Virtual Library

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    GR 02 - Difficult Mesothelioma Cases (ID 15)

    • Event: WCLC 2015
    • Type: Grand Rounds
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 5
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      Introduction (ID 2062)

      • Abstract

      Abstract not provided

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      GR02.01 - Case 1: A 70 Year Old with a Biphasic Stage I MPM (ID 1832)

      H.I. Pass

      • Abstract
      • Presentation
      • Slides

      Abstract:
      A 70 year old retired insulator presented to the emergency room with progressive shortness of breath limiting his ability to complete his daily 5 mile runs. Physical examination reveals minimal breath sounds and dullness to percussion on the right side. The patient denies chest pain or weight loss. There is no history of cardiac disease and he is a never smoker. Family histroy reveals a brother with cured uveal melanoma. Chest radiography reveals a completely opacified right hemithorax. WBC is 7000, platelet count 245,000, and his HgB is 13.2 gms. A thoracentesis reveals 3.5 liters of serosanguinous fluid, and post thoracentesis radiograph reveals complete expansion. Fluid is sent for culture and cytology, and the patient is discharged to home with a 2 day supply analgesics. The culture report at 5 days reveals no growth and the cytology reveals atypical mesothelial hyperpplasia. Two months after his thoracentesis he returns to see his PCP with similar complaints of shortness of breath with exertion without chest pain. 1. What is the proper further management of this patient? 2. What is unusual about his family history, and what are the possible implications?

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      GR02.02 - Case 2: A 65 Year Old with an Uncytoreduceable MPM (ID 1833)

      P. Baas

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Malignant Pleural Mesothelioma: A patient with unresectable disease It is generally accepted that only a minority of patient are candidates for combined modality treatment. Surgery or radiation alone is not able to achieve a complete pathological control of the tumor. Therefore most patients have to be considered for a systemic treatment. Since the nineties of last century only a slow progress has been achieved with the advent of chemotherapy. Single agents were tried but failed to achieve durable responses and did not achieve response rates over 20%. It was until the beginning of the current century that a standard therapy was defined using platin and an anti-folate. The response rate was 30-35% and the median survival increased from 9 to 13 months. Unfortunately 80% of the patients succumbed to the disease in the 2 years after chemotherapy. The new approaches that are currently available can be grossly divided into a maintenance; immunological and signal-pathway approach. For the case presented to our tumor board it is the challenge to decide which treatment is the most successful with acceptable toxicity. The choice of treatment strongly depends on the patients’ characteristics since cure is not very realistic. The standard of treatment consists of the administration of 4-6 courses of (cis)platin with pemetrexed given every 3 weeks. MPM is well known to respond slowly to chemotherapy and ongoing responses can be seen even after 6 courses of therapy. This has lead to the idea of maintenance therapy. In line with the results in NSCLC one can choose to continue with single agent pemetrexed but to date no randomized study has addressed this issue. Switch maintenance is currently under study with different drugs. The most mature phase III study is with bevacizumab (MAPS study), which showed an improvement in survival in the combination arm. This randomized study showed a very high survival in the control arm of 16 months. The addition of bevacizumab increased the OS to 18.8 months with statistical significance. The full data have not yet been presented and selection of the very best patients might account for this success. An ongoing randomized phase II study with defactinib tests the effect in a maintenance setting. The drug inhibits the Focal Adhesion Kinase pathway, rendering cells susceptible for apoptosis and it reduces the stem cells after chemotherapy. The results are expected in 2016. Since the disease recurs within 1 year, often second line therapy is offered. In table 1 a summary of different approaches is presented. Besides different chemotherapy regimens, inhibition of signal transduction pathways or immunotherapy has been tested. Until now no chemotherapeutic agent or oral TKI has been identified as promising agent. Immunotherapy however, is now one of the new and perhaps most promising developments of this decade. In this particular anti-PD-1 monoclonal antibodies and antibody drug conjugates have shown interesting results in phase I setting. There are a few issues to be resolved in the near future: How to select the best drug for each patient. How to compare study results in patients with different pathology/biological characteristics With a relatively small number of patients per year we must not embark blindly in to large phase 3 studies. We must try to personalize the treatment by increasing our TR efforts. Pre- and post-treatment biopsies can help to identify promising drugs at an early stage. Pre-treatment cell cultures can help to improve the selection of patients who might be good responders to certain chemical compounds. And finally we must improve our collaboration between centers to offer optimal service to our patients. Table 1

      Agent group line Recommended Agents LoE Remark
      Chemotherapy 1 cis/pem I Standard since 2003 (1)
      2 pem; vin II pem showed improved PFS (2)
      Maintenance 1 bev I Reported at ASCO 2015 (3)
      TKI 2 none - Many tested; no conclusive results
      Immunotherapy 2 Immunotoxins III Phase I study of pseudomonas toxin (4)
      a-CTL4; a-PD1 III Trametinib now tested in maintenance setting in phase III; pembrolizumab showed promising results in phase I (5)
      cis: cisplatin; pem: pemetrexed; vin: vinorelbine; bev: bevacizumab; a-CTL4: anti cytotoxic lymphocyte 4; a-PD1: anti-programmed death; LoE: level of evidence; PFS: progression free survival Selected references 1.Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. J Clin Oncol 2003;21:2636–44 2, Jassem J, Ramlau R, Santoro A, et al. J Clin Oncol 2008;26:1698-1704 3. Zalcman et al. pASCO 2015 4. Hassan R, Miller AC, Sharon E et al. Sci Transl Medicine. 2013;5(208):208ra147. 5. Alley E et al. pAACR 2015

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      GR02.03 - Case 3: A 65 Year Old with a Clinical Stage II MPM and Chest Pain (ID 1834)

      J. Friedberg

      • Abstract
      • Presentation

      Abstract not provided

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      GR02.04 - Addressing the Needs of the Mesothelioma Patient Who Has Exhausted Treatment Options: Palliation and Support for Family and Patient (ID 1835)

      H. Clayson, L. Darlison, M. Hesdorffer

      • Abstract

      Abstract:
      The care of people with end-stage mesothelioma is complex due to the interplay of severe physical symptoms, intense psychological distress, and social factors related to mesothelioma being a fatal occupational disease. In comparison with people suffering from lung cancer, patients with mesothelioma experience more pain and greater negative impact on role and functioning and insomnia (1). Patients and family members should expect effective management of symptoms, support during the continuum of the illness and a rapid response to crisis. The high symptom burden experienced by patients with mesothelioma in the last year of life is shown in the table below (2):

      Pleural mesothelioma: Symptoms in the last year of life
      Breathlessness 96% Social 16%
      Pain 91% Nausea 14%
      Cough 41% Fatigue 13%
      Weight loss 41% Dysphagia 11%
      Anxiety 31% Psychiatric 10%
      Anorexia (loss of appetite) 25% Constipation 8%
      Depression 19% Ascites 8%
      Sweating 18% Vomiting 5%
      Emotional disturbance 16% Painful metastasis 5%
      Patients with incurable disease deserve and need to receive clear information and to share in the decision-making about each stage of their cancer journey. Once oncological treatments are exhausted, healthcare professionals hold the responsibility for helping patients and their families shift their expectation from “cure” to palliation of symptoms. A care plan for a good death needs to be sensitively eased into the clinical discussions, taking into account each individual patient’s preferences (3). In rare diseases such as mesothelioma a feeling of isolation tends to overwhelm the patient and their family. Unlike most cancers mesothelioma has an explained occupational and/or environmental cause. In many cases understanding that the fatal illness was caused by asbestos exposure due to neglect of health and safety precautions at work can lead to blame, anger, depression and inability to cope. The complicated processes concerning claims for welfare benefits and civil compensation litigation often exacerbate this psychological distress. Meeting the care needs of patients and their families in this situation requires a compassionate and specialised multi-disciplinary approach. Expert timely supportive and palliative care can address the burdens associated with advanced disease and guide the patient and family in accepting and planning for a good death. Transition to focus care on the family during the grief process completes the cycle in the care of the mesothelioma patient and family. Panel discussion will include the following areas: · Advanced education and the expanded role of a nursing team solely focused on mesothelioma (4). · The roles and availability of on-line, in person and telephone support groups · The need for early referral into palliative, supportive and hospice care References 1. Nowak AK, Stockler MR, Byrne MJ (2004) Assessing quality of life during chemotherapy for pleural mesothelioma: feasibility, validity, and results of using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire and Lung Cancer Module. J Clin Oncol. Aug 1;22 (15):3172-80. 2. Clayson H (2007) Thesis: The Experience of Mesothelioma in Northern England. University of Sheffield. Available online at etheses.whiterose.ac.uk/1775/ 3. Pass HI, Hesdorfer M, Lake SE, Lake SA. (2012) 100 Questions and Answers about Mesothelioma. Third Edition 4. Moore S, Darlison L (2011) Improving the nursing care of patients with mesothelioma. Nurs Stand May 25-31;25(38):35-8

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    GR 03 - Extensive Small Cell with Excellent Response to 1st Line Rx (PCI, Chest and/or Oligomet RT) and Second Line and Treatment of Thymic Malignancies (ID 16)

    • Event: WCLC 2015
    • Type: Grand Rounds
    • Track: Small Cell Lung Cancer
    • Presentations: 7
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      Introduction (ID 2063)

      • Abstract

      Abstract not provided

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      GR03.01a - SCLC Therapy (ID 1838)

      R.U. Komaki

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The incidence of lung cancer has been declining since the advent of tobacco cessation efforts, and screening has improved 5-year overall survival rates among smokers to some extent. Nevertheless, about 13% of lung cancers are of the small cell subtype (SCLC), and many such cases present as extensive disease. Outcomes for patients with extensive SCLC remain poor, with median times to progression of 4–6 months, median survival times of 7–11 months, and 2-year survival rates of <5%.[1] Chemotherapy has been the cornerstone of treatment, with the current standard being 4–6 cycles of platinum-based chemotherapy. Other approaches involving other chemotherapeutic agents, molecular targeted drugs, or maintenance chemotherapy have not led to improvement. A notable exception, however, is prophylactic cranial irradiation (PCI) for patients who experience a complete response after induction chemotherapy. PCI has been shown to eliminate the progressive increase in the risk of brain metastasis that accompanies extended survival in patients with SCLC, and in that context is important for maximizing the probability for cure for such patients.[2] Indeed, PCI has led to extended survival among patients with limited-stage SCLC and some patients with extensive SCLC. A randomized phase III trial of patients with extensive SCLC reported by Slotman et al.[3] showed that PCI reduced the incidence of symptomatic brain metastases (15% versus 40% in a no-PCI control group) and increased the 1-year overall survival (OS) rate from 13% to 27%. However, a benefit of PCI for patients with extensive SCLC has not been noted consistently. A multicenter trial from Japan (UMIN000001755, reported in abstract form at ASCO 2014)[ 4] was terminated early because the futility boundary was crossed for OS. That study indicated that receipt of PCI after response to chemotherapy for extensive SCLC reduced the risk of developing brain metastases but had a negative effect on OS (median OS time 10.1 months for PCI vs. 15.1 months for observation, HR=1.38, 95% CI 0.95-2.01, stratified log-rank test P=0.091). Differences between that study and the phase III trial reported by Slotman included the use of magnetic resonance imaging to rule out brain involvement at enrollment, use of only platinum-based doublet chemotherapy, and use of a single PCI schedule (25 Gy in 10 fractions). Another multicenter study involving PCI, RTOG 0937, was also closed early for crossing a survival futility boundary. Further, although the Japanese study showed no difference between the PCI vs. observation groups in terms of incidence of grade >2 adverse events, a disproportionate distribution of grade 4 and 5 events in RTOG 0937 between groups (PCI with or without consolidative extracranial irradiation) also contributed to the early closure of that trial. In addition to PCI, thoracic radiation therapy can improve local control and extend survival for patients with limited-stage disease and possibly for some patients with extensive disease. Controlling intrathoracic tumors remains problematic in SCLC, as such disease remains after induction chemotherapy in most patients and progresses in nearly all patients within the first year after diagnosis. Evidence of benefit for patients with extensive disease includes a single-institution trial of patients with a complete response to induction chemotherapy at distant disease sites, and a complete or partial local response, who received additional low-dose chemotherapy with or without thoracic radiotherapy; that study showed significant improvements in local control and survival after thoracic radiotherapy.[5] Other evidence of benefit comes from two retrospective analyses,[6,7] one non-randomised phase II trial,[8] and a recent phase III multicenter trial of thoracic radiotherapy with PCI for patients with extensive SCLC that had responded to chemotherapy.[9] The latter study involved 247 patients who received thoracic radiation and PCI and 248 who received PCI only after responding to chemotherapy. Although OS at 1 year was no different between groups (33% [95% confidence interval {CI} 27–39] thoracic vs. 28% [95% CI 22–34] control), a secondary analysis showed that the 2-year OS rate was better (13% [95% CI 9–19] vs. 3% [95% CI 2–8], P=0.004) and progression was less likely in the group that received thoracic radiotherapy (hazard ratio 0.73, 95% CI 0.61–0.87, P=0.001). These findings, in combination with low rates of severe toxic effects (no grade 5; grade 3-4 in 26 thoracic and 18 control patients), led the authors to recommend that thoracic radiotherapy be considered, in addition to PCI, for all patients with extensive SCLC who respond to chemotherapy. References 1. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the Surveillance, Epidemiology, and End Results database. J Clin Oncol 2006;24:4539–44. 2. Komaki R, Cox JD, Whitson W. Risk of brain metastasis from small cell carcinoma of the lung related to length of survival and prophylactic irradiation. Cancer Treat Rep 1981;65(9-10):811-814. 3. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007;357:664–672. 4. Seto T, Takahashi T, Yamanaka T, et al. Prophylactic cranial irradiation has a detrimental effect on the overall survival of patients with extensive disease small cell lung cancer: results of a Japanese randomized phase III trial (abstract). J Clin Oncol 2014;32:5s (suppl; abstr 7503). 5. Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: a randomized study. J Clin Oncol 1999;17:2092–2099. 6. Giuliani ME, Atallah S, Sun A, et al. Clinical outcomes of extensive stage small cell lung carcinoma patients treated with consolidative thoracic radiotherapy. Clin Lung Cancer 2011; 12: 375–379. 7. Zhu H, Zhou Z, Wang Y, et al. Thoracic radiation therapy improves the overall survival of patients with extensive-stage small cell lung cancer with distant metastasis. Cancer 2011; 117: 5423–5431. 8. Yee D, Butts C, Reiman A, et al. Clinical trial of post-chemotherapy consolidation thoracic radiotherapy for extensive-stage small cell lung cancer. Radiother Oncol 2012;102:234–238. 9. Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 2015;385:36–42.

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      GR03.01b - Systemic Therapy of Extensive Stage Small Cell Lung Cancer (SCLC): Contrasting Therapeutic Principles for SCLC and Non-small Cell Lung Cancer (NSCLC) in 2015 (ID 1839)

      N. Murray

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      • Presentation

      Abstract:
      Since the 1960’s, SCLC has been recognized as a distinct lung cancer subtype with unique sensitivity to chemotherapy and radiotherapy. Indeed SCLC and NSCLC are generally discussed as separate topics. After 50 years of investigation, it may be useful to recognize similarities as well as differences in therapeutic principles for systemic therapy. For metastatic disease, palliative first-line systemic therapy for SCLC and NSCLC patients without a drugable driver mutation is a platinum-based two drug chemotherapy combination. For SCLC, platinum and etoposide has generally prevailed as standard although platinum plus irinotecan is widely used in Asia. The platinum doublet used for first-line chemotherapy for NSCLC has had a more complex evolution with many variations, however, the evidence for improved survival with modern platinum doublets can be questioned, even for non-squamous cancers.(1) In both pathologic types, single agents or dose attenuation with first-line therapy result in inferior outcomes. Three and four drug chemotherapy regimens are not better than two drug regimens. Dose-dense and high dose cytotoxic regimens do not generate superior survival results. Non-platinum regimens are not superior to platinum-based two drug combinations. Four to six cycles of first-line therapy is sufficient for most patients. Maintenance chemotherapy is not recommended for SCLC whereas it is an option for NSCLC that confers a survival advantage if patients fail to receive second-line therapy. Second-line treatment for both types of lung cancer is single agent chemotherapy and the survival benefit is worthwhile but modest. Topoisomerase-1 inhibitors have been extensively investigated and used in SCLC. Docetaxel is standard second-line therapy for squamous cancers whereas docetaxel and pemetrexed have equal efficacy in second-line chemotherapy of non-squamous cancers. For both types of lung cancer, second-line chemotherapy is usually unrewarding for cases progressing on first-line chemotherapy or relapsing within less than three months as these tumors have demonstrated chemotherapy resistant biology with response rates of about 10%. Tumors that are sensitive to first-line chemotherapy with a long time to progression are somewhat more tractable with second-line therapy. Third line chemotherapy is not evidenced-based for either SCLC or NSCLC, but may be a reasonable option in selected patients that have responded to second-line treatment. The survival outcome for metastatic SCLC and metastatic NSCLC (without EGFR or ALK mutations) is similar with a median survival of 11-12 months and a two-year survival of 5-10%. Although the initial response rate of SCLC of 60-70% is about double that of NSCLC, the median time for chemotherapy resistant clones to cause a fatal outcome is about the same for both diseases. Without doubt, the natural history of metastatic lung cancer unrestrained by any chemotherapy is worse for SCLC than NSCLC. With respect to trials of SCLC with new chemotherapy agents, it is important to recognize themes of investigation that have been unrewarding. Generally speaking, analogues of active drugs have failed to show evidence of improved survival compared to the parent compounds. This has been shown for alkylating agents, platinum compounds, vinca alkaloids, epipodophylotoxins, and anthracyclines. Moreover, randomized trials have demonstrated statistically significantly inferior survival outcomes for two novel analogues when compared to regimens considered to be standard-of-care. The folate antagonist pemetrexed was studied in a phase III trial of first-line chemotherapy. The GALES (Global Analysis of Pemetrexed in SCLC Extensive Stage) randomized pemetrexed/ cisplatin versus etoposide/ cisplatin.(2) Accrual was terminated early by the data safety and monitoring committee. Survival was inferior in the pemetrexed-platinum arm (median survival 8.1 months) compared to 10.6 months for etoposide-cisplatin (p <0.01). Time to progression (TTP) and response rates (RR) were worse as well. The inferior result was not explained by thymidylate synthase expression or other folate pathway biomarkers.(3) Pemetrexed is simply a bad drug for treatment of SCLC. Similarly, the taxane analogue cabizitaxel was tested in the second-line setting against topotecan.(4) Cabizitaxel was signifantly inferior to topotecan for RR, TTP and survival. This result stands as another example of analogue investigation failure and makes one wonder about the use of any taxane in SCLC. The discovery of treatable molecular targets in adenocarcinomas with approved drugs is a conspicuous difference in systemic therapy of NSCLC compared to SCLC. No molecular targets that can be treated with drugs with proven efficacy have as yet been approved for SCLC.(5) This is not due to a lack of trying. A large number of molecular targeted agents have already been studied in SCLC without a signal of sufficient activity to continue development.(6) The roster includes pathways suggested by analysis of the SCLC genome but numerous other molecular targeted drugs of interest in other cancers were also tested. Drugs with better efficacy may be identified by more extensive SCLC genome analysis,(5) but there is no escaping the fact that results reported to date have been disappointing. Data from genome analysis have shown a bewildering array of abnormalities in this tobacco hyper-mutated tumor. Like squamous carcinomas, the SCLC molecular battlefield is bleak and complex with little opportunity for even temporary respite by identification of mutually exclusive oncogenic drivers. An intriguing possibility is that the numerous mutations in SCLC may be an asset for immunotherapy studies. Checkpoint inhibition has already been demonstrated superior to standard of care in second-line therapy of both squamous (8) and non-squamous NSCLC.(9) At ASCO 2015, two phase II studies of immunotherapy in previously treated SCLC were presented and the results are provocative. Nivolumab produced a RR of 18% and nivolumab plus ipilumimab had a RR of 17% in a population unselected for PD-L1 positivity.(10) In patients selected for PD-L1 positivity, pembrolizumab produced responses in 35%.(11) Although data is preliminary, some responses in these immunotherapy studies may be long-lasting. . The therapeutic principles of systemic therapy of SCLC and NSCLC may be converging again with immunotherapy becoming the most exciting advance in both histologic types. References (1) Murray N. Reality check for pemetrexed and maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol 2014 Feb 10;32(5):482-483. (2) Socinski MA, Smit EF, Lorigan P, Konduri K, Reck M, Szczesna A, et al. Phase III Study of Pemetrexed Plus Carboplatin Compared With Etoposide Plus Carboplatin in Chemotherapy-Naive Patients With Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol 2009 October 1;27(28):4787-4792. (3) Smit EF, Socinski MA, Mullaney BP, Myrand SP, Scagliotti GV, Lorigan P, et al. Biomarker analysis in a phase III study of pemetrexed-carboplatin versus etoposide-carboplatin in chemonaive patients with extensive-stage small-cell lung cancer. Ann Oncol 2012 Jul;23(7):1723-1729. (4) Evans TL, Kim J, Shepherd FA, Syrigos KN, Udud K, Chubenko V, et al. Cabazitaxel (Cbz) versus topotecan in patients (pts) with small cell lung cancer (SCLC) that has progressed during or after first-line treatment with platinum-based chemotherapy: A randomized phase II study. ASCO Meeting Abstracts 2013 June 17;31(15_suppl):TPS7609. (5) Rudin CM, Durinck S, Stawiski EW, Poirier JT, Modrusan Z, Shames DS, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 2012 Oct;44(10):1111-1116. (6) Murray N, Noonan K. Can we expect progress of targeted therapy of small cell lung cancer? In: Dingemans A, Reck M, Westeel V, editors. Lung cancer Sheffield: European Respiratory Society; 2015. p. 234. (7) Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015 May 31. (8) Paz-Ares L, Horn L, Borghaei H, Spigel DR, Steins M, Ready N, et al. Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). ASCO Meeting Abstracts 2015 June 22;33(18_suppl):LBA109. (9) Antonia SJ, Bendell JC, Taylor MH, Calvo E, Jaeger D, De Braud FG, et al. Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032. ASCO Meeting Abstracts 2015 May 18;33(15_suppl):7503. (10) Ott PA, Fernandez MEE, Hiret S, Kim D, Moss RA, Winser T, et al. Pembrolizumab (MK-3475) in patients (pts) with extensive-stage small cell lung cancer (SCLC): Preliminary safety and efficacy results from KEYNOTE-028. ASCO Meeting Abstracts 2015 May 18;33(15_suppl):7502.

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      GR03.02 - Treatment of Thymic Malignancies - Surgery (ID 1840)

      F. Detterbeck

      • Abstract
      • Presentation

      Abstract not provided

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      GR03.03 - Treatment of Thymic Malignancies - Radiotherapy (ID 1841)

      D. Gomez

      • Abstract
      • Presentation

      Abstract:
      Indications and techniques for radiation therapy for thymic malignancies have evolved over the past decade. The primary indication for radiation has historically been mediastinal radiation in the adjuvant setting (postoperative radiation therapy, PORT). The recommendations for PORT vary by stage. As increased evidence suggests high local control rates with surgery alone in Masaoka-Koga stage I-II disease, there is a general consensus that in early stages PORT can be omitted. Several studies have demonstrated that local control rates after surgery alone in stage I disease are excellent, and thus there is no indication for PORT in this setting[1-3]. In contrast, for stage III disease, many studies have shown increased rates of local failure after surgery alone, and with an improvement in outcomes with PORT[3-5]. Indeed, common approaches in stage III disease include neoadjuvant chemotherapy, followed by surgery, and then PORT, based on institutional results that demonstrate high levels of disease control with this approach[6-8], and neoadjuvant chemoradiation followed by surgery[9]. Similar to other thoracic malignancies, the advent of advanced radiation techniques has allowed for increased sparing of mediastinal structures such as the heart, great vessels, and lung. This reduction in dose may ultimately lead to lower side effects, thus enhancing the quality of life for survivors of this malignancy. It is recommended that all patients undergo computed tomography-based simulation and radiation treatment with conformal techniques, to minimize dose to the surrounding structures such as the lungs, heart, and underlying vasculature. If possible, motion management should be performed during treatment planning to encompass the extent of respiratory motion. The radiation treatment field should encompass the preoperative extent of disease, including regions of surgical clips. Radiation oncologists should consult the surgeon in the design of their field to ensure that high-risk operative regions are included. Elective nodal radiation is not indicated, based on studies showing that there are minimal to no recurrences in elective nodes after mediastinal radiation. In addition to PORT to the mediastinal bed, as patterns of failure analyses have demonstrated a propensity for pleural failure, there has been interest in utilizing more extensive radiation fields (e.g. hemithoracic radiation therapy), either as prophylaxis or when pleural recurrence occurs[10]. Given the lack of strong evidence supporting this approach, it is recommended that this treatment primarily be performed in the context of a clinical trial. At this time, there is not an established role for radiation in stage IV disease, and studies assessing this technique using modern radiation modalities are ongoing. References 1. Park HS, Shin DM, Lee JS, et al. Thymoma. A retrospective study of 87 cases. Cancer. 1994;73: 2491-2498. 2. Forquer JA, Rong N, Fakiris AJ, Loehrer PJ, Sr., Johnstone PA. Postoperative radiotherapy after surgical resection of thymoma: differing roles in localized and regional disease. Int J Radiat Oncol Biol Phys. 2010;76: 440-445. 3. Fernandes AT, Shinohara ET, Guo M, et al. The role of radiation therapy in malignant thymoma: a Surveillance, Epidemiology, and End Results database analysis. J Thorac Oncol. 2010;5: 1454-1460. 4. Weksler B, Shende M, Nason KS, Gallagher A, Ferson PF, Pennathur A. The role of adjuvant radiation therapy for resected stage III thymoma: a population-based study. Ann Thorac Surg. 2012;93: 1822-1828; discussion 1828-1829. 5. Gao L, Wang C, Fang W, Zhang J, Lv C, Fu S. Outcome of multimodality treatment for 188 cases of type B3 thymoma. J Thorac Oncol. 2013;8: 1329-1334. 6. Kim ES, Putnam JB, Komaki R, et al. Phase II study of a multidisciplinary approach with induction chemotherapy, followed by surgical resection, radiation therapy, and consolidation chemotherapy for unresectable malignant thymomas: final report. Lung Cancer. 2004;44: 369-379. 7. Huang J, Riely GJ, Rosenzweig KE, Rusch VW. Multimodality therapy for locally advanced thymomas: state of the art or investigational therapy? Ann Thorac Surg. 2008;85: 365-367. 8. Modh A, Rimner A, Allen PK, et al. Treatment Modalities and Outcomes in Patients With Advanced Invasive Thymoma or Thymic Carcinoma: A Retrospective Multicenter Study. Am J Clin Oncol. 2014. 9. Korst RJ, Bezjak A, Blackmon S, et al. Neoadjuvant chemoradiotherapy for locally advanced thymic tumors: a phase II, multi-institutional clinical trial. J Thorac Cardiovasc Surg. 2014;147: 36-44, 46 e31. 10. Sugie C, Shibamoto Y, Ikeya-Hashizume C, et al. Invasive thymoma: postoperative mediastinal irradiation, and low-dose entire hemithorax irradiation in patients with pleural dissemination. J Thorac Oncol. 2008;3: 75-81.

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      GR03.04 - Treatment of Thymic Malignancies - Biology and Standard Treatment (ID 1842)

      G. Giaccone

      • Abstract
      • Presentation

      Abstract:
      Thymic epithelial tumors (TETs) are rare malignanices of the thymic epitehlial cells. Recent research has identified recurrent mutations in these tumors, using NextGen sequencing (Petrini et al. Nature Gen 2014; Wang et al Sci. Rep. 2015). GTF2i, a general transcription factor has been found to have a high frequency of a unique muation in over 70% of type A and AB, whereas this mutation decreases in frequency in thymic carcinomas. Mutation in GTF2i may represent an oncogenic event in TETs. Common recurrent mutations in known cancer genes have been found more frequenty in thymic carcinomas, where the number of mutations is higher than in more indolent forms of TETs. In particular genes involved in epigenetic regulation have been found recurrently mutated. Presence of P53 mutations was also found to be related to poorer survival, as well as the number of recurrent mutations. The implications of molecular characterization of TETs on treatment are still relatively small, but they represent a first step toeards more targeted treatments. Chemotherapy remains the standard treatment for first line therapy of patients with un-resectable disease, or as neoadjuvant therapy in large tumors before surgery or radiation. The more commonly employed regimes still are represented by the PAC regimen, PE regimen and more recently carbo-taxol. Targeted therapies have been studied in unselected patients and of all of those tested in properly conducted phase II studies, sunitinib appears to be the most effective in thymic carcinoma (25% response rate; Thomas et al. Lancet Oncol 2015). A phase II of pembrolizumab is actively accruing in patients with thymic carcinomas, where PDL-1 expression is relatively high.

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      GR03.05 - Thymic Epithelial Tumors: New Hope on the Horizon with Novel Therapeutic Strategies (ID 1843)

      J. Remon-Masip, B. Besse

      • Abstract
      • Presentation

      Abstract:
      Thymic Epithelial Tumors (TET) comprised of thymoma (T) and thymic carcinoma (TC) are rare cancers with an incidence of 1.7 and 1.3 per million per year in Europe[i] and the US[ii], respectively. Five-year overall survival (OS) varies significantly sitting at > 80% for T compared with ~40% for TC[iii],[iv]. Surgery remains the treatment of choice for operable TET, whereas chemotherapy is standard of care for metastatic or inoperable / recurrent disease. The response rate (RR) of TET to current chemotherapy agents differs by histological features: T responds better to first-line platinum based chemotherapy than TC (69% vs. 41%)[v]. No standard treatments are available for advanced TET after failure of first-line platinum-based chemotherapy, although single agents are generally used with modest benefit. For example pemetrexed, has been associated with a 17% partial response (PR) rate in T and 10% of PR in TC, with a median progression free survival (PFS) of 13.8 months and 6.5 months, respectively[vi]. Other drugs have recently been tested in second-line with promising results. In a phase II trial which recruited 14 T and 19 TC patients, amrubicin (a topoisomerase II inhibitor) was administered at 35 mg/m[2] IV days 1-3 on a 21-day cycle, producing an 18% RR (n=6, all PR: 29% in T and 11% in TC) without unexpected toxicity or cardiotoxicity[vii]. Another phase II trial investigated the combination of capecitabine plus gemcitabine in 30 pretreated TET patients (22 T and 8 TC). Overall RR was 40% (3 CR and 8 PR, with 3 PR in TC 3), PFS for T and TC was 11 months and 6 months, respectively and median OS was 16 months[viii]. In octreoscan positive patients with TET, somatostatin analogs with or without prednisone have also been shown to be effective as maintenance or as second-line treatment[ix][,[x]]. Given the poor survival of advanced TET, especially TC, there is a clear need for new treatment options. However, the molecular pathogenesis of TET is poorly understood at present. Profiled somatic genetic variations in 78 advanced-TET[xi] cases showed higher a incidence of somatic non-synonymous mutations in TC compared to T (62% vs. 13%; p<0.0001). TP53 was the most frequently mutated gene (overall in TET was 17% and especially in TC, 26%) and was associated with poorer OS (p<0.0001). Moreover, genes invovlved with histone modification (e.g. BAP1), chromatin remodelling, DNA methylation genes and c-KIT were also frequently mutated in advanced TCs. Although the presence of activating mutations is low in TET, the SPECTA-lung trial (NCT02214134) will allow analysis of more than 360 genes in patients with thoracic tumors, including T and TC. In this EORTC/ETOP umbrella study, eighteen European centres will allocate patients to different treatment arms based on the molecular characteristics of their disease, suggesting that basket trials allow the study of the genetics of less common malignancies[xii]. Despite data demonstrating EGFR and KIT overexpression in TET, EGFR and c-KIT mutations are rare, reported at 2%-10% and 9%, respectively[xiii]. This low percentage could explain the lack of RR observed in phase II studies evaluating Gefitinib, Erlotinib plus bevacizumab, and Glivec. In a recent retrospective analysis of 48 TC and thymic neuroendocrine tumors, the probability to finding c-KIT mutations was higher in CD117-positive thymic squamous cell carcinoma with poorly-differentiation and co-expression of CD5 and p63 in the absence of neuroendocrine markers (6 out of 23, 26%)[xiv], suggesting that a subgroup of TC might respond to c-KIT inhibitors. Recently SRC inhibitors (AZD0530) reported no RR in a phase II trial[xv]. Angiogenesis is another relevant pathway in TET. VEGF-A, -C, -D and VEGFR-1,-2,-3- are all overexpressed in high risk T and TC[xvi]. Sunitinib is an oral tyrosine kinase inhibitor (TKI) of VEGFR, KIT, and PDGFR. In a single arm phase 2 trial of sunitinib (50 mg/day for 4 weeks on, 2 weeks off) after at least one previous line of chemotherapy, a PR was reported in 26% of TC and 6% in T, with a mPFS of 7.2 months and 8.5 months, respectively. Main adverse events (AE) reported were lymphocytopenia, fatigue, and oral mucositis[xvii]. Although response was mainly limited to TC, sunitinib demonstrated an unprecedented activity for a targeted agent so far. Other antiangiogenic compounds that could be of value include Lucitanib, a selective TKI of FGFR1-3, VEGFR1-3, and PDGFR α/β. Efficacy data in 15 patients will be reported for this drug at the WCLC 2015. Insulin-like growth factor-1 receptor (IGF-1R) over-expression has been reported in 86% of TC and 43% of T[xviii], and carries poor prognosis. In a recent phase II trial of 49 patients with recurrent TET (37 T and 12 TC), single agent cixutumumab (a fully human IgG1 monoclonal antibody anti-IGF-1R, 20 mg/kg every 3 weeks), reported clinical activity only in T (14% PR, 28% SD, TTP 9 months and OS 27.5 months). No activity was recorded in the TC cohort (42% SD, TTP 1.7 months and OS 8.4 months). The most common toxicity in both groups was hypoglycemia (10%). Of note, 9 patients with T experienced autoimmune disorders[xix]. A phase II trial, Belinostat (PXD101, a pan-histone deacetylase inhibitor, 1g/m2 on days 1 through 5 in a 3-week schedule) among 41 patients (25 T and 16 TC) has reported only modest activity, with an 8% RR in T and no responses observed in TC. However, based on the duration of response and disease stabilization (median TTP and OS were 5.8 and 19.1 months, respectively), additional testing of belinostat in this disease may be warranted[xx]. Milciclib (PHA-848125AC) is an inhibitor of cyclin-dependent kinase2/cyclin A and SRC family members. Milciclib (150 mg/d 7 days on / 7 days off, 2-week cycles) has been evaluated in a phase II trial with 43 patients (26 TC and 9 B3-T). Out of 30 patients, 14 cases (46.7%) reached the primary end point and were PFS at 3 months, including PR. Five cases of SD lived longer than 1 year. The median PFS was 8.2 months and median OS has not been yet reached. The toxicity profile appeared favourable with nausea, asthenia and neutropenia (8.3%) reported as the most common severe AEs[xxi]. The mTOR inhibitor everolimus (10 mg/d) has been tested in a phase II trial in 50 patients with advanced or recurrent T (n=30) or TC (n=19) previously treated with cisplatin-containing chemotherapy. Preliminary data among the 43 evaluable patients showed a disease control rate (DCR) of 86% (1 CR, 10 PR, 32 SD) that was beyond the pre-specified endpoint of 40% DCR. The median PFS was 11.3 months (T not reached vs. 5.5 months in TC), and median OS was 18.6 months for TC and not reached for T. Few severe AEs were reported (asthenia, dyspnoea, neutropenia and hyperglycemia)[xxii]. Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has clinical activity in many tumors types. In a cohort of 139 TET, retrospective PDL-1 expression by IHC with the E1L3N antibody has been reported in 70% of TC and 23% of T, respectively. PDL-1 expression was not a significant prognostic factor in multivariable analysis[xxiii], although in other reported cohorts overexpression of PD-L1 was associated with worse prognosis [xxv, xxiv]. These results generally support immunotherapeutic strategies in TET (NCT02364076). At present, antiangiogenics, mTOR and CDK inhibitors, are the most promising drugs in TET treatment. Consensus on meaningful end-points, and knowledge of predictive biomarkers are challenges in this disease. [i] Siesling S, van der Zwan JM, Izarzugaza I et al. Rare thoracic cancers, including peritoneum mesothelioma. Eur J Cancer 2012; 48: 949-60. [ii] Engels EA. Epidemiology of thymoma and associated malignancies. J Thorac Oncol 2010; 5 (10 Suppl 4): S260–S265. [iii] Mariano C, Ionescu DN, Cheung WY et al. Thymoma. A population-based study of the management and outcomes for the province of British Columbia. J Thorac Oncol 2013; 8: 109–117. [iv] de Jong WK, Blaauwgeers JLG, Schaapveld M et al. Thymic epithelial tumours: a population-based study of the incidence, diagnostic procedures and therapy. Eur J Cancer 2008; 44(1): 123–130. [v] Okuma Y, Saito M, Hosomi Y et al. Key components of chemotherapy for thymic malignancies: a systemic review and pooled analysis for anthracyclines-, carboplatin- or cisplatin-based chemotherapy. J Cancer Res Clin Oncol 2015; 141: 323-31 [vi] Liang Y, Padda SK, Riess JW et al. Pemetrexed in patients with thymic malignancies previously treated with chemotherapy. Lung Cancer 2015, 87: 34-8 [vii] Wakelee HA, Padda SK, Burns M et al. Phase II trial of single agent amrubicin in patients with previously treated advanced thymic malignancies. J Clin Oncol 2015; 33 (suppls; abstr 7580) [viii] Palmieri G, Buonerba C, Ottaviano M, et al. Capecitabine plus gemcitabine in thymic epithelial tumors: Final analysisof a phase II trial. Future oncology 2014; 10: 2141-7 [ix] Palmieri G, Ottaviano M, Nappi L et al. Somatostatin analogs as maintenance therapy in heavily pretreated thymic epithelial tumors. J Clin Oncol 2015; 33 (suppl; abstract 7581) [x] Ottaviano M, Damiano V, Nappi L et al. Effectiveness of somatotstain analogs plus prednisone in aggressive histotype and advanced stage of thymic epithelial tumors. J Clin Oncol 2015; 33 (suppl; abstract 7582) [xi] Wang Y, Thomas A, Lau Ch et al. Mutations of epigenetic regulatory genes are common in thymic carcinomas. Scientific Reports 2014; 4: 7336 [xii] Lopez-Chavez A, Thomas A, Rajan A et al. Molecular profiling and targeted therapy for advanced thoracic malignancies: A biomarker-derived, multiarm, multihistology phase II basket trial. J Clin Oncol 2015; 33: 1000-7 [xiii] Yoh K, Nishiwaki Y, Ishii G et al. Mutational status of EGFR and KIT in thymoma and thymic carcinoma. Lung Cancer 2008; 62: 31-20 [xiv] Schirosi L, Nannini N, nociloi D et al. Activating c-KIT mutations in a subset of thymic carcinoma and response to different c-KIT inhibitors. Ann Oncol 2012; 23: 2409-14 [xv] Gubens MA, Burns M, Perkins SM et al. A phase II study of saracatinib (AZD0530), a SRC inhibitor, administered orally daily to patients with advanced thymic malignancies. Lung Cancer 2015; 89: 57-60 [xvi] Lattanzio R, La Sorda R, Facciolo F et al. Thymic epithelial tumors express vascular endothelial growth factors and their receptors as potential targets of antiangiogenic therapy: A tissue micro array-based multicenter study. Lung Cancer 2014; 85: 191-6 [xvii] Thomas A, Rajan A, Berman A et al. Sunitinib in patients with chemotherapy-refrtactory thymoma and thymic carcinoma: an open-label phase 2 trial Lancet Oncol 2015; 16: 177-86 [xviii] Girard N, Teruya-Feldstein J, Payabyab EC et al. Insulin-like growth factor-1 rceptor expression in thymic malignancies. J Thorac Oncol 2010; 5: 1439-46 [xix] Rajan A, Carter CA, Berman A et al. Cixutumumab for patients with recurrent or refractory advanced thymic epithelial tumours: a multicentre, open-label, phase 2 trial. Lancet Oncol 2014; 15:191–200. [xx] Giaccone G, Rajan A, Berman A et al. Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors. J Clin Oncol 2011; 29: 2052-9 [xxi] Besse B, Garassino MA, Rajan A et al. A phase II study of milciclib (PHA-848125AC) in patients with thymic carcinoma. J Clin Oncol 2014; 32 (suppl; abstract 7526) [xxii] Zucali PA, Martino de Pas T, Palmieri G et al. Phase II study of everolimus in patients with thymoma and thymic carcinoma previously treated with cisplatin-based chemotherapy. J Clin Oncol 2014; 32 (suppl; abstract 7527) [xxiii] Katsuya Y, Fujita Y, Horinouchi H et al. Immunohistochemical status of PD-L1 in thymoma and thymic carcinoma. Lung Cancer 2015; 88: 154-9 [xxiv] Programmed cell death 1 (PD-1) and its ligand (PD-L1) expression in thymic epithelial tumors (TETs): Impact on the treatment efficacy and alteration in expression after chemotherapy (C) J Clin Oncol 2015; 33 (suppl; abstr 7515) [xxv] Padda SK, Riess JW, Schwartz EJ et al. Diffuse high intensity PDL-1 staining in thymic epithelial tumors. J Thorac Oncol 2015; 10: 500-8

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    MINI 24 - Epidemiology, Early Detection, Biology (ID 140)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 15
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      MINI24.01 - Pleural and Peritoneal Malignant Mesothelioma in Women Correlated to Occupational, Domestic and Environmental Asbestos Exposure (ID 1361)

      V. Panou, Ø. Omland, C. Meristoudis, L. Hoffmann, O.D. Røe

      • Abstract
      • Presentation
      • Slides

      Background:
      Malignant Mesothelioma (MM) is an aggressive neoplasm affecting the pleura and more rarely the peritoneum. Occupational exposure to asbestos is the most common cause, but domestic exposure through cohabitation with an asbestos worker and environmental exposure by living in proximity to an asbestos emitting industry are acknowledged risk factors. The Region of North Jutland in Denmark hosted two large shipyards and the only Danish asbestos cement factory in the period 1928-1986, using mainly chrysotile asbestos and resulting in high MM incidence (5/100,000 in 2011). In our patient cohort the proportion of MM cases in peritoneum (MAM) is larger for females than males, also noted by others. We examined whether this could be related to the source of asbestos exposure

      Methods:
      A retrospective investigation of medical records (Departments of Pathology and Medicine, Aalborg University Hospital) was performed, concerning females diagnosed with pleural MM (MPM) and MAM between January 1992 and February 2015. We focused on the correlation between the source of asbestos exposure and the development of either pleural or peritoneal disease. The asbestos exposure source was divided in two categories; primary, representing occupational asbestos exposure and secondary, including domestic and environmental exposure. Patients with unknown asbestos exposure or habitation history were excluded. We hypothesized that the site of MM development, pleura or peritoneum, is independent from primary or secondary asbestos exposure. Fischer´s exact test was applied to test the hypothesis.

      Results:
      Out of 67 women with MM, 27 were excluded due to insufficient information about asbestos exposure or habitation (data not shown). Of the remaining 40 females, 33 were diagnosed with MPM (83%) and 7 with MAM (17%). The median age for MAM and MPM diagnosis was 60 and 72 years respectively. Among the 40 MM patients, 25% (n=10) had a history of occupational asbestos exposure, 57.5% (n=23) had domestic and 17.5% (n=7) had environmental exposure. Importantly, secondary asbestos exposure was documented for 85% of the MPM patients (n=28) while primary in only 15% of them (n=5). On the contrary for the MAM patients, secondary asbestos exposure was reported for 29% (n=2) and 71% of them had primary exposure (n=5). The correlation between the source of asbestos exposure and the MM site was significant (p= 0.006, OR= 0.078).

      Conclusion:
      The majority of female MM patients have a non-occupational asbestos exposure, with a considerable rate of environmental exposure. Furthermore, the source of asbestos exposure seems to play an important role in determining the site of MM development. Primary asbestos exposure, inferring more intense exposure through occupation, may predispose to peritoneal while secondary, lighter asbestos exposure to pleural disease. This may also be indicated by younger age at MAM diagnosis and is in line with previous reports. Anatomical, biological or other genetical differences related to the site of MM cannot be excluded, as some studies indicate that asbestos exposed women develop MAM more often than men. Our study of large Danish population cohorts is in progress and aims to elucidate these questions (updates will be presented at the conference).

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      MINI24.02 - Mesothelioma Risk in Turkey (ID 462)

      M. Metintas

      • Abstract
      • Presentation
      • Slides

      Background:
      Turkish Mesothelioma Working Group; Drs. Abdurrahman Abakay, Sedat Altın, Güntülü Ak, Şule Akçay, Hasan Bayram, Mehmet Bayram, Hasan Fevzi Batırel, Serdar Berk, Mehmet Bilgin, Nilgün Yılmaz Demirci, Figen Deveci, Levent Elbeyli, Ahmet Erbaycu, Dilek Ernam, Sebahat Genç, Murat Gültekin, Ezgi Hacikamiloğlu, Hüseyin İlter, Selahattin Kadir, Hasan Kahraman, Mehmet Karadağ, Özkan Kaan Karadağ, Talat Kılıç, Gamze Kırkıl, Berna Kömürcüoğlu, Muzaffer Metintaş, Selma Metintaş, Arzu Mirici, Tevfik Pınar, Ömer Özbudak, Sibel Özkurt, Önder Öztürk, Mutafa Taşdemir, Dursun Tatar, Engin Tutkun, Umran Toru, Toros Selçuk, Zehra Seyfikli, Nazan Şen, Abdurrahman Şenyiğit, Gaye Ulubay, Ülkü Yılmaz, Adil Zamani In this study, we aimed to detect the current and future mesothelioma risk for Turkey to guide the studies for the elimination of asbestos exposure in the rural areas.

      Methods:
      Thirty-eight faculty members who were members of the Turkish Mesothelioma Working Group and and 4 foreign consultants took part in this study. In hospitals of 30 provinces where mesothelioma cases were most diagnosed, the patients diagnosed with "mesothelioma" under the code of C45 between 2008 and 2012 (for five years) were identified. The cases were checked one by one according to their identity, name, age, birth place, register and address information with their national identification numbers from the Central Register System (MERNIS). The deceased cases were identified; their dates of death and age were determined and these were also verified by the national registers. Following the identification of all deceased cases, the median survival was determined according to their diagnoses dates. After obtaining the final records of the cases with mesothelioma, the cases born in villages/rural areas were determined. Finally, "population exposed to asbestos in rural areas for a risky period of time" was determined. The number of mesothelioma to develop in the risky populations for the next 20 years was estimated based on those findings.

      Results:
      7,789 cases with C45 code between 2008 and 2012 in Turkey was collected and the demographic information was collected from 5,617 mesothelioma cases whose data were reliable. Out of these cases, 3,718 were born/lived in villages. 3,495 of the 5,617 mesothelioma cases had died until July 2014. The median survival was 8 months. 1,879 cases were not born and/or lived in a village with known asbestos exposure. These cases were most possibly related with occupational exposure. Between 2013 and 2033, it was projected that 15,450 mesothelioma will emerge in the population exposed to asbestos in the above mentioned rural areas. Moreover, it was projected that 2,511 new mesothelioma cases will emerge in the population who are still being exposed to environmental asbestos after 2013.

      Conclusion:
      We determined that mesothelioma caused by environmental and occupational asbestos exposure in Turkey is a more serious problem than previously anticipated. This is a unique epidemiological study that has determined the magnitude of an environmental/occupational carcinogen induced cancer problem through data collection from patients. Country wide measures are being implemented by the Public Health Institute of Turkey and Turkish Mesothelioma Working Group.

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      MINI24.03 - Asbestos Knowledge and Awareness Level (ID 2610)

      S. Metintas, G. Ak, F. Bogar, M. Metintas

      • Abstract
      • Presentation
      • Slides

      Background:
      Asbestos is an important carcinogen and people can be exposed to asbestos either occupationally or environmentally. There is naturally occurring asbestos in some regions of Turkey. The soil including asbestos was commonly used for plastering, whitewashing and roofing to build village house in these regions. The aim of this study is to determine knowledge and awareness level of people about asbestos in a region of Turkey where asbestos related diseases is endemic due to environmental exposure to asbestos in the rural area.

      Methods:
      The study is a questionnaire-based cross-sectional study included patients and their relatives admitted to a tertiary hospital in Eskisehir located central part of Turkey, in 2015. The questionnaire was applied by face-to-face interview after verbal consent from each participant. The questionnaire included 19 questions. The data was determined by percent and confidence interval. Chi-square test was used to compare the groups and multiple logistic regression analysis was used to determinate variables affecting knowledge level of asbestos.

      Results:
      A total number of 505 participants were included in this study. The mean age of them was 52.6±15.2 years (15-89) and 51.9% of them were male. About 41.2% of participants were born in the rural area and 14.5% of them still live in the villages. The educational status: 8.3% never, 55.7% elementary school; 19.0% secondary school; 17% university. About 4.4% of the participants were unemployed, 13.5% official, 20.8% worker, 2.8% farmer, 34.5% housewife and 24.2% others including retired, barber etc. About 76.4% of the participants who live in the villages had history of asbestos-contaminated soil in their villages. Only 20.5% of the group knew that white soil included asbestos. About 3.5% of the group mentioned that asbestos was useful, 44.1% harmful, 3.5% ineffective and the rest of them had no idea. Regarding the knowledge about asbestos related diseases among them, 34.9% stated that asbestos can cause lung cancer, 18.3% benign pleural or lung diseases and 23.1% mesothelioma. Most of the participants who never live in the village or moved to the city (62.9%) stated that asbestos was harmful and 30.9% had no idea. About 53.1% of them mentioned that asbestos can cause lung cancer, 26.9% benign pleural or lung diseases and 33.5% mesothelioma. In this group, the rate of true answers regarding usage of asbestos at workplace was 12.9% (8%-20%). Their knowledge about environmental usage of asbestos was low (16.6%) in this group. More than half of the participants (53.5%) pointed out that it is necessary to avoid from asbestos. The factors affecting knowledge level of asbestos were found to be young (p=0.016), live in the city (p=0.016) and high education level (p<0.001) by multiple logistic regression analysis.

      Conclusion:
      Although approximately 30 years passed after the first scientific report about hazards of environmental asbestos exposure on the respiratory system in this region, knowledge and awareness level of asbestos was quite low by sampling of this population. Health and environment authorities should inform the people as quickly and intensely about asbestos.

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      MINI24.04 - Cluster Analysis of Malignant Mesothelioma Incidence in Louisiana (ID 1568)

      E.G. Levitzky, E. Trapido

      • Abstract
      • Presentation
      • Slides

      Background:
      Exposure to asbestos fibers is the predominant causal factor in malignant mesothelioma (MM). The higher than expected incidence of MM in Louisiana, particularly among males, has been attributed to occupational exposure at facilities engaged in the shipping, ship construction and manufacturing industries that utilized substantial quantities of materials containing asbestos fibers. The primary aim of this study was to investigate the locations and demographic characteristics of spatial clusters of malignant mesothelioma (MM) cases reported in Louisiana between 1992 and 2011.

      Methods:
      Incident case data reported to the SEER Louisiana Tumor Registry (LTR) were geocoded by census tract and stratified into four categories based on gender and age at diagnosis - Males under 60 years, Males 60 years and over, Females under 60 years and Females 60 years and over. Investigation of probable spatial clusters for each gender/age group combination was conducted using a Poisson-based model for the LTR incidence data. The ratio of male to female cases in the probable clusters was utilized to assess environmental versus occupational exposure. Locations of possible spatial clusters and locations of facilities processing, manufacturing and utilizing asbestos materials were illustrated graphically using geographic information system software.

      Results:
      The most likely clusters of MM for each age/gender group were located in the Greater New Orleans area and were statistically significant. There was substantial overlap of the boundaries for the four clusters located in Jefferson Parish with 15 census tracts included in all four clusters. The overall ratio of male to female cases in the most likely clusters was 1.35:1. A statistically significant secondary cluster was identified for males under 60 years of age northwest of Baton Rouge, LA. A pair of spatial clusters was identified for Males under 60 years and Females 60 years and older south of Lafayette.

      Conclusion:
      Our results of a most likely cluster of MM for males 60 years and older in Jefferson Parish was expected given the presence of large business enterprises known to have processed, manufactured and used asbestos materials since the 1930s. The presence of probable spatial clusters of MM cases of females in both age groups and males under 60 years of age was unexpected. The spatial clusters reported for Males under 60 years and Females 60 years and older near Lafayette and no cluster for Males 60 years and older in the area also suggested possible environmental exposure in the area. These results, along with the ratio of male to female cases among the four combined spatial clusters in the Greater New Orleans area suggested that exposure to asbestos was likely a combination of occupational and environmental exposure. Spatial analysis of MM incidence is an effective approach for investigating geographic areas with elevated rates of the disease, especially where exposure to asbestos has not been investigated. Further research is needed to evaluate occupational and environmental exposure sources in these populations by gathering detailed asbestos exposure measurements, demographic and health data among cases by gender and age group.

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      MINI24.05 - Discussant for MINI24.01, MINI24.02, MINI24.03, MINI24.04 (ID 3427)

      M.G. Zauderer

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI24.06 - Mesothelioma in Finland: 10 Year Population-Based Cohort Between 2000-2009 (ID 1048)

      I. Ilonen, S. Laaksonen, J.A. Salo

      • Abstract
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) is associated with high morbidity and poor prognosis. We evaluated in population-based analysis the impact of enhanced diagnostics like positrone emission tomography (PET) and thoracoscopy. Also introduction of new medical therapy, Pemetrexed in 2004 could also benefit overall survival.

      Methods:
      Complete national data on 763 patients from the Finnish Cancer Registry sampled from 2000 to 2009 are presented. Survival for 1 year and 2 years and median survival were calculated. Survival data was acquired in February 2013.

      Results:
      During study period the incidence of MPM has been significantly and steadily increasing. The incidence was highest among men in all time periods (fig 1). Median age at the diagnosis was 68 years (range: 25-94 years). Reported histology was epitheloid in 211 (27.7%), sarcomatoid in 79 (10.4%), biphasic 33 (4.3%) and non-specified in 437 patients (57.3%). Median survival was 10 months (range 0 - 150 months), Fig 2. Between two 5-year cohorts (2000-2004 and 2005-2009) no significant difference in overallsurvival was observed (0.537). One year survival was 43.1% and two year 18.7%, with no differences were noted in the 5-year cohorts (0.826 and 0.402 respectively). Primary diagnosis was made in autopsy in 50 (6.6%) patients. A total of 27 patients (3.7% of deceaced) died for other reasons than MPM. 34 patients (4.5%) lived over 5 years and 16 (2.1%) of these are still alive. Figure 1Figure 2





      Conclusion:
      Despite significantly increased availability of new diagnostic tools like thoracoscopy, PET, and pemetrexed therapy during this cohort, no significant difference in overall survival was noted in this population based analysis. In order to facilitate better outcomes nationaly, new means are needed to coordinate both diagnostic and therapy of MPM.

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      MINI24.07 - Infrared Spectroscopy as a Novel Approach in Differential Diagnosis of Malignant Pleural Mesothelioma from Lung Cancer Using Pleural Fluid (ID 2601)

      S. Abbas, N.S. Ozek, D. Koksal, M. Severcan, S.A. Emri, F. Severcan

      • Abstract
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) is an aggressive and rare form of cancer which arises from mesothelial cells lining pleural cavity. Since it is difficult to differentiate the benign pleural thickenings from carcinomas, MPM can only be diagnosed in the advanced stage. To decrease the mortality rate of this disease highly sensitive and specific diagnostic methods are required. In the current study we propose Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectroscopy coupled with chemometrics as a novel approach in diagnosis of MPM from pleural fluids with better sensitivity and specificity values than the other biomarker analysis methods that are currently used.

      Methods:
      The pleural fluid samples from MPM (n=24), lung cancer (LC, n=20) and benign transudate (BT, n=20) patients were collected to perform FTIR spectroscopic experiments. Recording and analysis of the spectral data were performed by using Spectrum One software. Unsupervised chemometric analysis methods including hierarchical cluster (HCA) and principal component analysis (PCA) were applied to discriminate MPM from BT and LC groups. To develop a diagnostic method, SIMCA, a supervised chemometric method was also performed.

      Results:
      Quantitative spectral analysis indicated that lipid, triglyceride, cholesterol ester, protein and nucleic acid contents of MPM group differ from BT and LC groups. The score plots obtained from PCA analysis of pleural fluid at whole (4000-650 cm[-1]), lipid (3000-2800 cm[-1]) and fingerprint (1800-650 cm[-1]) spectral regions showed that BT, LC and MPM groups are successfully discriminated from each other (fig 1.).Figure 1 Figure 1. PCA scatter plots for all BT, LC and MPM pleural fluid samples in the 4000–650 cm-1 spectral region. Moreover, the loading plots obtained from these spectral regions supported the differences in molecular content of all three groups. SIMCA results performed at whole and fingerprint regions also revealed high accuracy values for the diagnosis of MPM and LC.



      Conclusion:
      The results demonstrated that ATR-FTIR spectroscopy together with chemometric tools can be used for successful and rapid differential diagnosis of MPM from LC and BT groups . *This work was supported by the Scientific and Technical Research Council of Turkey (TUBITAK), SBAG-113S294 Research Fund.

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      MINI24.08 - Breath Analysis by Ion Mobility Spectrometry Allows Discrimination of Pleural Mesothelioma Patients From Controls (ID 1508)

      K. Lamote, M. Vynck, J. Van Cleemput, O. Thas, K. Nackaerts, J.P. Van Meerbeeck

      • Abstract
      • Slides

      Background:
      Despite the use of asbestos has been banned in many countries, 125 million people worldwide are still exposed to asbestos and at risk for developing malignant pleural mesothelioma (MPM). Since MPM is a lethal tumor, with diagnosis mainly at advanced stage due to non-specific symptoms and investigations, it is thought that only an early diagnosis will improve patient’s outcome (van Meerbeeck et al., 2011). Breathomics has emerged as a new research field, allowing to detect volatile organic compounds (VOCs) in breath which can be used as non-invasive markers for disease (Lamote et al., 2014). We investigated if asbestos induces VOCs and how breath VOCs could help discriminating MPM patients from occupational asbestos-exposed and non-exposed controls.

      Methods:
      Twenty-three MPM patients, ten healthy asbestos-exposed (AEx) individuals and twelve healthy non-exposed (HC) persons were included. After a fasting period of 2 hours before the breath sampling, participants breathed tidally for 3 minutes through a mouthpiece connected to a bacteria filter. Subsequently, ten ml alveolar air was sampled via a CO~2~-controlled ultrasonic sensor and analyzed using the BioScout Multicapillary Column/Ion Mobility Spectrometer (MCC/IMS, B&S Analytik, Dortmund, Germany). Per subject a background sample was taken. VOCs were visually selected and their intensity (V) was calculated via on-board VisualNow 3.7 software. After calculating the alveolar gradient, we performed a lasso regression in R to search for peaks that have the most discriminative power to distinguish MPM patients from controls. Predictions were made by leave-one-out cross-validation. The use of breath VOCs on the diagnostic performance was investigated by ROC-analysis.

      Results:
      Eighty-nine VOCs were selected in breath and background samples. The VOCs P25, P8 and P7 were able to discriminate HC from AEx controls with 91% accuracy (AUC~ROC~=0.95), yielding a sensitivity, specificity and positive (PPV) and negative predictive value (NPV) of respectively 90%, 92%, 90% and 92%. MPM patients were discriminated from AEx by the VOCs P5, P3, P30, P1 and P54 with 82% accuracy (AUC~ROC~=0.73), yielding a sensitivity, specificity and PPV and NPV of respectively 91%, 60%, 84% and 75%. When discriminating MPM patients from pooled HC and AEx controls, the VOCs P5, P3 and P1 were found to be important, yielding 73% accuracy (AUC~ROC~=0.71) and a sensitivity, specificity and PPV and NPV of respectively 70%, 77%, 76% and 71%.

      Conclusion:
      Breath analysis can discriminate MPM patients from healthy asbestos-exposed persons with 82% accuracy and from combined asbestos-exposed and non-exposed controls with 73% accuracy while healthy asbestos-exposed persons can be discriminated from non-exposed persons with 91% accuracy. The VOCs P25, P8 and P7 seem markers for asbestos-exposure while VOCs P5, P1 and P3 seem linked to MPM pathogenesis after exposure. For screening and to rule out diagnosis, a high sensitivity and NPV are mandatory and to rule in diagnosis, a high specificity and PPV are mandatory, which can enrich a population at risk for follow-up with (annual) CT scans or chest radiography. Hence, our results hold promise to use the breath test for screening of asbestos-exposed healthy seniors.

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      MINI24.09 - Cell-Free MicroRNA miR-625-3p Is Elevated in the Blood of Patients with Thoracic Malignancies (ID 1282)

      M.B. Kirschner, M. Williams, S. Burgers, M.A. Hoda, C.M. Korse, D. Van Den Broek, T. Klikovits, B. Hegedus, B. Dome, M. Grusch, W. Klepetko, N. Van Zandwijk, G. Reid

      • Abstract
      • Slides

      Background:
      In most instances definitive diagnosis of malignant pleural mesothelioma (MPM) requires a tissue biopsy of sufficient size. As a biopsy is not always feasible, the identification of an accurate biomarker easily measured in blood would represent an important step forward. A recent study indicated that microRNA miR-625-3p was present in elevated concentration in plasma or serum of MPM patients compared to healthy controls and asbestosis patients. (Kirschner et al, JTO; 7:1184). In this study, we have further investigated the diagnostic potential of miR-625-3p.

      Methods:
      MiR-625-3p and other microRNAs were measured by RT-qPCR in two independent series of MPM patients and controls. After exclusion of haemolysed samples and those yielding RNA of insufficient quality, series 1 consisted of serum samples from 73 MPM patients, 69 healthy volunteers and 64 patients with non-small cell lung cancer (NSCLC) collected at the Netherlands Cancer Institute (NKI) between 1994 and 2013. The second series consisted of plasma samples from 29 MPM patients and 35 healthy volunteers collected in Vienna and Hungary (V/H) between 2011 and 2013. Additionally levels of soluble mesothelin-related protein (SMRP) were assessed (ELISA) in the NKI series.

      Results:
      Analyses of samples from patients and controls in the NKI series revealed that serum miR-625-3p concentrations were on average 5.35-fold higher (p=0.0054) in MPM, and 3.47-fold (p=0.003) in NSCLC than in control samples. Levels in MPM patients were 1.54-fold higher than in NSCLC patients but this did not reach statistical significance (p=0.273). Compared to healthy controls, the areas under the ROC curve (AUC) were 0.82 (95% CI: 0.75-0.89) for MPM and 0.75 (95% CI: 0.67-0.84) for NSCLC. In the samples of the V/H series, plasma miR-625-3p concentrations were on average 1.98-fold (p<0.001) higher in MPM patients than in healthy volunteers, with an AUC of 0.80 (95% CI: 0.69-0.91). Assessment of SMRP in the NKI series revealed AUCs of 0.69 (95% CI: 0.59-0.78) differentiating MPM from healthy individuals and 0.65 (95% CI: 0.54-0.75) separating MPM from NSCLC, comparable to AUC values reported earlier.

      Conclusion:
      Data from two independent validation series confirms the previously observed increased abundance of miR-625-3p in blood from MPM patients. However, the miR-625-3p levels observed in NSCLC patients show that elevation of the level of this microRNA in plasma/serum is not restricted to MPM. Further studies into combinations of microRNAs and SMRP (diagnostic signature) in MPM are warranted.

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      MINI24.10 - Discussant for MINI24.06, MINI24.07, MINI24.08, MINI24.09 (ID 3428)

      T. Nakano

      • Abstract
      • Presentation

      Abstract not provided

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      MINI24.11 - Expression of PD-1 and Its Ligands in Human Malignant Pleural Mesothelioma (ID 1676)

      E. Marcq, J. De Waele, J. Van Audenaerde, K. Zwaenepoel, P. Baas, E.L.J. Smits, P. Pauwels, J.P. Van Meerbeeck

      • Abstract
      • Presentation
      • Slides

      Background:
      The discovery of immune checkpoint receptors as cytotoxic T lymphocyte antigen-4 (CTLA-4) and more recently programmed death-1 (PD-1) introduced a new era in cancer immunotherapy. Immune checkpoints are responsible for controlling and inactivating the immune system in order to avoid autoimmunity and prevent tissue damage. PD-1 is expressed primarily on activated effector T lymphocytes. Its natural ligands are programmed death ligand-1 (PD-L1) and programmed death ligand-2 (PD-L2). Expression of PD-L1/PD-L2 on tumor cells or in stroma impairs effector T lymphocyte activity within the tumor microenvironment. Trials with antibodies that block the ligand-immune checkpoint interaction have shown promising results in several cancer types.Data on few mesothelioma patients suggest that blocking immune checkpoints could offer new opportunities for treatment of this very aggressive tumor.. We investigated PD-1, PD-L1 and PD-L2 expression in MPM. Furthermore the effect of interferon-gamma (IFNg), an important cytokine for immune-mediated tumor control, on their expression pattern was analyzed.

      Methods:
      Flow cytometry and immunohistochemistry (IHC) were used for the expression of PD-1, PD-L1 and PD-L2 on human primary MPM and T cells and on MPM cell lines that cover the three major histological subtypes of of MPM, i.e. epitheloid (M28, H2795, H2818), sarcomatoid (VAMT-1, H2731, H-Meso-1) and mixed (NKI04, MSTO-211H) mesothelioma cells. The effect of stimulation with IFNg on expression of PD-1 and its ligands was measured.

      Results:
      PD-1 surface expression was found on T cells and not on MPM tumor cells, corresponding to literature showing that PD-1 is only expressed on T cells, B cells and macrophages. Different expression patterns were observed regarding PD-L1 and PD-L2. Flow cytometry showed significant PD-L1 expression on all the epitheloid and sarcomatoid mesothelioma cell lines. Two out of three cell lines tested positive for PD-L2, both for the epitheloid and the sarcomatoid subtype. The mixed cell lines were negative for PD-1 and its ligands. Following IFNg stimulation, PD-L1 and PD-L2 expression was induced or upregulated on all cell lines. Primary MPM cells showed variable expression of PD-L1. IHC data for PD-1 and PD-L1 expression correspond to the flow cytometry results.

      Conclusion:
      Taken together, these data on PD-1, PD-L1 and PD-L2 expression on human MPM cells and T cells support further investigation of the expression profile of the immune checkpoint PD-1 and its ligands in MPM patients samples. We are currently performing this using multicolor flow cytometry and IHC.

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      MINI24.12 - Assessment of PD-L1, TGF-β Expression and Tumor-Infiltrating CD8+ T Cells in Advanced Thymic Epithelial Tumors (ID 2373)

      J. Wang, H. Chen, H. Bai, J. Zhao, S. Wang

      • Abstract
      • Presentation
      • Slides

      Background:
      “Avoiding immune destruction” is one of the emerging hallmarks of cancer, as proposed by Weinburg and Hanahan. High expressions of immunosuppresive proteins strongly links to prognosis and cancer treatment. This study aimed to exam the expressions of immunosuppressors programmed death receptor ligand-1 (PD-L1) and transforming growth factor –β (TGF-β), and CD8+ tumor-infiltrating lymphocytes (TILs) in pre-treatment specimens from patients with advanced thymic epithelial tumors (TETs) including advanced thymic carcinoma and advanced invasive thymoma. To our knowledge, this is the first report to demonstrate the expression of PD-L1, TGF-β and CD8 and their clinical relevance in advanced TETs in Chinese population.

      Methods:
      Retrospective analysis was performed using tumor specimens from 20 patients with stage IV thymic carcinoma and 13 patients with stage III/IV invasive thymoma. Tissue biopsies were obtained before the first-line chemotherapy with (or without radiotherapy). The expression level of PD-L1, TGF-β and the prevalence of CD8+ TILs were assessed using immunohistochemistry (IHC). Their prognostic value for predicting overall survival (OS) and progression-free survival (PFS) were statistically analyzed using the SPSS software.

      Results:
      Higher expression levels of PD-L1 and TGF-β were detected in advanced thymic carcinoma than in advanced invasive thymoma (65.0% vs. 46.2%, 65.0% vs. 15.4%, respectively). Low level of CD8+ TILs was presented in 45.0% cases with advanced thymic carcinoma. In advanced thymic carcinoma, higher TGF-β expression was strongly associated with worse OS, with a p-value almost reaching statistical significance (p = 0.052). Median OS of patients with TGF-β high and low expression was 29.5 ms (95%CI: 18.6-40.4) and 62.9 ms (95%CI: 15.6-110.1), respectively. Higher PD-L1 expressions significantly predicted worse PFS after firs-line chemotherapy with (or without) radiotherapy (p =0.043). Median PFS was not estimable in PD-L1 low expression group. Mean PFS of patients with PD-L1 high and low expression was 13.3ms (95%CI: 8.0-18.6) and 23.5ms (95%CI: 13.9-33.2), respectively. An additional radiation treatment was particularly needed for CD8 low expression patients, in which first-line treatment with “chemotherapy + radiotherapy” significantly prolonged PFS compared to “chemotherapy-alone” (median PFS = 6.8ms, 95%CI: 0.0-2.7 vs. 3.5ms, 95%CI: NE, p = 0.015).

      Conclusion:
      Our results documented the clinical relevance of PD-L1, TGF-β, and CD8 in advanced TETs, with the prognostic value of predicting OS and PFS, as well as a potential association of immune conditions with therapeutic benefits.

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      MINI24.13 - Molecular and Pathological Features of Different Malignant Pleural Mesothelioma (MPM) Histologic Subtypes (ID 2121)

      G. Pasello, L. Urso, M. Mencoboni, F. Grosso, G.L. Ceresoli, F. Lunardi, R. Bertorelle, V. Ciminale, F. Rea, A.G. Favaretto, P. Conte, F. Calabrese

      • Abstract
      • Presentation
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited treatment options. Sarcomatoid/biphasic mesotheliomas are characterized by more aggressive behaviour, characterized by a higher resistance to systemic treatments, more frequent distant spread and a poorer prognosis compared with the epithelioid subtype. To date prognostic and tailored therapeutic biomarkers are lacking

      Methods:
      The present study analyzed the expression levels of MDM2 and HIF1alpha and the presence of inflammation, necrosis and proliferation in different histologic subtypes from chemonaive MPM patients. Diagnostic biopsies of MPM patients from four Italian cancer centers were centrally collected and analyzed. MDM2, and HIF1alpha expression levels were investigated through immunohistochemistry and RT-qPCR. A pathological assessment of necrosis, inflammation and proliferation index (through Ki67 immunostaining) was also performed. Molecular markers, pathological features and clinical characteristics were related to overall (OS) and progression free survival (PFS).

      Results:
      Sixty MPM patients were included in the study (32 epithelioid and 28 non-epithelioid). Higher levels of MDM2 (p<0.001), HIFalpha (p=0.013), necrosis (p=0.013) and proliferation index (p<0.001) were significantly associated with sarcomatoid/biphasic subtypes, while higher levels of inflammation were significantly associated with epithelioid subtype (p=0.044). MDM2 expression levels were correlated with HIF1alpha (p=0.0001), necrosis (p=0.008) and Ki67 (p=0.009). Univariate analysis showed a significant correlation of non-epithelioid histology (p=0.04), high levels of necrosis (p=0.037) and proliferation index (p=0.0002) with shorter PFS. This finding, however, was not confirmed by the multivariate analysis.

      Conclusion:
      Sarcomatoid/biphasic and epithelioid mesotheliomas show different MDM2 and HIF1alpha expression levels and are characterized by different levels of necrosis, proliferation and inflammation. Further studies are warranted in order to confirm a prognostic and predictive role of such markers and features.

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      MINI24.14 - Use of Next Generation Sequencing to Improve Lung Tumor Immunotherapy (ID 1749)

      B.W.S. Robinson, S. Ma, S. Sneddon, M.R. Tourigny, I. Dick, J.S. Leon, A. Khong, S.A. Fisher, R.A. Lake, W.J. Lesterhuis, A.K. Nowak, S. Leary, M.W. Watson, J. Creaney

      • Abstract
      • Presentation
      • Slides

      Background:
      Immunotherapy of pulmonary tumors is now a clinical reality, however most patients do not respond. To convert non-responders into responders one potential approach is to identify the tumor‐specific ‘neo‐antigens’ that arise from DNA mutations in order to follow tumor-specific responses and to design therapeutic vaccines to try to ‘enforce’ a response against these resistant tumors.

      Methods:
      First, in order to identify tumor neo-antigens we performed RNAseq and exome analysis to identify single nucleotide variants (SNV) in murine pulmonary tumors. An average of 485 SNVs was found. We focused on AB1 and AB1-HA (asbestos-induced mesotheliomas, which mimic human mesothelioma) and Line 1 (lung cancer). We used the NetMHCpan 2.8 algorithm to identify candidate mutation‐carrying peptides and screened them in an interferon‐γ ELISPOT assay. Second, to determine if more neo-antigens could be ‘unmasked’ by therapy, we tested three candidate therapies in our murine model then reanalyzed neo-antigen responses a) Treg depletion using Foxp3-DTR mice, b) gemcitabine, an immunogenic cytotoxic chemotherapy commonly used for pulmonary malignancies, and c) antiCTLA4 (a checkpoint blockade therapy).

      Results:
      We identified 20 candidate mutation‐carrying peptides in the ELISPOT assay. A strong spontaneous endogenous pre-treatment immune response was demonstrated to DUqcrc2, a component of the respiratory chain protein ubiquinol cytochrome complex. It was found to stimulate a strong response at a similar magnitude to the model neo-antigen viral haemagglutinin (HA). The DUqcrc2 peptide sequence (amino acid 405-413) is predicted to bind the H-2Kd, and the mutant has a proline to alanine substitution mutation at position 408. Treg depletion unmasked a second neo-antigen, DGANAB. GANAB is an alpha glucosidase which cleaves the 2 innermost alpha-1,3-linked glucose residues from the Glc-2-Man-9-GlcNAc-2 oligosaccharide precursor of immature glycoproteins. There is an arginine to glutamine substitution mutation at position 969 of DGANAB (965-972) sequence. This observation supports the theory that removing Treg cells may broaden the immune response to a greater number of neo-antigens, a response presumably otherwise restrained by Treg suppression. Gemcitabine and antiCTLA4 checkpoint blockade did not unmask any additional neo-antigens.

      Conclusion:
      Thus, removing some immune restraints may expose a greater number of neo-antigens as potential clinical targets. The results from these approaches suggest novel ways to improve the immunotherapy of lung tumor and are the basis for planning current clinical trials.

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      MINI24.15 - Discussant for MINI24.11, MINI24.12, MINI24.13, MINI24.14 (ID 3429)

      E. Felip

      • Abstract
      • Presentation

      Abstract not provided

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    MINI 28 - Psychological Impact of Lung Cancer and its Treatment (ID 150)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Palliative and Supportive Care
    • Presentations: 13
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      MINI28.01 - The Impact of Physical Activity on Fatigue and Quality of Life in Lung Cancer Patients: A Randomized Controlled Trial (RCT) (ID 3173)

      J. Vardy, M.L. Bell, H.P. Van Der Ploeg, J. Turner, M. Kabourakis, L. Spencer, C. Lewis, R. Hui, P. Blinman, S. Clarke, M. Boyer, H. Dhillon

      • Abstract
      • Presentation
      • Slides

      Background:
      Physical activity (PA) has been shown to improve fatigue and quality of life (QOL) in a range of cancer populations. Little research has been done in the advanced lung cancer setting. This RCT evaluated a 2-month PA intervention in patients with unresectable lung cancer.

      Methods:
      Participants were stratified (disease stage, performance status [PS] 0-1 vs 2, centre) and randomized (1:1) to usual care (UC) (general nutrition and PA education materials) or UC plus 2-month program of supervised weekly PA and behaviour change sessions and home-based PA. Assessments were completed at baseline, 2, 4 and 6 months. The primary endpoint was fatigue (FACT-F subscale) at 2-months. Secondary endpoints included: QOL, functional abilities, physical fitness, activity (accelerometers), mood, dyspnea, survival and blood results. Intention-to-treat analysis using linear mixed models was done.

      Results:
      111 patients were randomized: male 55%, median age 62 (35-80); 95% NSCLC, 5% SCLC; 95% Stage IV. At baseline 77% were on active treatment. Baseline characteristics, including PA levels, comorbidities and Glasgow Prognostic Score (GPS) were well balanced between groups. Attrition was 22, 36 and 50% at 2, 4 and 6 months respectively; no difference between groups. Adherence to intervention sessions: behavioral 77%, PA 69%. There were no significant differences in fatigue, QOL, symptoms, mood, distress, sleep, dyspnea, activities of daily living, GPS between the groups at 2, 4 or 6 months. Patients over report PA levels compared to accelerometer data. Using accelerometer data, PA only increased in the PA group from 0 – 2 months, but the difference in PA between groups was not significant. Median survival (months): PA 13.7 vs UC 12.6 (p= 0.76): 38 participants remain alive.

      PA n=55 UC n=56 p-value
      FACT-F Fatigue: 0 2 4 6 38.4 37.5 39.6 36.6 36.3 36.3 35.4 34.5 0.61 0.10 0.44
      EORTC Global QOL 0 2 4 6 63.8 63.2 64.2 60.8 58.9 64.3 60.2 54.2 0.81 0.45 0.26
      Performance Status 0 2 4 6 0.8 0.8 0.8 0.7 0.9 1.0 1.0 1.2 0.30 0.16 0.01


      Conclusion:
      Adherence to the 8-week intervention was good but did not increase PA levels compared to education materials alone. No difference was seen in fatigue, QOL, symptom control or functional status.

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      MINI28.02 - Utilization of Survivorship Care Plans and Analysis of Patient Reported Outcomes in Multinational Lung Cancer Patients (ID 2269)

      A.T. Berman, C. Decesaris, C.B. Simone, C. Vachani, M. Hampsire, J.M. Metz, C. Hill-Kayser

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is the leading cause of cancer death in the United States and is also a significant source of morbidity. Patient-reported outcomes (PROs) are prognostic for survival. Herein we report our analysis of emerging patterns of longitudinal PROs collected in the development of survivorship care plans (SCPs) using an anonymous web-based program.

      Methods:
      OncoLife and the LIVESTRONG Care Plan are web-based programs that generate unique SCPs and are accessed via OncoLink (www.oncolink.org), the world’s first cancer website. We selected all consecutive patients identifying as primary lung cancer survivors creating SCPs. Patient-reported demographics, treatment and toxicity were examined. For toxicity data, questions with > 10 “yes” responses were included, and were categorized into: cardiovascular; genitourinary; neurocognitive; endocrine; speaking, breathing, swallowing (SBS); thoracic; and musculoskeletal/dermatologic symptoms. Research was conducted under an IRB-approved protocol.

      Results:
      Overall, 689 plans were created for users self-identifying as primary lung cancer survivors. Average time from diagnosis to reporting was 1.68 years (0-24). Most were Caucasian (85.9%), well-educated (67.3% > “some college”), and lived in a suburban area (45.6%) and the United States (91%). Table 1 shows treatment modalities . Neurocognitive symptoms (e.g. fatigue and cognitive changes) were most common (48.8%), followed by musculoskeletal/dermatologic (14.1%), and thoracic (13.5%). Figure 1 shows symptoms analyzed by treatment. Only 11.2% were initially offered a SCP, and of those, 54.5% were offered by their healthcare provider, most often at a non-university-based cancer center (66.2%).

      TREATMENT N (689 total) %
      Any Surgery 375 54.4
      Any Chemotherapy 522 75.8
      Any Radiation 377 54.7
      Surgery Alone 98 14.2
      Surgery + Chemotherapy 119 17.3
      Surgery + Radiation 15 2.2
      Surgery + Chemotherapy + Radiation 143 20.8
      Chemotherapy Alone 70 10.2
      Chemotherapy + Radiation 190 27.9
      Radiation Alone 29 4.2
      Not Specified 25 3.6
      Figure 1



      Conclusion:
      For lung cancer patients worldwide, it is feasible to obtain PROs and create SCPs through a web-based program. As lung cancer survivors live longer, further attention should be paid to PROs, and our data indicates that, surprisingly, the most common symptoms to address are neurocognitive. As very few patients were offered SCPs, increased effort should be made to provide SCPs, particularly in urban and university cancer center settings. This study was funded in part by the LIVESTRONG Foundation.

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      MINI28.03 - Causes of Death and Hospitalization in Long-Term Lung Cancer Survivors: A Population-Based Appraisal (ID 740)

      G.X. Wu, P.H.G. Ituarte, B. Ferrell, V. Sun, D.J. Raz, J.Y. Kim

      • Abstract
      • Presentation
      • Slides

      Background:
      Survivorship care has emerged as an important topic in lung cancer due to advances in screening and treatment that have led to prolonged survival. These survivors may have pre-existing comorbidities or health impairments from their treatments that impact quality of life. A better understanding of the healthcare needs of lung cancer survivors will assist in the development of patient-centered, comprehensive survivorship care. We used a population dataset to assess the most common reasons for hospital admission and causes of death among long term (5-year) survivors of lung cancer.

      Methods:
      Using linked data from the California Cancer Registry and Office of Statewide Health Planning and Development database, we identified all in-state lung cancer patients diagnosed from 2000-2009. Patients of all stages were included. We used ICD-9 codes to identify causes of death and primary admission diagnoses in survivors after 5 years of lung cancer diagnosis. Annual proportional distribution of reasons for admission and causes of death for survivors were calculated over time.

      Results:
      Among 157,236 lung cancer patients, 80.6% (n=126,775) died within 5 years of diagnosis. Although lung cancer accounted for the majority of hospital admissions in the initial years post-diagnosis, nonmalignant pulmonary disease, (n=7,102, 23.3%) replaced lung cancer progression (n=2,047, 6.7%) as the most common principal diagnosis in 30,461 admissions among 9,166 survivors who were admitted after 5 years from initial lung cancer diagnosis (Figure 1A). Cardiovascular (n=5,712, 18.8%), gastrointestinal (n=2,901, 9.5%), and infectious diseases (n=2,819, 9.3%) also surpassed lung cancer progression as reasons for admission after 5 years of survival. However, lung cancer progression remained the leading cause of death in long-term lung cancer survivors (Figure 1B). Among 5-year survivors, 46.2% (n= 2,855) eventually died from lung cancer progression. The next most common causes of death were cardiovascular disease (n=947, 15.3%), nonmalignant pulmonary disease (n=776, 12.6%), and secondary malignancy (n=605, 9.8%). Figure 1



      Conclusion:
      Most lung cancer patients died within 5 years of diagnosis. Among remaining survivors, cardiovascular, pulmonary, and gastrointestinal diseases rather than lung cancer were the primary reasons for hospital admission 5 years after diagnosis. However, lung cancer progression remained the dominant cause of patient death even beyond 5 years of survival. Cardiopulmonary disease and other malignancies were secondary competitors for mortality. Active control of chronic cardiopulmonary disease in addition to lung cancer surveillance should be priorities in long-term lung cancer survivors.

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      MINI28.04 - Discussant for MINI28.01, MINI28.02, MINI28.03 (ID 3382)

      B. Slotman

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI28.05 - Depression and Anxiety in Lung Cancer Patients: The Unmet Need for Recognition and Early Detection (ID 2407)

      T. Kovacevic, B. Zaric, J. Stanic, B. Perin, D. Bokan

      • Abstract
      • Presentation
      • Slides

      Background:
      Anxiety and depression are present in significant number of patients with lung cancer. Aims of this trial were to examine the frequency of depression and anxiety in lung cancer (LC) patients and to investigate relations between clinico-pathological characteristics (CPC) and depression and anxiety disorders.

      Methods:
      This prospective observational trial was conducted at Institute for Pulmonary Diseases of Vojvodina, Serbia. Two hundred and eight LC patients at various stages of disease and treatment rated themselves on the Hospital Anxiety and Depression Scale (HADS). Investigated CPC among other were Eastern Cooperative Oncology Group Performance Status (ECOG PS), tumor type and tobacco abuse. In order to correlate the data univariate and multivariate analysis was performed.

      Results:
      Of total 208 enrolled patients 76% (158) were males and 24% (50) females. Majority of patients were with ECOG PS 1 75% (156), smokers (58.7%), in stage III and IV (42.3% each) LC. Most frequent LC type was adenocarcinoma 46.6% (97) while squamous, small-cell and other types were confirmed in 38% (79), 13.5% (28) and 1.9% (4) respectively. Patients with brain metastasis and known depression and/or anxiety disorder before LC diagnosis were excluded from the trial. HADS-defined depression and/or anxiety were identified in 39.5% (82) patients. Frequency of anxiety was 22.6% (47) and of depression 36.1% (75). Both depression and anxiety severity were ranged from mild to severe. Combined depression with anxiety was identified in 19.2% (40) patients. We identified significant relation (p=0.003) between ECOG PS and anxiety. There is positive correlation between depression and ECOG PS (p=0.007). When depression and anxiety are present as combined disorders severity of each anxiety and depression are significantly higher (p<0.0001).

      MALE FEMALE
      N (%) 158(76%) 50(24%)
      ECOG PS 0 32(20.3%) 7(14%)
      1 115(72.8%) 41(82%)
      2 10(6.3%) 1(2%)
      3 1(0.6%) 1(2%)
      SMOKING Never 16(10.1%) 11(22%)
      Ex smoker 46(29.1%) 13(26%)
      Smoker 96(60.8%) 26(52%)
      PCKY Ex smoker 50,7 37,7
      (mean) Smoker 40,9 37,2
      TUMOR TYPE Adenocarcinoma 68(43%) 29(58%)
      Squamouse carcinoma 65(41.1%) 14(28%)
      Small-cell carcinoma 22(13.9%) 6(12%)
      Other 3(1.9%) 1(2%)
      STAGE I 14(8.9%) 2(4%)
      II 14(8.9) 2(4%)
      III 63(39.9%) 25(50%)
      IV 67(42.4%) 21(42%)
      DEPRESSION 59(37.3%) 16(32%)
      ANXIETY 37(23.4%) 10(20%)
      SEVERITY OF DEPRESSION Mild 34(21.5%) 8(16%)
      Moderate 20(12.7%) 8(16%)
      Severe 5(3.2%) -
      SEVERITY OF ANXIETY Mild 22(13.9%) 5(10%)
      Moderate 10(6.3%) 3(6%)
      Severe 5(3.2%) 2(4%)


      Conclusion:
      Anxiety and depression are diagnosed in significant number of lung cancer patients. Presence of these disorders can significantly influence quality of life of lung cancer patients. The results of this trial suggest that screening on depression and anxiety should be performed at any stage of disease course. Early recognition, detection and therapy can help in better control of depression and anxiety with aim to increase patients quality of life.

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      MINI28.06 - Patterns of Palliative and Psychosocial Care in Stage IV NSCLC in South Western Sydney (ID 118)

      K.J. Duggan, J. Wiltshire, R. Strutt, M. Boxer, A. Berthelsen, J. Descallar, S.K. Vinod

      • Abstract
      • Presentation
      • Slides

      Background:
      South West Sydney (SWS) is a region of greater ethnic diversity and poorer socioeconomic status than the Australian average. Over half of all patients with Non-Small Cell Lung Cancer (NSCLC) in SWS present with metastatic disease. The primary goals of management are palliation of symptoms and maintenance of quality of life. Patients need adequate access to specialist palliative care (PC) and psychosocial care (PSC) in order to achieve these goals. The aims of this study were to evaluate referrals to PC and PSC services in SWS residents with Stage IV NSCLC and identify factors associated with utilisation of these services.

      Methods:
      SWS residents diagnosed with Stage IV NSCLC between January 2006 and December 2012 were identified from the SWS Local Health District Clinical Cancer Registry. Supplementary information was sourced from oncology and hospital electronic medical records and palliative care databases. Modified Poisson regression was used to analyse significant factors associated with referrals to PC and PSC. Cox regression was used for multivariate survival analysis.

      Results:
      A total of 923 patients were identified. The median age was 69 years, 63% were male and 54% were born overseas. Active treatment was received by 65% of patients with 34% receiving chemotherapy and 65% receiving radiotherapy. Eighty-three percent of patients were referred to PC, with 67% occurring within 8 weeks of diagnosis. Eighty-two percent of patients were referred to PSC, with referrals to social workers being most frequent (76%) followed by specialist nursing (26%) and psychology/psychiatry (16%). On multivariate analysis, radiotherapy treatment, M1b disease and residential location were associated with PC referrals, and radiotherapy treatment, PC referral and residential location were associated with PSC referrals. Age, language spoken, country of birth, socioeconomic status, year of diagnosis and multidisciplinary team discussion were not significant factors in referral to either service. The median overall survival was 4.3 months and one year survival was 19%. On multivariate analysis, factors associated with improved survival were active treatment, chemotherapy and multidisciplinary team discussion.

      Conclusion:
      Rates of referral to PC and PSC services were high in this cohort suggesting good access to care. Greater referrals were particularly associated with patients undergoing radiotherapy. There were no sociodemographic barriers to referral. Some geographic differences were noted in referrals to both services. Further investigation into referral gaps will guide service delivery to improve quality of life and care for future patients.

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      MINI28.07 - Interdisciplinary Palliative Care for Lung Cancer Patients and Family Caregivers (ID 379)

      M. Koczywas, V. Sun, A. Hurria, M. Cristea, D.J. Raz, J.Y. Kim, K. Reckamp, F. Zachariah, A.C. Williams, T. Borneman, R. Fujinami, C. Del Ferraro, G. Uman, B. Ferrell

      • Abstract
      • Presentation
      • Slides

      Background:
      Palliative care is focused on supporting the best possible quality of life (QOL) for patients and family caregivers (FCGs) coping with serious and complex illnesses such as lung cancer. Although the accepted definition of palliative care encompasses the entire trajectory of the cancer continuum from diagnosis to the end of life, the majority of published palliative care trials focused primarily on patients with metastatic disease. The purpose of this National Cancer Institute-supported Program Project (P01) was to test the effect of a concurrent, interdisciplinary palliative care intervention in patients with Stage I-IV non-small cell lung cancer (NSCLC) and FCGs in an ambulatory care setting, comparing the usual care and intervention groups.

      Methods:
      Patients undergoing treatments for NSCLC and their FCGs were enrolled in a prospective, sequential design whereby the usual care group was accrued first followed by the intervention group. Patients and FCGs in the intervention group completed a comprehensive QOL assessment at baseline, and were presented by nurses at weekly interdisciplinary care meetings. They also received four educational sessions that addressed physical, psychological, social, and spiritual well-being needs. Patients and FCGs in the usual care group received disease-focused therapies and procedures and were referred by their treating oncologist to palliative care services as needed per standard of care. Patients’ QOL, symptoms, and psychological distress were assessed at baseline and 12 weeks using validated measures which included the FACT-L, FACIT-Sp-12, LCS, and the Distress Thermometer. FCG outcomes included QOL, psychological distress, perceived burden, and caregiving preparedness, with validated measures that included the COH-QOL-FCG, Distress Thermometer, Caregiver Burden Scale, and Caregiver Skills Preparedness Tool. Outcomes were tested using factorial ANOVAs controlling for baseline scores, with disease stage as a blocking variable and group (usual care versus intervention) as the factor.

      Results:
      A total of 491 patients (219 = usual care; 272 = intervention) and 354 FCGs (157 = usual care; 197 = intervention) who completed baseline assessments were included in the primary analysis. Patients who received the intervention had significantly better scores for QOL (109.1 vs. 101.4; p<.001), symptoms (25.8 vs. 23.9; p<.001) spiritual well-being (38.1 vs. 36.2; p=.001), lower psychological distress (2.2 vs. 3.3; p<.001), and more advance care planning (44% versus 9%; p<.001) at 12 weeks compared to patients in the usual care group. FCGs in the intervention group had significantly better scores for social well-being (5.84 vs. 6.86; p<.001) and lower psychological distress (4.61 vs. 4.20; p=.010) at 12 weeks compared to FCGs in the usual care group. Survival analysis for stage IV patients using the Kaplan-Meier approach did not achieve statistical significance but showed a 6 month difference in favor of the intervention group. t included the COH-QOL-FCG, Distress Thermometer, Caregiver Burden Scale, and Caregiver Skills Preparedness Tool. Outcomes were tested using factorial ANOVAs controlling for baseline scores, with disease stage as a blocking variable and group (usual care versus intervention) as the factor.

      Conclusion:
      Interdisciplinary palliative care in the ambulatory care setting resulted in significant improvements in QOL, symptoms, and psychological distress for NSCLC patients and FCGs.

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      MINI28.08 - Discussant for MINI28.05, MINI28.06, MINI28.07 (ID 3551)

      J. Youngwerth

      • Abstract
      • Presentation
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      Abstract not provided

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      MINI28.09 - Can WBRT Be Omitted in NSCLC Patients with Inoperable Brain Metastases? Results from the UK MRC QUARTZ Randomised Clinical Trial (ID 2914)

      P. Mulvenna, M. Nankivell, C. Faivre-Finn, R. Barton, P. Wilson, D. Ardron, E. McColl, B. Moore, I. Brisbane, B. Sydes, R. Stephens, M. Parmar, R. Langley

      • Abstract
      • Presentation
      • Slides

      Background:
      Brain metastases affect up to 40% of patients with non-small cell lung cancer (NSCLC), and for patients not suitable for surgical resection or stereotactic radiosurgery, whole brain radiotherapy (WBRT) and dexamethasone is standard treatment. However there are no randomised clinical trials showing whether WBRT improves either quality of life (QoL) or survival.

      Methods:
      A phase III randomised non-inferiority trial with a primary outcome measure of quality adjusted life years (QALYs). Patients with brain metastases from NSCLC who were not suitable for resection or stereotactic radiotherapy, irrespective of any other clinical characteristics, were randomly allocated to either optimal supportive care, including dexamethasone, plus WBRT 20 Gy/5f (OSC+WBRT) or OSC alone. QALYs were generated from overall survival and patients’ weekly completion of the EQ-5D questionnaire. OSC alone was considered non-inferior if not greater than 7 QALY days worse than OSC+WBRT (80% power and a one sided significance level of 5% requiring 534 patients). Secondary outcome measures include sub-group analyses to identify/validate predictive classifications.

      Results:
      From 2007-2014 538 patients were recruited from 69 UK and 3 Australian centres. Summary trial information is presented in table 1, with baseline characteristics well balanced between trial arms. Median survival was 65 days (OSC+WBRT) vs 57 days (OSC), hazard ratio 1.05 (95% CI 0.89 – 1.26). The mean QALY was 43.3 days (OSC+WBRT) vs 41.4 days (OSC), difference -1.9 days (90% CI -9.1 – +6.6). More OSC patients received additional anti-cancer treatment (39% vs 25%, p-value=0.0004), particularly radiotherapy (22% vs 13%, p-value=0.0067), with palliative thoracic irradiation in the two weeks following randomisation accounting for most of the difference. At 4 weeks post-randomisation, 36% of patients in each arm were alive with maintained or improved QoL compared to baseline. This fell to 17% in each arm at 8 weeks. The most commonly reported problems at 4 weeks concerned mobility (73% WBRT vs 79% OSC) and the ability to perform usual activities (68% vs 67%). Table 1. Summary of main trial data

      OSC+WBRT (N=269) OSC (N=269)
      Sex Male 157 (58%) 157 (58%)
      Age Median 66 67
      IQR 60 – 72 62 – 72
      Range 38 – 84 45 – 85
      KPS <70 101 (38%) 102 (38%)
      ≥70 168 (62%) 167 (62%)
      Extra-cranial mets No 122 (45%) 124 (46%)
      Number of brain mets Solitary 80 (30%) 82 (30%)
      Time since brain mets diagnosis <= 4 weeks 165 (61%) 153 (57%)
      > 4 weeks 104 (39%) 116 (43%)
      Median (days) 23 26
      Range (days) 2 – 235 0 – 196
      Survival (weeks) Deaths 260 262
      One-year (95% CI) 2.6% (1.1%, 5.1%) 2.7% (1.2%, 5.3%)


      Conclusion:
      This is the only large randomised trial evaluating the utility of WBRT in this disease. Although the results include the pre-specified non-inferiority margin, the estimate of the difference in QALYs suggests WBRT provides no additional clinically significant benefit for this group of patients. Additionally there were no significant differences in overall survival or quality of life. .

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      MINI28.10 - C-Type Natriuretic Peptide Attenuates Bleomycin-Induced Fibrosis and Inflammation in Murine Lung (ID 471)

      T. Kimura, T. Nojiri, H. Hosoda, Y. Shintani, M. Inoue, M. Miyazato, M. Okumura, K. Kangawa

      • Abstract
      • Presentation
      • Slides

      Background:
      Interstitial lung diseases (ILDs) are sometimes seen in patients with primary lung cancer. Therapeutic interventions for lung cancer patients with ILDs occasionally induce acute exacerbation (AE), which is a potentially fatal complication. However, no prophylactic treatments have been established. Although the etiology of ILD-related AE is unknown, management of the ILD disease process, including fibrotic changes and inflammatory reactions, is thought to lead to the prophylaxis of AE. C-type natriuretic peptide (CNP) is a member of the natriuretic peptide family, which includes atrial and brain natriuretic peptides. CNP has cardioprotective effects, such as anti-fibrotic and anti-inflammatory effects, in animal models of myocarditis and myocardial infarction. The objective of the present study was to investigate the anti-fibrotic and anti-inflammatory effects of CNP on bleomycin (BLM)-induced lung injury.

      Methods:
      C57BL/6 mice were divided into two groups, vehicle- and CNP-treated groups, for evaluation of pulmonary fibrosis and inflammation induced by BLM. CNP (2.5 µg/kg/min) or vehicle were subcutaneously infused using an osmotic mini-pump from 24 h before BLM administration until the mice were euthanized. On 14 days after intratracheal administration of BLM (1 mg/kg), histological changes, collagen content, and mRNA expression of inflammatory cytokines in lungs and bronchoalveolar lavage fluid (BALF) were assessed.

      Results:
      Continuous infusion of CNP attenuated BLM-induced fibrotic changes. Quantitative histological analysis showed that BLM-induced fibrotic lesions were significantly smaller in CNP treated mice compared to vehicle mice. The collagen content, determined with the hydroxyproline assay, increased in BLM-administered lung and CNP treatment reduced BLM-induced collagen production. CNP treatment tended to improve body weight loss after BLM administration. In BALF, BLM administration augmented the number of inflammatory cells in the vehicle group, which was significantly lower in CNP treated mice. The expression of IL-1β, IL-6, and bFGF mRNA were significantly elevated by BLM administration, and CNP treatment significantly attenuated these increases. Figure 1



      Conclusion:
      These results indicate that CNP attenuates fibrotic changes, namely the accumulation of inflammatory cells, and the increased expression of inflammatory cytokines in BLM-induced pulmonary fibrosis. CNP may have therapeutic potential in patients with ILD and lead to prophylaxis for AE.

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      MINI28.11 - Randomised Study of Acupuncture, Morphine and Combination in NSCLC/Mesothelioma (ID 108)

      M.E.R. O'Brien, A.R. Minchom, R. Punwani, J. Bhosle, K. Nimako, R. Gunapala, S. Popat, J. Filshie

      • Abstract
      • Presentation
      • Slides

      Background:
      Dyspnoea is a common symptom of lung cancer. Morphine is widely used to control dyspnoea.

      Methods:
      We randomised 173 patients with advanced non-small cell lung cancer or mesothelioma with a dyspnoea score ≥ 4 on visual analogue scale (VAS) to one of three arms (acupuncture [A], morphine [M] or combination [AM]). A was delivered to upper sternal, paravertebral, hand and trapezius trigger points. Patients on arm A were given rescue morphine if needed. We recorded VAS dyspnoea and relaxation, lung function tests, respiratory rate, and EORTC QLQ-30/ QLQ-LC13 questionnaires at baseline, 30mins, 90mins, 4 hours, day 2, 7 and 14. Primary endpoint was proportion of patients achieving ≥1.5 improvement in VAS dyspnoea at 4 hours.

      Results:
      The median age of the study population was 73. 53% were performance status 2-3. The baseline median VAS dyspnoea score was 6.5. All patients scored >7 on HAD depression score. 44.3% scored >10 on HAD anxiety. Dyspnoea improved by ≥1.5 points on the VAS in 74% of patients in arm A, 60% in arm M and 66% in arm AM (A versus M p-value 0.12, AM versus M p-value 0.50). On VAS scales there was improved anxiety, relaxation and tiredness of A over M. Analysis of EORTC questionnaire data showed a mean change from baseline global health % score for arm A of 7.08 compared to -2.08 for arm M (p-value = 0.009). There was a mean change from baseline in dyspnoea % score for arm A of -7.89 compared to -1.05 for arm M (p=0.029, not significant at 1% level). There was no improvement in lung function or respiratory rate. 21% of patients in arm A, 87% in arm M and 87% in arm AM took one of more doses of morphine (p<0.001). 123 patients had toxicity data. All toxicities were CTCAE grade 1/2 and in line with morphine’s toxicity profile, with 8% of patients in arm A, 35% in arm M and 39% of patients in arm AM reporting toxicities. Two patients stopped morphine because of side effects. There were two cases of skin irritation attributable to acupuncture site dressings. Score Changes from Baseline

      A M AM
      Mean VAS relaxation (SD) -1.06 (±2.60) 0.19 (±2.43) -1.48 (±2.05) p<0.001
      Day 7 median LAR relaxation (range) -1 (-6.7–4.5) 0 (-3.5–4.4) -0.9 (-5.6–4) p=0.006
      Day 7 median LAR anxiety (range) 1.5 (-2.5–8) 0 (-4–6.2) 1.2 (-5.4–6.3) p=0.003
      Mean LAR tiredness (SD) -0.82 (±2.61) 0.02 (±2.20) -0.94 (±2.37) p=0.002
      Mean EORTC global health % (SD) 7.08 (±25.54) -2.08 (±17.70) 2.72 (±16.96) p=0.009
      Mean EORTC dyspnoea % (SD) -7.89 (±17.382) -1.05 (±17.704) -6.37 (±17.797) p=0.029
      Median dose morphine (range) 32mg (1-60) 53mg (13-163) 40.63mg (3-154) p=0.007


      Conclusion:
      This study population was of poor performance status. A is as effective as M in the treatment of dyspnoea and has additive value for anxiety, relaxation and global health. Acupuncture is morphine sparing. Acupuncture should be a treatment available to lung cancer patients with dyspnoea and as a morphine adjunct.

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      MINI28.12 - A Meta-Analysis of Clinical Trials on the Risk of Hyponatraemia in Cancer Patients Treated with Targeted Therapies (ID 2994)

      R. Berardi, S. Rinaldi, M. Santoni, E. Nunzi, A. Smerilli, M. Caramanti, F. Morgese, M. Torniai, A. Onofri, M. Pistelli, A. Taccaliti, S. Cascinu

      • Abstract
      • Presentation
      • Slides

      Background:
      The incidence of hyponatremia in non-small cell lung cancer (NSCLC) varies from 1% to 50%. Early recognition and a prompt treatment of this electrolytic imbalance could prevent clinical complications and improve survival. Hyponatraemia has recently been reported with targeted therapies in cancer patients. Aim of the study was to perform an up-to-date meta-analysis in order to determine the incidence and relative risk (RR) in cancer patients treated with these agents.

      Methods:
      The published scientific literature regarding hyponatremia in peer-review journals was extensively reviewed using the MEDLINE and Pubmed databases till January 2015. Eligible studies were selected according to PRISMA statement. Summary incidence, RR, and 95% Confidence Intervals were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies.

      Results:
      A total of 4803 potentially relevant trials were identified: of them, 13 randomized phase III studies were included in this meta-analysis. A total number of 6670 patients treated with 8 distinct targeted agents were available for this analysis: 648 patients had NSCLC and were treated with afatinib or gefitinib (vs. placebo) and vorinostat + chemotherapy (vs. placebo + chemotherapy). The highest incidences of all-grade hyponatraemia were observed with the combination of brivanib and cetuximab (63.4) and pazopanib (31.7), while the lowest incidence was reported by afatinib (1.7). The highest incidence of high-grade hyponatraemia was reported by cetuximab (34.8), whilst the lowest incidences were reported by gefitinib (1.0). Summary RR of developing all-grade and high-grade hyponatraemia with targeted agents was 1.36 and 1.52, respectively. The highest RRs of all-grade and high-grade hyponatraemia were associated with brivanib (6.5 and 5.2, respectively). Grouping by drug category, the RR of high-grade hyponatraemia with angiogenesis inhibitors was 2.69 compared to anti-Epidermal Growth Factor Receptors Tirosine Kinase Inhibitors or monoclonal Antibodies (1.12).

      Conclusion:
      Treatment with biological therapy in cancer patients is associated with a significant increased risk of hyponatraemia, therefore frequent clinical monitoring should be emphasized when managing these and newer targeted agents.

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      MINI28.13 - Discussant for MINI28.09, MINI28.10, MINI28.11, MINI28.12 (ID 3384)

      E. Santos

      • Abstract
      • Presentation

      Abstract not provided

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    MS 01 - How to Treat Multiple GGO's (ID 19)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 5
    • +

      Introduction (ID 2066)

      M. Tsuboi

      • Abstract
      • Slides

      Abstract not provided

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      MS01.01 - What Is the Appropriate Diagnostic Technique in the Setting of Multiple GGO's? (ID 1848)

      C.A. Powell

      • Abstract
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      Abstract not provided

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      MS01.02 - What Is the Role of Surgical Resection in the Setting of Multiple GGO's? (ID 1849)

      R. Flores

      • Abstract
      • Presentation

      Abstract:
      Main point: Given the nonspecific nature of a GGO or multiple GGOs, a conservative approach to GGOs without a solid component is suggested. Ground glass opacity is a localized nodular lesion which appears as an undetermined finding ‘of hazy lung opacification, without obscuration of the underlying vascular markings’ on a CT scan. Any condition that decreases the air content of the lungs without totally obliterating the alveoli can produce ground glass opacity. GGOs, also known as nonsolid nodules, have been known to decrease or increase in size and/or disappear. There are benign and malignant causes of GGOs. A GGO can be indicative of inflammation, infection and fibrosis that are usually not fatal: pulmonary edema, alveolar proteinosis, many causes of alveolitis or interstitial pneumonitis, including idiopathic pulmonary fibrosis, sarcoidosis, hypersensitivity pneumonitis, early radiation pneumonitis, aspergillus infection, pneumonia, and bronchiectasis. GGOs can also be an early finding of neoplasms such as bronchioalveolar carcinoma (BAC). A recent study has shown that lung cancers appearing as nonsolid nodules were Stage I adenocarcinomas. Analysis of 57,496 participants in the International Early Lung Cancer Action program has shown a 100% survival rate regardless of the time from diagnosis to treatment and tumor size. There are methods to indicate malignancy without surgery: marginal characteristics, the size and development of the solid component or the attenuation on the CT scan, patient’s medical history of cancer, and fine needle aspiration. These are not without some controversy. A solid component is concerning because they are areas of collapsed alveoli or fibroplastic proliferation which signifies more invasive lesions. However, nonsolid nodules can be followed safely by CT screening annually to see if they transition to a part-solid component. Lung cancers diagnosed among nonsolid nodules tend to be slow growing and indolent in nature. The recent I-ELCAP study shows that until the identification of molecular markers, CT imaging can differentiate among different levels of lung cancer sufficiently early so delay in treatment did not change prognosis. A surgeon has to weigh the risks inherent to surgery while leaving the patient with as much lung as possible. Note that a patient’s desire to have the nodule removed may factor in. If feasible, follow the patient and if the GGO’s morphologic characteristics begin to change dramatically, proceed with surgical intervention, preferably VATS. In most cases, with a conservative approach, the patient has enough pulmonary reserve for aggressive action if required. Location of the lesions may make surgical resection challenging. The decision to perform a lobar versus sublobar resection is based on multiple factors and varies from patient to patient. REFERENCES Cho J, Ko SJ, Kim SJ, Lee YJ, Park JS, Cho YJ, Yoon HI, Cho S, Kim K, Jheon S, Lee JH, Lee CT1. Surgical resection of nodular ground-glass opacities without percutaneous needle aspiration or biopsy. BMC Cancer. 2014 Nov 18;14:838. Cho JH, Choi YS, Kim J, Kim HK, Zo JI, Shim YM. Long-term outcomes of wedge resection for pulmonary ground-glass opacity nodules. Ann Thorac Surg. 2015 Jan;99(1):218-22. Engeler CE, Tashjian JH, Trenkner SW, Walsh JW. Ground-glass opacity of the lung parenchyma: a guide to analysis with high-resolution CT. AJR Am J Roentgenol. 1993 Feb;160(2):249-51. Kim HK, Choi YS, Kim J, Shim YM, Lee KS, Kim K. Management of multiple pure ground-glass opacity lesions in patients with bronchioloalveolar carcinoma. J Thorac Oncol. 2010 Feb;5(2):206-10. Miettinen OS, Henschke CI, Smith JP, Yankelevitz DF. Is ground glass descriptive of a type of pulmonary nodule? Radiology. 2014 Jan;270(1):311-2. Mirtcheva RM, Vazquez M, Yankelevitz DF, Henschke CI. Bronchioloalveolar carcinoma and adenocarcinoma with bronchioloalveolar features presenting as ground-glass opacities on CT. Clin Imaging. 2002 Mar-Apr;26(2):95-100. Yankelevitz DF, Yip R, Smith JP, Liang M, Liu Y, Xu DM, Salvatore MM, Wolf AS, Flores RM, Henschke CI; As the Writing Committee for The International Early Lung Cancer Action Program Investigators Group. CT Screening for Lung Cancer: Nonsolid Nodules in Baseline and Annual Repeat Rounds. Radiology. 2015 Jun 23:142554. [Epub ahead of print]

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      MS01.03 - Is There a Role for Targeted Therapy or Conventional Chemotherapy in Patients with Multiple GGO's? (ID 1850)

      B.P. Levy

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Recent advances in diagnostic imaging and the use of low dose screening CT scans for high risk individuals has increased detection of ground-glass opacities (GGOs). These lesions are defined as hazy lung opacities on CT with preservation of bronchial and vascular markings, and are typically classified as pure, without a solid component, or mixed,with a solid component[1, 2]. While GGOs have historically been characterized by slow growth and indolent tumor biology, their pathogenesis is poorly understood, and progression can be variable. It remains unclear whether these lesions represent dissemination of malignant cells from a single primary tumor (intrapulmonary spread) or synchronous development of multifocal independent clones [3]. In addition, depending on their size and solid component, GGOs can exist anywhere along the histological spectrum from adenomatous hyperplasia (AAH) to invasive adenocarcinoma (AC). Histologic heterogeneity can be reflected in uncertain growth rates, making therapeutic decision making challenging. While historically GGOs have been managed surgically or with close surveillance, chemotherapeutic strategies have been employed. In addition, recent identification of relevant, driver mutations within GGOs has allowed for consideration of targeted therapies including tyrosine kinase inhibitors (TKIs). Given that GGOs frequently represent bronchioloaveolar carcinoma (BAC) (recently reclassified as adenocarcinoma in situ, lepidic predominant adenocarcinoma or mucinous adenocarcinoma), an overview of chemotherapeutic and targeted strategies for such lesions would require extrapolation from the BAC literature. Despite longstanding recognition of BAC as a distinct subclass of lung adenocarcinoma, few completed prospective trials are available to inform on therapy decisions. To date, only two, small phase II prospective studies evaluating cytotoxic chemotherapy for treatment naïve patients with multi-focal BAC have been published. Both trials evaluated single agent paclitaxel and resulted in disappointing response rates (RR) of 11% and 15%, respectively [4, 5]. Post hoc analysis from the sentinel ECOG 1594 study demonstrated a response rate of only 6% to platinum chemotherapy in patients with BAC [6]. In contrast, the French IFCT-0401 trial demonstrated a RR of 21% and PFS of 3 months in 43 patients with BAC who received chemotherapy (platinum doublet; N=38) after disease progression on first line gefitnib[7]. Experience with third-generation agents such as pemetrexed or gemcitabine has been described only in case reports or retrospective series; however, these agents have demonstrated acceptable outcomes and may be considered in systemic treatment plans Subgroup analysis of early studies evaluating the role of EGFR TKIs in NSCLC demonstrated disproportionate and often dramatic responses in those tumors formally classified as BAC. This observation led to several trials exploiting gefitinb or erlotinib as initial therapy for patients with BAC. While overall responses rates in these studies were similar to studies evaluating chemotherapy (RR: 15 to 25%) patients with EGFR mutations derived greater benefit. For example, in a study evaluating erlotinib as initial therapy for patients with advanced BAC, the RR for those with EGFR mutations was 87% compared to 7% for those without EGFR mutations [8]. The association of EGFR mutations with GGOs and the non-mucinous subtype of BAC is supported by multiple studies including a recent comprehensive analysis evaluating genetic alterations in 217 resected GGOs from 215 lung cancer patients[9]. In this study, EGFR mutations were detected in 119 (54.8%). Other relevant driver mutations, including ALK mutations (2.8% in the aforementioned study evaluating resected GGOs) and KRAS mutations in mucinous subtype of AIS, have also been identified. This allows for consideration of other targeted therapies including ALK directed therapies (crizotinib, certinib, alectinib) and those targeting KRAS (selumetinib). Despite the well-established paradigm of offering targeted therapy to molecularly characterized subgroups, the clinical scenarios for patients with multiple GGO’s can be unique in several ways. Should these patients, if confirmed to have EGFR mutations, be treated with TKIs if lesions are slow growing or not growing at all? Or, should the indolent biology of such lesions trump the actionable mutation when making a therapeutic decision? In addition, the notion that a mutation discovered on a biopsied or resected GGOs is representative of all GGOs within a patient may be incorrect. A recent analysis evaluating 72 resected GGO lesions from 35 patients, all with more than one GGO, demonstrated a high rate of mutation discrepancy. In this study, 80% of patients (24/30) who harbored at least one genetic alteration had a driver mutation discrepancy within another GGO supporting the hypothesis that multiple GGOs seem to arise from different primary clones [10]. Given that patients with GGOs represent a spectrum of tumor biology and clinical behavior, an individualized approach that affords flexibility should be employed when implementing treatment strategies (Figure 1). Management decisions need to factor in the potential for indolent disease with consideration of a watch and wait approach for stable or slow growing lesions. If the clinician identifies progressive disease, systemic options should be entertained and include both chemotherapy and TKIs for patients who harbor actionable mutations. Further studies are needed to better define the clonal relationship of GGOs in an effort to optimize targeted approaches for such patients.Figure 1 References: 1. Hansell, D.M., et al., Fleischner Society: glossary of terms for thoracic imaging. Radiology, 2008. 246(3): p. 697-722. 2. Godoy, M.C. and D.P. Naidich, Subsolid pulmonary nodules and the spectrum of peripheral adenocarcinomas of the lung: recommended interim guidelines for assessment and management. Radiology, 2009. 253(3): p. 606-22. 3. Chung, J.H., et al., Epidermal growth factor receptor mutation and pathologic-radiologic correlation between multiple lung nodules with ground-glass opacity differentiates multicentric origin from intrapulmonary spread. J Thorac Oncol, 2009. 4(12): p. 1490-5. 4. West, H.L., et al., Advanced bronchioloalveolar carcinoma: a phase II trial of paclitaxel by 96-hour infusion (SWOG 9714): a Southwest Oncology Group study. Ann Oncol, 2005. 16(7): p. 1076-80. 5. Scagliotti, G.V., et al., A phase II study of paclitaxel in advanced bronchioloalveolar carcinoma (EORTC trial 08956). Lung Cancer, 2005. 50(1): p. 91-6. 6. Schiller, J.H., et al., Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med, 2002. 346(2): p. 92-8. 7. Duruisseaux, M., et al., Chemotherapy effectiveness after first-line gefitinib treatment for advanced lepidic predominant adenocarcinoma (formerly advanced bronchioloalveolar carcinoma): exploratory analysis of the IFCT-0401 trial. J Thorac Oncol, 2012. 7(9): p. 1423-31. 8. Miller, V.A., et al., Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol, 2008. 26(9): p. 1472-8. 9. Ko, S.J., et al., Epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangements in lung cancer with nodular ground-glass opacity. BMC Cancer, 2014. 14: p. 312. 10. Wu, C., et al., High Discrepancy of Driver Mutations in Patients with NSCLC and Synchronous Multiple Lung Ground-Glass Nodules. J Thorac Oncol, 2015. 10(5): p. 778-83.



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      MS01.04 - The Pathologic Classification of GGO's - Clinical Pathologic Correlation (ID 1851)

      E. Thunnissen

      • Abstract
      • Slides

      Abstract:
      Definition. Ground glass opacity (GGO) is a finding on thin-section CT that is defined as “hazy increased attenuation of the lung with preservation of bronchial and vascular margins”.[1]This is in contrast to consolidation that is defined as a “homogeneous increase in pulmonary parenchymal attenuation that obscures the margins of vessels and airway walls” (also called ‘solid´ component). Introduction. The resolution of the CT differs few orders of magnitude from the resolution of the microscope. Therefore, GGO is not one disease: pathological examination reveals several different diseases. The radiological GGO change is actually due to a reduction of air, while a certain amount of air remains present. At the microscopic level this may be caused by either i) partial filling of the alveolar airspaces, ii) thickening of the parenchymal interstitium and alveolar walls, iii) relative increase in perfusion, or iv) any combination of these factors.[1,2]Alveolar spaces may become partially filled by several ways, such as transudative fluid, blood, inflammatory cells or debris, or amorphous material as seen in cardiogenic pulmonary edema, diffuse alveolar hemorrhage, pneumonia, and pulmonary alveolar proteinosis. Alveolar walls and septal interstitium may become thickened secondary to edema, neoplastic proliferation, fibrosis, and noncaseating granulomatous deposition as seen in cardiogenic pulmonary edema, nonspecific interstitial pneumonia, and sarcoidosis. Partial alveolar filling and interstitial thickening coexist in many disease entities. Thus GGO is a non-specific finding that may be caused by various disorders, including inflammatory disease, pulmonary fibrosis, alveolar haemorrhage or neoplasms. GGO may be either (multi)focal (=localised GGO) or diffuse (present bilaterally in most of the lobes, nicely reviewed by El-Sherief et al.[1]), usually associated with inflammatory diseases. Localized GGO may be pure associated with a solid component (mixed GGO) or without (pure GGO). Localized GGO may contain benign[3,4](organising pneumonia, non-specific fibrosis, atypical adenomatous hyperplasia: AAH; aspergillosis) premalignant (adenocarcinoma in situ: AIS, formerly also called BAC)[5]and malignant diseases[3]((minimal) invasive adenocarcinoma with prominent lepidic component[4,5]). The clinical significance of localized GGO is its high incidence of malignancy compared with solid nodules. The reported range varies from 10-90%.[6–8] CT-guided thoracic needle biopsy is a useful tool for tissue diagnosis and may support the patient management with GGO lesions.[9]Fluoroscopic or image guidance has been studied as well.[10–12] The core biopsy procedure is preferred over aspiration.[13]As usual with biopsies underestimation/ underdiagnosis due to sampling variation is not excluded.[11,14]As GGO contains many diseases the term “Natural history of GGO” is a misnomer.[15,16] Radiology To distinguish GGOs with growth from those without growth, a 3-year follow-up observation period is a reasonable benchmark based on the data that the volume-doubling time (VDT) of pure GGOs ranges from approximately 600 to 900 days and that of part-solid GGOs ranges from 300 to 450 days.[7,8,17] AAH is often associated with malignancy and is shown on CT as persistent well-defined oval or round nodular GGOs without solid components, and it does not change on the follow-up CT.[18] Clinicoradiological characteristics of a benign course are smaller size (< 10 mm.), round/oval shape, lack of consolidation[18,19]or scattered consolidation.[20] Clinicoradiological characteristics of a progressive course are smoking history[21]and initial lesion diameter (> 1 cm) [5,19,22,23], lobulated or speculated margin,[4]growth[16], increase in attenuation,[24]greater irregularity of pixel texture (entropy).[5]Growth of localised GGO may be slow: for one case progression was reported within 10 years.[25] Biomarkers EGFR mutations may be present in pure and mixed GGO lesions, representing preinvasive and invasive cancer.[26–28]Interestingly, for p53 immunohistochemistry positive staining was seen in a small group (n=6) associated with growth or a solid component.[26]MIB1 (ki67) is higher in mixed GGO than in pure GGO.[29]CEA not relevant for the distinction of the progressive GGO.[30] Remarkably, with laborious cytogenetic analysis spontaneous metaphases appeared after 24-48 h. in 9 cases of pure GGO. Abnormal FISH was associated with poor outcome.[15] In case of multiple GGO synchronous BAC and/or ADC can have different EGFR or K-ras mutational profiles suggesting these lesions arise as independent events rather than intrapulmonary spread or systemic metastasis.[31] Management Surgical handling is hampered since AAH not or much less well easy palpable than AIS.[30] Since GGO may contain only AIS or minimal invasive adenocarcinoma partial resection may be the method of choice.[30]and systematic lymph node dissection may be avoided.[32] For multiple localized GGO wait and see is an option[33] Prognosis of mixed GGO invasive adenocarcinomas better for solid size than size including the GGO.[34,35]A larger solid component is worse than less solid component.[36] References 1. El-Sherief, A. H. et al. Clear Vision Through the Haze: A Practical Approach to Ground-Glass Opacity. Curr. Probl. Diagn. Radiol. 43, 140–158 (2014). 2. Hewitt, M. G., Miller, W. T., Reilly, T. J. & Simpson, S. The relative frequencies of causes of widespread ground-glass opacity: A retrospective cohort. Eur. J. Radiol. 83, 1970–1976 (2014). 3. Lee, H. J. et al. Nodular ground-glass opacities on thin-section CT: size change during follow-up and pathological results. Korean J. Radiol. 8, 22–31 4. Kim, H. Y. et al. Persistent Pulmonary Nodular Ground-Glass Opacity at Thin-Section CT: Histopathologic Comparisons 1. Radiology 245, 267–275 (2007). 5. Son, J. Y. et al. Quantitative CT Analysis of Pulmonary Ground-Glass Opacity Nodules for the Distinction of Invasive Adenocarcinoma from Pre-Invasive or Minimally Invasive Adenocarcinoma. PLoS One 9, e104066 (2014). 6. Ichinose, J. et al. Invasiveness and malignant potential of pulmonary lesions presenting as pure ground-glass opacities. Ann. Thorac. Cardiovasc. Surg. 20, 347–52 (2014). 7. Lee, H. Y. & Lee, K. S. Ground-glass Opacity Nodules. J. Thorac. Imaging 26, 106–118 (2011). 8. Kobayashi, Y. & Mitsudomi, T. Management of ground-glass opacities : should all pulmonary lesions with ground-glass opacity be surgically resected ? 2, 354–363 (2013). 9. Yang, J.-S. et al. Meta-analysis of CT-guided transthoracic needle biopsy for the evaluation of the ground-glass opacity pulmonary lesions. Br. J. Radiol. 87, 20140276 (2014). 10. Hur, J. et al. Diagnostic Accuracy of CT Fluoroscopy–Guided Needle Aspiration Biopsy of Ground-Glass Opacity Pulmonary Lesions. Am. J. Roentgenol. 192, 629–634 (2009). 11. Yamagami, T. et al. Diagnostic performance of percutaneous lung biopsy using automated biopsy needles under CT-fluoroscopic guidance for ground-glass opacity lesions. Br. J. Radiol. 86, 20120447 (2013). 12. Chavez, C. et al. Image-guided bronchoscopy for histopathologic diagnosis of pure ground glass opacity: a case report. J. Thorac. Dis. 6, E81–4 (2014). 13. Choi, S. H. et al. Percutaneous CT-guided aspiration and core biopsy of pulmonary nodules smaller than 1 cm: analysis of outcomes of 305 procedures from a tertiary referral center. AJR. Am. J. Roentgenol. 201, 964–70 (2013). 14. Lu, C.-H. et al. Percutaneous Computed Tomography-Guided Coaxial Core Biopsy for Small Pulmonary Lesions with Ground-Glass Attenuation. J. Thorac. Oncol. 7, 143–150 (2012). 15. Bettio, D., Venci, A., Cariboni, U., Di Rocco, M. & Infante, M. Fluorescent in situ hybridization (FISH) in the differential diagnosis of ground-glass opacities in the lung. Lung Cancer 71, 319–322 (2011). 16. Chang, B. et al. Natural History of Pure Ground-Glass Opacity Lung Nodules Detected by Low-Dose CT Scan. CHEST J. 143, 172 (2013). 17. Oda, S. et al. Volume-Doubling Time of Pulmonary Nodules with Ground Glass Opacity at Multidetector CT. Acad. Radiol. 18, 63–69 (2011). 18. Park, C. M. et al. CT findings of atypical adenomatous hyperplasia in the lung. Korean J. Radiol. 7, 80–6 19. Lee, S. M. et al. Invasive Pulmonary Adenocarcinomas versus Preinvasive Lesions Appearing as Ground-Glass Nodules: Differentiation by Using CT Features. Radiology 268, 265–273 (2013). 20. Matsunaga, T. et al. Lung cancer with scattered consolidation: detection of new independent radiological category of peripheral lung cancer on thin-section computed tomography. Interact. Cardiovasc. Thorac. Surg. 16, 445–449 (2012). 21. Kobayashi, Y. et al. The association between baseline clinical-radiological characteristics and growth of pulmonary nodules with ground-glass opacity. Lung Cancer 83, 61–66 (2014). 22. Kitami, A. et al. One-dimensional mean computed tomography value evaluation of ground-glass opacity on high-resolution images. Gen. Thorac. Cardiovasc. Surg. 60, 425–430 (2012). 23. Fan, L., Liu, S. Y., Li, Q. C., Yu, H. & Xiao, X. S. Multidetector CT features of pulmonary focal ground-glass opacity: Differences between benign and malignant. Br. J. Radiol. 85, 897–904 (2012). 24. Eguchi, T. et al. Tumor Size and Computed Tomography Attenuation of Pulmonary Pure Ground-Glass Nodules Are Useful for Predicting Pathological Invasiveness. PLoS One 9, e97867 (2014). 25. Min, J. H. et al. Stepwise evolution from a focal pure pulmonary ground-glass opacity nodule into an invasive lung adenocarcinoma: An observation for more than 10 years. Lung Cancer 69, 123–126 (2010). 26. Aoki, T. et al. Adenocarcinomas with Predominant Ground-Glass Opacity: Correlation of Morphology and Molecular Biomarkers. Radiology 264, 590–596 (2012). 27. Usuda, K. et al. Relationships between EGFR mutation status of lung cancer and preoperative factors - are they predictive? Asian Pac. J. Cancer Prev. 15, 657–62 (2014). 28. Yoshida, Y. et al. Molecular Markers and Changes of Computed Tomography Appearance in Lung Adenocarcinoma with Ground-glass Opacity. Jpn. J. Clin. Oncol. 37, 907–912 (2007). 29. Ohta, Y. et al. Pathologic and Biological Assessment of Lung Tumors Showing Ground-Glass Opacity. Ann. Thorac. Surg. 81, 1194–1197 (2006). 30. OHTSUKA, T., WATANABE, K., KAJI, M., NARUKE, T. & SUEMASU, K. A clinicopathological study of resected pulmonary nodules with focal pure ground-glass opacity. Eur. J. Cardio-Thoracic Surg. 30, 160–163 (2006). 31. Chung, J.-H. et al. Epidermal Growth Factor Receptor Mutation and Pathologic-Radiologic Correlation Between Multiple Lung Nodules with Ground-Glass Opacity Differentiates Multicentric Origin from Intrapulmonary Spread. J. Thorac. Oncol. 4, 1490–1495 (2009). 32. Ye, B. et al. Factors that predict lymph node status in clinical stage T1aN0M0 lung adenocarcinomas. World J. Surg. Oncol. 12, 42 (2014). 33. Kim, H. K. et al. Management of Multiple Pure Ground-Glass Opacity Lesions in Patients with Bronchioloalveolar Carcinoma. J. Thorac. Oncol. 5, 206–210 (2010). 34. Nakamura, S. et al. Prognostic impact of tumor size eliminating the ground glass opacity component: modified clinical T descriptors of the tumor, node, metastasis classification of lung cancer. J. Thorac. Oncol. 8, 1551–7 (2013). 35. Tsutani, Y. et al. Prognostic significance of using solid versus whole tumor size on high-resolution computed tomography for predicting pathologic malignant grade of tumors in clinical stage IA lung adenocarcinoma: A multicenter study. J. Thorac. Cardiovasc. Surg. 143, 607–612 (2012). 36. Shimada, Y. et al. Survival of a surgical series of lung cancer patients with synchronous multiple ground-glass opacities, and the management of their residual lesions. Lung Cancer 88, 174–180 (2015).

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    MTE 06 - Survivorship After Combined Modality Therapy (Imaging, Salvage Therapy) (Ticketed Session) (ID 58)

    • Event: WCLC 2015
    • Type: Meet the Expert (Ticketed Session)
    • Track: Treatment of Locoregional Disease – NSCLC
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/07/2015, 07:00 AM - 08:00 AM, 102+104+106
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      MTE06.01 - Curative Radiotherapy for Local or Locoregional Disease (ID 1985)

      Y. Nagata

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Radiation and chemotherapy are usually combined in the treatment of locally advanced lung cancer. Therefore, survivorship after chemoradiotherapy is important. The most frequent pattern of failure is distant metastases, followed by lymph nodal failure and local failure. Periodical examination by CT and/or FDG-PET as imaging method is important. However, its optimal frequency and timing are still unknown. Palliative radiotherapy is indicated for several metastases. Stereotactic radiosurgery (SRS) is usually indicated for single or multiple brain metastases less than 4 in number. Whole brain radiotherapy is indicated for multiple brain metastases. Single or fractionated radiotherapy is indicated for bone metastases in combination with Zoledronic acid Hudrates. Strontium-90 can be indicated for multiple bone metastases when tumor has its uptake. Stereotactic body radiotherapy (SBRT) is a technique, introduced in the late 1990s. SBRT is a method of using single 10-20Gy of high dose and hypofractionated radiotherapy. Recently, many papers have been published on its clinical results, especially in early stage lung cancer. SBRT can also be used for lung metastases.

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      MTE06.02 - Survivorship After Combined Modality Therapy (Imaging, Salvage Therapy) (ID 1986)

      J.K. Salama

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      Abstract not provided

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    MTE 17 - Dealing with Metastatic Bone Disease in Lung Cancer - Prevention of SREs and Pain (Ticketed Session) (ID 69)

    • Event: WCLC 2015
    • Type: Meet the Expert (Ticketed Session)
    • Track: Palliative and Supportive Care
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2015, 07:00 AM - 08:00 AM, 102+104+106
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      MTE17.01 - Dealing with Metastatic Bone Disease in Lung Cancer - Prevention of SREs and Pain (ID 2002)

      V. Hirsh

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Approximately 30-40% of patients with advanced lung cancer develop bone metastases, but as the newer therapies are extending survival, the chance of developing bone metastases increases. Bone metastases cause skeletal-related events (SREs) such as pathologic fractures, spinal cord compression, radiation therapy or surgery to bone, or hypercalcemia – all of which can have debilitating consequences (including pain) affecting patients' health-related quality of life (HR-QOL) and performance status (PS)[1]. Bone metastases are the most common cause of cancer-associated pain in patients with advanced malignancies[2]. Poor PS prevents the patients from receiving further lines of treatments available today. SREs are associated with increased economic costs. In one clinical trial, the median time to first SRE was only 5 months[3]. Early detection of bone metastases can prevent SREs and avoid inappropriate implementation of major surgery or chemoradiation therapy. With the new generation bisphosphonate zoledronic acid or denosumab (anti-RANKL activity), one can reduce the number of patients who experience SREs, decrease the annual incidence of SREs, and delay the median time-to-first SRE[3]. These agents are effective even after the onset of SREs. They are well tolerated, with manageable side effects. The biochemical markers of bone metabolism especially N-telopeptide of type I collagen (NTX) and bone specific alkaline phosphatase (BALP) can be both prognostic and predictive markers for the patients with bone metastases from NSCLC[4-6]. Anticancer activity of zoledronic acid and denosumab further supports their use as soon as bone metastases are diagnosed in patients with non-small cell lung cancer (NSCLC). Further trials will inform us about the efficacy of these agents for prevention of bone metastases and even about possible effects on visceral metastases, with a significant impact on overall survival[7, 8]. These trials will be discussed, as well as the explanation for the longer survival on the bone-targeted agents. The new targeted agents which are being investigated will be mentioned too[9, 10]. References 1. Coleman RE (1997). Skeletal complications of malignancy. Cancer 80 (suppl.): 1588- 1594 2. Mercadante S (1997). Malignant bone pain: pathophysiology and treatment. Pain 69: 1-18. 3. Rosen LS, Gordon D, Tchekmedyian S, et al (2003). Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial – the Zoledronic Acid Lung Cancer and other Solid Tumors Study Group. J Clin Oncol 21: 3150-3157. 4. Coleman RE, Major P, Lipton A, et al (2005). Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonatezoledronic acid. J Clin Oncol 23: 4925-4935. 5. Lipton A, Cook R, Saad F, et al (2008). Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid. Cancer 113: 193-201. 6. Hirsh V, Major PP, Lipton A, et al (2008). Zoledronic acid and survival in patients with metastatic bone disease from lung cancer and elevated markers of osteoclast activity. J Thorac Oncol 3: 228-236. 7. Luo FR, Camuso A, McGlinchey K, et al (2005). Evaluation of anti-osteoclastic activity of the novel, oral multi-targeted kinase inhibitor Dasatinib (BMS- 354825). AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, November 14-18, 2005, Philadelphia, PA, p173 [Abstract B178]. 8. Borgstein NG, Yang Y, Condon CH, et al (2008). ACE-011, a soluble activin receptor type IIA IgG-Fc fusion protein decreases follicle stimulating hormone and increases bone- specific alkaline phosphatase, a marker of bone formation in postmenopausal healthy women. Cancer Research 69 (2 Suppl): Abstract 1160. 9. Hellerstedt BA, Edelman G, Vogelzang NJ, et al (2012). Activitiy of cabozantinib (XL 184) in metastatic NSCLC: Results from a phase II randomized discontinuation trial (RDT). J Clin Oncol 30(suppl): Abstract 7514. 10. Parker C, Nilsson S, Heinrich D, et al (2013). Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. New Engl J of Med 369(3): 213-223.

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    MTE 28 - Need for Team Building in Caring for Patients with Thoracic Malignancies (Ticketed Session) (ID 80)

    • Event: WCLC 2015
    • Type: Meet the Expert (Ticketed Session)
    • Track: Nursing and Allied Professionals
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/09/2015, 07:00 AM - 08:00 AM, 102+104+106
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      MTE28.01 - Need for Team Building in Caring for Patients with Thoracic Malignancies (ID 2015)

      M. Culligan

      • Abstract
      • Presentation

      Abstract not provided

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      MTE28.02 - Need for Team Building in Caring for Patients with Thoracic Malignancies (ID 2016)

      R.J. Gralla

      • Abstract
      • Presentation

      Abstract not provided

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    ORAL 07 - Lung Cancer Pathogenesis (ID 91)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 8
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      ORAL07.01 - Evaluation of Epigenetic Mechanisms of Pluripotency in Human Respiratory Epithelia (ID 3041)

      V. Shukla, M. Rao, J. Beers, H. Zhang, D. Wangsa, D. Wangsa, E. Reardon, J.A. Hong, M. Zhang, S. Davis, G. Chen, T. Ried, M.M. Miettinen, D.S. Schrump

      • Abstract
      • Presentation
      • Slides

      Background:
      Smoking is the number one risk factor for lung cancer worldwide. Recent data indicate that stem cells situated throughout the small airway epithelium may initiate cancer formation following direct exposure to inhaled carcinogens. In the present study we sought to generate induced pluripotent stem cells (iPSCs) from normal human small airway epithelial cells (SAECs) in order to investigate epigenetic mechanisms contributing to the cancer stem cell initiation process, and possibly identify novel targets for lung cancer therapy.

      Methods:
      Several different stocks of SAEC were transduced with Stemcca virus containing OKSM (Yamanaka factors); multiple randomly selected clones were expanded for further analysis. Spectral karyotyping was performed to confirm the purity of pluripotent cells. iPSC cells were injected in SCID mice to study teratoma formation. RNA and DNA were extracted from iPSC and parental SAEC for qRT-PCR and RNA-Seq analyses, as well as pyrosequencing of LINE-1, NBL2 and D4Z4 DNA repetitive elements, and promoter regions of several differentially regulated genes.

      Results:
      SAEC were reprogrammed to a pluripotent state. Generated iPSCs demonstrated hallmarks of pluripotency including morphology, proliferation, expression of surface antigens, stemness gene expression, and in vivo teratoma formation. Interestingly, no chromosomal aberrations were observed in iPSCs. Pyrosequencing did not demonstrate any significant changes in LINE-1, NBL2 and D4Z4 DNA methylation levels in iPSC compared to parental SAEC, suggesting relatively limited global hypomethylation following reprogramming. Consistent with these observations, cancer-testis genes such as NY-ESO-1, MAGE-A1 and MAGE-A3, which are frequently upregulated by DNA demethylation in lung cancer cells, remained transcriptionally repressed in the iPSC. On the other hand, NANOG and POU5F1 genes were hypomethylated in iPSCs relative to SAEC, correlating with their over-expression in iPSCs. RNA-Seq analysis revealed up-regulation of genes encoding components of Polycomb-Repressive Complex 2 (PRC2), and down-regulation of several tumor suppressor genes such as DKK1, p16 and p21 in iPSC relative to parental SAEC. Several novel pluripotency associated genes were also noted to be up-regulated in pulmonary iPSC, which are the focus of ongoing mechanistic studies.

      Conclusion:
      This is the first report demonstrating successful reprogramming of human respiratory epithelia to pluripotency. This model may prove useful for elucidating fundamental epigenomic mechanisms of pulmonary carcinogenesis and identification of novel targets for lung cancer therapy.

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      ORAL07.02 - Metabolic Reprogramming in the Airway Epithelium of Individuals at High Risk for Lung Cancer (ID 2493)

      S.M.J. Rahman, X. Ji, L.Z. Zimmerman, M. Li, B.K. Harris, M.D. Hoeksema, Y. Zou, J. Qian, R. Slebos, Y. Shyr, A. Spira, J.D. Young, D.C. Liebler, P.P. Massion

      • Abstract
      • Presentation
      • Slides

      Background:
      What defines the high risk airway epithelium for lung cancer remains a major challenge. Airway epithelium is prone to assault by the risk factors and considered to be the primary cell type involved in the field cancerization. Transcriptomic aberrations in the airway epithelium of individuals at risk for lung cancer have been reported earlier. However, very limited information exists about proteomic alterations in the airway epithelium. We investigated the molecular underpinnings of risk from proteomic alterations in the cytologically normal airway epithelium from individuals at risk for developing lung cancer.

      Methods:
      Bronchial brushings specimens were collected from individuals categorized as low, medium and high risk groups based on Bach risk model. Shotgun proteomic profiling data were acquired by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Proteins were identified using a combination of database search tools and candidate proteins were selected based on Jonckheere-Terpstra trend analysis. Pathway analysis was performed using WebGestalt. In vitro model of human bronchial epithelial cell line treated with cigarette smoke condensate (CSC) was used for metabolic flux experiments by gas chromatography mass spectrometry (GC MS) analyses.

      Results:
      We identified 2901 proteins in bronchial epithelial cells from risk stratified individuals. Jonckheere-Terpstra trend test resulted significantly altered expression of 315 proteins (trend p <0.05) with 238 up and 77 down trends. KEGG pathway analysis with the 315 proteins revealed very early events of possible metabolic reprogramming in the cytologically normal bronchial epithelium of individuals at high risk for lung cancer development. Fourteen enzymes of the glycolytic pathway, TCA cycle, pentose phosphate pathway, and glycogenolysis were over expressed. Six of these fourteen enzymes, PYGB, PFKP, PFKL, PKM2, IDH1, and IDH2 were rate limiting enzymes. In in vitro culture of human bronchial epithelial cells treated with CSC, lactate production and glucose consumption were increased suggesting Warburg effect and metabolic reprogramming. Evidence of glutamine metabolism through reductive carboxylation in CSC treated cells was obtained from the metabolic flux analyses of cells from this in vitro model. Contribution of labeled carbon from [U-[13]C5]-glutamine to TCA cycle in CSC treated cells were more than untreated control cells and there was strong M+5 citrate labeling in CSC-treated cells.

      Conclusion:
      Shotgun proteomic analysis of cytologically normal bronchial epithelial cells in individuals at increasing risk for lung cancer revealed over expression of carbohydrate metabolic enzymes in high risk individuals suggesting possible metabolic reprogramming. The altered profile of metabolic enzymes may provide a signature of lung cancer risk assessment and serve as the basis of patient selection for surveillance programs and chemoprevention.

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      ORAL07.03 - MMP12 and LMO7 Are Key Genes Involved in the Early Pathogenesis of Squamous Cell Carcinoma of the Lung (ID 1173)

      V.H. Teixeira, S. Lourenco, B. Carrol, M. Falzon, A. Capitanio, J. Brown, J.P. George, S.M. Janes

      • Abstract
      • Slides

      Background:
      Lung cancer is the most lethal cancer type worldwide. In order to increase patient survival it is important to improve our understanding of the early changes associated with lung cancer progression. The progression of lung squamous cell carcinoma (SqCC) from pre-invasive lesions involves a series of histological changes which includes squamous metaplasia, mild, moderate and severe dysplasia, and carcinoma in situ (CIS). In these pre-invasive lesions the basement membrane is intact and there is no possibility of metastatic spread, which is in contrast to SqCC where there is the potential for metastasis as soon as invasion occurs. Our laboratory has a unique cohort of patients with pre-invasive lung SqCC lesions. Within this cohort there is a discrepancy between the prevalence of pre-invasive lesions and the incidence of invasive lung cancer, which suggests that not all pre-invasive lesions progress to invasive carcinomas. This tissue collection forms an internationally unique resource of lesions and will shed light on the molecular characteristics of lesions that progress compared to those that either regress or remain stable. The aim of this study was to identify and characterize key genes involved in the early pathogenesis of lung SqCC.

      Methods:
      Following histological review by two histopathologists to confirm that pre-malignant tissue is present in the biopsy specimens, the epithelial component of interest was laser-capture micro-dissected. This is vital in order to eliminate any cross-contamination from unwanted cells and to ensure that pre-invasive CIS specific gene expression profiles are generated. We have performed genome-wide gene expression Illumina’s Whole-Genome DASL® arrays in 20 progressive and 19 regressive pre-invasive lung SqCC lesions. The protein expression of Matrix metallopeptidase 12 (MMP12) and LIM domain 7 (LMO7) was also determined in the 39 pre-invasive lung cancer lesions by immunostaining analysis. The functional role of MMP12 and LMO7 in cell migration and invasion was demonstrated by MMP12 and LMO7-shRNA knockdown in different squamous cell carcinoma cell lines and human bronchial epithelial cells (HBECs), respectively.

      Results:
      We found 939 genes significantly differently expressed between the progressive and the regressive pre-invasive lung SqCC lesions. We identified a remarkably elevated expression of a spectrum of genes in the progressive lung SqCC lesions involved in different related cancer pathways including chromosome instability, p53 signalling and Wnt/β-catenin signalling. MMP12 and LMO7 were found within the highest significantly differently expressed genes and were therefore chosen to pursue studies focused on understanding the potential mechanisms leading to the development of lung SqCC. In agreement with the gene expression data the expression of MMP12 and LMO7 proteins were up-regulated and down-regulated, respectively, in progressive when compared with regressive lesions. Inhibiting MMP12 by MMP12 knockdown significantly reduced the migration and invasion of different squamous cell carcinoma cell lines (A431, H357 and H376). We also established HBECs knockdown targeting LMO7. We observed a significant increase in the migration and invasion of HBECs cells in the LMO7 shRNA knockdown compared to control.

      Conclusion:
      Our results suggest that MMP12 and LMO7 may be potential therapeutic markers for lung cancer at early stage.

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      ORAL07.04 - Discussant for ORAL07.01, ORAL07.02, ORAL07.03 (ID 3304)

      M.B. Beasley

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ORAL07.05 - Differential Tumorigenic Properties of Mesenchymal Cells From Neoplastic and Non-Neoplastic Human Lung in NSCLC (ID 1006)

      D. Madeddu, A. Falco, L. Ampollini, C. Lagrasta, C. Frati, A. Gervasi, B. Lorusso, F. Saccani, G. Graiani, R. Alfieri, P. Petronini, P. Carbognani, L. Gnetti, P. Rossetti, G. Bocchialini, F. Ricci, E. Quaini, K. Urbanek, F. Quaini

      • Abstract
      • Presentation
      • Slides

      Background:
      Cancer Initiating Cells (CICs) and their niches may open new avenues in the pathogenesis and management of lung cancer. A relevant component of the niche is represented by supportive stromal cells that control the fate of CICs by a reciprocal cross-talk. The understanding of these cellular events could represent a significant advancement in cancer biology and treatment. Recent observations by our and other laboratories have suggested that mesenchymal stromal cells (MSC) regulate lung cancer growth and resistance, thus generating large expectations in novel anti-cancer strategies. The aim of our study was to determine whether MSC isolated from NSCLC and from non-neoplastic human lung samples possess different biologic properties and tumorigenic potential.

      Methods:
      Fresh samples of neoplastic and spared lungs from 58 male patients (80% smokers) affected by primary pulmonary adenocarcinoma undergoing surgical resection were processed. Stromal cells were separated from epithelial cells by negative selection using EpCAM (CD326)-based immunomagnetic sorting. After further enrichment, we could expand for at least 14 passages a population of CD90, CD105, CD73 and CD44 positive MSC from lung cancer (Lc-MSC) and non-neoplastic (Nn-MSC) lung tissue. The oncogenic potential of these cells from the same patient was tested on a Calu-3-based in vitro model of NSCLC by co-culture and conditioned media (CM) and in vivo by xenotransplantation in Balb/c Nude mice. In vivo cell tracking was achieved by pre-labeling MSC with Quantum dots 585 (Qdots). Morphometric assessment of tissue composition and immunofluorescence combined with FISH analysis of human X and Y chromosomes was performed on xenografted tumors.

      Results:
      Nearly 30x10[6] cells could be typically obtained after 3 passages in each case, however, compared to Nn-MSC, cultures of Lc-MSC displayed lower growth kinetic and mitotic index while higher survival and HIF-1-alpha (Hypoxia-inducible-factor-1) upregulation in response to hypoxia was observed. A larger fraction of Lc-MSC expressed transcription factors involved in stemness (Oct3/4, SOX2) and in bronchioalveolar (TTF1, ETS-1, CCL10) commitment. Co-cultures demonstrated that Lc-MSC significantly increased Calu-3 growth as compared to Nn-MSC in transwell assay and by contact. CM from Lc-MSC similarly promoted Calu-3 expansion as compared to Nn-MSC. When 2.5x10[6] Lc-MSC or Nn-MSC from the same patient were subcutaneously co-injected with Calu-3, a 38% and 17% increase in tumor volume was respectively observed, compared to the injection of an equal number of Calu-3 alone (CTRL). Lc-MSC or Nn-MSC injected alone did not generate tumors. Quantitative estimation of the in vivo expansion of neoplastic cells indicated that the addition of Lc-MSC increased by 6-fold and 29-fold Calu-3 replication compared to Nn-MSC and CTRL, respectively. Cell tracking documented that Qdots labelled MSC were located at the boundary of neoplastic epithelial glands generated by X-chromosome polysomic Calu-3 cells. A comparative molecular analysis of Lc-MSC and Nn-MSC is ongoing for the identification of distinctive signalling pathways implicated in the microenvironemental control of CIC on NSCLC development.

      Conclusion:
      Profound differences exist in the biology and oncogenic potential of intratumoral and normal lung MSC strongly supporting the notion that the tumor microenvironment may represent a potential target of new customized therapeutic strategies.

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      ORAL07.06 - Sox2 Cooperates with Lkb1 Loss to Promote Mouse Model of Squamous Cell Lung Cancer (ID 2910)

      A. Mukhopadhyay, G. Mollaoglu, B. Witt, T.G. Oliver

      • Abstract
      • Presentation
      • Slides

      Background:
      Squamous cell carcinoma (SCC) of the lung is the second most common subtype of lung cancer with limited treatment options and a poor survival rate. Until recently, mouse models of SCC have been limited.

      Methods:
      Using lentiviral delivery of Sox2 and Cre recombinase to the mouse lung, we tested the ability of Sox2 to promote tumorigenesis in multiple tumor suppressor backgrounds. Mouse lungs were imaged for tumor formation using micro-CT imaging. Resulting mouse tumors were evaluated for histological markers including Nkx2.1, Sox2, p63, cytokeratin-5, cytokeratin-14 and compared to human squamous tumors. Phospho-signaling proteins including pAkt, pErk, pStat3, pAMPK, p4EBP1 were also evaluated in mouse and human tumors by immunohistochemistry.

      Results:
      Expression of Sox2 specifically cooperates with loss of Lkb1 to promote squamous lung tumors. Importantly, Sox2 expression and mTOR pathway activation frequently co-occur in human squamous tumors. Mouse squamous tumors exhibit characteristic histopathology and biomarker expression similar to human SCC. They also mimic human SCCs by activation of therapeutically relevant pathways including STAT and mTOR. Sox2 expression is sufficient to induce phosphorylated Stat3 in vitro (Mukhopadhyay et al, Cell Reports, 2014). Sox2-driven tumors also exhibit immune cell infiltration consistent with other squamous lung cancer models.

      Conclusion:
      This mouse model of Sox2-driven squamous lung cancer may be a useful model to study immunotherapies and their mechanism of action. This model may also be used to test the contribution of additional driver alterations in SCC, as well as for preclinical drug discovery. Our data suggest mTOR, Jak-Stat and immunotherapies may be relevant targets for squamous lung cancer.

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      ORAL07.07 - Evidence and Mechanism for the Transdifferentiation of Lung Adenocarcinoma to Squamous Cell Carcinoma (ID 2550)

      H. Ji, F. Li, X. Han

      • Abstract
      • Slides

      Background:
      Non-small-cell lung cancer (NSCLC) is featured with genetic and histopathological heterogeneity. LKB1-mutant NSCLC represents a unique and prevalent molecular subtype with limited treatment options. Originally characterized as a tumor suppressor, LKB1 phosphorylates and activates several downstream targets to inhibit cell growth; on the other hand, LKB1 also regulates cellular energy sensing and metabolic homeostasis. This raises an interesting question about how LKB1 inactivation coordinates in vivo lung tumor progression with metabolic adaptation. We have shown recently that the Kras/Lkb1 lung tumor heterogeneity results from p63-mediated ADC to SCC transdifferentiation (AST) through mixed Ad-SCC at late stage, suggesting an unexpected plasticity upon LKB1 inactivation in NSCLC. However, it remains unclear how LKB1 inactivation coordinates tumor progression with metabolic adaptation in orchestrating this tumor plasticity.

      Methods:
      We integratively analyze the transdifferention process of mouse lung adenocarcinoma to squamous cell carcinoma in Kras/Lkb1 Adeno-Cre nasal inhalation model as well as the lineage-defined Kras/Lkb1 model. Moreover, we have also systematically analyzed the clinical lung adenosquamous cell carcinoma to prove the findings from our animal models.

      Results:
      Here in Kras[G12D];Lkb1[lox/lox ](KL) mouse model, we reveal differential reactive oxygen species (ROS) levels in lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). ROS can functionally modulate the ADC-to-SCC transdifferentiation (AST). Furthermore, pentose phosphate pathway deregulation and impaired fatty acid oxidation collectively contribute to the redox imbalance and functionally affect AST. Similar tumor and redox heterogeneity also exist in human NSCLC with LKB1 inactivation. In preclinical trials towards metabolic stress, certain KL ADC can develop drug resistance through squamous transdifferentiation. This study uncovers critical redox control of tumor plasticity that may affect therapeutic response in NSCLC.

      Conclusion:
      LKB1-mutant tumor represents a unique and prevalent molecular subtype of NSCLC with limited treatment options. Through integrative human lung cancer sample analysis and modeling tumor development in mouse model, we have uncovered the accumulation of ROS during ADC progression, which modulates the phenotypic transition as squamous transdifferentiation and metabolic adaptation. This metabolic adaptation reflects the dynamic function of LKB1: a tumor suppressor at early lung ADC progression and an essential metabolic regulator at late phenotypic transition. The redox-controlled tumor plasticity for squamous transdifferentiation enables ADC to progress under stress, and more importantly to escape certain treatment towards cancer metabolism. The plasticity represents as a potentially important mechanism for lung cancer metabolic adaptation and drug resistance, and holds important therapeutic implications.

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      ORAL07.08 - Discussant for ORAL07.05, ORAL07.06, ORAL07.07 (ID 3470)

      Y. Yatabe

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    ORAL 15 - Outcome Management in Lung Cancer Patients (ID 113)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Nursing and Allied Professionals
    • Presentations: 8
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      ORAL15.01 - Changes in Symptom Occurrence Rates from Before Through 12 Months Following Lung Cancer Surgery (ID 2877)

      T. Oksholm, C. Miaskowski, T. Rustoen

      • Abstract
      • Presentation
      • Slides

      Background:
      Knowledge about how symptoms change following lung cancer surgery is important. Patients want information about the usual course of recovery including information about when they need to contact their clinician if symptoms persist. To our knowledge, only three studies have evaluated the occurrence of symptoms in patients prior to and following lung cancer surgery. The purpose of this study was to evaluate changes in symptom occurrence from the preoperative period to 1 year after surgery using a multidimensional symptom assessment scale (i.e., Memorial Symptom Assessment Scale (MSAS).

      Methods:
      Patients were recruited from three university hospitals in Norway. They completed a number of self-report questionnaires prior to and again at 1, 5, 9, and 12 months following surgery. The questionnaires provided information on demographic and clinical characteristics as well as on symptoms. Patients’ medical records were reviewed for disease and treatment information. Descriptive statistics were used to present demographic and clinical characteristics. Analysis of variance (ANOVA) was used to compare the total number of symptoms across the 5 assessments.

      Results:
      At 12 months after surgery, the sample consisted of 113 (58%) men and 81 (43%) women who had a mean age of 66 years (SD 8.1, range 30 to 86). Findings from the ANOVA demonstrated significant changes in total number of symptoms over time. Compared to the preoperative assessment ( =8.7 + 6.8), patients reported a higher number of symptoms at 1 month ( =12.4 + 6.3), 5 months ( =10.2 + 6.6), 9 months ( =9.3 + 7.0), and 12 months ( =10.6 + 7.2). Post hoc contrasts found no differences in the number of symptoms at the 5, 9, and 12 month assessments. The occurrence of the five of the most frequent symptoms (i.e., pain, lack of energy, shortness of breath (SOB), feeling drowsy, worrying) increased significantly from before to one month after surgery and then decreased at 5 months. At 5 and 12 months, 78% of the patients reported SOB. Lack of energy was reported by 70.8% and 66.5% of the patients at 5 and 12 months, respectively. Forty-seven percent of the patients reported worrying and 65% of the patients reported drowsiness at the 5 and 12 month assessments. Finally, the occurrence of pain decreased from 56% at 5 months to 49% at 12 months. Cough and difficulty sleeping persisted over the first five months of the study. From 5 months to 12 months, 51% continued to report difficulty sleeping. The occurrence of cough was reduced from 60% at 5 months to 54% at 12 months.

      Conclusion:
      Findings from this study suggest that patients experience a high number of symptoms for up to 12 months after lung cancer surgery. The reduction in symptom burden is relatively modest from 5 to 12 months. These findings can be used to educate patients about the course of postoperative recovery after lung surgery. In addition, clinicians need to assess for these symptoms and develop effective interventions to improve symptom management for this vulnerable group of patients.

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      ORAL15.02 - Identification and Management of Unique Immune Mediated Toxicities (ID 221)

      M. Davies, E. Duffield, E. Rowen

      • Abstract
      • Presentation
      • Slides

      Background:
      Various approaches to immunotherapy have shown promise in the treatment of lung cancer. Checkpoint inhibitors have been used to enhance T-cell immune response against lung cancers. The inhibitors include drugs that target cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1). Immune checkpoint inhibitors promote t-cell proliferation allowing the immune system to recognize tumor antigens. If the t-cells become over active, they can attack healthy tissue, a process referred to as auto immunity. These adverse events (irAEs) differ from typical cytotoxic therapy side effects. Early identification and management of irAEs can help minimize advanced toxicities. An assessment algorithm was developed to help guide nurses and other health care providers in the assessment and management of irAEs.

      Methods:
      Immune checkpoint inhibitors are associated with immune related adverse events, referred to as irAEs. Immune checkpoint inhibitors promote t-cell proliferation allowing the immune system to recognize tumor antigens. However, if the t-cells become overactive, they can start to attack healthy tissue, a process referred to as auto-immunity. This process can occur in any organ of the body. Typically it occurs in systems that contain significant T cells. IrAEs are usually low grade. However, grade 3-4 toxicity has been noted in up to 15% of patients across studies. There have been treatment related deaths as a result of unidentified or managed side effects. There are variable patterns of presentation of irAEs. They may occur immediately after infusion or several months after treatment completion or discontinuation. The risk of irAEs may be increased with combination checkpoint therapy and combination with radiation therapy. The mechanism of the adverse event is immune mediated. Therefore, treatment may differ from the traditional management of the symptom. IrAEs are typically managed by drug discontinuation or administration of local or systemic corticosteroids. Hormone replacement may also be necessary for more advanced toxicities. Utilization of monitoring and treatment algorithms is essential for optimal control of irAEs.

      Results:
      An assessment algorithm was developed to help guide health care providers in the assessment, monitoring and management of immune related adverse events associated with immune checkpoint inhibitors.

      Conclusion:
      Patients and other healthcare providers must be educated about potential irAEs prior to treatment with checkpoint inhibitors. Members of the multidisciplinary team must be diligent in screening for the onset of irAEs during and after the completion of treatment. Early identification and treatment of irAEs can help minimize the risk for advanced toxicities and long term complications. In some cases, prompt management may allow for re-initiation of treatment.

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      ORAL15.03 - Application of Ultrasound-Guided Femoral Venous Catheters Inserted at Various Sites in Patients with Superior Vena Cava Obstruction (ID 531)

      Z.J. Hui, T.S. Yuan

      • Abstract
      • Presentation
      • Slides

      Background:
      The aim was to investigate the clinical effect and complication incidence of placing femoral venous catheters (FVCs) at different sites in patients with superior vena cava obstruction (SVCO). This study provides a basis for optimized vascular access in SVCO patients.

      Methods:
      Patients who underwent advanced lung cancer plus SVCO and received initial chemotherapy were treated in our hospital from July 2013 to January 2015. These patients were randomly divided into the observation and control groups. The observation group received “mid-thigh femoral venous catheters,” whereas the control group was treated with “groin femoral venous catheters.” The effect of catheter placement as well as the incidence of complications were compared between these two groups.

      Results:
      The bleeding scores (2.44±0.62 vs. 1.36±0.49), the retention time (195.08±39.19 days vs. 91.53±32.88 days), the patient comfort scores (4.20±0.87 vs. 1.35±0.91), and the pain scores (1.64±0.91 vs. 2.42±1.08) were all recorded and compared between the observation and control groups. The differences are statistically significant (P<0.001). Moreover, there are statistically significant differences in catheter-associated thrombosis (1.69% vs. 14.55%), catheter entry site infection (1.69% vs. 21.82%), and the incidence of total complications (11.86% vs. 45.45%) between the observation and control groups (P<0.05). However, the differences in both the one-time success rate of catheterization (98.32% vs. 98.18%) and the catheter occlusion (8.48% vs. 9.09%) are not significant between the observation and control groups (P>0.05).

      Conclusion:
      Compared to groin femoral venous catheters, mid-thigh femoral venous catheters have good catheter placement effect, low complication incidence rate, and little influence on patients’ degree of comfort; therefore, it is a suitable treatment for SVCO patients.

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      ORAL15.04 - Discussant for ORAL15.01, ORAL15.02, ORAL15.03 (ID 3405)

      B. Eaby-Sandy

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ORAL15.05 - Using Your Voice (UYV) - How to Use Your Nursing Voice at the Multi-Disciplinary Team (MDT) Meeting (ID 1604)

      L. Magee, J. Roberts, V. Beattie, C. De Normanville, D. Borthwick

      • Abstract
      • Presentation
      • Slides

      Background:
      The role of the lung cancer nurse specialist (LCNS) varies across the UK, some working within teams and others as lone workers. Each LCNS brings strengths to the role and are individual in their approach. Over several years the National Lung Cancer Audit has highlighted the association between access to a LCNS and receipt of anti-cancer treatment. In 2013, 65.6% of patients who saw a LCNS received anti-cancer treatment, compared to 27.1% of those who did not see a LCNS[1]. A more detailed analysis has been carried out at Sheffield Hallam University Opening doors to treatment[2]. In the time-pressured setting of a MDT meeting it can be difficult to get your point across. This is where a real impact can be achieved in acting as patient advocate. A joint working initiative between Lilly Oncology and the National Lung Cancer Forum For nurses (NLCFN) has developed with the aim to help improve the contribution of the LCNS in the MDT meeting.

      Methods:
      LCNSs, particularly those new in post, were invited to apply for a place in the first UYV workshops on 6[th] and 7[th] October 2014 in London. Experienced professionals delivered the UYV programme including: - insights training - building confidence in order to effectively represent your patient in the MDT meeting - developing skills to manage challenging conversations - invaluable communication skills and strategies - greater understanding of Performance Status assessment A 12 week reflection period requiring submission of 3 reflective pieces of work followed the workshops. A mentor scheme was facilitated by 4 NLCFN committee members with teleconference calls organised by Lilly Oncology between the participants, their mentor and expert speakers. A final How you were heard closing workshop 19/01/2015, completed the training.

      Results:
      20 applications were received and all were offered and accepted a place. Formal evaluation of the workshops will be led by the Faculty of Health and Wellbeing, Sheffield Hallam University using mixed methods of data collection and analysis against: - the extent to which the LCNS feels more confident and competent to effectively influence patient outcomes at the MDT as a result of attending the workshop - the potential impact of using this model of training in comparison to other courses Initial feedback evaluation indicates that 100% of the delegates agreed that the programme was of value to their clinical practise and influenced how likely they are to contribute to the MDT. Emergent themes include perceived power relationships, confidence, self-efficacy and self-belief. Increased insight into own and others communication styles has been enlightening, with improved knowledge and confidence in assessing Performance Status. Post course online survey results are awaited which we are keen to share.

      Conclusion:
      This collaboration has proved very successful and repeat UYV Workshops for 2015 have been planned. Confidence / self-efficacy development for specialist practitioner roles and inter-professional working will be considered for future development. 1. http://www.hqip.org.uk/assets/NCAPOP-Library/NCAPOP-2014-15/HSCICNLCA-2014finalinteractivereport.pdf 2.http://www.shu.ac.uk/research/hsc/sites/shu.ac.uk/files/REVISED%20FINAL%20DRAFT%20GNC%20T%20LCNS%207%203%2014%20(2).pdf

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      ORAL15.06 - A Prospective Audit on Smoking Cessation and Lung Cancer Nurse Specialist Intervention within a Thoracic Oncology Service (ID 1605)

      M. King, L. Magee

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is the most common smoking-related malignancy in the UK. Smoking cessation can improve survival, treatment efficacy and overall quality of life. The Lung Cancer Nurse Specialist (LCNS) is in a unique position to assess smoking history and the motivation/willingness of the patient to quit. The aim of this audit is to assess the effectiveness of the LCNS at assessing, actioning and documenting the smoking history and smoking cessation input of patients attending the Papworth Thoracic Oncology Service (PATHOS).

      Methods:
      A formic form was designed to include the audit criterion and aid data collection. Patients attending PATHOS from 01/09/2012 to 07/12/2012, with suspected or confirmed lung cancer, underwent a smoking assessment by one of 6 LCNSs.

      Results:
      Of 199 patients attending PATHOS 148 were suspected of having primary lung cancer. 118 (80%) had smoking audit forms completed by the LCNS. Of the 30 patients where no audit form was completed, 29 had smoking history recorded in nursing documentation and actioned as appropriate, 1 patient had no smoking history recorded. Expected audit standards of 100% were: All LCNSs (keyworkers) will have level 1 smoking cessation training - 83% (5/6) All patients assessed will have smoking assessment documented in holistic care plan - 80% (118/148) LCNS will discuss with all smokers the benefits of cessation and document - 100% (32/32) All smokers will be offered the NHS leaflet “It’s so much easier since I quit” or individualised Information Prescription and document in holistic assessment care plan - 97% (31/32) All smokers willing to consider quitting will be signposted to a smoking cessation service / GP clinic / National Helpline - 67% (18/27) Via audit forms received 16 (14%) patients never smoked, 70 (59%) ex-smokers, 32 (27%) current smokers. Of the current smokers the mean age to start smoking was 16.5 years. 21 (66%) smoked within 30 minutes of waking, 3 (9%) 31-60 minutes of waking and 8 (25%) after 60 minutes. 27 (84%) of smokers were willing to quit.

      Conclusion:
      Smoking cessation is an integral part of the LCNS role to help improve clinical outcomes and effectiveness. Meeting patients at various stages of the diagnosis and treatment pathway they are in a privileged position to affect change. Continued skill developments and improved understanding of smoking cessation strategies will increase their effectiveness. Recommendations: All LCNS to complete smoking cessation training level 1 and level 2 training within 1 year with annual update. Use: Ask / Assess / Advise / Assist / Arrange protocol to assist smoking cessation intervention. Nursing notes to include assessment of patient's progress in smoking cessation in order to monitor impact of intervention. Include smoking cessation advice as part of hospital Comissioning for Quality and Innovation (CQUIN).

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      ORAL15.07 - I Am Dying of Mesothelioma (ID 2698)

      C.A. Davies, N. Horne

      • Abstract
      • Presentation
      • Slides

      Background:
      Malignant Mesothelioma is a devastating disease associated with poor outcome and highly complex symptoms. The disease is frequently linked to past asbestos exposure, for many via occupational exposure. A Mesothelioma patient approached the lung cancer CNS expressing his wish to share his experience with others. Therafter, with the patient's consent, the content of this information continues to be used as an educational tool to enhance patient care.

      Methods:
      The format agreed was interview. Consent obtained. For maximum impact the interview was video recorded. It followed the patient story, told in his words from beginning to present: 1. Investigations and diagnosis 2. Treatment 3. The here and now It was very important to both authors that this be the patient’s story. Technical support used was recommended by Macmillan.

      Results:
      Diagnostic delays Angry cause occupational exposure. Imperitive doctors ask! Told Mesothelioma. No Cure. Devistated Prognosis 2 years: Chemotherapy recommended. ‘It was bad. If someone had said to me do you want to die, I would have said yes’. Lack of support group – all dying! Supportive lung nurses . Breathless – ‘Cannot walk anymore, have to take car’. ‘Unable to talk in groups, too breathless’. I’d rather put up with pain than take something stronger’ which takes away my quality of life. ‘Know things will get worse’. ‘I’m remote from my wife’. ‘I have a death sentence’. ‘I’m living it and at the end of it I’m gone’.

      Conclusion:
      A patient story is emotive and powerful. This story highlights in part the complexities associated with the Mesothelioma pathway. It also identifies various multifaceted difficulties patient’s face. This video is used as an educational tool for professionals in mesothelioma care within the UK.

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      ORAL15.08 - Discussant for ORAL15.05, ORAL15.06, ORAL15.07 (ID 3406)

      M. Duffy

      • Abstract
      • Presentation

      Abstract not provided

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