Virtual Library

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.

Abstract:
The Fleischner Society guidelines (most recently revised in 2017) [1,2] are the most referenced guidelines for management of pulmonary nodules detected incidentally on CT images. In 2014, the American College of Radiology produced the Lung-RADS assessment categories specifically to guide management of nodules detected by Low Dose CT screening for lung cancer [3]. Nodule management guidelines have also been published by the American College of Chest Physicians (ACCP) in 2013 [4] and the British Thoracic Society (BTS) in 2015 [5]. Whilst the Fleisher guidelines and Lung-RADS predominantly offer specific recommendations for interpretation of CT images and guidance for surveillance imaging, the ACCP and BTS guidelines in addition offer more proscriptive recommendations for ongoing investigation or treatment of larger nodules with PET-CT, biopsy techniques, and surgical/non-surgical treatment. There is much common ground between the four proposals. Most of the high quality evidence for nodule management comes from screening studies that only included patients at high risk of lung cancer, and there is an acknowledged paucity of evidence for guiding nodule management in patients with a lower background risk of cancer. There is agreement about the need to minimise radiation dose for CT surveillance for nodules, and an acknowledgement of the low likelihood of malignancy in small nodules detected through any route. All guidelines recognise that sub-solid nodules require a different management algorithm which incorporates a less interventional approach (acknowledging the more indolent nature of the tumours that these may represent) but by implication the need for longer follow-up before nodules can be deemed benign or harmless. Differences between the recommendations are summarised in Table 1. The size below which nodules can be ignored differs slightly between the guidelines. Lung-RADS recommends no intervention for nodules <6mm (or <4mm for new nodules) on the assumption that the patient continues with annual LDCT screening. Determining a threshold for discharge of small nodules detected out a screening program is of potentially greater significance, as a patient with a small malignant nodule discharged in this context is likely to have a poor outcome if that nodule subsequently presents as a symptomatic lung cancer. The Fleischner Society guidelines select a threshold of 1% lung cancer risk (roughly equating to 6mm diameter) below which surveillance is not routinely recommended (although is an option if the patient is high risk). The BTS guidelines base their discharge threshold of 80mm­[3] (5mm) on data from the NELSON screening trial which demonstrated this to be the threshold below which the presence of a nodule did not appear to increase the likelihood of subsequently diagnosed lung cancer above that seen in screening participants with no nodules [6]. More recent data from NELSON has suggested a different size threshold for nodules newly appearing during the screening process. New incident nodules above 27mm[3] appeared to confer an increased risk of cancer [7], and this is reflected in the Lung-RADS category 3 which suggests a 6 month surveillance scan for new incident nodules ≥4mm. When an incidentally detected nodule can be shown to be new compared to recent CT imaging, a lower threshold for ongoing surveillance is probably merited, although not currently recommended in the three relevant guidelines. The use of composite risk-prediction scores in guiding nodule management differs between the various guidelines. The Fleischner guidelines highlight the various risk factors to be considered when deciding management but do not recommend use of a risk prediction score. The ACCP guidelines recommend either qualitative assessment of the probability of malignancy, or quantitative assessment using a validated model (referencing the Mayo model [8]). The BTS guideline recommend use of the Pancan lung cancer risk calculator [9] to decide which nodules should be evaluated with PET-CT on the basis of a validation study in a UK population [10]. Subsequent studies from Australia and Denmark have also demonstrated the utility of the Pancan model in screening studies. The guidelines also differ in the extent to which they promote use of semi-automated volumetry. No reference to volumetry is made in Lung-RADS assessment categories. Both the Fleischner and BTS guidelines acknowledge the better reproducibility of volumetry over diameter measurements and the superior sensitivity in detecting growth. Both however highlight the need to use identical software versions if comparing nodule volumes between scans due to clearly demonstrated variability between different software programs/versions. The Fleischner guidelines comment that robust validated volumetry is not currently widely used hence continuing to base recommendations predominantly on caliper long and short-axis diameter measurements, whereas the BTS guidelines have strongly recommended volumetry in an attempt to drive uptake of this technology. The definition of what constitutes nodule growth also differs between the guidelines. Lung-RADS and the Fleischner guidelines define growth as an increase is diameter of >1.5mm and ≥2mm respectively, reflecting possible inaccuracy in smaller increments in size according to caliper measurements. The threshold of 25% change in volume recommended in the BTS guideline is based on the nodule management stategy used in both NELSON and UKLS. By way of comparison, nodule growth from 7mm to 9mm represents a 113% increase in volume (from 180mm[3] to 381mm[3]). All four guidelines/assessment categories have been published within the last 5 years, and there have been few validation studies published to date. Lung-RADS was compared to the National Comprehensive Care Network guidelines for lung cancer screening and was shown to increase the positive predictive value without increasing false-negative results. Prospective comparisons between these guidelines/approaches are needed to guide future practice.

	Fleischner [1,2]	Lung-RADS [3]	BTS [4]	ACCP [5]
Remit	Incidentally detected nodules	Screen-detected nodules	Incidentally and screen-detected nodules	Incidentally and screen-detected nodules
Assessment of size	Average of long & short axis diameter	Average diameter	Semi-automated volumetry	As per Fleischner guidelines
Threshold for discharge	<6mm - optional follow-up below this size if high risk	<6mm (revert to annual screen)	<80mm[3]	<5mm - optional follow-up below this size if high risk
Selection of further investigation for larger nodules	>8mm consider PET, PET-CT or biopsy	≥8mm PET-CT, biopsy or assess with Brock/Pancan score	≥8mm Brock/ Pancan score to guide PET-CT/other tests	≥8mm clinical judge-ment or validated model (e.g. Mayo)
Assessment of growth	Increase in size of ≥2mm	Increase in size of >1.5mm	Increase in volume of >25%	Not specified
Pure Ground Glass Nodules	Surveillance only for 5 years duration	Revert to annual screen (unless >20mm)	Risk assess, but surveillance pref-erred (for 4 years)	CT surveillance for 3 years

Table 1: Summary of significant differences between nodule management strategies recommended by various guidelines/assessment categories Fleischner [1,2] Lung-RADS [3] BTS [4] ACCP [5] Remit Incidentally detected nodules Screen-detected nodules Incidentally and screen-detected nodules Incidentally and screen-detected nodules Assessment of size Average of long & short axis diameter Average diameter Semi-automated volumetry where possible As per Fleischner guidelines Threshold for discharge <6mm - optional follow-up below this size if high risk <6mm (revert to annual screen) <80mm3 <5mm - optional follow-up below this size if high risk Selection of further investigation for larger nodules >8mm - consider PET, PET-CT or biopsy ≥8mm - PET-CT, biopsy or assess with Brock/ Pancan score ≥8mm - Brock/ Pancan score to guide PET-CT/other tests ≥8mm - clinical judgement or validated model (e.g. Mayo) Assessment of growth Increase in size of ≥2mm Increase in size of >1.5mm Increase in volume of >25% Not specified Pure Ground Glass Nodules Surveillance only for 5 years duration Revert to annual screen (unless >20mm) Risk assess, but surveillance preferred (for 4 years) CT surveillance for 3 years References [1] MacMahon H, Naidich DP, Goo JM, et al. Guidelines for Management of incidental pulmonary nodules detected on CT images: from the Fleischner Society 2017. Radiology 2017;284:228-243 [2] Bankier AA, MacMahon H, Goo JM, et al. Recommendations for measuring pulmonary nodules at CT: a statement from the Fleischner Society. Radiology 2017, epub ahead of print. [3] American College of Radiology. Lung CT Screening Reporting and Data System (Lung-RADS). Available at : https://www.acr.org/Quality-Safety/Resources/LungRADS . Release date April 28, 2014, Accessed August 1, 2017. [4] Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e93s-e120S. [5] Callister ME, Baldwin DR, Akram AR, et al. British Thoracic Society guidelines for the investigation and management of pulmonary nodules. Thorax 2015;70:ii1-ii54 [6] Horeweg N, van Rosmalen J, Heuvelmans MA, et al. Lung cancer probability in patients with CT-detected pulmonary nodules: a pre-specified analysis of data from the NELSON trial of low-dose CT screening. Lancet Oncol. 2014;15:1332–41. [7] Walter JE, Heuvelmans MA, de Jong PA, et al. Occurrence and lung cancer probability of new solid nodules at incidence screening with low-dose CT: analysis of data from the randomised, controlled NELSON trial. Lancet Oncol. 2016;17:907-16. [8] Swensen SJ, Silverstein MD, Ilstrup DM, et al. The probability of malignancy in solitary pulmonary nodules. Application to small radiologically indeterminate nodules. Arch Intern Med 1997;157:849–55. [9] McWilliams A, Tammemagi MC, Mayo JR, et al. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med 2013;369:910–9. [10] Al-Ameri AMP, Malhotra P, Thygesen H, et al. Risk of malignancy in pulmonary nodules: a validation study of four prediction models. Lung Cancer 2015;89:27-30

Abstract:
Marked heterogeneity exists in clinical, radiologic, molecular, and pathologic features among adenocarcinoma cases. Therefore, a new Classification of Lung Adenocarcinoma was proposed by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society in 2011 (1). The 2011 classification addressed three important weaknesses in the previous classification. First, it eliminated the term bronchioloalveolar carcinoma (BAC). Second, it added new terminologies of carcinoma-in-situ (CIS), and minimally invasive adenocarcinoma (MIA) to recognize that minimal invasion (< 5mm) had nearly similar clinical outcome as noninvasive nodules. Third, it replaced the terminology of mixed subtype of adenocarcinoma. In this revised classification, invasive lung ADCs were divided into the five subtypes; lepidic, acinar, solid, papillary, and micropapillary patterns primarily based on histologic features. The term predominant is appended to all categories of invasive ADC, as most of these tumors consist of mixtures of the subtypes (1). The widespread availability of MDCT and abundance of new information obtained especially from low-dose CT lung cancer screening programs, have increased our understanding of the types and management of small peripheral lung nodules encountered in daily clinical practice, in particular, the importance and prevalence of subsolid pulmonary nodules (atypical adenomatous hyperplasia (AAH), ground glass nodules (GGN) and part-solid nodules). Thin-section CT has emerged as a new biomarker for lung adenocarcinoma subtypes. The approval of CT as a screening tool for lung cancer was based primarily on National Lung Screening Trial (NLST) results. The NLST recently found that Low Dose Helical Computed Tomography (LDCT) reduces lung cancer specific mortality by 20% relative to chest x-ray screening in a cohort at high risk of lung cancer (2). However, significant concerns remain regarding its high false positive rate, overdiagnosis, cost effectiveness and concerns related to radiation burden from repeat CT screens. There is a trade-of between early detection of lung cancer vs unnecessary work-up of indeterminate nodules resulting in many side effects including anxiety, radiation exposure from CT follow-up to assess for growth, cost and morbidity and mortality related to biopsy or resection of a benign nodule. It is expected that false positive rate would decrease by 50% using more accurate phenotyping of a nodule using the lung CT reporting and data system (Lung-RADS) appropriately (3). One of the major changes proposed in Lung-RADS is the size threshold for positive screen, from 4 mm in NLST to 6 mm for solid nodules and 20 mm for nonsolid nodules. Tissue sampling would be used primarily for larger than 15 mm solid nodules or PET positive nodules with larger than 8 mm solid component. False positive rate would still be likely not acceptable for an individual using this approach. There is need for more accurate nodule assessment and risk stratification as given our current understanding that genetic make-up of a nodule is the ultimate determinant of clinical outcome (4). Further improvements in stage discrimination and management of lung nodules could be expected in the future, as more robust data related to texture analyses of tumors, their genetic profiles and impact of those on clinical outcome becomes available (5-8). Simple measuring the tumor size with one-dimentional (Response Evaluation Criteria in Solid Tumors (or RECIST) long-axis measurements do not reflect the complexity of tumor morphology or behavior. Also, it may not be predictive of therapeutic benefit. In contrast, the emerging field of radiomics is a high-throughput process in which a large number of shape, edge, and texture imaging features are extracted, quantified, and stored in databases in an objective, reproducible, and mineable form. Once transformed into a quantifiable form, radiologic tumor properties can be linked to underlying genetic alterations and to medical outcomes. Marked heterogeneity in genetic properties of different cells in the same tumor is typical and reflects ongoing intratumoral evolution. Clinical imaging is well suited to measure temporal and spatial heterogeneity. Subjective imaging descriptors of cancers are inadequate to capture this heterogeneity and must be replaced by quantitative metrics that enable statistical comparisons between features describing intratumoral heterogeneity and clinical outcomes and molecular properties. A recent study adds further support toward taking a conservative approach in the management and treatment of patients with part-solid nodules especially when the solid component is small. This strategy is already reflected in the Lung-RADS guidelines, which recommend focusing on the size of the solid component in the part-solid nodule instead of on the overall nodule size. For the future, the critical issue will be further refinements for the follow-up of nonsolid and part-solid nodules based on the size or volume that allow a process of shared decision making in selecting appropriate management and treatment (9-10). This lecture will address the radiologic implications of this new lung adenocarcinoma classification. References: 1. Travis W, Brambilla E, Noguchi M, et al. IASLC/ATS/ERS International multidisciplinary classification of lung adenocarcinoma. J Thoracic Oncol 2011;6:244-285 2. Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409 3. American College of Radiology: Lung-RADS Version 1.0 Assessment Categories Release date: April 28, 2014. Accessed on 17 March, 2015 4. McWilliams, A. et al. Probability of cancer in pulmonary nodules detected on first screening CT. The New England journal of medicine 2013;369: 910-919, doi:10.1056/NEJMoa1214726 5. Lambin P, et al. Radiomics: extracting more information from medical images using advanced feature analysis. Eur J Cancer 2012;48 (4):441-446 6. Gatenby RA, Grove O, Gillies RJ. Radiology 2013;269:8-15 7. Bartholmai BJ, Koo CW, Johnson GB, et al. Pulmonary nodule characterization including computer analysis and quantitative features. J Thorac Imaging 2015;30 (2) 139-156 8. Song SH, Park H, Lee G, et al. Imaging phenotyping using Radiomics to predict micropapillary pattern within lung adenocarcinoma. JTO 2017;12:624-632 9. Rowena Yip, Henschke CI, Xu DM, et al. Lung cancers manifesting as part-solid nodules in the National Lung Screening Trial. AJR 2017;208:1011-1021 10. American College of Radiology website. Lung CT Screening Reporting and Data System (Lung-RADS). Accessed January 11, 2016 11. MacMahon H, Naidich DP, Goo JM, et al. Guidelines for management of incidental pulmonary nodules detected on CT images: FROM THE Fleischner Society 2017. Radiology 2017;284:228-243

Abstract:
Recent advances molecular target therapies have provided a remarkable benefit to patients harboring specific genetic alterations. Most patients treated against molecular targets eventually develop resistance even after initial dramatic response. T790M mutation is a major mechanism for clinical failure in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. Osimertinib has been recently approved and demonstrated dramatic response in NSCLC patients with T790M mutation. In tumors with anaplastic lymphoma kinase (ALK) or ROS-1 rearrangement, cereitinib has been approved and recommended in case of crizotinib resistance. Therefore, clinical demand for rebiopsy to identify these druggable mutations has been increasing, and rebiopsy plays an important role in clinical application for exploring resistant mechanisms and determining further therapeutic strategies. This session will focus on rebiopsy issues in relapsed NSCLCs. We will describe the growing need for rebiopsy and review the current data about rebiopsy, both published and unpublished. We will discuss the technical aspects of interventional radiology-guided rebiopsy; patient selection, guiding-modalities, lesion targeting, and tissue sampling. Hurdles and solutions for rebiopsy will be discussed with appropriate examples. Current role of liquid biopsy in comparison with conventional tissue biopsy will be briefly covered. Finally, we will discuss how to collaborate more effectively as a lung cancer multidisciplinary team from radiologists’ perspective.

Abstract:
Since magnetic resonance imaging (MRI) was introduced for the assessment of thoracic and lung diseases, various limitations. However, from 2000, various techniques have been demonstrated their utility for lung cancer evaluations, and is now covered by health insurance in many countries including North America, Eastern Asia and Europe. In this lecture, I will show you these recent advances in lung MRI focusing on its application in lung cancer evaluation, especially with regard to 1) pulmonary nodule detection, 2) pulmonary nodule and mass assessment, and 3) lung cancer stage and recurrence evaluations.

Background:
Malignant pleural mesothelioma (MPM) is a rare and highly aggressive malignancy with poor prognosis and limited treatment options beyond progression after platinum-based combination with pemetrexed chemotherapy. Nivolumab (anti-PD-1, ONO-4538, BMS-936558), a humanized monoclonal antibody, PD-1 immune-checkpoint inhibitor, has demonstrated antitumor activity and a manageable safety profile in several advanced malignancies. Here, we report the preliminary results of a phase II study to evaluate the efficacy and safety of Nivolumab in previously treated Japanese MPM patients (pts): ONO-4538-41/JapicCTI-No.163247.

Method:
This open-label study enrolled advanced or metastatic MPM pts previously treated with up to two regimens of chemotherapy including platinum-based combination therapy with pemetrexed. Enrollment criteria also included histologically-confirmed, unresectable MPM without prior surgery, measurable disease and ECOG performance status 0-1. There was no restriction of PD-L1 status. Pts received Nivolumab 240 mg flat dose Q2W until progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) (modified RECIST by independent review committee, expected response rate was 19.2%); secondary endpoints included disease control rate (DCR), duration of response, progression-free survival (PFS), and overall survival (OS).

Result:
From July to October 2016, 34 pts were enrolled in 15 centers. Males: 85.2%, median age: 68.0 years (range 43-78), PS 1: 61.8%, epithelial/sarcomatoid/biphasic: 79.4%/8.8%/11.8%, 1 prior regimen: 70.6%. Median follow-up was 6.7 months. Independent review committee-assessed 6-month ORR was 29.4% (n=10, 95%CI: 16.8-46.2) and objective responses were observed across tissue types, epithelioid 7/27 (25.9%), sarcomatoid 2/3 (66.7%), biphasic 1/4 (25.0%). 13 pts (38.2%) had stable disease, resulting in a 6-month DCR of 67.6%. Median PFS was 6.1 months (95%IC: 2.9-NR). Median OS has not been reached. 6-month PFS and OS rates are 50.9% (95%CI: 32.7-66.5) and 85.3% (95%IC: 68.2-93.6). 23 (67.6%) pts experienced drug-related adverse event (DRAE), and 7 (20.6%) experienced grade 3/4 DRAEs. 2 pts required dose discontinuation because of pneumonitis (Grade2 and 3).

Conclusion:
Single-agent Nivolumab has significant activity in 2[nd]/3[rd] line MPM pts and met the primary endpoint, suggesting that Nivolumab has a potential to be a new therapeutic option for MPM.

Background:
The anti-CTLA-4 tremelimumab as monotherapy showed initial signs of activity in second-line malignant mesothelioma (MM) patients (Calabrò et al., Lancet Oncol, 2013; Calabrò et al., Lancet Respir Med, 2015), though it failed to improve the overall survival (OS) of second or third line mesothelioma patients compared to placebo in the DETERMINE study (Maio et al., Lancet Oncol, in press). These results and the efficacy of targeting the PD-1/PD-L1 axis in a variety of tumor types, prompted the NIBIT-MESO-1 study aimed at investigating the activity and safety of tremelimumab combined with the anti-PD-L1 durvalumab in MM patients. Here, we report conclusive efficacy and safety analysis from the fully-enrolled NIBIT-MESO-1 study.

Method:
The NIBIT-MESO-1 is a phase II, open-label, single Center study. Forty MM patients received tremelimumab at 1 mg/Kg i.v. every 4 weeks (Q4W) for 4 doses, and durvalumab at 20 mg/Kg i.v. Q4W for 13 doses. Primary objective is immune-related (ir)-objective response rate; secondary are ir-disease control rate, ir-progression free survival, OS, and safety. Tumor assessment per ir-modified RECIST or ir-RECIST 1.1 for pleural or peritoneal MM, respectively, was performed at baseline and q12 weeks. Adverse events (AEs) were recorded according to CTC v4.0.

Result:
From October 2015 to October 2016, 40 MM patients (38 pleural and 2 peritoneal), median age 64 years (range 41-80), ECOG performance status 0 (n = 19) or 1 (n = 21) were enrolled in the study. MM histology was epithelioid (n = 32), biphasic (n = 5), sarcomatoid (n = 2) or undefined (n = 1). As of April 2017, 12 first or 28 second-line MM patients received a median of 6 doses of therapy (range = 1-13). Ten ir-objective responses (9 confirmed) were observed (25%), and 25 patients reached an ir-disease control rate (62.5%). The median OS was not reached with a median follow-up of 9.5 months (inter-quartile range: 6.2-12.5 months). Thirty patients (75%) experienced any grade irAEs: grade 1-2 irAEs were observed in 67.5% and grade 3-4 irAEs in 17.5%. AEs were generally manageable and reversible per protocol guidelines.

Conclusion:
These data suggest that the combination of tremelimumab and durvalumab is active, with a good safety profile in MM patients, and warrant further exploration. Clinical trial information: .

Background:
Nintedanib is a triple angiokinase inhibitor. LUME-Meso (NCT01907100) is a randomised, Phase II/III study of ≤6 cycles of nintedanib+pemetrexed/cisplatin versus placebo+pemetrexed/cisplatin, followed by nintedanib or placebo maintenance, in chemo-naïve patients with MPM. In Phase II results, nintedanib+pemetrexed/cisplatin improved progression-free survival (PFS) versus control (hazard ratio [HR]=0.54; p=0.010), with a trend for prolonged overall survival (OS; HR=0.77; p=0.319). Benefit was most pronounced in patients with epithelioid tumours. Since no pharmacodynamic/predictive biomarkers are validated for anti-angiogenic therapies, exploratory analyses were conducted to investigate potential associations of plasma-derived angiogenic factors and genomic markers with treatment outcome in the LUME-Meso Phase II epithelioid population.

Method:
Blood samples were collected at baseline and, for patients receiving maintenance, at monotherapy Cycle 3 (C3mono) and end of monotherapy (EoTmono). Analyses focused on 58 angiogenic factors (Human AngiogenesisMAP[®] panel, Myriad RBM) and single-nucleotide polymorphisms (SNPs) in genes implicated in mesothelioma and/or associated with response to anti-angiogenic therapies in other tumour types (VEGFR1, VEGFR3 and mesothelin). Associations of biomarkers with treatment effect were evaluated by Cox regression and tested for interaction with false discovery rate (FDR) adjustment. Adjusted mean changes in angiogenic factor levels were compared between arms by ANCOVA. Analyses were exploratory, limited by small sample size, and considered hypothesis generating.

Result:
Of 77 patients with epithelioid tumours, angiogenic factor and genomic data were available for 71 and 67 patients, respectively. PFS/OS benefit of nintedanib appeared potentially more pronounced in patients with baseline plasma endoglin level below the median. There were possible weak associations between major homozygous genotypes for two VEGFR3 SNPs (rs307821 G/G and rs307826 A/A), and OS benefit and between VEGFR1 SNP rs9582036 A/A genotype and PFS benefit. Biomarker treatment associations were limited by small subgroup size, especially for low-frequency SNPs, and interaction tests were not significant after FDR adjustment. Regarding pharmacodynamic effects, adjusted mean change in interleukin-8 levels with nintedanib was greater from baseline to C3mono and lower from C3mono until EoTmono, compared with placebo. Nintedanib showed lower adjusted mean changes versus placebo for VEGFR2 from baseline to C3mono, and for VEGFR2 and VEGFR3 from baseline to EoTmono.

Conclusion:
These analyses represent the first biomarker results for nintedanib-treated MPM. While there seemed to be signals for greater PFS and OS improvement in patients with low plasma endoglin and major homozygous VEGFR1/3 genotypes, no biomarkers showed clear significant association with treatment benefit. These findings warrant further evaluation in the Phase III study.

Abstract not provided

Background:
Malignant pleural mesothelioma is a difficult to treat asbestos-driven cancer that is on the increase globally. The urea cycle and tumor suppressor enzyme argininosuccinate synthetase 1 (ASS1), involved in arginine synthesis, is downregulated in half of mesotheliomas which are then sensitive to arginine deprivation therapy. Trials of the arginine depletor pegylated arginine deiminase, ADI-PEG20, have confirmed single-agent and combination safety and efficacy in patients with mesothelioma. Here, we explored the immunometabolic consequences of ASS1 loss in mesothelioma uncovering a role for combining ADI-PEG20 with PD1/PD-L1 checkpoint blockade.

Method:
Three ASS1-negative and one ASS1-positive MPM cell lines were assessed for PD-L1 expression by real-time quantitative PCR, western blot and FACS analysis. Cell lines were manipulated for ASS1 overexpression (endogenous and genetic) and siRNA followed by gene expression analysis. Cell lines were cultured with and without ADI-PEG20 and assessed for PD-L1 expression and cytokine production by ELISA. An immunocompetent murine tumor model of ASS1 loss mimicking aggressive mesothelioma was treated with PBS control, ADI-PEG20, anti-PD-1 antibody, and ADI-PEG20 plus anti-PD-1 antibody. Tumors were harvested and analysed for immune cell subsets by FACS. Finally, human mesothelioma biopsies from trials of ADI-PEG20 were analyzed for ASS1 and PD-L1 and immune cell subsets.

Result:
PDL1 protein was absent in the three ASS1 negative MPM cell lines but was present in the ASS1 positive cell line. Transfection of ASS1 in the ASS1 negative MPM cell lines led to an increase in PD-L1 expression, which was reversible following ASS1 knockdown. Induction of PD-L1 expression by forced ASS1 overexpression was accompanied by an increase in interferon type I signaling. Similar results were obtained in a mesothelioma cell line developing resistance to ADI-PEG20 under long-term culture. Next, ADI-PEG20 treatment triggered release of interferon-alpha/beta which induced PD-L1 expression by 24hrs in the ASS1-negative MPM cell lines before declining by 48hrs. Analysis of MPM biopsies of patients progressing on ADI-PEG20 revealed upregulation of ASS1 and a concomitant increase in tumoral PD-L1 and CD3 positive T cells. ADI-PEG20 synergized with PD-1 blockade in the immunocompetent murine tumor model that was refractory to PD-1 inhibition.

Conclusion:
ASS1 and ADI-PEG20 modulate PDL1 expression via type I interferon signaling in malignant mesothelioma cell lines. Arginine deprivation with ADI-PEG20 combined with PD-1 blockade is synergistic and warrants further exploration in the clinic. A phase 1 trial of ADI-PEG20 combined with PD1 blockade is planned in patients with ASS1-negative cancers, including malignant mesothelioma.

Background:
Malignant pleural mesothelioma (MPM) is a disease with an almost invariably fatal diagnosis with limited therapeutic options. Characteristic patterns of deregulated microRNA expression have been demonstrated in MPM, and many downregulated microRNAs have been shown to have tumour suppressor activity. However, apart from silencing of miR-34b/c by promoter hypermethylation and co-deletion of miR-31 with the CDKN2A locus, the mechanisms responsible for downregulation of other tumour suppressor miRNAs such as miR-16 are yet to be elucidated.

Method:
Tumour samples (n=60) were from MPM patients undergoing extrapleural pneumonectomy, and samples of pleura (n=23) collected from patients undergoing cardiac surgery were used as normal controls. MPM cells lines were obtained from the ATCC. Expression levels of mature microRNAs in MPM tumour samples and cell lines, and pri-miRs and miRNA host genes in cell lines, were determined by RT-qPCR. Copy number variation (CNV) was analysed by droplet digital PCR (ddPCR), and methylation was inferred by miRNA expression following decitabine treatment. MYC was analysed by Western blot, and expression modulated by siRNAs.

Result:
Analysis of microRNA expression in tumour samples revealed a consistent and significant downregulation of miR-15a (4-fold, P<0.01), 15b (10-fold, P<0.01), 16 (22-fold, P<0.05), 34a (1.6-fold, P<0.05), 34b (1.8-fold, P<0.01), 34c (2.3-fold, P<0.0001) and 193a (3.1-fold, P<0.001) compared with normal pleura. Copy number variation analysis showed evidence of heterozygous loss for miR-193a (4 of 5 cell lines) and miR-15a/16-1 (2 of 5), but no change in miR-15b/16-2. Treating cell lines with the demethylating agent decitabine resulted in dramatic upregulation only in the case of miR-34c. RNAi-mediated knockdown of c-MYC led to upregulation of miR-15b and 16, and to a lesser extent miR-15a, as well as a consistent increase in the miR-15b/16-2 host gene SMC4 and the miR-15a/16-1 host gene DLEU2. Analysing the expression of these microRNAs in the tumour samples revealed a strong correlation between miR-15b and 16 (R[2]=0.793) and miR-34b and 34c (R[2]=0.753), but not between others.

Conclusion:
Our data suggest that a combination of deletion, hypermethylation and transcriptional regulation contribute to the downregulation of miR-15a/b, 16, 34a/b/c and 193a. In MPM, unlike other cancers, the downregulation of miR-15a/16-1, miR-15b/16-2 appears to be due to transcriptional changes rather than deletion or promoter hypermethylation. MYC appears to contribute to miR-16 downregulation primarily via control of SMC4 and the miR-15b/16-2 locus, suggesting that the transcriptional control of miR-16 expression by c-Myc contributes to the malignant phenotype of MPM.

Background:
Malignant pleural mesothelioma (MPM) is characterized by aggressive growth, limited therapeutic options and rapid recurrence following treatment. A better understanding of biological factors underlying MPM aggressiveness offers the chance to improve therapeutic strategies. Growth factors of the TGF-beta superfamily including TGF-beta itself, activins and BMPs have been repeatedly linked to MPM growth. In the current study, we focus on the role of Smad7, a key intracellular antagonist of TGF-beta and activin signaling, in MPM.

Method:
A panel of 17 human MPM cell lines was screened for tumorigenicity in SCID mice. Comparative genomic hybridization and whole genome gene expression arrays were used for identification of genes correlating with tumorigenicity. Immunoblotting and qPCR were used to detect Smad7 expression levels in cell lines. For ectopic overexpression of Smad7 in MPM cells, a retroviral expression system was used. Various in vitro assays, immunoblotting and reporter gene assays were employed to characterize the effect of Smad7 overexpression on MPM cell proliferation, migration, signal transduction and drug response.

Result:
When human MPM cell lines were dichotomized into tumorigenic ones and non-tumorigenic ones based on their ability to form tumors in SCID mice, loss of Smad7 was one of the most conspicuous associations with tumorigenicity identified in CGH arrays. The tumorigenic group also showed a reduced Smad7 transcript expression in gene expression microarrays. Based on these data we screened a larger panel of MPM cell lines for Smad7 mRNA and protein expression and identified cell lines with high, medium and low Smad7 expression. We generated a retroviral expression construct and established an isogenic subline overexpressing Smad7 from the MPM cell line VMC33 that shows low endogenous Smad7 expression. Compared to parental VMC33 cells or VMC33-RFP cells, which overexpress red fluorescent protein and were used as control, VMC33-Smad7 cells showed a reduced growth rate and diminished clone forming capacity in vitro. VMC33-Smad7 also showed reduced cell migration, but no difference in invasion could be detected. Since Smad7 was described as antagonist of TGF-beta, we tested its effect on TGF-beta signaling with a reporter gene assay and indeed found a blunted response to TGF-b in Smad7 overexpressing cells. With respect to sensitivity against kinase inhibitors targeting TGF-beta receptors, VMC33-Smad7 showed a decreased response to galunisertib and SB-431542 compared to VMC33-RFP.

Conclusion:
Taken together, these data suggest that Smad7 may have a growth limiting function in MPM, possibly by antagonizing growth-promoting TGF-beta and/or activin signals.

Abstract not provided

Background:
The treatment of localized malignant pleural mesothelioma (MPM) involves multimodality therapy, however, there is no standard of care with respect to operative procedure and timing of chemotherapy. We analyzed data from a single institution to identify whether the use of pemetrexed-platinum neoadjuvant chemotherapy impacts survival.

Method:
Patients with histologically-proven MPM who had surgery from 1996 to 2016 were identified. Follow-up was complete for a median of 24 months. Survival was calculated from time of diagnosis to last follow up or death. Univariate and multivariate Cox proportional hazards were used.

Result:
From 1996 to 2016 we identified 376 patients. Mean age was 66+/-8 years and 54 (14%) were female. There was no difference in survival for pleurectomy/decortication or extrapleural pneumonectomy. Neoadjuvant chemotherapy significantly improved survival compared to surgery followed by chemotherapy (table 1). Multivariate analysis was significantly associated for increased survival for epithelioid histology, T-status, node positivity, and neoadjuvant chemotherapy (table 2).

Table 1. Univariate Analysis

Variable	(n)	Median survival (mo.)	P value
Gender	Male (322) Female (54)	13.6 17.2	P=0.043
Histology	Epithelial (252) Mixed (91) Sarcomatoid (26)	18.3 12.1 6.5	P<0.0001
T stage	T 1-2 (33) T 3-4 (343)	42.6 14.3	P=0.0002
N status	N 0 (129) N 1-2 (113)	23.1 11.3	P<0.0001
Neoadjuvant chemotherapy	Yes (153) No (223)	19.8 11.3	P<0.0001

Table 2. Cox Proportional Hazards Model

Covariate	Hazard Ratio	95% CI	p-value
Histology (ref: Epithelioid) Biphasic Sarcomatoid	ref 1.66 4.24	[ref] [1.17-2.36] [1.77-10.1]	ref 0.005 0.001
T-status 3-4 vs 1-2	3.07	[1.32-7.15]	0.009
Node-positivity	1.93	[1.40-2.66]	<0.001
Neoadjuvant chemotherapy	0.65	[0.47-0.91]	0.011

Cox proportional hazards model including histology, t-status, n-status, and neoadjuvant chemotherapy C-index: 0.69

Conclusion:
Our results suggest that neoadjuvant chemotherapy increases survival and likely enhances the complete resection rate. These data are being evaluated in a multi-institutional cohort of five major mesothelioma programs in North America to improve guidelines for mesothelioma therapy.

Background:
Tumor volumetrics is currently being explored as a means of enhancing the accuracy of clinical staging of malignant pleural mesothelioma (MPM). In a recent multicenter study (JTO 2016, 11(8):1335-1344) evaluating feasibility of volume estimation using CT (VolCT), clinical staging by CT was poorly correlated between readers and underestimated pathological stage, but correlation of VolCT estimates between two experienced readers was high (rho = 0.82). MR has been found superior to CT in evaluating certain staging parameters, and may enhance volumetrics based on improved contrast. Here we evaluate the relative performance and reproducibility of MR for volumetrics (VolMR) and clinical staging of MPM in a single institution cohort.

Method:
Patients with MPM who underwent surgical resection between 2009 and 2014 with preoperative CT and MR imaging were studied. MR images were acquired using a uniform clinical protocol. VolMR was performed independently by two observers, one an experienced radiologist and one fellow. Vitrea (Vital Images) software was used for volumetric calculations and estimates were compared using Spearman correlation. Clinical staging accuracy (AJCC 7[th] edition criteria; versus pathological stage) and interobserver variability were also evaluated. VolMR and VolCT were performed for all cases by the experienced radiologist and qualitatively compared.

Result:
The study cohort comprised 139 patients, 113 (81%) men, median age 68 (30-82), with 74 (53%) epithelioid subtype tumors. Pathological stage was I: 14 (10%); II: 16 (12%); III: 75 (54%); IV: 34 (24%). Clinical staging by MR was concordant between reviewers for 86 (62%) cases, and with pathological stage for 65 (47%) and 63 (45%) respectively. VolMR was significantly correlated both between reviewers (rho = 0.99) and with VolCT (rho = 0.68). VolMR tended to result in higher volume estimates (median 633, IQR 365-885 cc) than VolCT (median 239, IQR 75-597 cc).

Conclusion:
VolMR was found to be feasible and reproducible, independent of observer experience. Clinical AJCC staging by MR was found to compare favorably to staging by CT in terms of both interobserver variablilty and prediction of pathological stage. Although MR is not yet universally available and has the disadvantages of higher cost, requirement for optimization and longer scan times, it may neverthheless offer improved accuracy and reproducibility of clinical staging and volumetric analysis. Further evaluation in larger multi-institutional cohorts is warranted.

Abstract not provided

Abstract:
The history of global tobacco control starts at the beginning of the twentieth century with early data linking the smoking of tobacco with the risk of lung cancer, a previously rare disease. The build up of scientific evidence for the link gained pace toward the middle of century when landmark publications brought more widespread recognition of the phenomenon[1][,][2]. The pivotal US Surgeon General Report from 1964 gave a clear message that tobacco smoking was unequivocally associated with an increased risk of developing lung cancer[3]. Over the following decades the paradigm of tobacco control recognizable today culminated in the development the first global public health treaty, the World Health Organization Framework Convention on Tobacco Control (WHO FCTC), which came into force in 2005 and currently lists 181 countries as Parties to the Convention[4]. In 2008, the FCTC launched the MPOWER measures (Table 1.), six steps proven to lead to reduction in tobacco use around the world[5] and that provide the ability to benchmark the effects of tobacco control strategies between countries[6]. In countries with robust implementation, these measures have achieved what may have once been unthinkable, the saving of millions of lives[6] and the reduction in smoking rates to historic post-WWII lows[6]. There have been enormous benefits, with a reduction in cigarette consumption, altered rates of disease and a reduction in smoking uptake. But the inconsistencies in regulation and in MPOWER implementation around the world have led to problems with the shifting of tobacco industry efforts to the developing world[7], the targeting of vulnerable groups for new market share[7] and the entrenchment, in some countries, of the tobacco industry in the halls of government. New threats to global tobacco control are starting to appear from the impacts of globalization of trade[7], newer products whether “low-harm” or otherwise and from focused, covert attacks by the tobacco industry itself. This presentation aims to review the development and impact of current tobacco control policy, to examine emerging threats to tobacco control, to focus on evasive manoeuvres of the globalizing tobacco industry and to discuss possible future tobacco control strategies that these developments will require. Over the last half century the tobacco industry in the developed world has become globalized. Four companies have come to dominate the global tobacco trade, Philip Morris International, British American Tobacco, Japan Tobacco International and Imperial Tobacco[8]. This has given companies such as PMI the economic clout to oppose, delay and threaten tobacco control strategies such as plain packaging and smoking bans[9]. The tobacco industry in Asia, a region of the world with very high smoking rates, is heading towards globalization. Companies such as Korean Tobacco and Ginseng (KT&G) and the China National Tobacco Corporation (CNTC) have developed foreign exports with government support[8] and have strengthened their domestic operations with consolidation and restructuring[8]. New global tobacco players have the potential to generate new competition, innovation and price reduction, all with detrimental impacts on public health[8]. The development of “low-harm” products such as electronic nicotine delivery systems (ENDS), including e-cigarettes, has opened new frontiers in regulatory control with concerns that such products may open new developed world markets for tobacco companies that otherwise continue to sell tobacco cigarettes in low and middle-income countries[7]. Tobacco companies use international trade relations to oppose the implementation of tobacco control measures; in the fight against plain packaging in Australia, the tobacco industry invoked trade treaties and the possibility of unfair trade restrictions. The tobacco industry holds to a culture of political sabotage that includes infiltration of government by lobbyists and open recognition of the value of political skills in undermining public health initiatives in tobacco control All of these developments call for a modernization of the tobacco control paradigm. This may include financial pressures such as disinvestment in the tobacco industry by pension funds[10], staunch regulatory approaches to ENDS and perhaps the development of finely honed political skills to match or surpass those of the tobacco industry. Even creative approaches to the dissemination of data, such as maps showing countries moving towards plain packaging or graphical presentation of the country-by-country distribution of tobacco factories may help inform the community and subvert the newer “low-harm” messages of the large tobacco companies. Many successes over many years can be attributed to traditional tobacco control, the emphasis on the science and the FCTC and MPOWER measures. However, the tobacco industry has very strong drive for survival with multiple strategies for evasion of control. The scientific arguments are irrefutable but are not enough to overcome an industry prepared to either deny the science, to ignore it while developing market share where regulations are weak or to espouse overt evasion techniques in company documents. MPOWER is no longer enough as the opposition does not play by the rules. Effective long-term global tobacco control will need to draw upon many resources including scientific evidence, economic pressure, the ability to avoid distractions and delaying tactics, resolute evaluation and regulation of ENDS and, ultimately, political dexterity in dealing with an industry prepared to do just about anything to maintain profit.

Table 1. MPOWER Measures

MPOWER Measures

Monitoring tobacco use and prevention policies Protecting people from tobacco smoke Offering help to quite tobacco use Warning about the dangers of tobacco Enforcing bans on tobacco advertising, promotion and sponsorship Raising tobacco taxes

References 1. Wynder EL, Graham EA. . Bull World Health Organ 2005;83(2):146–53. 2. Doll R, Hill AB. Bull World Health Organ 1999;77(1):84–93. 3. Health USSGAC on S and, General USPHSO of the S. Smoking and Health. http://profiles.nlm.nih.gov/NN/B/B/M/Q/ 4. United Nations Treaty Collection https://treaties.un.org/pages/ViewDetails.aspx?src=TREATY&mtdsg_no=IX-4&chapter=9&clang=_en 5. WHO | MPOWER [Internet]. WHO. [cited 2015 Jun 1];: http://www.who.int/tobacco/mpower/en/ 6. Levy DT, Yuan Z, Luo Y, Mays D. Tob Control 2016;tobaccocontrol-2016-053381. 7. Gilmore AB, Fooks G, Drope J, Bialous SA, Jackson RR. Lancet Lond Engl 2015;385(9972):1029–43. 8. Lee K, Eckhardt J. Glob Public Health 2017;12(3):367–79. 9. Peeters S, Costa H, Stuckler D, McKee M, Gilmore AB. Tob Control 2016;25(1):108–17. 10. Tobacco Free Portfolios http://www.tobaccofreeportfolios.org/

Abstract:
Tobacco use has been recognized by the World Health Organization as the number one preventable cause of premature death and disability. In the 21st Century, hundreds of millions of people will die because of tobacco use, with 70% of the toll occurring in low and middle-income countries. To magnify the horror of these projections, the tobacco epidemic, unlike other threats to global health, is a direct result of the activities of the most profitable industry in history. In recognition of this current and future epidemic, countries of the world negotiated and adopted in 2003 the WHO Framework Convention on Tobacco Control, the first-ever treaty of the WHO. The WHO FCTC has been ratified by 180 countries and the European Union, is an example of the promise of international health governance and highlights the central role of scientific evidence in tackling the global tobacco epidemic. A decision adopted by the FCTC Conference of the Parties at its 6th Session (Moscow, Nov 2014) called for an independent expert group to conduct an impact assessment of the treaty in its first decade. The expert group used three sources of evidence. The first source was a global evidence review of the scientific research on the impact of the FCTC across 17 of its articles; this review was conducted by the ITC Project. The second source was two reports prepared by global experts, of which one was prepared by the MacCabe Centre for Law and Cancer that reviewed the impact of the FCTC in legislative action taken by governments in tobacco control and in the use of the FCTC by governments in defense of legal challenges, and the second was prepared by Dr. Stella Bialous on the actions of the tobacco industry to weaken the FCTC. The third source was from evidence gathered by the expert group on country missions to 12 FCTC Parties, two from each of the six WHO Regions, and 3 from each of the four World Bank income levels. The main findings of the Impact Assessment Expert Group were the following: • FCTC has played an instrumental role as catalyst and framework for action— foundation for legislation and in defense against legal challenges. • FCTC has promoted tobacco control action in countries where little had been done, and has helped to strengthen action in countries where it was in place before ratification. • FCTC has broadened tobacco control across government and administration. And it has had impact on a range of international and global institutions and agendas. • FCTC has strengthened the role of civil society in tobacco control • FCTC has contributed to reductions in prevalence among Parties that have implemented FCTC policies at high levels, thus contributing to reductions in tobacco-related mortality and morbidity. • Tobacco industry continues to be the greatest threat to the implementation of the WHO FCTC. The expert group also cited the findings of a seminal study conducted by Gravely et al. on the impact of the FCTC on reductions in smoking prevalence. In an analysis of 126 countries, Gravely et al., found that over the first decade of the treaty, those countries that had implemented a greater number of key demand-reduction FCTC policies at the highest level (i.e., implementing those policies at sufficient strength to meet the standards of the FCTC Guidelines adopted for each of those policy domains: tax (Article 6), smoke-free (Article 8), labelling/warnings (Article 11), banning tobacco advertising, promotion, and sponsorship (Article 13), and cessation (Article 14)) experienced substantially greater decreases in smoking prevalence. On average, each additional policy implemented at the highest level was associated with a decrease in smoking prevalence of 1.57 percentage points (equivalent to a relative decrease of 7.09%). The Gravely et al. article, published in Lancet Public Health, demonstrates the power and potential of the FCTC to achieve its ultimate objectives. However, the article also presented findings on the current gap between the potential and the reality: that there have been very slow progress in the implementation of just these high-priority policies, consistent with the ITC Project’s global evidence review of the rate of implementation as well as the WHO’s assessment, which showed that by 2014, only 18% of the world’s population were living in countries with comprehensive smoke-free policies, and only 20% of the world’s population were living in countries with large pictorial warnings on tobacco product packaging. Why has implementation of the FCTC been so slow and in many cases at levels below the standards set by the FCTC Guidelines? All of the evidence gathered by the Expert Group points to one cause: the tobacco industry. Through their political influence, both explicit and covert, the tobacco industry has been quite effective in defeating efforts in many countries to implement the FCTC in accordance with their obligations under the treaty. It is necessary for all parties to engage in strong and vigilant implementation of Article 5.3, which forbids industry involvement in the process of formulating tobacco control policies, to advance the treaty and to more fully achieve its demonstrated potential to combat the global tobacco epidemic. The conclusions and take-home messages are: 1. FCTC Impact Assessment has demonstrated that the FCTC has great potential in reducing the number one preventable cause of death and cancer (esp. lung cancer) 2. BUT: FCTC implementation has been slow and in many cases is not at levels called for by the FCTC Article Guidelines. 3. Number of deaths and DALYs attributable to tobacco has increased since 1990. 4. Must SIGNIFICANTLY accelerate and strengthen FCTC implementation, especially in fully implementing Article 5.3. 5. Must expand implementation to other Articles (e.g., illicit trade, alternative livelihoods) 6. Research on evaluating FCTC implementation is essential for fighting industry attempts to weaken and slow the treaty.

Abstract:
WHO estimates that tobacco kills more than 7 million people each year. More than 6 million of these deaths are the result of direct tobacco use while around 890,000 deaths are the result of non-smokers being exposed to second-hand smoke. Around 60-70% of smokers want to quit smoking. However, the success rate for quitting smoking is quite low without a systematic approach. Counselling and medication can help increase the success rate. Only 24 countries provide national comprehensive cessation services with full or partial cost-coverage to assist tobacco users to quit. This represents merely 15% of the world's population. FCTC article 14 concerns the provision of support for reducing tobacco dependence and cessation, including counselling, psychological support, nicotine replacement, and education programs. Parties are required to develop and disseminate national guidelines on tobacco cessation and are encouraged to establish sustainable infrastructure for such services. Tobacco use treatment are not only clinically effective, but are cost-effective as well. Tobacco use treatments, ranging from clinician advice to medication to specialist-delivered intensive programs, are cost-effective in relation to other medical interventions such as treatment of hypertension, hyperlipidemia and to other preventive interventions such as periodic mammography. Even though a single application of any effective treatment for tobacco dependence may produce sustained abstinence in only a minority of smokers, tobacco use treatment remains highly cost effective. For example, Fiore and colleagues estimate the cost per life-year saved of tobacco dependence treatment to be $3,539. These estimates compare favorably with other health interventions in the U.S. like statins (which costs $50,000 per life-year saved), and diabetes treatment ($34,000 per life-year saved). Most effective way for more clinicians to intervene is to provide them with information regarding multiple effective treatment options and to ensure that they have ample institutional support to use these options. Clinicians, administrators, insurers, and purchasers can cooperate to encourage a culture in which intervention for smokers is an essential part of standard care. Korea is one such successful example. Eighty percent increase of price for a pack of cigarette since 1[st] of Jan, 2015 provided the momentum for other kinds of tobacco control activities. Even though only a small portion of increased tobacco tax was distributed to tobacco control activity, the tobacco control budget in 2015 has jumped by 13 times compared to previous year. 1. 246 Smoking Cessation Clinic in Health centers : All the health centers in Korea have smoking cessation clinic and gives counselling and NRTs for free. 2. Quitline : Nationwide quitline service is located in National Cancer Center. It gives counselling over the phone with proactive service for free. 3. Hospital based smoking cessation service : If a smoker visits hospital and gets counselling and medication(NRTs, bupropion, and varenicline) the fees for counselling and medication is actually free. National Health Insurance Foundation supports this program. 4. Community Smoking Cessation Center: There are 18 community smoking cessation centers in Korea. They provide three different services. 1) Residential 5 days smoking cessation program : intensive program which gives counselling, medication, etc. for free. 2) Residential 2 days smoking cessation program : short-term education program for free 3) Visiting program : Some underprivileged smokers, such as female smokers or adolescents who does not go to school, disabled smokers, or college students tend to not use smoking cessation programs due to various reasons. So community smoking cessation centers visit those special underprivileged populations. This service gives counselling and NRTs for free. References Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. May 2008. Cromwell J, Bartosch WJ, Fiore MC, et al. Cost-effectiveness of the clinical practice recommendations in the AHCPR guideline for smoking cessation. Agency for Health Care Policy and Research. JAMA. 1997; 278: 1759-1766. Guerriero C, Cairns J, Roberts I, Rodgers A, Whittaker R, Free C. The cost-effectiveness of smoking cessation support delivered by mobile phone text messaging: Txt2stop. Eur J Health Econ. 2013; 14: 789-797. Krumholz HM, Weintraub WS, Bradford WD, Heidenreich PA, Mark DB, Paltiel AD. Task force #2--the cost of prevention: can we afford it? Can we afford not to do it? 33rd Bethesda Conference. J Am Coll Cardiol. 2002; 40(4): 603-615. Stapleton JA, Lowin A, Russell MAH. Prescription of transdermal nicotine patches for smoking cessation in general practice: evaluation of cost-effectiveness. Lancet. 1999; 354: 210-215. Tengs TO, Adams ME, Pliskin JS, Safran DG, Siegel JE, Weinstein MC, Graham JD. Five hundred life saving interventions and their cost effectiveness. Risk Analysis. 1995; 15: 369-390. Linda Bauld, Ph.D., Kathleen A. Boyd, MSc., Andrew H. Briggs, D.Phil., John Chesterman, Ph.D., Janet Ferguson, MPH., Ken Judge, Ph.D., Rosemary Hiscock, Ph.D.; One-Year Outcomes and a Cost-Effectiveness Analysis for Smokers Accessing Group-Based and Pharmacy-Led Cessation Services, Nicotine & Tobacco Research, Volume 13, Issue 2, 1 February 2011, Pages 135–145, Parrott S, Godfrey C, Raw M, et al. Guidance for commissioners on the cost-effectiveness of smoking cessation interventions. Thorax. 1998;53:S1-38.

Abstract:
Tobacco use is well known as a carcinogen linked to many malignacies and also linked to non-oncologic diseases such as cardiovascular disease, chronic lung disease, and respiratory infections. The majority of lung cancer patients do have a history of smoking; often many are actvely smoking at the time of diagnosis and many struggle with cessation during treatment and through survivorship. Patients may have a perception of futility and lack of perceived benefit regarding cessation, and some clinicians may view tobacco cessation with a pessimistic perspective in that "the damage is already done." One of the first steps toward cessation in lung cancer patients is to make patients, families, and physicians aware of the continued harms of smoking, the negative impact on efficacy of treatment, and for those who may be treated with curative intent, the potential for development of malignacy in the future. As the potential benefits range widely and may apply differently to different patients, the ability to individualize a message regarding relevant positive impacts of cessation is crucial. For cancer patients overall, there is survival advantage in those who are able to quit, compared to continued smoking. Nicotine and its metabolic products can promote tumor growth through increased proliferation, angiogenesis, and other pathways. Furthermore, nicotine can decrease the biologic effectiveness of conventional cancer treatments such as chemotherapy and radiotherapy. For patients undergoing surgery, smoother recovery and avoidance of perioperative complications such as respiratory infection, wound complications, and perioperative cardiovascular events is critical. For those treated with curative intent, continued smoking can clearly be a significant risk factor for metachronous lung cancer, or development of different primary tumors. Even in those with incurable disease, overall survival benefit of cessation has been demonstrated. In addition, many patients with lung cancer and a smoking history have significant burden of respiratory symptoms, including dyspnea, wheezing, exercise intolerance, cough, pneumonia, etc. From a palliative standpoint, cessation can ameliorate some of the respiratory symptoms, and improve quality of life. Physician advice is a powerful tool and should be part of every encounter. Ask-Advise-Refer is a simple standard strategy which can be integrated into even the busiest of workflows. This involves asking every patient about tobacco use, advising cessation and referral to a tobacco treatment resource. That resource may be a Certified Tobacco Treatment Specialist, a telephone counseling service (such as a 'quitline'), a group counseling setting or other specialist. A more indepth cessation strategy involves the "5 As": Ask, Advise, Assess, Assist, Arrange. In addition to asking every patient about use and advising them to stop, a physician should Assess their use, prior quit attempts, and willingness to make a quit attempt. Then a provider should Assist the patient with their quit attempt with counseling and pharmacotherapy. Motivational interviewing is a standard counseling strategy in which a process of questioning and interviewing which strengthens and engages intrinsic motivation within the patient in order to change behavior. Pharmacotherapy consists of nicotine replacement therapy, varenicline, and/or buproprion. Previous concerns regarding severe psychiatric side effects such as suicidal ideation with varenicline have made some patients and physicians wary to use it; however, a recent trial shows varenicline to be very safe with no higher incidence of psychiatric side effects than placebo. Nicotine replacement therapy (NRT) can be delivered in a slow continuous format via a nicotine patch, and/or via short acting NRT such as gum, lozenges, nasal spray, or prescription inhaler. Often times a long acting modality (nicotine patch) can be used in combination with a short acting NRT as combination therapy. Overall pharmacotherapy increases success of quit attempts, and should be integrated as a part of the patient's overall healthcare plan. Often times the choice of pharmacotherapy is guided by what has or has not worked for that patient in the past. Electronic Nicotine Delivery Systems (ENDS) or e-cigarettes have recently become widespread and commonly available in many countries. The nicotine content is widely variable, and other componenets of the vaporised liquid make comparison and quantification much more difficult than that for approved pharmacotherapy where dosing is consistent and predictable. It is true that ENDS may not contain the same level of carcinogens as cigarettes, but in reality many users of ENDS are not able to quit conventional cigarettes, but use ENDS when not able to smoke and then use conventional cigarettes when they can smoke. At current, data is lacking and does not support e-cigarettes above approved pharmacotherapy. For those patients who are using e-cigarettes, the primary goal to complete cessation of conventional cigarettes. Patients who are using e-cigarettes and unable to quit smoking should be steered toward approved pharmacotherapy. Multiple different strategies exist to support patients during cessation attempts. There is no universally applicable single way to approach cessation. Counseling and pharmacotherapy are mainstays of cessation support and best outcomes result from using them together. A concerted, consistent message combined with appropriate pharmacotherapy and counseling may help many patients with lung cancer to quit smoking and gain the benefits of cessation.

Abstract not provided

Abstract:
The 2016 FCTC Report of the Conference of Parties (COP 2016) alerts that tobacco is the only legal non-prescription product that can kill between 33% and 50% of consumers when used as recommended by the tobacco industry [[1]]. The tobacco industry is also the only industry that, due to the potential lethality of its products and their impact on public health, has elicited a legally-binding intergovernmental treaty for protecting public health policies from the interference by the industry and by those who act to protect their interests. Besides the heavy political lobbying for blocking, delaying or weakening public health policies on tobacco control, the industry frequently resorts to legal disputes on the basis of international free trade agreements and bilateral agreements to revert governmental policies1. During the 6th COP, in 2014, the FCTC adhering State Parties have declared that the tobacco industry interference in public health policy for tobacco control continues to represent the main hindrance for full implementation of FCTC articles [[2,3]]. According to the WHO’s global report on tobacco industry interference of 2012, the most common tactics used by the industry are [[4]]: • maneuvering to hijack the political and legislative process; • exaggerating the economic importance of the industry; • manipulating public opinion to gain the appearance of respectability; • fabricating support through front groups; • discrediting proven science; • intimidating governments with litigation or the threat of litigation. Despite the tobacco industry claiming otherwise, the Director-General of the World Trade Organization (WTO) has declared that there is no inherent conflict between FCTC implementation by the ratifying countries and the WTO rules [[5]]. He enlightens that there are two WTO principles that should be respected: the non-discrimination and the necessity principles. The first one implies that the implemented tobacco-control policy does not treat an imported product differently than its domestic equivalent; whereas the necessity principle states that such measure, law or provision “must be necessary for complying with the proposed health goal and that it should not be more restrictive than necessary on trade in order to achieve this goal”[[6]]. Furthermore, according to the WTO, a “Member States have the right to determine the level of health protection that they wish to promote…” and, “when considering the less restrictive alternatives, these must meet the regulatory goal and be reasonably available, as well as genuinely alternative and not complementary measures”[[6]]. As far as bilateral agreements are concerned, the industry has used them in some countries to revert or impede the FCTC provision on cigarette packaging and labeling, by claiming that it breaches bilateral trade provisions that protect trademark and property rights [[6]]. Therefore, legislators should consider four basic principles when implementing tobacco control regulations: 1), to make sure that the law “only restricts property rights to the extent of achieving a public health objective”; 2), to avoid raising expectations of tobacco-industry investors that they will not be subjected to the regulation in question; 3), to ensure legislation’s compliance with the principles of due process and natural justice; and 4), to make sure that the new regulation will not be discriminatory. The careful application of these principles in the legislation wording and form will not only reduce international litigation but also protect the FCTC-ratifying Party from having to pay the tobacco industry compensation for damages [[6]]. In 2014, the COP participants unanimously decided to accelerate the full implementation in all public administration sectors and diplomatic missions of Article 5.3 and its guidelines [[3]]. Article 5.3 of the Framework Convention for Tobacco Control (FCTC) offers essential guidelines that were unanimously approved by the FCTC-ratifying countries in 2008. Article 5.3 thereby obligates ratifying countries to protect their health policies from tobacco manufacturers’ interference and to recognize that the tobacco industry bears fundamental and irreconcilable conflict of interests with public health and the FCTC implementation. In fact, Article 5.3 guidelines are the backbone of the FCTC treaty and help to prevent and reduce litigations aiming at reversing or halting the implementation of further anti-tobacco policies [[1]]. According to Article 5.3, countries should refuse to treat tobacco companies as “collaborators” in public health policy making; should not invest in the tobacco industry; should not receive contributions or grants from the tobacco industry; should not partner with tobacco industry either for health or other purposes – including their so-called social responsibility programs; should not celebrate non-binding or non-enforceable agreements; nor admit tobacco industry representatives on FCTC delegations or on other tobacco-control administrative agencies. Another relevant provision of Article 5.3 concerns transparency[[7]] in the interactions between government agencies and the tobacco industry by promoting afore public notices and free public access to reports, records, and documents about such interactions, besides promoting public hearings about the meetings. Moreover, it recommends the disclosure or registration of tobacco-affiliated organizations, advocacy groups and lobbyists; legal penalties on tobacco business for disseminating false or misleading information or propaganda; disclosure of tobacco industry business, such as market share, revenues, production, manufacture, relationship with tobacco farmers, investments in marketing, analysis of tobacco products chemical contents, and “social responsibility” actions and related activities; obligatory disclosure of current or past work with tobacco industry by applicants to jobs in governmental bodies involved in health policy-making, policy execution or surveillance[[7]]. The 2016 PAHO Report for the Region of Americas alerts that there are more than one billion smokers in the world and that 11.4% of them live in the Region of the Americas, which represents a population of 127 million smokers in our continent [[1]]. Prevalence shows that 21.2% of adults or teenagers older than 15 are smokers [[1]], which poses a heavy burden on public health, especially because it is among the youth and the lower income segments that the prevalence is higher. However far we had already progressed in fighting smoking and the consumption of other tobacco products, we are still very far from eradicating this addiction that responds for the vast majority of lung cancer cases, not to mention Head & Neck tumors and cardiovascular diseases. The implementation by all ratifying Parties of the FCTC six provisions that comprise the MPOWER package may drastically reduce in the coming two decades the morbidity and mortality associated with tobacco consumption. Our struggle is just beginning. References Pan American Health Organization. WHO FCTC. Report on Tobacco Control for the Region of the Americas. Who Framework Convention on Tobacco Control: 10 Years Later. Washington DC: PAHO, 2016. World Health Organization. FCTC/COP6/16, Implementation of Art. 5.3 of the WHO Framework Convention on Tobacco Control: questions related to tobacco industry interference. Report of the Secretariat of the Convention. Conference of the Parties in the WHO Framework Convention on Tobacco Control, 6th Meeting; 13-18 October; Moscow, Russian Federation. Geneva: WHO; 2014. Available at: . Accessed on June 10, 2017.

Abstract not provided

Abstract:
Despite fast growing information of tumor molecular biology, the increase in the therapeutic portfolio, and a significant improvement in diagnostic radiology, treatment of advanced NSCLC in 2017 remains palliative with still no curative perspective for the vast majority of patients. Therefore, the main treatment goals include the change from an acute into a chronic disease, extending survival times as well as improving or just maintaining quality of life. In order to assure an optimal palliation the majority of patients with advanced NSCLC – considering the high age and concomitant comorbidities - frequently may require modifications of the treatment standard. Furthermore, it can also not be ignored that recently approved novel agents and innovative diagnostic technology represent a growing burden of financial toxicity leading to regional differences in the availability of modern therapy and in the access to molecular testing and modern imaging. Nonetheless, treatment algorithms for advanced NSCLC have over the last decade gradually gained in complexity by incorporating a number of diagnostic and therapeutic achievements allowing personalization, individualization, and precision of therapy. Not only patient factors such as performance status (PS), comorbidity, and patients’ treatment expectation must lead to treatment differentiation and modification but also disease characteristics such as tumor stage, tumor load, histological type (squamous vs non–squamous) and the molecular profile of the tumor (mutant vs wild type) influence the process in reaching the goal of optimal sustainable palliation. Other critical elements in realizing personalized therapy and precision medicine within the process of optimal palliation consist in a rational selection of anti-cancer agents (predictive factors, mode of action, toxicity profile) and their appropriate application (single agent, concomitant combinations, drug sequencing) as well as other novel therapeutic actions such as interventional radiology, modern radio therapy, and minimal surgery. Optimal therapeutic management for sustainable palliation should definitely be based on clinically reliable evidence presented by frequently updated treatment recommendations: Today’s treatment algorithm for advanced NSCLC is challenged by a number of newer agents, such as tyrosine kinase inhibitors, monoclonal antibodies, checkpoint inhibitors (Table 1),

2nd-line	Docetaxel, Pemetrexed, EGFR-TKI	1st-line	Bevacizumab - non-squamous NSCLC
|	Ramucirumab / Doc - NSCLC	|	Bevacizumab/Erl. – EGFRm NSCLC
|	Nintedanib / Doc - non-squamous	|	Pemetrexed - non-squamous NSCLC
|	Nivolumab - NSCLC	|	Pemetrexed, Erlotinib - maintenance
|	Osimertinib - EGFRmT790M	|	Gefitinib, Erlotinib, Afatinib - EGFRm
|	Crizotinib, Ceritinib – ALK	|	Necitumumab - squamous NSCLC
|	Alectinib - ALK	|	Crizotinib - ALK/ROS
|	Pembrolizumab – PD-L1-low	|	Ceritinib – ALK
|	Atezolizumab - NSCLC	|	Alectinib -ALK
		|	Pembrolizumab - PD-L1-high

Table 1 and the incorporation of new treatment strategies such as continuation or switch maintenance therapy (Figure 1).Figure 1 Figure 1 For advanced NSCLC (Figure 2) it is generally accepted that platinum based doubled chemotherapy remains the backbone for the majority of our patients with good PS and this combination therapy should be modified according to feasibility and tolerability, comorbidity, patients’ age over 70 years, PS. Figure 2 Figure 2 For wild type non-squamous NSCLC there is pemetrexed which has been shown to be favorable over older cytotoxic agents if combined with platinum based components. In addition, pemetrexed has also sufficiently demonstrated that if it is continued in case non-progression under four cycles of standard platinum based doublet chemotherapy not containing pemetrexed (switch maintenance) or containing pemetrexed (continuation maintenance) prolongs survival. Another agent, the small molecule and EGFR-tyrosine kinase inhibitor erlotinib also prolongs survival if used in the switch maintenance setting but its benefit depends on the quality of response to the chemotherapy and is restricted to patients which have experienced disease stabilization only. The VEGFR-targeting antibody, bevacizumab, if added to platinum based doublet therapy, specifically to carboplatin/paclitaxel significantly improves response rate, duration of response, progression free survival, as well as overall survival in eligible patients. Human immune checkpoint inhibitor-antibodies inhibiting the PD-1 receptor or PD-1 ligand have recently been integrated into the treatment algorithms of wild type NSCLC. Pembrolizumab is currently the only checkpoint inhibitor approved and recommended for first line therapy in patients with a PD-L1 expression level ≥ 50 % and with negative or unknown EGFR/ALC/ROS1 testing. In wild type squamous NSCLC the given treatment options are still limited and platinum based therapy (no pemetrexed, no bevacizumab) remains the recommended treatment standard. Nonetheless, just recently the EGFR-targeting monoclonal antibody necitumumab has shown to significantly improve survival if combined with the standard doublet regimen cisplatin/gemcitabine in comparison to cisplatin/gemcitabine only and therefore, has just recently approved. Maintenance therapy in squamous tumors with docetaxel or erlotinib (switch) or gemcitabine (continuation) may be justified in some patients even here the statistical evidence is weak. For about 10-30% of NSCLC (in Europe < 15%) non-squamous tumors expressing specific molecular features first-line treatment by genotype has been established. Tumors with sensitizing EGFR mutations have been exposed by gefitinib, erlotinib, and afatinib and have shown to prolong progression free survival over standard platinum based doublet standard therapy. In tumors bearing ALK-/ROS1-gene-rearrangements crizotinib and ceritinib have also shown to prolong progression free survival if compared to platinum based / pemetrexed doublet chemotherapy. Therefore, EGFR-TKI therapy (erlotinib, gefitinib, afatinib) should be prescribed for patient with tumors bearing sensitizing EGFR-mutations and for patients with tumors bearing ALK-/ROS1-gene-rearrangements ALK-/ROS1-targeted therapy (crizotinib, ceritinib) should be prescribed. However, for these patients molecular testing is critical and should be used to select patients for EGFR/ALK/ROS1 targeted therapy. Patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics (ethnicity, gender, smoking status). Last but not least, second-/subsequent-line therapy is another strong element contributing to sustainable palliation in patients with advanced NSCLC. For tumor without driver mutations agents available before 2014 include docetaxel, pemetrexed (for non-squamous cell tumors only) and erlotinib. In recent years the two antiangiogenic agents nintetanib and ramucirumab (both in combination with docetaxel) and three immune checkpoint inhibitors (nivolumab, pembrolizumab, azetolizumab) have been added to the armentarium to treat patients with advanced non-mutated NSCLC who have progressed on or after first-line therapy (Figure 2). In mutated NSCLC several therapeutic options for second-/subsequent line-therapies are recommended depending on the type of progression and the molecular profile of the tumor. Osimertinib has been just recently approved for EGFRm/790M expressing tumors. For ALK-positive tumors ceritinib, alectinib, and crizotinib can be prescribed. In general, selection of agents for second-/subsequent-line therapies is based on whether the drugs have been used earlier, or toxicity or patients view. References are available by the author.

Abstract:
Lung cancer is the leading cause of death in the world. Approximately 85% of patients are diagnosed with advanced disease, associated with high morbidity and mortality. Lung cancer is associated with a higher burden of symptoms compared to other cancers. Patients may experience symptoms from disease such as cough, dyspnea, anorexia, malaise, pain and anxiety. Lung cancer patients often report symptom clusters (2 or more symptoms occurring simultaneously). Patients may also experience symptoms secondary to immediate and chronic side effects of treatment. Treatments for lung cancer include surgery, radiation therapy, chemotherapy, targeted therapy and immunotherapy. Patients may receive a combination of these therapies either concurrently or sequentially. Each therapy is associated with a unique adverse symptom profile. Collectively these symptoms negatively impact clinical outcomes. High symptom burden is associated with poorer clinical outcomes such as survival and health related quality of life (HRQOL). HRQOL is the evaluation of the patients own life situation from their perspective. HRQOL may also be referred to as patient reported outcomes (PROS) and the measurement referred to as patient reported outcome measures (PROMs). HRQOL is subjective and multidimensional. HRQOL measures include physical, psychological, cognitive, social and life roles. Quality of life may be negatively influenced by risk factors such as co-morbid medical conditions, poor nutritional status, emotional distress, sleep disturbances, poor pulmonary function, poor financial resources, poor social support and past family history. Poor nutritional status, including malnutrition, sarcopenia and cachexia, is associated with poor quality of life, poor response to treatment and decreased survival. Emotional distress, anxiety and depression, is linked to lower HRQOL, increased symptom burden and poorer prognosis. Previous experience with family cancer and perceived risk of cancer, specifically among women, is associated with poorer reported HRQOL. Caregivers of patients with poorer HRQOL have a greater caregiver burden. This in turn negatively impacts the patients HRQOL further. Maximizing quality of life is an essential component of lung cancer management. Pre-diagnosis HRQOL and HRQOL at diagnosis are a strong prognostic factor for survival in lung cancer. HRQOL measurements are useful to evaluate treatment efficacy. HRQOL is an important clinical outcome measure to consider as newer treatments and improved therapeutics are providing the opportunity for long term survival for some patients. It is especially important in cases when therapy is unlikely to be curative, as patients often report that HRQOL is more important than short term survival benefits. Several instruments have been developed to assess HRQOL (Table 1). Some of the tools are generic, some specific to cancer and others that specifically focus on lung cancer. Most of the instruments are questionnaires. Several tools developed demonstrate correlation with performance status, symptoms and survival. Studies suggest that disease specific instruments may enhance outcome measures and be more useful in predicting outcomes. The tools specific to lung cancer include: The Lung Cancer Symptom Scale (LCSS), the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTIC-QLQ), Functional Assessment of Cancer Therapy-Lung (FACT-L) and the Short Form Health Survey (SF). The City of Hope Quality of Life Family Care Giver Tool (COH-QOL-FCG) focusses specifically on the quality of life impacted by the family care giver. Table 1

Tool	Questions	Context Areas
The Lung Cancer Symptoms Scale (LCSS)	15	Patient and observer (healthcare professional) forms. Measures physical and functional dimensions
EORTC-QLQ C30	30	Cancer symptoms, physical symptoms, 5 functional areas (physical, role, cognitive, emotional, social), overall financial impact.
EORTC-QLQ-LC 13	13	Developed as supplement to the QLQ-C30 above. 13 items assess lung cancer symptoms, treatment related side effects (chemotherapy specific) and pain
Functional Assessment of Cancer Therapy-Lung (FACT-L)	37	Combination of the FACT-generic 27 questions on general QOL (physical, social and family, emotional, functional well-being and relationship with physician), and 10 items on lung cancer specific symptoms.
Short Form Health Survey (SF-36)	36	General health (physical function, role physical function, bodily pain, general health perception, vitality, social functioning, role emotional, mental health) with 2 summary scales measuring physical and mental component scales.
City of Hope Quality of Life Family Care Giver Tool (COH-QOL-FCG)	37	Measures physical, psychological, social and spiritual

There are some inherent limitations of the instruments. The scales have been developed by health care providers who may have different biases on what defines HRQOL. Therefore, there are likely metrics that are missing from the measures obtained. Accurate and consistent data collection may be influenced by fluctuations in the patients’ health status and symptom burden, making it difficult for them to complete questionnaires. If instruments are completed by a caregiver or healthcare provider, performance status may be used as a proxy for overall HRQOL. While performance status is correlated with HRQOL, it does not include all parameters. Operational barriers may be time demands on the health care provider, space limitations or technology breakdown when using online access. Other barriers may be the influences of language, culture, religion, age and educational level. Health care providers should continue to explore other strategies for capturing HRQOL data. The overall goal of health care providers is to improve the lives of patients. Better HRQOL is associated with better performance status, less frequent symptoms, lower anxiety, and improved response to treatment. Therefore, health care providers should continue to develop strategies that enhance HRQOL. HRQOL assessment provides an opportunity to assess for symptoms and potentially modifiable risk factors that negatively impact HRQOL and long term outcomes. This provides the bases for designing interventions that enhance HRQOL. Ongoing efforts include: refining surgical procedures, radiation techniques, selection of systemic therapeutics (chemotherapy, targeted therapy and immunotherapy) and combinations, with on maintaining efficacy with improved HRQOL outcomes. Focused interventions on modifiable factors may include: aggressive symptom management, structured supportive and palliative care, structured distress screening, resilience building, nutritional support, physical therapy and activity, family caregiver support. Consideration of HRQOL is an integral responsibility of all members of the healthcare team. References Borges, E.L., Franceschini, J., Costa, L.H.D., Gernandes, A.L.G., Jamnik, S. & Santoro, I.L. (2017). Family caregiver burden: the burden of caring for lung cancer patients according to stage and patient quality of life. J. Bras Pneumol. 43 (1): 18-23. Bye, A., Sjøblom, B., Wentzel-Larsen, T., Grønberg, B.H., Baracos, V.E……Jordhøy, M. (2017). Muscle mass and association to quality fo life in non-small cell lung cancer patients. Journal of Cachexia, Sarcopenia and Muscle. May 10. doi: 10.1002/jcsm.12206. [Epub ahead of print] Chabowksi, M, Polanski, J, Mazur, G, Janczak, D. & Rosinczuk, J. (2017). Sociodemographic and clinical determinants of quality of life of patients with non-small cell lung cancer. Advs Exp Medicine, Biology-Neuroscience & Respiration. Jun 2. doi: 10.1007/5584_2017_36. [Epub ahead of print] Delibegovic, A., Sinanovic, O., Galic, G., Sabic, A. & Sabic, D. (2016). The influence of palliative care on quality of life in patients with lung cancer. Mater Sociomed. 28 (6): 420-423. Eser, S., Göksel, T., Erbaycu, A.E., Baydur, H., Başank, B….Eser, E. (2016). Comparison of generic and lung cancer-specific quality of life instruments for predictive ability of survival in patients with advanced lung cancer. Springer Plus.5: 1833. Lou, V.W.Q., Chen, E.J., Jian, H., Zhou, Z., Zhu, J, Li, G. & He, Y. (2017). Respiratory symptoms, sleep, and quality of life in lung cancer. Journal of Pain and Symptom Management. 53 (2): 250-256. Morrison, E.J., Novotny, P.J., Sloan, J.A, Yang, P., Patten, C.A., Ruddy, K.J. & Clark, M.M. (2017). Emotional problems, quality of life, and symptom burden in patients with lung cancer. Clinical Lung Cancer. Mar 2. pii: S1525-7304(17)30051-7. doi: 10.1016/j.cllc.2017.02.008. [Epub ahead of print] Pinheiro, L.C., Zagar, T.M. 7 Reeve, B.B. (2017). The prognostic value of pre-diagnosis health related quality of life on survival: a prospective cohort study of older Americans with lung cancer. Qual Life Res. 26: 1703-1712. Polanski, J, Jankowska-Polanska, B., Rosinczuk, J., Chabowski, M & Szymanska-Chabowska A. (2016). Quality of life of patients with lung cancer. Onco Targets Ther. 9:1023-8.

Abstract:
In the lung cancer field, several studies have described the relationship between prognosis and quality of life (QoL), with most reports (Table 1), concluding a QoL evaluation of patients with advanced lung cancer before the start of chemotherapy could predict a patient’s prognosis. Such reports described common features: a poor prognosis for investigated patients whose disease was at an advanced stage and/or who were elderly, and the use of cytotoxic agents or irradiation, with poor efficacy. Molecular targeted drugs for epidermal growth factor receptor (EGFR) mutations and the anaplastic lymphoma kinase (ALK) fusion gene have recently been used in clinical practice. Such agents have led to dramatic improvements in patients with driver mutations. Indeed, we witnessed a “Lazarus response” during the NEJ001 study [1], which investigated the efficacy of an EGFR–tyrosine kinase inhibitor (TKI), gefitinib, for advanced non-small cell lung cancer (NSCLC) patients harboring EGFR mutations with a poor performance status (PS): The PS improvement rate was 79% (p<0.00005); in particular, 68% of 22 patients improved from ≥PS 3 at baseline to ≥PS 1. And median survival time of the EGFR-mutated patients was 17.8 months, while that of the patients without EGFR mutations was 3.5 months. Unfortunately, following the introduction of “precision medicine” for lung cancer, few reports have described the relationship between prognosis and QoL. Herein, we describe NSCLC patients with an EGFR mutation treated with gefitinib or chemotherapy as first-line treatment in a randomized phase III study, termed NEJ002 [2]. The patients’ QoL was assessed prior to treatment and, thereafter, weekly by the Care Notebook [3]. The relationship between prognosis and QoL data, employed before and 4 weeks after the initiation of treatment, was analyzed by univariate and multivariate Cox regression. QoL data from 148 patients (72 in the gefitinib arm and 76 in the chemotherapy arm) were analyzed. Multivariate Cox regression showed that only a fatigue score on the Care Notebook assessed 4 weeks after the start of gefitinib could predict a patient’s prognosis. Other QoL scores, including those before starting not only gefitinib but also chemotherapy, did not affect survival. Estimating Prognosis - How Accurate Can We Be as the QoL Researcher? We hypothesize answers fall into two patterns: In the case of employing agents with a poor efficacy, such as cytotoxic agents, the QoL score before treatment should be evaluated as done previously. However, when treating with a very effective agent, the QoL score under treatment should be employed because any improvement in prognosis and QoL is strongly dependent on the efficacy of the agent. The next theme is “Estimating Prognosis of the Patient - How Accurate Can We Be as the Attending Physician? Unfortunately, we do not have rigid evidence for employing QoL assessments. Measuring QoL can have clinical benefits as well as research benefits. These include fostering patient–provider communication, helping clinicians and patients to identify problems and set priorities, and to assess therapy, palliative care, and rehabilitation. However, in my experience of validating the Japanese version of the EORTC QLQ-C30 [4], the answering rate for PS 0–2 patients was over 99% (225/228), but the corresponding rates for PS 3 and PS 4 patients were 81% (38/47) and 13% (9/69), respectively. Furthermore, multiple regression analyses showed that Symptom scale (coefficient: 0.188, p=0.001) and Emotional functioning (coefficient: 0.156, p=0.004) significantly related to Global QoL functioning in patients with PS 0-2; however, Symptom scale alone (coefficient: 0.220, p=0.042) significantly correlated to it in those with PS 3-4. Thus, when the patient concentrates on his/her symptoms and/or fails to respond a QoL questionnaire due to poor PS, a known adverse prognostic factor in advanced cancers, the attending doctor could recognize the patient’s short survival. Two studies have succeeded in showing the prolongation of patients’ survival under palliative care. Jennifer et al. [5] randomly assigned patients with newly diagnosed metastatic NSCLC to receive either early palliative care integrated with standard oncologic care or standard oncologic care alone. The FACT-L scale, including the lung cancer subscale (LCS) and Trial Outcome Index (TOI), measured at 12 weeks revealed that patients assigned to early palliative care had a better QoL than did patients assigned to standard care (p = 0.03). In addition, median survival was longer among patients receiving early palliative care (11.6 months vs. 8.9 months, p = 0.02). Basch et al. highlightened the importance of monitoring symptoms at ASCO 2017 [6]. Patients receiving routine outpatient chemotherapy for metastatic solid tumors, including lung cancer, were randomly assigned to self-report 12 common symptoms via tablet computers (“PRO intervention”), or to usual care. Median overall survival in the PRO intervention arm was 5 months longer than the control arm (31.2 vs. 26.0 months, HR, 0.832, p = 0.03). These two studies indicate that symptomatic QoL monitoring is critical for clinical practice and for predicting prognosis. Table 1 Studies on relationship between baseline QoL score and survival in advanced NSCLC patients

Reference	Therapy type	Number of patients	Questionnaire	Prognostic, baseline scale/item
Herndon et al. Cancer 1999, 85:333-340.	Cisplatin/vinblastine	206	EORTC QLQ-C30	Pain
Langendijk et al. Radiother Oncol 2000,55:19-25.	External irradiation (>/=60 Gy)	198	EORTC QLQ-C30	Global QOL
Moinpour et al. Qual Life Res 2002,11:115-26.	Cisplatin+vinorelbine or Carboplatin+paclitaxel.	222	FACT-L	Total FACT-L score
Eton et al. J Clin Oncol 2003, 21:1536-1543.	Cisplatin+etoposide or Cisplatin+paclitaxel	573	FACT-L + TOI	Physical well-being and TOI
Maione et al. J Clin Oncol 2005, 23:6865-6872.	Vinorelbine+gemcitabine, Vinorelbine alone, or Gemcitabine alone	566	EORTC QOL-C30	Global QOL
Sundstrøm S, et al, J Thorac Oncol. 2006;1(8):816-24.	Palliative radiotherapy	301	EORTC QOL-C30	Appetite loss
Efficace et al. Ann Oncol 2006, 17:1698-1704.	Paclitaxel+cisplatin Gemcitabine+cisplatin Paclitaxel+gemcitabine	391	EORTC QLQ-C30 + QLQ-LC13	Pain, and dysphagia

[1] Inoue A, et al. First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy. J Clin Oncol. 2009;27(9):1394-400. [2] Maemondo M, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380-8. [3] Kobayashi K, et al. Validation of the care notebook for measuring physical, mental and life well-being of patients with cancer. Qual Life Res. 2005;14(4):1035-43. [4] Kobayashi, K, et al. A cross-validation of the European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30) for Japanese with lung cancer Eur J Cancer 1998;34:810-815. [5] Temel JS, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733-42. [6] Basch EM, et al. Overall survival results of a randomized trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment. (Abstract LBA2) presented in ASCO2017.

Abstract not provided

Abstract:
The incidence rate of lung cancer has declined in males and increased in females in Korea (Jung et al., 2017). In the United States, lung cancer incidence rates began declining in the mid-1980s in men and in the mid-2000s in women because of reductions in smoking prevalence that began decades earlier. Contemporary differences in lung cancer incidence patterns between men and women reflect historical differences in tobacco use (Siegel, Miller, & Jemal, 2016). Women took up smoking in large numbers decades later than men, first initiated smoking at older ages, and were slower to quit, including recent upturns in smoking prevalence in some birth cohorts (Giovino, 2002; Jemal, Ma, Rosenberg, Siegel, & Anderson, 2012). In the United States, the 3 most commonly diagnosed cancers are breast, lung and bronchus, and colorectum, representing one-half of all cases for women (Siegel et al., 2016). The purpose of this study is to analyze the correlation among mood state, distress, symptom experience, inner strength, and quality of life(QoL) in female patients with lung cancer. Also, this study includes descriptive research regarding the influence factors on QoL in them. A total of 206 research subjects who diagnosed with primary lung cancer at a cancer hospital in Gyeonggi, Korea were examined from 1 July 2016 to 31 October 2016. Several instruments were used for research methods: K-POMS-B for mood state, NCCN Distress Thermometer for distress, NCC for understanding aspect of distress, MDASI-LC for symptom experience, ISQ for inner strength, and FACT-G for QoL. Data of this study was analyzed by using SPSS Ver. 23.0 for Windows. The general and diseased characteristics of patients were analyzed through descriptive statistics, frequency, percentage, average, and standard deviation. Independent t-test and One-way ANOVA were used to examine differences according to their characteristics. Bonferroni correction, Pearson correlation coefficient, and hierarchical multiple regression for impact factors of QoL were also used. For reliability, Cronbach’s α was calculated. The results of this study are as fellows; 1. The mean score of the mood disorder was 20.74, symptom experience was 2.88, symptom degree was 2.76, disturbance of daily life was 3.01. The mean score of the inner strength was 97.98. Among sub-categories, the mean score of the searching for meaning on disease was 18.53, fellowship was 27.0, self-determination was 25.2, activity and rest was 27.1. The total mean score of QoL was 66.69, physical stability was 19.13, social stability was 18.04, emotional stability was 16.19, function status was 13.32. The highest result was in physical stability, whereas function status gained the lowest result. The mean score of distress was 4.19, sleep disorder was 3.2, insomnia affecting daily life was 2.45, anxiety symptom was 2.79, anxiety symptom affecting daily life was 2.25, depression was 1.92, depression affecting daily life was 1.68. In categories asking the needs of medical care, it was measured that insomnia was 38.5%, anxiety was 41,7%, depression was 19.9%. 2. The factors affecting in QoL were occupation, expectation of treatment outcome, activity ability, inner strength, symptom experience (the severity of symptom, the severity of disturbance of daily life), and mood state. 3. Higher scores in symptom experience, distress, and mood disorder categories have lower quality of life than those with higher scores of inner strength. 4. As a result of hierarchical analysis, these suggested that occupation status, expectation of treatment outcome (life extension), activity ability, inner strength, and symptom experience (the severity of symptom, the severity of disturbance of daily life) can be beneficial variables of QoL. The model was explained 70.7% of the total variance of quality of life. Cancer as a chronic illness places new demands on patients and families to manage their own care, and it challenges old paradigms that oncology's work is done after treatment. Therefore, to improve the quality of life in women survivors with lung cancer, we need to apply nursing interventions strengthening inner strength, activity ability, performance status, and symptom control.

Abstract:
This presentation will discuss 3 discoveries that radically changed our understanding of lung cancer. It will also address the challenges faced in communicating these life-saving “bench to bedside” discoveries to patients. In 2007, the National Science Foundation (NSF) released a report on the meaning of “transformative research” (TR) as follows: "Transformative research involves ideas, discoveries, or tools that radically change our understanding of an important existing scientific or engineering concept or educational practice or leads to the creation of a new paradigm or field of science, engineering, or education. Such research challenges current understanding or provides pathways to new frontiers.” Discoveries that changed our understanding of lung cancer: 1. PD-1/PD-L1: The discovery of PD-1 leads to development of PD-1/PD-L1 inhibitors i.e. immunotherapy. 2. Gene Defects: The discovery of gene defects/mutations leads to understanding that lung cancer is in fact many lung cancer mutations and leads to development of targeted therapies and precision medicine. 3. National Lung Cancer Screening Trial (NLST): The NLST lead to the conclusion that low dose CT scans can detect lung cancer earlier and lead to better treatment options and increased survivorship for lung cancer. In the United States, according to a recent study by Northwestern University’s Kellogg MBA program, the public is dangerously uninformed about our nation’s second leading cause of death; only behind heart disease. Lung cancer accounts for more deaths than any other cancer. More than breast, prostate and colon cancer combined! An estimated 155,870 deaths are expected to occur in 2017 in the United States, accounting for about 26% of all cancer deaths. However, federal funding for lung cancer research per death was just $1,680 compared to $24,846 for breast, $12,644 for prostate and $6,344 for colon. Not surprisingly, lung cancer has the lowest 5-year survival rate of the other most common cancers: only 18%, versus prostate at 99%; breast at 89%; and colorectal at 65%. It is clear that lung cancer is the leading cause of cancer death, and yet, it is tragically underfunded in terms of research. We will explore communication tactics including multimedia public awareness campaigns, public service announcements and social media most effective in raising the voice of lung cancer and the impact of “transformative research” in the community.

Abstract:
A Harmonized Strategy for Lung Cancer Awareness Month – November 2016 In early 2016, IASLC proposed a common strategy for the benefit of all lung cancer organizations during Lung Cancer Awareness Month. It was agreed by advocates and advocacy groups that IASLC is in a unique position to lead this unified effort among advocacy organizations. This campaign was supported by independent educational grants from Merck & Co., Inc., Eli Lilly and Company and Helsinn. Objectives for the common strategy for Awareness Month: Inform the public that everyone can get lung cancer (e.g. break down stigma) and share stories. Raise money, increase resources for research. This was done via individual organizations, not a common donor campaign, so we do not necessarily have metrics on funds raised. Reduce mortality & suffering by communicating to the public the exciting scientific advancements, which provide HOPE and PROGRESS in lung cancer. The joint public awareness campaign, supported by all the organizations, included the development of a common logo (seen above); common infographics featuring clear messages and vibrant photos showing people living their lives with lung cancer. The campaign shared stories that represented the demographics of spouses/caregivers/family and tried to show the diversity of all types who will get lung cancer. The common website (www.LCAM.org) was the focus and link shared during LCAM. We developed an advertising and public awareness campaign that included both print, digital and social media outlets. The advertising campaign included print advertising in New York Times and Wall Street Journal (Rocky Mountain Edition); a digital campaign featuring banner ads and video “pre-roll” ads; and a social media campaign utilizing both organic and paid campaigns. Key Metrics: More than 60 Survivors & Caregivers shared their stories on . More than 20 partners participated in the campaign. More than 25,000 pins, t-shirts, bracelets and posters were distributed in November.

Facebook	Twitter	LCAM Youtube Channel
9,500 Likes in November 2016	#LCAM Impressions - over 51M in November	15 Videos (:30 Seconds to 2 minutes long)
38,000 Likes as of January 31, 2017	Daily Tweets of Survivor Stories	Over 2,000 Views
28,000+ Post Likes/Shares/Clicks	Over 100 Followers
	Re-tweets by Alec Baldwin, US Actor

Digital Analytics	Print Ads
Over 30,000 Website Visitors	1/2 page full color ad New York Times - Page A8
Video and Web Banner Impressions - More than 18M	NYT Circulation = 651,458
Video Views & Web Banner Clicks - 78,202	(2) 1/2 page full color ads WSJ Rocky Mountain Edition
Click-through-rate 8x industry benchmark	WSJ Rocky Mountain Edition Circulation = 45,000
View-through-rate of 80-84%

Major Highlights/Activities: Organized Kickoff Event at the National Press Club in Washington, DC on November 1[st] 3 Travel Awards granted for LCAM 2016 Meeting in September 2016 2017 Objectives: Expand to include more global partners – Latin America, Asia, Rest of World Expand to include more Cancer Center/institutional partners Improve the diversity of the participants Improve website technology and social sharing Include more scientific advances linked with survivor stories Expand media kit and social sharing tools Increase sponsorship to support an expanded campaign Thank you to our Partners! Caring Ambassadors Dusty Joy Foundation (LiveLung) LUNGCAN Free Me From Lung Cancer Free To Breathe Lung Cancer Foundation of America Lungevity Lung Cancer Research Foundation Chris Draft Family Foundation Faces of Lung Cancer Clifton Mountain Foundation Bonnie J. Addario Foundation American Lung Association Lung Cancer Initiative of North Carolina Lung Cancer Europe Women Against Lung Cancer Europe Patient Power Rexanna’s Foundation Upstage Lung Cancer University of Colorado Cancer Center …and many lung cancer survivors and researchers Special thanks to the LCAM 2016 working group: Janet-Freeman Daily, Dusty Joy Donaldson, Cynamon Frierson and Mary Henningfield. Participants: A consortium of individuals, including lung cancer survivors, and more than 20 different advocacy organizations in the USA and Europe, with IASLC coordinating the effort. There is potential for a worldwide campaign in the future.

Abstract:
In May 2015, I attended a conference for lung cancer patients in Washington DC. There were close to 200 patients in attendance, but only five with my specific diagnosis: ROS1+ Adenocarcinoma. We saw what a minority we were within the lung cancer community and knew it would be up to us to find and create our own “tribe.” The five of us met up in the hotel bar to discuss how we might find other ROS1+ patients to share knowledge and improve our survival odds. Our first step was to create an online presence. Upon returning home from the conference, Tori Tomalia, Janet Freeman-Daily and I started a private Facebook group for people with ROS1+ cancer. We welcomed patients and caregivers and invited them to share their diagnosis stories, treatment paths and other experiences related to having ROS1+ cancer. We combed the internet searching for other ROS1+ patients, and we spoke to our doctors and friends in the lung cancer community to try to spread the word. In the first few months, membership ramped up fairly slowly, but we were a close knit group, sharing critical information, and making a difference in each other’s lives. The more I learned, the more it became apparent that essentially no one was conducting research focusing on ROS1+ cancer. We had gotten lucky that the ROS1 fusion was similar enough to the ALK mutation (which occurs with more frequency and has a larger patient population), that ROS1 had been able to piggyback on the ALK research. But no one was specifically examining ROS1, and while the first generation ALK research generated Crizotinib, a therapy that proved exceptionally effective for ROS1, some of the most exciting second generation ALK research was not looking as promising for ROS1. Obviously, this was disconcerting. So, while attending WCLC in Denver in September of 2015, Janet and I pulled Dr. Ross Camidge (Univ. of Colorado) aside to ask him one very important question: How can we get ROS1-specific research going? His answer: Organize. Research cannot happen without a cohort of patients to study, and gathering enough ROS1+ patients is difficult for researchers. Dr. Camidge’s words lit a fire under us. Janet, Tori and I decided to increase our efforts to recruit ROS1 patients to our Facebook group. All three of us published blogs, redoubled our efforts scouring the web and contacting doctors, and sought out other media opportunities. Within a couple of months, we’d doubled our membership, including many international patients, and we decided it was time to seek outside help. I contacted Bonnie Addario, a long-term lung cancer survivor and founder of the Addario Lung Cancer Foundation (ALCF). I knew Bonnie was a strong proponent of “patient centric” research, and I also knew the ALCF (and its sister organization, Addario Lung Cancer Medical Institute (ALCMI)) had successfully launched the “Young Lung Study” the previous year. Since both young lung cancer, and ROS1+ lung cancer, are minorities in the lung cancer space, requiring researchers to cast an international net to gather a critical mass, I felt that the ALCF and ALCMI had demonstrated both the interest and experience necessary to help shepherd a global ROS1 research effort. Luckily, Bonnie agreed, and soon the ALCF and ALCMI joined our team. As patients and caregivers, we began calling ourselves the “ROS1ders” (pronounced “ross-wonders”). A core group of about 5 ROS1ders did most of the work, but we would check in with the broader Facebook group for feedback periodically. By December 2015, the ROS1ders delivered a list of our research priorities to ALCF. Dr. Guneet Walia, ALCF’s Senior Director of Research and Medical Affairs then began reaching out to researchers and industry--and the Global ROS1 Initiative (the “Initiative”) was born. The first project of the Initiative was an epidemiological survey. ROS1ders worked together with Dr. Walia and a Stanford University researcher to develop a survey, designed to uncover commonalities which might indicate causes for the ROS1 oncogene, and help direct where to focus future research. Over 100 ROS1ders from around the world filled out the survey. Data analysis is underway, and a second generation follow-up survey is coming. Guneet discussed some of the initial findings of this study at WCLC 2016 in Vienna. Our second project is even more ambitious. Only a few models of ROS1 cancer exist. To encourage more research into ROS1 cancer, we are partnering with researchers and organizations to create new ROS1 cancer models (both cell lines and mouse models) using fresh biopsy and surgery specimens donated by ROS1ders. Models created by ROS1der donations will be made available (freely or at minimal cost) to academic researchers. Orchestrating the Initiative is a major undertaking. A group of the most involved ROS1ders and ALCF and ALCMI members have weekly conference calls. In between calls, each of us work on our individual pieces, such as meeting with researchers, negotiating contracts, writing content for websites, speaking at conferences, and fundraising. Since this project is the first of its kind, it’s not surprising that sometimes we face hiccups and hurdles. Patients, caregivers, researchers, advocacy organizations and industry are learning how to work with each other as peers, and occasionally the learning curve is steep. The global nature of our project adds legal complexities, language barriers and time zone juggling to the mix. We are all evolving and changing the way research can be done. The Initiative is a groundbreaking example of international patient-driven research. Its success reflects the collaborative efforts of so many dedicated to achieving something truly special. From its inception at a hotel bar in Washington DC to today, ROS1der voices have been involved every step of the way. We hope the Initiative not only changes the lives of ROS1ders, but paves the way for other motivated patient groups to pursue their own goals. We are so proud and excited to see our vision manifest.

Abstract:
Background/History A lung cancer diagnosis can be devastating to both the patient and their loved ones. Often times, lung cancer patients and caregivers report feeling isolated and hopeless. In 2004, there were very few events across the United States which connected the lung cancer community. One advocate, whose husband was fighting lung cancer, sought to change that and held the very first Shine a Light event in November 2004 in Santa Rosa, CA. Little did they know, this local event would turn into a movement. In 2006, a few advocates in Boston held a similar Shine a Light on Lung Cancer Vigil—a “rally” for lung cancer on the steps of the Massachusetts state house, to honor and remember those who have been touched by the disease and to raise awareness during Lung Cancer Awareness Month (LCAM). In 2008, they were determined to grow this event and offer local communities an opportunity to connect with others impacted by this disease and Lung Cancer Alliance was there to help them achieve their vision. Purpose Shine a Light on Lung Cancer’s primary purpose was and continues to be raising awareness about lung cancer and connecting the community. The events are always free to attend and free to host as we want to eliminate any barriers to participation. Shine a Lights began as “vigils”, and have always incorporated a moment of silence and the literal act of shining a light—whether that be a glow stick, flashlight, candle, or illumination of a room or building—to remember those we’ve lost to this disease. In 2014, Lung Cancer Alliance decided to drop the word “vigil” from the program title, as vigils often connote a feeling of sadness or mourning, and the purpose of Shine a Lights were to provide hope, support and inspiration to all those impacted. Each Shine a Light program still incorporates a moment of silence and shining of lights, however, we focus that moment to celebrate the survivors in attendance, while also remembering those who have passed away from this disease. This signature element of Shine a Lights can often be emotional and is typically the culminating activity of the event. Shine a Lights are also a great platform for local media attention. In an effort to leverage this attention, from 2008 through 2015, we encouraged organizers to host their event on the official Shine a Light date (voted on by past organizers and ultimately chosen by LCA). However, due to lack of national coverage and confusion from potential organizers on the official date, in 2016, we stopped choosing an official national date. Impact The impact of our Shine a Light on Lung Cancer program has far exceeded our initial expectations. The initiative continues to grow and evolve year after year and we continually adapt and improve the program based on feedback from organizers and attendees. When Shine a Light began, events were typically organized by individuals in communities who wanted to do something during Lung Cancer Awareness Month. They incorporated survivors, caregivers, physicians and local notable members of their communities (i.e. news reporters, local politicians, and entertainers) into their programs, to educate attendees about lung cancer and inspire action with a unifying national call to action. In 2013, Lilly Oncology came on board as a national title sponsor and their sales force began to spread the word about these unique events to their customers—healthcare providers. Shine a Lights are a great way for nurse navigators to celebrate their patients during Lung Cancer Awareness Month and highlight their programs and services—particularly on the heels of Breast Cancer Awareness Month—and especially with our “event in a box”. Organizers complete a very simple online LOA which contains all of their event information, after which they receive access to our online resources (i.e. template flyers, programs, sponsor logos, media outreach instructions, and more). In October, each organizer will receive their Shine a Light “kit” in the mail, which contains bracelets, flashlights, a poster and educational materials for their attendees. Although we had had a handful of Shine a Lights taking place in healthcare facilities before 2013, with Lilly’s involvement, the numbers grew. Simultaneously, we noticed Shine a Lights which were hosted by individuals were becoming more unique and personalized to their local community (i.e. paint and sip parties, yoga classes, and backyard barbecues). Because of this natural distinction, we evolved the program in 2016 to include Shine a Light, traditional events hosted by a healthcare facility during LCAM, and Shine a Light Your Way, unique awareness and fundraising events hosted by individuals in their local communities throughout the year. Due to this split, our traditional Shine a Light numbers saw a slight dip in 2016 as they no longer included events being hosted by individuals, but we anticipate continued growth in 2017 as the program evolves. Future Goals In 2016, 166 Shine a Light events were held in 38 states. Our goal for 2017 is to reach 200+ events in all 50 states and Washington, DC. We are also looking to make an even bigger global impact in 2018. The first international Shine a Light was held in partnership with the Australian Lung Foundation in 2011 and we have had seven unique countries host at least one Shine a Light since then. We hope to expand our national reach while bringing this unique program to many more worldwide, and continue connecting the lung cancer community—offering hope and inspiration, letting those who are impacted know they are not alone.

Abstract:
It is estimated that in 2015, approximately 3 million people in Italy have received a cancer diagnosis during their lifetime. While in men cancer has decreased of 2.5%, in women the cases have risen from 168,000 to 176,000. Epidemiological data of lung cancer reveal a dramatic increase of the incidence and mortality in women, mainly due to the tobacco consumption in the female population during the past 60 years and since the 1980s, the gap between the two genders has narrowed. Nowadays lung cancer represents a global women’s health issue and every year more women die due to lung cancer than for breast, ovarian and uterine cancer all together and receiving a cancer diagnosis together with the communication about treatment and care can lead to a series of extremely stressful and frightening events that cause both patients and their relatives to suffer emotionally. Psychological distress, depression and anxiety are related to poor quality of life in all its shapes and forms, including the physical-side. The disease and the treatments alter the patient body image and consequently change the personal identity; the body is no longer recognized and accepted in its new condition, and this may undercut the sense of femininity and diminish the confidence in the physical appearance and the self-esteem. It gets difficult for a woman to face the daily life because she is exposed to the external world with a body revealing visible signs of the illness and care. For addressing these issues, it is necessary to implement an holistic approach and this is one of the objectives behind the active commitment of WALCE (Women Against Lung Cancer in Europe) since 2006, when it was established. In 2009, it started the collaboration with “La forza e il sorriso – L.G.F.B. Italia”, the Italian version of a well-known program called “Look Good ... Feel Better®”, launched in US in 1989 and currently active in 26 countries worldwide. It is a free make-up workshop project for women diagnosed with cancer who are undergoing chemotherapy, radiotherapy or other cancer treatments. Beauty workshops are offered to help women to cope with treatment side effects and to regain the femininity and the self-confidence in their body with the aim to improve their quality of life by simple beauty techniques to enhance the appearance. Following this positive experience, WALCE designed a lung cancer awareness campaign, called: “How to beauty your day”, a make-up session program for women of all ages affected by cancer with the aim to reach little and peripheral hospitals in Italy, where the initiative “La forza e il sorriso” has not been provided yet and hospitals, where no general support programs for women with cancer have been developed. This initiative was launched in November 2010, during the World Lung Cancer Awareness Month and in some way it recalls the other one, but with some new addition. Together with the beauty sessions, educational events are organized with the aim to improve and reinforce the knowledge of people about the disease, the current treatment options, the side effects and any other related issues. This program was firstly carried out just in Italy and later on, it was expanded in other European countries (Spain, Serbia and Greece). From November 2010 to November 2016, WALCE organized 76 make-up workshops in several Italian locations and in Europe, in collaboration both with cancer centres and no profit organizations working in these areas; about 750 ladies attended the make-up workshops, guided by 7 voluntary beauticians and with the support of a psycho-oncologist. At the end of the session, the women are invited to complete a survey to assess the event and benefits received. The general response received until now is positive; most of participants declare to have learnt useful advice and to be very enthusiastic, whereas very few are a little doubtful. The most common adjectives used to describe patient feelings at the end of the experience are: beautiful, happy, positive, pretty and attractive. From the survey results, it seems that most of the ladies don’t think about the illness during the event and meeting other women in a similar situation is considered a positive experience. Cancer patients tend to better cope with the illness when self-confidence and self-esteem are regained. The sense of well-being shared in a relaxed atmosphere, acknowledging social, emotional and psychological needs and being amongst other ladies who feel the same fears or anxieties, has proven to be an incentive to fight against cancer. Figure 1 Pikler VI, Brown C: Cancer Patients’ and Partners’ Psychological Distress and Quality of Life: Influence of Gender Role. Journal of Psychosocial Oncology, 28:43–60, 2010 Honda K, Goodwin R: Cancer and mental disorders in a national community sample: Findings from the national comorbidity survey. Psychotherapy and Psychosomatics, 73: 235–242, 2004 Tuinstra J, Hagedoorn M, Van Sonderen E et al: Psychological distress in couples dealing with colorectal cancer: Gender and role differences and intracouple correspondence. British Journal of Health Psychology, 9: 465–478, 2004 Fife B, Kennedy V, Robinson L: Gender and adjustment to cancer: Clinical implications. Journal of Psychosocial Oncology, 12: 1–21, 1994 Phillips C: Images, femininity and cancer: an analysis of an international patient education programme. Health, 13: 67, 2009

Abstract:
This session will focus on some new definitions and concepts in the recently published 2015 WHO classification of lung tumors (1), some of which were showcased in the 2011 IASLC/ATS/ERS lung adenocarcinoma classification (2), while others are introduced for the first time. We will focus on resected lung adenocarcinoma as well resected squamous cell carcinoma, large cell carcinoma and the neuroendocrine tumor spectrum. Adenocarcinoma: In the 2015 WHO classification, the definition of adenocarcinoma has been expanded from a malignant epithelial tumor with glandular differentiation or mucin production to include tumors that also express pneumocyte immunomarkers (e.g. TTF1, Napsin A). This means that undifferentiated carcinomas formerly classified as large cell carcinoma that express pneumocyte immunomarkers, like undifferentiated carcinomas that show mucin expression, are now included in the solid adenocarcinoma category. Invasive adenocarcinomas account for >70% of all surgically resected cases and consist of a complex admixture of histologic subtypes. In an effort to represent this morphologic complexity, comprehensive histologic subtyping was introduced in the 2011 IASLC/ATS/ERS classification. A number of recent studies have demonstrated the utility of comprehensive histologic subtyping in identifying prognostically significant groups of tumors . Studies published both before and after the 2011 IASLC/ATS/ERS classification have highlighted the importance of the secondary patterns in addition to the predominant pattern in resected lung adenocarcinoma. Comprehensive histologic subtyping, its pitfalls and the emerging significance of secondary patterns in tumour recurrence and prognosis will be discussed further in this session. Grading: There is no well-established, internationally accepted grading system in resected lung adenocarcinoma. A simple grading system based on predominant histologic subtype has been proposed due to the prognostic significance of predominant histologic subtype. Other suggested grading schemes include different combinations of mitotic count, second predominant pattern and nuclear features with predominant histologic subtype. The emerging concept of an objective grading system for pulmonary adenocarcinomas will be briefly explored in this session. Another newly introduced concept in the 2015 WHO classification is that of tumour spread through alveolar spaces (STAS) which may occur with micropapillary clusters, solid nests or single cells. STAS was found to be associated with an increased recurrence rate in patients with stage I adenocarcinomas <2cm who underwent sublobar resections (3). Tumour size and staging: A recent study confirmed that in resected non-mucinous adenocarcinoma, the size of the invasive component, excluding the lepidic (equated with in situ) component of the tumor, correlates better with patient outcome than total tumour size (4). This finding has been supported by other studies and is expected to be included in the upcoming 8[th] edition TNM staging system for the T descriptor for pathologic staging in resected non-mucinous adenocarcinoma (5). Squamous cell carcinoma (SQCC) is the second most prevalent Non-small cell lung cancer (NSCLC), behind adenocarcinoma. Contrary to the latter where most changes in nomenclature, diagnosis and molecular pathology have occurred, SQCC has a strong association to smoking and remains a challenge for oncologists with few therapeutic advances. To reduce the risk of over diagnosing SQCC, the definition of SQCC became stricter in the 2015 WHO classification. For the diagnosis of this entity it is necessary to have evidence of keratinization and intercellular bridges. For non-keratinizing SQCC it is necessary to demonstrate evidence of squamous differentiation by immunohistochemical (IHC) stain (diffuse positivity for p40 or p63 and absence of adenocarcinoma markers such as TTF-1 and napsin-A). Non-keratinizing SQCC shares a solid pattern of growth with adenocarcinoma; in addition, solid type adenocarcinomas can have squamoid features such as glassy and abundant cytoplasm that can mimic SQCC (6), therefore it is recommended the use of IHC for any NSCLC with solid pattern of growth. Presence or absence of mucin is not a criterion for diagnosis of SQCC. Similar to adenocarcinoma, there is no grading system for SQCC. There is evidence that tumour budding is associated with worse prognosis (7). Basaloid carcinoma is now classified in the same group of SQCC and no longer part of large cell carcinoma. In contrast, Lymphoepithelioma-like carcinoma of the lung that share IHC profile with squamous cell carcinoma is grouped in the category of other undifferentiated tumours that also include NUT carcinoma. Large cell carcinoma: remains a separate category; however, the diagnosis of this entity is greatly reduced. Large cell carcinoma is an undifferentiated carcinoma (positive for cytokeratin markers), which lacks evidence of differentiation by morphology and lineage specific immunohistochemical profile (TTF-1/Napsin-A and p40 negative). This classification is supported by molecular profile (8). High Grade Neuroendocrine Carcinomas. This tumour category remains largely the same from previous classification with the exception that Large Cell Neuroendocrine Carcinoma (LCNC) is now grouped with neuroendocrine tumours. It is no longer part of a Large Cell Carcinoma category. Recent studies have suggested that LCNEC is a heterogeneous group ranging in the spectrum from NSCLC-like to small cell carcinoma-like tumours (9). LCNEC that resemble NSCLC have higher incidence of KRAS mutations, whereas those morphologically closer to small cell carcinoma have higher incidence of RB mutation. The significance of these findings for tumour classification and especially for therapeutic options are still unknown as more studies need to be done. There have been several studies on the genetic and epigenetic profile of small cell carcinoma that could lead to new therapeutic options (10). However, the diagnosis and classification of this tumour remains the same. Carcinoid Tumours: Typical and atypical carcinoid tumours maintained the same morphological criteria for diagnosis and classification. Recent molecular studies have showed however that these tumours have distinct molecular profiles from the high grade relatives (LCNC and small cell carcinoma) (10). References: Travis WD, Brambilla E, Nicholson A, Noguchi M, et al, (eds). (2015) WHO Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. 4[th] ed., Lyon: IARC. Travis WD, Brambilla E, Noguchi M, et al. (2011). International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 6: 244-85 Nitadori J, Bograd AJ, Kadota K, et al. (2013) Impact of micropapillary histologic subtype in selecting limited resection vs lobectomy for lung adenocarcinoma of 2cm of smaller. J Natl Cancer Inst. 105:1212-10. Yoshizawa A, Motoi N, Riely GJ, et al. (2011). Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Mod Pathol. 24: 653-64. Travis WD, Asamura H, BAnkier AA et al. (2016) The IASLC Lung cancer Staging Project: Proposal for coding T category for subsolid nodules and assessment of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol. 11:1204-23. Rekhtman N, Paik P, Arcila M, et al (2012). Clarifying the spectrum of driver oncogene mutations in pure, biomarker-verified squamous cell carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations. Clin Cancer Res. 18:1167-76. KAdota K, Nitadori J, woo KM et al. (2014). Comprehensive pathological analyses in lung squamous cell carcinoma:single cell invasion, nuclear diameter, and tumor budding are independent prognostic gfactors for worse outcomes. J Thorac Oncol. 9:1126-39 Rekhtman N, Tafe LJ, Chaft JE et al. (2013) Distinct profile of driver mutations and clinical features in immunomarker-defined subsets of pulmonary large cell carcinoma. Modern Pathol. 26:511-22. Rekhtman N, Pietanza MC, Hellman M, et al. (2016) Next-Generation Sequencing of Pulmonary Large cell neuroendocrine Carcinoma Reveals Small Cell Carcinoma-like and Non-Small Cell Carcinoma-like subsets. Clin Cancer Res. 22:3618-29. Bunn PA, Minna J, Augustyn A et al. (2016). Small cell Lung Cancer: can recent advacnes in biology and molecular biology be translated into improved outcomes? J Thorac Oncol. 11:453-74

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Background:
There is currently no completed randomized controlled trial data comparing stereotactic ablative radiotherapy (SABR) and surgery in operable patients with early-stage non-small cell lung cancer (ES-NSCLC). Propensity score methods are increasingly utilized in oncology to balance the baseline characteristics of non-randomized cohorts, mimicking the setting of a clinical trial. No previous meta-analysis of propensity score analyses comparing a surgical and non-surgical modality has been conducted. Our goal was therefore to perform a systematic review and meta-analysis of all propensity score analyses comparing SABR and surgery in patients with ES-NSCLC.

Method:
A systematic review was carried out according to PRISMA guidelines by querying the MEDLINE and Embase databases from inception until December 2016. Hazard ratios (HR) with confidence intervals (CI) for overall survival (OS) and disease-specific survival (DSS) were directly extracted, if available, or estimated from Kaplan-Meier curves. Meta-analysis was carried out with inverse variance-weighted random-effects models.

Result:
After reviewing 1039 records, 17 PS-adjusted studies with a total of 20151 patients were included in the final analysis. Overall survival (OS) favoured surgery over SABR (HR = 1.52 [95% CI: 1.33-1.74], p < 0.001). However, the rate at which patients died from lung cancer (DSS) was not significantly different (HR = 1.13 [95% CI: 0.86-1.49], p = 0.38). On subgroup analysis, OS was superior for both lobectomy (HR = 1.61 [95% CI: 1.27-2.03], p < 0.001) and sublobar resection (HR = 1.33 [95% CI: 1.15-1.55], p < 0.001) versus SABR while DSS again did not significantly differ (HR = 1.35 [95% CI: 0.70-2.62] and HR = 1.18 [95% CI: 0.84-1.67], respectively). On secondary analysis, meta-analysis of proportions revealed a lymph node upstaging rate of 16.0% (95% CI: 13.6%-18.6%) and adjuvant chemotherapy usage rate of 11.5% (95% CI: 8.6%-14.8%) among patients who received surgery. On meta-regression, with every increase of 0.1 in the maximum allowable difference in propensity score within a matched pair - representing increases in imbalance between cohorts, DSS outcomes increasingly favoured surgery by 1.36-fold. Critical appraisal revealed inconsistent reporting of propensity score methods.

Conclusion:
Overall survival favoured surgery over SABR in this meta-analysis of 17 propensity score analyses. However, the effectiveness of SABR was reflected in a similar DSS to surgery, supporting ongoing clinical equipoise. A direct relationship between propensity score methodology and DSS outcomes were demonstrated. Whether this observed benefit in OS for surgery is real or due to limitations in the propensity score methodology requires confirmation through randomized data.

Background:
In last years, an increasing interest emerges on the role of sub-lobar resection and lobe-specific lymphnode dissection in the treatment of early stage lung cancer. The aim of our study was to define impact on Cumulative incidence of recurrence (CIR) of type of surgical resection and type of nodal staging. Furthermore, we evaluated the effect of interactions between the different kinds of procedure.

Method:
An analysis of 969 consecutive stage I pulmonary adenocarcinoma patients, operated in six Thoracic Surgery Institutions between 2001 and 2013, was conducted. Type of surgical resection included lobectomy and sub-lobar resection; pneumonectomy and bilobectomy were excluded from the analysis. Nodal staging procedures were classified in nodal sampling (NS), lobe-specific lymph node dissection (LS-ND) and systematic lymph node dissection (SND). Multivariable-adjusted comparisons for CIR was performed using Fine and Grey model, taking into account death by any cause as competing event. Test of interaction between type of surgical resection and type of nodal staging was carried out and results presented in a stratified way. Missing data were multiple-imputed, combined estimates were obtained from 5 imputed datasets.

Result:

Multivariable-adjusted Fine and Grey model for Comulative Incidence of Recurrence (take into account age, gender, smoking habit, side of intervention, pTNM stage, vascular invasion, pTNM stage, predominant histologic pattern and histologic grade)(Results of test of interaction presented in a stratified way)

Sub-lobar resection vs. Lobectomy HR (95%CI) P INTERACTION P-value Overall 1.52 (1.07 to 2.17) 0.02 0.268 SND 1.98 (1.14 to 3.42) LS-ND 1.87 (0.94 to 3.74) NS 1.08 (0.61 to 1.93) LS-ND vs SND HR (95%CI) P INTERACTION P-value Overall 1.74 (1.16 to 2.6) 0.007 0.903 Lobectomy 1.66 (1.03 to 2.69) Sub-lobar resection 1.58 (0.75 to 3.32) NS vs. SND HR (95%CI) P INTERACTION P-value Overall 1.49 (1.12 to 1.98) 0.007 0.131 Lobectomy 1.61 (1.18 to 2.19) Sub-lobar resection 0.88 (0.43 to 1.82)

Median follow-up was 63 months. Eight-hundred forty-six (87%) patients were submitted to lobectomy, while 123(13%) to sub-lobar resection. Four-hundred fifty-five (47%) patients received SND, 98(10%) LS-ND and 416(43%) NS. Two-hundred forty-seven (26%) patients developed a local/distant recurrence with a 5-year CIR of 24%. Multivariable-adjusted comparisons showed an independent negative effect of sub-lobar resection(HR 1.52;95%CI:1.07-2.17), LS-ND(HR 1.74;95%CI:1.16-2.6) and NS(HR 1.49;95%CI:1.12-1.98) on CIR(Table). Test of interaction showed an homogeneity of results among subgroups.

Conclusion:
In our series, lobectomy and systematic lymph node dissection confirmed to be the optimal strategy to achieve a favorable prognosis in stage I adenocarcinoma of the lung. The real value of sub-lobar resection and less aggressive nodal staging should be assessed by randomized clinical trial before being integrated in clinical practice.

Background:
The IFCT-0302 trial is the first large randomized phase III multicenter trial which compared two follow-up modalities after surgery for early stage non-small cell lung cancer (NSCLC).

Method:
After complete resection of a stage pI, II, IIIA or T4 (pulmonary nodules in the same lobe) N0-2 NSCLC (TNM 6[th] edition), patients were randomized (1/1) between 2 follow-up programs: - arm 1, clinical examination and Chest X-ray, - arm 2, clinical examination, Chest X-ray, thoraco-abdominal CT-scan plus bronchoscopy (optional for adenocarcinomas). In both arms, procedures were repeated every 6 months after randomization during the first 2 years, and yearly until 5 years. The primary endpoint was overall survival (OS). Distinction between lung recurrences and 2[nd] primary lung cancer was assessed by investigators, using the Martini and Melamed definition (J Thorac Cardiovasc Surg 1975).

Result:
1775 patients were randomized (arm 1: 888; arm 2: 887). Patient characteristics were well-balanced between the two arms: males 76.3%, median age 63 years (range: 34-88), squamous and large cell carcinomas 39.5%, stage I 68.1%, stage II 13.7%, stage III 18.3%, lobectomy or bilobectomy 86,6%. OS and DFS were not significantly different between arms (OS: HR=0.92, 95% CI: 0.8-1.07; p=0.27). Median disease-free survival was 4.95 years (95% CI: 4.4- not reached) in arm 1 and not reached in arm 2, respectively. A recurrence was diagnosed in 245 patients (27.6%) in arm 1, and in 291 patients (32.8%) in arm 2. Recurrences were symptomatic in 203 (82.9%) and 163 (56.0%) patients, respectively. The most frequent sites of recurrence were: ipsilateral lung (42.0 and 33.0%), brain (29.4 and 23.4%), and contralateral lung (24.9 and 22.3%), respectively. Treatment of recurrence achieved complete remission in 25 (10.2%) and 52 (17.9%) patients (p=0.01), respectively. Second primary cancers (SPC) were diagnosed in 101 patients (11.4%) in arm 1, and 97 patients (10.9%) in arm 2, with symptoms at diagnosis in 64 (63.4%) and 37 (38.1%) patients, respectively. The most frequent sites of SPC were: lung (25.7 and 41.2%), prostate (14.8 and 11.3%), and ENT (11.9 and 7.2%), respectively. Treatment of SPC achieved complete remission in 30 (29.7%) and 40 (41.2%) patients (p=0.10), respectively.

Conclusion:
Although OS and DFS were not significantly increased by thoraco-abdominal CT-scan-based follow-up, recurrences or SPCs were more frequently asymptomatic and amenable to curative treatment in patients followed by thoraco-abdominal CT scan compared to those followed by chest X-ray only.

Background:
Adjuvant chemotherapy remains the most important treatment for stage IIIA non-small cell lung cancer (NSCLC) after radical operation, but its benefits has reached plateau and high risk of recurrence. Previous studies SELECT and RADIANT have suggested a trend of improving DFS of erlotinib as adjuvant therapy for patients with activating mutations. This study is designed as prospective, open-label, randomized, multicenter phase II trial to investigate the efficacy and safety of erlotinib (E) as adjuvant therapy in comparison with vinorelbine/cisplatin (NP) chemotherapy in completely resected stage IIIA EGFR mutant patients.

Method:
Patients aged between 18 – 75 with ECOG PS 0–1, stage IIIA, EGFR-activating mutation (exon 19 or exon 21 L858R), reached R0 resection NSCLC were eligible. And patients were randomized(1:1) into either erlotinib (orally 150mg/day for 2 years, util relapse or unacceptable toxicity) or NP (vinorelbine 25mg/m[2] i.v. day 1, 8 and cisplatin 75mg/m[2] i.v. day 1, every 3 weeks for 4 cycles) group. Random assignment was stratified by EGFR mutation type (exon 19 vs exon 21), histology (adenocarcinoma vs non- ) and smoking status (smoker vs non-). The primary endpoint was 2-year disease free survival rate (DFSR), secondary endpoints include disease free survival (DFS), overall survival (OS), safety (NCI CTCAE 4.0) and quality of life (QoL), and exploratory biomarker analysis.

Result:
From Sep, 2012 to May, 2015, in total 102 patients from 16 centers across China were randomized to receive E (N=51) or NP (N=51). Median follow-up time was 33 months for E and 28 months for NP. Baseline characteristics of age, sex, PS, histology, smoking status, EGFR mutation subtypes were well balanced in each arm. Two-year DFSR was 81.35% (95%CI: 69.63-93.08) in E arm and 44.62% (95%CI: 26.86-62.38) in NP arm respectively (P<0.001) in ITT population. DFS was significantly prolonged with E vs NP (median, 42.41 vs 20.96 months, HR 0.271, 95% CI: 0.137-0.535; P<0.001). OS data from our trial are still immature. In current, the number of death events were 2 (E) and 13 (NP) arm. Safety profile was similar to previous studies of each agent in NSCLC, no new unexpected AE were observed in each arms.

Conclusion:
As compared with NP, E showed superior efficacy and should be considered therapeutic option for patients with R0 resected stage IIIA NSCLC with EGFR-activating mutation. (EVAN, NCT01683175).

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Background:
A fourth of patients with cN1-NSCLC based on PET-CT imaging are at risk for occult mediastinal nodal involvement. In a previous prospective study, endosonography alone had an unsatisfactory sensitivity (38%) to detect mediastinal nodal disease. This prospective multicenter trial investigated the sensitivity of preoperative mediastinal staging by video-assisted mediastinoscopy (VAM) in patients with cN1 (suspected) NSCLC.

Method:
Consecutive patients with operable and resectable cN1 (suspected) non-small cell lung cancer (NSCLC) underwent a VAM or VAM-lymphadenectomy (VAMLA). All patients underwent FDG–PET and CT-scan. The primary study outcome was sensitivity to detect N2-disease. Secondary endpoints were the prevalence of N2-disease, negative predictive value (NPV) and accuracy of VAM(LA).

Result:
Figure 1 Out of 105 patients with cN1 on imaging, 26% eventually had N2-disease. Invasive mediastinal staging with VAM(LA) reached sensitivity of 73% to detect N2-disease. The median number of assessed lymph node stations during VAM(LA) was 4. In 96% ≥3 stations were assessed. VAMLA was performed in 31%, 69% underwent VAM.

		N	Prevalence of mediastinal disease	Sensitivity OR(95%CI)	Negative Predictive Value OR(95%CI)	Negative Posttest probability OR(95%CI)
Dooms et al. Chest. 2014; 147(1): 209–15.	Endosonography alone	100	24%	0.38 (0.18-0.57)	0.81 (0.71-0.91)	0.19 (0.13-0.27)
	Endosonograpy, if negative followed by mediastionoscopy			0.73 (0.55-0.91)	0.91 (0.83-0.98)	0.09 (0.04-0.17)
Current Study	Mediastinoscopy	105	26%	0.73 (0.54-0.86)	0.92 (0.83-0.97)	0.08 (0.03-0.17)

Conclusion:
VAM(LA) has a satisfactory sensitivity of 73% to detect mediastinal nodal disease in cN1-NSCLC and could be the technique of choice for pre-resection mediastinal lymph node assessment in this patient group with 26% chance of occult positive mediastinal nodes after negative PET-CT. (ClinicalTrials.gov NCT02222194)

Background:
The limited resection for lung cancer has become more prevalent for patients who show a compromised pulmonary or cardiac function. As of now standard care of lung cancer is lobectomy with lymph node dissection or sampling even for early lung cancer. Japan clinical oncology group (JCOG) study 0201 has proposed the criteria to diagnose pathological less-invasive lung adenocarcinoma by using consolidation to tumor ratio (CTR) on preoperative thin-sliced computed tomography (TSCT) scan. Three clinical trials have been ongoing based on this result, but the TNM classification was drastically revised in 2016, especially in T category. The aim of this study is to propose the new radiological criteria to predict pathological less-invasive lung cancer before surgery in accordance with the new TNM classification.

Method:
We analyzed the 744 patients who have peripheral Tis-T1cN0M0 non-small cell lung cancer with 3cm or less in size and underwent complete resection by lobectomy from 2003 to 2011. We defined a lung cancer with no nodal involvement and no vessel invasion pathologically as a pathological less-invasive cancer, and investigated the radiological criteria corresponding to the new T category by using TSCT to predict a pathological less-invasive cancer with the specificity of 97% or more. We also re-evaluated the criteria by adding the parameter of CTR and presence of ground-glass opacity (GGO), and prognostic parameters; overall survival (OS) and relapse-free survival (RFS).

Result:
The cTis/T1ami/T1a patients showed no pathological invasive cancer except for only 1 patient (specificity: 99%). In the cT1b/T1c patients, the specificity of cT1b with CTR 0.5 or less, cT1b with C/T ratio 0.75 or less, and cT1b with GGO presence were 100%, 97.1%, 94.4%, respectively. The new criteria of cT1a or less and cT1b with CTR 0.75 or less showed excellent prognosis for OS and RFS.

Conclusion:
As most of the patients with cTis/T1ami/T1a and cT1b with CTR 0.75 or less showed pathological less-invasive cancers and extremely good survival, they will be more likely to be obtained good outcomes by sublobar resection including wide-wedge resection as well. The further prospective study will be required to confirm the hypothesis.

Background:
It is necessary to apply a precise standard to predict the oncological outcomes among heterogeneous subgroups of N1 disease ranging from level 10 to 14. Although International Association for the Study of Lung Cancer (IASLC) proposed a new N descriptor in the 8[th] edition of the TNM Classification, lack of dissection on level 13 and level 14 may affect the efficacy of new classification. In this study, we tested a hypothesized classification strategy based on systematic dissection of N1 node from level 10 to level 14.

Method:
From March 2007 to December 2014, 156 consecutive patients of non-small cell lung cancer, treating with lobectomy and systematic mediastinal lymphadenectomy, were investigated. Nodes from level 10 to 12 were dissected during operation. Intrapulmonary lymph nodes (level 13-14) were retrieved after surgery. The data were prospectively collected and retrospectively analyzed. All cases were divided into two categories according to the 8[th] edition of the TNM Classification: pN1a was defined as N1 at a single station, while pN1b was defined as N1 at multiple stations. Then, in our proposed classification, N1a (modified) was defined as single level of N1 station involved (not including single level 10 or 11 spread) or level 13 and/or 14 involved, while N1b (modified) was defined as single level 10 or 11 spread or multiple levels of N1 node involvement (not including level 13 and 14 spread). The association between the N1 subgroup status and survival was explored separately using 8[th] IASLC classification and hypothesized classification.

Result:
In the whole cohort, a mean±SD of 13.1±7.1 N2 nodes and 12.0+5.2 N1 nodes per case were collected.There were 4.7±3.1 nodes from level 13 and 14. The difference in 5-year overall survival between pN1a and pN1b was not significant (73.9% versus 65.7%, p=0.371). However, the difference in 5-year overall survival between N1a (modified) and N1b (modified) was significant (79.1% versus 60.2%, p=0.018). Multivariate analysis showed the revised N1 classification was an independent prognostic factor for NSCLC (versus N1a, the hazard ratio [HR] of N1b for OS was 2.120, 95% confidence interval [CI]: 1.083-4.151, p=0.028). However, the 8[th] edition IASLC N1 descriptors was not an independent prognostic factor (versus pN1a, HR of pN1b was 1.419, 95% CI: 0.710-2.837, p=0.322).

Conclusion:
The hypothesized N1 classification in present study was shown to be a better descriptor to express the outcome than 8[th] edition of the TNM Classification of IASLC. More data are needed to validate this proposal.

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