Virtual Library

Abstract:
On October 14th, the Fifth IASLC Strategic Screening Workshop will be held in Yokohama Convention Center with the following objectives: 1.) provide the state of art methodology for undertaking lung CT cancer screening, 2.) provide discussions and recommendations around implementation, which will have impact on all health services, 3.) develop a resource toolkit to support national screening implementation efforts when based on current knowledge and international expectations, 4.) propose recommendation for the IASLC Executive Committee to consider regarding how they can support leadership in this forefront area of lung cancer for the Association, 5.) produce a document outlining the summary status from this workshop. The IASLC has been a robust supporter of research and progress with lung cancer screening especially working to integrate tobacco control and cessation measures with low dose CT-based early detection efforts in high risk populations. As the world’s leading multi-disciplinary lung cancer care professional society and with the quality of the lung cancer screening process fundamentally linked to the proper coordination of all of the health professionals required for this service, IASLC has a critical role in facilitating rapid progress for this validated approach to reducing lung cancer mortality. This Workshop brings leading experts in screening from across the world to discuss best practices as well as to consider new collaborations to advance best practice. In light of the great demand from the IASLC membership, we have also organized a second screening forum for October 14, which is a Symposium on Advances in Lung Cancer CT Screening. In this forum, a number of international leaders will present their experiences with aspects of CT screening process. These presentations are more in-depth than in the Workshop forum but still providing ample time for interaction with the attendees. The intention is to provide the membership with a comprehensive emersion into the rapidly moving field of lung cancer screening. This is a new, complex and demanding service. Implementing a high quality screening process while maintaining low cost can be done, but many institutions have benefitted from a collaborative approach to share institutional practices. The goal of the current IASLC Workshop and Symposium is to encourage and facilitate such collaborative interactions.

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In 2011, my husband Dan was 69 years old. He had quit smoking 11 years prior but had an 80 pack year smoking history. Dan also had COPD. His sister, also a former smoker, had died of lung cancer at age 62, six months after being diagnosed. In January 2012, I read an article in Prevention magazine, a health and fitness magazine, about recommended screening tests. One of the tests was a spiral CT to screen for lung cancer. I knew Dan was at risk so I asked our primary care physician about getting Dan tested. Our physician did not know about the test. When I discussed the test with Dan, he did not want to do it because it was not covered by Medicare. Dan was diagnosed 9 months later with Stage 4 Adenocarcinoma. For the next 18 months taking care of Dan, I immersed myself in reading about and looking for all of the possible treatment options for him. However, it was too late for Dan. He died in April 2013, eighteen months after his diagnosis. During this eighteen months, I realized how little the general public, and in many cases medical professionals, knew about lung cancer risks, early detection, and the latest research. I decided to become an advocate for people with lung cancer. I started my advocacy in April 2013. Despite the lack of insurance and Medicare coverage, some institutions in the United States started lung cancer screening programs in 2012 and 2013. Many professional societies and advocacy groups had endorsed lung cancer screening based on the National Lung Screening Trail (NLST) results and published screening recommendations and guidelines. In the United States, lung cancer screening is now recommended by the US Preventive Services Task Force and by Medicare and covered for eligible patients without a co-pay. However, based on National Health Interview Survey results, in 2015 the year private insurance and Medicare coverage began, only 2.1% of those eligible for screening had an LDCT. This is actually less than the 2.7% of respondents in the high risk category that indicted they had a chest x-ray to screen for lung cancer. Obstacles to lung cancer screening mentioned by healthcare professionals include high false positive rates, potential for invasive procedures for benign disease, and need for follow-up for positive scans and incidental findings. Also mentioned were lack of time for the shared decision making discussion required by Medicare prior to screening, the lack of validated decision aids, and that patients don’t ask about screening. There is a lack of understanding among healthcare professionals about quality metrics achieved in screening programs with current screening quality processes that are updated from those used in the NLST. In particular, positive rates with LungRADS structured reporting guidelines are approximately 10% as compared to 26% in the NLST. Additionally, the return for follow-up testing in less than one year after an annual scan is much lower than after the baseline, prevalence scan (Figure 1). Figure 1 Figure 1. Lung Cancer Screening Quality Metrics in an Established Clinical Lung Cancer Screening Program There is a general lack of awareness among the high risk population about their risk of lung cancer and about the opportunity for lung cancer screening for current and, especially former smokers. Many former smokers think once they quit smoking, they are no longer at high risk. About 50% of lung cancers are diagnosed in former smokers so this is an important group to reach. The recently launched American Lung Association “Saved by the Scan” campaign is designed to target this group. One of the differences between lung cancer screening and other cancer screening tests is the stigma associated with lung cancer. Because of the close link between smoking and lung cancer, many people with lung cancer are blamed, or blame themselves, for their disease. People at high risk for lung cancer often express denial, self-blame, nihilism and fear of stigma and anger from loved ones and others and decline the opportunity for screening. “I smoked. If I get lung cancer it will be my fault. I don’t want to get screened. I don’t want to know” are comments I have heard too often during my community outreach activities. Similar to other screening tests, the main reason people decide to get tested is because of a recommendation by their healthcare provider. Educating and raising awareness among both medical professionals and the high risk population needs additional focus to reach the 9 million people at high risk for lung cancer in the US. In Europe, lung cancer screening is not yet recommended. Europeans are awaiting the results of the NELSON screening trial to evaluate the best approach to screening for their population. Although there have been numerous small lung cancer screening trails in European countries, in general they were underpowered and the results mixed and inconclusive. 51% of the world’s lung cancer cases and 21% of lung cancer deaths occur in Asia. China alone has 300 million current smokers. The opportunity to save lives with the implementation of lung cancer screening in this region is huge. From a patient advocate perspective, the results of the NLST and the US experience with screening should be used to accelerate implementation of lung cancer screening programs worldwide. The world loses 1.6 million people every year to lung cancer. The test for early lung cancer detection is available now. Every day of delay results in additional unnecessary deaths.

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Lung cancer is the commonest cancer and cause of cancer death in the UK, and Liverpool has over twice the national incidence. In addition, the city has high rates of socioeconomic deprivation, smoking, and respiratory morbidity. Most lung cancer patients present through clinical routes, but symptoms are poor at defining the disease: risk scores have low predictive values, and in Liverpool 75% of cases present at stage 3 or 4. National guidance (NICE) suggests clinical referral with a risk score >3%. Although screening is well established for breast, colon and cervical cancer (which are less prevalent and cause fewer deaths) there is no lung cancer screening program. Liverpool was one of the pilot sites for the United Kingdom Lung Screening Trial (UKLS), where 2.4% of patients entered locally had lung cancer with a resection rate of 83%. Following this, 2 local proposals were developed for risk-stratified case finding. The first, involving CT scans for the high risk cohort already attending secondary care sector clinics, was refused funding. The second, the ‘Liverpool Healthy Lung Project’ (LHLP) secured funding (£3.3M), started in April 2016, and is described below. Firstly, a series of coordinated focused public engagement ‘Healthy Lung Events’ were arranged in areas with a high lung cancer incidence, aimed at promoting positive messages around lung health, and addressing the fear and fatalism surrounding lung cancer Secondly, in localities of the highest lung cancer risk, from GP records all those age 58-70 with COPD, who smoke, or had asbestos exposure were invited to a face to face lung health check by a respiratory nurse who promotes positive lifestyle messages and calculates a 5-year personal lung cancer risk (www.MyLungRisk.org): those > 5% threshold were offered a low dose CT scan. In the first year 87 Healthy Lung Events attracted 1943 interactions and 813 completed spirometry of which 146 (18%) were abnormal, triggering a primary care consultation. 2911 (40%) of 7274 eligible individuals attended the lung health check, where 1107 (38%) were offered a CT scan: of 1064 performed, 414 (39%) were abnormal (102 [9.6%] lung nodules and 17 [1.6%] lung cancer (65% resected). 726 (44%) of the 1658 (57%) without previously diagnosed COPD had abnormal spirometry. In the UK the cost/benefit ratio is paramount and provisional analysis suggests that the LHLP costs £4000 per QUALY (COPD 63%, 22% Lung cancer, 15% smoking cessation). Extending the CT scan screen to include cardiac disease may improve this further. What has been learned so far from LHLP? The 40% uptake was lower than anticipated, but disadvantaged groups are the hardest to engage. “Ownership” of the project is important: eligible patients receive letters from their own GP, who also manages abnormal findings. The use of existing community networks, events and resources, and local advertising and promotion aids recruitment: although 25% attended after the first letter, a further 48% attended after a second letter and 27% after a follow-up telephone call, increasing participation by 300%. Texting is being introduced, and social marketing strategies (used in commercial marketing), with client profiling to determine the best ways to achieve contact are being considered. Lung health checks are face to face with the project nurse, occur locally (often in patient’s own GP practice), and are invaluable in health promotion (smoking cessation, diet, exercise), and defining spirometry and cancer risk score and often facilitate onward referral. Some of the targeted areas had high levels of mental illness and foreign language speakers, and the approach has been modified to engage more with these groups. The eligible age range has been extended to 75 years for the second year. Radiology report need to be clear: potential cancers are automatically managed by the local lung cancer team, and pulmonary nodules are managed within the project. Other reported abnormalities are referred back to the GP - a not insubstantial workload. Conclusions This innovative project has improved access to respiratory healthcare in a deprived area of Liverpool. Screening for both lung cancer and COPD, linked with health promotion has shown that economic viability is achievable. Fear and fatalism is common in respiratory disease, and this disadvantaged population is hard to engage. Lessons re engagement have been learned. The positive health messaging, and promotion of early diagnosis and curability of lung cancer can only bring benefits to both patients and the health care community.

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“If you build it, they will come.” This slogan represents an easy assumption that screening availability and/or coverage necessarily leads to screening uptake. But unlike the mystical ballplayers from Field of Dreams, those at high risk for lung cancer possess neither a preternatural awareness of nor attraction toward lung cancer screening. Lung Cancer Alliance (LCA) made early detection a core organizational priority a decade before widespread insurance coverage finally made screening accessible to those at high risk. At each step we advocated for the key building blocks--funding, research, and policymakers’ attention and decision-making--that made community-level screening implementation possible. Following the National Lung Screening Trial’s publication, LCA established the National Framework for Excellence in Lung Cancer Screening and Continuum of Care to prioritize the dissemination and implementation of best practices for safe and responsible screening and to help guide the transition to community-level screening. Likewise, recognizing the need for a timely public awareness strategy, LCA developed and launched the “Live More Moments” media campaign that encouraged people to know their lung cancer risk and learn more about early detection through screening. Additionally, the growing network of screening programs receiving LCA’s designation as a Screening Center of Excellence helped ensure those at high risk who chose to be screened could do so with a screening program committed to best practices. In the midst of this landmark movement toward increased public awareness of lung cancer risk and the right to responsible screening and care, the USPSTF released their “Grade B” recommendation and established screening as a covered preventive service for those meeting the specified high risk criteria. It is undeniable that efforts to increase public awareness of lung cancer screening are far more complex than other population-level prevention and early detection awareness strategies. There are distinct difficulties associated with identifying who is at high risk and targeting a message to them that is clear and easily understood and that compels them toward an action step in a responsible, patient-centered manner. Intensifying this difficulty are unique psychosocial barriers experienced by many of those at high risk for lung cancer: stigma from one’s smoking status or history, fear of the test and possible diagnosis, denial about one’s risk status or the benefits of early detection, and distrust or suspicion of the healthcare industry. Responsible lung cancer screening programs will clearly identify and communicate the criteria they use to determine whom they will screen. Many utilize CMS eligibility criteria while others screen the slightly broader age range recommended under USPSTF criteria, and some also include NCCN group 2 if the patient and referring provider have determined through a shared decision-making process that screening is appropriate. To facilitate and ease the patient engagement process, LCA has developed educational materials that can be used to help patients understand the process of lung cancer screening: what screening is; who should consider being screened; the benefits and risks of screening; and what to consider in choosing a high quality screening program; as well as a brochure addressing smoking cessation in the context of their screening decision. Drawing upon insights provided by recent research into psychosocial barriers to screening, we have begun development of educational materials and messaging to specifically address these barriers and have intensified ongoing efforts to address stigma in particular. Because the early detection benefit of lung cancer screening is realized through adherence to repeat annual screening as well as compliance with nodule follow-up, it is essential that screening participants are engaged in a process of shared decision making. This allows for their full and deliberate consideration of the benefits, risks and potential harms of lung cancer screening in the context of their own priorities and values, which likewise deepens their understanding of and commitment to screening as a process rather than a discrete test. In addition, improved patient and provider communication can lead to improved screening adherence. LCA has worked with the network of Screening Centers of Excellence to collect adherence-building best practices to compile and share with programs needing to increase their own return rates. In addition to addressing awareness, knowledge, beliefs and attitudes about screening, engagement strategies should also acknowledge and address logistical barriers to screening. While insurance coverage removes a tremendous cost barrier, continued billing and coding challenges result in unanticipated and often erroneous bills for patients. This creates a burden on both the patient and the screening program staff to correct the situation and may result in added distrust toward the screening process on the part of the patient. Screening programs need a strategy to identify and assist patients in these circumstances. And while most U.S. insurance plans must cover screening for eligible plan-holders without co-pays or cost-sharing, patients need to know ahead of time that follow-up testing may bring considerable cost. Distance and transportation are also potential logistical barriers. As the ranks of LCA’s more than 500 Screening Centers of Excellence continues to grow, more and more people at high risk for lung cancer will be able find a program committed high quality lung cancer screening in their local community. Additionally, the prospect of telehealth delivery of shared decision-making will help even more patients overcome access barriers and ease their engagement in the lung cancer screening process. References: Carter-Harris, L., Ceppa, D. P., Hanna, N. and Rawl, S. M. Lung cancer screening: what do long-term smokers know and believe? Health Expect. 2017; 20: 59–68. doi:10.1111/hex.12433 Carter-Harris, L., Gould, M. K., Multilevel Barriers to the Successful Implementation of Lung Cancer Screening: Why Does It Have to Be So Hard? Ann Am Thorac Soc. 2017; 14(8). doi:10.1513/AnnalsATS.201703-204PS Gressard, L. et al. A qualitative analysis of smokers’ perceptions about lung cancer screening. BMC Public Health. 2017; 17:589. doi 10.1186/s12889-017-4496-0 Peckham, J. Engaging Patients & Assisting Primary Care Physicians in Lung Cancer Screening. accc-cancer.org. Oncology Issues. July-Aug 2016: 31-35.

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Modeling smoking trends and lung cancer screening to 2060 in the US; changes in screening eligibility and the potential impact of joint screening and cessation programs on smoking and lung cancer. Introduction. Annual lung cancer screening with low-dose computed tomography (LDCT) has been recommended in the US for current and former smokers with ≥30 pack-years of exposure and ≤15 years. Since about 50% of eligible individuals are current smokers, the implementation of lung cancer screening programs presents a unique opportunity to develop cessation programs targeting high-risk individuals at the point of screening. Despite its potential, since screening eligibility is based on cumulative smoking exposure, the continuing decreases in smoking in the US should lead to reductions in the number of screening-eligible individuals reducing the potential impact of screening and of cessation programs within lung cancer screening. It is thus important to investigate the possible interplay that screening and smoking cessation will have in short and long-term tobacco and lung cancer outcomes. Methods. We used a previously validated smoking and lung cancer microsimulation natural history model and census population forecasts to project smoking trends, the number and percentage of individuals eligible for screening, and the potential costs of screening in the US from 2015-2060. We then used the model to project the impact that hypothetical cessation programs within the context of lung cancer screening with varying efficacy could have on smoking, lung cancer and overall mortality. Results. We found that given current smoking prevalence and cessation trends, the number and percentage of screening-eligible individuals in the US will decrease dramatically in the next few decades, reaching under 5 million by 2035, and that the potential costs associated to lung cancer screening will decrease considerably as fewer individuals satisfy current eligibility criteria. Preliminary simulations of cessation interventions targeting smokers considering (or receiving) lung cancer screening, suggest that effective cessation programs within lung cancer screening could have significant benefits and lead to considerable reductions in lung cancer and overall tobacco-related mortality. For example, under a 40% lung cancer screening uptake scenario, the model predicts that a smoking cessation program with a 10% success rate would lead to 160,000 fewer lung cancer deaths, and 1.4 million life years gained by 2060. Conclusions. Although the number of lung cancer screening eligible individuals in the US is expected to decrease considerably in the next decades, effective cessation interventions within the context of lung cancer screening have the potential to greatly enhance the impact of screening programs and lead to considerable reductions in lung cancer mortality and tobacco-related diseases. Figure 1 Figure 1. Projected life-years gained from lung cancer screening and a one-time cessation intervention within the context of lung cancer screening for different values of the probability of cessation due to the intervention. The projections consider the dynamical changes in population structure, smoking prevalence and screening eligibility, and assume that 60% of screening-eligible individuals would be screened and that all screened smokers receive the cessation intervention after receiving their first screen.

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In this session, the focus will be on comparison of existing screening guidelines and the rationale for how they have developed. It will also highlight the similarities and the areas where different approaches have been taken. Among the guidelines that will be compared will be the Lung-RADS, National Comprehensive Cancer Center (NCCN), International Early Lung Cancer Action Program (I-ELCAP), British Thoracic Society (BTS), and Fleischner Society. We will also discuss the protocols previously recommended during the National Lung Screening Trial (NLST) and the NELSON trial as points of reference as these trials have been completed. The main points of similarity among these various protocols is there are various size criteria for workups to be initiated, with increasing size raising the suspicion of lung cancer. The differences in size threshold, especially in the baseline round for determining a positive result has had the greatest impact in terms of limiting the number of positive results. Many protocols now have moved to the six millimeter threshold which has lowered positive results in the baseline round into the range of 10-15%. Aside from different size threshold cutoffs, a main area of difference has been the way size is measured. Some rely on uni or bi-dimensional measures while others use volumetrics. For those uni-and bi-dimensional measures there are also differences in terms of whether to perform rounding. The effect of rounding is most pronounced in that baseline round where the frequency of the smaller nodules is highest, and rounding up to the nearest whole number can substantially increase the rate of positive results. The protocols also differ in terms of the number of size categories given and the options within each category. For any given size threshold that initiates further work up, there are various options that are considered. The most common includes the use of repeat imaging prior to the next annual screening round. While there are differences in terms of the length of these intervals in part based on the nodule size, all include a three or six month follow-up and some also include a one month follow up under certain conditions, As a general principle the time interval between scans is provided so as to allow for change to occur. The protocols all seek to measure this change either in terms of change in diameter or change in volume. The extent to which the amount of change is measured also varies. Some protocols include a fixed amount of change regardless of size while others require the extent of change to differ depending on size. Each of these has implication towards how often a result will be considered as positive. Most recently the Quantitative Imaging Biomarkers Alliance has provided additional guidance in this regard, and there are similar recommendations being developed by European and Japanese counterparts. One of the most important considerations in terms of management protocols is the differentiation between findings made on the baseline round compared to the annual repeat round. Findings on baseline occur only once while those on repeat rounds potentially can occur on numerous rounds throughout the course of screening and all protocols treat findings in each repeat screening round the same regardless of whether it is the first repeat screen or the tenth. Cancers in the baseline round tend to be larger and also more slowly growing compared to annual cancers, and similarly there are many more nodules found on the baseline round compared to new nodules found on repeat rounds. These factors all influence the way protocols are designed. While all protocols provide guidance for when to perform more invasive procedures, there tends to be several options. These factors allow for differences between institutions where there are differences in expertise in performing these procedures as well as availability of equipment. Another area of difference between protocols relates to how results are defined in terms of “positive” or “false positive” or “semi-positive.” An approach adopted in the NELSON trial allowed for positive result to only be determined for a certain size category of nodules based on the combination of results from the initial scan where a finding was made and the determination of whether growth had occurred. This approach allows for dramatically lowering the rate of positive results because it implies that the initial test needs to be thought of as being a test to measure growth which requires two time separated scans. A final area of difference has been the treatment of nonsolid and part-solid nodules. Here there is a general recognition that even those these nodules may be cancers, they are of a more indolent nature and there is relative safety in terms of following them over time. Some differences between the protocols include the amount of time allowed between scans and the trigger for more invasive management. Direct comparison of the different protocols will be made and examples will be provided to highlight some of the differences.

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Planning for European Registries for CT Screened Images – What Are Their Objectives? In 2011, the National Lung Screening Trial (NLST) showed that lung cancer screening by annual low-dose chest CT saves lives.[1] Currently, lung cancer screening is being implemented in routine clinical care in the United States for a high-risk population of current and former heavy smokers. Prior to a definitive recommendation on lung cancer screening in Europe, the mortality results of the Dutch-Belgian randomized controlled lung cancer screening trial (NELSON trial) are awaited.[2] However, different European societies, such as the European Respiratory Society and the European Society of Radiology, currently advice to already prepare for implementation.[3] In case screening becomes part of clinical practice in Europe, both a national and a European registry for all low-dose CT screened individuals should be set up as a tool for quality assurance.[4] Trough these registries, it can be ensured that all (reports of) CT images performed in a screening setting meet a uniform high standard. Given this requirement, radiologists in Europe involved in low-dose CT lung cancer screening should be trained, a.o. in performing volumetric measurements of CT detected nodules. By saving all screening results in a European registry, a Europe-wide analysis of the efficacy of screening programs will be facilitated.[4] Besides assurance of image and report quality, and the possibility to perform a Europe-wide analysis on the effect of lung cancer screening, monitoring of given radiation dose per individual during the course of a CT lung cancer screening program can be achieved via a European registry. References 1. National Lung Screening Trial Research Team, Aberle DR, Berg CD, et al. The National Lung Screening Trial: overview and study design. Radiology. 2011;258(1):243-253. 2. Postmus PE, Kerr KM, Oudkerk M, et al. Early-Stage and Locally Advanced (non-metastatic) Non-Small-Cell Lung Cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2017; 28 (suppl 4): iv1–iv21. 3. Kauczor HU, Bonomo L, Gaga M, et al. ESR/ERS white paper on lung cancer screening. Eur Respir J. 2015;46(1):28-39. 4. Field JK, Zulueta J, Veronesi G, et al. EU policy on lung cancer CT screening 2017. Biomedicine Hub. In press

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The reimbursement of low dose CT lung cancer screening for high risk populations in the United States by the Centers for Medicare and Medicaid Services (CMS) [1] has been implemented with a requirement to participate in a nationwide registry run by the American College of Radiology (ACR) [2]. This registry’s main purpose is to enable the collection of basic information on lung cancer screening including patients’ demographic information, medical history and risk factors, procedure indications, and follow-up information. Owing in part to the large data sizes of low dose CT lung cancer screening studies, which can exceed 500 MB for each 3D CT scan acquisition, this important US lung cancer screening registry is not collecting CT image data. However, the I-ELCAP study has been collecting international lung cancer screening data, including CT scan images, for over two decades [3]. There are several important benefits to collecting CT lung cancer screening image datasets in addition to basic lung cancer screening information. CT image data provides important information on the quality of actual scans and findings in the field, which can help identify areas of improvement for national screening efforts as well as for the local lung cancer screening site. One of the most important benefits is that expert review of these scans and findings can help train local radiologists on how to improve delivery of lung cancer screening. In addition, many image acquisition characteristics can be automatically evaluated that influence lung cancer screening performance. Determining whether patients are being over scanned (outside the lung region), whether the CT table was properly positioned, and whether the CT reconstruction field of view was properly set can be evaluated are some of the areas that can be evaluated using automated analysis methods provided that the CT scan datasets are available for processing. Also, new image quality standards for CT lung cancer screening data acquisition are becoming available and these requirements can potentially be evaluated against actual scans acquired. Another important benefit that is enabled by CT lung cancer screening image data registries is the potential to identify new imaging biomarkers as well as help improve existing imaging biomarkers. A persistent challenge for lung cancer imaging research groups is to continuously collect lung cancer screening image data obtained from current day patients and using modern CT scanners. Given that CT scanner technology and methods are changing rapidly it is particularly important to have a large continuous source of imaging data, which a large image-based registry can provide. In addition to informed consent to conduct research and patient privacy protections, studies based on registry data can support the lung cancer imaging research community by further collecting additional quantitative metadata with each CT scan. The collection of images allows for retrospective reviews of imaging findings that were not known to be important for the different diseases that may occur in the lungs. One such example is recognition of early interstitial lung disease which can be as deadly as lung cancer [4]. Having the prior images for review once a diagnosis is made allows for future early recognition and for development of follow-up recommendations. Growing recognition of subtypes of nodules (subsolid and solid), both solitary and multiple ones, and review of prior imaging has been important in limiting invasive procedures for certain subtypes [5, 6]. Automated methods can potentially be used by image-based registries to calculate and store the location, surface geometry, and volume of the lungs, suspicious nodules, cancer tumors, and relevant anatomy and pathology. If data transmission bandwidth is a roadblock to collecting image data, automated methods can be employed to at least collect images of identified lung cancers and other targeted areas (e.g. suspicious lung nodule regions). Another opportunity is to document the fundamental image quality characteristics of CT scans, as is becoming available using automated methods. Documenting image quality information within large lung cancer screening image datasets will enable the research community to better understand the relationship between image quality and measures of lung cancer screening success, such as the ability to detect and measure small lung nodules. This data will be critical to help inform the establishment of new minimum imaging standards that are being developed for lung cancer screening studies. Over the next few years several new lung cancer screening initiatives will launch in the United States including an effort to deploy lung cancer screening services at US Department of Veterans Affairs Medical Centers. These lung cancer screening studies will offer a fresh opportunity to collect lung cancer screening image data with modern tools, research targets, and methods. References 1. CMS recommendation to support reimbursement for lung cancer screening, , February 5, 2015. 2. Pederson JH, Ashraf H, Implementation and organization of lung cancer screening, Ann Transl Med. 2016 Apr; 4(8): 152. 3. Yankelevitz DF, Henschke CI, Advancing and sharing the knowledge base of CT screening for lung cancer, Ann Transl Med. 2016 Apr; 4(8): 154. 4. Salvatore M, Henschke CI, Yip R, Jacobi A, Eber C, Padilla M, Koll A, Yankelevitz D. Journal Club: Evidence of Interstitial Lung Disease on Low-Dose Chest CT: Prevalence, Patterns and Progression. AJR AM J Roentgenol 2016: 206:487-94 5. Yankelevitz DF, Yip R, Smith JP, Liang M, Liu Y, Xu DM, Salvatore M, Wolf A, Flores R, Henschke CI. CT screening for lung cancer: nonsolid nodules in baseline and annual repeat rounds. Radiology 2015; 277: 555-64 6. Henschke CI, Yip R, Wolf A, Flores R, Liang M, Salvatore M, Liu Y, Xu DM, Smith JP, Yankelevitz DF. CT screening for lung cancer: part-solid nodules in baseline and annual repeat rounds. AJR Am J Roentgenol 2016; 11:1-9

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Next Generation CT Scanners for Lung Cancer Screening – Way Forward Sebastian Schmidt, Siemens Healthcare GmbH, Siemensstr. 3, 91301 Forchheim, Germany After the publication of the NLST (National Lung Cancer Screening Trial) in 2011, lung cancer screening with low dose computed tomography gained more and more attention and was formally established in the USA in 2016 and other countries afterwards. The increasing use of CT for screening created new requirements for computed tomography scanners: - Further reduction of radiation dose: As the target population is healthy and gets repeated scans, cumulative dose is an important topic. This is addressed by technologies like improved spectral shaping and iterative reconstruction. - Quality control and standardization: A homogeneous high quality is extremely important in screening. This will be enabled by cloud-based technologies for distribution of protocols, central registration of scan parameters and radiation exposure and collection and distribution of images between many scanners and many radiologists. - Affordability: Lung cancer screening should be economically feasible in different healthcare systems. Therefore new technologies are required to improve throughput and decrease effort as well as to provide ultra-low-dose technologies on cost efficient CT systems. - Ability to combine lung cancer screening with other biomarkers for common diseases like COPD or arteriosclerosis. The academic community and the CT vendors spent significant effort into development and clinical validation of CT systems meeting these requirements. Many technologies are already available today, others are under development. Some research and development activities: - Ultra-low-dose CT with less than one tenth of the natural background radiation. - Cloud-based systems for distributed standardization, reporting and quality control of large fleets of scanners. - Highly cost-efficient systems with these technologies. - Semi-automated scanning and reporting aids to reduce the workload of the technologist and the radiologist. - Development of protocols to assess several parameters in an ultra-low-dose scan. Some of these technologies are already commercially available on the latest systems, others are under research. Help from the clinical community is required in validation of these technologies and the definition and standardization of the best clinical and scanning protocols.

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Background There is an urgent need for methods to detect lung cancer earlier. If detected early, over half of lung cancer patients could be cured with existing treatments. Therefore, our greatest opportunity lies in increasing rates of early diagnosis through improved cancer screening. Exhaled breath contains over 1,000 Volatile Organic Compounds ﴾VOCs﴿, which are the products of metabolic activity, hence they directly reflect the current state of cells and represent a valuable source of information about the health of an individual. As the earliest stages of tumour development are characterized by profound changes in cellular metabolic activity, VOCs are potential non‐invasive biomarkers for early detection of lung cancer. The LuCID study aims to collect breath samples and evaluate VOCs in exhaled breath as non‐invasive biomarkers for early detection of lung cancer. Method LuCID is an international multi‐centre prospective case‐control cohort study ﴾ClinicalTrials.gov ID NCT02612532﴿ currently in progress, evaluating breath VOCs in patients with a clinical suspicion of lung cancer. A clinical suspicion is based on symptoms and/or suspicious finding on incidental imaging. Using tidal breathing, patients breathe into the ReCIVA Breath Sampler for 7 minutes to collect alveolar‐ and bronchial enriched breath fractions on stable sorbent tubes for later analysis by Gas Chromatography‐Mass Spectrometry and Field Asymmetric Ion Mobility Spectrometry ﴾FAIMS, Owlstone Medical Ltd﴿. A classification algorithm will be constructed from chemical spectral data, and undergo internal and external blinded validation to provide a ROC‐curve detailing diagnostic accuracy. The LuCID study has an adaptive trial design, recruiting up to 2,600 patients depending on interim results. Figure 1 Results The LuCID study has recruited 980 patients to date from 20 centres ﴾mean age 67.5, SD 12.0﴿. Of patients with completed follow‐up ﴾n=802﴿, 33% have histologically confirmed lung cancer ﴾of those with lung cancer: 40% early stage 1a‐2b, 60% advanced stage 3a‐4﴿. Non Small Cell Lung Cancer ﴾NSCLC﴿ comprised 87% of these cancers, and Small Cell Lung Cancer 9%. NSCLC were further categorized as adenocarcinoma ﴾50%﴿, squamous cell carcinoma ﴾38%﴿, with the remaining 12% belonging to other categories. Most recent data on study progress and results will be presented at the conference. Conclusion The LuCID study is evaluating the analysis of exhaled VOC biomarkers as a new diagnostic modality for early detection of lung cancer. Successful completion of the LuCID study will pave the way for the development of a non‐invasive, easy‐to‐implement test that could markedly improve screening and early detection rates, reducing lung cancer morbidity and mortality.

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An effective CT screening program relies on numerous health care professionals from different areas of expertise. Evidence-based guidelines established by professional organizations provide a framework for programs to achieve an optimal balance between the benefits and risks of screening. Interaction and constructive communication among the providers involved is essential for implementation and maintenance of a high quality screening program. This presentation will discuss opportunities for quality control through interdisciplinary collaboration at different phases of the screening process: Program Design Lung cancer screening processes involve numerous components of the health care delivery system. Engaging individuals with relevant expertise and those whose workflow will be affected can help obtain a program structure best adapted to local resources. Patient Eligibility Determination Current guidelines restrict CT screening to persons who meet a specific lung cancer risk profile, understand the benefits and risks, and are able and willing to pursue diagnosis and treatment. Some health care providers may not be familiar with this, and refer patients for CT screening in whom the risks outweighs the benefits. Direct interaction with referring providers may be needed in order to ensure quality in this component of the screening process. A dedicated program nurse navigator or other paraprofessional can be invaluable for this and other components of the screening process. Smoking Cessation Patients pursue CT screening to reduce the risk of lung cancer death. Quitting smoking is an important additional means to this goal, but support for smoking cessation is beyond the expertise of most screening providers. Collaboration with smoking cessation services and professionals is essential for providing encouragement and access in the most effective manner. CT Imaging To ensure adequate image quality at the lowest radiation dose, current guidelines recommend reducing the dose for persons smaller than average, and increasing dose for those larger than average. Quantitative nodule volumetry requires attention to additional technical details. Care should be taken that the CT technology staff efforts are closely aligned with image quality goals. CT Interpretation Screening exam interpretation dictates management and is the central component of lung cancer screening. Use of a standardized reporting and management system based on current evidence is advised, for consistency in the quality of care and assessment of outcomes. Reporting Results Prompt and effective communication of results facilitates timely management of screening abnormalities. This can include written notification of the ordering provider, and ideally the patient, direct telephone contact for findings that need further management, and documentation of communication. A dedicated nurse navigator or other paraprofessional is an ideal reporting liaison for a busy program. Management of Abnormalities Abnormalities may be managed by referring providers or by dedicated clinical collaborators within a comprehensive screening program. Patient tracking using lung cancer screening database software can help monitor compliance with recommendations and can prompt inquiries if diagnostic testing has not been pursued. Collaboration through working clinical conferences may facilitate decision-making regarding diagnosis and treatment. Program Assessment Comparison of program performance metrics with published data and goals may help identify program strengths and deficiencies, and suggest means of quality improvement for individuals or processes.

Abstract:
Screening programs require the coordination of multiple disciplines, including radiology, pulmonology, thoracic surgery and pathology. Each provides critical components for the management of screening findings beginning with the initial screening finding and all the way through treatment. In addition, there needs to coordination with the necessary support staff, including coordinators, nurse practitioners and radiology technologists. Screening programs are typically led by radiologists, but this varies with some programs led by pulmonary medicine and others by thoracic surgery, nevertheless integration is required. Part of the challenge of screening is the information that is provided by the initial screening test, the low dose CT scan, involves an extensive amount of information. First and foremost, it provides information regarding findings related to potential lung cancer, notably lung nodules. These are now typically managed through a protocol that has been adopted by that institution. In the United States, typically Lung–RADs is followed, although others are also used and outside the US other countries also have various protocols. Beyond the findings related to potential lung cancer, the CT scan also identifies findings related to a variety of other illnesses. Most prominent has been coronary artery calcium. Currently, in the US, it is required to make note of this findings in order to submit insurance claims. Recently, a joint statement was developed by the Society of Cardiovascular Computed Tomography and Society of Thoracic Radiology for how to manage these findings. In addition to the cardiac findings there are other findings that can be made on the CT scan where there is already evidence of their importance. One of the most common findings in screening exams includes emphysema. While the majority of participants in screening programs know that they have emphysema, a substantial minority are unaware including even a small percentage with CT evidence of severe emphysema. While this finding is routinely reported, no specific recommendation is made regarding what to do in terms of seeing a pulmonologist or even getting pulmonary function studies. A variety of other findings can also be made and quantified such as pulmonary artery size, aortic calcification, breast density, bone density and even liver density. In each of these examples various quantitative metrics can be ascertained, the challenge remains as to how to utilize these measures in a clinical management protocol that fits within the framework of a particular health care institution. In a recent editorial published in Radiology regarding the ability to now measure and quantify these types of findings, the authors noted the following, “Rather than shying away from this new responsibility, the radiology leadership should embrace the possibility of adding a new dimension to our profession…In doing so, we can also expand our role and value in the overall well-being of patients in the current climate of health care reform.” Beyond the issue of reporting findings and developing management plans, potentially specific to the institution, there are two additional areas where deep integration within the healthcare system are necessary. First and perhaps most important is smoking cessation. While some form of smoking cessation counseling is required in the US in order to obtain reimbursement from CMS, full deployment of resources in this would seem to be a natural extension of any screening program and here the health care benefits, especially in regard to heart disease become apparent quickly. A second and more challenging area in regard to integration is the actual message regarding screening and potential benefits. Here there is great confusion is not only among the radiologists, but among referring clinician as well. Results of the NLST underestimate the benefit for a person enrolled in a screening program over the long term. The challenge of understanding that clinical trials do not fully reflect what will happen once they are brought out into the community is becoming an increasingly important topic in therapeutics, but it is particularly evident in screening where by necessity, the screening is only provided for a very limited time frame for those in the trial, but in fact, people enrolled in a trial will have ongoing screening perhaps for as long as 20 years. The potential benefit here is substantially different than what can be directly measured based on just results from a trial such as NLST with only 3 rounds of screening and a follow up period that does not include screening. Specific examples of various image findings and recommendations will be provided. In addition, examples of what might be told to people who are interested in enrolling in a screening program will also be explored.

Abstract:
The integration of biomarkers into lung cancer CT screening programmes remains an ‘unfulfilled promise’ in lung cancer research. There are two specific areas that biomarkers could contribute: (i) identification of high risk individuals for future Lung cancer CT screening programmes (ii) management of CT detected ‘indeterminate’ nodules (Figure 1). Figure1. Potential for the integration of biomarkers into Lung cancer CT screening programmes Figure 1 The choice of potential risk biomarkers has been recently reviewed by Atwater & Massion (1), however, the major issue is that none of the candidate biomarkers have been shown to have any impact on the reduction of cancer mortality. The question is whether we have been undertaking the correct design to identify such a molecular biomarker, which will need to add significant worth to the current risk models based on lifestyle and medical history or to the developing image-based “radiomic” biomarkers. Many diagnostic biomarkers have been described, but often these have not been designed to work alongside Lung cancer CT screening. Lung cancer risk prediction models based on epidemiological parameters and history of lung disease have made a major contribution to how we select participants for lung cancer screening trials, the two risk modes which have been used in recent lung cancer screening trials are the LLPv2 (2) (UKLS) and the PLCO2012 (3) used in the Pan Canadian trial. However, no biomarkers or genetic susceptibility markers have made any impact on these risk prediction models to date(4). The recent new set of SNPs identified in the Lung cancer OncoArray publication (5) may provide a new research avenue. Also utilising the Cancer Genome Atlas (TCGA) project dataset, 8 SNPs were found to be significantly associated with lung cancer risk ( P 0.05) in both discovery and validation phases (6). Some biomarker modalities, e.g. breath testing and liquid biopsies for microRNA (miRNA) or circulating tumour DNA (ctDNA) could impact either on risk models for selection or for managing nodules. The advent of Breath tests for early lung cancer detection has come of age and has demonstrated potential by Owlstone Medical who are in discussion with the NHS to roll out the device across GP surgeries in the UK in 2017, based on the results of the PAN Cancer Clinical trial. [https://www.owlstonemedical.com/]. It will be important to assess how best to integrate such GP-based tests with wider screening programmes. Early lung cancer breath tests recently reviewed (7) (8). A major effort is currently been undertaken in ctDNA, the presence of cell free DNA in either plasma or serum has been described in multiple publications, however the presence of ctDNA in early disease remains elusive (9) and ctDNA is more likely to be employed in nodule management. However, circulating protein biomarkers have a more established history in lung cancer diagnosis (10) (11). The management of CT scan detected indeterminate nodules presents a major issue to the clinicians managing these patients, a number of nodule risk models have been developed, based on the characteristics of the nodules with specific epidemiological criteria (12) and pulmonary management guideline have been drawn up (13). A range of other models have been recently reviewed (14). This is now considered the forefront area of molecular biomarker research, could potentially make an enormous contribution to the management of indeterminate nodules. Liquid biopsies for microRNA (miRNA) have diagnostic and prognostic potential for CT screen detected cancers (15) (16) and may impact of nodule management (17). Pomising new research into the evaluation of tumor-derived exosomal miRNA using next-generation sequencing as a diagnostic maker for early disease has also been developed (18) (19). Circulating miRNA may also be used to improve risk models including clinical factors, imaging and serum protein levels (20). One challenge for validation and evaluation of the required molecular and imaging biomarkers is the availability of low dose CT scan data and related samples, especially in countries that have not yet instigated national screening programmes. This may be met in part by current initiatives to establish registry studies and to make imaging data available as currently been planned in the IASLC CCTRR project, but a parallel effort for access to associated minimally invasive samples (e.g. plasma and serum) would be welcomed. References 1. T. Atwater, P. P. Massion, Ann Transl Med 4, 158 (2016). 2. J. K. Field et al., Health Technol Assess 20, 1-146 (2016). 3. C. M. Tammemagi et al., J Natl Cancer Inst 103, 1058-1068 (2011). 4. M. W. Marcus et al., Int J Oncol 49, 361-370 (2016). 5. J. D. McKay et al., Nat Genet 49, 1126-1132 (2017). 6. Y. Zhang et al., Ann Oncol, (2017). 7. S. A. Hayes et al., J Breath Res 10, 034001 (2016). 8. I. Taivans et al. Expert Rev Anticancer Ther 14, 121-123 (2014). 9. C. Perez-Ramirez et al., Liquid biopsy in early stage lung cancer. Transl Lung Cancer Res 5, 517-524 (2016). 10. C. E. Hirales Casillas et al., Future Oncol 10, 1501-1513 (2014). 11. X. Wang et al., Oncotarget 8, 45345-45355 (2017). 12. A. McWilliams et al., CT. N Engl J Med 369, 910-919 (2013). 13. G. British Thoracic Society Pulmonary Nodule Guideline Development. (2016), vol. 2017. 14. J. K. Field et al. Transl Lung Cancer Res 6, 35-41 (2017). 15. M. Boeri et al.,. Proc Natl Acad Sci U S A 108, 3713-3718 (2011). 16. S. Sestini et al., Oncotarget 6, 32868-32877 (2015). 17. J. Shen et al., BMC Cancer 11, 374 (2011). 18. X. Jin et al., Clin Cancer Res, (2017). 19. Y. Lin et al., Int J Cancer, (2017). 20. Li et al. World J Surg Oncol 15, 107 (2017).

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Abstract:
CT screening for lung cancer is a process that involves both potential benefits and harms. In order to minimize harms and maximize benefits thoracic surgeons should play a key role in any CT screening program, as recommended by ESTS (1), ATS and ACCP (2,3), NCCN (4), IASLC (5). Thoracic surgeons should also be involved in the planning of a screening program in order to integrate surgical expertise in the design of the program and the diagnostic protocols, potentially in order to achieve better results than in the National Lung Screening Trial (NLST) (6). Surgical contributions are most important for the following issues. Minimizing false positive diagnoses by optimal management of screen detected nodules. The target population should be defined as selection of a higher risk cohort may influence the false positive rate. The NLST criteria [6] have been widely endorsed by organisations engaged in screening, but also higher risk groups selecting individuals with a 5-year lung cancer risk > 5% or 2% have been suggested (7) . Nodule characteristics and criteria determine follow-up examinations or referral for noninvasive or invasive tests to determine the indication for surgical excision. The lower cut-off size for defining a positive nodule has great impact on the false positive rate, and a change to higher cut-offs has been shown to be possible without a major reduction in sensitivity (8). Reduction of surgery for benign lesions. Prior to resection of screen-detected nodules, a preoperative diagnosis is preferred. In patients with peripheral nodules with high likelihood of malignancy, VATS wedge resection prior to anatomic resection may be justifiable . For larger or more central lesions, obtaining a preoperative diagnosis would be possible also with CT-guided transthoracic needle aspiration, trans-bronchial needle aspiration, navigational bronchoscopy, or endobronchial ultrasound guided aspiration. In any case, a diagnosis should be secured prior to proceeding with lung major resection. In case of suspicious lung lesions less than 2 cm with no preoperative diagnosis, resectable in the volume of an anatomical segmentectomy, it can be acceptable to perform a diagnostic and therapeutic minimally invasive segmental resection using both VATS or Robotics, while diagnostic lobectomy should be avoided or limited to extremely rare cases (1). In all of the published studies of CT screening for lung cancer, surgery has been performed for benign lesions. The reported extent varies from 2–45% (4,9,10), and current recommendations are to keep this rate below 15% (4).The best way to reduce surgery for benign lesions is to have an accurate preoperative/diagnostic biopsy algorithm, as this reduces the number of indeterminate nodules referred for surgery (1,9). Surgeons should be closely involved in diagnostic work-up to locate and mark or biopsy small indeterminate pulmonary nodules. In difficult cases time should be allowed for watchful waiting to verify growth and calculation of tumor volume doubling time and repeated biopsies to substantiate or verify a suspicion of malignancy. In a screening setting a delay in diagnosis under close monitoring is preferable to unnecessary surgery. The extent of surgery for benign lesions during CT screening should be monitored and reported as an indication of surgical quality (1,3,10). Reduction of surgical incision-related trauma. Minimally invasive thoracic surgical procedures should be performed by specialists board certified in thoracic surgery. In anatomic resections of screen detected cancers that are less than 3 cm, the mortality would be less than 1%, major morbidity would be less than 5%, and the length of hospital stay should be approximately 3 days (1,10) . Close collaboration between surgeon and pathologist. Close cooperation of surgeon and on site pathologist using a standardized pathology reporting may enhance effectiveness of diagnostic work-up. The resection of an adenocarcinoma in situ, minimally invasive adenocarcinoma and a lepidic-predominant adenocarcinoma have almost 100% 5-year survival rate, and therefore such patients in the near future may be candidates for sublobar resection (1). Reduction of overdiagnosis. GGO lesions may represent a wide spectrum of disease from benign lesions to invasive carcinoma. Therefore GGO nodules are a diagnostic challenge requiring a MDT approach to ensure correct work-up. Apparently the development and the size of a solid component is more important than the nonsolid/lepidic component for the assessment of prognosis and risk of invasive carcinoma Most GGOs have an indolent clinical course, especially in a screening situation. Careful consideration of the indications for surgery and invasive procedures and longer follow-up, even for more than 4 years, of GGO nodules, to ensure safe management and reduce overdiagnosis and overtreatment (1,10) Qualifications of surgeons involved in a screening program.. Surgeons involved in lung cancer screening should be familiar with minimally invasive thoracic surgery (1,2,3,5,10). Thoracic surgeons have a crucial role in tailoring the procedure to the screen detected lesion and the individual patient prognostic factors including age, comorbidities, performance status and life expectancy. Surgeons must be experienced in the interpretation of lung cancer imaging and tumor variables such as volume doubling time, standardized uptake value at CT/PET, and nodule density. In addition they should be trained in the diagnosis and management of screen detected nodules, and be able to recognize potentially false positive and false negative lesions as well as interval cancers. Surgeons should have propensities to consider follow-up instead of immediate surgery for indeterminate nodules, and in cases with comorbidities, multi-focal disease, or with previous lung lobectomy, to consider non-surgical treatments including stereotactic ablative radiotherapy (1,10). Integration of the smoking cessation policy. The adoption of a tobacco cessation program based on a close cooperation with other specialties managing population diseases (i.e. pulmonologists, cardiologists) will be important (1,2,3). A tobacco cessation program is potentially associated to a reduction in lung cancer specific mortality that exceeds that from lung cancer screening as well as leading to an improvement of the cost-effectiveness of the program. Precise data collection on interventions like enrolment, completion, and ‘quit’ rates are of utmost importance to monitor the outcomes of the screening program (1,2). . References: 1) Pedersen JH, Rzyman W, Veronesi G, D’Amico TA, Van Schil P, Molins L et al. Recommendations from the European Society of Thoracic Surgeons (ESTS) regarding computed tomography screening for lung cancer in Europe. Eur J Cardiothorac Surg 2017; 411–20. 2) Mazzone P , Powell PA, Arenberg D, Bach P , Detterbeck F,; Gould MK , Jaklitsch MT, Jett J , Naidich D, Vachani A , Wiener RS , Silvestri G . Components Necessary for High-Quality Lung Cancer Screening. American College of Chest Physicians and American Thoracic Society Policy Statement. CHEST 2015; 147(2): 295 – 303 3) Mulshine JL, D’amico TA. Issues with implementing a high-quality lung cancer screening program. CA Cancer J Clin. 2014;64: 352–363. 4) Wood DE. National Comprehensive Cancer Network (NCCN) clinical practice guidelines for lung cancer screening. Thorac Surg Clin. 2017;25(2):185–197. 5) Field JK, Smith RA, Aberle DR, et al. International Association for the Study of Lung Cancer Computed Tomography Screening Workshop 2011 Report. J Thorac Oncol. 2012;7:10–19. 6) Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395–409. 7) Field JK, Duffy SW, Baldwin DR, Brain KE, Devaraj A, Eisen T, et al. The UK Lung Cancer Screening Trial:a pilot randomised controlled trial of low-dose computed tomography screening for the early detection of lung cancer. Health Technol Assess 2016;20(40). 8) Gierada DS, Pinsky P, Nath H, Chiles C, Duan F, Aberle DR. Projected outcomes using different nodule sizes to define a positive CT lung cancer screening examination. J Natl Cancer Inst 2014;106. DOI: 10.1093/jnci/dju284. 9) Flores R, Bauer T, Aye R, Andaz S, Kohman L, Sheppard B et al. I-ELCAP Investigators. Balancing curability and unnecessary surgery in the context of computed tomography screening for lung cancer. J Thorac Cardiovasc Surg 2014;147:1619–26. 10) Grondin SC, Edwards JP, Rocco G. Surgeons and lung cancer screening. Rules of engagement. Thorac Surg Clin 2015, 25, 175-184

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Abstract:
Cancer has been the most common cause of death since 1981, accounting for 30% of all deaths recently in Japan. The mortality rate of lung, pancreas, and colon/rectum has been increased, and lung cancer is the leading cause of cancer-related death in Japan as well as western countries. Therefore, smoking cessation as primary prevention should continue to be a major focus of public health campaigns. Moreover, early detection and treatment for lung cancer is one of the important issues in cancer care. According to the current guidelines for lung caner screening in Japan from Ministry of Health, Labour and Welfare, chest radiography (chest radiography and sputum cytology for heavy smokers) is recommended to perform as opportunistic screening as well as population-based screening due to a significant evidence of reduction of lung caner mortality rate based on the results of 4 case-control studies in 1990s in Japan. While, low-dose CT is not recommended to perform as population-based screening because the evidence of reduction of lung caner mortality rate is insufficient, but low-dose CT is accepted to perform as opportunistic screening with informed consents of its potential benefits and harms. In Japan, CT screening for lung cancer was initiated first in the world, and several single-group cohort studies found a high frequency of early stage lung cancer. After initial results of low-dose CT screening for lung cancer were reported, low-dose CT screening for lung cancer has been implemented at community and workplace settings. An ecological/time series study was performed in Hitachi area, where the largest-scale chest CT screening program for lung cancer has been introduced in Japan. This study, where non-/light smokers account for approximately half of the CT screening examinees, showed that wide implementation of CT screening can decrease lung cancer mortality at community level (figure 1). Currently, a randomized controlled trial (JECS Study) is underway in Japan with non-/light smokers as the subjects, and this trial is very important in terms of cancer prevention (figure 2). The interpretation of CT findings and the follow-up of undiagnosed nodules are to be carried out according to the guidelines from The Committee for Management of CT-screening-detected Pulmonary Nodules, The Japanese Society of CT Screening. In this lecture, I will talk about the current status of low-dose CT screening for lung cancer in Japan briefly. Figure 1Figure 2

Abstract:
The Prince Charles Hospital (TPCH) and UQ Thoracic Research Centre is partnering several sites in Australia to undertake an international lung cancer CT screening trial with the British Columbia Cancer Centre in Canada. The Australian sites include The Prince Charles Hospital, St Vincents Hospital in Sydney, Royal Melbourne Hospital and the Epworth Hospital Box Hill in Victoria, Sir Charles Gardiner Hospital and the Fiona Stanley Hospital in Western Australia. Around the world, lung cancer causes over one million deaths each year – more than any other cancer. In Australia alone, some 12,000 new cases of lung cancer will be diagnosed each year, while about 8,880 Australians will succumb to this terrible disease. It is the biggest cause of cancer deaths and only 15% survive beyond 5 years after diagnosis currently. Lung cancer is typically diagnosed at an advanced stage, when treatments are effective. So this international trial aims to identify how we can best detect lung cancer earlier, using modern low dose CT scanners and computerised detection. This trial will prospectively compare the effectiveness of the USPTSF and the PLCOm2012 risk stratification models for improving the effectiveness and cost effectiveness of CT screening for lung cancer. Substudies planned include QoL, smoking cessation, CAD and comorbid diseases.

Abstract:
Screening for diseases - such as breast, prostate and lung cancers - has always been a topic beset with arguments, as well as debates about the pros and cons. The discussion has taken place for some time on both sides of the Atlantic and shows no sign of abating any time soon, with many arguing, for example, that over-testing can very easily lead to over-treatment, including unnecessary invasive surgery. Some have even suggested that the intensive screening for cancer in women’s breasts is due to cosmetic reasons - relating to the perceived attractiveness of breasts and the way that society views a woman with missing breasts - to the detriment of screening for other parts of the body. The latter is surely a patent nonsense, given the number of deaths that could occur with this type of cancer and the amount of fatalities that are actually avoided. Screening should not be about cosmetic issues. Nor should be about cost or, indeed, politics (sexual or otherwise). However, the over-treatment argument has also been used in respect of the aforementioned breast cancer screening, although the figures tend to show that it works very well in a preventative sense and even better in detecting early breast cancer in target age groups. PSA testing for prostate cancer has also come in for similar criticism. The counter-arguments - and they are very strong ones - is that our ‘social contract’ has obligations to ensure to the highest standards possible regarding the health of citizens and that, fiscally, forewarned is forearmed and can save a great deal of money down the line. The majority of experts (and, importantly, patients) would argue that there is a clear added value in properly run screening programmes, although this may vary - as do resources - across the 28 EU Member States. These differences also affect data collection, storage and sharing, the general delivery of healthcare, and levels of reimbursement, to name but a few. The US approach to screening is similar to that found in Europe, but clearly we should be relying on our own data, findings and - crucially - recommendations, without totally relying on theirs. Without doubt, all screening programmes - wherever on the planet they take place - have to be based on gathered evidence of efficacy, cost effectiveness and risk. Any new screening initiative should also factor in education, testing and programme management, as well as other aspects such as quality-assurance measures. Two vital bottom-lines are that access to such screening programmes should be equitable amongst the targeted population, and that benefit can be clearly shown to outweigh any harm. Key to screening will be the issues surrounding how healthcare is governed in the EU and what influence, in effect, Brussels can and does have, bearing in mind that much of the areas of health come under Member State competence (although Europe has stepped up of late in areas such as clinical trials and IVDs). EU healthcare governance can be divided in general into two paradigms - these are top-down regulatory frameworks and/or bottom-up frameworks. Stakeholders will remember the admin and voting nightmare that was the general data protection regulation (which saw more than 4,000 amendments), as well as the clinical trials regulation, which took more than a decade to revise. Arguably, today, guidelines (on screening and more) may well be the way forward, given that they potentially have less rigidity and therefore more flexibility (within strict standards of safety and ethics, of course). We can clearly see that innovation has brought about a greater need for adaptation through appropriate frameworks that must be designed by experts, in consensus - albeit with plenty of necessary input from regulatory bodies. It is vital to ensure that any and all agreed standards can be met down the line. These include the aforementioned ethical considerations, patient safety, certainty within timeframes and facilitation of advancements for the benefit of Europe’s patients and our society in general. Screening needs to be continuously reassessed, with guidelines updated when applicable. Despite arguments of over-treatment and issues of cost, it is one of the most potent preventative tools available to us today.

Abstract:
Lung cancer screening in a high risk cohort was validated by the National Lung Screening Trial reported in 2011( 1) and then endorsed by the United States Preventive Services Task Force in late 2013 ( 2). Under US law, this resulted in the Centers for Medicare & Medicaid Services issuing a National Coverage Decision supporting reimbursement of this screening service for federally beneficiaries on August 21, 2015(https://www.cms.gov/Outreach-and-Education/Medicare-Learning-Network-MLN/MLNMattersArticles/Downloads/mm9246.pdf). A recent letter published from the American Cancer Society Surveillance and Health Services Research group, reported that use of annual LDCT screening in the recommended target population was low and unchanged from 5 years earlier when no national endorsement of screening yet existed (3). Therefore, what is the lesson that we should share in this international forum from the US screening experience regarding key determinants of success in the process of national implementation of lung cancer screening? Implementing a new cancer screening service is a remarkably complex process as previously experienced in many countries with implementation of breast and colon cancer screening services. In the US, federal reimbursement for lung cancer screening was issued in August of 2015. It is overly optimistic to look for utilization trend changes in 2015 national survey data. However, there is progress such as with the advocacy foundation, Lung Cancer Alliance established a consortium called the National Framework of Excellence in Lung Cancer Screening and Continuum of Care in February 2012. Through this effort the foundation has worked with over 500 institutions in implemented comprehensive lung cancer screening sites according to evolving best practices. This experience has been instructive as they work to communicate about learning curve with on-boarding high quality screening practices (4). Since the launch of the National Lung Screening Trial in 2002, a vast number of screening reports have been published reporting significant progress with improving the many discrete screening steps as reflected by information submitted to this IASLC Workshop. However, there is a considerable lag in assimilating this newer information about screening into the informed decision making discussions about the risk/ benefits issues associated with this screening service. An example of the consequence of the concerns about risk/ benefit profile with lung cancer screening was demonstrated in a pilot Veterans Administration experience in which over 40% of the subjects eligible for lung cancer screening declined to participate in this service (5). The challenge is to reliably ascertain the issues that may have discouraged such a large fraction of potential candidates to opt out of the lung cancer screening process? For some it may have been related to concerns about cumulative medical radiation dose. When CT-based lung cancer screening first emerged, there was discussion about the potential for annual CT screening subjects to accrue dangerous cumulative medical radiation exposure. In light of the wide adoption of low-radiation- dose imaging techniques and CT manufacturers’ efforts to reduce the radiation dose required to obtain an informative lung cancer screening image, medical radiation is a much less significant objective source of concern as a potential harm (6). There have been concerns about the cost of providing lung cancer screening services. Pyenson and co-workers in an actuarial analysis reported that screening costs were favorable and subsequent reports have confirmed this point (7, 8). These studies also found that the cost benefit was enhanced when the screening was delivered in the conjunction with smoking cessation. The preponderance of evidence supports that lung cancer screening is at least as economical as other routinely offered health services. Further economies will be accrued as progress with improving false-positivity rate with the screening work-up, which already ranges from 3-12%, continue to evolve (9, 10). Therefore the critical lesson learned from this initial US experience is that the communications issues are a foundational in gaining broad support for the screening implementation process. The people that potentially could receive lung cancer screening services and the people who deliver the service as well as the national policy people who decide on what services are to be offered, all need to have a clear understanding of the value of screening service based on objective evidence regarding the harms and benefits of lung cancer screening. Fortunately, there are many areas of progress from enhancing the efficiency of the diagnostic screening work-ups to improving the therapeutic index with curative, minimally invasive lung cancer surgery (11, 12). The message needs to be communicated that lung cancer screening continues to be the most promising tool for reducing lung mortality today and its health benefits will be markedly enhanced as it is integrated with the administration of existing smoking cessation measures. Conclusion: Having a communications strategy to ensure that national policy leaders, care providers as well as potential screening subjects get access to objective, up-to-date evidence about the true benefit of lung cancer screening could greatly accelerate progress with reducing the mortality burden of lung cancer in an accessible and economical fashion. References: National Lung Screening Trial Research Team. Radiology. 2011 Jan;258(1):243-53. doi: 10.1148/radiol.10091808. Moyer, V.A., Ann Intern Med, 2014. 160(5): p. 330-338. Jemal A, Fedewa SA. JAMA Oncol. 2017 Feb 2. doi: 10.1001/jamaoncol.2016.6416. PMID: 28152136 Mulshine JL, Ambrose LF. J Thorac Dis. 2016 Oct;8(10):E1304-E1306. PMID: 27867613 Kinsinger LS, Anderson C, Kim J, et al. JAMA Intern Med. 2017 Mar 1; 177 (3):399-406. doi: 10.1001/jamainternmed.2016.9022. Mulshine JL, D'Amico TA. CA Cancer J Clin. 2014 Sep-Oct;64(5):352-63. doi: 10.3322/caac.21239. PMID: 24976072. Pyenson B, Sander MS, Jian Y, Mulshine JL. Health Affairs Apr;31(4):770-9,PMID: 22492894, 2012. Cressman S, Peacock SJ, Tammemägi MC et al. J Thorac Oncol. 2017 Aug;12(8):1210-1222. doi: 10.1016/j.jtho.2017.04.021. PMID: 28499861 Kazerooni EA, Armstrong MR, Amorosa JK, et al. J Am Coll Radiol. 2015 Jan;12(1):38-42. doi: 10.1016/j.jacr.2014.10.002. PMID: 25455196 Field JK, Duffy SW, Baldwin DR, Brain KE, Devaraj A, Eisen T, et al. Health Technol Assess. 2016;20(40):1-146. Henschke, C.I., R. Yip, D.F. Yankelevitz, and J.P. Smith, Ann Intern Med, 2013. 158(4): p. 246-252. White A, Swanson SJ. Oncology (Williston Park). 2016 Nov 15;30(11):982-7.

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Abstract:
Background Lung cancer is the most important tobacco-related health problem worldwide, accounting for an estimated 1.3 million deaths each year, representing 28% of all deaths from cancer. Lung cancer screening aims to reduce lung cancer-related mortality with relatively limited harm through early detection and treatment. The US National Lung Screening Trial showed that individuals randomly assigned to screening with low-dose CT scans had 20% lower lung cancer mortality than did those screened with conventional chest radiography. On the basis of a review of the literature and a modelling study, the US Preventive Services Task Force (USPSTF) recommends annual screening for lung cancer for high-risk individuals. However, the balance between benefits and harms of lung cancer screening is still greatly debated. Some investigators suggest the ratio between benefits and harms could be improved through various means. Nevertheless, many questions remain with regard to the implementation of lung cancer screening. Whether nationally implemented programmes can provide similar levels of quality as achieved in these trials remains unclear. The NELSON trial is Europe’s largest running lung cancer screening trial. The main purposes of this trial are; (1) to see if screening for lung cancer by multi-slice low-dose CT in high risk subjects will lead to a 25% decrease in lung cancer mortality or more; (2) to estimate the impact of lung cancer screening on health related quality of life and smoking cessation; (3) to estimate cost-effectiveness of lung cancer screening. The NELSON trial was set up in 2003 in which subjects with high risk for lung cancer were selected from the general population. After informed consent, 15,792 participants were randomised (1:1) to the screen arm (n=7,900) or the control arm (n=7,892). Screen arm participants received CT-screening at baseline, after 1 year, after 2 years and after 2,5 years. Control arm participants received usual care (no screening). In the NELSON trial a unique nodule management protocol was used. According to the size and volume doubling time of the nodules, initially three screen results were possible: negative (an invitation for the next round), indeterminate (an invitation for a follow-up scan) or positive (referred to the pulmonologist because of suspected lung cancer). Those with an indeterminate scan result received a follow-up scan in order to classify the final result as positive or negative. All scans were accomplished at the end of 2012. The lung cancer detection rate across the four rounds were, respectively: 0.9%, 0.8%, 1.1% and 0.8%. The cumulative lung cancer detection rate is 3.2% which is comparable with the Danish Lung Cancer Screening Trial (DLCST). Relative to the National Lung Screening Trial (NLST), more lung cancers were found in the NELSON: 3.2% vs. 2.4%. However, the NLST had less screening rounds and a different nodule management protocol and a different study population. False-positive rate after a positive screen result of the NELSON is 59.4%. The overall false-positive (over four rounds) is 1.2% in the NELSON study, which is lower compared to other lung cancer screening studies. A 2-year interval did not lead to significantly more advanced stage lung cancers compared with a 1-year interval (p=0.09). However, a 2.5-year interval led to a stage shift in screening-detected cancers that was significantly less favourable than after a 1-year screening interval (e.g. more stage IIIb/IV cancers). It also led to significantly higher proportions of squamous-cell carcinoma, boncho-alveolar carcinoma, and small-cell carcinoma (p<0.001). Compared with a 2-year screening interval, there was a similar tendency towards unfavourable change in stage distribution for a 2.5-year screening interval although this did not reach statistical significance. Also, the interval cancer rate was 1.47(28/19) times higher in the 2.5-year interval compared with the 2-year interval. Moreover, in the last six months before the final fourth screening round the interval rate was 1.3(16/12) times higher than in the first 24 months after the third round, suggesting that a 2.5-year interval may be too long. On average, 69.4% of the screening-detected lung cancers across the four screening rounds in the NELSON trial were diagnosed in stage I and 9.8% in stage IIIb/IV. This cumulative stage distribution of the screening-detected lung cancers in the NELSON trial appears to be favourable compared to those of the DLCST and the NLST (68.1% and 61.6% of cancers at stage I, and 15.9% and 20.0% at stage IIIb/IV, respectively).However, this finding should be interpreted with caution because 1) the NLST used the 6th edition of the TNM staging system, while the NELSON trial used the 7th edition, 2) the NLST and DLCST applied different eligibility criteria than the NELSON trial, and 3) the proportion of over-diagnosed lung cancers in the screening group is yet unknown. The lung cancers found in the NELSON control group have yet to be investigated.

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1. Introduction of CT screening and showing its value. First to introduce CT screening in a novel cohort design comparing CT with chest radiography, providing a workup strategy for screen-detected nodules. Predicted outcome of well-designed and correctly powered RCT studies Henschke C, McCauley D, Yankelevitz D, Naidich D, McGuinness G, Miettinen O, Libby D, Pasmantier M, Koizumi J, Altorki N, and Smith J. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999; 354:99-105. 2. Long-term survival rates of patients diagnosed with lung cancer in a program of CT screening. First to provide estimated cure rates under screening by measuring long-term survivial. The International Early Lung Cancer Action Program Investigators. Survival of Patients with Stage I lung cancer detected on CT screening. NEJM 2006; 355:1763-71 3. First to provide information on the value of CT scans in delivering smoking cessation advice. Ostroff J, Buckshee N, Mancuso C, Yankelevitz D, and Henschke C. Smoking cessation following CT screening for early detection of lung cancer. Prev Med 2001; 33:613-21. Anderson CM, Yip R, Henschke CI, Yankelevitz DF, Ostroff JS, and Burns DM. Smoking cessation and relapse during a lung cancer screening program. Cancer Epidemiol Biomarkers Prev 2009; 18:3476-83. 4. First to introduce computer-assisted CT determined growth rates into the workup of pulmonary nodules. Yankelevitz DF, Gupta R, Zhao B, and Henschke CI. Small pulmonary nodules: evaluation with repeat CT--preliminary experience. Radiology 1999; 212:561-6. Yankelevitz DF, Reeves AP, Kostis WJ, Zhao B, and Henschke CI. Small pulmonary nodules: volumetrically determined growth rates based on CT evaluation. Radiology 2000; 217:251-6. Kostis WJ, Yankelevitz DF, Reeves AP, Fluture SC, Henschke CI. Small pulmonary nodules: reproducibility of three-dimensional volumetric measurement and estimation of time to follow-up CT. Radiology 2004; 231:446-52. Henschke C, Yankelevitz D, Yip R, Reeves A, Farooqi A, Xu D, Smith J, Libby D, Pasmantier M, and Miettinen O. Lung cancers diagnosed at annual CT screening: volume doubling times. Radiology 2012; 263:578-83. 5. Development of size threshold values and short-term followup and importance of a regimen of screening. Henschke C, Yankelevitz D, Naidich D, McCauley D, McGuinness G, Libby D, Smith J, Pasmantier M, and Miettinen O. CT screening for lung cancer: suspiciousness of nodules according to size on baseline scans. Radiology 2004; 231:164-8. Libby DM, Wu N, Lee IJ, Farooqi A, Smith JP, Pasmantier MW, McCauley D, Yankelevitz DF, and Henschke CI. CT screening for lung cancer: the value of short-term CT follow-up. Chest 2006; 129:1039-42. Henschke C, Yip R, Yankelevitz D, and Smith J. Definition of a positive test result in computed tomography screening for lung cancer: a cohort study. Ann Intern Med 2013; 158:246- 52. Yip R, Henschke CI, Yankelevitz DF, and Smith JP. CT screening for lung cancer: alternative definitions of positive test result based on the national lung screening trial and international early lung cancer action program databases. Radiology 2014; 273:591-6. Yip R, Henschke C, Yankelevitz D, Boffetta P, Smith J, The International Early Lung Cancer Investigators. The impact of the regimen of screening on lung cancer cure: a comparison of I-ELCAP and NLST. Eur J Cancer Prev. 2015;24(3):201-8. 6. Nomenclature and management protocols for nonsolid and part-solid nodules. Henschke C, Yankelevitz D, Mirtcheva R, McGuinness G, McCauley D, and Miettinen O. CT screening for lung cancer: frequency and significance of part-solid and nonsolid nodules. AJR Am J Roentgenol 2002; 178:1053-7. Yankelevitz DF, Yip R, Smith JP, Liang M, Liu Y, Xu DM, Salvatore MM, Wolf AS, Flores RM, Henschke CI, and International Early Lung Cancer Action Program Investigators Group. CT Screening for Lung Cancer: Nonsolid Nodules in Baseline and Annual Repeat Rounds. Radiology 2015; 277:555-64. Henschke CI, Yip R, Wolf A, Flores R, Liang M, Salvatore M, Liu Y, Xu DM, Smith JP, Yankelevitz DF. CT screening for lung cancer: part-solid nodules in baseline and annual repeat rounds. AJR Am J Roentgenol 2016; 11:1-9. 7. Differences in management of nodules found in baseline and annual repeat rounds of screening. International Early Lung Cancer Investigators. Baseline and annual repeat rounds of screening: implications for optimal regimens of screening. Eur Radiol 2017. In press. 8. Assessment of risk of lung cancer among women and never smokers. International Early Lung Cancer Action Program Investigators. Women’s susceptibility to tobacco carcinogens and survival after diagnosis of lung cancer. JAMA 2006; 296:180-4. Yankelevitz DF, Henschke CI, Yip R, Boffetta P, Shemesh J, Cham MD, Narula J, Hecht HS, FAMRI-IELCAP Investigators. Second-hand tobacco smoke in never smokers is a significant risk factor for coronary artery calcification. JACC Cardiovasc Imaging 2013; 6:651-7. Henschke CI, Yip R, Boffetta P, Markowitz S, Miller A, Hanaoka T, Zulueta J, Yankelevitz D. CT screening for lung cancer: importance of emphysema for never smokers and smokers. Lung Cancer 2015; 88:42-7 PMID:25698134. Yankelevitz DF, Cham MD, Hecht HS, Yip R, Shemesh S, Narula J, Henschke CI. The Association of Secondhand Tobacco Smoke and CT angiography-verified coronary atherosclerosis. JACC Imaging. 2016. 9. Determination of cardiac risk on nongated, low-dose CT scans and development of an ordinal scale. Shemesh J, Henschke CI, Farooqi A, Yip R, Yankelevitz DF, Shaham D, and Miettinen OS. Frequency of coronary artery calcification on low-dose computed tomography screening for lung cancer. Clin Imaging 2006; 30:181-5. Shemesh J, Henschke CI, Shaham D, Yip R, Farooqi AO, Cham MD, McCauley DI, Chen M, Smith JP, Libby DM, Pasmantier MW, and Yankelevitz DF. Ordinal scoring of coronary artery calcifications on low-dose CT scans of the chest is predictive of death from cardiovascular disease. Radiology 2010; 257:541-8. 10. Recommendations for reporting findings of emphysema, coronary arteries, breast, and abdomen on low-dose CT scans. Zulueta JJ, Wisnivesky JP, Henschke CI, Yip R, Farooqi AO, McCauley DI, Chen M, Libby DM, Smith JP, Pasmantier MW, and Yankelevitz DF. Emphysema scores predict death from COPD and lung cancer. Chest 2012. Henschke CI, Lee IJ, Wu N, Farooqi A, Khan A, Yankelevitz D, and Altorki NK. CT screening for lung cancer: prevalence and incidence of mediastinal masses. Radiology 2006; 239:586-90. Salvatore M, Margolies L, Kale M, Wisnivesky J, Kotkin S, Henschke CI, and Yankelevitz DF. Breast density: comparison of chest CT with mammography. Radiology 2014; 270:67-73. Hu M, Yip R, Yankelevitz D, and Henschke C. CT screening for lung cancer: frequency of enlarged adrenal glands identified in baseline and annual repeat rounds. Eur Radiol 2016. Chen X, Li K, Yip R, Perumalswami P, Branch AD, Lewis S, Del Bello D, Becker BJ, Yankelevitz DF, and Henschke CI. Hepatic steatosis in participants in a program of low-dose CT screening for lung cancer. European Journal of Radiology 2017. In Press. 11. Quantatative assessment of the vascular system on low-dose CT scans. Fully automated evaluation of quantitaive image biomarkers for multple organs and anatomic regions including: pulmoanry nodules, lungs (emphysema, ILD, major airways), coronary arteries, aorta, pulmoanry artery, breast, and vertebra. Kostis, W. J., Reeves, A. P., Yankelevitz, D. F., and Henschke, C. I. Three-dimensional segmentation and growth-rate estimation of small pulmonary nodules in helical CT images. IEEE Transactions on Medical Imaging 2003; 22: 1259-1274. Enquobahrie, A., Reeves, A. P., Yankelevitz, D. F., and Henschke, C. I. Automated detection of small solid pulmonary nodules in whole lung CT scans from a lung cancer screening study. Academic Radiology 2003; 14, 5: 579-593. Keller, B. M., Reeves, A. P., Henschke, C. I., and Yankelevitz, D. F. Multivariate Compensation of Quantitative Pulmonary Emphysema Metric Variation from Low-Dose, Whole-Lung CT Scans. AJR 2011; 197, 3: W495-W502. Xie Y. Htwe YM, Padgett J, Henschke CI, Yankelevitz DF, Reeves AP. Automated aortic calcification detection in low-dose chest CT images. SPIE Medical Imaging 2014; 9035:90250P. Xie Y, Cham M, Henschke CI, Yankelevitz DF, Reeves AP. Automated coronary artery calcification detection on low-dose chest CT images. SPIE Medical Imaging 2014; 9035:90250F.

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Abstract:
Around one billion people on the planet are regular smokers. And lung cancer is one of the biggest killers. We all now know that there is a direct connection in many cases. Non-smokers do get lung cancer, but the risks if you are a smoker are significantly. Undoubtedly, tobacco smoking is the major risk factor for lung cancer, although passive smoking, and a family history of lung, head and neck cancer are, among other factors, also important. Figures show that lung cancer causes almost 1.4 million deaths each year worldwide, representing almost one-fifth of all cancer deaths. Within the EU, meanwhile, lung cancer is also the biggest killer of all cancers, responsible for almost 270,000 annual deaths (some 21%). It is at the very least surprising that the biggest cancer killer of all does not have a solid set of screening guidelines across Europe, Doctors need to quickly identify high quality, trustworthy clinical practice guidelines, in order to improve decision making for the benefit of their patients. The Alliance has turned its attention to need for more guidelines across the arena of healthcare, especially in screening for lung cancer. There is a need for agreement and coordination across the European Union’s 28 Member States. In the US, the American Cancer Society has stated that it had “thoroughly reviewed the subject of lung cancer screening” and issued guidelines that are aimed at doctors and other health care providers. Europe, among other things, is looking at risk prediction models to identify patients for screening, plus determination of how many annual screening rounds is enough. Of course, cost-effectiveness questions arise whenever population-wide screening is considered, especially in relation to frequency and duration. Yet, the potential benefit of low-dose CT lung cancer screening would almost certainly see an improvement in the lung cancer mortality rate in Europe. Stakeholders are aware that screening for lung cancer also has potential harms. These include radiation risks (increased risk of other cancers), identification of often harmless nodules, which could lead to further evaluation (including biopsy or surgery), unnecessary fear in the patient and those close to him or her, and over-diagnosis and possibly subsequent treatment of cancerous cells that would cause no ill effects over a lifetime. Often, malignant small lesions are found that would not grow, spread, or cause death. This could lead to over-diagnosis or over-treatment, bringing about extra cost, anxiety and ill-effect (even death) caused by the treatment itself. On the other hand screening can help to ensure that surgery in lung cancer’s early stages can continue to be the most effective treatment for the disease. As it stands, most patients are diagnosed at an advanced stage - usually non-curable. EAPM, along with other aforementioned stakeholders, believes that there is a strong case for lung cancer screening programmes across the 28 EU Member States to reduce the cases of advanced-stage lung cancer. Among recommendations currently being discussed in European forums are the setting of minimum requirements, which should include standardised operating procedures for low-dose imaging, criteria for inclusion (or exclusion) for screening and, of course, smoking cessation programmes. Also important are improving the quality, outcome and cost-effectiveness of screening, reducing radiation risks, and making thorough assessments of other risks, such as co-morbidities. ERS and ESR have stated that “the establishment of a central registry, including biobank and image bank, and preferably on a European level, is strongly encouraged”, and EAPM is in full support of this. Current situation In the US, lung cancer screening has been the subject of major policy decisions and investigations. One finding showed that a screening trial brought about a 20% drop in lung cancer mortality. On the back of this, several mainstream clinical and professional organisation recommended the implementation of screening. In Europe, the Dutch and Belgian NELSON lower-dose computed tomography (CT) trial is producing data on mortality rates (and, of course, cost effectiveness). The NELSON study was designed to investigate whether screening for lung cancer by low-dose CT in high-risk subjects would lead to a decrease in 10-year lung cancer mortality of at least 25%. This to be looked at in comparison to a control group which was not undergoing screening. The NELSON study began in 2003, using men aged 50–75 years from seven districts in the Netherlands and subjects from both sexes from 14 close geographical areas in Belgium. Initially, these subjects were sent a questionnaire about general health, how much they smoked, their cancer history, and several other lifestyle and health factors. Based on the smoking history, the estimated lung cancer mortality risk of the respondents was determined. Next, the required sample size including required participation rate was determined. Thirteen years on and the results from the final, fourth round of what is EU’s largest trial have found that leaving a two-and-a-half-year interval reduced the effect of screening. In essence this means that the cancer rate showed higher levels than found with one-year and two-year screening intervals. Crucially, in the final round, occurrences of the advanced-stage disease were higher than previous rounds and, as discussed above, that invariably means more deaths. Further EU pooled trial results are expected to come along soon, in the wake of NELSON.Conclusions Findings in both Europe and the US strongly suggest that lung cancer screening works. Current evidence is, as yet, limited and the discussion continues. But there is hard evidence, although debate continues about the best way to implement screening of this kind, and even how to properly evaluate ‘cost effectiveness’ - who should decide? Of course, guidelines could help to tether costs, by bringing in improvements to the efficiency of screening methodologies and, thus, programmes themselves. Key to such a situation would be making the best use of efficient risk-assessment methods, top-of-the-range imaging technology, and guidelines that encourage the minimisation of invasive procedures and risk to the patient.

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Are we screening the at risk population? How can we bring imaging and molecular tools to improve the early detection/treatment rates of lung cancer and decrease the false positive rates? The National Lung Screening Trial (NLST) demonstrated that low dose CT screening among high risk individuals reduces the relative risk for lung cancer mortality by 20%. Yet the poor specificity of chest CT, which forces us to deal with large proportions of false positive results, morbidity and cost, pushes us to improve the risk assessment and diagnostic accuracy of the tests offered. A large proportion of individuals will be diagnosed with lung cancer and still do not meet the population criteria studied in NLST trial. So the scientific community is charged to improving early detection of invasive lung cancers to a definitive treatment. An estimated 43% of individuals diagnosed with lung cancer meet the NLST criteria, thus missing an opportunity to screen another large at-risk population. There are currently no accepted strategies for screening patients who fall outside of these criteria. Therefore tools of risk assessment and early detection could profoundly reduce lung cancer mortality. Considerations for familial history with or without germline DNA mutation carriers, exposure to carcinogens, chronic pulmonary obstructive lung disease, are being proposed for integration in risk prediction strategies. The reporting tools for findings at the time of CT screening have been replaced by the American Radiology Association’s LungRADS score which reduces the false positives rate among the most highly suspicious lesions from 27% to 13%. On the imaging diagnostic side, the emerging field of radiomics involves computational analysis of extracted quantitative data from clinical radiology images. Rapid progress in this field offers the promise of diagnostic accuracies that will surpass the one of expert radiologists. On the molecular diagnostic side, diagnostic tools for risk adjustment and to augment current lung cancer detection strategies are urgently needed. Circulating tumor cells are shed from primary tumors into the blood stream, so is circulating tumor DNA naked or in microvesicles. Proteins, RNA moieties and epigenetic changes can be captured in the circulation and also have the promise of changing the landscape of non-invasive diagnosis of early lung cancer. Some of these strategies will be discussed to illustrate the impressive and rapid progress soon coming to the clinic to address the primary goals of early detection.

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Computed Tomography (CT) imaging of the lung has been routinely used over the last few decades to detect and treat early lung cancer and other related diseases. As CT image acquisition technology has improved, the use of CT for quantitative and precise lung imaging clinical applications has greatly expanded. High resolution CT studies, which now easily obtain sub-millimeter resolution of the entire chest within a breath-hold, are now widely used to detect and measure changes in early lung cancer lesions and COPD. Traditionally, several concurrent methods have been used to ensure that the quality of acquired CT images is adequate for general clinical use. This includes regular scanning and analysis of CT quality control phantoms from ACR (as well as from individual CT scanner manufacturers) and visual inspection of acquired images by radiologists for significant image artifacts. While these methods have served the field of radiology well for identifying and correcting major image quality issues, there has not been standard image quality assessment methods available for specific clinical applications that require precise image-based measurements. To improve global quality control of lung imaging studies, several clinical societies and organizations have provided image acquisition and measurement guidance documents intended to be followed by clinical sites [1, 2, 3]. We are entering a new era of quantitative imaging where easy to use tools are available that ensure that precise quantitative image measurements can be routinely and reliably obtained. To achieve this goal, a new set of task-based image quality control measures is being developed by research groups and radiology societies such as the RSNA’s Quantitative Imaging Biomarkers Alliance [4]. Each major quantitative imaging-based clinical task is being extensively studied to determine the fundamental image quality properties needed (e.g. resolution, sampling rate, noise, intensity linearity, spatial warping) to achieve a minimum level of measurement performance. In addition, new low-cost phantoms are being developed that can be quickly scanned and automatically analyzed to estimate these fundamental properties throughout the full three-dimensional CT scanner field of view. Deploying these low-cost phantoms and automated phantom analysis software on the cloud further enables global clinical sites to quickly and easily verify the quality of a CT scanner and acquisition protocol for a specific quantitative clinical task. In addition to providing a fast method for verifying conformance with minimum quantitative imaging performance standards, the reports generated can provide guidance as to the best protocols observed for a particular CT scanner model, thereby allowing a clinical site to optimize image acquisition protocols with the best evidence obtained through crowd-sourcing task-specific image quality information. The QIBA CT lung nodule task force is now preparing to launch a pilot project to evaluate the utility of these new image quality control measures for the quantitative measurement of the change in volume of solid lung nodules (6mm to 10mm diameter) [5]. Over the coming months this new “active” and cloud-based analysis approach will be deployed at international lung cancer screening institutions and use statistics will be assembled. The data collected has the potential not only to inform the lung cancer screening community on the global quality of lung cancer screening imaging, but also to establish early data on whether these new methods can one day serve as a more effective approach to providing quality control for quantitative imaging methods. References 1. Kauczor HU, Bonomo L, Gaga M, Nackaerts K, Peled N, Prokop M, Remy-Jardin M, von Stackelberg O, Sculier JP; European Society of Radiology (ESR); European Respiratory Society (ERS), ESR/ERS white paper on lung cancer screening, ESR/ERS white paper on lung cancer screening. 2. IELCAP, IELCAP Protocol Document, http://www.ielcap.org/sites/default/files/I-ELCAP-protocol.pdf Accessed May 31, 2017. 3. Fintelmann FJ, Bernheim A, Digumarthy SR, Lennes IT, Kalra MK, Gilman MD, Sharma A, Flores EJ, Muse VV, Shepard JA, The 10 Pillars of Lung Cancer Screening: Rationale and Logistics of a Lung Cancer Screening Program, Radiographics. 2015 Nov-Dec;35(7):1893-908. 4. https://www.rsna.org/QIBA/ 5. RSNA QIBA, Draft QIBA Profile: Lung Nodule Volume Assessment and Monitoring in Low Dose CT Screening, http://qibawiki.rsna.org/images/e/e6/QIBA_CT_Vol_LungNoduleAssessmentInCTScreening_2017.05.15.docx, May 15, 2017.

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Lung cancer screening offers a unique opportunity for medicine to closely partner with nursing in detecting lung cancers at earlier, treatable stages, address other tobacco related diseases, and assist patients in smoking cessation efforts. Foundational nursing principles are universal around the world with an emphasis on clinical care, research and implementation science, patient education and health coaching, performance improvement and quality outcomes processes, and patient-centered care. Given this preparation, nursing professionals can be potent if positioned predominantly at the helm of lung cancer screening programs with the most touch-points and direct interaction with screening recipients, over the screening continuum. Lung cancer screening encounters present an opportunity for early rather than late detection of preventable and treatable diseases through low dose CT scan. Additionally, lung cancer screening can be utilized as a transformational health tool by positioning nursing at the center of the integrative care delivery model and drive beneficial health outcomes through direct counseling, and health coaching. This includes facilitating preventive measures that directly impact the natural history of tobacco related diseases through smoking cessation counseling and treatment services and health coaching as it relates to the individual patient, their current health state, and low dose CT scan results. The professional services that nursing is keenly positioned to offer within the multidisciplinary lung cancer screening setting hold great potential for an international sustainable screening model. This presentation will discuss pragmatic, approaches to evidence based screening programs, led by nursing, in which high-risk patients receive the care they need and deserve, encourages active engagement in the critical continuum of screening and opens opportunity for improvements in individual and population health.

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Immunotherapy gets the breakthrough after almost 100 years of silence. PD1/PD-L1 inhibitors as the representative has been extensively studied in various human malignant tumors and get promising long term response with relatively fewer adverse event. The first PD1 inhibitor indication was approved for melanoma in Japan on July 2014. By the end of December 2016, the US Food and Drug Administration had approved several PD-1 pathway blockade treatments including nivolumab, pembrolizumab and atezolizumab using in first line and second line of NSCLC. But In China, no PD-1 or PD-L1 inhibitors have received marketing approval from the Chinese Food and Drug Administration (CFDA) until July 2017. One sides, IO arena faces intense in-class competition from both MNC (Multi-National Corporation) and domestic pharmaceutical company in China. Now there are 20 IO antibodies from 7 MNCs and 10 pharmaceutical companies in China. But all the antibodies only confined to PD1/PD-L1 and CTLA4, no other hot IO drugs such as IDO or Lag3 et al. In the field of innovation, China is several years behind research in other areas of the world. The other sides various clinical trials are actively investigating MNC and domestic drugs in China. Between January 1, 2013 and April 6, 2017, Clinical Trials.-gov registered 270 international clinical trials using PD-1/PD-L1 therapies for NSCLC (e.g.nivolumab,pembrolizumab,atezolizumab,and durvalumab). These 270 trials included 61 studies that involved East Asian sites and 14studies that involved Chinese sites (12 multinational trials and 2 trials that only evaluated Chinese patients). These trials cover from second line and first line to adjuvant therapy in NSCLC. Most of the ongoing MNC NSCLC clinical trials joined in global study design that may accelerate the patient access to PD1/PD-L1. But Chinese population has relatively high rates of hepatitis B virus infection and much higher proportion of EGFR mutation. The delightful changing recently is some studies emerging to consider the characteristics of the Chinese or Asian populations. Domestic company clinical trials focus on GI (Gastrointestinal) and only 1 NSCLC study in China. Chinese clinical trials using IO remain in their early stages, and further efforts are needed to improve the design of future clinical trials. Meanwhile, the other hot IO drug phase I study need speed up in China.

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Background:
ADJUVANT (CTONG 1104) is the first randomized trial shows significantly prolonged disease-free survival (DFS) in completely resected stage II-IIIA (N1-N2) epidermal growth factor receptor (EGFR)-mutation positive non-small-cell lung cancer (NSCLC) through adjuvant gefitinib compare with vinorelbine plus cisplatin (VP). Further we aim to analyze the treatment failure pattern in ADJUVANT study.

Method:
In the ADJUVANT trial, a total of 222 patients with completely resected stage N1–N2 EGFR-mutation positive NSCLC were randomized 1:1 into gefitinib group (250mg, QD, 24 months ) or vinorelbine (25mg/m[2] Day 1/Day 8) plus cisplatin (75mg/m[2] Day 1) group (every 3 weeks for 4 cycles) respectively. Any recurrence or metastases occurred during the follow-up period was defined as treatment failure. Recurrent pattern in both group were analyzed with follow-up data (until Mar 9[th] 2017) integrated.

Result:
At the Data cut-off date for the primary analysis of DFS, 124 progression events (55.9% maturity overall) had occurred; 114 patients had disease recurrence，10 patients died before disease recurrence. Analysed recurrent pattern include lung, brain, liver, bone adrenal gland, pleura, pericardium, spleen and regional lymph nodes metastasis. Even no significant differences were found, highest proportion of patients in both group(18.9% for VP and 26.1% for gefitinib, p=0.199) surfer brain metastasis with lung metastases being the second common recurrent site. Time to brain metastases showed no significantly difference between the two groups (not reach vs 40.8m, p>0.05). Among the 29 brain metastases patients with gefitinib, the brain metastases occurred in 17 patients during the gefitinib treament, and 12 patients relapse after the gefitnib termination. Figure 1



Conclusion:
Compared with other site metastases, lung, brain and regional lymph nodes metastases account for major proportion of recurrence in ADJUVANT study. (NCT01405079)

Background:
EGFR mutation plays a dominant role in the precise treatment of non-small cell lung cancer (NSCLC), and EGFR-TKIs has been recommended for patients with positive EGFR-sensitive mutation as a standard regimen in clinical practice. In China, application of EGFR-TKIs without knowing EGFR mutation status has been a common phenomenon due to various reasons including the vast territory, uneven distribution of medical resources, differences level of testing technology and others. Therefore, we prospectively conducted a real-world investigation to understand the actual situation of EGFR testing in Northern China, and identify the underlying causes affecting EGFR detection, in order to provide references to improve the standardized treatment (NCT02620657).

Method:
The patients with IIIB/IV NSCLC who were firstly diagnosed or postoperative recurrence between 2014-1-1 and 2014-12-31 in 28 research centers of Northern China were analyzed. The primary endpoint was testing rate，the secondary endpoints were factors affecting EGFR testing, EGFR mutation status, detection methods and the survival outcomes of patients.

Result:
Among 2809 patients, 2250 (90.78%) were adenocarcinoma, 208 (7.40%) were squamous carcinoma, 51 (1.82%) were other pathologic types. Testing rate was 42.54% (1195/2809) and was significantly related to city level (first-tier cities vs. new first-tier cities vs. second-tier cities vs. third-tier and above cities : 69.04% vs. 38.08% vs. 34.05% vs. 14.11%, P < 0.001, smoking status (never smoking vs. ever smoking vs. smoking: 45.42% vs. 51.10% vs. 33.37%, P<0.001, ECOG PS (0 vs.1vs.2vs.≥3:47.93%vs. 44.48vs.34.89%vs.20.37%, P=0.011), pathological type (adenocarcinoma vs. squamous carcinoma: 44.94% vs.19.23%, P=0.003 and medical insurance situation (social basic medical insurance vs. new rural cooperative medical insurance vs. own expense: 44.98% vs. 36.49% vs. 29.55%, P=0.001. EGFR sensitive mutation rate was 46.44%, the most common subtype was 19Del (42.16%), followed by L858R(40.00%), Exon 20 insertions (1.62%) and other subtypes (16.20%). The most common methodology is ARMS (63.77%), the second common one is DNA sequencing (5.36%). The 1-year and 2-year survival rate in patients receiving EGFR testing was 73.6% and 51.9%, compared with 64.3% and 43.7% respectively in patients without EGFR testing.

Conclusion:
There were regional differences in EGFR testing rates among IIIB/IV NSCLC patients in Northern China. The intention of doctors and patients, medical insurance coverage and differences technical level are major factors affecting the testing rate of EGFR. Approaches should be taken to improve the situation, such as strengthening the training, expanding the coverage of medical insurance, and relying on commercial gene detection companies, and further standardize the molecularly pathological diagnosis and treatment of NSCLC.

Background:
Seveal studies have demonstrated targeting EGFR mutations and tumor angiogenesis simultaneously has synergistic effect in the 1[st] line setting in EGFR mutant NSCLC. However, in JO25567 trial, the ≥grade 3 hypertension incidence with combination therapy was much higher (60%) when compared to historic incidence of hypertension with bevacizumab (10-15%). Considering relatively shorter half-lives for small molecule tyrosine kinase inhibitors, it might be a better choice to combine EGFR TKI and VEGFR TKI when it comes to hypertension management. Fruquintinib is a potent and highly selective oral kinase inhibitor targeting VEGFR and it has demonstrated favorable benefit-to-risk profile in third line treatment in NSCLC patients.Thus it is important to assess safety, tolerability and efficacy of this new combination in the 1[st] line setting in EGFR mutant NSCLC patients. NCT02976116

Method:
This is a single arm, open-label, multi-center study. All patients will receive gefitinib continuously at 250 mg qd. Fruquintinib will be given at 4 mg as starting dose for 3 weeks followed by 1 week off in the first 4-week cycle. Fruquintinib dose can be escalated to 5 mg with the same 4-week cycle if no ≥grade 3 adverse event (AE) or ≥grades 2 liver dysfunction occurs in the first cycle. Treatment continues until disease progression, unacceptable toxicity, or patient withdrawal. The primary objective is to assess the safety and tolerability of this combination. Key eligibility criteria include: histologically or cytologically confirmed NSCLC, ECOG PS 0-1, no prior systematic treatment, no brain metastasis. Key exclusion criteria include: known T790M mutation and bleeding history within 1 month before enrollment.

Result:
As of Jun 20, 2017, 9 patients have been enrolled and received at least one dose of fruquintinib and gefitinib. Six patients had L858R mutations, and three patients had exon 19 deletions. All patients reported AEs, but only one patient (11.1%) had grade 3 proteinuria. No SAE was reported. The most common AEs were increased ALT (3 [33.3%] patients), increased AST (3 [33.3%] patients), increased TBIL (3 [33.3%] patients), proteinuria (3 [33.3%] patients) and rash (3 [33.3%] patients). Fruquintinib dose reduction occurred in 3 patients due to grade 3 proteinuria, grade 2 increased ALT and grade 2 hemoptysis, respectively.

Conclusion:
The study is ongoing. As of the cut-off date, no unexpected toxicities were identified. The combination of fruquintinib and gefitinib showed an expected and manageable preliminary safety profile. Additional patients and follow-up data are required to further confirm the full potential of this combination treatment.

Abstract not provided

Abstract not provided

Background:
Large-scale genomic characterization of large-cell neuroendocrine carcinoma (LCNEC) has revealed several putative oncogenic drivers. There are, however, little data to suggest that these alterations have clinical relevance.

Method:
We performed comprehensive genomic profiling of 68 stage IV LCNECs of the lung (including next-generation sequencing) and analyzed differences in the clinical characteristics of two major LCNECs subtypes: KRAS mutation and PIK3CA mutation. In order to better understand the divergence that might exist between brain metastases and their lung primaries, we performed whole-exome sequencing of paired lung primaries and brain metastases from four lung LCNEC patients.

Result:
Patients with PIK3CA mutation tumors had aggressive disease marked by worse survival (median OS 7.9 vs. 18.6 mo, P = 0.002), higher metastatic burden (> 3 organs 15.2% vs. 4.7%, P = 0.029), and greater incidence of brain metastases (19.0% vs.2.3% in others, P = 0.001). Whole-exome and RNA sequencing on paired brain metastases and primary LCNECs of the lung revealed that LCNEC primaries that gave rise to brain metastases harbored PIK3CA mutation. Significant tumor growth inhibition with GDC0941 was observed exclusively in the LCNEC patient-derived xenograft model that harbored PIK3CA mutation.

Conclusion:
PIK3CA mutation defines a distinct disease phenotype characterized by brain metastasis in LCNEC of the lung. The result may be relevant for targeted therapy and prophylaxis of NSCLC brain metastases.

Background:
Rovalpituzumab tesirine is a promising first-in-class DLL3-targeted antibody-drug conjugate for the treatment of HGNECs. In clinical practice, biopsies are often rendered for diagnoses of HGNECs before treatment. We tested DLL3 in paired biopsy and surgical specimens, aiming to assess the reliability of the scoring system in biopsy specimens and the correlation with HGNEC clinical characteristics and prognoses.

Method:
A total of 378 patients with de novo HGNECs, including 43 LCNECs and 335 SCLCs, were recruited between 2006 and 2015. All 43 LCNECs and 42 of 335 SCLCs had paired biopsy and surgical excision specimens, and the remaining 293 SCLCs had only biopsies. Immunohistochemical evaluation of DLL3 expression was performed using anti-DLL3 antibody (Abcam, ab103102) and was determined using immunohistochemical H score (HS).

Result:
No significant differences of DLL3 expression levels were observed in paired biopsy and excision specimens of LCNECs and SCLCs (Figure B-C). Discordant DLL3 results (high, HS > 150 vs low, HS ≤ 150) in paired specimens were observed in none of LCNECs and 2 of 42 SCLCs. DLL3 levels were significantly higher (p = 0.015) in all SCLCs (n = 335, median HS 200, IQR 100-300) than in LCNECs (n = 43, HS 160, IQR 100-200; Figure D). SCLCs with high DLL3 levels were more frequently male (p = 0.037), smokers (p = 0.019), and TTF-1 positive (p = 0.005) than SCLCs with low DLL3. SCLCs with low DLL3 experienced a superior overall survival compared with SCLCs with high DLL3, with the difference, however, not reaching statistical significance (p = 0.077; Figure F). Figure 1



Conclusion:
Biopsy specimen is a reliable material for evaluating DLL3 expression, which is equivalent to surgical specimen in a large percentage of HGNECs. High DLL3 level in SCLCs demonstrate a correlation with smoking history, TTF1 (neuroendocrine differentiation) and a trend of poor survival.

Background:
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. However, the efficacy of EGFR-TKIs in patients with these uncommon EGFR mutations (other than exon 19 deletions or exon 21 L858R mutation) remains undetermined.

Method:
Seven hundred and fifty-five non-small cell lung cancer (NSCLC) patients with EGFR mutation analyses for TKI therapy were identified between October 2010 and December 2015 in East of China. And 66 patients bearing uncommon EGFR mutations were included to collect data from TKI response and prognosis.

Result:
Rare sensitive mutations (G719X, L861Q, S768I), primary resistant mutation (Ex20 ins), and complex mutations (G719X + L861Q, G719X+S768I, 19 del+T790M, 19 del+L858R, L858R+S768I, and L858R+T790M) of EGFR were identified in 37 (56.1%), 9 (13.6%), and 20 (33.3%) patients, respectively. TKI treatment in patients harboring uncommon EGFR mutations exhibited a tumor response rate of 28.8% and a median progression-free survival (PFS) of 4.8 months. Importantly, patients with complex EGFR mutations had significantly longer PFS when compared with the remaining sensitizing rare mutations or Ex20 ins (8.6 versus 4.1 versus 3.1 months; p=0.041). Furthermore, complex EGFR mutations were independent predictors of increased overall survival in NSCLC patients (Hazard Ratios=0.31; 95% confidence intervals: 0.11-0.90; p=0.031). Among them, patients harboring Del-19 compound L858R mutations showed a tendency to have higher response rate and improved median PFS than those regarding patients with other complex mutations patterns (66.7% verse14.3%, p=0.021; 10.1 verse 8.6 months, p=0.232).

Conclusion:
Personalized treatment should be evolving in different types of uncommon EGFR mutations. And complex mutations of EGFR may benefit more from EGFR-TKIs than other uncommon mutations in Chinese NSCLC patients.

Background:
To evaluate (1) the potential effect of primary tumor resection, an aggressive local consolidative therapy, for patients with oligometastatic NSCLC on 3 year overall survival; (2) the surgical outcomes in the treatment of patients with oligometastatic NSCLC; (3) the potential clinical factors predicting survival in order to better select patients for surgery.

Method:
According to the extent of pulmonary resection, the patients were divided into two subgroups. A. intent to cure (ITC: removal of total or primary pulmonary lesions); B. intent to biopsy (ITB: preservation of major lesions, only diagnostic biopsy via minimally invasive approach). M stage classified based on 8th UICC/AJCC TNM M categories.

Result:
From Jan 2002 through Dec 2015, a total of 115 consecutive metastatic NSCLC patients were enrolled from Peking University Cancer Hospital. The 3-year overall survival (OS) of ITC and ITB were 64.3% and 34.9% (log-rank p = 0.0009), respectively. Multivariate cox proportional regression analysis identified multiple station lymph nodes (LN) and bone involvement may be prognostic indicators. Figure 1Figure 2





Conclusion:
The current findings suggest that aggressive surgical therapy can extend the survival in selected stage IV NSCLC patients, and should be further explored in phase 3 trials as a standard treatment option in this clinical scenario.

Background:
Programmed cell death ligand 1 (PD-L1) expression had been proposed as predictive biomarker to immune-checkpoint inhibitors. Yet treatment responses are not always consistent with this single agent in the second-line therapy of NSCLC. Whether combination of PD-L1 and clinicopathologic characters could circle out optimal beneficiaries are still unknown.

Method:
We performed a meta-analysis of randomized control trials that compared immune-checkpoint inhibitors against chemotherapy in second-line therapy. Data including smoking status, EGFR status, KRAS status and histology were extracted as subgroup analyse to estimate the potential predictor of efficacy for anti PD-1/L1.

Result:
Five clinical trials that compared immune-checkpoint inhibitors against chemotherapy for second-line therapy were included. Both PD-L1 positive (HR=0.64, 95%CI=0.56-0.73, P<0.00001) and PD-L1 negative (HR=0.88, 95%CI=0.78-1.00, P=0.05) favored anti PD-1/L1. Subgroup analyse indicated that adenocarcinoma (ADC) as well as squamous cell carcinoma (SCC) preferred anti PD-1/L1. Never smokers may not benefit from anti PD-1/L1 but current/ever smokers did (HR=0.70, 95%CI=0.63-0.79, P<0.00001). Patients with EGFR mutation could not gain benefit from anti PD-1/L1 while the EGFR wild type could (HR=0.67, 95%CI=0.60-0.76, P<0.00001). Both KRAS mutation (HR=0.60, 95%CI=0.39-0.92, P=0.02) and wild type/unknown (HR=0.81, 95%CI=0.67-0.97, P=0.02) were apt to anti PD-1/L1. Figure 1



Conclusion:
Regardless of PD-L1 status, immune-checkpoint inhibitors could achieve better efficacy than chemotherapy in second-line therapy. Current/ever smokers without EGFR mutations may benefit more from anti PD-1/L1. Combination of PD-L1 and strongly relevant clinicopathologic characters should be considered to tailor optimal patients for anti PD-1/L1.

Background:
NSCLC patients with activating EGFR mutations benefit from 1[st] generation EGFR-TKIs. It eventually develops acquire resistance after 10-12 months during of response. Of note, approximately one-third of those patients develop brain metastases, which deteriorate their quality of life and survival. Few effective therapeutic options are currently available for BM patients. Several case studies have showed the well response with osimertinib in BM patients. BM model also found the high penetration rate of Osimertinib into blood-brain barrier. This study evaluated the feasibility of osimertinib treatment on BM patients after 1st generation EGFR-TKI resistance.

Method:
Patients with advanced or recurrent NSCLC who had progressed during EGFR-TKIs treatment were collected from our previous clinical trial (NCT02418234) from March 2015 to March 2016. Blood samples were drawn within two weeks from PD occurred. T790M mutations were evaluated by droplet digital PCR. We undertook follow-up every 3 months by phone until April 2017. The median follow-up time was 11 months (range, 2 to 22 months).

Result:
Fifty NSCLC patients with BM after EGFR-TKI resistance were collected from our previous trials. After TKI resistance, ten patients received subsequent osimertinib treatment. Finally, ten patients included three males and seven females were included in the study. The median age was 66.5 (56 to 73). Seven were detected acquired T790M mutation. The median survival was 15.3 months (95% CI, 10.1 to 20.6 mo), 15.3 mo for T790M negative and 12.9 mo for T790M positive patients.

Conclusion:
Our preliminary study showed the well efficacy of osimertinib on NSCLC patients with BM. It provides well survival benefit. Randomized control trials should be required before it is widely used.

Background:
All patients with advanced stage NSCLC should have their EGFR and ALK mutation status known prior to initiation of first line therapy. Multiple plasma-based technologies such as ARMS and ddPCR are available for rapid detection of EGFR mutation, while only the more laborious Next Generation Sequencing (NGS) may cover EGFR, ALK and other uncommon mutations in a single blood test. cSMART is a novel NGS-based technology with rapid turnaround time that can detect EGFR, ALK and KRAS mutations plus others less common lung cancer specific driver oncogenes (BRAF, ROS-1, HER-2, PIK3CA, RET, MET14skipping).

Method:
Objectives of this study is to investigate the clinical application of cSMART on patients with advanced NSCLC. In cSMART assay, each cfDNA single allelic molecule is uniquely barcoded and universally amplified to make duplications. The amplified products are circularized and re-amplified with target-specific back-to-back primers. These DNA are then ligated with sequencing adapters and pair-end sequenced (>40,000x) with illumine sequencers. The original cfDNA molecules are reconstituted by multi-step bioinformatics pipeline for censor and correction. The final products are quantified for calculation of allele frequencies

Result:
Out of the 1664 samples tested, total of 1469 were of advanced stage NSCLC. We detected EGFR mutations in 758 (51.6%), ALK translocation in 34 (2.3%) and KRAS mutation in 78 (5.8%) patients. Among the patients with activating EGFR mutations, 301(39.7%) have exon 19 deletion and 279 (36.8%) have exon 21 point-mutation. Total of 6 (0.8%) patients with EGFR mutation have concurrent presence of ALK translocation. Incidence and mean allele frequency of the less common target mutation is summarized in Table. Median sample turnaround time is 7 days.

Incidence (%) Median Mutation Allele frequency (%) BRAF 29 (1.97%) 0.08% ROS1 2 (0.14%) 0.77% HER-2 19 (1.29%) 0.20% PIK3CA 70 (4.77%) 0.17% RET 14 (0.95%) 0.57% MET14skipping 63 (4.29%) 0.08%

Conclusion:
cSMART is a novel plasma cfDNA-based technology that can detect the actionable target oncogenes for patients with advanced NSCLC. This is a sensitive method with capacity of detecting the uncommon targets at relatively low allele frequency.

Background:
Osimertinib is used to treat patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC). Detection of the T790M mutation in tissue samples may not be possible in some patients due to unfeasible or unsuccessful rebiopsies; detection in circulating cell-free tumor DNA (ctDNA) may represent a promising alternative. Here we evaluated four platforms to detect T790M using ctDNA in plasma from Chinese patients as part of the ADELOS study.

Method:
ADELOS is being conducted in China in 256 patients with advanced NSCLC, sensitizing mutations and progression on previous tyrosine kinase inhibitor. T790M was detected in plasma ctDNA by cobas® real-time polymerase chain reaction (PCR), super amplification refractory mutation system (Super-ARMS) PCR, QuantStudio3D digital PCR, and next-generation sequencing (NGS). T790M positive patients by any of the four platforms received osimertinib 80 mg/day orally. The relationship between T790M detection by each platform and objective response rate (ORR) was investigated. Concordance, sensitivity and specificity, and positive/negative predictive value between platforms were assessed. T790M mutation level in ctDNA was dynamically monitored every 6 weeks using digital PCR and NGS during osimertinib treatment, and its correlation with clinical outcome was evaluated. NGS also provided information about the heterogeneity of other genetic alterations in patients before osimertinib treatment.

Result:
Section will be completed in late-breaking abstract submission

Conclusion:
Section will be completed in late-breaking abstract submission

Background:
Leptomeningeal metastases (LM) are more frequent in non-small cell lung cancer (NSCLC) patients with oncogenic drivers. Resistance mechanisms of LM with ALK rearrangement remained unclear due to limited access to leptomeningeal lesions.

Method:
Primary tumor, cerebrospinal fluid (CSF) and plasma in patients with suspected LM of NSCLC were tested by Next-Generation Sequencing.

Result:
In patents with ALK rearrangement, driver genes were detected in 66.7%, 50.0% and 28.6% patients of CSF cfDNA, CSF precipitates and plasma, respectively; and all of them had much higher allele fractions in CSF cfDNA than the other two media. The diagnosis criteria of LM were positive in brain MRI or CSF cytology, and driver genes were identified in CSF cfDNA of all patients with positive CSF cytology while in those CSF cytology negative all genes were negative. Resistance mutations including gatekeeper genes ALK G1202R and ALK G1269A were identified in CSF cfDNA but they were absent in their plasma. Moreover, tailor therapy based on CSF cfDNA obtained surprising outcomes, and genetic profiles of CSF cfDNA showed dynamic changes, suggesting the potential role of CSF for follow-up studies. Figure 1



Conclusion:
CSF cfDNA could reveal the driver and resistant genes of LM, and it may function as the media of liquid biopsy for LM in NSCLC with ALK rearrangement.

Background:
Patients with ALK-positive NSCLC have seen significant advances and increased options in ALK targeted therapies recently, and therefore rely on high quality, robust ALK status testing. Fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) are the most common methods to determine ALK status for ALK tyrosine kinase inhibitor (TKI) treatment. However, availability of clinical outcome data from randomized trials linked directly to specific methods is limited. The ALEX trial (BO28984, NCT02075840) provides a unique dataset to assess ALK IHC- and FISH-based assays regarding clinical outcome for alectinib and crizotinib, particularly for the subset of patients with IHC-positive/FISH-negative NSCLC.

Method:
The VENTANA ALK (D5F3) CDx Assay (ALK IHC) performed in central laboratories was used as an enrollment assay for the selection of patients with ALK-positive NSCLC for inclusion in the ALEX trial. Additional samples from these patients were retrospectively tested in central laboratories with the Vysis ALK Break Apart FISH Probe Kit (ALK FISH).

Result:
Overall, 303 patients all with ALK IHC-positive NSCLC were randomized in the ALEX trial, of those 242 patients also had a valid ALK FISH result, with 203 patients having ALK FISH-positive disease and 39 patients having ALK FISH-negative disease (alectinib, n=21; crizotinib, n=18). For 61 of 303 (20.1%) patients with an ALK IHC-positive result, a valid ALK FISH result could not be obtained due to the test leading to an uninformative FISH result (10.9%), or not having adequate/no tissue available (9.2%). Ventana IHC staining success rates were higher than for Vysis FISH testing for the ALEX samples. Exploratory analysis of investigator-assessed progression-free survival (PFS) in patients with a FISH-positive result (HR 0.40, 95% CI 0.27–0.61; p<0.0001; median not reached [alectinib] versus 12.7 months [crizotinib]) was consistent with the primary endpoint analysis in the Ventana ALK IHC-positive population. Patient outcome data show that 28% of central ALK IHC-positive/ALK FISH-negative samples were from patients who responded to ALK TKI treatment (complete response or partial response) and 33% had stable disease according to investigator assessment.

Conclusion:
This analysis shows that ALK IHC is a robust testing approach, which may identify more patients with a valid ALK testing result who benefit from ALK TKI treatment than ALK FISH testing. While PFS of patients with ALK FISH-positive NSCLC was similar to that of patients with ALK IHC-positive NSCLC, the analysis also revealed that the majority of patients with ALK IHC-positive/ALK FISH-negative NSCLC may derive clinical benefit from ALK TKI treatment.

Background:
Human epidermal growth factor 2 (HER2, ERBB2) mutations / amplifications have been identified as oncogenic drivers in 2-5% of lung cancers. It has been reported that hybridization capture-based next-generation sequencing (NGS) could reliably detect HER2 amplification in qualified breast and gastroesophageal tumor tissue samples. However, there is little data in lung cancer, especially for advance NSCLC with only ctDNA samples available.

Method:
We reviewed 2000 consecutive samples from advanced NSCLC patients sequenced in our institute between 2015 and 2016. Tumor biopsy and/or ctDNA samples were analyzed using hybridization capture-based NGS ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations at least 59 genes (range 59 – 1021 genes).

Result:
We identified 54 samples from 48 patients with HER2-mutation or amplification in the cohort (54/2000=2.7%). The 54 samples included 14 tissue biopsy samples, 37 ctDNA samples, and 3 pleural effusion samples. Thirty-six samples carried HER2 mutations, and 23 samples carried HER2 amplification with 5 samples have concurrent HER2 mutation and amplification. A 9-base pair (bp) in-frame insertion in exon 20 (Y772_A775dup) was detected in 18 samples (18/36=50%). In addition, there were 5 other insertions in exon 20; eight single bp substitutions (S310F) in exon 8; three exon 17 V659E mutations (from the sample patient with 3 ctDNA samples submitted at different time); one exon 19 D769H mutation; and one exon 21 V842I mutation. Amplification were identified in 23 samples, with copy number range from 3.8 to 19.6 in tissue samples (n=7, medium 11.6); from 4.3 to 51.8 in ctDNA samples (n=16, medium 7.3); 3.2 and 6 in the 2 pleural effusion samples. Interestingly, the allele frequency (AF) of HER2 mutation was the maximal in 4 of the 5 patients with concurrent HER2 mutation and amplification. Two patients were EGFR-TKI resistant with EGFR L858R mutation remaining and HER2 mutation and amplification might be the major reason for the resistance.

Conclusion:
HER2 mutations might coexist with HER2 amplification in advanced NSCLC patients, and it could be detected simultaneously with hybridization capture-based NGS sequencing both in tissue and liquid biopsy samples. Further quantative analysis of HER2 amplification / mutation and anti-HER2 therapeutic effects are underway.

Abstract not provided

Abstract:
Decision making in life is not always easy. This is applicable not just for patient care but also for matters related to our own-self and is particularly true in the context of career options in medicine. Over the past few decades, the level of expertise provided by health-care providers has enhanced considerably from having comprehensive ‘all-in-one’ doctors to specialists to super-specialists and currently focused super-specialists. This has been associated with the practice of medicine having changed from ‘evidence-based-medicine’ to ‘personalized medicine’ and currently of ‘precision medicine’ and ‘tailor-made’ therapies. This has largely been based on an increase in the quantity and quality of research being conducted worldwide. A majority of this research occurs in academic medical centers/university hospitals wherein faculty/attending consultants are not just involved in patient care but have to devote a substantial percentage of their time in planning and conducting research as well as teaching undergraduate/postgraduate residents and fellows. So the natural questions that crop up for someone in training are: 1) ‘How do I decide whether I am inclined to be working in an academic institute?’ [Will I be able to ‘gel-in’ or be a complete misfit?] ‘2) What is the time-point during my training/post-training period when I need to take the decision of pursuing an academic career?’ 3) ‘What are the essential and desirable qualities/traits that are conducive to working in an academic set-up?’ There are no straightforward answers to any of these. However, generally during the final year of fellowship, most individuals are able to decide whether they would like to continue working in an academic centre or not. This is often possible with guidance from course faculty. The chief-guide under whom the individual has been pursuing research (thesis/dissertation) may be able to identify if the latter has an ‘academic bent of mind’ and provide mentorship and help the transition from ‘fellow’ (in-training) to full-time faculty [‘attending’ consultant]. It is important for anyone intending to pursue an academic career to realize that conducting and participating in research is an integral part as opposed to working in non-academic centers where patient care is the primary focus. Inclination towards research may sometimes manifest as being able to identify ‘grey’ areas in practice of medicine (clinical situations for which there are no clear-cut answers). The best researchers are and often have been those who are able to identify these areas of uncertainty related to diagnosis and treatment of a particular condition or disease and carry out research directed to answer the queries that they had in their minds when picking up these uncertainties. Keeping abreast of the latest developments in one's focus area (by regularly accessing and reading the latest publications in peer reviewed journals) as well as publishing one's own experience/research in such journals is thus part and parcel of one's job profile while working in an academic center. For lung cancer – a disease that carries the highest cancer-related mortality amongst both gender combined and the commonest cancer in males, there have been very encouraging developments in the last couple of decades and especially the last five years. We now have five pillars for treatment – targeted therapy and more lately immunotherapy coming in as very useful additions to traditional modalities (surgery, chemotherapy and radiotherapy). And these are truly exciting times for carrying out research in lung cancer in several ways: 1) Number of investigational molecules (targeted therapy and immunotherapy) being developed/tested in preclinical/clinical trials is increasing at an unparalleled rate 2) Conventional pathway followed for testing [preclinical, phase-1, phase-2, phase-3 clinical trials] is being modified to reduce time to clinical approval for successful drugs by having combined phase 1/2 or phase 2/3 trials. 3) Intense efforts are being made to expand indications for already approved/available drugs e.g. assessing utility of targeted agents in early stage/resectable NSCLC and of combination regimens (EGFR-TKIs/ALK inhibitors+ chemotherapy, PD-1/PD-L1 immune check-point inhibitors+ chemotherapy). Several unaddressed issues exist in lung cancer currently which require concerted efforts and inputs from researchers worldwide including: 1) Improving the screening algorithm for early detection such that false positive results and need for/number of invasive procedures required is reduced. Development of blood, sputum or exhaled-breath based screening tests could find greater acceptability and applicability worldwide. 2) Improving the genomic understanding of SCLC – a histological subtype without significant advances in the past leading treatment to be essentially with two modalities (chemotherapy and radiation). Identifying ‘targetable’ molecular aberrations can revolutionize management of this aggressive histological type while ongoing efforts to establish the role of immune check-point inhibitors continue. 3) Detection of EGFR sensitizing mutations and acquired T790M resistance-conferring mutation (for initiating 1[st]/2[nd] generation EGFR-TKIs and osimertinib respectively) in circulating tumor DNA (ctDNA; sometimes called circulating free tumor DNA - cfDNA) is already applicable in clinical practice and potentially can be used for monitoring treatment responses also. Next-generation-sequencing(NGS) platforms appear promising in detecting both somatic point-mutations and rearrangements/fusions with minimal tissue and/or ctDNA. Development and validation of methods for non-invasive biological monitoring of responses to chemotherapy, radiation, immunotherapy and non-EGFR targeted therapies in the complete spectrum of histological types (SCLC, squamous and non-squamous NSCLC) and disease stage distribution (neoadjuvant treatment preceding surgery, post surgery – adjuvant setting, locally advanced NSCLC following induction concurrent chemo-radiation and metastatic setting) will make it more convenient for patients and treating oncologists alike. The advantages of working in an academic setup in lung cancer are apparent both for the clinician and his/her colleagues in other clinical departments/basic sciences. Current research and clinical practice requires collaboration of different disciplines [pulmonology, diagnostic and interventional radiology (including nuclear imaging), pathology (histopathology, cytopathology, molecular pathology), thoracic surgery/surgical oncology, radiation oncology and medical oncology]. Based upon the academic institute’s geographical location, the number/work profile of departments that exist for a given discipline may vary considerably. These variations notwithstanding, the bottom-line is that reaching out to and working together with colleagues from other departments and disciplines [multidisciplinary team approach] is mandatory for attempting conduct of high-quality research and delivery of high-quality patient care in thoracic oncology. This potential advantage and benefit also comes with several challenges. One is required to carefully balance and utilize working hours for patient care, research and training while attempting to do the best in all three fields. This invariably, if not mandatorily, leads to spill-over of work into ‘off-work’ hours and impinges on ‘family-hours’ or ‘personal-time.’ The support of one's spouse, parents and children in such settings cannot be undermined or understated. One needs to keep a balance between ‘All-work-and-no-play makes Jack a frustrated man’ versus ‘Jack-of-all-trades and master-of-none’. Neither is desirable and the ultimate aim is to have a satisfying career in thoracic oncology while working in an academic setting wherein one is able to: 1) provide patients (often under-privileged and belonging to poor socio-economic strata) the best diagnostic and treatment facilities (despite presence of resource constraints) – Patient Care 2) be involved in clinically relevant basic and translational research that has the potential to improve patient care in one’s own geographical location – Research 3) share one’s experience with residents/fellows and colleagues within the institute and outside – Medical Education Navneet Singh MD DM Email: [The author is a thoracic medical oncologist-cum-pulmonologist currently working as an Associate Professor of Pulmonary Medicine at the Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. He is a member of IASLC’s Staging & Prognostic Factors Committee; Publications Committee and is IASLC’s Regent for the Indian Subcontinent. Additionally, he is Chair-Elect of the American Society of Clinical Oncology’s (ASCO) International Development and Education Award (IDEA) Working Group and a member of its Multidisciplinary Cancer Management Course Working Group and Thoracic Cancer Guideline Advisory Group. His detailed profile is accessible at http://www.linkedin.com/in/navneet-singh-160012.]

Abstract:
Relatively little information is available for hematology oncology fellows to inform their choice for an academic oncology(AO) vs a community oncology(CO) career. In 2006, Desch and Blayney(1) described practical differences between AO and CO careers which are still pertinent today. A more recent report from Vanderbilt(2) describes factors which appear to influence oncology fellows’ career decisions. Once a career path has been selected, does this choice affect career and work-life balance satisfaction? Shanafelt and his colleagues have described the impact of career choice and related factors on job satisfaction(3,4). This review will summarize the results of these reports and share a perspective regarding possible changes in oncology practices which could impact career choice. Desch and Blayney(1) describe mission, governance, patient care, financial considerations, referral bases, career flexibility, and determinants of success. The mission for community oncologists(COs) consists of delivering excellent patient care and running a successful business. In contrast, the mission for academic oncologists(AOs) encompasses patient care, research and teaching. CO governance offers more autonomy and usually consists of a doctor owned corporation with equal ownership. AOs work in a hierarchical system with multiple levels between the physician and senior leadership. There are significant differences in delivering patient care. Desch and Blayney point out that “ COs are intern, resident, fellow, and attending all rolled into one. ” COs have more weekend and night call. In addition, COs provide care for multiple types of cancer patients , while AOs’ practice is usually limited to one or two types of malignancy. Patient referrals for COs depend upon building relationships with primary care physicians and surgeons in their community. AOs also get patient referrals from primary care physicians and surgeons, but they rely heavily on institutional reputation, the reputation of disease specific experts, and a robust clinical trial program. Publishing and giving presentations at local and national meetings establishes AOs as disease specific experts which results in physician referrals and in patient initiated consultations. Revenue for COs depends upon fees for physician services, for administration of intravenous treatment , for laboratory tests, for imaging, and revenue from chemotherapy/immunotherapy treatments. For AOs, revenue comes from fees for physician services, grants, clinical trial revenue, and philanthropy. In some academic institutions, revenue may also come from the ancillary sources, similar to private practice. Starting and subsequent compensation is higher for COs who receive significant salary increases when they become full partners in the corporation, 2-5 years after joining the practice. Salary for AOs increases with increasing academic rank and may be supplemented with bonuses and honorariums for lectures and participation in advisory boards. Desch and Blayney(1) suggest that there are critical success factors for COs and AOs. . Building a reputation as a local expert and being readily available to referring MD’s and partners is essential for COs. . They also point out that it is essential for COs to invest time to understand bonuses and to show that they value and support the practice staff. AOs must focus on area of expertise, choose a good mentor, publish results of research, and apply for grants. It is not realistic to expect AOs with a large clinical practice to be the principal investigator on a grant. However, these clinicians can learn the concepts of basic science and partner with laboratory investigators in translational research grant proposals. Horn and her collegues(2) studiedfactors associated with selecting an AO or CO career. They invited program directors at 56 NCI designated and National Comprehensive Cancer Network cancer centers. Fellows at these institutions were asked to complete a questionnaire regarding their interest in AO vs CO careers. . Fellows with a high interest in AO were more likely to be women, have an additional graduate degree, and to have participated in basic research. Also fellows who were more interested in AO gave more presentations at scientific meetings and had more publications. Having an influential mentor and a desire to teach were also related to pursuing a career in AO. . Fellows who were more interested in CO were motivated by work-life balance and autonomy. This study suggest that fellows who are primarily motivated by being involved in identifying new information and teaching are more likely to pursue AO , while fellows who are motivated by favorable work-life balance and having more autonomy are more likely to pursue a CO career. How do practicing oncologists feel about their careers? Shanafelt and colleagues(3,4) have published two reports describing results of a survey which evaluated burnout, career satisfaction, life – work balance satisfaction and retirement. They(3) found that COs spent more time in clinic and saw more patients.. Younger age and more hours in clinic were associated with increased risk of burnout, which was defined as a combination of emotional exhaustion and depersonalization (loss of concern for patients),. There was a trend for higher rate of emotional exhaustion and a significantly higher rate of depersonalization in community oncologists. Although the majority of oncologists would choose a career in oncology, there was a higher number of COs who stated they would not choose an oncology career. In the second report(4), they did not compare AOs and COs. They saw that although most oncologists find meaning in their work, 52% were dissatisfied with work-life balance. “They like their work but want to do less of it.” Work-life balance was affected by more night and weekend call, while method of compensation salary +/- bonuses (most AOs) versus incentive (most COs) was not related work-life balance. For oncologists who planned to reduce work hours, the most common reason was to spend more time with family. In summary, when making a career choice, oncology fellows should identify what motivates them. I suspect that the majority of oncologists will continue to be happy with their career choice and that the current differences between AO and CO careers may decrease because more COs will be employed by hospital systems. References 1.Desch CE, Blayney DW. Making the Choice Between Academic Oncology and Community Practice: The Big Picture and Details About Each Career. Oncol Pract 2:132-138, 2006 2.Horn L, Koehler E, Gilbert J, et al. Factors Associated with the Career Choices of Hematology and Medical Oncology Fellow Trained ar Academic Insitutions in the United States. J Clin Oncol 29: 3932 - 3938, 2011 3.Shanafelt TD, Gradishar WJ, Kosty M, et al.Burnout and Career Satisfaction Among US Oncologists. J Clin Oncol 32: 678-686, 2016 4.Shanafelt TD, Raymond M, Kosty M, et al.Satisfaction with Work-Life Balance and the Career and Retirement Plans of US Oncologists.J Clin Oncol 32:1127-1135, 2014

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I received the WCLC 2016 Young Investigator Travel Award for my presentation entitled “Immunogram for cancer-immunity cycle towards personalized immunotherapy of lung cancer”. It was my great honor to receive the award, and I want to thank the conference committee and all the conference attendees. This was my first time to attend the WCLC, and I enjoyed the conference and my stay in Vienna. I was given the opportunity to join the Faculty Dinner held in Vienna City Hall. It was a fabulous experience, and I thoroughly enjoyed sitting at the same table as world-renowned surgeons and oncologists. During the conference, I mainly attended immunotherapy sessions where I learned about the results of the most recent clinical studies. Furthermore, while attending the biomarker session, I realized that biomarkers in this field are still inadequate and the development of useful biomarkers in immunotherapy is an urgent need. Receiving the young investigator scholarship has encouraged me to continue our efforts to unveil the tumor microenvironment in each patient using individual next-generation sequencing data in order to develop “next-generation biomarkers” and achieve optimal personalized immunotherapy. Last year, in a Perspectives article in Science, Blank et al. proposed the concept of the cancer immunogram, a framework to illustrate multiple parameters that influence the cancer-immunity interaction (1). In their article, the concept was applied theoretically to patients but not tested in practice. To accomplish this, we developed an immunogram reflecting the cancer immunity cycle using next-generation sequencing data, and applied it to real patients with lung cancer. An immunogram for the cancer immunity cycle is a radar chart that consists of eight molecular profiles relevant to the development of T-cell immunity to tumor cells. We sought to translate cumbersome omics data into easily comprehensible “report cards” for clinicians. Immunograms can be used as integrated biomarkers, and may become a valuable resource for optimal personalized immunotherapy. After the presentation at the WCLC 2016, our findings were published in the Journal of Thoracic Oncology in May (2). It was an honor that our article was chosen by the Editor to be a featured article and was introduced by an elegant review (3). We recently updated our method by normalizing the immunogram score using TCGA data. We are pleased to share the details of this improvement during the present conference. Although we are working in a challenging field and there is still a long way to go, we are encouraged by the award and will continue to struggle toward further breakthroughs.　 References (1) Blank CU, Haanen JB, Ribas A, Schumacher TN. Cancer immunology. The “cancer immunogram” Science. 2016;352:658-60. (2) Karasaki T, Nagayama K, Kuwano H, et al. An Immunogram for the Cancer-Immunity Cycle: Towards Personalized Immunotherapy of Lung Cancer. J Thorac Oncol.2017;12(5):791-803. (3) Botling J, Sandelin M. Immune Biomarkers on the Radar-Comprehensive "Immunograms" for Multimodal Treatment Prediction. J Thorac Oncol.2017;12(5):770-2.

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The IASLC (International association for the study of lung cancer) WCLC (World Conference on Lung Cancer) is world’s largest academic platform dedicated for the study of lung cancer and other thoracic malignancies which not only caters to physicians but also includes active participation from each discipline of medicine involves in patient care. In addition health advocacy groups and patients will also join WCLC to obtain and exchange the information. The focus of the meeting is on the biology, diagnosis, pathogenesis, treatment and management of lung cancer so to begin from active prevention and accurate diagnosis to advanced care. Because of advancing science of lung cancer, IASLC decided to hold WCLC every year so people will be kept abreast with the current knowledge and updates in this field. There are many academic opportunities for the young investigators or first-time attendee to pursue their career in the field of thoracic oncology. They can meet the experts during the conference, attend various educational sessions and take guidance in the field of basic, translational and clinical research. There are many awards which help in not only enhancement of academic career but also in attending conference from resource poor countries. Travel awards given to developing nation investigators so that they can attend the conference and present their latest research in addition to make collaborations and academic networking. International mentorship program of IASLC is very useful professional development and education program for early-career doctors from economically-developing countries in which you get an opportunity to spend a week time in a well established hospital or laboratory under the mentorship of an international expert in that field. This year, the Core Program Committee has organized a scientific program that includes more than 450 presentations. The conference motto is “Synergy to Conquer Lung Cancer” which will be very overwhelming at both scientific and educational fronts. The education sessions include state-of-the-art talks by experts on academically challenging and evolving topics. The scientific program includes research presentations in the form of posters and platform formats. There are many events and platforms where first time attendees can interact and do networking for future collaborations. It is certain that the 18[th] WCLC will help young investigators and first time attendees to build and shape-up their career in thoracic oncology.

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Abstract:
Along with the prevalence of screening with computed tomography (CT), small pulmonary ground-glass density nodules (GGN) have been detected more frequently. A GGN is a round area of increased pulmonary opacity with intact bronchial and vascular structures. GGNs showing no or slow growth during follow-up period are most likely to be “early” adenocarcinomas showing lepidic pattern pathologically. There are three problems in diagnostics and therapeutics of GGNs. First, should they be treated or not? They might not change for years. We might take a risk of postoperative comorbidity for a harmless disease. Some large prospective observational studies on these pulmonary small GGNs have been performed: From clinical practice performed in these clinical trials, We found that 5-30% of GGN were resected during the observation period, because of the increased size or appearance of solid part in the GGN. Almost all of the pathologies of the resected GGN were adenocarcinomas. Part-solid GGNs were more likely to be diagnosed as invasive adenocarcinomas than pure GGNs. That is, we can correctly diagnose small pulmonary GGNs as adenocarcinomas when their CT images are changed. However, it is still unclear whether surgical intervention will contribute to increased survival from lung cancer. Second, how to detect pulmonary GGOs at surgery, if they are located deep in lung parenchyma? GGNs are difficult to identify even by bimanual palpation through open thoracotomy, because they are as soft as lung parenchyma if they show pure GGN appearance. Preoperative marking of these GGN is mandatory to ensure a definite resection. Many methods for detecting small pulmonary nodules have been developed: Preoperative hookwire placement under CT observation has been most widely performed. The punctured hook wire with thread can easily be identified that excisional biopsy may be done through thoracoscopy. However, arterial air embolism is reported to be occasionally associated with the placement of hookwire which can cause lethal results. Instead, dye marking, or fiducial placement through bronchoscopy has been revived to replace the hookwire method. We have recently developed Virtual-assisted lung mapping (VAL-MAP), a relatively brand-new lung marking technique using dye multiple dye markings through bronchoscope. Before bronchoscopy, we create a virtual 3-D bronchoscope map with CT and plan where to mark. Multiple dye markings enable us to determine the extent of resection with safe margin from the tumor. Actually safer margin from the tumor was shown to be secured by this method. Third, how to determine the extent of pulmonary resection for these small GGNs? Still there is no evidence other than lobectomy and lymph node dissection for early non-small cell lung cancer (NSCLC), clinical trials have been performed to prove feasibility and no-inferiority of sublobar resections (wedge resection and segmentectomy) for small NSCLC, especially those ≤2cm in diameter. In Japan and USA, prospective randomized studies are on the way to obtain more reliable evidence. In conclusion, management of small pulmonary nodules suspected of an early carcinoma includes the determination of operative indication, detection technique of the tumor, aiming to safer and effective treatment of these tumors.

Abstract:
Erik Thunnissen[1], Chris Dickhoff[2,3], Rutger Lely[4], MA (Rick) Paul[3] Departments of [1]Pathology, [2]Surgery, [3]Cardiothoracic Surgery and [4]Radiology, VU University Medical Center, Amsterdam, the Netherlands. Guidelines for gross handling are to our knowledge not formulated in the literature. However, the College of American Physicians (CAP) formulates "required elements" for synoptic reporting regarding gross handling of pulmonary resection specimen, mainly focusing at pathology staging, but does not include grossing requirements[1]. The current practice of handling resection specimen in Amsterdam involves interaction with surgeons for submission of specimen. This includes i) Information about pretreatment, type of surgery (including pneumonectomy, (sleeve) lobectomy, segmentectomy, and wedge resection), site of specimen, number of tumors; ii) eventual frozen section for diagnosis and/or resection margin; iii) eventual additional information of specimen e.g. adhesion from parietal pleura, additional wedge from adjacent lobe adhesion; iv) agreement on marking the ‘cold’ side from bronchial resection slice [see note A]; For the pathologist, the order of handling the fresh specimen is i) to maintain the 3 dimensional orientation of the resection specimen along the axial, coronal and sagital planes; ii) to describe outer surface of specimen; iii) to photograph overview from medial and lateral side; iv) to cut slice of bronchial resection margin; v) to cut tumor, preferably in axial plane for sampling of normal lung tissue and tumor for research (culture, freezing) [see notes B and C]; vi) to perform perfusion fixation of peripheral lung; vii) and to immerse whole specimen in large volume neutral buffered formalin. After 24 hours, fixation the specimen is handled in the following way: i) Intrapulmonary lymph nodes are separately embedded ii) the specimen is further cut in slices along the same plane as done for the fresh specimen; iii) the slices are positioned in order of cutting, numbered and photographs taken; iv) description of specimen with tumor characteristics: focality (size; vital, necrosis, fibrosis), distance from tumor to margins recorded (to bronchial resection, pleura). If tumor is present in sequential slices, cumulative tumor thickness is measured; v) other characteristics are described (mucus in dilated bronchi; post-obstruction pneumonia; emphysema etc.) vi) sample representative blocks from tumor, normal tissue, resection margin arteria pulmonalis, and nearest point(s) to pleura for embedding in paraffin; vii) annotate the location of sampled blocks on a copy of the gross slices. After a few days during first microscopy, the 3 dimensional orientation can be reconstructed and the pTNM parameters extracted from the gross and microscopic information. If needed, additional samples can be taken [see note C]. Classification is performed for most parts according to the WHO[2], except for not reproducible categories and immature concepts. Pathology reporting contains pTNMR [see note D]. The pathology report is usually made within 9 working days, except if bony structures are included, then the process will contain an additional week. If postoperative radiotherapy is indicated, the 3 dimensional approach also supports determination of the position(s) for radiation, especially if clips were not placed during surgery. Note A As for frozen section, the cold side of the bronchial resection margin [i.e. the side distant from the patient] is placed downwards on the frozen template, the first cut frozen section sections [representing the nearest to the patient tissue margins (warm side)] are sequentially placed on the microscope slide. In case of uneven surface maximally 6 sections, until complete circumference is achieved, are placed on two microscopic slides, and stained for H&E The bronchial resection margin is considered tumour-free, if the complete circumferential margin does not contain tumor. If needed, in this judgement sequential complementarity of the 6 sections may be taken into account. The sleeve lobectomy has two resection margins: one on the cold side and the other on the warm side (larger bronchial diameter). These are separately examined. If only tumor cells are found in lymph vessels (but no direct tumor spread), this will be reported, but not considered necessary for indication of additional bronchial margin, as lymphangitic distribution is associated with N2 disease[3,4]. Note B As it has been proven that loose tissue fragments are caused by gross cutting[5,6], the knife is rinsed and quickly wiped after each slice that happens to contain tumor. STAS is considered to be an artifact and in contrast to CAP and WHO classification, is not considered as part of the tumor. Note C In Pancoast tumor, the ‘en-bloc resection’ incorporates extrapulmonary structures directly invaded by tumor, usually ribs. During the fresh handling, the thoracic wall is cut from the lung. Subsequently, both cut surfaces are coloured to denote the artifical edges. Bone requires after fixation extra time for decalcification, extending reporting with one week. Note D The R = defined as follows: R0 = free resection margins; R1 = microscopic margins not free; R2 = margins not free during gross examination/surgery;. Peripheral wedge resections contain a parenchymal margin, which is represented by the tissue at the staple line(s). The staples are cut from the specimen, but not further examined. Adjacent tissue is sampled for microscopic examination. If this section does not contain tumor, the margin is free (R0). However, if this contains tumor, an educated guess is reasonable, encompassing the amount of tumor compared to the other sections, and the estimation of the staple thickness (±2mm). 1. College of American Pathologists. Cancer Protocol Templates. Lung cancer vs4. http://www.cap.org/web/oracle/webcenter/portalapp/pagehierarchy/cancer_protocol_templates.jspx?_afrLoop=445529225217710#!%40%40%3F_afrLoop%3D445529225217710%26_adf.ctrl-state%3Dxmm1doio_4. 2. Travis W., Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. (Travis W., Brambilla E, Burke AP, Marx A, Nicholson AG, eds.). Lyon: IARC; 2015. 3. Thunnissen FBJM, den Bakker MA. Implications of frozen section analyses from bronchial resection margins in NSCLC. Histopathology. 2005;47(6):638-640. doi:10.1111/j.1365-2559.2005.02263.x. 4. Vallières E, Van Houtte P, Travis WD, Rami-Porta R, Goldstraw P. Carcinoma in situ at the bronchial resection margin: a review. J Thorac Oncol. 2011;6(10):1617-1623. doi:10.1097/JTO.0b013e31822ae082. 5. Blaauwgeers H, Flieder D, Warth A, et al. A Prospective Study of Loose Tissue Fragments in Non–Small Cell Lung Cancer Resection Specimens. Am J Surg Pathol. June 2017:1. doi:10.1097/PAS.0000000000000889. 6. Thunnissen E, Blaauwgeers HJLG, de Cuba EM V, et al. Ex Vivo Artifacts and Histopathologic Pitfalls in the Lung. Arch Pathol Lab Med. 2016;140(3):212-220. doi:10.5858/arpa.2015-0292-OA.

Abstract:
The recent advance in personalized medicine along with minimally invasive endoscopic techniques in the field of lung cancer has brought significant complexities to handling of tissue samples. Due to the histology-directed therapy, additional stains are frequently required to achieve accurate histologic subtyping on small biopsy and cytology samples. It is recommended that epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and ROS1 testing be performed for patients with advanced non-squamous small cell lung cancer (NSCLC) in a reflex manner. In addition, multiplex assays, including next generation sequencing (NGS), are increasingly being used for detection of the molecular targets. Furthermore, immunohistochemistry (IHC) for programmed death ligand-1 (PD-L1) is now routinely performed in NSCLCs with wild type EGFR and ALK to determine eligibility for PD-1/PD-L1 blockade.(1) In most advanced NSCLC patients, a small biopsy or cytology specimen is often the only sample available for the diagnosis and biomarker analyses. Thus, appropriate tissue acquisition, processing and management for multiple tests are crucial and are best achieved by the interaction of all physicians involved in the patient care.(2, 3) Tissue acquisition All the necessary work-up is usually performed on a small biopsy or cytology specimen taken from a patient with advanced disease, tissue sampling should be aimed at obtaining the largest yield of tumor in the safest and least invasive manner.(4) Tissue processing Appropriate pre-analytic tissue handling is one of the keys to successful implementation of IHC-based and molecular assays in general.(3, 5) An ischemia time from tissue procurement to the initiation of fixation should be short (as short as possible), and biopsies should immediately be immersed in fixative for 6-48 hours. Of note, multiple tissue fragments in a biopsy sample (obtained from one lesion) may be submitted in a few tissue cassettes to avoid tissue exhaustion that is not infrequently seen when the single available tissue block is cut and used for multiple purposes. Neutral buffered formalin is historically the preferred and most common fixative used in the practice of histopathology.(6) Consequently, the majority of pathology laboratories typically perform the initial validation of IHC and molecular protocols on FFPE tissue. Decalcifying solutions used for bony specimens vary in their effects on retention and integrity of nucleic acids and proteins. Thus, results of IHC on decalcified specimens are unpredictable because of wide variations in specimen types and sizes, fixation time, and the particular solution(s) used.(7) Similarly, alcohol fixation used for cytology specimens, including alcohol-fixed cell blocks, decreases IHC accuracy by causing loss or decrease of immunogenicity when IHC protocols optimized with FFPE tissue samples are used.(8) For molecular assays, samples fixed with acidic solutions (including decalcifying salutations) and heavy metal fixatives are not recommended due to further degradation of nuclear acid and heavy metals hampering PCR reaction, respectively.(9) Thus, tissue sampling of a bone metastasis for this purpose should be avoided, if possible. In case the bone metastasis is the only accessible lesion for sampling, the pathologist may try to separate a soft tissue component submitted in the formalin. Up to 40% of advanced NSCLC patients are diagnosed by cytology alone. Cytology smears, cytospins and liquid-based cytology (LBC), processed from fine needle aspiration (FNA) or other modalities, are typically treated with alcohol-based solution or sprays devoid of exposure to formalin that leads to fragmentation of nuclear acids, thus often contain tumor cells with intact nucleic acid ideal for molecular testing. However, formalin-fixed paraffin-embedded (FFPE) cell blocks processed from the residual material from FNA or LBC or body fluid are the preferred samples for ancillary testing in many laboratories, since they can be handled in the same way as biopsy/resection specimens.(2) Tissue management To maximize small samples, the number of times when the tissue block needs to be cut for diagnosis, IHC and molecular testing should be minimized. It is because a decent amount of tissue is cut and wasted for trimming of the block at each round of sectioning. Thus, extra sections may be cut up front at the first cutting for diagnostic histology sections. Many pathology laboratories already have protocols in place per local requirements under close supervision by pathologists. It is also important that the pathologist is in close communication with oncologists and proceduralists to ensure that relevant clinical information is provided before sectioning is done. Diagnostic work-up between the lesion with high probability of a lung primary and a possible metastasis, and that between primary diagnosis and progression/recurrence after targeted therapy are often different, thus lack of the critical information may lead to unnecessary IHC. Last, but not least, the pathologist needs to evaluate tissue adequacy (tumor cellularity, the presence or absence of necrosis and tissue quality, etc.) before submitting samples for molecular testing. References: 1. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 8.2017 – July 14, 2017. 2. Bubendorf L, Lantuejoul S, de Langen AJ, et al. Nonsmall cell lung carcinoma: diagnostic difficulties in small biopsies and cytological specimens: Number 2 in the Series "Pathology for the clinician" Edited by Peter Dorfmuller and Alberto Cavazza. Eur Respir Rev. 2017;26(144). 3. Tsao MS, Hirsch FR, Yatabe Y. IASLC atlas of ALK and ROS1 testing in lung cancer. 2nd ed. Colorado: Editorial Rx Press; 2016. 4. Thunnissen E, Kerr KM, Herth FJ, et al. The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach of a working group. Lung Cancer. 2012;76(1):1-18. 5. Mino-Kenudson M. Programmed death-ligand 1 immunohistochemistry testing for non-small cell lung cancer in practice. Cancer. 2017;125(7):521-8. 6. Thavarajah R, Mudimbaimannar VK, Elizabeth J, et al. Chemical and physical basics of routine formaldehyde fixation. J Oral Maxillofac Pathol. 2012;16(3):400-5. 7. Fitzgibbons PL, Bradley LA, Fatheree LA, et al. Principles of analytic validation of immunohistochemical assays: Guideline from the College of American Pathologists Pathology and Laboratory Quality Center. Arch Pathol Lab Med. 2014;138(11):1432-43. 8. Zhou F, Moreira AL. Lung Carcinoma Predictive Biomarker Testing by Immunoperoxidase Stains in Cytology and Small Biopsy Specimens: Advantages and Limitations. Arch Pathol Lab Med. 2016;140(12):1331-7. 9. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med. 2013;137(6):828-60.

Abstract:
T4 lung cancers invading neighboring structures comprise a heterogenous group of locally invasive tumors. In a small subset of these localized tumors whose extrapulmonary invasion preceded any lymphatic extension, an adequate excisional procedure can achieve surprising long term survivals. The indications for such procedures and the anticipated outcomes should be weighed on a case by case basis, in terms of potential perioperative complications and expertise of the surgical team. Advanced surgical techniques are now being applied for T4 lesions due to improvements in surgery and anesthesiology and progress in combined treatment modalities. In the present staging, T4 tumors without mediastinal nodal metastasis are now considered to be potentially curable if complete resection is possible. A summary of the literature, under the light of personal experience allows a critical point of view, knowing that a surgical procedure which would not be reproducible in other centers would never be recognized as an option for practice. Therefore among the published series it is important to distinguish the real progress given by innovative techniques or procedures that could be applied throughout the world, even only in selected centers, from the simple reports of individual performances or exploits. Proximal tumors from the lower lobe may involve the atrial wall of the heart. In some cases a left atrial resection can be performed, followed by direct closure, or replacement of the atrial wall. Fukuse reported a series of 42 patients, from which left atrium was resected in 14 patients, Mortality rate was low (2.4%), regarding complexity of the procedures [1]. Low stages in nodal status were associated with increased survival (p = 0.0013). More recently was reported a series of 19 patients who underwent extended lung resection involving the left atrium without cardiopulmonary bypass [2]. An interatrial septum dissection is performed, thus increasing the length of the atrial cuff. R0 resections were observed in 89% of the patients. Ninety-day mortality rate was 16%. Five-year survival rate is 44%, and 3 patients (16%) are alive more than 6 years after surgery. Other reports advocate the use of cardiopulmonary bypass in these occasional situations [3-5]. Invasion of the superior vena cava (SVC) by a T4 non small cell lung c ancer (NSCLC) led surgical teams to attempt lobectomies or pneumonectomies extended to the vena cava [6]. Actually direct extension to the vessel by the tumor mass itself is a rare situation. SVC involvement generally results from a bulky disease, in which the nodal disease is the greatest component. The rationale of resecting SVC in N2 disease remains questionable, in view of the high potential of metastatic spread and the poor prognosis. Nevertheless, different techniques were proposed, including lateral clamping of SVC, partial, or total reconstruction. These procedures are associated with high morbidity rates. A multicentric international review of prosthetic replacement after SVC resection for nsclc in 28 patients (N2 involvement in 50%) showed morbidity and mortality rates of 39% and 14%, respectively. Overall 5-year survival rate was 15% [7]. Despite some reports who claim better survival rates, close to 50% at five years, the latter seems more realistic, and this warrants a thorough evaluation with the aim to preclude these patients from surgery in case of N2 involvement. A bronchial carcinoma extended to the tracheal bifurcation can be resected in selected patients [8]. A high rate of post-operative morbidity (10 to 30%), including bronchial dehiscences, jeopardizes the outcome, but long-term survivals have been observed in 15 to 23% of the cases. A meticulous mediastinal assessment is mandatory to eliminate invasion of the airway by a bulky disease. Only patients with T-invasion will be offered surgical resection. NNSCLC invading the thoracic inlet can easily penetrate spinal structures because of their particular anatomic situation. The best local control for resectable tumors is achieved by surgical operation, provided the resection is complete and respecting oncologic principles. Direct invasion of the vertebral body became an option following the first report in 1996 of a successful en bloc total vertebrectomy for lung cancer invading the spine [9]. Reported experiences from Europe, North-America and Asia demonstrate feasability and encouraging results of these challenging procedures, . Recently a comprehensive literature search, on a total of 1,001 abstracts and 93 articles found overall 5-year survival rates ranging from 37% to 59% and the mortality rate ranged from 0% to 6.9% [10]. Undoubtly enbloc resection for lung cancer invading the spine is reaching the stage of current practice in expert centers. This is probably due to a particular biology of these tumors which are peripheral and whose noisy symptoms lead to a relatively early diagnosis, thus permitting a high rate of complete resections. Evidence suggests that triple modality therapy with complete resection of locally advanced Pancoast tumors with involvement of the spine offers an advantage over other therapeutic modalities. Despite the absence of such an evidence in other T4 lung cancers, recent advances in patient's care and surgical techniques allowed surgeons to become more aggressive, and to propose occasionally extended resections with encouraging long-term survival rates to patients suffering from tumors invading the tracheal bifurcation, the left atrium, or the great vessels. The 8[th] edition of TNM classifies,T4N0-1 tumors in a "surgical" category, stage IIIA. 1. Fukuse T, et al. Extended operation for nsclc invading great vessels and left atrium. Eur J Cardiothorac Surg 1997;11:664–9 2. Galvaing G, et al. Left atrial resection for T4 lung cancer without cardiopulmonary bypass: technical aspects and outcomes.Ann Thorac Surg 2014;97:1708-13 3. Klepetko W, et al. T4 lung tumors with infiltration of the thoracic aorta: is an operation reasonable? Ann Thorac Surg 1999;67:340–4 4. De Perrot M, et al. Resection of locally advanced (T4) nsclc with cardiopulmonary bypass. Ann Thorac Surg 2005; 79:1691–6 5. Langer NB, et al. Outcomes after resection of T4 nsclc using cardiopulmonary bypass. Ann Thorac Surg 2016;102:902-10 6. Grunenwald DH. Resection of lung carcinomas invading the mediastinum, including the superior vena cava. Thorac Surg Clin 2004;14:255–63 7. Spaggiari L, et al. Superior vena cava resection with prosthetic replacement for nsclc: long term results of a multicentric study. Eur J Cardiothorac Surg 2002;21:1080–6 8. Mathisen DJ, Grillo HC. Carinal resection for bronchogenic carcinoma. J Thorac Cardiovasc Surg 1991;102:16−23 9. Grunenwald D, et al. Total vertebrectomy for en bloc resection of lung cancer invading the spine. Ann Thorac Surg 1996;61:723–6 10. Setzer M, et al. Management of locally advanced pancoast (superior sulcus) tumors with spine involvement. Cancer Control 2014;21:158-67