Virtual Library

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    E12 - Symptom Control - Pain, Dyspnoea and Fatigue (ID 12)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Supportive Care
    • Presentations: 3
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      E12.1 - Dyspnoea (ID 428)

      14:00 - 15:30  |  Author(s): D. Currow

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      E12.2 - Pain (ID 429)

      14:00 - 15:30  |  Author(s): M.J. Johnson

      • Abstract
      • Presentation
      • Slides

      Abstract
      Pain in lung cancer Lung cancer is the most common cancer globally with 1.6 million people diagnosed with the disease during 2008; over half of them in the developing world. Nearly 90% are due to smoking, or passively smoking, tobacco. The mortality to incidence ratio is 0.86, reflecting dismal survival [http//:globocan.iarc.fr/factsheet.asp] . Therefore, the focus of care remains one of palliation despite increased options for cancer directed treatment. Optimal symptom relief must play a central role. A systematic review of pain in people in with lung cancer found an overall weighted mean prevalence of pain in 47% patients (6 – 100%); the wide variation reflecting the different patient settings (1). However, for studies in general hospitals, just over one third of lung cancer patients had pain, and the weighted mean prevalence in a cancer treatment centre was 65%. Most pain is attributed to the cancer, either directly, or due to treatment (weighted mean prevalence; 13%). Pain is most common in the chest, then, pain in the spine. Patients may have multiple sites of pain, with other symptoms such as breathlessness, cough, and fatigue; pain considered to be one of the top three most distressing. Severe pain is associated with reduced survival, and interferes with function, enjoyment of life, mood and work(2). According to surviving relatives, of the 85% patients who had pain in the last year of life, over 50% found it very distressing(3). Management Assessment. All symptom management should start with a full assessment which extends beyond physical concerns into psychosocial and spiritual domains, and treatments (and involvement of relevant team members) tailored to the needs of the individual, remembering the effect on their family and friends. There are many extensive pain assessment tools which are not easy to use in daily clinical practice. Systematic assessment of every patient attending clinic, or admitted to hospital is often overlooked, but simple aide memoirs for the busy clinician are available and effective(4), or simple screening patient report scales. Where patient reported symptoms have been embedded in oncology clinical practice and linked to symptom management protocols, outcomes have improved(5-7). Symptom monitoring should be related to factors that patients rate as important such as effect on function and relationships with family and friends rather than a score(8). The linking of assessment to education (clinician and patient) and clinical guidance is important and shown to be more effective than education alone(9). Interventions for pain control Radiotherapy. Most pain is from the primary tumour, often with haemoptysis and cough. Palliative radiotherapy is effective but not extensively documented. One RCT study in non-small cell lung cancer shows improvement in pain in three quarters. Other symptoms also improved, along with function and wellbeing(10). Bony metastases are common in lung cancer, if present over 55% lead to one or more skeletal related events. Palliative radiotherapy is the most effective treatment. Onset of relief is between a few days and 1 month, and lasts between 3 to 6 months(11;12). A Cochrane review in 2000 calculated a number needed to treat to give complete relief in one patient at one month as 4.2 (95% CI 3.7 – 4.7)(13). A single fraction of 8Gy is as effective as higher multi-fractionated doses for the acute relief of pain, although of shorter duration(14). Opioids and other analgesics. The WHO analgesic ladder remains the standard approach to analgesic use in cancer pain with morphine still the most cost-effective first line strong opioid; cheaper than the equally effective oxycodone(15;16). In the presence of significant renal dysfunction, fentanyl, alfentanil and methadone are the least likely to cause harm (17). A systematic review confirms a small further benefit with the addition of a non-steroidal anti-inflammatory drug (NSAID), although the contributory studies were too small to comment on toxicity(18). Given the recent data on cardiovascular toxicity of NSAIDS, naproxen and low dose ibuprofen appear to be the safest in this group(19). Incident pain due to bone metastases is difficult to manage with analgesics alone because the direct relationship to periods of activity; the average duration of incident pain is 60 minutes and so may be improving before oral morphine may be fully absorbed. The newer transmucosal fentanyl preparations may be more helpful, with an onset of action of 10 minutes(20). Neuropathic pain often contributes to difficult to manage cancer pain. Opioids may provide benefit and a trial should be given. Standard adjuvant analgesics such as tricyclic antidepressants (duloxetine, amitriptyline) and anticonvulsants (gabapentin and pregabalin) and topical agents (capsaicin and lidocaine) may help but good quality trials in cancer pain are lacking(21). A recent RCT of ketamine for the palliation of refractory cancer pain found no benefit with ketamine(22). Another in patients with better performance status and where neuropathic pain is deemed to be the primary aetiology is almost closed to recruitment [ClinicalTrials.gov Identifier: NCT01316744]. Corticosteroids are commonly used for cancer pain although the evidence base is scant; a systematic review only found “low level evidence” for benefit (23). Bisphosphonates. Bisphosphonates are not routinely used for patients with lung cancer. A recent systematic review of bisphosphonate use in small cell lung cancer demonstrated improved pain control (RR 1.18; 95% CI 1.0 – 1.4), reduced skeletal related events (RR 0.81; 95% CIs 0.67 – 0.97) (24). However, many of the studies were of poor quality. Toxicity is usually restricted to transient flu-like or gastro-intestinal symptoms, but 15% of those with zoledronic acid developed renal dysfunction and 5% the distressing side-effect of osteonecrosis of the jaw. Newer agents such as denosumab may be tolerated better, but comparative trials in lung cancer are awaited. For the future In spite of these options, cancer pain, in general, is under-treated even where there is good access. Barriers include fear of, and poor education about, opioids in both patients and clinicians with consequent respective poor compliance and prescribing, and a lack of systematic screening of patient symptoms with full assessment if needed. Until assessment and management of pain is embedded into daily clinical practice, this feared symptom will remain a problem.

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      E12.3 - Fatigue and Exercise (ID 430)

      14:00 - 15:30  |  Author(s): S. Kilbreath

      • Abstract
      • Presentation
      • Slides

      Abstract
      Cancer-related fatigue (CRF) is a well-acknowledged, very common, phenomena arising from treatment of cancer. It is defined as ‘a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer treatment that is not proportional to recent activity and interferes with usual functioning’ [1]. In particular, the characteristics of CRF are different to those of fatigue experienced in the general population. In persons with lung cancer, the prevalence of CRF is very high, with 75 - 100% presenting with this symptom, and ≥50% reporting severity to be moderate to marked [2, 3]. The mechanisms underpinning CRF are multi-dimensional. These mechanisms include both central and peripheral components resulting from disturbances occurring across several systems, including physiological, biochemical, and psychological systems [4]. Factors that may contribute to CRF include side-effects of treatment such as anaemia, nutrition and fluid imbalance, sleep disturbances and systemic reactions to tissue injury induced by the disease and/or the treatment [5]. In addition, psychological factors can trigger or exacerbate CRF. Examples of psychological factors include anxiety and depression and difficulty in coping with treatments. Physical fatigue, often expressed as a feeling of weakness, lack of energy, or exhaustion associated with conducting activities of daily living, is thought to be due to a peripheral component. It is postulated that these sensations are a consequence of muscles having reduced capacity for a contractile response [4]. Several factors can conspire during cancer treatment to affect the contractile response of muscles, including insufficient oxygen transport and insufficient blood pumping to muscles, and severe impairment of skeletal-muscle function [5]. In persons with physical fatigue, sedentary habits reinforce fatigue, resulting in a vicious cycle. Exercise has the capacity to interrupt this downward decline. There is compelling evidence that exercise can address cancer-related physical fatigue. A recent Cochrane Review on the role of exercise for management of cancer-related fatigue identified 56 randomised controlled trials (RCTs); however, the majority were carried out in women with early breast cancer [6]. Not surprisingly, timing of interventions varied, with some occurring during treatment and others after cessation of adjuvant therapies. Mode and intensity of exercise also differed across studies: some interventions occurred in the home, while others were supervised at institutions or used a combined supervised/home based intervention. The major finding from this review was that aerobic exercise, including walking programs, or stationary arm or leg cycling significantly reduced fatigue both during and following cancer therapy. In addition, approximately half of the studies that included quality of life measures (n=17/35 studies) reported beneficial effects from exercise. In contrast, no consistent benefit from exercise was observed for anxiety or depression. Persons living with lung cancer, from Stage I to IV, appear to have the capacity to be physically active. In a systematic review on exercise interventions to improve exercise capacity and health-related quality of life in patients with non-small cell lung cancer, it was concluded that exercise is safe before and after treatments [7]. However, it was also noted that the studies reviewed were either case reports or small RCTs. Well-designed, appropriately powered RCT’s are required in this area. Two such studies are currently under way: Jones et al [8] are currently recruiting Stage I-IIIA non-small cell lung cancer patients treated surgically to participate in a study in which participants are randomised to one of four 16 week conditions: aerobic training alone; resistance training alone; combination of aerobic and resistance training; and attentioncontrol; and Vardy et al [9] are currently exploring the role of supervised aerobic physical activity with behavioural support specifically on fatigue. One finding from the systematic review [7] was that lung cancer patients who exercised following surgery, chemotherapy, or radiotherapy consistently reported improvements in fatigue. In addition, other symptoms such as dyspnoea, pain and cough were also reduced with exercise. The interventions were predominantly supervised aerobic training, lasting from 10 to 45 minutes, performed at moderate to high intensity, 3 times per week over a set period of weeks. Interval training of 3 – 5 minutes duration, repeated several times per day, is a common feature of exercise programs designed for lung cancer. In contrast, and similar to the findings from the Cochrane Review on exercise and fatigue [6], progressive resistance training was not effective in reducing fatigue in lung cancer patients who had completed 10 weeks of resistance training (n=17). Further clarity on the role of resistance training for management of fatigue in patients living with lung cancer will be determined from the study currently underway by Jones et al [8]. In conclusion, exercise is likely to be effective in reducing fatigue for persons living with Stage 1 – IV non-small cell lung cancer. However, it is important to recognise the support and supervision used in the interventions that demonstrated a significant reduction in fatigue. References: 1. Mock V. Evidence-based treatment for cancer-related fatigue. Journal of the National Cancer Institute. Monographs 2004:112-8 2. Iyer S, et al. The symptom burden of non-small cell lung cancer in the USA: a real-world cross-sectional study. Support Care Cancer 2013; epub ahead of print. 3. Sanders SL, et al. Supportive care needs in patients with lung cancer. Psychooncology 2010: 19:480-9 4. Ryan JL, et al. Mechanisms of cancer-related fatigue. Oncologist 2007:12 Suppl 1:22-34 5. Lucia A, Perez M. Cancer-related fatigue: can exercise physiology assist oncologists? The Lancet Oncology 2003:4: 616-25 6. Cramp F, Byron-Daniel J. Exercise for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev 2012:11:CD006145 7. Granger CL, et al. Exercise intervention to improve exercise capacity and health related quality of life for patients with Non-small cell lung cancer: a systematic review. Lung Cancer 2011: 72: 139-53 8. Jones LW, et al. The lung cancer exercise training study: a randomized trial of aerobic training, resistance training, or both in postsurgical lung cancer patients: rationale and design. BMC Cancer 2010:10:155 9. Dhillon HM, et al. The impact of physical activity on fatigue and quality of life in lung cancer patients: a randomised controlled trial protocol. BMC Cancer 2012:12:572

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    MO04 - Lung Cancer Biology I (ID 86)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 12
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      MO04.01 - Molecular mechanisms of cigarette smoke induced hyper-proliferation of human lung cells and its prevention. (ID 2636)

      16:15 - 17:45  |  Author(s): N. Dey, D. Chattopadhyay, I.B. Chatterjee

      • Abstract
      • Presentation
      • Slides

      Background
      Lung cancer is the leading cause of cancer-deaths throughout the World. Cigarette smoke (CS) is the strongest risk factor of lung cancer. Cigarette smoking and exposure to environmental tobacco smoke account for 90% of lung cancer cases, and smokers have a 20-fold increased risk of death from lung cancer compared to non-smokers. Unregulated cell proliferation together with suppressed apoptosis is a contributory factor for lung-carcinogenesis. However, the carcinogenic mechanism of cigarette smoking is not well understood. This is particularly because CS is a complex mixture of about 4000 compounds. We consider that identifying the risk factor(s) in CS and its prevention might be a novel way to prevent lung cancer.

      Methods
      Cytotoxicity was evaluated by the MTT assay. Cell cycle analysis was performed by propidium iodide (PI) staining followed by flow-cytometry. Apoptosis was assessed by AnnexinV- PI staining followed by flow-cytometry, phosphorylation of p53 and activation (cleavage) of caspase 3. Reactive Oxygen Species (ROS) production was detected by 2’, 7’-dichlorodihydrofluorescein diacetate (H~2~DCFDA) using confocal microscope. Cell proliferation was assessed using “In Situ Cell Proliferation Kit, FLUOS” (Roche Applied Science, Germany). DNA double-strand break was detected using “OxiSelect DNA Double Strand Break (DSB) Staining Kit” (CELL BIOLABS, INC.).

      Results
      We have identified p-benzoquinone (p-BQ) as a major risk factor that is derived from CS. p-BQ has a biphasic-nature as evidenced by MTT assay, AnnexinV-PI staining, cell cycle analysis and BrdU-incorporation assay. Low concentrations of p-BQ mimicked CS-induced proliferation of cultured lung adenocarcinoma cells (A549) as well as normal human primary small airway cells (ATCC[®] PCS-301-010[™]). On the contrary, high concentrations of CS/p-BQ resulted in cell death caused by oxidative stress and apoptosis. No such cell death was observed with low concentrations of CS/p-BQ. Coimmunoprecipitation and immunoblot experiments indicated that p-BQ-induced proliferation was mediated via aberrant phosphorylation of EGFR that lacked c-Cbl mediated ubiquitination and degradation. This resulted in prolonged EGFR signaling leading to persistent activation of Ras (a potent oncoprotein), the downstream survival and proliferative signaling molecules Akt and ERK1/2, as well as the transcription factors c-Myc and c-Fos. It is known that patients with lung cancer generally have a smoking history of more than 30-40 years. We therefore exposed A549 cells repeatedly to CS/p-BQ for 2 months. Repeated exposure of AECS/p-BQ generated high levels of DNA double-strand breaks in A549 cells that might lead to genomic instability as well as mutation of different proto-oncogenes and tumor suppressor genes – the hallmark events in cancer. In addition, CS/p-BQ altered the acetylation pattern of different histone epigenetic marks, thereby regulating the transcription of several candidate genes responsible for proliferation and apoptosis. Both anti-p-BQ antibody and vitamin C (a strong reductant of p-BQ) prevented CS/p-BQ-induced proliferation of lung cells.

      Conclusion
      Despite major advances in the treatment and management of lung cancer, most patients eventually die. Consequently, newer approaches such as chemoprevention(s) are necessary. We consider that prevention of CS-induced proliferation of lung cells by vitamin C and/or anti-p-BQ antibody may provide a novel intervention for preventing initiation of CS-induced lung cancer.

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      MO04.02 - Paclitaxel resistance is associated with drug accumulation in intracellular compartments and paclitaxel-binding proteins in human lung cancer cell lines (ID 75)

      16:15 - 17:45  |  Author(s): M. Shimomura, T. Yaoi, D. Kato, J. Shimada, S. Fushiki

      • Abstract
      • Presentation
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      Background
      Several mechanisms have been suggested for paclitaxel resistance in cancer cells, including overexpression of the multidrug transporter gene, ATP-binding cassette, sub-family B, member 1 (ABCB1), and the presence of a point mutation in the β-tubulin gene at the paclitaxel-binding site. However, the mechanisms underlying resistance to this agent have not yet been completely elucidated.

      Methods
      Three human lung cancer cell lines, II18, A549, and RERF-LC-KJ, were analyzed; their 50% inhibitory concentrations of paclitaxel were -8.33, -7.69, and -4.51 logM, respectively. The cell lines did not have any β-tubulin mutation. We evaluated the expression levels of ABCB1, intracellular accumulation of paclitaxel, paclitaxel-induced stabilization of microtubules, and intracellular localization of Oregon Green[®] 488-conjugated paclitaxel in these cell lines. Moreover, we prepared paclitaxel conjugated ferriteglycidyl metacrylate (FG) beads to purify paclitaxel-binding proteins from whole cell lysates of these cells.

      Results
      The ABCB1 expression level was strongly correlated to intracellular [[3]H]-paclitaxel accumulation (r[2] = -0.804) but was not related with paclitaxel resistance. The changes in the quantities of polymerized tubulin and acetylated tubulin after paclitaxel exposure were not related to paclitaxel resistance. Differences were observed between the intracellular localization of paclitaxel in RERF-LC-KJ, the most resistant cell line, and in the other 2 cell lines. The use of Oregon Green[®] 488-conjugated paclitaxel enabled visualization of not only the normal microtubule formation in the partial cells but also the aggregated vesicle formation in RERF-LC-KJ cells; aggregated vesicle formation was not remarkable in the other cell lines. Affinity purification by paclitaxel immobilized beads revealed several specific bands in RERF-LC-KJ; these bands were not revealed in the other cell lines.

      Conclusion
      We propose that paclitaxel resistance is associated with intracellular compartments in which paclitaxel accumulates and paclitaxel-binding proteins expressed specifically in resistant cell line.

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      MO04.03 - Chromosomal and mutational analysis of the cisplatin resistant phenotype in NSCLC cells (ID 3313)

      16:15 - 17:45  |  Author(s): M.P. Barr, L.C. Alcock, R.L. Stallings, S. Toomey, A. Carr, B.T. Hennessy, D. Richard, K. O'Byrne

      • Abstract
      • Presentation
      • Slides

      Background
      Primary and acquired resistance to platinum agents such as cisplatin have become a major obstacle in the management of lung cancer patients, in particular non-small cell lung cancer (NSCLC). The availability of comprehensive genomic data on DNA copy number changes in cisplatin resistant NSCLC is limited, and little is known about the genes driving this chemoresistant phenotype. Detailed molecular portraits through high density genomic DNA arrays and genome wide mutation profiles will aid in understanding the molecular basis of individual responses to new molecular therapies.

      Methods
      A panel of cisplatin resistant (CisR) NSCLC cell lines were recently generated and characterised in our laboratory. In this study, high resolution array-based comparative genome hybridization (aCGH) was performed on a panel of five CisR NSCLC cell lines to examine DNA copy number gains, losses and amplifications. Cellular DNA (500ng) and control DNA was differentially labelled with Cy3 and Cy5, respectively. Labelled test (4µg) and reference DNA were hybridised to a 12-plex 135,000 probe array (Roche NimbleGen) for 18 hours in a MAUI hybridisation station (BioMicro Systems) at 42°C. Fluorescent intensities were extracted and log 2 ratios calculated and normalized using NimbleScan Software (version 2.4). Chromosomal aberrations were identified using the CGH-segMNT algorithm (NimbleScan 2.4). A significance log 2 ratio threshold of <−0.25 for loss and >0.25 for gain was used to identify DNA copy number imbalances. For mutational analysis, Sequenom®, a mass-spectrometry-based SNP genotyping technology, was used to identify mutations in our panel of resistant cell lines. Using a literature search and the Catalogue of Somatic Mutations in Cancer (COSMIC) database, a mutation panel was identified for the detection of 547 frequently occurring and potentially clinically relevant mutations in 49 cancer-related genes. Some of these include KRAS, NRAS, BRAF, PIK3CA, MET, CTNNB1, STK11, AKT, and EGFR. Matrix chips were analysed on a Sequenom® MassArray MALDI-TOF system. Visual inspection and Sequenom® typer software were used to perform genotyping based on mass spectra.

      Results
      Using aCGH arrays, a number of gains, losses and amplifications of various chromosomes were found across a panel of CisR cell lines, relative to corresponding PT cells. The most frequently occurring of these chromosomal imbalances included gains, losses and homozygous deletions on chromosome 3 (MOR, A549, H1299), deletions and amplifications on chromosome 7 (H460, A549, H1299) and deletions and gains on chromosome 15 (MOR, A549, H1299) and chromosome X (MOR, H460, SKMES-1). Deletions on chromosomes 4, 6, 11, 12, 14, and amplification of chromosome 5, were also identified among the different CisR cell lines. The collation and analysis of data arising from mutation analysis of CisR cells using the Sequenom® platform are currently being completed.

      Conclusion
      High-resolution mapping of chromosomal imbalances may offer potential in the identification of genes, including oncogenes and tumour suppressor genes, affected by these imbalances. These findings may further contribute to the delineation of the genomic profile of cisplatin resistant lung cancer, and offer perspectives for the identification of genes contributing to this disease phenotype and in assessing the response to new molecular treatments.

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      MO04.04 - Aerosol Azacitidine Reduces Methylation Levels of Tumor Suppressor Genes and Prolongs Survival in the Orthotopic Lung Cancer Models in Mice. (ID 1621)

      16:15 - 17:45  |  Author(s): X. Qiu, Y. Liang, B. Piperdi, R. Perez-Soler, Y. Zou

      • Abstract
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      Background
      Promoter hypermethylation plays an important role in lung cancer carcinogenesis by silencing key tumor suppressor genes (TSG). Reversing the hypermethylation of TSG by direct aerosolized administration of a demethylating agent may have a potential to inhibit lung cancer growth and development. This study examines the therapeutic potential of aerosolized azacytidine (Aza) in the orthotopic mice model of human NSCLC.

      Methods
      Vidaza® (the clinical grade Aza formulation for IV administration) was dissolved into sterile water for injection and aerosolized in a clinical standard aerosol system. The aerodynamic size, the lung deposition, and the Aza level in the lung and circulation of mice were measured by previously described methods. The demethylation and gene reactivation functions of aerosolized Aza were detected by qPCR methylation array and western blotting assay in the human non-small cell lung cancer (NSCLC) tumor tissues from the orthotopic intratracheally inoculated xenograft models in nude mice. The therapeutic efficacy and toxicity of the aerosolized Aza were also evaluated in mice. Mice treated with an intravenously administered Aza with clinically equivalent dose and schedules were used as a comparison.

      Results
      The aerosolized Aza is an appropriate pharmaceutical inhalation formulation with size distribution of about 80% of droplets from 0.1 to 5 micron. This dynamic size range ensures the aerosol droplets depositing in the lower airway as indicated by the recovery of approximately 80% Aza from the lung tissue 20 min after the aerosol administration. In efficacy and toxicity studies, aerosol administration of Aza significantly prolonged the survival of nude mice with intratracheally inoculated human NSCLC tumors. The %-increased in life span was 5- to 10-fold higher than that of a systemic treatment of Aza at a clinically equivalent dose. The aerosolized Aza, at a potentially therapeutic dose, did not cause any detectable lung toxicity or systemic toxicity (myelosuppression). After the aerosolized Aza treatment, the lung tumors were resected and the methylation levels of the 24 promoters driving the lung cancer related tumor suppressor genes (TSGs) in the lung tumors were examined by qPCR methylation array. The aerosolized Aza significantly reduced the methylation level in 9 of the 24 promoters examined. This demethylating effect also resulted in the gene reactivation at the protein level in several tested genes.

      Conclusion
      In our orthotopic NSCLC model, aerosolized Aza was well tolerated with good drug delivery to bronchial epithelium at non-cytotoxic doses. The pharmacodynamic effect of the TSG demethylation and reactivation was observed. Interesting therapeutic efficacy of prolonging survival was observed in our model from aerosolized 5-Aza over intravenous administration in mice. The phase I clinical trial of aerosolized Aza with pharmacodynamic endpoints will be conducted. Acknowledgement: Supported by a NIH (NCI) grant 5R01CA154755-02

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      MO04.05 - Tracheal basal cells in the lung squamous dysplasia: moving proximal. (ID 1700)

      16:15 - 17:45  |  Author(s): M. Ghosh, L.D. Nield, J. Kwon, D.T. Merrick, R.L. Keith

      • Abstract
      • Presentation
      • Slides

      Background
      Squamous cell carcinoma (SCC) is the second most common form of lung cancer, a disease primarily observed in smokers. Studies have shown that preneoplastic dysplasias are the precursors for SCC. However, only a subset of these lesions progress to invasive carcinoma and predicting the fate of individual lesions is difficult. Understanding the processes associated with the development of dysplasia would therefore have significant impact on preventative therapy for high-risk lesions. To this goal we have studied N-nitroso-tris chloroethyl urea (NTCU) model of premalignant murine squamous dysplasia. Bi-weekly topical application of NTCU for 32-weeks caused endobronchial dysplasias that were pathologically similar to dysplasias encountered in human smokers. In the current study we used NTCU model to identify the events that precede dysplastic changes in murine airways.

      Methods
      Immunofluorescence analysis of NTCU treated airways showed abundant expression of keratin 5 positive (K5+) basal cells. In normal mouse respiratory epithelium K5+ cells are confined only in the trachea and are absent in the bronchial epithelium. Ectopic expressions of K5+ cells in the mouse bronchial epithelium therefore suggested a role for tracheal basal cells in the pathogenesis of NTCU-induced dysplasia. To explore this possibility we analyzed tracheal and bronchial histology after vehicle and 20mM NTCU treatment at 4, 8, 12, 16, 25 and 32 weeks.

      Results
      Low-grade dysplasia of the tracheal epithelium was observed as early as 4 weeks of NTCU exposure. On the contrary, squamous metaplasia or low-grade dysplasia of the bronchial epithelium was not seen until 25 weeks. Morphometric analysis of immunostained tracheal tissue showed a time-dependent increase in the numbers of K5+ cells and a concomitant loss of cells expressing Clara cell secretory protein (CCSP) and ciliated cells. We have shown previously that injury to the trachea upregulates expression of keratin 14 (K14) in basal cells. Consistent with this phenomenon, NTCU exposure showed a time-dependent increase in the number of K5/K14 dual-positive basal cells. To understand the mechanism by which NTCU treatment mediates ectopic expression of basal cells in the lung, we used flow-cytometry to analyze cell-surface markers expressed by tracheal basal cells. These studies revealed a time-dependent decrease in the level of integrin a6b4 (CD49f). CD49f is a hemidesmosomal protein that facilitates attachment of basal cells to the basement membrane. These findings suggested that NTCU treatment might promote migration of tracheal basal cells by destabilizing their adherence to the basement membrane.

      Conclusion
      Collectively, our results showed an early involvement of tracheal basal cells in the generation of dysplastic lung lesions in a murine model of SCC. By moving the focus proximal, we have discovered a realm of biological developments in the trachea that had not been previously examined. Further research of these processes will aid in the elucidation of dysplastic development in SCC.

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      MO04.06 - DISCUSSANT (ID 3894)

      16:15 - 17:45  |  Author(s): G.R. Simon

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MO04.07 - Chronic lung injury by constitutive expression of AID leads to focal alveolar regeneration and cancer (ID 116)

      16:15 - 17:45  |  Author(s): J. Kitamura, K. Kinoshita, M. Uemura, M. Sonobe, H. Hiai, H. Date

      • Abstract
      • Presentation
      • Slides

      Background
      Activation-induced cytidine deaminase, AID, is an enzyme required for somatic hypermutation and class-switch recombination which diversify immunoglobulin genes and causes DNA mutations and strand breaks. Uncontrolled expression of AID is cytotoxic. AID transgenic mice invariably develop lung lesions morphologically similar to human atypical adenomatous hyperplasia (AAH), which can be a precursor of bronchioloalveolar carcinoma. About 10 % of these mice develop visible lung tumor including adenocarcinoma. However, the relationship between this mouse AAH-like lesion (MALL) and lung cancer is unclear. In the present study, we examined MALLs to elucidate their characteristics and involvement in lung cancer.

      Methods
      p53, KRAS, and EGFR mutation status in each laser-microdissected MALL were analyzed. The expression of airway epithelial cell markers and lung alveolar regeneration markers in MALLs were investigated by immunohistochemistry. Apoptosis assay were performed in murine lungs. For cell proliferation assay, AID Tg mice were received a daily intraperitoneal injection of 1 mg 5-ethynyl-2’-deoxyuridine (EdU) for 7 days. Then, mice were studied 1 day (day 1) or 3 weeks (day 20) after the last injection.

      Results
      We found mutations of p53 in 10.5% of MALLs (4/38), but no mutations of KRAS and EGFR. In immunohistochemistry, MALLs were partially positive for SP-C (lung alveolar type II cell-specific marker), but negative for CC-10 (clara cell-specific marker) and podoplanin (lung alveolar type I cell-specific marker). Frequency of apoptotic cells among lung alveolar wall cells was significantly higher in AID transgenic mice than in wild type mice. Moreover, frequency of Edu-positive MALL decreased significantly at day 20 compared to that at day 1. The expressions of p63, cytokeratin 5/14, and E-cadherin/Lgr6, the recently described markers of lung alveolar regeneration, were observed in MALLs.

      Conclusion
      Based on these observations, we speculate that MALL is a regenerating tissue compensating for alveolar epithelial cell loss caused by AID-induced genotoxic stress. AID expression in such regenerating tissue should predispose cells to malignant transformation by its mutagenic activity. AID transgenic mice could be a mouse model that may provide the link between lung regeneration after injury and the development of lung cancer.

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      MO04.08 - Activation of liver X receptor induces interferon-gamma production and inhibits tumor growth (ID 705)

      16:15 - 17:45  |  Author(s): Q. Wang, X. Ma, Y. Duan

      • Abstract
      • Presentation
      • Slides

      Background
      Interferon-γ (IFN-γ) has been well documented to have multiple functions including anti-tumorigenesis. Liver X receptors α and β (LXR) are members of ligand- activated nuclear receptor superfamily. LXR can be ac- tivated by natural ligands of some oxysterols and by numerous synthetic ligands (e.g. T317).The LXR-induced ABCA1 expression promotes free cholesterol efflux from macrophages thereby inhibiting the development of atherosclerosis. LXR has also been demonstrated the important functions in immune system . Here we tested the hypothesis that IFN-γ is a target for LXR activation, and the induction of IFN-γ expression by LXR can lead to inhibition of tumor growth.

      Methods
      C57 wild type or IFN-γ-/- mice (same background) in two groups were s.c. injected with2×10 5 LLC1 cells (ATCC) in the right flank to establish a carcinoma tumor model. For carcinogen-induced tumor: at the first week, C57 mice were i.p. injected with MCA (15 mg/kg body); from the second week, the mice were i.p. weekly injected with BHT for 6 weeks. The doses of BHT were: 1st injection, 150 mg/kg body weight; 2nd to 6th injections, 200 mg/kg.

      Results
      In this study, we observed that LXR ligand (T317) induced IFN-γ protein expression which was associated with increased mRNA and secreted protein levels in culture medium. In vivo,T317 increased wild type mouse serum IFN-γ levels and IFN-γexpression in tissues. T317 inhibited the inoculated LLC1 tumor growth in wild type mice but not in IFN-γ knockout (IFN-γ-/-) mice. In addition, T317 displayed inhibitory and therapeutic effects on 3-methylcholanthrene/butylated hydroxytoluene (MCA/BHT)-induced pulmonary carcinomas. T317 inhibits the growth of inoculated LLC1 tumor in wild type mice but not in IFN-γ-/- mice Wild type or IFN-γ-/- mice. Figure 1 T1317 inhibits MCA/BHT-induced pulmonary tumors Figure 2

      Conclusion
      Our study demonstrates IFN-γ is a target gene of LXR activation. LXR-induced IFN-γ expression can be attributed, at least in part, to the anti-tumorigenic properties of LXR.

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      MO04.09 - Exercise Induced Lung Cancer Tumor Growth Suppression via Activation of p53: Mechanistic Findings from a Mouse Model (ID 182)

      16:15 - 17:45  |  Author(s): K.A. Higgins, D. Park, W.J. Curran, X. Deng

      • Abstract
      • Presentation
      • Slides

      Background
      Regular exercise has been shown to improve the quality of life in patients undergoing treatment for lung cancer and has been associated with reductions in cancer-specific mortality in patients with colon and breast cancer. The direct effects of cardiovascular exercise on lung cancer tumor biology, however, remain unknown. This study evaluated cardiovascular exercise in a mouse model of lung adenocarcinoma, including clinically relevant endpoints such as lung tumor growth and distant metastasis. Furthermore, biologic mechanisms of action underlying clinical findings were also explored.

      Methods
      Luciferase-tagged A549 lung adenocarcinoma cells were injected through the tail vein of nude male mice. Mice underwent weekly bioluminescent imaging until lung tumors were clearly identified. After lung tumors were identified, mice were randomized to daily wheel-running versus no wheel-running. Mice were imaged weekly. After 4 weeks, all mice were euthanized and lung tumors were harvested. Western blots and immunohistochemistry (IHC) studies were undertaken on tumor tissue to identify potential differences in protein expression levels in exercise versus sedentary mice.

      Results
      Exercising mice tumors grew significantly more slowly relative to sedentary mice (figure 1). There was no change in development of metastatic lesions between the two groups. Protein analysis by Western blot or IHC demonstrated increased p53 protein levels in exercising mice relative to sedentary mice, as well as increased mediators of apoptosis including Bax, Bak and active caspase 3 in tumor tissues (figure 2 and data not shown). No normal tissue toxicity in other organs was observed in the two groups of mice. Figure 1. Figure 1 Figure 2. Figure 2

      Conclusion
      Daily cardiovascular exercise appears to mitigate growth of lung adenocarcinoma tumors by activation of p53 tumor suppressor function and increased apoptosis.

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      MO04.10 - Identification of biological properties of intralymphatic tumor related to the development of lymph node metastasis in lung adenocarcinoma (ID 1724)

      16:15 - 17:45  |  Author(s): K. Kirita, G. Ishii, R. Matsuwaki, Y. Matsumura, S. Umemura, S. Matsumoto, K. Yoh, S. Niho, K. Goto, H. Ohmatsu, Y. Ohe, K. Nagai, A. Ochiai

      • Abstract
      • Presentation
      • Slides

      Background
      Intralymphatic tumors in the extratumoral area are considered to represent the preceding phase of lymph node (LN) metastasis. The aim of this study was to clarify the biological properties of intralymphatic tumors susceptible to the development of LN metastasis, with special reference to the expression of cancer initiating/stem cell (CIC/CSC) markers in cancer cells and the number of infiltrating stromal cells.

      Methods
      A total of 2087 consecutive adenocarcinoma patients underwent complete resections and systematic LN dissections between May 1998 and December 2012 were identified. Among these cases, we selected those that had been diagnosed as having lymphatic permeation in the extratumoral area (n = 107). We examined the expression levels of CIC/CSC related markers including ALDH1, OCT4, NANOG, SOX2 and Caveolin-1 in the intralymphatic and primary tumor cells to evaluate their relationship to LN metastasis. The number of infiltrating stromal cells expressing CD34, α-smooth muscle actin, and CD204 were also evaluated. Moreover, we measured E-cadherin expression to identify a correlation between CIC/CSC related molecules and epithelial - mesenchymal transition (EMT) process.

      Results
      Intrathoracic LN metastases were detected in specimens from 86 patients (80%). Among the intralymphatic tissues, low ALDH1 expression in cancer cells, high SOX2 expression in cancer cells, and a high number of CD204(+) macrophages were independent predictive factors for LN metastasis (odds ratio [95%CI] = 3.25 [1.11 – 9.82], P = 0.031 for ALDH1; 4.09 [1.38 – 13.4], P = 0.011 for SOX2; and 3.45 [1.16 – 11.4], P = 0.026 for CD204(+) macrophages). However, in the primary tumors, only a high SOX2 expression level in the cancer cells within the primary tumor was significantly correlated with LN metastasis (p=0.008); ALDH1 expression in the cancer cells and the number of CD204(+) macrophages were not correlated with LN metastasis (P = 0.230 and P = 0.088, respectively). Among these factors, only low ALDH1 expression in intralymphatic cancer cells was significantly correlated with the farther spreading of LN metastasis (mediastinal LN, pN2) (P = 0.046) and higher metastatic LN ratio (metastatic/resected) (P = 0.028). Intralymphatic cancer cells expressing low ALDH1 levels exhibited lower E-cadherin expression levels than cancer cells with high levels of ALDH1 expression (P = 0.015). The expressions of other CIC/CSC related markers, including OCT4, NANOG, SOX2, and Caveolin-1, were not correlated with the E-cadherin expression.

      Conclusion
      Intralymphatic cancer cells expressing low levels of ALDH1 and infiltrating macrophages expressing CD204 have a critical impact on LN metastasis. Especially, intralymphatic cancer cells expressing low levels of ALDH1 might acquire a metastatic aggressiveness by the EMT process. Our study highlighted the significance of evaluating the biological properties of intralymphatic tumors for tumor metastasis and suggested the possibility of usefulness as a new molecular target, especially as an adjuvant therapy.

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      MO04.11 - The tumor microenvironment expression of the Inhibitor of Differentiation-1 (Id1) is determinant of the development of liver metastasis from lung cancer through gene regulation of tumor cells (ID 2429)

      16:15 - 17:45  |  Author(s): I. Gil-Bazo, E. Castañón, I. López, M. Ponz-Sarvisé, J.M. López-Picazo, M. Collantes, M. Ecay, I. Gil-Aldea, A. Calvo

      • Abstract
      • Presentation
      • Slides

      Background
      Liver metastases appear in about 30% of non-small cell lung cancer (NSCLC) patients during the disease course with a dramatic impact on clinical outcome and quality of life. TME gene expression might be crucial for allowing tumor cells to migrate and spread to the liver. However, no candidate genes have ever been proposed as responsible for this process. Id1, a member of the gene signature that facilitates breast cancer cells to disseminate to the lungs, might be determinant for NSCLC LM development.

      Methods
      For the first time, a mouse model of LM from lung cancer was developed. Two cohorts of mice were compared; C57BL/6 females vs. Id1-knockout (KO) females (gently provided by Dr. Benezra, MSKCC, New York). Lewis lung carcinoma cells (500,000) were selected for intrasplenic injection. Five minutes after tumor cells injection all mice were splenectomized to avoid bulky flank tumor formation. Mice were closely followed after tumor cells inoculation. Weekly FDG-micro-positron emission tomography (PET) scans were performed to study liver metastasis formation in both groups of mice. Animals were sacrificed at the time of LM development. Liver metastatic lesions were obtained for RNA extraction (Qiagen kit). A microarray gene expression analysis (Affymetrix) with the support of Ingenuity Pathways Analysis (IPA) was performed to evaluate the potential impact of Id1 genotype on the regulation of genes mediating proliferation, invasion, migration, angiogenesis and metastasis in LM.

      Results
      The first week after tumor cells intrasplenic injection, FDG-PET scans showed no liver metabolic uptake in any of the mice. By week 2 however, 70% of C57BL/6 mice and 10% of Id1-KO mice showed clear LM by FDG-PET (p=0.02). Three weeks after intrasplenic tumor cells injection, 100% of C57BL/6 animals showed LM compared to 30% of Id1-KO mice (p=0.03). In addition, 50% of Id1-KO mice remained LM-free 4 weeks after tumor cells injection. No other metastatic sites were indentified at the time of necropsy. In the mircroarray gene expression analysis, only a set of 50 out of nearly 900 genes appeared upregulated in the LM of Id1-KO mice compared to C57BL/6 animals whereas the rest of the genes were downregulated. Interestingly, amphiregulin, caveolin-1, aurora kinase B, MMP3, Hsp90aa1, Cdk1, Hif1a, Cyclin D2 were among the significantly downregulated genes in the Id1-KO LM.

      Conclusion
      A novel mouse model for liver metastasis from lung cancer has been developed allowing the study of this complex and unexplored process. Id1 gene expression seems to be a key mediator of the development of liver metastasis from lung cancer in this in vivo model. The absence of Id1 expression in the tumor microenvironment of Id1-KO mice was sufficient to significantly delay and impair the metastatic process of lung cancer tumor cells to the liver. Id1 might be able to modulate LM through a direct downregulation of genes involved in proliferation, invasion, migration, angiogenesis and metastasis. This study has been partially funded by "UTE project CIMA" and an ISCIII-FIS grant 2011.

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      MO04.12 - DISCUSSANT (ID 3895)

      16:15 - 17:45  |  Author(s): N. Watkins

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS02 - Stem Cells and Epigenetics in Lung Cancer (ID 19)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Biology
    • Presentations: 4
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      MS02.1 - Stem Cells & the Cell of Origin of Lung Cancer (ID 462)

      14:00 - 15:30  |  Author(s): K. Sutherland

      • Abstract
      • Presentation
      • Slides

      Abstract
      The cellular hierarchy of the lung is quite complex and it is believed that different progenitor cells and stem cell populations residing within distinct spatial regions of the lung are responsible for orchestrating lung development, regeneration and repair. These different stem cell populations are also likely to be instrumental in the development of the various cancers in lung as particular lung tumour subtypes are almost exclusively found in distinct compartments within the lung. Squamous cell carcinomas are thought to arise from the proximal airways, small cell lung cancer are predominantly located in the bronchioles while adenocarcinomas are more frequently detected the in the distal part of the lung. To investigate the cellular origin of lung cancer, we utilized Cre-loxP recombination technology, which is an effective method for expressing or deleting a target gene in Cre-expressing cells. We generated a series of recombinant adenoviruses expressing Cre recombinase from specific lung epithelial gene promoters. For these studies we chose to target Clara cells, alveolar type 2 (AT2) cells and neuroendocrine (NE) cells. Comprehensive experiments performed in Rosa26R-lacZ and mT/mG reporter animals showed that these viruses exhibit a high level of cell selectivity in the adult mouse lung. To address the cellular origins of small cell lung cancer (SCLC) we have utilised a sporadic mouse model of small cell lung cancer based on the conditional inactivation of the tumour suppressor genes Tp53 and Rb1. We infected Tp53F/F;Rb1F/F animals with our cell type-restricted Adeno-Cre viruses: Ad5-CC10-Cre, Ad5-SPC-Cre and Ad5-CGRP-Cre. Results from these studies show that inactivation of Trp53 and Rb1 can efficiently transform neuroendocrine (CGRP-positive) and to a lesser extent, alveolar type 2 (SPC-positive) cells leading to SCLC. In contrast, CC10-expressing cells were largely resistant to transformation. The results clearly indicate that neuroendocrine cells serve as the predominant cell-of-origin of SCLC in this model. Interestingly a different, cell type specificity was observed when a K-rasG12D oncogene-driven non-small cell lung cancer (NSCLC) model was used to reveal the cell of origin of NSCLC (mostly of adenomas and adenocarcinomas). In this case we noted a difference between K-rasLSL-G12D/+ and K-rasLSL-G12D/+;Trp53F/F animals following infection with our cell type-restricted adenoviruses. In K-rasLSL-G12D/+ mice alveolar type 2 cells appeared to be the most effective target cell for inducing adenomas, whereas in K-rasLSL-G12D/+;Trp53F/F mice multiple cell types had the capacity to give rise to adenomas and adenocarcinomas. Moreover, preliminary data from these experiments indicates that the cell-of-origin may also influence the characteristics and behaviour of the resulting tumours. Taken together, our data show that both cell specific features and the nature of the genetic lesion(s) are critical factors in determining the tumour initiating capacity of lung (progenitor) cells to give rise to various lung cancer subtypes.

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      MS02.2 - Targeting Hedgehog Signaling in Small Cell Lung Cancer (ID 463)

      14:00 - 15:30  |  Author(s): N. Watkins

      • Abstract
      • Presentation
      • Slides

      Abstract
      Small cell lung cancer (SCLC) is a malignant neuroendocrine tumour responsible for 20% of all lung cancer deaths. Despite the effectiveness of platinum-based chemotherapy, the overwhelming majority of patients succumb to a chemoresistant recurrence within 2 years of diagnosis. Therefore, the discovery of novel strategies to prevent disease recurrence may have a significant impact on outcome. Many groups, including our own, have identified the importance of embryonic signaling pathways in promoting tumor-regeneration through the regulation of self-renewal. Activation of self-renewal pathways such as Notch, Hedgehog (Hh) and WNT is also thought to contribute to the survival of cancer cells with innate resistance to chemotherapeutic agents. Since the naturally occurring Hh inhibitor cyclopamine can block self-renewal in SCLC cells in vitro, we postulated that this pathway might be targetable following platinum-based chemotherapy. The Hh pathway is a highly conserved signaling system that specifies cell fate and self-renewal in development and homeostasis. The Hh ligand Sonic Hh (Shh) binds to, and inactivates, the receptor Patched (Ptch). This prevents Ptch from inhibiting Smoothened (Smo), the molecular target of the small molecule Hh inhibitors. Smo activation requires translocation to the tip of the primary cilium, a single, immotile, tubulin-based organelle present on most vertebrate cells. The ciliary motor protein Kif3a is essential for Smo translocation to the ciliary tip, and is required for Smo signaling in development. The importance of primary cilia in cancer is poorly understood. In addition, the formation of cilia is normally restricted to cells in the G0 of G1 phases of the cell cycle. In order to better understand how Hh signaling is regulated in SCLC, we investigated pathway activation in the context of cilia formation, and the expression of Smo protein in these cilia. Using a genetic mouse model of SCLC, we observed that approximately 25% of tumour cells express primary cilia, with a variable number expressing Smo at the cilia tip. Clonal growth of these tumour cells could be inhibited by blocking the Shh ligand with a monoclonal antibody, or by inactivating Smo with the small molecule LDE225 (Novartis). These data suggest that activation of Smo by Hh ligand at the level of the primary cilium is a crucial step in the initiation and self-renewal of SCLC. By contrast, cilia were rarely observed in human SCLC cells, both in vitro and in vivo. Based on our hypothesis that Hh signaling may be important in the regeneration of SCLC stem-like cells following chemotherapy, we employed a primary xenograft model in which we could identify minimal residual disease following treatment with single-agent carboplatin. Following chemotherapy, more than 50% of the residual tumour cells expressed primary cilia, and in the majority of these, Smo could be detected in the tip. In addition, marked upregulation of Shh ligand expression was observed. However, when these tumours were allowed to regrow to their original size, expression of Shh and cilia returned to the same pattern as seen in the treatment naive tumour, once again supporting a role for cilia-dependent activation of Smo by Hh ligand in SCLC stem-like cells. Furthermore, treatment of mice following chemotherapy with several small molecule inhibitors of Smo, including LDE225, delayed the regeneration of these tumours in vivo. One major controversy surrounding the role Hh signaling in cancer relates to the role of tumour stroma as a target of Shh signaling. To exclude this as a potential mechanism, we used two approaches. First, we crossed the mouse genetic model of SCLC referred to above with a reporter mouse in which LacZ activity can be used to measure Hh pathway activation. In this model, heterogeneous LacZ expression was clearly seen in tumour cells, but not stromal cells. Second, we recreated the carboplatin regeneration model of human SCLC in vitro using a three dimensional, stroma-free clonogenic assay. Transient manipulation of Hh signaling at all levels of the pathway by antibody blockade, siRNA, transfection or small molecule treatment dramatically affected long term cloning capacity in SCLC cells. Moreover, SCLC cells that survived an LD~95~ treatment with carboplatin in vitro demonstrated a marked increase in clonal capacity that was even more sensitive to Hh pathway blockade. Confocal immunofluoresence imaging of these cells revealed expression of Smo in the tips of numerous primary cilia, demonstrating that cell autonomous Hh pathway activation could be observed in a subset of innately chemoresistant, stem-like cells. In the last 5 years, targeted deletion of different components of the primary cilium in mice has dramatically expanded our understanding of the role of these structures in cell signaling. Once considered vestigial, cilia are now recognised as key signaling nodes for Hh, WNT, Notch, PDGF and mTOR signaling. In addition, we have identified heterogeneous expression of primary cilia in several other tumour models, most strikingly in osteosarcoma. More recently, we have shown that knockdown of KIF3a, an essential component of cilia assembly, causes a more dramatic loss of cloning capacity than inhibition of Hh signaling alone. These data suggest that in a subset of self-renewing tumour cells, cilia-dependent signaling pathways in addition to Hh are of importance, and may represent novel therapeutic targets. We are currently using genetically modified mouse models of cancer in which we can conditionally knockout Kif3a to address this question.

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      MS02.3 - Micro-RNA in Lung Cancer (ID 464)

      14:00 - 15:30  |  Author(s): G. Sozzi, M. Boeri, U. Pastorino

      • Abstract
      • Presentation
      • Slides

      Abstract
      Lung cancer, for its high incidence and mortality, is the most common cause of death from cancer in many developed countries. In contrast to other cancers, there has been almost no improvement in the 5-year survival rates of lung cancer in the past 30 years, rate just above 10% in Europe, primarily because lung cancer is detected in most cases in an advanced stage. Detecting lung cancer at an earlier stage and, ideally, predicting who will develop the disease and particularly the most aggressive forms of cancer are the biggest challenge. Imaging via low-dose computed tomography (LDCT) scanning is being actively evaluated as a screening tool for early detection of lung cancer in high risk patients but, although the positive results in mortality reduction reported in the large NLST trial (1) were very promising, at present, the real efficacy of LDCT lung cancer screening in heavy smokers remains a controversial issue (2). Nonetheless, the high false positive rates of LDCT, leading to multiple screening rounds, the issue of over-diagnosis, the unnecessary and sometimes harmful diagnostic follow-up and the costs underscore the need for non-invasive complementary biomarkers for standardized use. MicroRNAs are small, non coding, endogenous single–stranded ribonucleic acids with regulatory functions that are involved in tuning of many important pathways, including developmental and oncogenic pathways. Because of their fundamental role in development and differentiation, their involvement in the biological mechanisms underlying tumorigenesis, as well as their low complexity, stability and easily detection, they represent a promising class of tissue and blood-based biomarkers of cancer (3). We explored miRNA expression profiles of lung tumors and normal lung tissues from cases with variable prognosis identified in a completed spiral-CT screening trial with extensive follow-up (4). We found a panel of deregulated miRNAs discriminating normal lung tissue versus lung cancer and significant association of miRNA expression profiles in both tumor and non-involved lung tissue with clinical-pathological characteristics of the patients such as tumor histotype, tumor growth rate, disease free survival. miRNA expression profile in tumor and normal lung tissues from patients identifed in the first two years of the screening, including mainly Stage Ia ADC with excellent survival, was found to be significantly different from the profile of subjects with more aggressive tumors appearing in later years of screening, independently from tumor Stage. Overall these results indicate that, both in tumors and in non involved lung tissues, miRNA signatures are able to discriminate patients according to tumor aggressiveness, independently from Stage and type. We have then investigated mirRNA profiles in plasma samples from cases and controls belonging to two independent LDCT screening trials with extensive follow-up where multiple plasma samples, collected before and at time of disease detection were available. We reported that miRNA profiling in plasma samples collected 1–2 yrs before the onset of disease, at the time of lung cancer detection by LDCT and in disease-free smokers, resulted in the generation of four miRNA signatures with strong predictive, diagnostic, and prognostic potential (4). Overall, these results suggest that plasma miRNA profiles might be helpful in pinpointing those early stage tumors at high risk of aggressive evolution that would need additional treatments. We recently completed a large validation study where the diagnostic performance of the plasma-based miRNA test was retrospectively evaluated in samples prospectively collected from smoker subjects within the MILD trial. In this study, 1,000 consecutive MILD plasma samples collected from June 2009 to July 2010 among lung cancer-free individuals enrolled in the trial and all patients with lung cancer diagnosed by September 2012 (n=85) were obtained. In patients we analyzed plasma samples collected both pre-disease (four to 35 months before lung cancer detection, median lag time of 15 months) and at the time of diagnosis. Custom-made microfluidic cards containing the 24 microRNAs composing the signatures identified in the exploratory study were created, and on each card eight plasma samples were analyzed per time. Since the goal of this study was to combine the plasma miRNA assay with LDCT results, in order to have a clinical useful tool to classify plasma samples, we developed a three-level miRNA signature classifier (MSC) of Low, Intermediate, or High risk of disease with subject categorization to one of these three risk groups based on pre-defined cut-points of positivity for the four different expression signatures of the 24 miRNAs previously identified. The results of this large validation study indicates that MSC is a significant diagnostic instrument for lung cancer detection with prognostic performance and support the combined use of MSC and LDCT to improve the efficacy of lung cancer screening (5). References 1. Kramer BS, Berg CD, Aberle DR et al. Lung cancer screening with low-dose helical CT: results from the National Lung Screening Trial (NLST). J Med Screen. 2011;18:109-111. 2. Pastorino U, Rossi M, Rosato V, Marchianò A, Sverzellati N, Morosi C, Fabbri A, Galeone C, Negri E, Sozzi G, Pelosi G, La Vecchia C. Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial. Eur J Cancer Prev. 2012 May;21(3):308-15 3. Boeri M., Pastorino U. and Sozzi G. Role of MicroRNAs in Lung Cancer: MicroRNA Signatures in Cancer Prognosis. Cancer J. 2012 May;18(3):268-74 4. Boeri M, Verri C, Conte D, Roz L, Modena P, Facchinetti F, Calabrò E, Croce CM, Pastorino U, Sozzi G. MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3713-8. 5. Sozzi G, Boeri M, Rossi M, Verri C, Suatoni P, Bravi F, Roz L, Conte D, Grassi M, Sverzellati N, Marchiano’ A, Negri, La Vecchia C, Pastorino U. Clinical Utility of a Plasma-based microRNA Signature Classifier within Computed Tomography Lung Cancer Screening: A Correlative MILD Trial Study. Submitted

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      MS02.4 - Targeting Epigenetic Changes in Lung Cancer (ID 465)

      14:00 - 15:30  |  Author(s): C.M. Rudin

      • Abstract
      • Presentation
      • Slides

      Abstract
      The process of carcinogenesis is driven by clonally maintained genetic and epigenetic events that lead to aberrant cell proliferation, inhibit cell death, promote cell dissemination, and affect other key pathways. Research in the past decade has led to new insights into the epigenetic mechanisms controlling gene expression, and into the multiple ways in which these mechanisms are specifically disrupted in cancer. Epigenetic control of gene expression is dependent on modifications of the DNA itself, primarily methylation at CpG dinucleotides, and also by a host of site-specific protein modifications of histones, histone modifiers, and transcriptional machinery. Progress in understanding the multiple layers of epigenetic control is leading to the development and clinical testing of anti-cancer agents specifically targeting these aberrant pathways. DNA methylation and histone acetylation are two well established epigenetic control mechanisms that are known to be aberrantly regulated in essentially all cancers, including lung cancer. We conducted an exploratory phase I/II trial combining an inhibitor of DNA methyltransferase, azacitidine, and an inhibitor of histone deacetylase, entinostat, in patients with recurrent metastatic non-small cell lung cancer. DNA methylation of gene promoters, and loss of histone acetylation, are coordinately regulated processes that can lead to selective silencing of gene expression: this mechanism has been implicated in silencing key tumor suppressor genes in cancer. Treatment with the combination of azacitidine and entinostat led to rare but impressive objective responses, including a complete response in a patient with extensively pretreated disease. In addition, a surprising fraction of patients experienced objective responses to the immediate subsequent therapy, including standard cytotoxic agents and investigational agents targeting the PD-1/PD-L1 immune checkpoint pathway. Preclinical data offer some potential explanations for this observation: many relevant immunoregulatory pathways in both tumor cells and immune effectors are markedly affected by azacitidine. We are now following up on the priming hypotheses suggested by these data, in randomized phase II studies assessing whether limited duration epigenetic therapy can enhance subsequent chemotherapy or immunotherapy efficacy in patients with advanced non-small cell lung cancer. This study represents an initial foray into combinatorial epigenetic strategy in lung cancer: many other strategies are now possible and are being pursued. “Second generation” agents targeting DNA methyltransferase, including an oral formulation of azacitidine and a prodrug, SG-110, are in early phase clinical development. So too are newer histone deacetylase inhibitors differing in specificity, selectivity, route of administration, and pharmacokinetics. Among the exciting new horizons in epigenetic therapy are new agents targeting more recently defined modifiers of epigenetic control, including many of the readers, writers, and erasers of histone modification. The recent remarkable expansion in knowledge about epigenetic regulatory pathways, and how they become dysregulated in cancer, is opening new therapeutic opportunities in lung cancer and other diseases.

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    MS12 - Loco-Regional Management of MPM (ID 29)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Mesothelioma
    • Presentations: 5
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      MS12.0 - Chair Intro (ID 510)

      14:00 - 15:30  |  Author(s): T. Nakano

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS12.1 - How Has the 'MARS' Trial Affected the Surgical Approach to MPM? (ID 511)

      14:00 - 15:30  |  Author(s): J. Edwards

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS12.2 - Pleurectomy Decortication Vs. Extrapleural Pneumonectomy (ID 512)

      14:00 - 15:30  |  Author(s): J. Donington

      • Abstract
      • Presentation
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      Abstract

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      MS12.3 - Peri-Operative Radiotherapy: Current Data and State of the Art (ID 513)

      14:00 - 15:30  |  Author(s): A. Price

      • Abstract
      • Presentation
      • Slides

      Abstract
      Formal prospective evidence of benefit from cancer treatments for patients with mesothelioma exists only for the small survival increment obtained from combinations of cisplatin and anti-folate agents in those with inoperable disease. Despite this absence of evidence of benefit, and some evidence of detriment, trimodality therapy including neoadjuvant chemotherapy, surgery and adjuvant radiotherapy continues to be regarded as a widespread standard of care in early disease. Only one very small randomised trial has addressed this question[1], and the evidence from that trial suggesting a substantial increase in mortality has been disputed by many believers in trimodality therapy. The surgical literature has recently been extensively reviewed, revealing the paucity of high level evidence for these treatments[2-3]. One Swiss trial investigated the role of radiotherapy in this combination, but closed last year because of poor accrual due to changes in surgical fashion (NCT00334594)[ 4]. The two major surgical approaches to early mesothelioma have been extrapleural pneumonectomy (EPP), first described over 30 years ago, and presented in 16 published reports of which 5 were prospective and only 1 randomised[2]. None of these studies directly compare radiation doses or techniques, and no firm conclusions are possible regarding dose response, or the superiority of techniques as variable as a simple opposed pair with or without electrons to intensity modulated radiotherapy (IMRT) or protons. It seems extremely unlikely that such data will ever exist, and what radiotherapy is used will continue to depend mainly on the expertise, technology and time available locally. There have been publications[5,6], reporting an unexpectedly high morbidity and mortality following IMRT and there may be an argument that simplest is best given the general lack of fatal outcomes with conventional radiotherapy, although dose coverage of certain areas is poor. One report suggested lower local failure with IMRT[7], but this may have related to the higher dose given (50.4 Gy vs 30 Gy) and it was unclear why the slightly higher dose (54 Gy)[ 8] normally used postoperatively was not possible. If IMRT is to be used then treatment times may be shorter with volumetric modulated arc therapy[9]. Whether as a result of the MARS trial, or the disappointing outcomes from prospective trials conducted by the EORTC and in the US[8, 10], surgical fashion has moved in the last few years from EPP to various extents of pleurectomy, where the underlying lung is preserved. This is not a conventional cancer operation involving en bloc resection of tumour with a defined margin, and adjuvant radiotherapy is rendered more difficult, if not impossible, by the residual lung. Attempts to spare the lung at least partially must of necessity involve sparing the pleura overlying the fissures, and significant rates of pneumonitis have been reported, albeit less than in the early reports of IMRT[11]. The doses achievable by these techniques remain relatively low by cancerocidal standards in the context of a disease believed to relatively radioresistant. Cao has also reviewed the 34 publications on pleurectomy, none of which are randomised and very few prospective[3]. Radiotherapy in most series, when it is described at all, seems to be at relatively low dose to the port sites, of questionable benefit since 2 randomised trials have shown no effect from this intervention at the time of diagnosis[12, 13]. The MARS group also plan to look at the benefits of pleurectomy, but radiotherapy is not currently included in the trial outline. Currently this is an area in which virtually no data exist to support decision making. Radiotherapy is likely to remain part of the trimodality recipe for those who continue to believe in EPP, at least until the postulated trial of 670 participants is completed[14], and single centre reports on small numbers of patients with more complex treatment techniques likely to continue. If the next generation of larger trials of radiotherapy looking at port site prophylaxis confirm the lack of utility of this intervention, it is difficult to see that there will be a role for radiotherapy after pleurectomy. Rather than assume such a role, it is to be hoped, but not expected, that randomised trials of the benefits of radiotherapy be instituted. 1. Treasure T et al, Lancet Oncol. 2011 Aug;12(8):763-72. 2. Cao CQ et al, J Thorac Oncol. 2010 Oct;5(10):1692-703. 3. Cao CQ et al, Lung Cancer. 2013 Jun 12. doi:pii: S0169-5002(13)00212-2. 4. http://clinicaltrials.gov/show/NCT00334594 5. Allen AM et al., Int J Radiat Oncol Biol Phys. 2006 Jul 1;65(3):640-5. 6. Patel PR et al., Int J Radiat Oncol Biol Phys. 2012 May 1;83(1):362-8. 7. Buduhan G et al., Ann Thorac Surg. 2009 Sep;88(3):870-5. 8. Van Schil PE et al., Eur Respir J. 2010 Dec;36(6):1362-9. 9. Scorsetti M et al., Int J Radiat Oncol Biol Phys. 2010 Jul 1;77(3):942-9. 10. Krug, LM et al., J Clin Oncol. 2009 Jun 20;27(18):3007-13. 11. Rosenzweig KE et al., Int J Radiat Oncol Biol Phys. 2012 Jul 15;83(4):1278-83. 12. Bydder S et al., Br J Cancer. 2004 Jul 5;91(1):9-10. 13. O’Rourke N et al., Radiother Oncol. 2007 Jul;84(1):18-22. 14. Weder W et al, Lancet Oncol. 2011 Nov;12(12):1093-4.

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      MS12.4 - Adjuvant Intracavitary Treatments in Mesothelioma (ID 514)

      14:00 - 15:30  |  Author(s): J. Friedberg

      • Abstract
      • Presentation
      • Slides

      Abstract
      Mesothelioma remains an incurable disease. Although there is compelling evidence that some patients can benefit from radical surgery, this modality remains surrounded by controversy and true Level I evidence in the form of a randomized prospective trial has yet to establish surgery as the standard of care. The driving principles behind utilizing surgery-based treatments for this cancer are that: these tumors are not curable with other modalities, they can reach enormous volumes where surgery is the only current modality that has expectation of achieving a significant response, as a general rule these cancers tend to progress locally to the point of patient demise without extrahemithoracic disease being present or of clinical significance. Because it is not possible to achieve completely negative margins in the overwhelming majority of pleural cancers, the realistic goal of any radical surgical procedure is to achieve a macroscopic complete resection. It is logical, therefore, to employ intraoperative adjuvant therapies in an effort to control the microscopic disease that remains after surgery. To date there are several different intraoperative adjuvants that have been employed with any regularity in the treatment of pleural mesothelioma: intraoperative radiation, heated perfusion with either chemotherapy or povidone iodine and photodynamic therapy. Each has its own advantages and disadvantages, from both oncologic and technical perspectives. Intraoperative radiation does not appear to be in active use at this time. The advantages of radiation are the established track record in treating mesothelioma and the penetrating nature of the modality with the disadvantages being damage to normal tissue, from the same penetrating nature. Employment of intraoperative radiation is likely the most expensive and logistically complicated of the intraoperative adjuvants. The technique that has been employed with heated povidone iodine has the advantages of logistical simplicity, with the treatment being delivered as sequential dwells, and low expense. In addition, there is the advantage of povidone iodine being an easy and safe material with which to work, with a high safety profile for both the patient and health care staff delivering the treatment. The disadvantages of this technique include the unclear benefit of povidone iodine as a therapeutic agent against this cancer and the certainty that unifom hyperthermia is not maintained during a dwell, working under the assumption that hyperthermia is an effective modality in and of itself. There is recent evidence, however, that mesothelioma may be resistant to hyperthermia. The common technique utilized for heated chemotherapy perfusion, typically platin-based, is significantly more involved than the dwell technique. In this situation a perfusion pump is employed. Disadvantages include increased expense and logistical complexity and utilization of an agent with a significant toxicity profile for both the patient and health care staff delivering the treatment. Advantages include assurance that hyperthermia is maintained, along with control of the temperature, and application of a perfusion agent that has an established track record in treating malignant pleural mesothelioma. With inflow and outflow catheters, this technique has the ability to simultaneously perfuse both the chest cavity and the abdomen, theoretically of benefit to treating occult peritoneal metastases or cells that are disseminated during surgery. Both perfusion techniques have the additional limitation that they are likely purely surface treatments, without any depth of penetration for the treating agent. Photodynamic therapy is a unique treatment modality and, as such, has unique advantages and limitations. Although it is simple to perform, it is likely the most logistically complex of the currently employed modalities. It requires delivery of visible laser light, pretreatment with a photosensitizing drug and employment of special “light precautions” for some period of time before, during and after surgery. Although the cost and availability of lasers has dropped dramatically, it is still a treatment that currently comes with a significant cost. The advantages are that the treatment works by a unique set of mechanisms, delivers treatment at and below the surface for short distance and is known to incite a significant immune response against treated cancers. Whether or not that tumor-directed immune response occurs with pleural mesothelioma is under investigation. Currently it is not possible to rigorously determine which, if any of these treatments is superior. Factors contributing to this dilemma are among the same that limit comparison of any surgery-based treatments. These include: small numbers of patients, colossal variability in patients not only between series but within series, lack of a highly effective staging system to allow rigorous analyses and comparisons, enormous variability in surgical techniques, lack of prospective randomized trials and the fact that essentially all patients suffer recurrence and overall survival may be greatly affected by subsequent treatments. This presentation will review the different intraoperative modalities, present current results and speculate about future directions.

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    MTE06 - Molecular Pathology Approach for Early Clinical Stage Mesothelioma: Cytological Diagnosis, and Reactive Mesothelial Hyperplasia (ID 50)

    • Event: WCLC 2013
    • Type: Meet the Expert (ticketed session)
    • Track: Mesothelioma
    • Presentations: 1
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      MTE06.1 - Molecular Pathology Approach for Early Clinical Stage Mesothelioma: Cytological Diagnosis, and Reactive Mesothelial Hyperplasia (ID 599)

      07:00 - 08:00  |  Author(s): S. Klebe

      • Abstract
      • Presentation
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      Abstract not provided

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    MTE11 - How Do PDXs Help Us In the Clinic (ID 55)

    • Event: WCLC 2013
    • Type: Meet the Expert (ticketed session)
    • Track: Biology
    • Presentations: 1
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      MTE11.1 - How Do PDXs Help Us In the Clinic (ID 604)

      07:00 - 08:00  |  Author(s): P. Mack

      • Abstract
      • Presentation

      Abstract
      Patient-derived xenotransplant (PDX) models are generated by engrafting human tumor material directly from surgery or biopsy into an immune-compromised mouse without any intervening in vitro culturing. Previous efforts to accomplish this were hampered by poor tumor “take rates” of all but the highest grade tumors, limiting the spectrum of cancer types available for study. Several technical advances have led to improved model formation, including the advent of the NOD.Cg-Prkdc[scid] Il2rg[tm1Wjl]/SzJ (NSG) mouse by The Jackson Laboratories: a new immunodeficient strain that, in addition to a compromised complement system, have defective dendritic cell and macrophage activity, lack mature T and B cells, and have no functional NK cells. This strain has demonstrated high rates of engraftment of a wide variety of tumor types, with the resulting xenografts retaining the tumor heterogeneity and oncogenic driver activity of the patient’s tumor; thus providing a model system that more closely reflects what is seen in the clinic. The University of California, Davis Comprehensive Cancer Center and The Jackson Laboratory have collaborated to establish over 50 fully functional NSCLC PDX models. Testing to date has demonstrated a high fidelity between the contributing patient tumor and the resultant PDX model (at passages 1 and 2) in terms of driving mutations, histology and treatment response. Models developed from tumors known to harbor alterations in EGFR, KRAS or ALK all retain the exact mutational characteristics of the donor tumor. Additionally, these models clearly recapitulate the tumor histologic characteristics and grade of their donors. Squamous cell carcinoma PDX models in this panel have a high incidence of p53 mutations, with several models harboring PIK3CA or PTEN mutations, amplification of PIK3CA and FGFR1. KRAS-mutant models have a high incidence of KRAS and MYC amplification. EGFR-mutant positive adenocarcinomas include models derived from patient tumors prior to or following acquisition of resistance to erlotinib, and in models tested to date recapitulate the clinical results of the contributing patient when treated with the matching therapy. By the third passage, a large number of matched sister models can be generated, sufficient for multi-armed therapeutic testing with an n of 10 or more per arm. Additionally, short-term molecular effects of targeted agents, particularly kinase inhibitors, can easily be measured. Inhibition of drug target and the resultant downstream effects on kinase pathways have already been documented in ongoing studies (Mack et al, WCLC 2013), granting unique insight into drug activity, resistance and cellular compensatory effects. Such studies provide a rational basis for determining appropriate therapeutic combinations of signal transduction inhibitors and receptor tyrosine kinase inhibitors to achieve complete signaling blockade. Similarly, PDX models should aid in identification of targeted strategies to improve activity of chemotherapy. The use of early passage (or passage 0) PDX models as “avatars” for patient response to therapy is also under investigation, although the parameters in which models can be treated in a time-frame sufficient for patients with advanced NSCLC need to be determined. In summary, the PDX platform, with its high degree of fidelity to patient tumors and minimized culture-induced artifacts, should significantly improve the predictive ability of preclinical modeling in the era of personalized therapy.

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    MTE20 - Pathology of Mesothelioma (ID 64)

    • Event: WCLC 2013
    • Type: Meet the Expert (ticketed session)
    • Track: Mesothelioma
    • Presentations: 1
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      MTE20.1 - Pathology of Mesothelioma (ID 617)

      07:00 - 08:00  |  Author(s): V. Roggli

      • Abstract
      • Presentation
      • Slides

      Abstract
      Malignant mesothelioma is an uncommon malignancy that may involve the pleura, peritoneum or pericardium. Mesothelioma may assume a variety of histological appearances ranging from epithelial to sarcomatoid to mixed. Because of its histologic similarity to a variety of other malignancies and because other malignancies may metastasize to serosal membranes, the diagnosis of mesothelioma may be challenging. A variety of immunohistochemical stains have been developed to aid in the distinction between mesothelioma and other malignancies with which it may be confused. It is currently recommended that at least two positive (mesothelial) and two negative (carcinomatous) markers should be used. The differential diagnosis may differ depending on the particular histologic pattern under consideration and the location of the tumor. This will in turn affect what immunohistochemical panel is chosen. It is also recommended that the markers used should have a specificity and sensitivity of at least 80%. For epithelial pleural mesothelioma, the main differential diagnostic consideration is adenocarcinoma of the lung. For such cases the author uses a panel of four positive markers and two negative markers. Positive markers include calretinin, cytokeratins 5/6, WT-1 and D2-40. Negative markers include carcinoembryonic antigen (CEA) and TTF-1. The author has used this panel since 2004 and has had experience with more than 500 mesotheliomas to date. Epithelial pleural mesotheliomas were positive for calretinin in 98% of cases, and this was the most sensitive mesothelial marker. Cytokeratins 5/6 and D2-40 were each positive in 92% of cases, and WT-1 was positive in 91% (nuclear staining only counted). For the negative markers, pCEA was positive in 10% and TTF-1 in 0.5% (nuclear staining only counted). More recently we have used mCEA and thus far have not identified any positive cases. We have seen some cases where mesothelioma was confused with squamous cell carcinoma. Cytokeratins 5/6 are not useful in this scenario since nearly all squamous cell carcinomas are positive for this marker. Similarly, TTF-1 is not useful since squamous cell carcinomas are expected to be negative. For this differential diagnosis, WT-1 and p63 (or p40) are a good pair of nuclear markers to use. Biphasic pleural mesotheliomas are more poorly differentiated so it is not surprising that one often observes a drop-out of one or more of the positive mesothelial markers in these tumors. We find calretinin positivity in 92% with positive staining for D2-40 in 83%. The corresponding values for WT-1 and cytokeratins 5/6 are 80% and 78%, respectively. CEA was positive in only 4% and none was positive for TTF-1. If one grades the intensity of staining, the epithelial tumors show higher scores on average than the biphasic. Peritoneal mesotheliomas usually involve a different set of diagnostic considerations. Since lung cancer is unlikely to be in the differential, TTF-1 has limited usefulness in this setting. Similarly, many of the tumors in the abdomen with which mesothelioma may be confused are negative for CEA. Therefore our panel for peritoneal tumors includes the same four positive markers noted above, and we substitute B72.3 and BerEP4 as negative markers. Epithelial peritoneal mesotheliomas are positive for calretinin in 98% of cases, identical to pleurals. Positive staining for WT-1 and D240 is seen in 91% of cases, and 89% are positive for cytokeratins 5/6. BerEP4 was focally positive in 9% of peritoneal mesotheliomas but B72.3 was uniformly negative. For biphasic peritoneal mesothelioma, calretinin is positive in 80% and cytokeratins 5/6 positive in 75%. Only 60% were positive for D2-40 and 50% for WT-1. None of the biphasic peritoneal cases was positive for B72.3 or BerEP4. Peritoneal mesotheliomas in women present a special diagnostic problem since many of the malignancies involving the peritoneal cavity in women stain for one or more of the mesothelial specific markers. For this reason, we add estrogen and progesterone receptor immunohistochemical staining to the panel for peritoneal mesothelioma in women. Strong diffuse nuclear staining for these markers would favor a diagnosis of ovarian carcinoma over mesothelioma. Also, histochemical staining for PASD is useful in this setting. We also use a broad spectrum cytokeratin marker in our panel, with cytokeratins positive in 100% of our epithelial or biphasic pleural and peritoneal mesotheliomas. The intensity of staining for these broad spectrum cytokeratins was a little greater for epithelial as compared to biphasic mesotheliomas. Complete absence of staining for cytokeratins in an epithelioid serosal based malignancy should alert the pathologist to the possibility of melanoma, lymphoma or epithelioid hemangioendothelioma and appropriate follow-up immunostains examined to rule out these considerations. Sarcomatoid mesotheliomas account for 16.5% of our cases, and these are the least differentiated form. This is reflected in their immunohistochemical profile, which is typically negative for mesothelial specific markers. For example, in 76 cases of sarcomatoid mesothelioma, we found positivity for calretinin in only 47% and D2-40 in 55%. The other two markers we use in the sarcomatoid panel are vimentin (95%) and broad spectrum cytokeratins (92%). Vimentin is important as an antigenic preservation marker: if vimentin is negative in a sarcomatoid tumor, then one should suspect poor tissue preservation with less concern for a negative keratin stain. Strong diffuse staining for cytokeratins is the most useful marker for sarcomatoid mesotheliomas. However, sarcomatoid carcinomas may be similarly positive, so one should pay close attention to the gross distribution of tumor in these cases. Although diffuse and moderate to strong staining for cytokeratins was seen in more than 70% of our sarcomatoid mesotheliomas, it should be noted that focal staining or less intense staining may also be seen in some cases. REFERENCES: Husain AN, Colby T, Ordonez N, et al. Guidelines for pathologic diagnosis of mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med 137: 647, 2013. Klebe S, Brownlee NA, Mahar A, et al. Sarcomatoid mesothelioma: a clinical-pathologic correlation of 326 cases. Mod Pathol 23: 470, 2010. Churg A, Cagle PT, Roggli VL. Tumors of the Serosal Membranes, AFIP Atlas of Tumor Pathology, Series IV, Fascicle 3, American Registry of Pathology: Washington, DC, 2006.

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    O18 - Cancer Control and Epidemiology II (ID 133)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 8
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      O18.01 - Multi-'omic analysis of an arsenic-associated lung squamous cell carcinoma reveals specific DNA level signatures (ID 283)

      10:30 - 12:00  |  Author(s): V.D. Martinez Zamora, K.L. Thu, E.A. Vucic, R. Hubaux, M.I. Adonis, L. Gil, C.E. Macaulay, S. Lam, W.L. Lam

      • Abstract
      • Presentation
      • Slides

      Background
      Chronic low-level exposure to arsenic is an emerging cancer risk factor in many parts of the world, including North America. The lung is one anatomical site prominently affected by the carcinogenic effects of arsenic, evident by the striking incidence of lung cancer in never smokers with chronic exposure. Histologically, arsenic related lung tumors are indistinguishable from those induced by other lung carcinogens, and molecularly, arsenic specific DNA copy-number, methylation and expression changes have been identified. Arsenic mediated carcinogenesis occurs through a combination of molecular mechanisms; however, high resolution, multi-'omic analyses of arsenic related tumors have been difficult due to the lack of fresh frozen samples required to obtain high quality DNA and RNA. In this study, we sought to characterize global changes in DNA sequence and methylation levels and their impacts on gene expression in a lung tumor from a patient with chronic arsenic exposure (As-LUSC).

      Methods
      Tumor and non-malignant lung tissues were obtained from a never smoker with lung squamous cell carcinoma (LUSC) who had no family history of lung cancer and 50 years of chronic exposure to high levels of arsenic-contaminated drinking water. Whole genome sequencing was performed and the tumor's mutational signature was compared to those observed in 194 previously characterized NSCLC tumors from the cancer genome atlas (TCGA). DNA methylation was measured using high density methylation arrays and gene expression by RNA sequencing.

      Results
      The As-LUSC exhibited alterations typical of LUSC, such as copy number gains at 3q26 (SOX2 locus) and expression of squamous markers including up-regulation of KRT6B, DSG3, MMP12, KRT5, and down-regulation of PDK4, which are consistent with LUSC histology. However, the As-LUSC harbored a low number of point mutations (only 49 non-synonymous mutations affecting coding DNA sequences) and had a remarkably high fraction of T>G/A>C and low fraction of C>A/G>T transversions, which are features uncharacteristic of LUSCs that suggest arsenic is associated with a distinct mutational spectrum. Furthermore, at the gene level, we identified a G>C mutation in TP53 which is rare in lung tumors (<0.2%) but has been observed in other arsenic-related malignancies. Clustering analysis using ~450,000 methylation probes revealed that the As-LUSC methylation profile was completely distinct from never smoker LUSCs from the TCGA. Of interest, the As-LUSC exhibited lower levels of methylation at CpG islands sores that are not associated with genes, although have been described to exhibit cell type specific methylation patterns.

      Conclusion
      By applying whole genome sequencing, methylation and expression profiling of a LUSC from a never-smoker patient chronically exposed to arsenic, we identified a distinct mutational spectrum and methylation pattern in the As-LUSC. Our results support the concept that arsenic induces lung cancers through mechanisms different from tobacco smoke and other carcinogens. Further study of the mutational profiles of additional arsenic-related cancers is warranted and may yield valuable insight into arsenic associated tumourigenesis, leading to the development of novel diagnostic and therapeutic targets for environmental monitoring and treatment.

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      O18.02 - Impacts of environmental tobacco smoke on EGFR mutations and ALK rearrangements in never smokers with non-small cell lung cancer: Analyses on a prospective multinational ETS registry (ID 1255)

      10:30 - 12:00  |  Author(s): A. Kubo, M. Ando, R. Soo, T. Kawaguchi, S.I. Ou, M. Ahn

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR and ALK are important driver mutations in never smokers. While we reported the significant association of increased environmental tobacco smoke (ETS) with EGFR mutations in Japanese cohort (Kawaguchi, Clin Cancer Res, 2011), it has not been fully understood in other ethnicities and also the correlation of ETS with ALK has not been reported yet. In this study, we evaluated the association of ETS with the prevalence of EGFR mutations and ALK translocations in various ethnicities including East-Asia (Japan, Korea, China, and Singapore) and the USA.

      Methods
      ETS exposure on never smokers with non-small cell lung cancer (NSCLC) was evaluated using the standardized questionnaire including exposure period, place, and duration. Cumulative dose of ETS (CETS) was defined as a sum of the number of the exposure years in childhood/ adulthood and at home/ workplace, and was treated as a continuous variable or quintile. EGFR mutations and ALK rearrangements were tested by PCR-based detection and fluorescence in situ hybridization, respectively. Multivariate analyses were done using the generalized linear mixed model (GLIMMIX procedure, SAS v9.3).

      Results
      From March 2008 to December 2012, 498 never smokers with NSCLC were registered with the following patient characteristics: ethnicity (nationality) of Asian/ Caucasian/ others, 425 (Japanese 250, Korean 102, Chinese 46, others 2)/ 48/ 25; male/ female, 114/ 384; age <65/ >=65, 286/ 212; histology of adenocarcinoma/ BAC/ squamous cell carcinoma/ adenosquamous cell carcinoma/ other NSCLC, 459/ 12/ 13/ 5/ 9; frequency (%) of CETS < median CETS (40 years) in Japanese/ Korean/ Chinese/ Caucasian, 32.8/ 44.1/ 71.7/ 83.3. EGFR status was wild type 43.6%, exon 19 deletion 25.3%, L858R 21.5% and other mutations 9.6%. ALK status was wild type 52.0%, rearranged 10.6% and unknown 37.3%. Average CETS (years) of NS with EGFR (+), ALK (+) and wild type tumors were 45.4, 26.9 and 37.7, respectively. In multivariate generalized linear mixed model, incidence of activating EGFR mutations, not ALK rearrangements, was significantly associated with the increment of CETS in female, not in male gender. Odds ratios (OR) for EGFR mutations in female (n=384) were 1.084 (95% CI, 1.003-1.171; p=0.0422) for each increment of 10 years in CETS while OR in male (n=114) were not significant (OR 0.890; 95% CI, 0.725-1.093; p=0.2627). OR for ALK rearrangements in female (n=238) and those in male gender (n=74) were 0.930 (0.791-1.094; p=0.3814) and 0.854 (0.620-1.178; p=0.3319).

      Conclusion
      Increased ETS exposure was closely associated with EGFR mutations in never smokers with female gender and NSCLC in the expanded multinational cohort. However, the association of ETS and ALK rearrangements in never smokers with NSCLC was not significant.

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      O18.03 - The BioCAST / IFCT-1002 study: a comprehensive overview of demographic, risk exposure and somatic mutations of non-small cell lung cancer occurring among French never smokers (ID 3293)

      10:30 - 12:00  |  Author(s): S. Couraud, P. Souquet, C. Paris, R. Gervais, H. Doubre, E. Pichon, A. Dixmier, I. Monnet, B. Etienne-Mastroianni, M. Vincent, J. Tredaniel, M. Perrichon, P. Foucher, B. Coudert, D. Moro-Sibilot, E. Dansin, S. Labonne, P. Missy, G. Zalcman

      • Abstract
      • Presentation
      • Slides

      Background
      Lung cancer occurring in never-smoker (LCINS) is a particular entity. Although the definition is strict (less than 100 cigarette in lifetime) never-smokers are frequently misclassified and no study gives a comprehensive analysis of this group, particularly in a European setting.

      Methods
      All consecutive never-smoker patients diagnosed with a non-small cell lung cancer in one of the 75 participating centers throughout France, between November 2011 and January 2013, were included in this prospective survey. All patients underwent a detailed questionnaire supported by a trained staff during a phone interview. Somatic mutations and cancer clinical and histological data were also recorded from medical charts.

      Results
      Overall, 384 never-smokers were included and 336 interviews were completed. Most of them were women (n=319, 83.1%). The mean age at diagnosis was 69.8 ± 12.02 and 10.9% were under 55 years-old. None reported alternative smoking (pipe, cigar, water-pipe, gum, or cannabis). Most of them originated from Western and Southern Europe (90.5%). Overall, 219 (65.6%) reported a passive smoking exposure in a domestic setting (n=198; 59.3%), and/or at workplace (n=60; 18.0%). Patients had a personal history of pneumonia in 6.2%, tuberculosis in 8.3%, COPD in 13.0%, and a cancer at another site in 16.6%. Eighty patients reported at least two relatives with lung cancer (24.0%). Definite occupational exposure was observed in 12.0% (n=44) for diesel, 7,1% (n=26) for asbestos, 3.3% (n=12) for poly-aromatic hydrocarbons, 2.4% (n=9) for silica, 0.8% (n=3) for chrome, and 0.5% (n=2) for painting. Exposure to cooking oil was noted in 123 patients (36.8%) with a mean of 49.4 ± 356.7 cooking-dish year. Moreover, 79.7% (n=259) patients were ever exposed to solid fuel fumes for cooking or heating (21.2% during more than 50% of their lifetime). Among women, 91.7% already reached menopause (mean age 49.3 ± 5.6 years-old), 115 (41.7%) were ever-exposed to oral contraceptive (mostly oestrogen-containing drugs), and 25.5% to post-menopause hormone replacement therapy (oral or transdermal). Most of lung cancers were adenocarcinoma (n=327, 85.2%) followed by squamous cell carcinoma (n=29, 7.6%) and large cell carcinoma (n=17; 4.4%). Among adenocarcinoma, 71% were invasive, 4% in-situ, 2% minimally-invasive, 2% variant of invasive, and 20.0% were NOS. Cancer stage was I in 9.2%, II in 5.8%, III in 11.8% and IV in 73.2%. At least one biomarker was tested in 359 patients (93.5%). We found 148 patients with EGFR mutations (43.5% out of the EGFR-tested patients), 20 with KRAS mutations (6.8%), 24 with ALK translocation (12.5%), 10 with BRAF mutation (4.5%), 8 with HER2 mutation (4.0%) and 4 with PIK3CA (2.1%). Overall, 27.0% samples remain wild type, 2.1% with multiple mutations, 71.0% with a single mutation, and 20.6% with missing data.

      Conclusion
      We provide here the largest cohort of LCINS in a European setting with reliable data on tobacco intoxication, occupational exposure, and hormonal treatments, since collected by a trained staff through phone interview. In this perfectly clinically characterized cohort, molecular analyses showed that 72% of tumors exhibited oncogenic targetable mutations.

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      O18.04 - Impact of Passive Smoking on molecular pattern in Never Smokers with Non-Small Cell Lung Cancer: Findings from the BioCAST / IFCT-1002 Study (ID 3305)

      10:30 - 12:00  |  Author(s): S. Couraud, P. Dumont, L. Moreau, D. Debieuvre, J. Margery, E. Quoix, B. Duvert, L. Cellerin, N. Baize, B. Taviot, M. Coudurier, J. Cadranel, P. Missy, G. Zalcman, P. Souquet

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR and HER2 mutations are usually associated with never-smokers while KRAS and BRAF mutations are thought to be link with smoking behavior in Non-Small Cell Lung Cancer (NSCLC). Passive smoking exposure is a well-known risk factor for lung cancer. Only EGFR and KRAS mutations were investigated in association with passive smoking and showed conflicting results. We aimed to investigate mutation rate of EGFR, HER2, KRAS, BRAF and ALK in a cohort of never smokers regarding their passive smoke exposure.

      Methods
      The BioCAST / IFCT-1002 study is a prospective cohort of NSCLC patients diagnosed in French never-smokers patients (less than 100 cigarettes in lifetime) between November 2011 and January 2013, Passive smoking exposure was evaluated through standardized questionnaire. We obtained biomarkers mutation results through routine testing. We used Fisher, Chi-square, median test and Mann-Whitney U test for comparisons as appropriate. We used logistic regression to calculate adjusted odds ratio for risk of each mutations.

      Results
      Out of the 384 patients included in the BioCAST database, 334 (87.0%) had available data on passive smoking exposure. Among them, 219 patients (65.6%) were ever exposed to passive smoking in their lifetime. 198 (59.3%) reported a domestic exposure (122 during childhood at least) and 60 (18.0%) a workplace exposure. Result of at least one biomarker mutation was available in 313 patients (93.7%). including 128 EGFR mutations in 297 patients, 8/174 HER2 mutations, 18/256 KRAS mutations, 10/196 BRAF mutations, and 20/171 ALK gene rearrangements. We found no difference in mutation rate according to passive smoke exposure (cf. Table 1). There was no difference when comparing cumulative year of exposure, smoker-year or passive-pack year (as continuous variable) to the mutation rate, for any biomarker. When considered as categorical variable – after division in quartiles – we found also no difference. Results were similar when focusing on domestic (childhood versus adulthood included) and workplace exposure only. Finally, we found no significant increased risk for mutation for any biomarker in logistic regression adjusted for most of other lung cancer risk factors.

      EGFR Mt (n=297) HER2 Mt (n=171) KRAS Mt (n=256) BRAF Mt (n=196) ALK Fusion (n=171)
      % % % % %
      Overall exposure Never 46.5 3.5 6.7 5.9 13.0
      Ever 41.3 5.1 7.2 4.7 11.1
      Domestic exposure Never 45.8 2.9 7.7 6.4 11.1
      Ever 41.3 5.7 6.6 4.2 12.0
      Exposure at workplace Never 43.3 5.5 7.0 5.4 12.2
      Ever 42.3 0 7.0 3.6 8.3
      Total 43.1 4.6 7.0 5.1 11.7
      Exposure in childhood Ever 40.5 3.0 6.5 2.7 14.7
      Only in adulthood 42.6 10.3 6.8 6.7 7.5

      Conclusion
      Although we report the largest and more comprehensive study focusing on this topic, we found no significant difference in the biomarker mutation profile of NSCLC occurring in French never-smokers regarding their exposure to passive smoking as compared with the pattern of mutations described never-smoker patients with any passive smoking.

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      O18.05 - DISCUSSANT (ID 3998)

      10:30 - 12:00  |  Author(s): P.P. Massion

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      O18.06 - Vietnamese non-small cell lung cancer patients in California: molecular profiles and clinical characteristics (ID 1079)

      10:30 - 12:00  |  Author(s): K.H. Nguyen, M. Das, K. Ramchandran, J. Shrager, R.E. Merritt, C. Hoang, B. Burt, A. Tisch, J. Pagtama, J. Zehnder, G. Berry, H.A. Wakelee, A. Nguyen, J.W. Neal

      • Abstract
      • Presentation
      • Slides

      Background
      Lung cancer is the leading cause of cancer-related deaths worldwide with 1.3 million deaths per year. Discoveries of oncogenic mutations in non-small cell lung cancer (NSCLC) over the past decade have led to targeted therapies against epidermal growth factor receptor (EGFR) activating mutations, anaplastic lymphoma kinase (ALK) gene rearrangement, and repressor of silencing 1 (ROS1) gene rearrangement. The frequencies of these mutations and gene rearrangements have been elucidated in the Western and East Asian populations. However, the frequencies of these oncogenic alterations remain unknown in Vietnam, where lung cancer is one of the leading causes of cancer mortalities but molecular testing is not routinely performed due to limited resources. In this project, we aimed to analyze the Vietnamese patients treated at Stanford, California, with a future plan to compare with another cohort inside Vietnam.

      Methods
      We collected molecular and clinical variables of NSCLC patients of Vietnamese origin, based on patients' self-reported ethnicity, language, or country of origin, treated at Stanford from 2009 to 2012. Comparison of the molecular and clinical characteristics of never smokers versus smokers was performed with Pearson's chi-squared test for nominal variables and Student's t test for continuous variables. Survival analyses were done using the Kaplan-Meier method and Cox proportional hazards modeling.

      Results
      Forty-six patients of Vietnamese origin were seen at the Stanford thoracic oncology clinic from 2009 to 2012, including 22 men and 24 women with a mean age of 58 years. Twenty-seven (58.7%) were never-smokers. Forty-two (91.3%) of the tumors were adenocarcinoma. Ten patients (21.7%) presented at stage I, none at stage II, 8 patients (17.4%) at stage III, 28 patients (60.9%) at stage IV. Fifteen patients out of 28 tested for EGFR (53.6%) had an activating mutation; 14 of these 15 patients were never-smokers. Five patients out of 16 tested for ALK (31.3%) had ALK gene rearrangement. No ROS1 gene rearrangement out of 3 patients tested was found. Only one patient, a former smoker, out of 23 tested (4.4%) was found to have a KRAS mutation. Eighteen out of 27 never-smokers (66.7%) and 3 out of 19 smokers (15.8%) had a targetable driver mutation (EGFR, ALK, or ROS1). For all stages, the median overall survival (OS) for never-smokers was 22.3 months (95% confidence interval (CI); 11.9 months, 24.3 months) compared to 12.9 months (95% CI; 5.8 months, 20.0 months) for smokers. For only stage IV, the median OS for never-smokers was 21.2 months (95% CI; 13.0 months, 24.3 months) compared to 11.6 months (95% CI; 1.4 months, 30.9 months) for smokers.

      Conclusion
      Approximately two-thirds of never-smoker patients of Vietnamese origin had NSCLC with a targetable driver mutation. OS differ markedly by smoking status. The high percentage of Vietnamese patients in California with driver mutations warrants further studies to evaluate the frequencies of NSCLC driver mutations inside Vietnam, strongly suggesting that nationwide implementation of routine molecular testing will have a positive impact on clinical management of Vietnamese patients with NSCLC.

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      O18.07 - A Retrospective Cohort Mortality Study in Jingchuan of china - the Largest Nickel Population in World (ID 94)

      10:30 - 12:00  |  Author(s): N. Cheng, L. Ma, T. Zheng, J. He, M. Dai, Y. Zhang, Y. Bai

      • Abstract

      Background
      Nickel is an essential trace metal used in the occupational setting and is naturally found in the general environment, resulting in both occupational and nonoccupational exposures to individuals at varying levels. Exposure to nickel has been associated with several toxicites and the International Agency for Research on Cancer has concluded that there is sufficient evidence in humans associating exposure to nickel or nickel compounds with risk of lung cancer. We evaluated overall and cause-specific mortality among Chinese workers involved in nickel production or utilization in order to examine the long-term health effects of occupational exposure to nickel compounds.

      Methods
      The study design was a retrospective cohort mortality study including 432,526 workers who were involved with nickel mining or smelt between 2001 and 2010. We calculated standardized mortality ratios (SMR) using the death rates of Gansu Province in China, and estimated by the exact probabilities of the Poisson distribution.

      Results
      Overall, the all-cause mortality was decreased in all workers compared to the general population of Gansu province (SMR= 0.53, 95%CI: 0.51-0.55). Analyses examining cause-specific mortality revealed an increase in the mortality from bronchogenic carcinoma and lung cancer (SMR = 2.05, 95% CI = 1.84-2.29), cor pulmonale (SMR =4.08, 95% CI = 3.25-5.01), and silicosis (SMR = 13.59, 95%CI =11.90-15.52) in the workers exposed to nickel.

      Conclusion
      This study confirmed a significant excess of mortality from diseases of the lung including silicosis , lung cancer, and cor pulmonale among workers involved in nickel mining or smelt in China.

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      O18.08 - DISCUSSANT (ID 3999)

      10:30 - 12:00  |  Author(s): C. Amos

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    O24 - Cancer Control and Epidemiology III (ID 134)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 6
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      O24.01 - Lung cancer risk attributable to occupation: in a case control study in black South Africans 2001-2008 (ID 3421)

      16:15 - 17:45  |  Author(s): C. Nattey

      • Abstract
      • Presentation
      • Slides

      Background
      Worldwide, lung cancer is the leading cause of death by cancer and most common cancer among occupational related cancers. Approximately 90% of men and 60% of women. developing lung cancer are smokers. Cancer Morbidity and the increase in cancer mortality in South Africa is well documented and has been attributed to different factors, including tobacco consumption, occupational exposures, infections, changing lifestyles, ageing population and environmental pollution The International Agency for Research on Cancer (IARC) has estimated that almost 40 000 deaths from cancer (58 000 cases) occur annually in South Africa. In men the leading causes of deaths were lung cancer (comprising 16% of all cancer deaths). Environmental and occupational risk factors contribute to the burden of lung cancer, but the extent of this contribution is still unclear in most settings especially in Africa, confirmed in a review by McCormack and Schuz Estimating the attributable fraction for specific risk factors helps to assess the potential impact the preventive interventions could have on the population. The proposed study will estimate lung cancer risk attributable to the different occupations and types of workplaces in black South African population represented in the data base while controlling for smoking and domestic fuel use. Identification of the role of occupation on the risk of lung cancer may enhance the ability to prevent the disease by permitting better focused occupational health and other preventive strategies in the fight against non-communicable diseases in black South Africans. There is very limited research on cancers and occupations in Africa; hence findings will contribute to the knowledge of lung cancer in relation to occupations in South Africa.

      Methods
      Data from the on-going Johannesburg Cancer Case-Control Study (JCCCS) of black African adult cancer patients (2001-2008) was used. Information from 579 lung cancer cases and 1120 frequency matched controls was analysed. Controls were randomly selected from cancers not known to be associated with the effects of tobacco, matched by sex and age (±5years). Usual occupation and/or workplace stated at interview were used as an indicator of occupational exposure. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression and attributable fraction (AF) by Miettinen’s formula, adjusted for smoking pack years, HIV status and domestic fuel type use.

      Results
      The mean age of cases and controls was 56.0 and 57.1 respectively. Among men the adjusted OR for lung cancer was 3.0 (95% CI 1.4-6.4) in miners and 1.7 (95% CI 1.3-3.2) in those working in transport occupations. In women working as domestic worker (maids, child minders etc) the adjusted OR was 7.3 (95% CI 1.7-11.3) whereas working in the food & beverage industry, the adjusted OR was 4.9 (95% CI 1.4-26.8). Occupation / workplace resulted in an AF of 14% in men and 26% in women.

      Conclusion
      Occupational risk factors for lung cancer in South Africa are gender-specific, having more impact in women than in men. Further studies are needed to assess possible specific exposures in the mining and transport industries for men, and food industry and private homes for women.

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      O24.02 - Lung cancer in South East Scotland, are we still making progress? (ID 1320)

      16:15 - 17:45  |  Author(s): S.C. Erridge, G. Kerr, C. Dodds, S. Campbell, J. Ironside, F. Little, M. Mackean, A. Price, J. Gysin, L. Bhatti, C. Selby

      • Abstract
      • Presentation
      • Slides

      Background
      South-East Scotland Cancer Network (SCAN) serves 1.4 million people using unified protocols collecting prospective data. We published population-based data from 1995 and 2002 (J Thorac Oncol. 2008;3(5):491-8) demonstrating increased cancer treatment and improved overall survival. This review investigates whether this has been sustained.

      Methods
      Patients were identified from Scottish Cancer Registry (SCR), SCAN audit and Edinburgh Cancer Centre databases to extract tumour characteristics, initial management (usually ≤6 months of diagnosis) and overall survival (OS). Missing data was sought from patients’ health records. Multivariate analysis (MVA) examined sex, age(<60,60-69,70-79,80+), deprivation, Healthboard of residence, performance status (PS), pathology and stage (localised, regional, metastatic) affecting use of any treatment, potentially curative treatment (PCT) defined as surgery (S) or potentially curative radiotherapy (PC-RT - ≥50Gy for NSCLC or ≥40Gy+chemo for SCLC) using Cox’s proportional hazards model to obtain factors affecting survival.

      Results
      1117 patients were identified in the audit. 51.5% were men, median age 72 (range 31-98) years. 47.3% were from the two most deprived quintiles. 49.5% had WHO PS 0-1, 23.5% WHO2, 24.2% WHO3-4. 58.5% NSCLC (23.5% Stage I-II, 25.7% III, 48.8% IV), 13% SCLC (37.9% stage I-III, 61.4 stage IV) and 28.5% radiology-only diagnosis (24.5% Stage I-II, 19.5% III, 52.8% IV). 59.9% received some form of treatment; 28.4% with PCT ((126 S+/-chemo(C) = 19% of NSCLC), 190 PC-RT +/- C), and 31.5% palliatively. 467 (41.8%) received any RT, 268 (24%) any C. MVA showed age >70, PS≥2, metastatic disease, ‘not-SCLC’, but not sex, deprivation or Healthboard, were associated (all p<0.01) with lower treatment delivery, and only age > 80, PS≥2, radiology-only diagnosis and non-localised disease (all p<0.01) with reduced PCT. Median survival was 5.03 months (95%CI 4.3-5.8) with 46.8% alive at 6 months, 32.0% 12 and 17.7% 24 months following diagnosis. Male sex, PS≥2 and non-localised disease were associated with increased HR for death (all p<0.01). Comparison with the 2002 cohort (n= 971, Dumfries excluded from both cohorts) showed similar age and pathology profile, but increased women, residents from most deprived quintile and metastatic disease. Uni-variate analysis showed a similar proportion received treatment (62.3% 2002 v. 59.9% 2010 p=0.14) but more received PCT (23.6% v. 28.2% p=0.02) principally through increased use of PC-RT (13.1% v. 17.1% p=0.01). On MVA (without PS) the use of any treatment reduced (OR 0.73 (0.59-0.92) however, use of PCT increased (OR 1.84 (1.37-2.47) due to more PC-RT (1.57 (1.18-2.08)), but not surgery. Median (5.16 v. 4.90 months p=0.65), 1 year (29.0% (31.9-26.1) v. 31.4% (34.3-28.5) and 2 year (14.9% (17.3-12.5) v. 17.4% (19.8-15.0) survival were unchanged.

      Conclusion
      In the last 8 years in SCAN, there has been an increase in the number of women with lung cancer along with a worsening deprivation profile and increased identification of stage IV disease, possibly through improved staging. There has been an increase in potentially curative, but reduction in all therapy delivered without any apparent impact on survival. This analysis demonstrates the challenges of improving population-based outcomes in a disease where most present with advanced disease and are often unfit for treatment .

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      O24.03 - Lung cancer incidence trends among Asian-American ethnic populations in the United States, 1990-2010 (ID 1969)

      16:15 - 17:45  |  Author(s): S. Lin Gomez, I. Cheng, K. Gali, M.I. Patel, R. Haile, A. Noone, H. Wakelee

      • Abstract
      • Presentation
      • Slides

      Background
      In the United States (US), anti-smoking policies have resulted in a population-wide decline in lung cancer rates over the past decade. However, little is known about how lung cancer incidence trends vary among Asian-American ethnic populations, the largest growing population in the US.

      Methods
      For the first time, annual population estimates for Asian-American ethnic populations were developed for the regions in the Surveillance, Epidemiology, and End Results program, comprising half of the total U.S. Asian-American population. From 1990-2010, incidence rates and average annual percentage change (APC) were computed for each racial/ethnic group for lung cancer overall and by gender and histology.

      Results
      Among Asian-American males, trends were either stable or declining in all groups (Figure 1). The declines were statistically significant among Koreans (APC = -3.0), Hawaiians (APC = -2.3), Vietnamese (APC = -1.4), Filipino (APC = -1.9 from 1996-2010), and Chinese (APC = -1.5). Among Asian-American females, declining trends were seen among Hawaiians (APC = -5.9 from 2002-2010) and Vietnamese (APC = -1.5). In contrast, increasing trends were seen among Japanese (APC = 1.7) and Filipinas (APC = 1.5). Among Asian-American males, all histologies exhibited stable or declining trends with the exception adenocarcinoma, which increased among Chinese males from 1997-2010, appearing independent of the decrease in NOS, which occurred much later in this group. Among Asian-American females, declining or stable trends were seen for most histologies, with the exception of adenocarcinoma among Filipina and Korean females (APC = 2.5 and 3.0, respectively), and squamous cell carcinoma among Japanese females (APC = 2.4). Figure 1

      Conclusion
      To the extent that Asian-Americans have distinct primary and second-hand smoking profiles, unique environmental exposures , and population-specific genetic predisposition, analysis of incidence trends by histology suggests that, among Asian-American females, additional risk factors beyond primary and perhaps secondary smoking may be important for lung cancer etiology. The continued increase of lung cancer incidence among Filipina, Korean, and Japanese American females, especially in adenocarcinomas and squamous cell carcinomas, warrants further attention.

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      O24.04 - Risk of second primary lung cancer (SPLC) in patients (pts) with previously treated lung cancer: Analysis of the Surveillance, Epidemiology and End Results (SEER) data (ID 2204)

      16:15 - 17:45  |  Author(s): A.J. Wozniak, A. Schwartz, F.D. Vigneau, R.D. Shore, M.K. Islam, S. Gadgeel

      • Abstract
      • Presentation
      • Slides

      Background
      BACKGROUND: Second primary lung cancer (SPLC) in patients who have been treated for a prior lung cancer is a recognized phenomenon. There has been an improvement in the staging and treatment of lung cancer in the last several decades resulting in longer survival for pts and affording an opportunity for the development of SPLCs. The objective of this study was to establish the frequency of SPLCs and to characterize the demographics, histology and stage at presentation, time interval between diagnoses, and cumulative risks of developing a SPLC in this pt population.

      Methods
      METHODS: The pts were identified from population-based SEER-9 Registries Data Base. All pts with a primary lung cancer between 1973 and 2004 were included with follow-up to 2009. The histology and stage of the SPLCs were evaluated in comparison to the initial primary lung cancer (IPLC). The incidence of SPLCs was compared to the expected incidence by calculating multiple primary-standardized incidence ratios (MP-SIRs) using the SEER Stat program. Selected cohorts were stratified by sex, race, age at diagnosis, and date of diagnosis. Sex-specific cumulative risks of developing SPLCs were calculated using the Kaplan-Meier method.

      Results
      RESULTS: 208,486 pts had an IPLC diagnosed from 1973-2004. No smoking history was available. Patient Characteristics at time of IPLC: 60.4% male; 84.3% white; 8.5% (20-49 yr), 55.9% (50-69 yr), 35.6% (≥ 70 yr); 84% non-small cell lung cancer (NSCLC); 33.8% distant disease, 23.5% regional, 29.9% local. 5,302 pts developed SPLC. The majority were male (56.6%), white (84.9%), and in the 50-69 yr age group (68%). Females had the highest SIR values across all ethnicities and age groups particularly in the youngest cohort (20-49 yr) where the SIR was 8.58. The SIR values were ≥ 2 for all cohorts expect for males ≥ 70 yr (SIR=1.65). The predominant histologic types for IPLCs were adenocarcinoma (ADC) and squamous cell cancer and the associated SPLCs were usually of the same histology. IPLC ADC and BAC pts were most likely to develop a SPLC. Most SPLCs (50%) presented with regional or distant disease, while only 37% were localized at diagnosis. The median time to development of SPLCs was 68 mo for males and 74 mo for females. The risk of developing a SPLC continually increased as a function of time for both sexes.

      Conclusion
      CONCLUSION: Patients with a history of IPLC are at high risk for developing SPLC and this risk increases over time. This is especially true of females who are diagnosed at an early age with their initial lung cancer. The majority of SPLCs present late and at a more advanced stage. These findings could have major implications with regard to the length and type of surveillance in pts who survive their initial lung cancer diagnosis.

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      O24.05 - The impact of body mass index on survival in stage 3 and 4 lung cancer (ID 663)

      16:15 - 17:45  |  Author(s): K.M. Wong, S. Cuffe, L. Coate, O. Espin-Garcia, K. Boyd, R. Feld, N. Leighl, F.A. Shepherd, W. Xu, G. Liu

      • Abstract
      • Presentation
      • Slides

      Background
      Obesity has been shown to be an adverse prognostic factor in several cancers, including breast, colorectal, endometrial, ovarian, pancreatic and prostate. However, studies of body mass index (BMI) and outcomes in lung cancer are lacking. Understanding the clinical impact of body weight on cancer outcomes is important given the high prevalence of obesity globally. We retrospectively evaluated the distribution of BMI at diagnosis and its effects on survival in stage 3 and 4 lung cancer patients.

      Methods
      1,121 patients with stage 3 or 4 lung cancer from a single institution were analyzed. Clinicopathologic data were collected retrospectively. Adjusted hazard ratios (aHR) for overall survival (OS) and progression-free survival (PFS) were generated by Cox regression for each BMI (kg/m[2]) category (underweight: <18.5, normal: 18.5-24.9, overweight: 25.0-29.9, obese: ≥30), after adjusting for age, gender, Charlson Comorbidity Index, performance status (PS), clinical stage and treatment regimen.

      Results
      In this cohort (n=1,121), the frequencies of stage 3A, 3B and 4 lung cancers were 35%, 32% and 33%, respectively. There were 633 (57%) adenocarcinomas, 238 (21%) squamous cell carcinomas, 38 (3%) small cell lung cancers, and 210 (19%) other histologies. Patients had variable BMI: 82 (7%) underweight, 550 (49%) normal weight, 333 (30%) overweight, 156 (14%) obese. Being overweight/obese was associated with older age (p=0.002) and stage 3A disease (p=0.001); underweight patients were more likely current smokers (p<0.001). OS was significantly decreased with age ≥65, males, PS 2-3, stage 4, and lack of systemic treatment (p<0.001). Median OS in underweight, normal weight, overweight and obese patients were 14, 23, 24 and 26 months, respectively. Compared with BMI ≥18.5, being underweight was associated with significantly poorer OS (aHR 1.33, 95% CI 1.01-1.77, p=0.045), but not PFS (aHR 1.12, 95% CI 0.86-1.46, p=0.414). The magnitude of this association was greatest among those aged less than 65 years (aHR 1.57, 95% CI 1.11-2.22, p=0.011).

      Conclusion
      In stage 3 and 4 lung cancer, being underweight at diagnosis is associated with significantly poorer OS, especially in patients younger than 65 years of age. Lower BMI is mostly observed in current smokers, while above normal BMI is seen in older patients and stage 3A disease. Unlike other malignancies, obesity does not increase mortality in this population. The BMI-survival relationship in lung cancer requires further study.

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      O24.06 - DISCUSSANT (ID 4001)

      16:15 - 17:45  |  Author(s): I.N. Olver

      • Abstract
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      Abstract not provided

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    O29 - Cancer Control & Epidemiology IV (ID 132)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 8
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      O29.01 - Awareness about the signs and symptoms of lung cancer in Australia, a mixed methods study (ID 2583)

      10:30 - 12:00  |  Author(s): M. Crane, S. Aranda, I. Stacey, M. Lafontaine, N. Scott, B. O'Hara, D. Currow

      • Abstract
      • Presentation
      • Slides

      Background
      The risk of developing lung cancer increases with age and is highly associated with exposure to tobacco smoking. This study aimed to understand public awareness about the risk of developing lung cancer in New South Wales (NSW), Australia and to investigate attitudes and beliefs about lung cancer which could potentially impact health seeking behaviours regarding symptoms of lung cancer. The risk of developing lung cancer increases with age and is highly associated with exposure to tobacco smoking. This study aimed to understand public awareness about the risk of developing lung cancer in New South Wales (NSW), Australia and to investigate attitudes and beliefs about lung cancer which could potentially impact health seeking behaviours regarding symptoms of lung cancer.

      Methods
      A mixed methods triangulation approach was used, with a sequential-parallel design which incorporated 16 qualitative focus groups (n=125) to explore themes. Participants were aged 45+ from metropolitan and regional centres and grouped according to smoking status (current, former and never smokers). Data were analysed by content and thematically. A cross sectional quantitative telephone survey (n=1,000) followed to determine overall awareness and generalisability of findings amongst adults >45 years across NSW.

      Results
      The qualitative research highlighted that symptoms of haemoptysis, dyspnoea and an unusual or persistent cough were well recognised symptoms of lung cancer however participants were more likely to assume these symptoms were related to other health problems. Haemoptysis was the only symptom which created a sense of urgency to seek immediate medical attention. A ‘wait and see’ attitude towards any concerning symptom was prevalent across groups, only severe/ long term persistent symptoms would induce action. Smokers and former heavy smokers were more likely to say they would delay seeing their doctor because of perceived stigma associated with smoking. Older participants were more likely to rely on previous experiences of symptoms to govern their health seeking behaviour. Perceived susceptibility and understanding of causes of lung cancer differed by smoking status; smokers more likely to down-play the risk of smoking or attempt to offset their risk through lifestyle choices. Former smokers were more likely to perceive their risk comparative with a never smoker. The quantitative research findings suggested that unprompted awareness of lung cancer related symptoms was high with 88.5% able to correctly identify ≥1 symptoms however symptoms were more typical of late stage cancer. Age(<65 years), sex(female) and high socio-economic status were associated with higher recognition of symptoms (p<0.05). The majority of the survey respondents identified smoking as a cause of lung cancer (90.6%, 95%Confidence Interval (CI) 88.4-92.8) however fewer recognised the risk from second-hand smoke (25.6%,95%CI22.3-28.9). Ever-smokers were less likely to recognise the risk of smoking (odds ratio 0.7 95%CI0.5-0.9).

      Conclusion
      These findings provide evidence that while awareness of lung cancer symptoms and causative factors is reasonably understood in the community, perceived susceptibility is low (particularly among current and former smokers). A lack of urgency in seeking medical attention for symptoms considered not severe, together with other smoking-related barriers, may lead to further delays in diagnosis and missed opportunity for surgical treatment.

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      O29.02 - Impact of a national Lung Cancer Awareness Campaign in Merseyside (ID 2768)

      10:30 - 12:00  |  Author(s): J. Maguire, V. Kelly, A. McIver, C. Smyth, M. Ledson, M. Walshaw, J. Littler

      • Abstract
      • Presentation
      • Slides

      Background
      In May 2012 the United Kingdom Department of Health initiated a centrally funded National Lung Cancer Awareness Campaign. This campaign was influenced by encouraging results from local pilot studies, and featured news items and public health awareness adverts in national and local media, including nationwide television and radio exposure, accompanied by celebrity involvement and endorsements. The cost of this initiative has not been disclosed. Liverpool has the highest lung cancer incidence and mortality in England, and our Lung Cancer Unit, providing a service for patients in South Liverpool, is the largest in the Cancer Network and the largest in the country

      Methods
      To assess the impact of the national campaign we have reviewed referrals to our Rapid Access Lung Cancer Service from General Practice via the two week suspected cancer pathway, during the months of April to December 2012; we have also reviewed referrals during the same months in 2011 and 2010. For these time periods we have compared the total number of referrals, the number and proportion of referrals judged as unsuitable for immediate investigation with CT scan and bronchoscopy, the number and stage distribution of cancers diagnosed and the proportion of patients undergoing potentially curative surgery.

      Results
      In the period May to December 2012 a total of 323 patients were referred to our Rapid Access Service; of these, 140 (43%) did not have any features suggestive of a possible lung cancer - these patients were reviewed in a routine chest clinic. A total of 103 patients (32% of referrals in this time period) were diagnosed as having lung cancer. Of these 34 (33%) had stage I or II disease on CT staging and 30 patients (29%) underwent potentially curative surgery. The corresponding figures for 2011 are: total referrals 283, 93 (33%) sent to routine chest clinic, 88 (31%) diagnosed lung cancers, 17 (20%) stage I and II and 16 (18%) potentially curative operations. In May to December 2010 we received 274 referrals. 75 (27%) were referred on to routine chest review. 106 patients (39%) were diagnosed as having lung cancer. 23 (21%) were stage I or II and 24 (23%) underwent potentially curative surgery.

      Conclusion
      In the 8 months following the initiation of a National Lung Cancer Awareness Campaign, the largest lung cancer unit in England recorded a 14% increase in patients referred from General Practice with suspected lung cancer. There was a 17% increase in diagnosed lung cancers, and the percentage of patients undergoing potentially curative surgery for stage I and II disease increased from 18% to 29%. Compared to the same time period in 2010, an additional 6 patients underwent surgery for stage I and II disease in 2012, an increase of 6% in the surgical resection rate. We have observed a beneficial effect from the National Lung Cancer Awareness Campaign, with significant increases in our lung cancer diagnosis rates and the number of patients undergoing curative surgery.

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      O29.03 - DISCUSSANT (ID 3996)

      10:30 - 12:00  |  Author(s): M.D. Peake

      • Abstract
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      Abstract not provided

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      O29.04 - A new medical device for in vivo isolation of circulating tumor cells in non-small cell lung cancer (NSCLC) patients and immunofluorescence identification of ALK (ID 2659)

      10:30 - 12:00  |  Author(s): L. Gasiorowski, K. Haubold, S. Herold, B. Nowack, K. Pantel, T. Krahn, G. Dworacki, K. Lücke, W. Dyszkiewicz

      • Abstract
      • Presentation
      • Slides

      Background
      Circulating tumor cells (CTCs) in the bloodstream of lung cancer patients provide a source for early detection, prognosis, and therapy monitoring. CTCs are currently mostly isolated in vitro from small volumes of patient blood samples. In order to increase the sensitivity of the CTC detection in the peripheral blood GILUPI has developed a novel in vivo method, the CellCollector, which enables the capture of CTCs from the patient´s blood stream with a higher sensitivity and efficacy than existing methods. Enumeration and characterization of those CTCs will serve to improve and monitor clinical cancer early detection and treatment. The aim of this study was to assess the Detektor CANCER01 (DC01) for in vivo isolation of CTCs directly from the blood of NSCLC patients, and to compare it to the CellSearch® method.

      Methods
      The device was inserted in a cubital vein through a standard cannula for thirty minutes. The interaction of target CTCs with the DC01 was mediated by an antibody directed against the epithelial cell adhesion molecule (EpCAM). To confirm the CTCs binding to the wire, the immunohistochemical staining against EpCAM and/ or Cytokeratins as well as CD45 for negative cell selection and nuclei counterstaining was performed. There were enumeration data available for 34 stage I-IIIB NSCLC patients and 8 non cancer patients. For 34 patients, samples were also tested with the CellSearch® method.

      Results
      In this study, we successfully isolated EpCAM-positive tumor cells in the peripheral blood originating from NSCLC patients. We obtained in vivo CTC detection rate of 94% in 32 of 34 NSCLC patients with a median (range) of 13 (0-300) CTCs. In 2 of 34 samples (5.8 %), CTCs were detected by the CellSearch® method. In all matched pairs, the DC01detected the same number or more CTCs compared to the CellSearch® method. The sensitivity was similar for early and late stage NSCLC patients. In the non-cancer patients, no CTCs were detected (100 % specificity). ALK gene rearrangements in NSCLC patients are an indication for targeted therapy with crizotinib. Therefore the staining for CTCs on the CellCollector was enhanced to identify the anaplastic lymphoma kinase (ALK). It could be identified by capturing cells and immunohistochemical staining.

      Conclusion
      Due to a detection rate of over 90% this new device might overcome present limitations in the enrichment of CTCs. This proof of concept study may have important clinical implications, as the implementation of the device into clinical practice may improve early detection, prognosis and therapy monitoring of NSCLC patients. The performed IHC for ALK expression on samples using a novel combination of a new ALK antibody with the high detection rate of the CellCollector offers an alternative to FISH or IHC on tumor tissue. This new technology also allows, as the captured tumor cells are ready using immunofluorescence approaches or qPCR, the possibility of establishing more personalized treatment regiments.

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      O29.05 - Prognostic Impact of the Tumor Size Eliminating the Ground Glass Opacity Component: Modified Clinical T Descriptors of the TNM Classification of Lung Cancer (ID 751)

      10:30 - 12:00  |  Author(s): S. Nakamura, T. Fukui, T. Taniguchi, N. Usami, K. Kawaguchi, F. Ishiguro, A. Hirakawa, K. Yokoi

      • Abstract
      • Presentation
      • Slides

      Background
      The presence of ground glass opacity (GGO) on high-resolution computed tomography (HRCT) is well known to be pathologically closely associated with adenocarcinoma in situ. Recently, measuring the tumor diameter including areas of GGO on HRCT has been reported to possibly overestimate the T status. The purpose of this study was to evaluate the significance of the tumor size measured eliminating the area of GGO on HRCT as a prognostic factor and to propose a refined TNM classification based on modified T descriptors.

      Methods
      Four hundred and seventy-five patients with clinical T1a-T2bN0M0 non-small cell lung cancer underwent surgical resection. All tumors were reclassified based on the diameter measured eliminating the GGO area on HRCT according to the 7th TNM classification of lung cancer. We defined this new classification as modified T descriptors categorized into four groups: mTis+T1a, mT1b, mT2a and mT2b. The overall survival rates of the patients in the current and modified staging groups were evaluated.

      Results
      The 5-year survival rates were 88% and 82% in the patients with T1a and T1b tumors and 90% and 75% in the patients with mTis+T1a and mT1b tumors, respectively. The differences in the survival of the patients classified using mTis+T1a and the other modified T descriptors were more clearly separated statistically than those of the patients classified using the current T1a and other T descriptors.

      Conclusion
      The use of clinically modified T descriptors of the tumor size measured eliminating the GGO component on HRCT may more clearly classify the prognoses of patients with early lung cancer.

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      O29.06 - Prognostic Value of FDG-PET/CT Volumetric Prognostic Staging System in Non-small Cell Lung Caner (ID 2278)

      10:30 - 12:00  |  Author(s): Y. Pu, H. Zhang, B. Penney, M.C. Shih, Y. Jiang, C. Chen, D. Appelbaum, C. Kao, G. Carey, R. Salgia

      • Abstract
      • Presentation
      • Slides

      Background
      Whole-body metabolic tumor volume (MTV~WB~) is a prognostic index independent of TNM staging, age, gender, performance status and treatment in non-small cell lung cancer (NSCLC). The current TNM staging system is also a prognostic index. However, it lacks advanced quantitative volumetric measurement in the 7[th] edition NSCLC TNM staging system. Integrating quantitative MTV~WB~ measurement into the current NSCLC staging system may make the staging system more quantitative and probably more prognostic. This study’s aim was to determine the utility of a FDG-PET volumetric prognostic (PVP) staging system based on univariate Cox regression models as a new prognostic index in NSCLC.

      Methods
      328 consecutive patients (156 males,172 females) with histologically proven NSCLC and median age of 68.3 years were identified for this retrospective analysis. The PET metabolic tumor volume in the whole body (MTV~WB~) was measured using a semi-automated 3D contouring program on baseline FDG PET/CT scans. The prognostic power for survival status of the PVP staging system was evaluated using the Kaplan–Meier method, Cox regression models, and compared with those of TNM staging system and ln(MTV~WB~) using C-statistic index (Gönen and Heller’s K concordance statistic).

      Results
      There were 46 cases with stage IA, 43 stage IB, 19 stage IIA, 18 stage IIB, 52 stage IIIA, 39 stage IIIB and 111 stage IV NSCLC. At the end of this investigation, 249 patients had died (88.4%). Median follow-up of 79 lost follow-up and known surviving patients was 58 months. On univariate survival analysis the HR of ln(MTV~WB~) was 1.56, and the HRs of TNM stages 2.25, 1.96, 2.89, 4.24, 4.93 and 7.63 for TNM stages IB, IIA, IIB, IIIA, IIIB and IV in reference to stage IA, respectively. These HRs were used for computing the PVP stage of each patient using following equation; PVP stage = [Hazard ratio of ln(MTV~WB~) × ln(MTV~WB~)] × [Hazard ratios of TNM stage]. There was a statistically significant association of better overall survival with lower PVP stage on both univariate [HR of 1.033 (95%CI =1.027 to1.039)] and multivariate [HR of 1.03 (95%CI =1.02 to1.04)] survival analyses. The range of the PVP stage were 0.06 to 87.57. For comparison with 7[th] edition of TNM stage and ln(MTV~WB~), the PVP stage and ln(MTV~WB~) were divided into 7 groups with similar numbers of patients. The C-statistic value of PVP staging system (mean±SE = 0.70±0.014) was statistically significantly higher than those of TNM stage (0.67 ±0.015, p=0.002) and ln(MTV~WB~) (0.67±0.015, p=0.02) on univariate survival analysis. In multivariate Cox regression models adjusted by patient’s age, gender, treatment types, tumor histology and tumor SUV~max~, the C-statistic value of PVP staging system (mean±SE=0.73±0.013) was also statistically significantly higher than that of TNM stage (0.71 ±0.015, p=0.036).

      Conclusion
      The PVP staging system from FDG-PET/CT has better prognostic ability and may prove to be a useful prognostic index in NSCLC. It can be treated as a complement to the TNM staging system.

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      O29.07 - The clinical outcome of non-small cell lung cancer patients with adjacent lobe invasion: proposal for optimal classification according to the status of interlobar pleura in invasion point (ID 1168)

      10:30 - 12:00  |  Author(s): T. Hishida, Y. Ohtaki, J. Yoshida, G. Ishii, K. Aokage, K. Shimizu, I. Takeyoshi, K. Nagai

      • Abstract
      • Presentation
      • Slides

      Background
      In the 7th TNM classification, non-small cell lung cancer (NSCLC) with adjacent lobe invasion (ALI) is classified as T2a regardless of whether across the complete or incomplete fissure. However, no validation analysis has been conducted on this classification. The aim of this study was to analyze the survival of NSCLC patients with ALI with emphasis on the interlobar fissure status at invasion point.

      Methods
      We retrospectively evaluated 2097 consecutive patients with surgically resected NSCLC from 1993 through 2006. Of these, 90 (4.3%) patients had tumors with ALI. Interlobar fissure status of tumors with ALI was examined by using elastic stain. We classified ALI into 2 types: direct ALI beyond incomplete interlobar fissure (no visceral pleurae separating two lobes; ALI-D) and ALI across complete fissure (two lobes separated by 2 visceral pleurae; ALI-A), and compared the clinicopathological features and survival between the groups.

      Results
      The patients with ALI without any other criteria higher than T2b category (n = 60) demonstrated intermediate survival between T2a and T2b tumors (5-year overall survival [OS]: T2a, 61.0%; ALI, 59.6%; T2b, 49.2%). Distinct survival difference was observed between the patients with ALI-A (n = 46) and ALI-D (n = 14) (5-year OS: ALI-D, 85.7%; ALI-A, 52.0%; p = 0.01). The survival of patients with ALI-A was not statistically different from that of patients with T2b tumors, regardless of tumor size (p = 0.85). Conversely, the survival of the patients with ALI-D did not statistically differ from those with T1a or T1b tumors (p = 0.77 and 0.42, respectively).Figure 1Figure 2

      Conclusion
      Interlobar fissure status clearly affected survival of the patients with ALI. ALI should be examined by elastic stains and only ALI-A should be classified as true ALI. We propose that ALI-A tumors ≤ 5 cm should be assigned to T2b but ALI-D tumors do not require adjustment of T descriptor.

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      O29.08 - DISCUSSANT (ID 3997)

      10:30 - 12:00  |  Author(s): M. Reck

      • Abstract
      • Presentation
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      Abstract not provided

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