Virtual Library

Abstract:
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

Abstract:
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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Abstract:
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.

Abstract:
The definition of staging in Lung Cancer is the determination of the anatomic extent of three tumor components: the primary tumor (T), the lymph nodes (N), and the metastases (M). Their accurate evaluation allows grouping patients in stages that is one, and perhaps the single most important, of several prognostic factors that guide the appropriate treatment option(s) to offer the patient. The clinical classification cTNM (Pre-treatment clinical classification), is based on evidence acquired before treatment The pathological classification pTNM (Post-surgical histopathological classification), is based on the evidence acquired before treatment, supplemented or modified by the additional evidence acquired from surgery and from pathological examination. A minimum number of tests is not required to define the extent of the disease, but it’s very clear that as more exhaustive the explorations more accurate and precise the staging will be. This may be strongly affected by the availability of physical and human resources, multidisciplinary work and adherence to clinical practice guidelines. After the changes proposed by the new IASLC-ATS-ERS lung adenocarcinoma classification and the IASLC proposals for revision of the T, N and M descriptors and stage groupings in the forthcoming (Eighth) edition of the TNM Classification for Lung Cancer, we must incorporate this new information into our clinical practice. (1, 2) The changes that The IASLC Staging Committee recommends for the T, N and M components and the resulting new stage grouping and their survival are summarized in table 1 and figure 1. The main changes in T components are the relevance of the size of the tumor for each cm, grouping of the involvement of the main bronchus or partial and total atelectasis or pneumonitis as a T2 descriptor and the reclassification of diaphragm invasion as T4. (3) N component remains without changes. (4) In M component a new M1b category includes patients with a single metastatic lesion in a single organ site and a new M1c category was introduce for patients with multiple lesions in a single organ or multiple lesions in multiple organs. (5) Some new stage groupings are proposed. The new size cut points of T1-N0-M0 tumors has been assigned to stage IA1, IA2, and IA3. The new stage IIIC (T3 and T4-N3-M0) reflects their worse outcome. Finally, stage IV disease has been divided into IVA (M1a, M1b) and IVB (M1c). The new IVA stage grouping should be used in trials analyzing patients with oligo-metastasis or pleural or pericardial disease. (2) For the newly described types of adenocarcinoma of the lung, The IASLC recommends incorporating the coding of AIS as Tis (AIS) and of MIA as T1mi into the traditional TNM classification. For part-solid tumors, the size of the invasive component should be used to assign a T category, but the whole tumor size should also be recorded. However, the measurements will be influenced by a number of observer-dependent and technical factors. It is important to perform the measurements for clinical staging on contiguous thin CT sections reconstructed with a high-resolution algorithm with multiplanar reconstruction. (6) For pathologic staging, attention should be given to the assessment of invasive and lepidic components. It can be helpful to correlate microscopic findings with measurements made on gross examination, particularly in inflated specimens or with CT findings. Patients who present with more than one pulmonary site of lung cancer may represent different patterns of disease as synchronous primary lung cancers, those with a separate solid tumor nodule(s) (intrapulmonary metastases), multifocal lung cancer presenting as multiple nodules with ground glass/lepidic features, and diffuse pneumonic-type adenocarcinoma. It is proposed that the T category of patients presenting ground glass/lepidic (GG/L) tumors be classified using the T category of the highest T lesion and in parentheses either the number of GG/L tumors or simply m for multiple (#/m). A single N and M category is assigned for all GG/L tumors combined. (7) Both clinical information (the presence of additional lesions identified by imaging) and the pathologic information (from resected lesions) should be used to determine the TNM classification. Lesions smaller than 5 mm or AAH are not counted. The pneumonic type of adenocarcinoma should be classified according to the size of the area of lung involved, or as T4 or M1a in the case of involvement of more than one lobe (i.e., either ipsilateral or contralateral). A single N and M category is assigned. In patients with separate tumor nodules (intrapulmonary metastases), it is proposed that the seventh edition classification of same-lobe nodules as T3, same side (different lobe) nodules as T4, and other-side nodules as M1a be carried forward. (8) It is easier to establish that two pulmonary foci of cancer are separate primary tumors than that they are metastatic from one another. Few features are sufficiently reliable by themselves, such as different histologic type and differences by a comprehensive histologic assessment of resected specimens or by matching breakpoints by DNA sequencing. Most criteria can be suggestive, but are associated with potential misclassification. These include biomarker patterns, imaging characteristics, and the presence or absence of nodal involvement. The fact that generally only biopsy specimens are available at the time of clinical decision making further adds to the uncertainty and difficulty of the assessment. A constellation of factors is better than any single factor; it is best to make a determination of separate primary versus metastatic lesions through a collective judgment of a multidisciplinary tumor board after taking into account all of the available information. (9) Synchronous primary cancers are classified with a T, N, and M category for each tumor; separate tumor nodules result in a T3, T4, or M1a category depending on the separate nodule’s location relative to the primary tumor. (10) Despite these proposals of staging, there will always be areas of difficulty and tumors that are challenging to classify. The prognostic value of clinical and pathological TNM staging in patients with SCLC was also confirmed, and the continued usage is recommended for SCLC in relation to proposed changes to T, N, and M descriptors for NSCLC in the eighth edition. (11) Table 1 Descriptors and T and M categories in the seventh edition and as proposed for the eighth edition. Figure 1 *Where there is a change, the resultant stage groupings proposed for the eighth edition are in bold, and the stage in the seventh edition is given in parenthesis. Figure 1 Overall survival by clinical and pathological stage according to the proposed eighth edition groupings using the entire database available for the eighth edition. Figure 2References: 1. Travis WD, et al. The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification. J Thorac Oncol. 2011;6: 244–285. 2. Goldstraw P et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer Journal of Thoracic Oncology, Vol. 11, Issue 1, p39–51 3. Rami-Porta R et al. The IASLC Lung Cancer Staging Project: Proposals for the Revisions of the T Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. Journal of Thoracic Oncology, Vol. 10, Issue 7, p990–1003 4. Asamura H et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revision of the N Descriptors in the Forthcoming 8th Edition of the TNM Classification for Lung Cancer. Journal of Thoracic Oncology, Vol. 10, Issue 12, p1675–1684 5. Eberhardt W E.et al. The IASLC Lung Cancer Staging Project: Proposals for the Revision of the M Descriptors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. Journal of Thoracic Oncology, Vol. 10, Issue 11, p1515–1522 6. Travis WD, 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. Journal of Thoracic Oncology, Vol. 11, Issue 8, p1204–1223 7. Detterbeck FC et al. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Application of TNM Staging Rules to Lung Cancer Presenting as Multiple Nodules with Ground Glass or Lepidic Features or a Pneumonic Type of Involvement in the Forthcoming Eighth Edition of the TNM Classification. Journal of Thoracic Oncology, Vol. 11, Issue 5, p666–680 8. Detterbeck FC et al. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Classification of Lung Cancer with Separate Tumor Nodules in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. Journal of Thoracic Oncology, Vol. 11, Issue 5, p681–692 9. Detterbeck FC et al. The IASLC Lung Cancer Staging Project: Background Data and Proposed Criteria to Distinguish Separate Primary Lung Cancers from Metastatic Foci in Patients with Two Lung Tumors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. Journal of Thoracic Oncology, Vol. 11, Issue 5, p651–665 10. Detterbeck FC et al. The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification. Journal of Thoracic Oncology, Vol. 11, Issue 5, p639–650 11. Nicholson AG et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revision of the Clinical and Pathologic Staging of Small Cell Lung Cancer in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. Journal of Thoracic Oncology, Vol. 11, Issue 3, p300–311

Abstract:
Malignant pleural mesothelioma (MPM) is a highly lethal malignancy arising from the serosal lining of the pleural cavity [1]. In up to 80% of patients, asbestos is considered to contribute to the development of this tumor within about 20 to 40 years of exposure time [2]. The incidence of MPM is expected to increase dramatically over the next few decades. It has been estimated that 250 000 people will die of MPM in Europe in the next three decades, and 2500–3000 new cases are diagnosed each year in the USA [3]. The macroscopic appearance of MPM depends on disease stage. In early stage MPM, the cancer presents as multiple small nodules on the surface of both pleural linings. In advanced stages, the multiple small nodules form a tumor plate which surrounds the lung like a cage and in most cases invades the lung parenchyma, diaphragm and pericardium [4]. The establishment of the pathological diagnosis of MPM and the classification in three main histological subtypes (namely epitheloid, biphasic and sarcomatoid) is important and has an impact on therapy and prognosis. Epitheloid MPM is more therapy responsive and associated with better outcome compared to biphasic and sarcomatoid histotypes. Other very important simple prognostic factors for MPM are disease stage and lymph node involvement. Therefore an adequate staging of MPM patients is crucial for therapy decision-making. The currently widely used staging system is the one according to International Mesothelioma Interest Group (IMIG) established in 1996 [5]. Based on the TNM (tumor-node-metastasis) system for malignant tumors, this staging system describes: the extent and size of the primary tumor, lymph node involvement and distant metastases. By the different TNM descriptors, MPM can be classified and summarized in four different tumor stages (IMIG I-IV). Patients suffering from stage I-III are considered for surgery within multimodality protocols, while palliative systemic or local treatment is indicated for stage IV in accordance with the current classification. Butchart et al. [6]proposed in 1976 an alternative staging system, referred to as the Butchart Staging. Contrary to the IMIG system (based on lung cancer staging) the Butchart system is particularly set up for MPM. Therefore, several differences between both staging systems exist. However, the IMIG in collaboration with the International Association for the Study of Lung Cancer (IASLC) have proposed a new T, N and M descriptors for in the forthcoming 8[th] edition of the TNM classification for MPM with significant changes to the 7[th] TNM edition and proposals have been very recently published [7-9]. With regard to the T descriptor, a fusion of both, clinical and pathological T1a and T1b into a T1 was recommended [7]. Regarding the N descriptor, a summary of the clinical and pathological N1 and N2 categories into a single category with the classification into ipsilateral, intrathoracic nodal metastases (N1) was proposed [8]. No changes have been recommended for the M descriptor in the 8[th] edition of the TNM [9]. In this presentation, 4 patient cases of different stages of MPM patients will be presented and the newly proposed TNM descriptors and IMIG staging will be applied. Cases and changes in the staging system will be discussed together with the attending audience in an interactive manner. After the presentation, the participants will be able to understand and practically apply the forthcoming changes in the TNM system for staging of MPM patients. 1. Whitaker, D., J.M. Papadimitriou, and M.N. Walters, The mesothelium and its reactions: a review. Crit Rev Toxicol, 1982. 10(2): p. 81-144. 2. Lanphear, B.P. and C.R. Buncher, Latent period for malignant mesothelioma of occupational origin. J Occup Med, 1992. 34(7): p. 718-21. 3. Peto, J., et al., The European mesothelioma epidemic. Br J Cancer, 1999. 79(3-4): p. 666-72. 4. Rudd, R.M., Malignant mesothelioma. Br Med Bull, 2010. 93: p. 105-23. 5. Rusch, V.W., A proposed new international TNM staging system for malignant pleural mesothelioma from the International Mesothelioma Interest Group. Lung Cancer, 1996. 14(1): p. 1-12. 6. Butchart, E.G., et al., Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura. Experience with 29 patients. Thorax, 1976. 31(1): p. 15-24. 7. Nowak, A.K., et al., The IASLC Mesothelioma Staging Project: Proposals for Revisions of the T descriptors in the forthcoming Eighth edition of the TNM classification for pleural mesothelioma. J Thorac Oncol, 2016. 8. Rice, D., et al., The IASLC Mesothelioma Staging Project: Proposals for Revisions of the N Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Pleural Mesothelioma. J Thorac Oncol, 2016. 9. Rusch, V.W., et al., The IASLC Mesothelioma Staging Project: Proposals for the M Descriptors and for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Mesothelioma. J Thorac Oncol, 2016.

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Abstract:
Despite the reduction in cigarette consumption in many parts of the world, the incidence and mortality rate of lung cancer will remain high in the year 2030[1]. Over the last 50 years major advances in the treatment of lung cancer have included early detection by screening CT, improved cure rates with neo-adjuvant and adjuvant chemotherapy, the successful integration of chemotherapy with radiation for locally advanced disease, and prolonged survival times with chemotherapy in the metastatic setting. More recently, the discovery of targetable mutations and development of a myriad of small molecule tyrosine kinase inhibitors have transformed the natural history of lung cancer in select subsets. Furthermore, immunotherapy is now a reality in the treatment of patients with stage IV non-small cell lung cancer (NSCLC). Today, the integration of targeted agents and immunotherapy are being investigated in earlier stages of disease. With these recent advances, what does the future of chemotherapy hold in the treatment of stage I-IV NSCLC? Is there a future at all? Can we eliminate the need for chemotherapy altogether for most patients at any point in their disease history? The dream of replacing chemotherapy with more active, less toxic, and more convenient therapy for patients with stage I-IV NSCLC is a laudatory goal. Is it realistic by the year 2030? Certainly not. Chemotherapy is currently the only systemic therapy that has ever been known to cure patients in the neo-adjuvant or adjuvant setting for stage I-III NSCLC[2]. While many targeted agents can prolong life in the metastatic setting, to date all of those tested in the adjuvant setting have failed to improve upon standard therapy[3-5]. The graveyard of negative trials in the adjuvant setting includes those evaluating angiogenesis inhibition, epidermal growth factor tyrosine kinase inhibition, and vaccine therapy. The same can be said for locally advanced, unresectable NSCLC. While the integration of chemotherapy with radiation improves survival rates compared with radiation alone[6], thus far no other agents have successfully done so, including tyrosine kinase inhibitors, angiogenesis inhibitors, or monoclonal antibodies[7-8]. In the metastatic setting, chemotherapy improves survival whether given as induction therapy or as maintenance therapy. Chemotherapy is also more active than targeted therapy in the vast majority of patients who do not harbor targetable mutations. Even with the stunning success of immunotherapy for some patients with advanced NSCLC, it appears this will not be curative in this setting and nearly all patients will still be getting chemotherapy at some point of their disease history. In other words, chemotherapy works for patients with stage I-IV NSCLC. Just as we will do with targeted therapy and immunotherapy, we will not abandon what works, but rather we will improve upon it. Chemotherapy works in a broad group of patients with lung cancer. It targets DNA, topoisomerase, and the mitotic spindle, which are the key targets in all cells. The majority of patients’ tumors do not have targetable mutations and most patients do not respond to immunotherapy. While gains are expected over the next 15 years in targeted therapy and immunotherapy, it is likely that we will discover the plateau in the benefit to these strategies and eventually nearly all patients will develop resistance. While predicting the future is usually only a fool’s errand, the past is prologue. So, what is the future of chemotherapy in NSCLC? Better drug delivery systems; developing combination therapy with DNA repair agents, cell cycle checkpoint modulators, and immunotherapy; and improved biomarkers for efficacy and toxicity are each on the horizon. Improved targeting of the cancer cell, increased cancer cell drug concentrations, and reduction of normal cell toxicity can be accomplished through nano-carriers[9]. Nano-carriers can deliver chemotherapy directly to cancer cells by protecting these agents from being degraded in the circulation and being excessively protein bound, limiting active drug exposure. Nano-carriers include liposomes, carbon nanotubes, dendrimers, and polymeric compounds (micelles, conjugates, nanoparticles). These carriers are typically 100-150 nm in size but have large surface-to-surface volume ratios, enabling them to encapsulate cytotoxic agents and enhancing drug deliver to tumors. Thus far 8 have been FDA approved, including 2 polymer-protein conjugates, 5 liposomal formulations, and 1 polymeric nanoparticle, in various cancers. Another strategy to enhance drug delivery to tumors is through antibody-drug conjugates (ADC). These agents link an antibody to a protein overexpressed on the surface of a cancer cell to a potent cytotoxic such as a microtubule inhibitor or an alkylating agent. The cytotoxic is released only in the cancer cell after the ADC complex is internalized. Examples include TDM-1 and Brentuximab. Over 30 ADC’s are under clinical investigation, including several against lung cancer including Rova-T and Sacituzumab. Another promising strategy for the future treatment of lung cancer involves combining chemotherapy with drugs that interfere with DNA repair, silence DNA repair genes, or inhibit cell cycle arrest [10]. Examples of this approach include PARP inhibitors, DNA methylation agents, and checkpoint modulators. Combination trials of chemotherapy and immunotherapy are also underway. In this regard, ADC technology may prove a more effective strategy when combining cytotoxic drugs with immunotherapy. By improving chemotherapy drug delivery to cancer cells and reducing off-target toxicities, nanotechnology has the potential to most effectively combine chemotherapy with immunotherapy. Lastly, despite decades of clinical investigation, most patients are empirically treated with chemotherapy, regardless of the molecular characteristics of the tumor and the pharmacogenomics of the patient. Refinements in these areas are expected in the upcoming years. In conclusion, for better or worse, in the year 2030 chemotherapy will remain standard of care for the majority of patients with stage I-IV NSCLC. But, the year 2040 or 2050 may be a different story. References 1. Rahib L, Smith B, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancer in the United States. Cancer Res 2014;74(11):2913-2921. 2. Burdett S, Pignon J, Tierney J, et al. Adjuvant chemotherapy for resected early-stage non-small cell lung cancer. Cochrane Database Syst Rev 2015;2(3):doi: 10.1002/14651858.CD011430 3. Wakelee H, Dahlberg S, Keller S, et al. E1505: Adjuvant chemotherapy +/- bevacizumab for early stage NSCLC—Outcomes based on chemotherapy subsets. J Clin Oncol 2006;34(abstract 8507). 4. Kelly K, Altorki N, Eberhardt W, et al. Adjuvant Erlotinib Versus Placebo in Patients With Stage IB-IIIA Non–Small-Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial. J Clin Oncol 2015;33:4007-4014. 5. Van Steenkiste J, Zielinski M, Linder A, et al. Adjuvant MAGE-A3 Immunotherapy in Resected Non–Small-Cell Lung Cancer: Phase II Randomized Study Results. J Clin Oncol 2013;31(19):2396-2403. 6. O’Rourke N, Roque i Figuls M, Farre Bernado N, et al. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev 2010; DOI: 10.1002/14651858.CD002140. 7. Kelly K, Chansky K, Gaspar L, et al. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 2008;26(15):2450-6. 8. Bradley J, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015;16(2):187-199. 9. Fanciullino R, Ciccolini J, Milano G. Challenges, expectations and limits for nanoparticles-based therapeutics in cancer: a focus on nano-albumin-bound drugs. Crit Rev Onc Hemat 2013;88:504-513. 10. Helleday T, Petermann E, Lundin C, et al. DNA repair pathways as targets for cancer therapy. Nature Rev 2008;8:193-204.

Abstract:
By 2030 Chemotherapy will Remain Standard of Care for the Majority of Patients with NSCLC Stages I-IV: Contra Chemotherapy Cytotoxic chemotherapy has undeniably provided benefit for our patients with non-small cell lung cancer (NSCLC). However its nondiscriminatory application based on general tumor biology principles and not on the underlying biology of lung cancer has hampered its ability to dramatically improve survival and cures for lung cancer. Over the last twenty years we have seen multiple examples of how molecular characterization of lung tumors coupled with advances in drug development, have led to astonishing improvements in cancer outcomes. Hence, it is time to set a course toward abandoning chemotherapy. In addition to their superior efficacy, targeted therapies and immunotherapy have milder toxicity profiles compared to chemotherapy that all patients appreciate. We have already made significant progress in this quest. Our journey began with the discovery of EGFR (epidermal growth factor receptor) mutations and their exquisite sensitivity to EGFR-TKI (tyrosine kinase inhibitors). This observation was confirmed in the landmark IPASS trial that demonstrated the superiority of EGFR-TKIs over platinum-based chemotherapy for the first line treatment of patients whose tumors harbor these mutations (1). On the heels of this therapeutic advancement came the discovery of ALK (anaplastic lymphoma kinase) gene rearrangements and the replacement of doublet chemotherapy with an ALK-TKI in patients with ALK positive tumors (2). To date actionable driver mutations are found in at least 50% of patients with adenocarcinoma (3) and inhibitors to all of these mutations are in clinical development with the hope that they will have similar success as their predecessors. Of particular interest is developing inhibitors to KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) because it is the most frequent driver mutation occurring in approximately 20-25% of tumors. Today there is optimism that we will achieve this goal given it is the focus of the Stand Up To Cancer (SU2C) lung cancer dream team initiative and several novel agents are in development including direct KRAS therapy. Driver mutations are typically identified in patients who are never smokers, light former smokers or have a lengthy quit time. The remaining groups of patients’ (i.e. current smoker or recent former smokers) have a different biology that has been successfully exploited with immunotherapy. Immune checkpoint inhibitors have replaced single agent docetaxel as the standard of care for second line treatment of lung cancer for all histological subtypes of NSCLC (4-6). Most recently the KEYNOTE-024 a randomized trial of pembrolizumab versus doublet chemotherapy for untreated patients with advanced NSCLC whose tumor have > 50% PD-L1 (programmed death-ligand 1) IHC (immunohistochemistry) expression met its primary progression-free survival (PFS) endpoint and also improved overall survival (7). This will represent a new standard of care for approximately 25% of patients and will serve as the backbone for immune combinations. We are anxiously awaiting the results of a randomized trial of a PD-1 (programmed cell death protein 1) inhibitor plus a CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor versus platinum-based chemotherapy that is expected to report out in mid 2017. A similar study is actively accruing patients. The preliminary results on this dual immune combination were very promising and if positive would increase the number of patients receiving upfront immune therapy over chemotherapy (8). Additionally, there are numerous immune combinations involving drugs that target immune evasion and even more drugs that stimulate the immune system including cellular therapies that are being evaluated. The success of targeted therapy and immunotherapy in the advanced setting has quickly led to their evaluation in earlier stages of disease. There is a lot of enthusiasm for combining immunotherapy with radiation for patients with locally advanced lung cancer given the well-known immune modulatory effects of radiation. Moreover the bar for replacing weekly low dose concurrent chemotherapy with immunotherapy is low. In the adjuvant setting our Asian colleagues designed and conducted two randomized phase III trials in patients whose tumors have an EGFR sensitizing mutation to replace chemotherapy with an EGFR-TKI. Accrual is completed and we are awaiting the results. In regard to immunotherapy, enrolling phase III trials are evaluating immune checkpoint inhibitors as maintenance therapy but the pursuit of immunotherapy as a replacement for chemotherapy will follow. Beyond treatment of lung cancer, on the horizon is the exploration of targeted agents and immunotherapy as preventive agents. It is important to emphasize that our current and future success is the consequence of many factors: 1) the exponential advances in technology that has driven the science and drug development 2) rapid trial accrual and 3) regulatory authorities’ responsiveness to bringing efficacious treatments to patients as quickly as possible. This momentum is what will lead us to replacing chemotherapy for lung cancer. With 20%+ of patients with driver mutations and 25% of all NSCLC with high PD-L1 already benefiting from non-chemotherapy treatment, we are well on our way to ousting chemotherapy in NSCLC by 2030. References Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma. N Engl J Med 2009, 361:947-57. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013, 368:2385-94. Vigneswaran J, Tan YH, Murgu SD, et al. Comprehensive genetic testing identifies targetable genomic alterations in most patients with non-small cell lung cancer, specifically adenocarcinoma, single institute investigation. Oncotarget 2016, 7:18876-86. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015, 373:123-35. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015, 373: 1627-39. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized controlled trial. Lancet 2016, 387:1540-50. MERCK press release, July 2016 Hellman MD, Gettinger SN, Goldman JW, et al. CheckMate 012: Safety and efficacy of first-line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. J Clin Oncol 34, 2016 (suppl; abstr 3001).

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Abstract:
Discovery of activating mutations of the EGFR gene in adenocarcinoma of the lung in 2004 opened the door to a new era for personalized therapy in thoracic oncology. Lung cancers with EGFR mutation are highly sensitive to EGFR-tyrosine kinase inhibitors (TKI) such as gefitinib, erlotinib, or afatinib, resulting in significantly prolonged progression free survival compared with those treated with platinum doublet chemotherapy. However, acquired resistance inevitably develops usually after a median of 10~12 months. The mechanisms for this resistance have been extensively studied and can be classified into 1) target gene alteration, 2) activation of bypass / accessory pathway, and 3) histologic transformation (Fig.).Figure 1 The most common (50~60%) mechanism for acquired resistance to the EGFR-TKI is a missense mutation at codon 790 of the EGFR gene resulting in substitution of threonine to methionine (T790M). This amino acid change reduces affinity between EGFR kinase and EGFR-TKI compared with that between EGFR-kinase and ATP, leading to reactivation of down-stream pathways. L747S, D761Y, and T854A are also known as secondary mutations that cause acquired resistance, but they are very rare. In these cases, cancer cells are still addicted to or dependent on EGFR pathway. Amplification of the MET gene which codes for a receptor of hepatocyte growth factor (HGF) was the first that was identified as a bypass track resistance mechanism against EGFR-TKI. Following this report, aberrant activation of other receptor tyrosine kinases such as HER2, HER3, AXL, IGF1R, have been reported. It is also shown that some ligands for the receptor tyrosine kinases such as HGF, FGF or IGF cause acquired resistance to EGFR-TKIs. Similarly, alteration of downstream molecule cause resistance. These molecules include BRAF, PTEN, JAK2, CRKL, DAPK, NF-kB, or PUMA. The third mechanism of acquired resistance is histologic transformation that includes small cell lung cancer transformation and epithelial-mesenchymal transition EMT). Exact mechanisms of these histologic changes are not fully understood. However, AXL, Notch-1, TGFb pathway activation as well as down regulation of MED12 ((Mediator Complex Subunit 12) have been proposed as mechanisms of EMT. Then, How are we able to cope with these resistance? For T790M gatekeeper mutations, the third generation EGFR inhibitors that selectively inhibit EGFR-T790M while sparing the wild-type EGFR are active. One of these drugs, osimertinib is already approved and gives a response rate of ~60% and progression free survival of ~11 months. Therefore, identification of T790M at the time of disease progression by rebiopsy is important. We have recently found that three other secondary EGFR mutations implicated in acquired resistance are also sensitive to osimertinib. Tumor resistance caused by activation of accessory pathways can be theoretically coped with by combination of the inhibitor of EGFR and involved molecules. However, because of rarity of each mechanism, there is no clear evidence whether these combination therapies will actually improve patient outcome In other cases, cytotoxic chemotherapy is still an important strategy. According to the IMPRESS study, median progression free survival for patients without T790M who received cisplatin plus pemetrexed was 5.4 months. Eeven with these strategies, cancer cells are smart enough to escape from the therapy using other mechanisms. Heterogeneities in terms of resistant mechanisms within a single patient become evident when specific therapeutic pressure persists. Therefore, we also need to have armamentarium that utilizes other mechanisms to cure lung cancer. Recent advances of immunotherapy targeting immune checkpoints appear attractive in this respect. These mechanism-driven therapeutic approaches will convert this fatal disease into a more chronic disorder, and eventually into a curable disease with the least patient burden.

Abstract:
Figure 1. Sequence of EGFR TKIsFigure 1 Sequencing of EGFR Tyrosine Kinase Inhibitors Keunchil Park, MD, PhD Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Treatment of EGFR-mutant(EGFRm) lung cancer with specific EGFR TKIs, such as gefitinib, erlotinib or afatinib, has opened the door to the precision medicine in the management of advanced non-small cell lung cancer with remarkable tumour shrinkage and improvement in progression-free survival (PFS) and quality of life compared to standard chemotherapy. Despite such a remarkable initial clinical response with EGFR TKIs in patients with EGFR+ NSCLC, however, the disease eventually comes back with the emergence of acquired resistance and median PFS is ~ 1 year. The most common mechanism of resistance is acquisition of the T790M gatekeeper mutation and the 3rd-generation EGFR TKIs irreversibly inhibit mutant EGFR, esp. T790M, with sparing wild-type(WT) EGFR. There are several EGFR mutant specific inhibitors(EMSIs) under development including AZD9291, CO-1686, BI1482694 /HM61713, ASP8273, etc. All these 3rd-generation EGFR TKIs have shown a promising early clinical efficacy in T790M(+) EGFRm NSCLC patients with ORR of ca. 60% and PFS of 9.6 – 10.3 months and appear to be well tolerated. Based upon these encouraging early results many confirmatory phase 3 trials(e.g., NCT02151981, NCT02322281) comparing to the standard chemotherapy in the 2nd-line setting are underway. It is very tempting that one might like to move the 3rd-generation EGFR TKI to 1st-line setting. The development of the 3rd-generation agents as the first-line therapy for patients with EGFRm disease has already started. Recently AZD9291 demonstrated an encouraging clinical activity and a manageable tolerability profile in 1st-line: confirmed objective response rate of 77% (95% CI 64, 87) and mPFS of 19.3 months (investigator-assessed). Currently it is being compared with the 1st/2nd-generation EGFR TKI in the 1st-line setting. The Phase III FLAURA study (NCT02296125), comparing AZD9291 80 mg once daily versus current standard of care EGFR-TKIs for treatment-naïve patients, is enrolling. Though the preliminary result in the 1L setting is quite provocative, extreme caution needs to be exerted since the currently available data are not mature enough to determine which agent is the best in its class and only from a small subset of patients. Though it is hoped that the T790M-mediated resistance can be delayed or prevented by using the EMSIs in the TKI-naïve setting, it is also possible that other less well known escape mechanisms might emerge. Given that EMSI works well after failing 1st/2nd-generation EGFR TKI I believe it seems to be a more reasonable approach to investigate if EMSI in the TKI-naïve setting is more effective than 1st/2nd-generation EGFR TKI followed by EMSI when failing 1st/2nd-generation EGFR TKI with acquired resistance. One of the biggest questions to emerge in the era of next-generation inhibitors that have activity against the basic driver oncogene is whether it makes sense to use this approach before the development of acquired resistance to prevent it from occurring in the first place. Can its use in the 1st-line(TKI-naïve) setting prevent the development of acquired resistance and lead to a longterm control of the disease? Considering the well-known genomic heterogeneity with its possible association with resistance to EGFR TKIs we need better understanding of the biology and resistance mechanisms to this class of new generation EGFR TKIs in order to develop better strategies for subsequent therapies to overcome the resistance including how to best sequence the available EGFR TKIs in the clinic as well as combination therapies. It is fair to say that during the past few years we’ve clearly made another progress in the management of NSCLC patients with EGFRm, including those who failed previous EGFR TKIs. However, the currently available data are not mature enough to determine which agent is the best in its class, with the notable differences primarily related to toxicity and we’re not there yet and still lots of unanswered questions remain and further researches are warranted. References 1. DR Camidge, et al. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol 2014;11: 473–481 2. SS Ramalingam, et al. The Next Generation of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Treatment of Lung Cancer. Cancer 2015;121:E1-E6 3. GR Oxnard et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M. Nature Med 2015;21:560-564 4. LV Sequist et al. Heterogeneity Underlies the Emergence of EGFR T790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor . Cancer Discov 2015;5(7): 713–22 5. CM Lovly et al. Shades of T790M: Intratumor Heterogeneity in EGFR -Mutant Lung Cancer. Cancer Discov 2015;5(7): 694–6. 6. S Ramalingam, et al. ELCC 2016; Abstract LBA1_PR

Abstract:
Somatic mutations clustering in exons 18 to 21 of the EGFR gene characterize distinct lung cancer biologies. Patients with metastatic EGFR-mutated lung cancer are exquisitely sensitive to targeted agents inhibiting the EGFR tyrosine kinase, which have demonstrated superior progress-free survival and, in some instances, overall survival when compared to platinum-based chemotherapy in first-line treatment. Several studies have shown that EGFR mutations can be detected by highly sensitive assay technology in free DNA circulating in the blood from patients with EGFR-mutated lung cancers 1,2,3. Circulating EGFR-mutated DNA may drop below the level of detection in patients responding to EGFR-TKI, and persistence or reoccurrence of circulating EGFR-mutated DNA may associate with primary and acquired resistance 1,3. In addition, clonal evolution of EGFR-mutated lung cancers under EGFR-TKI therapy can be mirrored by the detection of gatekeeper mutations, such as EGFR T790M or the EGFR C797S, in circulating DNA 4,5. Hence, mutation analysis in circulating free DNA has been suggested as a clinically more feasible and less invasive method for detection of predictive genomic biomarkers and treatment monitoring in advanced lung cancer. The development of more sensitive technologies and bioinformatic algorithms enables the study of comprehensive genomic biomarker panels in blood-derived DNA, which cover a broader spectrum of actionable mutations in treatment-naïve patients and those with acquired TKI resistance. Currently, there are still several limitations to overcome. First, the predictive value of a mutation detected in blood-derived DNA cannot be simply extrapolated from validation studies conducted with tumor-derived DNA. In consequence, prospective clinical validation of blood-based biomarkers is mandatory. Secondly, most studies comparing EGFR mutation detection in tumor and “liquid” biopsies side-by-side reveal inferior sensitivity of blood-based assays. Also, there is a considerable degree of discordance between such assays 4,6,7. Thus, “negative” findings in circulating tumor DNA have to be confirmed by a second assay in tumor-derived DNA. Apart from inflating spending on molecular diagnostics, this may result in further treatment delays, which is hard to bear for patients in particular in the first-line setting. While these obstacles may be soon overcome by technological advances and evolving data from validation studies, “liquid biopsies” focusing on DNA and/or RNA will always miss out on the histopathological information that can be derived from a biopsy of a tumor or metastasis. In the era of immunomodulatory antibody therapy information of tumor-infiltrating immune and stromal cells as well as expression of biomarkers by specific cell populations or with spatial variation become increasingly important. Until this information cannot be reproducibly derived by novel assay technologies the detection of genomic biomarkers in blood-derived DNA will become a highly valuable, additive modality for specific scenarios of primary diagnosis and treatment monitoring. References: 1 N Engl J Med. 2008 Jul 24;359(4):366-77. 2 Clin Cancer Res. 2009 Apr 15;15(8):2630-6. 3 PLoS One. 2014 Jan 21;9(1):e85350. 4 Lung Cancer. 2015 Dec;90(3):509-15. 5 Nat Med. 2015 Jun;21(6):560-2. 6 Clin Cancer Res. 2016 Mar 1;22(5):1103-10. 7 J Clin Oncol. 2016 Jun 27. pii: JCO667162.

Abstract:
Introduction Due to general ageing population, many patients with lung cancer are elderly and with frequent underlying co-morbidities. The most frequent co-morbidities associated with lung cancer are cardiac (i.e. coronary artery disease) and pulmonary diseases (i.e. COPD). Cardiac co-morbidity Coronary artery disease (CAD) is present in approximately 10-15% of lung resection candidates. The risk of major adverse cardiac events (MACE) and cardiac mortality is 4-fold higher in patients with previous history of CAD1 and patients with a previous coronary stent procedure within 1 year from lung resection had MACE and mortality rates of 9.3% and 7.7% after surgery, respectively2. Cardiac evaluation is therefore particularly important in this population to optimize their treatment and reduce surgical risk. A specific cardiac risk score was recently developed and is named Thoracic RCRI (ThRCRI). Patients in the highest class of risk had a incidence of MACE of 23% versus only 1.5% in those in the lowest class of risk1. These findings were subsequently validated by a number of independent studies. Detailed evaluation for coronary heart disease is not recommended in patients who have an acceptable exercise tolerance and with low cardiac risk score. For patients whose exercise capacity is limited, those with a ThRCRI > 1.5 or those with known or newly suspected cardiac condition, non-invasive cardiac evaluation is recommended as per AHA/ACC guidelines3 to identify patients needing more invasive interventions. Appropriately aggressive cardiac interventions should be instituted prior to surgery only in patients who would need them irrespective of the planned surgery. However, prophylactic coronary revascularization prior to surgery in patients who otherwise do not need such a procedure does not appear to reduce perioperative risk4. Pulmonary co-morbidity Approximately 20-25% of patients with early stage lung cancer have a concomitant moderate to severe COPD (FEV1<80% and FEV1/FVC ratio < 70%). Many studies have shown the association between FEV1 or predicted postoperative FEV1 (ppoFEV1), and surgical risk. In particular the risk of pulmonary morbidity and mortality has been shown to increase when FEV1 is below 50-60% or ppoFEV1< 30-40%. However, recent evidence has shown that even patients with moderate to severe COPD and lung cancer can undergo safely to lung resection. In these patients, the resection of the most affected parenchyma containing the tumor may determine a minimal loss or even an improvement in respiratory mechanics and elastic recoil, similar to what happens in typical end-staged emphysema patients candidates to lung volume reduction surgery. Nearly one third of COPD patients may actually improve their FEV1 3 months after pulmonary lobectomy for cancer. Therefore, although a reduced FEV1 or ppoFEV1 is associated with increased morbidity and mortality, most recent guidelines recommended against using this parameter alone to exclude patients from surgery even in case of very low values5,6. Patients with idiopathic pulmonary fibrosis (IPF) and lung cancer are a more challenging population to manage. Surgical treatment of these patients is high risk for postoperative acute exacerbations of IPF, which is associated with 80-100% mortality rate. The postoperative mortality rate of these patients has been reported to range between 7 and 18%. Moreover, long-term prognosis of IPF itself affects long term survival following surgery for cancer. Additional fitness tests Carbon monoxide lung diffusion capacity (DLCO) appears to be a more sensitive indicator of poor pulmonary function and more reliably associated with postoperative respiratory complications and mortality. Until recently, DLCO measurement has been mainly reserved to patients with abnormal FEV1. However, recent studies have shown that FEV1 and DLCO are poorly correlated and that more than 40% of patients with normal FEV1 (>80%) may have reduced DLCO. A low DLCO or ppoDLCO is a reliable predictor of cardiopulmonary morbidity and mortality not only in patients with COPD but also in those with normal respiratory function. This is the rationale behind the most recent recommendations to measure DLCO systematically in all lung resection candidates. Cardiopulmonary exercise test: Cardiopulmonary exercise test is the gold standard in preoperative evaluation of lung resection candidates. In addition to the most frequently used parameter, VO2max, it provides several other direct and derived measures that permit, in case of a limited aerobic reserve, to precisely identify possible deficits in the oxygen transport system. Several series have shown that a VO2max>20 mL/kg/min is safe for every extent of resection, whilst values < 10 mL/kg/min are associated with a high risk of potoperative mortality. We recently found that VO2max<12 mL/kg/min was associated with 13% in-hospital mortality rate following open major anatomic lung resections7. A parameter, which has gained recent interest in our specialty is the minute ventilation to carbon dioxide output (VE/VCO2) slope, also named as ventilatory efficiency slope. VE/VCO2 slope can be increased due to either pulmonary or cardiac diseases. Several studies have shown that a value greater than 35 is associated with increased respiratory complications and mortality after lung resection. We found that the mortality rate of patients with VE/VCO2>35 was 7% versus only 0.6% of those with lower values. The association between this parameter and respiratory complications remained the same for patients with and without COPD and for those with VO2max greater or lower than 15 mL/kg/min. VATS and sublobar resections Videoassisted thoracoscopic surgery (VATS) has been recommended as the approach of choice for stage I lung cancer patients. Several studies showed that this approach is associated with lower incidence of complications, shorter hospital stay and in some cases lower mortality rates compared to thoracotomy. The benefits of VATS are particularly evident in patients with poor pulmonary function. Large series found that the difference in pulmonary complication rates after lobectomy by VATS versus thoracotomy was present only in patients with a FEV1<60%. Burt and coll.8 found that patients with ppoFEV1<40% or ppoDLCO<40% and submitted to VATS lobectomy had a markedly reduced incidence of mortality compared to those operated on through thoracotomy (ppoFEV1<40%: 0.7% vs. 4.8%, p=0.003; ppoDLCO<40%: 2% vs. 5.2%, p=0.003). Recent evidences have shown that anatomic segmentectomies provide equivalent oncologic results compared to lobectomy for tumours smaller than 2 cm, whilst preserving much more respiratory function and being associated with lower incidence of postoperative complications9,10. This extent of resection appears therefore ideal for patients with a limited baseline pulmonary function. Selected references 1. Brunelli A, et al. Recalibration of the revised cardiac risk index in lung resection candidates. Ann Thorac Surg. 2010;90(1):199-203. 2. Fernandez FG, et al. Incremental risk of prior coronary arterial stents for pulmonary resection. Ann Thorac Surg. 2013 Apr;95(4):1212-8 3. Fleisher LA, et al. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery): developed in collaboration with the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. Circulation 2007: 116(17): 418-499. 4. McFalls EO, et al. Coronary-artery revascularization before elective major vascular surgery. N Eng J Med 2004; 351(27): 2795-2804 5. Brunelli A, et al. ERS/ESTS clinical guidelines on fitness for radical therapy in lung cancer patients (surgery and chemo-radiotherapy). Eur Respir J 2009; 34:17-41. 6. Brunelli A, et al. Physiologic Evaluation of the Patient With Lung Cancer Being Considered for Resectional Surgery: Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2013 May;143(5 Suppl):e166S-90S 7. Brunelli A, et al. Peak Oxygen Consumption During Cardiopulmonary Exercise Test Improves Risk Stratification in Candidates to Major Lung Resection. Chest 2009; 135:1260-1267. 8. Burt BM, et al. Thoracoscopic lobectomy is associated with acceptable morbidity and mortality in patients with predicted postoperative forced expiratory volume in 1 second or diffusing capacity for carbon monoxide less than 40% of normal. J Thorac Cardiovasc Surg. 2014 Jul;148(1):19-28 9. Okada M, et al. Radical sublobar resection for small-sized non-small cell lung cancer: a multicenter study. J Thorac Cardiovasc Surg. 2006 Oct;132(4):769-75 10. Yano M, et al. Survival of 1737 lobectomy-tolerable patients who underwent limited resection for cStage IA non-small-cell lung cancer. Eur J Cardiothorac Surg. 2015 Jan;47(1):135-42

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In recent years, the number of early stage lung cancers has enormously increased and this tendency is more prominent in octogenarians. Both curability and non-inavasiveness should be required for such situation. Surgery is the standard treatment for early stage lung cancer and VATS lobectomy or sublobar resection have been routinely performed for selected patients to maintain performance status[1)]. Especially, the indication of sublobar resection is considered to be related to the aggressive nature of tumors, thus several studies by HRCT findings and PET-CT were performed to predict the invasive nature as well as clinical stage. In JCOG 0201, 545 case who received lobectomy and mediastinal lymph node dissection due to stage I NSCLC were enrolled prospectively. Pathological non-invasive cancer (both vascular and lymphatic invasion negative) was evaluated by the consolidation/tumor ratio on preoperative HRCT. Adenocarcinoma <2.0 cm with <0.25 consolidation to the maximum tumor diameter (35 patients, 12.1%) revealed pathological non-invasiveness in 98.7% (95% CI: 93.2–100.0%), and this criterion could be used for radiological early lung cancer[2)]. The prognostic study of cases enrolled in JCOG0201 revealed that 5 year OS and RFS survivals of the entire patients were 90.6% and 84.7%, respectively. The 5-year OS of radiologic early and invasive adenocarcinomas were 97.1% and 92.4%, respectively (p=0.259). If the consolidation/tumor ratio lower than 0.5 in cT1a-b was used as a cutoff, the 5-year OS of radiologic early (121 patients, 22.2%) was 96.7% and invasive adenocarcinomas, 88.9% (p<0.01)[3)]. Based on the criteria of radiologic early cancer obtained by JCOG0201, randomised phase 3 trial to evaluate non-inferiority in OS of segmentectomy compared to lobectomy (JCOG0802)[4)]. The maxSUV of the primary tumor on PET/CT could be used as a prognostic marker of early stage lung cancer. Analyses of 610 resected stage IA adecocarcinoma showed that maxSUV and GGO ratio cutoffs to predict recurrence were 2.9 and 25%, respectively. They were also related to nodal metastasis, histological tumor invasiveness and recurrence. The 5-year RFS of cases with maxSUV <2.9 (n=456) was 95%, while cases with maxSUV>2.9 (n=154), 72% (p<0.001)[5)]. Surgical management of early stage lung cancer should be selected by based on the tumor size, GGO ratio and maxSUV to predict the biological malignancy of each case. Streotactic ablative radiotherapy (SABR) has attained importance for efficacy and safety for the treatment of early cancers located in the peripheral lung. There are two representative randomised phase 3 trial (STARS and ROSEL) to compare SABR and surgery. Eligible patients of these studies were T1-2a (<4cm) N0M0 and a total of 58 cases were registered (31 received SABR and 27, surgery). The combined analysis of these two studies revealed that 3 year OS in SABR (95%) was superior to that of surgery (79%) (p=0.037) and RFS at 3 years was similar; 86% in SBRT and 80% in surgery (p=0.54). Only 10% of cases in SBRT group suffered grade 3 toxicity but 44% of surgery group developed grade 3 and 4 toxicities. The pooled analysis of the two studies showed SBRT had similar treatment efficacy to that of surgery in spite of the small sample size[6)]. Japan Clinical Oncology Group evaluated the efficacy and safety of SBRT for operable/inoperable T1N0M0 patients (JCOG 0403). A total of 164 patients (100 inoperable and 64 inoperable) were treated by 48 Gy. The 3 year OS was 59.9% in inoperable patients and 76.5% in operable patients[7)]. Investigations into the effectiveness of SABR for operable patients as well as the optimal indication, dose and fraction should be clarified by prospective manner. SABR has become a radical treatment for inoperable stage I lung cancer. In addition, if operable cases treated by SABR in JCOG0403 show favorable outcome, further comparable trial of SABR versus less invasive surgery should be warranted. References 1) Committee for Scientific Affairs The Japanese Association for Thoracic Surgery, Thoracic and cardiovascular surgery in Japan during 2013 : Annual report by the Japanese Association for Thoracic Surgery. Gen Thorac Cardiovasc Surg.2015;63:670-701. 2) Suzuki K, Koike T, Asakawa T, 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;6:751-756 3) Asamura H, Hishida T, Suzuki K, et al. Radiographically determined noninvasive adenocarcinoma of the lung: Survival outcomes of Japan Clinical Oncology Group 0201 J Thorac Cardiovasc Surg 2013;146:24-30 4) Nakamura K, Saji H, Nakajima R, et.al. A Phase III Randomized Trial of Lobectomy Versus Limited Resection for Small-sized Peripheral Non-small Cell Lung Cancer (JCOG0802/WJOG4607L) Jpn J Clin Oncol 2010;40:271–274 5) Uehara H, Tsutani Y, Okumura S, et al. Prognostic Role of Positron Emission Tomographyand High-Resolution Computed Tomography in Clinical Stage IA Lung Adenocarcinoma Ann Thorac Surg 2013;96:1958–1965 6) Chang JY, Senan S, Paul MA et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: A pooled analysis of two randomized trials. Lancet Oncol 2015;16:630–637. 7) Nagata Y, Hiraoka M, Shibata T, et al. Prospective trial of stereotactic body radiation therapy for both operable and inoperable T1N0M0 non-small cell lung cancer: Japan Clinical Oncology Group Study JCOG0403. Int J Radiat Oncol Biol Phys 2015;93;989-996.

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Preclinical drug screening and biomarker discovery in the NCI-60 cancer cell line panel as well as the xenograft developed by growing these cell lines subcutaneously in immunodeficient mice have repeatedly failed to predict clinical responses. In an attempt to circumvent the limited predictive values of conventional preclinical models, there has been increasing attention in the development and characterization of Patient-derived tumor xenograft (PDX) models. The PDX models, which were created by direct implantation of patient’s tumor in immunodeficient mice, have shown to reflect principal histologic and genetic characteristics of original patient tumors and retain tumor heterogeneity better than any other preclinical model. These models have been shown to be predictive of clinical outcomes and are being used for translational research, preclinical drug screening and biomarker identification and validation. The PDX model may also be used in the application of ‘co-clinical trial’ approach, in which it is developed from a patient enrolled in a clinical trial and treated with the same experimental agents to emulate clinical response. This strategy permits the assessment of drug response simultaneously in the patient and mouse model, providing an interesting platform to investigate resistance mechanism, predictive biomarkers and novel combination strategies in a real-time manner. I will present the utility of PDX models, which faithfully replicated the histologic, genomic and pharmacologic features observed in the original patients, and ‘co-clinical trial’ that mirror a phase II trial of agents targeting fibroblast growth factor receptor (FGFR) in non-small cell lung cancer.

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WCLC Extended Abstract: The Role of Scientific Organizations Paul A. Bunn, Jr, MD, FASCO The goal of scientific organizations is to facilitate progress in a specific area through promotion of research, training and education. In some instances the scientific area may be a single discipline such as medical, surgical or radiation oncology, pathology, radiology and so on. In some instances the scientific area may be a single geographic region such as Europe, North America or Asia. Examples of such organizations would be the European Respiratory Society (ERS), the American College of Radiology, the College of American Pathology (CAP) and many, many others. In some instances the organization might focus its efforts on training and research grants and in other instances the organization might focus on education of the public and in public programs such as prevention. In some instances the organization may conduct research or may solely sponsor research to be done by others. Some scientific organization chose to develop guidelines for clinical care. All of these efforts are important and different organizations focus on different aspects of a problem. In this presentation I will focus my attention on The International Association for the Study of Lung Cancer (IASLC) since it is the sponsor of the World Conferences on Lung Cancer and since is programs are dedicated to reducing the world wide burden of thoracic cancers. Lung Cancer is the leading cause of cancer death worldwide and the most preventable. When the IASLC was organized in 1974 it was recognized not only that lung cancer was the leading cancer killer but also that it would take an international and multidisciplinary effort to make progress. The very international and multidisciplinary nature of the IASLC are what set it apart from other organizations. Many of the unique contributions of the IALSC rely on these differentiating aspects. For example, the IASLC has contributed all the cases and evaluation of the world wide lung cancer, mesothelioma and thymoma TNM staging classifications. The IASLC Pathology committee has formulated all of the changes to the pathologic classification of thoracic cancers. The IASLC has worked with other organizations such as the College of American pathology and Association of Molecular Pathology to develop guidelines on molecular characterization of lung cancer. To enhance worldwide collaboration and education the IASLC began the World Conferences on Lung Cancer and rotated these conferences to different regions around the world. Originally, these conferences were held every 3 years as progress was slow but as research and research advances have quickened, the WCLCs are ow held annually. In addition the IASLC sponsors regional meetings on a routine basis including the European Lung Cancer Conference (ELCC), the Latin America Lung Cancer Conference (LALCA), the Asia Pacific Lung cancer conference and the Chicago Multidisciplinary Lung Cancer conference. The IASLC also sponsors workshops on various timely topics such as a conference on Small cell lung cancer held in 2015. To support its educational and research missions the IASLC publishes a scientific journal entitled Journal of Thoracic Oncology which has continually increased its circulation and impact factor. More recently, the IALSC has reinstituted a weekly newsletter and has published monographs on time issues such as ALK and PD-L1 testing. The IASLC has sponsored research grants especially for junior faculty and fellows to support and nurture their research careers. The IASLC has also sponsored travel fellowship awards for junior investigators and for young faculty from developing countries. The IASLC had worked with advocacy groups from around the world to provide information and support to these groups and to individuals and families afflicted by lung cancer. These efforts have led to a sharing of efforts and to publications directed to patients and their families. The IASLC’s tobacco committee has worked tirelessly to combat the worldwide tobacco epidemic. References: Tan DS, Yom SS, Tsao MS, Pass HI, Kelly K, Peled N, Yung RC, Wistuba II, Yatabe Y, Unger M, Mack PC, Wynes MW, Mitsudomi T, Weder W, Yankelevitz D, Herbst RS, Gandara DR, Carbone DP, Bunn PA Jr, Mok TS, Hirsch FRThe International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation-Positive Non-Small Cell Lung Cancer: Status in 2016.. J Thorac Oncol. 2016 Jul;11(7):946-63. doi: 10.1016/j.jtho.2016.05.008. Epub 2016 May 23. Review Bunn PA Jr, Minna JD, Augustyn A, et al. Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes?J Thorac Oncol. 2016 Apr;11(4):453-74. doi: 10.1016/j.jtho.2016.01.012. Epub 2016 Jan 30. Review Goldstraw P, Chansky K, Crowley J, Rami-Porta R, Asamura H, Eberhardt WE, Nicholson AG, Groome P, Mitchell A, Bolejack V; International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee, Advisory Boards, and Participating Institutions. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer.J Thorac Oncol. 2016 Jan;11(1):39-51. doi: 10.1016/j.jtho.2015.09.009 Hirsch FR.International Association for the Study of Lung Cancer (IASLC): celebrating 40 years with scientific and educational achievements!J Thorac Oncol. 2014 Oct;9(10):1424-5. doi: 10.1097/JTO.0000000000000340. Bhora FY, Chen DJ, Detterbeck FC, Asamura H, Falkson C, Filosso PL, Giaccone G, Huang J, Kim J, Kondo K, Lucchi M, Marino M, Marom EM, Nicholson AG, Okumura M, Ruffini E, Van Schil P; Staging and Prognostic Factors Committee; Advisory Boards. The ITMIG/IASLC Thymic Epithelial Tumors Staging Project: A Proposed Lymph Node Map for Thymic Epithelial Tumors in the Forthcoming 8th Edition of the TNM Classification of Malignant Tumors. J Thorac Oncol. 2014 Sep;9(9 Suppl 2):S88-96. doi: 10.1097/JTO.0000000000000293. Tsao MS, Travis WD, Brambilla E, Nicholson AG, Noguchi M, Hirsch FR; IASLC Pathology Committee. Forty years of the international association for study of lung cancer pathology committee..J Thorac Oncol. 2014 Dec;9(12):1740-9. doi: 10.1097/JTO.0000000000000356. Leighl NB, Rekhtman N, Biermann WA, Huang J, Mino-Kenudson M, Ra malingam 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 Association for the study oflung cancer/association for molecular pathology guideline. J Clin Oncol. 2014 Nov 10;32(32):3673-9. doi: 10.1200/JCO.2014.57.3055. Epub 2014 Oct 13 Hung JJ, Yeh YC, Jeng WJ, Wu KJ, Huang BS, Wu YC, Chou TY, Hsu WH. Predictive value of the international association for the study of lung cancer/American Thoracic Society/European Respiratory Society classification of lung adenocarcinoma in tumor recurrence and patient survival. J Clin Oncol. 2014 Aug 1;32(22):2357-64. doi: 10.1200/JCO.2013.50.1049. Epub 2014 May 5 Detterbeck FC, Asamura H, Crowley J, Falkson C, Giaccone G, Giroux D, Huang J, Kim J, Kondo K, Lucchi M, Marino M, Marom EM, Nicholson A, Okumura M, Ruffini E, van Schil P, Stratton K; Staging and Prognostic Factors Committee; Members of the Advisory Boards; Participating Institutions of the Thymic Domain The IASLC/ITMIG thymic malignancies staging project: development of a stage classification for thymic malignancies. J Thorac Oncol. 2013 Dec;8(12):1467-73. doi: 10.1097/JTO.000000000000001

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The role of Patient Advocacy organizations in the oncology health care delivery ecosystem is ever evolving and has moved well beyond its original role of solely advocating for services, research, care and understanding. The current field of patient advocacy has its roots in the patient rights movement of the 1970’s with groups like The National Welfare Rights Organization being instrumental in getting a patient bill of rights accepted by the Joint Commission on Accreditation of Healthcare Organizations in 1972[1]. The transformation was further accelerated in 1991 with the formation of the FDA Patient Representative Program and has continued to expand over time with patient advocates now being involved in the entire care continuum. In this presentation I will focus my attention on examples of the ever evolving and expanding role of patient advocacy highlighted by projects developed and led by "partner" foundations the Bonnie J. Addario Lung Cancer Foundation (ALCF) and the Addario Lung Cancer Medical Institute (ALCMI). Addressing Disparities in Care The disparities in lung cancer treatment and outcomes among underserved populations are well documented[2]. Further, 80% of cancer patients are treated in the community hospital setting yet may not receive the same level of care as those treated at leading academic centers. The ALCF Community Hospital Centers of Excellence (COE) program addresses this unmet need. The COE program is a patient-centric model for lung cancer that establishes a standard of care for community hospitals which often treat underserved patient populations. The COE program, which currently includes 13 hospitals in regions of high unmet need, aims to improve the standard of care, patient experience and patient outcome by offering patients and caregivers the same type of multi-disciplinary and comprehensive care provided at leading academic centers. ALCF also provides lung cancer education and services to patients, caregivers and the community. The COE program tracks patient process data longitudinally for multiple quality-of-care metrics, including disease stage at diagnosis; molecular testing; tumor board review; time from diagnosis to treatment; treatment type; and clinical trial participation. Site data will also be monitored to provide a contextual picture of the program including total patients seen, demographics, insurance mix, rates and outcomes of molecular testing among other metrics. Data is analyzed across the COE community and against comparator groups to demonstrate impact of the COE program[3]. Accelerating Clinical Trial Accrual The U.S. National Institutes of Health database currently lists over 45,000 cancer-related clinical trials worldwide[4]. Unfortunately, more than 20% of these trials will never complete, for reasons unrelated to the effectiveness of the intervention that’s being tested. The most common reason for 20% of all clinical trials never finishing is poor patient accrual. One of the most common reasons for low accrual is procedural inefficiencies such as complexities in enrolling in the trial itself and the informed consent process. In 2014, ALCMI launched a prospective study to characterize somatic and germline genomics of adolescents and young adult (AYA) patients[5]. It is estimated that less than 2% of those newly diagnosed with lung cancer globally are AYA, thus presenting a striking recruitment challenge. To address this challenge, ALCMI's study workflow included building a dedicated website[3] enabling remote screening and e-consenting so patients could participate from their homes anywhere in the world while, in parallel, ALCF employed social media to educate patients on the importance of comprehensive genomic profiling and increasing awareness of the study via grass-roots patient blogging. Together, ALCMI and ALCF bring "research to the patient". Accrual opened July 23, 2014 and in the first 5 weeks of the study, 37 subjects consented. Of the 37 initially consented, 35 enrolled via the remote web-portal. As of June 15 2016, 104 subjects are enrolled (128 consented) in the study from 10 countries following a social media campaign. Of the 104 subjects enrolled to date, 49% entered the study via the remote study portal with the balance recruited locally by participating ALCMI study sites Conclusion As briefly outlined above, patient advocacy organizations have moved well beyond their original patient supportive role and have become key players in the oncology healthcare delivery and clinical research ecosystems. As the healthcare system continues to evolve and become more complex so will the role of patient advocacy organizations. To address these challenges, there will be even greater need for innovation, sharing of data and resources, increased infrastructure and mission sophistication, the need to avoid overlap and duplication, and a laser focus on providing meaningful improvement in the availability, transparency and affordability of healthcare. References: 1. Ruth R. Faden, Tom L. Beauchamp, A History and Theory of Informed Consent, (Oxford University Press, 1986), 93 2. http://www.gotoper.com/publications/ajho/2015/2015feb/lung-cancer-disparities-in-the-era-of-personalized-medicine 3. Leah Fine[1], Guneet Walia[1], Raymond U. Osarogiagbon[2]; [1]Addario Lung Cancer Foundation, San Carlos/United States of America, [2]Baptist Cancer Center, Memphis, TN/United States of America. The ALCF Centers of Excellence Model Delivers a Standard of Care to the Community Similar to Academic and Research Centers. World Conference on Lung Cancer, Abstract 6334, December 2016 4. https://clinicaltrials.gov. 5. Barbara J. Gitlitz, Alicia Sable-Hunt, Steven W. Young, Andreas Kogelnik, Danielle Hicks, Deborah Morosini, Tiziana Vavala, Marisa Bittoni, S. Lani Park, Silvia Novello, Geoffrey R. Oxnard, Bonnie Addario (in press). Employing Remote Web Consenting and Social Media to Facilitate Enrollment to an International Trial on Young Lung Cancer. World Conference on Lung Cancer, Abstract 4180, December 2016 6. https://www.openmednet.org/site/alcmi-goyl

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The role of medical journals David Collingridge Editor-in-Chief, The Lancet Oncology and Publishing Director, The Lancet Specialty Journals, 125 London Wall, London EC2Y 5AS, United Kingdom; Clinical Associate Professor of Radiation Medicine, Hofstra/Northwell Health, Lake Success, NY, USA. For many years the traditional peer-reviewed medical journal was seen to be the only reliable place to obtain the latest advances in science and medicine. But, with the advent of online depositiories, information services and feeds, news services, preprint servers, data-sharing, and open access, to name just a few recent innovations, the role of the medical journal is changing. Whilst it is true to say that for many physicians, certain journals are still seen as an authorative voice and a vital source of validated data to inform practice, this isn’t the case for all—indeed, any reasonably reputable source of information, especially if easily available online, is increasingly considered to be a valid fount of medical evidence. So what is the role of the medical journal in the online era? How do medical journals remain relevent, continue to offer a valuable resource of practice-defining information, and play a important and collaborative role with their respective communities? How do medical journals not succumb to the fate of the newspaper or music industries, in which the online revolution has caused considerable upheaval—which many might argue has not resulted in a postive evolutionary change for the betterment of all stakeholders? The central tenet for any medical journal is publication of trustworthy data that have been thoroughly reviewed and challenged prior to publication to ensure the interpretation is accuate, honest, and will not cause harm if used in the real world. Moreover, a good medical journal should be much more than this, and must show leadership; take risks; distil the most important information to a time-poor readership; provide innovative ways of linking disparate, but inter-related, strands of information to a readership that no longer reads cover-to-cover; and encourage scientific debate rather than simply reporting it. A good contemporary medical journal therefore needs to be more than just a mirror reflecting the lastest research or thinking without contest: it must inform and drive research and clinical practice forwards. There are multiple ways in which this can be achieved. First, a journal must offer a impartial platform for presentation of data and discussion of ideas without prejudice, and ensure studies are reported rigourously, transparently, and honestly. The activities of an unconflicted editorial team and well-qualified peer reviewers are vital in this regard, as is the application of reporting standards to ensure all data and analyses are captured accurately. Second, journals have a responsibility to ensure the ethical integrity of everything they publish. Journals should be active members of independent ethics organisations and uphold the highest standards. If any suspicion of misconduct occurs surrounding a published article, reputable journals should always investgiate such allegations, which often relate to issues such as: research conduct; reproducibility of data; unethical behaviour in the laboratory or institution; plagarism; withholding of pertinent data and misreporting; conflicts of interests; authorship disputes; or compliance with prevailing governance structures. Academic institutions take these issues very seriously because of the ramifications for their own integity, and thus journals and instititions must work together to root-out any misconduct and ensure the medical literature is trustworthy and organisations practice science and medicine of the highest standards. Third, journals can help further the practice of good science by taking a leadership role in forward-focused programmes. Recent examples include the team science programmes in the UK and USA, and the REWARD initiative. The UK Academy of Medical Sciences Team Science project has been focused on how biomedical researchers can be encouraged, supported, and rewarded for participating in team-based collaborations—editors and publishers are clear stakeholders in this debate; whilst the REWARD (REduce research Waste And Reward Diligence) campaign encourages everyone involved in biomedical research to critically examine the way they work to reduce waste and maximise efficiency via five guiding principles: setting the right research priorities; using robust research design, conduct, and analysis; making sure regulation and management are proportionate to risks; ensuring all information on research methods and findings are accessible; and guaranteeing reports of research are complete and usable. Finally, a fifth role for medical journals is to take an dynamic part in advocating change, leading the direction of future research, and actively participating in health policy reform and in initiatives to promote universal access to medicine. The Lancet Oncology’s advocacy programme, for example, maps out the inequalities and inequities in health systems worldwide, and highlights deficiencies in all aspects of cancer care, health policy, structural organisation, and leadership. The programme offers a impartial platform that brings together thought-leaders from across different disciplines and organisations to offer solutions to those barriers that hinder provision of high quality cancer control, irrespective of socioeconomic status or country of residence. The journal achieves this via specific, dedicated undertakings including Commissions, series of inter-related papers on specific themes, targeted articles, conferences, and events. The medical journal in the 21[st] century must evolve from being a simple record of research to an engaged stakeholder advocating and leading change in the practice of medicine. Journals should aim to be platforms that bring together communities and thought-leaders rather than disenfranchise groups in to silos. The world has never been as interconnected as it is today, and it is only by working together with a clear vision that journals, hand-in-hand with the communities they serve, will achieve the progress needed to promote the best research and health policies to improve healthcare for all.

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Lung Cancer – What media can/should do Oncology today is one of the main topics of health/medicine media coverage. With the advent of targeted and immunotherapies there’s been a shift towards presenting the rapid advances in this field. But contrary to topics like skin cancer, breast and colorectal cancer lung cancer has stayed in the shadows of reporting until now. It has all been anti tobacco campaigns often regarding smokers immoral, stigmatizing the patients. Late diagnosis and advanced disease plus bad prognosis have not made lung carcinoma a hot topic – and patient advocacy groups, often key players in getting topics into the broad public, are rare. What we have to do (besides non smoking campaigns): Produce valid information on the developing field of early diagnosis (in risk groups). Inform about advancing science and medical procedures to overcome this old nihilistic view of lung cancer as something too poor and bad to speak and write about.

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