which majority (83%) were aged between 61 to 80 years old. A total of 51 scans were done, 37 (72.5%) were positive and 14 (27.5%) were negative. Almost a quarter of PET/CT scans were referred for staging (25.3%), about half for detection of residual disease (47.1%) and the remaining for the detection of recurrence (13.8%) and assessment of treatment response (13.8%). At initial imaging, metastases were visualized in 44% of patients; two-thirds of the metastases being in the adrenal, bone and contralateral lung. Nodal disease on the initial scans was noted in 56% of patients. We compared the findings in patients with FU studies. The changes from the initial studies and the first FU showed a tendency towards a significant difference (p=0.05; Pearson Chi-square). When the rest of FU scans were compared, there was no significant difference (p=0.66 for FU1 Vs FU2) and (p=0.71 for FU2 Vs FU3). PET/CT correctly up staged 29.4% and down stage 5.9% of patients and at the same time falsely down staged 5.9% and upstaged 2.9% of patients.

      Conclusion:
      [18]F-FDG PET/CT is useful in staging, early detection of recurrence, detection of residual disease and monitoring of treatment response in patients with non-small cell cancer. The tendency noted in comparing the initial and FU scans is due to lower power of this study.

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      P1.06-027 - Role of Brain MRI and PET-CT in Follow-Up after Lung Cancer Surgery (ID 1674)

      A. Sakurada, C. Endo, H. Notsuda, K. Onodera, Y. Okada

      • Abstract
      • Slides

      Background:
      Standard follow-up method after pulmonary resection for lung cancer is not determined. While chest computed tomography (CT) is widely utilized, brain magnetic resonance imaging (MRI) and positron emission tomography (PET) are also used as follow-up examination to detect cancer recurrence recently. Object of this study is to clarify the ability of MRI and PET to detect recurrence as follow-up examination setting.

      Methods:
      Medical records of 281 patients with lung cancer who underwent complete pulmonary resection for lung cancer from 2009 to 2012 were retrospectively reviewed. Information regarding recurrence, such as site of recurrence, time after surgery, tumor markers, and survival, were collected. Pathological stage according to 7[th] version of TNM staging was IA/IB/IIA/IIB/IIIA for 143/75/23/16/24 patients, respectively. Number of the patients with adenocarcinoma/squamous cell carcinoma/large cell carcinoma/small cell carcinoma/pleomorphic carcinoma/others was 190/71/2/2/7/9, respectively. All PET images were combined with simultaneously performed CT scan. Statistical analysis was performed using Mann-Whitney test for comparing groups and log-rank test for survival analysis. P-values less than 0.05 were regarded as significance.

      Results:
      CT was utilized for 255(90.7%), brain MRI for 130 (46.3%), and PET for 102 (36.3%). Recurrence of lung cancer was observed in 58 patients (20.6%).  Pathological stage was IA/IB/IIA/IIB/IIIA for 11/14/12/7/14 patients, respectively. Initial recurrent site was intrathorax/bone/brain/adrenal gland/liver for 34/15/5/3/1 patients, respectively. Motive to detect initial recurrence was patients’ symptom/CT/MRI/PET for 16/24/3/15 patients, respectively. Brain MRI detected 3 out of 5 (60%) of brain metastasis as an initial recurrence in asymptomatic status. PET detected 8 out of 15(53.3%) of bone metastasis as an initial recurrence in asymptomatic status. In 19 of 48 (39.6%) patients, elevation of tumor markers beyond normal range was observed before detection of metastasis by diagnostic imaging examination. Time after surgery to initial recurrence was shorter in symptom-detected group than in examination-detected group (median 233 versus 404 days, p<0.001). Similarly, survival after initial recurrence was shorter in symptom-detected group than in examination-detected group (median 149 versus 916 days, p<0.001).

      Conclusion:
      Follow up after lung cancer surgery utilizing brain MRI and PET effectively detect ansymptomatic metastasis to brain and bone. Survival benefit need be concluded by different setting. Furthermore, economic efficiency are also warranted to be analyzed.

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      P1.06-028 - Distribution of Stage, Surgical Methods and Prognosis of Lung Adenocarcinoma According to the Initial Diagnostic Patterns (ID 2333)

      E. Yi, H.H. Shin, H. Jang, M.K. Bae, S. Cho, K. Kim, S. Jheon

      • Abstract
      • Slides

      Background:
      Early detection of lung adenocarcinoma is important for reducing cancer mortality. We investigated how lung adenocarcinoma has been diagnosed in our institute, and evaluate the effects on the treatment and prognosis.

      Methods:
      Medical records of 1065 patients who had undergone lung cancer treatment including surgery in our institute between 2003 and 2012 were reviewed retrospectively. We excluded patients who lacked data for diagnostic process (3 patients) and underwent neoadjuvant therapy (38 patients). Patients were categorized into 3 groups, (1) group1; patients who were diagnosed during routine medical examination, (2) group2; patients with symptoms, and (3) group3; patients who were diagnosed during the treatment of other diseases. Surgical methods, stages and diagnostic tools were compared and survival analysis was done.

      Results:
      A total of 1024 patients were included. The mean follow-up periods were 55.8 months (± 29.00, range from 0.00 to 139.20). The number of sublobal resection (wedge resection and segmentectomy) in group1, 2, and 3were 85, 37 and 89 respectively. Group1 and group3 underwent significantly more limited resection than group 2 (p<0.000). The number of VATS approaches were 341 (80.6%), 148 (52.7%) and 231 (70.3%) in group1, 2, and 3 respectively. Group2 and group3 had significantly more open thoracotomy than group1 (p<0.000 for group2 and p=0.042 for group3). Early stage lung adenocarcinoma (including 0, IA and IB) was found more in group1 (318 patients, 75.2%) and in group3 (251, 78.4%) than in group 2 (150, 53.4%). Overall and disease-free survival periods of group1 (57.0 ± 27.60 and 50.4 ± 30.89) and group3 (54.6 ± 27.67 and 46.9 ± 29.57) were significantly higher (p <0.000 and p=0.002 for overall survival, P<0.000 for disease-free survival) respectively than those of group2 (55.5 ± 32.38 and 42.6 ± 34.92). Group 1 and group3 has no significant differences both in overall and disease free survival periods. Chest computed tomography was most commonly used diagnostic tool in group2 and group3 (48.4% and 35.6% respectively), on the contrary, chest roentogram in group1.

      Conclusion:
      Incidentally found lung adenocarcinoma during treatment for other diseases has no differences with those in regular health examinations in stages, surgical extent and prognosis. Careful inspection for those patients could contribute equally for early detection of lung adenocarcinoma as routine screening.

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      P1.06-029 - Serum Glutathione Peroxidase 3 as a Biomarker of Postoperative Relapse in Patients with Lung Cancer (ID 892)

      I. Oh, H. Cho, C. Park, Y. Kim, J. Yun, S. Song, K. Na, M.S. Yoon, S. Ahn, H. Seon, Y. Choi, S. Lee

      • Abstract
      • Slides

      Background:
      Glutathione peroxidase 3 (GPx3) which is an extracellular secretory protein is down regulated in patients with early stage lung cancer. We examined the usefulness of serum GPx3 as a biomarker for monitoring of relapse after surgery.

      Methods:
      We prospectively collected serial serum samples at baseline, 3 months (3m), 6 months (6m), and 12 months (12m) after operation from the patients who underwent surgery during the year 2013. GPx3 levels were measured three times per sample using the enzyme-linked immunosorbent assay, and the mean values were analyzed by repeated measure analysis of variance.

      Results:
      A total of 126 (73 adenocarcinoma, 31 squamous cell carcinoma, 22 others) patients were analyzed in this study. Median age of patients was 66 years old (range, 39-80) and 19 (15.4%) out of 123 lung cancer patients were confirmed relapse during the follow-up period of 2 years. In squamous cell carcinoma, the changes of mean serum GPx3 were significantly different between relapse (baseline: 13.3 ± 1.1 μg/mL, 3m: 17.1 ± 4.6 μg/mL, 6m: 14.8 ± 2.7 μg/mL, 12m: 17.9 ± 1.7 μg/mL) and control group (baseline: 10.8 ± 2.3 μg/mL, 3m: 13.4 ± 3.4 μg/mL, 6m: 12.4 ± 2.6 μg/mL, 12m: 13.5 ± 4.7 μg/mL, p=0.043). The changes of mean serum GPx3 levels were not different between two groups in all histology (p=0.258) and adenocarcinoma (p=0.701).

      Conclusion:
      Postoperative serum GPx3 levels were significantly elevated only in relapsed squamous cell histology, not in adenocarcinoma. More large scaled validation studies are warranted.

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    P1.07 - Poster Session/ Small Cell Lung Cancer (ID 221)

    • Type: Poster
    • Track: Small Cell Lung Cancer
    • Presentations: 16
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      P1.07-001 - Preoperative Serum proGRP as a Predictor for Lung Tumor Histology (ID 2561)

      M. Lund-Iversen, O.T. Brustugun, M.N. Broughton, J. Wang, N. Bolstad, D. Warren, Z. Sou

      • Abstract
      • Slides

      Background:
      Progastrin-releasing peptide (proGRP) is the stable precursor of gastrin-releasing peptide, a hormone secreted by neuroendocrine cells. Serum measurements of proGRP are helpful to detect relapses of small cell carcinoma during follow up, but its usefulness as a preoperative marker to distinguish between different lung tumors is unclear.

      Methods:
      Preoperative serum proGRP was determined in 116 patients with primary pulmonary tumors. 31% of the tumors displayed endocrine features (19 carcinoids, 8 small cell carcinoma, 9 large cell carcinomas) whilst the remainder were non-small cell carcinomas (40 adenocarcinomas and 40 squamous cell carcinomas). The presence of proGRP in tumors with possible endocrine features was evaluated by immunohistochemistry using two in-house anti-proGRP monoclonal antibodies (mAb M16 and mAb E149]. Tumors with less than 2 % positive cells were considered negative for proGRP expression. Serum levels of proGRP above 70 ng/L were considered elevated.

      Results:
      Mean serum proGRP (s-proGRP) was 267 ng/L (median: 96.5 ng/L, [range 25 – 2080 ng/L] for the neuroendocrine tumors, while adenocarcinomas and squamous cell carcinomas had mean values of 50 and 60 ng/L respectively [19,137] and median values 53.5 ng/L and 59.6 ng/L respectively (table 1). Among the tumors with possible endocrine features, serum levels of proGRP reflected the IHC score (Wilcoxon rank-sum test, p<0.0005). We did not find any relationship between tumor size and s-proGRP levels, but values >70 ng/L were predictive of either carcinoid tumor or small cell carcinoma. Table 1: Tumor characteristics

      Histology ProGRP IHC positives (n/total) S-proGRP (median) S-proGRP (mean) Mean tumor size (mm)
      Carcinoid 9/19 127 424 26.1
      Small cell carcinoma 5/8 75.5 145 30.2
      Large cell carcinoma 3/9 46 72.8 42.2
      Squamous cell carcinoma NA 59.6 60 NA
      Adenocarcinma NA 53.5 50 NA


      Conclusion:
      The correlation between s-proGRP and IHC scores suggest that the elevated s-proGRP results from proGRP produced by the tumor. The lack of correlation between s-proGRP and tumor size might be explained by variations in number of proGRP producing cells within the different tumors and/or to the amount proGRP secreted by different tumors. For lung tumors with unclear preoperative histology or cytology, s-proGRP-levels can be helpful as an adjuvant diagnostic marker to differentiate between tumors with and without endocrine features, but the test is not robust enough for final decision making.

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      P1.07-002 - FAK Inhibition by PF228 Has Anti-Tumoral Effects Associated with Inhibition of Histone 3 and Aurora Kinases A/B Phosphorylation in SCLC (ID 2844)

      F. Aboubakar Nana, M. Lecocq, L. Maha, S. Dupasquier, B. Detry, P.P. Massion, C. Pilette, C. Pilette, Y. Sibille, Y. Sibille, S. Ocak, S. Ocak

      • Abstract
      • Slides

      Background:
      Lung cancer is the most common cancer and the leading cause of cancer-related death worldwide. Small cell lung cancer (SCLC) accounts for 15% of all lung cancer cases and is the most aggressive histologic type, with a five-year overall survival as low as 5%. Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase, which regulates integrin and growth factor signaling pathways involved in cell proliferation, survival, migration, and invasion. FAK is overexpressed and/or activated in many cancers,including SCLC. We hypothesized that FAK may represent a good target for therapeutic intervention in SCLC and tested the changes of cell phenotype and signaling events following FAK inhibition, by using PF-573,228 (PF-228) in SCLC cell lines.

      Methods:
      Two SCLC cell lines growing in suspension (NCI-H82 and NCI-H146), an adherent SCLC cell line (NCI-H196), and a mixed morphology SCLC cell line (NCI-H446) were treated with increasing concentrations of PF-228. Cell proliferation was evaluated by WST-1 assay, cell cycle by flow cytometry following propidium iodide (PI) and bromodeoxyuridine (BrdU) staining, and apoptosis by flow cytometry after intracellular caspase 3 staining. FAK expression/activity and signaling events downstream of FAK were evaluated by Western blotting (WB).

      Results:
      While PF-228 did not modify total FAK expression, it decreased the phosphorylation of FAK (Tyr 397) in a dose dependent manner in all tested SCLC cell lines. Inhibition of FAK activity by PF-228 significantly decreased cell proliferation, induced cell cycle arrest in G2/M phases,decrease DNA replication and increased apoptosis in all tested cell lines proportionally to the dose. Regarding signaling events, we observed that inhibition of FAK activity induced the inhibition of phosphorylation of histone-3 (Ser 10) and Aurora Kinase A (Thr288) and B (Thr232). Figure 1



      Conclusion:
      These results show that FAK activity is required for proliferation, cell cycle progression, and survival in SCLC cell lines, suggesting that this pathway is central to SCLC biology. The antitumoral effects of PF-228 may occur through (1) the inhibition of histone-3 phosphorylation mediated by the inhibition of Aurora kinase B and leading to cell cycle arrest in G2/M phase and (2) the inhibition of Aurora kinase A leading to decreased DNA replication.

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      P1.07-003 - Role of Tumor Infiltrating Lymphocytes in Small Cell Lung Cancer (ID 1486)

      I. Bhavsar, I. Mehmi, D. Griswald, T. Gress, Y. Lebowicz

      • Abstract
      • Slides

      Background:
      Small-cell lung cancer (SCLC), a histological subtype of lung cancers, carries a very poor prognosis. Female sex, performance status (PS), and stage are known prognostic markers for SCLC. Lymphocytes have been observed and described in SCLC biopsies from the lung. However, no information is available that defines the correlation of these lymphocytes to SCLC outcomes. To identify this correlation of TiLs to overall survival (OS) and progression free survival (PFS) in SCLC, we carried out a retrospective analysis of SCLC cases diagnosed at our hospital 2008-2013.

      Methods:
      53 patients’ biopsies of SCLC stained with hematoxylin and eosin were examined with light microscopy at 40X by in-house hematopathologist . Lymphocytes that were interspersed among the tumor cells were counted, and then obtained the pertinent data. Spearman rank correlation analysis was used to assess correlation.

      Results:
      Among the 53 patients 30 (57%) females and 23 (43%) male, age mean 62.87 years (35-89), average PS 1.53 (0-4), 99% of the patients Caucasian, TiLs mean 70 (10-400), 18 (34%) had LS-SCLC, and 35 (66%) had EX-SCLC Progression free survival (data available for total of 36 patient, of which 16 LS-SCLC, 20 ES-SCLC): LS-SCLC 20.84 months (95% CI; 13.76-27.92), ES-SCLC 5.7 months (95% CI; 4.17-7.23) OS: LS-SCLC 22.97 months (95% CI; 16.16-29.78), ES-SCLC 8.21 months (95% CI; 5.30-11.13) Correlation between TiLs and OS Spearman’s rho was calculated at 0.15, p=0.28; indicating no correlation between TiLs and OS. Correlation when stratified by stage: In LS-SCLC, no correlation between OS of LS-SCLC and number TiLs’s found (Spearman’s rho=0.19, p=0.45 for total of 18 patients). In ES-SCLC, no correlation between OS of ES-SCLC and TiLs (Spearman’s rho=-0.02, p=0.91).

      Conclusion:
      Recent data in breast cancer (1) and melanoma indicate the presence of TiLs is a positive prognostic marker. However, we were not able to find a positive or negative correlation of TiLs to SCLC outcomes. It is possible that small sample size failed to show a correlation. However, the known prognostic markers for SCLC i.e. female sex, PS, and stage of disease showed correlation with OS in our sample size (data not shown). This indicates that a) our sample size is a good representation of previously studied larger samples, and b) a likely accurate assessment of this correlation. Previously, Wang et al (3) has described FOXP3+ T cell lymphocytes as negative prognostic maskers for SCLC. However, our clinical data fails to provide additional support. Taken together, these studies advocate for larger sample size evaluation. References: 1)Loi et al. Prognostic and Predictive Value of Tumor-Infiltrating Lymphocytes in a Phase III Randomized Adjuvant Breast Cancer Trial in Node-Positive Breast Cancer Comparing the Addition of Docetaxel to Doxorubicin With Doxorubicin-Based Chemotherapy: BIG 02-98. JCO September 20, 2014;32;2935-2937 2)Thomas et al. Tumor-Infiltrating Lymphocyte Grade in Primary Melanomas Is Independently Associated With Melanoma-Specific Survival in the Population-Based Genes, Environment and Melanoma Study. JCO November 20, 2013;31:4252-4259 3)Wang et al. Small cell lung cancer tumor cells induce regulatory T lymphocytes, and patient survival correlates negatively with FOXP31 cells in tumor infiltrate. IJC April 24, 2012; 131:E928–E937

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      P1.07-004 - Efficacy of Endostar Combined with Chemotherapy and Endostar Maintenance Treatment for Patients with Extensive Small-Cell Lung Cancer (ID 1639)

      L. Chen, Y. Wu

      • Abstract
      • Slides

      Background:
      EP scheme is a standard regimen ad the first-line treatment for small cell lung cancer, with the complete remission of 10~25% and overall survival up to 10 months. However, almost all patients reoccur or progress within 1 year after first-line treatment. Endostar combined with chemotherapy had synergistic effect and slight toxic effect.

      Methods:
      Patient, female, was admitted in the hospital in March, 2010 because of cough and hemoptysis and diagnosed as small cell lung cancer by bronchoscopic biopsy. Patient was finally diagnosed as extensive small-cell lung cancer by pathology and imaging (CT, MRI), who was treated by EP scheme (etoposide and cisplatin) and endostar for 6 months from July, 2010—Jan. 2011. Patient was remitted completely after treated by EP scheme (etoposide and cisplatin) and endostar. However, patients had brain metastases in Jan., 2011 and received radiotherapy and endostar maintenance treatment for 4 cycles. And patient was partially remitted. The reoccurrence of lung was considered in Nov., 2011 and treated by EP plus endostar for 2 cycles and patients was remitted completely until Feb., 2012.

      Results:
      During the course of treatment, patient was well tolerated to chemotherapy and had no intolerant toxic effects. Performance status of patients scored 0 point. Extra-cerebral progress Free Survival (PFS) reached 13 months and the follow up on overall survival is up to 33 months.

      Conclusion:
      Endostar combined with chemotherapy and endostar maintenance treatment is effective and safe for the treatment of extensive small-cell lung cancer.

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      P1.07-005 - Paclitaxel and Irinotecan in Platinum Refractory/Resistant Small Cell Lung Cancer: Final Analisis of One Galician Lung Cancer Group Experience (ID 1441)

      F.J. Afonso-Afonso, N.F. Núñez, M.J. Villanueva Silva, J.L. Fírvida Pérez, M. Amenedo, U. Anido Herránz, L.M. De Paz Arias, M. Covela Rúa, G. Huidobro Vence, M.C. Areses, L. Cadavid Vieitez, N. Garcia Cid, S. Vzsquez-Estevez

      • Abstract

      Background:
      Patients with Small Cell Lung Cancer (SCLC) whose disease progresses during or shortly after treatment with platinum, have a poor prognosis. Paclitaxel (P) and irinotecan(I) have demonstrated activity both as monotherapy as in combination regimen for this neoplasm. We have previously presented data from our experience with this agents in patients with SCLC . Here, we present a final analysis of survival and security.

      Methods:
      We included patients with measurable disease that had progressed during or within six months of first-line chemotherapy based on platinum, with an Eastern Cooperative Oncology Group (ECOG) performance status <2, adequate liver, renal and bone marrow function. They were treated with (P): 75 mg/m2 and (I): 50 mg/m2, both drugs administered on days 1 and 8 of a 21 day cycle. Treatment was maintained until disease progression and/or unacceptable toxicity.

      Results:
      We included 50 patients with a mean age of 65 years (43-77) and with metastases in two or more locations in 39 of them (78%). A median of 4 cycles of treatment was administered and eight patients (16%) received six or more cycles. The main reason for discontinuation of chemotherapy was disease progression, observed in 22 patients (44%). Partial response was documented in 18 patients (36%), stable disease in 20 (40%) and disease progression in 7 (14%). There were five patients in whom it was not possible to evaluate response. The median progression free survival was 4.09 months (CI 95%: 2.13-6.05) and the median overall survival was 5.092 months (CI 95% 4.22 – 5.96). No treatment-related deaths were described. The clinical and hematologic toxicities most frequently observed were grade 1 and 2: asthenia (n:20; 40%), diarrhea (n:14; 28%), anorexia (n:12; 24%), alopecia (n:11; 22%), neutropenia (n:5; 10%) and anemia (n:4; 8%). There was one (2%) grade 4 and four (8%) grade 3 neutropenia. There were no cases of grade 4 clinical toxicity and there were 16 (32%) grade 3 : nine of diarrhea (18%), three of asthenia (6%), one of vomiting (2%), one of hiponatremia (2%), one hepatic (2%) and one hyperglycemia (2%).

      Conclusion:
      This (P) and (I) regimen is an effective and well tolerated option for this subgroup of very poor prognosis patients with SCLC.Future explorations using this therapeutic regimen are warranted.

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      P1.07-006 - Final Results of Randomized Phase II Study of Carboplatin plus Irinotecan vs. Carboplatin plus Amrubicin for ED-SCLC (ID 931)

      Y. Fujita, N. Morikawa, S. Sugawara, M. Maemondo, T. Harada, M. Harada, A. Inoue, T. Katoh, H. Yokouchi, T. Nukiwa

      • Abstract
      • Slides

      Background:
      Carboplatin-based regimens, such as carboplatin plus etoposide (CE), are among the standard regimens for the management of extended disease small-cell lung cancer (ED-SCLC). However, the efficacy of carboplatin-based regimens is unsatisfactory. Carboplatin plus irinotecan (CI) and carboplatin plus amrubicin (CA) are promising new carboplatin-based regimens identified in our previous studies. Accordingly, we conducted this randomized phase II study to identify the appropriate regimen for comparison with CE in future phase III trials.

      Methods:
      Chemotherapy-naïve patients with ED-SCLC were randomly assigned to receive 4–6 cycles of carboplatin (area under the curve [AUC] 5.0, day 1) plus irinotecan (70 mg/m[2], days 1 and 8) every 3 weeks (CI arm) or carboplatin (AUC 4.0, day 1) plus amrubicin (35 mg/m[2], days 1–3) every 3 weeks (CA arm). The primary endpoint was the overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity.

      Results:
      Between December 2009 and March 2013, 71 patients were enrolled. One patient in each arm did not receive any protocol treatment owing to rapid disease progression. The characteristics of the treated patients were as follows: median age, 70 years (range 51–84 years) and proportion of males, 84%. Delivered mean dose intensities (mean actual dose/mean planned dose) were similar for both arms: carboplatin 98% and irinotecan 94% for CI arm, and carboplatin 97% and amrubicin 94% for CA arm. The ORRs were 79% and 89%, median PFS was 5.1 and 6.2 months (CA; hazard ratio [HR] = 0.59, 95% CI: 0.35–0.98, P = 0.042), and median OS was 12.2 and 15.9 months in the CI and CA arms, respectively (CA; HR, 0.77; 95% CI: 0.49–1.29; P =.318). Grade 3 or higher neutropenia (CI, 53% and CA, 89%), anemia (CI, 26% and CA, 20%), thrombocytopenia (CI, 18% and CA, 14%), and febrile neutropenia (CI, 12% and CA, 29%) were observed. No treatment-related deaths were observed. Overall, 25 patients (74%) in the CI arm and 28 patients (80%) in the CA arm received post-discontinuation therapies.

      Conclusion:
      CA was numerically effective than CI in chemotherapy-naïve patients with ED-SCLC, with acceptable toxicity. Therefore, CA could be selected for future phase III trials.

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      P1.07-007 - Prophylactic Cranial Irradiation in Extensive Stage Small Cell Lung Cancer: The Ottawa Hospital Experience (ID 1446)

      A. Bang, W. Kendal, G. Cook, R.M. Macrae

      • Abstract
      • Slides

      Background:
      The role of radiation has been investigated in extensive stage small cell lung cancer (ES-SCLC) in two-fold: prophylactic cranial irradiation (PCI) and consolidative radiotherapy. A randomized control trial was published in 2007 (Slotman) which showed benefits for PCI in median survival and decreased cumulative risk of symptomatic brain metastases. We conducted a retrospective study to evaluate the uptake of PCI at The Ottawa Hospital (TOH) for ES-SCLC and its impact on time to brain metastasis and survival. TOH is the sole provider of cancer services for a population of 1.3 million.

      Methods:
      The medical records of 605 patients (206 limited stage, 399 extensive stage) with small cell lung cancer between Jan. 1, 2005 and Dec. 31, 2011 were reviewed. The cumulative incidence of brain metastases and cumulative proportion surviving was estimated using the Kaplan–Meier method comparing patients receiving PCI or not. Differences between the groups with covariates including age, gender, smoking status, ECOG score, extrathoracic involvement, and response to chemotherapy were analyzed using t-test.

      Results:
      158 out of 399 ES-SCLC patients (39.6%) had no brain metastases at diagnosis, received chemotherapy, and had a partial or complete response. Of the 158 patients with these criteria, 69 patients received PCI and 89 did not. 90 patients had brain metastasis on diagnosis, and 151 patients were not eligible or had no response/progression to chemotherapy. On multivariate analysis, the only statistically significant predictors of overall survival were initial performance status and use of PCI. Using t-test, only partial vs. complete response to chemotherapy was found to be significantly different between the PCI and no PCI groups. There was a statistically significant difference in survival (p= 0.0021) and time to brain metastasis curves (p = 0.00029). Median survival for PCI and non-PCI groups was 14.0 and 8.2 months respectively. Median time to brain metastasis was 18.0 and 9.0 months respectively. There was no significant difference in incidence of brain metastases (40.6% vs. 43.8%) in either group. With regards to uptake of PCI for ES-SCLC at The Ottawa Hospital, 24.2% (16/66) of patients before Jan. 1, 2008 were treated with PCI compared to 57.6% (53/92) after 2008. Figure 1



      Conclusion:
      PCI in the setting of at least partial response to chemotherapy was found to have a survival benefit and prolongation of time to brain metastasis. This has corresponded with an increased uptake of PCI at The Ottawa Hospital since publication of the EORTC 22993-08993 in 2007.

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      P1.07-008 - Preliminary Results from a Phase Ib/II Trial of Belotecan plus Ifosfamide in Patients with Extensive-Stage Small-Cell Lung Cancer (ID 1325)

      Y.S. Kim, E.K. Cho, M.Y. Baek, E.Y. Kim, H.K. Ahn

      • Abstract
      • Slides

      Background:
      Belotecan is a novel camptothecin analogue, topoisomerase I inhibitor. Belotecan, alone or in combination with cisplatin, has shown activity in small cell lung cancer. The objective of the phase Ib part was to determine the maximum tolerated dose (MTD) and safety of belotecan plus ifosfamide in patients with extensive-stage small-cell lung cancer.

      Methods:
      Patients with age ≥ 18 years, no previous chemotherapy, measurable disease, ECOG PS 0-2, and adequate organ function were eligible. The phase Ib portion of the trial is a conventional 3+3 dose-escalation design. The following dose levels (belotecan/ifosfamide, mg/m[2]) were explored: 0.5 x 4d/1200 x 2d (level 1), 0.5 x 4d/1000 x 3d (level 2, starting dose), 0.5 x 4d/1000 x 4d (level 3), 0.5 x 5d/1000 x 4d (level 4), and 0.5 x 5d/1000 x 5d (level 5) every 21 days.

      Results:
      Here we report the phase Ib portion of the trial. Thirteen patients were enrolled and completed at least one cycle. The median age is 68 years (range, 48-77). ECOG PS was 0/1/2:1/6/6, respectively. A total of 53 cycles (median, 5; range, 1-6) of chemotherapy were administered. The MTD was belotecan 0.5 mg/m[2] on days 1-4 in combination with ifosfamide 1000 mg/m[2] on days 1-4 (level 3). Three patients experienced dose-limiting toxicities; death from neutropenic sepsis and grade 3 fatigue at dose level 4, and febrile neutropenia at dose level 3. The most frequent grade 3-4 toxicities were myelosuppression, including neutropenia (54%), anemia (23%), and febrile neutropenia (23%). Eleven patients were evaluable for response and 9 (82%) had partial responses.

      Conclusion:
      The combination of bleotecan and ifosfamide is feasible and active. The recommended phase II dose is belotecan 0.5 mg/m[2] on days 1-4 and ifosfamide 1000 mg/m[2] on days 1-4 of a 21-day cycle. The phase II trial is currently ongoing. Clinical trial information:NCT01784107.

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      P1.07-009 - Effect of Accurate Heart Outlining on Cardiac Dose - the CONVERT Trial Experience (ID 1378)

      N. Groom, E. Wilson, C. Faivre-Finn, S. Falk

      • Abstract
      • Slides

      Background:
      RTOG 0617 showed greater one year overall survival of 81% in the 60Gy group versus 70.4% in the 74Gy group, supporting the hypothesis that cardio pulmonary effects of radiotherapy can contribute to death. It has demonstrated that the percentage of heart receiving ≥5 and ≥30Gy is correlated with survival. Hence there is a need to improve planning and delivery of radiotherapy to avoid irradiating normal lung and heart wherever possible. This current study investigates the effect on cardiac dose of inaccurate cardiac outlining (non compliant to protocol) for a selection of plans submitted as part of the CONVERT Trial quality assurance programme.

      Methods:
      The CONVERT Trial is a multicentre phase III study which recruited 547 patients with limited-stage small cell lung cancer from April 2008 to November 2013. Patients were randomised to receive once daily (66Gy in 33 fractions) or twice daily (45Gy in 30 fractions) radiotherapy concurrently with chemotherapy. The primary endpoint was overall survival. The spinal canal, lungs, oesophagus and heart were contoured as organs at risk for dose-volume histograms. The trial protocol specified that the heart and pericardial sac should be contoured. Outlining should extend superiorly to the inferior aspect of the aortic arch and inferiorly to the apex of the heart. An atlas was provided to each centre which included example organ at risk contours. In this current study, heart outline volumes (in cm[3]) provided by participating centres have been compared to gold standard heart outlines (in cm[3]) drawn according to the trial protocol for 50 patients. The impact of the change in heart volume on heart dose (V30) is also presented. The CT and structure set for each case was imported into Eclipse (Version 11), and the heart was re-outlined according to the trial protocol. The plan data were then imported into Vodca along with the dose cube provided by the centre so that DVH data could be extracted.

      Results:
      The mean difference in cardiac volume between the gold standard and that provided by the centre was 80.0cm[3 ](range: 1.9cm[3] to 248.2cm[3]). In the experimental trial arm (66Gy), an increase in calculated cardiac dose (V30/%) was seen in 22/28 cases (78.6%) by using the gold standard cardiac outline rather than that provided by the centre. The mean increase in V30 was 5.7% (range: 0.92% to 15.29%). In the control dose arm (45Gy), an increase in calculated cardiac dose (V30/%) was seen in 17/22 cases (77.3%). The mean increase in V30 was 6.9% (range: 0.93% to 14.1%).

      Conclusion:
      In this study we have shown that in 86% of cases reviewed the heart was not delineated according to protocol. As a result the mean heart dose was underestimated by an average of 2.3Gy. In conclusion, this study highlights the importance of collecting radiotherapy plans to check heart contours as part of a QA programme and to feedback deviations to investigators.

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      P1.07-010 - Hyperfractionated Versus Hypofractionated Radiotherapy for Limited-Stage SCLC: A Retrospective Comparison of Two Prospective Studies (ID 592)

      X. Hu, B. Xia, Y. Bao, Y. Xu, X. Fu, M. Chen

      • Abstract
      • Slides

      Background:
      The optimal thoracic radiation dose/fraction for limited-stage small cell lung cancer (SCLC) is not yet established at present. This study mainly aims to retrospectively compare the impact on local/regional control of different thoracic radiation dose/fraction schedules from two prospective trials.

      Methods:
      Patients received thoracic radiotherapy consisted of 1.5 Gy twice a day in 30 fractions over a 19-day period to a total of 45 Gy (hyperfractionated arm, BED=53.3 Gy) or 2.5 Gy daily in 22 fractions over a 30-day period to a total of 55 Gy (hypofractionated arm, BED=62.6 Gy) combined with concurrent chemotherapy were included into this study. A statistical software package SPSS 13.0 was applied, and Kaplan-Meier method was used to estimate survival data. Fisher’s exact test was used for comparisons of categorical data.

      Results:
      From 2005 to 2014, nighty-two patients were accrued into to the hyperfractionated arm. From 2005 to 2012, nighty-one patients were accrued into the hypofractionated arm. The 1-year, 2-year local/regional progression free survival rates of hyperfractionated arm and hypofractionated arm were 82.1%, 60.7% and 83.8%, 67.9%, respectively (P=0.33). The median survival time (months) of hyperfractionated arm and hypofractionated arm were 27.9 (95% CI: 15.7-40.1) and 22.0 (95% CI: 16.4-27.5) respectively, while 1-year, 3-year, 5-year overall survival rates of the two arms were 85.2%, 39.4%, 26% and 77.1%, 34.4%, 26.9% respectively (P=0.48). Grade 2 and 3 acute radiation esophagitis were observed in 28.3%, 8.7% and 15.5%, 2.1% of patients in hyperfractionated arm and hypofractionated arm (P=0.009). Figure 1 Figure 2





      Conclusion:
      This study indicated that the use of hypofractionated radiotherapy failed to significantly improve the local regional control rate and overall survival time compared with hyperfractionated radiotherapy. However, the incidence of grade 2 and 3 acute radiation induced esophagitis was significantly more common in the hyperfractionated arm than in hypofractionated arm.

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      P1.07-011 - 'Peripheral Limited' Small Cell Lung Cancer (SCLC). Does Surgical Resection Have a Role in Primary Management? (ID 3138)

      L.Y. Schumacher, M.A. Vandeusen, A.H. Zaidi, S.A. Martin, E.J. Lloyd, G.G. Finley, A. Colonias, B.A. Jobe, R.J. Landreneau

      • Abstract
      • Slides

      Background:
      Limited stage SCLC, even peripheral completely resectable disease, is considered by many thoracic oncologic specialists to be a systemic process with a limited role of surgery beyond diagnosis. We hypothesized that surgical resection may improve local control, and potentially enhance survival for the small subset of SCLC patients (pts) with peripheral, resectable disease.

      Methods:
      Retrospective review of outcomes of all pts (n=127) with “limited stage” SCLC treated at our Institution from 2004-2014. Local disease progression and distant recurrence among pts undergoing primary systemic therapy +/- radiation therapy (n=106, 83%) were compared to pts with peripheral SCLC (n=21, 17%) undergoing surgical resection as first line therapy + adjuvant therapy. Patient demographics, surgical mortality, disease-free and overall survival outcomes were compared between the non-surgical and surgical groups. Systemic therapy was Platinum agent based. Survival was estimated using Kaplan-Meier survival analysis. Groups were compared using a log-rank test.

      Results:
      Pts demographics were similar between non- surgical and surgically treated SCLC pts. Systemic therapy / radiation was utilized for 88 (83%) non-surgical pts. Systemic therapy alone was utilized for 18 (16.9%) pts, and 2 (1.8%) patients received radiotherapy alone. Local disease progression represented first site of treatment failure in 19 (17.9%), while distant metastases was first noted in 65 pts (61.3%). Of the 65 distant metastasis first site of progression, 27 (41.5%) were cerebral. First site of progression was unable to be verified 16 (26.2%) medically treated pts. Among the 21 pts having “surgical resection” of peripheral, limited SCLC, there was no perioperative (30 day) mortality. Local recurrence was noted first in 7 (33.3%) of surgical pts. Distant metastases was discovered first in 3 (14.3%), and cerebral metastasis was found in 2 of these 3 pts. Nine (42.9%) surgical pts were recurrence free (mean 43 months), while only 7 (5.7%) medically treated pts were free of recurrence (mean 31 months). The 5 year survival among medially treated pts was 8% compared to 21% among patients undergoing surgical resection of peripheral SCLC (p= 0.008). (See figure 1. below) Figure 1



      Conclusion:
      Survival for all SCLC patients is affected by the common presence of systemic disease, despite an apparently limited, peripheral disease presentation. Surgical resection as “First line” therapy combined with adjuvant systemic + radiation therapy for peripheral, limited small cell lung cancer may be beneficial. Cerebral metastases are important sites of first distant recurrence for all limited stage SCLC.

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      P1.07-012 - Hypo- or Conventionally Fractionated Radiotherapy in Patients with Limited Stage Small Cell Lung Cancer (LS-SCLC): A Retrospective Analysis (ID 2565)

      J. Zhang, M. Fan, D. Liu, Y.X. Shen, K.L. Zhao, K.L. Wu, W.X. Zhao, L. Li, X.L. Fu, Z.F. Zhu

      • Abstract
      • Slides

      Background:
      Previous data from our institution showed that hypofractionated thoracic radiotherapy (HypoTRT) concurrently with etoposide/platinum chemotherapy yielded favorable survival in patients with LS-SCLC. The aim of the present study was to compare the survival outcomes, failure patterns and toxicities between groups of LS-SCLC patients treated with conventionally fractionated radiotherapy (ConvTRT) or HypoTRT combined with etoposide/platinum chemotherapy.

      Methods:
      Medical records of LS-SCLC patients between January 2010 and December 2013 at Fudan University Shanghai Cancer Center were retrospectively reviewed. All patients treated with chemotherapy and ConvTRT (2.0 Gy per faction daily, DT≥56Gy) or HypoTRT (2.5 Gy per faction daily, DT= 55Gy) were eligible for analysis. The progression-free survival (PFS) and overall survival (OS) were generated for different populations using the Kaplan-Meier method and compared by log-rank test. The comparison of failure patterns and toxicity were analyzed with the χ[2] test.

      Results:
      One hundred and seventy-nine patients were indentified. All patients received 1-6 cycles of Etoposide/Platinum chemotherapy. Except for nine patients who received hyperfractionated regimen, 170 of 179 patients treated with were eligible for analysis (median age 58 years; male 85.3%). Sixty-nine patients received HypoTRT and 101 patients received ConvTRT (median 60Gy/30Fx). PCI (25Gy/10Fx) was given to patients with partial or complete remission in chest tumor. PCI was administered to 46 (66.7%) and 48 (47.5%) patients in HypoTRT and ConvTRT cohorts (p=0.014), respectively. Except for PCI, the patient- or treatment-related variables were similar between the two cohorts. With a median follow-up of 23 months, the median OS was 26.7 months (95%CI: 23.2-30.2) in the ConvTRT cohort and 30.4 months (95%CI: 25.6-35.2) in the HypoTRT cohort (p=0.221). The 2-year OS for the ConvTRT and the HypoTRT cohort were 56.0% and 62.8%, respectively. The median PFS was 19.3 months for patients received HypoTRT, which was similar to that of the ConvTRT group (13.7 months, p=0.375). Sixty-three patients(62.4%) experienced disease progression in ConvTRT cohort, compared with 41 patients(59.4%) in HypoTRT cohort. The patterns of failure (stratified by local-regional recurrence, distant metastasis or both as first relapse) were also similar between the two dose cohorts (p=0.219, p=0.466, p=0.724). The 2-year local-regional progression free survival rates for the ConvTRT and HypoTRT cohorts were 59.7% and 70.6% (p=0.128), respectively. PCI reduced the incidence of brain metastasis by 31% at 20 months. Patients who received PCI had a significant longer survival with a 2-year OS rate of 69.8%, as comparing 44.4% of those who did not (p=0.000). Concurrent chemoradiotherapy was another predictor for favorable survival. However, patients who were treated with concurrent approach tended to be younger, receive early thoracic radiotherapy, more cycles of chemotherapy and PCI. No differences in treatment-related toxicity rates were demonstrated between the two dose-prescription cohorts (p=0.815). Grade ≥3 esophagitis and pneumonitis occurred in 9.9% and 9.9% in ConvTRT cohort, whereas 11.6% and 8.6% in HypoTRT cohort, respectively.

      Conclusion:
      In this retrospective analysis, HypoTRT or ConvTRT combined with etoposide/platinum chemotherapy yielded statistically similar survival, treatment failure outcomes, and toxicity profiles.

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      P1.07-013 - Real-Life 2-Year Therapeutic Strategies in the Management of 525 Small-Cell Lung Cancers: The ESCAP Study Preliminary Results (ID 1657)

      D. Debieuvre, F. Goupil, P. Brun, A. Dixmier, G. De Faverges, C. Nocent-Ejnaini, J. Crequit, S. Vuillermoz-Blas, C. Perrin, O. Leleu, M. Carbonnelle, F. Goutorbe, B. Asselain, F. Blanchon, F. Martin, M. Grivaux

      • Abstract
      • Slides

      Background:
      In the last years, new drugs and strategies have emerged in the management of lung cancer (LC). The French College of General Hospital Respiratory Physicians therefore promoted a prospective multicenter epidemiological study: the ESCAP study. This study was aimed to describe the therapeutic strategies implemented during the first 2-year after diagnosis in patients with LC followed in French General Hospital chest departments. We report below descriptive results for small-cell lung cancer (SCLC).

      Methods:
      For each patient with a LC diagnosed in 2010, a standardized form was completed at diagnosis and following each change in treatment strategy up to at least 2 years after diagnosis.

      Results:
      53 centers participated in the ESCAP study, and included 3,943 LC patients. Of these, 525 patients had a SCLC. Characteristics of SCLC patients at diagnosis were: mean age +/- standard deviation (SD), 65.6 +/- 10.8 years; male, 77%; never-smokers, 4.8%. The mean follow-up in SCLC patients was 10.5 months (SD: 8.8) and median number of strategies was 2 (Interquartile range: 1-3). Main strategy characteristics are summarized in the following table.

      First strategy (N=525) Second strategy (N=309) Third strategy (N=153)
      Duration (months): mean+/-SD 5.4 +/- 4.5 3.6 +/- 3.5 2.7 +/- 2.4
      Curative surgery 2% 1% -
      Radiotherapy 10% 47% 20%
      Radiochemotherapy 15% - -
      Chemotherapy 75% 55% 61%
      Exclusive supportive care 8% 14% 27%
      Patients died during the strategy 195 (37%) 134 (43%) 90 (59%)
      Patients with a new strategy 309 (59%) 153 (50%) 54 (35%)
      As regards first strategy, cisplatin (46%) and carboplatin (42%) were the most frequent used drugs associated with etoposide. As regards second strategy, the most frequently used drugs were topotecan (22%), etoposide (21%), or carboplatin (20%). Few patients received targeted therapy (< 1% in strategies 1 and 2).

      Conclusion:
      The ESCAP study describes the 2-year management of SCLC on real-life settings in France. Its preliminary results showed that 3 or 4 strategies were not uncommon in the management of SCLC patients.

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      P1.07-014 - Predictors of Survival in Small Cell Lung Cancer (SCLC) Patients (pts) < 50 Years of Age: Results from the California Cancer Registry (CCR) (ID 2416)

      A. Brunson, J.D. Lara, J.W. Riess, K. Kelly, P. Lara Jr., D.R. Gandara

      • Abstract
      • Slides

      Background:
      SCLC is an often lethal disease that commonly occurs in older individuals with a history of heavy tobacco use. Limited epidemiologic and outcomes data are available for young SCLC pts (< 50 years of age). We analyzed the CCR to explore the clinical variables related to cause specific survival (CSS) of young pts.

      Methods:
      SCLC pts diagnosed between 1998-2012 were included. Primary outcome was CSS. Hazard ratios (HR) for CSS were calculated using Cox Proportional Hazards (PH) models for all ages & for pts <50 years, adjusted for baseline variables: age, gender, stage, race, year of diagnosis, treatment, socioeconomic status (SES), and location (urban vs. rural).

      Results:
      We identified 22,863 SCLC pts, of which 975 were <50 years of age (4.2%). Demographics for pts <50 years: Males-51%; White-71%; Stage IV-60%; Chemotherapy-79%; Urban location-92%; high SES-28%. Fewer pts < 50 years were diagnosed in later years: from 40% in ‘98-’02 to 24% in ‘08-‘12. Results of multivariate Cox PH models are shown. (HR=Hazard Ratio).

      Select Variables All pts Pts<50 years of age
      HR P-value HR P-value
      Age at diagnosis (vs. ≥50yrs) 0.82 <0.0001 N/A N/A
      Female sex (vs.Male) 0.91 <0.0001 0.81 0.0045
      Race (vs.White)
      Asian 0.84 <0.0001 0.57 0.0075
      Year of Dx (vs.'88-'02)
      2003-'07 0.96 0.0096 0.95 0.5562
      2008-'11 0.94 0.0017 0.89 0.2796
      Stage (vs.I)
      Stage II 1.22 0.0111 1.20 0.7255
      Stage III 1.80 <0.0001 1.81 0.0282
      Stage IV 2.93 <0.0001 3.81 <0.0001
      Treatment (vs.None)
      Surgery 0.43 <0.0001 0.37 0.004
      Chemotherapy 0.44 <0.0001 0.49 <0.0001
      Radiation 0.66 <0.0001 0.71 <0.0001
      Rural (vs.Urban) 0.97 0.3042 0.75 0.0419
      Low SES {vs.High SES(4,5)} 1.05 0.0011 1.04 0.6306


      Conclusion:
      Age < 50 years was an independent predictor of improved CSS (HR 0.82, p<0.0001). In younger pts, female sex (HR 0.81, p=0.0045), Asian race (HR 0.57, p=0.0075), and rural residence (HR 0.75, p=0.042) were associated with better CSS, among other variables. Analyses for relevant interactions within subgroups will be presented.

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      P1.07-015 - The Prognostic Value of the Neutrophil Lymphocyte Ratio in Patients with Small Cell Lung Cancer (ID 964)

      H. Kaur, K. Arnaoutakis, A.L. Dunn, E.R. Siegel, F.A. Socola

      • Abstract
      • Slides

      Background:
      A high neutrophil to lymphocyte ratio (NLR) is reported to be a poor prognostic indicator in several malignancies and is associated with inferior survival. There is limited data exploring the prognostic role of NLR in small cell lung cancer (SCLC). The aim of the study was to evaluate the prognostic role of the NLR at the time of diagnosis in patients with SCLC.

      Methods:
      We retrospectively analyzed data from July 2010 to June 2013 of patients diagnosed with SCLC at a single tertiary care center. NLR ≥4 at the time of diagnosis was correlated with other prognostic variables to estimate its effect on the overall survival (OS).

      Results:
      There were a total of 80 eligible patients, including 33 males and 47 females. At the time of diagnosis, NLR ≥4 was seen in 36 (45%) patients. Overall, median absolute neutrophil count was 6.15 K/uL and absolute lymphocyte count was 1.6 K/uL. Both groups were comparable for age, gender, body mass index and ECOG functional score. We found 31/36 (86.11%) patients with NLR ≥4 who had extensive stage disease. In contrast, only 24/44 (54.55%) patients with NLR <4 had extensive stage disease (P= 0.0024). All 25/25 (100%) patients with limited stage disease received chemoradiation, while 44/55 (80%) of patients with extensive stage disease received chemotherapy. The median overall survival was 8.7 versus 11.2 months for patients with NLR ≥4 versus NLR <4 (log-rank P=0.014) (Figure 1). Multivariate Cox regression detected a strong interaction (P=0.0024) between NLR and the combined status of chemotherapy and stage. In the limited stage group, NLR ≥4 patients had slightly worse OS (HR=2.13, 95% CI: 0.66-6.86; P=0.20), whereas in the extensive stage group which received chemotherapy, NLR ≥4 patients had slightly better OS (HR=0.80, 95% CI: 0.42-1.53; P=0.50). In the extensive-stage group which did not receive chemotherapy, NLR ≥4 patients had significantly worse OS (HR=12.7, 95% CI: 2.94-55.2; P=0.0007).

      Conclusion:
      Similar to the other studies in solid tumors, we found a prognostic value of NLR in all patients with SCLC. However, NLR was prognostically significant only among patients with extensive-stage disease who did not receive chemotherapy. Among patients of both stage groups who received chemotherapy, NLR had little prognostic value. NLR ≥4 appears to be more prevalent in patients with extensive stage disease probably reflecting an impaired immune system. Further research exploring the role of immune system and associated immune surrogate markers in SCLC is needed. Figure 1



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      P1.07-016 - Comparison of PET/CT, 99mTc-MDP Bone Scan and Serum Alkaline Phosphatase for Detecting Bony Metastasis in Patients with Small Cell Lung Cancer (ID 2107)

      J. Zhang, M. Fan, D. Liu, Y.X. Shen, X.L. Fu, K.L. Zhao, K.L. Wu, W.X. Zhao, L. Li, Z.F. Zhu

      • Abstract
      • Slides

      Background:
      The data on the diagnostic ability of 18F-FDG positron emission tomography/computed tomography (PET/CT) compared that of 99mTc-MDP bone scan (BS) or serum alkaline phosphatase (ALP) for the detection of bone metastasis in patients with small cell lung cancer (SCLC) was sparse. The aimed of this study was to compare the diagnostic accuracy and agreement among PET/CT, BS and serum ALP for detecting bone metastasis in SCLC patients.

      Methods:
      The database at Fudan University Shanghai Cancer Center was retrospectively reviewed to identify all patients with SCLC who underwent both integrated whole-body PET/CT and BS between January 2010 and December 2013. In addition, serum ALP concentration of all eligible patients was recorded. The interval between PET/CT and BS was less than two weeks. Bone metastasis was confirmed if any of the following criteria were met: histology or pathology, concordance between PET/CT and BS, results of supplemental examinations (magnetic resonance imaging) or progression of bony lesions seen on follow-up studies. The sensitivity, specificity and accuracy of each modality were calculated. The overall differences were analyzed using the McNemar’s paired-sample test. The comparison of sensitivity, specificity and accuracy were analyzed with the χ2 test or Fisher exact test. Agreement between PET/CT, BS and ALP was assessed by kappa statistic. The κ-value was categorized as follows: poor (< 0.30), good (0.31–0.60), and excellent (0.61–1.0).

      Results:
      Of 368 patients with SCLC, a total of 30 patients were enrolled in this retrospective analysis. Six (20%) of thirty eligible patients were confirmed with bone metastasis, while 24 patients (80%) were found free from bone metastasis. The corresponding sensitivity, specificity, accuracy, positive and negative predictive value of PET/CT in detecting bone metastasis were 66.7%, 100%, 93.3%, 100% and 96.2% as compared to those of BS which were 100.0%, 70.8%, 76.7%, 46.2% and 100%, respectively. PET/CT had much higher specificity than BS (p=0.009). No statistically significant differences in sensitivity and accuracy were demonstrated between PET/CT and BS (p=0.455; p=0.145). Elevated serum ALP alone has the lowest sensitivity in detecting bone metastasis (16.7%), with the specificity of 87.5% and the accuracy of 73.3%, respectively. Combining the results of ALP and BS will significantly improve the specificity as compare to BS alone (100% vs 70.8%, p=0.009), while the sensitivity remains low (16.7%) and the accuracy remain unchanged (83.3% vs 76.7%, p=0.519). The κ-values were 0.276 between PET/CT and BS, 0.092 between PET/CT and serum ALP, and 0.099 between BS and serum ALP, indicating poor agreement among the three modalities in detecting bony metastasis.

      Conclusion:
      PET/CT had statistically higher specificity and numerically higher accuracy than BS in detecting bone metastasis in this group of patients with SCLC. The addition of serum ALP to BS improved the detection specificity comparing BS alone. There was still controversy involving in the use of PET/CT in SCLC. The diagnostic value of PET/CT needed to be validated in prospective and larger clinical trials.

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    P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)

    • Type: Poster
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 39
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      P1.08-001 - Rituximab for Treatment of Lymphoma Induced Marked Regression of Malignant Mesothelioma with Dynamic Changes of Serum Cytokine Profiles (ID 1192)

      K. Aoe, S. Kuyama, Y. Mimura, Y. Mimura-Kimura, T. Murakami, T. Matsumoto, H. Ueoka

      • Abstract
      • Slides

      Background:
      Malignant mesothelioma (MM) is a highly aggressive tumor with poor prognosis. As an effective therapy remains to be established, increased attention has been given to immunotherapy in MM.

      Methods:
      We experienced a patient with malignant lymphoma and MM who showed marked regression of MM after the anti-CD20 monoclonal antibody rituximab therapy. Here we investigated the mechanism underlying this response by immunohistochemical staining and serum cytokine assay.

      Results:
      A 78-year-old man with diffuse large B-cell lymphoma and epithelioid MM was treated with rituximab for malignant lymphoma. The lymphoma responded well to rituximab, and the pleural thickening of MM regressed markedly after this treatment without therapy for mesothelioma. Immunohistochemical stainings revealed negative expression of CD20 on mesothelioma cells, indicating that rituximab did not directly attack the mesothelioma cells. The serum levels of 27 cytokines were measured 12 days before and 16, 45 and 54 days after this treatment to compare with those in 24 untreated MPM patients. The serum levels of cytokines of this patient including IL-12, INF-g, TNF-a, VEGF and IP-10 were higher than those of other mesothelioma patients before the rituximab treatment. Notably, during the treatment the level of IL-12 increased approximately 10-fold, relative to its baseline level. In addition, the levels of IL-2, Eotaxin, G-CSF, and TNF-a transiently increased several fold as compared with their baseline levels. In contrast, the levels of VEGF, PDGF, IP-10, and IL-8 which are associated with mesothelioma proliferation, decreased after the treatment. These results suggest that the mechanism of mesothelioma regression in this case involves antitumor immunity enhanced with high baseline levels of IL-12 and other Th1 cytokines and B-cell depletion by the rituximab treatment.

      Conclusion:
      The relationship between these cytokine profiles and the clinical outcome might provide a potential immunotherapeutic strategy for MM.

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      P1.08-002 - Stat3 Is a Potential Target for Malignant Pleural Mesothelioma (MPM) Treatment (ID 1649)

      S. Matsumoto, T. Nakamichi, A. Kuroda, M. Hashimoto, T. Takuwa, N. Kondo, S. Hasegawa

      • Abstract

      Background:
      The prognosis of malignant pleural mesothelioma (MPM) is very poor; thus, a new drug treatment is necessary. Serum IL-6 is high in patients with MPM because of the activation of IL-6/Stat3 pathway. Thus, we investigated Stat3 as a potential target for the treatment of MPM.

      Methods:
      Cell viability was examined using the Cell Counting Kit-8 (CCK-8: WST-8 Dojindo). MPM cell lines (NCI-H28, NCI-H226, NCI-H2052, NCI-H2452, and MSTO-211H) were seeded onto 96-well plates. After treatment with Stattic, a Stat3 inhibitor, CCK-8 solution was added to each well and absorbance was measured using a microplate reader. Phosphorylated Stat3 levels (p-Stat3) were measured in cell lysates using the InstantOne ELISA assay (eBioscience). The expression of p-Stat3, E-cadherin, and vimentin was determined by western blot analysis. Translocated p-Stat3 was analyzed by confocal immunofluorescence microscopy. Cells were plated onto chamber slides containing medium. After the Stattic treatment, cells were fixed and cell membranes permeabilized. p-Stat3 antibody was added to chamber slides and incubated overnight at 4°C. Images were captured using a Zeiss LSM780 confocal microscopy system. Apotosis induced by Stat3 inhibitor was measured using the Caspase-GloR 3/7 assay (Promega). Cells were seeded onto 96-well plates. After the Stattic treatment, Caspase-GloR 3/7 reagent was added to each well, and the luminescence of each sample was measured in a plate-reading luminometer. For our in vivo study, H226 cells were subcutaneously injected into the flank region of nude mice. Mice were randomly assigned into two groups, with 5 mice in each group: vehicle control and Stattic (treated with10 mg/kg po 5 days per week).

      Results:
      Stattic inhibited viability of all MPM cell lines in a dose-dependent manner. IC50 values ranged from 3.3–106.0 μM. p-Stat3 levels decreased by 50% with 1 μM Stattic treatment in H226 cells. H226 cells were treated with 0.01 to 10 μM Stattic. Vimentin expression was stable; however, E-cadherin expression increased with 0.1, 1, and 10 μM Stattic treatment. In untreated H226 cells, p-Stat3 was observed in the cytoplasm and localized in the nucleus. In contrast, in Stattic-treated cells, decreased p-Stat3 was observed in the cytoplasm only, and it did not localize to the nucleus. Caspase 3/7 cleavage increased with Stattic treatment after 12 h and decreased after 48 h. In vivo mouse xenograft model, Stattic suppressed tumor growth (vehicle control vs.Stattic, P < 0.05).

      Conclusion:
      In this study, we have shown that Stattic inhibits proliferation of all MPM cell lines and suppresses tumor growth in a mouse model. In addition, we have demonstrated that Stattic inhibits Stat3 phosphorylation and blocks nuclear translocation. Furthermore, Stattic inhibits EMT. Thus, the STAT3 inhibitor is a promising candidate in MPM therapy.

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      P1.08-003 - Minimal Asbestos Exposure in Germline BAP1 Heterozygous Mice Is Associated with Deregulated Inflammatory Response and Increased Risk of MM (ID 1483)

      A. Napolitano, L. Pellegrini, A. Dey, D. Larson, M. Tanji, A. Powers, S. Kanodia, S. Pastorino, H.I. Pass, V. Dixit, H. Yang, M. Carbone

      • Abstract
      • Slides

      Background:
      Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma. Mesothelioma is an aggressive malignancy generally associated to professional exposure to asbestos. However, to date we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos. We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after even minimal exposure.

      Methods:
      We experimentally tested in a BAP1[+/-] murine model whether germline BAP1 heterozygosity would result in alterations of the asbestos-induced inflammatory response, and whether low doses of asbestos might be sufficient to cause MM.

      Results:
      Germline BAP1 heterozygosity is associated with a significantly altered peritoneal inflammatory response upon exposure to asbestos fibers and to an increased risk of MM following exposure to even minimal amounts of asbestos that rarely cause MM in wild type animals.

      Conclusion:
      Our findings support our hypothesis that germline BAP1 heterozygosity increases susceptibility to the carcinogenic effects of low doses of asbestos. Based on these results, we suggest that prevention programs of MM in individuals carrying germline BAP1 mutations should focus on reducing exposure to even minimal indoor and/or naturally occurring outdoor sources of carcinogenic fibers, levels that are within the acceptable “safe” limits for the population at large.

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      P1.08-004 - Aki1 as a Potential Therapeutics Target in CREB1 Signaling in Malignant Mesothelioma (ID 234)

      T. Yamada, S. Yano, J.M. Amann, K. Shilo, D.P. Carbone

      • Abstract

      Background:
      Malignant pleural mesothelioma (MPM) is an aggressive tumor arising from the mesothelial cells of serosal membranes. Since current treatment options are largely ineffective, novel therapeutic strategies based on molecular mechanisms and the disease characteristics are needed to improve its prognosis. Akt kinase-interacting protein 1 (Aki1)/Freud-1/CC2D1A known as a scaffold protein of PI3K/PDK1/Akt that determines receptor signal selectivity for EGFR has been suggested as a therapeutic target in lung cancer. The aim of this study was to elucidate the role of Aki1 and its potential for treatment of MPM.

      Methods:
      We tested the effects of the treatment with Aki1 or CREB1 siRNAs on cell viability by MTT assay, cell cycle by FACS analysis, cell signaling by WB, and CREB transcriptional activity in 7 MPM cells and 1 mesothelial cells using in vitro experiments. We investigated the efficacy of Aki1 siRNA against growth of 211H cells in an orthotropic implantation model using SCID mice. We further examined Aki1 and p-CREB1 expressions in MPM tumors from 35 patients by TMA specimens and from 33 patients by the tissues.

      Results:
      Cell based assay showed that silencing of Aki1 inhibited cell viability and caused cell arrest of some of MPM cells but not mesothelial cells. Importantly, we identified that the efficacy of Aki1 is regulated by CREB1 signaling which is involved in cell viability, cell cycle, and transcriptional activity. Aki1 and phosphorylated CREB1 were frequently expressed in MPM patients (65/68 cases) (30/35 cases), respectively. Furthermore, the expression of Aki1 correlated with phosphorylation of CREB1 (Spearman rank correlations = 0.521; p = 0.002). Furthermore, direct application of Aki1 siRNA into the pleural cavity significantly inhibited growth of 211H cells compared with that of control siRNA in an orthotropic implantation model using SCID mice.

      Conclusion:
      Our data suggest an important role of Aki1/CREB axis in pathogenesis of MPM and provide a rationale for targeting Aki1 by intrathoracic therapy in locally advanced tumors.

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      P1.08-005 - Met and PI3K/mTOR as a Potential Combinatorial Therapeutic Target in Malignant Pleural Mesothelioma (ID 1700)

      R. Kanteti, J.J. Riehm, W.T. Vigneswaran, F. Lennon, R. Hasina, H.L. Kindler, R. Salgia

      • Abstract
      • Slides

      Background:
      There are a number of genetic alterations such as BAP1 and NF2 that can occur in malignant pleural mesothelioma (MPM). Various studies have shown that both MET and its downstream key intracellular signaling partners PI3K and mTOR are known to be overexpressed and frequently mutated in MPM. Here we have examined the therapeutic efficacy of a new generation small molecule inhibitor of MET receptor tyrosine kinase ARQ 197 and phosphatidylinositol 3-kinase and mTOR (PI3K/mTOR) inhibitors BEZ-235 and GDC-0980 in MPM.

      Methods:
      The mesothelioma cells were treated with ARQ 197, NVP-BEZ235, or GDC-0980 alone or in combination for 72 hours and cell proliferation was measured by using Alamar Blue assay. Synergistic efficacy was determined by isobologram and combination-index methods of Chou and Talalay. Signaling was assessed by immunoblotting. The mechanism of inhibition was further studied by using apoptosis assays and cell cycle analysis. Cell motility was studied by using scratch assays. We also examined efficacy of the combination of ARQ 197 and GDC-0980 on in vivo tumor growth by using mouse xenograft models.

      Results:
      MPM cell lines over-express MET and its active form p-MET, PI3K, and p-AKT and total AKT. ARQ 197, NVP-BEZ235, and GDC-0980, when used alone, significantly inhibited the cell proliferation of mesothelioma cells in a dose dependent manner. The combination of MET and PI3K/mTOR inhibitors was synergistic in suppressing MPM cell growth as compared to any single drug alone. Treatment of ARQ 197, NVP-BEZ235, and GDC-0980 alone or in combination inhibited the phosphorylation of AKT and S6 kinase in mesothelioma cells. MET and PI3K/mTOR inhibitors affect cell growth of mesothelioma cells by cell cycle inhibition (cyclin D1) and induction of apoptosis (presence of cleaved PARP, by IF/ confocal microscopy). MET inhibitor ARQ 197 alone inhibits the cell motility of mesothelioma cells in scratch assay. The combination of ARQ 197/ GDC-0980 was much more effective than each single agent alone in inhibiting the tumor growth of mesothelioma xenografts in nude mice. Compared to the control mice (2946±403 mm[3]), the tumors of mice treated with ARQ 197(2262±317 mm[3]) and GDC-0980 (1631±229.57mm[3]) alone had a significant decrease in the tumor volume. The tumor volume of mice treated with the combination of ARQ 197 and GDC-0980 further decreased it to six fold (475±97.43 mm[3]) compared to the control mice.

      Conclusion:
      Our results suggest that the combined use of ARQ 197/NVP-BEZ235 and ARQ 197/GDC-0980 is far more effective than single drug use in suppressing MPM cell motility and growth in vitro and tumor growth in vivo and therefore merits further translational studies.

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      P1.08-006 - Lung Toxicity after Post-Operative Radiotherapy after EPP for Mesothelioma and Pneumonectomy for Non-Small Cell Lung Cancer (ID 2863)

      A. Botticella, C. Draulans, G. Defraene, K. Nackaerts, C. Deroose, J. Coolen, P. Nafteux, S. Peeters, D. De Ruysscher

      • Abstract
      • Slides

      Background:
      Our hypothesis is that MPM patients treated with post-operative RT after EPP are more prone to develop lung toxicity compared to non-small cell lung cancer (NCSLC) patients treated with post-operative RT after pneumonectomy, since their higher baseline inflammation status.

      Methods:
      We retrospectively reviewed the records of 39 consecutive patients with MPM who received post-operative RT after extrapleural pneumonectomy (EPP), and of 10 consecutive patients with non-small cell lung cancer who received post-operative RT after pneumonectomy between March 2003 and March 2012 at the University Hospitals of Leuven. For MPM patients, the planning target volume was defined as the entire hemi-thorax, chest wall incisions, drain sites, and involved nodal stations. Prescription dose was 54 Gy in 2-Gy fractions delivered to the planning target volume (PTV). For NSCLC patients, the planning target volume was defined as mediastinal nodal stations according to the pathologic nodal involvement. Prescription dose was 54-66 Gy in 2-Gy fractions delivered to the PTV. Both cohorts received induction systemic chemotherapy before surgery. Primary endpoint was lung toxicity. Dyspnea was graded using the Common Toxicity Criteria (CTC) v. 4.03 and was recorded before RT, 45 days after the completion of RT and every 3 months thereafter until the completion of the follow up. Dosimetric dose-volume parameters (lung V5, lung V20, mean lung dose [MLD], mean heart dose, heart V45) were retrieved for both cohorts. The correlation between the dosimetric parameters and the toxicity (dyspnea score) was investigated.

      Results:
      In MPM patients, the dyspnea score was 0-1 in 24/39 patients (61.5%), 2 in 11/39 patients (28.2%), 3 in 3/39 patients (7.7%) and 4 in 1/39 patients (2.5%). No grade 5 toxicity was recorded. In NSCLC patients, only grade 0-1 dyspnea was registered (grade 0: 4/10 patients; grade 1: 6/10 patients). Mean MLD was 7.56 Gy (range: 1.60-14.80; SD: 3.65) for the MPM group and 5.96 Gy (range: 3.2-14.5; SD: 3.57) for the NSCLC group. Univariate analysis showed a significant correlation between grade > 2 dyspnea and MLD, lung V5 and lung V20.

      Conclusion:
      Post-operative radiotherapy after EPP is well-tolerated, with 10% of patients experiencing grade > 3 dyspnea. Strict dose-constraints should be applied when radiotherapy is administered in multimodality treatment.

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      P1.08-007 - Programmed Cell Death 1 Ligand 1 (PD-L1) Expression in Thymoma (ID 46)

      S. Yokoyama, H. Miyoshi, T. Nishi, R. Matsumoto, T. Hashiguchi, D. Murakami, M. Kashihara, S. Takamori, Y. Akagi, K. Ohshima

      • Abstract
      • Slides

      Background:
      Programmed cell death 1 ligand-1 (PD-L1) has been reported to be expressed in various malignancies, and is considered to be a prognostic factor and an immunotherapeutic target. The aim of this study was to characterize PD-L1 expression in thymoma and statistical associations between this expression and clinical features.

      Methods:
      We reviewed formalin-fixed paraffin-embedded tissue specimens from 82 thymoma cases at Kurume University. PD-L1 expression was evaluated by immunohistochemistry (IHC). Statistical associations between PD-L1 expression and clinicopathological features were evaluated by using chi-square test and Fisher’s exact test. Disease-free survival (DFS) analysis, the end event of which is recurrence, was performed by the Kaplan-Meier method.

      Results:
      A total of 44 thymoma cases (54%) revealed high PD-L1 expression by IHC. No significant differences were observed between high and low PD-L1 expression with respect to sex (P = 0.938), age (P = 1.000), symptomatic myasthenia gravis (P = 0.471), anti-acetylcholine receptor antibody titer (P = 0.513), primary tumor size (P = 0.527), or curability (P = 0.620). However, high PD-L1 expression was statistically associated with Masaoka’s stage III/IV disease (P = 0.043) and WHO type B2 or B3 thymoma (P = 0.044). DFS after complete resection in high PD-L1 expression cases was significantly worse than that in low PD-L1 expression cases (P = 0.021). Figure 1Figure 2





      Conclusion:
      Characterization of PD-L1 expression in thymoma should enable more effective clinical approaches, including prognostic stratification of patients and use of anti-PD-L1 antibody immunotherapy.

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      P1.08-008 - Efficacy of Palliative Chemotherapy in Malignant Pleural Mesothelioma from Spanish BEMME Database. The Spanish Lung Cancer Group (SLCG) (ID 2356)

      J. Remon, N. Reguart, E. Nadal, R. López-Caastro, P. Martin Martorell, E. Olmedo, J.L. González-Larriba, S. Ponce, L. Molins, M. Majem, B. Massuti, R. Porta, M.A. Sala, L. Calera, P. Diz, J. Calzas, B. Rubio, J. Garde, A.L. Ortega, E. Galvez, R. Rosell

      • Abstract
      • Slides

      Background:
      Palliative chemotherapy with cisplatin and antifolate (pemetrexed or raltitrexed) conferred a median overall survival of 12 months with a response rate of 24% to 43% in malignant pleural mesothelioma (MPM) patients. BEMME (Base Epidemiológica Mesotelioma Maligno en España) is an observational and retrospective study sponsored by the Spanish Lung Cancer Group that aimed to characterize the patient’s and tumor’s features as well as the treatment modalities outcomes of patients diagnosed with mesothelioma in Spain.

      Methods:
      Clinical records of patients with malignant pleural mesothelioma were retrospectively reviewed to collect epidemiological and survival data into an electronic and anonymous database. Thirty-five Spanish hospitals participated in the project and 538 MPM patients were included in the BEMME database. Here we present a descriptive analysis of MPM patients (stage III and IV) treated with palliative chemotherapy.

      Results:
      From January 2008 to December 2013, 297 of 538 patients (p) (55%) with MPM were treated with palliative chemotherapy. Most patients were males (79%), aged between 60-70y (40%), and 60% had a performance status 1 at diagnosis. No exposure to asbestos was reported in 54% of patients. Epithelioid was the most frequent histological subtype (66%), followed by sarcomatoide (12%), biphasic (9%) and not specified (14%). In stage IV, the most frequent metastatic site was lung (35%). Among patients who received chemotherapy, 55% were treated with palliative intent and reached a disease control rate (CR+PR+SD) of 62%. Platinum plus pemetrexed was the most common schedule used as a palliative treatment, without differences in ORR according to platinum-based agent used (Cisplatin: 36% vs. Carboplatin: 32%). A total of 61 of the 297p (21%) received maintenance treatment with an ORR of 10% and stable disease in 50% of p. The median overall survival (OS) for all patients was 12.6 months (95% CI 10.8 – 14.3). There were statistically significant differences in OS according histological subtype. The median OS for epithelioid was significantly longer (15 months, 95% CI 13.8-18) as compared with non-epithelioid (7 months 95% CI 4.3-9, p<0.001). There were no statistically significant differences in OS according to gender, asbestos exposure or type of platinum chemotherapy (Cisplatin 15.2 months 95% CI: 13.7-18.75; vs. Carboplatin 18 months 95% 12-25.3, p=0.32).

      Conclusion:
      In Spain, OS of MPM patients treated with platinum palliative chemotherapy exceeded the median OS reported in phase III trials.

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      P1.08-009 - Hepatocyte Growth Factor (HGF) Expression in Malignant Mesothelioma: A Potential Predictive Marker for <em>met/</em>HGF-Targeted Therapy? (ID 2908)

      M.L. Cowan, M. Yaylaoglu, J. Bailey, S. Sa, P.B. Illei

      • Abstract
      • Slides

      Background:
      Malignant mesothelioma (MM) is an aggressive neoplasm predominantly involving the pleura with less than 2 years median patient survival time and limited systemic therapeutic options. The HGF-MET axis is important in cell proliferation and homeostasis. Dysregulation of the pathway has been linked to tumorigenesis. Met overexpression has been used as a predictor of response to Met-targeted therapy with limited success. HGF is the only known ligand for Met, but intratumoral HGF levels have not been studied in MM. In a preclinical glioblastoma model autocrine signaling by HGF was predictive for Met-Targeted therapy. Our aim was to evaluate HGF expression patterns and to assess the feasibility of non-isotopic bDNA in situ hybridization to reliably detect HGF expression in MM.

      Methods:
      We analyzed HGF expression using non-isotopic branched-DNA in situ hybridization on an automated platform in 39 samples of MM. In a subset of cases manual in situ hybridization was also performed. Immunohistochemistry for c-met using a rabbit monoclonal antibody and semiquantitative scoring system proposed for NSCLC was also available for 33 tumors. The cohort included 10 peritoneal (3 male and 7 female, age range 15-77; median 64.5) and 29 pleural tumors (24 male and 5 female, age range 24-88; median 67.4). There were 28 epithelioid, 10 biphasic and 1 sarcomatoid tumors. HGF expression was scored as none, weak, moderate or strong (normal placenta and surrounding benign tissue served as controls).

      Results:
      Moderate to strong HGF expression was seen in 7 cases (6 strong, 1 moderate), weak expression was noted in 10 tumors while 22 were negative. Met IHC was only available for 3 of the 6 strong HGF expressing tumors. Of the 16 met positive tumors only 1 showed strong HGF expression while the majority were HGF negative (10) or weak positive (5). Intratumoral heterogeneity and both paracrine and autocrine HGF expression were also observed. The automated and manual in situ hybridization methods showed concordant results.

      Conclusion:
      Non-isotopic bDNA assay can be used to reliably detect HGF mRNA in mesothelioma tissue sections. A range of HGF expression levels can be seen with a subset of cases showing moderate to strong (18%) expression. Intratumoral heterogeneity is present and both paracrine and autocrine sources of HGF can be identified. The majority of c-met positive (2+ and 3+) tumors exhibit weak or no HGF expression with only 1 of 3 HGF strongly positive tumor showing positive (2+) c-met staining. Further studies are needed to determine if HGF expression can be used as a predictive marker for c-met/HGF targeted therapy in malignant mesothelioma.

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      P1.08-010 - Understanding the Genetic Landscape of Malignant Mesothelioma - A Comparison of Human and Murine Mesothelioma Cell Lines (ID 1641)

      J. Creaney, S. Sneddon, N. Waddell, J. Pearson, S. Grimmond, B.W.S. Robinson

      • Abstract
      • Slides

      Background:
      Malignant mesothelioma (MM) is predominantly caused by exposure to asbestos. Next generation sequencing is being used in MM to understand the nature of the genetic lesions that underlie the disease and to identify potential new therapeutic targets. MM has the unusual distinction of having a mouse homologue that largely replicates the human cancer. This provides an opportunity to use murine tumor sequence data to understand mesothelioma pathogenesis, examine asbestos mutational signatures and test potential treatment strategies predicted by the genetic landscape. We have undertaken exome sequencing of asbestos induced murine MM, and compared our findings with human MM.

      Methods:
      Whole exome sequencing (WES) was performed on the Ion Torrent Proton platform on 15 early passage MM cell lines developed from ascites induced following asbestos exposure and tumour development in three wild-type mouse strains (BALB/c, CBA and C57BL/6 strains). Wild type germline murine normal samples were sequenced concurrently. Somatic single nucleotide variants (SNVs) were identified using publicly available algorithms with a subset being validated using Sanger sequencing. Copy number variation was analysed using GISTIC. Mutation signatures were identified using the Somatic Signatures algorithm in R.

      Results:
      There were on average 760 SNV identified in mouse MM cell lines (range 212-2234) equivalent to a median of approximately 9 mutations per Mb. There were significantly more SNV detected in the BALB/c strain than the CBA and C57Bl/6 strains. As previously observed there was a tendency for chromosome deletion rather than amplification in MM. Deletions in chromosome 4 in the region of p16 were common. Non-synonymous mutations accounted for 60-80% of all exonic mutations. C>T and G>A transitions were more prevalent than other mutation types across all tumours. Mutation signature analysis showed a higher rate of C>A, C>G and C>T mutations in specific dinucleotide contexts, which was mirrored in the human MM tumours.

      Conclusion:
      Genetic analysis of murine models of MM enables the identification of candidate mutational changes that can help inform about changes in human tumors. These models also provide excellent opportunities for pre-clinical proof-of-principle therapeutic studies of the use of sequence information in clinical trials.

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      P1.08-011 - Clinical Outcome and Prognostic Factors for Advanced Malignant Mesothelioma (MM) Patients (pts) Treated on Phase I Trials (ID 2595)

      D. Papadatos-Pastos, D. Roda, M.J. De Miguel Luken, V. Michalarea, J. Lima, N. Diamantis, M. Capelan, A. Jalil, S. Bodla, J. Bhosle, R. Molife, M. O'Brien, U. Banerji, S. Popat, T.A. Yap

      • Abstract
      • Slides

      Background:
      Relapse after approved anticancer treatments is inevitable in MM pts. Novel agents in phase I trials may benefit such pts and the development of a prognostic score can help identify those who are likely to benefit most. We review the outcome of pts with relapsed MM who have participated in phase I trials in the drug development unit (DDU) of the Royal Marsden Hospital (RMH).

      Methods:
      The RMH prognostic score (RPS) (albumin < 35 g/L, lactate dehydrogenase [LDH] > upper limit of normal [ULN], and > 2 sites of metastases) is an objective tool used to select pts for phase I trials. In view of the pattern of disease spread in MM, we sought to define a MM-specific RPS (m-RPS), by assessing baseline patient factors. Data from consecutive patients who participated in 33 phase I trials between 09/2003 and 12/2014 were included in this analysis. The endpoints were time to progression (TTP) overall survival (OS) and safety. Kaplan-Meier analysis using a log rank test was used to determine survival outcomes.

      Results:
      Data from 54 pts, M:F (36:18), median age 62 years (range, 25-76) were studied. All pts had ECOG PS 0-1. TTP was 2.5 (95% CI 1.7-3) months, OS was 7.6 (95% CI 5.3-8.4) months and the clinical benefit rate was 15%; Three (6%) pts had RECIST confirmed partial response (to PI3K pathway inhibitors [n=2] and immunotherapy [n=1]); 5 (9%) pts had RECIST stable disease ³6 months. Male gender was highlighted as a factor of poor prognosis (p=0.004) in a multivariate analysis and therefore, we propose m-RPS for MM pts that now incorporates gender instead of the number of metastatic sites (Table). The good prognosis group [A] (m-RPS 0-1; n=23) had a median OS of 13.7 (95% CI 7.9-24) months and the poor prognosis group [B] (m-RPS 2-3; n=28) had a median OS of 4 (95% CI 2.8-7.5) months, p<0.001. 13 pts (24%) had an OS < 12 weeks: 3 (11%) pts from Group [A] and 10 (36%) pts from Group [B]. 39 (72%) pts experienced G1-G2 toxicities, ³G3 toxicities were seen in 8 (15%) pts and 7 (13%) pts discontinued trial due to toxicity.

      Variable Score
      LDH
      ≤Upper limit of normal (ULN) 0
      >ULN 1
      Albumin
      ³35g/L 0
      <35g/L 1
      Gender
      Female 0
      Male 1
      Table. modified RMH prognostic score (m-RPS)


      Conclusion:
      Experimental agents in the phase 1 setting appeared to be well tolerated with preliminary signals of benefit in selected advanced MM pts. The m-RPS should be prospectively validated as a screening tool for MM pts considered for phase I studies

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      P1.08-012 - Immunohistochemistry as Prognostic Markers for Malignant Pleural Mesothelioma (ID 1663)

      T. Otsuki, N. Maehashi, Y. Kataoka, T. Terada, K. Kuribayashi, M. Hirabayashi, R. Ieki, T. Nakano

      • Abstract

      Background:
      Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy of the mesothelium. Several previous studies reported the prognostic ability of immunohistochemistry markers. But there are few reports adjusted for confounding appropriately.

      Methods:
      A retrospective cohort study was performed using epithelial and biphasic MPM patients treated in two tertiary hospitals in Japan between 2007 and 2014. Candidate prognostic factors were as follows: age; gender; performance status; stage; treatment modality; NLR (neutrophil lymphocyte ratio); calretinin expression; D2-40 expression; WT1 (Willms’ tumor 1). The primary outcome was overall survival (OS). The log-rank test and the Cox proportional hazards model were used for analyses to detect prognostic factors. We defined p<0.05 was statistically significant.

      Results:
      Total 371 patients comprised 309 epithelioid, 62 biphasic subtype of MPM. Median OS was 12.9 months. On univariate analysis all variables except for WT1 were associated with OS. On multivariate Cox proportional regression analysis PS (1<), Stage (II<), treatment modality, NLR (3<=), D2-40 negative expression were associated with shorter OS.

      Conclusion:
      Positive expression of D2-40 were associated with longer OS of epithelial and biphasic MPM. Further studies are warranted.

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      P1.08-013 - Long Non-Coding RNAs Associated with Lysine Demethylases Are Overexpressed and Epigenetically Regulated in Malignant Pleural Mesothelioma (ID 1757)

      A.S. Singh, L. Quinn, S.P. Finn, S. Cuffe, S.G. Gray

      • Abstract
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) is an aggressive rare cancer affecting the pleura and is predominatly associated with prior exposure to asbestos. Treatment options are limited, and most patients die within 24 months of diagnosis. The current standard of care for MPM patients is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed), yet most patients die within 24 months of diagnosis. Lysine Demethylases (KDMs) containing a JmjC domain regulate gene expression by “erasing or removing” methylation on histones in chromatin. Members of this family are frequently found to have aberrant expression in cancer and currently are actively pursued as candidate pharmaceutical therapeutic targets. We have shown that various members of the JmjC family of KDMs have significantly altered expression in MPM. Long non-coding RNAs (lncRNAs) belong to a group of RNAs that are usually more than 200 nucleotides long and play important roles in different regulatory processes, including regulation of gene expression. Several lncRNAs have also been shown to play a role as oncogenic molecules in different cancer cells (one example being HOTAIR). Altered expression of lncRNAS therefore make them candidate biomarkers with diagnostic and therapeutic potential in cancer. Several such lncRNAs have now been shown to locate to the same chromosomal region as various KDMs. These are KDM4A/KDM4A-AS1, KDM5B/KDM5B-AS1 (also known as PCAT6), KDM5C/ AY927613.1 and JARID2/JARID2-AS1. We therefore examined the expression of these lncRNAs in MPM.

      Methods:
      A panel of MPM cell lines were screened for expression of KDM4A-AS1, KDM5B-AS1, AY927613.1 and JARID2-AS1 by RT-PCR. lncRNA transcript levels were subsequently examined by RT-PCR in a cohort of snap-frozen patient samples isolated at surgery comprising benign, epithelial, biphasic, and sarcomatoid histologies. The effects of KDM and HDAC inhibitors on their expression was also examined.

      Results:
      The expression of the various lncRNAs was detectable across our panel of cell lines. In primary tumours the expression of these lncRNAs were significantly elevated in malignant MPM compared to benign pleura (p<0.05), and significant differences were also observed when samples were analysed across different histological subtypes.

      Conclusion:
      The expression of these lncRNAs are significantly altered in MPM. We have cloned KDM4A-AS1 and PCAT6 into overexpression constructs and future studies will assess the effects of these lncRNAs overexpression on mesothelioma proliferation, cellular health and gene expression to determine their potential role in mesothelioma.

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      P1.08-014 - The Small Molecule Inhibitor, LCRF004, Is Effective in Targeting the RON/MST1R Pathway in Malignant Pleural Mesothelioma (ID 1311)

      A. Baird, K.J. O'Byrne, D. Easty, L. Shiels, A. Byrne, S. Raeppel, B. Stanfill, A. Soltermann, D. Nonaka, D.A. Fennell, L. Mutti, H.I. Pass, I. Opitz, S.G. Gray

      • Abstract
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer. We have previously identified RON as frequently activated in MPM patient samples and cell lines. RON is a member of the MET proto-oncogene family and is bound by macrophage stimulating protein (MSP). High positivity for total RON by IHC was an independent predictor of favourable prognosis. Additionally, elevated expression levels of MSP correlated with better survival. The aim of this study was to further examine the MSP-RON signalling axis in MPM using a RON inhibitor, LCRF004.

      Methods:
      MPM cell lines and a normal mesothelial cell line were screened for the expression of RON and MSP at the protein (Western) and mRNA (RT-PCR) level. Downstream mediators affected by MSP stimulation and LCRF004 were identified using a proteome profiler array. The effect of LCRF004 and MSP were examined using proliferation (BrdU ELISA), viability (High Content Analysis), migration (xCELLigence), apoptosis and cell cycle (HCA) assays. A xenograft study was also completed.

      Results:
      Treatment with LCRF004 resulted in a significant decrease in proliferation, viability and migration in vitro and reduced tumour growth in vivo (p<0.05, compared with vehicle control). In addition, LCRF004 significantly increased apoptosis. In terms of cell cycle, drug treatment decreased cells in 2n, whilst increasing cells in the G0/G1 phase. Experiments are on going to further characterise the mechanism of action of LCRF004.

      Conclusion:
      The in vivo and in vitro data generated in this study, indicates that the MSP-RON signalling axis is a potential target in MPM. Targeting the RTK domain of the RON receptor with a small molecule inhibitor is an effective interventional strategy in MPM.

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      P1.08-015 - Malignant Pleural Mesothelioma: Observational and Retrospective Analysis of Spanish Database (BEMME). The Spanish Lung Cancer Group (SLCG) (ID 2355)

      N. Reguart, J. Remon, F. Cardenal, E. Nadal, Y. Garcia, M..R. Garcia-Campelo, Ó. Juan Vidal, J.R. Jarabo, M. Domine, C. Martinez-Barenys, D. Cumplido, S. Bolufer, D. Rodríguez, M. Martinez-Barenys, S. Peralta, I. Barneto, P. Lianes, M.P. Lopez, N. Martinez, I. Gil-Bazo, N. Martinez-Lago, M. Provencio

      • Abstract
      • Slides

      Background:
      Malignant Pleural Mesothelioma (MPM) is a rare but aggressive malignancy of the pleura, with a strong causal link to asbestos exposure. Although in Spain asbestos was banned in 2002, it is estimated that occupationally related deaths due to MPM will continue to occur until 2040. BEMME (Base Epidemiológica Mesotelioma Maligno en España) is an observational and retrospective study sponsored by the Spanish Lung Cancer Group that aimed to characterize the patient’s and tumour’s features as well as the treatment modalities of patients diagnosed with mesothelioma in Spain.

      Methods:
      Clinical records of patients with malignant pleural and peritoneal mesothelioma were retrospectively reviewed to collect epidemiological data, diagnostic tests, treatment modalities and survival data into an electronic and anonymous database. Thirty-five Spanish hospitals participated in the project and 570 mesothelioma patients were included in the BEMME database. Here we present a descriptive analysis of MPM patients based upon these data.

      Results:
      From January 2008 to December 2013, 538 patients (p) had MPM. Most patients were males (77%) and 74% of patients were ≥ 60 years (60-70y: 33%, >70y: 41%). Most patients (49%) had a performance status 1 at diagnosis. Only 32% of patients were recorded as positive for asbestos exposure and 77% of patients were never-smokers. Dyspnoea (35%) and thoracic pain (26%) were reported as the most frequent symptoms at diagnosis. Epithelioid was the most frequent histological subtype (63%), followed by sarcomatoid (12%), biphasic (8%) and not specified (17%). Disease stages at diagnosis were: stage I, 7%; stage II, 9%; stage III, 17%; stage IV, 45%; not specified, 22%. Surgery was performed in 41p: extrapleural neumonectomy 16p, extended pleurectomy 15p and partial pleurectomy 10p. Palliative pleurodesis was performed in 22% of patients. A total of 70% of patients received chemotherapy (55% palliative, 11 neoadjuvant and 6% adjuvant). The median overall survival (OS) for all patients was 13.2 months (95% CI 12.2 – 15.2). There were no statistically significant differences in OS according to age, gender and asbestos exposure. In the univariate analysis, higher stage (III-IV vs. I-II, p=0.0003) and non-epithelioid subtype (non-epithelioid vs. epithelioid, p=0.00001) were significantly associated with shorter OS.

      Conclusion:
      In Spain, most MPM patients are diagnosed at advanced stages and are treated with palliative modalities: mainly chemotherapy and pleurodesis. Stage and histologic subtype were prognostic factors for survival. BEMME database is a helpful tool to describe the therapeutic strategies employed in MPM patients in Spain.

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      P1.08-016 - Ponatinib Shows Promise in Malignant Pleural Mesothelioma Cells with Abl Pathway Dysregulation (ID 723)

      Y. Yang, G. Woodard, J. Chase, A. Marrufo, D. Jablons, H. Lemjabbar-Alaoui

      • Abstract
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) remains a lethal cancer with limited treatment options. Various tyrosine kinases including c-Abl/Arg, FGFR1, Src and PDGFRa/b have been implicated in driving the growth of MPM. Ponatinib is an FDA approved potent multi-target inhibitor of cAbl/Arg, PDGFRα, VEGFR2, FGFR1, and Src. The aim of this study was to investigate the effects of ponatinib on MPM cells.

      Methods:
      The in vitro effect of ponatinib on different MPM cell lines (H2052, MSTO211H, H2452, H28) were evaluated by MTS assay and the effect on cell migration was determined using a “scratch wound” assay. Levels of phosphorylated-Crkl (pCrkl) were evaluated by western blot and double-strand DNA breaks (DSDBs) measured via the surrogate marker γ-H2AX in an ELISA assay. A xenograft MPM model was used to examine the effects of ponatinib on tumor grown in vivo.

      Results:
      High levels of pCrkl were expressed in all MPM cell lines studied indicating c-Abl/Arg pathway activation. In vitro, ponatinib was effective against all MPM cell lines by cytotoxicity assay, led to dramatic cell migration inhibition, significantly reduced pCrkl expression, and increased DSDBs. In vivo, ponatinib blunted tumor growth in a xenograft model. Reduced pCrkl levels were observed in xenograft tumor specimens following ponatinib treatment.

      Conclusion:
      Inhibition of Abl kinase activity with ponatinib is a potential therapeutic approach in MPM patients with Abl pathway dysregulation. pCrkl shows promise as a biomarker of increased Abl kinase activity and may be useful in identifying MPM patients most likely to benefit from ponatinib.

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      P1.08-017 - microRNAs Expression in Malignant Pleural Mesothelioma, Asbestosis and Benign Pulmonary Disease (ID 2663)

      L. Ampollini, P. Mozzoni, L. Gnetti, M. Tiseo, L. Rolli, M. Solinas, L. Ventura, E.M. Silini, M. Goldoni, R. Alinovi, M. Rusca, M. Corradi, P. Carbognani, A. Mutti

      • Abstract
      • Slides

      Background:
      To evaluate the diagnostic potential of a panel of microRNAs in plasma samples of patients with malignant pleural mesothelioma (MPM).

      Methods:
      A group of patients with pathological diagnosis of MPM were randomly selected from a prospective mesothelioma database. Similarly, a group of patients with asbestosis and one with benign pulmonary disease, were chosen for comparison. A panel of miRNA including miR-16, miR-17, miR-21, miR-126 and miR-486 were evaluated. VEGF (vascular endothelial growth factor) was evaluated in plasma samples of patients with mesothelioma. Analysis of covariance (ANCOVA) followed by Bonferroni post-hoc test were used for multiple comparisons. P<0.05 was considered significant.

      Results:
      14 patients with malignant pleural mesothelioma, 14 patients with asbestosis and 21 patients with benign pulmonary disease were studied. The expression of miR-16 (p=0.018), miR-17 (p=0.024) and miR-126 (p=0.019) was significantly lower in patients with MPM compared with patients with benign pulmonary disease. Interestingly, miR-486 was able to discriminate patients with MPM compared to patients with asbestosis (p=0.004). Considering patients with MPM, miR-17 (p=0.023) and miR-486 (p=0.015) were significantly more expressed in patients with epithelial type than in patients with sarcomatoid and biphasic type. Moreover, the expression of miR-16 (p<0.0001), miR-17 (p<0.0001), miR-21 (p=0.004), miR-126 (p=0.0016) and miR-486 (p=0.003) was significantly lower in patients with asbestosis compared with subjects with benign pulmonary disease. In MPM plasma samples, VEGF expression was negatively correlated to miR-126 (p=0.004).

      Conclusion:
      The expression of miR-16, miR-17 and miR-126 was able to distinguish patients with MPM compared with patients with benign pulmonary diseases. miR-17 and miR-486 were significantly higher in patients with epithelial mesothelioma. An immunohistochemistry analysis evaluating the expression of VEGF in MPM tissue samples is ongoing. The available data support the role of miRNAs in the aetiology of MPM, suggesting their possible use as diagnostic markers of the disease.

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      P1.08-018 - Spontaneous Regression of Mesothelioma (ID 1046)

      G.N. Hillerdal, O. Grundberg

      • Abstract
      • Slides

      Background:
      Malignant pleural mesothelioma is a progressive disease with a poor prognosis. However, a few cases of spontanous regression has been reported in the literature. We here report another case.

      Methods:
      Not applicable

      Results:
      A 68-year old woman was referred to the clnic because of increasing dyspnoea and changes on her chest roentgenogram. She had never smoked and had worked in an office all life and denied all exposure to asbestos or other dangerous substances. CT scan revealed an irregular pleural thickening all around the right lung, in the interlobar fissure, and some enlarged mediastinal lymph nodes on the right side. Bronchsocpy, ultrasound biopsy of the pleura, and mediastinosccopy yielded no diagnosis, and therfore the thoracic surgeons made a pleural biopsy. This showed an epitheloid tumor , and the immune staining onfirmed that it was a malignant mesothelioma. The patient was offered cytostatic treatment but refused; she wanted to try with cost changes. She excluded meat in her diet, ate broccoli, nuts etc, and at check-up 3 months later the chest X-ray and the CT scan were normal. At follow-up, however, 18 months later there was a recurrence, ans she has now been started on chemotherapy.

      Conclusion:
      We have in the literature managed to find only three case reports similar to this one. An immunological reaction has been postulated to be the cause. In at least two of the cases, as in this one, there was none or only slight exposure to asbestos. In one case, there was no recurrence after 7 years, in another a single local recurrence after 6 years which was surgically removed. Odd patients which have lived for many years, even decades, without any treatment have also been described. In our own experience, the longest survivor survived 20 years with minimal symptoms. It is important to realize that good otcomes not always are due to the actions of doctors.

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      P1.08-019 - Pure Bronchoplasty without Lung Parenchyma Resection for Central Carcinoid (ID 311)

      O. Pikin, A. Ryabov, V. Sokolov, V. Glushko, K. Kolbanov, L. Telegina, A. Amiraliev, V. Barmin

      • Abstract
      • Slides

      Background:
      The aim of the study is to evaluate the efficacy of combined approach (endoscopic resection followed by pure bronchoplasty without any pulmonary resection) in patients with endobronchial carcinoids.

      Methods:
      We applied two-staged technique (endoscopic resection first followed by pure bronchoplasty) to 25 patients (males – 10) with endobronchial carcinoid. The median age was 32,4 years with a range from 19 to 64 years. The indications to this technique were pure endobronchial carcinoid without lymph node involvement. Tumour was located on the right side in 18 (72%), on the left – in 7(28%) patients. Endoscopic resection/desobliteraton of central airway was performed to all patients as the first stage procedure to resolve the obstructive pneumonia and to localize the pedicle of the tumour for proper planning of further bronchoplasty followed by endobronchial ultrasound to detect the peribronchial component. Different types of pure bronchoplasty were performed as the second stage surgery with systematic mediastinal lymph node dissection (table 1). Table 1.Types of bronchial sleeve resections in our series

      type of resection right side left side
      main stem bronchus 7 5
      bronchus intermedius 7 -
      main stem bronchus+upper lobe bronchus 2 2
      bronchus intermedius+middle lobe bronchus 1 -
      bronchus intermedius+lower lobe bronchus 1 -
      Total 18(5)* 7(2)*
      * polybronchial anastomosis was performed


      Results:
      The resection was complete (R0) in all cases. No lymph node metastases were observed, and tumours were pathologically staged as pT1aN0 in 18, pT2N0 – in 5, pT3N0 – in 2 patients and that all cases had invasive components limited to the bronchial wall. Twenty three tumours were typical and only two - atypical carcinoids. Morbidity was 33,3% (only minor complications) with no mortality. The stenosis of bronchial anastomosis was observed in one patient treated by endoscopic intervention. Overall 5- and 10-years survival was 100,0% and 96,0% (one patient died from myocardial infarction 8 years after surgery). No recurrence of the primary tumour was observed in any case.

      Conclusion:
      Two-staged surgery (endoscopic resection+pure bronchoplasty without lung parenchyma resection) is an effective technique for treatment of endobronchial carcinoids with excellent oncologic outcome.

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      P1.08-020 - Survival Impact of Adjuvant Radiation and Chemotherapy in Patients with Typical and Atypical Pulmonary Carcinoids (ID 3054)

      L.M. Hannan, J. Switchenko, Y. Liu, M. Behera, K.A. Higgins, F. Fernandez, R.N. Pillai, F. Khuri, S.S. Ramalingam, T.W. Gillespie, T.K. Owonikoko

      • Abstract
      • Slides

      Background:
      Adjuvant chemotherapy or radiation is commonly employed after resection of primary pulmonary carcinoid especially for patients with advanced stage disease with expectation of survival benefit. The indication for adjuvant therapy is poorly defined and there are limited data in support of this clinical practice. We therefore evaluated predictors and potential benefit of adjuvant chemotherapy and radiation using the National Cancer Database (NCDB), an oncology outcomes database administered by the American College of Surgeons and the American Cancer Society

      Methods:
      The NCDB was queried for patients who had undergone surgical resection of pulmonary carcinoid tumors between 2003 and 2006. Patients younger than 18 years and those with incomplete survival data were excluded from this analysis. Overall survival was defined as time from date of definitive surgery to date of death or last follow-up. Univariate and multivariable models were employed to assess for association between patient survival and variables of interest. Gender, age, and race were fit in a multivariable Cox model with treatment, and backward selection criteria (alpha = 0.1) were used to determine whether education, urban/rural, tumor size, income, laterality, insurance, or comorbidity score were included in the model. The proportional hazards assumption was checked for all models.

      Results:
      We included 4984 eligible patients diagnosed between 2003 and 2006 in the analysis. Post resection adjuvant radiation was administered to 4.2% of the patients; 1.9% received chemotherapy while the remaining patients did not receive any adjuvant therapy. Patients treated with adjuvant chemotherapy or radiation had worse survival at 2 years post surgery (75.7% and 70.8%% respectively) in comparison to patients managed with surgical resection only (94.2%). This survival difference was still significant in multivariable Cox models after adjusting for relevant patient and prognostic factors including gender, age, race, stage, lymph node involvement, tumor size, education level and co-morbidity score (HR: 2.35, 95% CI: 1.43 - 3.85, p<0.001 and HR: 1.97, 95% CI:1.48 - 2.61, p<0.001 for adjuvant chemotherapy and radiation, respectively). Decreased survival persisted in analyses restricted to patients with lymph node involvement (HR 1.58, p 0.084 and 3.21, p<0.001 for chemotherapy and radiation, respectively), and with advanced stage cancer (HR 4.10, p <0.001 and 2.04, p=0.036 and for radiation and chemotherapy, respectively) . Results did not differ by histology

      Conclusion:
      We observed worse outcomes in patients with typical and atypical carcinoid treated with adjuvant chemotherapy and radiation post surgery. The poor outcome associated with adjuvant therapy may be explained in part by the fact that patients considered for adjuvant therapy are more likely to have advanced stage disease and adverse tumor characteristics. However, contribution from potential toxicities of chemotherapy and radiation cannot be entirely excluded pending additional analysis in propensity-matched cohorts of patients.

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      P1.08-021 - Role of Surgery in Sarcomatoid Tumors of the Lung: A Multicentre Analysis (ID 44)

      F. Lococo, C. Rapicetta, G. Cardillo, A. Stefani, S. Margaritora, G. Leuzzi, L. Petracca, G. Rossi, U. Morandi, F. Facciolo, T. Ricchetti, M. Paci, G. Sgarbi

      • Abstract
      • Slides

      Background:
      Sarcomatoid lung carcinoma (SaLC) is a very rare and aggressive subtype of non-small cell lung cancer (NSCLC). To better understand the long-term results after surgical treatment and the main prognostic factors of such rare entities, we have revisited the clinical records of patients affected by SaLC in a large multicentre surgical series.

      Methods:
      Among 6569 patients who underwent curative resection for NSCLC from 01/2003 to 12/2013 in 5 Institutions, 148 patients (2.2%) had sarcomatoid carcinoma. Clinical and pathological data were retrospectively reviewed. Kaplan-Meier method, log-rank test and Cox-regression analysis were used for the statistical analysis when indicated.

      Results:
      Mean age and male/female ratio were 66.6±9.9 yrs and 120/28, respectively. The main clinical, surgical and pathological features of the population are summarized in Table 1. Thirty-six pts (24.3%) had pathologic stage-I disease and 70 pts (47.3%) presented with mixed histological tumor (SaLC combined with NSCLC). The overall median and 5-year (LTS) survivals were 17 months and 11.3%, respectively. During follow-up, 101 patients (68.2%) experienced a relapse of disease (84 pts (57%) at distance). Log-rank analysis identified the administration of pre-op PET/CT scan (LTS: yes=17.9% vs no=5.5%; p=0.040), the surgical radicality (LTS: R0=13.2% vs R+=0%, p<0.001), the pStage (LTS: p-I=13.2%, p-II=10.6%, p-III=6.3%, p-IV=0%; p<0.001) as prognostic factors in SaLC patients. Finally, Cox regression analysis confirmed the administration of pre-op PET/CT scan (p=0.021), the surgical radicality (p<0.001) and the p-Stage (p=0.022) as independent prognostic factors in such cohort of patients.

      Conclusion:
      Primary SaLC presented a poor prognosis after surgical treatment (overall 5-yr survival=11.3%), even in early stages (LTS: 13.2% in pStage-I). Such results imply that the role of surgery for primary SaLC is questionable and eventually limited (after an accurate preoperative staging) to “early-stage” tumors only. In this framework, stronger efforts should be made for target therapies development for such rare entity. Figure 1



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      P1.08-022 - Intraoperative Brachytherapy for Thoracic Malignancies Resected with Close or Positive Margins (ID 2795)

      C. Fleming, A. Rimner, G.N. Cohen, K. Rosenzweig, K.M. Alektiar, M.J. Zelefsky, M.S. Bains, A.J. Wu

      • Abstract
      • Slides

      Background:
      Local recurrence is a significant problem after surgical resection of thoracic tumors, particularly when close or positive margins are anticipated. As intraoperative radiotherapy (IORT) can deliver radiation directly to the threatened margin, we used this technique in an attempt to reduce local recurrence, particularly for patients who had already received external beam radiation. We updated our experience with thoracic IORT to assess disease control and toxicity outcomes.

      Methods:
      We performed a retrospective review of patients undergoing permanent I-125 mesh placement or temporary Ir-192 afterloading therapy during surgical resection of primary or metastatic thoracic tumors between 2001 and 2013. In general, for I-125 brachytherapy, iodine seeds were sutured into a mesh at 1cm intervals to form a planar implant delivering 85-250Gy to the MPD, which was then sutured onto the at-risk site. For Ir-192 brachytherapy, a HAM applicator was apposed to the at-risk site, then connected to the afterloader to deliver 7.5-16Gy to a depth of 0.5cm from the applicator surface. Kaplan-Meier method was used to estimate local control and overall survival, and logrank test was used to assess the impact of various clinical or treatment factors on local control.

      Results:
      Fifty-nine procedures (41 permanent, 18 temporary) were performed on fifty-eight patients (median 56 years old, range 19-77). Most common tumor histologies were NSCLC (n=23), sarcoma (n=18), thymic carcinoma (n=10), and mesothelioma (n=3). Treated sites were chest wall/paraspinal (n=31), lung (n=16), and mediastinum (n=12). Thirty-four procedures were performed on patients who had previously received external beam RT (EBRT) to the area (median 53.1 Gy). Final margins were microscopically negative in 25 cases (42.4%) and positive or not assessed in the remainder. The median size of the treated area was 27cm[2] (range: 4-152cm[2]). Median followup was 28.5 months. Actuarial local control at 1 and 2 years was 68.1% and 63.4% respectively. Median survival was 46.2 months. Overall survival at 1 and 2 years was 80.2% and 70.4% respectively. No perioperative deaths occurred. There was no significant difference in local control according to margin status, brachytherapy technique, use of adjuvant EBRT, or metastatic vs. primary tumor. Two patients (3.4%) experienced grade 3+ toxicities possibly related to IORT: one patient who also received preoperative EBRT developed pneumonitis; a second patient with prior EBRT for lymphoma died from complications of SVC syndrome likely induced by radiation fibrosis. An additional 8 patients had grade 3+ postsurgical complications (such as empyema, chylothorax, and pulmonary emboli) unlikely related to IORT. Four patients had grade 2 nerve injury also unlikely related to IORT.

      Conclusion:
      Intraoperative brachytherapy is associated with good local control after resection of thoracic tumors felt to be at very high risk for recurrence due to close or positive margins. There is a very low incidence of severe toxicity attributable to brachytherapy. Intraoperative brachytherapy should be considered in situations where the oncologic completeness of thoracic tumor resection is in doubt.

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      P1.08-023 - Induction Chemotherapy Increases the Survival of Patients with Primary Neuroectodermal Tumors of the Thorax (ID 2415)

      A. Demir, A. Turna, E. Hekimoglu, A. Toker, N. Molinas Mandel, Z.H. Turna, K. Kaynak

      • Abstract
      • Slides

      Background:
      Primary neuroectodermal tumors (PNETs) of the thorax are rare, small-round cell tumors with a poor prognosis despite multimodal therapy, including surgery and chemoradiotherapy. The ideal treatment was unknown since no comparative clinical series with surgical therapy had been reported. We evaluated the results of multimodal treatment in patients with PNETs located in the thoracic region.

      Methods:
      Between 2000 and 2013, 27 patients with PNETs in the thoracic region were treated in 3 tertiary-care hospitals. There were 15 males and 10 females with a mean age of 26.3 years (range, 6 – 60). The tumor was located in the chest wall in 21 (involving the costovertebral junction in 7), the lung in 6 patients. Thirteen patients had induction chemotherapy, whereas 22 patients underwent resectional surgery. All the patients received adjuvant chemo/radiotherapy.

      Results:
      There was no hospital mortality. The overall 5-year survival rate was 42% and median survival was 36±14 months in all patients. Five year survival in patients who had induction chemotherapy was 56%, whereas it was 36% in cases who did not receive induction chemotherapy (p=0.045). The 5-year survival rate of patients with and without costovertebral junction involvement was 21% and 64%respectively(p=0.076). The 5-year survival in the patients who had pulmonary involvement without vertebral or chest wall invasion had 50%.

      Conclusion:
      Primary thoracic PNET is an aggressive entity that often requires multimodal therapy. Induction chemotherapy seems to lead a greater complete resection rate and better survival, while involvement of the costovertebral junction indicates a slightly worse prognosis.

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      P1.08-024 - Large Cell Neuroendocrine Carcinoma: How Accurate Are the WHO 2004 Classification Criteria Applied? (ID 2127)

      J.L. Derks, E.M. Speel, R.J. Van Suylen, A. Dingemans

      • Abstract
      • Slides

      Background:
      According to the WHO 2004 (and 2015) classification, the diagnosis large cell neuroendocrine carcinoma (LCNEC) is established on presence of neuroendocrine morphology (i.e. organoid nesting/trabecular pattern, palisading cells and/or rosette formation) and neuroendocrine staining by immunohistochemical (IHC) markers. Furthermore, large cells should be present. However, diagnosis of LCNEC is restrained by the need of a resection or large biopsy specimen. Nonetheless, lung cancer is often diagnosed on small biopsies and therefore application of these WHO criteria in daily practice can be difficult. In this nationwide study we investigate on what tissue the diagnosis of LCNEC was established and to what extend the WHO 2004 criteria are reported in pathology reports established in the daily pathology practice in the Netherlands.

      Methods:
      Written conclusions (diagnoses) of pathology reports (2003-2012) were retrieved from the Dutch Pathology Registry (PALGA). Conclusions describing LCNEC were selected by queries on anatomic location, diagnosis and keywords (e.g. large cell + endocrine) and screened in accordance with a pathologist (JLD & RJS). Histologically diagnosed LCNEC cases were then selected and pathology centers were requested to send the report. After screening (JLD), consultation reports were excluded and the following data were extracted and compared: 1) mitotic index, 2) necrosis, 3) growth pattern (reported ≥1 feature(s) according to WHO or mentioning neuroendocrine morphology) and 4) neuroendocrine IHC marker staining. Additionally, the sampling method was recorded and retrieved diagnoses were clustered.

      Results:
      N=892 (72%) of 1235 requested reports were received (43 centers, mean 20 (range 1-67) reports). In N=869 pathology reports the conclusion was LCNEC including 759 original and 110 consultation reports. Most diagnoses were established on resection specimens (N=404, 53%) followed by needle (N=195, 26%) and small biopsies (N=160, 20%). Retrieved diagnoses could be clustered into LCNEC (N=658, 87%), combined LCNEC (N=41, 5%) and carcinoma favor LCNEC (N=60, 8%) respectively. Presence of mitoses was reported in N=541 (71%) yet only N=121 (16%) mentioned the mitotic index (≥10 mitoses 2mm[2] N=107). Necrosis was described in N=466 (61%) reports, most had central/abundant necrosis N=317 (68%) but in N=84 (11%) necrosis was undefined. Neuroendocrine morphology or a feature of neuroendocrine morphology was described in N=452 (60%) reports and in all except N=13 reports a neuroendocrine IHC marker was positive. When combining the WHO criteria, only N=66 (9%) of reports described all criteria, this increased to N=253 (33%) when mitosis without description of an index was included and N=403 (53%) if the report described either mitosis or necrosis. Lowest reported rates were observed in reports of needle biopsy (8-27%) and biopsy (4-15%) specimens.

      Conclusion:
      In 91% of retrieved pathology reports the WHO criteria for the diagnosis LCNEC could not be retrieved. Although 53% of reports included descriptions of neuroendocrine growth pattern and mitosis or necrosis, these regularly were incomplete or not quantifiable. Most commonly this was observed in reports from (needle) biopsy specimens. Whether the WHO criteria could not be established or if it is due to preference of the pathologist remains unclear and requires further investigation. Nevertheless, implementation of structured pathology reporting protocols for LCNEC should be considered.

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      P1.08-025 - Tumor Control of Advanced Pulmonary Neuroendocrine Tumors (Carcinoids) with Somatostatin Analogs: Experience at Gustave Roussy (ID 2758)

      I. Sullivan, E. Baudin, J. Guigay, J. Scoazec, S. Leboulleux, A. Berdelou, C. Caramella, M. Ducreux, B. Besse, D. Planchard

      • Abstract
      • Slides

      Background:
      Pulmonary carcinoids are rare neuroendocrine tumors (puNETs) of the lung with no standard therapeutic option. Antitumor control benefit of somatostatin analogs (SSAs) has been demonstrated in gastroeneropancreatic (GEP)-NETs, but only a few data have been published in puNETs.

      Methods:
      Data from advanced puNETs patients treated with SSAs in monotherapy between 1986 and 2014 at Gustave Roussy were retrospectively collected. Demographical, clinical and tumor-related features were recorded. Patients had a tumor evaluation by CT-scan and/or MRI every 3 months. Progression-free survival (PFS) and Overall survival (OS) were estimated using Kaplan-Meier. Response rate and toxicity were assessed according to RECIST (v1.0 until 2008 and v1.1 since 2009) and NCI.CTC v4.03 criteria respectively.

      Results:
      Sixty-one metastatic patients with a median follow-up of 5.8 yrs (0.4-13.0 yrs) were included, with a median age of 55 yrs (13-84 yrs), 55.7% were male, 29% current or former smokers, and 95% had PS ≤1. At diagnosis, 20 patients were classified as typical carcinoids (TCs) and 41 as atypical carcinoids (ACs) according to 2004 WHO classification. Before SSAs initiation, 49 patients (80%) showed uptake at somatostatin receptor scintigraphy (SRS) (grade ≥2) and 29 (52%) showed hormone-related symptoms. The majority of patients (75.4%) presented at least two metastatic sites, liver being the most frequent one (80.3%). Forty-six (75%) patients received SSAs as first-line therapy: 32 patients (70%) for disease progression and 14 patients (30%) for symptomatic carcinoid syndrome. The median duration of SSAs was 13.7 months (3.0-155.1). Overall, median PFS (mPFS) and OS (mOS) were 17.4 [95% CI=8.7-26.0] and 58.4 months [44.2-102.7], respectively. Best response was stable disease (SD) for 43 patients (70.5%) and progression disease (PD) for 14 patients (23%). All PD were ACs. The number of events and deaths was 46 (75%) and 29 (48%), respectively. mPFS was 24.8 months [10.1-36.3] for the TCs and 12.8 months [6.2-26.0] for the ACs patients (p=0.32). mPFS was significantly longer in functional puNETs with a mPFS of 28.7 months [13.2-55.6] vs. 8.7 months [5.8-21.2] in non-functional tumors (p=0.01). The most common adverse event was grade 1 diarrhea in 43% of patients. Only one grade 3 (abdominal pain) was reported with a consequent withdrawal of treatment.

      Conclusion:
      In the real-world setting, SSAs are safe and potentially effective for the antitumor control of puNETs. Our results suggest that patients with typical carcinoids and functional puNETs seem to benefit most from SSAs therapy.

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      P1.08-026 - First Case of SMARCB1(INI1)- Deficient Squamous Cell Carcinoma of the Pleura (ID 978)

      K. Yoshida, Y. Fujiwara, H. Shiraishi, K. Goto, K. Tsuruoka, K. Itahashi, Y. Goto, H. Horinouchi, S. Kanda, H. Nokihara, N. Yamamoto, K. Tsuta, Y. Ohe

      • Abstract
      • Slides

      Background:
      SMARCB1(INI1) is a tumor-suppressor gene located at 22q11.2. It is considered an integral component of the chromatin remodeling complex SW1/SNF. Loss of SMARCB1 expression has been reported to be associated with atypical teratoid/rhabdoid tumors and malignant rhabdoid tumors of the kidney and extrarenal tissues. In addition, sinonasal basaloid carcinomas and neoplasms arising from the gastrointestinal tract, pancreas and uterus with SMARCB1 deficiency have been reported.To date, however, SMARCB1-deficient carcinoma of the pleura has not been reported.

      Methods:
      We report the first case of SMARCB1-deficient squamous cell carcinoma of the pleura in a patient, and describe the clinical course from initial presentation to diagnosis with pathological findings.

      Results:
      The case was a 33-year-old female never smoker with no previous medical or family history of malignant disease. She visited a previous hospital with a one-month history of worsening cough and dyspnea. Chest X-ray and computed tomography (CT) showed left pleural tumors with a large amount of pleural effusion. She underwent the diagnostic thoracoscopy to obtain sufficient tumor tissue from the parietal pleura. Systemic work-up including CT identified no other lesions apart from those in the left thoracic cavity. Pathological diagnosis in the previous hospital was squamous cell carcinoma of the pleura. She received six cycles of cisplatin plus gemcitabine therapy and achieved stable disease an overall best response. After progression, she transferred to our institution for expected further treatment. Although she received TS-1 therapy as second-line treatment, her disease progressed rapidly with worsening chest pain and dyspnea, and she died at 10 months after diagnosis. On pathological review of formalin-fixed, paraffin-embedded tissues of parietal pleura obtained in the previous hospital, primary tumors were composed of morphologically poorly differentiated cancer cells with characteristics of squamous cell carcinoma. Tumor cells were completely negative for INI1 protein expression by immunohistochemistry. Malignant pleural mesothelioma, thymic carcinoma and NUT midline carcinoma were ruled out. Claudin4 and MOC31 were positive, and C-kit and NUT were negative by immunohistochemistry suggesting that the tumor was primary squamous cell carcinoma of the pleura with SMARCB1 deficiency. Genome analysis using next-generation sequence data revealed no oncogene mutations, such as EGFR mutation, ALK, RET or ROS1 rearrangement.

      Conclusion:
      To our knowledge, this is the first report of SMARCB1-deficient squamous cell carcinoma of pleura. The tumor was highly aggressive and carried a poor prognosis with short survival. The existence of other SMARCB1- deficient tumors is likely, such as atypical teratoid/rhabdoid tumors and malignant rhabdoid tumors of the kidney and extrarenal tissues. The clinical features and treatments of this tumor are not clear, and additional cases wiii assist the establishment of treatments and improve the poor prognosis.

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      P1.08-027 - Clinicopathologic Study and Prognostic Analysis of Bronchial Mucoepidermoid Carcinoma (ID 1133)

      J. Ni, Z. Sheng, C. Wu, L. Hou, J. Xu

      • Abstract
      • Slides

      Background:
      Bronchial mucoepidermoid carcinoma (MEC) is a rare type of lung cancer. The present study tried to establish the clinicopathologic characteristics and prognostic factors of patients with this cancer who were treated in Shanghai Pulmonary Hospital. In addition, the common genetic changes were analyzed here.

      Methods:
      Sixty-four cases of bronchial MEC treated in Shanghai Pulmonary Hospital between 1995 and 2013 were collected for our study. Retrospective cohort study was performed to analyze the relationship between clinical characteristics and prognosis. The common genetic changes of non-small cell lung cancer, such as EGFR, ALK ,ROS1,BRAF, KRAS status were tested.

      Results:
      All 64 MECs were reconfirmed by pathologists and tumor staging of all patients were reevaluated according to AJCC 7th edition system. There were 35male patients and 29 females with median age of 40.5 years old. Cough and hemoptysis were the most common clinical manifestations. The mean time between symptom appearance and going to see doctors was 8.7months. Fibre optic bronchoscopy confirmed the presence of bronchial tumor in 48 of 64 patients, but only half of them were diagnostic of MEC by endobronchial biopsies. The pathological findings were cellular mixture consisting of mucus-secreting cells, squamous cells and mesenchymal cells. There were 52 and 4 patients who were in an early stage (stage I-II) and stage IIIA at the time of diagnosis. All those patients underwent surgical resection with lymph node sampling and dissection and 10 patients received adjuvant chemotherapy, 2 patients adjuvant radiocherapy. There were 5 and 3 patients in stage IIIB and IV. Among them, 4 were treated by chemotherapy. The median survival time for patients with stage I-II ,IIIA and IIIB-IV were 71months (10-223months), 35 months (5.3-126months) and 4 months (1-51months) respectively. Single factor analysis showed that the early TNM staging (p=0.000), no mediastinal lymph node involvement or N1 involvement (p=0.000) and surgery (p=0.001) were the positive prognostic factors for MEC patients. There was a trend that shorter disease course might benefit for survival (p=0.09). Multi-factor analysis showed that TNM staging was an independent prognostic factor for the patients suffering from bronchial MEC. Genetic testing showed that 1of 38 patient presented T790M mutation, 17 of 32 patients had KRAS positive staining and no BRAF mutation was found. Interestingly, we found 3 ALK rearrangement which accounted for 7.5% of all tested patients.

      Conclusion:
      TNM staging is an independent prognostic factor for bronchial MEC patients. Mediastinoscopy should be performed on patients who are clinically N2 stage to get precise stage and treatment decision. Early diagnosis and early surgery may improve patients’ survival. For advanced MEC patients, ALK fusion gene may be routinely tested so as to provide patients with more therapy options.

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      P1.08-028 - PD-L1 Expression in Neuroendocrine Tumors of the Lung (ID 2217)

      H. Horinouchi, K. Tsuruoka, Y. Goto, S. Kanda, Y. Fujiwara, H. Nokihara, N. Yamamoto, S. Watanabe, K. Tsuta, Y. Ohe

      • Abstract
      • Slides

      Background:
      The World Health Organization (WHO) classification recognizes four major types of neuroendocrine tumors of the lung: typical carcinoid, atypical carcinoid, small cell lung cancer (SCLC), and large-cell neuroendocrine carcinoma (LCNEC). These diagnostic categories have different prognostic implications and require distinct treatment strategies. The PD-1/PD-L1 pathway is a major target of anti-tumor immunotherapy. PD-L1 expression has been reported to cause local immune suppression and is considered as a predictive marker of immune checkpoint therapeutics. In order to clarify any differences in the expression of PD-L1 according to the type of neuroendocrine tumor in the lung, we investigated the expression levels of PD-L1 by immunohistochemistry in neuroendocrine tumors of the lung.

      Methods:
      The subjects of this study were patients who were diagnosed as having lung neuroendocrine tumors and were treated at the National Cancer Center Hospital from 1982 to 2010. A tissue microarray (TMA) made from the surgical specimens was analyzed. After the rabbit monoclonal PD-L1 antibody was validated (clone E1L3N, Cell Signaling Technology, Danvers, MA), the TMA was stained and the tumor PD-L1 expression score was calculated by a semiquantitative method (by multiplying the intensity [0–3] by the staining area [0–100%]). To determine the PD-L1 expression, 3 (1%) was used as the cutoff score.

      Results:
      A total of 227 patients were included in this study. The characteristics of the entire patient population were as follows; median age, 65 years (range: 19-84 years); gender, male 168 (74.0%) / female 59 (26.0%); smoking status, smokers 191 (84.1%)/non-smokers 36 (15.9%); pStage: IA 79 (34.8%)/IB 36 (15.9%)/IIA 25 (11.0%)/IIB 29 (12.8%)/IIIA 47 (20.7%)/IIIB 6 (2.6%)/IV 5 (2.2%); histology, typical carcinoid 46 (20.3%)/atypical carcinoid 6 (2.6%)/SCLC 69 (30.4%)/LCNEC 106 (46.7%). Of the 227, samples from 15 (6.6%) showed positive staining for PD-L1. The characteristics of the patients showing positive staining for PD-L1 were as follows; median age, 71 years (range: 37-84 years); gender, males 12 (7.1%)/females 3 (5.1%); smoking status, smokers 13 (6.8%)/non-smokers 2 (5.6%); pStage, IA 3 (3.8%)/IB 2 (5.6%)/IIA 2 (8.0%)/IIB 5 (17.2%)/IIIA 2 (4.3%)/IIIB 0 (0%)/IV 1 (20.0%); histology, typical carcinoid 0 (0%)/atypical carcinoid 0 (0%)/SCLC 4 (5.8%)/LCNEC 11 (10.4%). In 31 of the 69 cases of SCLC who were treated by surgery, the disease recurred; of these 31 patients who developed disease recurrence, positive expression for PD-L1 was noted in 2 patients (6.5%). Furthermore, the disease recurred in 33 of the 106 cases of LCNEC treated by surgery; of the 33, 2 (6.1%) showed expression of PD-L1.

      Conclusion:
      None of the tumors in the patients with typical or atypical carcinoid in our study showed expression of PD-L1. Only the tumors in 4 of the 69 patients (5.8%) with SCLC and 11 of the 106 patients (10.4%) with LCNEC showed positive staining results for PD-L1. The data suggest that drugs directed against PD-1/PD-L1 might be potentially useful in the immunotherapy of SCLC and LCNEC.

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      P1.08-029 - Combination Treatment of Intrathoracic Esofageal Cancer (ID 3018)

      O. Lebedieva, Y. Kondratsky, R. Fridel

      • Abstract

      Background:
      Introduction. Esophageal cancer (EC) is the sixth most common cause of death in cancer patients in the world. EC is classified into squamous cell carcinoma (80%) and adenocarcinoma (20%). Squamous EC is more sensitive to chemoradiotherapy (CRT) than adenocarcinoma, but long-term results of their treatment are similar. Combination therapy is used for EC treatment due to poor overall survival performance in patients who received only surgical treatment. Neoadjuvant CRT followed by surgical treatment is the most common treatment paradigm in patients with resectable EC. According to results of meta-analyses, neoadjuvant CRT in combination with surgical treatment significantly improves 3-year survival and reduces the incidence of local recurrence in comparison with surgery alone. Objective. To study and compare short-term results of treatment in patients with EC using intravenous and intra-arterial neoadjuvant CRT.

      Methods:
      using intravenous and intra-arterial neoadjuvant CRT. Materials and methods. 54 patients with verified squamous EC of intrathoracic esophagus (T2-3N0-1M0) were enrolled into the study and randomized into two groups. Group I patients (n = 26) received neoadjuvant CRT with intra-arterial injection, while group II patients (n = 28) - intravenous CRT. In accordance with standards, chemotherapy, radiotherapy and surgery were performed. Operation was performed 2-3 weeks after CRT.

      Results:
      Therapeutic pathomorphism was detected in 75% of group I patients and in 81% of group II patients. Complete tumour regression occurred in 4% and 11%, partial regression - in 73% and 68%, stabilization process - in 4% and 7%, and progression of the disease was observed in 19% and 14% of patients in groups I and II, respectively.

      Conclusion:
      Tumour response to neoadjuvant treatment is evident in both groups. Short-term results of treatment demonstrate no advantages of intra-arterial chemotherapy, which is economically unjustified compared to intravenous chemotherapy. The ultimate conclusions regarding the advisability of intra-arterial neoadjuvant CRT injection of drugs in patients with intrathoracic esophageal cancer may be drawn after studying of the long-term results.

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      P1.08-030 - Increasing the Interval between Neoadjuvant Chemoradiotherapy and Surgery in Esophageal Cancer. A Meta-Analysis of Published Studies (ID 2472)

      G. Lin, S. Han, M. Yan, X. Shun, Y. Xu, W. Mao

      • Abstract
      • Slides

      Background:
      Neoadjuvant chemordiotherapy followed by surgery was the most common approach for patients with resectable esophageal cancer. Operation was performed within 2 to 8 weeks after nCRT were completed. The aim of this meta-analysis was to clarify whether a longer interval between the end of neoadjuvant chemoradiotherapy (nCRT) and surgery was associated with a better overall survival in esophageal cancer.

      Methods:
      We performed a systematic literature search in MEDLINE, EMBASE, Cochrane Central Register of Contralled Trials (CENTRAL/CCTR), Clinical Trials from January 2000 to December 2014. Eligible studies were prospective or retrospective studies of esophageal cancer that assessed the effects of intervals longer or shorter than 7 to 8 weeks between the end of nCRT and surgery. The primary endpoint was the overall survival (OS) and pathologic complete response (pCR). Secondary endpoints were anastomotic leak, R0 resection and postoperative mortality rate. A meta-analysis was performed to estimate odds ratios (ORs) , using the fixed- or random-effects model, with review manager 5.2.

      Results:
      Five studies met the eligibility requirements, including 1016 patients, with 520 in the shorter interval group (≦7~8 weeks) and 496 in the longer interval group (>7~8 weeks). The results of our meta-analysis showed that the longer interval between nCRT and surgery may be at a disadvantage in 2-year overall survival (OR =1.40 ,95% CI: 1.09–1.80, P=0.010) and R0 resection rate (OR =1.71, 95%CI:1.14-2.22, P=0.009 ). The pCR, anastomotic leak rate and postoperative morbidity were similar in the two groups.

      Conclusion:
      A longer waiting interval (more than the classical 6–8 weeks) from the end of preoperative CRT is not an increases the rate of pCR in esophageal cancer, with similar anastomotic leak rate and postoperative mortality rates. However, the longer interval between nCRT and surgery may be at a disadvantage in the long-term overall survival, thus it may be reasonable to perform surgery for patients at the esrliest opportunity after adequate recovery form nCRT, especially, who have clinical pCR. These results should be validated prospectively in a randomized trial.

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      P1.08-031 - Induction of Protein Citrullination and Auto-Antibodies Production in Murine Exposed to Nickel Nanomaterials (ID 2827)

      B.M. Mohamed, A. Prina-Mello, N. T. Boyle, A. Schinwald, B. Murer, T. Rakovich, K. Crosbie-Staunton, O. K Mahfoud, S.G. Gray, Y. Volkov

      • Abstract
      • Slides

      Background:
      Citrullination, or the post-translational deimination of polypeptide-bound arginine, is involved in several pathological processes in the body, including autoimmunity and tumorigenesis. This enzymatic conversion is governed by the family of Ca[2+]-dependent peptidylarginine deiminases (PAD). Citrullinated proteins are recognised as non-self-proteins, and subsequently can induce an autoimmune response. Recent studies have shown that nanomaterials of diverse origin can trigger protein citrullination, which might constitute a common pathogenic link to disease development.

      Methods:
      Engineered nickel nanomaterials, which can mimic environmental filamentous materials were hypothesised to trigger similar pathophysiological responses. Mice were injected intraperitoneally with either nickel nanomaterials or phosphate buffered saline. Murine sera samples for anti-CCP3 detection and tissue samples for immunohistochemical analysis were collected at day 1 and day 14.

      Results:
      Auto-antibody production was detected in serum of nickel nanomaterials-treated mice. Citrullination-associated phenomena and PAD levels were found to be elevated in nanomaterials -treated cell lines as well as in the spleen, kidneys and lymph nodes of mice, suggesting a systemic response to nickel nanomaterials injection, and validated in human pleural and pericardial malignant mesothelioma (MM) samples.

      Conclusion:
      The observed systemic responses in mice exposed to nickel nanomaterials support the evidence linking exposure to environmental factors with the development of autoimmunity responses and reinforces the need for comprehensive safety screening of nanomaterials. Furthermore, these nanomaterials induce pathological processes that mimic those observed in Pleural MM, and therefore require further investigations into their carcinogenicity.

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      P1.08-032 - Primary Pulmonary Lymphoma: Clinical Analysis of 34 Cases (ID 635)

      N. Duma, C. Glisch, L. Sanchez, T. Feldman, A. Goy, M. Gutierrez

      • Abstract

      Background:
      Primary pulmonary lymphoma (PPL) accounts for only 0.5% of all primary lung cancers and 10% of all extranodal lymphomas. Though the majority are non-Hodgkin lymphomas (NHL), PPL can easily be misdiagnosed or missed due to their nonspecific clinical features and imaging findings. Our goal was to investigate the clinical characteristics, treatment and prognosis of PPL.

      Methods:
      We reviewed the clinical data of 34 patients diagnosed with PPL at our cancer center from 2005 to 2013. Initial diagnosis at our institution and minimum 24 month follow up were required. Kaplan-Meier method was used for survival analysis.

      Results:
      A total of 34 patients were identified. Median age at diagnosis was 55 years (range: 35-84), 53% were males and 47% females. 61% were current or former smokers. 14 patients (41%) had an autoimmune disorder (8 patients had Hashimoto’s hypothyroidism, 4 rheumatoid arthritis and 1 DM type 1). 32% had family history of cancer and 27% of autoimmune disorders. The major clinical manifestations were: cough (53%), weight loss (41%), incidental finding on chest x-ray (29%) and only 11% presented with B symptoms. Regarding tumor characteristics, 41% of the patients were stage I, 18% stage II, 6% stage III and 35% stage IV. Marginal zone B-cell lymphoma and mucosa-associated lymphoid tissue lymphoma were the most prevalent subtypes, representing 97% of the cases. Patients were more likely to have upper lobe lesions (50%) vs. middle (29%) or lower lobe (21%) lesions. Regarding treatment, 15 patients (44%) were treated with surgery, 79% with chemotherapy (44% CHOP vs. 35% Rituximab monotherapy) and 24% with radiation (+/- chemotherapy or surgery). Overall median survival was 67.5 months (95%CI: 48.0-87.2) Factors associated with poor prognosis were: bilateral lung disease, presence of B symptoms and pleural involvement.

      Conclusion:
      PPL is a rare type of primary lung malignancy with an equal gender distribution. It is usually seen in middle-aged patients with history of autoimmune disorders and carries a good overall survival. The high incidence of misdiagnosis in PPL is associated with the lack of specific clinical features, making preoperative diagnosis difficult with most of the patients requiring lung tissue biopsy and immunohistochemistry studies.

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      P1.08-033 - pRb and p16INK4 in Human Thymic Epithelial Tumors in Relation to Human Polyomavirus 7 (ID 249)

      M. Keijzers, D. Rennspiess, S. Pujari, M. Abdul Hamid, A. Dingemans, M. Hochstenbag, A. Haugg, M. De Baets, A.K. Kurz, J. Maessen, A. Zur Hausen

      • Abstract
      • Slides

      Background:
      We have recently reported the presence of the Human polyomavirus 7 (HPyV7) in human thymic epithelial tumors as assessed by diverse molecular techniques. Here we report on the co-expression of p16, retinoblastoma protein (pRb) and phosphoralized retinoblastoma protein (phospho-Rb) in human thymic epithelial tumors in relation to HPyV7.

      Methods:
      PRB, phospho-RB and p16 expression was assessed by immunohistochemistry in 37 thymomas and 2 thymic carcinomas. 17 thymomas (46%) and 1 thymic carcinoma (50%) were recently tested positive for HPyV7. In addition, 20 follicular hyperplasias were tested.

      Results:
      Expression of pRb was observed in 35 thymomas (94.6%), in 16 thymomas (43.2%) the expression was strong. Phospho-Rb was observed in 31 thymomas (83.8%). 19 thymomas (51.4%) showed immunoreactivity for p16 of which 8 thymomas revealed very strong p16 expression. No p16 expression was detected in thymic carcinomas. In addition, no significant correlation between the presence of HPyV7 and pRb-, phospho-Rb- and p16-expression could be established. No correlation between pRb, phospho-Rb, p16 and WHO staging, Masaoka-Koga staging or the presence of MG was found. All 20 follicular hyperplasias showed expression of pRb and less expression of phospho-Rb.

      Conclusion:
      Although polyomaviruses have been shown to interact with cell cycle proteins no correlation between the presence of HPyV7 and the expression of pRb, phospho-Rb and p16 in human thymic epithelial tumors was observed. In as much HPyV7 contributes to human thymomagenesis remains to be established. Our data indicate pRb, phospho-Rb and p16 expression are rather unlikely to be involved in HPyV7 related thymomagenesis.

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      P1.08-034 - The Clinicopathological Significance of PD-L1 Expression in Thymoma (ID 1572)

      Y. Takumi, A. Osoegawa, T. Hashimoto, M. Abe, S. Suehiro, M. Miyawaki, K. Sugio

      • Abstract
      • Slides

      Background:
      Programmed Death Ligand 1 (PD-L1) is an immune checkpoint molecule that binds to the PD-1 receptor, thereby suppressing the activity of tumor infiltrating cytotoxic T cells. On the other hand, the immune checkpoint inhibitors (PD-L1, PD-1, CTLA-4) are notorious for causing autoimmune disorders. Ipilimab, an anti-CTLA-4 antibody, and nivolumab, an anti-PD-1 antibody, have been shown to induce myasthenia gravis (MG) in clinical trials. Although it has been hypothesized that the binding of PD-L1 to PD-1 is essential for T cell maturation, the role of PD-L1 in thymoma and autoimmune disorders remains unclear.

      Methods:
      We studied 52 consecutive patients who underwent resection for thymoma in our institution from 1995 to 2013. The median age of the 52 patients was 59 years (range: 21-77), 46% were male, and 31%, 52% and 15% corresponded to the WHO types of A or AB, B1 or B2, and B3, respectively. Thirty-five percent of the patients had MG, and 23% had advanced disease (Masaoka stage IV). Formalin-fixed paraffin embedded tissue sections were stained with PD-L1 rabbit monoclonal antibody (Cell Signaling Technology). The PD-L1 staining scores were calculated by multiplying the staining intensity (0: negative to 3: strong) of the membrane / cytoplasm in the tumor cell by the proportion of stained tumor cells. The staining score, WHO classification, Masaoka stage and the coexistence of MG were compared using the Mann-Whitney U -test.

      Results:
      The mean PD-L1 score was 45 (range: 0-300). The PD-L1 scores were higher in patients with more advanced disease (Masaoka stage IV; median 60, range 10-300) than in those with localized disease (Masaoka stage I-III; median, 20; range 0-160; p=0.047). Furthermore, the score was also related with the WHO classification; it was high in WHO type B3 patients (median, 60; range, 10-300), despite the fact that it remained low among types A, AB, B1 and B2 (median 20, range 0-160, p=0.033). There was no statistically significant association between the presence of MG and a high PD-L1 score.

      Conclusion:
      PD-L1 was highly expressed in more aggressive and advanced stages of thymoma. No prior studies have so far reported the significance of the PD-L1 expression on thymoma. Further studies are warranted to utilize immune checkpoint targeting therapies for thymoma.

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      P1.08-035 - Pan-European Survey on Thymic Malignancies: A Collaboration of the EORTC Lung Cancer Group (LCG) with the RYTHMIC Network (ID 690)

      J. Menis, N. Girard, B. Hasan, B. Besse

      • Abstract
      • Slides

      Background:
      Thymic malignancies are rare tumors with an incidence of over 0.15 cases per 100.000 persons/year. Because of the indolent course and sporadic occurrence, the management of this disease has been mainly based on single-institution retrospective, observational studies. Clinical trials have been run in the recent years but no uniformly accepted guidelines are available so far. For advanced disease at diagnosis or with relapse/ progression treatment options are limited in first line and there is no standard treatment for second line treatment. The EORTC Lung Cancer Group (LCG) and French RYTHMIC network developed a survey with the aim of assessing the current treatment strategies and respective outcomes, thus providing an overview on the management of these tumors in advanced stage.

      Methods:
      We conducted a 25-item survey disseminated as dedicated mailing in the EORTC LCG and RYTHMIC network. Descriptive statistical analysis was applied to assess and present the preliminary replies.

      Results:
      At the time of the analysis, a total of 45 physicians from 11 countries participated in the study, the majority of participants were EORTC members (60.8%) and 11.1% were both EORTC and RYTHMIC members. About half of the institutions have a dedicate team for thymic malignancies (46.7%) but almost all of them have in place multidisciplinary meeting to discuss new diagnosed patients (91.1%).Diagnosis is made on surgical sample in 53.4% of the cases flowed by core needle biopsy (33.6%) and open biopsy (13%). For both thymoma and thymic carcinoma, the preferred choice for induction chemotherapy is CAP (cisplatin, doxorubicin and cyclophosphamide) (42.2% and 31.1% respectively) followed by cisplatin and etoposide (13.3% and 13.3% respectively). Also for first line chemotherapy, for both thymoma and thymic carcinoma, the preferred choice is CAP (35.6% and 28.9% respectively). For first line treatment the reported Overall Response Rate (ORR) is about 40% for thymoma and 31% for thymic carcinoma, the median Progression Free Survival (PFS) is 8 months for thymoma and 3 months for thymic carcinoma and the reported median Overall Survival (OS) is 28 months for thymoma and 18 months for thymic carcinoma. For both thymoma and thymic carcinoma, the preferred first choice for second line chemotherapy is carboplatin and paclitaxel (35.6% and 31.1% respectively) and the prefered second choice is cisplatin and etoposide (13.3 and 17.8% respectively). For second line treatment the reported ORR is about 36% for thymoma and 23% for thymic carcinoma, the median reported PFS is 8 months for thymoma and 4 months for thymic carcinoma; the median OS is 15 months for thymoma and 9 months for thymic carcinoma. No testing for c-kit or EGFR mutations is routinely performed.

      Conclusion:
      The survey provides a large, multi-institutional overview of the clinical practice in the management of thymic tumors in Europe, and provides relevant and updated background for the development of future collaborative trials. The survey is still ongoing and final results will be presented at the conference.

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      P1.08-036 - Long-Term Survival after Surgical Treatment for Thymic Carcinoma (ID 262)

      H. Fu, Z. Gu, W. Fang, J. Fu, Y. Shen, Y. Han, Y. Li, Z. Yu, L. Pang, L. Tan, K. Chen

      • Abstract
      • Slides

      Background:
      Thymic carcinoma is a type of highly malignant tumor that originates from the thymic epithelium. It is rare and distinct from thymoma. Treatment methods and prognosis of thymic carcinoma remain controversial. To date, three studies with relatively large sample populations have been conducted based respectively on the Surveillance, Epidem iology and End Results database in the United States, the European Society of Thoracic Surgeons, and the Japanese multicenter database. This paper retrospectively analyzes survival data from a large-sample multicenter database in China.

      Methods:
      The Chinese Alliance for Research of Thymoma (ChART), established in June 2012 in China, constructed a retrospective database of patients with thymic epithelial tumors. This database enrolled 1,930 patients, including 369 with thymic carcinoma. In this study, we analyzed clinical, pathologic and treatment imformation, measured long-term survival rates, and identified relevant prognostic factors.

      Results:
      Among 369 thymic carcinoma underwented radical intended surgery, 211 underwent R0 resection; 34, R1 resection; and 84, R2 resection. The 3-, 5-, and 10-year survival rates were 78.3%, 67.1%, and 47.9%, respectively. The survival rates of the patients at different Masaoka-Koga stages were significantly different (P < 0.001). The survival rate of the patients who underwent complete resection (R0) was significantly higher than that with incomplete resection (R1/R2)(P < 0.001). Postoperative chemotherapy did not significantly affect patient survival (P = 0.873). Postoperative radiotherapy significantly improved the overall survival not only of the patients with R1/R2 resection but also of those with stage III/IV disease who underwent R0 resection. Multivariate analyses showed that R0 resection, Masaoka-Koga stage and postoperative radiotherapy were major prognostic factors of overall and disease-free survival. Figure 1



      Conclusion:
      Surgery remains the primary treatment for thymic carcinoma. R0 resection was the main factor of prognosis. For patients with stage III/IV disease who had undergone R0 resection and all the patients who had undergone R1+R2 resection, postoperative radiotherapy should be administered.

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      P1.08-037 - PD-L1 Expression in Surgically Resected Thymic Epithelial Tumor (ID 1488)

      S.J. Lee, S.Y. Ha, I. Do, J. Han, M. Kwak, M. Han, J. Sun, J.S. Ahn, J. Kim, Y.M. Shim, K. Park, M. Ahn

      • Abstract

      Background:
      Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has recently shown clinical activity across many tumor types. PD-L1 protein expression by immunohistochemistry (IHC) is emerging as a predictive biomarker of response to these therapies. Hence, we studied PD-L1 expression in a thymic epithelial tumor (TET).

      Methods:
      Of the patients who previously underwent resection of TET at Samsung Medical Center between January 2000 and January 2013, 220 patients who had available tissue block for immunohistochemistry were included. Formalin-fixed paraffin embedded tumor samples were stained with murine monoclonal antibody (clone h5H1) to human PD-L1. PD-L1 staining was classified based on intensity and moderate or strong intensity in 5% or more of tumor tissues was considered as positive PD-L1 expression.

      Results:
      The median age was 52 years (range, 18-81), and 57.7% of patients were male. WHO histologic type was mostly B2 (N=96, 43.6%), followed by C (N=48, 21.8%), B3 (N=47, 21.4%) and neuroendocrine tumor (N=17, 7.7%). R0 resection was possible in 193 patients (87.7%). Positive PD-L1 expression was observed in 83 samples (37.7%). PD-L1 expression and histologic type was significantly correlated, with high PD-L1 expression in histologic type B2/B3/C (7.1% vs. 42.4% in type A/AB/neuroendocrine tumor vs. type B2/B3/C; P<0.001). PD-L1 expression did not affect overall survival both in univariate and multivariate survival analysis.

      Conclusion:
      In TET, PD-L1 expression was positive in 37.7% and it was more frequently observed in aggressive histology (B2/B3/C). PD-1/PD-L1 targeting agents could be a promising therapy for TET.

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      P1.08-038 - The Effect of the WHO Histologic Classification on Thymic Specific Survival and Overall Survival (ID 2616)

      K. Uy, J.M. Varlotto, M. Decamp, D. Zander, S. Ali, Y. Yonan, G. Graeber, D. Maddox, S. Quadri, C. Stock, F. Gu, J. Liebmann, V. Kasturi, W. Walsh, J. Flickinger, J. Glanzman, A. Yao

      • Abstract
      • Slides

      Background:
      In 1999 the World Health Organization published a histologic classification system for thymoma that divided it into 5 categories (A, AB, B1-B3). We investigated the effect that this classification has on outcomes and determined if there was a role for radiotherapy in patients undergoing resection.

      Methods:
      The SEER database was used to retrospectively analyze thymomas from 2000-2011. Only those patients having first primary thymic neoplasia and undergoing resection were included in the analysis. Overall survival (OS) and thymic-specific survival(TSS) were evaluated by Kaplan-Meier Methods. Propensity Score was used to determine the role of radiotherapy.

      Results:
      1047 patients had median follow-up of 53 months. In patients not receiving radiation (N=428), multivariate analysis found that worse OS was associated with older age, unmarried status, advanced stage, and partial resection. Better TSS was associated with white race and early stage. Histologic classification did not have any effect on OS or TSS. In patients with stage I and II disease (N=541), the 5-year OS and cumulative incidence rates of thymic death were 87.5% and 3.0%. In 483 stage III/IVA patients, propensity match of 153 patients treated with or without radiation demonstrated that radiation was associated with a significantly better OS (HR=0.400, p= 0.001) and TSS (HR=0.473, p=0.034), and that the effect of radiation did not depend upon histologic subtype. Selection factors for radiation included younger age and tumor size. Radiation was not associated with an increase in cardiopulmonary deaths or deaths due to second malignancies. Only 36.6% of patients had any lymph nodes explored, and 12.0% were positive. WHO Histology B3 was most likely to have involved lymph nodes (20%), while histology A (0%) and B2 (2%) were least likely. 125 (11.9%) patients have developed secondary malignancies.

      Conclusion:
      Radiation may be beneficial for surgically-resected advanced-stage thymoma. Neither OS or TSS was affected nodal involvement or histology. The lack of correlation of histology with outcomes may demonstrate that the current histologic system is not predictive of outcomes or that it does not translate to the broad spectrum of pathologists in SEER registry areas.

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      P1.08-039 - Adjuvant Treatment of Thymic Carcinoma (ID 1139)

      Y. Tseng, Y. Chen, Y. Lee, Y. Wu, W. Hsu, S.-. Yen

      • Abstract
      • Slides

      Background:
      Thymic carcinomas are rare tumors. Surgical resection is first considered. However, data for adjuvant treatment after surgery is limited

      Methods:
      We retrospectively reviewed records of our thymic carcinoma patients who were treated between 2004 and 2014. Data on age, smoking or not, performance status of each patient, TNM staging, surgical margin, type of adjuvant therapy, and type of chemotherapy were collected.

      Results:
      Thirty-two patients received surgical resection and 49 patients did not. Both PFS and OS were significantly longer among patients who received surgical resection (26.0 months vs 7.2 months, p<0.001; 37.8 months vs 14.8 months, p<0.001). Patients with stage III thymic carcinoma had a longer overall survival when they received surgical resection. (70.1 months vs 23.9 months, p=0.017). Among stage IV patients, those received extended thymothymectomy had a longer PFS than did not received surgery (10.6 months vs 7.0 months, p=0.003). Among all 32 patients (stage I-IV) who received surgery, twenty-one patients were R0 resection, 6 patients were R1 resection, and 5 patients were R2 resection. Among 21 patients who were R0 resection, 10 received adjuvant radiotherapy and had better PFS than those received adjuvant chemotherapy (n=2) or concurrent chemo-radiotherapy after surgery (n=4) (50.3 months vs 5.9 months vs 7.5 months, p=0.001).

      Conclusion:
      Surgical resection should always be considered first whenever possible in thymic carcinoma patients. Adjuvant radiotherapy had better PFS after R0 resection.

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    P1.10 - Poster Session/ Advocacy (ID 228)

    • Type: Poster
    • Track: Advocacy
    • Presentations: 8
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      P1.10-001 - EGFR Mutation Testing Patterns and Results in Brazil and the Need for Greater Public Health Awareness of Molecular Testing (ID 1540)

      G. De Lima Lopes, E. Prado

      • Abstract
      • Slides

      Background:
      Epidermal growth factor receptor (EGFR) mutation testing allows for optimal selection of therapy with tyrosine kinase inhibitors in patients with non-small-cell lung cancer (NSCLC). Previous studies have shown a variation in EGRF genotype according to ethnic background, with scarce data about EGFR mutation status and testing patterns among Brazilian patients with NSCLC.

      Methods:
      Between 2011 and 2013, as part of a program sponsored by a pharmaceutical company in Brazil, tumor samples of patients with stage IIIb/IV NSCLC were submitted, at the discretion of the attending physicians, for EGFR mutation testing. All analyses were performed at 02 reference laboratories, as follows: after microdissection, DNA was isolated from serial sections of formalin-fixed, paraffin-embedded tumor tissue to obtain at least 70% tumor cells. Exons 18, 19, 20 and 21 of the EGFR gene were analysed using Sanger sequencing. EGFR mutation rate was calculated and its frequency compared between clinical subgroups using chi-square test. Data about smoking status was incomplete and thus not included in this analysis. Furthermore, a commercial database with 3,296 patients treated in Brazil in 2014 was evaluated for mutation testing patterns.

      Results:
      3,364 tests out of 3,771 samples analyzed (1,799 male; 1,942 female) yielded informative results. EGFR mutation was present in 25.5% (857/3364) of informative samples. Deletions in exon 19 were the most frequent alteration detected (54%), followed by point mutations in exon 21 (28%) and exon 20 (9.7%). The most important predictors for the presence of EGFR mutations were adenocarcinoma histology (p<0.001), 89% of positive tests occurred in this histology; and female gender (p<0.001), for which 30.2% of the patients tested were positive. No differences in EGFR mutation frequency were found between age groups or regions within the country. In the commercial database of patients with NSCLC treated in the country in 2014, 1,792 patients had adenocarcinomas, 930 had squamous cancer, 71 had large cell cancer and 99 had other histologies. Overall, 34% of patients were tested for mutations (47% in the private sector and 20% in public centers); the corresponding number was 50% for patients with adenocarcinoma (62% of cases in the private and 33% in the public settings, respectively) and 10% for patients with squamous cancer. Of note fewer than 5% of patients overall were tested for ALK alterations.

      Conclusion:
      To the best of our knowledge, this is the largest study to assess EGFR mutation status in Latin America and in Brazil. Our findings suggest that the frequency of EGFR mutation in this cohort was lower than that found in Asia, but higher than in Caucasian populations, confirming findings seen in other Latin American countries. Despite this high prevalence, a significant number of patients, especially in the public sector, are not currently tested for mutations in the country, and further advocacy efforts are necessary to improve this situation.

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      P1.10-002 - Lung Cancer Patients' Perspectives on Multi-Disciplinary Care in a Community Setting (ID 2183)

      O. Osborne, K.D. Ward, S. Kedia, F.E. Rugless, B. Jackson, K.S. Roark, L. McHugh, C. Foust, M. Sheean, R.U. Osarogiagbon

      • Abstract
      • Slides

      Background:
      Lung cancer causes 27% of all cancer deaths in the United States, with very modest improvement in patient survival in the past 30 years. In addition to cancer biology, adverse patient factors such as cumulative age- and tobacco-related co-morbidities, and care-delivery factors such as the need for multiple physician involvement, contribute to the paucity of progress. The standard serial model of care, involving sequential referrals to specific care providers, if not carefully coordinated, may delay care and enable discordance between patient needs and provider priorities. The multidisciplinary model, widely touted as potentially superior, has never been rigorously evaluated. Leading up to a comparative effectiveness study of the serial and multidisciplinary care models, we closely examined patient experiences with lung cancer care delivery.

      Methods:
      We conducted a qualitative study, in 5 focus groups of 22 patients (10 males/12 females; 15 White/7 Black) receiving care within the previous 6 months for confirmed or suspected lung cancer at a community-based hospital, the Baptist Memorial Health Care System. Stage distribution was: 6 stage I lung cancer, 2 stage II, 3 stage III, 3 stage IV, 5 undetermined; 3 patients had a non-lung primary malignant lung lesion. A standardized script was used to ensure consistency of questions across all focus groups. Saturation of emergent themes determined the number of focus groups conducted. We used verbatim transcripts and field notes to analyze the content of each focus group, and Dedoose Software to identify recurring themes and variants.

      Results:
      Patients perceived that the multidisciplinary care approach enabled more timely care-delivery, better physical collaboration, improved patient-physician communication, and reduced redundant testing. Use of a nurse navigator in this model also helped decrease confusion, stress, and anxiety associated with care-coordination. There was a perception of the multidisciplinary model as providing a ‘one-stop shop’, a central point of contact that reduces the amount of travel and coordination required between multiple specialists. Among those patients who had prior encounters with serial care, some had experienced insensitive disclosure of diagnosis, poor physician communication, redundant testing, delays in diagnosis and treatment, misdiagnosis, and mistreatment. Patients involved in serial care were also more likely to seek a second opinion after initial diagnosis. The multidisciplinary care model was believed to provide multiple opinions in one visit.

      Conclusion:
      Lung cancer patients strongly preferred the multidisciplinary model of care, perceiving it to be more patient-centered and efficient than serial care. These data provide useful information on important patient-centered benchmarks that should be incorporated into rigorous comparisons of the effectiveness of these two care delivery models. Additional work is needed to examine barriers to program development through meaningful input from other key stakeholders, such as healthcare providers, institutional administrators, third party payers, and healthcare policymakers.

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      P1.10-003 - Lung Cancer in Ireland 2010 - 2015 - Are We Making Progress? (ID 1654)

      A. McNamara

      • Abstract
      • Slides

      Background:
      The burden of lung cancer: According to the National Cancer Registry in Ireland (NCRI) lung cancer was the single most common cause of cancer death during 2010-2012, with approximately 1,780 deaths annually, just over one-fifth of all cancer deaths. The lung cancer mortality rate in Ireland decreased significantly, by almost 2% annually, in males but increased by 0.5% annually in females during 1994-2012. These trends reflect smoking prevalence from decades earlier, but the contrast between males and females is striking (1). Since 2010, lung cancer detection and awareness has changed considerably in Ireland. Health Services: In 2010, the National Cancer Control Programme (NCCP) and Health Service Executive (HSE) distributed General Practitioner (GP) Guidelines on the management of suspected lung cancers. At the same time, rapid access clinics were established in the eight National designated cancer centres. National Awareness: In 2011 the Irish Cancer Society (the Society) launched a five year advertising and PR campaign to raise awareness of lung cancer in a novel and engaging way. The aim of the campaign was to avoid adding to the stigmatisation of lung cancer, but instead encourage people concerned about lung cancer and those already affected by it to contact the Society’s National Cancer Helpline.

      Methods:
      Since 2010, substantial changes have been put in place to manage the burden of lung cancer in Ireland. An audit was performed in 2015 to measure the impact of these changes and ask if we are making progress.

      Results:
      Health Services: In 2013; a total of 869 primary cancers were detected by the eight NCCP rapid access lung cancer clinics. This represents a 30% detection rate (2). National Awareness: Behaviour & Attitudes undertook market research (commissioned by the Society) in 2011 and 2013 to evaluate the impact of the advertising and PR campaign and found just under three million adults recall some media attention on the issue of lung cancer in February (2013). This was up considerably on 2011 levels (2.1 million Vs. 2.8 million).

      Conclusion:
      The NCRI state that lung cancer incidence is rising and by 2040 the rate is projected to increase by 136% in females and 52% in males (3). While the burden of lung cancer increases in Ireland, the changes in health services has ensured that anyone concerned about lung cancer can go to their GP and be referred to a rapid access clinic if necessary. A dedicated pathway to allow for suspect cases to be fast tracked and diagnosed on an urgent basis is now in place (2). At the same time, awareness is on the increase; by removing the link between lung cancer and grim tobacco messaging and instead communicating a message of empowerment, more people engaged with the Society’s campaign and it was deemed a success. The Society continues to utilise a variety of mediums in future campaigns to support people concerned about lung cancer without stigmatising them.

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      P1.10-004 - Novel Survey to Identify Single Greatest Challenge for Lung Cancer Patients and Carers (ID 2593)

      A. McNamara, W. Boerckel, A. Van Eijk

      • Abstract
      • Slides

      Background:
      People living with lung cancer (LC), LC survivors and carers are impacted by LC in different ways. The Global Lung Cancer Coalition (GLCC) recognises lung cancer patients’ and carers’ isolation and the challenges they face (GLCC, 2015). However for those affected by LC, limited data exists on the priority of their challenges, their ability to cope with these challenges and if enough relevant information and support is available. Identifiable variances between patient and carer experience and how challenges differ based on gender, age and nationality are also unknown. In 2013, The GLCC and Boehringer Ingelheim collaborated to create a global survey to identify these priorities and variances.

      Methods:
      A unique web-based survey was designed to isolate the single greatest challenge faced by individuals affected by LC. 200 specific and globally relevant challenges related to medical and psychosocial topics were identified by LC experts from the GLCC, grouped into categories and illustrated, with a small text descriptor. Each illustration was designed to represent a specific challenge, to be culturally sensitive and to overcome potential language barriers. At survey entry, respondents identified their greatest challenge as relevant to either daily life or medical care. Via an associated illustration, respondents chose subsequent sub-categories of challenges until one specific challenge was identified as being the most significant. Respondents answered 3 questions in relation to that challenge regarding: 1) availability of information 2) ability to cope 3) level of support required. Screening was conducted for age, gender, treatment and nationality. Respondents were asked whether they were living with LC, a LC survivor or a carer. The survey was available in 11 languages and promoted through the GLCC, LC clinicians, charities and associated support groups.

      Results:
      2871 individuals visited the survey site. 725 (25%) completed the survey. 17% were from North America, 38% Europe, 31% Asia/Pacific, 7% Central/ South America, 7% Middle East / Africa. 52% were carers, 18% were LC survivors and 30% were living with LC. 64% of LC patients chose a daily life challenge as their most significant, compared to a medical care challenge (36%); 55% of carers also chose a daily life challenge, compared to a medical care challenge (45%).

      Conclusion:
      A unique survey to effectively isolate the single greatest challenge for individuals affected by LC and to identify current gaps in care, support and information. Bespoke illustrations, combined with a simple and easy-to-complete method, created a globally relevant tool that could produce specific, action-orientated results in order to shape global and local approaches to LC patient care and carer support; alleviate potential shortcomings and optimise patient experience.

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      P1.10-005 - Immunotherapy, What Lung Cancer and Melanoma Patients ...and Physicians, Know (ID 1058)

      E. Capelletto, S. Novello, P.A. Ascierto, M. Michiara, F. Hauber, R. Furia, M. Gianetta, S. Vallone, C. Pinto

      • Abstract

      Background:
      Advances in the understanding of the role of the immune system in tumor immune-surveillance have led in the last few years to the development of a series of new drugs rapidly affirmed as new paradigm of treatment for certain cancers, like advanced melanoma. The recent re-evaluation of the immunogenicity of Non-small Cell Lung Cancer (NSCLC) has opened a new field of research, with a new attempt to apply immunotherapy also to this disease.

      Methods:
      A 9 question-anonymous survey has been carried out by AIOM (Associazione Italiana di Oncologia Medica) and supported by WALCE (Women Against Lung Cancer in Europe) with the purpose to investigate patients’ knowledge about the immunotherapy, their expectations in terms of toxicity and efficacy, but also to evaluate how much physicians are becoming confident about the immunotherapy and their expected impact on daily clinical practice. The survey has been distributed, between 10th of November 2014 and 19th of March 2015, to 77 NSCLC patients (prevalently men and over 60 years old) and 89 melanoma patients (equally distributed for gender and age) within various Italian Oncologic Units. A similar electronic survey has been filled out by 128 and 68 physicians dealing with NSCLC and Melanoma, respectively, who reported to employ immunotherapy in their clinical practice in 55% and 74% of cases, respectively, and to have participated into clinical trials with immunotherapy in 39% and 41% of cases.

      Results:
      Patients' knowledge and expectations about immunotherapy resulted to be extremely heterogeneous. Only 19% of NSCLC patients, compared to 73% of melanoma patients, declared to have performed immunotherapy in their clinical history. Main results about patients' perception about immunotherapy are shown in Table 1. NSCLC and melanoma physicians globally reported a positive attitude for this new kind of treatment, postulating a general improving of their clinical practice in the next future (88% and 99% of cases, respectively). They have speculated a non-limiting toxicity profile of this drugs in 77% and 76% of cases, respectively. Figure 1



      Conclusion:
      Although the role of immunotherapy for NSCLC treatment, as already happened for melanoma in the past few years, still need a confirmation by the results of the ongoing clinical trials, patients and physicians widely express great expectation on this kind of treatment, waiting for a large anti-cancer efficacy together with a low toxicity.

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      P1.10-006 - Defining a Standard Set of Patient-Centered Outcomes for Patients with Lung Cancer (ID 78)

      J.P. Van Meerbeeck, K.S. Mak, A.C. Van Bommel, C. Stowell, M.D. Peake, I.C. Ichom

      • Abstract
      • Slides

      Background:
      Value-based healthcare improves outcomes while controlling costs. Registries and clinical trials frequently capture survival outcomes for lung cancer, but a unifying set of outcomes that matter to patients is lacking. Our objective was to define a Standard Set of multi-dimensional patient-centered health outcomes for measuring, comparing, and improving lung cancer treatment quality. This Set applies to all patients with newly diagnosed lung cancer, including non-small cell and small-cell lung cancer, treated with either curative or palliative intent.

      Methods:
      The International Consortium for Health Outcomes Measurement (ICHOM) convened an international, multi-disciplinary working group of medical oncologists, surgeons, radiation oncologists, pulmonologists, palliative care specialists, registry experts, patient representatives, and specialist nurses to review existing data and practices. Using a modified Delphi method, the group developed a consensus Set of important outcomes and case-mix variables for risk adjustment to enable meaningful benchmarking.

      Results:
      The outcome variables included in the Standard Set are overall survival, disease-specific mortality, cause of death, and treatment-related mortality. We recommend that complications during or within six months of treatment be collected. Patient reported outcomes should be tracked regularly using the EORTC QLQ-C30 core quality of life questionnaire and lung-cancer specific module (EORTC QLQ-LC13). Baseline demographic, clinical, and tumor information is also included in the Standard Set to improve interpretability of comparisons.

      Conclusion:
      We defined a Standard Set of outcomes that we believe should be measured in all patients with lung cancer. The Set provides a universal rubric for outcome comparisons, with the ultimate goal of improving the value of care. The Lung Cancer Standard Set is made possible through the generous support of the Alliance of Dedicated Cancer Centers

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      P1.10-007 - Impact of Intensive Interprofessional Perioperative Management on Clinical Outcome in the Elderly Patients with Lung Cancer Surgery (ID 1564)

      H. Torigoe, J. Soh, T. Ashiwa, T. Kurosaki, S. Ohtani, Y. Maki, K. Miyoshi, H. Yamamoto, S. Sugimoto, M. Yamane, S. Toyooka, T. Oto, S. Miyoshi

      • Abstract

      Background:
      Perioperative assessment and care, such as enhanced recovery after surgery(ERAS), are important to improve clinical outcome in the patient who receive surgery. Standard therapy for the patients with clinical stage I non-small-cell lung carcinoma (NSCLC) is radical surgery. However, the elderly patients often suffer from several comorbidities, poor performance status (PS) and/or poor respitary/motor function, causing high incidence of postoperative complication and resulting in a limited resection or other alternative therapy. In September 2008, our hospital launched a perioperative management center (PERIO) to improve perioperative management and clinical outcome of patient receiving surgery, which was organized with dedicated nurses, anesthesiologists, dentists, physiotherapists, pharmacist and nutritionist. All patients, not only elderly patients, who are scheduled to receive thoracic surgery present to PERIO center which perform intensive perioperative assessment and care with interprofessional collaboration consistently from before hospitalization until discharge after surgery. In this study, we investigated the impact of introduction of PERIO on clinical outcome in the elderly patients who received thoracic surgery due to clinical stage I NSCLC.

      Methods:
      Ninety-one elderly patients (over 80 years old) who received pulmonary resection were enrolled in this study. We excluded patients harboring ground glass opacity-dominant tumor in the diameter less than 2cm because of high curative rate even if it is treated with limited resection. We categorized those patients into non-PERIO group among January 2000 to August 2008 (n = 42) and PERIO group among September 2008 to November 2014 (n = 49). We compared perioperative factors between the two groups.

      Results:
      The median age, PS (0-1 / 2-4) and median FEV1.0 were 81.5 vs 82.0 years old, 38/4 vs 42/7, 1.9L vs 1.8L in non-PERIO and PERIO groups, respectively. The patient with comorbidity were significantly more frequent in PERIO group (75.5%) than non-PERIO group (52.4%, P =0.025 ). Although the radical surgery (lobectomy or segmentectomy with systemic lymph node dissection) were more frequently performed in PERIO group (75.5%) than non-PERIO group (52.4%, P =0.022 ), there was no significant difference in the incidence of postoperative complication ( 24.4% and 28.6% in non-PERIO and PERIO groups, respectively) and post-operative hospital days (median 15 days in both group) in both groups.

      Conclusion:
      Radical surgery was more frequently performed after introduction of PERIO without increase of postoperative complication rate and hospital days, suggesting that PERIO may play an important role to improve perioperative clinical outcome in elderly patients treated with thoracic surgery.

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      P1.10-008 - Stigma in Lung Cancer Patients (ID 1721)

      S. Kukulj, B. Aukst Margetic, K. Galic, M. Jakopovic

      • Abstract
      • Slides

      Background:
      The burden of stigma in cancer patients is a significant problem, but it is especially emphasised problem in lung cancer patients due to their tendency to believe that their behaviour was the cause of the cancer.

      Methods:
      We included consecutively 39 newly hospitalised patients (58%male) with the diagnosis of lung cancer (mean age 59.3 SD 6.9 years). Stigma was assessed with 31-item Cataldo Lung Cancer Stigma Scale ( mean value 45.4 SD 11.05). Each stigma item was measured using a four-point Likert-type scale ranging from 1 (strongly disagree) to 4 (strongly agree). Cronbach alpha for the scale was 0.96. Patients gave informed consent after the purpose of the study was thoroughly explained. Of the 45 patients approached, four refused to participate and two questionnaires were incomplete.

      Results:
      Stigma in the sample was not associated with age or gender. Contrary to expectations it was not It was not associated with current smoking status.

      Conclusion:
      Stigma in lung cancer patients is significant problem, but in our sample it was not associated with age gender or current smoking status. This issue needs further research.

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    P1.11 - Poster Session/ Palliative and Supportive Care (ID 229)

    • Type: Poster
    • Track: Palliative and Supportive Care
    • Presentations: 13
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      P1.11-001 - Short Form Chronic Respiratory Questionnaire Validation in a Lung Cancer Population (ID 28)

      A. Charalambous, A. Molasiotis

      • Abstract
      • Slides

      Background:
      The Chronic Respiratory Questionnaire short form (SF-CRQ) is frequently used in patients with obstructive pulmonary disease and it has demonstrated excellent psychometric properties. The CRQ (both in its original or short form) has not been previously used in the assessment of lung cancer patients’ HRQL. Therefore this study, being part of a larger therapeutic trial, aims to evaluate the psychometric properties of the SF-CRQ in patients diagnosed with thoracic malignancies.

      Methods:
      Forty-six patients were assessed at two time points (with a four-week interval) using the SF-CRQ, the modified Borg Scale, five numerical rating scales related to perceived severity of breathlessness, and the Hospital Anxiety & Depression Scale. Internal consistency reliability was investigated by Cronbach’s α reliability coefficient, test-retest reliability by Spearman-Brown reliability coefficient (p) and convergent validity by Pearson’s correlation coefficient between the SF-CRQ, and the conceptual similar scales mentioned above and content validity was also explored. A principal component factor analysis was performed.

      Results:
      The internal consistency was high, indicated by an α=0.88 (baseline) and 0.91 (after one month). The SF-CRQ had good stability with test-retest reliability ranging from r=0.64 to r=0.78, p<0.001. Factor analysis suggests a single construct in this population showing that the items of the SF-CRQ scale are strongly correlated and represent the conceptual meaning of the underlying construct, which is the quality of life of lung cancer patients as related to breathlessness.

      Conclusion:
      The data analyses supported the convergent, content, and construct validity of the SF-CRQ indicating this is a valid and reliable instrument for the assessment of quality of life related to breathlessness in lung cancer patients. This study is the first study that provides initial data of the psychometric properties of the SF-CRQ in lung cancer patients, and further validation with larger sample sizes and across different settings and dyspnea severity is needed.

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      P1.11-002 - The Impact of Gastric Acid Suppressive Therapy on Treatment Outcomes of EGFR Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer (ID 804)

      N.B. Kumarakulasinghe, Y.Y. Soon, H. Zheng, E.Y. Loy, B. Pang, R. Soo

      • Abstract
      • Slides

      Background:
      Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors such as gefitinib and erlotinib are dependent on gastric pH for absorption which may be affected by concomitant gastric acid suppressive therapy (AS) with proton pump inhibitors and histamine 2 antagonists. We sought to determine the effect of gastric acid suppressive therapy on overall survival (OS) in patients treated with EGFR tyrosine kinase inhibitors.

      Methods:
      Patients with advanced stage non-small cell lung cancer harboring EGFR mutations treated with EGFR tyrosine kinase inhibitors were retrospectively identified. Medical records in our single institution were reviewed from 1[st] January 2008 to 30[th] December 2013. Patient clinico-pathological characteristics,use of gastric acid suppressive therapy and the overall survival were obtained. Statistical analysis was performed using chi[2], log rank test and cox regression where indicated

      Results:
      We identified 191 patients. The median age of patients was 64 years (range: 30-89) ,109 (57.1%) were female, 117(61.3%) were never smokers, 91 (47.6%) harbored EGFR exon 19 deletion and 144 (75.4%) received EGFR tyrosine kinase inhibitors as first line treatment. 55 (28.8%) patients received gastric acid suppressive therapy The groups of patients who received gastric acid suppressive therapy and those who did not receive gastric acid suppressive therapy were similar with regards to gender, smoking status, and type of EGFR mutations, Charlson co-morbidity score and Kanorfsky performance status. Brain metastasis at the time of diagnosis was more frequent in the group who received gastric acid suppressive therapy compared with the group who did not receive gastric acid suppressive therapy (61.8% v 35.3% respectively, p= 0.001). The median overall survival in the total patient population was 13.1 months (95%CI 11.7-15.2 months). On multivariate analysis, presence of visceral metastasis at diagnosis was associated with a worse overall survival (HR: 1.53, 95% CI:1.10-2.13 p value: 0.012). However a Karnofsky performance score of 90-100 was associated with an improved overall survival (HR: 0.69, 95% CI; 0.49-0.97 p value: 0.031). The median overall survival OS in patients with gastric acid suppressive therapy was 11.9 months (95%CI: 9.90-16.94 months) and 14.5 months (95%CI: 11.74-15.95 months) in the group not receiving gastric acid suppressive therapy. (HR: 0.98, 95% CI: 0.69-1.40 p value: 0.934)

      Conclusion:
      Although the group of patients who were treated with gastric acid suppressive therapy had a numerically poorer overall survival compared to the group who did not receive gastric acid suppressive therapy, this difference was not statistically significant. Based on the our analysis, the use of gastric acid suppressive therapy concurrent with EGFR tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer harboring EGFR mutations did not affect overall survival.

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      P1.11-003 - New Clinical and Biologic Insight Into Lung Cancer-Associated Cachexia From a Large Cohort Study (ID 1085)

      B.S. Gannavarapu, K. Carter, C. Ahn, N. Cannon, J. Meyer, P. Iyengar

      • Abstract
      • Slides

      Background:
      Cancer cachexia (CC) is a wasting syndrome without durable palliative intervention observed in 50% of all solid tumors and responsible for 20-30% of all cancer-related deaths. Knowledge of prevalence and survival outcomes for lung CC patients by clinical and pathologic parameters is scarce due to limited series. We provide the largest, most detailed evaluation of lung cancer patients for cachexia, enabling new clinical and biologic insight.

      Methods:
      A retrospective review of 1627 patients with non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) treated at UT Southwestern Medical Center between 1/1/2006 and 12/31/2013 was performed. Patient demographics and tumor characteristics including histology, stage, grade, and size were collected. Each patient was assessed for CC at diagnosis, retrospectively identified by the presence of significant weight loss (>5% loss over 6 months in patients with BMI >= 20; >2% in patients with BMI <20). Overall Survival (OS) was evaluated, and clinicopathologic factors predicting for cachexia development were identified with stepwise logistic regression (SLR).

      Results:
      Overall, CC independently predicted reduced OS on stepwise Cox regression (1.21 OR). 419/1468 (28.5%) of all NSCLC and 57/159 (35.8%) of all SCLC patients had CC. Within NSCLC, CC was documented in 107/350 (30.6%) of squamous carcinomas and 208/761 (27.3%) of adenocarcinomas. CC significantly reduced NSCLC OS across all stages: 21.0 vs. 9.9 months (log-rank P<0.0001). However, CC did not significantly affect SCLC OS: 10.5 vs. 9.9 months (log-rank P=0.46). Prevalence of CC in NSCLC for stages 1, 2, 3, and 4 was 48/309 (15.5%), 16/124 (12.9%), 118/377 (31.3%), and 237/658 (36.0%), respectively. OS for NSCLC -/+ CC for stages 1, 2, 3, and 4 were 67.1 vs. 45.0, 35.4 vs. 37.2, 20.9 vs. 14.3, and 11.4 vs. 6.6 months, respectively (log-rank P=0.0427, =0.5803, =0.0155, <0.0001). OS for squamous histologies -/+ CC for stages 1, 2, 3, and 4 were 56.9 vs. 22.7, 19.3 vs. 19.5, 18.6 vs. 14.3, and 7.8 vs. 5.8 months, respectively. OS for adenocarcinoma histologies -/+ CC for stages 1, 2, 3, and 4 were 86.4 vs. 51.1, 43.9 vs. 23.3, 28.6 vs. 19.2, and 13.0 vs. 8.2 months, respectively. On univariate analysis, grade, stage, tumor size, and tobacco use were significant factors in the development of CC in adenocarcinomas, while stage alone was significant in squamous carcinomas. On SLR, stages 3+4 were associated with increased odds of CC development as compared to stages 1+2 (OR 2.6, P=0.0004) in squamous histologies. On SLR, tumor size >50mm was associated with increased odds of CC development when compared to 0-20 mm (OR 4.3, P<0.0001) in adenocarcinomas.

      Conclusion:
      Cachexia significantly impacts OS in lung cancer, primarily for NSCLC. Fundamental differences of CC prevalence and associated OS were observed for the first time between different histologies and stages. Though CC can manifest in all stages, increased stage and tumor size were independent, significant predictors for CC in squamous and adenocarcinoma populations, respectively. Understanding which clinicopathologic characteristics impact CC prevalence and OS may offer insight into the syndrome’s clinical and biologic underpinnings, providing impetus for novel therapeutics and prediction methods.

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      P1.11-004 - Impact of Lung Cancer Surgery on Quality of Life of Family Caregivers (ID 1431)

      J.Y. Kim, V. Sun, D.J. Raz, A.C. Williams, R. Fujinami, K. Reckamp, M. Koczywas, M. Cristea, A. Hurria, B. Ferrell

      • Abstract
      • Slides

      Background:
      Family caregivers (FCGs) of lung cancer patients experience decreased quality of life (QOL) and psychological distress related to their caregiving role. Although there is extensive data about the significant impact of lung cancer surgery on patient QOL, little is known about the impact on FCGs. We describe QOL, psychological distress, and perceived caregiver burden outcomes among FCGs of patients undergoing lung cancer surgery.

      Methods:
      As part of a National Cancer Institute-supported Program Project (P01) testing the effect of a palliative care intervention in patients with non-small cell lung cancer, patients and their FCGs were sequentially enrolled into a usual care group or an intervention group, which received interdisciplinary care planning as well as a comprehensive assessment and education by an advanced practice nurse. For this subset analysis, we included only those patients who underwent surgery and their FCGs. Outcomes were assessed at baseline (pre-operatively), at 6-7 weeks, and 12 weeks after surgery. FCGs were assessed using the following validated measures: distress thermometer for psychological distress, family version of QOL scale in four domains (physical, psychological, social, and spiritual well being), and Caregiver Burden Scale. Patients were assessed using distress thermometer and FACT-L for QOL domains.

      Results:
      QOL data were available for 41 pairs of patients and FCGs (10 usual care and 31 intervention). Psychological distress levels were highest for patients (3.8/10) and FCGs (5.1/10) before surgery, then decreased six weeks after surgery for both groups respectively (2.9/10 and 4.2/10). Patients’ distress continued to decrease at 12 weeks (2.2/10, p = .001), but FCGs did not (4.4/10, p = .0.157). Although patients had improvements in all domains between 6 and 12 weeks, FCGs did not experience similar improvements in most domains (Figure 1). Likewise, there was no significant decrease in caregiver objective burden over the 12 weeks (21.1 vs. 21.3, p = 0.942). Patients in the intervention group had improved total QOL at 12 weeks compared to usual care (Total FACT-L 116 vs. 94, p <.001). In contrast, there were no significant differences between the usual care and intervention groups in QOL of FCGs.

      Conclusion:
      FCGs of lung cancer patients experience significant psychological distress. FCGs continue to have decreased QOL 3 months after lung cancer surgery. The trajectory of QOL for FCGs does not mirror that of patients. FCGs play an important role in patient recovery and greater research is needed to understand how they are impacted by thoracic surgery. Figure 1



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      P1.11-005 - Enhancing Evaluation of Cancer Cachexia in Patients with NSCLC by Assessing Change in Skeletal Muscle Mass at the L1 Level on Routine Chest CT (ID 2761)

      J.N. Galeas, A. Recio Boiles, L.M. Man, R.D. Gentzler, P. Hollen, R.J. Gralla

      • Abstract
      • Slides

      Background:
      Cancer cachexia (CC) and sarcopenia occur in up to 60% of patients with lung cancer. With better knowledge of the pathophysiology leading to cancer cachexia, multiple recent therapeutic trials have been directed at these mechanisms. Additionally, it is clear that cancer cachexia is associated with several negative outcomes. Inherent in all studies for this problem, is the ability to measure components of cancer cachexia, such as skeletal muscle mass (SMM). SMM assessment by CT scanning (SD <1.2kgs) is more accurate than either Dual X ray absorptiometry (DXA, SD 3kgs) or than bioelectrical impedance (SD 9.3kgs). A single slice on CT at the third lumbar vertebra (L3) correlates highly (r=0.924) with total body SMM in healthy individuals. While CT measurement at L3 is often used in cancer cachexia trials, the problem exists that routine chest CT scans rarely extend to L3; thus routine chest CTs will not allow inclusion of most patients. Importantly, prior studies in normal subjects demonstrated high correlation (r = 0.903) of SMM measurement at L1 with L3; however, the utility and feasibility of L1 measurement of SMM has not been assessed in patients with cancer.

      Methods:
      We enlisted patients with NSCLC and performed SMM measurements at L1 using Slice-O-Matic software for muscle mass in the Hounsfield unit range of -29 to +150. Patients were assessed for accuracy of using the L1 level for imaging quality and the ability to use the software properly.

      Results:
      56 patients with NSCLC (99 CT assessments) were enlisted at three institutions. Characteristics: 45% female; medians: age 60, KPS 80%; BMI 24.96, weight 72.38 kg, SMM index 58.89. Sarcopenia was detected in 29% of patients (58% of males <55.5 cm2/M2; 6% of females <38.5cm2/M2) with all having normal or overweight BMI. Overall, of the 99 CT images, 92.9% (95% CI = 88%-98%) included L1. 5 additional images (5%) were difficult to evaluate for SMM due to ascites or effusions; also, 1 patient was too obese for proper imaging; 2 had poor quality scans. Importantly, inclusion of L1 differed among the 3 institutions ranging from 80.6% to 97.2%. Also noted, as previously reported with assessment at L3 (r = 0.35), the correlation of BMI with SMM in this study at L1 was low (r = 0.36) as well.

      Conclusion:
      This study indicates that: 1) SMM assessment at L1 is achievable on routine chest CT in patients with lung cancer, with 93% of patients having images at this level, and 93% have acceptable quality for SMM evaluation; 2) although L1 is included in the majority of patients at all 3 institutions, this may vary by different radiologic protocols; 3) the low correlation and poor sensitivity of BMI to identify muscle mass loss is equally demonstrated at both L3 and L1, and 4) use of L1 enhances patient evaluation for SMM without needing additional testing or radiation exposure, and allows many more patients with NSCLC to have assessment of SMM in clinical trials and patient management. Funding in part: NIH/NCI 1 R01 CA157409-01A1

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      P1.11-006 - Association between Nutritional Status Variables and Fatigue Diagnosis in Patients with Non Small Cells Lung Cancer (ID 3013)

      J.L. Morales, J.T. Chaparro, M. De La Torre-Vallejo, L.F.O. Ocaña, O. Arrieta Rodriguez

      • Abstract
      • Slides

      Background:
      Cancer-related fatigue (CRF) is a common and persistent symptom experienced by patients with Non Small Cells Lung Cancer (NSCLC). It is produced by multifactorial factors including those associated to the disease itself, comorbidities, life style and/or treatment. Malnutrition is found in up to 80% of patients with advanced cancer and could be associated with the presence of CRF. Both, malnutrition and fatigue have a negative impact on many aspects of patients’ Health-related quality of life, treatment compliance and prognosis. The aim of this study was to associate nutritional status variables with the occurrence of CRF in patients with advanced NSCLC.

      Methods:
      Patients with advance stage NSCLC under different lines of treatment were prospectively evaluated. Fatigue was assessed by the FA-13 (EORTC) test; malnutrition and anorexia were diagnosed using Subjective Global Assessment (SGA) and (S/AC-12) FAACT, respectively. Weight loss in the last six months was calculated, albumin and hemoglobin levels were used as biochemical parameters of nutrition.

      Results:
      129 patients were included, 75 were female (58%), the mean age was 61.9±13.8 years, Adenocarcinoma histology was present in 92 patients (71.4%) and the rest were classified as other histology, 90 patients (69.8%) were in ≤2[nd ]line of treatment, 106 patients (83.5%) had a functional status between 0-1 and the rest between 2-3, according to SGA 79 patients (64.8%) had any grade of malnutrition, 94 patients (75.8%) had a weight loss ≥10kg in six months, 25 patients (19.4%) were diagnosed with anorexia, albumin mean was 3.8mg/dl and 55 patients (32%) had less than that, as well as Hemoglobin level mean was 12.7 mg/dl and 61 patients (35.5%) had a valor less than it. Nutritional variables associated with CRF are shown in Table 2. Nutritional variables as Malnutrition, weight loss ≥10% and albumin were related with higher presence of physical, emotional, cognitive and daily-life fatigue. Clinical variables as histology, line of treatment and functional status were analyzed and just poor functional status was associated with higher presence of physical, emotional, cognitive and daily-life fatigue (p≤0.01). Table 2.- Nutritional status variables related fatigue

      n=129 Physic-FS p Emotional-FS p Cognitive-FS p Daily-life-FS p Social-FS p
      Nutritional-Status Malnourished Wellnourished 42 25 <0.01 42 25 <0.01 42 25 0.001 33 33 0.001 0 0.224
      Weight-loss (≥10% 6 months) ≥10 <10 50 33 0.003 50 33 0.001 42 25 0.002 67 33 0.006 0 0.273
      Anorexia Yes No 67 33 <0.01 58 33 <0.01 58 25 <0.01 67 33 <0.01 33 0 0.02
      Albumin-(gr/dL) <3.8 ≥3.8 42 33 0.004 42 25 0.003 42 25 0.004 33 33 0.002 0 0.212
      Hemoglobin-(gr/dL) <12.7 ≥12.7 42 33 0.077 42 25 0.04 42 25 0.012 33 33 0.227 0 0.023
      FS: fatigue score

      Conclusion:
      Malnutrition, weight loss, anorexia, hypoalbuminemia and low hemoglobin are associated with CRF. Hence, timely nutritional evaluation should be considered in NSCLC patients. Early nutritional treatment could help to reduce treatment and disease related fatigue. Nutritional and psychological support might confer beneficial effects.

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      P1.11-007 - To Determine Whether Psychosocial Factors Predict Depression among Older Indian Lung Cancer Patients (ID 3161)

      G.S. Bhattacharyya, P.M. Parikh, G. Biswas, R. Dhar, S.A. Bondarde, H. Malhotra, A. Vora, K. Govindbabu, A.A.B. Ranade

      • Abstract
      • Slides

      Background:
      Depression is extremely common in elderly lung cancer patients. However, it is extremely difficult to predict or develop predicting tools. There is some early studies suggesting using psychosocial factors. Unfortunately there appears to be no data from developing countries, more so from India. This is an attempt to initiate the process.

      Methods:
      Design: A descriptive correlational study. Setting: Multispeciality Hospitao Oncology OPD Sample: Indian Lung Cancer Patients with cancer aged 50–88 years. Methods: Fisher’s exact and Wilcoxon rank-sum tests were used to evaluate differences between patients who were possibly depressed (Geriatric Depression Scale) or not.Multivariate linear regression statistics were used to identify the psychosocial factors that predicted higher depression scores. Education and gender were included as covariates. Main Research Variables: Religiosity, emotional support, collectivism, perceived stigma, and depression.

      Results:
      Participants (N = 67) had a mean age of 65 years (SD = 8.4), and a majority were well-educated, insured, religiously affiliated, and currently in treatment. Participants who were in the lowest income category, not married, or male had higher depression scores. The multivariable model consisting of organized religion, emotional support, collectivism, education, and gender explained 52% (adjusted R2) of the variation in depression scores. Stigma became insignificant in the multivariable model

      Conclusion:
      Psychosocial factors are important predictors of depression. Emotional support and organized religious activities may represent protective factors against depression, whereas collectivism may increase their risk Implications for Management : Care providers need to be particularly aware of the potential psychological strain for patients with collectivist values, experienced stigma, disruptions in church attendance, and lack of emotional support. In addition, the treatment plans for these patients should ensure that family members are knowledgeable about cancer, its treatment, and side effects so they are empowered to meet support needs. Knowledge Translation: Among Indian Lung Cancer Patients patients with cancer, emotional support and reassurance from family and friends that they will not abandon them decreases the likelihood of depressive symptoms and minimizes the impact of stigmatizing responses, but the perception that the illness is placing a strain on the family increases the likelihood of such symptoms. Emotional support likely is a stronger predictor of depressive symptoms than religious service attendance

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      P1.11-008 - What Happens to the Pleural Space Affected by Malignant Effusion after Bedside Pleurodesis? (ID 439)

      P.N. Araujo, R.M. Terra, T.S. Santos, R.C. Chate, A.L. Paiva, P.M. Pêgo-Fernandes

      • Abstract
      • Slides

      Background:
      The treatment of recurrent malignant pleural effusion (RMPE) has a palliative purpose. Pleurodesis is the most used method. However, not all the procedures are effective, in part because of the lung entrapment by the visceral pleura, preventing the contact between the pleural surfaces. The behavior of the pleural cavities submitted to pleurodesis has not been studied more objectively to date. Moreover, how evolve cases with good initial lung expansion and those with poor expansion?

      Methods:
      Prospective study including 131 patients with recurrent malignant pleural effusion candidates for treatment with bedside pleurodesis with silver nitrate or mineral talc. Each patient underwent two chest CT scans, one right after the drainage (CT1) and another 30 days after pleurodesis (CT30). A thoracic radiologist has calculated pleural volume using the software Aquarius Intuition Viewer® (Terarecon). The evaluation of lung expansion was based on residual pleural volume on CT1 and the radiological evolution on the difference between the pleural volumes on CT30 and CT1 (Delta volume). The pleural volumes on CT1 were arbitrarily classified into small cavity after the drainage (volume <500mL) and large cavity after the drainage (volume ≥500 mL). After that, the Delta volume was classified in unchanged (≥-268.77 and ≤254,49 mL), negative (<-268.77 mL) and positive (> 254.49 mL). For such we used the average of the numerical variable and half of the standard deviation upwards and downwards. The clinical effectiveness was evaluated as the need for additional procedures to control symptoms.

      Results:
      We evaluated 87 patients of a total of 131 recruited. The median pleural volume on CT1 was 377 (IR: 171-722) mL and 386 (IR: 164-726) mL on CT30, and has no significant difference between them (p= 0.753). The clinical effectiveness was observed in 86.2% of patients. We found 54 patients (62.06%) in the small cavity after the drainage group and 33 (37.93%) in the large cavity group. Clinical effectiveness was 92.6% and 75.8% respectively. There was significant difference (p= 0.051), with an odds ratio of 4.00 (CI: 1.098 to 14.570) in favor of the small cavity. Among patients with small pleural cavity, 27.77% progress with a significant accumulation of fluid, 66.66% did not show significant changes and 5.55% have decreased pleural volume. Clinical effectiveness was 86.7%, 94.4% and 100% respectively with no significant difference (p= 0.552). Among patients with large pleural cavity, 21.21% progress with an even greater volume of pleural cavity, 27.27% did not show significant changes and the majority (51.51%) evolves with a decrease in the pleural volume. Clinical effectiveness was 57.1%, 77.8% and 82.4% respectively with no significant difference (p= 0.418).

      Conclusion:
      Almost two third of the patients with RMPE treated with pleurodesis had good lung expansion, while just over one-third had a bad one. Those with good expansion had 4 times higher chances of clinical success. Among poor lung expansion patients, more than half had significant reduction of pleural volume in 30 days, while a fifth had a significant accumulation.

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      P1.11-009 - Predictors of Hospital Discharge in Cancer Patients with Pericardial Effusion Who Undergo Surgical Pericardial Drainage (ID 2500)

      T. Kazantzis, R.M. Terra, B.J. Bibas, L.L. Lauricella, P.N. Araujo, A.J.M. Dela-Vega, P.M. Pêgo-Fernandes

      • Abstract
      • Slides

      Background:
      Pericardial effusion (PE) is a complication of late-stage cancer and operative pericardial drainage is its standard treatment. However, in many patients PE is an end-of-life event and some never leave the hospital despite the procedure. The main objective of this study was to identify predictors of hospital discharge in patients with cancer who coursed pericardial effusion and underwent operative pericardial drainage. We also looked at predictors of ICU discharge and overall survival and also factors that might be associated with paradoxical hemodynamic instability (PHI).

      Methods:
      Retrospective study carried out in a tertiary cancer center. We included all patients with known malignancy who coursed with PE and underwent surgical pericardial drainage from 2011 to 2014. Patients who underwent previous pericardial drainage or only needle pericardiocentesis were excluded from the study.

      Results:
      Out of the 90 patients included in this study, fifty one were discharged from hospital (56%). Renal failure and pulmonary embolism negatively influenced the chances of hospital discharge [OR 0,247; p=0,039 and OR 0,293; p=0.089, respectively]. On the other hand, patients who received recent chemotherapy were more likely to leave the hospital (OR 3,9; p=0,009). 55 patients (61%) were discharged from ICU. Renal failure was the main determinant of that (OR 0,284 (p=0,047)). Mean survival was 138.2 days (95% CI 84,48-189,90), influenced only by ECOG status (OR 1,258; p=0,047). PHI occurred in 6 patients and all of them died within 30 days after surgery. In our series, we could not identify predictors for PHI.

      Conclusion:
      In this study we demonstrated that almost half of cancer patients admitted with PE requiring drainage never leave the hospital. Renal failure and pulmonary embolism are strong predictors of in-hospital death. PHI remains a serious condition with causes unknown.

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      P1.11-010 - Therapeutic and Supportive Care Unmet Needs in Lung Cancer Patients  (ID 548)

      R. Savla, C. Stamoran

      • Abstract
      • Slides

      Background:
      The current drug evaluation model is designed at primarily optimizing therapeutic outcomes. Measures of quality of life and patient reported outcomes are often relegated as secondary endpoints. Even with excellent outcome results, there are many aspects of the patient journey that need to be addressed and improved. It is possible to improve therapeutic outcomes by addressing these other aspects of patient care. This study was concerned with elucidating these areas of unmet therapeutic and supportive needs.

      Methods:
      An online survey tool was used to collect lung cancer patient responses to questions about treatments, quality of life, and supportive therapies during their lung cancer treatment regimens. The various measures of outcomes, disease progression, treatments, quality of life, and side effects and their management were stratified according to lung cancer stage at diagnosis and other patient factors.

      Results:
      Responses from 106 lung cancer (non-small cell and small cell) patients were collected and analyzed. The study population had a significantly better 5-year survival rate compared to the national average for lung cancer patients. Only 2% of patients reported financial difficulties as a result of lung cancer. The patient population was quite homogenous (89.3% females and 90.4% white). Eighty percent of patients reported experiencing side effects from chemotherapy and of those, 86% reported that taking chemotherapy was difficult because of the side effects. Patients diagnosed at Stage II and III experienced the most side effects and received the highest average number of treatment modalities. Patients who agreed/strongly agreed that side effects affected ability to take chemotherapy experienced a significantly higher number of side effects than those patients who reported that side effects were not as bothersome. The same was seen with patients who agreed/ strongly agreed that side effects caused lifestyle disturbance. A subset of side effects negatively affected quality of life to a greater extent than other (nausea, vomiting, diarrhea, loss of appetite, and fatigue). Neuropathy and loss of appetite were the most poorly managed side effects. When asked what changes to chemotherapy administration they would like, the most common responses were oral agents or no changes.

      Conclusion:
      Even with excellent therapeutic outcomes, there continue to be unmet needs that can improve patient experience and quality of life. Side effects continue to be troublesome and common in cancer therapy. Side effects had negative impact on lifestyle and ability to take chemotherapy. Certain side effects are poorly managed. Better supportive care for chemotherapy-related issues can enhance patient quality of life and may further improve quality of life.

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      P1.11-011 - Taste Disorder in Patients with Thoracic Malignancy Who Received Chemotherapy (ID 1322)

      K. Azuma, H. Yokouchi, R. Togawa, Y. Suzuki, Y. Sato, K. Hirai, M. Uematsu, K. Misa, H. Minemura, K. Kanazawa, Y. Tanino, M. Munakata

      • Abstract

      Background:
      Recent development of novel cancer treatments have enabled patients to have prolonged survival; however, some patients cannot receive benefits from those effective therapies because of severe adverse effects. One of the major adverse effects that are recognized by medical staff in patients who undergo chemotherapy is taste disorder, although little is known about how to treat it. To overcome this problem, accumulating fundamental data, such as incidence rate and timing of taste disorder in cancer patients who have undergone chemotherapy, is necessary. With this in mind, we attempted to collect the data regarding taste disorder in patients with thoracic malignancy after initiation of chemotherapy as a pilot study, in order to determine the primary endpoint for subsequent intervention studies.

      Methods:
      All eligible patients had treatment-naive non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC) or malignant pleural mesothelioma (MPM) with ECOG performance status (PS) 0-2, and underwent chemotherapy. Written informed consent was obtained from all participants. We prospectively investigated the incidence rate and timing of taste disorder in these patients using the following two methods: i) analysis of gustatory threshold for salty taste using a sodium-impregnated test strip (SALSAVE, Advantec Toyo Co. Ltd., Tokyo, Japan); and ii) analysis of responses of a questionnaire which asked about the patient’s appetite, the timing of each taste change (sweet, salty, sour, and bitter taste), the presence of a taste in the mouth without eating any food, changes in sense of smell, tolerability against taste disorder, and the condition of the mouth and stomach after each cycle (1-4 cycles) of chemotherapy. This study was registered with the University Hospital Medical Information Network Clinical Trials Registry, identification number UMIN00007879, and approved by the Institutional Review Board of our institution.

      Results:
      From June 2012 to August 2014, 36 pts were enrolled. The average age was 64.5 years (range: 37-83); male/female=29/7 (81/19%); ECOG PS 0/1/2=20/12/1 (56/33/3%); NSCLC/SCLC/MPM=25/8/3 (69/22/8%), clinical stage IIIA/IIIB/IV/adjuvant of lung cancer =2/6/23/2 (6/18/70/6%), and IMIG stage III/IV of MPM=2/1. Chemotherapy regimens were as follows; cisplatin/carboplatin/pemetrexed/etoposide/ paclitaxel/others=18/14/16/8/3/7. There was a trend of increased threshold for salty taste detected by a test strip after one or two cycles of chemotherapy (p=0.10, each). Questionnaire analysis demonstrated that patients felt changes in taste after two or three cycles of chemotherapy (p=0.04, 0.005, respectively), felt changes in their sense of smell after one to three cycles (p=0.04, 0.002, 0.001, respectively), and had a reduced sensitivity to salty tastes after three cycles (p=0.02).

      Conclusion:
      These results suggest that using a salt test strip may detect salty taste disorder earlier than analysis of the patient’s subjective symptoms as answered in a questionnaire. The questionnaire evidently demonstrated taste disorder from various aspects in patients with thoracic malignancy receiving chemotherapy, and thus intervention using novel drugs is necessary. Further accumulation of such data is definitely warranted for further studies.

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      P1.11-012 - Process for Developing a Rapid Tissue Donation Program in a Thoracic Program: Ethical and Logistical Considerations (ID 1602)

      G. Quinn, M.B. Schabath, T.M. Anotnia, C. Pratt, I. Sehovic, E. Haura

      • Abstract
      • Slides

      Background:
      Rapid tissue donation (RTD), also known as “warm autopsy,” is a novel method of tissue procurement for research purposes where tissues from the primary tumor and metastatic sites are collected within 24 hours of patient death. These tissues provide tremendous research possibilities and hope for new cancer treatments. However, recruiting for RTD has ethical challenges such as diminishing patients’ hope and causing distress to Next of Kin (NoK). Presently there is limited RTD education, training, or protocols for biomedical researchers and healthcare professionals (HCPs) to address the psychosocial and ethical aspects of the request for postmortem tissue donation. The purpose of this study was to: i) identify barriers and facilitators to RTD recruitment and tissue collection from key stakeholders; ii) identify the RTD processes used in other organizations and programs; and iii) establish a standardized process for RTD in a Thoracic Oncology Program at a Comprehensive Cancer Center.

      Methods:
      Mixed methods were used for each of the 3 purposes of the study: i) formative research (surveys and focus groups) was conducted to explore knowledge, perceptions, and barriers and facilitators to patient recruitment to RTD across key stakeholders including HCPs (n= 91), cancer patients/survivors and advocates, caregivers, physicians and clinic staff (n=42); ii) semi-structured interviews with hospice staff, morgue pathologists, funeral home directors, national organ/tissue donation programs (n= 27); and iii) conducted an extensive review of the literature regarding existing models of RTD.

      Results:
      Results from part 1 of the study identified several barriers including use of the word “autopsy”; discussing RTD during an initial appointment; approaching patients who attended visits alone; having staff discuss RTD with patients; and expecting all physicians would want to assist with recruitment. Facilitators included identifying enthusiastic physicians; establishing that the treating physician should identify who would be a good candidate (interest and willingness); use of the word “donation”; only approaching patients who have expressed interest and are coping well with their diagnosis; engaging family members in the consenting process; developing written educational materials about RTD; and allowing family members the authority to revoke consent after patient death. Results from part 2 identified the need to use a body map to indicate metastatic sites, developing a standardized operation procedure (SOP); restricting the geographic area where patients reside to facilitate quick retrieval; enlisting the help of Hospice, providing training to staff and physicians and developing a mechanism to provide study results to NoK and recognition for donors. Results from part 3 revealed that despite more than 300 publications using tissue collected via RTD, only 1 study actually described the process for obtaining the tissues and consent. Based on these results, a 12-step RTD SOP was developed.

      Conclusion:
      Ethical guidelines, an SOP, and training for HCPs is needed prior to initiation of an RTD program. A verbatim script is necessary for physicians’ comfort level and to ensure consistent messaging. Our study provides important information about knowledge, attitudes, and logistics related to RTD from all stakeholders and guided the development of a RTD at a Comprehensive Cancer Center.

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      P1.11-013 - Place and Cause of Death in Patients with Lung Cancer in the United Kingdom (ID 2735)

      E.L. O'Dowd, T. McKeever, D.R. Baldwin, S. Anwar, R.B. Hubbard

      • Abstract
      • Slides

      Background:
      Many patients with cancer die in an acute hospital bed, which has been frequently identified as the least preferred location, with psychological and financial implications. This study aims to look at place and cause of death in patients with lung cancer to identify which factors are associated with dying in an acute hospital bed versus at home.

      Methods:
      We used data from the National Lung Cancer Audit (NLCA) linked to Hospital Episode Statistics (HES) and Office of National Statistics (ONS) records to determine cause and place of death in those with lung cancer overall. England was divided into 28 cancer Networks at the time these data were collected so we used these to assess geographical variation in place of death. We used multivariate logistic regression to compare demographic, co-morbid and tumour-related factors between those who died in an acute hospital versus those who died at home.

      Results:
      Of 143627 patients identified 40% (57678) died in an acute hospital, 29% (41957) died at home and 17% (24108) died in a hospice. Individual factors strongly associated with death in an acute hospital bed compared to home were male sex, increasing age, poor performance status, social deprivation and diagnosis via an emergency route (table 1). There was marked variation between cancer Networks in place of death. The proportion of patients dying in an acute hospital ranged from 28% to 48%, with variation most notable in provision of hospice care (9% versus 33%). Cause of death in the majority was lung cancer (86%), with other malignancies, chronic obstructive pulmonary disease (COPD) and ischaemic heart disease (IHD) comprising 9% collectively.

      Conclusion:
      A substantial proportion of patients with lung cancer die in acute hospital beds and this is more likely with increasing age, male sex, social deprivation and in those with poor performance status. There is marked variation between Networks, suggesting a need to improve end-of-life planning in those at greatest risk, and to review the allocation of resources to provide more hospice beds, enhanced community support and ensure equal access. Figure 1



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    P1.12 - Poster Session/ Community Practice (ID 232)

    • Type: Poster
    • Track: Community Practice
    • Presentations: 11
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      P1.12-001 - Trends in Accuracy and Comprehensiveness of Pathology Reports of Resected Non-Small Cell Lung Cancer (NSCLC) in a High Mortality Area of the US (ID 1571)

      M.P. Smeltzer, F.E. Rugless, N. Faris, X. Yu, R. Eke, G. Relyea, C. Fehnel, N. Chakraborty, C. Houston-Harris, F. Lu, D. Spencer, A. Berry, E. Sales, C. Finch Cruz, R.U. Osarogiagbon

      • Abstract
      • Slides

      Background:
      Pathologic examination of NSCLC resection specimens is vital to optimal treatment. In 2004, the College of American Pathologists (CAP) issued guidelines for NSCLC reporting, which were most recently updated in 2013. We evaluated the adoption of CAP reporting elements in a regional database.

      Methods:
      The Mid-South Quality of Surgical Resection (MS-QSR) database includes detailed information on 2,593 NSCLC resections in 11 institutions in 5 Dartmouth Hospital Referral Regions in Eastern Arkansas, North Mississippi and Western Tennessee from 2009-2014. In 2009, we started a multifaceted educational intervention: 1. Analyzed 2004-2008 pathology reports demonstrating the quality deficit in pathology reporting. 2. Recommended adoption of synoptic reporting of CAP checklist items. 3. Embedded a surgical intervention to improve mediastinal lymph node examination at some institutions. To allow for comparisons between eras and across the post-intervention era by intervention and type of hospital, we evaluated 4 groups: pre-intervention (pre-int), post-intervention participating hospital with surgical intervention (post-int/surg), post-intervention participating hospital without surgical intervention (post-int/non-surg), and non-participating non-surgical intervention hospital (post-int/non-part). We evaluated the inclusion of each CAP checklist item and the percent of cases with all items and 6 key items reported. We also evaluated the accuracy of T and N-stage categorization. Proportions reporting each item were compared between groups using Fisher’s Exact test.

      Results:
      Details of the completeness of pathology reporting are shown in Table 1 by group. The percent reporting the 6 key checklist items improved significantly from 63% pre-int to 76% post-int/non-part, 86% post-int/non-surg, and 95% post-int/surg (p-value<0.0001). A similar pattern of improvement was observed for N-stage (p-value<0.0001) and T-stage (p-value<0.0001) reporting. However, we observed significant decreases in the reporting of M-stage, and therefore all key items, post-intervention (p-value<0.0001). The accuracy of N-stage reporting improved significantly from 66% pre-int to 72% post-int/non-part, 86% post-int/non-surg, and 97% post-int/surg (p-value<0.0001). A similar trend was observed for T-stage accuracy (p-Value<0.0001).

      %Reporting Pre-Int (N=1390) Post-Int/ Non-Part (N=271) Post-Int/ No-Surg (N=645) Post-Int/ With-Surg (N=310) P-Value
      Specimen* 98.4 100 100 100 <0.0001
      TumorSize* 97.2 99.6 98.1 99.4 0.0094
      Histology* 99.8 99.6 99.5 99.7 0.59
      MarginStatus* 97.1 98.5 92.6 98.7 <0.0001
      T-Stage* 67.8 76.4 92.1 97.1 <0.0001
      N-Stage* 66.3 76.8 89.8 97.7 <0.0001
      *All Key-Items 62.7 75.7 85.7 94.8 <0.0001
      Laterality 99.8 100 99.5 100 0.56
      HistologicGrade 99.9 100 99.5 100 0.18
      M-Stage 75.8 31.4 25 21.6 <0.0001
      VascularInvasion 28.6 10.7 25 11.9 <0.0001
      All Items 10.7 4.1 6.2 3.2 <0.0001
      %Accurate
      N-Stage 66.2 71.6 86.2 96.8 <0.0001
      T-Stage 55.3 61.6 83 84.8 <0.0001


      Conclusion:
      There was significant improvement in reporting of CAP checklist items and the accuracy of pT- and pN-categorization. After the introduction of synoptic reporting, we observed a secular trend of improvement, shown by our post-int/non-part external control. Direct educational intervention in 2009-2010 further improved the completeness and accuracy of reports in participating hospitals. The surgical intervention provided additional benefit. Interventions to improve the quality of reporting for NSCLC are impactful on accuracy and thoroughness of reporting, thereby improving the quality of care.

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      P1.12-002 - International Online Tool for Therapeutic Decision Making in NSCLC (V2.0) (ID 2160)

      T.A. Quill, D.R. Gandara, W.E.E. Eberhardt, T. Mok, N. Saijo, Y. Wu, K. Obholz, A. Bowser, H. Chow, G.V.V. Scagliotti

      • Abstract

      Background:
      Practice guidelines in non-small-cell lung cancer (NSCLC) list multiple therapy choices based on levels of evidence but cannot account for variability in patient (pt)-tumor characteristics between individual patient cases. To provide oncologists with expert guidance and feedback on choice of treatment (Tx) for specific pt scenarios, we previously implemented an interactive Web-based decision support tool in 2012, in which oncologist users input specific pt characteristics and selected among treatment options, then compared their selection with that of an NSCLC expert panel for that scenario. (Chow JTO 2015). Here we report data from version 2.0 of this tool, capturing current Tx trends for advanced NSCLC and investigating the impact of this online tool on oncology practitioners.

      Methods:
      V2.0 was developed based on input from 6 international NSCLC experts who provided Tx recommendations for 1st-line treatment in 96 pt case variations based on histology (nonsquamous vs squamous), EGFR mutational status (positive [+] vs negative [-]), ALK rearrangement (+ vs -), age (< 70 vs ≥ 70 years), performance status (0, 1 vs 2), smoking history (never/former light vs former heavy/current), and pt primary Tx goal (response and survival vs quality of life and low adverse events). As in V1.0, oncologist users input specific pt scenarios, then were prompted for their treatment choice. Once completed, recommendations for that scenario from each of the experts were displayed, and users were prompted to indicate whether the expert recommendations changed their treatment choice. Statistical methods: as previously described (Chow JTO 2015).

      Results:
      V2.0 oncologist users (N = 218 unique users) contributing 314 unique cases were 87% non-USA, 13% USA. As in V1.0, experts agreed on selection of targeted therapies (TKIs) for cases with actionable EGFR mutations and ALK translocations. Choice of a specific EGFR inhibitor by experts varied depending on region and clinical factors. By comparison, among online users of V2.0, an EGFR inhibitor was selected for 67% of EGFR-mutated cases (n = 78), while an ALK inhibitor was selected for 61% of ALK cases (n = 31). For nonsquamous histology cases without actionable mutations, use of pemetrexed was more common among experts compared with oncologist users (91% vs 48% of case scenarios). In 182 cases entered by users who reported on the impact of expert recommendations, treatment choice was affected in 86% of cases (confirmed in 71%); 5.5% disagreed with expert recommendations and 8% indicated barriers to implementing the recommendations. In comparing overall results from V1.0 (2012) to V2.0 (2014), more oncologist users were likely to select TKIs in both EGFR mutation (49% vs 67%) and ALK translocation (35% vs 61%), with a corresponding decrease in use of chemotherapy. A detailed analysis of expert vs user data will be presented, comparing V1.0 (2012) and V2.0 (2014).

      Conclusion:
      Expert opinions were largely unchanged between V1.0 and V2.0, while oncologist users increased use of TKIs. Most oncologist users of V2.0 either confirmed or changed treatment choices based on expert recommendations. This online tool can aid decision making, serve an educational purpose, and capture practice trends.

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      P1.12-003 - Acquistion of and Early Clinical Results of Electromagnetic Navigational Bronchoscopy for Diagnosis of Lung Cancer in a Community Setting (ID 956)

      A. Reichman, J. Parkyn, J. Birk, L. De La Cruz, R. Calhoun

      • Abstract

      Background:
      Electromagnetic Navigational Bronchoscopy (ENB) is an emerging technology to assist in obtaining a tissue diagnosis from suspicious lung nodules or masses. Despite the recognized advantages of having access to ENB technology, there are barriers to procure such expensive technology and effectively implement it. Acquiring and leveraging ENB technology is dependent on diverse considerations for community need, financial feasibility, patient / referral work flow and synergy with complimentary diagnostics and programs, proper coding and revenue cycle management and associated service development and marketing. There are many elements to implementing and achieving acceptable results which include the initial capital planning and service optimization, maximizing utilization, learning the techniques with enhanced competency and the handling and management of the specimens once obtained. Herein, we describe our approach to procuring the technology and early clinical results.

      Methods:
      ENB technology was purchased after partnering with the parent company (Covidien) and our health system's business development department, to perform a market analysis as well as a return on investment that integrated multiple service lines and hospital costs centers. From these data, a business plan was created and ultimately approved by the Foundation Board. All ENBs (SuperDimension®) were performed under general anesthesia by a single thoracic surgeon in the operating room, using a therapeutic bronchoscope inserted through a 9 endotracheal tube. Almost all procedures utilized fine needle aspiration, brushings, biopsies and washings. The biopsy phase of the procedure was done under fluoroscopy. Cytologic slide review via Rapid Onsite Evaluation (ROSE) was performed by a pathologist in the operating room in 100% of the cases. Results were obtained by retrospective review of a prospective database. Time period of study was 12/11/13-03/30/14.

      Results:
      72 total ENB cases were performed in the time period of which 52 were for suspected malignancy. There were no pneumothoraces or bleeding complications. Two patients had to be admitted for 23 hours secondary to poor respiratory function following procedure. Of the 52 suspected malignancies, 33 (64%) were found to be a primary lung cancer, 7 were atypical and 12 benign or non-diagnostic. 5 of the patients with atypia went on to surgical resection and were found to have lung adenocarcinoma.

      Conclusion:
      ENB is an emerging technology with promising results for tissue diagnosis of lung nodules suspected of being malignant. Implementing new and costly technologies in smaller healthcare systems, such as a regional hospital, can be challenging. Some of the barriers to implementation are finding the capital and justification for procuring the technology, perfecting the technique and securing support from pathology, anesthesiology and operating room time. By partnering with industry and our business department, we were able to justify procurement of ENB technology. In our first 72 cases, 52 were for suspected malignancy. A diagnosis of lung cancer was achieved in 64% of lung lesions, with a low complication rate (2/72). Our results compare favorably to published results of trans thoracic needle biopsies as well as within our own health system. Initiating and implementing an ENB program in a community setting is feasible with acceptable results.

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      P1.12-004 - Early Results of Endobronchial Ultrasound for Lung Cancer Mediastinal Nodal Staging in a Community Setting (ID 1610)

      A. Reichman, J. Parkyn, L. De La Cruz, R. Calhoun

      • Abstract

      Background:
      Endobronchial Ultrasound (EBUS) has become an established modality for pathological mediastinal staging for lung cancer and in some centers, is used at the exclusion of mediastinoscopy, the traditional gold standard. Herein, we describe our early results of EBUS, in a community setting, for mediastinal pathologic staging for lung cancer and compare it to concomitant mediastinoscopy.

      Methods:
      All EBUS procedures were performed in the operating room under general anesthesia, with a Pentax scope introduced through a 9 endotracheal tube, by a single thoracic surgeon. The Pentax needle was used early in the series and the Cook needle later. Rapid Onsite Evaluation (ROSE) for immediate cytologic evaluation of specimens was performed in 100% of the cases. For lung cancer staging patients, mediastinoscopy was performed immediately after the EBUS under the same anesthetic. This was an outpatient procedure. Study period was 04/21/14-04/13/15. Data was collected from a retrospective review of a prospective database.

      Results:
      There were 40 EBUS cases performed during the study period. There were no complications. 36 were performed for cancer diagnosis/staging and 21 for lung cancer staging specifically. 27 cases had EBUS and mediastinoscopy performed concomitantly under one anesthetic and thus could be directly compared. 46 total # of lymph node stations were evaulated with EBUS and 16 (35%) resulted in no lymphocytes or diagnosis. Regarding the 21 lung cancer patients who were being evaluated for pre-treatment pathologic mediastinal staging, the average # of lymph node stations was 1.1 for EBUS vs. 3.4 for mediastinoscopy. Using mediastinoscopy as the reference for pathologic staging, the sensitivity of EBUS was 80% and specificity 100%. If the EBUS stations that yielded no lymphocytes or diagnosis were eliminated from the analysis, the sensitivity was 89% and specificity 100%.

      Conclusion:
      EBUS has become an established technique to pathologically stage mediastinal nodes for lung cancer. In some centers, it is used at the exclusion of mediastinoscopy (the gold standard) and in others, selectively. Our early results with the adoption of this technique and comparing it to mediastinoscopy performed concommitantly, has an acceptable sensitivity and specificity. However, we experienced a relatively high rate of absence of lymphocytes/non-diagnostic (35%), compared to mediastinoscopy (0%), and fewer nodal stations biopsied per procedure (avg. 1.1) compared to mediastinoscopy (avg. 3.4). This does represent an early experience and likely not beyond the learning curve. We will continue to utilize EBUS for lung cancer staging but will be liberal to employ concomitant mediastinoscopy until we can approach the results of our mediastinoscopy with respect to yield of lymphocytes/diagnosis and # of stations biopsied per procedure.

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      P1.12-005 - Concomitant Electromagnetic Navigational Bronchoscopy and Endobronchial Ultrasound to Diagnose and Stage Lung Cancer in a Community Setting (ID 2410)

      J. Parkyn, A. Reichman, L. De La Cruz, R. Calhoun

      • Abstract

      Background:
      Delays in lung cancer diagnosis and adequate staging can both delay and affect appropriate care. It is not uncommon to take months from the time of the first suspicion of lung cancer on imaging to diagnosis, staging and treatment. We have recently adopted both electromagnetic navigational bronchoscopy (ENB) and endobronchial ultrasound (EBUS) technologies as part of our comprehensive lung cancer program. By cultivating an early referral system, within the primary care network, of suspected lung cancer and with the understanding of which patients should have pathologic mediastinal staging, we are able to both diagnose a primary lung cancer and pathologically stage the mediastinal nodes in one setting under the same anesthetic. This combined approach by a lung cancer expert, saves many potential delays of separate serial procedures often ordered by those not as familiar with lung cancer evaluation and staging. Herein, we describe our early results with this approach.

      Methods:
      Criteria for patient selection was a lung nodule/mass suspicious for lung cancer and either clinically positive hilar or mediastinal lymph nodes (>1cm on short axis or > 2.5 SUV on PET) or central primary, >4 cm primary or >10 SUV of suspected primary lung cancer. All procedures were performed by a single thoracic surgeon, in the operating room with the patient under general anesthesia. The Superdimension® ENB system was utilized and the Pentax® EBUS system. Rapid Onsite Evaluation (ROSE) for immediate cytologic evaluation of specimens was performed in 100% of the cases. The study period was 04/21/14-04/13/15. Data was evaluated retrospectively from a prospective collected database.

      Results:
      21 patients had a combination of ENB and EBUS and/or mediastinoscopy or both. 19 patients had lung cancer and constitute this analysis. A diagnosis of lung cancer was achieved in 16 patients (84%). EBUS/Mediastinoscopy was negative for cancer in 11 (59%) patients and positive for cancer in 8. (41%). There were no complications and all procedures were outpatient. The subsequent treatment of the patients were as follows: 5 definitive chemoradiation, 3 lobectomy followed by chemotherapy, 1 lobectomy followed by radiation to chest wall, 1 lobectomy, 2 clinical trials, 1 neoadjuvant chemotherapy followed by lobectomy (intent), 2 chemoradiation followed by lobectomy (intent), 1 radiation, 2 chemotherapy, 1 hospice.

      Conclusion:
      The ability to both diagnose lung cancer and pathologically stage the mediastinum under one anesthetic with utilization of ROSE, has several potential advantages. It allows an efficient and expeditious diagnosis and staging in select patients so they move expeditiously to the appropriate treatment and potentially skip several serial appointments and tests. Like most centers, we selectively pathologically stage the mediastinum for lung cancer patients and this is likely why in this series there is a relatively high percentage of pathologic N2 nodes (41%) found on pre-treatment pathologic staging and relatively high percentage of patients having adjuvant treatment after lobectomy. We believe this is an efficient approach for patients with a suspected lung cancer and meet criteria for pathologic mediastinal staging. Future studies will focus on quantifying the time savings differential between this approach and the more traditional approaches.

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      P1.12-006 - Factors That Influence Tobacco Consumption Among Portuguese Adolescents (ID 2294)

      D. Silva, J.A. Fernandes, A. Valente, C. Dias, A. Pereira, H. Queiroga, A. Caldas Afonso, A. Guerra

      • Abstract
      • Slides

      Background:
      The majority of smokers start smoking at a very early age. Many teenagers, who start smoking at school age, are at increased risk of becoming adult smokers. The purpose of this study was to evaluate family and social factors that might contribute to the acquisition of smoking in Portuguese adolescents.

      Methods:
      A cross-sectional study was conducted in 285 healthy adolescents (15–19 years old) of both sex attending 3 high schools (public and private) from northern Portugal. The smoking habits of teenagers were evaluated according to a protocol adapted from the Global Youth Survey (GYTS), Center of Disease Control and Prevention (2001). The questionnaire consisted of 34 questions related to tobacco consumption, knowledge and attitudes towards smoking, smoking cessation, school regulation and the family role in preventing smoking. Participants were classified as: 1 - never having tried smoking; 2 - have just tried smoking (not smoked in the previous month); 3 - occasional smokers (smoked at least 1 day during the previous month); 4 - current smokers (smoked at least 20 days in the previous month). The protocol was approved by the School Direction and statistical analysis was performed with SPSS ® for the entire sample and by gender.

      Results:
      Of the total sample (n=285), 46% were males and 54% females with an average age of 16.6±1.2 years (minimum:15; maximum:19). About 59.6% of adolescents have experienced smoking at least once, 54% of whom were female. Although the average age of tobacco onset was between 12-15 years (64%), we found that 21% of subjects experienced smoking before 11 years of age. Regarding parents tobacco use, there is a higher percentage of smoking fathers (30.2%) versus 15.2% of mothers. 38% (n=170) of smoking adolescents do it in public places, mainly in social events (65%) and with friends (91%). It is noteworthy that the major causes referred by the adolescents to smoke were: have many smoking friends [girls: OR=44,0 (9,932- 194,92)] (p<0,001); boys: OR=33,21 (6,14-179,65)] (p<0,001) and a smoking mother [girls: OR=4,39 (1,417-13,637)] (p=0,010); boys: OR=2,627 (0,824-8,378)] (p=0,103).

      Conclusion:
      It should be noted that in addition to early initiation, a high percentage of adolescents smoke regularly. Having parents and/or friends who smoke are the highest prediction factors for adolescent smoking. This study highlights the importance for an effective intervention in respect to tobacco harmful effects, with strong family involvement, in order to reduce consumption and prevent its negative health consequences, as well as the morbidity and mortality associated.

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      P1.12-007 - Thoracic Surgery Information on the Internet: Multilingual Quality Assessment (ID 2517)

      M.T. Davaris, S. Barnett, N. Lawrentschuk, R. Abouassaly

      • Abstract
      • Slides

      Background:
      Previous data suggests quality of Internet information regarding surgical conditions and their treatments is variable. However, no comprehensive analysis exists for Thoracic surgery.

      Methods:
      World Health Organization Health on the NET (HON) principles may be applied to websites using an automated toolbar function. We used the English, French, Spanish and German Google search engines to identify 12,000 websites using keywords related to Thoracic conditions and procedures. The first 150 websites returned by each keyword in each language had HON principles examined. We compared website quality to assess for tertile (thirds) and language differences. A further evaluation of the English site types was undertaken, with a comparative analysis of website provider types.

      Results:
      ‘Lung Cancer’ returned over 150 million websites, whereas ‘Ravitch Procedure’ returned less than 250 thousand. Less than 10% of websites are HON accredited with differences by search term (p<0.05) and tertiles (p<0.05) of the first 150 websites but, in contrast to earlier work in other tumour streams, not between languages. Oncological keywords regarding conditions and procedures were found to return a higher percentage of HON-accreditation than cosmetic search terms. The percentage of HON-accredited sites was similar across all four languages (p<0.05). In general, the first tertile contained a higher percentage of HON-accredited sites for every keyword. Figure 1 Figure 2





      Conclusion:
      Clinicians should appreciate the lack of validation of the majority of thoracic websites, with discrepancies in quality and number of websites across conditions and procedures. These differences appear similar regardless of language. An opportunity exists for clinicians to participate in the development of informative, ethical and reliable health websites on the Internet and direct patients to them.

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      P1.12-008 - Components of Creating and Implementing a Comprehensive Lung Cancer Program in a Community Setting (ID 2424)

      J. Parkyn, A. Reichman, L. De La Cruz, J. Birk, H. Nguyen, C.M. Wilkinson, R. Suey, R. Calhoun

      • Abstract

      Background:
      Many communities do not have a comprehensive, evidence based approach to lung cancer diagnosis, staging and treatment. This is often secondary to lack of providers in the area with expertise in lung cancer as well as lack of appropriate diagnostic and treatment modalities. Herein we describe the creation and implementation of a comprehensive lung cancer program in a community setting.

      Methods:
      A regional health system that serves a population with a relatively high incidence of lung cancer, recruited an experienced general thoracic surgeon, with expertise in the diagnosis, staging and treatment of lung cancer. The community had a pre-existing cardiac surgery program, a cancer center that provided chemotherapy and traditional radiation, a PET scanner and 2 CT scanners.

      Results:
      The study period was 9/1-2012 to 4/1/2015 which spans the time after the introduction of the general thoracic surgeon in the community to present. Under the leadership of the thoracic surgeon, the following was accomplished: 1. An extensive outreach campaign to primary care physicians as well as directly to the community regarding lung cancer awareness, modern diagnostic, staging and treatment modalities. 2. Establishment of a pulmonary nodule clinic to provide expertise and continuity in the evaluation of pulmonary nodules. 3. The establishment of a lung cancer CT screening program, 4. Evolution of the tumor board from a once a month meeting, reviewing an average of 3.1 patients retrospectively and an average attendance of 3.6 attendees to currently meeting weekly, prospectively reviewing an average of 8.6 cases per meeting (>90% lung cancer) and an average attendance of 9.3 attendees including thoracic surgery, medical and radiation oncology, pathology, social work and a rotation of surgeons, pulmonologists and primary care physicians. 5. The procurement and implementation of Electromagnetic Navigational Bronchoscopy to the community to obtain tissue diagnosis of suspected lung lesions. 6. The procurement and implementation of Endobronchial Ultrasound for the minimally invasive pathologic staging of appropriate lung cancer patients. 7. The procurement and participation in the Society of Thoracic Surgery (STS) General Thoracic Surgery Database for registration of patient outcomes and national comparison. 8. The introduction of VATS lobectomies and complex open resections. 9 400 new thoracic surgical cases to the Regional Medical Center. 10. 54 cases of multimodallity therapy for lung cancer patients compared with 4 the previous two years. 11. The establishment of stereotactic body radiation therapy (SBRT) as a treatment alternative to surgery for medically inoperable stage I lung cancer patients.

      Conclusion:
      It is possible to create a de novo comprehensive lung cancer program in a community setting with the appropriate expertise and leadership. General thoracic surgeons with expertise in current lung cancer diagnostics, staging and treatment options are uniquely positioned to provide the expertise and leadership to create a comprehensive lung cancer program as they are integrally part of assessing pulmonary nodules, establishing diagnosis, rigorously staging lung cancer and treatments including surgery, radiation chemotherapy and multimodality regimens. This approach could serve as a paradigm for similar communities to bring current, evidence based lung cancer diagnostics and treatment to their region.

      • Abstract
      • Slides

      Background:
      Octogenarian patients with lung cancer are underestimated in the scientific literature. Since in our institution, the median age of patients with lung cancer is 71 years old, we decide to conduct a study to get specific data of our population over 80 years

      Methods:
      Retrospective observational cohort study of patients with lung cancer referred to Medical Oncology at our institution, during 4 years (2010-2013) and follow-up until April 2015. Inclusion criteria were age (80 years or older) and lung cancer diagnosis. The cohort was 41 patients

      Results:
      Our octogenarian patients were a 6.1% of our 672 patients seen in 2010-2013 interval. Of our 41 patients, 78% were male, and the median age is 81 years (80-87). Histologies are 88% NSCLC and 12% SCLC; in the NSCLC group, squamous carcinomas are most common (50%), followed by adenocarcinoma (26.8%). 51% patients were diagnosed in stages I-III, but only 3 patients were under radical treatment (2 surgery, 1 radiation therapy). 34% patients did not receive any oncologic treatment, only palliative care. Of the patients with active cancer treatment, 92% received first-line therapy. In the first-line group, 68% were under chemotherapy, 48% platinum doublet (more used schedules were carboplatin-vinorelbine, carboplatin-pemetrexed and carboplatin-paclitaxel), and 20% monotherapy (vinorelbine, pemetrexed and carboplatin) and 24% TKi (all EGFR mutated, with gefitinib and erlotinib). 26.8% (11) of patients received second-line treatment (10 erlotinib and 1 pemetrexed), and only 2 patients received 3 or more lines (1 patient up to 7 lines). 39 of 41 patients died (95%), and most patients die at home (95%). The median survival time is 11.19 months (CI 95% 7.84-14.53) and median overall survival is 8 months (CI 95% 4.51-11.48). In male patients, median survival time expected is 9.97 months, and in female patients, 14.88 months. Depending on the stage, stage IV patients had a expected survival of 9.94 months and stage I-III patients, 11.40 months, with no statistically significant diference. Depending on smoking status, survival is 8.95 months for ever-smokers, and 18.44 months for never-smokers (p-value: 0.035). Depending on therapy, survival in active cancer treatment group is 14.56 months, and in palliative care only group is 5.28 months (p-value: 0.001)

      Conclusion:
      In our cohort of elderly patients, with a small number of patients (a 6% of all the patients, maybe underreferred), we found some differences with our global lung cancer patients group. The ratio SCLC-NSCLC is quite similar (12-88% in elderly vs 14-86% in all our patients), but there is a different pattern according histological subtypes, with more squamous carcinomas in this cohort (44% vs 29.6%), and more EGFR mutations (24% vs 18%). We see that survival was better in patients receiving active cancer treatment plus best supportive care vs only palliative care. Factors influencing survival are smoking status (ever vs never-smokers) and sex. Although is essential a joint management with Palliative Care, in this particular group of patients, that are believed that cancer treatment is less useful, active cancer treatment is beneficial, if we always individualize decisions in each patient.

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      P1.12-010 - Bench to Bedside Detection of Actionable Genotypes by SNaPshot for Lung Cancer Panel (ID 314)

      A. Choughule, V. Trivedi, P. Chandrani, A. Dutt, K. Prabhash

      • Abstract
      • Slides

      Background:
      Conventional therapeutic solutions in NSCLC are not effective to treat the disease. Despite of all developments in understanding of the disease, mortality of lung cancer patients remains high. Recent developments of personalized therapy have given promising results in terms of improved survival of NSCLC patients. Thus, we were keen to develop a cost effective and sensitive diagnostic lung cancer panel assay for targetable mutation detection by using SNaPShot PCR technique on FFPE samples.

      Methods:
      Method: Multiplexed (SNaPShot) PCR was optimized to amplify hotspot regions from 9 targetable genes followed by single base extension reaction using fragment analysis on ABI 3500 Sequencer. Gene Mapper software was used for analysis

      Results:
      The successfully developed mutation profiling assay was divided into 3 multiplexed reactions, covering 23 actionable genotypes of EGFR, KRAS, BRAF, PIK3CA, Her2, AKT1, NRAS, MEK1 and PTEN genes. The assay was standardized and validated on 20 blood samples, 10 cell lines and 20 FFPE samples expressing good sensitivity and specificity for wild type and mutant genotypes.

      Conclusion:
      This In house developed SNaPShot PCR technology is robust, economical, specific and sensitive to detect actionable mutations in FFPE Adeno as well as in Squamous Carcinoma samples. Because these variants have differing genetic, biological, and clinical properties, including response to treatment, this Bench to Bedside research will lead us to correct classification of lung cancer cases and will assure that lung cancer patients receive optimum management.

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      P1.12-011 - Treatment Patterns and Overall Survival for Advanced NSCLC Following Platinum-Based Chemotherapy in US Community Oncology Clinical Practice (ID 3284)

      C. McKay, T. Burke, X. Cao, A. Abernethy, D.P. Carbone

      • Abstract
      • Slides

      Background:
      While clinical guidelines provide clinical decision support for selection of agent, combination, and order of administration, there are few studies that provide a comprehensive description of contemporary advanced NSCLC treatment patterns in patients following platinum therapy over time; there are limited recent US data on practice patterns and outcomes for advanced NSCLC patients following chemotherapy. The purpose of this study is (1) to describe patient flow from advanced NSCLC diagnosis to anti-cancer treatment following completion of a platinum regimen, and if EGFR mutation or ALK translocation positive, an appropriate TKI; (2) to describe the characteristics of advanced NSCLC patients treated with anti-cancer therapy following platinum therapy and, if EGFR mutation or ALK translocation positive, an appropriate TKI; to describe anti-cancer treatment patterns following completion of platinum therapy and, if EGFR mutation or ALK translocation positive, an appropriate TKI.

      Methods:
      Retrospective EMR database cohort study using data from a cloud-based Oncology Electronic Medical Record (EMR) system with 220 cancer clinics, 700 community-based cancer treatment clinics, 1750 clinicians, and 725,000 active cancer patients, representing 17% of incident cases in the United States. The data represents lab values and physician notes from both structured and unstructured data. Variables of interest include demographic, disease-related, biomarker testing-related, anti-cancer treatment. Treatment patterns include regimens by line of therapy, agents and number of doses administered or prescribed, and distribution of dosage strengths. Analyses will be conducted by histology and EGFR/ALK status (among non-squamous cell carcinoma patients). Data will be analyzed descriptively. Overall survival, if data are available, will be estimated using a series of Kaplan Meier curves, with median OS (95% confidence interval) reported.

      Results:
      Approximately 1598 patients with advanced NSCLC initiating a line of therapy after completing a platinum regimen and, if EGFR mutation or ALK translocation positive, an appropriate TKI between January 1, 2013 and October 31, 2014 will be followed until April 30, 2015. Preliminary results identified 6536 patients with advanced NSCLC; of these, 5048 (77.2%) received any 1L treatment after advanced NSCLC diagnosis with 3786 (57.9%) receiving platinum-based chemotherapy as 1L treatment. Among the final cohort of patients (n=1598), the majority were men (54.0%) initially diagnosed with stage IV disease (68.5%) at age 66. The distribution of histological subtypes in the sample included non-squamous (74.4%), squamous (21.0%), and NOS (4.6%). Treatment patterns will be described according to histology and biomarker status at index date. Patient characteristics and overall survival will be reported by histology, biomarker status at index date, and regimen type.

      Conclusion:
      Results from this study will describe treatment patterns in the second-line setting, prior to the introduction of newer therapies, such as anti-PD1/PD-L1 inhibitors and angiogenesis inhibitors. Additionally, it will advance current understanding of the specific patterns of 2L care for patients being treated with anti-cancer therapy in the real world of community settings.

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    PRC 02 - Press Conference 2 (ID 197)

    • Type: Press Conference
    • Track: Other
    • Presentations: 6
    • +

      Q&A (ID 3624)

      • Abstract

      Abstract not provided

    • +

      PRC02.01 - Daily Theme: Lung Cancer Prevention & Screening - Dr. Claudia Henschke, Professor of Radiology and Head of Lung and Cardiac Screening Program at Mount Sinai Medical Center, New York (ID 3619)

      C.I. Henschke

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      PRC02.02 - New Tobacco Declaration from IASLC - Dr. Kenneth Michael Cummings, Chair of Tobacco Control and Smoking Cessation Committee, IASLC (ID 3620)

      K.M. Cummings

      • Abstract
      • Presentation
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      Abstract not provided

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      PRC02.03 - Abstract – Impact of Time to Drug Approval on Potential Years of Life Lost: The Compelling Need for Improved Trial and Regulatory Efficiency - Dr. David Stewart, Head, Division of Medical Oncology, University of Ottawa/The Ottawa Hospital (ID 3621)

      D.J. Stewart

      • Abstract
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      Abstract not provided

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      PRC02.04 - Abstract – Results From Phase III Trials of Anamorelin in Advanced Non-Small Cell Lung Cancer Patients with Cachexia: ROMANA 1 and 2 - Dr. Amy Abernethy, Director, Center for Learning Health Care, Duke Clinical Research Institute, North Carolina (ID 3622)

      A. Abernethy

      • Abstract
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      Abstract not provided

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      PRC02.05 - Abstract – Bevacizumab 15mg/kg Plus Cisplatin-Pemetrexed (CP) vs CP in Malignant Pleural Mesothelioma (MPM): IFCT-GFPC-0701 MAPS Randomized Phase 3 Trial - Dr. Arnaud Scherpereel, Head of the Pulmonary and Thoracic Oncology Department and Professor at the University Hospital (CHU) of Lille, France (ID 3623)

      A. Scherpereel

      • Abstract
      • Slides

      Abstract not provided

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    MINI 01 - Pathology (ID 93)

    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 14
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      MINI01.01 - Immunohistochemical Distinction between Primary Lung Squamous Cell Carcinoma and Pulmonary Metastasis of Head and Neck Squamous Cell Carcinoma (ID 1525)

      J. Ichinose, A. Shinozaki-Ushiku, K. Nagayama, J. Nitadori, M. Anraku, M. Fukayama, J. Nakajima, D. Takai

      • Abstract
      • Presentation
      • Slides

      Background:
      It is extremely difficult to distinguish between primary lung squamous cell carcinoma (LUSq) and pulmonary metastasis of head and neck squamous cell carcinoma (HNSq) in patients with a past history of HNSq, even by histological examination of the resected specimen. This study aimed to establish an immunohistochemical scoring system for discrimination between LUSq and pulmonary metastasis of HNSq.

      Methods:
      We selected genes that were expressed in a markedly different manner in LUSq and HNSq using the results of expression microarrays and chose the antibodies for four proteins (CK19, MMP3, ZNF830, PI3) that had immunohistochemical results shown in the Human Protein Atlas (http://www.proteinatlas.org) that were distinguishable between LUSq and HNSq. We constructed the tissue microarrays using the resected specimens of 39 LUSqs and 48 HNSqs as the training set and evaluated the tendency of HNSq using the 16-grade system according to the positive staining of the four antibodies. Twenty-seven of the patients with pulmonary tumors that were resected and pathologically diagnosed as squamous cell carcinoma between 1999 and 2014 had a past history of HNSq. Their pulmonary tumors and primary HNSqs were analyzed immunohistochemically as the test set. We defined LU-associated recurrence as postoperative recurrence in the thoracic cavity, mediastinum, brain, bone, and liver and defined HN-associated recurrence as recurrence in the other sites. We compared the diagnosis of our immunohistochemical scoring system to the preoperative clinical diagnosis and the pathological diagnosis according to the predictive power of HN-associated recurrence.

      Results:
      The sensitivity, specificity, and accuracy of our immunohistochemical scoring system were 90%, 67%, and 79%, respectively in the training set, and our system correctly diagnosed 96% of HNSq specimens in the test set. Twenty-three out of 27 pulmonary tumors in the test set were diagnosed as pulmonary metastasis of HNSq, and four were diagnosed as LUSq. Eleven of 23 patients (48%) with pulmonary metastasis of HNSq developed HN-associated recurrence (3-year HN-associated recurrence-free probability was 46%), and 10 died because of HNSq, while none of the four patients with LUSq had HN-associated recurrence. Compared with the clinical diagnosis (five LUSq, 14 pulmonary metastasis of HNSq, eight uncertain) and the pathological diagnosis (two LUSq, 17 pulmonary metastasis of HNSq, eight uncertain), our immunohistochemical scoring system could predict the risk of HN-associated recurrence more accurately. Figure 1



      Conclusion:
      Immunohistochemical analysis of four proteins (CK19, MMP3, ZNF830, PI3) was clinically useful for discrimination between LUSq and pulmonary metastasis of HNSq.

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      MINI01.02 - Is It Possible to Distinguish between Second Primary vs Metastasis in Resectable Synchronous Nodules with the Same Histotype of Lung Cancer? (ID 2122)

      G. Luciano, P. Viola, M. Al Sahaf, Z. Niwaz, H. Raubenheimer, M.E. Cufari, H. Chavan, C. Proli, M. Leung, V. Anikin, N. McGonigle, E. Beddow, G. Ladas, S. Jordan, M. Dusmet, A.G. Nicholson, E. Lim

      • Abstract
      • Presentation
      • Slides

      Background:
      The prognostic significance of additional lung nodules in the setting of lung cancer is important as the impact on survival is often considered for the justification of surgical selection in the management of patients with synchronous nodules. TNM 7 down staged the impact on T category but did not distinguish between second primary versus metastasis. Traditional distinctions such as the Martini criteria do not take the same histological type into account and classification continues to improve (e.g. IASLC classification of adenocarcinoma). The aim of our study is to determine if it is possible to distinguish between second primary versus metastases in patients with the same histological type and quantity any difference in survival.

      Methods:
      We retrospectively analysed data from a prospectively collated database at our institution. We collected all the records which included two resected nodules. The detailed pathology reports of these patients were retrieved and the histology, subtype and pTNM of tumours documented. Slides were re-reviewed to determine the histological subtypes according to the current IASLC adenocarcinoma classification. Survival was calculated using Kaplan Meier methods and adjusted survival compared using Cox regression on R (statistical software).

      Results:
      From April 1999 to February 2013, a total of 2925 lung cancer resection were performed. Of these, 379 (14%) operations fulfilled the inclusion criteria of multiple nodules with 316 having synchronous tumours (83.3%) and 63 having metachronous tumours (16.6%). The tumours were ipsilateral in 87.3% and the vast majority were in the same lobe (70.9%). For synchronous tumours, patients with the same histological type had a poorer 5-years survival rate compared to tumours with different histology (p=0.041). The pathologist’s designation between second primary versus intra-pulmonary metastasis distinguished between overall survival (p= 0.001) and this remained statistically significant in the tumours of the same cell type (p= 0.035). Figure 1. Survival outcomes between patients with multiple nodules classified as second primary versus intra-pulmonary metastasis Figure 1



      Conclusion:
      Our results suggest that distinction between second primary and intra-pulmonary metastasis remains important for staging as appreciable differences in survival were observed in patients with synchronous nodules. Survival was poorer in patients with multiple nodules of the same histologic type (compared to different histology) and within the same histological subtype it is possible for pathologists to distinguish between second primary and intra-pulmonary metastasis. As this is currently confirmed only on pathologic stage in the majority, it presently does not influence the selection for surgery.

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      MINI01.03 - Pathology-Imaging Agreement in Distinguishing Separate Primary Tumours and Intrapulmonary Metastasis in Staging of Multiple Lung Cancers (ID 2659)

      P. Viola, A. Devaraj, E. Lim, G. Luciano, S. Popat, A.G. Nicholson

      • Abstract
      • Presentation
      • Slides

      Background:
      The 7[th] TNM staging system for lung cancer recommended staging for cases with multiple nodules viewed as intrapulmonary metastases (IM) as T3 (same lobe), T4 (ipsilateral different lobe) and M1a (contralateral lobe), whilst those classified as separate primary tumours (SPTs) as T(x)NM where “x” is the number of primary tumours, either as a number or “m” for multiple. With an increase in patients presenting with multiple nodules, we sought to develop a set of criteria for c-staging on imaging and to determine the agreement between clinical and pathological staging in a cohort of resected lung cancers who had multiple nodules.

      Methods:
      In 2013 and 2014, there were a total of 48 consecutive cases with available imaging resected with multiple tumours, ranging from 2 to 5 nodules. Of these, one case was excluded as it was a carcinoid with background DIPNECH. These cases were classified as SPT or IM based on previously published criteria (Girard et al. Am J Surg Pathol 2009;33:1752-64). Imaging criteria were generated based on clinical experience in similar fashion with indicators of SPT being 1) Lesions of equivalent size (one not more than 100% of the other) 2) Smaller lesion is spiculated , 3) At least one lesion is subsolid, 4) Presence of field change. (For signs 1 and 2, if the lesions were in different lungs, an absence of mediastinal disease on imaging was required). Cases with at least one positive sign were classified as SPTs. The interobserver agreement between radiologists and pathologist were then generated.

      Results:
      Of the 47 cases, the additional nodules were not identifiable on CT in 7 cases. In the remaining 40 cases, there was agreement in 28 cases, of which 16 were SPTs and 12 were IM. Of 12 cases where there was disagreement, only 3 were SPTS and the majority were cases classified on pathology as IM. There was 70% agreement, greater than that expected by chance (p = 0.002) with a kappa value of 0.41.

      Conclusion:
      Moderate agreement can be achieved in terms of clinical and pathological staging of lung cancers presenting with multiple nodules using imaging and pathologic criteria. Using pathology as the gold standard, there was greater agreement in categorisation of SPTs (84% (16/19)) than IM (57% (12/21)).

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      MINI01.04 - Discussant for MINI01.01, MINI01.02, MINI01.03 (ID 3296)

      N. Rekhtman

      • Abstract
      • Presentation
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      Abstract not provided

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      MINI01.05 - Local Diagnostic Practices for Advanced Non-Small-Cell Lung Cancer in Europe and Japan: ASSESS Study (ID 2629)

      N. Normanno, K. Hagiwara, B. Han, S. Tjulandin, C. Grohé, T. Yokoi, A. Morabito, S. Novello, E. Arriola, O. Molinier, R. McCormack, M. Ratcliffe, M. Reck

      • Abstract
      • Presentation
      • Slides

      Background:
      ASSESS (a large, multicentre, non-interventional, diagnostic study; NCT01785888) evaluated local diagnostic practices for patients with advanced non-small-cell lung cancer (aNSCLC) in Europe/Japan.

      Methods:
      Eligible patients: local/metastatic aNSCLC; chemotherapy-naïve, newly diagnosed/recurrent disease after resection; ineligible for curative treatment. We report diagnostic assessments and epidermal growth factor receptor (EGFR) mutation test turnaround times (secondary endpoints) associated with tissue/cytology samples from patients in Europe/Japan.

      Results:
      1311 patients enrolled (300 Japan). Immunohistochemistry (IHC) was used to confirm pathological diagnosis in 727/960 (76%) and 142/146 (97%) patients in Europe and Japan, respectively (where data were available); the following markers were assessed using IHC: TTF-1 (Europe 96% and Japan 79%); p65 (4% and 8%); and p40 (9% and 24%). EGFR mutation tests were not performed on samples from 110 patients and tested samples from 17 patients did not yield results. The most common reason for not testing was insufficient material provided (Europe 60% [47/78 responses]; Japan 56% [5/9 responses]). The percentages of neoplastic cells in samples (data available: Europe n=281; Japan n=20) were: <20% tumour cells: Europe 15% vs Japan 35%; 20–50% tumour cells: 23% vs 45%; >50% tumour cells: 61% vs 20%. Considering sampling methodologies, the most common sampling sites (data available: Europe n=996; Japan n=291) were the lung parenchyma (Europe 73%; Japan 79%) or lymph nodes (Europe 9%; Japan 9%); the most common sample collection method was bronchoscopy (Europe 39%; Japan 68%; Table 1). Median EGFR mutation test turnaround time was longer in Europe (11 days) versus Japan (8 days; Table 2). Mutation test success rates for Europe and Japan were 98.3% and 99.6%, respectively.

      Conclusion:
      Diagnostic assessments, sampling methodologies and EGFR mutation testing practices vary between and within Europe and Japan; further understanding of local practices will drive improvements and enable more patients to receive appropriate personalised treatment. Figure 1 Figure 2





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      MINI01.06 - Pathological Second-Predominant Component Predicts Recurrence in Lung Adenocarcinoma (ID 1070)

      M. Ito, Y. Miyata, Y. Tsutani, T. Mimura, S. Murakami, H. Ito, H. Nakayama, M. Okada

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung adenocarcinoma is pathologically subdivided according to its predominant component. Approximately 50–70% of invasive adenocarcinomas are diagnosed as adenocarcinomas of either papillary or acinar predominant subtype. The prognostic difference between these subtypes has not been revealed, and these 2 similar subtypes may further be classified. This study aimed to investigate whether the pathological second-predominant component that follows the most predominant component predict recurrence in adenocarcinoma.

      Methods:
      We retrospectively reviewed 347 consecutive cN0 lung adenocarcinoma cases resected between April 2006 and December 2010 at Hiroshima University Hospital and Kanagawa Cancer Center. We further classified papillary and acinar predominant adenocarcinomas into either the papillary/acinar-lepidic type (Pap/Aci-Lep type) or the papillary/acinar-nonlepidic type (Pap/Aci-NonLep type). Tumor recurrence and the frequency of each invasion status such as lymphatic, vascular, and pleural invasion were compared between Pap/Aci-Lep type and Pap/Aci-NonLep type adenocarcinomas. In addition, we estimated the correlation between the radiological and pathological characteristics of these subtypes. Whole-tumor size, ground-glass opacity (GGO) ratio, solid size, and tumor disappearance ratio (TDR) on high-resolution computed tomography and maximum standardized uptake value (SUVmax) on positron emission tomography (CT) were measured as radiological parameters.

      Results:
      Papillary (n = 70) and acinar predominant adenocarcinomas (n = 61) were subdivided into the Pap/Aci-Lep type (n = 72) and Pp/Aci-NonLep type (n = 59). Compared with the Pap/Aci-NonLep type, the Pap/Aci-Lep type showed a significantly higher disease-free survival rate (5-year DFS: 89.4% vs 70.6%, p = 0.0374) and fewer cases of lymphatic invasion (15.3% vs 30.5%, p = 0.037), vascular invasion (15.3% vs 33.9%, p = 0.013), and pleural invasion (9.72% vs 25.4%, p = 0.031). Furthermore, radiological findings significantly differ between the Pap/Aci-Lep and Pap/Aci-NonLep types as follows: GGO ratio (μ ± 1 ´ SD: 34.4% ± 25.2% vs 3.81% ± 18.0%, p < 0.01), CT solid size (μ ± 1 ´ SD: 1.35 ± 0.65 cm vs 1.73 ± 0.55 cm, p = 0.015), TDR (μ ± 1 ´ SD: 41.8% ± 26.7% vs 17.5% ± 22.6%, p < 0.01), and SUVmax (μ ± 1 ´ SD: 2.37 ± 2.15 vs 3.96 ± 3.06, p < 0.01). Significant recurrence-free survival and prevalences of lymphatic and vascular invasion were observed between the lepidic predominant type (n = 109) and Pap/Aci-Lep type.

      Conclusion:
      The pathological second-predominant component allows for subclassification of papillary and acinar predominant adenocarcinomas with prognostic significance. Pathological features of these subtypes can be represented on clinical imaging. Not only the most predominant component but also the second-predominant component should be given clinical and pathological attention in order to predict malignant potential or decide indication for adjuvant therapy.

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      MINI01.07 - Comparison of Grading Systems Based on Histologic Patterns and Mitotic Activity to Predict Recurrence in Stage I Lung Adenocarcinoma (ADC) (ID 3030)

      K.S. Tan, K. Kadota, A. Moreira, P.S. Adusumilli, W.D. Travis

      • Abstract
      • Presentation
      • Slides

      Background:
      An established grading system for lung adenocarcinoma does not exist but is greatly needed. The histologic classification proposed by the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS) and the European Respiratory Society (ERS) has been shown to define prognostically significant subgroups of lung adenocarcinoma (ADC). Since then, various grading systems based on histologic patterns have emerged as promising methods to further discriminate patient risk of clinical outcomes. The aim of this work is to quantitatively assess the discrimination properties of a set of grading systems proposed in recent years to identify the best grading scale(s) independent of other clinical factors to predict recurrence.

      Methods:
      We considered five grading systems: (1) single predominant pattern as six subtypes; (2) as three grades of low (lepidic), intermediate (acinar, papillary) and high (micropapillary, solid); (3) two most predominant grades; (4) predominant grade with mitotic grade; and (5) predominant grade with cribriform pattern and mitotic activity criteria. We evaluated the performance of each grading system with the concordance predictive estimate (CPE). The CPE represents the probability that for any pair of patients, the patient with the better predicted outcome from the Cox model had the longer survival time. CPE > 0.80 demonstrates strong performance. To compare the performance of the grading systems, we determined the significance of the differences between the CPEs. Five-year recurrence-free probability (RFP) was derived using the Kaplan-Meier method.

      Results:
      We applied the grading systems to a uniform large cohort of stage I lung ADC (N=909). The scale based on the single predominant pattern as five subtypes yielded a CPE of 0.63 (95% CI, 0.59-0.67), indicating moderate discrimination. Our analysis showed that grading systems (1), (2), and (3) were not significantly different from each other, suggesting that identifying finer subtypes and second predominant pattern may not improve discrimination. Grading system (4) [CPE, 0.67; 95% CI, 0.63-0.71] yielded a significantly higher CPE than (1), (2) and (3) [p<0.01]. Grading system (5) [CPE, 0.67; 95% CI, 0.63-0.71] was significantly better than (1), (2) and (3) but not (4) [p=0.776]. The lack of improvement in discrimination with the inclusion of cribriform between (4) and (5) can be attributed to the significant relationship between cribriform pattern and mitoses. As the proportion of cribriform pattern increased, the amount of mitotic activity also increased (p<0.001). Under (2), the 5-year RFP of the intermediate grade was 0.81. The addition of cribriform and mitotic counts further classified the intermediate (acinar, papillary) grade such that those with <10% cribriform and low mitotic count had 5-year RFP of 0.89, while the 5-year RFP for the other combinations are between 0.73-0.75.

      Conclusion:
      Grading systems based on histologic patterns and mitotic activity out-perform those with only histologic pattern. This comparison study suggests that proposed grading systems (4) or (5) provide valuable information in discriminating patients with different risks of disease-recurrence in patients with lung ADC.

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      MINI01.08 - Survival Differences of Adenocarcinoma Lung Tumors with Squamous Cell Carcinoma or Neuroendocrine Profiles by Gene Expression Subtyping (ID 384)

      G. Mayhew, N. Hayes, C. Perou, M. Lai-Goldman, H. Faruki

      • Abstract
      • Presentation
      • Slides

      Background:
      Gene expression profiling can provide valuable information beyond the morphologic diagnosis. A previously validated 52-gene Lung Subtype Panel (LSP) for differentiating lung tumors into Adenocarcinoma (AD), Squamous Cell Carcinoma(SQ), and Neuroendocrine (NE) was explored in several publically available lung tumor datasets, including the TCGA RNAseq dataset.

      Methods:
      The LSP 3-class nearest centroid predictor developed in array data was applied to AD and SQ samples in TCGA (RNAseq, n=1,160), the Director’s Challenge (Affy array, n=442), and Tomida et al. (Agilent array, n=117) datasets. Each sample was predicted as AD, SQ, or NE. Kaplan Meier plots and log rank tests were used to assess and compare 5-year overall survival in two gene expression groups, AD predicted AD (AD-AD) and AD predicted SQ or NE (AD-notAD). Cox models were used to assess survival differences while controlling for T stage, N stage, and proliferation (as measured by the PAM50 score). The distribution of samples among the AD subtypes (Terminal Respiratory Unit(TRU), Proximal Proliferative(PP), and Proximal Inflammatory(PI)) was investigated.

      Results:
      The predictor confirmed AD in 80% of the AD samples. AD samples were called SQ and NE by the LSP in 8% and 12% of cases, respectively. The AD-notAD group (AD by histology and SQ or NE by gene expression LSP) had worse survival than the AD-AD group (AD by both histology and LSP) in each data set (logrank p-value in TCGA, Director’s Challenge, and Tomida were 1.17e-06, 0.0009, and 0.0001, respectively). Pooling the 3 data sets and using a stratified cox model that allowed for different baseline hazards in each study, the hazard ratio comparing AD-notAD to AD-AD was 2.14 (95% CI 1.70-2.70). When we fit the model adjusting for T stage, N stage, and proliferation score, the HR was 1.70 (95% CI 1.31-2.20). Adenosubtype profiling of AD-notAD samples indicated that tumors were overwhelmingly of the PP or PI gene expression subtypes (209/213).

      Conclusion:
      Gene expression tumor subtyping may provide valuable clinical information identifying a subset of AD samples with poor prognosis. Poor prognosis adenocarcinoma samples belong to the PI and PP expression subtypes, and demonstrate elevated proliferation scores. This subset of AD tumors may be less responsive to standard adenocarcinoma management.

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      MINI01.09 - Discussant for MINI01.05, MINI01.06, MINI01.07, MINI01.08 (ID 3297)

      E. Thunnissen

      • Abstract
      • Presentation
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      Abstract not provided

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      MINI01.10 - Analysis of the Status of Lymphocyte Infiltration in Patients with NSCLC (ID 2292)

      E.A. Richardet, M.E. Richardet, P.A. Hernandez, E. Pets, M. Cortes, M. Molina, A.A. Riso, C. Di Tada, L.P. Acosta, P. Companys, M. Paradelo

      • Abstract
      • Presentation
      • Slides

      Background:
      Current evidence highlights the potential role of tumor-infiltrating lymphocytes (TILS) as a prognostic factor in many types of tumors; in non-small cell lung cancer (NSCLC), this relationship is not well determined. TILs are being studied with different methods such as immunohistochemistry and optical microscopy. The primary endpoint is to identify TILS in patients with NSCLC, classified as present or absent, and its relation to progression-free survival (PFS) and overall survival (OS). Our secondary endpoint is to establish the relationship between the TILS and treatment received.

      Methods:
      Retrospective and analytical case study of Instituto Oncológico de Córdoba, from 2004 to 2014. 166 patients with stage IIIB and IV NSCLC were analyzed. TILS are descriptively classified as present or absent. Survival curves were calculated using the Kaplan-Meier method.

      Results:
      59% of patients had adenocarcinoma and 41% squamous cell carcinoma. 70% were men. 82% were smokers. 58% of patients with squamous histology and 65% with adenocarcinoma, showed TILS. In relation to first-line chemotherapy, 63,8% of patients received carboplatin-paclitaxel (CP) and 36,2% gemcitabine-cisplatin (GC). Patients with adenocarcinom with TILS present had higher PFS and OS; 8.86 and 13.43 months respectively, compared to patients with absent, 3.78 and 7.9 months. These differences were statistically significant (PFS: p = 0.000002 and OS: p = 0.003). The patients with squamous cell carcinoma with TILS had 6.78 and 12 months PFS and OS respectively. Those who had infiltrated absent had a PFS of 3.96 months and OS of 6.37 months. These differences were also statistically significant (PFS: p = 0.003 OS p = 0.001).

      Conclusion:
      Our study shows that patients whose pathological samples presented inflammatory infiltrate had higher OS and PFS. The presence of TILS could be used as an important prognostic factor in this patient population.

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      MINI01.11 - Transcriptome Sequencing of Tumor vs. Surrounding Non-Malignant Lung Tissue in Non-Small Cell Lung Cancer (ID 1765)

      K. Reynders, E. Wauters, J. Vansteenkiste, H. Decaluwé, P. De Leyn, K. Nackaerts, S. Peeters, C. Dooms, W. Janssens, D. Lambrechts, D. De Ruysscher

      • Abstract
      • Slides

      Background:
      Both the response and the therapeutic ratio of targeted agents in NSCLC may depend on the expression of the target molecules in the tumor and the surrounding non-malignant lung tissue. We therefore performed transcriptome analysis and investigated correlations with histology, gender, age, CRP level and smoking status as well as evaluated the differential pathway expression in primary resected NSCLC and the surrounding non-malignant lung of the same patient.

      Methods:
      Transcriptome sequencing was performed on the primary tumor and distant lung tissue of the same patient from resection specimens of NSCLC patients. Differential gene expression between different conditions was identified using the statistical algorithms Cufflinks, EdgeR and DeSeq. Differential expression with P-values <0.05 after Benjamini-Hochberg correction was considered significant. Pathway analysis for overall tumor versus distant lung tissue was performed with the PANTHER gene classification platform using the Cufflinks, DeSeq and EdgeR differentially expressed gene sets as input.

      Results:
      Twenty-five patients were studied, 19 males and 6 females, with a median age of 69 years. Ten were current smokers, 14 former smokers (>4 weeks before surgery) and 1 non-smoker. Eleven patients had squamous cell carcinoma, 14 adenocarcinoma. A heat map with the results for the most commonly targeted genes in NSCLC is represented in figure 1. When compared to distant lung tissue, PD-L1 was downregulated in tumor tissue of adenocarcinoma and active smokers, but not in squamous cell carcinoma or ex-smokers. Internal control of tumor tissue of squamous vs. adenocarcinoma and ex-smokers vs. active smokers shows an important trend towards a higher expression of PD-L1 in squamous cell carcinoma and ex-smokers in both Cufflinks and EdgeR algorithms. Additional pathway analysis revealed 188 differentially regulated pathways. The most notable were downregulation of VEGF signaling, angiogenesis and B and T cell activation in tumor tissue when compared to distant lung tissue. Figure 1



      Conclusion:
      Our first results show a higher expression of PD-L1 in squamous tumors than in adenocarcinoma and a higher expression in tumors of ex-smokers than in those of active smokers. This may have consequences for the therapeutic ratio with anti-PD-L1 treatment. Downregulation of VEGFR-genes in tumor tissue was observed across almost all conditions. We will make this data more complete by adding methylation data as well as immunohistochemistry for protein localization.

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      MINI01.12 - Implementation of a Molecular Tumor Board: The Impact on Treatment Decisions for NSCLC Patients Evaluated at Dartmouth-Hitchcock in One Year (ID 2719)

      L.J. Tafe, I.P. Gorlov, F. De Abreu, J.A. Lefferts, X. Liu, J.R. Pettus, J.D. Marotti, K.J. Bloch, V.A. Memoli, A.A. Suriawinata, C.E. Fadul, G.N. Schwartz, C.R. Morgan, B.M. Holderness, J.D. Peterson, G.J. Tsongalis, T.W. Miller, M.D. Chamberlin, K.H. Dragnev

      • Abstract
      • Presentation
      • Slides

      Background:
      Genetic profiling of tumors is a powerful approach to predict drug sensitivity and resistance. Definitive interpretation of the clinical significance of somatic mutations is possible for only a few well studied mutations. For the majority, prediction of clinical significance is challenging. We established a Molecular Tumor Board (MTB) at our Cancer Center to interpret individual patients’ tumor genetic profiles and provide treatment recommendations.

      Methods:
      DNA from tumor specimens was sequenced in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory to identify coding mutations in a 50-gene panel. Cases were evaluated by a MTB composed of molecular and anatomic pathologists, medical oncologists, basic research scientists, and genetic counselors.

      Results:
      35 cases were evaluated in 1 year by the MTB including 8 metastatic NSCLC cases. The most common reason for MTB referral was for recommendations on targeted therapies (91.9%), and for potential germline mutations. Tumors exhibited genetic heterogeneity: 71 different mutations were found across 300 genes (for NSCLC 18 mutations across 10 genes). In 18/32 of advanced/metastatic cases, MTB recommended non-standard therapy with a specific targeted agent (11 clinical trials; 7 off-label use), 4 of the 18 patients were subsequently treated with a MTB-recommended targeted therapy. The remaining 14 patients continued on current therapy because disease was stable (n=4), were treated with non-MTB-recommended standard therapy (n=4), declined conventional therapy (n=5), or died prior to receiving further therapy (n=1). For 4 out of the 8 NSCLC cases MTB recommended a BRAF inhibitor (1), RET inhibitor (1), or MET inhibitor (2). One patient received a BRAF inhibitor, 6 continued on current standard of care therapy, one declined therapy.

      Conclusion:
      Case evaluation by a multidisciplinary group of individuals in the context of a MTB frequently shapes treatment options and decisions. Importantly, anticipated obstacles to capitalizing on the benefits of a MTB such as access to drugs were rarely encountered in the entire cohort and in the NSCLC patients. Instead, the most commonly encountered reasons that MTB-recommended therapy was not administered stemmed from patient preferences, and genetic profiling at a very late stage of disease.

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      MINI01.13 - Biologically Driven Sub-Classification of Early Lung Adenocarcinomas (ID 2418)

      D.A. Moore, E. Al Dujaily, J. Le Quesne

      • Abstract
      • Presentation
      • Slides

      Background:
      Early lung adenocarcinomas have previously been successfully sub-classified by Noguchi et al on the basis of histopathological characteristics, in particular the pattern of growth exhibited by the tumour and the response of the adjacent stroma. A wholly in situ pattern of growth characterises preinvasive lung lesions, namely atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS). It is not uncommon for large areas of an invasive tumour to show this in situ pattern of growth. Metastases to the lung from other organs can also show areas of in situ spread, and this shows that truly invasive malignant clones of cells can grow along the alveolar surface. This study aimed to identify whether the characteristics of in situ growth in an individual tumour may give an indication of the underlying tumour biology, and be of prognostic value.

      Methods:
      We reviewed all small (sub 35 mm) lung adenocarcinomas resected with curative intent over a 4 year period from our thoracic surgical centre. Nodal metastasis data was also collected, which the reviewing pathologists were blinded to. All tumour sections were reviewed by 2 thoracic histopathologists, who separated these into 4 categories, based on the patterns of growth, stromal changes, cytological changes between in situ and invasive components and overall symmetry of the lepidic growth. On the basis of these appearances early lung adenocarcinomas were divided into 4 groups. Type 1 showed minimal stromal reaction analogous to Noguchi A/B tumours. Types 2 and 3 are subdivisions of mixed in situ/invasive adenocarcinomas (equivalent to the Noguchi C group). Type 2 showed marked stromal changes in the invasive component and a cytologically lower grade asymmetrical lepidic component. Type 3 showed a concentric rim of lepidic growth cytologically similar to the invasive disease. Type 4 were wholly invasive tumours. Tumour type was subsequently correlated to pathological lymph node staging.

      Results:
      156 tumours were included and sub-classified. Of these 12 were type 1, 30 were type 2, 46 were type 3 and 68 were type 4. The rate of nodal metastasis was increased across the tumour types from 1 to 4, at 0%, 7%, 24% and 29% respectively.

      Conclusion:
      We find that partly invasive lung adenocarcinomas fall into two histologically and biologically distinct groups with different potential toward nodal metastasis. We suggest the type 2 tumours represent the emergence of an invasive subclone in an in situ adenocarcinoma lacking this property. The type 3 tumours have a lepidic region at their edge which represents infiltration of normal structures by migratory malignant cells but may have no truly biologically ‘in situ’ disease. This group also shows more tendency toward metastasis. Type 4 lesions without any kind of lepidic growth have the highest rate of nodal involvement, and their destructive pattern of growth represents the most aggressive form of early tumours. Future molecular characterisation of these lesions and their various components may further inform our understanding of the pathways of tumorigenesis in lung adenocarcinoma.

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      MINI01.14 - Discussant for MINI01.10, MINI01.11, MINI01.12, MINI01.13 (ID 3298)

      K. Politi

      • Abstract
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      Abstract not provided

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    MINI 02 - Immunotherapy (ID 92)

    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 14
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      MINI02.01 - Pulmonary Large Cell Carcinoma and Solid Adenocarcinoma Are Highly Mutated with Frequent Expression of PDL1 (ID 2257)

      D.H. Hwang, A. Perry, F. Kuo, S.J. Rodig, J.L. Hornick, L. Sholl

      • Abstract
      • Presentation
      • Slides

      Background:
      Large cell carcinoma (LCC) is an uncommon lung tumor that arises predominantly in smokers and shares many features of solid adenocarcinoma (ADC). 40% of LCC/solid ADC harbor mutations in KRAS; EGFR and ALK alterations are rare in this tumor type. The majority of these tumors, however, lack one of the commonly queried oncogenic driver alterations, thus therapeutic options are limited for patients with this tumor type. Immunomodulatory therapies, including targeting PDL1, have shown promise in a variety of tumor types. Tumor neo-antigens, including those induced by smoking, are associated with mutational burden and may predict susceptibility to cytolytic immune response; in addition, high PDL1 expression in non small cell lung carcinoma has been associated with response to anti-PDL1 drugs. Given the high prevalence of smoking in patients with LCC and solid ADC, we hypothesize that these tumors may be amenable to immunomodulatory therapy and sought to define the frequency of PDL1 expression in tumors lacking an oncogenic driver mutation.

      Methods:
      This study was restricted to 27 LCC and solid ADC known to be negative for KRAS, EGFR, ALK and ROS1 alterations. Hybrid capture targeted next generation sequencing (NGS) on an Illumina HiSeq 2500 was performed using a cancer genomic assay to detect mutations, copy number variations (CNVs) and structural variants. The assay captures exonic sequences of 275 cancer genes and 91 introns across 30 genes for rearrangement detection. Findings were compared to an institutional cohort of 732 consecutive lung tumors sequenced on the same platform. Immunohistochemistry for PDL1 was performed using a rabbit monoclonal antibody (Cell Signaling Technologies) at 1:100 dilution following pretreatment with citrate buffer/pressure cooker and detected using the Envision + polymer system (DAKO). Immunostaining was considered positive in the tumor component or the inflammatory component if ≥5% of the cells showed membranous staining.

      Results:
      Of the 27 tumors tested, 26 were resected from smokers. NGS revealed an average of 14.9 mutations per case for LCC/solid ADC cohort versus 8.1 mutations in the overall cohort of lung tumors (p<0.0001). 11 cases (41%) were positive for PD-L1. 7 cases (26%) showed strong, diffuse staining (≥70% of cells) for PD-L1. The inflammatory component was positive for PD-L1 in 25 cases (93%). Two cases with strong expression of PD-L1 by immunohistochemistry (>90% of cells) showed focal amplification of CD274 by NGS.

      Conclusion:
      LCC and solid ADC are strongly associated with a smoking history and harbor a significantly higher average mutational burden than other lung tumors. 41% of LCC/solid ADC are positive for PDL1 by immunohistochemistry with 26% showing very strong PDL1 expression and nearly all cases showing some degree of positivity in the associated inflammatory infiltrate. In some cases, high PDL1 expression is associated with focal amplification of CD274, the gene encoding PDL1. These findings suggest that LCC/ solid ADC is likely to have smoking-associated neo-antigen expression and that PDL1-directed immunotherapies may be a promising therapeutic approach in this otherwise poorly-characterized lung tumor.

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      MINI02.02 - Programmed Cell Death Ligand (PD-L1) Expression in Stage II and III Lung Adenocarcinomas and Nodal Metastases (ID 1519)

      H. Uruga, E. Bozkurtlar, T. Huynh, A. Muzikansky, A. Hata, J.F. Gainor, E. Mark, J.A. Engelman, M. Lanuti, M. Mino-Kenudson

      • Abstract
      • Slides

      Background:
      Inhibition of PD-L1 can lead to reactivation of tumor immunity and assist in cancer therapy. PD-L1 expression in tumor cells has been reported to correlate with clinicopathological parameters and prognosis in a variety of cancers including lung adenocarcinomas (ADC). However, it has not been well studied whether PD-L1 expression is altered along with tumor progression. In addition, little is known about the role of PD-L1 expression in predicting response to chemotherapy in ADC. Thus, we sought to compare PD-L1 expression in the main tumor and lymph node metastases of stage II and III ADC, and correlate PD-L1 expression with survival in patients who underwent adjuvant chemotherapy.

      Methods:
      The study cohort consisted of 109 ADC who underwent curative resection without neoadjuvant therapy and were diagnosed to have stage II or III disease. Of those, 60 cases received platinum-based adjuvant therapy and were followed at our institution. Immunohistochemistry for PD-L1 (E1L3N, 1:200, CST) was performed on sections of the primary tumor and/or metastatic lymph nodes and the primary tumor sections were also stained with CD8 (4B11, RTU, Leica Bond). Membranous staining of any intensity present in 5% or more of the tumor cells was deemed positive for PD-L1 expression. CD8+ tumor infiltrating lymphocytes (TILs) were evaluated using a 4-tier grading system (0-3). The PD-L1 expression in the primary tumor was correlated with that in lymph node metastases as well as clinicopathological parameters, including CD8+ TILs, and recurrence free survival (RFS).

      Results:
      Of the 109 cases, 53 (48.6 %) exhibited PD-L1 expression in the primary tumor, which was significantly associated with smaller tumor size, lower pT stage, nodal disease, solid-predominant pattern, the presence of tumor islands, necrosis and lymphovascular invasion, and increased CD8+ TILs (grade 2-3). Upon multivariate analysis, only increased CD8+ TILs remained significant (p=0.039). As for the primary – lymph node correlation, PD-L1 expression was seen in 57.6% of 59 N1 nodes, 53.1% of 32 N2 nodes, and 100% of one N3 node available for evaluation. The PD-L1 expression status was the same between the primary tumor and nodal metastases in the majority (76.3 % of N1 nodes, and 75.0% of N2; p<0.001 and p=0.005, respectively), and the upregulation of PD-L1 expression (positive expression was present in nodal metastasis with negative primary) was seen in only small fractions of the cohort (6.8% of N1 nodes and 9.3% of L2 nodes). Interestingly, PD-L1 expression in the primary tumor was associated with longer RFS in patients who underwent platinum-based adjuvant therapy (mean 84 months vs. 41 months in PD-L1 negative patients, p=0.016), but not in those without adjuvant therapy.

      Conclusion:
      PD-L1 expression in the primary tumor was associated with prominent CD8+ TILs as well as several adverse clinicopathological parameters including nodal disease, but PD-L1 expression in the nodal metastasis was similar to that in the primary tumor in the majority of cases. Although the evaluation was limited due to a small size of the cohort, PD-L1 expression in the primary tumor appears to be predictive of response to platinum-based adjuvant therapy.

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      MINI02.03 - Overexpression of CD47, Decrease of Apoptosis and Phagocytosis of Neutrophils in Advanced Non-Small Cell Lung Cancer Patients (ID 2265)

      L. Barrera, O. Arrieta Rodriguez, A. Garcia-Vicente, R. Morales-Flores, F. Salinas-Parra, E. Montes-Servín, A. Ramirez-Tirado

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is the leading cause of cancer death worldwide and most of the patients are diagnosed with advanced disease. Inflammatory components play a key role in tumor progression and survival. Neutrophils are increased in blood of patients with lung cancer and they are associated with poor clinical outcomes. CD47 is a protein which control cell communication, apoptosis, adhesion and proliferation and it has been found increased in cancer and related with phagocytosis evasion mechanism.The aim of this study was to evaluate CD47 expression levels on peripheral neutrophils, also assess the phenotype, apoptosis, activation state, reactive oxygen species production of neutrophils between patients with Non-Small Cell Lung Cancer (NSCLC) and healthy subjects.

      Methods:
      Fifty NSCLC patients (stage IIIB and IV) naive to treatment and 25 healthy subjects were analized for: CD47 peripheral blood expression, neutrophils phenotype and activation state, evaluation of apoptosis and phagocytosis by flow cytometry. Reactive oxygen species (ROS) production by circulating neutrophils upon stimulation with PMA was assessed by flow cytometry. For the phagocytosis assay, PMNC were labeled with CMFDA and were cultured in RPMI for 24 hrs. To obtain apoptotic target cells, 24h PMNC were labeled with Annexin-V. For the evaluation of phagocytosis, the neutrophils from NSCLC patients were co-cultured with THP-1 cells. The percentage of phagocytosis was assessed by flow cytometry.

      Results:
      Our results showed a lower percentage of total CD47 in peripheral blood cells in NSCLC patients compared to controls [P=0.042]. Mean Fluorescence Intensity (MFI) of CD47 was higher in patients [P<0.001]. The percentage of CD66b+ cells characterized as neutrophils was higher in patients as well as their MFI of CD47 [P< 0.001]. MFI of CD66b was higher in patients [P< 0.0178]. This would be related with a more activated state. We found that a higher disease stage (IIIB vs. IV) associated with a higher MFI of CD47 [P=0.020]. Plasma pro-inflammatory cytokines, was increased in patients compare to controls IL-6 (P<0.002), IL-8 (P<0.001), IL-12p70 (P<0.008), TNF (0.010) and IFN-g (P<0.001). MFI of CD47 >1635.5 was associated with a higher median Overall survival (P= 0.007). We found a decrease of AnnexinV+/7AAD+ in neutrophils of patients [P=0.0317]. Caspases 3 and 7 were found decreased in neutrophils of patients [P= 0.049]. Oxygen species (ROS) production of neutrophils upon PMA stimulation was increased in patients [P=0.029], suggesting it might play a role in immune effector function. Phagocytosis of apoptotic neutrophils by differentiated THP-1 cells was decrease in cancer patients cells (P=0.0445). Mean fluorescence Intensity of CD47 was increased after 24 hrs in patients [P=0.0408]. This result suggests that neutrophils from patients avoid being engulfed and this may be associated with overexpression of CD47.

      Conclusion:
      Taken together, these findings suggest that these are altered mechanisms by which neutrophils evade anti-tumor immune response and their increased expression of CD47 is a potential therapeutic target for NSCLC.

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      MINI02.04 - Sequential Assessment of DNA Damage Response and PD-L1 Expression in Circulating Tumor Cells of Lung Cancer Patients during Radiotherapy (ID 2511)

      S.H. Lin, J. He, M. Edelman, T. Xu, H. Gao, J. Reuben, Y. Qiao, H. Liu, P. Amstutz, S. Hahn, R.U. Komaki, Z. Liao, C. Tang, D. Adams

      • Abstract
      • Presentation
      • Slides

      Background:
      Recent evidence suggests that PD-L1 expression can be induced with radiotherapy and may be a mechanism for resistance to radiotherapy and immunotherapy. Sequentially assessing PD-L1 expression on cancer associated cells in circulation during treatment regimens may be a way to assess the efficacy of radiotherapy and immunotherapy in clinical trials. For this feasibility study, we evaluated the association of RAD50 induction, and PD-L1 expression, on CTCs and Cancer Associated Macrophage-Like Cells (CAMLs) in lung cancer patients (pts) before and during radiotherapy to determine expression changes of these markers.

      Methods:
      Eleven pts with stage I-IV lung cancer were included in this pilot study. Three pts received Stereotactic Body Radiation Therapy (SBRT) for stage I disease and 8 other pts received chemoradiation for stage II-IV disease. Baseline blood samples (7.5 ml) were drawn prior to the start of radiotherapy (T0) and a second blood sample was drawn at a follow up visit during radiotherapy; or for three pts, after completing SBRT (T1); for a total of 22 samples. Blood was processed using CellSieve™ microfiltration (Creatv Microtech), stained for cytokeratin 8, 18 & 19 and CD45, and imaged. Using the QUAS-R (Quench, Underivatize, Amine-Strip and Restain) technique to remove fluoresce signal, all cells were restained for RAD50-AlexaFluor550 and PD-L1-AlexaFluor 488, along with DAPI nuclear stain. The RAD50 foci numbers within nuclear regions were quantified. PD-L1 pixel intensity was measured by the ZenBlue software and grouped into 4 IHC groups: 0-negative (pixel average 0-215), 1-low (pixel average 216-300), 2-medium (pixel average 301-750), and 3-high (pixel average 751+).

      Results:
      There was at least one cytokeratin positive cell (i.e. CTC or CAMLs) found in each of the samples. Specifically CTCs were found in 82% of T0 and 64% of T1 samples, and CAMLs were found in 91% of T0 and 100% of T1 samples. RAD50 foci ranged from 0-16 per cell, with an average of 0.69 at T0 that increased to 3.46 at T1 (p=0.002) during radiotherapy. Distinctively, there were 6 pts with greater than 2 fold RAD50 foci increase at T1 and 5 pts with ≤ 2 fold induction. PD-L1 expression ranged from 34-2004 pixel intensity, with an average of 170 at T0 and 336 at T1 (p=0.08). Interestingly, 4 pts had no PD-L1 expression at T0 but an increase to 2 to 3+ at T1, 4 pts with low/no PD-L1 expression remained low at T1, and 3 pts had high PD-L1 expression that remained high or decreased at T1. There was no correlation between RAD50 induction and PD-L1 expression.

      Conclusion:
      Both RAD50 foci and PD-L1 expression were quantifiable in both CTCs and CAMLs, and had variable responses to radiotherapy +/- chemotherapy. These data suggest that sequential tracking of CTCs or immune-related cells from the primary lung tumor is feasible using microfiltration and potentially can serve as predictive biomarkers for cancer therapy.

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      MINI02.05 - Discussant for MINI02.01, MINI02.02, MINI02.03, MINI02.04 (ID 3299)

      D.P. Carbone

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI02.06 - Humanized Immuno-Mouse for Study of Anti-PD-1 Therapy in KRAS-Mutated Lung Cancer Patient Derived Xenotransplant (PDX) (ID 3104)

      M. Wang, J.W. Riess, J. Keck, K. Palucka, L. Shultz, M. Cheng, D. Cai, C. Bult, D.R. Gandara, P.C. Mack

      • Abstract
      • Presentation
      • Slides

      Background:
      Preclinical modeling of immunotherapeutics in PDX-bearing mice has been limited by the absence of a relevant immune microenvironment, as a highly immunosuppressive environment is often required for the implanted tumor to grow. Checkpoint inhibitors including anti-PD-1 and anti-PD-L1 antibodies (mAbs) are promising new treatments in non-small cell lung cancer (NSCLC). The creation of a PDX model system that supports human tumor growth and recapitulates the relevant genomics in NSCLC while providing the immune microenvironment necessary for anti-PD-1 and anti-PD-L1 mAb activity is critical for validation of combination checkpoint inhibitor strategies in NSCLC.

      Methods:
      Hematopoietic CD34+ progenitor stem cells (CD34+ HPC) were engrafted into the tail vein of sublethally irradiated NSG mice. A KRAS G12D PDX was assayed for PD-L1 expression by FACS (Biolegend; clone 29E. 2A3, San Diego CA) and implanted into Hu-CD34 NSG mice with > 25% Hu-CD45+ cells 12 weeks post CD34+ HPC injection. Multilineage engraftment of immune cell subsets was assayed in peripheral blood, spleen and tumor by FACS (CD45, CD3, CD4, CD8, CD19). PDX were treated with vehicle Q5D x 6, pembrolizumab (Merck, Whitehorse Station PA) 5 mg/kg Q5D x 6, and combination pembrolizumab and docetaxel (Hospira, Lake Forest) 10 mg/kg Q7D x4 at the same single agent dosages. Body weight and tumor growth were assessed twice weekly.

      Results:
      Hu-CD45+ cells were detected in peripheral blood, spleen and tumor by flow cytometry on single cell suspension. The majority of Hu-CD45+ cells were T-cells: CD3CD4+ (mean blood 50%, spleen 53%, tumor 52%) and CD3CD8+ (mean blood 14%, spleen 15%, tumor 39%). KRAS G12D tumor had 89% surface expression of PD-L1. No significant change in Hu-CD45+ cell composition was noted between the different treatment groups. Pembrolizumab both alone and in combination with docetaxel showed activity in KRAS G12D PDX with substantial tumor growth inhibition and decreased mean tumor volume at day 24 post-treatment.

      Conclusion:
      Multilineage engraftment of relevant immune cell subsets for PD-1 inhibition is present in the humanized immune-mouse (Hu-CD34 NSG). PD-1 inhibition in a KRAS G12D Hu-CD34 NSG with high PD-L1 expression demonstrated substantial tumor growth inhibition both alone and in combination with chemotherapy. Additional studies are underway exploiting the Hu-CD34 NSG mouse model for study of anti-PD-1/PD-L1 therapies in KRAS mutant and other important molecular subsets of NSCLC.

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      MINI02.07 - Preclinical Rationale for a Phase I/II Study of Pembrolizumab (P) and Vorinostat (V) in Immune Therapy Naïve and Pretreated Stage IV NSCLC (ID 734)

      N. Tchekmedyian, H. Zheng, A.A. Beg, E. Haura, D. Chen, S.J. Antonia, J. Gray

      • Abstract
      • Presentation
      • Slides

      Background:
      The WHO estimated that 1.6 million people died of lung cancer in 2012. Nivolumab, an anti-PD-1 immune checkpoint inhibitor, was FDA approved on March 4, 2015 for platinum-refractory, metastatic, squamous-cell NSCLC, based upon a RR to single agent nivolumab of ~15% and improved OS. Combinatorial strategies may enhance these outcomes. Increased tumor expression of T cell chemokines, such as CCL5 and CXCL10, is associated with a better response to immunotherapy. Furthermore, expression of T cell chemokines is strongly and positively associated with increased T cell infiltration and improved patient survival. Therefore, enhancement of expression of T cell chemokines may augment response to PD-1 blockade immunotherapy.

      Methods:
      FDA-approved oncology agents were utilized from the Approved Oncology Drugs Set (97 agents) from the Developmental Therapeutics program of NCI. LKR cells were plated in 96-well plates, and a viability assay was performed 48 hours after drug administration (Cell Counting Kit-8, Dojindo Laboratories). Mice were bred and housed in the animal facility at Moffitt Cancer Center. Cells were harvested in logarithmic growth phase after being cultured for less than 2 weeks. 1x10[6] LKR or 344SQ cells were injected s.c. and tumors were monitored for growth by measurements 2-3 times per week. Romidepsin was injected i.p. (2mg/kg) on days 14,16, and 18 after tumor inoculation. Anti-PD-1 was injected i.p. (300μg/mouse) on days 15, 17, and 19 after tumor inoculation. Relative tumor size between treatment groups was analyzed using the t test with Welch’s correction.

      Results:
      Histone deacetylase inhibitors (HDACi), including vorinostat, emerged as the only class of agents in a 97-drug screen capable of inducing expression of multiple T cell chemokines, including CCL5, CXCL9, and CXCL10, in mouse and human lung cancer cell lines and primary tumors. HDACi’s ability to induce T cell chemokine expression was dependent on both JAK-STAT and NF-kB pathways. HDACi (romidepsin) treatment of mice bearing LKR tumors did not substantially cause tumor shrinkage but significantly reduced growth (p<0.0001; final tumor volume). This effect of HDACi was completely T cell dependent. LKR tumor cells had low cell surface expression of PD-L1 but which was substantially increased by IFN-g. PD-1 blockade with mAb reduced tumor growth but rarely induced rejection. However, when PD-1 blockade was combined with HDACi, 9 out of 11 mice demonstrated complete tumor rejection. HDACi anti-tumor response correlated with T cell chemokine induction in tumors and greater presence of tumor-infiltrating lymphocytes (TILs). We next used a mouse tumor model (344SQ) that was relatively resistant to anti-PD-1 treatment. PD-1 blockade combined with HDACi significantly reduced growth of these tumors compared to untreated (p=0.0003), anti-PD-1 alone (p=0.01), or HDACi (p=0.004) alone treated mice.

      Conclusion:
      HDACi not only enhanced anti-tumor response against PD-1 blockade sensitive tumors (LKR), but also induced response against PD-1 blockade resistant tumors (344SQ). HDACi induces JAK-STAT and NF-kB dependent chemokine expression and may induce tumor-infiltrating lymphocytes. Thus, a Phase I/randomized Phase II clinical trial of vorinostat, an orally active, small molecule HDACi, plus pembrolizumab, an anti-PD-1 humanized monoclonal IgG4-kappa antibody, is planned in patients with immune therapy naïve and pre-treated metastatic NSCLC.

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      MINI02.08 - Bidirectional Cross-Talk between CD14+ Monocytes and Human Lung Cancer Cell Lines Results in Different Phenotypic and Functional Outcomes (ID 2497)

      E. Schenk, A. Mansfield, A. Dietz

      • Abstract
      • Presentation
      • Slides

      Background:
      Myeloid cell infiltration of the tumor microenvironment is associated with decreased overall survival in multiple tumor types, including lung cancer. This myeloid cell infiltration represents a tissue component of the heterogeneous group of cells termed myeloid derived suppressor cells (MDSC), which can inhibit the endogenous anti-tumor response, direct angiogenesis, and promote tumor progression. In several studies of patients with non-small cell lung cancer (NSCLC), there is wide variation in the presence of myeloid cells in the tumor with increasing levels peripheral blood MDSC associated with poor survival. We have previously shown that CD14+ monocytes can be converted by the tumor microenvironment to an immune suppressive phenotype in non-Hodgkin lymphoma and glioblastoma. In this work, we expand on our earlier observations to include recruitment of CD14+ cells by lung cancer cell lines and their conversion to an immune suppressive phenotype. While most models of myeloid cells in the microenvironment describe the effects of these cells on non-malignant systems, we show that myeloid cells may have profound direct effects on the tumor.

      Methods:
      Human lung cancer cell lines were cultured and supernatants collected for ELISA. CD14+ cells were isolated from the peripheral blood of healthy volunteers using anti-CD14 immunomagnetic beads. Lung cancer cell lines and CD14+ cells were cocultured under a variety of low serum conditions with or without cisplatin. Changes in CD14+ cell HLA-DR expression and tumor cell survival were measured by flow cytometry. CD14+ cell migration through a permeable transwell membrane was measured in real time with live cell imaging.

      Results:
      Under normal culture conditions, 7 of 8 human lung cancer cell lines secreted detectable levels of CCL2, a major chemoattractant for monocytes, ranging from 30 to 10,000 pg/ml of CCL2 found in culture supernatants. CD14+ cells more robustly migrated towards cell lines with higher production of CCL2. The coculture system showed a differential impact on monocytes by the tested lung cancer cell lines which either reliably upregulated or downregulated CD14+ cell expression of HLA-DR. In 3 of 8 lung cancer cell lines, CD14+ cell HLA-DR was downregulated in a manner expected to promote local immune suppression. Under serum starvation conditions, one lung cancer cell line showed improved survival when cocultured with CD14+ cells. Similarly, coculture with CD14+ cells enhanced tumor survival of two cell lines after exposure to cisplatin.

      Conclusion:
      The studied lung cancer cell lines differ in the degree of CD14+ cell recruitment, CD14+ cell HLA-DR expression after coculture, and level of conferred survival benefit under stressful conditions. Taken together these results suggest that the variable myeloid involvement in lung cancer patients can be modeled using lung cancer lines. In addition, we have identified that for some tumors, monocytes confer a significant survival advantage that is not associated with immune or angiogenic responses. Future work is needed to explore the impact of CD14+ cells on lung tumor invasiveness, angiogenesis, and the mechanisms underlying these pro-tumor effects.

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      MINI02.09 - ERK Activation Mediates Increased PD-L1 Expression in KRAS Mutated Premalignant Human Bronchial Epithelial Cells (ID 1620)

      M. Lee, J. Yanagawa, S. Wu, T. Walser, G. Wang, J.W. Goldman, E.B. Garon, G. Zeng, S. Sharma, J. Minna, D.P. Carbone, S.M. Dubinett, J.M. Lee

      • Abstract
      • Presentation
      • Slides

      Background:
      Immune checkpoint pathways including the PD-1/PD-L1 pathway are involved in tumor evasion from the immune system. Elevated PD-L1 expression in tumor cells inhibits tumor-infiltrating T cell function and may be associated with poor prognosis in lung cancer patients. There is increasing interest in developing immunotherapies that block the immunosuppressive effects of checkpoint pathways such as PD-L1, and identifying patients who may benefit from PD-L1 blockade. Activating KRAS mutations are common driver mutations in non-small cell lung carcinoma. Patients with mutated KRAS demonstrate less benefit from adjuvant chemotherapy and resistance to tyrosine kinase inhibitors. The effect of cancer cell driver mutations on immune checkpoint immune regulation is poorly understood. While recent clinical trials have suggested better response to PD-1 blockade in KRAS mutation subjects, it is unclear if this clinical finding is directly driven by KRAS regulating the PD-1/PD-L1 pathway with resultant improved efficacy to anti-PD-L1 immunotherapy or if the presence of a KRAS mutation is merely a surrogate marker of the overall mutational load and tumor immunogenicity. KRAS mutations are known to activate the RAF-MEK-ERK pathway. We hypothesize that KRAS mutation directly regulates the PD-1/PD-L1 pathway through ERK activation.

      Methods:
      Immortalized human bronchial epithelial cells (HBEC-vector control), KRAS–mutated (KRAS[v12]) HBEC cells (HBEC-KRAS), p53 knockdown HBEC cells (HBEC-p53), and p53 knockdown/KRAS mutated cells (HBEC-p53/KRAS) were used to assess mRNA and/or surface protein expression levels of immune checkpoints including Lag-3, Tim-3, PD-L1 and PD-L2 by real time-qPCR (RT-qPCR) and flow cytometry, respectively. HBEC-vector and HBEC-KRAS cells were treated with MEK (ERK kinase) inhibitor (PD0325901) at 1µM for 24hrs and evaluated for mRNA and surface protein expression of PD-L1. The premalignant HBEC cell lines were used instead of human lung cancer cell lines in order to assess the role of KRAS mutation in isolation without other mutations.

      Results:
      PD-L1 and PD-L2 mRNA levels increased 2.4 fold (p<0.001) and 3.6 (p<0.001) fold in comparing HBEC-KRAS to HBEC-vector (wild-type) cells, while Lag-3 and Tim-3 mRNA expression levels were unchanged. Based on mean fluorescence intensity on flow cytometry, cell surface PD-L1 protein expression level was 2.2 and 1.6 fold higher in HBEC-KRAS and HBEC-p53/KRAS, respectively, compared to HBEC-vector cells. There was no increase in surface PD-L1 expression in HBEC-p53 cells compared to HBEC-vector control, suggesting that p53 mutation did not alter PD-L1 expression in HBEC-p53/KRAS cells. With MEK inhibition, PD-L1 mRNA levels decreased 10 and 11 fold in HBEC-vector and HBEC-KRAS cells, respectively. Analogously, PD-L1 surface protein levels were reduced 2.7 fold in HBEC-vector and HBEC-KRAS cells, respectively. These findings suggest that ERK activation mediates intrinsic expression and KRAS mutation mediates over-expression of PD-L1 mRNA and protein.

      Conclusion:
      Here, we demonstrate that PD-L1 expression is elevated in premalignant KRAS mutated human bronchial epithelial cells, and ERK activation mediates constitutive and KRAS mutation driven up-regulation of PD-L1 in these cells. Our findings suggest that KRAS mutation may directly regulate the PD-1/PD-L1 immune checkpoint pathway. Further understanding of KRAS driven molecular pathways that modulate immune checkpoints may elucidate therapeutic targets for potential combinational drugs to PD-L1 inhibition.

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      MINI02.10 - Discussant for MINI02.06, MINI02.07, MINI02.08, MINI02.09 (ID 3300)

      I.I. Wistuba

      • Abstract
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      Abstract not provided

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      MINI02.11 - Immunological Markers Predict the Prognosis of Patients with Squamous Non-Small Cell Lung Cancer (ID 605)

      L. Jiang, S. Jiang, H. Long

      • Abstract
      • Presentation
      • Slides

      Background:
      As one of the novel therapy strategies, PD-L1 has been shown the function of down-regulating T-cell activation through receptor PD-1. Moreover, prognosis of cancer patients are based not only on tumor-related factors but also on host-related factors, particularly systemic inflammatory response. As significant indicators of patients’ inflammation status, circulating monocyte count, neutrophil ratio and lymphocyte ratio were proved as predictors of prognosis in various cancers. Squamous non-small cell lung cancer (NSCLC) revealed to be divergent clinical and molecular phenotypes compared with non-squamous NSCLC. Significantly, combining application of appropriate biomarkers in prognosis prediction is emerging its high importance in cancer research.

      Methods:
      Chart review was performed on 1286 consecutive patients, 156 of these patients were enrolled in the final analysis. Patients with squamous NCSLC were randomly assigned (2:1) centrally by computer into training group and validation group. Monocyte ratio, Neutrophils to Lymphocytes Ratio, PD-L1 immunostaining score and PD-1-positive stained tumor-infiltrating lymphocytes counts were assessed by Fisher’s linear discriminant analysis to discriminate if OS would exceeding 5 years. The final model was used to calculate the discriminant score in each study participant. And this prediction model was validated in a second set of squamous NCSLC patients. We internally validated the model using a cross-validation procedure.

      Results:
      4 independent predictors of OS were identified by using FLDA with stepwise variant-selection. The clinical classifying model was described by the following equation: Y = −1.212 + 0.211 × NLR ratio + 0.437 × monocyte ratio - 0.390 × PD-L1 + 0.035 × PD-1 (eigenvalue 0.673, canonical correlation 0.634, P < 0.001). In this equation, PD-L1 represented PD-L1 immunostaining score; and PD-1 represented PD-1 positive TILs counts. For the training set of 104 leave-one-out-cross-validated cases, 27 of 29 OS > 5 years (93.1% sensitivity) and 61 of 75 OS <= 5 years (81.3% specificity) were correctly classified with an overall accuracy of 84.6% (88 of 104) and an AUC of 0.938 [P < 0.001, 95% confidence interval (CI) 0.864–1] Next, the predicting model consisting of the 4 predictors (NLR ratio, monocyte ratio, PD-L1 and PD-1) we