Virtual Library

Abstract not provided

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

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

Abstract not provided

Abstract not provided

Abstract:
A cancer diagnosis is one of the most feared events rarely diagnosed before the late 20th century now competes with the Cardio-vascular disease, stroke, respiratory failure. The last half century has produced substantial advances in the treatment and early detection of few types of cancer and atleast modest gain in many other. Yet the reality is that half of the patients diagnosed with cancer will die within the first couple of years. With people living longer, the continued use of tobacco products, infectious disease that transmit cancer causing virus, and epidemic of obesity and arm-chair lifestyle, the cancer burden is projected to increase substantially over the decade. The delivery of high quality cancer care across the care continuum from diagnosis and treatment to maintaining the health of survivors and providing end-of-life care consistent with patients’ needs, values, and preferences. The provision of patient-centered care planning, palliative care, and psychosocial care; the prevention and management of long-term and late effects of cancer treatment; and family caregiver support should span the cancer care continuum from diagnosis through end-of-life care. The full cancer care continuum also includes the domains of prevention and risk reduction and screening. Cancer care for older adults, as noted throughout this report, is especially complex. Age is one of the strongest risk factors for cancer. The majority of cancer diagnoses and cancer deaths occur in individuals 65 years and older, and the majority of cancer survivors are in this age range. There are many important considerations to understanding the prognoses of older adults with cancer and formulating their care plans, such as altered physiology, functional and cognitive impairment, multiple coexisting morbidities, increased side effects of treatment, distinct goals of care, and the increased need for of social support. Their ability to participate in clinical trials has been limited, and thus the evidence base for informing treatment decisions in this population is lacking. The current health care delivery system is poorly prepared to address these concerns comprehensively. Thus, meeting the needs of the aging population will be an integral part of improving the quality of cancer care. Lung cancer is one of the commonest cancer causing death and it presents late. It is an extremely symptomatic disease and majority of the patients succumb to this disease. It is innately human to comfort and provide care to those suffering from cancer particularly who are close to death. Yet what seems evident as an individual’s personal level has by and large no guided policy all over the world. There is no argument that palliative care should be integrated into cancer care from diagnosis to death. Palliative care provides a specialized holistic approach to providing medical care with serious illness and the focus of Palliative Care is on providing relief from symptom and improving the quality of life of patients. Palliative Care is not End-of-Life or hospice but encompasses both. There is a dichotomy in the principle of medical care in cancer which single mindedly focuses on attempts to cure every patient at every stage. Recognition of the importance of symptom control and other aspects of Palliative care from diagnosis through dying process has been growing. Patients should not have to choose between treatment with curative intent or comfort care. There is need for both in varying degrees throughout the course of cancer whether the eventual outcome is survival or death. The goal is to maintain the best possible quality of life allowing the patients to choose whatever treatment they so wish while also meeting the needs of advanced disease through adequate symptom control. This goal is most often not met. For atleast half of those patients dying from cancer - most of whom are elderly and many vulnerable - death entails a spectrum of symptoms including pain, labored breathing, distress, nausea, confusion, and other physical and psychological conditions that go untreated and vastly diminishes the quality of remaining days. The patient is not the only one who suffers; family, care givers undergo unreleaved emotion and financial burden. This cannot be ignored within the context of the patients' who are terminally ill. A major problem in Palliative care is the under recognization, under diagnosis and thus undertreatment of the patients with significant stress ranging from existentional anguish, axiety and depression. Living with and eventually dying from a chronic illness runs substantial cost for patients, family, society and cost of those dying from cancer are 20% higher than average costs. Inadequacy of Palliative and End-of-Life care springs not from a single cause of a sector of society the separation of palliative and hospice care from potentially life prolonging treatment within the health care system, which is both influenced by and affects reimbursement policy; inadequate training of health care personnel in symptom management and other palliative care skills; inadequate standards of care and lack of accountability in caring for dying patients; disparities in care, even when available, for ethnic and socioeconomic segments of the population; lack of information resources for the public dealing with palliative and end-of-life care; lack of reliable data on the quality of life and the quality of care of patients dying from cancer (as well as other chronic diseases); and low level of public sector investment in palliative and end-of-life care research and training. This is not to suggest that there is no relevant ongoing research or relevant question or training program - there are - but the efforts are not coordinated and there is no focus for these activities in the Government agencies. What has resulted is under funding, lack of training and lack of research, leadership, with no sustained program for developing and disseminating Palliative treatment. Care for those approaching death is an integral and important part of health care. Everyone dies, and those at this stage of life deserve attention that is as thorough, active, and conscientious as that granted to those for whom cure or longer life is a realistic goal. Care for those approaching death should involve and respect both patients and those close to them. Particularly for patients with a grim prognosis, clinicians need to consider patients in the context of their families and close relationships and to be sensitive to their culture, values, resources, and other characteristics. Good care at the end of life depends on strong interpersonal skills, clinical knowledge, and technical proficiency , and it is informed by scientific evidence, values, and personal and professional experience. Clinical excellence is important because the frail condition of dying patients leaves little margin to rectify errors. Changing individual behavior is difficult, but changing an organization or a culture is potentially a greater challenge—and often is a precondition for individual change. Deficiencies in care often reflect flaws in how the health care system functions, which means that correcting problems will require change at the system level. The health care community has special responsibility for educating itself and others about the identification, management, and discussion of the last phase of fatal medical problems. Although health care professionals may not have a central presence in the lives of some people who are dying, many others draw heavily on physicians, nurses, social workers, and others for care—and caring. Thus, health care professionals are inescapably responsible for educating themselves and helping to educate the broader community about good care for dying patients and their families. More and better research is needed to increase our understanding of the clinical, cultural, organizational, and other practices or perspectives that can improve care for those approaching death. The knowledge base for good end-of-life care has enormous gaps and is neglected in the design and funding of biomedical, clinical, psychosocial, and health services research. Time is now to integrate Palliative care with mainstream care in cancer.

Abstract:
Southeast Asia comprises of 10 main countries including Malaysia, Indonesia, Thailand, Philippines, Singapore, Brunei, Cambodia, Laos, Myanmar and Vietnam. The concept of palliative care first developed around the mid-1980s in Singapore and the Philippines and later in the 1990s in Malaysia, Thailand and Indonesia. In other countries such as Brunei, Cambodia, Myanmar, Vietnam and Laos palliative care has only been developing more rapidly over the past 10 years. Levels of development of palliative care in Southeast Asia are highly variable depending very much upon factors such as availability of medical resources, funding, geography, demographics and the priorities of the country’s leadership. In 2011, the Worldwide Palliative Care Alliance(WPCA) mapped out the global development of palliative care dividing countries into 4 categories. Category 1 where there is no known development of palliative care, category 2 where development is at the level of capacity building, category 3 where there is isolated provision of palliative care services and category 4 where services are approximating integration into mainstream medicine. Among these countries, only Singapore and Malaysia have achieved category 4 status while majority are in category 3 (Indonesia, Thailand, Philippines, Myanmar, Cambodia, Brunei and Vietnam). Regardless of the level of development, challenges faced in developing palliative care in Southeast Asia are common throughout and include first and foremost barriers of drug availability and fear of using opioids amongst public as well medical practitioners. Apart from this is the challenge of public perceptions towards death and dying which have made development of this discipline difficult. Even till today there are many misconceptions regarding the role and concept of palliative care amongst healthcare professionals. For countries that are more advanced in their development, the key challenge now is how to continue development in a sustainable manner and how to improve and maintain standards of care. In Malaysia, palliative care began in the early 1990s with the development of voluntary organisations providing homecare services for patients with terminal cancer. In 1995 the concept was introduced into government hospitals and soon received nationwide support by the Ministry of Health in Malaysia. In 2005, the subspecialty of palliative medicine was established and a formalised training programme for medical specialists was developed. At present there are a total of 18 trained palliative medicine specialists in Malaysia with 2 more in training. In 2014, an advanced diploma programme for nurses, physiotherapists and occupational therapists was developed in the Ministry of Health which has now trained 38 nurses and paramedics who have now become permanent stakeholders in palliative care service provision and development. Apart from this, non-governmental organisations also serve as a backbone to community palliative care services in Malaysia and there are currently 25 services throughout the country providing homecare. It is with such initiatives that Malaysia hopes to create a sustainable and credible workforce to continue the development and growth of palliative care throughout the nation and possibly the region.

Abstract:
It is well known that palliative care is a necessity in cancer patients, as early on as the time of diagnosis. In adult oncology, there is evidence to suggest early specialist palliative care improves HRQOL, mood, treatment decision-making, health-care utilization, advanced care planning, patient satisfaction, and end-of-life care (1). Early admission to community-based palliative care also reduces the use of Emergency departments by cancer patients in the 90 days before death (2). Palliative care for cancer patients is rather new in Iran and has a history of less than 7 years. Here we give an overview on the status of palliative care in Iran. We also present the demographics of our patients in the first and largest palliative care ward in Iran over the last two years. Iran has a population of around 80 million people. In Iran, cancer is known as the third cause of death. Adult morbidity rate of cancer in different regions of Iran is estimated 48-112 cases per million people among the females and 51-144 cases per million people among the males (3). Also, mortality rate related to cancer was about 53500 people in 2014 (4). The majority of cancer patients expire in the intensive care units (ICU), whereas bed occupancy of ICUs is in crises, being about 100% in Iran. For each ICU bed, 4 people are applicants (5). We currently have around 8 active palliative care units for cancer patients and one palliative care ward in Iran, all run by charities. In these palliative care units, we have oncologists, palliative care specialists, pain specialists, psychologists, spiritual care specialists, social workers and dieticians. A total number of 3677 patients, ages between 16 and 94 (Median 61), of whom 3277 (89%) with a similar age distribution had a cancer diagnosis were referred to our palliative care unit in Firoozgar Hospital, which is run by the Ala Charity, in Tehran in the last three years. 1770 female (54%) and 1457 male (46%) advanced cancer patients were referred. A number of 388 (12%) patients had breast cancer, 339 (10%) had hematologic malignancies, 312 (10%) had esophageal or gastric cancer, 311 (10%) had colorectal cancer, 105 (3%) had a cancer of the CNS, 101 (3%) had lymphoma, 93 (3%) had renal cancer, 87 patients (3%) had ovarian cancer, 81 (2%) had lung cancer, 54 patients (2%) had prostate cancer and 50 (2%) had pancreatic cancer. The other 40% of the cancer patients had either less frequent cancers or their exact cancer site was not recorded. In most countries, the gap between death and specific therapies is considered as an indicator of the quality of physician services and more length of time will be a better indicator for physician services, while cancer patients in health system of Iran receive specific treatment and chemotherapy even to moment of death. To consider countless benefits of home care and the patients’ desire to receive services at home, if we can provide the conditions that at least 20% of end stage cancer patients receive home based palliative care, 1000 deaths will occur at home yearly, and 1000 ICU beds will be released for use for other patients with better prognosis for survival (5). For this reason, the Ala charity has also started free of charge home care services in Isfahan and Tehran. Iran, like many other countries, needs many more palliative care units as well as an expansion of home based palliative care services to advanced and very advanced cancer patients. As palliative medicine is not financially lucrative, charities play a major role in setting up, maintaining and expanding these units. References: Salins N, Ramanjulu R, Patra L, Deodhar J, Muckaden MA. Integration of Early Specialist Palliative Care in Cancer Care and Patient Related Outcomes: A Critical Review of Evidence. Indian J Palliat Care. (2016) 22:252-7 McNamara BA, Rosenwax LK, Murray K, Currow DC. Early admission to community-based palliative care reduces use of emergency departments in the ninety days before death. J Palliat Med. (2013) ;16:774-9 Mousavi SM, Gouya MM, Ramazani R, et al. Cancer incidence and mortality in Iran. Annals of Oncology. (2009) ;20:556–63. World Health Organization. Cancer country profiles in Iran 2014. Geneva: WHO; 2014. [cited 29 August 2015]. Avilable from: http://www.who.int/cancer/country-profiles/en/ Heydari H. Home-based Palliative Care: A Strategy for Keeping Intensive Care Unit Beds Vacant. Int J Community Based Nurs Midwifery. (2016);4:186-7.

Abstract not provided

Abstract not provided

Abstract not provided

Abstract:
In the diagnosis of lung cancer the primary diagnostic approach is microscopic evaluation of tissue biopsy. However, in many cases the only material for microscopic evaluation is cytological one. There are numerous types of cytological material in evaluation of lung tumors including sputum, bronchial brush, bronchial washing, transthoracic and transbronchial fine needle aspirates. Historically sputum was the most common diagnostic material but at present the most common types of cytological specimen are bronchial brush, and transthoracic or transbronchial FNAB. Nowadays worked out and recognized cytological criteria allows not only to diagnose carcinoma but in majority of cases to specify the histologic type of a tumor. This approach to microscopic diagnosis of lung carcinoma was incorporated to the latest WHO classification of lung tumors (ref). The key reason that cytodiagnosic criteria and terminology were included into WHO classification was that in about 30% cases of lung tumors the cytological specimen is the only material for microscopic evaluation. Similarly to evaluation of small tissue biopsies in cytopathology, in doubtful cases, immunocytochemistry may be implemented to determine histologic type of tumor. Most useful in evaluation of cytological specimen are IHC antibodies with nuclear presentation. (e.g. p40 for squamous cell carcinoma and TTF1 for adenocarcinoma). Cytological material may be utilized in evaluation and in differential diagnosis between primary and metastatic lung tumor. The panel of the antibodies (e.g. CDX2, PSA, Melan A ) may be used to indicate location of primary tumors mainly adenocarcinomas. Since cytological smears are of limited diagnostic value for immunocytochemistry, the so-called cell blocs technique is recommended. This technique allows to use larger panel of antibodies for immunohistochemical evaluation. Cytology become very useful for clinical staging of lung carcinoma routinely utilizing EBUS and EUS technique for obtaining material from parahilar and mediastinal lymph nodes. Cytological criteria are similar to that used for specimens obtained by transthoracic FNAB. In our center practice cooperation with adequately trained thorax surgeons provides adequate material for microscopic evaluation from EBUS and EUS obtained specimens in 94% cases. Currently one of the important task for pathologist in evaluating material from lung carcinoma is adequate selection of the material for molecular test. In case of lung carcinoma or to be specific lung adenocarcinoma â material is selected for evaluation of EGFR and K-RAS mutation. In our experience cytological material particularly fine needle aspirates - fulfill such demands. Percentages of tumors cells in the sample is often even higher than in tissue sections especially in fine needles of peripherally location lesions. Cytological material may be useful in evaluation of EGFR and K-RAS mutation as well as in determination of presence of translocations of ALK and ROS1 using FISH technique. Evaluation of ALK and ROS1 translocation remained in the hands of cytopathologists since the crucial point is the location of translocation in nuclei of tumors cells. Latest challenge for pathologists evaluating lung carcinoma specimen is to determine predictive criteria for immunotherapy in those tumors. At the moment it seems that cytological material may be not satisfactory for adequate evaluation of immunocytochemical expression of PD-L1 and PD-1. In summary cytological material from lung carcinoma is useful in establishing the firm microscopic diagnosis of malignancy, to determine histologic type and to be used for molecular tests. It also allows to differentiated between primary and metastatic lung malignancies as well as determined primary location of metastatic lung carcinoma. Cytological specimens obtained by EBUS and EBUS techniques are very useful in clinical staging of lung carcinoma. Reference Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG eds. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4[th] ed. Lyon, France: IARC Press; 2015

Abstract not provided

Background:
Early detection of LC has been well established as a significant key point for patient survival and prognosis. New sensitive nanoarray sensors for exhaled Volatile Organic Compounds (VOCs) were developed and coupled with powerful statistical programs; diseases such as LC could be suspected.

Methods:
Breath samples were taken from patients who were evaluated for pulmonary nodules, LC patients before treatment and other control patients. 'Breath-prints' were recognized by nanomaterial based sensor array/Artificial Olfactory System (NaNose®) and Pattern recognition methods were used.

Results:
A total of 139 patients participated in this study, 30 patients with benign nodules, 89 LC patients (16 early and 73 advanced disease) and 20 controls. We revealed significant discrimination between all groups with accuracy of 75.6% to 90.9%. Discrimination of LC from benign nodules had 79% accuracy, while benign nodules could be discriminated from early LC lesions with positive and negative predicted values (PPV and NPV) of 87.7 and 87.5% respectively, and accuracy of 87%. Also, we could discriminate LC patients who harbor EGFR mutations (19) from wild-type (34) with an accuracy of 83%, a sensitivity of 79% and a specificity of 85%. Figure 1



Conclusion:
Breath analysis could discriminate LC patients from benign pulmonary nodules and between EGFR positive and negative mutations. In future, a portable, non-expensive, simple and user-friendly device may support evaluation of pulmonary nodules.

Background:
The LuCED test for early stage lung cancer detects rare abnormal cells that are exfoliated from tumors into sputum and promotes cancer case detection with >92% sensitivity and >95% specificity. Additionally, the LuCED test detects endobronchial lung dysplasia to triage patients with pre-cancer to chemoprevention therapy involving drugs such as Iloprost that show potential for reversing dysplasia. This test is complementary to lung cancer screening methods such as LDCT that do not detect dysplasia. We discuss the performance of the LuCED test for the non-invasive detection of endobronchial dysplasia.

Methods:
We analyzed 23,188 normal, 690 cancer, and 65 moderate/severe dysplasia cells from patient sputum. Each individual cell was imaged in 3D using the Cell-CT. Cells were analyzed to measure 594 3D structural biomarkers. Classifiers were developed with cytopathology as the gold standard to predict stages of carcinogenesis, from normal to dysplasia and cancer. The classifier output was binned into two diagnostic indications: 1) cancer vs. all other cell types; and 2) moderate/severe dysplasia vs. all other cell types.

Results:
Areas under ROC curves for the two diagnostic bins were both = 0.993. Thresholds were chosen to yield case specificity >95%. Using these thresholds, cell classification sensitivity of 75% was measured for cancer and dysplasia detection. Since abnormal sputum typically contains at least three abnormal cells the cancer case detection sensitivity is at least {100% x [1 – (1 - 0.75)[3]]} = 98%.Figure 1 Figure 1 shows ROC curves plus examples of cells imaged in 3D by the Cell-CT.



Conclusion:
This study demonstrates the feasibility of using the LuCED test to detect endobronchial dysplasia in the lung, achieving an estimated 98% case sensitivity and 95% case specificity. Future efforts will include testing on independent sets. Importantly, the non-invasive detection of dysplasia by LuCED testing may enable chemoprevention of lung cancer using drugs such as Iloprost.

Background:
LDCT screening for lung cancer often triggers follow-up scans for indeterminate nodules. The non-invasive LuCED test for detection of early stage lung cancer may resolve nodule findings and reduce LDCT false positives. In LuCED, patient sputum is analyzed by the Cell-CT® which computes 3D images of single cells allowing measurement of 3D structural biomarkers to identify potential abnormal cells. Final case disposition is determined through cytology review of these cells. Example images of abnormal cells identified by LuCED are shown in the figure. Figure 1



Methods:
Sputum samples from 127 patients were processed by LuCED: 65 patients had biopsy-confirmed lung cancer; and 62 patients were normal controls. Sensitivity was computed as the percentage of cancer cases where abnormal cells were found by LuCED. Generally, abnormal cells found in a case otherwise understood to be normal could constitute a diagnostic overcall and counted as a false positive. However, a finding of abundant (>5) abnormal cells in cases understood to be normal indicates discovery of a possible occult cancer or dysplastic lesion. Accordingly, these cases were not included in specificity calculations.

Results:
For cancer cases, the histology included adenocarcinoma (29 cases), squamous cancer (24), small cell lung cancer (5) and undifferentiated cancer (7); representing stages 1 (14), 2 (11), 3 (25), 4 (14), and unknown (1). Abnormal cells were found in 61 of 65 cancer cases for sensitivity of 93.8%. For stage 1 and 2 cancer, sensitivity was 88%. Ten cells exhibiting changes consistent with atypical adenomatous hyperplasia were found in one case. After removal, there remained two false positive cases, leading to specificity of 96.7% (N = 61).

Conclusion:
The LuCED test demonstrates accurate detection of early stage lung cancer with the potential of detecting pre-cancerous conditions of the lung. Results suggest that suspicious nodules may be efficiently reconciled by LuCED when used adjunctively with LDCT.

Abstract not provided

Background:
It is uncertain how long persistent and stable ground-glass nodules (GGNs) should be followed although a minimum of 3 years is suggested. Here, we aimed to evaluate the proportion of GGNs showing subsequent growth after initial 3 years among GGNs that had been stable during the initial 3 years, and to determine clinical and radiologic factors associated with subsequent growth.

Methods:
We retrospectively analyzed patients who underwent further computed tomography after the initial 3-year follow-up period showing a persistent and stable GGN (at least 5-year follow-up from initial CT).

Results:
Between May 2003 and June 2015, 453 GGNs (438 pure GGNs and 15 part-solid GGNs) were found in 218 patients. Of the 218 patients, 14 patients had 15 GGNs showing subsequent growth after the initial 3 years during the median follow-up period of 6.4 years. For the person-based analysis, frequency of subsequent growth of GGNs that had been stable during initial 3 years was 6.7% (14/218). For the nodule-based analysis, the frequency was 3.3% (15/453). In a multivariate analysis, age ≥ 65 years (odds ratio [OR], 5.51; p = 0.012), history of lung cancer (OR, 6.44; p = 0.006), initial size ≥ 8 mm (OR, 5.74; p = 0.008), presence of a solid component (OR, 16.58; p = 0.009), and an air bronchogram (OR, 5.83; p = 0.015) were independent risk factors for subsequent GGN growth.Between May 2003 and June 2015, 453 GGNs (438 pure GGNs and 15 part-solid GGNs) were found in 218 patients. Of the 218 patients, 14 patients had 15 GGNs showing subsequent growth after the initial 3 years during the median follow-up period of 6.4 years. For the person-based analysis, frequency of subsequent growth of GGNs that had been stable during initial 3 years was 6.7% (14/218). For the nodule-based analysis, the frequency was 3.3% (15/453). In a multivariate analysis, age ≥ 65 years (odds ratio [OR], 5.51; p = 0.012), history of lung cancer (OR, 6.44; p = 0.006), initial size ≥ 8 mm (OR, 5.74; p = 0.008), presence of a solid component (OR, 16.58; p = 0.009), and an air bronchogram (OR, 5.83; p = 0.015) were independent risk factors for subsequent GGN growth.

Conclusion:
For the individuals with GGNs having risk factors described above, the longer follow-up period is required to confirm subsequent GGN growth.

Background:
The high number of false positive screen results is a major disadvantage of lung cancer screening by low-dose chest computed tomography (CT). Measurement strategy influences the false-positive rate, and nodule morphology may influence measurement of nodule size. Comparison between inter-reader variation for semi-automatic volume measurements and manual diameter measurements are scarce. Therefore, we aimed to evaluate the influence of nodule morphology on inter-reader variability and assessment of growth for semi-automatic volume measurements and manual diameter measurements, in intermediate-sized solid nodules found in CT lung cancer screening.

Methods:
Twenty-five nodules of each morphological category: smooth, lobulated, spiculated and irregular, were randomly selected from 93 participants of the Dutch-Belgian randomized lung cancer screening trial (NELSON). Semi-automatic volume measurements were performed using Syngo LungCARE[®] software. Two chest radiologists independently measured maximum and mean diameters manually. The impact of nodule morphology on inter-reader variability was evaluated based on the systematic error and 95% limits of agreement (LoA). Inter-reader variability was compared to volume change cutoff at 3-month follow-up based on NELSON for nodule growth and Lung-RADS diameter cutoff.

Results:
For manual diameter measurements, a significant systematic deviation was found between readers in smooth, lobulated, and spiculated nodules. The deviation was up to 1.5 mm based on maximum diameter measurements, and 1.2 mm based on mean diameter measurements. For semi-automatic volume measurements, no statistically significant systematic deviation was found. For lobulated, spiculated, and irregular nodules, the 95%-LoA for mean diameter measurements was up to 66% larger than the 1.5 mm cutoff for nodule growth. For volume measurements, the 95%-LoA exceeded the 25% growth cutoff for spiculated and irregular nodules, but only by up to 12%.

Conclusion:
Nodule morphology has a greater effect on size assessment based on manual diameter measurements than based on volume measurements. The larger inter-reader variability for manual diameter measurement may cause misclassification of spiculated nodules when assessing growth in 24% of cases. Therefore, semi-automatic volume measurement is recommended for nodule size and growth determination in CT lung cancer screening.

Abstract not provided

Background:
Low Dose Computed Tomography (LDCT) screening for lung cancer (LC) is still not recommended in Europe.

Methods:
71.232 invitation letters were sent to subjects registered with local General Practitioners, aged 55­69 years. (Fig.1) From eligible respondents, we randomised 3206 eligible subjects, smokers and ex- smokers (< 10 years), to the active arm receiving 4 annual LDCT (n=1613) and to control arm receiving usual care (n=1593). Each LDCT was read by 2 radiologists and size of Non Calcific Nodules measured manually. Study design and performance data were already published. All subjects, enrolled from 2004-2009,were followed up for lung cancer incidence and mortality (average: 8.3 and 9.3 years, respectively); characteristics of enrolled subjects are presented in Table1. Figure 1Figure 2





Results:
Reductions of 17% (RR=0.83; 95%: 0.67-1.03) for overall and 30% (RR=0.70; 95%CI: 0.47-1.03) for LC-specific mortality were estimated. 67 lung cancers were diagnosed in the active, compared with 72 in the control group (RR=0.92; 95%CI: 0.66–1.28). A greater proportion of Stage I (36% vs 6%, (p<0.0001) was observed in the active group.

Conclusion:
LDCT screening could reduce LC-specific and overall mortality. The number of Lung cancer diagnosed in the two groups did not suggest over-diagnosis, after 8.5 years of follow-up time.

Background:
In BRELT1 we found a significant number of low dose CT (LDCT) considered positive (nodules > 4mm). The aim of this study was to assess the effect of applying ACR Lung-RADS and Pre-Test Probability of Malignancy (PTPM) in suspicious nodules > 8mm founded in a clinical CT lung screening program.

Methods:
Clinical LDCT (baseline and follow up) containing nodules > 8mm were retroactively reclassified using the new ACR Lung-RADS™ structured reporting system and PTPM. The model used in this study to predict the probability of malignancy was designed by Swensen et al and included patient’s age, current or former smoker, diameter of the nodule, speculation and location. All LDCT had initially been interpreted by radiologists accredited in CT lung screening reporting following the National Comprehensive Cancer Network’s Clinical Practice Guidelines in Oncology: Lung Cancer Screening (version 1.2012), which considered as positive the same criteria from the National Lung Screening Trial.

Results:
In BRELT1 were recruited 790 current or former smokers, with a heavy smoking history. A total of 552 nodules were found in 312 positive LDCT at baseline (39%). LDCT follow up was performed in 89.1% of this population. From them 74 patients presented solid or semi solid nodules > 8mm in the highest diameter. According to ACR Lung-RADS™ 39 baseline LDCT were classified as 4A (52.7%), 6 as 4B (8.1%), 17 as 4X (22.9%) and 10 as 2 (13.5%). Follow-up LDCT showed reduction in the category in more than 80% of cases. Using the PTPM, 44 cases were considered at moderate risk (between 6 and 60%) and 30 cases of high risk for malignancy (over 60%). None was considered low risk (5% or less). Among 26 patients who underwent biopsy in BRELT1, we found 12 cases of lung cancer, of which 90% were stage IA or IB.

Conclusion:
The application of ACR Lung-RADS and PTPM associated with careful multidisciplinary assessment can help in the decision process. The follow-up of patients with positive nodules requires careful analysis of the main factors related to malignancy.

Background:
Lung cancer is the leading cause of cancer deaths both in men and women in either Wielkopolska and the whole Poland. Wielkopolska is one of Polish regions (voivodships) with about 3,4 mln inhabitants and incidence of lung cancer aprox. 1900 new cases every year. Screening by low dose computer tomography (LDCT) showed reduction of lung cancer mortality in NLST trial. Regional authorities covered this program from local budget beside Polish health system.

Methods:
Since october 2009 program of early detection of lung cancer started in 5 centers of Wielkopolska region. Till the end of 2015 N=17222 subjects were screened. The entry criteria were: age between 55 and 70 years and smoking ≥ 20 packyears. Every person has the LDCT performed. Results were first clasified as normal or abnormal. Abnormalities were divided into 6 categories: <5mm single, <5 mm multiple, 5-15 mm single, 5-15 mm multiple, >15 mm single, >15 mm multiple. Patient received also recomendation for further actions. Results presented are based on annual reports for regional authorities.

Results:
More than 85% of the images were clasified as abnormal. Nodes of any kind were found in about 47% of entire population. More than 3000 patient received recomendation for further diagnostic evaluation. Finally 108 patients underwent surgery (37 lobectomies, 41 wedge resections, 30 thoracotomies/thoracoscopies). There were 92 cases of lung cancer confirmed (11 SCLC, 78 NSCLC, 3 carcinoids) and 1 case of mesothelioma.

Conclusion:
Lung cancer screening program identifies magnitude of lung changes. Many patients requires further diagnostic procedures. Most of them are fibrotic, post inflammatory changes. It is possible to diagnose lung cancer in early presymptomatic stage but numbers are low and risk models or biomarkers should be implemented to better define patients / nodules at risk.

Abstract not provided

Background:
The balance of benefits and harms of screening programs depends on multiple factors such as the scenario of patient selection, the triage algorithm and the imaging methods. Because of the multifactorial nature of the outcome of screening programs, it is important to evaluate the performance of its components. We modeled the triage algorithm of the NELSON program for lung cancer screening in different scenarios in order to assess the robustness of the chosen approach. We are looking to develop a model that allows for testing the imaging protocol performance using various high-risk screening populations. Our Objective is to work out a simulator adaptive to multiple screening scenarios. In a first step, we tested a simulation of the NELSON triage algorithm by using published statistics as input data: the distribution of nodule size, the precision of nodule volume measurements and the distribution of nodules growth.

Methods:
We modeled the baseline round of NELSON triage algorithm. We simulated 10,000,000 ground truth (GT) data where the axial diameter of nodules followed a chi2 (df=1) distribution between 3 mm and 20 mm. For each of the GT nodule, we modeled also a chi2 (df=1) distribution of volume doubling time between 90 and 1000 days. We included into the model a Gaussian distribution of the time between visits (average: 105 days, standard deviation: 5 days). We modeled volume measurement of the nodules by adding a Gaussian random error as documented by the Quantitative Imaging Biomarker Alliance (QIBA) screening profile. We performed a by-nodule comparison between nodule classification by the triage algorithm and the corresponding GT in the first round. At each step of the triage algorithm, we evaluated Sensitivity (Se), Specificity (Sp), Positive Predictive Value (PPV) and Negative Predictive Value (NPV).

Results:
Sensitivity of the triage algorithm for classifying nodules into size categories was for 96,6% for NODCAT2, 86.9% for NODCAT3 and 90.7% for NODCAT4. Classification of GROWCAT C yielded Se=66.2% / Sp=21.2%. We found an overall performance of the NELSON triage algorithm of Se/Sp 94.0%/80.3%.PPV was 11.3%, and NPV was 99.8%

Conclusion:
Mathematical modeling gives valuable insights into the performance of different components of triage algorithms in lung cancer screening. We found a markedly different test performance for size versus growth assessment of the NELSON triage algorithm. Future work will extent the model to non-solid nodules and multiple rounds of screening. Moreover, it may have the potential to optimize triage algorithms in the design of screening programs.

Abstract not provided

Abstract not provided

Abstract not provided

Abstract:
Despite substantial reductions in smoking prevalence, lung cancer is the leading cause of cancer-related mortality for both genders in the United States. In 2016, lung cancer is expected to be responsible for 158,080 deaths. Tobacco smoking is still the number one risk factor for lung cancer and has been linked to 90% of all lung cancer cases. Currently, only 15% of all lung cancer cases are diagnosed at an early stage. Historically, these poor rates were due to the lack of effective routine screening. This changed dramatically in November 2011 when the National Lung Cancer Screening Trial (NLST), released their results that showed low-dose computed tomography (LDCT) could reduce lung cancer mortality by 20%. LDCT is now widely recommended for current and former smokers. Identification of all barriers and facilitators is essential for the successful promotion of lung cancer screening. Denormalization of smoking has been one of the most successful tobacco control measures and is associated with a sharp decrease in the prevalence of smoking. However, smoking is now concentrated in the most vulnerable populations (e.g. lower income groups and the mentally ill) who have the least ability and/or willingness to quit. In addition, denormalization has the effect of sanctioning smoking related stigma. A majority (95 %) of lung cancer patients experience stigma, with 48 % of lung cancer patients specifically reporting feeling stigmatized by their medical providers. Perceived lung cancer stigma is defined as a personal experience characterized by exclusion, rejection, blame or devaluation. Lung cancer conjures up attributions of blame because it is associated with smoking cigarettes and is perceived to be a controllable behavior. Perceived lung cancer stigma is a risk factor for poor psychosocial and medical outcomes in the context of lung cancer diagnosis and treatment. People often associate lung cancer with previous smoking behavior, regardless of whether the person with lung cancer was a smoker or not. There is growing body of evidence that patients, caregivers, healthcare providers, and members of the general public have negative implicit attitudes toward lung cancer. Perceived lung cancer stigma is one barrier that can delay the detection of lung cancer because of fear of health professionals’ censure associated with smoking. In our previous work we found that there were four beliefs associated with whether older (>55) current and former smokers would agree to lung cancer screening (LDCT): Perceives accuracy of the LDCT as an important factor in the decision to have a LDCT scan; Believes that early detection of LC will result in a good prognosis; Believes that they are at high risk for lung cancer; and is not afraid of CT scans. This study showed that older smokers are aware of the risks of smoking, are interested in smoking cessation, and most are interested in and positive about LDCT. There are no studies that have examined the impact of perceived lung cancer stigma on the decision to have an LDCT. To address this gap, we conducted a secondary analysis in which lung cancer stigma was measured by five true or false items: doctors treat smokers badly; doctors have a bias against smokers; cigarette smokers keep their smoking a secret from important people in their lives; cigarette smokers avoid talking about smoking with their doctor; cigarette smokers feel guilty about their smoking; and friends and family are upset that I smoke. Four variables demonstrated a significant association with LDCT agreement: People treat smokers badly; Doctors have a bias against smokers; Smokers feel guilt about smoking; and Friends and family do not approve of my smoking. Only two of the independent variables made a unique statistically significant contribution to the model. A test of the model against a constant only model was statistically significant, indicating that the predictors as a set, reliably distinguished between those who would agree to an LDCT and those who would not agree (chi square = 8.5 p. = <.1 with df = 4). The model as a whole explained between 43% of the variance in agreement to have a CT scan, and correctly classified 83.2% of cases. The strongest predictor for agreeing to a LDCT was “People treat smokers badly”, (OR 3.7, 95% CI .143-.971). Participants with this belief were almost 4 times less likely to agree to a CT scan than those who did not have the belief. The odds ratios for the remaining predictor, Doctors have bias against smokers, was OR 1.7, 95% CI 1.47- 4.90); Believes that they are at high risk for LC (OR 2.1, 95% CI 1.8 – 3.12). DISCUSSION The decision to agree to a LDCT is negatively associated with two indicators of perceived stigma, “people treat smokers badly” and “doctors have a bias against smokers.” These findings suggest that stigma is a barrier to preventative care utilization much like it is for patients with HIV, STDs, TB and mental health problems. Smokers from deprived communities are an important group to engage with lung cancer screening but thus far participation in trials has been skewed towards former smokers and better educated smokers. With the current demographic profile of smokers, the effectiveness of a lung cancer screening program depends in part on whether there are inequalities in participation which has the potential to exacerbate disparities in lung cancer survival. Given the impact of lung cancer stigma on satisfaction with care and patient outcomes it is imperative that further research explore the association of perceived lung cancer stigma and the decision to have LDCT.

Abstract:
Background As the most common cancer and the leading cause of cancer deaths worldwide, lung cancer has garnered increasing attention and efforts to reduce its toll. In contrast to the wealth of information on lung cancer burden for the general population, a rapid review of the academic literature (published in the past 10 years) to identify articles about lung cancer in Indigenous populations of four comparable OECD countries, found a paucity of information. The reasons for the paucity of articles are multi-faceted and most likely related to the lack of indigenous identification in health and cancer administrative datasets, among other issues. The search identified 62 articles which documented disparities in lung cancer outcomes for Indigenous peoples, identified likely reasons and made recommendations for better targeted prevention and management strategies. Indigenous people in all four countries, namely Aboriginal and/or Torres Strait Islanders in Australia; Māori in New Zealand; First Nations, Métis or Inuit in Canada; American Indians and/or Alaskan Natives (AIs/ANs) in the United States (US), have significantly lower life expectancy than their non-Indigenous counterparts, to which their lung cancer burden must surely contribute. The burden of lung cancer for Indigenous populations Lung cancer is one of the most commonly occurring cancers for indigenous people across all four countries. It has recently been reported that lung cancer incidence is higher in Indigenous men in Australia, Canada’s Métis and in Alaskan Natives than in their non-indigenous counterparts, and in Māori women, Alaskan Native women and Indigenous women in some Australian States [1]. Lung cancer is the leading cause of cancer deaths in Indigenous Australians (1 in 4 cancer deaths) and Māori where mortality rates were three times those of non-Māori (nearly 1 in 3 cancer deaths) [1, 2]. Lung cancer mortality among the Alaskan Native population is higher than the US white population, and among the highest of any racial/ethnic group in the US [3]. Survival following a diagnosis of lung cancer was lower for indigenous people in all four countries compared to their non-indigenous counterparts [4, 5, 6]. For example for Indigenous Australians five year survival following a diagnosis of lung cancer was 7% compared with 11%. Indigenous Australians are 1.7 times more likely to die from lung cancer than non-Indigenous Australians. In Australia, lung cancer accounted for 25% of all Indigenous deaths from cancer [2]. In the USA and Canada lung cancer survival rates improved over time for non-indigenous populations but remained unchanged or declined for the AI/AN and First Nations cohorts [6, 8], increasing disparities. Explaining the disparities The greater burden of lung cancer in indigenous populations is largely attributable to the higher prevalence of tobacco smoking. In both Australia and New Zealand, 39% of the Indigenous populations aged 15 and over were daily smokers – almost 3 times the rate of the non-Indigenous populations [4, 9]. AI/AN populations had the highest tobacco use (29%) of any population group in the USA [10]. Smoking rates among Canada’s Aboriginal populations are on average twice as high as those of non-Aboriginal Canadians, with nearly half of Inuit adults smoking daily or regularly [11]. While smoking rates in all four countries have decreased, the decline in indigenous smoking prevalence has occurred at the same or slower rate than for non-indigenous people, meaning the gap in smoking rates has remained. Although higher lung cancer incidence and mortality rates for indigenous peoples is related to patterns of tobacco use, they also reflect the significant disparities in terms of socio-economic disadvantage, social dislocation, geographic/remoteness and related stressors indigenous people face [1]. Poorer survival of indigenous people with lung cancer is attributed to a greater likelihood of advanced disease at diagnosis [12], lower rates of treatment, not receiving optimal lung cancer care concordant with clinical guidelines care [1, 7, 13, 14], and higher prevalence of comorbidities [2]. But these factors do not explain all the survival disparities. Recent research has shifted focus from patient and community-level factors to examining system-level and societal factors that affect lung cancer care and outcomes for indigenous patients including difficulty accessing health services and the cultural appropriateness of healthcare services [6]; lack of coordination and follow-up processes [15, 16]; health professional behaviours including knowledge about lung cancer, relationships with patients and carers, communication and responsiveness to needs [15, 16]; and the impact of stigma and shame on delays in medical help-seeking and lung cancer patients’ quality of life [16]. Strategies to reduce the disproportionate burden The current evidence highlights that significant disparities exist in lung cancer outcomes between indigenous and non-indigenous peoples and that multiple strategies are required to reduce the burden of lung cancer for indigenous people. At the systems level, inclusion of an indigenous identifier in administrative data is required to accurately identify and monitor lung cancer outcomes. The provision of and timely access to medically effective and culturally accepted diagnostic, treatment and support services, and personalised care that addresses the social-cultural needs of indigenous patients, is required to improve indigenous patients engagement with cancer care services and, in turn, cancer outcomes [12]. Tobacco control and smoking cessation initiatives are critical – but there is limited evidence about what works in indigenous populations. While public policy initiatives have reduced overall smoking prevalence, they appear to have had less impact on smoking rates among indigenous populations. Well-targeted tobacco control strategies need to consider historical, social, economic and cultural reasons why indigenous people smoke – factors that also can undermine efforts to reduce smoking uptake and encourage indigenous people to quit. The use of both comprehensive and tailored interventions has been recommended, including culturally appropriate health materials and activities, with indigenous peoples’ engagement and control [17]. It is also essential to increase symptom awareness to expedite diagnoses, and there are novel initiatives aimed at improving awareness of lung cancer risk factors and symptoms among indigenous communities and health professionals. Reducing the disproportionate burden of lung cancer on indigenous peoples requires targeted and multifaceted approaches that recognise and address the broad and interconnected web of factors at patient, provider and system levels that impact on optimal care and outcomes. References 1. Moore, S.P., et al., Cancer incidence in indigenous people in Australia, New Zealand, Canada, and the USA: a comparative population-based study. Lancet Oncol, 2015. 2. Australian Institute of Health and Welfare, Cancer in Australia: an overview 2014. Cancer series No 90. Cat. no. CAN 88. 2014, AIHW: Canberra. 3. Lanier, A.P.D., G. E.;Kelly, J. J.;Provost, E., Disparities in cancer mortality among Alaska Native people, 1994-2003. Alaska Med, 2008. 49(4): p. 120-5. 4. Australian Institute of Health and Welfare & Cancer Australia 2013. Cancer in Aboriginal and Torres Strait Islander peoples of Australia: an overview. Cancer series no 78. Cat. No. CAN 75. Canberra:AIHW 5. NZ Ministry of Health (2015) Cancer Patient Survival: 1994 to 2011 Wellington 6. Nishri, E.D.S., A. J.;Withrow, D. R.;Marrett, L. D., Cancer survival among First Nations people of Ontario, Canada (1968-2007). Int J Cancer, 2015. 136(3): p. 639-45. 7. Smith CB, Bonomi M, Packer S, Wisnivesky JP. Disparities in lung cancer stage, treatment and survival among American Indians and Alaskan Natives. Lung Cancer. 2011 May;72(2):160-4. doi: 10.1016/j.lungcan.2010.08.015 8. White, M.C.E., D. K.;Swan, J.;Wiggins, C. L.;Eheman, C.;Kaur, J. S., Disparities in cancer mortality and incidence among American Indians and Alaska Natives in the United States. Am J Public Health, 2014. 104 Suppl 3: p. S377-87. 9. Ministry of Health, Tobacc use 2012/13: New Zealand health survey. 2014, Ministry of Health: Wellington. 10. Centers for Disease Control and Prevention, Current Cigarette Smoking Among Adults—United States, 2005–2014. Morbidity and Mortality Weekly Report, 2015. 64(44): p. 1233-40. 11. Statistics Canada, Select health indicators of First Nations people living off reserve, Métis and Inuit. Catalogue no. 82-6240X. 2013. 12. Moore, S.P.G., Adèle C.;Bray, Freddie;Garvey, Gail;Coory, Michael;Martin, Jennifer;Valery, Patricia C., Survival disparities in Australia: an analysis of patterns of care and comorbidities among indigenous and non-indigenous cancer patients. BMC Cancer, 2014. 14: p. 517-517. 13. Javid, SH, Varghese TK, Morris AM, Porter MP, He H, Buchwald D, Flum DR; Collaborative to Improve Native Cancer Outcomes (CINCO). Guideline-concordant cancer care and survival among American Indian/Alaskan Native patients. Cancer. 2014 Jul 15;120(14):2183-90. 14. Whop, LJ, Bernardes CM, Kondalsamy-Chennakesavan S, Darshan D, Chetty N, Moore SP, Garvey G, Walpole E, Baade P, Valery PC. Indigenous Australians with non-small cell lung cancer or cervical cancer receive suboptimal treatment. Asia Pac J Clin Oncol. 2016 Mar 21. doi: 10.1111/ajco.124632016 15. Dunn, J. , Garvey, G., Valery, P. C., Ball, D., Fong, K.M. , Vinod, S., O’Connell, DL. & Chambers, S.K. Barriers to Lung Cancer Care: Health Professionals’ Perspectives. Accepted for publication 24[th] September 2016. Journal of Supportive Care in Cancer 16. Chambers, S.K.B., P.;Youl, P.;Aitken, J.;Occhipinti, S.;Vinod, S.;Valery, P. C.;Garvey, G.;Fong, K. M.;Ball, D.;Zorbas, H.;Dunn, J.;O'Connell, D. L., Psychological distress and quality of life in lung cancer: the role of health-related stigma, illness appraisals and social constraints. Psychooncology, 2015. 24(11): p. 1569-77. 17. Minichiello, A., et al., Effective strategies to reduce commercial tobacco use in Indigenous communities globally: A systematic review.(Report). 2016. 16(21).

Background:
Institutional-level differences in NSCLC survival are associated with differences in the quality of oncologic care. We examined stage-stratified and overall survival of patients in different categories of US Commission-on-Cancer (CoC)-accredited institutions, to quantify inter-institutional differences in survival-impactful quality measures and estimate their relative survival impact, in order to identify the most impactful targets for improvement efforts.

Methods:
National Cancer Data Base (NCDB) institutions were grouped according to CoC category into: Community Cancer Program (CCP), Comprehensive Community Cancer Program (CCCP), Teaching Research Program (TRP), and NCI Program/Network (NCIP). Resections for stage I-IIIA NSCLC in the National Cancer Data Base from 2004-2013 performed within each category of institution were examined for specific quality parameters. Survival was estimated by the Kaplan-Meier method and compared with the log-rank test.

Results:
Of 125,408 NSCLC eligible patients, 8% received surgery at CCP, 52% at CCCP, 28% at TRP, and 12% at NCIP. The pNX rate was 8%, 5.7%, 5.5%, and 3.2% respectively (p<.0001); the median (IQR) nodal count for pN0/1 patients was 6 (7), 7 (7), 8 (9), and 10 (10) respectively, and the CoC quality criterion attainment rate (examination of >10 nodes for stage I/II patents) was 25.5%, 30.2%, 38.7%, and 51.4% (p<.0001). The nodal upstaging rate from clinical (c) N0 to pathologic N-positive was 10.4%, 10.8%, 10.7% and 13.1% (p<.0001); for cN1, nodal upstaging rate was 9.4%, 10.5%, 10.4% and 15.5% (p<.0001). There was no significant inter-institutional difference in 5-year OS for stage I/II patients with pNX resections: 0.47 v 0.50 v 0.51 v 0.54 (log-rank p=.27), whereas stage I/II patients with resections meeting or failing the CoC quality standard had persistent inter-institutional survival differences. For those with <10 nodes, 5-year survival was 0.59 v 0.63 v 0.65 v 0.69 (log-rank p<.0001) and for those with >10 nodes, it was 0.62 v 0.64 v 0.67 v 0.69 (log-rank p<.0001).

Conclusion:
Striking differences in the quality and accuracy of NSCLC pathologic nodal staging exist between the different categories of CoC-accredited facilities. Institutions with higher quality staging have significantly better stage-stratified OS. This inter-institutional survival difference disappears in the patients without examination of any lymph nodes, who arguably have similarly bad quality pathologic nodal staging. However, adjustment for other measures of pathologic nodal staging quality failed to eliminate the inter-institutional survival disparity. Further investigation of inter-institutional practice differences is needed to understand the institutional-level difference in survival after lung cancer surgery.

Background:
Low-dose computed tomography lung cancer screening has been demonstrated to increase detection of cases at an early-stage and reduce lung cancer mortality (vs. x-ray or no screening). However, screening benefits are greatly reduced in persons who are poor candidates for curative intent surgery in the event of screen-detected early-stage disease. To date, no practical tools have been developed to assess potential suitability for surgical treatment at the time of screening shared decision-making. The objective of this study was to use readily available socio-demographic and medical history variables to develop a prediction model that estimates the risk of 30-day mortality following surgical treatment for early-stage non-small cell lung cancer (NSCLC).

Methods:
We used logistic regression to develop a risk-prediction model for 30-day mortality following surgical treatment for Stage I/II NSCLC in patients age 65 to 79 using SEER-Medicare linked databases (2007-2012). Additionally, all patients had at least 1 year of Medicare enrollment prior to NSCLC diagnosis and received initial surgical treatment within 6 months of diagnosis. We developed the model with a training sample of 1,571 surgical cases and conducted internal validation exercises with a sample 4,632 independent surgical cases. Models included age, sex, race, country of birth, urban-rural status, and comorbidities in the year prior to NSCLC diagnosis. The Hosmer-Lemeshow test (by decile) and area under the receiver-operating characteristic curve (AUC) were assessed as measures of model calibration and discrimination, respectively.

Results:
Within the full sample of 6,203 cases, 201 deaths were identified within 30 days of surgical treatment (3.2% of sample). In the training and internal validation sets, the AUC was 0.831 and 0.734, respectively. The observed risk of 30-day mortality was 9.3-fold greater in the highest decile of predicted risk (8.3%) vs. the lowest decile (0.7%), and the Hosmer-Lemeshow test indicated satisfactory model fit (p=0.92). The model had similar performance in women, men, whites, and non-whites; and also had similar calibration and discrimination for 60- and 90-day mortality.

Conclusion:
Our risk-prediction model has good ability to identify patients at increased risk of mortality following surgical treatment for early-stage NSCLC, and pending additional development and validation, can potentially be applied in clinic to inform lung cancer screening shared decision-making with minimal time or resource impacts.

Background:
At the time of diagnosis, two-thirds of patients with lung cancer are ≥65 years of age with significant comorbidities. We sought to determine the short- and long-term cancer- and noncancer-specific mortality and morbidity in patients who underwent resection for stage I non-small cell lung cancer (NSCLC).

Methods:
Of 5371 consecutive patients who had undergone curative-intent resection of primary lung cancer (2000–2011), 2186 patients with pStage I NSCLC were included in the analysis. All preoperative clinical variables known to affect outcomes were considered, including, Charlson comorbidity index, predicted postoperative (ppo) diffusion capacity of the lung for carbon monoxide (DLCO), and ppo–forced expiratory volume in 1 second (FEV1). Association between factors and cause-specific mortality was performed using competing risks approach.

Results:
Of 2186 patients, 1532 patients (70.1%) were ≥65 years of age, including 638 patients (29.2%) ≥75 years of age. In patients ≥65 years of age, for up to 2.5 years after resection, noncancer-specific CID was higher than lung cancer–specific CID, the higher noncancer-specific early-phase mortality was enhanced in patients ≥75 years of age compared with 65-74 years of age (Figure 1a). Multivariable analyses adjusted by age, sex, smoking status, comorbidities, tumor size, and surgical procedures showed that low ppoDLCO was an independent predictor for severe morbidity (p<0.001), 1-year mortality (p<0.001), and noncancer-specific mortality (p<0.001), whereas low ppoFEV1 for lung cancer–specific mortality (p=0.002). PpoDLCO can be used for estimation of 5-year cumulative incidence of noncancer death (Figure 1b, right, red curve) because of its linear relation, whereas ppoFEV1 for lung cancer-specific death (Figure 1b, left, black curve).

Conclusion:
In patients undergoing curative-intent resection of stage I NSCLC, noncancer-specific mortality is a significant competing event, with increasing impact as patient age increases. Figure 1

Abstract not provided

Background:
Postoperative complications after pulmonary resection may cause morbidities such as prolonged hospitalization. Recently, combined pulmonary fibrosis and emphysema (CPFE) have reportedly been linked to a high risk for postoperative complications following lung cancer surgery. Moreover, some studies have claimed that lung age (LA) is associated with postoperative complications. Here we clarify the relationship between LA and postoperative complications in lung cancer patients with CPFE.

Methods:
Among a total of 1166 consecutive patients who underwent curative resection for lung cancer from January 2004 to April 2016 at the Kitasato University Hospital, Japan, a dataset of 36 patients with CPFE was retrospectively analyzed. Lungs with CPFE were defined based on preoperative chest computed tomography (CT) findings. LA was determined using the methods advocated by the Japanese Respiratory Society. The difference between “real age” (RA) and LA was calculated as “RA−LA,” and patients were classified into three groups: group A, RA−LA > 0 (n = 10); group B, −15 ≤ RA−LA ≤ 0 (n = 13); group C, RA−LA < −15 (n = 13).

Results:
The average age was 70 (males, 69.1; females, 73.2) years. Thirty two patients were male and four were female. Almost all patients were ex- or current smokers. The average postoperative hospital stay was 16 (range, 7–56) days. There were no significant differences in age, gender, smoking history, and postoperative　hospital stay among the three groups. The surgical procedures were lobectomy (n = 29), segmentectomy (n = 2), and wedge resection (n = 5). Histologically, the tumors were squamous cell carcinoma (n = 22), adenocarcinoma (n = 9), and other types (n = 4). Postoperative complications were arrhythmia (4 cases), hypertension (4 cases), air leakage (3 cases), pneumonia (5 cases), hypoxemia (3 cases), and others (5 cases). There were no significant differences in postoperative complications among the groups (p = 0.69). However, cardiovascular complications in group C were significantly higher than those in the other groups (p = 0.008). There were 26 patients with postoperative acute exacerbation, but there were no significant differences among the groups.

Conclusion:
LA accurately predicted postoperative cardiovascular complications in lung cancer patients with CPFE.

Background:
The occurrence of minimally invasive thoracic surgery interventions has grown steadily since the early 1990s, yet practice patterns for peri-operative management of these patients has lagged behind technical progress. Our thoracic program has created WAVE (Walking After VATS Experiment) which focuses on a multidisciplinary approach to early ambulation after thoracic surgery. A report from our first 3 years of data (July 2010 - July 2013) was presented at the 2013 IASLC meeting in Sydney, Australia. In response to the positive comments, we have continued our endeavor and in addition, investigated 30 day outcomes and length of stay for the homogeneous subset of anatomic lobectomy.

Methods:
Data was collected from a single surgeon at a single center and includes all consecutive thoracic surgical patients recovered through the WAVE program from July 2010 - July 2016. We excluded patients undergoing tracheostomy, endoscopic only procedures, and mediastinoscopy. Data was collected prospectively and analyzed retrospectively.

Results:
From July 2010 - July 2016, 1152 patients were included for analysis. Within the 6 year period, 798/1152 patients (69%) walked any distance within one hour of extubation, 945/1152 patients (82%) walked 250 feet at any time while in the PACU, 721/1152 patients (63%) successfully walked the targeted distance of 250 feet within one hour of extubation and only 37/1152 patients (3%) were unable to ambulate at all in the PACU. There were no adverse events. The subset of anatomic lobectomies included 290 patients of which 197/290 patients (68%) walked any distance within one hour of extubation, 239/290 patients (82%) successfully walked 250 feet at any time while in the PACU, 175/290 patients (60%) achieved the target distance of 250 feet within one hour of extubation and only 5/290 patients (1.7%) were unable to ambulate at all in the PACU. The rate of 30 day post-operative complications compares favorably with the literature and are as follows: 4.1% atrial arrhythmia, 1.0% pneumonia, 6.6% air leak > 5 days, 0.7% DVT, 0.3% acute renal failure, 0.3% pulmonary embolism, 0% stroke, 0% myocardial infarction, 4.8% readmission and 0% mortality. Mean length of hospital stay was 1.6 days with a median of 1 day.

Conclusion:
Our “WAVE” experience reveals that aggressive early ambulation is effective in reducing post-operative complications and shortening length of stay. The platform is simple, reproducible and feasible for any thoracic surgical program. Key features for successful implementation include patient and family engagement, a multi-disciplinary team and administrative support.

Background:
There is no consensus for the appropriate follow-up of patients after complete resection of non-small cell lung cancer (NSCLC). Our study was designed to visually represent postoperative recurrence patterns for NSCLC with the use of event dynamics and to optimize postoperative follow-up schedule based on risk factors for recurrence.

Methods:
A total of 829 patients with NSCLC who underwent complete pulmonary resection were studied. There were 538 men and 291 women with a mean age of 69.2 at the time of operation. The majority of the patients had adenocarcinoma (62.5%), underwent lobectomy (85.9%) and pathological stage IA (47.3%). Event dynamics, based on the hazard rate, were evaluated and only first events (distant metastases or local recurrence) were considered. The effects of sex, histological type and pathological stage were studied.

Results:
On non-parametric kernel smoothing, the resulting hazard rate curves indicated that the recurrence risk pattern was definitely correlated to sex, with a sharp peak in the first year for men and broad peak during the 2 to 3 years for women. This finding was also confirmed by the analysis of histological type. Although pathological stage IA patients lacked such a large peak in both sexes during the follow-up period, gender difference was shown in pathological stage IB and stage IIA to IIIB patients. Figure 1



Conclusion:
The use of recurrence dynamics allows the times of peak recurrence to be visualized. The hazard rate and the peak times of recurrence differed considerably between genders in pathological stage IB or higher. Postoperative follow-up methods should be based on currently recommended follow-up guidelines, give adequate consideration to the recurrence patterns, and be modified individually.

Abstract not provided

Background:
Malignant pleural mesothelioma (MPM) is a highly aggressive, asbestos-related malignancy characterized by poor outcome and limited therapeutic options. Fibroblast growth factor (FGF) signals play important roles in mesothelioma cell growth and malignant behavior and their inhibition leads to reduced tumor growth. MicroRNAs (miRNAs) are conserved noncoding RNAs controlling gene expression via translational repression of target mRNAs. The miR-15/16 family is downregulated in MPM and has tumor suppressor functions. Several FGFs/FGFRs are predicted miR-15/16 targets. The aim of this study was to explore the link between the miR-15/16 and the FGF/R family in MPM.

Methods:
Gene and microRNA expression was determined by RT-qPCR or Taqman Low Density Arrays (TLDAs). Mimics were used for restoring microRNA expression. Stimulation or inhibition of FGF signals or bcl-2 was achieved by recombinant FGF2, siRNAs, or small-molecule inhibitors, respectively. A SYBR green-based proliferation assay and colony formation assays were used to monitor effects on cell growth.

Results:
Expression analysis showed a consistent downregulation of target FGF/FGFR genes after transfection with miRNA mimics. Restoration of miR-15/16 led to dose-dependent growth inhibition, which significantly correlated with sensitivity to the specific FGFR1 inhibitor PD166866. Re-expression of microRNAs in combination with FGFR knock-down or pharmacological inhibition resulted in reduced activity, indicating target competition. Combined inhibition of the FGF-axis and bcl-2, another established target of miR-15/16, resulted in enhanced activity. Treatment with recombinant FGF2 further reduced mature as well as pri-microRNA levels and also could prevent/reduce growth inhibition by mimics, but only when added within 24 hours after transfection. TLDA screens after stimulation/inhibition of FGF signals identified regulation of several other miRNAs involved in pathways relevant for tumour growth and aggressiveness.

Conclusion:
Our data shows that the post-transcriptional repression of FGF-mediated signals contributes to the tumour-suppressor function of the microRNA-15/16 family. Impairing hyperactivated FGF signals as well as the anti-apoptotic protein bcl-2 through the restoration of this miRNA family might serve as a novel therapeutic strategy in mesothelioma.

Background:
Malignant mesothelioma is an aggressive cancer that develops from mesothelial cells, most often in the pleural lining of the lung. We have previously shown that the BMP inhibitor protein gremlin-1 is highly expressed in mesothelioma and induces a mesenchymal and chemoresistant phenotype in mesothelioma cells. Since mesothelioma tumors are locally highly invasive, we analyzed the role of gremlin-1 in mesothelioma cell migration and invasive growth.

Methods:
Primary mesothelioma cells isolated from patient pleural fluid as well as mesothelioma cell lines were used for in vitro studies. Cells were transfected with siRNAs or transduced with lentiviral expression vectors. Invasive growth was analyzed in 3D matrigel or collagen I matrices. mRNA expression was analyzed using a commercial PCR array and quantitative RT-PCR. Migration assays were performed using scratch wound assay or Transwell migration assay with fibronectin or collagen coating. TGF-β and BMP signaling activity was measured with reporter-luciferase assays. For in vivo mouse xenograft experiment cells were additionally transduced to express a luciferase marker. Subcutaneous cell injection with matrigel matrix was performed in the flank of nude mice.

Results:
Mesothelioma cells expressing gremlin-1 showed invasive sprouting when tumor cell spheroids were imbedded into 3D collagen matrix. Silencing of gremlin-1 expression significantly reduced invasive growth. In addition, cells overexpressing gremlin-1 gained invasive growth ability. This was associated with increased mRNA expression levels of Slug and matrix metalloproteinases (MMP) as well as reduced expression of E-cadherin. The cells were more migratory and exhibited increased expression of certain integrins, especially the α~v~ subunit. Gremlin-1 induced invasive growth was dependent on MMP activity and associated with increased TGF-β activity. Intrapleural injection of gremlin-1 overexpressing mesothelioma cells isolated from a patient with epithelioid mesothelioma, produced tumors in 2/4 mice over 4 months after injection. Cells transduced with vector only did not produced tumors (0/4). When cells were injected subcutaneously together with matrigel gremlin-1 overexpressing tumors appeared more slowly, but exhibited comparable luciferase signal 2.5 months after injection. However, gremlin-1 tumors showed more local spreading and in contrast to control tumors some also developed metastasis (2/6 mice).

Conclusion:
Mesothelioma invades locally and has poor prognosis. We have identified gremlin-1 as an important regulator of mesothelioma chemoresistance and invasive growth behavior. Blocking gremlin function may overcome drug resistance and reduce invasion of mesothelioma.

Background:
Malignant pleural mesothelioma (MPM) is a rare but devastating malignancy. Despite the search for new promising treatment approaches, the outcome for most MPM patients remains dismal. Therefore, the identification of novel biomarkers is urgently needed in order to identify patients with a better prognosis and to support personalized therapeutic decisions. In our previously published study, we were able to show that fibroblast growth factor 18 (FGF18) is overexpressed in MPM tissue specimens and cell models. The objective of this study was the evaluation of FGF18 as a circulating biomarker in MPM.

Methods:
Plasma was collected from 107 MPM patients at the time of diagnosis or before surgical resection. Samples were included from the Medical University of Vienna, University Hospital Center in Zagreb and from The Concord Repatriation General Hospital and Strathfield Private Hospital in Sydney. Samples from 49 healthy volunteers and from 8 patients with non-malignant pleural diseases served as controls. Circulating FGF18 was measured by enzyme-linked immunosorbent assay and correlated to clinical, pathologic and radiologic parameters.

Results:
Plasma FGF18 level was significantly elevated in MPM patients vs. healthy controls (P<0.0001). A slight increase of circulating FGF18 level was also detected in patients with pleuritis or fibrosis (vs. control, P=0.0067). Sarcomatoid (n=7) morphology was associated with high FGF18 levels when compared to the epithelioid (n=77) histology (P=0.0064). Importantly, MPM patients presenting with FGF18 levels below the median had a significantly longer overall survival when compared to those with high FGF18 levels (median survival 625 versus 382 d, P=0.0038). Data on multivariate analysis, disease-free survival, correlation with other biomarkers and tumor volume will be presented at the conference.

Conclusion:
Our findings reveal that FGF18 is a promising blood-derived candidate biomarker in MPM. Furthermore FGF18 may support the histological classification of MPM and the identification of MPM patients with poor prognosis. .

Abstract not provided

Background:
Malignant pleural mesothelioma (MPM) is an aggressive cancer caused by asbestos exposure with limited therapeutic options. Dysregulated microRNAs play an important role in MPM biology and candidate microRNAs have been investigated as diagnostic and prognostic biomarkers or as a potential treatment targets. The role of miR-223 has previously been investigated in MPM tumour cells and was shown to act as a tumour suppressor by regulating cell mobility. Previous research indicated miR-223 to be primarily expressed by myeloid progenitor derived cells during differentiation of granulocytes and monocytes. This suggests miR-223 might have a more significant role in the inflammatory response during tumourigenesis. In this study we aimed to investigate the origin of miR-223 using mesothelioma xenograft and syngraft models.

Methods:
Human and mouse mesothelioma cell line-derived xenograft (MSTO-H211 and H226) and syngraft (AB1) models were established. MicroRNA profiles of xenografts were compared against profiles of their corresponding in vitro cultured cells to determine candidates. RT-qPCR using TaqMan MicroRNA assays was used to validate expression levels of miR-143-3p, miR-214-3p and miR-223-3p in tumour xenografts and syngrafts with those in corresponding cell lines in vitro. Species-specific ddPCR analysis was performed on RNA from xenograft tumours to determine the expression of human and mouse pri-miR-223.

Results:
MicroRNA profiles of xenograft tumours showed significant upregulation (p < 0.05) of miR-143-3p, miR-214-3p and miR-223-3p compared to corresponding in vitro mesothelioma cell lines. Only miR-223 showed significant upregulation in both xenograft and syngraft tumours compared to corresponding in vitro mesothelioma cell lines (>10000-fold increase). Other microRNAs were not significantly different between cell lines and tumours. RNA isolated from xenograft tumours contained significantly more mouse pri-miR-223 than human pri-miR-223 (p < 0.001), with only minimal expression levels of human tumour pri-miR-223 within xenograft tumours.

Conclusion:
Mature miR-223 is significantly overexpressed in xenograft tumours compared to corresponding in vitro mesothelioma cell lines suggesting stromal contribution. Species-specific pri-miRNA confirmed miR-223 is almost exclusively expressed by the mouse stromal cells in xenograft tumours. Ultimately, localising the expression of miR-223 to specific cell types (such as myeloid derived cells) through in situ hybridisation should help identify a more biologically relevant role for miR-223 in the tumour microenvironment.

Background:
To overcome tumor-mediated inhibition of chimeric antigen receptor (CAR) T cells, we herein investigated the impact of tumor PD-L1 upregulation on CAR T-cell exhaustion and anti-tumor efficacy, and further developed clinically translatable T-cell extrinsic as well as intrinsic strategies to overcome PD-L1 inhibition in models of lung cancer (LC) and malignant pleural mesothelioma (MPM).

Methods:
Human T cells were transduced with MSLN-specific CAR with CD28 and CD3zeta domains (M28z) were tested in vitro and in clinically-relevant LC and MPM mouse models by bioluminescence imaging, BLI of tumor burden progression. To counteract PD-1/PD-L1 inhibition in vivo, we evaluated the efficacy of PD-1 blocking antibody or cell-intrinsic genetic-engineering strategies by cotranducing M28z CAR T cells with a PD-1 dominant negative receptor (PD1-DNR) or with PD-1/4-1BB fusion protein.

Results:
A single, low-dose of M28z CAR T cells is able to resist the progression of established tumor for 40 days, but mice eventually died with progressing tumor. Tumor harvest analysis demonstrated the PD-1 and PD-L1 upregulation on CAR T cells and tumor cells (Figure panel A). We then confirmed in vitro that PD-L1 inhibits M28z T-cell effector functions (proliferation, cytotoxicity and cytokine secretion). The addition of PD-1 blocking potentiates CAR T-cell therapy in vivo but its efficacy requires multiple injections (Panel B). In contrast, a single dose of M28z T cells coexpressing PD1-DNR restore effector functions, enhance tumor burden control (Panel C) and prolong median survival (56 vs 82 days, p=0.001). Converting PD-L1 inhibition into a positive costimulatory signal by PD-1/4-1BB construct cotransduction into M28z CAR T cells enhanced cytokine secretion and T-cell accumulation (Panel D). Figure 1



Conclusion:
Our results demonstrate the therapeutic benefit of providing optimal costimulation and coinhibitory blockade to counteract PD-L1/PD-1 immunosuppression, thus potentiate CAR T-cell therapy for lung cancer and mesothelioma.

Background:
Malignant pleural mesothelioma (MPM) is an aggressive cancer with a poor prognosis and an increasing incidence, for which novel therapeutic strategies are urgently required. Since the immune system has been described to play a role in protection against MPM, characterization of its tumor immune microenvironment (TME) and immune checkpoints might help to identify new immunotherapeutic targets and their predictive and/or prognostic value.

Methods:
Immunohistochemistry (IHC) was performed on tissue samples of untreated (n=40) and chemotherapy-pretreated (n=14) MPM patients. Different subsets if immune cells were identified based on staining for CD4, CD8, FoxP3, CD68, CD45RO and granzyme B. The expression of the immune checkpoints TIM-3, LAG-3, PD-1 and its ligand PD-L1 was also investigated. The relationship between the immunological parameters and survival, as well as response to chemotherapy was analyzed using the R statistical software.

Results:
All patients had CD8+ tumor infiltrating lymphocytes (TILs), CD68+ histiocytes and macrophages and CD45RO+ T cells in their stroma, with CD8+ TILs being the predominant cell type of the immune infiltrate. Stromal CD4+ TILs were found in 75% of the untreated and 71% of the pretreated samples. A subset of those cells was also FoxP3+ and these CD4+FoxP3+ cells were positively correlated with stromal CD4 expression (p<0.001). Less than half of the samples showed positivity for granzyme B. Both, untreated and pretreated patients had PD-1+ TILs, while only 10% of the untreated patients also had PD-1+ tumor cells. PD-L1 positivity on lymphocytes and/or tumor cells was observed for more than half of the patients, with significant differences according to the histological subtype (p<0.001). Patients with a sarcomatoid histology showed the most PD-1 expression. TIM-3 was expressed in tumor cells, stromal lymphocytes and plasma cells, less often in pretreated samples compared to untreated samples. All samples were negative for LAG-3. After multivariate analysis stromal CD45RO expression was found to be an independent negative predictive factor for response to chemotherapy (p=0.017) and expression of CD4 and TIM-3 in lymphoid aggregates were good prognostic factors (p=0.008; p=0.001).

Conclusion:
Our data reveal the diversity of immune cells present in MPM and point to TIM-3 as a new target in mesothelioma. Administering chemotherapy before or together with PD-1/PD-L1/TIM-3 blocking agents may not be the best combination sequence and further research on the predictive value of CD45RO in the stroma might guide patient selection for chemotherapy.

Abstract not provided

Background:
Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor antibody, has demonstrated improved efficacy and tolerability vs docetaxel in patients with advanced NSCLC that progressed on or after platinum-based chemotherapy and is approved in >50 countries in this patient population. We report efficacy and safety data from a phase 1 study (CheckMate 012; NCT01454102) evaluating first-line nivolumab in patients with advanced NSCLC.

Methods:
Patients (N=52) with advanced, chemotherapy-naive NSCLC (any histology) were treated with nivolumab monotherapy at 3 mg/kg IV Q2W until disease progression or unacceptable toxicity. Safety and tolerability was the primary study objective. Efficacy, as measured by objective response rate (ORR) and 24-week progression-free survival (PFS) rate per RECIST v1.1, was the secondary objective. Overall survival (OS) was an exploratory endpoint.

Results:
Treatment-related adverse events (TRAEs) were reported in 71% (any grade) and 19% (grade 3‒4) of patients. The most frequent select TRAEs (those with potential immunologic causes) by category were skin, endocrine, and gastrointestinal (Table). With a median follow-up of 14.3 months (range, 0.2 to 30.1), the confirmed ORR was 23% (12/52) and 8% (4/52) of patients had complete responses. Of the 12 responses, 8 (67%) were ongoing at the time of database lock; median duration of response was not reached. Median OS was 19.4 months (range, 0.2‒35.8+). The 24-week PFS rate was 41% (95% CI: 27‒54); 18-month OS rate was 57% (95% CI: 42‒70). Updated long-term data will be presented, including 2-year OS and will represent the longest follow-up to date for a PD-1/PD-L1 inhibitor for first-line advanced NSCLC. Updated data from patients treated with nivolumab plus ipilimumab (N = 77) will also be presented.

Background:
Atezolizumab, a humanized anti-PDL1 mAb, inhibits the PD-L1/PD-1 pathway to restore tumor-specific T-cell immunity, resulting in durable anti-tumor effects. BIRCH (NCT02031458) is a single-arm Phase II study of atezolizumab monotherapy in PD-L1–selected advanced NSCLC patients, across multiple therapy lines. Primary analyses (median follow-up, 8.5 months) demonstrated a meaningful ORR with durable response in chemotherapy-naive 1L and 2L+ PD-L1–selected patients. Here we report updated efficacy data in 1L patients.

Methods:
1L eligibility criteria included PD-L1–selected, advanced-stage NSCLC with no CNS metastases or prior chemotherapy. PD-L1 was centrally evaluated (VENTANA SP142 IHC assay). Patients expressing PD-L1 on ≥5% of tumor cells (TC) or tumor-infiltrating immune cells (IC), ie, TC2/3 or IC2/3, were enrolled. Patients with EGFR mutation or ALK rearrangement must have had prior TKI treatment. Atezolizumab 1200mg was administered IV q3w until radiographic disease progression or unacceptable toxicity. The primary endpoint was independent review facility(IRF)-assessed ORR. Secondary endpoints included investigator(INV)-assessed ORR, DOR, PFS (RECIST v1.1) and OS.

Results:
With a median follow-up of 14.6 months, median OS was not reached in TC3 or IC3 patients and was 20.1 months in TC2/3 or IC2/3 (ITT) patients; INV-assessed ORR was 32% and 24%, respectively (Table). Furthermore, ORR was 31% for mutant EGFR (n=13) vs 20% for wild-type EGFR patients (n=104), and 27% for mutant KRAS (n=33) vs 21% for wild-type KRAS patients (n=67). No new safety signals were observed. Updated efficacy (including IRF ORR), safety and exploratory biomarker analyses will be presented.

Conclusion:
With longer follow-up, atezolizumab continued to demonstrate promising efficacy in 1L NSCLC. These results indicate that atezolizumab has durable efficacy in the 1L setting, in EGFR and KRAS mutant and wild-type tumors, and support ongoing Phase III trials evaluating atezolizumab vs chemotherapy in 1L NSCLC.

Background:
Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody that has shown antitumour activity in various malignancies. We report safety and clinical activity of avelumab as first-line therapy in a cohort of patients with non-small–cell lung cancer (NSCLC) from a phase 1b trial (NCT01772004).

Methods:
Patients with advanced NSCLC not previously treated systemically for metastatic or recurrent disease, without an activating EGFR mutation or ALK rearrangement, and not preselected for PD-L1 expression, received avelumab 10 mg/kg IV over 1 hour Q2W until progression, unacceptable toxicity, or study withdrawal. Objective response rate (ORR) and progression-free survival (PFS) were evaluated by RECIST v1.1. Adverse events (AEs) were graded by NCI-CTCAE v4.0.

Results:
As of 23 Oct 2015, 145 patients had received avelumab (median 10 weeks of treatment; range 2-30) and were followed for a median of 13 weeks (range 0-31). Median age was 70 years (range 41-90), ECOG PS was 0 (31.0%) or 1 (69.0%), and tumour histology was adenocarcinoma (63.4%) or squamous (26.9%) in most patients. Eighty-two patients (56.6%) had a treatment-related (TR) AE; those occurring in ≥10% were infusion-related reaction (IRR; n=24, 16.6%) and fatigue (n=21, 14.5%). Thirteen patients (9.0%) had a grade ≥3 TRAE; only IRR and fatigue occurred in >1 patient (each n=3, 2.1%). Four patients (2.8%) had a potential immune-mediated TRAE, all grade 1-2 (pneumonitis n=3, 2.1%; hypothyroidism n=1, 0.7%). There were no treatment-related deaths. Among 75 patients with ≥3 months’ follow-up, unconfirmed ORR was 18.7% (95% CI: 10.6, 29.3) based on 1 complete response and 13 partial responses; 12 were ongoing. Thirty-four additional patients (45.3%) had stable disease as best response (disease control rate 64.0%). Updated analysis will be presented, including efficacy data with ≥3 months’ follow-up in all patients and PD-L1 analysis.

Conclusion:
First-line avelumab monotherapy showed clinical activity and was well-tolerated in patients with EGFR-wildtype/ALK-negative NSCLC unselected for PD-L1 expression. A phase 3 trial of avelumab vs platinum-doublet in first-line NSCLC is in progress. *Proposed nonproprietary name.

Abstract not provided

Background:
Nivolumab significantly improved OS versus docetaxel in patients with previously treated advanced non-squamous NSCLC (CheckMate 057; NCT01673867). Kaplan−Meier OS curves for nivolumab and docetaxel crossed at ~7 months, suggesting non-proportional hazards between arms.

Methods:
Post-hoc analyses were conducted to explore relationships between baseline patient/disease characteristics, including PD-L1 expression, and death within the first 3 months of treatment (3motx). Additionally, the association between PD-L1 expression level and magnitude of clinical benefit was explored.

Results:
During the first 3motx, risk of death (rDt) was numerically higher with nivolumab versus docetaxel (59 versus 44 deaths among 292 and 290 patients, respectively). Early deaths were most commonly attributed to disease progression (no treatment-related deaths occurred). At 3motx, 80% of nivolumab-treated patients (233/292) and 85% of docetaxel-treated patients (246/290) were alive. After 3motx, the rDt was consistently higher in the docetaxel arm. In univariate analyses, no single baseline factor, including PD-L1 expression, EGFR mutation, ECOG PS, or smoking status, reliably characterized the rDt within the first 3motx with nivolumab. Among patients alive >3 months, the OS HR (95% CI) favored nivolumab in the overall population (0.59 [0.47−0.74]) and PD-L1 non-expressors (PD-L1 expression <1%; 0.66 [0.45−0.97]). In a multivariate analysis, factors associated with higher rDt within the first 3motx on nivolumab versus docetaxel were ECOG PS=1, time since last treatment <3 months, and/or progressive disease as best response to prior treatment combined with lower or no PD-L1 expression. However, the majority of nivolumab-treated patients with these attributes (including PD-L1 non-expressors), did not die within the first 3motx and experienced subsequent benefit. PD-L1 expression was a continuum, ranging from 1 to 100%, with increasing expression associated with enhanced ORR/OS benefit from nivolumab.

Conclusion:
In CheckMate 057, the benefit−risk profile of nivolumab versus docetaxel was favorable across the overall patient population. During the first 3motx, a small difference in the number of deaths (n=15) was observed; thereafter the OS rate consistently favored nivolumab (2-year OS was >2-fold higher with nivolumab versus docetaxel). Patients with poorer prognostic factors and/or more aggressive disease combined with lower or no PD-L1 expression appeared to be at higher rDt within the first 3motx on nivolumab versus docetaxel. With the exception of PD-L1 status, these are recognized prognostic factors. While PD-L1 expression may help inform individual treatment decisions, PD-L1 status alone is not considered an appropriate biomarker for nivolumab treatment selection in pre-treated advanced NSCLC, but rather should be considered in the context of other patient/disease characteristics.

Background:
Monoclonal antibodies against Programmed Death 1 (PD-1) and Programmed Death Ligand 1 (PD-L1) have emerged as effective therapies in NSCLC. We updated our initial systematic review of trials investigating differences in the toxicities of PD-1 and PD-L1 inhibitors.

Methods:
An electronic literature search was performed of public databases (MEDLINE, EMBASE) and conference proceedings for trials utilizing PD-1 inhibitors (nivolumab, pembrolizumab) and PD-L1 inhibitors (atezolizumab, durvalumab, avelumab) in NSCLC patients. Studies that did not report toxicities were excluded. A formal meta-analysis was conducted with Comprehensive Meta-Analysis software (Version 2.2). Clinical and demographic characteristics, response, and toxicity data were compared between the two groups.

Results:
Twenty-two studies reported between 2013-2016 were eligible for this analysis. The total number of patients evaluated for toxicities were 2,863 patients in the PD-1 group and 2,006 patients in the PD-L1 group. Patient characteristics % (PD-1/PD-L1): median age 64/65, male 58/56, smokers 82/83, squamous histology 25/32, performance status 0-1 98/100. There was no difference in response rate between PD-1 (17%) and PD-L1 (18%) inhibitors, p=0.3. The incidence of overall adverse events (AEs), immune related AEs, and pneumonitis trended in favor of the PD-L1 group but did not reach statistical significance (see table). Figure 1



Conclusion:
In this updated systematic review involving 4,869 patients, the toxicity profiles of PD-1 and PD-L1 inhibitors in NSCLC patients are not significantly different.

Background:
Checkpoint inhibitors such as the anti–PD-1 monoclonal antibody pembrolizumab have demonstrated antitumor activity and a manageable safety profile in several advanced malignancies. Although checkpoint inhibitors are rapidly becoming a standard-of-care therapy in multiple tumor types, the optimal treatment duration has not been established. We assessed outcomes in patients who completed the maximum 24 months of pembrolizumab in the phase 3 KEYNOTE-010 study (NCT01905657), in which pembrolizumab provided superior OS over docetaxel in patients with previously treated, PD-L1–expressing advanced NSCLC.

Methods:
1034 patients with advanced NSCLC that progressed after ≥2 cycles of platinum-based chemotherapy (and an appropriate therapy for targetable EGFR and ALK aberrations if present) and had a PD-L1 tumor proportion score ≥1% were randomized 1:1:1 to pembrolizumab 2 or 10 mg/kg Q3W or to docetaxel 75 mg/m[2] until disease progression, intolerable toxicity, or physician or patient decision; the maximum duration of pembrolizumab was 24 months of uninterrupted treatment or 35 cycles, whichever was later. Response was assessed per RECIST v1.1 by independent central review every 9 weeks. After completion of 24 months/35 cycles, patients continued to undergo imaging every 9 weeks; patients with subsequent disease progression were eligible for a second treatment course if they did not receive other anticancer therapy after stopping pembrolizumab.

Results:
In the overall population, median OS was longer (10.5 months for pembrolizumab Q2W, 13.4 months for pembrolizumab Q3W, and 8.6 months for docetaxel) and 24-month OS rates were higher (30.1%, 37.5%, and 14.5%, respectively) with pembrolizumab compared with docetaxel. Of the 691 patients allocated to pembrolizumab, 47 patients received 35 cycles of pembrolizumab and were included in this analysis. As of the September 30, 2016 data cutoff date, all patients had completed all 35 cycles of treatment, but one withdrew from the study treatment after completing 35 cycles. Best overall response (ORR) among these 47 patients was complete response (CR) in 3 (6%) patients and partial response (PR) in 39 (83%) patients, for an ORR of 89%; 5 (11%) patients experienced stable disease (SD). Two of these patients experienced disease progression since stopping pembrolizumab and two of these patients resumed pembrolizumab therapy. As of the cutoff date, none of the 47 patients had died.

Conclusion:
With long-term follow-up, the OS benefit has been maintained and pembrolizumab continues to demonstrate superiority over docetaxel. Pembrolizumab provides durable clinical benefit with few patients progressing after completing two years of therapy.

Abstract not provided

Background:
To support health policies and place monitoring systems to tackle socio-economic inequalities in tobacco use in low-and-middle-income countries (LMIC) are seldom reported. We aimed to describe, sex-wise, educational and wealth-related inequalities in tobacco use in low-and-middle income countries.

Methods:
We analyzed DHS data on tobacco use collected in 54 countries. We calculated weighted prevalence estimates of current tobacco use (any type of tobacco) in each country for five wealth groups and four educational groups. We calculated both absolute and relative measures of inequality, i.e., the Slope Index of Inequality (SII) and Relative Index of Inequality (RII), which take into account the distribution of prevalence across all wealth and education groups and account for population size. We also calculated the aggregate SII and RII for low-income (LIC), lower-middle income (lMIC) and upper-middle-income (uMIC) countries as per World Bank classification.

Results:
Male tobacco use among was highest in Bangladesh (70.3%) lowest in Sao Tome (7.4%); whereas female tobacco use highest in Madagascar (21%) and lowest in Tajikistan (0.22%). Among men educational inequalities varied widely between countries but aggregate RII and SII showed an inverse trend by country wealth groups. RII was 3.61 (95% CI 2.83-4.61) in LICs, 1.99 (95% CI 1.66-2.38) in lMIC, and 1.82 (95% CI 1.24-2.67) in uMIC. Wealth inequalities among men varied less between countries but both RII and SII showed an inverse pattern where RII was 2.43 (95% CI 2.05-2.88) in LICs, 1.84 (95% CI 1.54-2.21) in lMICs, and 1.67 (95% CI 1.15-2.42) in uMIC. For educational inequalities among women, the RII varied much more than SII varied between the countries, and aggregate RII was 14.49 (95% CI 8.87-23.68) in LICs, 3.05 (95% CI 1.44-6.47) in lMIC and 1.58 (95% CI 0.33-7.56) in uMIC. Wealth inequalities among women showed a pattern similar to that of men: the RII was 5.88 (95% CI 3.91- 8.85) in LICs, 1.76 (95% CI 0.80 -3.85) in lMIC, and 0.39 (95% CI 0.09 -1.64) in uMIC. In contrast to men, among women the SII was pro-rich (higher smoking among the more advantaged) in 13 of the 52 countries (7 of 23 lMIC and 5 of 7 uMIC).

Conclusion:
Our results confirm that socio-economic inequalities tobacco use exist in LMIC, varied widely between the countries, and were much wider in the lowest income countries. These findings are important for better understanding and tackling of socio-economic inequalities in health in LMIC.

Background:
Approximately 85% of lung cancer is related to cigarette smoking. Smoking cessation has been reported to benefit patients even after the diagnosis of lung cancer. We studied the smoking behavior of patients with lung cancer in a phase 3 study for early stage lung cancer.

Methods:
The ECOG-ACRIN 1505 study enrolled patients with stages IB, II and IIIA non-small cell lung cancer (NSCLC) after they had undergone surgical resection. It was designed to evaluate whether the addition of bevacizumab would improve survival relative to cisplatin-based chemotherapy alone. Studying the correlation between smoking status and outcome was a secondary endpoint. Patients completed a questionnaire about their smoking habits at baseline, 3, 6, 9 and 12 months after study entry.

Results:
Out of 1501 patients enrolled, 99%, 90%, 85%, 82% and 80% responded to the questionnaire at baseline, 3, 6, 9 and 12 months respectively. Nearly 90% reported having smoking during their lifetime. At study entry, 12% reported ongoing smoking. The median age patients started smoking was 17 years and the median age at which they quit smoking was 55 years. The median number of cigarettes smoked per day was 20. Approximately 4% smoked cigars (median number 2/day). Of the 40% that reported smoking after the diagnosis of lung cancer, only 15% reported smoking at 12 months. At 12 months after study entry, among those who continued to smoke, 79% reported smoking fewer cigarettes/day, whereas 11% smoked more cigarettes. When asked about the number of cigarettes smoked at 12 mos, 63% reported smoking fewer than 10 cigarettes/day. The incidence of grades 3-5 toxicity was 76% in smokers versus 69% in non-smokers (p=0.06). There were no differences in dose reductions for chemotherapy (P=0.55) or bevacizumab (P=0.90) between smokers and non-smokers. The median number of chemotherapy cycles were nearly identical for smokers and never-smokers. The disease-free survival (DFS) and OS for smokers relative to never-smokers were 0.97 (P=0.83) and 1.54 (P=0.01) respectively.

Conclusion:
This is the first comprehensive, prospective report of smoking habits of patients with lung cancer. There were a high rate of smoking cessation and reduction in number of cigarettes smoked, that was maintained at 12m after study entry. Toxicity and DFS did not differ significantly between smokers and never-smokers, though overall survival was more favorable with the never-smokers. Study was coordinated by ECOG-ACRIN (Robert L. Comis, M.D., Chair) and supported in part by Public Health Service Grants CA180820, CA180888, CA180821, & CA180863.

Background:
Tobacco cessation is critical for both population and individual health, and especially so in the context of a lung cancer screening program. Our institution initiated formal lung caner screening in 2013. In preparation for this we audited randomly selected clinic visits to assess adherence to published tobacco cessation guidelines. Our findings in that study prompted us to initiate a systematic multi-step program to improve tobacco practices from assessing tobacco use to presribing pharmacotherapy, and referral to tobacco cessation counselors.

Methods:
The project included four separate but related interventions; 1) Inviting clinic directors to send a clinic staff member of their choice for formal training in a specialize Tobacco treatment Specialist (TTS) course. 2) Generating monthly reports showng completeless of tobacco history (Current/Former/Never), pack-years recording, and (for former smokers) quit dates, use of pharmacotherapy for current smokers, and referrals for either tobacco cessation or formal lung cancer screening. 3) Providing monthly feedback to clinic directors comparing their performance to others in the project, and 4) Initiation of an electronic Best Practice Alert prompt for smokers including links to a Lung Cancer Screening Questionaire & decision aid and referral to Tobacco Counselor.

Results:
This University Health System is affiliated with over 150 satellite clinical sites. 20 sites delivering mostly adult primary care were invited to participate. Individuals from 14 sites completed TTS training. Initial assessment of tobacco use (Current/Former/Never) was excellent (>99%) across all clinical sites, including those who did not particpate in TTS training. However, pack-years were recorded on average less that 40% of the time and quit dates for former smokers were recorded less than 30% of the time at baseline. After training clinic staff in the TTS course, and regular ongoing feedback to clinical directors, we observed a significant initial increase in accurate recording of pack-years and quit dates (two points of emphasis) for all sites involved in the project, as well as referals to tobacco counselling. Over this time, unfortunately we did not detect an increase in the rate of prescription of tobacco pharmacotherapy. The There was a gradual increase in the the number of referrals for lung cancer screening Cts increased from an average of 30 per month to an average of over 70.

Conclusion:
This project to disseminate the skills of a TTS training course to clinics within a large University Health System has led to modest improvements in overall practices and demonstrated areas where additional improvements are needed.

Abstract not provided

Background:
Chronic inflammation appears to heighten the risk of lung cancer and, reciprocally, agents that reduce inflammation have been found to reduce this risk. Nevertheless, few prospective studies have examined associations between lung cancer and the intake of nonsteroidal anti-inflammatory drugs (NSAIDs). In the current study, we examined associations between fatal lung cancer and NSAIDs using prospective data from the Third National Health and Nutrition Examination Study.

Methods:
Baseline data on smoking, NSAIDs and other lifestyle variables were collected for 10,735 participants during 1988-1994, and cause-specific mortality status was ascertained through probabilistic record matching using the National Death Index through 2006. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) to quantify associations between NSAID use and lung cancer death, with adjustment for current smoking and other variables.

Results:
During 18 years of follow-up, 269 individuals died from lung cancer of which 252 (93.6%) reported a history of cigarette smoking. Since all but 17 of the 269 fatal lung cancer cases occurred among current or former smokers, estimates of NSAID effects were ascertained from a sub-cohort of 5,882 individuals who reported a history of past or current cigarette smoking. Multivariate regression models revealed that regular use of ibuprofen reduced the risk of lung cancer death by 48% (HR=0.52, 95% CI=0.33-0.82, P<0.01). Main effects of other compounds tested (aspirin or acetaminophen) were not statistically significant.

Conclusion:
Prospective data from NHANES III showed that among adults with a history of past or current smoking, ibuprofen intake was associated with a substantial (48%) reduction in the risk of dying from lung cancer. Effects of aspirin and acetaminophen were not statistically significant. These results suggest that regular use of certain NSAIDs may be beneficial for high-risk subgroups of smokers as a lung cancer prevention strategy.

Background:
Tobacco smoke is the primary cause of chronic obstructive pulmonary disease (COPD) and lung cancer, and among smokers, COPD is associated with increased lung cancer risk. However, fewer than 30% of smokers are diagnosed with either disease, suggesting that genetic factors also influence the pathogenesis of both diseases. Despite the plausibility for shared genetic predisposition, knowledge about pleiotropy between COPD and lung cancer is limited.

Methods:
Using the Genetic Epidemiology Research on Adult Health and Aging cohort established at Kaiser Permanente Northern California (KPNC), an integrated healthcare system, we examined non-Hispanic white smokers aged ≥40 years diagnosed with lung cancer (n=489), including those with COPD (n=243) or without COPD (n=174), and neither disease (n=26,553) through January 31, 2014. Those with lung cancer were identified from KPNC Cancer Registry data. Those with COPD were identified from electronic health record data, requiring at least one hospitalization with a principal discharge diagnosis or two outpatient visits with a diagnosis of chronic bronchitis, emphysema, or COPD (ICD-9 codes: 491.*, 492.*, 496.*). We examined 16 single nucleotide polymorphisms (SNPs) in 10 risk loci identified previously for COPD or airflow obstruction by genome-wide association studies (1q41, 4q22.1, 4q31.21, 5q32, 6p21.32, 11q22, 14q32, 15q25.1, 16p11.2, 19q13) for their associations with lung cancer risk, overall and stratified by COPD. SNPs were examined individually and also jointly as an unweighted 16-SNP risk score. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression, adjusted for age, sex, pack-years of smoking, and principal components of genetic ancestry.

Results:
Only two SNPs at 15q25.1, a risk locus also known for lung cancer and nicotine dependence, were associated with overall lung cancer risk: rs8034191 (per-allele OR=1.22, 95% CI: 1.07-1.39, p=0.003) and rs12914385 (per-allele OR=1.23; 95% CI: 1.08-1.40, p=0.002). In stratified analyses, associations were marginally stronger for lung cancer without COPD (rs8034191: OR=1.36, 95% CI: 1.09-1.69; rs12914385: OR=1.24, 95% CI: 1.00-1.54) than lung cancer with COPD (rs8034191: OR=1.09, 95% CI: 0.90-1.31; rs12914385: OR=1.17, 95% CI: 0.97-1.40). The 16-SNP risk score was suggestively associated with overall lung cancer risk (highest vs. lowest quintile: OR=1.31, 95% CI: 0.97-1.76), with the magnitude of association somewhat stronger for lung cancer with COPD (OR=1.28, 95% CI: 0.84-1.97) than without COPD (OR=1.16, 95% CI: 0.72-1.88).

Conclusion:
Our preliminary results provide minimal evidence of pleiotropic associations of identified genetic variants for COPD with lung cancer risk, although analyses are limited by the number of lung cancer patients examined.

Background:
Background: Lung cancer is increasingly recognized as a heterogeneous disease comprised of genomically defined subtypes with distinct targetable genomic alterations. However, it is unknown whether established lung cancer risk factors differ between these genomically distinct subtypes. In this study of the genomics of young lung cancer (GoYLC), we present preliminary results of lifestyle risk factors by specific genomic alteration to better characterize lung cancer in the young.

Methods:
Methods: Beginning in July of 2014, patients diagnosed with a bronchogenic lung cancer under the age of 40 were recruited to the GoYLC study. Informed consent was obtained in-person and virtually (online), allowing patients to participate globally, regardless of proximity to study sites (https://www.openmednet.org/site/alcmi-goyl). To date, this study has accrued a total of 101 cases, of which 85 are adenocarcinoma (AC). Stage 4 AC is the focus of this analysis.

Results:
Results: Among the 63 stage 4 AC cases, the most common genomic alterations were ALK rearrangements (n=28; 44% of stage 4 AC cases) and EGFR mutations (n=17; 27%) while the other genomic alterations (n=18; 29%) include ROS1, BRCA2, HER2, P53, RET and ATM. The prevalence of active smoking and/or exposure to passive smoking was highest among those with ALK (64%), intermediate for those with EGFR (47%) and lowest for those with other genomic alterations (39%). However, the prevalence of only active smoking was lowest among those with ALK (28%), followed by EGFR (35%) and highest for those with other genomic alterations (39%). The majority of patients with ALK rearrangements or EGFR mutations reported no family history of lung cancer (82% and 88%, respectively), compared with 67% among those with other genomic alterations.

Conclusion:
Conclusion: These preliminary results suggest that lifestyle characteristics and family history in young lung cancer patients may differ by genomic alteration. Passive smoke exposure was more prevalent among those with ALK rearrangements or EGFR mutations. Those with other genomic alterations, albeit, a heterogeneous group, were least likely to be exposed to passive smoking and more likely to be active smokers. We are continuing to enroll participants and are expanding the epidemiologic characterization to all study patients to evaluate if risk factors also differ by tumor stage and histology (Data to be presented). Importantly, this analysis lays the groundwork for the development of our more comprehensive epidemiology of young lung cancer study that may identify potential lifestyle and environmental risk factors related to specific genomic alterations.

Abstract not provided