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Abstract not provided

Abstract:
While cigarette smoking is clearly the major cause of lung cancer, only 11% of female and 24% of male lifetime smokers will get lung cancer by age 85 or greater, and this relatively small percentage is not due to competing causes of death from smoking (1) The major goal of the research approach discussed in this presentation is to identify individuals who are highly susceptible to the carcinogenic effects of cigarette smoke. These individuals would be candidates for intensive lung cancer surveillance and screening, increasing the probability of detection of a tumor at an early stage. We are not proposing methods for early detection of tumors such as the identification of metabolites or proteins characteristic of lung tumors, but rather early identification of susceptible individuals. While there are already algorithms relating various parameters to lung cancer susceptibility, they are mostly retrospective in nature, with pack-years of cigarette smoking being a major prognostic factor (2,3). Thus, these algorithms are typically applied to subjects who are older, when the process may be more advanced. Our ultimate goal is to develop a risk model that is prospective in nature. Overall, there would be a greater probability of success if one could identify high risk individuals early in the carcinogenic process. Even if this were effective in only 10% of tobacco users, the outcome could be prevention of more than 15,000 lung cancer deaths per year in the U.S. alone and massive financial savings. Among the more than 7,000 identified chemical compounds in cigarette smoke, there are 72 fully characterized carcinogens among which at least 20 are known to cause lung tumors in laboratory animals (4,5). Important among the lung carcinogens are polycyclic aromatic hydrocarbons (PAH) such as benzo[a]pyrene, tobacco-specific nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and volatiles such as 1,3-butadiene. Other related volatile compounds that may contribute to the carcinogenic process include acrolein, crotonaldehyde, and benzene. Perhaps the most important compound in tobacco smoke is nicotine – while not a carcinogen, it is the addictive constituent of smoke that causes people to continue to inhale this incredibly unhealthy mixture. In pursuit of our goal of identifying smokers susceptible to lung cancer, we have focused on several tobacco smoke toxicant and carcinogen parent substances and metabolites in urine (6). Thus, we and others have developed and applied analytically validated mass spectrometric methods for total nicotine equivalents (the sum of nicotine and six metabolites: nicotine glucuronide, cotinine, cotinine glucuronide, 3′-hydroxycotinine and its glucuronide, and nicotine-N-oxide); total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a metabolite of NNK; phenanthrene tetraol (PheT) and 3-hydroxyphenanthrene (3-PheOH), metabolites of a representative PAH; S-phenylmercapturic acid (SPMA), a metabolite of the carcinogen benzene; 3-hydroxypropylmercapturic acid (HPMA), a metabolite of acrolein; and 3-hydroxy-1-methylpropylmercapturic acid (HMPMA), a metabolite of crotonaldehyde. We have collaborated with epidemiologists to evaluate the relationship of these urinary metabolites to cancer, as determined in prospective cohort studies. These studies collect and store bio-samples from large numbers of healthy subjects, then follow the subjects until sufficient numbers of cancer cases occur for statistical analysis. Samples from the cases and matched controls without cancer are retrieved from biorepositories and analyzed for specific biomarkers. The results of these studies have been reviewed (7,8). In summary, statistically significant relationships of urinary total cotinine (cotinine plus its glucuronide, the major metabolite of nicotine), total NNAL, and PheT with lung cancer risk were observed among male smokers in Shanghai. Urinary total cotinine and total NNAL were related to lung cancer risk in a study of male and female smokers in Singapore, and total NNAL in serum was related to lung cancer risk in a study of male and female smokers in the U.S. (7,8). Levels of urinary SPMA , HPMA, and HMPMA were not independently related to lung cancer in the Shanghai study. These results indicate that total cotinine, total NNAL, and PheT are possible biomarkers of lung cancer risk. We are also collaborating with scientists from the Multiethnic Cohort study, a prospective cohort study investigating the association of genetic and lifestyle factors with chronic diseases in a population with diverse ethnic backgrounds. They have reported that, for the same number of cigarettes smoked, and particularly at lower levels of smoking, African Americans and Native Hawaiians have a higher risk for lung cancer than Whites while Latinos and Japanese Americans have a lower risk (9). We are investigating the mechanistic basis for these remarkable differences. We analyzed urine samples from 300-700 subjects per group for total nicotine equivalents, total NNAL, PheT, 3-PheOH, SPMA, HPMA, and HMPMA. The results demonstrated that African Americans, although smoking fewer cigarettes per day than any of the other groups except Latinos, had significantly higher levels of total nicotine equivalents, total NNAL, PheT, 3-PheOH, and SPMA compared to Whites while Japanese Americans had significantly lower levels of most of these biomarkers than Whites. The relatively low level of urinary total nicotine equivalents in the Japanese American smokers was related to a high prevalence of CYP2A6 polymorphisms in this group (10). CYP2A6 is the primary catalyst of nicotine metabolism and the CYP2A6 alleles common in Japanese Americans code for low activity and non-functional enzyme. Therefore, Japanese Americans on the average have more unchanged nicotine circulating and will not need to obtain as much nicotine per cigarette. The biomarker profiles of Native Hawaiians and Latinos did not clearly relate to their relative lung cancer risks, but Native Hawaiians had high levels of the acrolein biomarker HPMA compared to other groups while those of Latinos were low. These results provide important new data pertinent to the relatively high risk of African Americans and the lower risk of Japanese Americans for lung cancer. Collectively, our results support the use of urinary nicotine metabolites, total NNAL, and PheT as biomarkers of lung cancer risk in cigarette smokers. Further studies are required to produce a reliably predictive algorithm for lung cancer susceptibility in cigarette smokers. These studies are likely to require the analysis of DNA adduct levels and to incorporate genetic and epigenetic information. Reference List 1. International Agency for Research on Cancer (2004) Tobacco Smoke and Involuntary Smoking. In IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol. 83 pp 174-176, IARC, Lyon, FR. 2. Tammemagi, C. M., Pinsky, P. F., Caporaso, N. E., Kvale, P. A., Hocking, W. G., Church, T. R., Riley, T. L., Commins, J., Oken, M. M., Berg, C. D., and Prorok, P. C. (2011) Lung cancer risk prediction: prostate, lung, colorectal and ovarian cancer screening trial models and validation. J. Natl. Cancer Inst. 103, 1058-1068. 3. Weissfeld, J. L., Lin, Y., Lin, H. M., Kurland, B. F., Wilson, D. O., Fuhrman, C. R., Pennathur, A., Romkes, M., Nukui, T., Yuan, J. M., Siegfried, J. M., and Diergaarde, B. (2015) Lung cancer risk prediction using common SNPs located in GWAS-identified susceptibility regions. J Thorac. Oncol. 4. Hecht, S. S. (1999) Tobacco smoke carcinogens and lung cancer. J. Natl. Cancer Inst. 91, 1194-1210. 5. Rodgman, A. and Perfetti, T. (2009) The Chemical Components of Tobacco and Tobacco Smoke. CRC Press, Boca Raton, FL. 6. Hecht, S. S., Yuan, J.-M., and Hatsukami, D. K. (2010) Applying tobacco carcinogen and toxicant biomarkers in product regulation and cancer prevention. Chem. Res. Toxicol. 23, 1001-1008. 7. Yuan, J. M., Butler, L. M., Stepanov, I., and Hecht, S. S. (2014) Urinary tobacco smoke-constituent biomarkers for assessing risk of lung cancer. Cancer Res. 74, 401-411. 8. Hecht, S. S., Murphy, S. E., Stepanov, I., Nelson, H. H., and Yuan, J.-M. (2012) Tobacco smoke biomarkers and cancer risk among male smokers in the Shanghai Cohort Study. Cancer Lett. 334, 34-38. 9. Haiman, C. A., Stram, D. O., Wilkens, L. R., Pike, M. C., Kolonel, L. N., Henderson, B. E., and Le Marchand, L. (2006) Ethnic and racial differences in the smoking-related risk of lung cancer. N. Engl. J. Med. 354, 333-342. 10. Park, S.-L., Tiirikainen, M., Patel, Y., Wilkens, L. R., Stram, D. O., Le Marchand, L., and Murphy, S. E. (2016) Genetic determinants of CYP2A6 activity across racial/ethnic groups with different risk of lung cancer and effect on their smoking behavior. Carcinogenesis in press.

Abstract:
Advances in sequencing technologies have made it possible to characterize and catalogue genomic alterations in several cancers in an unbiased manner. Multiple individual groups and large-scale consortia such as The Cancer Genomic Atlas (TCGA), have sequenced close to a thousand lung cancer samples to date. [1-8]Apart from furthering our understanding of the frequently altered pathways in common histological subtypes of lung cancer, data from these studies have also highlighted the molecular heterogeneity underlying this disease. Investigators from TCGA initially reported genomic, transcriptomic, methylation and copy-number alterations in 230 adenocarcinoma (LUAD) and 178 squamous cell carcinoma (SQCC) samples.[1][,][2]An updated analysis, that included a total of 660 LUAD and 484 SQCC samples, was subsequently published in early 2016.[9] While the majority of lung cancer patients have a history of cigarette smoking, nearly 10% of patients are lifelong never-smokers.[3]Lung cancers that arise in smokers exhibit some of the highest mutational burdens across all human cancers (8-10 mutations/Mb). The vast majority of these mutations are C>A transversions. On the contrary, tumors from never smokers demonstrate a much lower mutational burden (0.8-1 mutations/Mb) and are enriched for C>T transitions. [1][,][2] Single nucleotide variations (SNVs) and copy number alterations (CNAs) While both LUAD and SQCC show frequent inactivation of the tumor suppressors TP53 and CDKN2A, these alterations are considerably more common in SQCCs. CDKN2A harbors the loci for two isoforms, p14ARF and p16INK4A, and is inactivated in SQCC through homozygous deletion (29%), methylation (21%), inactivating mutations (18%), or exon 1b skipping (4%). [1][,][2]These findings indicate a strong selective pressure for the loss of these tumor suppressors in NSCLC. The pattern of oncogenic alterations varies considerably between LUAD and SQCC. While LUADs typically showed activating RTK/RAS/RAF pathway mutations, these mutations are highly infrequent in SQCCs - which predominantly showed alterations in oxidative stress response (NFE2L2, KEAP1 and CUL3) and squamous differentiation pathways (SOX2, TP63, NOTCH1, etc.) in 44% of samples. [1,2]KRAS is the most commonly mutated oncogene in LUAD, followed by EGFR, BRAF, PIK3CA, and MET. The majority of EGFR mutations in LUAD are targetable (L858R or exon 19 deletion) with tyrosine kinase inhibitors (TKIs).[1]In contrast, such alterations are absent in SQCC. Two SQCC samples however demonstrated L861Q mutations in EGFR, which are potentially targetable with TKIs. [1][,][2]Although SQCC and LUAD shared several CNAs at the chromosomal arm level, amplification of 3q was frequent in SQCC. This region harbors important oncogenes such as SOX2, PIK3CA, and TP63. LUADs frequently showed amplifications in genes such as NKX2-1, TERT, MDM2, KRAS, and EGFR.[1][,][2]Oncogenic activation of kinases such as ALK, ROS1, and RET through rearrangement has been well described in LUAD, and these fusions are targetable with TKIs. These fusions were seen in 1-2% (ALK : 3/230, ROS1: 4/230, and RET: 2/230 samples) of LUADs. [1][,][2] Transcriptome analysis Deregulated splicing can be a consequence of mutations that alter splice-sites within a gene or splicing factors. Mutations in the proto-oncogene MET that lead to exon 14 skipping, and abnormal splicing of proto-oncogenes such as CTNNB1 as a result of U2AF1 mutation have been described in LUAD. [1] Transcriptome analyses have also enabled a reclassification of LUADs and SQCCs into three and four distinct subtypes, respectively. LUAD samples can be categorized as terminal respiratory unit (enriched for EGFR mutations and fusions; favorable prognosis), proximal-inflammatory (NF1 and TP53 co-mutation), or proximal-proliferative (KRAS and STK11 alterations) subtypes. Similarly, SQCCs can be classified as classical, basal, secretory, or primitive. Alterations in genes that participate in the oxidative stress response pathway, hypermethylation, and chromosomal instability are characteristic of the classical subtype (associated with heavy smoking and poor prognosis). [1][,][2] Key pathogenic alterations TCGA analysis revealed alterations in well known oncogenic drivers involving RAS signaling pathway in 62% of LUAD.. These samples with readily identifiable oncogenic driver alterations were collectively labeled ‘oncogene-positive’. Additional analyses of the ‘oncogene-negative’ sample cohort showed enrichment for RIT1, and NF1 mutations. Given the role of RIT1 and NF1 in RTK/RAS/RAF signaling, samples with these mutations were reclassified as oncogene positive, increasing the overall percentage of oncogene positive samples in LUAD to 76%. Nearly 69% of SQCC samples showed alterations in genes regulating PI3K/AKT, or RTK/RAS signaling. [1][,][2] The inability to readily identify an oncogenic driver in nearly a third of sequenced lung cancer samples highlights the need for greater powering of subsequent studies to identify novel low frequency genomic alterations. For instance, previously uncharacterized alterations in the RTK/RAS/RAF pathway were observed in RASA1, SOS1 in the updated TCGA analysis which analyzed a much larger cohort of samples.[9] Overall, despite showing a few similarities between LUAD and SQCC, investigators of TCGA reported prominent differences between the genomic landscapes of these subtypes. These subtypes have more of their alterations in common with other cancers than with one another. SQCCs more closely resembled head and neck squamous cell and bladder cancer, while LUAD resembled glioblastoma multiforme and colorectal cancer in this regard. [9] Immunotherapies The vast majority of lung cancers do not harbor alterations that are targetable by TKIs. [1][,][2 ]Immune checkpoint inhibitors are approved for use in patients with metastatic NSCLC. There is a clear need to develop optimal predictive biomarkers to identify those who are likely to respond to immune checkpoint inhibitors. Mutational burden has been correlated with better response to checkpoint inhibitors. Furthermore, using exome and transcriptome sequencing and sophisticated bioinformatics, it is now possible to identify mutated and expressed genes that could potentially serve as a trigger for immune response (so called neoantigens) once immune checkpoints like programmed death-1 or programmed death ligand-1 are inhibited.. Swanton and colleagues performed a neoantigen and clonality analysis on TCGA samples to examine characteristics such as neoantigen burden and intratumor heterogeneity (ITH), and their impact on survival. In LUAD, a higher neoantigen burden was significantly associated with longer survival. Although not statistically significant, there was a trend towards longer survival in molecularly homogeneous tumors (<1% ITH) as opposed to heterogeneous tumors. The updated TCGA analysis showed that 47% of LUAD and 53% of SQCC samples exhibited at least five predicted neoantigens. Efforts are ongoing to develop personalized vaccine therapy using predicted neoantigens in lung cancer and other malignancies. Outcomes for patients with advanced lung cancer are likely to improve in the near future with further advances in genome sequencing, molecularly targeted therapies and immunotherapies . [12] References 1. Network CGAR. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014;511:543-50. 2. Network CGAR. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012;489:519-25. 3. Govindan R, Ding L, Griffith M, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 2012;150:1121-34. 4. Imielinski M, Berger AH, Hammerman PS, et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 2012;150:1107-20. 5. George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature 2015;524:47-53. 6. Rudin CM, Durinck S, Stawiski EW, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 2012;44:1111-6. 7. Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 2012;44:1104-10. 8. Seo JS, Ju YS, Lee WC, et al. The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res 2012;22:2109-19. 9. Campbell JD, Alexandrov A, Kim J, et al. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat Genet 2016;48:607-16. 10. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med 2012;4:120ra17. 11. Choi YL, Soda M, Yamashita Y, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 2010;363:1734-9. 12. McGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016;351:1463-9.

Abstract:
Despite many countries signing and ratifying the Framework Convention on Tobacco Control (FCTC), the prevalence of tobacco continues to be on the rise in the Middle East. For example, in countries like Jordan and Tunisia, tobacco prevalence among males is close to 5o% and in Jordan specifically it is estimated to increase to 88% over the next 5 years according to the World Health Organization (WHO). In 2008 it was estimated that five million people died due to tobacco related illnesses. This number is expected to increase to eight million in the year 2030 with individuals from low- and middle-income countries making up approximately 80% of these deaths. Tobacco is a risk factor for all major non-communicable diseases (NCDs) such as cardiovascular diseases, cancer, pulmonary diseases and diabetes mellitus. The developing countries and the Middle East in particular is bracing for at least a 25% increase in such diseases over the next few years. The world economic forum estimates that the cost for such chronic disabling diseases will exceed USD 15 trillion with cancer costs specifically reaching close to USD 3 trillion. The WHO outlined six strategies that, when implemented simultaneously, will result in significant reduction in tobacco prevalence and its related morbidity and mortality. Those strategies known as MPOWER (Monitor tobacco use and prevention policies, Protect people from tobacco smoke, Offer help to quit tobacco use, Warn about the dangers of tobacco, Enforce bans on tobacco advertising, promotion and sponsorship, Raise taxes on tobacco) when implemented in a country like Jordan, for example, close to 180,000 deaths can be prevented over 5 years. Despite the documented benefits of these six strategies, compliance with implementing them across the Middle East remains low. Only few countries have pictorial warnings, exposure to second hand smoke (SHS) is high, tobacco prices remain low and smoking cessation services are scarce. As the population in the Middle East age and with the ongoing rise in tobacco prevalence and obesity, cancer is expected to be on top of the list of diseases causing death and disability in the region. For that reason, King Hussein Cancer Center (KHCC), one of the leading cancer centers in the region, took on the challenge of fighting tobacco across the region in collaboration with regional and international partners. KHCC became the regional host for Global Bridges (an international TDT healthcare alliance co-founded by the Mayo Clinic, the American Cancer Society, and the University of Arizona). The main mission of this collaboration is to address the implementation of article 14 of the FCTC agreement and design and implement effective programmes to promote the cessation of tobacco use and provide adequate treatment for tobacco dependence (TDT). This will also serve to address one of the six strategies recommended by the WHO; Offer help to quit tobacco use. Tobacco dependence in the region is severe. The high number of cigarettes smoked per capita and the significant exposure to SHS make people less capable of quitting on their own. Availing TDT across the region would respond to the high demand for such service (more than 65% of smokers are interested in quitting) and help curb the expected epidemic of NCDs. Long term, quitting tobacco generally reduces the risk of disease and premature death by 90% for those who quit before the age of 30 and by 50% for those who quit before the age of 50. In addition, TDT will optimize the management of certain NCDs such as cancer resulting in better treatment outcomes and long-term survivals. Over the past 5 years, KHCC developed partnership with countries across the Middle East and worked on training healthcare providers (HCPs) on how to treat tobacco dependence (figure 1). More than 2000 HCPS were trained to date (figure 2). Furthermore, 4 hubs designated for TDT training were established in Oman, Egypt, Tunisia and Morocco. In addition, an evidence-based TDT training curriculum specifically designed for the Middle East was developed and in the process of being made available in 3 languages; Arabic, English and French. In conclusion, tobacco dependence represents a major threat to the health and wellbeing of the people in the Middle East. Significant rise in NCDs including cancer is expected over the next few years. Many collaborative initiatives are underway to address this sever epidemic. Figure 1

Abstract:
This presentation will outline the developments that have led the international tobacco industry to describe Australia as "the darkest market in the world". This will be presented in the context of international developments, with implications and recommendations for other countries, and researchers, clinicians, health professionals,health organisations and governments There will be discussion of the origins and early history of tobacco control in Australia; the components of comprehensive tobacco control programs; policy-relevant research; successes, failures and distractions; and the roles of key organisations and individuals. This will be followed by an outline of major developments, including the establishment of a consensus approach; national and local approaches; activity by key groups; progress across a range of key areas including public education, advocacy, tobacco advertising bans, taxation, health warnings, smoke-free, exposing tobacco industry activities, cessation supports; and other measures. There will be discussion of the Australian world-leading tobacco plain packaging legislation, which is now being replicated in many other countries, and the very encouraging resultant trends. The Australian experience and successes will be presented in a global context, with recognition that the tobacco industry will always oppose any measures that might reduce smoking and is constantly looking for new ways to resist action and promote its products. From this conclusions will be drawn and recommendations made for all concerned to reduce smoking, with consideration of next possible developments.

Abstract not provided

Abstract:
Abstract for IASLC – Vienna conference ‘Trumping Big Tobacco’ Dr. Bronwyn King, CEO Tobacco Free Portfolios I never would have imagined my work as a doctor would take me to corporate boardrooms across the globe, from Melbourne to London, Paris, New York and more. But then I never would have imagined I would be invested in the tobacco industry either. In my early time as a doctor, I did a placement on the lung cancer ward of the Peter MacCallum Cancer Centre in Melbourne. Despite being able to offer the very best medicine available, the majority of my patients died, many of them in their 50’s and 60’s, some as young as 40. It was shocking to bear witness to the true impact of tobacco. Whilst the treatment and care of patients is paramount, we must deal with the source of the problem – tobacco and the companies that manufacturer it. Once I discovered that through my compulsory pension fund, I was invested in and actually owned a part of a several tobacco companies, I couldn’t just do nothing – I had to take action. In my quest to disentangle the Australian pension sector from tobacco I’ve become well informed about tobacco and the extent of the ‘tobacco epidemic’, as it is referred to by the World Health Organisation. The numbers astound me. Six million deaths per year are attributed to tobacco and we are on track for one billion tobacco related deaths this century. Many, including investors (both individual mums and dads as well as big financial institutions), aren’t actually aware of the extent of their tobacco exposure. Tobacco stocks are generally picked up in standard products. Often, tobacco companies have not been selected specifically for investment, but they are wrapped up within default investment products, so they still find a way into your portfolio. I founded Tobacco Free Portfolios to collaboratively engage with leaders of the finance sector to encourage tobacco free investment. Finance executives have been alarmed also, at the scale of the tobacco problem and have deeply considered the role they can play in addressing this pressing global issue. One by one, they have acted and are now proud to lead organisations that are tobacco free. There are now 35 tobacco free pension funds in Australia – just over 40% of all funds. Many more will soon follow. Each tobacco free announcement is met with resounding public support. Tobacco Free Portfolios recently took a global step and we were delighted to work with the global insurance giant AXA who announced a tobacco free decision in May 2016, divesting $1.8B Euro of tobacco assets. More organisations are soon to follow suit. That is the way of the future. Affiliations with the tobacco industry are no longer wanted. There are very few individuals or organisations that actively seek to be a part of the tobacco industry. The associations are often so deep and longstanding that it can seem overwhelming – but they must be addressed and they must be undone. Momentum for tobacco-free investment continues to grow steadily and I can confidently say that the conversation in Australian has largely moved from ‘should we go tobacco-free?’ to ‘how can we go tobacco-free?’ This is a pleasing development and a terrific case study, however, there is still much to do to accelerate action across the globe. The good news is that conversations I have in Vienna, Paris, Singapore, London and New York are received with exactly the same concern as the conversations I have in Melbourne, Sydney and Canberra. The devastating impact of tobacco is felt everywhere on Earth. Tobacco is everyone’s problem, not just the doctors that provide the care and treatment. We should all feel obliged to do something about it and all those with investments, including those through compulsory pension schemes have a role to play. It’s up to us to keep tobacco control on the agenda and in public dialogue. A tobacco free future that will allow our children and the generations to come to enjoy long and healthy lives should be our shared hope. If you are interested in supporting this work, please come along to the Tobacco Free Portfolios workshop on the morning of Wednesday 7[th] December. Further details available at www.tobaccofreeportfolios.org

Abstract:
The tumor, node and metastasis (TNM) classification for malignant tumors has been periodically revised in the International Union for Cancer Control (UICC) and American Joint Committee on Cancer (AJCC). As for lung cancer, the process of revision is quite unique compared with malignancies of other organs in that the corresponding professional society, the International Association for the Study of Lung Cancer (IASLC), has been playing a principal role in database construction, making revision agenda, simulation, and validation as a proposal to UICC and AJCC. The agenda articles have been already published for T, N, M, and stage grouping in the official journal of IASLC. In brief, the IASLC database included 77,156 evaluable patients diagnosed with lung cancer from 1999 to 2010, originating from 35 different databases in 16 countries of 5 continents. Among these, the data of 3905 patients were given by electric data capturing. In the T descriptors, new tumor-size groups were created: T1a 1-2 cm; T1c >2-3cm; T2a >3-4cm; T2b >4-5cm; T3 >5-7cm; and T4 >7cm. Endobronchial l ocation <2cm from the carina has better prognosis than any other T3 descriptor and will be classified as T2. Total atelectasis/pneumonitis will be classified as T2 because it has a T2 prognosis. Diaphramatic invasion will be T4. Visceral pleural invasion remains the same, and mediastinal pleura invasion, seldom used, disappears as a T descriptor. The N component remains the same, but the number of involved nodal stations has prognostic impact. Therefore, it was proposed to divide N1 into N1a (single station N1) and N1b (multiple station N1), N2 into N2a1 (single station N2 without pN1 involvement), N2a2 (single station N2 with pN1 involvement) and N2b (multiple station N2) for testing. For the M component, M1a (intrathoracic metastases) remains the same, but extrathoracic metastases are divided into single extrathoracic metastasis (new M1b) and multiple extrathoracic metastases in a single or multiple organs (M1c). Regarding stages, stage IA is divided into IA1, IA2 and IA3 to accommodate T1a, T1b and T1cN0M0 tumors; all N1 disease are stage IIB except for T3-T4N1M0 that are IIIA; a new stage IIIC is created for T3-T4N3M0 tumors; and stage IV is divided into IVA (M1a and M1b) and IVB (M1c). The 8[th] edition of the TNM classification of lung cancer defines new tumor-size groups, confirms the prognostic relevance of quantifying nodal disease, establishes a new category for single extrathoracic metastasis, and creates new stage groupings. Looking at these, the importance of the accurate measurement of tumor diameter and accurate counting of the swollen nodes and lesions of distant disease has been raised. In this way it improves our understanding of the anatomic extent of the tumor, enhances ,our capacity to indicate prognosis at clinical and pathologic staging, and increases the possibilities of research by facilitating tumor stratification for future clinical trials.

Abstract:
The initial TNM staging classification for malignant pleural mesothelioma (MPM), published in the 6th edition of the UICC and AJCC staging manuals, was derived from analyses of small retrospective surgical series. It has been criticized for being insufficiently evidence-based and difficult to apply to clinical staging. To identify potential deficits in the MPM staging classification, the IASLC Staging and Prognostic Factors Committee (ISPC), in collaboration with members of the International Mesothelioma Interest Group (IMIG), initiated a large multinational database in 2009. This approach was modeled on methods used by the IASLC to revise the lung cancer staging system. Data were submitted on 3,101 patients from 15 centers on 4 continents, all of whom had some form of surgical management, and an initial analysis was published in 2012. Overall survival (OS) data largely supported continued use of the original MPM staging classification but identified several important areas for improvement, particularly for the T and N components. To address issues raised by this initial analysis, a second iteration of the IASLC MPM database was started in 2013 to inform revisions for the 8th edition of the AJCC / UICC staging systems. The data dictionary was revised to provide more granular information for the T, N and M descriptors and a new electronic data capture (EDC), housed at the biostatistical center CRAB (Cancer Research and Biostatistics, Seattle, WA, USA), was developed. Additional investigators who could provide valid information on patients with tumors staged clinically and managed non-surgically were recruited. Data to inform revisions for the 8th edition of the MPM staging classification originated from 29 centers on 4 continents and included 3,519 cases of which 2,460 passed the initial eligibility screen. As planned, this dataset included both patients managed surgically and non-surgically. OS examined for T categories according to the current 7th edition staging classification showed a clear difference between all clinically staged categories except for T1a versus T1b and T3 versus T4. Pathological staging failed to demonstrate a survival difference between adjacent categories with the exception of T3 versus T4. Performance improved with collapse of T1a and T1b into a single T1 category. Analyses suggested that all current T descriptors should be maintained. Tumor thickness and morphology were also significantly associated with OS. Consequently, a recommendation was made to collapse both clinical and pathological T1a and T1b into a T1 category. Because simple measurement of pleural thickness had prognostic significance, it was felt that this should be examined further with a view to incorporation into future revisions of the staging classification. With respect to the N categories (as defined in the 7th edition staging classification), there was no significant difference in OS between cN0, cN1 and cN2, likely reflecting the inaccuracies of current methods for clinical lymph node staging in MPM. For pathologically staged tumors, patients with pN1 or pN2 tumors had a worse OS than those with pN0 tumors but no OS difference was noted between those with pN1 and pN2. Exploratory analyses found that tumors with both pN1 and pN2 nodal involvement had a poorer OS than those with pN2 only. Consequently, a recommendation was made to collapse N1 and N2 into a new N1 category and to relabel the current N3 category as N2. Larger numbers of well staged cases are needed to determine whether this new N1 category should be subdivided in the future according to the number of involved lymph node stations. Of the 3,519 submitted cases, 84 were cM1 at diagnosis. Median OS for cM1 was significantly worse than for T4 or N3 (as defined in the 7th edition) supporting inclusion of only cM1 in the stage IV group. Exploratory analyses suggested a possible difference in OS for single versus multiple site cM1 but additional data are needed in the future to determine the validity of this finding. Candidate stage groups were developed using a recursive partitioning and amalgamation (RPA) algorithm applied to all cM0 cases. Based on these analyses, optimal stage groupings proposed for the 8th edition of the staging classification were: stage IA (T1N0), stage IB (T2-3N0), stage II (T1-2N1), stage IIIA (T3N1), stage IIIB (T1-3N2 or any T4) and stage IV (any M1). These new stage groupings are substantially different from what is currently used in the 7th edition. The IASLC database is the largest available multinational database in this rare malignancy and has provided the first evidence-based revisions of the TNM classification for MPM leading to substantial changes in the T and N components and the stage groupings. Continued efforts to accrue to this database will be important to inform further changes for the 9th edition of the staging classification.[1-7] Reference List (1) Rusch VW, The International Mesothelioma Interest Group. A proposed new international TNM staging system for malignant pleural mesothelioma. Chest 1995;108:1122-8. (2) Rusch VW, Giroux D, Kennedy C, Ruffini E, Cangir AK, Rice D, et al. Initial analysis of the International Association for the Study of Lung Cancer Mesothelioma Database. J Thorac Oncol 2012;7:1631-9. (3) Pass HI, Giroux D, Kennedy C, Ruffini E, Cangir AK, Rice D, et al. Supplementary prognostic variables for pleural mesothelioma: A report from the IASLC Staging Committee. J Thorac Oncol 2014;9(6):856-64. (4) Pass HI, Giroux D, Kennedy C, Ruffini E, Cangir AK, Rice D, et al. The IASLC Mesothelioma Database: Improving staging of a rare disease through international participation. J Thorac Oncol. In press 2016. (5) Nowak AK, Chansky K, Rice DC, Pass HI, Kindler HL, Shemanski L, et al. The IASLC Mesothelioma Staging Project: Proposals for revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for mesothelioma. J Thorac Oncol. In press 2016. (6) Rice DC, Chansky K, Nowak AK, Pass HI, Kindler HL, Shemanski L, et al. The IASLC Mesothelioma Staging Project: Proposals for revisions of the N descriptors in the forthcoming eighth edition of the TNM classification for malignant pleural mesothelioma. J Thorac Oncol. In press 2016. (7) Rusch VW, Chansky K, Kindler HL, Nowak A, Pass HI, Rice DC, et al. The IASLC Malignant 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. In press 2016.

Abstract:
Thymic epithelial tumors are rare tumors. The clinical staging system for thymoma was introduced first by Bergh and associates in 1978 and later modified by Wilkins and Castleman (1), and was almost established by Masaoka and associates in 1981 (2). In France, multiple centers have adopted the Groupe d’Etudes des Tumeurs Thymiques (GETT) staging system (1). The Masaoka classification is the most widely accepted now and is an excellent predictor of the prognosis of thymoma (3, 4). And a modification of this classification was suggested by Koga et al. in 1994 (5) The International Thymic Malignancies Interest Group (ITMIG) has chosen to use the Masaoka-Koga stage classification system (1). There has never been an official TNM system classification of thymic epithelial tumor by American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) stage classification due to their relative rarity. Yamakawa and Masaoka presented a tentative TNM system classification of thymoma in 1991. Then Tsuchiya et al. (1994) in National Cancer Center Hospital of Japan, the WHO (2004) and Bedini et al.(2005) in National Cancer Institute of Italy proposed a TNM staging system (1). The ITMIG and the International Association for the Study of Lung Cancer (IASLC) simultaneously set out to accomplish a staging system for thymic epithelial neoplasms, and subsequently joined forces in 2010, partnering to create a Thymic Domain of the Staging and Prognostic Factors Committee (TD-SPFC), charged with the development of proposals to AJCC/UICC for the eight edition of the stage classification system. The ITMIG and IASLC assembled and analyzed a worldwide database of 10,808 patients with thymic malignancies from 105 sites. They made a stage classification that was tumor, node, metastasis (TNM) based, and applicable to thymoma as well as thymic carcinoma (6-9) (Tables). The T component is divided into 4 categories (Table 1). A tumor is classified in a particular “level” if one or more structures in that level is involved, regardless of whether other structures of a lower level are involved or not. The encapsulation of the tumor is not included, because this did not have a clinically significant difference of prognosis in the retrospective database. The T1 includes tumors that were classified as stage I or II in the Masoaka or Masaoka-Koga stage classification systems. The involvement of the pericardium pathologically is designated as T2, and several neighboring organs (potentially resectable) are included in the T3 category because they had similar prognosis. The T4 includes several organs with more extensive local invasion (potentially unresectable). The TD-SPFC decided to subcategorize T1 into T1a (no mediastinal pleural involvement) and T1b (involvement of the mediastinal pleura) to gain more prospective data for further testing, as there is a slight difference in cumulative incidence of recurrence in patients from Japan submitted by the Japanese Association for Research in the Thymus (6, 7). Lymph node involvement is common in thymic carcinoma (more than 27%) but is relatively uncommon in thymoma (2%) (4). The N component is divided into 3 categories (Table 1). No lymph node metastasis is classified as N0. Lymph nodes are assigned in 2 groups according to their proximity to the thymus: anterior (perithymic) (N1) and deep cervical or thoracic nodes (N2). The anterior region (N1) encompasses the space surrounding the thymus that is bordered by the hyoid bone and diaphragm craniocaudally, the medial edge of the carotid sheaths and mediastinal pleura laterally, the sternum anteriorly, the pericardium and great vessels posteriorly in the middle, and extending to the level of the phrenic nerves posterolaterally. The deep region (N2) describes the space distant to the anterior region within the mediastinum. It is situated posterior to the anterior mediastinum, anterior to the esophagus, and among the pulmonary hila; it extends into the neck on either side of the anterior cervical nodes. Involved nodes outside these regions are outside the N category and considered a distant metastasis (M1) (6, 8, 9). The M component is divided into 3 categories (Table 1). Absence of tumor outside the primary mass (or nodal metastases) is classified as M0. M1a is used to designate pleural or pericardial nodules. M1b designates pulmonary intraparenchymal nodules or distant metastases (6, 8). The TNM categories are organized into distinct stage groups as shown in Table 2. Stages I, II, IIIa, and IIIb are determined primarily by the T component. Stages IVa and IVb are determined by the presence of N1 or M1a disease for IVa and N2 or M1b disease for IVb (6-9). Figure 1 Figure 2 References 1. Detterbeck FC, Nicholson AG, Kondo K, Van Schil P, Moran C. The Masaoka-Koga Stage Classification for Thymic Malignancies Clarification and Definition of Terms. J Thorac Oncol. 2011;6: S1710–S1716. 2. Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981;48:2485–92. 3. Detterbeck FC, Parsons AM. Thymic tumors. Ann Thorac Surg 2004;77:1860-9. 4. Kondo K, Monden Y. Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg 2003;76:878–84. 5. Koga K, Matsuno Y, Noguchi M, et al. A review of 79 thymomas: modification of staging system and rappraisal of conventional division into invasive and non-invasive thymoma. Pathol Int 1994;44:359–67. 6. Detterbeck FC, Stratton K, Giroux D, et al. The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: Proposal for an Evidence-Based Stage Classification System for the Forthcoming (8th) Edition of the TNM Classification of Malignant Tumors. J Thorac Oncol. 2014;9: S65–S72 7.Nicholson AG, Detterbeck FC, Marino M, et al.,,The ITMIG/IASLC Thymic Epithelial Tumors Staging Project: Proposals for the T component for the Forthcoming (8th) Edition of the TNM Classification of Malignant Tumors. J Thorac Oncol. 2014;9: S73–S80 8. Kondo K, Schil PV, Detterbeck FC, et al. The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: Proposals for the N and M Components for the Forthcoming (8th) Edition of the TNM Classification of Malignant Tumors. J Thorac Oncol. 2014;9: S81-S87 9. Bhora FY, Chen DJ, Detterbeck FD,et al., 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;9: S88–S96

Abstract:
What’s New in Esophageal Cancer Staging? Thomas W. Rice, MD The 8th edition cancer staging manuals will be published later this year,[1,2] and the new staging recommendations will go into effect January 1, 2017. Staging cancer of the esophagus and esophagogastric junction for the 8th edition of the AJCC/UICC manuals was developed on a strong 7th edition foundation.[3,4] A greatly enhanced Worldwide Esophageal Cancer Collaboration (WECC) database, with a substantial increase in both numbers of patients (22,654) entered and variables (39) collected,[5-7 ]permitted a more dynamic and dependable Random Forest–based machine learning analysis. Random Forest analyses provided risk-adjusted survival estimates for all patients, from which distinctive and homogeneous stage groups with monotonically decreasing survival were identified.[8-10] Cancer Categories There were no major changes in cancer categories; however, there were some important refinements for T, N, grade, and location. Subcategorization of pT1 into pT1a and pT1b enhanced and improved Stage I grouping. Regional lymph nodes (N) were clarified in a new and simplified map. Undifferentiated cancers now require additional analyses to expose histopathologic cell type. If glandular origin can be determined, the cancer is staged as Grade 3 adenocarcinoma; if squamous origin can be determined or if the cancer remains undifferentiated after full analysis, it is staged as Grade 3 squamous cell carcinoma. Cancer location, not important for adenocarcinoma stage grouping, in conjunction with grade is necessary to subgroup only pT3N0M0 squamous cell carcinoma. The definition of the esophagogastric junction was revised; cancers involving the esophagogastric junction with epicenters 2 cm or less into the gastric cardia are staged as adenocarcinomas of the esophagus, while those with more than 2-cm involvement are staged as stomach cancers. Stage Groupings Pathologic Stage Grouping (pTNM) Historically, pathologic stage after esophagectomy alone has been the sole basis for all cancer staging, regardless of classification (c, yc, yp, r, and a). Today, pathologic stage has lost some of its clinical relevance for advanced-stage cancer as neoadjuvant therapy replaces esophagectomy alone. However, it remains important for early-stage cancers and as a key reference point. Dissimilar stage group composition and survival profiles necessitated separate staging groupings for adenocarcinoma and squamous cell carcinoma. Neoadjuvant Pathologic Stage Grouping (ypTNM) New to the 8th edition is stage grouping of patients with esophageal cancers who have had neoadjuvant therapy and pathologic review of the resection specimen (ypTNM). Drivers of this addition include absence of equivalent pathologic (pTNM) categories for the peculiar neoadjuvant pathologic categories (ypT0N0-3M0 and ypTisN0-3M0), dissimilar stage group compositions, and markedly different survival profiles. Grade and location play no role in neoadjuvant pathologic stage grouping. The groupings are identical for both histopathologic cell types. Clinical Stage Grouping (cTNM) Also new to the 8th edition is clinical stage grouping (cTNM) prior to treatment decision. Clinical staging is done typically in the absence of complete histologic cancer data, because clinical TNM categories are typically defined by imaging and examination of needle aspiration and biopsy specimens. Dissimilar stage group composition and survival profiles necessitated clinical stage grouping (cTNM) distinct from pathologic stage grouping (pTNM). There is separate clinical staging for adenocarcinoma and squamous cell carcinoma. How to proceed with TNM-8? 8th edition staging for cancer of the esophagus and esophagogastric junction are data driven and expanded from pathologic stage (pTNM) to include also pathologic stage after neoadjuvant therapy (ypTNM) and clinical stage (cTNM) before treatment decision. Critical evaluation of 8th edition staging, intensive data collection, in-depth analyses, and further consensus appraisal are necessary to proceed from the 8th to the 9th edition. References 1) American Joint Committee on Cancer Staging Manual. 8th ed. In press. 2) TNM classifications of malignant tumors. International Union Against Cancer. 8[th] ed. In press. 3) Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. American Joint Committee on Cancer Staging Manual. 7th ed. New York: Springer-Verlag; 2010. 4) Sobin LH, Gospodarrowicz MK, Wittekind C, editors. TNM classifications of malignant tumors. International Union Against Cancer. 7th ed. Oxford, England: Wiley-Blackwell; 2009. 5) Rice TW, Chen L-Q, Hofstetter WL, et al. Worldwide Esophageal Cancer Collaboration: pathologic staging data. Dis Esophagus. In press. 6) Rice TW, Lerut TEMR, Orringer MB, et al. Worldwide Esophageal Cancer Collaboration: neoadjuvant pathologic staging data. Dis Esophagus. In press. 7) Rice TW, Apperson-Hansen C, DiPaola LM, et al. Worldwide Esophageal Cancer Collaboration: clinical staging data. Dis Esophagus. In press. 8) Rice TW, Ishwaran H, Hofstetter WL, Kelsen DP, Blackstone EH. Recommendations for pathologic staging (pTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals. Dis Esophagus. In press. 9) Rice TW, Ishwaran H, Kelsen DP, Hofstetter WL, Blackstone EH. Recommendations for neoadjuvant pathologic staging (ypTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals. Dis Esophagus. In press. 10)Rice TW, Ishwaran H, Blackstone EH, Hofstetter WL, Kelsen DP. Recommendations for clinical staging (cTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals. Dis Esophagus. In press.

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Abstract:
The 2015 WHO Classification of Neuroendocrine Tumors Elisabeth Brambilla, Professor of Pathology, Department of Pathology; CHU Grenoble INSERM U 1209; Institute of Advanced Biosciences; University Grenoble Alpes; France Neuroendocrine lung tumors were considered as separate entities in the previous WHO classification 2004: the carcinoid tumors, small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) were grouped separately. However, in the current WHO 2015 classification, they are grouped together [1]. They are listed in the order of their frequency with SCLC first as it is the most common. SCLC (15% of lung tumors) is a malignant epithelial tumor which consist of densely packed small cells with scant cytoplasm, finely dispersed granular chromatin and absent or inconspicuous nucleoli. In contrast LCNEC is made of large cells and should show both neuroendocrine morphology (rosettes, palisades) and immunohistochemical neuroendocrine markers (at least one). Both SCLC and LCNEC can be pure or combined with NSCLC components but keep their diagnostic priority (SCLC-or LCNEC- combined). Carcinoid tumors are neuroendocrine malignancies accounting for <1% of all lung cancer, divided in two categories with highly different frequencies, the typical and atypical carcinoid, the last being extremely rare. Typical carcinoids are carcinoid tumors with <2mm[2] and lacking necrosis. They measure ≥0.5 cm in size. Atypical carcinoids are carcinoid tumors with 2-10 mitoses per 2mm[2] and/or foci of necrosis. Despite the grouping of these tumors together, it is clear that the carcinoids have major clinical, epidemiologic, histologic and genetic differences compared to the high grade SCLC and LCNEC. Carcinoid patients are significantly younger, have a better prognosis and lack the strong association with smoking that applies for SCLC and LCNEC. Also compared to carcinoid tumors, SCLC and LCNEC have much higher mitotic rates (more than 11 per 2mm[2]), more necrosis and can show combinations with other lung cancer types including adenocarcinoma or squamous cell carcinoma, which testify of a common progenitor cell derivation, not shared by carcinoid which is never mixed with a non-neuroendocrine (NE) tumor type. Carcinoid tumors also have very few genetic abnormalities compared to SCLC and LCNEC which show the highest rate of mutations per megabase among all cancer[3,4,5] . While in many cases, SCLC and carcinoid tumors can be diagnosed on good quality tumor material with a high quality H&E stained section and in well preserved cytological samples, immunohistochemistry (IH)/neuroendocrine markers can be very helpful in diagnosing pulmonary NE tumors especially in small biopsies with crushed artefact. Endocrine morphology and neuroendocrine IH markers are both required for the diagnosis of LCNEC. The cases with one missing (endocrine morphology or NE markers) are considered as large cell carcinoma in the absence of other differentiation marker on resection specimens, and as non-small cell lung carcinoma on small samples (cytology or biopsy) Mitotic counts are still retained to differentiate typical carcinoids (less than 2 mitoses per mm[2]) from atypical carcinoids (2 to 10 per 2mm[2]) and from high grade NE tumors SCLC and LCNEC (more than 11 mitoses per 2 mm[2 ], for being more reproducible than KI-67 evaluation. The role of Ki-67 is mainly to separate the high grade SCLC (more than 50%) and LCNEC (more than 40%) from the carcinoid tumors (from 1 to 15%) especially in small biopsies with crushed and/or necrotic tumor cells. It is recommended to avoid the diagnosis of SCLC or LCNEC for tumors with less than 50% and 40% MIB1/KI67 index respectively. Data are conflicting regarding the use of KI-67 in separating typical from atypical carcinoid tumors, so it is not recommended in this setting. Careful counting of mitoses is essential as it is the most important histologic criteria for separating typical from atypical carcinoid and the carcinoids from the high grade SCLC and LCNEC. Due to recognition of the potential overlap in the morphology of LCNEC and basaloid squamous cell carcinoma, it can be helpful to confirm negative squamous markers (i.e. p40) in TTF-1 negative tumors that otherwise meet criteria for LCNEC. Many recent progress have been made on the comprehensive genomic profiles of SCLC [3,4 ], LCNEC [5] and carcinoids [6]. Although sharing NE features, these 3 tumors group show substantial and significant differences.Recent comprehensive genomic analyses have established the genomic profile of SCLC [3,6.] Their unique and remarkable characteristic is the universal bi-allelic alteration of both TP53 and RB1 gene (100% for P53 and 93% for RB1) by different alterations of each of the 4 alleles: non synonymous mutations, damaging mutations by complex genomic rearrangements. Locally clustered mutations, indicative of functional selection, occurred on CREBBP (15%) and EP300 (13%) genes, inactivating their histone acetylase functions. Notch family genes inactivating their protein functions occurred in 25% of SCLC [4]. Notch is considered as a master regulator of NE differentiation. LCNEC genomics share characteristic features with SCLC for a part of LCNEC (SCLC-like LCNEC) or with AD /SQC for another part (about 25%). Mutations pattern and frequency of combined cases imply a considerable plasticity of theses tumours which might represent an evolutionary trunk branching SCLC to NSCLC. Carcinoid is a unique example of a tumor driven entirely by chromatin modifiers and remodeling genes, which are not mutant in SCLC. In summary, 51% of carcinoid carried mutations in chromatin remodeling genes. In addition, the eukaryotic translation initiation factor (EIF1AX) was mutated in 9% of cases, genes of the E3 ubiquitin ligases system were mutated or rearranged in 18%. Altogether 73% of carcinoids have driver genes that are candidates for targeted therapy [6.] New evidence is provided that carcinoid is not an early progenitor of high grade NE tumors SCLC and LCNEC. References: 1. Travis WD, Brambilla E, Burke A, Marx A, Nicholson A. WHO Classification of the Tumours of the Lung, Pleura, Thymus and Heart. 4th Edition. Lyon: IARC Press; 2015. 2. Clinical Lung Cancer Genome Project (CLCGP), Network Genomic Medicine (NGM). A genomics-based classification of human lung tumors. Sci Transl Med. 2013;5(209):209ra153. doi:10.1126/scitranslmed.3006802. 3. Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet. 2012;44(10):1104-1110. doi:10.1038/ng.2396. 4. George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524(7563):47-53. doi:10.1038/nature14664. 5. Fernandez-Cuesta L, Peifer M, George J, et al. Genomic Characterization of Large-Cell Neuroendocrine Lung Tumors. J Thorac Oncol. 2015;10(9 - WCLC 2015 Abstracts: PDF Only):S185. doi:10.1097/01.JTO.0000473439.77589.a7. 6. Fernandez-Cuesta L, Peifer M, Lu X, et al. Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Nat Commun. 2014;5:3518. doi:10.1038/ncomms4518.

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Abstract:
Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease characterized by either locally advanced tumor infiltration and/or mediastinal lymph node involvement. Due to improvements in chemo (CT)- and combined chemoradiation (CRT) therapy protocols, patients with locally advanced stage III NSCLC become potential candidates for curative resection more frequently. According to the TNM-7 classification, stage III NSCLC can be defined by the following T and N subsets: stage IIIA: T3 N1-2, T4 N0-1, T1-2 N2; stage IIIB: T4 N2, T1-4 N3. Five-year survival of stage III is generally around 25% taken all different therapy strategies together. Several studies have shown that induction treatment before surgery is beneficial in resectable cases and selected patients undergoing radical resection may have encouraging 5-year survival rates up to 60%. However, to date, no worldwide consent exists on the general role of surgery in curative attempt. Furthermore, it is still unclear if resectable patients might have greater benefit from induction CT compared to combined induction CRT and if concomitant CRT should be preferred over a sequential treatment. Only a small number of prospective phase II/III trials are available addressing these issues. A phase III trial comparing induction CRT plus surgery (S) with definitive CRT in patients with stage IIIA/N2 published in 2009 has questioned the role of surgery since there was no difference in overall survival (OS) between the two groups [1]. However, the 30-day mortality was unacceptably high (26%) in the subgroup of patients undergoing pneumonectomy and thus patients with CRT and lobectomy had significantly improved OS compared to those with CRT alone. Moreover, several other retrospective series have reported encouraging long-term survival in selected patients undergoing induction treatment followed by radical surgery. The benefit of adding sequential RT to CT prior to surgery (S) in stage IIIA/N2 has been investigated in a recent phase III trial [2]. Patients undergoing CRT/S had a non-significant superior median OS of 37 months compared to 26 months with CT/S. Both groups had similar disease free survival (DFS) and it was concluded that RT did not add any benefit to induction CT prior to surgery. However, those with CRT/S had an objective response, pathological complete response, a R0 resection rate and a mediastinal downstaging more frequently and less local progression compared to CT/S. The question whether to apply RT concomitantly or sequentially to CT has been investigated in a recent meta-analysis [3]. Pooled data from six prospective trials suggested that concomitant CRT, as compared with sequential CRT, improved survival of patients with locally advanced NSCLC, primarily because of a better locoregional control. However, these patients were treated without surgery and caution should be taken when transferring these conclusions to the neoadjuvant setting before surgery. From the surgical point of view, patients with local tumor invasion (T3-4 N0-1 including Pancoast tumors) have to be treated by different oncological principles than those with mediastinal lymph node (LN) involvement (N2). In patients with T3 tumors invading the chest wall, diaphragm, mediastinal pleura, phrenic nerve or parietal pericardium and N1 involvement, primary resection can be undertaken. Induction therapy may improve local control rates in larger tumors but it remains unclear if systemic treatment is beneficial prior to or after local resection. Intraoperative frozen section of resection margins should be mandatory and reconstruction of resected structures with synthetic material may be necessary. T4 tumors with invasion to the mediastinal structures or vertebral bodies are a unique subset of locally advanced NSCLC and multidisciplinary treatment can be challenging. Well selected patients may benefit from multimodality therapy including surgery and should be treated in well experienced centers [4, 5]. In patients with suspected N2 disease, invasive staging for histological confirmation has been widely accepted as a standard procedure [6]. In case of multilevel and/or bulky N2 disease, surgery should be avoided due to the expected poor outcome. However, it has been well shown that patients in good performance status with single or two level N2 disease with good response after induction therapy may have improved OS when undergoing curative resection [7, 8]. On the other hand, patients with persistent N2 disease after induction treatment tend to have worse OS and high recurrence rates and thus should not undergo surgery. This finding strengthens the impact of invasive re-staging after induction treatment as proposed by recent staging guidelines. In conclusion, selected patients with stage III NSCLC may have beneficial outcome after surgery combined with CT or CRT. However, this holds truth only for cases with response to induction treatment, nodal downstaging and when R0 resection is deemed achievable. Surgery should be avoided in patients with multilevel/bulky N2 disease or persistent mediastinal LN after induction treatment due to the expected poor outcome. The optimal sequence and modality of induction treatment has yet to be defined in larger prospective trails. References [1] Albain KS, Swann RS, Rusch VW, Turrisi AT, Shepherd FA, Smith C, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009;374:379-86. [2] Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015;386:1049-56. [3] Aupérin A, Le Péchoux C, Rolland E, Curran WJ, Furuse K, Fournel P, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:2181-90. [4] Collaud S, Fadel E, Schirren J, Yokomise H, Bolukbas S, Dartevelle P, et al. En Bloc Resection of Pulmonary Sulcus Non-small Cell Lung Cancer Invading the Spine: A Systematic Literature Review and Pooled Data Analysis. Ann Surg. 2015;262:184-8. [5] Rusch VW. Management of Pancoast tumours. Lancet Oncol. 2006;7:997-1005. [6] De Leyn P, Dooms C, Kuzdzal J, Lardinois D, Passlick B, Rami-Porta R, et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg. 2014;45:787-98. [7] Friedel G, Budach W, Dippon J, Spengler W, Eschmann SM, Pfannenberg C, et al. Phase II trial of a trimodality regimen for stage III non-small-cell lung cancer using chemotherapy as induction treatment with concurrent hyperfractionated chemoradiation with carboplatin and paclitaxel followed by subsequent resection: a single-center study. J Clin Oncol. 2010;28:942-8. [8] Hancock J, Rosen J, Moreno A, Kim AW, Detterbeck FC, Boffa DJ. Management of clinical stage IIIA primary lung cancers in the National Cancer Database. Ann Thorac Surg. 2014;98:424-32; discussion 32.

Abstract:
NSCLC accounts for 80-85% of all lung cancers, and stage III disease constitutes about 40% of the total cases. The main treatment modality in these patients is radiotherapy, usually combined with concurrent chemotherapy. Five-year overall survival in stage III disease is merely 10-15%. Radiotherapy of thoracic tumors poses several challenges, such as tissue heterogeneity, tumor and organ motion and changing anatomy over the treatment course. Main approaches addressing these problems include dose intensification, altered fractionation and advanced radiotherapy techniques. Until recently, dose escalation was considered the main means to increase radiotherapy efficacy. Despite encouraging results of phase I–II studies, the results of recent RTOG trial 0617 were disappointing (1). This study compared high-dose radiotherapy (74 Gy/37 fractions) to a standard-dose (60 Gy/30 fractions) concurrently with weekly paclitaxel/carboplatin, with or without cetuximab. Surprisingly, median overall survival in the high-dose arms was significantly shorter (20 months vs. 29 months in the standard-dose arms; p=0.004) (1). It was speculated that the inefficacy of high-dose radiotherapy could be due to long overall treatment time and accelerated tumor repopulation. Shortening treatment time may be accomplished by accelerated radiotherapy. A phase III study investigating continuous hyperfractionated accelerated radiotherapy (CHART; 54 Gy/36 fractions of 1.5 Gy delivered 3 times daily over 12 consecutive days) showed increased efficacy compared to conventional fractionation (2). A CHARTWEL study, using the same fractionation but with weekend breaks, was not superior to conventional fractionation (3). A meta-analysis of 10 trials (2000 patients) demonstrated an absolute 5-year survival benefit of 2.5% with hyperfractionated and/or accelerated radiotherapy over conventional fractionation, at the expense of significantly increased grade 3–4 acute esophagitis (4). Important developments in lung radiotherapy represent new imaging techniques. PET-CT, currently a routine procedure, allows better patient selection for radical radiotherapy and facilitates selective irradiation of involved volumes (5). Image guided radiation therapy (IGRT), such as daily volumetric kilovoltage cone-beam computed tomography (CBCT), provides actual positional information, allowing for online repositioning and more precise tumor localization. Image-guided adaptive radiotherapy (IGART) additionally accounts for changes and deformations occurring during the radiotherapy course, thus allowing treatment re-planning (6). Currently, dose delivery in NSCLC is commonly accomplished by intensity modulated radiotherapy (IMRT). This technique improves the conformality of radiotherapy by modulating the radiation beam intensity profile, and allows decreasing the mean lung dose, particularly in patients with larger tumor volumes (7). The problem of intrafraction motion in thoracic malignancies has been traditionally managed by extension of treatment margins, leading to excessive radiation to normal tissues. Currently, tumor motion may be managed individually by respiratory-correlated 4-dimensional CT (4DCT) based on the acquisition of organ and tumor imaging data at extreme phases of the breathing cycle. An innovative option allowing for safe dose intensification is isotoxic therapy (8). This approach includes dose prescription defined by the maximal doses achievable to normal tissues. More recently, several clinical studies investigated the role of proton beam therapy in NSCLC. A dosimetric advantage of proton- over conventional photon radiotherapy is mediated by its unique properties: low doses upon tissue penetration, maximal dose deposition towards the end of the beam’s path (Bragg peak) and finite range with minimal dose beyond the tumor. Retrospective data and phase II studies suggested promising survival rates, and reduced pulmonary and esophageal toxicity with protons. However, the results of recent phase III trial did not confirm the superiority of this method over IMRT (9). In summary, recent diagnostic and therapeutic advances the use of radiation in stage III NSCLC allow for more accurate treatment planning, more precise dose delivery and managing tumor and organ motion. Some of these developments have been adopted in clinical practice, despite relatively few evidence of their advantages in terms of better local control and survival. The paucity of phase III trials testing new radiotherapy approaches is partly due to relying on better dose distribution and reduced exposure of normal tissues, making comparisons with less advanced techniques an ethical dilemma (10). References 1. Bradley JD, 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;16:187-99. 2. Saunders M, Dische S, Barrett A, et al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. Lancet 1997;350:161–5. 3. Baumann M, Herrmann T, Koch R, et al. Final results of the randomized phase III CHARTWEL-trial (ARO 97–1) comparing hyperfractionated-accelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC). Radiother Oncol 2011;100:76–85. 4. Mauguen A, Le Pe´choux C, Saunders MI, et al. Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis. J Clin Oncol 2012;30:2788–97. 5. Chang JY, Dong L, Liu H, et al. Image-guided radiation therapy for non-small cell lung cancer. J Thorac Oncol 2008;3:177–86. 6. Sonke JJ, Belderbos J. Adaptive radiotherapy for lung cancer. Semin Radiat Oncol 2010;20:94-106. 7. Bezjak A, Rumble RB, Rodrigues G, and al. Intensity-modulated radiotherapy in the treatment of lung cancer. Clin Oncol 2012;24:508–20. 8. De Ruysscher D, van Baardwijk A, Steevens J, et al. Individualised isotoxic accelerated radiotherapy and chemotherapy are associated with improved long term survival of patients in stage III NSCLC: a prospective population-based study. Radither Oncol 2012;102:228-233. 9. ZX Liao, J. JJ Lee, R Komaki, et al. Bayesian randomized trial comparing intensity modulated radiation therapy versus passively scattered proton therapy for locally advanced non-small cell lung cancer. J Clin Oncol 2016;34(15S):435s. 10. Dziadziuszko R, Jassem J. Randomized clinical trials using new technologies in radiation oncology: ethical dilemma for medicine and science. J Thor Oncol 2007;7:3-4.

Abstract:
Concomitant chemoradiotherapy is currently the most widely accepted standard of care for patients with locoregionally advanced NSCLC. Induction chemotherapy represents an evidence-based alternative and is a particular attractive prior to surgery in patients with marginally resectable disease (1). Over the past two decades, the regimens of cisplatin and etoposide and carboplatin and paclitaxel with concurrent radiotherapy, respectively have been most widely used, with cisplatin and vinorelbine with radiotherapy as possible alternative. More recently interest in the cisplatin/pemetrexed/radiotherapy combination has gained interest based on the superior toxicity and efficacy profile of this regimen in the stage IV setting for patients with non-squamous cell malignancies (2). In addition, it is possible to administer this combination of drugs at systemic doses together with radiotherapy (3). In the randomized phase III PROCLAIM study, this regimen was directly compared with etoposide and cisplatin. The goal of this trial was to establish superiority of this regimen. The trial was closed prior to full enrollment with approximately 300 patients per arm evaluated, due to futility for superiority. Median survival for both study groups was very similar at 26.8 and 25.0 months, respectively and better than statistically assumed (4). Additional chemoradiotherapy regiments of current interest include the addition of the PARP inhibitor veliparib to chemoradiotherapy as recently presented (5). Over the last decade, systemic therapy for patients with metastatic lung cancer has been transformed through the use of tumor mutation analyses and targeted therapies as well as the emergence of immune-oncology. However, application of these strategies to the stage III setting has been slow and no definitive data exist currently to support these strategies in the curative intent setting. The addition of cetuximab to chemoradiotherapy did not result in a survival benefit in RTOG 0612 (6). There are, however several ongoing trials that will be described, including RTOG 1306-Alliance 31101. In this trial patients with EGFR mutation or an alk translocation are randomized to either induction chemotherapy with the appropriate targeted agent (erlotinib and crizotinib, respectively) followed by concurrent chemoradiotherapy or concurrent chemoradiotherapy alone. This trial is actively accruing patients. Regarding immune-oncology, a trial evaluating a liposome-based MUC vaccine (tecemotide) has been completed. MUC1 is a mucinous glycoprotein that is overexpressed and aberrantly glycosylated in NSCLC and a vaccination strategy was supported by preclinical studies as well as clinical data in a stage III subgroup analysis of an earlier exploratory trial. Butts et al (7) reported on a randomized trial in which patients completing locoregional sequential or concurrent therapy were randomized to placebo versus tecemotide vaccination therapy reporting a trend for improved overall survival that was statistically significant in the subset analysis of patients receiving concurrent radiotherapy as their primary therapy. Further investigations of this agent however were halted following emergence of additional negative data from a Japanese phase II trial that remains unpublished. Regarding PD-1 or PD-L1 inhibitors, trials have recently been activated investigating the addition of such agents in the consolidation setting following primary treatment of patients with unresectable SCLC. For example, in the ‘Pacific’ trial patients are randomized in a 2-1 fashion to durvalumab for up to 12 months or placebo. In the Alliance, a trial looking at induction chemotherapy with atezolizumab is currently in the process of activation. Here patients will receive induction chemotherapy with atezolizumab for up to four cycles followed by concurrent chemoradiotherapy and additional adjuvant immune therapy. These strategies are well supported by preclinical data showing irradiation upregulating PD1 expression on myeloid and tumor cells and synergistic amplification of radiation antitumor effects by PD-L1 blockade (8). Updated information on these trials and relevant preclinical data will be presented. References: 1. Schild SE, Vokes EE. Pathways to improving combined modality therapy for stage III nonsmall-cell lung cancer. Ann Oncol 2016 Apr;27(4):590-9. 2. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. 3. Govindan R, Bogart J, Stinchcombe T, Wang X, Hodgson L, Kratzke R, Garst J, Brotherton T, Vokes EE. Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B trial 30407. J Clin Oncol. 2011 Aug 10;29(23):3120-5. 4. Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. 5. Cristea MC, Miao, J, Argiris A, Chen AM, Daly ME, Decker RH, Garland LL, Wang D, Koczywas M, Moon J, Kelly K, Gandara DR. SWOG S1206: A dose-finding study of veliparib added to chemoradiotherapy with carboplatin and paclitaxel for unresectable stage III non-small cell lung cancer. J Clin Oncol. 2016 34:(suppl; abstr 8537). 6. Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H. 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 Feb;16(2):187-99. 7. Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, Nawrocki S, Ciuleanu TE, Bosquée L, Trigo JM, Spira A, Tremblay L, Nyman J, Ramlau R, Wickart-Johansson G, Ellis P, Gladkov O, Pereira JR, Eberhardt WE, Helwig C, Schröder A, Shepherd FA; START trial team. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014 Jan;15(1):59-68. 8. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu YX. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014 Feb;124(2):687-95.

Abstract not provided

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

Abstract not provided

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

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

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

Abstract not provided

Abstract:
Thymic epithelial tumors Thymic epithelial tumors are the most common malignancy among mediastinal tumors according to Japanese thoracic surgery survey (1). Surgical resection is generally the treatment of choice for thymic epithelial tumors. Thymic epithelial tumors are classified into thymoma, thymic carcinoma (TC), and thymic neuroendocrine carcinoma (TNEC). Retrospective surgical database of Japanese Association for Research of the Thymus (JART) revealed that recurrence free 10-year survival after macroscopic complete resection was 88% in thymoma, 51% in TC, and 11% in TNEC. Thymomas are further classified mainly into 5 pathological subtypes, WHO type A, AB, B1, B2 and B3. Pathological subtype of thymoma has been shown to reflect the oncological behaviors, and post-operative recurrence rate increases in this order. JART database study revealed that nearly 3 quarters of thymoma surgical cases have Masaoka stage I or II disease. Pleural dissemination is often encountered either before or after resection in thymoma while hematogenous or lymphatic spread seldom occurs. On the other hand, TC is often associated with metastasis to distant organs as well as nodal involvement in the mediastinum and cervical region. Approximately 3 quarters of surgically treated TC have Masaoka Stage III or IV disease in surgical cases. While most thymomas are treated by surgical resection, a considerable portion of TC are judged unresectable at initial presentation. TNEC often has nodal involvement. Initial resection is indicated when clinical diagnosis is a thymic epithelial tumor with Masaoka stage I or II. The standard procedure is extended thymectomy through median sternotomy even for tumors with Masaoka stage I or II disease because of the possibility of post-thymectomy myasthenia gravis, intrathymic metastasis and multiple foci of tumor. JART database study, however, revealed that recurrence rate in thymoma with T1N0M0 by UICC was not significantly different between two procedures, thymothymomectomy (1.4%) and thymomectomy (2.8%) (p = 0.192) (2). Furtheremore, systematic dissection of mediastinal lymph nodes is not supposed essential in thymoma because incidence of nodal involvement is negligible. Advancement in video-assisted thoracic surgery (VATS) has prompted endoscopic operation also for thymoma, and currently, partial resection of the thymus by VATS seems accepted for less-invasive thymoma when myasthenia gravis is not associated, but careful observation by annual examination by CT scan is recommended after partial thymectomy. Highly invasive thymomas should be treated by preoperative induction chemotherapy to reduce the tumor size. Pathological diagnosis by biopsy is required before chemotherapy to differentiate between invasive thymoma and TC. Resection of the pericardium, lung, great vessels, and thoracic wall is sometimes required. JART database study revealed that invasion of the thoracic wall was the independent factor of recurrence after complete resection. (3) Even subtotal resection sometimes results in long-term survival. If complete resection is not achieved, radiotherapy is supposed to control the remaining tumor. Surgery for thymoma with pleural or intrapericardial dissemination can be indicated. JART database study revealed that the number of the disseminated lesions is a prognostic factor and that patients with less than 10 lesions had better survival. (4) Operative procedure varies from partial pleurectomy to extrapleural pneumonectomy with resection of the primary lesion. The recommended procedure depends on the spread of disseminations. Although intrapericardial implantation is commonly thought to be hard to resect, resection can be achieved in some cases because thymomas usually do not invade into the heart muscle severely. Preoperative chemotherapy is supposed to enable complete resection of intrapericardial implantations through reduction of the tumor volume. Most of the hematogenous metastases of thymoma occur in the lung probably because the neoplastic cells can directly enter the blood stream through thymic veins. Surgical treatment for thymomas with lung metastasis is feasible, but indication of surgery for thymoma with extrathoracic distant metastasis should be determined carefully. Recurrence often occurs on the pleural surface followed by the lung metastasis. Surgical resection of the recurrent lesions in the intrathoracic cavity is generally thought to contribute to survival. (5) Preoperative induction therapy is almost mandatory in highly invasive TC and poorly-differentiated NEC. Concurrent chemoradiotherapy is effective in reducing the tumor size. Resection and reconstruction of even the ascending aorta under cardiopulmonary bypass can be attempted. Systematic mediastinal and cervical lymph node dissection is recommended because of high incidence of nodal involvement. Malignant germ cell tumors (GCT) Malignant GCT is a highly aggressive neoplasm arising in young males. Chemotherapy is recommended without pathological diagnosis when serum tumor marker is extraordinarily elevated. In case of non-seminomatous GCT, complete resection of the tumor after normalization of tumor marker value by chemotherapy should be achieved, or otherwise, tumor recurrence is highly possible. Resection and reconstruction of the great vessels under cardiopulmonary bypass is often necessary. Liposarcoma Mediatinal liposarcoma is a rare neoplasms and sometimes appears as a huge tumor. This neoplasm is supposed to be resistant to chemotherapy, and complete surgical resection is required. Local recurrence occurs frequently because obtaining safe surgical margin is difficult. Radiotherapy could be a treatment of choice for recurrent tumors. Lymphoid malignancies Role of surgery is limited. Surgical biopsy is sometimes required when ML is suspected by imaging and high value of serum sIL-2 receptor. When tumor remains after chemotherapy, surgical resection is sometimes indicated. Low-grade malignancy including MALT and Castleman’s disease can be exceptionally treated by initial surgery. References 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. Nakagawa K, et al. Is thymomectomy alone Appropriate for stage I (T1N0M0) thymoma? Results of a propensity-score analysis. Ann Thorac Surg. 2016;101:520-6. Yamada Y, et al. Surgical outcomes of patients with stage III thymoma in the Japanese nation-wide database. Ann Thorac Surg 2015;100:961–7. Okuda K, et al. Thymoma Patients With Pleural Dissemination: Nationwide Retrospective Study of 136 Cases in Japan. Ann Thorac Surg 2014;97:1743–9. Mizuno T, et al. Surgical management of recurrent thymic epithelial tumors. A retrospective analysis based on the Japanese nationwide database. J Thorac Oncol. 2015;10:199–205.

Abstract:
Radiation therapy (RT) plays an important role in the multimodality management of thymic malignancies. It can be employed in the neoadjuvant, adjuvant, definitive or palliative setting. Adjuvant RT is the most extensively studied setting for RT in thymic malignancies. After complete resection there is likely no role for adjuvant RT for patients with stage I thymomas, a possible role for patients with stage II thymomas, and likely a survival benefit in patients with stage III and IV thymomas. Several recent large database and population-based studies have detected a survival benefit for advanced thymomas, while the results for stage II thymomas have been mixed. For thymic carcinomas the impact of adjuvant RT appears more significant. Several large database and population-based studies have consistently reported a survival benefit with adjuvant RT for thymic carcinoma across various disease stages. For incompletely resected thymic tumors there is a stronger rationale for adjuvant RT based on emerging data and general oncologic principles. Neoadjuvant RT has been mostly explored in thymic carcinoma and demonstrated high response and operability rates. Definitive RT is an excellent treatment option for patients with unresectable thymic malignancies. While most thymic tumors are resectable, a subset of patients is technically or medically inoperable, due to invasion of critical structures or comorbidities. In general, thymic malignancies are radiosensitive, allowing for long-term local control rates. Palliative RT should be considered even in the recurrent or metastatic setting. Image-guided hypofractioned ablative RT may be used for oligometastatic disease as an alternative to surgical resection and has been shown to be a highly effective treatment modality with >90% long-term local control rates and minimal morbidity. Conventional palliative RT is an important modality to improve quality of life by alleviating pain, treating SVC syndrome, airway compression and other symptoms. Modern radiation therapy techniques such as 3D conformal radiation therapy or intensity-modulated radiation therapy should be used to minimize morbidity from treatment. Proton therapy may have advantages in certain clinical scenarios and is currently under investigation.

Abstract:
Thymic malignancies represent a heterogeneous group of rare thoracic cancers. The histopathological classification distinguishes thymomas from thymic carcinomas. Thymomas are further subdivided into different types (so-called A, AB, B1, B2, and B3) based upon the atypia of tumor cells, the relative proportion of the associated non-tumoral lymphocytic component, and resemblance to the normal thymic architecture. Thymic carcinomas are similar to their extra-thymic counterpart, the most frequent subtype being squamous cell carcinoma. The management of thymic epithelial tumours is a paradigm of multidisciplinary collaboration. The treatment strategy is primarily based on the resectability of the tumour. If complete resection is deemed not to be achievable upfront based on imaging studies, what is the case in Masaoka-Koga stage III/IVA tumors (classified as stage IIIA/IIIB/IVA in the 2015 IASLC-ITMIG TNM proposed system), after a biopsy is performed, primary/induction chemotherapy is administered, part of curative-intent sequential strategy integrating subsequent surgery or radiotherapy. Cases not eligible for local treatment receive definitive chemotherapy. Primary/induction chemotherapy is then standardin non-resectable advanced thymic epithelial tumors. Cisplatin-based combination regimens should be administered; combinations of cisplatin, adriamycin, and cyclophosphamide, and cisplatin and etoposide are the most usually used. Primary chemoradiotherapy with platin and etoposide is an option, especially for thymic carcinomas. Usually 2-4 cycles are administered before imaging is performed to reassess resectability of the tumor. Surgery should be offered to patients for whom complete resection is thought to be ultimately achievable; extended resection may be required. Hyperthermic intrapleural chemotherapy, as well as extra-pleural pneumonectomy may be discussed in case of stage IVA tumor. Postoperative radiotherapy is usually delivered. When the patient is not deemed to be a surgical candidate - either because R0 resection is not thought to be achievable, or because of poor performance status or co-existent medical condition, definitive radiotherapy is recommended part of a sequential chemoradiotherapy strategy. Combination with chemotherapy (including cisplatin, etoposide chemotherapy and a total dose of radiation of 60 Gy) may be considered as well. Chemotherapy should be offered as the single modality treatment in advanced, non-resectable, non-irradiable or metastatic (stage IVB) thymic epithelial tumor to improve tumor-related symptoms the aim is to improve tumor-related symptoms through obtention of tumor response, while prolonged survival is uncertain. Cisplatin-based combination regimen should be administered. No randomized studies have been conducted, and it is unclear which regimens are best; multi-agent combination regimens and anthracycline-based regimens appear to have improved response rates compared to others, especially the etoposide, ifosfamide and cisplatin combination. Combinations of cisplatin, adriamycin, and cyclophosphamide is preferred. Combination of carboplatin and paclitaxel is an option for thymic carcinoma. Surgery or radiotherapy is possible in rare and selected cases with unknown survival benefit. Recurrences of thymic epithelial tumors should be managed according to the same strategy as newly diagnosed tumors. Complete resection of recurrent lesions represents a major predictor of favorable outcome, and surgery is then recommended in case of resectable lesion. In non-resectable recurrences, several consecutive lines of chemotherapy may be administered when the patient presents with tumor progression. The re-administration of a previously effective regimen has to be considered, especially in case of previous response, late occurring recurrence, and for anthracyclins, a patient in a good medical condition and not having received cumulative doses precluding the safe delivery of at least 3 additional cycles. Preferred regimens for second-line treatment include carboplatin plus paclitaxel, and platin plus etoposide; capecitabine plus gemcitabine is an option. These regimens were evaluated in dedicated phase II trials. Options for subsequent lines include pemetrexed, oral etoposide. In patients with octreoscan-positive thymoma, not eligible to receive additional chemotherapy, octreotide alone or with prednisone may represent a valuable option. The use of targeted agents may be done in an off-label setting in advanced thymic malignancies. While KIT is overexpressed in 80% of thymic carcinomas, KIT gene mutations are found only in 9% of cases, consisting of mutations observed in other malignancies (V560del, L576P) or mutations unique to thymic carcinomas (H697Y, D820E). Responses and possibly prolonged survival was reported with the use KIT inhibitors - imatinib, sunitinib, or sorafenib - , mostly in single-case observations. Non-pretreated reported KIT mutants are not uniformly sensitive to imatinib, based on the clinical and/or the preclinical evidence in thymic carcinoma and/or other KIT-mutant malignancies. KIT sequencing (exons 9-17) is an option for refractory thymic carcinomas in the setting of possible access to off-label use of such inhibitors. KIT inhibitors also potently inhibiting other kinases, including Vascular Endothelial Growth Factor Receptors and Platelet-Derived Growth Factor Receptors activated in thymic malignancies. A phase II trial recently demonstrated the efficacy of sunitinib in terms of response and disease control rate in thymic epithelial tumors, including thymic carcinomas (ORR 26%; DCR: 91%) and, to a lesser extent, thymomas (ORR:6%; DCR:81%). Sunitinib may then represent an option as second-line treatment for thymic carcinomas, independantly from KIT status. There is no clinical data reporting on antitumor efficacy of other antiangiogenic drugs. mTOR is emerging as a potential target in thymic epithelial tumors, following tumor responses observed in phase I trials. Everolimus (10 mg daily) was evaluated in thymic epithelial tumors in a recently reported phase II trial reporting on a 22% response rate, as well as a 93% disease control rate. Everolimus may then represent an option for refractory tumors. Several trials assessing the efficacy of PD-1 checkpoint inhibitors are currently ongoing. A phase II study of pembrolizumab, a fully humanized IgG4 Ab that targets the PD-1 receptor, was recently reported; the study has accrued 30 patients. Four serious autoimmune disorders developed. Out of 30 patients evaluable for response so far the response rate is 24%. The off-label use of checkpoint inhibitors is currently not recommended. Overall, a dramatic improvement in our knowledge of the management of thymic tumors has occurred in the last few years. This improvement has primarily resulted from an increased interest in these rare tumors at some dedicated centers, and from the development of international efforts that succeed in putting together large-volume, top-quality centers all over the world, for databases, translational research, and clinical trials.

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Abstract:
A life in Thoracic Oncology – Reflections from a pathologist. While many regard a pathologist as a physician involved in laboratory diagnosis, by definition Pathology is the science or the study of the origin, nature and course of diseases. This broader definition of pathology, which basically encompasses all of the study of medicine, is what first attracted me to the field. After my residency I joined the NCI as a research pathologist studying viral oncology in rodents. However a few years later John Minna gave me the opportunity to return to the study of human cancer when he was appointed the head of the NCI-VA Medical Oncology Branch in Washington, DC, with a focus on lung cancer therapy. Our branch was fortunate to have an outstanding lung pathologist, Mary Matthews who taught me most of what I know about lung pathology. Mary also had a profound effect on the understanding and treatment of lung cancer. In 1973 she established that small cell lung cancer (SCLC) was almost always metastatic at the time of diagnosis, and that surgery was unlikely to be curative.[1]These observations, plus the finding that SCLC showed initial responses to the therapy then currently available, helped establish the fundamental distinction of lung cancers into SCLC and NSCLC categories. The Mary Matthew award for Pathology and Translational Research is one of the distinguished awards of the IASLC and I was fortunate and honored to be the fourth recipient in 2003. John Minna assembled an outstanding group of physicians/scientist many of whom became pioneers in the field of lung cancer. Of interest, all three past and present Chief Executive Officers of the IASLC, Heine Hansen, Paul Bunn and Fred Hirsch, spent time at the NCI-VA Medical Oncology Branch. John preached that new approaches for the therapy of lung cancer were needed, that this would require understanding biology, and to understand biology we needed preclinical models. My job was to establish such models and help “translate” them into clinical care. By the early 1980s we had established and characterized large banks of SCLC cell lines and demonstrated that they expressed the entire neuroendocrine (NE) cell program.[2] The cell lines were widely distributed to the scientific community, and in the absence of reliable tumor tissue sources, became the major source of biologic and molecular knowledge of SCLC. Within that decade our group, largely from the use of cell lines, described chromosome 3p loss, MYC family amplification, RB1 and TP53 loss as being characteristics of SCLC and also discovered the MYCL oncogene. The NCI-VA Medical Oncology Branch later relocated to the Bethesda Naval Hospital, MD. In 1991, John Minna accepted a position at the University of Texas Southwestern Medical Center, Dallas, and I was his first recruitment. Thus, during my long career I have only had two employers! I believe this continuity has helped establish strong, long term collaborations and boosted overall productivity. One of the interests of Mary Matthews and me was the heterogeneity of SCLC. It became obvious to us that the so-called oat cell variant was an ischemic artifact. However we were intrigued by the plasticity of SCLC, with a substantial percentage of cases having abnormal (“variant”) morphologies or combined with NSCLC elements, especially after therapy.[3] The variant morphology and its relationship to NEUROD1 as the driver transcription factor (as opposed to ASCL1 as the driver in typical or “classic” SCLC) has recently been highlighted.[4] By the mid 1980s, advances in SCLC biology and therapy had hit a stonewall, and funding dried up. It was time to move onto NSCLC! We established a large collection of NSCLC cell lines and these also formed much of the basis of our understanding of this disease, although tumor tissues were much more readily available. While cell lines have their pluses and minuses, they are excellent for identifying driver mutations and testing targeted therapies. They contributed to the identification of the role of EGFR mutations in lung cancer.[5, 6] Soon after this discovery we used our international fellows and contacts to perform the first large multinational study of geographic and ethnic variations in mutation frequencies, and also demonstrated that mutations were largely absent in tumors other than NSCLC.[7] The advent of Precision Medicine has highlighted the crucial role of the pathologist. Instead of the image of a pathologist looking at microscope slides in isolation in a basement office, he or she plays a crucial role as an integral part of the diagnostic and therapeutic team involved in every aspect of patient management. The pathologist assumes further responsibilities such as tissue procurement and optimal utilization, triaging scant resources for clinical trial requirements, involvement in molecular testing, performing requested or required immunostaining, establishing tissue repositories etc. Previously clinical decision making required the pathologist only to make a diagnosis of SCLC or NSCLC. Precision Medicine has highlighted the importance of accurate classification of NSCLC. Classification is required for mutation testing, therapy selection (or exclusion) and entry onto histology dependent clinical trials. While the introduction of immunostains has greatly facilitated the classification of poorly differentiated NSCLC, the SEER database indicates that up to 14% of NSCLC may remain unclassified throughout the USA. For these reasons we developed a molecular classifier for NSCLC that can be applied to formalin fixed paraffin embedded (FFPE) materials and small core biopsies.[8] The assay is highly accurate and quantitative, and also provides information on grading and survival. While SCLC languished for three decades, its recent designation as a recalcitrant cancer by the US Congress has resulted in a dramatic resurrection of interest, funding and achievement.[9] This has highlighted the importance of preclinical models for SCLC.[10, 11] I feel very humbled and privileged to have lived through and contributed to the seminal advances in our understanding of the biology and therapy of lung cancer. This would not have been possible without the many wonderful and talented people I have worked with. I am reminded of the quote of Isaac Newton: “If I have seen further than others, it is because I have stood on the shoulders of giants”. References 1. Matthews MJ, Kanhouwa S, Pickren J, et al. Frequency of residual and metastatic tumor in patients undergoing curative surgical resection for lung cancer. Cancer chemotherapy reports Part 3 1973;4:63-67. 2. Gazdar AF, Carney DN, Russell EK, et al. Establishment of continuous, clonable cultures of small-cell carcinoma of lung which have amine precursor uptake and decarboxylation cell properties. Cancer Res 1980;40:3502-3507. 3. Gazdar AF, Carney DN, Nau MM, et al. Characterization of variant subclasses of cell lines derived from small cell lung cancer having distinctive biochemical, morphological, and growth properties. Cancer Res 1985;45:2924-2930. 4. Borromeo MD, Savage TK, Kollipara RK, et al. ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs. Cell reports 2016;16:1259-1272. 5. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-1500. 6. Sharma SV, Bell DW, Settleman J, et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007;7:169-181. 7. Shigematsu S, Lin L, Takahashi T, et al. Clinical and biological features associated with Epidermal Growth Factor Receptor gene mutations in lung cancers. J Natl Cancer Inst 2005;97:339-346. 8. Girard L, Rodriguez-Canales J, Behrens C, et al. An Expression Signature as an Aid to the Histologic Classification of Non-Small Cell Lung Cancer. Clin Cancer Res 2016. 9. Gazdar AF, Minna JD. Developing New, Rational Therapies for Recalcitrant Small Cell Lung Cancer. J Natl Cancer Inst 2016;108. 10. Gazdar AF, Hirsch FR, Minna JD. From Mice to Men and Back: An Assessment of Preclinical Model Systems for the Study of Lung Cancers. J Thorac Oncol 2016;11:287-299. 11. Gazdar AF, Savage TK, Johnson JE, et al. The comparative pathology of genetically engineered mouse models for neuroendocrine carcinomas of the lung. J Thorac Oncol 2015;10:553-564.

Abstract:
WCLC2016 Abstract for Closing Plenary Session A Life in Thoracic Oncology - Reflections on Treatment Advances: Surgery The speaker began his training in Cardiothoracic surgery in 1973 and was appointed as a Consultant in 1979. He will introduce this topic by describing a typical case undergoing surgical treatment for lung cancer in the 1970s, the patient journey and outcomes at that time. From that basis he will detail the changes in the surgical treatment of lung cancer in the last 40 years. This will include: · Changes in the epidemiology of lung cancer. · Improvements in pre-operative selection. · Improvements in the staging process prior to surgery, during surgery and post-surgery. · Differences in surgical approach and the anatomical extent of resection. · Changes in the stage classification over that period. · The establishment of effective adjuvant therapy. · Improved outcomes in morbidity, mortality and survivorship. None of these improvements has been of itself a game changer but collectively they amount to a fundamental change in the surgical management of this disease. A brief mention will be made of advances in the surgical treatment of other thoracic malignancies. Peter Goldstraw

Abstract:
When I commenced training in radiation oncology in 1973, there were no CT scanners, calculations were done with slide rules, and chemotherapy, let alone combined modality therapy, had no established role in the treatment of non-small cell lung cancer. An influential trial published in the Lancet in 1971(1) had shown no difference in survival whether patients were randomized to radiotherapy, chemotherapy, a combination of the two or a policy of wait-and–see. Yet within 30 years, the standard of care for patients with inoperable lung cancer being treated for cure, both small cell and non-small cell, had, ironically, become, and remains, concomitant chemotherapy and radiotherapy. The outlook for patients generally regarded as incurable at the outset of my career is that up to one in three selected patients can now expect to live five years as a result of chemoradiation. Patients with stage I non-small cell lung cancer can have their cancer successfully ablated by non-invasive stereotactic radiotherapy in 90% of cases. The developments which led to these changes can be grouped according to three main themes: the impact of the computer revolution; a better understanding of the natural history and biology of the disease, and the introduction of mutimodality therapy. The computer revolution: imaging, treatment planning and delivery Better identification and delineation of the tumor are critical to the success of radiotherapy, in particular avoidance of the catastrophic “geographic miss”. Without computers, the CT and hybrid PET/CT scanners could not have been possible. These dramatically improved the accuracy of staging as well as providing 3D information on the relationship of the soft tissue target to the nearby dose-limiting organs at risk. As computing power increased it became possible to create 4D images of moving tumours, and to image the target with on-board CT scanners attached to the linac immediately before treatment, so making image guided stereotactic ablative radiotherapy possible. Powerful computerised treatment planning systems are now able to create complex dose distributions conforming to the irregularities of any target volume, and to provide dose-volume metrics predictive of risks of normal tissue damage. Improved understanding of the natural history and biology of the disease The recognition that the central nervous system is a sanctuary site which can harbour metastatic disease leading to treatment failure in spite of successful chemotherapeutic eradication of extracranial disease, particularly in small cell lung cancer, led to the introduction of prophylactic cranial irradiation. The British study of continuous hyperfractionated accelerated radiotherapy (CHART) which was given over 12 days to patients with inoperable non-small cell lung cancer resulted in better survival than treatment given over six weeks, even though the total dose was lower. This trial provided clinical support for the notion of treatment induced accelerated repopulation, and reinforced the principle that total treatment times should be kept short in both small cell and non-small cell lung cancer, both when radiotherapy is used alone, and when in combination with chemotherapy. Multimodality therapy The limitations of single modality therapy for a disease with a high propensity for developing genetically determined resistance have long been recognised, and have stimulated the development of strategies simultaneously employing non-cross resistant therapies to maximise tumor cell kill, in line with the principles espoused by Goldie and Coldman.(2) The use of concomitant platinum based chemotherapy with high dose radiotherapy is now well established by meta analysis as improving survival of both non-small cell and small cell lung cancers, but it is also more toxic. Amelioration of these toxicities represents a major challenge for the future. Future directions It is likely that the technical progress in radiation treatment planning and delivery is close to a plateau, and that future progress will depend more on understanding the biology of the disease and its response, and that of the normal tissues, to radiation damage. Biomarkers of response and toxicity, so spectacularly harnessed to advantage by our medical oncology colleagues, are desperately needed to tailor the radiotherapy prescription to the needs of each individual and their cancer. Finally, it is evident that in many jurisdictions, including industrialised wealthy nations, that many patients are either receiving substandard radiotherapy that might increase their chances of cure, or are not receiving treatment at all.(3) Unless these problems can be addressed, the benefits of the remarkable advances in technology and biology documented above will shamefully be restricted to only a fraction of those afflicted with locoregional disease. 1. Durrant KR, Berry RJ, Ellis F, Ridehalgh FR, Black JM, Hamilton WS. Comparison of treatment policies in inoperable bronchial carcinoma. Lancet. 1971;1(7702):715-9. 2. Goldie JH, Coldman AJ, Gudauskas GA. Rationale for the use of alternating non-cross-resistant chemotherapy. Cancer Treat Rep. 1982;66(3):439-49. 3. Vinod SK. International patterns of radiotherapy practice for non-small cell lung cancer. Semin Radiat Oncol. 2015;25(2):143-50.

Abstract:
Lung cancer is a leading cause of cancer death in the world.　The survival benefit of chemotherapy was rarely observed in NSCLC until the development of Cisplatin. Platinum doublets including 2nd/3rd generation cytotoxic drugs showed minor prolongation of survival but the effect reached a plateau. JCOG conducted key RCTs to develop new standards against SCLC but a breakthrough has not been observed yet. Two recent major therapeutic advancements in NSCLC are immunotherapies to inhibit immune checkpoints and development of targeted drugs for driver mutations. Translational Research in Immune Checkpoint inhibitors Immunotherapy of cancer has a long history without success because of wrong strategy of immune stimulation with non-specific immunostimulators, biological response modifiers and recently by peptide antigens. After introduction of idea on immune checkpoint inhibition by Dr. James Allison, the studies of this fields were dramatically activated. Currently two anti-PD-1 antibodies such as Nivolumab and Pembrolizumab have been approved for the treatment of NSCLC based on reproducible effects of tumor shrinkage and survival benefit. In second line treatment, both antibodies significantly improved survival compared with standard care of cytotoxic chemotherapy irrespective of patient selection. Recent press release announced that Nivolumab failed to demonstrate benefit for PFS compared to cytotoxic chemotherapy (CheckMate-026), on the other hand Pembrolizumab demonstrated superior PFS and OS (KEYNOTE-024). Both of the trials patient selection was done based on PD-L1　expression in lung cancer cells. In spite of positive data on survival, RR in various trials against advanced NSCLC with or without prior chemotherapy ranges from 15-25% for both drugs and median survival is almost same in anti-PD1 Ab and cytotoxic drugs. The most important issue will be how to concentrate responsive patient population or how to eliminate in effective patients. Although there is a tendency of correlation between PD-L1 expression and objective response/survival, responders to Ab are experienced even in PD-L1 negative patients. There are many problems in PD-L1 screening. There is no comparative data of various PD-1 tests used in various clinical trials. Each PD-1 test uses different antibody. Each test uses a different definition and cut off point that defines PD-1 positivity. There is no data on best sample, paraffin-fixed vs fresh tissue, primary site tumor vs metastatic tissue. PD-1 expression is not stable and influenced by many factors. There is no reliable validation and standardization. In tumor cells, mutation burden may influence on antigenicity. In colorectal cancer, microsatellite instability has related with response to anti-PD-1 antibody, but it is not yet clear whether mutation burden really increases antigenicity. CD8 lymphocytes infiltration is also considered to be one of the biomarkers for anti-PD-1 Ab response. However, it is too objective and seems to be quite difficult to quantify CD 8 lymphocytes infiltration. The most important thing will be the function of killer T lymphocytes which can respond to target antigens and to kill tumor cells. The best method may be quantitative measurements of cytotoxicity in killer T cell on tumor cells. The techniques to demonstrate this process are mandatory for successful patient selection in the treatment with anti-PD-1 antibody. Translational Drug Development for Precision Medicine Recent development of molecular target drugs in lung cancer　really reflects progress of translational studies. EGFR-TKIs are one of the most important drugs and changed concept of treatment of lung cancer. Finding on many rare driver mutations forced to reclassify lung cancer to various genomic subtypes. Innovative technologies for genomic medicine changes one size fit medicine to precision medicine. For discovery of drugs to each genomic subtype of lung cancer, nationwide and global screening network should be mandatory. In Japan LC-SCRUM Japan leaded by Dr. Koichi Goto, National Cancer Center Hospital East, started in February 2013 to find out new seeds against lung cancer by the support of government.. At the beginning, tumor tissues were analyzed for ALK/ROS1/RET fusions using RT-PCR in EGFR –Mt negative patients and the detected fusions were confirmed by FISH. From March 2015, multiplex diagnostic kit using NGS was introduced and this project expanded as SCRUM-Japan including other histological types of lung cancer such as SQ and SM as well as GI malignancy. 14 pharmaceutical companies started to support this project. No. of institutions joined in the network increased to 200 In Non-SQ NSCLC, 159 and 96 for SQ and SM, respectively on March, 2016. More than 2,500 samples were analyzed. Rare mutations including ROS(91), RET(54) and ALK(40) fusions, ERB2 mutation/amplification(48), BRAF mutation(16), MET amplification/ex14 skip(16) and PIK3A mutation(22) have been screened in 287 Non-SQ-NSCLC patients and 67(23%) have been accrued to more than 12 clinical trials. In LURET trials against RET fusion gene + patients, 19 patients have been accrued and 17 are eligible. The response rate of vandetanib was 53%and PFS was 4.7 months. In 0012-01 trial against ROS fusion gene + patients, 129 patients (74 from china, 26 from Japan, 15 from Taiwan and 12 from Korea)has been accrued. Response rate of crizotinib was 69%in 127 evaluable patients. J-AlEX trial was a phase III randomized controlled trial comparing alectinib(ALE) and crizotinib(CRI) in ALK-positive NSCLC. Response rates for ALE and CRI were 85.4% and 70.2% respectively. PFS was not reached and 10.2 months(P<0.0001), respectively. Other clinical trials are ongoing. Samples from SQ and SM are increasing and interesting mutations and amplifications have been detected in these materials. Accordingly this nationwide and population enrichment screening system enabled various rare driver mutations to be efficiently detected in lung cancer, contributing to the rapid accrual of matched patients in translational clinical trials.

Abstract:
Chemotherapy has long been the only available systemic treatment for Non-Small Cell lung Cancer. In the late 70’s, there were a multitude of triplets and quadruplets with response rates ranging from 20-35% in patients with stage IV disease. In 1980, cisplatin, a cytotoxic agent initially developed for germ-cell tumors, showed some activity, mostly when combined with a vinca-alkaloïd or with etoposide. At the time Vinorelbine was registered by the FDA in 1994, alone or in combination with cisplatin, only 3 drugs were approved for NSCLC, nitrogen mustard, methotrexate and doxorubicin! Metastatic Disease The individual data-based meta-analysis published in 1995 established the superiority of chemotherapy over supportive care in patients with advanced NSCLC. These results have been recently updated and confirmed in 2714 patients from 16 trials with an overall survival benefit of 9% at 1 year. Chemotherapy also improves quality of life and symptom control in patients with good performance status. It is classically recommended to use platin compounds (mostly cisplatin and carboplatin) in combination with third generation agents including vinorelbine, gemcitabine, taxanes (paclitaxel, docetaxel, nab-paclitaxel) or pemetrexed (in non-squamous NSCLC). Integrating palliative care at an early stage of the treatment also prolongs survival and improves quality of life. Second line chemotherapy with docetaxel or pemetrexed has also been demonstrated active even if the benefit on overall survival remains modest. The use of biological markers such as ERCC1, RRM1, beta-tubulin or thymidilate synthase has not yet proven efficacy on the choice of cytotoxic agents. Maintenance: Up to 2009, it was generally accepted that 4 to 6 cycles of induction chemotherapy followed by a rest till progression were the standard. The switch to a new drug as maintenance after 4 cycles of a platin-based doublet showed a benefit for PFS and OS. Maintenance is now considered a standard in the management of metastatic NSCLC. Chemo-radiotherapy for locally advanced disease: The benefit obtained with radiotherapy and chemotherapy given sequentially in locally advanced inoperable NSCLC is modest but significant and well established. Several randomized trials comparing radiotherapy-chemotherapy given sequentially or concomitantly have suggested a better outcome when both modalities were given early and simultaneously. A meta-analysis based on individual patient data from published and unpublished randomised trials which compared radiotherapy alone with the same radiotherapy combined with concomitant cisplatin- or carboplatin-based chemotherapy was recently performed. The analysis was based on 9 trials including 1764 patients. The hazard ratio of death among patients treated with radio-chemotherapy compared to radiotherapy alone was 0.89 (CI 95%: 0.81-0.98; P = 0.02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years. There was some evidence of heterogeneity among trials and sensitivity analyses did not lead to consistent results. The available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy in combination with radiotherapy. Adjuvant chemotherapy: In the meta-analysis published in 1995, a 13% reduction in the risk of death was observed, suggesting an absolute benefit of 5% at 5 years with adjuvant chemotherapy. These results constituted the rationale for a new generation of randomized studies with platinum-based regimens. The LACE meta-analysis, which was reported at ASCO 2006, pooled a total of 4584 patients accrued in the five largest cisplatin-based adjuvant trials launched after the results of the meta-analysis. It confirmed the benefit of adjuvant chemotherapy with a 5.3% improvement of survival at 5 years (p=0.0043). Disease-free survival was also improved (5.2% at 5 years, p<0.0001). There was a negative effect of adjuvant chemotherapy for stage IA. The risk reduction was 8% for stage IB, 17% for stages II and III. The effect of chemotherapy did not vary according to age, gender, PS, type of surgery and histology. In parallel, the adjuvant UFT meta-analysis also confirmed a significant advantage of the drug compared to control in 2003 Japanese patients (p<0.001). The individual-data-based meta-analysis was updated in 2007. It confirmed the significant effect of postoperative chemotherapy, with or without postoperative radiotherapy. Neoadjuvant chemotherapy : Several phase II trials have been carried out in the 80’s to evaluate the benefit of preoperative chemotherapy in operable NSCLC with encouraging results. In the mid 90’s, two randomized phase III trials had a significant impact on the medical community due to their impressive results. Both trials randomized 60 stage IIIA patients and were interrupted after positive interim results were observed. Only two published randomized phase III studies comparing front-line surgery to pre-operative chemotherapy followed by surgery accrued the number of patients that were initially planned: a French study that included 373 patients and the Medical Research Council LU22 trial that included 519 patients. None of the large randomized studies could demonstrate a significant advantage in favor of pre-operative chemotherapy. A recent individual patient data-based meta-analysis of pre-operative chemotherapy trials has included 2385 patients from 15 trials. A HR of 0.87 (CI 95%: 0.7_–0.96, p=0.007) was observed, equivalent to an absolute improvement in survival of 5% at five years, similar to the benefit observed with postoperative chemotherapy. Preoperative or postoperative chemotherapy? A comparison of preoperative versus postoperative chemotherapy has been did not show any difference. In fact, the key issue may be to determine which patients should be treated with adjuvant and/or neo-adjuvant therapy. The neo-adjuvant approach offers a unique opportunity to test new drugs and to compare the tumor characteristics prior to and following induction therapy. Developing molecular based therapeutic strategies will certainly be one of the major challenges over the next few years. Several randomized adjuvant studies have recently been initiated in Europe and in America, based on the molecular characteristics of patients tumor. In conclusion, chemotherapy remains the main systemic treatment for most patients with lung cancer and the only one able to increase the cure rate. Unfortunately, very few drugs have been developed in the last decade in spite of a clear unmet medical need. A better individual selection of drugs/drug combinations according to pharmacogenomic data might encourage the community to optimize the use of cytotoxic agents.

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Abstract:
The past decade has seen more advances in diagnosis and management of lung cancer than were available in the previous 30 years. Fifty years ago, the association of cigarette smoking in lung cancer was firmly established by the Surgeon General's report in the United States. During the past decade, major efforts by IASLC and other organizations have greatly reduced the use of tobacco and, thus, we will be seeing a decrement in morbidity and mortality from lung cancer. However, in the United States last year, there were still 228,000 new cases and 160,000 deaths from lung cancer. It remains the number one cause of cancer death in both American men and women, and the same is true in most developed and developing countries. Over 28% of all cases of cancer death in the United States are due to lung cancer. IASLC has been a leader in updating the TNM classification for non-small cell lung cancer. This allows for uniformity of data results in surgical and adjuvant studies. Cisplatin-based adjuvant chemotherapy has been demonstrated to improve the surgical cure rate by 5-10%. In the future, we hope to be able to identify by molecular, rather than just clinical characteristics, those patients with resected lung cancer who are cured with surgery and do not need to be subjected to adjuvant chemotherapy, as has been similarly accomplished in breast cancer. Also, we hope to have better definition of tumors that are inherently platinum resistant and, therefore, would need alternative strategies to try to improve the surgical cure rate. For the last two decades of the 20th century, chemotherapy has been the backbone for treatment of stage IVB lung cancer. Most studies have been built around platinum combination chemotherapy. Earlier studies pre-platinum utilized inactive drugs such as cyclophosphamide and doxorubicin. In the 1980s, cisplatin and etoposide was a common platinum doublet, and in the 1990's, carboplatin + paclitaxel. A review of phase III trials in North America from 1973-1994 demonstrated very sobering results. Thirty-three trials in 8,434 patients were performed and 23 of these 33 included a platinum compound. Only 5 of the 33 trials demonstrated a statistically significant difference in survival with a median increase of 2 months (range 0.7 to 2.7 months). It thus became clear that we need to personalize therapy rather than giving all patients the same chemotherapy. Modest success was seen by adding Bevacizumab to carboplatin + paclitaxel. Major advances have been made during the past decade with the identification of specific mutations that can be therapeutically exploited. EGFR and ALK were the first to be identified and subsequently ROS-1. Molecular targeted agents demonstrated spectacular responses in the great majority of patients, compared to the usual 25% brief responses that were achieved previously with platinum-based combination chemotherapy. These driver mutations were predominantly in adenocarcinomas and non-smokers or never smokers. More recent mutations have included smokers and non-smokers such as BRAF V600E and MET Exon-14 skipping mutation which can be seen in smokers as well as non-smokers. During the past five years, immunotherapy has been an exciting new addition to the armamentarium for treatment of patients with metastatic lung cancer. Immune checkpoint inhibitors are still in the nascent phase and the optimal duration of therapy for stage IVB disease, combination with other immunotherapeutic agents, chemotherapy, or radiotherapy, as well as use of adjuvant therapy, will be awaited with eager anticipation. Exciting new technology such as CRISPR-cas9 to gene edit PD-1 holds great potential future promise to make these immune checkpoint inhibitors more effective in a larger percentage of patients with lung cancer, as well as those responses being more durable.

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