Virtual Library

Abstract:
Oncogene-driven lung cancer remains the embodiment of personalized medicine. Since the first description of EGFR activating mutations found in patients with what was then called bronchiolalveolar carcinoma of the lung (BAC) in 2004, the topic of oncogene-driven lung cancer has grown rapidly and expanded to now encompass a number of additional mutation- and fusion-related entities. Recent updates to molecular testing guidelines, such as those of IASLC, have added several new oncogenes to the initial EGFR and ALK recommendations, including ROS1 and RET fusions, MET amplification or mutation, and HER2 mutations (1,2,3). Although the efficacy of tyrosine kinase inhibitors (TKI) in the treatment of some of these disease subsets is well established, the treatment decision-making process at the time of each relapse is becoming more complex as our knowledge of resistance pathways grows and more treatment options become available, with 2[nd] and 3[rd] generation drugs now in play. Subtping of progressive disease (PD) in oncogene-driven lung cancer into systemic PD versus oligo-PD or CNS-santuary PD can assist in determining the most appropriate therapeutic approach, as shown in Figure 1 below(4).Further, the methods by which we assess tumor at the time of initial or re-biopsy are also rapidly evolving, from single gene or multiplexed gene panels to highly sensitive and specific next generation sequencing (NGS). Lastly, we and others (4,5) have proposed algorithms for possible substitution of plasma cell free DNA by NGS platforms for tissue re-biopsy or for serial monitoring in plasma, as demonstrated in Figure 2.In this presentation we will present a step-wise approach to molecular testing and personalizing treatment for patients with oncogene-driven NSCLC, focusing on EGFR-mutated and ALK-rearranged subsets, since the treatment paradigms are most well established. We will emphasize some of the real world challenges faced by treating physicians. Decision criteria for selecting the best first-line therapy will be reviewed, the importance of re-biopsy upon disease progression to determine the most appropriate next-line therapy highlighted, and third line therapy and beyond discussed. The emerging role of liquid biopsy for assessment of plasma cell free DNA will be discussed, as well as a rationale for substituting liquid biopsy for initial or repeat tumor biopsy in some clinical settings. Algorithms designed to facilitate treatment decision-making will be presented. Two examples in EGFR-mutated lung cancer are shown below.Figure 1: Algorithm for management by Progressive Disease SubtypingEGFR-mutated NSCLCFigure 1Figure 2: Algorithm for Re-Biopsy and/or Plasma cf DNA AnalysisIn EGFR-mutated NSCLCFigure 2 References 1. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J et al: Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2013, 8(7):823-859. 2. Leighl NB, Rekhtman N, Biermann WA, Huang J, Mino-Kenudson M, Ramalingam SS, West H, Whitlock S, Somerfield MR: Molecular Testing for Selection of Patients With Lung Cancer for Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Society for the Study of Lung Cancer/Association of Molecular Pathologists Guideline. Journal of Clinical Oncology 2014. 3. Ettinger, D. S., Akerley, W., Borghaei, H., Chang, A. C., Cheney, R. T., Chirieac, L. R., ... & Grant, S. C. Non–small cell lung cancer, version 2.2013. Journal of the National Comprehensive Cancer Network, 2013, 11(6), 645-653. 4. Gandara DR, Li T, Lara PN, Kelly K, Riess JW, Redman MW, Mack PC: Acquired resistance to targeted therapies against oncogene-driven non-small-cell lung cancer: approach to subtyping progressive disease and clinical implications. Clinical lung cancer 2014, 15(1):1-6. 5. Oxnard, G. R., Thress, K. S., Alden, R. S., Lawrance, R., Paweletz, C. P., Cantarini, M., ... & Jänne, P. A. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non–small-cell lung cancer. Journal of Clinical Oncology, 2014, JCO667162.

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According to the regional distribution of the World Health Organization (WHO), Europe extends from the Atlantic Ocean to Central Asia, encompassing states of the former Soviet Union. In political terms however, Eastern Europe refers to countries located on the eastern border of the European Union (EU). Consequently, in our presentation we focus on how smoking status has changed in some of the policy-wise emerging countries located here – namely the Czech Republic, Hungary, Poland and Romania – and how these data compare to Austria’s indicators. We present data on smoking prevalence and trends, restricting use, taxation and average cigarette prices, as well as the distribution of tobacco products in specific countries. Reference is made to restricting advertising and tobacco industry sponsorship activities. Smoking cessation support practice is another important aspect, while electronic cigarette (e-cigarette) regulation is a relatively new issue. Table 1 presents smoking prevalence and trends of specific countries.

	CZE	HUN	POL	ROM	AUT
1980	26,2	34,8	42,5	26,8	27,8
1996	26,6	31,1	33,7	30,6	29,6
2006	26,3	32,9	30,5	26,7	32,5
2012	24,4	28,5	27,6	27,5	32,3

Table 1. Smoking prevalence (%) (+15 years old) It is striking that while the proportion of smokers has decreased in Hungary and Poland, an opposite tendency may be observed in Austria. Smoking prevalence stagnated in Romania and the Czech Republic. It is noteworthy that the proportion of women smokers is high in Austria (28.3%), in Hungary (25.8%) and in Poland (24.1%). Smoke-free laws were adopted in the beginning of this Century in North America and Western Europe, and soon resulted in decreasing the proportion of smokers. Although there were smoking and trade control laws earlier in the presented countries, effective legislation has only been promulgated a few years ago and in some countries it hasn’t even been published. Hungary applies total ban on smoking in enclosed public places (with the exception of psychiatric units) since 2011. In Poland, a partial ban is in place, smoking is allowed in certain restaurants. The Czech Republic exercises a slightly more liberal regulation regarding restaurants. A partial ban exists in Romania in restaurants and there may be designated smoking areas in enclosed places where smoking is prohibited. Smoking is allowed in restaurants in Austria. Smoking is otherwise banned in all other enclosed places in these countries as well. It is well known that raising the price of tobacco products is the best tobacco control measure, we therefore compared tax rates and prices of popular cigarette brands. Although EU member states must comply with EU tax regulation requirements, recently joined members are allowed several years to converge, therefore significant differences may be observed in this manner between discussed countries. Countries generally apply combined taxation policy on cigarettes in agreement with Article 6 of the WHO Framework Convention on Tobacco Control Guideline: apart from the value added tax (VAT), the excise duty consists of an ad valorem and a specific element In 2015, the average 20 piece pack price (in Euro) was 4.6 in Austria, 3 in the Czech Republic, 3.2 in Hungary, 3.2 in Poland and 2.8 in Romania. Regulating the distribution and limiting the access to certain tobacco products is an important tool in tobacco control, and even more so in the prevention of youth smoking. The sale of tobacco products to minors is generally prohibited under 18 years (in Austria, under 16 years), however there are noteworthy differences where vending machines are concerned, e.g. in Austria these are allowed to operate. Sale of cigarettes over the internet is legal in the Czech Republic. Directly accessible distribution of tobacco products is allowed in Poland and Romania. Hungary applies the highest degree on distribution restriction: tobacco may only be purchased in supervised tobacco stores, vending machines and internet sale are prohibited. Advertising and tobacco industry sponsorship activities are uniformly forbidden in these countries. Yet another important issue of tobacco control is the accessibility and financial support of smoking cessation programs. Austria focuses its efforts on youth smoking prevention, nevertheless cessation programs are also coordinated nationally. The Czech Republic lays great effort on disseminating brief intervention practice among physicians and nurses. Health insurance covers smoking cessation programs, however pharmacotherapies are excluded. The National Health Fund partially covers smoking cessation programs in Poland. Romania has established specialized quit centers whose activities are partially covered by health insurance. In Hungary, the Methodological Centre coordinates cessation activity in nearly one hundred pulmonary outpatient clinics around the country, offering individual and group cessation counseling. Counseling is covered by health insurance, excluding pharmacotherapy. In addition, telephone counseling and cessation support is also available free of charge. Regarding e-cigarettes, diverse regulatory schemes are detected across Europe. In Hungary, the distribution of nicotine containing e-cigarette cartridges fall under the drugs act, whereas the same regulation applies to the use as to regular cigarettes. The latter is observed also in Poland. Promotion and distribution of e-cigarettes is prohibited in Austria. In the Czech Republic however, both advertising and distribution is analogues to that of regular cigarettes. The Association of European Cancer Leagues (ECL) assesses European countries’ efforts in tobacco control every three years using the Tobacco Control Scale (TCS). The TCS quantifies the implementation of tobacco control policies based on six strategies described by the World Bank: price increases, public information campaigns, bans on advertising and promotion, smoke free work and other public places, health warnings and treatment to help smokers stop. It is informative to observe the 2013 ranking of the discussed countries: the Czech Republic had a continuously deteriorating position and ranked 31[st], while Austria earned the 34[th], Poland the 20[th] and Romania the 19[th] position among the 34 surveyed countries. Hungary has significantly improved its position between 2010 and 2013, and due to fierce government measures in recent years it ranked 11[th] as compared to the previous 27[th] spot. References: 1. World Health Organization Framework Convention on Tobacco Control Implementation Database. 2. Ng, M., et al.: Smoking Prevalence and Cigarette Consumption in 187 Countries, 1980-2012. JAMA. 2014;311(2):183-192. doi:10.1001/jama.2013.284692

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Tobacco Control: The Turkish Experience Turkey has been a tobacco producing country since Ottoman time. At that time tobacco production mostly was in the hands of foreign companies. Following the establishment of Turkish Republic in 1923, the State Monopoly on tobacco was established and tobacco production and sales was nationalized by the government, therefore production and sales of tobacco was planned and implemented by the State Monopoly (TEKEL). Only domestic tobacco products were on sale in the country, and importation and sales of foreign tobacco products was not allowed. TEKEL provided tobacco products for the smokers, but did not make any effort to increase its use; i.e. did not make any advertisement of tobacco. The tobacco monopoly has been the only responsible body on tobacco production and sales, until 1980’s. In 1984 the law passed at the Parliament allowing importation of foreign cigarettes into the country, and then tobacco advertisements started. In 1987 Minister of Health invited some interested scientists to discuss the way to control tobacco use in the country. The first tobacco control law was drafted by the Ministry and adopted at the Parliament in 1991; but vetoed by the President. Same year another law passed from the Parliament to allow multinational tobacco companies to establish tobacco production factories in the country. As the result of these changes, tobacco use started to increase, more than the population increase (Table 1) [(][1][)]. The first large-scale survey in 1988 [(2][)] on tobacco use revealed that 63% of males and 24% of females smoke. Table 1. Cigarette sales, Turkey, 1925 - 2011 As reaction to these developments, a civil society organization was established in 1993; “National Coalition on Tobacco or Health, SSUK”. By this way an organized fight against the multinational tobacco companies started. In 1995 a large scale survey on tobacco use among role model groups revealed that 43% of physicians, almost 50% of teachers, 27% of members of the Parliament and 24% of religious leaders were smoking [(3][)]. At the same time, draft tobacco control law was in the agenda of the Parliament. SSUK worked closely with some of the “sensitive” MP’s, participated in the Parliamentary Commissions to discuss the draft tobacco control law, and visited Head of the Parliament, Parliamentary Groups of the political parties. At the end of these efforts, Tobacco Control Law was adopted by the Parliament in November 1996. The Law banned smoking at some of the indoor public places, i.e. heath and education facilities and public transport, banned all kinds of advertisement and promotion of tobacco products, banned selling of tobacco products to children, etc. After more than 10 years of implementation, the Law was amended in 2008, to cover all indoor public places, including restaurants, cafes and tea houses etc. as smoke-free. In the meantime, the WHO, FCTC was adopted and MPOWER policies were announced. At that time National Tobacco control Program and Action Plan was prepared; and several studies were performed to demonstrate the results of smoke-free implementation. Three kinds of studies were done [(4)]: · Indoor air quality measurements: PM2.5 levels at various indoor public places were measured before and after the implementation of smoke-free law, (in offices, shops, restaurants, etc.) and considerable decrease were observed (Figure 1). · Complaints of the workers at hospitality workplaces: Some symptoms (watering in eyes, stuffy nose, cough, etc) of the same workers at the restaurants and cafes were inquired before and after the implementation of the smoke-free law at the same places, and good reductions in the presence of symptoms were observed. · Health consequences of passive exposure to tobacco smoke: Admissions due to acute cardiovascular and/or respiratory conditions to the emergency medical services were evaluated before and after the implementation of smoke-free policies, and some reductions were observed, particularly among males. Figure 1. Indoor air quality of some indoor public places before and after the implementation of smoke-free policies In conclusion, implementation of comprehensive tobacco control measures help to improve indoor air quality; reduces the health complaints of the workers at hospitality workplaces and reduces the emergency admissions due to acute cardiovascular and respiratory conditions. Also smoking prevalence was reduced during the 20 years period between 1993 (before the introduction of first tobacco control law) and 2012 (5 years after the comprehensive tobacco control law). In addition to smoke-free policy, Turkey is implementing more than 80% of tax to tobacco products, bans all kinds of advertisement and promotion of tobacco products and sponsorship by tobacco industry, monitors tobacco use prevalence at 4 years intervals (Global Adult Tobacco Surveys in 2008 and 2012, and was planned in 2016) [(5][)], prohibits selling of tobacco products to children less than 18 years of age and provides free treatment for tobacco dependency. As a result, Turkey was declared as the single country in the world implementing all six MPOWER measures with great success, and was awarded by WHO. Political commitment of the government and active participation of civil society and the academia were the major keys to success [(6)]. References 1. Tobacco and Alcohol Market Regulatory Authority. 2. PIAR. Public Research on Smoking Habits and Campaign against Smoking in Turkey, Ministry of Health, 1988. 3. Bilir N, Güçiz B, Yıldız AN. Smoking Behaviors and Attitudes, Ankara, Hacettepe Public Health Foundation, International Development Research Centre, Ankara, 1997. 4. Expansion of Smoke-free Public Places and Workplaces, Evaluation of Impact of Tobacco Control Policies, Turkey; Project conducted by Society of Public Health Specialists, in collaboration of Ministry of Health, H. Özcebe, N. Bilir and D. Aslan, Ankara 2011. 5. Global Adult Tobacco Survey, Turkey Report, Ministry of Health, 2012. 6. Bilir, N, Özcebe H, Ergüder T and Mauer-Stender K., Tobacco Control in Turkey; Story of Commitment and Leadership, WHO Euro, 2012.

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Background Although Japan ratified the FCTC in 2004, progress in tobacco control is still limited. In the WHO report on the global tobacco epidemic, 2015,[1)] Japan was scored “No or weak policy” for smoke-free policies, mass media and advertising bans, “Minimal policy” for health warnings, and “Moderate policy” for cessation program and taxation. In order to accelerate tobacco control activities, evidence-based official summary report on health effects of tobacco products and effectiveness of tobacco control is needed.　A report of Surgeon General in the US[ 2)] and Monograph series from International Agency for Research on Cancer [3)] are the examples. In these reports, causal relationship was judged systematically considering scientific evidences through systematic review comprehensively based on certain criteria. A causal conclusion conveys the inference that changing a given factor will actually reduce a population’s burden of disease, either by reducing the overall number of cases or by making disease occur later than it would have. So far in Japan, although such official summary reports were published three times, judgement on the causal relationship was not included. Here we report the 4th version of the report which contain judgement on the causal relationship between smoking and various diseases.[4)] Methods Health effect of active and passive cigarette smoking was categorized into 4 levels (sufficient/suggestive causal relation, insufficient evidence and suggestive no causal relation). Causal relationship was judged comprehensively in terms of consistency, strength, time-relation, biological plausibility, dose-response relation and risk reduction after cessation, which are similar to US Surgeon General Report.[5) ]It was judged by each corresponding writer of the disease first, then discussed in the committee and determined by consensus. Effectiveness of tobacco control activities and economic impact was also evaluated. Results Based on the previous evidence reports (domestic and international), health effects of active cigarette smoking were evaluated for cancer, cardiovascular diseases, respiratory diseases, reproductive effects, and other effects, such as diabetes and dental diseases. Health effects of passive smoking and adolescence use was also evaluated. It is judged that the evidence is sufficient to infer a causal relationship with active smoking (Level 1) for cancer of the lung, oral cavity/pharynx, larynx, nasal cavity, esophagus, stomach, liver, pancreas, bladder and cervix uteri. For cardiovascular diseases, ischemic heart disease, stroke, abdominal dissecting aneurysm and peripheral arteriosclerosis, and for respiratory diseases, chronic obstructive pulmonary diseases (COPD), decline of pulmonary function and deaths due to tuberculosis are judged as Level 1. Active smoking of pregnant women is judged as causally related to preterm delivery, low birth weight, fetus growth retardation and sudden infant deaths syndrome (SIDS). For other diseases, type 2 diabetes mellitus, periodontitis and nicotine dependency are judged as Level 1. For passive smoking, it is judged to be sufficiently causally related (level 1) for lung cancer and ischemic heart disease and stroke in adulthood. Odor annoyance and nasal irritation as acute effect for respiratory system, and asthma and sudden infant death syndrome (SIDS) for children are judged as level 1. For smoking in adolescence, deaths due to all cause deaths, cancer and circulatory disease and increased risk of cancer incidence are judged as level 1. Tobacco control activities were summarized according to the MPOWER. Although prevalence of current smokers has decreased (32.2% for males and 8.5% for females in 2014), pace of decrease slowed recently.

Although the Health Promotion Act (2003) and revision of the Industrial Safety and Health Act (2015), which mandates company to protect workers from passive smoking with best efforts, have made some progress to promote smoke-free environment, especially in schools, hospitals and governmental offices, problems still remain in other places, such as restaurants and bars. Cessation support in the community and workplace, cessation support using OTC cessation medicines at pharmacy and cessation treatment using health insurance are the 3 pillow conducted in Japan. Warning labels on tobacco packages in Japan uses only characters and too many words, which results in few impact on smokers. Almost no mass media campaign has been conduct to provide information to the public. Regulation to tobacco industry mostly relies on voluntary basis and their CSR activities have been conducted with no regulation. Although after recent tax increases, tax rate became almost in the middle among developed countries and tobacco consumption decreased, tobacco price is still low (Fig 1).[6-8)] It is summarized that activities were weak for smoke-free policies, mass media advertising bans and health warnings in Japan. Regarding smoke-free policy, Tokyo Olympic/Paralympic 2020 will be the best occasion to further promote the policy at national level. Conclusion Evidence-based summary reports should be effectively used in order to accelerate tobacco control activities in Japan. References 1) WHO Tobacco Free Initiative （TFI）. 2015. 'Tobacco control country profiles', Accessed 2016/01/31. http://www. who. int/tobacco/surveillance/policy/country_profile/en/ 2) The Health Consequences of Smoking - 50 Years of Progress A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Coordinating Center for Health Promotion, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014. 3) IARC. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol 100E, Personal Habits and Indoor Combustions. Lyon, France: International Agency for Research on Cancer; 2012 4) Committee on the health effect of smoking. Smoking and Health – report from the committee on the health effect of smoking, 2016. 5) The Health Consequences of Smoking: A Report of the Surgeon General. In: Service USPH, ed. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2004. 6) Ministry of Finance. Tax and stamp revenue settlement amount investigation. List of statistical tables. 7) Ministry of Internal Affairs and Communications. White paper for local finance. 8) Tobacco Institute of Japan. Statistical data on cigarette. Time trend table for sales performance by fiscal year. Fig 1. Trends of tax income, tobacco consumption and smoking rate in Japan.[6-8)] Figure 1

Abstract:
Introduction Smoking is the single most important cancer risk factor and accounts for 26% of all cancer deaths and 84% of lung cancer deaths in Latin America[1]. Lung cancer is one of the most preventable cancer types; and doctors of all expertise are essential to impart to patients and their families the idea of smoking prevention, thereby contributing to the reduction of mortality from lung cancer. There are around 145 million smokers age 15 years or older in Latin American. Adult smoking prevalence varies from 35% in Chile and 30% in Bolivia to 11% in Panama and 11∙7% in El Salvador[2, 3]. The continuing popularity of smoking among adolescents is particularly worrisome as smoking rates among teens and young adults predict future lung cancer rates. Smoking rates among young people aged 13–15 years are now higher than in adults in many Latin American countries. Prevalence among female adolescents has surpassed their male counterparts in Argentina, Brazil, Chile, Mexico, and Uruguay. Unless these high rates of smoking are curtailed, cancer mortality rates will continue to rise[3]. We have assessed the impact on smoking rates of anti-tobacco policies adopted by five Latin American countries, in compliance to the WHO’s Framework Convention on Tobacco Control (FCTC). Argentina, Brazil, Mexico, Peru, and Uruguay were used as case studies to illustrate the challenges and ways in which governments and civil society organizations can effectively work together to reduce lung cancer deaths and other tobacco-related diseases. Since the endeavor for approving anti-tobacco policies was met with a strong lobby against it in these countries, different degrees of compliance with the FCTC terms were reached. We analyzed reports issued by local governments and epidemiologic surveys found in the literature. Tobacco farming in Latin-America has increased in recent years, representing almost 16% of the global production. Argentina and Brazil are among the ten largest world producers and the cultivated area in Latin America reaches 13.55% of the global land dedicated to tobacco farming worldwide. The prices paid by the tobacco industry to farmers are also increasing since 2007, and the sector employs 650,000 people. Tobacco farming is also present in Colombia, Dominican Republic, Honduras, Ecuador, Guatemala, Mexico, Nicaragua and Paraguay[4]. Therefore, tobacco control policies must necessarily include solutions to help tobacco growers to escape from the influence of the tobacco industry without loss of income and jobs. Results We have found a differential decrease (and increase) in smoking among the population of the studied countries in the last decades: Argentina: (from 29% in 2007 to 22.1% in 2014); Brazil (from 34.8% in 1989 to 14.7% in 2013); Mexico (21.7% in 2008-2011 to 23.6% in 2014); Peru (from 44.5% in 1998 to 21.1% in 2010 and 13.3% in 2013); Uruguay (from 34% in 1998 to 23.5% in 2011)[5 – 11]. Discussion According to the 2014 FCTC Progress Report[12], the implementation degree of the articles among the countries varied from <20% to more than >75% in most cases. One-third of all FCTC signing countries have not enacted anti-tobacco legislation or reached the full implementation of at least two important time-bound articles: tobacco advertising ban and health warnings on cigarette packages and at the selling points. Our data also showed uneven degrees of implementation among the studied countries. One of the underlying causes for slow implementation in some countries, like Mexico and Argentina, is the strong political lobby by the tobacco industry. In our study, Argentina has come in third in smoking prevalence, with a 22.1% smoking rate among adults, due to the strong pressure upon legislators by the tobacco industry that so far has prevented the FCTC ratification by the Congress. Nevertheless, the Argentinean political environment was more sensitive than the Mexican, to the persistent anti-smoking advocacy by the medical associations and organizations of the civil society. Therefore, some of the FCTC tobacco control policies were enacted by legislators in 2011 and implemented in 2013. Mexico, however, was the one with the poorest implementation of tobacco control policies and the highest in smoking prevalence among adults (23,60%), seconded by Uruguay (23.5%), where the past administration has neither enforced the already existing tobacco-control policies, nor promoted new ones, such as heavy taxes upon tobacco products. One of the important measures recommended by the FCTC - which has proved to be effective in smoking prevention among children and teenagers - is high taxation (over 75%) of tobacco products[12]. Conclusion The degree of compliance with the terms of the Convention seems to have a direct impact on the reduction of smoking rates in the countries studied. Other solutions should contemplate tobacco farmers, whose fear of shifting to new unfamiliar cultures is exploited by the tobacco industry to prevent FCTC ratification in many countries. But farmers should not stop growing tobacco plants, but just shift to transgenic tobacco farming[13]. Transgenic tobacco is being successfully tested for expression of for more than fifteen human therapeutic proteins, including antibodies, antigens for vaccines, and autoimmune inhibitor factors. [(14-17)]. Pharmaceutical companies could benefit from the existing agricultural tradition of tobacco farming in Brazil, Argentina, and elsewhere by fostering the commercial production of those molecules. Transgenic tobacco is improper for smoking and could also have the nicotine gene knocked out to discourage misuse. Therefore, the pharma industry could open new roads to smoking eradication while preserving the economic activity and profitability of traditional tobacco farmers. Effective tobacco control requires a close cooperation between health institutions, medical societies, NGOs, and the press - and the regular funding of surveillance programs and educational campaigns. Smoking prevention programs must be part of the educational curricula from the pre-school onwards.

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Introduction: Malignant pleural mesothelioma (MPM) is difficult to diagnose and accurate prediction of patient outcomes still relies on a range of clinical scores. Despite extensive efforts in the last decade, there are few tumour-based molecular markers that can accurately contribute to diagnosis and prediction of disease course. Recent reports describing the mutational and transcriptional landscape of MPM tumours have revealed a number of changes that may yield clinically useful biomarkers following further development and validation studies. Diagnosis: The definitive MPM diagnosis relies on a tissue biopsy and demonstration of invasion. Diagnostic markers consist of a combination the expression of mesothelial-specific proteins and absence of markers of adenocarcinoma. Recent advances have shown that the mutation of the tumour suppressor BAP1 leads to loss of nuclear staining, and that this is highly specific for discriminating mesothelioma from benign conditions. As in some cases MPM has neither BAP1 mutation nor loss of nuclear staining, sensitivity is lacking, but this can be improved by incorporating detection of CDKN2A genomic loss using FISH. Assessment of additional mutations and fusion genes recently identified in MPM may represent useful markers for future development. Characteristic changes in microRNA expression are present in MPM, and these form the basis of a highly accurate molecular test for the differential diagnosis of MPM from other tumours affecting the pleura. Prognosis: Clinical and pathological parameters remain the best predictors of disease outcome, and although some molecular markers have demonstrated prognostic significance, these are yet to be validated. Histopathological subtype is an accurate prognostic indicator, with the epithelioid subtype associated with significantly better outcomes than the non-epithelioid biphasic and sarcomatoid types. The variation within epithelioid tumours is well recognised, and epithelioid tumours with a pleomorphic morphology have poor prognosis, similar to patients with non-epithelioid tumours. Recent results from transcriptomic analyses have revealed subsets within epithelioid and non-epithelioid tumours which more accurately describe prognosis. These include the two-cluster C1/C2 classification system based on a 3 gene predictor, and the 4 clusters (sarcomatoid, epithelioid, biphasic-epithelioid and biphasic-sarcomatoid) derived from RNA-seq analysis. MicroRNA expression has also been linked to outcome. Early studies revealed prognostic significance of miR-29c-3p, with higher levels corresponding to longer survival. More recently, microRNA expression profiles differing between long and short survivors yielded a 6-microRNA score that predicted outcome in two surgical series. Whether TCGA data confirm these observations remains to be determined. In addition to RNA and protein biomarkers, the cellular composition of tumours influences patient outcomes. It is likely that the mix of cell types within tumour samples also contributes to biomarker expression, especially for RNA extracted from whole tumours. For some proteins, differential expression in the stromal and tumour compartments is of prognostic value, for example in the case of SPARC expression. The importance of the immune cell infiltrate was recently investigated in a large number of epithelioid samples revealing that greater numbers of tumour-infiltrating CD4+ and CD8+ T lymphocytes (TILs), as well as fewer tumour-associated macrophages (TAMs) of the M2-type correlate with survival. In addition, the ratio of the TAMs/TILs was also shown to predict outcome in epithelioid MPM. Other cell populations associated with vascular and lymphatic invasion are also linked to survival. Prediction: Unlike lung cancer, few actionable mutations are present in MPM that predict sensitivity to targeted agents, and clinical trials with these drugs have yielded disappointing results. Markers for single agent chemotherapy and the standard cisplatin/pemetrexed doublet have also been investigated in retrospective studies attempting to link patient outcomes with gene (mRNA and protein) expression and polymorphisms. Multiple reports have linked levels of TS protein, but not mRNA, to outcomes with pemetrexed-based chemotherapy. As expected from a multi-targeted agent, other levels of other proteins such as folypoly-glutamate synthase (FGPS) and the reuced folate carrier (RFC) were also associated with tumour response and patient outcomes. However, a subsequent study with a similar number of patients suggested that both TS and FPGS lack predictive value. With respect to DNA repair genes involved in cisplatin activity, ERCC1 and others have been evaluated, but results are again inconclusive. The picture is complicated by assessment of target genes in patients treated with two interacting agents (with or without subsequent surgery), and the true value of these genes awaits carefully controlled prospective analyses. The recent breakthrough success of immune checkpoint inhibiting antibodies targeting CTLA4 and the PD-1/PD-L1 axis in melanoma and lung cancer has seen these agents applied to MPM patients. With response rates of around 25% for PD-1 targeting antibodies pembrolizumab and nivolumab in MPM, new predictive markers are needed to improve patient selection and for health economics reasons. Although the Keynote trial included patients based on positivity of PD-L1 staining, PD-L1 status appears to have little value in predicting response rate. Ongoing research into immune cell involvement may shed more light on this. Future directions: Continuing research in this area should learn from limitations of the biomarker studies of the last decades to improve the search for useful molecular markers. Large prospective trials are needed to carefully evaluate predictive markers. Alternative approaches such as the analysis of live cell populations taken from fine-needle aspirates and investigation of circulating tumour cells and tumour-derived markers in the circulation (DNA, exosomes) may yield novel markers. Conclusions: Extensive research into tumour-based markers for MPM is gradually making progress. New markers to assist in diagnosis and prognosis have been identified, but the selection of accurate predictive markers has so far remained elusive. Next-generation sequencing has identified multiple new candidate markers requiring further investigation, and may provide breakthroughs in the future.

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Over the last 3 decades clinical researchers have focused on the optimal treatment of patients with mesothelioma (MPM). In the 80’s surgery had become a standard approach in some centers but it became clear that a complete resection (R0) was not achievable. The anatomical location of the mesothelioma simply does not allow a resection with save margins of normal tissue. Therefore additional therapies were looked for and a different number of approaches have been taken. To answer the question if any systemic induction therapy is considered the best, this can be answered with a clear No. reasons for this is the lack of randomized studies in this patient population and the fact that patients with MPM are grouped together despite differences in pathology, surgical approach (EPP vs Pleurectomy decortication) and biological behavior. There has been a number of preferential approaches with chemotherapy in this disease ranging from Induction chemotherapy; Intracavitary therapy and Adjuvant chemotherapy. (table) In the case of induction therapy it is clear that one aims at reducing the tumor bulk and to prevent metastases during surgery. The preferred treatment is cisplatin with pemetrexed since this is considered to be the standard of this disease.(1) Other regimens have been tested in small extend but usually involved. The use of intra-cavitary treatment has attracted attention since MPM cells show the tendency to stay localized in the thoracic cavity for a relative long period. The administration of a local cytotoxic drug would allow an improvement in local control and limited systemic effects. Cisplatin has been used frequently during surgery and were combined with heating of the lavage fluid to 40[0]Celsius. (2) Special precautions for this so-called Hyperthermic lavage approach have to be taken in the operating suite with protection of the staff to avoid exposure to the drugs. In general the lavage procedure adds another hour to the debulking surgery. Measurements of platin adducts in the blood during this procedure have shown that there is no important systemic levels measured. Unfortunately there has not been any comparison of these approaches. Most series only report the feasibility of the treatment with sometimes impressive survival figures. These are partly due to the strong selection of patients for the studies. A relative new approach is the use of a platin containing fibrin glue that can be applied to the thoracic wall after debulking using a spray system. The initial results indicate that the treatment is fast and serial biopsies show that the effect is sustained for many weeks.(3) Finally, adjuvant therapies can be applied. In this field, there are no data to support any specific treatment and the choices are generally defined based on the study protocol. No prospective trials have been reported Most of the studies are trimodality therapies where RT is an important part of the protocol. One typical example is the EORTC study where the feasibility of trimodality therapy in a phase II trial (EORTC 08031) with clearly defined timelines was tested(5). Patients with pathologically proven mesothelioma received induction chemotherapy (3 courses cisplatin and pemetrexed ) followed by EPP within 21–56 days after the last dose of chemotherapy in the absence of progressive disease and unacceptable toxicity. A ‘‘success of treatment’’ was defined as a patient who had received the full protocol and was alive after 90 days without progressive disease and without grade 3 or 4 toxicity. Of the 57 patients included, 42 had EPP (73.7%) after induction therapy. The 90-day mortality was 6.5% with an overall survival time of 18.4 months and progression-free median survival time of 13.9 months. Only 24 (42.1%) patients met the definition of success, thereby failing the primary endpoint. This study shown how difficult it is to complete a trimodality study in this patient group and only when a standard is defined, proper comparative studies can be performed. Other important studies addressing the neo-adjuvant approach are presented in the table. 1.Baas P, Fennel D, Kerr K, van Schil PE. Malignant Pleural Mesothelioma: Guidelines for Diagnosis, treatment and follow-up. Annals Oncology 2015 2.Sugarbaker DJ, Gill RR, Yeap BY, Wolf AS, DaSilva MC, Baldini EH, Bueno R, Richards WG. Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural Mesothelioma undergoing surgical macroscopic complete resection. J Thorac Cardiovasc Surg. 2013 Apr;145(4):955-63. 3.Opitz I. Use of fibrin glue in malignan pleural mesothelioma, presented at the xxth IMIG conference Birmingham UK 4.Van Schil P, Baas P, Gafaar R, Maat AP, van der Pol M, Hassan B et al. Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial. 5.Weder W, Stahel RA, Bernhard J, Bodis S, Vogt P, Ballabeni P, et al. Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. Ann Oncol 2007;18:1196-202 6.Cao C, Tian D, Manganas C, Matthews P, Yan TD. Systematic review of trimodality therapy for patients with malignant pleural mesothelioma. Ann Cardiothor Surg 2012;1:428-37 Table

Study	type	# pts	drugs	Completed Chemotherapy	Completed Surgery	Completed Radiotherapy	Outcome (mOS)
SAKK 17/04 Lancet Onc 2015;16;1651	Neo-adj	151	Cis/pem	145	125	23/27 in 2nd stage	7.6-9.4
Frederico BMC Cancer 2013;13;22	Neo-adj	54	Cis/pem	96%	83%	41%	15.5
Krug JCO 2009;27;3007	Neo-adj	77	Cis/pem	83%	74%	52%	16.8
Weder JCO 2004;22;3451	Neo-adj	20	Cis/gem	90%	80%	n.a.	23
Van Schil ERJ 2010;36;1362	Neo-adjuvant	59	Cis/pem	93%	79%	65%	18.4
Richards JCO 2006;24;1561	intracavitary	61	Cispl 50-225	n.a.	72%	n.a.	9.0
Tilleman JTCS 2009;138;405	intracavitary	121	Cispl 225	n.a	79%	n.a.	12.8

Abstract:
To date, the treatment of malignant pleural mesothelioma (MPM), a rare and aggressive tumor usually induced by previous asbestos exposure, relies mostly on chemotherapy and best supportive care (BSC). But medical treatment has been so far quite deceptive with median overall survival (mOS) about one year at its best for the last 13 years with recommended first line chemotherapy by cisplatin (or carboplatin) and pemetrexed in patients fitted for it. The optimal duration of first line chemotherapy is unknown but a maximum of 6 cycles is recommended. There was no evidence supporting maintenance treatment by pemetrexed or other drug. Pathogenesis of MPM includes overexpression of growth factors, many genetic and epigenetic alterations and/or mutations of malignant cells responsible for cell proliferation and resistance to apoptosis, pleural inflammation and local immunosuppression induced by the tumor and favoring its growth. These elements provide the rationale for many targeted therapies and immunotherapy. But so far, very few drugs exhibited sufficient value to deserve further trials. Thus, first trials assessing anti-angiogenic drugs in MPM did not support their use in this cancer despite the key role of VEGF. A phase III testing thalidomide as maintenance treatment after cisplatin/pemetrexed (Cis/Pem) was negative, as well as phase II trial of bevacizumab (anti-VEGF antibodies) combined with first line cisplatin/gemcitabine. But other phase II trials evaluating bevacizumab with Cis or Carbo/Pem were promising with progression-free survival (PFS) of 6.9 months. Therefore, a phase III randomized (1:1) « MAPS » trial recruited 448 unresectable MPM patients to test Cis/Pem with (arm B) or without (arm A) bevacizumab. Arm B non-progressive patients received bevacizumab maintenance until progression or toxicity. Median overall survival (mOS) was significantly longer in the B arm: 18.8 [95%CI: 15.9-22.6] vs. 16.1 months [14.0-17.9] in the A arm, (adj.HR= 0.76, p=0.012). Thus, bevacizumab addition to Cis/Pem provided a significantly longer survival in MPM patients with acceptable toxicity, making this triplet a new treatment paradigm for this cancer. Moreover, there was no detrimental effect of bevacizumab on quality of life (QoL) despite its higher specific but manageable toxicity. There was no significant difference between arms for the percentages of drug delivery or of second line treatment to explain why adding bevacizumab to Cis/Pem significantly increased mOS, even if MAPS standard arm patients had a longer OS than patients from historical series or previous trials. Based on the same rationale than the MAPS trial, nintedanib, a drug targeting VEGF, FGF and PDGF receptors, is currently tested versus placebo in MPM patients treated by first line Cis/Pem chemotherapy in a large phase II/III randomized trial. Early I or II trials assessing drugs targeting mesothelin, a mesothelial cell surface molecule overexpressed in (mostly epithelioïd) MPM, showed promising results in combination with first-line Cis/Pem, justifying further, randomised and larger studies. Thus, very interesting trials are ongoing with anti-mesothelin monoclonal antibodies (mAbs) alone (amatuximab, a chimeric IgG1 antibody), or planned with immunotoxins (mAbs combined with anti-tubulin (anetumab ravsantine) or Listeria toxins (CRS-207) versus placebo combined with Cis/Pem too. For non-epithelioïd MPM patients, another hope might come from the dependence to arginin exhibited by argininosuccinate synthetase -1 (ASS-1) tumors such as mesothelioma, and the good results of Pegylated Arginine Deiminase (ADI-PEG 20) alone or in combination with Cis/Pem, assessed in the phase I « TRAP » trial recently presented by Szlosarek and al. A phase II/III trial (Polaris), comparing first line Cis/Pem with ADI-PEG 20 or placebo, will start in 2017 for biphasic (mixed) or sarcomatoïd MPM only because they exhibit ASS-1 defect twice more frequently than epithelioïd subtype. Finally, other innovative drugs also candidates for first line treatment in combination with Cis/Pem, after preliminary positive clinical trials, include gene therapy, cell therapy using chimeric antigen receptors (CARs) or dendritic cells (DC), or oncovirotherapy, and will be assessed as first line treatment in MPM very soon or later. For example, the European “DENIM” phase III trial will test DC based immunotherapy with allogenic tumor cell lysate as maintenance treatment after Cis/Pem chemotherapy in MPM patients. But, as in lung cancers, immune checkpoint inhibitors (ICI) seem to represent presently the most exciting tool for MPM patients. In fact, even if a recent, large phase II trial (n=564; “Determine”) with anti-CTLA-4 mAb (tremelimumab) versus placebo in 2[nd]/3[rd] line treatment did not meet its first endpoint (mOS) (21), early data of a phase Ib basket trial with anti-PD-1 mAb (pembrolizumab) showed promising response rate (RR) of 28% and DCR of 76% in PD-L1 positive MPM (22). Other trials with checkpoint inhibitors are ongoing with anti-PD-1 alone (nivolumab, pembrolizumab), or a combination of anti-PD-1 (nivolumab) or anti-PD-L1 (durvalumab) and anti-CTLA-4 (tremelimumab or ipilimumab) as first or 2[nd]/3[rd] lines treatment. Interestingly, new clinical trials are already underway to assess value of ICI, such as nivolumab + ipilimumab combo, versus Cis/Pem as first line treatment. In conclusion, the triplet cisplatin/pemetrexed/bevacizumab may be a new first line standard of care for patients eligible for bevacizumab, and not candidate to multimodal treatment trials. Second line and further lines treatments are very limited with no validated options except pemetrexed in case of late relapse after platinum/pemetrexed. But exciting drugs and strategies were tested in this testing, in particular ICI. But remaining key questions include which predictive biomarkers for these innovative, thrilling but expensive treatments to target the best patients for each drug? And how to potentially combine these drugs versus, or in combination with, standard chemotherapy? Thus real hopes seem closer for our MPM patients with new systemic treatments.

Abstract:
Individuals that are born with germline BAP1 mutations are affected by the BAP1 cancer syndrome. All individuals affected by this cancer syndrome have developed one or more malignancies in the course of their life. Mesothelioma, uveal and cutaneous melanomas –tumors often associated with exposure to environmental carcinogens-, are the most common malignancies, although almost any tumor type has been detected in carriers of this cancer syndrome. In addition, BAP1 mutant carriers develop multiple benign melanocytic tumors –histologically different from other SPITZ-like tumors- that we have called melanocytic BAP1 associated intradermal tumors (MBAITs) that can alert the physician that the patients is a carrier of the BAP1 cancer syndrome. Most malignancies develop after the 4[th] decade of life, although cancers in individuals as young as 19 years old have been detected. Because many of these malignancies, for example melanomas, can be cured by early detection, it is important to identify BAP1 mutant carriers that can be screened for early detection and curative resection. Moreover, carriers of germline BAP1 mutation may be at increased risk of developing mesothelioma and melanoma following exposure to low doses of asbestos, sunlight and X-Rays, thus cancer preventive measures can be implemented. When cancer develops in a setting of BAP1 germline mutations, these patients have a much better prognosis compared to patients with the same malignancies when they occur sporadically (i.e., not in carriers of BAP1 mutations). Familial mesotheliomas in these individuals occur in either the pleura or peritoneum (frequency ratio 1:1) at a median age of 56.3 years, have a male-to-female ratio of 0.73:1, and are associated with prolonged survival of 5 to 10 or more years, compared with a median age at diagnosis of 72, a pleural-to-peritoneal ratio of 86:14, a male-to-female ratio of 4:1, and a median survival of less than 1 year in sporadic mesothelioma. About 100 families with this mutated BAP1 cancer syndrome have been described in the United States, Europe, and New Zealand. Genetic studies demonstrated that these mutations are transmitted across multiple generations over the course of several centuries, and some US families carrying BAP1 mutations descend from a Swiss family that immigrated in the US in the early 1700s. An International Consensus Meeting sponsored by the IASLC supported medical screening for at-risk people who are carriers of BAP1 germline mutations as follows: (1) annual dermatological screening for early detection of melanoma at age 18 or younger; (2) annual eye examination/ophthalmoscopy for uveal melanoma at age 18 or younger; and (3) skin and eye examinations every 6 months after age of 30, when the frequency of cancer among carriers of germline BAP1 mutations starts to increase. It was also recommended that genetic counseling should be offered to all individuals tested for BAP1. Moreover, those with BAP1 germline mutations should be ncouraged to participate in studies to improve early detection of mesothelioma (Carbone M. et al., Journal of Thoracic Oncology 11, 1246-1262, 2016).

Background:
Thymic Epithelial Tumors (TET) are rare intrathoracic malignancies, for which surgery represents the mainstay of the treatment strategy. Current practice for postoperative mediastinal radiotherapy is highly variable, and there is paucity of prospective, multicentre evidence. RYTHMIC is the nationwide network for TET in France, established in 2012. Whether postoperative radiotherapy (PORT) should be delivered was the most frequent question raised at the RYTHMIC multi-disciplinary tumor board (MTB) over the past 3 years, accounting for 494 (35%) of a total of 1401 questions.

Methods:
All consecutive patients for whom postoperative adjuvant radiotherapy was discussed at the RYTHMIC MTB from 2012 to 2015 were identified from the RYTHMIC prospective database.

Results:
285 patients were identified, 274 (52% men, 48% women) of whom fulfilled inclusion criteria. Average age at time of TET diagnostic was 60 years. TET histology was thymoma in 243 (89%) cases - including type A in 11% of cases, type AB in 28%, type B1 in 17%, type B2 in 29%, and type B3 in 14% -, and thymic carcinoma in 31 (11%) of cases. Complete resection was achieved in 81% of patients. Masaoka-Koga stage was stage I in 29% of cases, IIA in 21%, IIB in 21%, III in 18%, and IVA/B in 11%. Decision of the MTB was consistent with guidelines in 221 (92%) assessable cases. Clinical situations for which PORT was indicated in accordance with guidelines (84 cases) were thymoma/R1 resection (30 patients), thymoma/R0 resection/stage III (22 patients), thymoma/R0 resection/stage IIB/type B2/B3 histology (11 patients), thymic carcinoma/R1 resection (6 patients), thymic carcinoma/R0 resection (13 patients), thymoma/R0 resection/stage IIA/type B3 histology (2 patients). Inconsistencies between decision of the MTB and guidelines – 20 (8%) cases - consisted of abstention related to poor general condition (10 patients), carcinoid histology (2 patients), and discordance in staging (1 patient), and of delivery of radiotherapy related to peroperative tumor fragmentation (2 patients); for 5 patients who received PORT, a clear explanation for inconsistency with guidelines was not found, but those cases actually corresponded to those in a “grey zone” of guidelines. MTB decision for PORT was actually implemented for 99 (85%) of patients; most frequent reason for not delivering radiotherapy was prolonged delay since surgery.

Conclusion:
Our data provide with a unique insight into the decision-making process for PORT in thymic epithelial tumors, highlighting the need for a systematic discussion at an expert MTB, while stressing the value of current available guidelines.

Background:
Sunitinib is active in patients with recurrent thymic carcinoma (TC). We have previously reported an objective response rate of 26% and disease control rate (partial response and stable disease) of 91% in patients with TC when sunitinib is administered at a dose of 50 mg once daily for 4 weeks followed by 2 weeks off (4/2 dosing schedule). Grade 3 or 4 treatment-related adverse events (TEAEs) occurring in more than 10% of patients included fatigue, oral mucositis and lymphocytopenia (20% each), and hypertension (13%). Grade 3 decrease in left ventricular ejection fraction (LVEF) was observed in 8% of patients. Alternative dosing schedules have been evaluated in solid tumors to improve tolerability. As part of an ongoing phase II study (NCT01621568), we evaluated the clinical activity and tolerability of sunitinib in patients with TC using a 2-weeks-on/1-week-off (2/1) dosing regimen.

Methods:
Patients with progressive TC after at least one prior platinum-containing chemotherapy regimen, measurable disease, and adequate end organ function were enrolled and received sunitinib at a dose of 50 mg orally once daily using a 2/1 schedule until disease progression or development of intolerable adverse events. The primary objective was evaluation of response rate. Tumor assessments were performed every 6 weeks using RECIST version 1.1 and toxicity was assessed every 3 weeks using CTCAE version 4.0. Exploratory correlative studies including evaluation of immune cell subsets will be reported separately.

Results:
Between July 8, 2014 and January 14, 2016, 15 patients were enrolled. Median age was 62 years (range, 41-76), and 33% were male. A median of 4 (range, 1 – 33+) cycles of sunitinib was administered. Among 13 evaluable patients, there was 1 (8%) partial response, 11 (85%) stable disease and 1 (8%) progressive disease. After a median follow-up of 16 months, the median progression-free survival was 5 months and median overall survival was 16 months. Grade 3 or 4 TEAEs occurring in more than 10% of patients included lymphocytopenia (40%), neutropenia and leucopenia (20% each), thrombocytopenia and oral mucositis (13% each). Grade 3 decrease in LVEF was observed in 1 (7%) patient.

Conclusion:
Sunitinib, administered using a 2/1 dosing schedule, has clinical activity in patients with TC, and the frequency of clinically significant TEAEs (fatigue, mucositis, hypertension) is acceptable. Studies are ongoing to identify novel immunological biomarkers of activity.

Background:
Avelumab (MSB0010718C) is a fully human, IgG1 anti-PD-L1 antibody under clinical development. We report safety and clinical activity in patients with relapsed TETs enrolled in a phase I trial (NCT01772004).

Methods:
Patients previously treated with one or more standard therapies, no prior immune checkpoint inhibitors, and with no history of autoimmune disease were eligible. Treatment consisted of avelumab at doses of 10-20 mg/kg iv q2 weeks until disease progression or toxicity. Responses were assessed q6 weeks by RECIST 1.1. Correlative studies included evaluation of tumor cell PD-L1 expression and peripheral blood immune subset analysis.

Results:
7 patients with thymoma and 1 with thymic carcinoma (TC) were treated with avelumab; 3 patients with thymoma (2 B3, 1 B2/B3) received avelumab 20 mg/kg; 4 patients with thymoma (1 B1, 3 B2) and 1 TC received 10 mg/kg. Two (29%) patients with thymoma had a confirmed partial response (PR;1 at 20 mg/kg, and 1 at 10 mg/kg), 2 (29%) had unconfirmed PRs, 2 (29%) stable disease (SD) and 1 (14%) progressive disease; the TC patient had SD. Most adverse events (AEs) were mild (grade 1 or 2). Grade 3 and 4 AEs were observed in 3 (38%) patients each, and included potential immune-related AEs (irAEs) in 5 cases. irAEs resolved completely with oral steroids in 3 patients, and incompletely in 1 patient. One patient required cyclosporine A for treatment of irAEs. All 4 responders experienced irAEs (myositis in 3 patients, all after 1 dose of avelumab, and enteritis in 1 patient). Pre- and post-treatment tumor biopsies were available for analysis of PD-L1 expression and intratumoral immune infiltrates from three patients treated at 20 mg/kg. In one case the post-treatment biopsy showed necrotic tissue with no viable tumor. In the other two cases diffuse, membranous PD-L1 staining of epithelial cells was seen in both pre- and post-treatment biopsies. The immune infiltrate consisted of immature T cells in pre-treatment tumor samples in both cases. The post-treatment biopsy showed continued presence of immature T cells in one case and a mature CD8+ T cell phenotype in the other case. Decreased CTLA4+ regulatory T cells and decreased ratio of granulocytic vs. monocytic myeloid-derived suppressor cells was seen post-treatment at the 20mg/kg dose.

Conclusion:
Avelumab is active in patients with recurrent thymoma. Strategies need to be developed to reduce the risk of development of irAEs in response to immune checkpoint inhibitor therapy in patients with thymoma.

Abstract not provided

Background:
[18]F-Fluorodeoxy glucose positron emission tomography (FDG- PET) is thought to be useful for predicting the histologic grade in thymic epithelial tumors (TETs). Although there have been many reports on the use of FDG-PET for evaluating TETs, no previous studies have included only resected cases. Therefore, we investigated the relationship between the degree of FDG-uptake in the tumor and either the WHO histologic subtype or the tumor stage in patients with resected TETs.

Methods:
We retrospectively reviewed FDG-PET findings in 112 patients with TETs (92 with thymomas and 20 with thymic carcinomas) resected at 2 institutes in Japan. The Spearman rank correlation coefficient was used to assess the association between the maximum standardized uptake value (SUV max) in the tumor and both the histologic subtype and tumor stage. The cut-off value of SUV max for differentiating thymoma from thymic carcinoma was calculated using a receiver operating characteristic (ROC) curve analysis.

Results:
The Table shows the relationship between SUV max in the tumor and the WHO histologic subtype. SUV max according to each tumor stage was 3.9 ± 1.7 (mean ± SD) in stage I (n = 89), 4.7 ± 1.7 in stage II (n = 3), 7.4 ± 5.3 in stage III (n =11), and 7.6 ± 3.9 in stage IV (n = 9). SUV max was strongly related to both the WHO histologic subtype and tumor stage (Spearman rank correlation coefficient = 0.485 and 0.432; p = 0.000 and 0.000, respectively). The optimal cut-off value of SUV max for differentiating thymoma from thymic carcinoma was 4.6, with a sensitivity of 80% and a　specificity of 70%.

		SUV max
~Histologic subtype~	No. of patients	~Mean ± SD~	Range
A	12	~3.5 ± 1.3~	~1.3 – 6.3~
AB	45	~3.5 ± 1.3~	[1.2 – 6.9]
B1	19	~4.1 ± 0.9~	[2.5 – 6.5]
B2	10	[4.2 ± 1.0]	[2.7 – 5.9]
B3	6	[4.8 ± 2.6]	[2.4 – 8.6]
Thymic carcinoma	20	[8.0 ± 4.7]	[3.0 – 21.8]
Total	112	[4.5 ± 2.8]	[1.2 – 21.8]

Conclusion:
Our results suggest that FDG-PET is useful for differentiating thymoma from thymic carcinoma. Further studies will be needed to assess other potential clinical applications of FDG-PET for the evaluation of TETs.

Background:
The treatment of patients with recurrent thymic tumors remains uncertain due to limited data because of the rare nature of this disease. This retrospective analysis was conducted to investigate clinical characteristics, outcomes and possible prognostic factors of patients presenting with a first recurrence of thymic tumors.

Methods:
107 patients with thymic neoplasms registered as C37 by ICD10 coding at Guy’s Hospital during the 2007-2016 period with first recurrence following primary treatment were selected and retrospectively reviewed via descriptive analysis. Differences in survival were assessed using Kaplan-Meier analysis and uni & multivariate Cox proportional hazards regression analyses.

Results:
25 patients (14 male & 11 female) with a median age of 51 years (range 36-80 years) experienced a first recurrence of thymoma (20 patients – 80%) or thymic carcinoma (5 patients – 20%) with a median time from diagnosis of 36 months (range, 7-270). At diagnosis, modified Masaoka disease stage was IIA/IIB/IIIA/IIIB/IVA/IVB in 4/0/8/2/6/5 patients; 18 patients’ (72%) primary resection was R0/R1/R2 in 11/3/4 patients; 9 patients (36%) received radiotherapy; 19 received chemotherapy (76%); CAP (n=10) and platinum-etoposide (n=6) regimens. At first relapse, 19 patients (76%) had thoracic recurrence and 6 patients (24%) extrathoracic recurrence. Nine patients (26%) underwent redo surgery, 3 of which recieved chemotherapy prior to resection. Overall resection status was 2/5/1 (1 patient’s data is not yet assessable) R0/R1/R2. Chemotherapy was administered in 17 patients (68%) with a median cycle of 4 (range, 1-6): 16 patients received combination chemotherapy consisting of platinum etoposide (n=10) or cisplatin-anthracycline based (CAP/CAV/AC n=5). Dose reduction and withdrawal were reported in 3 (18%) and 7 (41%) patients, respectively. In 4 out of these 7 patients withdrawal was due to PD; disease control rate (=CR+PR+SD) was 67% (in 10 out of 15 assessable patients). Three patients (12%) received radiotherapy of which one was treated exclusively with radiotherapy. Time to progression since the first recurrence was 12 months (range 2-52 months); in 16 patients extrathoracic recurrence was seen in 4 patients (25%) and thoracic in 12 patients (75%). Eight recurring patients (50%) received further chemotherapy. With a median follow-up of 32.5 months, 19 patients (75%) are alive and 2 (8%) disease-free; median OS has not been reached, median PFS was 29.5 months (range, 26.3-33.2). Analysis of possible prognostic factors will be presented.

Conclusion:
Patients with first recurrence of thymic tumors may benefit from combination chemotherapy and surgery when feasible.

Background:
Stage III TET represents a heterogeneous population and their optimal approach remains unclear; most of the available literature is composed of small series spanned over extended periods of time. RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a French nationwide network for TET with the objective of territorial coverage by regional expert centers and systematic discussion of patients management at national tumor board. We reviewed our experience in stage III thymic tumors in order to evaluate the value of tumor board recommendations and multidisciplinary approach.

Methods:
We conducted a retrospective analysis of patients (pts) with stage III TET discussed at the RYTHMIC tumor board from January 2012 to December 2015. Clinical, pathologic and surgical data were prospectively collected in a central database. Survival rates were based on Kaplan-Meier estimation. Cox proportional hazard models were used to evaluate prognostic factors for disease free survival (DFS) and overall survival (OS).

Results:
150 pts were included in the analysis. Median age was 64 years [18 – 91], 56% males, thymoma A-B2/ B3-thymic carcinoma in 52% and 47% respectively; 12% presented with autoimmune disorder (76% myasthenia). Local treatment was surgery in 134 pts (90%) followed by radiotherapy (RT) in 90 pts; 26 pts received preoperative chemotherapy (CT). Complete resection rate (R0) was 53%. Among 38 pts considered non-surgical candidates at diagnosis, 26 pts became resectable after induction CT with a R0 rate of 58%; 12 pts received CT-RT and/or CT as primary treatment. Recurrence rate was 38% (n=57), first sites were pleural (n=32) and lung (n=12). The 5-year OS and DFS were 88% and 32% respectively. Gender (HR: 0.2 [95%CI 0.04 - 0.97] p=0.04), histology (HR: 0.19 [95%CI 0.05 - 0.70] p=0.02) and surgery (HR: 0.4 [95%CI 0.01 - 0.20] p<0.001) as primary treatment modality were significant prognostic factors for OS in multivariate analysis. Histology (HR: 0.5 [95%CI 0.30 - 0.90] p=0.02) and adjuvant RT (HR: 0.4 [95%CI 0.20 – 1.00] p=0.05) were significantly associated with DFS. Completeness of resection was not associated with survival in our cohort.

Conclusion:
Surgery followed by radiotherapy improves outcome irrespectively of R0. Stage III TET not candidate to surgery should be reassessed for resection after induction chemotherapy.

Abstract not provided

Background:
High-throughput gene expression profiling led to proposal of multiple expression-based prognostic signatures for squamous cell lung carcinoma (SCC), but none has been validated. A multi-institutional squamous lung cancer consortium of investigators is developing prognostic signatures through the US NCI Lung SPECS (Strategic Partnership for Evaluation of Cancer Signatures) program. Six institutions contributed tumor specimens and published/unpublished expression-based prognostic signatures for validation using standardized sample cohorts (a primary validation cohort comprising institutional cases, and additional validation cohorts from two prospective cooperative group studies) and quality controlled assessment in independent laboratory and statistical cores. Here, we report the results of the primary validation.

Methods:
Cases of primary SCC (by central pathology review) meeting clinical (Stage I-II; surgical treatment only; 3-year followup) and specimen quality criteria (Tumor cellularity >= 50%; necrosis <= 20%) were submitted. Clinical, pathological and outcome data were uploaded to a central database. Frozen tumor samples underwent centralized mRNA extraction (Qiagen Symphony), quality control (RIN >= 6.0) and microarray profiling (Affymetrix U133) in core labs. An independent statistical core assessed validation of 7 pre-existing mRNA signatures and generated new models using MCP clustering.

Results:
Among 250 cases meeting entry criteria, median age was 70 (43-92), 161 (65%) were male, and most were former (70%) or current (28%) smokers. Surgery was pneumonectomy: 5%; bilobectomy: 2%; lobectomy: 74%; sublobar: 18%. Pathologic staging was T1: 49%; T2: 50%; T3: 1%; N0: 88%; N1: 12%, and grade was G1: 4%; G2: 50%; G3: 44%. At followup, 148 (59%) were deceased. Three mRNA signatures demonstrated significant univariable association with OS and added independent prognostic value (see Figure) to a multivariable model accounting for age, sex and stage (c-index = 0.641).

Conclusion:
The validated signatures, along with two novel signatures generated from the current dataset, are currently undergoing further validation studies using two prospective co-operative group cohorts. Figure 1

Background:
A number of studies have characterized TAICs in lung cancer and associated their levels of infiltration with patients’ outcome. There is limited information about the correlation of TAICs infiltration with clinical and pathological features of lung cancer. We investigated the association between patterns of tumor infiltrating lymphocytes and macrophages with detailed clinical and pathological features in lung adenocarcinoma.

Methods:
We studied archival tumor tissue from 93 surgically resected lung adenocarcinomas, stages I to III. Density of TAICs expressing CD3, CD4, CD8, and CD68 was evaluated using immunohistochemistry (IHC) and image analysis. TAICs density was correlated with tumor’s histological characteristics and patients’ characteristics.

Results:
We found significant differences in the TAICs infiltrate density of lung adenocarcinomas based on patients’ characteristics. Overall: a) females showed higher levels of CD8+ (P=0.01) and CD3+ (P=0.03) cell density than males; b) smaller tumors (<3cms) showed more CD4+ (P=0.01) and CD3+ (P=0.03) cells than larger tumors; and, c) tumors with solid histology pattern showed higher levels of CD8+ (P=0.03) cells than non-solid pattern. No overall significant differences on TAICs infiltrates were detected by age, tobacco exposure by pack-years and TTF-1 IHC expression score. However when TAICs density of tumors was examined by sex we found the following: a) in larger tumor (>3cms), females demonstrated higher levels of CD8+ cells (P=0.0007) than males; b) tumors from females older than the median age (63 years) showed more CD4+ (P=0.04), CD8+ (P=0.009) and CD3+ (P=0.042) cells than males; c) tumors from females with <40 pack-years of tobacco history showed significantly higher levels of CD3+ (P=0.004) and CD68+ (P=0.004) cells than males; d) tumors from females with high levels of TTF1 expression (score >150) showed higher levels of CD8+ cells(P=0.03) than males; e) females with tumors having non-solid histology pattern showed higher CD8+ (P=0.02) and CD3+ (P=0.02) cells than males. Finally, tumors expressing low levels of TTF-1 and lower CD4+ cells correlated significantly with worse overall recurrence free survival and overall survival in both males (P<0.0001) and females (P=0.0072).

Conclusion:
In lung adenocarcinoma, TAICs infiltration correlates with clinical characteristics of patients and pathological features of tumors, particularly, sex, age, size and TTF-1 expression. Compared with men, lung adenocarcinomas from females showed higher levels of TAICs, particularly at older age, larger tumor size, less exposure to tobacco, and more differentiated histological patterns. (UT Lung SPORE and MD Anderson Moon Shot Program).

Background:
The national lung cancer screening test (NLST) confirmed: low dose CT screening could reduce lung cancer mortality. However, the high false-positive rates of LDCT screening, especially the difficulty of diagnosis of micro-nodules with size less than 10 mm highlight the need of complementary biomarkers to discriminate micro-nodular lung cancer from benign pulmonary diseases.

Methods:
The blood gene expression profiles of 46 lung cancer patients, 38 pulmonary lesions and 51 healthy were investigated to identify the lung cancer-specific genetic signatures. The lung cancer patients containing micro-nodules less than 10 mm were surgically and pathologically diagnosed as lung adenocarcinoma in situ

Results:
A self-training logistic regression method was used to identify the lung cancer-specific gene signatures as we previously reported. Six genes, including DDX51, PSME2, ACTL6A, GMEB1, FAM200B, GEMIN6, were identified for discriminating lung adenocarcinoma in situ from health and benign pulmonary diseases. The performance of the six-gene panel for diagnosis of lung adenocarcinoma in situ identified was exhibited in Table 1. Through self-training SVM classifier, the logarithmic odds of each sample was calculated and exhibited, in which the cutoff value was set as zero in logarithmic odds for differentiating lung cancer from benign and control group. The predictive model based on 6-gene panel correctly classified 43 of 46 lung cancer, 39 of 42 benign pulmonary diseases with 93% accuracy, 94% sensitivity, and 93% specificity and 0.97 of ROC AUC.

Conclusion:
The predictive model based on 6-gene panel (DDX51, PSME2, ACTL6A, GMEB1, FAM200B, GEMIN6) can be used for discriminating between the malignant or benign nodules with size less than 10 mm

Abstract not provided

Background:
Most human cancers express proteoglycans modified with distinct oncofetal chondroitin sulfate (CS) chains that are normally restricted to placental tissue. Oncofetal CS chains can be conveniently detected and targeted by recombinant VAR2CSA (rVAR2) proteins derived from the malaria parasite Plasmodium falciparum. In the present study, we have analyzed the expression landscape of oncofetal CS modifications in early-stage non-small cell lung cancer (NSCLC).

Methods:
Tissue microarrays from four separate patient cohorts representing a total of 493 clinically annotated stage I-II NSCLC cases were stained for oncofetal CS using rVAR2. Data were analyzed for correlation between low and high oncofetal CS presentation by immunohistochemical (IHC) staining of tumor and stroma compartments in respect to EGFR and KRAS mutations, as well as to clinical characteristics including relapse-free survival (RFS) and overall survival (OS).

Results:
There were 351 patients with low (IHC score 0-1) and 142 with high (IHC score 2-3) expressing tumors. We identified 331 adenocarcinomas, 145 squamous cell carcinomas, and 12 cases with other NSCLC subtypes. There were 314 stage I and 179 stage II cases by AJCC 7[th] edition. High oncofetal CS expression was significantly associated with shorter RFS (vs. high expressiors; 58 vs. 39 months, respectively, p=0.034) and OS (vs. high expressors; 69 vs. 51 months, respectively, p=0.044). High oncofetal CS expression was significantly associated with shorter RFS vs. low expression in men (p=0.024), smokers (p=0.011), and in patients with squamous cell tumors (p=0.012). High oncofetal CS was also significantly associated with shorter OS in men (p=0.005) and smokers (p=0.028). There were no significant RFS or OS differences in oncofetal CS expressions when stratifying the patients according to their EGFR or KRAS statuses. In multivariate survival analyses, histology, stage, and high oncofetal CS expression was significantly associated with shorter RFS vs. high expression (HR, 1.8; 95% CI, 1.32–2.48; p < 0.001).

Conclusion:
This is the first study showing that high oncofetal CS expression is an independent prognostic factor of poor RFS in NSCLC and validates high oncofetal CS expression as a prognostic factor of poor OS. In contrast to non-smoker females, oncofetal CS appears to be a prognostic for OS in males and smokers. Our work promotes oncofetal CS as a candidate target for rVAR2-based therapeutic intervention in NSCLC patients with poor RFS/OS.

Background:
A clinically certified, 14-gene quantitative PCR expression assay has been found to assess mortality risk more accurately than clinicopathologic criteria in early-stage, non-squamous, non-small cell lung cancer (NSCLC). Clinically validated molecular stratification may provide a more informative approach to identify early stage NSCLC patients who are most likely to benefit from chemotherapy than current National Comprehensive Cancer Network (NCCN) high-risk clinicopathologic features.

Methods:
Prospective molecular risk-stratification by the 14-gene quantitative PCR expression assay was performed on 91 consecutive patients with stage I-IIA non-squamous NSCLC after complete surgical resection at a single institution. Information from molecular risk profiling was used in conjunction with pathologic stage and NCCN criteria to make adjuvant chemotherapy recommendations. Fisher’s exact test was used to compare recurrence rates, and Kaplan-Meier analysis and log-rank tests were used to evaluate differences in disease free survival.

Results:
Median age was 69 years, 57% were female and median follow up was 23±2 months. Among all patients, 33 (36%) met NCCN high-risk criteria for adjuvant chemotherapy and 27 (30%) were molecular high risk. Recommendations for adjuvant chemotherapy were discordant in 18 (55%) of NCCN high-risk patients and in 12 (44%) who were molecular high-risk. Twelve (44%) of molecular high-risk patients agreed to receive adjuvant chemotherapy. Whereas recurrence was observed in 33% of molecular high-risk patients who did not receive adjuvant chemotherapy, none of the molecular high-risk patients who underwent chemotherapy recurred (log-rank p=0.001).

Conclusion:
This prospective single-institution study demonstrates the clinical utility of molecular testing of early-stage NSCLC to supplement pathologic stage and NCCN guidelines in making adjuvant chemotherapy recommendations. Molecular risk scores better differentiated prospective recurrence rates than did NCCN risk criteria. This study provides preliminary evidence that molecular testing followed by adjuvant chemotherapy in molecularly high-risk patients may prevent a significant number of recurrences and improve outcomes.

Background:
Epidermal growth factor receptor (EGFR) gene mutation is a robust prognostic factor in patients with advanced lung adenocarcinomas. Recently, on the other hand, there are some reports proposing the difference of survival due to the type of EGFR mutation. In this study, we analyzed the difference of postoperative survivals between two most common mutations, that is, exon 19 deletions (DEL) and exon21 L858R (PM), using multi-institutional data of patients with surgically resected lung adenocarcinomas.

Methods:
We retrospectively collected 1,063 consecutive patients who underwent surgical resections for lung adenocarcinoma between 2005 and 2012 in five institutions, and who were examined their EGFR mutation status. The patients with minor EGFR mutations were excluded. We compared their clinicopathological characteristics among DEL, PM, and wild type (WT) group. We also analyzed postoperative recurrence-free survival (RFS) and overall survival (OS) according to the type of EGFR mutation.

Results:
The number of patients with DEL, PM, and WT was 218 (20.5%), 301 (28.3%), and 544 (51.2%) respectively, and their median follow-up period was 47.6 months. The patients of PM were older and earlier pathological staged than those with DEL, whereas no significant difference was observed among other clinicopathological factors. Five-year RFS and OS of DEL, PM, and WT were 67.3/85.9%, 76.4/88.6%, 59.2/71.5%, respectively, and both survivals of each mutant were significantly better than those of WT. Regarding the difference between DEL and PM, RFS curve of DEL was significantly worse than that of PM (p = 0.027), but OS curves of both mutant weren’t significantly different. (p = 0.16). In multivariate analysis, the type of EGFR mutation (DEL vs PM) was not an independent factor both in RFS and OS.

Conclusion:
Exon 21 L858R might be a more favorable recurrence-risk factor than exon 19 deletions in patients with surgically resected lung adenocarcinomas.

Abstract not provided

Background:
In NSCLC, atezolizumab (anti-PDL1) efficacy correlates with PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC). Here we examined the association between atezolizumab efficacy and TMB assessed by FoundationOne (F1) sequencing panel.

Methods:
Pretreatment tumor specimens from 102 1L and 465 2L+ NSCLC patients enrolled on three Ph 2 atezolizumab monotherapy trials (POPLAR: randomized 2/3L trial comparing atezolizumab vs docetaxel; BIRCH/FIR: single-arm, 1L/2L+ PD-L1‒selected trials) were available for targeted genetic sequencing using the F1 panel of 315 cancer-related genes. TMB was quantified using an updated TMB algorithm and efficacy was assessed in groups defined by the 75th (high) and 50th (median) percentile of each study-specific TMB. Atezolizumab efficacy was examined at Dec 1, 2015 (POPLAR and BIRCH); and Jan 7, 2015 (FIR) data cutoffs.

Results:
Across samples, median TMB was similar in 1L and 2L+ patients (9/MB and 9.9/MB, respectively). In 1L and 2L+ PD-L1–selected patients, atezolizumab benefit was increased in those with ≥ TMB cut-offs (Table). In unselected 2L+ patients from POPLAR, the OS, PFS, and ORR benefits of atezolizumab vs docetaxel were also enhanced in patients with increased TMB. TMB and PD-L1 expression were independently associated with improved atezolizumab efficacy. TMB associations with PD-L1 expression, tumor-infiltrating lymphocyte infiltration and T-effector cell gene expression will be presented.

Conclusion:
For the first time, we demonstrate that TMB assessed with F1 targeted sequencing is associated with improved atezolizumab outcomes in 1L and 2L+ NSCLC. Moreover, this is the first study demonstrating the association of TMB with improved anti-PD-L1/PD-1 efficacy in a randomized trial. Importantly, the association between TMB and atezolizumab efficacy occurred in both unselected and PD-L1-selected patients. Therefore, in addition to PD-L1, TMB may be an independent predictor of improved responsiveness to atezolizumab in advanced NSCLC.

Atezolizumab efficacy by TMB subgroups
	PD-L1‒selected
BIRCH+FIR	1L n=102		2L+n=371
	Median (≥9/MB)	High (≥13.5/MB)	Median (≥9.9/MB)	High (≥17.1/MB)
OS,HR[a] (95% CI)	0.79 (0.39-1.58)	0.45 (0.17-1.16)	0.87 (0.65-1.16)	0.7 (0.49-1.00)
PFS,HR[a] (95% CI)	0.58 (0.36-0.94)	0.54 (0.3-0.97)	0.64 (0.5-0.8)	0.5 (0.38-0.67)
ORR,above/below cutoff	28%/13%	25%/20%	25%/14%	29%/16%
POPLAR	2L+ unselected n=92
	Biomarker- evaluable population	Median (≥9.9/MB)		High (≥15.8/MB)
OS,HR[b ] (95% CI)	0.65 (0.38-1.12)	0.48 (0.23-1.04)		0.5 (0.15-1.67)
PFS,HR[b] (95% CI)	0.98 (0.63-1.53)	0.49 (0.25-0.93)		0.49 (0.19-1.3)
ORR,atezolizumab/docetaxel	13%/15%	20%/4%		20%/8%
[a]HR:efficacy-evaluable patients, atezolizumab at/above cutoff vs below.[b]HR:efficacy-evaluable patients, atezolizumab vs docetaxel at/above cutoff.

Background:
Anti-PD-1 immunotherapy has resulted in durable clinical responses in heavily pretreated patients with non-small cell lung cancer (NSCLC). While NSCLC is typically seen as non-immunogenic, there is a 15-20% objective response rate and a median duration of response of 17 months in patients treated with the PD-1 inhibitor, nivolumab. This duration of response has not been reported with other systemic therapies in advanced NSCLC. While tumor PD-L1 expression may be a biomarker of sensitivity to anti-PD-1 therapy, and the number of somatic mutations may play a role in PD-1 upregulation on T cells, the mechanisms underlying response vs. progressive disease have yet to be fully elucidated.

Methods:
Whole exome sequencing and mutation-associated neoantigen (MANA) prediction was performed on tumor sections from two advanced NSCLC patients with complete response to nivolumab. Peptides representing MANAs were synthesized and tested against PBMC in a 10-day cultured IFNg ELISpot assay. Reactive MANAs were assessed in binding and stability assays. TCR sequencing was performed on reactive cell cultures and on DNA obtained from tumor resections to match MANA-reactive TCR clones with clones that were infiltrating the tumor.

Results:
The mean mutational burden in NSCLC as reported previously is 360 sequence alterations. In our study, patient 1 had 30 sequence alterations and patient 2 had 314. Despite the difference in mutational load, MANA reactivity was detected in peripheral blood of both patients >1 year after being declared cancer-free. TCR clones of MANA-reactive peripheral T cells were detected in tumor resections and were expanded in MANA-stimulated T cell cultures. Binding and stability assays confirmed that these MANAs bind to their cognate HLA with high affinity and stability.

Conclusion:
These findings show that NSCLC tumors with differential mutational burden can show regression following checkpoint blockade and suggest that the quality of mutations may be more influential in immunogenicity than the overall quantity of mutations. Our data also show that MANA reactivity may be the underlying mechanism by which T cells eliminate tumor following anti-PD-1 immunotherapy. Additional studies should evaluate mechanisms of enhancing MANA reactivity in patients who do not respond to checkpoint blockade and should further validate the link between MANA reactivity and clinical response to anti-PD-1.

Abstract not provided

Background:
The clinical efficacy observed with PD-1/PD-L1 inhibitors in non-small cell lung carcinoma (NSCLC) has prompted to characterize the immune response in lung tumors treated with chemotherapy. Our goal was to determine the characteristics of immune microenvironment of localized, surgically resected, NSCLCs from patients who received and did not receive neo-adjuvant chemotherapy. Using multiplex immunofluorescence (mIF) and image analysis, we investigated PD-1/PD-L1 expression, and quantified tumor infiltrating lymphocytes (TILs) and tumor associated macrophages (TAMs).

Methods:
We studied formalin-fixed and paraffin embedded (FFPE) tumor tissues from 111 stage II and III resected NSCLC, including 61 chemonaïve (adenocarcinoma, ADC=33; squamous cell carcinoma, SCC=28) and 50 chemotherapy-treated (ADC=30; SCC=20) tumors. mIF was performed using the Opal 7-color fIHC Kit™ and analyzed using the Vectra™ multispectral microscope and inForm™ Cell Analysis software (Perkin Elmer, Waltham, MA). The markers studied were grouped in two 6-antibody panels: Panel 1, AE1/AE3 pancytokeratins, PD-L1 (clone E1L3N), CD3, CD4, CD8 and CD68; and Panel 2, AE1/AE3, PD1, Granzyme B, FOXP3, CD45RO and CD57.

Results:
Positive PD-L1 expression (>5%) in malignant cells (MCs) was detected in 48% (n=53/111) of NSCLCs. Overall, chemotherapy-treated tumors showed significantly higher percentages of MCs expressing PD-L1 (median, 18.2%) than chemo-naïve cases (median, 1.8%; P=0.033). Higher densities of inflammatory cells expressing granzyme B (P=0.036), CD57 (P=0.001) and PD-1 (P=0.016) were detected in chemotherapy-treated NSCLCs compared with chemo-naïve tumors. In contrast, lower densities of FOXP3-positive regulatory T cells were detected in chemotherapy-treated tumors when compared with chemo-naïve cases (P=0.032). Following chemotherapy ADCs exhibited significantly higher levels of CD57-positive cells (P<0.0001) and lower density of FOXP3-positive cells (P=0.002) than chemo-naïve tumors. Chemotherapy-treated SCCs demonstrated higher density of PD-1-positive cells than chemo-naïve tumors (P=0.004). In chemotherapy-treated cancers, lower levels of CD4 helper T positive cells and tumor associated macrophages (TAMs) CD68-positive cells were associated with worse overall survival (OS; P=0.04 and P=0.005, respectively) in univariate analysis. In chemotherapy-treated ADC patients, lower levels of CD68-positive (P=0.010) and higher levels of FOXP3-positive cells correlated with worse OS (P=0.044).

Conclusion:
We developed a robust mIF panel of 10 markers to study inflammatory cells infiltrates in FFPE NSCLC tumor tissues. Chemotherapy-treated NSCLCs exhibited higher levels of PD-L1 expression and T cell subsets compared to chemo-naïve tumors, suggesting that chemotherapy activates specific immune response mechanisms in lung cancer. (Supported by CPRIT MIRA and UT Lung SPORE grants, and MD Anderson Moon Shot Program).

Background:
Previous attempts to define tumor and stromal immunologic environment in non-small cell lung cancer (NSCLC) utilized archival tissue. We established prospective comprehensive immonogenomic profiling protocol in NSCLC (ICON Project). The goal is to integrate immunomic, genomic, transcriptomic, proteomic, demographic, clinical, pathologic, and outcome data from 100 surgically resected early stage NSCLC.

Methods:
Tumor and normal lung tissue are collected at the time of surgery, blood samples before and after surgery. Tumor samples are processed for tumor infiltrating lymphocyte (TILs) isolation and expansion; development of patient derived xenografts (PDX), immunohistochemical immune markers, and immunopeptidome profiling. Blood samples are analyzed with flow cytometry.

Results:
57 patients with median age of 65 years (27 males) have been enrolled within 5 months, of which 33 (66%) contributed samples to the study. Four were never smokers, with others being former or current smokers. Majority (N=27) had adenocarcinoma, 4 squamous cell carcinoma, and 2 pleomorphic carcinoma. 15 patients had stage I, 11 stage II, and 7 stage III disease; 5 patients received induction chemotherapy. Median tumor size was 3.5 cm and 29 underwent R0 and 4 R1 resection. Pre-REP TIL expansion was successful in the majority of samples (68.2%, n=22). Twelve PDX models with a take rate of 40% have been generated. Interim analysis of tumor samples by IHC demonstrated higher median distribution of all cell types: CD3+ T cells, cytotoxic T cells CD8+, PD1+ cells, tumor associated macrophages (TAM) CD68+, TAM CD68+PD-L1+, CD20+B cells, memory T cells CD45R0, natural killer cells CD57+, regulatory FOXP3+ T cells, and cytotoxic granzyme B cells (cells/mm[2]) in the stroma as compared to the tumor compartment. Intra-tumoral regulatory FOXP3+T cells were more abundant in squamous cell carcinomas compared to adenocarcinomas (median 312 vs 51 cells/mm[2], p = 0.05). Higher concentration of intra-tumoral CD68+PD-L1+ expressing cells was observed following neoadjuvant chemotherapy (median 97 vs 60 cells/mm[2] no chemo; p= 0.077), as was the concentration of memory T cells CD45R0 (median 129 vs 30 cells/mm[2], no chemo; p = 0.077). Mass spectrometry-based immunopeptidome analysis identified several thousand peptides, of which 4 promising antigens have been chosen for further development as immunotherapeutic T-cell targets.

Conclusion:
The ICON is an ongoing, ambitious prospective project that aims to define the baseline immunologic characteristics of surgically resectable NSCLC. The rapid enrollment illustrates the enthusiasm for tumor immunoprofiling amongst patients and physicians alike. Data from this patient cohort will serve as a baseline comparison for upcoming neoadjuvant immunotherapy trials.

Background:
Immunotherapy with antibodies against B7/CD28 family members, including PD-1, PD-L1, and CTLA-4 has shifted the treatment paradigm for non-small-cell lung carcinoma (NSCLC) with improved clinical outcome. HHLA2 is a newly discovered member of the family. By regulating T-cell function, HHLA2 could contribute to tumor immune suppression and thus be a novel target for cancer immunotherapy. There is limited information and critical need to characterize its expression profile and clinical significance in NSCLC.

Methods:
We performed immunohistochemistry with an HHLA2-specific antibody (clone 566.1) using tissue microarrays constructed from 679 NSCLC tumor tissues, including 392 cases in the discovery set and 287 cases in the validation cohort. We also studied clinico-pathological characteristics of these patients.

Results:
Overall, HHLA2 was not detected in most of normal lung tissue but expressed in 66% of NSCLC across different subtypes. In particular, EGFR–mutated NSCLC was significantly associated with higher tumor HHLA2 expression in both discovery (EGFR vs. WT: 76% vs. 53%, P=0.01) and validation cohorts (89% vs. 69%, P=0.01). In one of the two cohorts, HHLA2 expression was higher in lung adenocarcinoma as compared to squamous and large cell histology, non-Hispanic White vs. Hispanics, and tumors with high tumor infiltrating lymphocyte (TIL) density. In the multivariate analysis, EGFR mutation status and high TIL intensity were independently associated with HHLA2 expression in lung adenocarcinoma.

Conclusion:
HHLA2 is widely expressed in NSCLC and is associated with EGFR mutation and high TILs in lung adenocarcinoma. It is potentially a novel target for lung cancer immunotherapy.

Abstract not provided

Background:
IL-7/IL-7 receptor (IL-7R) interactions have been shown to prevent apoptosis in lung cancer cells and promote stromal pro-tumor immune cell homing and differentiation. The aim of this study is to investigate the correlation between tumoral IL-7R expression and stromal pro-tumor immune cells (FoxP3+ Tregs and CD163+ M2 macrophages) and to determine prognostic impact of the combination of these markers in lung adenocarcinomas.

Methods:
In resected stage I lung adenocarcinoma (n=913; 1995-2009), antigen expression of IL-7R, FoxP3 and CD163 was evaluated by immunohistochemistry (IHC) using tissue microarrays and mRNA expression was quantified by RT-PCR. Prognosis was analyzed by both recurrence free probability (RFP) and lung cancer-specific survival (LCSS).

Results:
In IHC analysis, high tumoral IL-7R, stromal FoxP3, and stromal CD163 expression were individually associated with lymphatic/vascular invasion, and increasing percentage of solid histological patten. A correlation was seen between IL-7R, FoxP3 and CD163 expression by mRNA and IHC analyses (Figure1). The co-existence of high expression of these 3 markers was found in 16% of patients and was associated with worse outcomes (Figure2). In multivariable analysis, triple marker co-existence was an independent risk factor for RFP (p=0.004) and LCSS (p=0.008).

Conclusion:
Tumoral IL-7 receptor is a potential target for lung adenocarcinoma immunotherapy. Figure 1 Figure 2

Background:
Blockade of programmed death 1 (PD-1), or its ligand, PD-L1, could restore T-cell immunity. Anti-PD-1/ or anti-PD-L1 antibodies have demonstrated promising efficacy in the treatment of cancer patients. The toxicity spectrum of PD-1/PD-L1 blockers is distinct from chemotherapy or other target agents. Pneumonitis is one of the major side effects of these drugs, and reported incidences vary substantially between clinical trials. We tried to investigate the overall incidence and risk of treatment-related pneumonitis with anti-PD-1/PD-L1 therapies in cancer patients.

Methods:
A systematic search of literature up to January 2016 was performed in EDLINE, EMBASE, and Cochrane databases to identify relevant clinical trials. Paired reviewers independently selected articles for inclusion and extracted data. Incidence and relative risk (RR) of hypertension were calculated using a random-effects or fixed effects model, depending on the heterogeneity of the included studies.

Results:
A total of 23 clinical trials with 5333 patients were included. The overall incidence of all- and high-grade pneumonitis in cancer patients receiving anti-PD-1/PD-L1 therapies were 3.5% (95% CI, 2.9% to 4.3%) and 1.3% (95% CI, 1.1% to 1.9%), respectively. Anti-PD-1/PD-L1 antibodies were associated with a significantly increased risk of all-grade pneumonitis in patients with cancer with an RR of 5.47 (95% CI, 2.17 to 13.81; p<0.001) compared with controls. The risk of high-grade pneumonitis was also increased with the use of anti-PD-1/PD-L1 antibodies, though not statistically significant (RR 3.86; 95% CI 0.98 to 15.22; p=0.054).

Conclusion:
Patients with cancer receiving anti-PD-1/PD-L1 therapies have a significant risk of developing pneumonitis. Early and appropriate management is strongly recommended to avoid unnecessary dose reductions and transitory or definitive treatment discontinuations due to pneumonitis.

Background:
Patients with lung cancer are at increased risk for venous thromboembolism (VTE), particularly those receiving chemotherapy. It is estimated that 8-15% of patients with advanced non-small cell lung cancer (NSCLC) experience a VTE in the course of their disease. The incidence in patients with specific molecular subtypes of NSCLC is unknown. We undertook this review to determine the incidence of VTE in patients with ALK-rearranged NSCLC.

Methods:
We identified all patients with ALK-rearranged NSCLC, diagnosed and/or treated at the Princess Margaret Cancer Centre (PM CC) in Canada between July 2012 and January 2015. Retrospective data were extracted from electronic medical records. We then included a validation cohort comprising all consecutive patients with ALK-rearranged NSCLC treated in two tertiary centers in Israel.

Results:
Within the PM CC cohort, of 55 patients with ALK-rearranged NSCLC, at a median follow-up of 22 months, 23 (42%) experienced VTE. Patients with VTE were more likely to be Caucasian (p=0.006). The occurrence of VTE was associated with a trend towards worse prognosis (overall survival HR=2.88, p=0.059). Within the validation cohort (N=43), VTE rate was 28% at a median follow-up of 13 months. Combining the cohorts (N=98) the VTE rate was 36%. Patients with VTE were younger (age 52 vs 58, p=0.04) and had a worse ECOG performance status (p=0.04). VTE was associated with shorter OS (HR=5.71, p=0.01)Figure 1.



Conclusion:
We found the rate of VTE in our ALK-rearranged cohort is 3-5-fold higher than previously reported for the general NSCLC population. This warrants confirmation in larger cohorts.

Background:
Previous research has shown that supportive care needs in lung cancer patients are high and that this population may have significantly more unmet care needs than other cancer patients. Our goals for this study were to determine the most prevalent and problematic side-effects of lung cancer and lung cancer treatment in our community and to understand where both patients and caregivers felt there were unmet needs.

Methods:
A Community Needs Assessment survey was distributed to lung cancer patients and caregivers electronically between 11/9/2015 and 2/8/2016. 820 people responded, including 471 patients/survivors and 349 caregivers, 181 of whom identified as the primary caregiver. The overall completion rate was 72.6%, similar for both groups. Respondents identified all side effects they or their loved one experienced during and after treatment, as well as 5+ years after diagnosis. They also indicated which of these side-effects were most problematic during those time periods. Respondents were also for demographic information and for open-ended responses about their unmet needs during care and follow-up.

Results:
Respondents indicated a high rate of side effects, with over 95% reporting at least one. Importantly, both patients and caregivers reported that physical side effects were significantly more problematic during treatment but that emotional side effects were more problematic after treatment and in the long-term. Patients rated anxiety, fatigue, and shortness of breath as the most problematic short and long-term post-treatment side effects, with 18-29% of patients indicating these items at a particular time period. During treatment, gastrointestinal issues including constipation (18%), diarrhea (17%), and nausea (14%) were also identified as highly problematic side effects by the patients. Caregivers reported similar effects but also rated pain as problematic across all time periods (15-24%) and identified loss of appetite (28%) and weight loss (25%) during treatment. When questioned about unmet needs during treatment and survivorship, respondents frequently commented that their treatment team focused on treatment and survival and not on managing side effects.

Conclusion:
Side effect management is a clear unmet need for lung cancer patients and to help support their caregivers. Our data show high levels of emotional and physical side effects and a perceived lack of support for proper management. Notably, emotional side effects are prevalent after treatment for lung cancer into long-term survivorship and are frequently cited as the most problematic issue for those no longer in active treatment.

Abstract not provided

Background:
Pleural and oncological treatment options for malignant pleural effusion (MPE) are increasing and hence, more accurate prognosis at presentation may help to identify patients with the higher risk of pleural recurrence, in order to individualize more intensive treatment strategies. The aim of this study was to identify predictors of malignant pleural effusion recurrence in patients with M1a non-small cell lung cancer (NSCLC)

Methods:
All patients with NSCLC and MPE submitted to pleural palliative procedures including simple pleural drainage, videothoracoscopic pleural drainage, pleurodesis and indwelling pleural catheter were enrolled in a prospective study between 2014 and 2015, and divided into two groups. Group I included patients who had pleural recurrence, and Group II with no pleural recurrence after the palliative procedures. Prognostic factors for pleural recurrence were identified by univariate analysis, using Fisher's exact test for the analysis of categorical variables and Student’s t test for quantitative variables. Subsequently the significant variables were entered into a multivariate logistic regression analysis (with p< 0.05 considered significant). The cutoff points for any significant continuous variables were determined by receiver operating characteristics (ROC) analysis.

Results:
A total of 82 patients were included in the analysis. Median follow-up time for surviving patients was 81 days (range 1 to 1070 days). There were 15 patients (18.3%) in Group I and 67 patients (81.7%) in Group II. Univariate analysis of factors affecting postoperative recurrence were: adenosine deaminase concentration in pleural fluid < 16 mg/dl (p=0.04), albumin concentration in pleural fluid < 2.4 mg/dl (p= 0.03), administration of second-line palliative chemotherapy (p= 0.018) and type of procedure (simple pleural drainage vs. videothoracoscopic pleural drainage, pleurodesis and indwelling pleural catheter) (p= 0.023). At the multivariate analysis, only the type of procedure (simple pleural drainage)( p= 0.031) was identified as independent predictor of recurrence.

Conclusion:
In our cohort of NSCLC patients with MPE submitted to pleural palliative procedures, simple pleural drainage was the only significantly factor associated with recurrence of MPE. The identification of this factor may assist the choice of the optimal palliative technique, at the first episode of MPE in NSCLC patients. Definitive procedure as pleurodesis is recommended, the indwelling pleural catheter or videothoracoscopic drainage are options for patients whom lung are trapped.

Background:
In South East Scotland, 40% of patients with newly-diagnosed lung cancer are unfit for anti-cancer treatment and are for ‘best supportive care’ (BSC). Many more become for BSC following palliative anti-cancer treatment or disease relapse. But there is no consensus about what constitutes BSC and who should deliver it. Patients and families are left unclear about realistic goals of care, and about what support and follow-up they can expect. Given the typically short prognosis (2012 data from NHS Fife reveals a median survival of 73 days), rapidly changing needs and high risk of hospital admission, the lack of consistency in BSC can be a serious barrier to high quality end of life care. Therefore, Fife Specialist Palliative Care have developed and piloted a model of 'proactive best supportive care' for patients with incurable lung cancer and those close to them.

Methods:
The new model of best supportive care was based around the following framework: *Robust identification of all patients for BSC *Comprehensive palliative care assessment and care planning *Care coordination and follow-up Every assessment began with sensitive discussion about the lung cancer diagnosis and BSC. Detailed assessments of physical, psychological, practical and spiritual needs followed and immediate care plans were agreed. Where appropriate, anticipatory care planning was started. Structured letters were available online to all health professionals within two days. Patients were followed-up and supported for as long as they lived.

Results:
246 patients were supported by the new model of care during its first 15 months. Patients were assessed wherever they were. Most were assessed and followed-up at home or in the acute hospital, with a minority fit to attend clinic. Unnecessary outpatient appointments were cancelled. Patients and families appreciated the potential to maintain independence afforded by knowing where to access support when needed. The process of care coordination was not directly visible to them, but the quality of care it provided was deeply appreciated. Under the new model of care, patients spent significantly less time in the acute hospital before they died, with both length of stay and total bed days reduced by almost a third (comparisons with local data from 2012).

Conclusion:
A new model of proactive BSC in lung cancer has been successfully developed and piloted in NHS Fife. Patients and those close to them are now consistently supported from the point of diagnosis, with the impact of improved quality of care and more appropriate use of healthcare resources.

Abstract not provided

Abstract:
Background Solitary pulmonary nodules are seen on approximately 0.1% of all chest X-ray films.[1] High-resolution computed tomography (HRCT), which is used in lung cancer screening programs, can detect pulmonary nodules that are smaller than those detected by conventional radiography. The radiological diagnosis and treatment of these small pulmonary nodules are now the focus of lung cancer research. The timely detection of lung cancers is essential for successful treatment. The guidelines and recommendations for the management of pulmonary nodules include follow up, nonsurgical biopsy, or surgery; and are based on the size of the nodule, and ground glass opacity (GGO) ratio or size of the solid component.[2-4] Diagnosis The diagnosis of a pulmonary nodule is frequently problematic. The management of pulmonary nodules is based on their characteristics. When a pulmonary nodule is monitored by CT, the important features include not only its size but also its density. According to the guidelines of the American College of Chest Physicians, solid nodules measuring > 8 mm in diameter need further examination.[3] The Fleischner Society for Thoracic Imaging and Diagnosis uses a cutoff diameter of 5 mm for decision making for subsolid nodules.[2] It should be kept in mind that solid nodules that are suspicious for lung cancer are frequently invasive. A subsolid nodule can be classified as a pure ground glass nodule (GGN) or part-solid nodule. Subsolid nodules grow slowly and may develop a solid component. The HRCT findings of early lung adenocarcinomas were significantly correlated with the histopathologic findings of the resected specimens.[5] In the evaluation of subsolid nodules, the features indicating noninvasive lung adenocarcinoma include tumor disappearance rate, diameter of consolidation, and GGO ratio.[6] However, even HRCT cannot accurately assess the areas of solid opacities or GGO, and results might vary between investigators. In the upcoming 8[th] TNM classification, the Lung Cancer Staging Project of the International Association for the Study of Lung Cancer showed that the solid part of a nodule on HRCT represents the clinical T factor, and that measurement of the solid part is essential for lung cancer staging.[5] Positron emission tomography (PET)-CT has a clearly established role in lung cancer clinical practice. Based on the pretest probability, PET-CT should be used for patients with a solid, indeterminate nodule > 8 mm in size.[3,4] For adenocarcinomas in situ (AIS) and minimally invasive adenocarcinomas (MIA) of the lung that show solid opacities on HRCT, the preoperative PET-CT and thin-section CT findings together can provide information on the aggressiveness of the tumor. Our study group found that these modalities used together could detect aggressive lung cancers in clinical stage IA (Fig. 1).[7] However, since PET-CT can show false-negative results for slow-growing and low-grade lung malignancies, we think that HRCT is the best modality for identifying indolent lung cancers. Transthoracic biopsy, bronchoscopy, or surgery is used for obtaining specimens for histopathological diagnosis. The definitive diagnosis of small pulmonary nodules, especially GGO-dominant nodules, is challenging. The diagnostic yields of percutaneous CT-guided fine needle aspiration biopsy for GGO-dominant and solid-dominant lesions were 51.2% and 75.6%, respectively (p = 0.018).[9] The diagnostic yield of GGO-dominant lesions < 10 mm was 35.2%. Since invasive biopsy is not without risk, a histopathological diagnosis should be limited to nonsurgical candidates. For cases with high likelihood of lung cancer, a surgical biopsy followed by lung resection might be warranted. Although surgery might be performed on patients with benign nodules, it does provide the definitive diagnosis. If surgery is performed after careful preoperative assessment, the surgical mortality is very low, and the surgical risk may be acceptable. Treatment While lobectomy is the standard procedure for lung cancers, sublobar resection, meaning segmentectomy or wedge resection, might be justified for patients with noninvasive small lung cancers. However, to date, which procedure, sublobar resection or lobectomy, provides a better outcome remains unclear in these cases, since prospective randomized control trials are ongoing (JCOG0802/WJOG4607L[8] and CALGB140503). One of the concerns in sublobar resection is recurrence at the surgical margin (Fig. 2). Recurrence at the surgical margin might be accounted for by tumor cells spreading via air spaces.[10] Accurate intraoperative cytology and adequate surgical margins have been reported to be important for preventing recurrence at the surgical margin. Another concern is lymph node metastasis. In a prospective radiological study for clinical stage IA lung cancer, 47 of 545 (8.6%) patients had lymph node metastasis.[6] Sublobar resection, especially wedge resection, dose not allow evaluation of lymph nodes for metastatic disease. Conclusion HRCT findings play an important role in discriminating the biological behaviors of pulmonary nodules. The definitive diagnosis by HRCT can be difficult, and the combination of HRCT and PET-CT might be beneficial. Randomized control trials should clarify the role of sublobar resection in treating patients with noninvasive lung cancer. Figure 1. Figure 1 Figure 2. Figure 2 References 1. Ost D, Fein AM, Feinsilver SH. The solitary pulmonary nodule. N Engl J Med 2003;348:2535-42. 2. Naidich D, Bankier AA, MacMahon H, Schaefer-Prokop CM, Pistolesi M, Goo JM, et al. Recommendations for the management of subsolid pulmonary nodules detected at CT: A statement from the Fleischner Society. Radiology 2013;266:304-17. 3. Gould MK, Donington J, Lunch WR, Mazzone PJ, Midthun DE, Naidich DP, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer 3[rd] ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e93s-120s. 4. National Comprehensive Cancer Network. Guidelines for surveillance following therapy for non-small cell lung cancer Ver 4.2016. Available at: www.nccn.com. 5. Travis WD, Asamura H, Bankier AA, Beaseley MB, Detterbeck F, Flieder DB, et al. The IASLC Lung Cancer Staging Project: Proposals for coding T categories for subsolid nodules and assessment of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol 2016;11:1204-23. 6. Suzuki K, Koike T, Asakawa T, Kusumot M, Asamura H, Nagai K, et al. A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan Clinical Oncology Group 0201). J Thorac Oncol 2011;6:751-6. 7. Shiono S, Yanagawa N, Abiko M, Sato T. Detection of non-aggressive stage IA lung cancer using chest computed tomography and positron emission tomography/computed tomography. Interact Cardiovasc Thorac Surg. 2014;21:637-43. 8. Nakamura K, Saji H, Nakajima R, Okada M, Asamura H, Shibata T et al. A phase III randomized trial of lobectomy versus limited resection for smallsized peripheral non-small cell lung cancer (JCOG0802/WJOG4607L). Jpn J Clin Oncol 2010;40:271–4. 9. Shimizu K, Ikeda N, Tsuboi M, Hirano T, Kato H. Percutaneous CT-guided fine needle aspiration for lung cancer smaller than 2 cm and revealed by ground-glass opacity at CT. Lung Cancer 2006;51:173-9. 10. Shiono S, Yanagawa N. Spread through air spaces is a predictive factor of recurrence and a prognostic factor in stage I lung adenocarcinoma. Interact Cardiovasc Thorac Surg. 2016 Jun 26. pii: ivw211.

Abstract:
Radiologic Techniques for the Evaluation of Pulmonary Nodules The incidental detection of pulmonary nodules has increased with improved CT technology and thin section imaging techniques[1][,][2]. Adding to this increased detection of nodules is the heightened interest in the purposeful search for nodules such as in oncology patients and lung cancer screening programs. The management of CT detected nodules is a subject of much debate and dependent upon the clinical setting. For instance, in a lung cancer screening setting, there has been a large volume of investigation of solid, semi-solid and ground glass nodules that is the foundation of management recommendations such as LungRads[3]. In patients with a known malignancy, there is minimal literature on management recommendations and thus more influenced by pulmonary metastatic potential of the malignancy and clinician experience[4]. Finally incidentally detected nodule management is greatly influenced by cancer risk factors and nodule texture; for these situations, the Fleischner criteria have been the most widely used and accepted management guidelines[5]. The radiologic evaluation of nodules most often utilizes conventional imaging techniques of chest radiographs, computed tomography (CT), PET/CT. Occasionally MRI and ultrasound may be employed. Most recent changes involve risk stratification, computer software applications to enhance nodule analysis such as nodule enhancement patterns, volumetric computations, and texture analysis[6-8]. Future directions include incorporation of genomics into imaging as well as radiomic analysis and machine learning[9][,][10]. This presentation will review the highlights of the radiologic methods for evaluating pulmonary nodules with a focus on current guidelines and future directions. Reference: 1. Frank L, Quint LE. Chest CT incidentalomas: thyroid lesions, enlarged mediastinal lymph nodes, and lung nodules. Cancer imaging : the official publication of the International Cancer Imaging Society 2012;12:41-8. 2. Jacobs PC, Mali WP, Grobbee DE, van der Graaf Y. Prevalence of incidental findings in computed tomographic screening of the chest: a systematic review. Journal of computer assisted tomography 2008;32:214-21. 3. Lung CT Screening Reporting and Data Systen (Lung-RADS). 2014. (Accessed March 27, 2015, at www.acr.org/Quality-Safety/Resources/LungRADS ) 4. Munden RF, Erasmus JJ, Wahba H, Fineberg NS. Follow-up of small (4 mm or less) incidentally detected nodules by computed tomography in oncology patients: a retrospective review. J Thorac Oncol 2010;5:1958-62. 5. McMahon PM, Meza R, Plevritis SK, et al. Comparing benefits from many possible computed tomography lung cancer screening programs: extrapolating from the National Lung Screening Trial using comparative modeling. PloS one 2014;9:e99978. 6. McWilliams A, Tammemagi MC, Mayo JR, et al. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med 2013;369:910-9. 7. Revel MP, Merlin A, Peyrard S, et al. Software volumetric evaluation of doubling times for differentiating benign versus malignant pulmonary nodules. AJR Am J Roentgenol 2006;187:135-42. 8. Talwar A, Gleeson FV, Rahman NM, Pickup L, Gooding M, Kadir T. A Review Of The Use Of Computer Aided Texture Analysis For Pulmonary Nodules Classification. American journal of respiratory and critical care medicine 2015;191. 9. El-Zein RA, Lopez MS, D'Amelio AM, Jr., et al. The cytokinesis-blocked micronucleus assay as a strong predictor of lung cancer: extension of a lung cancer risk prediction model. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2014;23:2462-70. 10. Gillies RJ, Kinahan PE, Hricak H. Radiomics: Images Are More than Pictures, They Are Data. Radiology 2016;278:563-77.

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Abstract:
Angiogenesis is an important process in the development and progression of tumours. Across a range of tumour types markers of angiogenesis, such as elevated VEGF levels or increased micro vessel density, have been shown to be associated with poorer patient outcomes. The recognition that VEGF mediated signalling is a key driver of angiogenesis within tumours led to the development of a range of anti-angiogenic approaches targeting this biological process. These approaches have included monoclonal antibodies (bevacizumab, ramucirumab), decoy receptors (aflibercept), and receptor tyrosine kinase inhibitors (nintedanib, sorafenib, sunitinib, motesanib, vandetanib, cediranib, pazopanib), all of which have been evaluated in lung cancer. Despite this volume of clinical research, only three of these agents have been shown to produce benefit in patients with advanced non-small cell lung cancer (NSCLC): bevacizumab, ramucirumab and nintedanib. No antiangiogenic agent has to date been shown to be of benefit in small cell lung cancer. Bevacizumab, an anti-VEGF monoclonal antibody, was the first antiangiogenic therapy to be evaluated in NSCLC. Early studies identified that patients with squamous cancers were at risk of increased toxicity due to haemorrhage so randomised trials have been restricted to patients with non-squamous tumours. The ECOG 4599 randomized trial evaluated treatment with carboplatin and paclitaxel with or without bevacizumab[1]. In this study, as in most other studies of antiangiogenics, bevacizumab was continued in a maintenance phase following the conclusion of chemotherapy. The study demonstrated an improvement in overall survival (HR 0.79, 95% CI 0.67 – 0.92 p = 0.003). A second phase 3 study, AVAiL, evaluated the addition of two different doses of bevacizumab to the combination of gemcitabine and cisplatin, in a double blind manner[2]. The study demonstrated an improvement in progression free survival, but with no difference in overall survival. Based on the results of these two trials, bevacizumab received approval in several jurisdictions, but there remained some doubts over the benefit to patients given the lack of a confirmatory trial showing improved overall survival. A recent meta-analysis[3] incorporating these and other randomised studies has shown that bevacizumab produces a modest, but statistically significant improvement in overall survival (HR 0.90, 95% CI 0.81 – 0.99; p=0.03). Subsequently, a further randomised trial, BEYOND[4], has been published, with bevacizumab added to the combination of carboplatin and paclitaxel in a purely Asian population. This trial showed an improvement in overall survival (HR 0.68, 95% CI 0.50 – 0.93 p=0.015), with median OS increasing from 17.7 to 24.3 months. Bevacizumab has also been evaluated in the second line setting in combination with erlotinib (in patients unselected for EGFR mutations), without significant impact on overall survival in the BeTa study[5]. Ramucirumab is a monoclonal antibody directed against the VEGFR2 receptor. It has been evaluated in a randomised trial in the second line setting. Patients were randomised to receive treatment with docetaxel with or without ramucirumab[6]. Treatment was continued till progression, with monotherapy ramucirumab continued if toxicity developed to docetaxel (and vice versa). The primary endpoint of the study was overall survival, and the results indicated an improvement in overall survival for patients receiving ramucirumab (HR 0.86, 95% CI 0.75 – 0.98; p=0.023), with median survival increasing from 9.1 to 10.5 months. By contrast to the various studies of bevacizumab, this study included patients with squamous cell cancer, as well as those with non-squamous tumours, with the magnitude of benefit being similar in both histologic types. Addition of ramucirumab resulted in an increase in toxicity, with more hypertension, bleeding, and febrile neutropenia. However the rate of serious adverse events and of deaths due to adverse events were similar between the two study arms. The results of this study led to the approval of ramucirumab for patients with previously treated in NSCLC in some parts of the world, including the USA and Europe. However, subsequently, the results of trials of immune checkpoint inhibitors in the same patient population has resulted in many of these patients not receiving docetaxel chemotherapy, making it difficult to assess the appropriate role for this agent. The addition of a tyrosine kinase inhibitor to chemotherapy has been evaluated extensively in patients with advanced NSCLC in both the first and second line settings. The results of these trials have been disappointing, with none of them demonstrating an overall survival benefit. Many, however, did show some improvement in progression free survival. Only one of these agents, nintedanib, is approved (in Europe) for the treatment of patients with NSCLC. This is based on the results of the LUME-1 study, which compared treatment with docetaxel alone with docetaxel plus nintedanib in patients with previously treated NSCLC[7]. In this study, progression free survival (the primary endpoint) was longer with the addition of nintedanib (3.4 vs. 2.7 months, HR 0.79, 95% CI 0.68 – 0.92; p=0.0019). Although there was no difference in overall survival in the whole study population, in the predefined subset of patients with adenocarcinoma and progression within 9 months of initial therapy median overall survival increased from 7.9 to 10.9 months (HR 0.75, 95% CI 0.60 – 0.92; p=0.007). Similar, though less extreme results occurred in all patients with adenocarcinoma. There was no effect on survival of patients with squamous histology. The combination resulted in an increase in the rate of adverse events, predominantly diarrhoea, liver function abnormalities and vomiting. To date, no biomarker of angiogenesis that allows the selection of patients for treatment with has been identified. As a consequence, patient selection (for bevacizumab) is based on the avoidance of toxicity, by excluding groups of patients known to be at higher risk (e.g. those with squamous cell histology, or a history of haemoptysis). Furthermore the inability to identify those patients most likely to benefit, along with the relatively small improvements in survival means that from an economic viewpoint, the cost per life year gained is high. This has resulted in antiangiogenics not being widely used in some countries. References 1. Paclitaxel Carboplatin alone or with bevacizumab for non-small-cell lung cancer. Sandler et al. N Engl J Med 2006; 355: 2542 – 2550 2. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for non-squamous non-small-cell lung caner: AVAiL. Reck et al. J Clin Oncol 2009; 27: 1227 – 1234 3.Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum based chemotherapy as first-line treatment in patients with advanced non-small cell lung cancer. Soria et al. Ann Oncol 2013; 24: 20 – 30. 4. BEYOND: A randomized, double-blind, placebo-controlled, multicentre phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent non-squamous non-cell lung cancer. Zhou et al. J Clin Oncol 2015; 33: 2197 – 2204 5. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind placebo-controlled phase 3 trial. Herbst et al. Lancet 2011; 377: 1846 – 1854 6. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre double-blind randomised phase 3 trial. Lancet 2014; 384: 665 – 673 7. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-1): a phase 3 double blind , randomised controlled trial. Reck et al. Lancet Oncol 2014; 15: 143- 155

Abstract:
The concept of tumor-induced neoangiogenesis has been shown to be a relevant factor for tumor proliferation and metastasis already a couple of years ago (1). Therefore interaction with proangiogenic pathways appears to be a promising therapeutic target across several solide tumors. In eligible patients with advanced non-squamous NSCLC the addition of the anti vascular endothelial growth factor (anti VEGF) antibody bevacizumab to platinum based chemotherapy has shown consistent improvement of response, progression free survival (PFS) and overall survival. However also the combination did increase the incidence of characteristic adverse events like hypertension, arterial and venous vascular events, bleeding events, proteinuria and other (2). Recently two large randomised phase III trials revealed a significant increase in efficacy by the combination of antiangiogenic agents and chemotherapy in pretreated patients with advanced NSCLC. In the LUME 1 trial the combination of the oral angiokinase inhibitor nintedanib and docetaxel revealed a significant improvement of PFS (median PFS 3.4 vs 2.7 months, HR 0.79, 95% CI 0.68-0.92) and OS in patients with adenocarcinoma histology (median OS 12.6 vs 10.3 months, HR 0.82, 95% CI 0.7-0.99) compared to docetaxel (3). The combination of the anti VEGF receptor 2 antibody ramucirumab and docetaxel did show a significant improvement of response (response rate: 23% versus 14%, p<0.0001), PFS (median PFS 4.5 versus 3.0 months, HR 0.76, 95% CI 0.68-0.86) and OS (median OS 10.5 versus 9.1 months, HR 0.86, 95% CI 0.75-0.98) compared to docetaxel in pretreated patients with NSCLC regardless of histology (4). The identification of potential predictive biomarkers remains a challenge due to the complexity of angiogenesis, the interaction between the tumor and the host and due to dynamic changes of the system. In a very large trial (Abigail), specifically designed to identify potential tissue based or blood based markers of efficacy, no predictive markers could be determined. However the relevant prognostic nature of angiogenesis marker could be confirmed (5). Recent analyses revealed that besides molecular markers clinical factors like rapid progressive diseases or tumors refractory to conventional chemotherapy could be associated with improved outcomes of angiogenesis inhibitors. Preplanned as well as exploratory analyses did show pronounced efficacy for the combination of antiangiogenic agents like nintedanib, ramucirumab and bevacizumab compared to chemotherapy alone supporting the hypothesis that fast progressing tumors are more dependant on neo angiogenesis. The translational exploration of these clinical findings is on the way in several programs and trials. The understanding of this correlation will be important for the optimal placement of antiangiogenic agents e.g. in the combination with immunotherapies. Folkman J, Merler E, Abernathy C et al. Isolation of a tumor factor responsible for angiogenesis. J Exp Med 1971; 133: 275-288 Soria JC, Mauguen A, Reck M et al. Systematic review and meta-analysis of randomised phase II/III trials adding bevacizumab to platinum based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 2013; 24: 20-30 Reck M, Kaiser R, Mellemgaard A et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double blind, randomised controlled trial. Lancet Oncol 2014; 15: 143-50 Garon E, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384: 665-773 Mok T, Gorbunova V, Juhasz E et al. A correlative biomarker analysis of bevacizumab and carboplatin-based chemotherapy for advanced nonsquamous non-small cell lung cancer: results of the phase II randomized ABIGAIL study (BO21015). J Thorac Oncol 2014; 9: 848-55.

Abstract:
Lung cancer is still the leading cause of cancer-related death in both men and women with 80% to 85% of cases being non-small-cell lung cancer (NSCLC).[1]The past fifteen years have brought significant breakthroughs in the understanding of the molecular biology of lung cancer. Signalling pathways and genetic driver mutations that are vital for tumour growth have been identified and can be effectively targeted by novel pharmacologic agents, resulting in significantly improved survival of patients with lung cancer.[2]Parallel to the progress in lung cancer treatment, imaging techniques aiming at improving diagnosis, staging, response evaluation, and detection of tumour recurrence have also considerably advanced in recent years.[3]However, standard morphologic computed tomography (CT) and magnetic resonance imaging (MRI) as well as fluor-18-fluorodeoxyglucose ([18]F-FDG) positron emission tomography CT (PET-CT) are still the currently most frequently utilized imaging modalities in clinical practice and most clinical trials.[4,5]Novel state-of-the-art functional imaging techniques such as dual-energy CT (DECT), dynamic contrast enhanced CT (DCE-CT), diffusion weighted MRI (DW-MRI), perfusion MRI, and PET-CT with more specific tracers that visualize angiogenesis, tumour oxygenation or tumour cell proliferation have not yet been broadly implemented, neither in clinical practice nor in phase I–III clinical trials [6]. In this context, Nishino et al.[4] published an article on personalized tumour response assessment in the era of molecular treatment in oncology. The authors showed that the concept of personalized medicine with regard to cancer treatment has been well applied in therapeutic decision-making and patient management in clinical oncology. With regard to imaging techniques, however, it was criticized that the developments in tumour response assessment that should parallel the advances in cancer treatment are not sufficient to produce state-of-the-art functional information that directly reflect treatment targets. Functional information on tumour response is highly required because there is growing evidence that the current objective criteria for treatment response assessment may not reliably indicate treatment failure and do not adequately capture disease biology. Molecular-targeted therapies and novel immunotherapies induce effects that differ from those induced by classic cytotoxic treatment including intratumorale haemorrhage, changes in vascularity, and tumour cavitation. Thus, conventional approaches for therapy response assessment such as RECIST or WHO criteria that exclusively focus on the change in tumour size are of decreasing value for drug response assessment in clinical trials.[7,8] Parallel to the development of novel imaging techniques automated and more detailed analysis of standard images is currently highly investigated and has led to the introduction of the term Radiomics. Radiomics refers to the comprehensive quantification of tumour phenotypes by applying a large number of quantitative image features that are standardized collected with specific software algorithms. Radiomics features have the capability to further enhance imaging data regarding prognostic tumour signatures, detection of tumour heterogeneity as well as the detection of underlying gene expression patterns which is of special interest in patients with metastatic disease. The aim of of this presentation is to provide an overview on state-of-the-art imaging techniques for the initial staging, response evaluation as well as surveillance in patients with lung cancer. The various techniques will be discussed regarding their pros and cons to further provide functional information that best reflects specific targeted therapies including anti-angiogenetic treatment, immunotherapies and stereotactic body radiation therapy. Moreover, imaging techniques and optimal time points after local minimally invasive treatments with microwave ablation or novel irreversible electroporation will be discussed. The second part of the presentation will focus on Radiomics and its potential value in lung cancer imaging. Literature: 1. Rami-Porta R, Crowley JJ, Goldstraw P. The revised TNM staging system for lung cancer. Ann Thorac Cardiovasc Surg 2009;15:4-9. 2. Rengan R, Maity AM, Stevenson JP, Hahn SM. New strategies in non-small cell lung cancer: improving outcomes in chemoradiotherapy for locally advanced disease. Clin Cancer Res 2011;17:4192-9. 3. Miles K. Can imaging help improve the survival of cancer patients? Cancer Imaging 2011;11 Spec No A:S86-92. 4. Nishino M, Jackman DM, Hatabu H, Janne PA, Johnson BE, Van den Abbeele AD. Imaging of lung cancer in the era of molecular medicine. Acad Radiol 2011;18:424-36. 5. Nishino M, Jagannathan JP, Ramaiya NH, Van den Abbeele AD. Revised RECIST guideline version 1.1: What oncologists want to know and what radiologists need to know. AJR Am J Roentgenol 2010;195:281-9. 6. Henzler T, Goldstraw P, Wenz F, et al. Perspectives of novel imaging techniques for staging, therapy response assessment, and monitoring of surveillance in lung cancer: summary of the Dresden 2013 Post WCLC-IASLC State-of-the-Art Imaging Workshop. J Thorac Oncol 2015;10:237-49. 7. Oxnard GR, Morris MJ, Hodi FS, et al. When progressive disease does not mean treatment failure: reconsidering the criteria for progression. J Natl Cancer Inst 2012;104:1534-41. 8. Stacchiotti S, Collini P, Messina A, et al. High-grade soft-tissue sarcomas: tumor response assessment--pilot study to assess the correlation between radiologic and pathologic response by using RECIST and Choi criteria. Radiology 2009;251:447-56.