Virtual Library

Abstract
The Cochrane Collaboration is an international, independent, not-for-profit organisation of over 28,000 contributors from more than 100 countries, dedicated to making up-to-date, accurate information about the effects of health care readily available worldwide. Cochrane contributors work together to produce systematic reviews of healthcare interventions, known as Cochrane Reviews, which are published online in The Cochrane Library. Cochrane Reviews are intended to help providers, practitioners and patients make informed decisions about health care, and are the most comprehensive, reliable and relevant source of evidence on which to base these decisions. Over 5,000 Cochrane Reviews have been published so far, online in the Cochrane Database of Systematic Reviews, part of The Cochrane Library. The Collaboration also prepares the largest collection of records of randomised controlled trials in the world, called CENTRAL, published as part of The Cochrane Library. Work from the Cochrane Collaboration is internationally recognised as the benchmark for high quality information about the effectiveness of health care. The Collaboration believes that effective health care is created through equal partnerships between researcher, provider, practitioner and patient. Cochrane Reviews are unique because they are both produced by, and are relevant to, everyone interested in the effects of human health care. Based on the best available evidence, healthcare providers can decide if they should fund production of a particular drug. Practitioners can find out if an intervention is effective in a specific clinical context. Patients and other healthcare consumers can assess the potential risks and benefits of their treatment. The Cochrane Collaboration's contributors are a mix of volunteers and paid staff who are affiliated to the organisation through Cochrane entities: healthcare subject-related review groups, thematic networks (called 'fields'), groups concerned with the methodology of systematic reviews, and regional centres. Many are world leaders in their field of medicine, health policy, research methodology or consumer advocacy, and our entities are situated in some of the world's finest academic and medical institutions. The Cochrane Collaboration is named after Archie Cochrane (1909-1988), a British epidemiologist, who advocated the use of randomised controlled trials as a means of reliably informing healthcare practice. The Collaboration is an independent, not-for-profit organisation, funded by a variety of sources including governments, universities, hospital trusts, charities and personal donations. The Collaboration is registered as a charity in the United Kingdom. To tie the organisation together, there are a number of overarching structures, led by the Steering Group, which provides policy and strategic leadership for the organisation. Members of this group are democratically elected from, and by, contributors. The Cochrane Operations Unit, is based in Oxford, UK, which manages the financial, legal and administrative work of the organisation, led by the Chief Executive Officer of the Collaboration; and a Cochrane Editorial Unit, based in London, UK, which supports Cochrane Review production, editorial processes, and training and methods development, led by the Editor in Chief of The Cochrane Library. There are annual conferences, known as "Colloquia", which are open to everyone. Colloquia are designed to bring people together in one place to discuss, develop and promote our work, and to shape the organisation's future direction In addition to the core mission of producing Cochrane Reviews, contributors are involved in a number of related activities, including advocacy for evidence-based decision-making, providing training in Cochrane Review preparation, developing the methodology for preparing reviews, and translating them from English into a variety of different languages. This session includes providing an introduction to developing a Cochrane Review and is kindly supported by the Cochrane Lung Cancer Review Group, based in Barcelona Spain (website ) and uses high quality training materials developed by the Cochrane Collaboration (grateful acknowledgement of for allowing the use of the training materials) delivered by volunteer Cochrane Collaborators. The session will address topics including; Introduction to systematic reviews, Writing a Cochrane protocol, Searching for studies, Collecting data, Risk of bias, Meta-analysis, Types of data, Heterogeneity, Analysing data and Interpreting results Other training resources include Online Learning Modules as part of a self-directed learning initiative of The Cochrane Collaboration. They provide an introduction to the core skills and methods required for new authors of Cochrane systematic reviews of interventions. The modules are intended to complement other learning opportunities such as face-to-face workshops and webinars, and the guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions.

Abstract
The Cochrane Collaboration was set up in 1993 with the aim of providing a library of high quality systematic reviews of healthcare interventions. Over the past 20 years it has grown and now involves more than 28,000 people from around the world in its work. The Cochrane Library [1] is now published by Wiley as part of their Online system and includes the following databases: the Cochrane Database of Systematic Reviews (CDSR), the Database of Abstracts of Reviews of Effects (DARE), the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Methodology Register (Methodology Register), the Health Technology Assessment Database (HTA), and the NHS Economic Evaluation Database (NHS EED). The CDSR now contains over 5520 systematic reviews and it impact factor was 5.912 in 2011. Although the great majority of reviews address questions of therapy based on evidence from controlled trials, there are also reviews of diagnostic interventions. The Cochrane Lung Cancer Group (LCG) is one of over 50 Cochrane Review Groups and is dedicated to conducting systematic reviews on all aspects of primary prevention, therapy, supportive care, psychological interventions, biological therapy, and complementary therapy for the prevention, treatment and care of people with lung cancer and other intra-thoracic tumours. Established in 1998 it was originally hosted by the Ibero American Cochrane Centre (IACC) in Barcelona but has recently moved to the University of Besançon, France. Prof Virginie Westeel and Dr Fergus Macbeth are the Coordinating Editors, supported by an international group of clinical and methodological editors. There are currently 37 lung cancer reviews either published or being worked on, with topics ranging from screening to chemotherapy and palliative radiotherapy. The authors of new reviews have to submit a title proposal and a protocol to the Managing Editor. These are peer reviewed, formally approved, and published in The Cochrane Library allowing opportunity for anyone interested to comment on the proposed content and methods. The review process requires: · a thorough literature search · careful selection of the relevant publications · assessing each publication’s Methods for any sources of bias and completing a ‘Risk of Bias’ table · extracting the key data · carrying out a meta-analysis if appropriate · summarising the findings · writing conclusions including a summary in non-technical language for patients and public After the draft review is submitted, it is refereed by three editors with the appropriate expertise. An external peer review is also obtained. This process is designed to maintain the rigour and quality of the reviews to the level expected by The Cochrane Library. Before publication, there is a second review for language, style, and clarity. Carrying out a systematic review to the required standards is therefore a demanding and rigorous process and should be regarded as a research project in itself. This session explains the process in more detail and will I hope engender enthusiasm and lead to the recruitment of new authors. 1. http://www.thecochranelibrary.com

Abstract
The Cochrane Collaboration is an international network of more than 28,000 dedicated people in over 100 countries. Our vision is that healthcare decision-making throughout the world will be informed by high-quality, timely research evidence. We prepare, update and promote the accessibility of Cochrane Systematic Reviews. The Lung Cancer Group editorial team oversees the process of review development from title registration through publishing a protocol to completion of the final systematic review. The scope of topics covered includes prevention, early detection, diagnostic test, all modalities of treatment for both lung cancer and mesothelioma and complementary therapies. The first stage in preparing a review is to identify the topic and register this as a title with the Cochrane group. From this point the authors have a six month time frame to develop a protocol which is essentially the outline plan for the full review. The protocol defines the question to be addressed and specifies the process for identifying, assessing and analysing studies in the review. This will include the inclusion criteria for studies, the search strategy used, the comparisons to be made, any sub-group analyses and their justification and the outcomes to be reported. Once the protocol has been reviewed by the editorial team and confirmed as appropriate for development to a full systematic review, it will be published by Cochrane as a public record of an intended review. This registration helps to minimize bias in the subsequent conduct and reporting of the review and also reduces duplication of effort between groups. This presentation will describe the process of protocol development for a Cochrane review.

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Abstract
The Cochrane Collaboration celebrates its 20th anniversary this year. (1, 2) With around 28,000 people involved in 53 Cochrane Review Groups in about 100 countries and more than 5,000 systematic reviews, the Cochrane Collaboration has assisted clinicians, patients, researchers, policy makers and other health professionals to make decisions on a large number of health-related topics. Around 400 systematic reviews are on screening, prevention or treatment of different cancers, and they collectively analyse nearly 5,000 studies. (2) Forty-one systematic reviews are on lung cancer and mesothelioma: 21 of them deal with non-small cell lung cancer and 8, on small cell lung cancer; 7 are related to general aspects of treatment; 3 are about prevention and early detection; and 2 are about mesothelioma. (3) A Cochrane systematic review is the final product of a highly elaborated process. Today’s Workshop has gone through all this process starting with the definition of a question that needs to be answered with the highest certainty. The question is reflected in the TITLE of the review, the first submission to the review group editors that the potential authors do. Once the title has been approved, potential authors have to write and submit a PROTOCOL, a larger document that includes the background of the topic, the methodology to be used, with inclusion and exclusion criteria of studies and patients, the therapeutic interventions that will be included, the search strategy, and relevant references. After approval of this second phase of the process by the review group editors, the authors have to write the final document, the SYSTEMATIC REVIEW, which is internally and externally reviewed. Most systematic reviews analyse randomised clinical trials only, because this is the best research instrument we have in clinical practice. The conclusions derived from these reviews have a high level of evidence - that can even be increased if meta-analyses can be done combining data from the different studies. (4) The meticulous search of published and unpublished data, the careful identification of biases and the sound methodology provide reliable information on the effectiveness of a certain therapeutic intervention, that can be recommended to patients with similar characteristics to those of the patients included in the reviewed studies. (5) Many questions need to be answer in lung cancer therapy. However, randomized clinical trials are relatively few, especially in my specific field: thoracic surgery. We all should feel the responsibility to participate and include patients in clinical trials. No doubt, participation demands an extra effort from us: selecting patients, taking the time to explain the trial to the patients, abiding by randomization rules, sticking to the protocol and so on. But the effort pays off, because the conclusions we draw from randomized clinical trials are the most reliable and solid we can now have on therapeutic interventions. I would like to encourage the audience to participate in clinical trials. The more randomized clinical trials we complete, the more systematic reviews and greater the level of evidence on specific issues of lung cancer and other health-related problems. References 1. Friedrich MJ. The Cochrane Collaboration turns 20: assessing the evidence to inform clinical care. JAMA 2013;309:1881-1882. 2. Tovey D, Maclehose H, Clarke M. The Cochrane Collaboration, its mission and the value of systematic reviews. Cancer Control 2013;155-159. http://globalhealthdynamics.co.uk/cc2013/wp-content/uploads/2013/04/155-159-David-Tovey_2012.pdf Accessed on 27th July 2013. 3. The Cochrane Library. http://www.thecochranelibrary.com/view/0/browse.html Accessed on 27th July 2013. 4. OCEBM Levels of Evidence Working Group. “The Oxford 2011 Levels of Evidence”. Oxford Centre for Evidence-Based Medicine. http://www.cebm.net/index.aspx?o=5653. Accessed on 27[th] July 2013. 5. Cochrane Consumer Network. http://consumers.cochrane.org/what-systematic-review Accessed on 27th July 2013.

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Abstract
Epidemiology and Burden of Smoking Related Diseases in China Prevalence of Smoking in China Being the largest producer and consumer of tobacco across the globe, China produces one-third (2.66 million tons/year) of the global tobacco leaves [1] and consumes 30% of the world’s cigarettes [2]. According to the Global Adult Tobacco Survey (GATS) Collaborative Group, China had the highest number of tobacco users (300.8 million) and a low quit ratio compared to 16 countries [3]. The International Collaborative Study of Cardiovascular Disease in Asia showed that 147,358,000 Chinese male and 15,895,000 Chinese female aged 35–74 years had been current cigarette smokers [4]. Regardless of gender difference, such prevalence was higher in the rural population compared to the urban population (male 61.6% vs 54.5% P <0.001; female 7.8% vs. 3.4% P<0.001) [4]. A growing prevalence of smoking was also observed in women [5], adolescents and young adults [2,6-8]. Even among non-smokers, the threat of tobacco smoke remained because airborne nicotine had been detected in 91% of the 273 public locations sampled in rural and urban China [9]. Specifically, an estimated 50-72% of Chinese non-smokers had been exposed to secondhand tobacco smoke [10,11]. Considering active and passive smoking altogether, 72% of the Chinese population were tobacco exposed [12]. Such common exposure has aggravated tobacco-related morbidity and mortality which create a direct economic burden accounting for 42.31 billion yuan [13]. By increasing mortality from cancer, respiratory disease and cardiovascular disease [14-18], smoking currently costs over 1 million Chinese lives per year. If the trend continues, a predicted sum of 2 million Chinese may die of tobacco-related diseases in 2025 [19]. COPD and Smoking Chronic obstructive pulmonary disease (COPD) had an estimated prevalence of 8.2% (>43 million) in the Chinese population > 40 years old [20] and was ranked the fourth/third leading cause of death in urban/rural area respectively [21]. Prompted by the causative roles of active [22-24] and passive smoking [25], a yet increasing prevalence of COPD would be expected in the Chinese population. In the meantime, the expensive treatments and compromised productivity of COPD patients had already created an enormous economic burden equaling to 110% and 34% of the annual incomes in rural areas and urban areas respectively [26]. Even so, the situation might have been undermined due to premature mortality and impaired working capabilities within affected families. Anti-smoking measures could be the best solution since the absolute risks of COPD would fall by 56% in Chinese male and 63% in Chinese female 5 years after smoking cessation [27]. Lung Cancer and Smoking Smoking is the main risk factor for lung cancer regardless of smoking experience (ever, current and ex smoking), tobacco product variety (pipes, cigars and cigarettes) and histological subtypes [28].\\Lee et al. demonstrated the dose-response relationship between smoking and lung cancer pathogenesis [28]. Specifically, risk of lung cancer decreased with duration of smoking cessation but increased with an earlier age of smoking and elevations in (i) the amount and fraction of smoking; (ii) duration of smoking; and (iii) tar level. Analyzing data from10 cancer registries, the crude incidence rate of lung cancer in China was estimated to be 49.35 per 100,000 population (63.7 per 100,000 men and 35.0 per 100,000 women) in 2005 [29]. Compared to lifelong non-smokers, the mortality rate of lung cancer was found to be approximately 23 times and 13 times higher in current male smokers and current female smokers respectively [30]. As prevalence of smoking rose during the past 3 decades, lung cancer mortality also increased by 464.84% [31]. Since 2008, lung cancer has surpassed other malignant tumors to become the most common cause of death in Chinese cancer patients [32]. At present, the mortality rate of lung cancer is 600,000 per year [33]. If the current trend continues, it may reach 1 million by 2025 [33]. With an increased prevalence of lung cancer and more advanced technology, the total number of lung cancer inpatients increased from 174,066 to 364,484 while medical costs increased from 2.16 billion yuan to 6.33 billion yuan between 1999 to 2005 as illustrated in the China Statistical Yearbook. Nonetheless, such dedication did not effectively prove its worth since the 5-year survival rate of lung cancer remained relatively low (10% - 14%) [34]. To relieve the socioeconomic burden, measures should be taken to reduce the incidence of lung cancer and relevant medical costs. CAD and Smoking Smoking has been associated with increased risk of coronary artery disease (CAD). In China, the reported crude odd ratio varied between 1.37 - 5.19 in former and current smokers [35-38]. In a study about risk ratio for CAD mortality, former smokers and current smokers had a risk ratio of 0.68 and 1.81 respectively when compared to never smokers [37]. Nonetheless, such figures bore no significant difference if stratified by co-morbidity of diabetes. Perhaps not surprisingly, passive smoking was verified to independently increase the risk of cardiovascular heart disease (CHD) by 25% - 30% [39,40]. While the prevalence of coronary artery disease (CAD) have fallen in developed countries through control of preventable risk factors, China witnessed an opposite trend as CAD climbed from the fifth most common heart disease in 1948-1957 to the most common in 1980-1989 [41]. As reported, CAD caused 51.4% and 32.8% of mortality related to cardiovascular disease (CVD) in urban and rural areas respectively. Projected from 1990, 72.7 million Chinese male and 72.1 million Chinese female will have been diagnosed with CAD in 2020 [42]. Smoking, one of the modifiable risk factors of CAD, should be tightly controlled in China if the socioeconomic burden has to be alleviated. Conclusion COPD, lung cancer and CAD are common smoking related chronic diseases which occupy a large share of medical resources yet cost a massive number of lives in China. In order to improve the current situation, smoking cessation should be reinforced in China through introduction of effective measures supported by favorable policy. Reference 1. Wang H. Tobacco control in China: the dilemma between economic development and health improvement. Salud Publica Mex. 2006; 48(Suppl. 1): S140–7.

Abstract
Lung cancer (LC) is the leading cause of cancer deaths in the world. While smoking is universally accepted as the major cause of lung cancer in tobacco users, lung cancer in lifetime never smokers (LCNS) is among the 10 major causes of cancer deaths. LCNS is a very different disease than LC arising in ever smokers (LCES), and these differences are discussed in this Abstract. Because LCNS is highly influenced by gender and ethnicity, we put special emphasis on LCNS arising in East Asians. The reader is referred to several recent review articles on this subject [1-5] Etiology: Unlike LCES, the etiology of LCNS is not fully elucidated. The suspected factors include exposure to environmental tobacco smoke (ETS), exposure to industrial or domestic carcinogens including coal smoke and volatile cooking oils, radon exposure, viruses including HPV, and genetic factors. While these factors may individually or in combination contribute to the pathogenesis of LCNS, none of them is likely to be the major causative factor. Further investigation of causation is required. Clinico-patholgoical differences. While adenocarcinoma is the predominant form of NSCLC, the vast majority of LCNS are of adenocarcinoma histology, or large cell carcinomas (which may represent poorly differentiated adenocarcinomas). Squamous cell histology is rare and small cell carcinomas almost never occur. A retrospective study from Singapore identified significantly better performance status, younger age at diagnosis, and higher proportion of females (68.5% vs. 12-13%) and more advanced stage at diagnosis in never smokers compared with current and former smokers [6]. The disease stage variation at diagnosis might be explained by late presentation of symptoms and delayed diagnosis by physicians. The survival outcome of never smokers was significantly better than smokers, with the 5-year overall survival rate of LCES, respectively [6]. The differences in the treatment response and survival outcome between never smokers and smokers with lung cancer may be attributed to the differences in molecular pathogenesis and tumor biology (see below). Genetics: While lung cancer prone families have been well described, the risk of affected subjects is greatly increased after smoke exposure. Recently the interest has focused on single nucleotide polymorphisms (SNPs). Genome wide association studies (GWAS) identified a locus in chromosome region 15q25 that was strongly associated with lung cancer. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits [7]. Such subunits are expressed in neurons and other tissues, including alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to potential lung carcinogens. Thus variants in this region undoubtedly code for increased susceptibility to smoke and are unlikely to be associated with LCNS. Not unexpectedly, GWAS studies indicate different patterns of susceptibility for Asians and never smokers and possibly related to gender [8, 9]. Molecular differences: The molecular differences between LCES and LCNS show marked differences and characteristic patterns. While TP53 mutations are common to all types of lung cancer, the mutational spectra are very different [10]. KRAS mutations are largely limited to LCES, and, along with TP53, show the typical smoking associated characteristic G to T transversions. In addition, the total numbers of non-synonymous and synonymous mutations in LCES tumors are much higher than that in LCNS, indicating that tobacco exposure results in in widespread genomic instability. Paradoxically, some of the most responsive currently available or potential molecular targets for precision medicine are more frequent in never smokers, including EGFR, BRAF and HER2 mutations and ALK translocations. Therapeutic options and precision medicine: While the overall treatment strategy is the same for LCES and LCNS, the differences in molecular profiles dictate differences in precision medicine and, response to targeted agents and overall survival. These factors are also influenced by gender and ethnicity. For instance, one study found that the frequency of driver mutations (EGFR, HER2, ALK, KRAS, or BRAF) in lung adenocarcinoma from female never-smokers in China was over 87% [11]. Summary: The differences between LCES and LCNS are major, and cover etiologic factors, clinic-pathological changes, genetic susceptibility genes, mutational and molecular changes and precision medicine. These differences are vast enough so that we can regard lung cancers arising in ever and never smokers as two different diseases. References: 1. Rudin CM, Avila-Tang E, Harris CC, et al. Lung cancer in never smokers: molecular profiles and therapeutic implications. Clin Cancer Res 2009;15(18):5646-61. 2. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers - a different disease. Nat Rev Cancer 2007;7(10):778-90. 3. StatBite lung adenocarcinoma in smoker vs. never smokers. J Natl Cancer Inst 2010;102(10):674. 4. Lee YJ, Kim JH, Kim SK, et al. Lung cancer in never smokers: change of a mindset in the molecular era. Lung Cancer 2011;72(1):9-15. 5. Subramanian J, Govindan R. Lung cancer in never smokers: a review. J Clin Oncol 2007;25(5):561-70. 6. Toh CK, Gao F, Lim WT, et al. Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity. J Clin Oncol 2006;24(15):2245-51. 7. Hung RJ, McKay JD, Gaborieau V, et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 2008;452(7187):633-7. 8. Shiraishi K, Kunitoh H, Daigo Y, et al. A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population. Nat Genet 2012;44(8):900-3. 9. Lan Q, Hsiung CA, Matsuo K, et al. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia. Nat Genet 2012;44(12):1330-5. 10. Pfeifer GP, Besaratinia A. Mutational spectra of human cancer. Hum Genet 2009;125(5-6):493-506. 11. Zhang Y, Sun Y, Pan Y, et al. Frequency of driver mutations in lung adenocarcinoma from female never-smokers varies with histologic subtypes and age at diagnosis. Clin Cancer Res 2012;18(7):1947-53

Abstract
Approximately 20% of patients with NSCLC present with early stage diseases. While with the advances in imaging and the success in low-dose CT screening in high risk patients, the proportion of patients diagnosed of stage I disease may increase. Radical surgery has been well established as the primary treatment for localized disease. However, a substantial number are ineligible for resection because of comorbidities that are associated inoperable medical condition or advanced age. Conventional fractionated therapy has had disappointing outcomes for stage I NSCLC, with reported local failure rates as high as 60–70% in some series, likely due of inadequate doses. Prior dose escalation study suggested that 70 Gy in 2 Gy fractionation would predict a local-progression free survival of only 24% at 30 months, while dose of 80 to 90 Gy were needed to achieve a recurrence-free survival rate of 50%. Utilizing the advances in radiotherapy planning and tumor targeting techniques, stereotactic body radiation therapy (SBRT) using ablative-range daily doses of 7.5–30 Gy (1-8 fractions), has achieved a biologically effective dose above 100 Gy. This biological unique treatment is associated with notable increases in tumoricidal effect. Reported local control rates have been repeatedly around 90% at 3 years. There is some uncertainty equating SBRT doses and fractionations. In a recent systemic review involving 1076 patients with stage I NSCLC with a follow up of at least 30 months (15 studies), no positive dose–response relationship for tumor control was revealed within different schemes. Current dose to eradicate stage I disease might thus be overestimated. Treating central lesions with hypo-fractionated radiotherapy or SBRT at lower biologically effective doses may be justified. Survival after SBRT is, in general, worse than that after surgery in indirect comparisons, probably because of the frail nature of the patients who receive SBRT. In a population-based study, SEER data showed that even though lobectomy were associated with the best long term outcomes in fit patients with early-stage NSCLC, the survival after SBRT was similar to that after lobectomy in the propensity-score matched analysis, suggesting comparable efficacy with in select populations. Further, the introduction of SBRT reduced the proportion of stage I NSCLC patients who received no local therapy. In north Netherlands population, the application of SBRT corresponded to a 16% absolute increase in the proportion of patients receiving radiotherapy, and this shift was associated with a 6-month median survival improvement SBRT is characterized by both high conformality of the ablative dose delivered to the target, and a sharp dose gradient at the edge of the target volume. This enables possibility for the physician to minimize treatment toxicity. Rate of symptomatic pneumonitis is usually less than 20%. Common, self-limited toxicities were revealed in approximately up to 40% of patients including fatigue, cough, dyspnea and chest pain. Hemoptysis and rib fracture can occur, whereas life-threatening complications are rare. Dose constraints have been investigated for SBRT, though the basic data are now being accrued. Nevertheless, clinical factors like gender, smoking history, and larger gross PTV may equally important or even overweight dosimetric metrics. Further research is required to better understand the tolerance of normal tissues and the long term quality of life after SBRT.

Abstract
Lung cancer and COPD frequently occur together in smokers, and COPD increases the risk of developing lung cancer in at-risk individuals. Exposure to cigarette smoke is clearly the most important causative factor. Other biological mechanisms for susceptibility to both lung cancer and COPD may involve inflammation, abnormal repair, oxidative stress, cellular proliferation, and epithelial-mesenchymal transition. In addition, genomic and epigenomic changes - such as single nucleotide polymorphisms, copy number variation, promoter hypermethylation and microRNAs - could alter biological pathways and enhance susceptibility to lung cancer and COPD. Approaches of studying genomics, epigenomics and gene-environment interaction will yield greater insight into the shared pathogenesis of lung cancer and COPD, leading to new diagnostic and therapeutic modalities. In addition to smoking cessation and preventing smoking initiation, understanding shared mechanisms in these smoking-related lung diseases is critical, in order to develop new methods of prevention, diagnosis and treatment of lung cancer and COPD.

Abstract
CT-guided percutaneous needle biopsy(CT-guided PTNB) of the lung, with its high sensitivity, specificity, and accuracy, is an important diagnostic tool in the evaluation of pulmonary lesion, especially in malignant disease . And it’s specificity can reach 95 percent to 100 percent in malignant disease. Although PTNB of the lung is a mature technique, careful case selection is necessary to increase diagnostic yield and avoid unnecessary complications. It is indicated for indeterminate pulmonary nodules or masses, particularly those that will likely require chemotherapy or radiation rather than surgery. Pneumothorax and pulmonary hemorrhage are the most common complications of PTNB, whereas air embolism and tumor seeding are extremely rare. Attention to biopsy planning and technique and postprocedural care help to prevent or minimize most potential complications. A retrospective investigation of patients with CT-guided PTNB in Jinling Hospital between January 2000 to October 2010 was performed. The risk factors for complications were determined by multivariate analysis of variables related to patients’ demographics, lung lesions, biopsy procedures, and individual radiological features.1014 biopsy prcedures were enrolled. The total complication rate was 18.5 percent with pneumothorax 12.9 percent (131/1014), hemoptysis 5.6 percent (57/1014), and with no mortality. The diagnosis was cofirmed by PTNB in 961 patients (94.8 percent) with 639 patients as malignant disease (63 percent) and 322 patients as benign diease (31.8 percent). Taken into all the evidence, CT-guided percutaneous needle biopsy is a safe and effective means in the diagnosis of pulmonary occupying lesions.

Abstract
Until recently the oncologist was only interested to know whether a lung cancer was SCLC or NSCLC. However, recent changes, particularly during this century, require more precise classification of lung cancer, and, in some cases, for subclassification [1]. The different classes of lung cancer respond differently to conventional therapy and to precision medicine. The patterns of driver mutations are highly tumor type dependent, with very little overlap between classes. Thus mutation testing depends of accurate classification. Other reasons for accurate classification include: 1) Adenocarcinoma histology is a strong predictor of response to pemetrexed therapy in patients with advanced disease; and 2) Serious hemorrhagic complications after bevacizumab therapy have been reported in patients with squamous histologies. With the development and application of newer agents for precision medicine, the need for accurate classification will only increase. Complicating the increased need for accurate classification is the fact that currently 70% of lung cancers are diagnosed from small biopsies or cytological samples. Thus more accurate diagnoses are demanded from smaller amounts of materials [1, 2]. A further complication is that large international clinical trials often require that tumor materials be reserved for entry requirements or various tests. In routine pathology practice, immunostains are often used to classify poorly differentiated lung carcinomas. While many immunostains have been proposed, a simple algorithm utilizing TTF1 and Napsin A for adenocarcinoma and p63 (or its isoform p40) and high molecular weight keratins have is effective [3]. However, even with excellent pathology practices, over 10% of cases will be incorrectly classified or be unclassified (undifferentiated large cell carcinoma or NSCLC-not other wise specified (NSCLC-NOS). Pathology practices and quality may vary from institution to institution or country to country. The SEER data on cancer incidence indicates that over 20% of lung cancer cases in the USA are not further classified. For these reasons we developed highly specific and sensitive RNA expression signatures as an adjunct test for routine pathological classification. The signatures not only classify the smaples, but provide a numeric scor ranging from 0-1.0, indicating the degree of differentiation. We utilized expression arrays from multiple public and private sources including The Tumor Cell Genome Atlas (TCGA), which used several platforms including Illumina, Affymetrix and RNA-Seq. For complete identification, four signatures had to be developed and validated and can be utilized independently or in combination. These signatures are: 1) Adenocarcinoma-squamous cell carcinoma discrimination, 2) lung specific neuroendocrine (NE)-non neuroendocrine lung cancer discrimination, 3) Non-malignant lung- lung carcinoma discrimination and 4) lung respiratory cell-lung carcinoma cell discrimination. The adenocarcinoma signature includesTTF1, the squamous cell carcinoma signature includes p63 and several high molecular weight keratins, and the NE cell signature includes chromgranin A, synaptophysin and dopa decarboxyase, adding credence to the signatures. These signatures have <10% discrepancy rates with expert pathology review and have helped n the correct classification of NSCLC, large cell and NSCLC-NOS carcinomas, NE lung tumors and lung cancer cell lines. John Minna and Alex Augustyn, in collaboration with us, have utilized their modification of the NE cell signature, and have identified two potential major clinical applications. These include identification of the full NE expression signature in a subset (5-10%) of NSCLC. While some of these may represent misclassified large cell neuroendocrine carcinomas, others appear to be typical adenocarcinomas. In addition, they have identified that BCL2 is one of the downstream targets of ASCL1, the driving force for NE differentiation in the lung, and that inhibition of BCL2 results in apoptosis of SCLC and NSCLC-NE tumors. Practical application of our signatures requires modification to a more practical platform such as Nanostring technology, and application to formalin fixed paraffin embedded small biopsies. These are currently in development. We are grateful to Drs. William Travis and Natasha Rehktman, members of the TCGA pathology panel and Ignacio Wistuba, John Minna and Alex Augustyn for their invaluable assistance. References 1. Gazdar AF. The evolving role of the pathologist in the management of lung cancer. Lung Cancer Management 2012;1(4):1-9. 2. Travis WD, Brambilla E, Noguchi M, et al. Diagnosis of Lung Cancer in Small Biopsies and Cytology: Implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification. Arch Pathol Lab Med 2012. 3. Travis WD, Rekhtman N. Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing. Semin Respir Crit Care Med 2011;32(1):22-31.

Abstract
Lung cancer remains as the most fatal disease world-wide.Non-small cell lung cancer (NSCLC) accounts for about 80% of all lung cancers. Incidence of pulmonary adenocarcinoma has been increasing in most countries and becomes a major histology. We had, up to the recent past, treated patients with chemotherapy without any clinical or biological selection. Unfortunately, the improvement in overall survival (OS) with platinum-based doublets is modest, although statistically significant when compared to best supportive care. We now, however, understand that adenocarcinoma could be divided into several subsets according to oncogenic drivers and each subset of adenocarcinoma has a different biology. So, targeted therapies against these drivers have been extensively studied and will play more and more important roles in treatment of advanced adenocaricnoma of the lung. Oncogenic drivers Adenocarcinoma is different in oncogenic drivers between East Asian and Caucasian patients. East Asian patients have more frequent epidermal growth factor receptor (EGFR) mutation but less frequent KRAS mutation. Incidence of EGFR mutation is about 50% - 78.8% but of KRAS mutation about 1.9% to 12%. Other oncogenic drivers include ALK or ROS1 rearrangement, BRAF mutation, HER2 amplification or mutation, c-MET amplification, etc, and arecomparable in their incidencesbetween Asian and Caucasian patients. These oncogenic drivers are mutually exclusive in majority cases. EGFR TKI Several phase II/III studies have investigated the efficacy of EGFR tyrosine kinase inhibitors (TKI) as front-line therapy of patients with advanced NSCLC. EGFR TKI is not appropriate for front-line therapy in unselected populations, in those without EGFR mutation, or those with unknown EGFR mutation status. Improvement in PFS with EGFR TKI is confined to those with EGFR mutation. In fact, first-line EGFR TKI seems to have a detrimental effect in those without an EGFR mutation. Clinical characteristics alone are not sufficient to correctly predict benefit from EGFR TKIs. Treatment with EGFR TKI in EGFR mutant NSCLC patients has also been found to be associated with improvement of progression-free survival (PFS) and quality of life and less toxicity profile. Both first-generation and second-generation EGFR TKIs are effective. Treatment of patients with acquired resistance to EGFR-TKI is wildly being studied. Switching to standard chemotherapy, continuation of an EGFR TKI beyond disease progression and/or plus local therapy, afatinib plus cetuximab are some options of treatment. ALK inhibitors Crizotinib proves effective in adenocarcinoma with ALKorRos1 rearrangement. Several studies (Profile 1001, 1005 and 1007) investigated crizotinib in advanced NSCLC with ALK rearrangement. Tumor response is about 51-61% and PFS 41.9-48.1 weeks. Second-line crizotinib was found more effective than chemotherapy in terms of tumor response rate and PFS. The compound was also found to be effective in those with ROS1 rearrangement. Among 35 patients, its tumor response rate was 60% and PFS was not reached. LDK 387 is a second-generation ALK inhibitor. Phase I study showed its promising efficacy in the patients with ALK rearrangement. It could overcome acquired resistance of NSCLC to crizotinib. Antiangiogenicagents Bevacizumab is approved to be combined with doublet chemotherapy as 1[st] line treatment of non-squamous NSCLC. The combination significantly improves tumor response, PFS and OS. But up to now, there is no biomarker for selection of non-squamous NSCLC patients to receive bevacizumab therapy. Many small molecular anti-angiogenicinhibitors plus standard chemotherapy have been investigated but failed in improvement of OS. Recently, LUME-Lung 1 trials suggested ninetedanib plus docetaxelsignificantly improved PFS and OS of patients with advanced adenocarcinoma of the lung in second line setting compared with docetaxel + placebo. KRAS inhibitors Some compounds are being investigated in those with KRAS mutation. Selumetinib, MKE1/2 inhibitor, combined with docetaxel significantly improved tumor response (37% vs 0%) and PFS (5.2 months vs 2.1 months, HR 0.58), compared with docetaxel alone.Trametinib plus second line chemotherapy produced about 12 to 28% of tumor response rate and 2.9 to 4.1 months of PFS. BRAF inhibitor Dabrafenib has been approved for treatment of melanoma harboringBRAF V600E mutation. Incidence of BRAF V600E mutation is about 1% in NSCLC. A phase II study investigated dabrafenib in adenocarcinoma of the lung withBRAF V600E mutation. Preliminary results in 20 patients showed 40% of tumor response rate and 60% of disease control rate with the compound. c-MET inhibitors c-METamplification is one of major mechanisms for acquire resistance of NSCLC to EGFR TKI. Several small molecular inhibitors of cMET and monoclonal antibodies against cMET are under clinical development. METmab plus erlotinib significantly improved PFS than erlotinib in those with MET high patients in the phase II trial. Crizotinib led to tumor shrinkage in a patient with MET amplification. HER2 inhibitors HER2 mutation and amplification are not frequently observed in adenocarcinoma of the lung. Mazieres and the colleagues reported that HER2-targeted therapies in additional lines of treatment produced 50% of overall response rate, 82% of disease control rate and 5.1 months of PFS. The disease control rate was 96% with trastuzumab-based therapies and 100% with afatinib monotherapy. The relative efficacy of these compounds deserves prospective evaluation in larger international clinical trials. Inhibitors of other oncogenic drivers Many inhibitors of other drivers including PDGFR, FGFR, RET rearrangement, PI3K, mTOR, MEK, AKT, STAT3, etc are under clinical development. We are just waiting for their results of clinical trials. In summary, EGFR TKI and ALK inhibitors are important agents for EGFR mutant and ALK or ROS1 rearranged adenocarcinoma of the lung, respectively. They become standard 1[st] line therapy for these patients. Bevacizumab plus doublet chemotherapy could be 1[st] line therapy for those with advanced adenocarcinoma harboring no oncogenic drivers. Many inhibitors of other oncogenic drivers are under clinical development and will become standard therapy for these patients in near future.

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Abstract
Despite progressive advances in biomarker-driven personalised therapeutic approaches to non-small cell lung cancer (NSCLC) in recent years, the efficacy of first-line treatment remains suboptimal. Most chemotherapy-treated patients experience disease progression within 3–6 months[1,2] and even those who initially benefit from tyrosine kinase inhibitor (TKI) therapy inevitably progress after 10–14 months.[3–6] However, 40–50% of patients have a good performance status at progression and are suitable for subsequent therapy.[7,8] Thus, improving second-line treatment has the potential to significantly impact patient outcomes. The success of several molecularly targeted therapies in the first-line setting in clinical trials has stimulated research interest in similar applications in the second-line setting. Data from the DELTA[9] and CTONG0806[10] studies presented at ASCO 2013 corroborate findings from the TAILOR[11] study which suggest that chemotherapy may be a marginally better option than epidermal growth factor receptor (EGFR)-TKI for EGFR wild-type patients beyond the first-line setting. It is now clear that treatment response varies widely between patients with different biomarker profiles and this underscores the increasing importance of biomarker testing prior to second-line therapy. For patients with unknown mutation status in the first-line setting, biomarker analysis upon progression is essential to guide second-line treatment decisions to optimise treatment response, both for targeted therapies and chemotherapy. In the pivotal BR.21 trial of erlotinib versus placebo in the second-line setting, response to erlotinib increased from 8.9% in the unselected population to 27.0% in the EGFR mutation-positive sub-population. Similarly, overall survival (OS) increased from 6.7 months to 10.9 months when the EGFR genotype was known.[12,13] In patients with anaplastic lymphoma kinase (ALK)-positive tumours, crizotinib has demonstrated superiority to chemotherapy in the second-line setting with improved progression-free survival (PFS; 7.7 vs. 3.0 months; p<0.001) and quality of life, an important second-line outcome.[14] Although improvements in chemotherapy efficacy seem to have reached a plateau, the use of molecular testing to identify patients who will benefit most from chemotherapy is being actively investigated. A recent study exploring the predictive role of BRCA1 and ERRC1 genes in patients receiving second-line platinum-based chemotherapy showed that low mRNA levels of both genes correlated with increased OS (16.0 vs. 5.4 months; p<0.001) and PFS (4.1 vs. 2.0 months; p=0.002) compared with high levels.[15] Although clinically validated biomarkers have not been identified for most therapies, they remain a critical focus of research and currently available information offers clinicians new insights into second-line management. For patients with known mutation status who experience disease progression following first-line therapy, biomarker testing prior to therapy allows identification of mechanisms of acquired resistance to enable clinicians to tailor subsequent treatment strategies. The most common mechanism of acquired resistance to EGFR-TKIs is the T790M mutation, which has been reported in up to 60% of patients with acquired EGFR-TKI resistance.[16–19] Oxnard et al. demonstrated favourable prognosis and more indolent disease progression in patients with T790M-mediated acquired resistance compared with other mechanisms of acquired resistance, and customised subsequent treatment based on these findings. Over 80% of T790M-positive patients were maintained on TKI therapy, along with chemotherapy, to help maintain the indolent characteristics of T790M-associated progression.[17] A re-response phenomenon has also been described in T790M-positive patients in whom TKI-sensitive cells repopulate upon cessation of TKI therapy, allowing the tumour to regain sensitivity to EGFR-TKI. Thus, re-treatment with EGFR-TKI and chemotherapy may be well suited to target both sensitive and resistant cell populations.[20] Other mechanisms of acquired EGFR-TKI resistance include secondary c-MET overexpression/amplification via HER3/erbB3 or KRAS activation (5–19%), AXL upregulation (20–25%) and phosphatidylinositol-3-kinase mutations (5%).[21,22] Similarly, secondary genetic alterations have been demonstrated in crizotinib-resistant ALK-positive tumours.[23,24] For patients with known mutation status who are still on first-line treatment, biomarker testing provides real-time information to monitor for the development of mutations and to uncover additional targetable tumour characteristics that may impact treatment response and warrant a change in therapy. Tumour characteristics may evolve following first-line treatment as tumour heterogeneity may exist at both genomic and morphological levels. Bai et al. investigated the impact of chemotherapy on EGFR mutation in advanced NSCLC patients who received first-line chemotherapy and patients with stage IIb–IIIb disease who received neoadjuvant chemotherapy, and found that mutation-positive rates were lower post-chemotherapy in both cohorts (p<0.01 and p=0.13, respectively). Importantly, patients who lost EGFR mutation positivity post-chemotherapy had a better partial response than patients with a reverse change (p=0.037).[25] Morphological tumour heterogeneity following first-line therapy has been increasingly reported in the literature. EGFR mutation-positive adenocarcinomas have been reported to transform to small cell histology with maintained EGFR mutation following progression.[16,18] In a study by Sequist et al., these observations allowed investigators to switch patients to small cell lung cancer chemotherapy regimens, with 75% responding to treatment.[18] Epithelial-mesenchymal transitions have also been reported.[18,26] Biomarker testing in the second-line setting is important to detect any changes in tumour characteristics before significant clinical deterioration when alterations to regimens might be most effective. The growing number of biomarker-targeted treatment options may create a need for biopsy or re‑biopsy during treatment. Recent guidelines by the College of American Pathologists, the International Association for the Study of Lung Cancer and the Association for Molecular Pathology recommends re-biopsies for EGFR and ALK mutation analysis to guide treatment decisions beyond the first-line setting.[27] Although re-biopsy may be challenging due to patients’ and/or clinicians’ reluctance, it has shown to be feasible and provides sufficient material for mutation analysis in most patients. High-sensitivity sequencing methods can detect T790M mutation in up to 68% of re-biopsy samples from patients with acquired resistance.[16,17,28,29] Nevertheless, promising surrogates for tumour tissue DNA, such as circulating blood biomarkers, are being investigated and may represent a less invasive approach. The BATTLE-1 trial, which employed real-time biopsies to match patients to targeted therapies, proved that a biomarker-driven treatment approach is feasible.[30] BATTLE-2, which involves more drug combinations, and real-time selection and validation of predictive biomarkers, is currently ongoing;[31] the highly anticipated results hold promise for revolutionising NSCLC treatment.

Abstract
ABSTRACT Rationale: Effective treatment for lung cancer requires accuracy in sub-classification of carcinoma subtypes. Objectives: To identify microRNAs in bronchial brushing specimens for discriminating small cell lung cancer (SCLC) from non-small cell lung cancer (NSCLC) and for further differentiating squamous cell carcinoma (SQ) from adenocarcinoma (AC). Methods: Microarrays were used to screen 723 microRNAs in laser-captured, microdissected cancer cells from 82 snap-frozen surgical lung tissues. Quantitative reverse-transcriptase PCR was performed on 153 macrodissected formalin-fixed, paraffin-embedded (FFPE) surgical lung tissues to evaluate 7 microRNA candidates discovered from microarrays. Two microRNA panels were constructed based on a training cohort (n = 85) and validated using an independent cohort (n = 68). The microRNA panels were applied as differentiators of SCLC from NSCLC and SQ from AC in 207 bronchial brushing specimens. Measurements and Main Results: Two microRNA panels yielded high diagnostic accuracy in discriminating SCLC from NSCLC (miR-29a and miR-375, AUC 0.991 and 0.982 for training and validation dataset, respectively) and in differentiating SQ from AC (miR-205 and miR-34a, AUC 0.977 and 0.982 for training and validation dataset, respectively) in FFPE surgical lung tissues. Moreover, the microRNA panels accurately differentiated SCLC from NSCLC (AUC 0.947) and SQ from AC (AUC 0.962) in bronchial brushing specimens. Conclusion: We found 2 microRNA panels that accurately discriminated between the 3 subtypes of lung carcinoma in bronchial brushing specimens. The microRNA panels could have considerable clinical value in differential diagnosis and play an important role in determining optimal treatment strategies based on the lung carcinoma subtype.

Abstract
Drug-associated interstitial lung disease (ILD) is not uncommon, but it may developed to fatal acute respiratory distress syndrome, so an accurate diagnosis based on clinical, radiological and histological manifestations is important. As an EGFR-TKI, Gefitinib or Erlotinib has been widely used in advanced NSCLC, although it may prolong the patient’s survival, the possibility of ILD associated with EGFR-TKI remains a big problem that we need to confront especially in Asian NSCLC patient. Diagnosis For the assignation of ILD, patient usually need to accord with the following requirements: (1) progressive dyspnea with or without cough or fever, (2) radiographic findings(HRCT recommended) show bilateral, diffuse, or patchy interstitial and/or alveolar opacifications, (3) lack of evidence of infection and progression of underlying lung cancer, (4) consistent pathologic findings if available. Establishing a diagnosis on EGFR-TKI associated ILD is often difficult, and is particularly challenging in a patient having been given chemotherapy and/or radiotherapy, chemotherapy and radiotherapy, either alone or in combination, have been associated with the development of ILD. In addition, infections, and other environmental exposures can also mimic ILD. The characteristic images of EGFR-TKI associated ILD were of patchy diffuse ground-glass shadows; several other characteristic HRCT patterns can also been observed. In acute forms of ILD, ground-glass attenuation is usually seen bilaterally in the lung fields. In chronic forms of the disease, “honeycombing” is seen that results from extensive pulmonary fibrosis and loss of acinar architecture of the lungs. Although ILD can occur during the first 3 months of treatment, the median time to onset was actually 24 to 42 days, and ILD developed in most patients within the first 4 weeks of treatment, with possibly rapid progression.On the other hand, ILD can develop in patients who are retreated with EGFR-TKI after a period of interruption. Therefore, all patients receiving EGFR-TKI who present with an acute onset of dyspnea, regardless of the presence of cough or low-grade fever, should be promptly evaluated, especially during the first month of treatment. Epidemiology There are more frequent reports of EGFR TKI-associated ILD in Japan than elsewhere in the world. The causes for this worldwide differences are unknown and require further scientific investigation. Several reasons have been suggested for this difference, including differences in follow-up period, the clinical characteristics of the study population, and the applied diagnostic criteria for ILD. Pre-existing ILD, including usual interstitial pneumonia, has been found in the reported EGFR-TKI induced ILD patients，the presence of IPF seems to be an important risk factor. Alternatively, there may be a specific increased genetic susceptibility to ILD among the Japanese population. However, this ethnic difference in reporting rates does not extend to other Asian countries, where the frequency of ILD is comparable with the rest of the world Mechanism of ILD The molecular mechanisms leading to ILD are also unclear. The distribution of EGF and EGFR in normal adult human lung has been demonstrated by immunohistochemistry, with expression observed in the basal cell layer of the bronchial epithelium . EGF signaling probably represents an important mechanism that helps coordinate the process of recovery from lung injury by stimulating epithelial repopulation and restoration of barrier integrity. Some investigator have suggested that EGFR-TKI therapy may augment any underlying pulmonary fibrosis via a decrease in EGFR phosphorylation with a coincident decrease in regenerative epithelial proliferation. Therefore, it is possible that EGFR inhibition will at least in part reduce the ability of pneumocytes to respond to lung injury. Compared with other EGFR inhibitors, the largest amount of information regarding the association with ILD is available for gefitinib, as this agent has been given to more patients than any other EGFR-TKIs. Treatment Treatment of EGFR TKI–induced ILD include supplemental oxygen, empirical antibiotics, and mechanical ventilation depending on the severity of the situation. Immediate discontinuation of the TKI drug is recommended . Acute pneumonitis commonly resolves on discontinuation of therapy, although in severe cases patients , systemic corticosteroids are usually prescribed, Prognosis with treatment is good if the diagnosis is made early; however, once fibrosis has occurred, the damage may be permanent with irreversible loss of lung function.

Abstract
The plasma protein complexes level was measured by electrophoresis analyses in 31 patients with advanced NSCLC treated with 125 or 150 mg/day icotinib hydrochloride until disease progression or unacceptable toxic effects or the patient refused further treatment. Eligibility criteria include performance status≤2, age≥18 years, and stage ⅢB-Ⅳ disease. Herein we found more than 87 % of the change in plasma IIRPCs appears at earlier time than histopathology occurs during the treatment with icotinib hydrochloride: (1) having a crest; (2) having a trough. The increasing or discreasing point always appears at earlier time in the treatment before histopathology occurs. There are no significant differences of the median PFS among the other clinical information groups, including: ages, gender, smoking history and EGFR mutation. Therefore, we showed that measurement of plasma protein complexes level during the treatment in patients with NSCLC may be a new surrogate marker for monitoring the therapeutic efficacy of icotinib and predicting the progression of the disease.

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There are many academic career opportunities for the young oncologist. Examples of career tracks include basic, translational and clinical research, education and administration. Finding a niche, or an unique area of contribution, is essential. Key elements for success include: 1. Finding a mentor - you can have more than one, and s/he doesn't need to be at your institution; 2. Spending time in academic training, such as pursuing formal research methodology training, administration or education training (e.g. Masters of Public Health, Business Administration or Education, and higher); 3. Developing a team to support you - include clinical support, research support or the personnel you need to achieve your career goals; 4. Build strategic partnerships and build a collaborative network - for example if you're not a scientist and wish to do translational research, partner with scientists. Engage statisticians, methods experts, and remember that collaboration is a two-way street; 5. Challenge yourself to ask important questions in your area of study, and focus on key issues - aim high and trust yourself; 6. Be a mentor to junior trainees - this is your best investment; 7. Publish your work; 8. Apply for grants (and don't give up - you will get some!); 9. Focus on your areas of interest - your areas of priority may not be where you spend most of your time, but they should be; 10. Keep your passion for your career alive - have a life outside academic oncology, enjoy your work and keep it fun. 11. Take advantage of opportunities for development - presentation skills, teaching skills, grant writing, paper writing, research methods - essential for a successful career, and not taught in medical school. 12. If you pursue a career in clinical research, join a cooperative group. Accrual is one way that young investigators can get themselves noticed, in addition to new ideas.

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HOW TO GET YOUR PAPERS PUBLISHED? James R. Jett, M.D. Professor of Medicine National Jewish Health Denver, Colorado, USA 80206 Scientific writing is not something that comes easily to most of us. I personally struggled with my own publications for the first five years of my academic career. However, I advise young colleagues that they should aim for three to five publications per year. If this is accomplished, then at the end of ten years, you would have 30-50 publications on your curriculum vitae. This would be enough to result in promotion from Assistant Professor to Associate Professor in most institutions. How does one get started with publishing articles? Before starting, I would suggest that you read about publishing scientific articles. An excellent book that covers all aspects of scientific writing is “How to Write and Publish a Scientific Paper” by Robert Day and Barbara Gastel. This book has individual chapters on preparing Abstract, Introduction, Methods, Results, Discussion, and References. This text is an excellent source on “how to do it”. There are also chapters on writing review papers, editorials, book chapters, and writing for the public. Additional chapters address ethics in publication, use and misuse of English, use of abbreviations. Especially useful to authors whose first language is not English is the chapter, “How to Write Science in English as a Foreign Language”. Another good source, available on the internet, is the International Committee of Medical Journal Editors (ICMJE) web site. Just type those initials into your web browser and review the “Uniform Requirements for Manuscript Submitted to Biomedical Journals: Preparing a Manuscript for Submission to a Biomedical Journal.” Major ethical issues include simultaneous submission to two journals, duplicate publication of the same data, plagiarism, and ghost writing. Violation of any of these issues will likely result in significant damage to your reputation and potential punishment by your institution. Violations often result in authors being banned from publishing in journals for several years. It can destroy your academic career. Needless to say, it will make your boss very unhappy! Before you submit a manuscript to any journal, it is mandatory that you review the “Instructions to Authors” for the specific journal. When I was Editor of Journal of Thoracic Oncology, one of the most common reasons for rejection was that authors did not follow the instructions. It is also advisable that you should read several articles, in the journal where you wish to publish, to be sure that you follow a similar style to articles that the journal has published. I also recommend searching for articles on the same topic in the journal for which you are planning the submission. If they have published several articles in the past year or two on this same topic, then you may want to consider a different journal, unless your article contains new and original information. The following are some of the most common reasons for articles to be rejected: Failure to read and follow instructions to authors Poor quality of English Non-structured Abstract Lack of novelty (me too articles) Dataset too small; flawed statistics The title and the abstract are extremely important. Often they are the only part of the article that is read. Readers decide, after reviewing these, if they wish to read the entire article. The words in the title should be carefully chosen. Pay careful attention to syntax. Avoid the temptation to be “too clever” in the title. Titles are used by indexing and abstracting services and help readers find your article in the morass of the medical literature. Write the abstract last. It should be a condensed version of the manuscript. Readers look at the abstract to see if they wish to read more. Sometimes an editor will read only the abstract and make a decision on rejection. I have done this many times. A poor abstract frequently means a poor manuscript. Most journals have a word limit for the abstract, frequently 250 words or fewer, and require a four-part structured abstract. Make sure that all of the numbers in the abstract match the numbers in the results section. This is a common error and reflects poorly on the author. Be concise! Remember that the abstract is your chance to get the attention of the reader (reviewer). Lastly, do not let a rejection discourage you. Pay careful attention to the critique that you have received and consider revising your article accordingly. Remember that the “peer review” process is not perfect. Reviewers can make mistakes and not recognize the merits of your manuscript. Revise your manuscript and send it to another journal. The majority of my own peer-reviewed publications were not accepted in the first journal where they were submitted. I have personally been rejected by many of the best medical journals. Do not take rejection personally. Try, try again!!!

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Abstract
The 15[th] World Conference on Lung Cancer (WCLC) is a highly interactive, collaborative, and intellectually enriching forum that focuses on the biology, diagnosis, and management of thoracic malignancies. For first-time attendees, the sheer scope and depth of the WCLC can be quite daunting. This educational session is designed for the young investigator or first time attendee. It aims to provide practical tools that will help the attendee navigate the 15[th] WCLC. This year, the Core Program Committee has organized a scientific program that includes more than 250 internationally renowned speakers and chairs participating in more than 100 sessions. The program can essentially be categorized as a component of either the Education Program or Scientific Program. The Education Program includes Invited Sessions wherein key faculty present state-of-the-art talks on relevant topics, as well as “Meet The Expert Sessions” that provide opportunities for attendees to directly interact with faculty . The Scientific Program includes cutting-edge and late-breaking research presented in oral, mini-oral, and poster formats. The Scientific Program also includes the Plenary Sessions, the Presidential Symposium (where the top rated abstracts are presented), and Highlights of the Day (where expert faculty summarize the past day’s most outstanding presentations), among others. There are also additional educational sessions such as Industry-Sponsored Symposia, a Patient Advocacy session, a Cochrane Workshop, and new to the 2013 meeting, a Chinese Alliance Against Lung Cancer session. First timers must carefully note that WCLC sessions can either be stand-alone (i.e, with no competing sessions such as the Plenary Sessions) or concurrent (e.g., oral and mini-abstract sessions). The organizers have developed a color-coded “session at a glance” diagram that clearly denotes each session’s schedule relative to others. (An online “virtual WCLC” will soon be developed to provide attendees access to concurrent sessions that they may miss because of a competing session.) There are also social events such as the Welcome Reception and the Gala Dinner that provide additional opportunities for first time attendees to interact with colleagues and faculty. It is thus anticipated that the 15[th] WCLC will provide young investigators and first time attendees a unique framework on which to build new collaborations that will ultimately have an impact on the future care of the patient with thoracic cancer.

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Staging is an objective measurement of the extent of cancer to allow logical grouping of patients with similar prognosis and pathobiological characteristics. Actually, the stage is expressed as combination of three factors: the size and invasion of the primary tumor (T), metastasis to the locoregional lymph nodes (N), and distant disease (M). Nowadays, any planning of the treatment is not possible without accurate staging. Moutain, who took the great leadership in the revision of TNM staging system, described staging as “assigning a simple coded designation to be a patient in accordance with an established set of rules”. Traditionally, UICC and AJCC have taken an initiative for the revision of the classification rules of TNM system. Since 7[th] edition which was published in 2009, IASLC was principally involved in the creation of proposals for revision to UICC and AJCC based upon the world-wide database. This process was known as “IASLC Lung Cancer Staging Project” lead by Goldstraw, and it is still underway for 8[th] edition. Although TNM staging system covers the malignant tumors of most organs, such aggressive intervention of international academic societies has been rarely seen except IASLC. The advent of mediastinoscopy, PET, and EBUS technique contrubuted to better staging. The IASLC Staging Project is now extended to cover not only lung cancer but also mesothelioma, thymic tumors, and esophageal cancer. As of 2013, surgery is still playing a principal role in the treatment of lung cancer especially for the relatively early stages of the disease with curative intent. Surgery is respected as the integration of two different parts: "art (surgical skill)" and "science". Therefore, we should realize that the evolution of lung cancer surgery has been achieved by the refinement of surgeons’ skills and advent of new technique (technology) as well as the accumulation of novel scientific evidence given by the well planned clinical trials. Surgery for lung cancer began as pneumonectomy as early as in 1930. However, the present-day gold standard surgery for lung cancer is defined as at least lobectomy and lymph node sampling/dissection. Series of clinical trials in 1980’s, mainly focusing upon the prognostic evaluation of adjuvant chemotherapy, were performed by Lung Cancer Study Group. The technically challenging surgery, such as those for superior sulcus tumor, has been also improved greatly. Even tumors located at the difficult potion of the thoracic inlet could be resected by refined method as shown by Grunenwald. How to manage the metastasis to the locoregional lymph nodes is also an important issue. Owing to the lymph node map originally drawn by Naruke and colleagues in 1970’s, the precise location of the metastatic nodes could be documented, and further analyses and comparison of the resected lung cancer with node metastasis became possible. The prognostic impact of the lymph node dissection was evaluated by the recent ACOSG study. In 1990’s, the minimally invasive technique (video-assisted thoracic surgery) was introduced in the surgery for lung cancer, and the comparison between open and VATS procedures were being performed. The trend toward the minimally invasive surgery is now generalized in the thoracic surgical community. The future directions in lung cancer surgery include the development of less invasive technique such as robotics, the improvement of the adjuvant treatment with new active drugs, the definition of the role of surgery in the multimodality treatment for advanced lung cancer, and the comparison between surgery and other local modalities (SBRT, ablation) as the treatment for pathologically early lung cancer. References 1970’s Pearson FG et al. The role of mediastinoscopy in the selection of treatment for bronchial carcinoma with involvement of superior mediastinal lymph nodes. J Thorac Cardiovasc Surg 1972;64:382-90. Naruke T et al. Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg 1978;76:832-9. 1980’s Holmes EC, et al. THE LUNG CANCER STUDY GROUP. A randomized comparison of the effects of adjuvant therapy on resected stages II and III non-small cell carcinoma of the lung. Ann Surg 1985;202:335-41 Mountain CF. A new international staging system for lung cancer. Chest 1986;89:225S-33S 1990-1995 Valk PE, et al. Staging of non-small-cell lung cancer by whole-body positron emission tomographic imaging. Ann Thorac Surg 1995;60:1573-82. Lung Cancer Study Group. Randomized trial of lobectomy versus limited resection for T12 N0 non-small cell lung cancer. Ann Thorac Surg 1995;60:615-23. 1995-2000 TNM Classification of Malignant Tumours. 5[th] Ed. Lung. International Union Against Cancer. Wiley-Liss, New York, pp93-97, 1997. Grunenwald D et al. Transmanubrial osteomuscular sparing approach for apical chest tumors. Ann Thorac Surg 1997;63:563-6. 2001-2005 Goya T et al. Prognosis of 6,644 resected non-small cell lung cancers in Japan: a Japanese lung cancer registry study. Lung Cancer 2005;50:227-34. Mateu-Navarro M et al. Remediastinoscopy after induction chemotherapy in non-small cell lung cancer. Ann Thorac Surg 2000;70:391-395. Van Schil PE et al. Remediastinoscopy after neoadjuvant therapy for non-small cell lung cancer. Lung Cancer 2002;37:281-285. Stamatis G et al. Repeat mediastinoscopy as a restaging procedure. Pneumologie 2005;59:862-866. De Leyn P et al. Prospective comparative study of integrated PET-CT scan versus re-mediastinoscopy in the assessment of residual mediastinal lymph node disease after induction chemotherapy for mediastinoscopy proven IIIA-N2 non-small cell lung cancer. A Leuven Lung Cancer Group study. J Clin Oncol 2006;24:3333-9. 2005-2010 The IASLC Staging Manual in Thoracic Oncology, Editorial Rx, Florida, 2009. Falcoz et al. The Thoracic Surgery Scoring System (Thoracoscore): Risk model for in-hospital death in 15,183 patients requiring thoracic surgery., J Thorac Cardiovasc Surg 2007;133:325-32. 2010- Yasufuku K et al. A prospective controlled trial of endobronchial ultrasound-guided transbronchial needle aspiration compared with mediastinoscopy for mediatinal lymph node staging of lung cancer. J Thorac Cardiovasc Surg 2011;142:1393-400. Darling GE et al. Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: Results of the American College of Surgery Oncology Group Z0030 Trial. J Thorac Cardiovasc Surg 2011;141:662-70. Swanson SJ et al. Video-Assisted Thoracoscopic Lobectomy Is Less Costly and Morbid Than Open Lobectomy: A Retrospective Multiinstitutional Database Analysis., Ann Thorac Surg 2012;93:1027-32

Abstract
Etiology and epidemiology Awareness that lung cancer is for many patients a self-inflicted disease has become common knowledge and its incidence can only be reduced by an active fight against smoking . The IASLC has always considered this as very important (1). The last decade much attention was given the non-smokers who developed lung cancer. These patients have specific characteristics, of which EGFR mutation is one (2). What is responsible for this class of lung cancer is unknown. With an estimated number of 300,000/year, it is far from an orphan disease (3). Early detection Lung cancer cure rates are far from impressive (4). For those diagnosed with symptoms the outcome is grim, cure is extremely rare, palliative needs are common (5). The 5 year survival rates in patients with resectable tumors is decreasing with increasing stage (6). Finding early stage lung cancer with state-of -the-art CT technology resulted in an impressive 10 yr survival rate of 88% (7). This modern CT technologywas evaluated in the largest lung cancer screening study ever performed (8). For the first time it was demonstrated that screening is effective and results in a relative reduction in mortality from lung cancer of 20.0%, and death from any cause by 6.7% (95% CI, 1.2 to 13.6; P = 0.02). Still many questions remain unanswered and confirmation is needed (9)? How to treat these lesions with minimal invasive surgery (10) or stereotactic radiotherapy (11). Pulmonology Autofluorescence bronchoscopy improves the detection of mucosal abnormalities (12) such as pre-invasive lesions (13), carcinoma in situ (14) and radiologically occult lung cancer (15). Through the EBUS (endobronchialultrasound) scope virtually every lymph node adjacent to the bronchial tree can be reached (16). In combination with the ultrasound from inside the oesophagus (17) this results in a sensitivity of > 90% (18). In a RCT it was demonstrated that combining these techniques should be done before thinking of a mediastinoscopy as their yield is comparable to mediastinoscopy (19). Bronchoscopy became important for treatment as well, ranging from palliative to really curative. Stenting the airway but should be used with great caution as migration is common, it seriously affects mucus clearance and narrowing of the airways through granulation tissue might develop (20). A desobstruction technique such as Nd-YAG laser, electrocautery or argon plasma coagulation can be used if intraluminal tumor gives obstruction (20). In specific situations with very limited cancer within the bronchial wall endobronchial treatment might even lead to cure, an example of this is photodynamic therapy (21). Radiology Within the last 40 years imaging techniques have improved considerably. With the introduction of computed tomography, it became possible to visualize the primary tumor as well as mediastinal lymphnodes in a much better way. A further technical improvement, the Positron Emission Tomography (PET) and the use of 18-fluorodeoxyglucose (18-FDG) improved this (22). Further developments of imaging may lead to decision making on treatment (23). References 1 Tobacco policy recommendations of the International Association for the Study of Lung Cancer (IASLC): a ten point program. Lung Cancer 1994; 11: 405-407 2 Ren JH, et al. EGFR mutations in non-small-cell lung cancer among smokers and non-smokers: a meta-analysis. Environ Mol Mutagen. 2012 Jan;53(1):78-82 3 Sun S, et al. Lung cancer in never smokers—a different disease. Nat Rev Cancer. 2007;7(10):778-790. 4 Goldstraw P, et al. The International Association for the study of lung cancer. The International staging project on lung cancer. J ThoracOncol 2006; 1: 281-286. 5 Ferrell B, et al. Palliative care in lung cancer. SurgClin North Am 2011; 91: 403-418. 6 Goldstraw P, et al. The IASLC Lung Cancer Staging Project: Proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification for Lung Cancer. J Thor Oncol 2007; 2: 706-714. 7 The International Early Lung Cancer Action Program Investigators. Survival of Patients with Stage I Lung Cancer Detected on CT Screening. N Engl J Med 2006; 355:1763-1771. 8 National lung screening trial research team, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011; 365: 395-409. 9 Field JK, et al. Prospects for population screening and diagnosis of lung cancer. Lancet 2013; 382: 732-741. 10 Nakamura K, et al. A phase III randomized trial of lobectomy versus limited resection for small sized peripheral non-small cell lung cancer. Jpn J ClinOncol 2010; 40: 271-274. 11 Senan S, et al. Treatment of early-stage lung cancer detected by screening: surgery or stereotactic ablative radiotherapy? Lancet Oncol 2013; 14: 270-274. 12 Venmans BJW, et al. Clinically relevant information obtained by performing autofluorescence bronchoscopy. J Bronchol 2000; 7: 118-121. 13 Breuer RHJ, et al. The natural course of preneoplastic lesions in bronchial epithelium - A longitudinal study. Clin Cancer Res 2005; 11: 537-543. 14 Venmans BJW, et al. Outcome of bronchial carcinoma in situ. Chest 2000; 117: 1572-1576. 15 Vonk-Noordegraaf A, et al.Bronchoscopic treatment of patients with intraluminal microinvasiveradiographically occult lung cancer not eligible for surgical resection: a follow-up study. Lung Cancer 2003; 39: 49-53. 16 Herth FJ, et al. Transbronchial and transoesophageal (ultrasound-guided) needle aspiration for the analysis of mediastinal lesions. EurRespir J 2006; 28: 1264-1275. 17 Silvestri GA, et al. Endoscopic ultrasound with fine-needle aspiration in the diagnosis and staging of lung cancer. Ann ThoracSurg 1996; 61: 1441-1445. 18 Wallace MB, et al. Minimally invasive endoscopic staging of suspected lung cancer. JAMA 2008; 299: 540-546. 19 Annema JT, et al. Mediastinoscopyvsendosongraphy for mediastinal nodal staging of lung cancer: a randomized trial. JAMA 2010; 304: 2245-2252. 20 Bolliger CT, et al. Therapeutic bronchoscopy with immediate effect: laser electrocautery, argon plasma coalgulation and stents. EurRespir J 2006; 27: 1258-1271. 21 Cortese DA, et al. Photodynamic therapy for early stage squamous cel carcinoma of the lung. Mayo ClinProc 1997; 72: 595-602. 22 Silvestri GA, et al Methods for staging lung cancer. Chest 2013; 143: 211S-250S. 23 Bahce I, et al. Development of [(11)C]erlotinib positron emission tomography for in vivo evaluation of EGF receptor mutational status. Clin Cancer Res. 2013; 19: 183-193.

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Abstract
Systemic Therapy of Early Stage NSCLC The addition of chemotherapy to surgery before or after surgery was studied because trials in the 1970’s demonstrated that cure rates were lower than in other cancers and because the majority of relapses were in distant sites (1). Initial adjuvant studies showed no survival advantage for single agent chemotherapy. Subsequent trials in the 1980’s and 1990’s established that cisplatin based 2-drug combinations produced a modest (4-5%) improvement in 5 year survival rates but only in stages II and IIIa (2). Adjuvant therapy has not been shown to improve outcomes in Stage I with the possible exception of Stage IB tumors larger than 4 cm (3). Neoadjuvant chemotherapy produces similar improvement compared to adjuvant therapy as demonstrated by randomized trials and metaanalyses (4,5). Post-operative radiotherapy has not shown benefits in stage I and II where it may be harmful and it role in stage IIIa after surgery is under evaluation as there are conflicting data on its role in this setting (6,7).Systemic Therapy of Stage III NSCLC Combinations of radiotherapy with chemotherapy were shown to produce superior survival compared to either alone based on randomized trials conducted in the 1990’s (8). Subsequent studies indicated that concurrent chemo-radiotherapy was superior to sequential therapy (9,10). There are conflicting data on whether two or four cycles of chemotherapy is best (11). There are also conflicting data on whether triple modality therapy is superior to two modalities for Stage IIIA N2 disease (12).Systemic Therapy of Stage IV NSCLC Chemotherapeutic agents and chemotherapy combinations were tested in the 1970’s and early 1980’s but failed to show any survival advantage. Two drug combinations combining cisplatin with vindesine or vinorelbine were shown to prolong survival compared to best supportive care in the 1980’s and 1990’s (13,14). Subsequent studies showed that 2-drug platinum based combinations were superior to a single active drugs (13,15,16). The survival advantage increased median survival times from 4-5 months to 8-12 months. Two-drug combinations with a platinum combined with gemcitabine, paclitaxel, docetaxel or pemetrexed were shown to produce equivalent survival in randomized trials conducted in the 1990’s and in the 2000’s (17,18). An exception to the equivalence was the finding that the pemetrexed/cisplatin combination was superior to gemcitabine/cisplatin in non-squamous cancer but inferior in squamous cancers (19). Three and 4 drug combinations were not superior to 2 drug combinations. These 2 drug combinations were superior in patients with PS 0-1 but benefitted elderly as well as younger patients (20). There is evidence that the paclitaxel/carboplatin combination may benefit PS2 patients (21). Thus, histology and performance status are key factors in therapy selection. Since the 1990’s, docetaxel, erlotinib, and pemetrexed have been shown to prolong survival when used in the 2[nd] line setting (22-24). For pemetrexed this improvement was limited to non-squamous histology (24). Since 2000 the use of targeted therapy began with the studies of inhibitors of VEGFR and EGFR signaling. Angiogenesis inhibitors were widely studied. Bevacizumab, a monoclonal antibody to VEGF, was shown to produce promising results in a randomized phase II trial (25). However, patients with squamous cell carcinoma had excess bleeding on this study and were excluded from all further trials. An ECOG randomized trial (4599) showed that bevacizumab improved survival in non-squamous histologies when combined with platinum doublets (26). However, the survival advantage is small and is less striking in elderly patients. The survival advantage was not observed in a randomized trial from Europe using gemcitabine/cisplatin as the chemotherapy backbone (27). As noted above, the EGFR TKI erlotinib was shown to prolong survival in unselected patients failing 1 or 2 chemotherapy regimens (23). In 2004 an association between mutations in the EGFR and response to EGFR TKIs was established (28,29). Subsequent randomized trials showed that EGFR TKIs were superior to chemotherapy in 1[st] line therapy of EGFR mutant patients but chemotherapy was preferred for those without mutations (30-35). In 2007, it was shown that EML4/ALK fusions could serve as driver molecular changes in up to 5% of NSCLC’s (36). Crizotinib, an ALK TKI was shown to produce high response rates and long PFS and was superior to chemotherapy in the second line setting (37-39). Patients with ALK fusions nearly always have adenocarcinoma histology, more often are younger and female sex and are light or never smokers (40) but clinical features should not be used to determine who should be tested (41). These and other molecular drivers may be present in more than 50% of lung adenocarcinomas (42). Molecular analyses of squamous and small cell cancers have recently been described (43-46). Checkpoint inhibitors such as PD1 and PDL1 were shown to be therapeutic targets since 2010. Antibodies to PD1 and PDL1 have produced responses in about 20% of patients who had failed multiple lines of chemotherapy and many of these were durable (46,47). PDL1 expression is being evaluated as a biomarker and many trials are in progress. Maintenance therapy with continuation of the original platinum doublet was shown in many trials to be associated with an increase in the PFS, an increase in toxicity but no increase in survival and therefore this approach was not adopted (48) . In 2009, Fidias et al reported that maintenance docetaxel could increase survival as well as PFS (49). This trial was followed by a trial showing that erlotinib could improve PFS and survival as maintenance after a platinum doublet (50). PFS and survival were improved in all histologies but the improvement in PFS and OS was most striking in patients with EGFR mutations. Pemetrexed was shown to improve PFS and survival as switch maintenance after a platinum doublet that did not contain pemetrexed (51). A subsequent trial showed that pemetrexed continuation maintenance also improved PFS and OS after induction therapy with a pemetrexed/platinum doublet induction (52). An unpublished trial, (POINTBREAK), comparing pemetrexed/carboplatin/bevacizumab with pemetrexed/bevacizumab maintenance compared to paclitaxel/carboplatin/bevacizumab followed by bevacizumab, showed no difference in survival. Thus, there is no evidence at presence that maintenance should contain two drugs although the ECOG is comparing pemetrexed with bevacizumab or the combination after induction therapy with paclitaxel/carboplatin/bevacizumab.Systemic Therapy of Early Stage SCLC Patients with Stage I and IIA SCLC, although infrequent, benefit from resection and adjuvant chemotherapy and the IASLC TNM classification is more accurate than the old VA classification (53). SCLC patients with stage IIB and III (limited stage SCLC) were shown to have prolonged survival when treated with chemotherapy and radiotherapy compared to either alone (54,55). An ECOG randomized trial showed that chest RT with BID radiation to 45 Gy was superior to once daily chest RT to the same dose when combined with etoposide/cisplatin (56). However, similar results were obtained with higher total doses of once daily RT and both once daily and twice daily are in routine practice. Concurrent chemoradiotherapy is superior to sequential therapy but results with radiotherapy starting at either cycle 1 or cycle 3 are similar. The combination of etoposide/cisplatin is the most frequent chemotherapy regimen because of reduced toxicities compared to Adriamycin or other combinations. Prophylactic cranial irradiation in good responders reduces brain relapse and prolongs survival (57). 25 Gy is the preferred dose (58).Systemic Therapy for Stage IV SCLC Both cisplatin and etoposide were first tested and shown to be active in the 1970’s. Studies in the 1980’s showed that the combination of etoposide and cisplatin produced high response rates (80%) with some complete responses (10-15% (59, 60). These results lead to randomized trials comparing etoposide/cisplatin to CAV, CAE or alternating combinations. Etoposide/cisplatin (EP) produced equivalent efficacy with less toxicity (60,61) and thus became the standard combination in the 1990’s. Pemetrexed/carboplatin was compared to etoposide/carboplatin and was inferior (62). Several trials have shown that irinotecan combined with cisplatin or carboplatin is equivalent to etoposide with cisplatin or carboplatin (63, 64). Thus EP remains the standard today. Topotecan is approved for used in the second line setting albeit at a dose and schedule rarely used due to toxicity (65,66). Both oral and intravenous topotecan produce similar results. Topotecan improved PFS as maintenance but did not improve survival and increased toxicity (67). Thus, use in the maintenance setting was not widely adopted. Retreatment with EP for those with late relapse has been the most successful retreatment approach and is standard in this setting (68). After 2000, randomized trials showed that PCI after induction response could prolong survival in extensive stage as well as limited stage SCLC and as now used routinely in this setting (69). There has been little change in chemotherapy options for SCLC over the past 20 years but there is some hope that the immune checkpoint inhibitors could improve outcomes (70).

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Abstract
The United States Preventive Services Task Force (USPSTF) has released a draft recommendation, a “B”, for lung cancer screening. This means that the USPSTF concluded with moderate certainty that there was substantial net benefit for screening healthy individuals (i.e. those able to withstand surgical intervention) with a 30 pack-year of more history of smoking, ages 55 to 79 years of age who have smoked within the past 15 years. This recommendation is based primarily upon the results of the National Lung Screening Trial (NLST)with some consideration of the emerging results from much smaller trials in Europe. While this “B” isreasonable, the criteria for whom to screen may need revision. Tammemagi et al (NEJM 2013; 368:728-736) have serially refined an incidence-based risk model. In the most recent model, PLCO~M2012~, lung cancer risk increases with age, African American race/ethnicity versus white, lower socioeconomic status (education), lower BMI, self-reported history of COPD, personal history of cancer, family history of lung cancer, being a current smoker, increased smoking intensity and duration, and shorter quit-time in former smokers. Applying the NLST criteria to the PLCO intervention arm smokers, 14,144 of 37,332 (37.9%) were eligible. To obtain an equal number of individuals using the PLCO~M2012~, individuals with a lung cancer risk >1.3455% were regarded as positive. Overall the PLCO~M2012~ risk method identified 81 more of the 678 lung cancers (11.9%) than did the NLST criteria (41.3% fewer lung cancers were missed: 115 versus 196). To include 80% of lung cancers in the PLCO control smokers, a PLCO~M2012~ risk probability of 0.016082 or higher would be used (specificity = 67.3%; PPV = 4.1%) and the proportion of smokers to be screened would be 33.6%. A spreadsheet calculator is available online, which calculates lung cancer risk according to PLCO~M2012~ given an individual’s predictor levels. http://www.brocku.ca/lung-cancer-risk-calculator An alternative approach looking at lung cancer mortality was developed by Kovalchik et al (NEJM 2013; 369:245-254). This analysis was limited to individuals who met the NLST entry criteria and used the NLST data for risk development with similar factors as Tammemagi et al. Five-year risk of lung cancer mortality ranged from 0.15-0.55% in the lowest risk group (Q1) to greater than 2% in the highest risk group (Q5). Sixty percent of NLST participants with the highest risk of lung cancer mortality accounted for 88% of LDCT-prevented lung cancer deaths. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of LDCT screening across rounds have now been reported. There is little variation across the rounds. At T0, the sensitivity and specificity were 93.8% and 73.4% for LDCT. In the LDCT arm, the PPV was 52.9% (265/501) for any positive finding that led to a biopsy procedure but only 3.8% (270/7,181) for positive findings overall Overall NPV was 99.9% (19,043/19,061). Among LDCT positive screenees undergoing thoracotomy at T1 and T2, 18.9% and 15.9% did not result in a lung cancer diagnosis, respectively. The frequent need for evaluation of positive screens increases the burdens of LDCT screening. Increasing the minimum size threshold for screen positivity can reduce the frequency of diagnostic work-up. Nodules 4-6 mm diameter accounted for roughly half of LDCT positive screens at T1 and T2, but were associated with lung cancer in less than 1% of cases. The variability in radiologists' interpretations of computed tomography (CT) studies in the NLST (including assessment of false-positive rates [FPRs] and sensitivity), was characterized and factors that contributed to variability, and trade-offs between FPRs and sensitivity among different groups of radiologists were evaluated. One hundred twelve radiologists at 32 screening centers each interpreted 100 or more NLST CT studies, interpreting 72 160 of 75 126 total NLST CT studies in aggregate. The mean FPR for radiologists was 28.7% ± 13.7 (standard deviation), with a range of 3.8%-69.0%. Aggregate sensitivity was 96.5% for radiologists with FPRs higher than the median (27.1%), compared with 91.9% for those with FPRs lower than the median (P = .02). In adjusted analyses, smoking cessation was strongly associated with the amount of abnormality observed in the previous year’s screening (P<0.0001). Compared to those with a normal screen, individuals were less likely to be smokers if their previous year’s screen had a major abnormality that was not suspicious for lung cancer (odds ratio (OR) = 0.790, P<0.001), was suspicious for lung cancer but stable from previous screens (OR = 0.777, P<0.001), or was suspicious for lung cancer and was new or changed from the previous screen (OR 0.593, P<0.001). Integration of effective smoking cessation programs within screening programs should lead to further reduction in smoking-related morbidity and mortality. Estimates suggest that the risk of radiation-induced lung cancer from three annual lung CT screens (average lung dose from a single LDCT estimates at 4 mGY) for older current smokers is likely to be in the range 1-10 deaths per 10,000 screened. However, because of the high probability of a positive screen (>20%) the follow-up procedures could double the risk of radiation-related lung cancer. The observed reduction in lung cancer mortality in the trial due to lung CT screening was 31 deaths prevented per 10,000 screened. The estimated radiation-related risks are therefore considerably smaller than the observed benefit. However, when the follow-up scans are included the benefit for current smokers is reduced by about 30% from 31 to about 20 lung cancer deaths per 10,000 screened. The impact on life-expectancy will be smaller, however, because the lung cancer deaths prevented occur at a younger age than the radiation-related cancer deaths. Estimates of the reduction in life-expectancy from radiation-related cancer were on average only 1-5 days. The advent of improved risk models demonstrates that more efficient criteria for selection of individuals for lung cancer screening than the NLST are feasible and effective. The various medical groups that have developed recommendations for lung cancer screening have primarily settled upon the NLST criteria. These groups should re-evaluate their criteria in light of the findings of these new risk models. This would have the salutary effect of making lung cancer screening more efficient and save more lives.

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