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  • WCLC 2013

    15th World Conference on Lung Cancer

    Access to all presentations that occurred during the 15th World Conference on Lung Cancer in Sydney, Australia.

    Presentation Date(s):
    • October 27 - 30, 2013
    • Total Presentations: 2517

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    P1.14 - Poster Session 1 - Mesothelioma (ID 194)

    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 13
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      P1.14-001 - Estimates of expected years of life lost and lifetime direct medical costs for malignant pleural mesothelioma patients: data from Taiwan and New South Wales, Australia (ID 108)

      M.J. Soeberg, L.J. Lee, S. Kao, N. Van Zandwijk, Y. Chang, J. Wang

      • Abstract

      Background
      Quantifying the burden of malignant pleural mesothelioma (MPM) is an important yet challenging task. Little is understood about the societal and economic costs following a diagnosis of MPM. We investigated survival, years of life lost, and direct medical costs associated with MPM using data from Australia and Taiwan.

      Methods
      159 and 136 MPM patients from New South Wales (NSW) Disease Dust Board data and Taiwanese Cancer Registry (TCR) data respectively were included in: (i) survival function analyses and (ii) analyses to estimate the years of life lost associated with a MPM diagnosis. Further, data on 428 patients from the Taiwanese National Health Insurance Research Database, and the NSW data linked to Medicare data, were also used to (iii) estimate lifetime healthcare expenditure following a MPM diagnosis.

      Results
      (i) The mean age at MPM diagnosis in NSW was 71 and 60 in Taiwan. Median survival in months for NSW MPM patients was 11.7 (95% CI 9.3, 13.5) and 6.0 (95% CI 5.1, 7.8) for TCR patients. Four and eight percent of patients in NSW and Taiwan respectively were estimated to survive up to five years following a MPM diagnosis. (ii) The lifetime survival difference between the MPM patient cohort and a comparable population free of the disease was estimated to be 13.6 (95% CI 13.4, 13.8) years in the NSW cohort and 18.8 (95% CI 18.5, 19.1) years in the TCR cohort. (iii) Using national health insurance data in Taiwan, we estimated that the direct heath care costs following a MPM diagnosis to be USD$18,812. In NSW, this cost was estimated to be USD$20,573.

      Conclusion
      We analysed MPM cohort data from Taiwan and Australia to estimate survival and expected life years lost, with possible differences in the age at diagnosis and median survival. We also analysed Taiwan and Australian data to estimate direct medical costs following a MPM diagnosis. The impact of selection bias in this study cannot be ruled out as there is likely under-ascertainment of MPM cases in the Taiwanese Cancer Registry and the NSW data is a subset of all MPM cases diagnosed in NSW. However, these estimates provide useful data to contribute to evidence-based clinical and policy decision-making in the area of MPM prevention and care services.

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      P1.14-002 - Lack of response to chemotherapy for previously treated malignant pleural mesothelioma (MPM) (ID 656)

      M.G. Zauderer, S.L. Kass, C.S. Sima, M.S. Ginsberg, L.M. Krug

      • Abstract

      Background
      After initial therapy with pemetrexed/platinum, second-line therapy options are not well established. Gemcitabine and vinorelbine are often used based on small trials and first-line data. To augment the existing data, we examined our institutional experience using vinorelbine and gemcitabine in patients with previously treated MPM.

      Methods
      We reviewed the records of all patients treated with vinorelbine and/or gemcitabine as second- or third-line therapy for MPM between 2003 and 2010. Vinorelbine was administered at a dose of 25 mg/m[2] days 1 and 8 in a 3-week cycle and gemcitabine was given at 1000 mg/m[2] days 1, 8, and 15 in 28 day cycles. CT scans were generally performed after every two cycles. Imaging studies were reviewed with a radiologist according to the modified RECIST criteria.

      Results
      60 patients were identified: 33 treated with vinorelbine, 15 with gemcitabine, and 12 with both. Patient characteristics are as follows: 78% men: median age 67 (range 41-85); 63% epithelioid, 19% mixed histology, and 18% sarcomatoid; 83% received first-line pemetrexed-platinum therapy and 10% gemcitabine-platinum therapy. One partial radiographic response was identified among the 56 patients with follow up imaging available for review (Figure 1) giving a response rate of 2% (95% CI 0-5%). With gemcitabine, 10 patients (37%) had radiographic progression, 6 (22%) had clinical progression, 6 (22%) had radiographic stable disease, 4 (15%) had clinically stable disease, and 1 (4%) had radiographic partial response. With vinorelbine, 20 patients (43%) had radiographic progression, 2 (4%) had clinical progression, 19 (42%) had radiographic stable disease, 4 (8%) had clinically stable disease, and there were no responses. 53% experienced at least one episode of grade 3-4 toxicity, most commonly anemia, neutropenia, fatigue, and neutropenic fever. 24 patients received more than 2 cycles. Median progression free survival was 1.6 months and median overall survival was 5 months. Figure 1

      Conclusion
      Response to second-line therapy with gemcitabine or vinorelbine is rare. The rate of stable disease suggests some level of activity of these agents. Therefore, it remains a reasonable standard therapeutic option. However, survival was comparable to the placebo arm in the phase III vorinostat trial (Krug, ECCO/ESMO, 2011). This lack of efficacy supports the use of placebo control arms in randomized second-line MPM trials. Novel therapies are desperately needed for this patient population.

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      P1.14-003 - The effect of front-line chemotherapy on overall survival in patients with malignant pleural mesothelioma. (ID 675)

      A. Sevinc, E.T. Elkiran, H. Harputluoglu

      • Abstract

      Background
      Background: Malignant pleural mesothelioma (MPM) is a relatively rare, but aggressive tumor that causes high mortality. The major risk factor involved in the etiology is environmental and occupational exposure to asbestos. The optimal modality of therapy is controversial.

      Methods
      Methods: The present study retrospectively evaluated the 141 patients from the database.

      Results
      Results: There were 80 males and 61 females with a mean age of 56 ± 1.07 years. The median survival in patients who were administered front-line chemotherapy was 17 months (95% CI: 13.19-20.81). 106 patients were administered pemetrexed-platinum combination and 35 patients were administered gemcitabine-platinum combination as front-line chemotherapy. For the patients who received pemetrexed-platinum regimen, a median of 6 cycles of chemotherapy was administered and 50 patients (47.2%) were able to receive all 6 cycles as planned. For the patients who received gemcitabine-platinum regimen, a median of 6 cycles of chemotherapy was administered and 19 patients (54.3%) were able to receive all 6 cycles. Median survival was found 16 months in the pemetrexed-platinum regimen and 26 months in the gemcitabine- platinum regimen. There was no statistically significant difference between the patients who received pemetrexed-platinum and gemcitabine-platinum regimens in terms of the median overall survival (p = 0.15).

      Conclusion
      Conclusions: Results of our study suggest that chemotherapy prolongs overall survival. Survival rates in patients who received combining platinum analogues with pemetrexed or gemcitabine as front-line chemotherapy were found to be similar.

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      P1.14-004 - Extended Survival Following Recurrence for Patients with Malignant Pleural Mesothelioma Treated with Radical Pleurectomy, Photodynamic Therapy and Chemotherapy: The potential role of STAT3. (ID 1686)

      J. Friedberg, C. Simone, M. Culligan, S.M. Hahn, E. Alley, D. Sterman, E. Glatstein, S. McNulty, M. Shin, S. Hagan, K.A. Cengel

      • Abstract

      Background
      Survival after recurrence following surgical management with curative intent for malignant pleural mesothelioma is typically measured in months. In this study, we compare survival after recurrence in patients progression free less than or greater than one year after radical pleurectomy.

      Methods
      67 consecutive patients with malignant pleural mesothelioma, epithelial subtype, who underwent radical pleurectomy and intraoperative photodynamic therapy were assessed in this IRB-approved study. Four patients who experienced perioperative mortality were excluded from this analysis. Local recurrence was defined as recurrent disease in the ipsilateral hemithorax. Early vs. late recurrence was defined as recurrence before versus after the median recurrence time, respectively. STAT3 expression was quantified in tissue microarrays using computer-based quantification of immunohistochemical staining.

      Results
      Among the 63 evaluable patients, 78% (n=49) were male, the median age of patients was 64 years, and the overwhelming majority (87.5%) had locally advanced (AJCC stage3/4) disease. 49 patients (78%) had lymph node metastases (N1/N2). 60 patients (95%) received neoadjuvant or adjuvant pemetrexed-based chemotherapy. With a median follow-up of 31 months, 42 patients demonstrated disease recurrence. Of these recurrences, 18 were isolated local recurrences and 24 were combined local + distant. The median time to recurrence was 11.6 months and patients who experienced an early recurrence (<11.6 mo) demonstrated significantly decreased survival as compared to patients experiencing a late recurrence (p < 0.0001, Figure 1). The median survival after recurrence was significantly decreased for patients who experienced an early vs late recurrence (54.7 mo [46.0-63.4 mo 95% CI] vs 10.8 mo [8.5-22.7 mo 95 % CI], respectively). We and others have previously shown that STAT3 expression can make mesothelioma more resistant to cytotoxic agents such as chemotherapy or photodynamic therapy. Preliminary analysis of TMA staining indicates that patients who experience an early disease recurrence in our series exhibit significantly higher STAT3 expression. Figure 1

      Conclusion
      This study is among the largest to describe the survival after initial recurrence for malignant pleural mesothelioma in patients undergoing definitive surgical management. Patients recurring prior to the median of 11.6 months experienced an aggressive tumor recurrence phenotype with a median 10.3 months from recurrence to death. Patients recurring after the median of 11.6 months experienced a relatively indolent disease course with a median survival of 37 months after recurrence. Further evaluation and additional studies are necessary to confirm if elevated STAT3 expression could be a poor prognostic factor for patients undergoing radical pleurectomy, photodynamic therapy and chemotherapy.

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      P1.14-005 - Preliminary Results - "A Phase I Trial of Oncolytic Measles Virotherapy in Mesothelioma" Investigating the Intrapleural Administration of the Modified Vaccine Strain Measles Virus (MV-NIS) to Patients with Malignant Pleural Mesothelioma (ID 1922)

      T. Peikert, J. Molina, I. Aderca, S. Albelda, S. Carlson, V. Lowe, F. Maldonado, S. Mandrekar, M. Patel, A. Roden, V. Van Keulen, R. Kratzke, E. Galanis

      • Abstract

      Background
      Malignant pleural mesothelioma (MPM) remains an almost universally fatal disease. Preclinical models indicate that the oncolytic modified vaccine strain measles virus (MV) carrying the gene for the human sodium-iodine symporter (NIS) - MV-NIS preferentially targets MPM tumors cell. In patients with refractory ovarian cancer the intraperitonial administration of MV-NIS was recently found to be safe and induced an anti-tumor immune response.

      Methods
      Phase I dose escalation study (3+3 design). MV-NIS is administered intrapleurally. Starting dose level was 10[8] TICID 50 (Level 1) and the current dose level is 3 x 10[8] TICID 50 (Level 2). In the absence of dose limiting toxicity and disease progression patients continue MV-NIS therapy for up to six 28-day cycles. MV-NIS infection and replication is monitored by Iodine[123] SPECT/CT and RT-PCR and anti-tumor and anti-viral immunity are monitored in correlative studies. Patients are followed clinically using modified RECIST criteria.

      Results
      Up to now 4 patients have received MV-NIS therapy. Three patients were treated at Level 1 and the fourth patient at Level 2. No dose limiting adverse events occurred. The best therapeutic response was stable disease, observed in patient #1 for 6 months and patient #2 for 2 months. The remaining two patients progressed radiologically after one treatment cycle. I[123] SPECT-CT imaging did not demonstrate changes in iodine uptake compared to baseline in any of these patients. However, we detected MV RNA by QRT-PCR within the pleural cells 24-48 hours after the intrapleural administration of MV-NIS in 3/4 patients. In patient #4, treated with 3x10[8] TCID 50, MV replication was detectable within the pleural space by plaque assay 24 hours after MV-NIS administration. Following MV-NIS therapy a profound influx of neutrophils into the pleural space occurred in 3/4 patients and pleural fluid cytokine concentrations changed significantly. In addition, a humoral anti-tumor immune response emerged in patients #2.

      Patient # Age Disease Stage Histology Line therapy
      1 75 II (T2N0M0) Epitheloid First
      2 53 IV (T4N0M0) Epitheloid Second
      3 84 IV (T4N0M0) Epitheloid First
      4 73 IV (T2N3M0) Mixed First

      Conclusion
      Thus far the intrapleural administration of MV-NIS appears to be safe and well tolerated in MPM. Our study will continue to enroll patients.

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      P1.14-006 - Catheter Tract Metastases Associated With Indwelling Pleural Catheters For Malignant Effusions (ID 2342)

      Y.J. Kuok, R. Thomas, S. Bydder, C. Budgeon, Y.G. Lee

      • Abstract

      Background
      Indwelling pleural catheter (IPC) is commonly used in managing malignant pleural effusion (MPE). Tumor spread along the catheter tract remains a clinical concern for which limited data exist. We report the largest series of catheter tract metastases (CTM).

      Methods
      All patients who had IPC inserted for MPE in our Pleural Service were entered prospectively into a database. A retrospective review of the cases for CTM over a 50-month period from Jan 2009 was conducted. CTM was defined as a new chest wall swelling over the IPC insertion site or the tunneled subcutaneous tract. Patient demographics and risk factors were recorded. Multivariate regression analysis was performed.

      Results
      108 patients (77% male; 60% had mesothelioma) underwent a total of 111 IPC insertions. CTM occurred in 11 (10.2%) patients; 7 were males and 9 had mesothelioma. CTM developed after a median of 280 days (range 56-692 days) post-IPC insertion. 7 patients were symptomatic with chest wall pain and 6 received palliative radiotherapy for CTM. Radiotherapy was tolerated well with no major complications. CTM occurred more commonly, OR 3.30 (0.68-16.06), in mesothelioma patients than those with metastatic pleural cancers. Patients who had CTM had a significantly longer survival (median 369 days) than those who did not, HR 0.24 (CI 0.08-0.68).

      Conclusion
      Clinicians and patients should be aware that CTM could complicate IPC, especially in mesothelioma patients. The longer the patient survived after IPC placement, the higher risk of developing CTM. Symptoms associated with CTM were generally mild and responded well to palliative radiotherapy.

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      P1.14-007 - Intrapleural Fibrinolysis Is Effective In Treating Symptomatic Loculation Complicating Indwelling Pleural Catheter Drainage (ID 3017)

      R. Thomas, C. Read, E. Fysh, Y.G. Lee

      • Abstract

      Background
      Indwelling pleural catheters (IPC) are commonly used in managing malignant pleural effusions (MPE). Development of loculations within the effusion can prohibit effective fluid drainage. Intrapleural instillation of fibrinolytics has been used though little data exist on this practice. Aim: To describe a single centre experience in the use of fibrinolytic therapy for symptomatic loculation in IPC patients.

      Methods
      We defined Symptomatic Loculation (SL) as presence of (a) residual pleural effusion that failed to be evacuated via a patent IPC, b) breathlessness clinically judged to be related to the residual effusion, and c) in the absence of pleural infection. All patients (n=108; 77% male) who had IPC (n=111) inserted for MPE (60% mesothelioma) were entered prospectively into a database over a 50month period. The incidence of SL and the effectiveness and safety of fibrinolytic therapy were analyzed.

      Results
      The incidence of SL was 1 case per 74.2 IPC person-months, affecting 9% (10/111) of the patients. Most affected were males (9/10) with a mean age of 74.2yrs and 7/10 had mesothelioma. Various fibrinolytics had been used: tPA 10mg (n=6), streptokinase 250000U (n=1), urokinase 100000U (n=2) and 1 patient received a combination of streptokinase followed by tPA. Outcomes: The majority (89%) of patients reported subjective symptomatic improvement in breathlessness. Fibrinolysis induced a significant increase in fluid output: 1459ml (mean after 24hrs) and 2136ml (72 hours after instillation). The mean hospital stay was 4.5 days from first treatment dose. Treatment was well tolerated. The most common symptom was pain on pleural drainage (8 patients) that resolved with cessation of drainage. There were no severe adverse events, such as pleural bleeding. However, SL recurred after fibrinolytic therapy in 5 (56%) patients after a mean period of 9.6 days with two needing further pleural interventions.

      Conclusion
      Intra-pleural fibrinolytic therapy is an effective and safe option for management of SL following IPC insertion for MPE. Support: Cancer Council WA; NHMRC Fellowship (YCGL) Conflict of interest: Nil.

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      P1.14-008 - Clinical features and current management of malignant pleural mesothelioma in France. TheGFPC 0804 study. (ID 2378)

      C. Raynaud, J. Mazieres, L. Greiller, C. Chouaid, P. David, G. Robinet, G. Fraboulet, H. Berard, R. Lamy, J. Letreut, H. Lena, J.Y. Delhoume, H. Janicot, I. Borget

      • Abstract

      Background
      Malignant pleural mesothelioma (MPM) is a rare and aggressive primitive pleural tumour, which is associated with exposure to asbestos. Chemotherapy is the main part of therapy with new cytotoxic agents resulting in superior survival time. Recently the European Respiratory Society and the European Society of Thoracic Surgeons proposed practical and up-to-date guidelines on the management of MPM. The objective of this study was to assess the current management of MPM in France between January 2005 and December 2008.

      Methods
      Observational, multicentric, national, study. The medical records of patients with MPM diagnosed during the study period in the 37 participating centers were retrospectively reviewed. Epidemiological data, clinical data, diagnosis procedures and several components of management were recorded. Mains inclusion criteria’s were a new diagnosis of MPM, a histology diagnosis and a management in the center.

      Results
      Four hundred and six patients (males: 76%) were included; median age: 68.9± 9.8 years; > 75 years: 27.8%; Asbestos exposure was found out in 259(63.8%) patients (251 professional exposure, 8 environmental exposure). Histological diagnosis was: epithelial MPM: 82.9%, sarcomatoid MPM: 10%, biphasic MPM 7.1%. The main diagnosis procedure was thoracoscopy (296 (73.1%)). Thirty patients underwent surgery (25 radical surgery, 5 pleurectomy). Pleurodesis was performed 191 times. Prophylactic drain site radiotherapy was performed in 268. Three hundred and three patients (74.6%) received first-line combination chemotherapy (mean cycles: 4.7 ± 1.7, median 6); 162 (40.2%) received second line chemotherapy (mean cycles: 3.5 ± 1.9, median 3); 56 ( 13 %) received third line chemotherapy (3.1± 2, median 3). One and two year survival rates will be updated at the congress.

      Conclusion
      This study provides an assessment of diagnosis modes and therapeutic strategies for the management of MPM in France. Further analyses are needed to model the management strategies and assess the cost-effectiveness of this disease.

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      P1.14-010 - Estimation of an optimal chemotherapy utilisation rate for malignant pleural mesothelioma: An evidence-based benchmark for patient care (ID 2535)

      A. Tognela, S. Kao, N. Van Zandwijk, S. Clarke, J. Vardy, V. Bray, S. Lumba, W. Ng

      • Abstract

      Background
      Chemotherapy has been shown to provide a survival benefit in malignant pleural mesothelioma (MPM). There are wide ranging chemotherapy utilisation rates internationally (18 – 61%). This study aims to determine the optimal proportion of patients with MPM that should receive chemotherapy at least once during the course of their illness, based on the best available evidence, so that it can be determined whether chemotherapy is under-utilised in MPM.

      Methods
      An optimal chemotherapy utilisation tree was constructed using indications for chemotherapy identified from evidence-based treatment guidelines. Epidemiological data on the proportion of patient and tumour-related attributes for which chemotherapy was indicated (resectability of the tumour, degree of comorbidities and patient performance status) were obtained and merged with the treatment indications to calculate an optimal chemotherapy utilisation rate, using the decision analysis software (TreeAge Pro 2007). Sensitivity analyses were performed to assess the impact of major variations in the epidemiological data on the overall utilisation rate. This optimal rate was compared with reported actual rates of chemotherapy utilisation in the literature.

      Results
      Chemotherapy is recommended at least once in 65% of all MPM patients. Sensitivity analyses indicate an optimal utilisation rate ranging from 50 to 65% for at least once during the course of their illness. The optimal utilisation rate is consistently higher than the reported actual chemotherapy utilisation rates in United Kingdom (18%), Netherlands (36%), United States (37%), and Australia (54%).

      Conclusion
      An evidence-based model provided an optimal chemotherapy utilisation rate for patients with MPM of 65%. It can serve as a feasible measure of the quality of cancer care. Chemotherapy appears to be under-utilised in the management of MPM in a number of high-income countries.

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      P1.14-011 - Changes in expression of cancer drug resistance genes in mesothelioma cells exposed to carboplatin (ID 2610)

      V. Relan, L.E. Morrison, K. Chee, K. Fong, I. Yang, R. Bowman

      • Abstract

      Background
      Background A proportion of patients with mesothelioma respond to chemotherapy consisting of pemetrexed and platinum, but tumour responsiveness most often becomes blunted after several cycles. To discover the mechanism of loss of sensitivity to chemotherapeutic agents, we compared expression of cancer drug resistance genes between platinum sensitive and resistant mesothelioma cells.

      Methods
      Mesothelioma cells generated from three chemo-naïve patients propagated in cell culture were exposed to increasing concentrations of carboplatin until in vitro resistance of at least one log10 concentration difference in IC50 was achieved in dose response cytotoxicity assays. For each individual, cells resistant to carboplatin at 8µg/ml and at 20µg/ml were generated. Control cells from each line were passaged in parallel in medium only. Cells were in log phase growth and culture medium was free of platinum for at least two weeks prior to extraction of RNA using Qiagen RNAeasy Mini kits. High quality RNA (assessed by denaturing gel electrophoresis) was then DNase treated and reverse transcribed using Qiagen RT² Profiler PCR Array reagents. Gene expression in control and platinum resistant cells was determined from the Cancer Drug Resistance PCR Array of (Catalogue Array PAHS-004Z) according to manufacturer’s instructions.

      Results
      SULT1E1 was overexpressed in one mesothelioma line resistant to carboplatin at 8µg/ml, and in two of three resistant to 20µg/ml carboplatin, in comparison with parallel passaged controls. One of three cell lines resistant to carboplatin at both the 8µg/ml and 20µg/ml level overexpressed ERBB3, and another resistant at 20µg/ml overexpressed PPARγ. Drug resistance genes displayed more aberrant expression in cells resistant to higher concentrations of carboplatin.

      Conclusion
      The increase in expression of these three genes in mesothelioma resistant to carboplatin suggests that they may be useful targets for circumvention of resistance, but their mechanistic role in development of platinum resistance requires demonstration. In particular, since PPARγ ligands (e.g. roglitazone) have been shown to sensitise cancer cells to chemotherapeutic agents, and are proposed as anticancer agents, it is possible that the functional effect of PPARγ upregulation is moderating rather than causal. Supported by Cancer Australia.

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      P1.14-012 - Activation of mTOR signal pathway is associated with prolonged survival in malignant pleural mesothelioma patients (ID 2715)

      A. Kuroda, S. Matsumoto, A. Nakamura, M. Hashimoto, T. Takuwa, N. Kondo, I. Torii, T. Tsujimura, T. Nakano, S. Hasegawa

      • Abstract

      Background
      Malignant Pleural Mesothelioma (MPM) is a rare disease with poor prognosis. The combination chemotherapy with cisplatin and pemetrexed is the first line of MPM. The AKT/mTOR (Mammalian Target of Rapamycin) pathways are known to be activated in some kind of cancer. The purpose of this study is to evaluate the correlation between the activation of these pathways and prognosis of MPM patients.

      Methods
      46 patients with MPM underwent a multimodality therapy including extrapleural pneumonectomy (EPP) at Hyogo College of Medicine, Nishinomiya, Japan from April 2004 to October 2012. The 46 cases included 35 males (76.0%) and 11 females (23.9%). Median Ages is 59.8 (ranged from 37 to 71 years). Histologic subtype is 42 epithelial type (91.3%), 2 biphasic type (4.3%), 1 desmoplastic type (2.1%), 1 small cell type (2.1%). Paraffin embedded surgical sample was used for immunohistochemistry to evaluate the expression of phospho- mTOR (p-mTOR) and phospho-S6 Ribosomal Protein (p-S6RP). Overall survival (OS) from the time of surgery was determined by Kaplan-Meier method and results were compared by log-rank test.

      Results
      OS was significantly better in phospho-S6RP positive patients (32/46) in comparative with phosphor-S6RP negative patients (14/46) (43.6 months vs. 14.4 months, P=0.03). OS was significantly better in phospho-mTOR positive patients (18/46) in comparative with phosphor-mTOR negative patients (28/46) (37.1 months vs. 14.4 months, P=0.08).

      Conclusion
      In MPM patients, high phospho-S6RP expression is predictive of improved OS. The assessment of phospho-S6RP expression is worth of prospective validation in future studies on a multimodality therapy of MPM. And this study support that the AKT/mTOR pathways is a promising candidate of molecular target therapy for MPM.

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      P1.14-013 - The effectiveness and safety of platinum based pemetrexed and platinum based gemcitabine treatment in the patients with malignant pleural mesothelioma (ID 3094)

      G. Ak, S. Metintas, M. Akarsu, M. Metintas

      • Abstract

      Background
      Chemotherapy schemas evaluated in terms of efficiency and safety are limited in malignant pleural mesothelioma treatment. In our study we aimed to evaluate efficiency and safety of cis/carbo+pemetrexed, which is known as effective in mesothelioma and cis/carbo+gemcitabine, which is used in the past for mesothelioma but doesn’t have proved information about its efficiency, in comparable historical groups of malignant pleural mesothelioma.

      Methods
      One hundred and sixteen patients received cis/carbo+pemetrexed (group 1) and 30 patients received cis/carbo+gemcitabine (group 2) between June 1999 and June 2012 composed study groups.

      Results
      The mean age of group 1 and 2 were 60.7 and 60.8 years. Female ratio of group 1 and 2 were 50% and 53%. Most of patients (98%) exposed to asbestos in part of their life. 78.1% of the patients have epithelial type tumor and 47% of patients have stage IV disease. There was no difference between two groups in terms of age, sex, asbestos exposure, histological cell type, stage and Karnofsky performance status. The median survival time and 95% confidence interval were 12±0.95 months (95% CI: 10.15 – 13.85) for group 1 and 11.0±1.09 months (95% CI: 8.85 – 13.15) for group 2. The median survival of two groups was not different (Log-Rank: 0.142; p=0.706). Stage and Karnofsky performance status were found as significant variables on median survival time by univariate analysis (p=0.002 and p=0.045 respectively). After adjusting for stage and Karnofsky performance status, chemotherapy schema was not impressive on median survival (OR: 0.837; 95% CI: 0.548 – 1.277; p=0.409). The treatment was generally well tolerated and side effects were similar in both groups.

      Conclusion
      This study confirmed that the activity of platinum based gemcitabine is as effective as platinum based pemetrexed and safe schema in malignant pleural mesothelioma.

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      P1.14-014 - Patients' Willingness to Participate in a Randomized Controlled Trial for Malignant Pleural Mesothelioma: A New Paradigm to Improve Accrual to Thoracic Oncology Trials (ID 3147)

      C.B. Simone, A. Shah, M.J. Culligan, J. Friedberg, D. Sterman, E. Alley, J.P. Stevenson, K.A. Cengel, S.M. Hahn

      • Abstract

      Background
      Predicting if a trial will accrue is critical, especially for thoracic oncology trials that have notoriously low accruals. Our group demonstrated unusually good results treating malignant pleural mesothelioma (MPM) with radical pleurectomy (RP), intraoperative photodynamic therapy (PDT), and chemotherapy. To establish if PDT is contributing to our results, a randomized trial of RP+/-PDT is needed. To determine if such a trial is feasible, we conducted a willingness to participate (WTP) study. We quantified differences in WTP before and after physician training designed to increase WTP.

      Methods
      All consecutive MPM patients who were candidates for RP+PDT were prospectively enrolled in this IRB-approved study. Patients participated in structured interviews, reviewed a written description of a hypothetical RCT comparing RP to RP+PDT, answered open-ended and focused questions regarding their motivations for and concerns about enrollment, and completed a written questionnaire. WTP was assessed using a 6-point Likert scale (1=definitely not, 6=definitely). Interview transcripts were analyzed using thematic data analysis and constant comparison techniques. Questionnaire and transcript data were used to educate physicians and modify their presentation of the RCT to subsequent patients.

      Results
      25 participants (median age 66yrs, 72% male, 88% epithelial histology) enrolled. Some had pre-existing knowledge of RP (44%) or PDT (40%). Following the first 8 patients enrolled, we identified 15 factors impacting WTP focusing on five themes: randomization, hope for cure, desire to compare treatments, altruism, and physician opinion (Table 1). Based on these findings, physicians were trained to more thoroughly explain the WTP and proposed RTC and addressed concerns raised by these initial 8 patients when meeting with subsequent patients. Physician time explaining the WTP increased following training (median 9min vs. 3min, p<0.0001). Overall, 56% “definitely” or “probably” would, 28% “may,” and 16% would “probably not” or “definitely not” participate. More patients would be “definitely” or “probably” willing to participate after physician training (71% vs. 25%, p=0.03). Furthermore, none of the initial 8 patients were “definitely” willing, compared with 8 of the subsequent 17 (p=0.02). Following consultation, 16 underwent surgical-based therapy, with no difference before or after training (50% vs. 71%, p=0.34).

      Table 1. Motivations (m) and concerns (c) reported by patients (N=25) when deciding if they would enroll in the proposed randomized clinical trial for malignant pleural mesothelioma
      Trial Design Factors N= Therapy-relate Factors N= Humanistic/Ethical Factors N=
      Randomization (c) 12 Hope for a cure (m) 10 Altruism towards other patients (m) 9
      Deference to physician opinion (m) 7 Desire to compare treatments (m) 8 Deference to family opinion (m) 4
      Concerns with experimentation (c) 2 PDT side effects (c) 6 Altruism towards science/physician/ hospital (m) 1
      Financial incentives (m) 1 Potential benefit of PDT (m) 3
      Reputation of the hospital (m) 1 Prior knowledge of PDT (m) 1
      Close follow-up (m) 1 Availability of alternative treatments (c) 1

      Conclusion
      This study demonstrated analyzing and addressing patient motivations and concerns about enrollment, physician training, and increasing time spent with patients can increase WTP. In this study, most patients expressed a WTP in a RCT of RP+/-PDT for MPM. Performing WTP studies prior to planned prospective thoracic oncology trials should be considered to optimize trial design and accrual strategies.

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    P1.15 - Poster Session 1 - Thymoma (ID 189)

    • Type: Poster Session
    • Track: Thymoma & Other Thoracic Malignancies
    • Presentations: 9
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      P1.15-001 - Postoperative radiotherapy for completely resected Masaoka stage III thymoma: a retrospective study of 65 cases from a single institution (ID 45)

      C. Fan, Q. Feng, Y. Chen, Y. Zhai, Z. Zhou, D. Chen, Z. Xiao, Z. Hui

      • Abstract

      Background
      The role of adjuvant radiotherapy (RT), especially three-dimensional conformal RT (3D-CRT)/intensity modulated RT (IMRT) for patients with stage III thymoma after complete resection was not definite. In this study, we retrospectively evaluated the effect of 3D-CRT/IMRT on survival as well as tumor control in this subgroup of patients.

      Methods
      Between September 1965 and December 2010, 68 patients who underwent complete resection of stage III thymoma entered the study. Fifty-six patients had adjuvant RT after surgery (S+R) and 12 had surgery only (S alone). Of patients who had adjuvant RT, 30 had 3D-CRT/IMRT and 26 had conventional RT.

      Results
      Five- and 10-year overall survival (OS) rates were 89.4% and 70.3%, respectively, for S+R and 81.5% and 65.2% for S alone (p=0.576). In the subgroup analysis, patients with 3D-CRT/IMRT showed a trend of improved 5-year OS compared with conventional RT (100% vs. 83.5%, p=0.093). Compared with S alone, the 5-year OS was significantly improved (100% vs. 81.5%, p=0.045). Recurrence rates were similar with and without adjuvant RT, but there was a significantly lower recurrence rate with 3D-CRT/IMRT compared with conventional RT (10% vs. 38.5%, p=0.Figure 1012).Figure 2

      Conclusion
      Adjuvant 3D-CRT/IMRT is potentially advantageous in improving survival rates and reducing recurrence in patients with completely resected stage III thymoma, but for the cohort as a whole, adjuvant RT did not significantly improve survival or reduce recurrence. This was a retrospective study, and a multicenter randomized trial will be necessary to verify the role of adjuvant 3D-CRT/IMRT in this disease.

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      P1.15-002 - Results and Prognostic Features of Recurrent Thymoma (ID 3020)

      C. Xu, Q. Feng, C. Fan, Y. Zhai, Y. Chen, H. Zhang, Z. Xiao, Z. Zhou, J. Liang, Z. Hui, D. Chen, J. He, L. Wang

      • Abstract

      Background
      This study sought to analyse the results and prognosis of recurrent thymoma.

      Methods
      Between 1991 and 2012, 32 patients who developed recurrence after radical resection of thymoma were reviewed.

      Results
      The initial Masaoka staging was stage I, 3; stage II, 14; stage III, 10; stage IVa, 4;and stage IVb, 1. World Health Organization tumor type: A and AB, 5; B1, 7; B2, 6; B3, 12; and unknown, 2. Among the 32 patients, relapses were found in the following sites: pleura (20 cases), tumor bed (10),non-tumor bed in mediastinum (one), lung (seven), chest wall (six), lymph node metastasis (four) , abdominal node metastasis (one),liver (one), pleural effusion (four), and overlapped recurrence (14).The patterns of recurrence: local recurrence, 6; regional recurrence, 8; distant recurrence, 5; local and regional recurrence, 6; regional and distant recurrence, 4; local, regional and distant recurrence, 3. The median recurrence interval was 42 months (range, 5–193 months). The median follow-up time after recurrence was 49.5 months (range, 1-136months). Overall 5-year survival after recurrence was 65.5%. 7 patients with relapse in the thorax are still alive after re-resection, with a median survival time of 26 months (range, 6-95 months). The perioperative mortality was 0% and the morbidity was 14%. 4 patients with local relapse were given radiotherapy (RT) alone, with a median survival of 60 months (range, 51-107months) and one was dead of progressive disease, probably due to lower reirradiation dose (50Gy), compared to others with radical radiation dose (60Gy). In patients with regional and/or distant relapse, 6 patients received chemotherapy, and had 37.5% of overall 5-year survival. 5 patients without re-treatment had 50% of overall 1-year survival, with median survival 3 months (range,1-20months). After re-treatment, 9 patients had re-relapse, and the re-relapse free survival rate was 63% at 5 years, with a median re-relapse free survival of 53 months (range, 11-69months). 1 of 15 patients with RT had radiation pneumonitis and recovered after management. In univariate analysis, age (<55y, ≥55y; p=0.009), patterns of relapse (p=0.042), and recurrence-free interval (<20months, ≥20months; p=0.038) were prognostic factors.

      Conclusion
      Reoperation for resectable thymoma recurrences is associated with better outcome and relative safety, and it should be recommended. In patients with local recurrence of thymoma, RT may get comparable survival to re-operation. RT/CT probably is the treatment of choice when re-resection is not feasible. Younger age, local and regional recurrence, and longer relapse-free interval are associated with positive prognosis.

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      P1.15-003 - Phase II study of amrubicin (AMR) and carboplatin (CBDCA) for invasive thymoma (IT) and thymic carcinoma (TC) : North Japan Lung Cancer Group 0803 (ID 951)

      S. Kuyama, A. Inoue, M. Nakanishi, Y. Kawashima, M. Harada, K. Kobayashi, T. Kozuki, T. Sakakibara, M. Maemondo, H. Asahina, A. Hisamoto, T. Nakagawa, T. Nukiwa

      • Abstract

      Background
      There has been no standard chemotherapy for advanced thymic malignancies including invasive thymoma(IT) and thymic carcinoma(TC) although anthracycline or platinum agents have been commonly used for them. AMR, a new anthracycline agent, was approved for lung cancer in Japan and we had previously conducted some prospective studies of AMR combined with CBDCA for patients with small-cell lung cancer, which revealed this regimen was active with acceptable toxicity. The objective of this study is to evaluate the efficacy and safety of this combination for patients with advanced thymic malignancies.

      Methods
      Patients with histologically confirmed thymic malignancies received AMR (35 mg/m2, day1-3) and CBDCA (AUC 4.0, day1) every 3 weeks. Patients who underwent previous chemotherapy received reduced dose of AMR (30 mg/m2). The primary endpoint was overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival and toxicity profile. Assuming that ORR of 75% and 45% would indicate the potential usefulness while ORR of 50% and 20% would be the lower limit of interest, with alpha = 0.10 and beta = 0.20, for IT patients and TC patients, respectively, 18 IT patients and 16 TC patients were at least required.

      Results
      From December 2008 to October 2012, 51 patients (18 IT and 33 TC) were enrolled from 20 institutions in Japan. The ORR and disease control rate were 17% and 89% in IT, and 30% and 85% in TC. Median PFS was 7.6 months in both groups. Toxicity was generally moderate and no treatment related death was observed.

      Conclusion
      This is the largest prospective study of chemotherapy for advanced thymic malignancies. AMR combined with CBDCA was effective for TC patients with acceptable toxicities.

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      P1.15-004 - Relationship of therapeutic results with immunohistochemical findings in thymic carcinoma cases (ID 1016)

      T. Kimura, Y. Shintani, T. Kawamura, S. Funaki, T. Nakagiri, M. Inoue, N. Sawabata, M. Minami, M. Okumura

      • Abstract

      Background
      A thymic carcinoma is a thymic epithelial neoplasm that has a large number of malignant features as compared to a thymoma. Since a thymic carcinoma is presented with locally advanced disease or distant metastasis, unresectable cases are frequently encountered at diagnosis, thus systemic chemotherapy is a key treatment strategy. Although cisplatin-based chemotherapy is usually administered for such cases, an optimal regimen has not been established. To determine a prognostic indicator for chemotherapy in patients with thymic cancer we evaluated the expressions of excision repair cross complementing-1 (ERCC1), class III β-Tubulin (TubIII), ribonucleotide reductase M1 (RRM1), and thymidylate synthase (TS)/orotate phosphoribosyltransferase (OPRT), which have been reported as possible indicators of the anticancer activity of cisplatin, taxanes, gemcitabine, and 5-fluorouracil drugs such as S-1, respectively.

      Methods
      Thymic carcinoma tissue samples obtained from 15 patients who underwent surgery or core-needle biopsy procedures between 1996 and 2007 at Osaka University Hospital were used. Immunohistochemical analysis was utilized to determine the expressions of ERCC1, TubIII, RRM1, TS, and OPRT in thymic cancer specimens, then the relationship between expression levels and clinical course were examined in a retrospective manner.

      Results
      Twelve males and 3 females (median age, 60.3 years) were studied. The histological subtype was squamous cell carcinoma in 10, small cell carcinoma in 2, large-cell neuroendocrine carcinoma in 2, and carcinoid in 1, while Masaoka classification was stage III in 4, IVa in 4, and IVb in 7. Surgical resection was performed as initial treatment in 8 patients. Chemotherapy, mainly platinum-based combinations, was administered in 12, including 6 who received combined radiotherapy. The median number of administered regimens and cycles were 2 (range, 1-9) and 7 (range, 2-44), respectively, for each patient. The response rate/disease-control rates following first- and second-line treatments were 83%/92% and 56%/78%, respectively. In 6 patients treated with gemcitabine, 3 tumors with a low expression of RRM1 showed a good response, whereas 2 of 3 tumors with a high expression of RRM1 showed a progressive disease response. S-1 was administered to 1 patient, which successfully suppressed tumor progression, and the specimen from that case demonstrated a low expression of TS and high expression of OPRT. We were able to obtain biopsy specimens before and resected tumors after treatment from 5 patients, in which the expressions of ERCC1, Tub III, and RRM1 were increased after treatment in 4, 3, and 4, respectively. Our results suggest that sensitivity to chemotherapy is lowered with additional courses in thymic carcinoma patients. The median survival was 36 months, while the 1-, 3-, and 5-year survival rates were 81.9%, 55.5%, and 23.1%, respectively.

      Conclusion
      First-line chemotherapy with platinum compounds may be effective treatment for patients with thymic cancer, while new drugs such as gemcitabine and S-1 might be useful in some cases. Prospective multi-institutional studies are required to ascertain the effectiveness of immunohistochemical evaluation used as a screening test for selecting the optimum chemotherapy regimen for thymic cancer patients.

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      P1.15-005 - Multimodality treatment for thymoma and thymic carcinoma: Results of a single center experience. (ID 1665)

      H. Mertsoylu, F. Köse, S. Muallaoğlu, A. Sezer, A.A. Beşen, C. Karadeniz, O. Ozyilkan

      • Abstract

      Background
      There are no randomized clinical trials that provide clear algorithm for the management of patients with thymoma or thymic carcinoma due to the rarity of these tumors.We review our experience with a multimodal approach in fourteen cases

      Methods
      Patients with thymoma and thymic carcinoma who were treated with multimodality treatment in our center between periods of 2006 and 2012 were retrospectively analyzed. Basic demographics, clinicalcharacteristics’ of the patients such as status of stage of tumor according to Masaoka Staging System, type of systemic chemotherapy, presence of paraneoplastic myasthenia gravis syndrome and surgical marginswere collected.

      Results
      Fourteen eligible patients were analyzed retrospectively. There were seven (50%) thymic carcinoma and seven (50%) thymoma. Included were 14 patients with a mean age of 50 years. Three patients (21.4%) had diagnosis of Myasthenia Gravis initially. There were four patients (28.6%), nine patients (64.3), one patient (7.1%) at stage II, Stage III, and stage IV, respectively. Nine patients were treated with multimodality treatment including surgery, chemoradiotherapy and adjuvant chemotherapy. Five patients were treated with chemoradiotherapy and adjuvant chemotherapy without surgical excision. Eight patients out of nine patients who were treated with primary surgery had positive resection margin (R1).Adjuvant protocol was consisted of cisplatin based chemotherapy. Median overall survival was 55 months (95% CI 11,4-98,5).One, two, and three year survival rate for thymoma was 85%, 85%, and 85%. Although, statistical analysis failed to show significant difference one, two, and three year survival rate for thymic carcinoma was inferior and found as 85%, 70%, and 43%, respectively. We were not able to show significant effects of patient and tumor baseline characteristics on overall survival.

      Conclusion
      Overall survival in our analysis seems to relatively inferior when compared with literature. We suggest that this result may be related with high rate of positive surgical margins and even absence of surgical excision in five patients a part of multimodal treatment.

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      P1.15-006 - Thymic malignancies. A single institution series from 2000-2012 (ID 2287)

      H. Jonker, M. Gomes, F. Shamji, P. Wheatley-Price

      • Abstract

      Background
      Thymoma and thymic carcinoma are rare malignancies, despite being amongst the most common tumours of the anterior mediastinum. The incidence of thymoma in the United States is approximately 0.15 per 100,000 person years. Thymoma research has proved challenging, and as such the International Thymic Malignancy Interest Group (ITMIG) has created an international database in an effort to promote the advancement of clinical and basic science research in thymic malignancies. We performed a single institution retrospective chart review to submit to ITMIG, collecting additional data regarding systemic therapy regimens.

      Methods
      With ethics approval, we performed a retrospective chart review of all patients seen at our institution between January 2000 and December 2012 with a diagnosis of thymic neoplasm. Data collected included baseline patient demographics, histology (WHO), staging (Masaoka), the presence or absence of associated paraneoplastic syndromes such as myasthenia gravis (MG), treatment decisions and survival. All lines and indications of systemic therapy were recorded.. The primary analysis is descriptive.

      Results
      In total 76 patients were included; 35 female (46%); median age at diagnosis 60 years (range 25-89) and 71 (93%) had a good performance status (ECOG 0-1). MG was present in 16 (21%). The WHO histological classification was: A (11, 15%), AB (23, 30%), B1 (12, 16%), B2 (10, 13%), B3 (13, 17%), C (5, 7%), NETT (1, 1%), and unclassified (1, 1%). Definitive surgery occurred in 64 cases (84%), with an R0 resection in 53 patients. For those who had surgery, 11 also received chemotherapy either as induction (6), adjuvant (4) or both (1); 27 received radiotherapy either as induction (2) or adjuvant therapy (25). Twelve patients (16%) were not treated surgically, and three patients received no therapy at all. In total only 14 patients (18%) received systemic therapy in any setting. Where evaluable, the first-line RECIST response rate was 55%, but no patients had progressive disease (Figure). Common first-line regimens were platinum/etoposide (8), carboplatin/paclitaxel (3) and CAP (cyclophosphamide, adriamycin, cisplatin, n=2). Only 3 patients received further chemotherapy (1 patient received 2 further lines; 2 patients received 3 more lines). The median follow up for all patients was 45 months, and 59 (78%) remain alive. Of the 5 thymic carcinoma patients, 4 have died (median survival 10 months).

      Conclusion
      While few patients received systemic therapy for thymic malignancies, it remains a chemosensitive disease, but surgical resection is the mainstay of treatment.Figure 1

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      P1.15-007 - Characteristics of thymomas diagnosed in National Tuberculosis and Lung Diseases Research Institute in Warsaw (Poland) (ID 2682)

      M. Szolkowska, R. Langfort, P. Rudzinski, E. Szczepulska-Wójcik, B. Maksymiuk, T. Orlowski

      • Abstract

      Background
      There were 152 thymomas diagnosed in Pathology Department of National Tuberculosis and Lung Diseases Research Institute from 1999 to the beginning of 2013. We performed a clinico-pathologic analyze of this rare group of neoplasms.

      Methods
      The diagnosis was establish on the investigation of totally resected tumors (126 cases) or small biopsied material (26). WHO histological classification of thymic tumors (2004) and Masaoka staging system were applied. The informations about patients age and gender, symptoms, other neoplasms, death and recurrence were collected.

      Results
      There were 86 (57%) women (median age 59 years) and 66 (43%) men (median age 54 years) in analyzed group. Myasthenic symptoms accompanied 50 (33%) tumors, 1 patient suffered from superior vena cava syndrom, the rest (101, 66%) was asymptomatic. In 6 (4%) patient another cancer was discovered: lung (3), renal (1), thyroid (1) and laryngeal (1) carcinoma. 147 thymomas were radiologically described as „mediastinal tumor”, 4 - „mediastinal cyst” and 1 thymoma on CT-scan was treated as mediastinal lymph node. Microscopic analysis revealed 9 (6%) type A thymoma, 42 (28%) AB, 27 (18%) B1, 16 (11%) B2, 4 (3%) B3, 4 (3%) micronodular, 2 (1%) metaplastic, 2 (1%) sclerosing and 1 (less then 1%) microscopic. 4 tumors were almost totally necrotized and the type could not be established, in 3 cases the specimen was to small to recognized the type. 38 (25%) tumors showed combined morphology composed of different types of thymomas, 1 tumor consisted of AB type and carcinoid. The most frequent combined thymomas were B2B3 (19) and B1B2 (8) types. The most histologic types appeared equally in both genders. B2B3 tumors concerned two times more frequent male patients and AB, B1 and micronodular were more common in women. Median age fell from micronodular type (78,5 years) followed by A (63 years), AB (58 years), B1 (55 years), B2 (52,5 years) and B3 (48 years). The tumors were usually in the 2nd stage. 18 (12%) patients died, 92 (60%) are still alive. The data were not available in 42 (28%) cases. The interval from resection to death was 1 month to 10 years. Histological types of thymomas diagnosed in patients who died included B1 (5 cases), AB (3), A (2), B2 (1) and 3 combined thymomas. The most tumors were in the 2nd stage. Recurrence occurred in 8 (5%) patients. Recurrent tumors appeared from 2 to 11 years after resection (median interval 8 years). The tumors were classified as B2 (2 cases), B2B3 (2), B1B2 (1), AB/B3 (1), AB/micronodular (1). The type was not determined in one case. Thymomas were in all stages except the 1st.

      Conclusion
      The thymomas appear mainly in 6th decade, more often in women. The most frequent histological type is AB and the tumors are usually microinvasive (the 2nd stage). High percentage of tumors has combined morphology. Recurrence can occur in any type of thymoma even considered as well-predicting but time to the progression often exceeds 5 years, so the tumors require long-term observations.

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      P1.15-008 - A multivariate analysis of factors predicting survival in 70 patients with thymic carcinoma: implications for treatment strategy (ID 2941)

      M. Harada, Y. Okuma, T. Hishima, S. Murakami, H. Horio

      • Abstract

      Background
      BACKGROUND: Thymic carcinomas are considered to be more aggressive than thymomas and carry a worse prognosis. Although a multimodality treatment is made in many cases as for thymic carcinomas, optimal therapeutic strategy still remains controversial especially in thymic carcinomas having poor prognostic factors. In the present study, we attempted to clarify the prognostic factors based on the survival to establish suitable treatment strategy.

      Methods
      METHODS: We performed a single-institution retrospective cohort study. Between June 1987 and October 2012, 70 patients were eventually given a diagnosis of thymic carcinoma. Data included patient demographics, stage, first treatment (e.g. chemotherapy (CT), chemoradiotherapy (CRT), and surgery (S)), pathologic findings, and outcomes. For the univariate analysis, we constructed survival curves using the Kaplan-Meier method and compared survival between groups using log-rank tests. Multivariate analysis was performed by constructing a Cox proportional hazards model using the significant factors from the univariate analysis. The analyses were performed with the Stat view v5.0 statistical software program.

      Results
      RESULTS: The overall 2- and 5-year survival rate was 61.9% and 36.4%, respectively ; mean and median observation time was 30M and 24M, respectively. Two-year survival rates in patients treated with CT, CRT, and S group were 38.7, 52.4, and 80.5%, and 5-year survival rates in patients treated with CT, CRT, and S group were 17.4, 21.0, and 55% for all patients. S group showed significantly better prognosis than the others in overall stage (p=0.0006). Patients undergoing S, however, had similar survival compared with undergoing CT or CRT alone in stage IV a,b subset; CT vs. CRT (p=0.6598), CT vs. S (p=0.1159), CRTvs.S (p=0.3030). Univariate analysis among patients underwent surgery revealed two significant prognostic factors (P <.05): stage by the Masaoka system and resection status. Based on the result, 5-year survival rate in each factor were compared statistically by Kaplan–Meier’s method; Masaoka stage II,III vs. IVa,b =82.5% vs.35.3% (p=0.0182), complete resection vs. incomplete resection=76.4% vs.34.1% (p=0.0173). Multivariate analysis revealed no statistically significant independent prognostic factor, probably due to confounding. The hazard ratio for death for being Masaoka stage II,III was 0.463【95%CI 0.082-2.623】(p=0.3843), for being complete resection was 0.552【95%0.110-2.762】(p=0.4701). According to the subset analysis on CT group, response to first-line chemotherapy was an independent prognostic factor.

      Conclusion
      CONCLUSIONS: Our analyses indicated that stage by the Masaoka system and resection status would have the prognostic impact. If complete excision is possible at earlier than Masaoka stage III, it may be cured completely. The role of debulking surgery at stage IV a,b was negative. Patient selection, accurate staging, and choice of anticancer drug with a high response rate may be critical to optimizing outcomes.

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      P1.15-009 - Outcomes and Predictors of Recurrence in Patients Treated with Risk-adapted, Post-operative Radiotherapy (RT) for Thymoma - A Single Institution, 30 Year Retrospective Study (ID 3124)

      A. Brade, N. Lalani, N. Safieddine, D. Hwang, S. Keshavjee, A. Bezjak

      • Abstract

      Background
      Thymoma is a rare epithelial cell tumour of the thymus, with an incidence of 0.15 per 100 000 persons. Thymic carcinomas comprise a distinct subset and have a greater propensity for capsular invasion and distant metastases when compared to thymomas. Resection is the standard of care for localized disease but local recurrence is generally incurable, thus post-operative RT is often employed for high risk cases. The optimal dose of RT has not been established, nor whether lower doses can be utilized in a risk-adapted fashion for cases where RT is recommended but the aggressiveness of the disease/risk of recurrence is felt to be at the lower end of the spectrum. Use of lower dose RT may help reduce the chances of late RT toxicity. Our institution employs such a risk adapted strategy and we present here our long term results.

      Methods
      Princess Margaret Cancer Center radiation and surgical oncology databases were queried from 1983-2012. Retrospective analyses using electronic patient records and Mosaiq radiotherapy database were performed to assess demographic data, clinical presentation and treatment. Descriptive statistics were used to report demographic data. Time to event analyses and correlation of outcomes with demographic and treatment variables are planned.

      Results
      Details on 104 patients treated with post-operative radiotherapy from 1983-2012 were available. The mean age was 52, range 29-73. Of patients assessed, 55/104 were male. Masaoka-Koga stage was assessed: 6% of patients were stage I, 31% IIA, 21% IIB, 27% III, 10% IV and 6% unknown. The most common WHO grade was B2 (37%) followed by B1 (16%). Complete surgical resection (R0) was obtained in 72% patients, R1 in 21%, R2 in 2% and 5% unknown. Radiotherapy doses ranged from 40 Gy – 66 Gy delivered in daily 2 Gy fractions; 57% patients were deemed low risk (typically R0 resection and WHO grade B2 or lower) and received 40Gy while 36% received between 45-66Gy. Neoadjuvant or adjuvant chemotherapy was delivered to 13% of all patients. The mean follow up period was 9.4 years, range 0.5-25.5 years, during which 22% patients experienced relapse. Of these, 43% experienced regional recurrence, defined as an intrathoracic relapse in an area not-contiguous with the thymic bed or original tumour; 39% local (intrathoracic relapse contiguous with original disease or thymic bed), and 17% distant recurrence defined as extrathoracic or intraparenchymal pulmonary nodules. For patients that experienced relapse, the median time to relapse was 8.7 years (range 1.3-18.3 years). Of the 59 patients who received 40 Gy/20 fractions, 8 developed local relapse (13.5%). Overall survival and multivariable analyses will be reported as will assessment of long term toxicities.

      Conclusion
      Risk-adapted RT prescription for patients with resected thymoma appears efficacious, and may result in an improved therapeutic ratio for these patients. Long-term, randomized controlled trials are required to further identify patients that are best suited to this approach.

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    P1.16 - Poster Session 1 - Other Thoracic Malignancies (ID 186)

    • Type: Poster Session
    • Track: Thymoma & Other Thoracic Malignancies
    • Presentations: 4
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      P1.16-001 - Outcomes of surgical resection and radiofrequency ablation for lung metastasis from hepatocellular carcinoma (ID 1219)

      T. Kobayashi, M. Kataoka, T. Kojima, T. Niguma, K. Yasui, K. Watanabe, H. Kawai, M. Muguruma, T. Mimura, T. Ohara

      • Abstract

      Background
      The lung is the most frequently targeted organ for extra-hepatic metastasis from hepatocellular carcinoma (HCC). Pulmonary metastases account for 33.1% of extra-hepatic metastases from HCC. However, in most cases, pulmonary metastatic lesions are multiple and the prognosis of patients is poor. No standardized treatment for this condition has been established to date. Radiofrequency ablation (RFA) is commonly used for the local control of hepatic tumors. Recently, computed tomography-guided RFA has been indicated for lung tumors, and promising results have been reported. We analyzed the outcomes of surgical resection and RFA, used either alone or consecutively, for pulmonary metastatic lesions from HCC.

      Methods
      Eleven patients with lung metastasis from HCC underwent surgical resection alone, RFA alone, or surgical resection followed by RFA for pulmonary metastases from HCC. The initial treatment for pulmonary metastasis was surgical resection in 7 cases and RFA in 4 cases. Two patients who underwent surgical resection as initial treatment also received RFA. Seven patients were male, and the average age at initial treatment for the lung lesions was 69.8 years (range, 50–78 years). Surgical resection was indicated especially for lesions close to the visceral pleura and RFA was indicated for relatively medial lesions.

      Results
      The average number of metastases per patient was 1.8 (range, 1–4). Tumor size ranged from 5 to 40 mm. No treatment-related deaths or severe complications were noted. The median survival time for all cases was 25 months. Three patients survived for more than 3 years after initial treatment. Of these 3 patients, 2 underwent both metastectomy and RFA and 1 underwent metastectomy alone. At initial presentation, none of these 3 patients had extra-pulmonary lesions and all 3 patients had solitary lung metastatic lesions.

      Conclusion
      Local therapy comprising surgical resection, RFA, or both might be beneficial for the treatment of lung metastasis from HCC in cases with no extra-pulmonary lesions and few lung lesions. RFA is minimally invasive and can be performed under local anesthesia, without the loss of lung volume.

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      P1.16-002 - Histological impact of primary tumor on indication of repeated pulmonary metastasectomy (ID 1346)

      T. Mizuno, T. Taniguchi, N. Usami, K. Kawaguchi, T. Fukui, F. Ishiguro, S. Nakamura, N. Ozeki, T. Kato, C. Yamatani, K. Yokoi

      • Abstract

      Background
      Lung is one of the most common metastatic sites from malignances. Although efficacy of pulmonary metastasectomy (PM) has been reported recently, the prevalence has not been enough among thoracic surgeons. Moreover, beneficial effects of repeated PMs for longer survivals have been poorly evaluated. The aims of this study are to examine the efficacy of repeated PMs (Re-PM) for re-recurred diseases and evaluate the histological impact of the primary tumor on the treatment.

      Methods
      We retrospectively reviewed 263 patients who underwent PMs for various malignancies from 1996 through 2011. These factors below were evaluated; age, gender, origin of primary tumors, disease free interval (DFI) to the first PM, surgical procedure of PM, number of resected tumors, frequency of PMs, DFI after the first PM, overall survival after the first PM and prognosis.

      Results
      Among 263 patients, 166 were male, and 98 were female. The median age was 60 years old (range: 7-85). Origins of primary tumors were following; 91 colorectum, 54 bone and soft tissue, 22 head and neck, 20 adnexa uteri, 17 urinary tract, 14 testis (germ cell tumor), 45 others. Mean number of resected nodules at the first PM was one, and the maximum was 19. Wedge resections were performed most frequently in 159 patients (60%), lobectomies in 69 (26%), segmentectomies in 32 (12%), and bilobectomies in 5 (2%). Re-PMs were indicated in 47 patients (18%). Among them, while the prevalence of Re-PM was 20% (18/91) in colorectal cancer patients, that is as high as 37% (20/54) in bone and soft tissue sarcoma patients. Estimated five-year survival rate of the whole patients was 50.6%. And that of patients without recurrence, with Re-PM and without Re-PM were 92.9, 58.5 and 14.5%, respectively. In univariate analyses, sublober resection of the first PM, DFI and presence of complete resection at the first PM were significant favorable factors for overall survival. In the multivariate analysis, sublober resection and presence of complete resection at the first PM were revealed to be the independent prognostic factors.

      Conclusion
      The large portion of Re-PM patients had colorectal cancer, or bone and soft tissue sarcoma as their primary tumor. Re-PM may improve the survival of selected patients who experienced re-recurrence in lung after PM. Primary tumor of bone and soft tissue sarcoma were the most applicable histology for Re-PM.

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      P1.16-003 - Features of computed tomography images and tumor viability: 141 lesions of pulmonary metastasis of non-seminoma (ID 1863)

      D. Kato, J. Shimada, M. Shimomura, H. Tsunezuka, S. Okada, S. Ishihara, H. Suzuki, M. Nishimura, K. Itoh

      • Abstract

      Background
      The standard treatment for advanced non-seminoma is to excise all residual masses, including pulmonary metastatic lesions, in patients whose tumor markers return to normal after chemotherapy. However, too many regions and too great a volume of the patient’s lung are often resected. On the other hand, viable cells are frequently not present in the resected tissue. This study therefore tried to identify distinct features of viable lesions on computed tomography (CT).

      Methods
      Figure 1From January 2008 to December 2011, 17 cases of non-seminoma with lung metastasis underwent lung resection after normalization of tumor markers (α-fetoprotein and hCG). To excise all very small or impalpable lesions, we performed lipiodol marking under computed tomography, for a maximum of 8 sites in one operation. CT images of the 141 resected lesions were investigated for size and properties, and compared with pathological findings. Statistical analysis was performed using the chi-square test.

      Results
      We confirmed viable cells in 8 of 17 cases and 47 of 141 lesions. In those cases, viable cells were detected in both lungs. However, no significant relationship was found between average size and cell viability. The minimum diameter of tumor showing positive pathological change was 3 mm. No significant relation was observed between pathological findings and CT characteristics such as solid, cystic, scar-like or clear boundary.Figure 1

      Conclusion
      The ability to excise tissue from the lung is limited, and we would like to avoid excision of lesions against which chemotherapy has already been successful and which do not contain residual cells. However, the present results suggest the difficulty of specifying regions with viable cells based on CT. For this reason, minute lesions should still be excised, and marking has a very important role to play.

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      P1.16-004 - Pleural Solitary Fibrous Tumor: a case series (ID 3402)

      H. Vidrio-Morgado, A. Herrera-Gomez, E. Jimenez-Fuentes, O. Arrieta, O. Macedo, M. Blake-Cerda, J.F. Corona-Cruz

      • Abstract

      Background
      Solitary fibrous tumors are rare neoplasm arising in the visceral pleura. Despite that most of them are known to have a benign course, caution is advocated because of their unpredictable clinical behavior. Surgery is the best treatment approach and longer survival is associated with complete resection.

      Methods
      Retrospective review from January 2005 to december 2012 for patients with diagnosis of pleural solitary fibrous tumor. Demographic and tumor variables were analyzed.

      Results
      Seven patients were treated at the National Cancer Institute in Mexico City with the clinical impression of a rare thoracic tumour. There were 5 females and 2 males with a mean age of 51.42 years old. After discarding other pleural and pulmonar malignancies, surgery was the only treatment modality used in the series with a curative intention. Tumorectomy with negative macroscopic margin was performed in 4 patients, a thoracoscopic wedge resection was performed in 1 patient, ; and 1 patient with a voluminous tumor required a pleuro-pneumonectomy to achieve a negative margin. One patient received only best supportive care because of the advanced of his disease and low performance status.. Resection was made by thoracotomy in 6 patients and only one patient was treated with thoracoscopy. The mean size of the primary tumour was 10.44 cm.. Median follow up was of 18 months (mean 42.4 months, range 3-158 months). Two patients developed a thoracic recurrence which could not be controlled with surgical resection and received only best supportive care.

      Conclusion
      Due to the rarity of this tumor there are no many tretament options. Most of this neoplasms have an indolent course with diagnosis only after they became larger and symptomatic. Complete surgical resection is by far the best chance for cure. However, in case of malignant solitary fibrous tumors, there are no established systemic therapy alternatives, either preoperatively or postoperatively.

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    P1.17 - Poster Session 1 - Bronchoscopy, Endoscopy (ID 182)

    • Type: Poster Session
    • Track: Pulmonology + Endoscopy/Pulmonary
    • Presentations: 10
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      P1.17-001 - Transumbilical versus conventional thoracoscopic lung wedge resection: safety and efficacy in a canine survival model (ID 246)

      Y. Liu, Y. Chu, Y. Wu, M. Hsieh, H. Liu

      • Abstract

      Background
      Transumbilical single-port surgery has been shown to be associated with less postoperative pain and offers better cosmetic outcomes than conventional 3-port laparoscopic surgery. This study compares the safety and efficacy of transumbilical and conventional thoracoscopy for lung wedge resection.

      Methods
      The animals (n = 16) were randomly assigned to the transumbilical approach group (n = 8) or conventional thoracoscopic approach group (n = 8). Transumbilical lung resection was performed via an umbilical incision combined with a diaphragmatic incision. In conventional thoracoscopic group, lung resection was completed through a thoracic incision. Surgical outcomes (operating time, operative complications), physiologic parameters, (respiratory rate, body temperature), inflammatory parameters [white blood cell (WBC), and pulmonary parameters (arterial blood gases) were compared for both procedures. The animals were killed at two weeks after surgery for gross and histologic evaluations

      Results
      The lung wedge resection was successfully performed in all animals. There was no significant difference between the mean operating times and complication for transumbilical or thoracoscopic approach group. Regarding the physiologic impact of the surgeries, transumbilical approach was associated with significant elevations in body temperature on postoperative days 1, when compared with the standard thoracoscopic approach.

      Conclusion
      This study suggests that both approach were comparable with respect to efficacy and post-operative complication in performing lung wedge resection.

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      P1.17-002 - The clinical significance of endobronchial ultrasound in the detection of peripheral pulmonary lesions (ID 339)

      I. Gkiozos, E. Syrigou, I. Kokkonouzis, A. Charpidou, S. Tsimpoukis, A. Vassias, K.N. Syrigos

      • Abstract

      Background
      Flexible fiberoptic bronchoscopy (FB) is the standard of care for the evaluation of pulmonary lesions. The aim of the current study is to investigate the effectiveness of EBUS-guided bronchoscopy compared to blind FB techniques in the study of non-visible pulmonary lesions.

      Methods
      We conducted a one year, retrospective, study comparing two populations: In the first one biopsies were performed conventionally (FB-B) with the help of static CT images and in the second biopsies were performed after EBUS- guidance (FB-EBUS). A 20- MHz radial- type ultrasound probe was used to obtain images. Sampling techniques, like bronchial brushing (BR) and transbronchial biopsies (TBB), were conducted in both populations by two separate bronchoscopists. If not a diagnosis was achieved a surgical biopsy or observation strategy was followed.

      Results
      Forty patients appeared with non visible lesions and were included in this study. Twenty patients were examined with the use of EBUS (FB- EBUS) and in twenty cases a conventional FB (FB-B) was conducted. Moreover left lower lobe was the most promising to obtain a diagnosis using ultrasonographic images.

      Conclusion
      Our results suggest that in patients with a non visible pulmonary lesion or SPNs a diagnostic strategy involving EBUS- guided biopsy techniques is a reasonable and effective choice.

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      P1.17-003 - Endobronchial valve treatment for pulmonary air leak after anatomical resection for cancer. (ID 1125)

      C. Dooms, H. Decaluwé, J. Yserbyt, P. De Leyn, D. Van Raemdonck, V. Ninane

      • Abstract

      Background
      Around 50,000 patients undergo each year a surgical resection for early stage lung cancer in the United States. Their median hospital stay after a lobectomy is 4-7 days. The European Society of Thoracic Surgery database shows that the percentage of pulmonary air leak present on day 5 is 6.8% for segmentectomy and 8.3% for lobectomy. This postoperative pulmonary expiratory air leak is usually managed conservatively. However, this is independently associated with prolonged hospital length of stay, decreased patient satisfaction, increased morbidity or postoperative complications. The use of endobronchial valves is a minimal invasive method that may be effective for the treatment of such a persistent postoperative pulmonary air leak.

      Methods
      In a prospective study, the efficacy of endobronchial valve treatment in 10 patients with a prolonged persistent pulmonary air leak after anatomic surgical resection for cancer was investigated. The primary study endpoint is the clinical efficacy on air leak cessation assessed using a digital thoracic drainage system and allowing chest tube removal. Other evaluations included avoidance of Heimlich valve, avoidance of additional surgical intervention, safety issues including complications related to endobronchial valve treatment, evaluation of consequences of airway closure on pulmonary function, and timing of endobronchial valve removal.

      Results
      Of all included patients, 90% was scheduled for valve treatment. We demonstrated air leak cessation at a median of 2 days after endobronchial valve placement, which resulted in chest tube removal at a median of 4 days after valve placement. Three patients were discharged with a Heimlich valve despite a significant reduction of their air leak after valve implantation. No single patient required additional surgical intervention. No deaths or implant-related events (such as infection distal to the endobronchial valve, hemoptysis, persistent cough, pneumothorax or expectoration of a valve) did occur. A significant decrease in FEV1 was found at airway closure by valve implantation, as compared to the functional status after valve removal (mean FEV1 53% versus 61% of predicted; p=0.0002). A 5-10% decrease in FEV1 was observed in patients when a right upper lobe was treated with endobronchial valves, while a 10-15% decrease in FEV1 was observed when a lower lobe was treated with endobronchial valves. Elective removal of the endobronchial valves was safely performed at a median of 23 days (range 14-28) after valve implantation.

      Conclusion
      Endobronchial valve treatment is an effective therapy for patients with a prolonged pulmonary air leak after anatomic resection for cancer. The aid of a digital thoracic drainage system is required as it guides endobronchial valve placement and allows a safe fast-tracking chest tube removal.

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      P1.17-004 - Bronchoscopy guided by fine mapping based on thin section CT. (ID 1633)

      R. Tong, L. Zhang, J. Wang, M. Li, S. He, G. Wang, S. Cheng

      • Abstract

      Background
      Diagnostic bronchoscopy has undergone a major shift in the past ten years, as the emerging of new guidance technologies, such as electromagnetic navigation bronchoscopy (ENB), virtual bronchoscopy (VB), radial endobronchial ultrasound (R-EBUS), ultrathin bronchoscope and guide sheath. These technologies have significantly enhanced the diagnostic capabilities of flexible bronchoscopy on peripheral pulmonary lesions (PPLs) compared with traditional methods. However, these procedures have not been routinely carried on in developing coutries, largely due to the high cost of both time and money. We invented a low cost and time-saving method, fine mapping by bronchoscopist based on thin-section CT, which could be extensively applied in developing countries to advance the diagnostic rate of PPLs.

      Methods
      This fine mapping method means bronchoscopist precisely analyzes the information of thin-section CT and targets the region of lesion, and draws the route from the segmental bronchial to the interested bronchial, including messages about relative spatial position and number of bronchial divarication along the route. The bronchoscopist inserts the bronchoscope according to the map, carefully observes the target, and then takes a brushing. The key point of this method is to comfirm the vertical sections of every bronchial divarication based on the multiplanner reconstruction (MPR) of CT scans. A cross-sectional study was conducted on 1148 PPLs of 1155 cases in terms of cytological diagnosis, lesion size, age, gender and histological type which cytological diagnosis all confirmed by histopathology, from July 2010 to June 2013 in the department of Endoscopy, Cancer Hospital, Chinese Academy of Medical Sciences. Between July 2010 and June 2012, traditional bronchoscopy and routine brush biopsy were done on 705 cases of PPLs. The new method of fine mapping was developed around June 2012, and selectivley carried on part of the PPLs from July to December 2012. Then we recruited 169 consecutive patients between January 2013 and June 2013 with records of possible related factors .

      Results
      The diagnostic rate on PPLs of these three groups was increased as 17.3%, 25.8% and 31.5% (P<0.001), while statistically significant was also revealed in lesion size as the average diameter of these each group was decreased as 3.02±1.538cm, 2.89±1.279cm, 2.72±1.227cm(P=0.04), and there was no significant difference between each groups in terms of age, gender, histological type. For PPLs of lesion size >3cm, these three groups’ diagnostic rate were 25.9%, 38.6% and 50.9% (P<0.001). For the third group that introduced the fine mapping method, according to the univariate logistic regression, the diagnostic yield of the 143 malignant PPLs were statistically significant with the lesion size, solid-appearing, relationship between lesion and targeted bronchus, distance from lesion to opening of the lobar bronchus and the mapping satisfaction degree (P<0.001, P=0.039, P<0.001, P=0.031 and P=0.012, respectively).

      Conclusion
      This convenient and economic method of fine mapping greatly advanced the cytology diagnositic rate of PPLs, especially for PPLs that of bigger size, solid-appearing, cut off sign of targeted bronchus, nearer to the lobar bronchial opening and clearer mapping to target. It showed that routine bronchoscopy introduced this new method might be necessary for selected patients of PPLs.

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      P1.17-005 - Evaluation of the implementation of interventional bronchoscopy: Local data from the Austin Hospital, Melbourne (ID 2169)

      Y.H. Khor, P. Wallbridge, B. Jennings

      • Abstract

      Background
      Newer interventional bronchoscopy techniques, including radial and linear endobronchial ultrasound (EBUS), and electromagnetic navigation bronchoscopy (ENB), have recently been established at the Austin Hospital, Melbourne. Linear EBUS has been recommended as the preferred method for preoperative invasive staging of non-small cell lung cancer with comparably high sensitivity compared to mediastinoscopy. Radial EBUS and ENB improve the sensitivity compared to conventional bronchoscopy for investigation of peripheral lung lesions. Radiologically guided transthoracic biopsy has superior diagnostic performance, radial EBUS and ENB are safer with significantly lower pneumothorax rate. We present our results of a newly established interventional bronchoscopy service in the evaluation of patients with suspected lung cancer.

      Methods
      A retrospective review was performed of all patients referred to our department for interventional bronchoscopy between April 2012 and June 2013 in whom lung cancer was suspected based on clinical presentation, radiographic imaging and/or positron emission tomography. Using physician-led conscious sedation, the procedures were performed or supervised by an experienced bronchoscopist. Procedure related complications were also recorded. Non-diagnostic procedures were classified as true negative if an alternative tissue diagnosis was found, the lesion resolved on follow up or if another diagnostic procedure confirmed the negative result. Patients with negative results with no follow up data available were included as false negative.

      Results
      Linear EBUS Of the total 92 cases, 43 (47%) were performed for investigation of suspected malignancy. TBNA was not performed in one of the cases as no abnormal lymph nodes were identified on EBUS. Sensitivity was 98%, specificity 100%, positive predictive value 100% and negative predictive value 91%.

      Malignanat Lesions Numbers (n)
      Primary Lung Cancer Small cell carcinoma Non-small cell carcinoma - unclassified Adenocarcinoma Adenosquamous carcinoma SquamousOthers Metastatic breast cancer Lymphoma 14 2 16 2 4 1 2
      Peripheral lung lesions 40 cases of radial EBUS and 16 cases of ENB were performed. For malignancy, the diagnostic yields for radial EBUS and ENB were 70% and 40%, respectively. Non-malignant diagnoses were found in 10 cases and an infective organism was identified in 8 of these. Complications There was no significant complication requiring hospital admissions, blood transfusions or surgical interventions. Minor complications include bleedings (3), tachycardia or arrhythmia (5), excessive cough (3), agitation (1), hypertension (1).

      Conclusion
      The results of the interventional bronchoscopy service at the Austin Hospital is comparable with published data on these procedures. This has improved the assessment of patients with suspected lung cancer.

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      P1.17-006 - Early Bronchoscopic Interventional Strategy in Highly at Risk Morbid Ageing Cohort (ID 2322)

      I. Smesseim, R. Boerdonk, K. Grünberg, J.M.A. Daniels, A. Maier, P.E. Postmus, T. Sutedja

      • Abstract

      Background
      We retrospectively reviewed our longitudinal data (1992 - 2012) with regard to early interventional techniques using advancements of non- and minimally invasive techniques (NiMiT) as alternatives for early intervention in squamous carcinogenesis in highly at risk -including frail elderly individuals. >50% lung cancer develops in >70 years age cohort and cancer and ageing are becoming an important health care issue in our society.

      Methods
      So far, 159 surgically non-resectable candidates with various comorbidities (Previous LC/ENT primaries, COPD, etc.) have been closely monitored using autofluorescence bronchoscopy for suspicious endobronchial lesions (e.g. dysplasia, carcinoma in situ and microinvasive squamous cancer). End points were the development of squamous cancer and its outcome with the use NiMiT (Chest 2001;120:1327; Respiration 2004;71:391

      Results
      Patient characteristics and outcome are shown in the table. Cohort analyses of age ≤70 years versus over, showed a significant longer time of survival in the elderly cohort (35.9 vs 18.5 months; p = 0.01). Lung cancer specific mortality was low ,respectively 15% and 22%. Table: Longitudinal carcinogenesis study in cohorts highly at risk to develop (subsequent) squamous cancer primaries and its outcome.

      Age cohort (years) n patients <70 112 >70 47 p-value
      Gender - Male - Female 93 (83%) 19 (17%) 39 (83%) 8 (17%) NS
      Mean age years (range) 60(42-70) 74(70-83)
      Indication for close surveillance: - Previous LC /ENT cancer - Suspicion occult lung cancer 55 (49%) 57 (51%) 19 (40%) 28 (60%) NS
      Mean pack-years smoked (range) 44(4-120) 49(20-137) NS
      COPD Non-COPD Unknown 72 (64%) 32 (29%) 8 (7%) 29 (62%) 10 (21%) 8 (17%) NS
      Interval to (subsequent) primaries (months) 69(0-198) 54(1-184) NS
      Acquiring (subsequent) squamous ca. Recurrences of previous primaries 41 (37%) 4 (4%) 12 (26%) 2 (4%) NS NS
      Death due to lung cancer Other causes 25 (22%) 31 (28%) 7 (15%) 17 (36%) NS NS
      Survival after curative treatment (months) 19 (0-110) 36 (0-106) 0,01

      Conclusion
      In contrast to the undocumented belief about less aggressive cancer, the need for less aggressive treatment, potential toxicities in the co-morbid elderly and their expected shorter life span, the outcome shows that early interventional strategy is warranted. LC mortality is relatively low despite the highly negative selection bias, especially in the frail – ageing – subcohort. This warrants further studies to increase the cost-effectiveness of NiMiT in our ageing population.

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      P1.17-007 - A proposal for a new clinical strategy and follow-up in patients with bronchial carcinoids initially treated bronchoscopically. (ID 2468)

      H.A.P. Brokx, M.A. Paul, K.J. Hartemink, J.M.A. Daniels, T. Sutedja, P.E. Postmus

      • Abstract

      Background
      Bronchial carcinoids (BC) belong to the wide spectrum of neuroendocrine tumors; ranging from tumorlets, typical carcinoid (TC), intermediate-grade atypical carcinoid (AC), to highly malignant large cell neuroendocrine and small cell carcinoma. The Travis classification (Am J SurgPathol 1998; 22:934) seems essential for choosing the best treatment strategy based on retrospective analyses of surgically resected specimens. We implemented an initial bronchoscopic treatment (IBT) strategy and its long term outcome have been reported with update of the final analysis (J Thorac Cardiovasc Surg. 2007 Apr;133(4):973; Abstract IASLC Sydney submitted). The long-term outcome seems to justify IBT and the histological differentiation between typical versus atypical seems to matter much less, while conservation of normal lung parenchyma is optimal. We question how optimal the close surveillance strategy of IBT protocol should be, i.e. in performing regular high resolution CT (HRCT) and/or bronchoscopy after the initial success of bronchoscopic treatment.

      Methods
      In the IBT protocol, HRCT and bronchoscopy were performed 6-monthly in the first two years and annually until the fifth year. Thereafter a yearly check-up was advised to the referring pulmonologists. We analyzed retrospectively the value of HRCT and/or bronchoscopy in this IBT cohort for early detection of local recurrences, that require surgical salvage.

      Results
      So far, IBT was successful in 57 of the 133 patients (43%). Sixty-seven patients (50%) could be immediately identified to be surgical candidates without further delay due to obvious extraluminal tumor growth. Four patients (3%) developed extraluminal tumor recurrence and surgical salvage was performed at 47, 104, 115, 192 months. In all four cases follow-up HRCT suggested local extraluminal tumor growth, which were confirmed by bronchoscopy. The surgical outcome was radical and did not lead to more extensive resections than initially anticipated. Detailed treatment results are shown in table 1. Table 1. Initial bronchoscopic treatment strategy in patients with bronchial carcinoids

      BT Completion Surgery Remark
      Number of patients 62 71
      Histology TC AC 56 (90%) 6 (10%) 43 (61%) 28 (39%)
      Follow up (median) in months 87.5 (2-223) 87 (12-264)
      Completely resected 57 (92%) 64 (90%)
      Residual after CT/recurrences Additional treatment bronchoscopy Additional treatment surgery 3 4 0 0 Interval in months: 10,13,63 47,104,115,192
      Alive with disease 5 0 2 unfit for surgery 3 refused surgery
      Alive with metastatic disease 0 1 40 months
      Carcinoid related mortalities 0 2 Pulmonary metastases
      Treatment related mortalities 0 1
      Non-carcinoid related mortalities 8 3

      Conclusion
      Initial bronchoscopic treatment strategy in patients with bronchial carcinoids is justifiable. Local regrowth after successful bronchoscopic removal was infrequent (3%) and was timely detected by HRCT. HRCT can be performed much less frequent and regular bronchoscopy was redundant if IBT attempt was successful. The significance of an iceberg phenomenon is questionable.

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      P1.17-008 - Results of a close surveillance strategy for subjects with pre-invasive endobronchial squamous lesions (ID 2678)

      I. Smesseim, R.A.A. Van Boerdonk, D.A.M. Heideman, V.M.H. Coupe, D. Tio, P.E. Postmus, E.F. Smit, P.J.F. Snijders, K. Grünberg, E. Thunnissen, J.M.A. Daniels, T. Sutedja, H.A.P. Brokx

      • Abstract

      Background
      The dismal overall 5-year survival of non-small cell lung cancer (NSCLC) patients is mainly due to advanced stage of disease at time of initial diagnosis in most and the inability to cure metastatic disease in all patients. In contrast, the prognoses of in situ mucosal and small parenchymal lesions are excellent. Early detection strategies might result in the identification of early-stage, (pre-)invasive lesions that are still eligible for curative treatment. The present study was set out to characterize the risk of lung cancer development in a cohort of high-risk subjects harboring pre-invasive endobronchial lesions and to assess the results of surveillance using autofluorescence bronchoscopy (AFB) and computed tomography (CT) scan.

      Methods
      Between November 1995 and December 2012, one hundred and sixty-four at risk individuals with pre-invasive endobronchial lesions were monitored by repeated AFB and CT. During the course of surveillance, progression of lesions to cancer (in situ), recurrences and second primary cancers were treated with different modalities (e.g. endobronchial techniques, surgery, radiotherapy), depending on tumor stage and location. Log-rank tests were performed to examine the relation between baseline characteristics and progression-free and overall survival (PFS and OS, respectively). Cox regression was used for multivariate survival analysis.

      Results
      Demographical and clinical variables of the cohort are shown (Table). At inclusion, 80 individuals were identified with one or more high-grade pre-invasive lesions (severe dysplasia or CIS; HGD), whereas 84 subjects were identified solely with lower grade pre-invasive lesions (LGD). During close surveillance (median follow-up (FU) of 30 months, range 4-152), sixty-one lung cancers were detected (26 CT-detected, 35 AFB-detected cancers) in 55 individuals within a median time to event of 16.5 months. Mean PFS was similar between individuals with radiographically occult lesions vs. FU after surgery for early-stage NSCLC/ENT ca (122.3 vs. 126.9 months, p=0.237) and COPD vs. non-COPD (118.8 vs. 136.8 months, p=0.162). There was a relatively large difference in PFS between LGD and HGD groups (142.6 vs. 93.7 months, p=0.057). Independent risk determinants for OS were indication for surveillance (FU after surgery for early-stage NSCLC/ENT ca vs. radiographically occult lesions, p=0.008) and COPD-status (COPD vs. non-COPD, p<0.001).

      Referral for radiographically occult lesion Follow-up after surgery for early-stage NSCLC / ENT ca
      total
      individuals, n 164 92 72
      Gender
      male 134 72 62
      female 30 20 10
      Age at baseline
      years, mean (range) 64.2 (42-83) 64.8 (42-81) 64.0 (43-82)
      Smoking status
      current smoker 75 44 31
      former smoker 74 36 38
      unknown 15 12 3
      Smoking history
      Pack-years, mean (range) 45 (4-137) 45 (4-120) 40 (15-137)
      COPD-status
      COPD 100 56 44
      non-COPD 45 22 23
      unknown 19 14 5
      AF Bronchoscopies
      Number, mean (range) 7 (1-27) 5 (2-27) 6 (1-18)
      CT-scans
      Number, mean (range) 3 (0-20) 2 (0-20) 3 (0-18)
      No. of detected lung cancers
      During surveillance period 61 29 32
      Parenchymal cancer 21 12 9
      Site-specific lesion progression 24 13 11
      Interval cancer 10 4 6
      Recurrences previous primaries 6 0 6
      Patient outcome
      alive 80 56 24
      died of lung cancer 33 13 20
      died of other/unknown cause 51 23 28

      Conclusion
      Our findings demonstrate that individuals with pre-invasive endobronchial lesions are at high risk of developing (second primary) lung cancers. Combined surveillance using AFB in addition to CT screening facilitated early detection and early (endobronchial) intervention in most patients. Future clinical trials are warranted to determine whether the current approach improves patient outcome.

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      P1.17-009 - What is the rate of surgical upstaging following negative EBUS-TBNA of mediastinal lymph nodes for NSCLC? (ID 2621)

      P.N. Antippa, M.G. Mehta, L. Irving, D. Steinfort, M.Y. Cheang, A. Tsui

      • Abstract

      Background
      Mediastinal lymph node evaluation is a critical determinant of treatment strategy in NSCLC. Many staging modalities, both invasive and non-invasive, have been evaluated over the past few decades with varying degrees of accuracy. Despite the fact that CT imaging is the preliminary investigation for diagnosis of lung cancer, various studies have shown that CT scanning is less accurate (sensitivity of 41% to 63%, a specificity of 43% to 57%, and an accuracy of 39% to 59%) for the detection of mediastinal nodal metastasis. According to a meta analysis looking at nodal disease, the sensitivity for PET is 79% to 84% and its specificity is 89% to 91%.The ability of PET CT to provide morphologic and functional information enhances the diagnostic accuracy of mediastinal nodal staging in NSCLC . Most guidelines would however need tissue confirmation which can be obtained by EBUS- TBNA. This procedure has the advantage that it can be performed under sedation , however , the downside to this is the small samples without accurate anatomical definition. In our institute we perform PET-CT scan followed by EBUS TBNA for pre operative staging of the mediastinal lymph node {in selected cases}. However, in cases where EBUS-TBNA of mediastinal lymph nodes is negative for malignancy, there is still a possibility that metastases to these lymph nodes are found at surgery. This will result in an upstaging of the NSCLC following surgery. We aimed to determine the rate of surgical upstaging following negative EBUS-TBNA of mediastinal lymph nodes for NSCLC.

      Methods
      This is a retrospective study. From January 2009 till May 2013, we identified 304 patients who underwent surgery for NSCLC. All the patients who were planned for surgical resection underwent a staging CT scan thorax or a PET CT scan. Only those patients with suspicious lymph nodes on either of the imaging, were subjected to EBUS TBNA. These lymph nodes were then re-evaluated by histopathology following surgery. Of these 65 patients who had EBUS-TBNA prior to surgery , fifty-three patients had negative EBUS-TBNA and they formed the basis of this report.

      Results
      Out of the 53 patients with a negative EBUS-TBNA, nine of them (17%) demonstrated positive lymph nodes in surgery, giving a negative predictive value of 83% for EBUS-TBNA in this selected group. The negative predictive value of PET CT was around 77% whereas negative predictive value for EBUS TBNA was 83%.

      Conclusion
      Our study confirms a negative predictive value (83%) of EBUS-TBNA in excluding N2/3 disease in patients diagnosed with NSCLC which is higher than PET CT scan (77%). The slightly lower negative predictive value of EBUS TBNA may be attributed to the fact that not all the surgical candidates were staged with a pre operative histological confirmation of the mediastinal lymph nodes. However a combination of PET CT scan and EBUS TBNA is a reasonable pre operative staging for mediastinal lymph nodes with low complication rates.

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      P1.17-010 - Diagnostic medical thoracoscopy for pleural effusions of unknown etiology: Inspection delay may cause non-deterministic endoscopic diagnosis (ID 3056)

      K. Kanazawa, T. Ishida, K. Hirai, H. Minemura, S. Sekine, H. Yokouchi, A. Fukuhara, S. Sato, Y. Tanino, M. Munakata

      • Abstract

      Background
      Thoracoscopy is a useful tool for diagnosis of exudative pleural effusion of unknown etiology, and the efficacy and safety have already been established. The procedure is relatively easy and can be performed under local anesthesia with conscious sedation. We investigated the factors associated with thoracoscopically undiagnosed patients in our hospital.

      Methods
      Clinical records were reviewed retrospectively. We found 101 patients who underwent medical thoracoscopy from April 2000 to May 2013, and then we identified 91 eligible patients for the detailed analysis. All the procedures were performed utilizing a flexible bronchoscopy (type-240, Olympus Corporation, Tokyo, Japan) or a semi-rigid thoracoscopy (LTF type-240, Olympus Corporation, Tokyo, Japan) from a single-port under local anesthesia.

      Results
      The median age of the patients was 69 years old (range, 32-89), and 79 (86.8%) were male. Affected sides of effusion were right/left/bilateral = 60/26/5. Definitive diagnoses were obtained in 73 (80.2%) cases. In 21 (23.1%) patients, the duration from the disease-onset to the examination was more than 3 months. In 18 (19.8%) thoracoscopically undiagnosed patients, the number of patients according to the time from disease-onset to the examination was as follows; none within 1 month, 7/46 patients (15.2%) in 2 to 3 months, and 11/36 patients (30.6%) in more than 4 months. No remarkable complications, other than a moderate hemoptysis, were seen.

      Conclusion
      Medical thoracoscopies were safe, and they contributed to definitive diagnoses. The delay of thoracoscopic examination from the disease-onset tended to lead non-specific findings in pathological diagnosis. Diagnostic medical thoracoscopy should be performed as soon as possible when the cause of pleural effusion is undetermined with thoracentesis.

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    P1.18 - Poster Session 1 - Pathology (ID 175)

    • Type: Poster Session
    • Track: Pathology
    • Presentations: 22
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      P1.18-001 - The prevalence and clinicopathologic feature of ALK, ROS1 and RET fusions in East Asian patients with lung adenocarcinoma (ID 49)

      W. Cai, C. Zhou, S. Ren, C. Su, X. Li, W. Li, S. Li

      • Abstract

      Background
      ALK, ROS1 and RET fusions have been demonstrated as oncogenic drivers in lung cancer. Of these, ALK fusions were shown to occur more frequently in patients with mucinous adenocarcinoma or solid histology with signet-ring cells. The association of ROS1 and RET fusions with the adenocarcinoma component remains unclear. We conducted this study to determine the prevalence and clinicopathologic characteristics of ALK, ROS1 and RET fusions in East Asian patients with lung adenocarcinoma, and investigate the association of the above-mentioned gene fusions with histological subtype of adenocarcinoma according to the IASLC/ATS/ERS Classification.

      Methods
      We screened 620 Chinese patients with histologically confirmed lung adenocarcinoma for ALK, ROS1 and RET fusions using multiplex RT-PCR and validated all fusion-positive patients using direct sequencing. The patterns of gene fusions screened in this study contained EML4-ALK (17 variants), CD74-ROS1, SLC34A2-ROS1, SDC4-ROS1, EZR-ROS1, TPM3-ROS1, LRIG3-ROS1, GOPC-ROS1, KIF5B-RET, CCDC6-RET and NCOA4-RET. The association of ALK, ROS1 and RET fusions with different subtype of adenocarcinoma were analyzed in 331 patients. The data for remaining 289 patients are being analyzed. All patients enrolled in this study were followed up for survival.

      Results
      Of the 620 patients with adenocarcinoma screened, 472 (76.1%) patients were never/light smokers (<10 pack-years), and 148 (23.9%) were smokers (≥10 pack-years), with the median age of 59 (range, 27-82) years; 348 patients were female, accounting for 56.1%. Patients with stage I, II, III, or IV disease accounted for 56.6%, 8.7%, 27.1% and 7.6%, respectively. The prevalence of ALK, ROS1 and RET fusions in this study was 8.1% (50/620), 3.5% (22/620) and 1.9% (12/620), respectively. Among the 331 patients diagnosed by the IASLC/ATS/ERS Classification, 15 patients were identified positive for EML4-ALK fusions (including 8 solid, 2 acinar, 2 colloid, 1 lepidic, 1 papillary and 1 micropapillary predominant), 7 patients were positive for ROS1 fusions (including 2 acinar, 2 papillary, 1 lepidic, 1 solid and 1 mucinous predominant), and 4 patients were positive for RET fusions (including 2 acinar, 1 micropapillary and 1 solid predominant).

      Conclusion
      These fusion-positive patients may have unique pathologic feature compared with fusion-negative patients. EML4-ALK fusions were shown to occur in solid predominant adenocarcinoma with a higher frequency in this study. The association of ALK, ROS1 and RET fusions with the subtype of lung adenocarcinoma and the data of survival are being analyzed in all patients and will be presented at the conference.

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      P1.18-002 - Epidermal Growth Factor Receptor Mutations in Primary and Metastatic Adenocarcinomas from a Tertiary Hospital in Sao Paulo, Brazil (ID 98)

      V.K. De Sa, E.C. Nascimento, S.I. Meireles, V.L. Capelozzi

      • Abstract

      Background
      Recently, the epidermal growth factor receptor (EGFR) mutation emerges promise as target for molecular therapy in Adenocarcinomas of the lung. However, a number of clinical features are associated with EGFR mutations: women, never-smokers than former or current smokers and Asians than other ethnic groups. Sao Paulo population is made up of a confluence of people of several different origins, from the original Native Americans, with the influx of Portuguese colonizers, Black African slaves, and recent European, Arab and Japanese immigration. Other significant groups include Koreans, Chinese, Paraguayans and Bolivians. The aim of this study was to evaluate the frequency and distribution of EGFR mutations in 100 consecutive patients with surgically excised primary and metastatic Adenocarcinomas.

      Methods
      Direct bidirectional sequencing evaluated EGFR gene mutations on exons 18 to 21 and was correlated with ethnia (East-Asian or European), gender, age, tobacco history, primary (N=75) or metastatic (N=25) and histologic subtypes.

      Results
      Twenty-eight tumors (28%) exhibited EGFR mutation. The most frequent EGFR mutation detected was a deletion in exon 19 (50%), followed by multiple mutations in the exon 20 (28%) and an L858R amino acid substitution in exon 21 (21,4%). EGFR mutation was significantly associated with men (N=59), older patients (>60yrs), smokers, non-East Asian or non-European origins, primary tumor and acinar predominant histologic subtype.

      Conclusion
      Our results indicate that if the current clinical features were strictly followed as the criteria for selecting patients for EGFR testing, a substantial number of patients who might benefit from treatment will be excluded.

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      P1.18-003 - Immunohistochemical detection of Epidermal Growth Factor Receptor Mutations in Patients with Non-Small Cell Lung Cancer. (ID 855)

      A. Bondgaard, E. Hoegdall, A. Mellemgaard, B.G. Skov

      • Abstract

      Background
      Determination of Epidermal Growth Factor Receptor (EGFR) mutational status has pivotal impact on treatment in non-small cell lung cancer (NSCLC). A standardized test has not yet been approved. DNA sequencing has previously been regarded as gold standard method. The rather low sensitivity of this method has led to development of more sensitive, but also more complicated methods including real-time PCR (RT-PCR). Immunohistochemistry (IHC) with mutation specific-antibodies may be a promising method for detection EGFR mutations in NSCLC.

      Methods
      This case-control study includes 191 patients (36 patients with an EGFR mutation and 155 wild type (WT) patients (randomly selected)) as detected by RT-PCR (Therascreen EGFR PCR kit, Qiagen, UK). This method identifies 29 somatic mutations from exons18-21 with a sensitivity of 1%. For EGFR IHC, antibodies against mutations in exon19 (clone 6B6) and exon21 (clone 43B2) by Cell Signaling Technology (USA) were used. All specimens were visualized according to the standardized protocol of EnVision FLEX+ system (DAKO, DK).The protein expression for each specimen was evaluated and a H-score, including intensity (graded 0-3) and percentages (0-100) of stained malignant cells, was calculated. A positive tumor was defined by a H-score value>0. The sensitivity (true positive/(true positive + false negative) and specificity (true negative/(true negative + false positive) were evaluated with the results from Therascreen EGFR PCR kit as reference.

      Results
      The sensitivity and specificity of the mutation-specific antibodies are presented in Table1.

      Sensitivity (%) 95% CI Specificity (%) 95% CI
      Exon19del(E746-A750) 60.0 32.3-83.4 99.3 96.3-100
      Exon21(L858R) 87.5 47.4-99.7 97.4 93.5-99.3
      Table1: Performance of the EGFR mutation-specific antibodies. CI = confidence interval, Del = deletion. For mutations in exon19, 5 specimens were false negative (IHC-, RT-PCR+) and 1 was false positive (IHC+, RT- PCR-). For mutations in exon21, 3 samples were false negative and 3 were false positive. 1 false positive for exon21 had maximal H-score (300).

      Conclusion
      We demonstrated a high specificity for IHC with mutation-specific antibodies for detecting EGFR mutations in patients with NSCLC. However, the sensitivity was low, especially for del19-mutations, and thus these antibodies are not yet ready as a screening method for detection of these mutations. We used RT- PCR as reference. This method is very sensitive compared to conventional Sanger sequencing being able to detect mutations present in 1% of the malignant cells. Some studies in NSCLC have questioned whether detection of such a small fraction of malignant tumor cells has clinical relevance for treatment of the whole tumor. The mutation-specific antibodies might be compared to highly sensitive methods, including RT-PCR and validated in clinical trials in order to detect the clinical impact of both methods.

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      P1.18-004 - The Relationship Between EGFR Mutations and the Clinicopathologic Features of Lung Adenocarcinomas Diagnosed by the Small Biopsies (ID 961)

      K. Shin, J.H. Chung, K.H. Lee, M.J. Kim

      • Abstract

      Background
      EGFR mutation analysis is necessary and important in clinical practice. But sometimes advanced lung cancer is diagnosed by cytology or inadequate specimens for DNA extractions. To decide the treatment of these patients, it is helpful to investigate the surrogate marker to predict EGFR mutation. There has been many reports about the association of EGFR mutation with clinicopathologic features, but most of them were investigated by the resection specimens. This study was aimed to find the relationship between EGFR mutations and clinicopathologic features in small biopsy specimens.

      Methods
      The medical records of 359 lung adenocarcinoma patients who diagnosed from 2008 to 2011 were reviewed. All the specimens of these patients were investigated for EGFR mutations (Exon 18-21) by direct sequencing method. 134 specimens were classified according to IASLC/ATS/ERS classification and studied the relationship between EGFR mutation and histologic subtype.

      Results
      We can ascertain that incidence of EGFR mutations is associated with gender and smoking history in small biopsy specimens(Table 1). This is already well-known, but almost researches were investigated by resection specimens. EGFR mutations were more frequently observed with acinar and lepidic components, conversely infrequently with solid and mucinous components. The positive expression of TTF-1 was also related with more frequent EGFR mutations than negative expression. Pathologic features that even if it is confirmed by small biopsy specimens can predict EGFR mutation status. Table 1. Relationship between EGFR mutation and clinical features Figure 1 Table 2. Relationship between EGFR mutation and histologic subtype by IASLC.Figure 2

      Conclusion
      Clinicopathologic features can predict the EGFR mutation status, but cannot replace the mutation analysis. Histologic subtypes of lung adenocarcinma, even if it confirmed by small biopsy specimens can be a good predictive marker of EGFR mutations.

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      P1.18-005 - Clinicopathological features and prognostic significance of tumor invasion into the interlobular septal area and perivascular area (ISA/PA) in lung adenocarcinoma (ID 1049)

      K. Kamiya, T. Fukutomi, A. Yoshizu, H. Hayashi

      • Abstract

      Background
      Lung interstitium is composed of the interlobular septal area (ISA), perivascular area (PA), and visceral pleural area. Tumor invasion into the visceral pleural area is recognized as a prognostic factor in lung cancer, whereas invasion into the ISA/PA has not been clearly examined. The aim of this study was to evaluate the clinicopathological features and prognostic significance of invasion into the ISA/PA in lung adenocarcinoma.

      Methods
      A total of 132 patients with pathological stage I lung adenocarcinoma who were treated with surgical complete resection from 2000 to 2006 in the Yokohama Municipal Citizen’s Hospital were retrospectively evaluated (mean follow-up period 79.1 months). Tumor invasion into the ISA/PA was defined as the existence of tumor cells in that area or septum discontinuity around the area due to tumor cells. Hematoxylin-eosin and Victoria-blue stained slides for each case were reviewed by two investigators. The correlation between a presence of the feature and clinicopathological characteristics or prognosis was analyzed using the chi-square test, log-rank test, and Cox proportional hazards regression model.

      Results
      In 53 cases, we were unable to identify the ISA/PA area adjacent to the tumor or the existence of the septum itself, particularly in those with small sized tumors or poorly differentiated cases; therefore, they were excluded from the analysis. We subsequently divided the remaining 79 cases into the following two groups: invasion in the ISA/PA-positive (n = 36) and ISA/PA-negative group (n = 43). Lymphatic and venous invasion was identified significantly more frequently in the positive than negative group (p = 0.012/0.001). No significant difference between the two groups in gender, age, smoking habit, tumor size, or visceral pleural invasion was observed. Disease-free and overall survival rates for the positive were significantly worse than those for the negative group (p = 0.002/0.012). Multivariate analysis demonstrated an independent prognostic effect of the feature (p = 0.04). Further, when we limited the analysis to lymphatic and venous invasion-negative cases (n = 42), we found that every relapsed case (n = 4) had the feature but no visceral pleural invasion.Figure 1

      Conclusion
      It is believed that invasion into the ISA/PA is a feature predictive of tumor invasiveness and may be a prognostic factor in stage I lung adenocarcinoma. This finding may portray the previous phase of lymphatic or venous invasion. Unfortunately, we were unable to evaluate the feature in many cases of this study. Further studies are needed to elucidate the clinical significance of this finding.

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      P1.18-006 - Clinicopathological features and outcome of gastric metastasis from primary lung cancer: a case report and systematic review (ID 1293)

      Q. Huang, X. Su, J. Fu, K. Luo, S. Zhang, T. Rong, A. Ela Bella

      • Abstract

      Background
      Primary lung cancer is one of leading cancer all over the world, while gastric metastasis from lung cancer is extremely rare. We know little about its clinicopathological features, prognosis and treatment strategy.Primary lung cancer is one of leading cancer all over the world, while gastric metastasis from lung cancer is extremely rare. Its clinicopathological features, prognosis and treatment strategy remain largely unknown.

      Methods
      We present a case of primary lung cancer metastasizing to the stomach. Furthermore, we systematically search the Medline database for similar cases from 1966 through 31 December 2012. Data concerning clinicopathological features, treatment strategies and outcomes were extracted and analyzed to explore the nature of gastric metastasis from primary lung cancer.

      Results
      A 61-year-old and asymptomatic woman was admitted for a mass shadow in chest X-ray (Fig A). A right lower lobectomy was performed and pathological examination revealed a poorly differentiated adenocarcinoma. Five months later, gastroscopy showed a mass with deep ulcer in the fungus of the stomach (Fig B). She underwent partial gastrectomy. The HE staining showed the same morphorlogy as the primary lung cancer, and the cancer tissue invaded the submucosa of esophagus and stomach. (Fig C) The diagnosis of gastric metastasis from primary lung cancer was confirmed by positive staining for TTF-1 (Fig D) and CK-7 (Fig E). In the systematic review, we identified 22 eligible cases from 16 articles. The average age at presentation was 67.3 years. There was a male predominance of 90.9% versus 9.1% female. Epigastric pain (45.5%) was the most common chief complaint, following by melena (22.7%), nausea/vomiting(13.6%), and hematemesis(9.1%). Three patients were asymptomic. Five patients firstly went to see doctors for gastrointestinal symptoms. The median time span between the diagnosis of lung cancer and gastric metastasis was 5 months.Endoscopically, gastric lesions are described as nodule or volcano-like ulcer. The body of stomach was the most common site (62.5%) of metastases. Gastric metastasis was reported in adenocarcinoma, squamous-cell cancer, small cell cancer and pleomorphic carcinoma of lung cancer. Comprehensive treatment was the strategy for these patients. The median survival was 4 months, and 1-year postmetastasis survival rate was 35.3%. Three of the five patients who were treated surgically for solitary gastric metastasis survived longer 1 year after detection of metastases.Figure 1

      Conclusion
      Primary lung cancer metastasizing to the stomach is an exceptional event, but doctors should be aware of the possibility. Comprehensive treatment and personalized treatment should be the strategy according to patients’ situation.

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      P1.18-007 - Multiplex testing of driver mutations in Non-Small Cell Lung Cancer (NSCLCs) of African-American (AA) patients (ID 1312)

      S. Gadgeel, M. Cote, A. Schwartz, A. Bollig-Fischer, S. Land, A. Wenzlaff, A.J. Wozniak, A. Sukari, L. Mantha, G. Bepler

      • Abstract

      Background
      Recently driver genetic alterations have been identified in NSCLC that can be targeted for therapeutic interventions. Previous reports have suggested that rates of certain mutations may vary according to ethnic background. We conducted multiplex testing of NSCLCs of AA and white patients to assess variability in the mutation rates by race.

      Methods
      We identified tumor tissues of 139 AA and 340 white NSCLC patients collected as part of three different institutional review board approved studies. Using the Sequenom MassArray system and a multiplexed panel, we analyzed tumor DNA for 214 oncogenic mutations in 26 genes previously identified in NSCLC. Estimated risk (Odds Ratios (OR)) of any mutation and specific gene mutations among AA patients compared to white patients were calculated after adjusting for age, sex, smoking status and histology (adenocarcinoma versus non-adenocarcinoma). Information on smoking status was unavailable on 45 patients and was not included in calculations of ORs for some genes (OR[b]).

      Results
      The median age at diagnosis was 60 vs 66 years in AA vs white patients; 42% of AA patients and 65% of white patients were males; 67% of AA patients and 49% of white patients had adenocarcinoma; 67% of AA patients and 85% of white patients had stage I/II NSCLC and 10% of AA patients and 6% of white patients were never smokers. 43% of the AA patients and 46% of white patients had at least one mutation detected (OR=0.8; 0.5-1.2). 19% of AA patients and 8% of white patients had more than 1 mutation detected (OR 2.1; 1.1-4.1) (Table 1). AA patients were more likely to harbor mutations in STK11 (LKB1) (OR=7.5; 3.1-18.2) and NOTCH1 (OR[b]=8.4; 2.2-31.7), and they were less likely to have MET mutations (OR[b]=0.2; 0.1-1.1) then white patients. While not statistically significant, AA had lower prevalence of Kras mutations (OR[b]=0.5, 0.2-1.0) and p53 mutations (OR= 0.7; 0.4-1.4). Table 1

      Outcome OR for African American Race 95% CI P
      Any driver mutation[a] 0.8 0.5-1.2 0.203
      >1 driver mutation[a] 2.1 1.1-4.1 0.036
      STK11 Mutation[a] 7.5 3.1-18.2 <.001
      P53 Mutation[a] 0.7 0.4-1.4 0.359
      Kras Mutation[b] 0.5 0.2-1.0 0.041
      NOTCH1 Mutation[b] 8.4 2.2-31.7 0.002
      MET mutation[b] 0.2 0.1-1.1 0.065
      [a]Adjusted for age, sex, ever/never smoking and adeno/non-adeno
      [b]Adjusted for age, sex, and adeno/non-adeno

      Conclusion
      Our analysis of NSCLCs shows that AAs were more likely to have multiple genetic mutations than whites and the mutation profile differs by race.

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      P1.18-008 - Clinical impact of the two types of mucin in the mucinous adenocarcinoma of the lung - Clinical differences between the bronchogenic-type and the gastric-type mucinous adenocarcinomas (ID 1372)

      R. Kondo, K. Ishii, M. Chino, K. Miura, M. Kurai

      • Abstract

      Background
      Mucinous adenocarcinoma is one histological-subtype of the lung cancer. The mucin produced by the tumor cell is usually acidic like as the bronchial gland-type mucin. However, there is one subtype of pulmonary mucinous adenocarcinoma designated as the gastric type, which differentiated into gastric pyloric mucosa and possessed neutral mucin (i.e. class III mucins). It is unclear whether dividing these two mucinous types of the pulmonary mucinous adenocarcinoma has a clinical meaning. This study was aimed for clarify the presence of clinical meaning between two types of the mucinous adenocarcinoma.

      Methods
      69 cases of the mucinous adenocarcinoma of the lung were performed curative operation in Matsumoto Medical Center between 2001 and 2012. HIK1083, designed as specific monoclonal antibodies against gastric pyloric mucin, and TTF-1 were used for judge whether the mucin of the tumor was gastric-type. We divided the mucinous adenocarcinoma into B-type which had the bronchial gland-type mucin (HIK1083 negative and TTF-1 positive), and G-type which had the gastric-type mucin (HIK1083 positive and TTF-1 negative). Then, we compared clinical features and prognoses of these two groups.

      Results
      In the mucinous adenocarcinoma, 34 cases were B-type and 35 cases were G-type. The clinical backgrounds of the two groups were similar including gender, age and smoking status. The locations of the tumor were different between B-type (24 on upper-middle lobes, 10 on lower lobes) and G-type (8 on upper-middle lobes, 27 on lower lobes). Histological-subtypes in B-type were 15 of pure- or mixed-BAC, 12 of papillary, 2 of aciner and 5 of solid. Those in G-type were all 35 of pure- or mixed-BAC. Lymph invasion has often seen in B-type (16 cases), and rarely seen in G-type (2 cases). The number of the cases of each pathological-stage of IA, IB, IIA, IIB, IIIA, IIIB and IV were 12, 5, 1, 4, 8, 3 and 1 in B-type, and were 17, 4, 2, 8, 0, 3 and 1 in G-type, respectively. Analysis of the gene for B-type mucinous adenocarcinoma revealed 38% of EGFR-mutation-positive, 18 % of EML4-ALK-positive, 9% of K-ras-mutation-positive and 35% of the others. On the other hand, the gene for G-type showed 3% of EGFR-mutation-positive, 55% of K-ras-mutation-positive and 42% of the others. About prognostic analyses, aerogenous metastases have occurred in 8 cases on both of B-type and G-type. However, there was no lymph-node recurrence in G-type, although 6 cases were seen in B-type. Distant-metastases were seen in 8 cases of B-type and 3 of G-type. Over all 5-year-survival-rates were 67.9% of B-type and 78.6% of G-type (p=0.34). Disease-free-survival-rates for 5-years were 51.2% in B-type and 73.0% in G-type (p=0.05). Median-survival-months from the post-operative-recurrence were 25.3 in B-type and 6.9 in G-type (P=0.016).

      Conclusion
      The present study showed many differences of the clinical characteristics between B-type and G-type mucinous adenocarcinoma in the lung. This study also suggests that there is a clinical meaning to classify mucinous adenocarcinoma of the lung into the two groups according to the mucin properties.

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      P1.18-009 - Clinicopathologic and Radiologic Characteristics of Lung Cancer Patients with Epidermal Growth Factor Receptor (EGFR), K-ras Mutation and Anaplastic Lymphoma Kinase (ALK) Rearrangement Presented as Nodular Ground-glass Opacity (ID 1388)

      J.H. Lee, S. Ko, Y.J. Lee, J.S. Park, Y. Cho, H. Yoon, J. Chung, S. Jheon, C. Lee

      • Abstract

      Background
      Nodular ground-glass opacity (nGGO) lesion at computed tomography (CT) is a pattern of lung cancer at early stage, and a few studies revealed the characteristics of lung cancer presented as nGGO. Recently, several driver mutations of lung adenocarcinoma such as epidermal growth factor receptor (EGFR), K-ras mutation and anaplastic lymphoma kinase (ALK) rearrangement were found, and EGFR mutation is considered to play a role in early tumorigenesis of nGGO lesion, but the role of ALK rearrangement and K-ras mutation in nGGO lesion is still unknown.

      Methods
      We studied 217 nGGO lesions of 215 patients with lung cancer presented as nGGO, who had undergone surgical resection, retrospectively. We measured sizes of nGGO lesions at chest CT and calculated tumor disappearance rate (TDR). Pathologic analysis and molecular biomarker examination of surgical specimens were performed. Correlation between clinicopathologic and radiologic characteristics and molecular biomarker status was investigated.

      Results
      EGFR mutations were found in 119 among 217 cases (54.8%), positive ALK FISH in 6 among 217 cases (2.8%), and K-ras mutations in 7 among 154 cases (4.5%). Progressed disease stage (p=0.018), larger tumor size (p=0.035-0.037) were observed in ALK-positive group. Lower TDR, i.e. more solid portion in nGGO were observed in ALK-positive group, but it was not statistically significant (TDR 0.533 vs. 0.700, p=0.209). Female (p=0.004) and non-smoker or less smoker (p<0.001) were characteristics of EGFR-positive group, but tumor size and TDR revealed no significant difference. K-ras-positive group revealed no meaningful clinicopathologic and radiologic difference compared to K-ras-negative group. Histologic invasiveness was associated with advanced disease stage (p<0.001), lower TDR (p<0.001), and tumor size (p<0.001), but could not predict molecular biomarkers status. Low TDR was associated with nodal involvement (p<0.001), advanced disease stage (p<0.001), but not with molecular biomarkers status.

      Conclusion
      ALK rearrangement is not common in lung cancer presented as nGGO lesion, and associated with progressive stage and larger tumor size, suggestive of aggressive feature in the progression of lung adenocarcinoma. Role of K-ras mutation in nGGO lesion is indefinite. The status of three molecular biomarkers was not associated with histologic invasiveness or proportion of GGO portion itself.

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      P1.18-010 - Running to keep up! The timeline of evolving research in EGFR testing and targeted therapies in New Zealand (ID 1577)

      H.S. Winter, C. Hardie, M. Holdaway, L. Batten

      • Abstract

      Background
      The rapid pace of the development of new knowledge that may impact on clinical practice means that the time between scientific developments and their implementation in clinical practice may be short. This makes research work rewarding and exciting, but also much more akin to sprinting than running a marathon. We use a Health Research Council-funded study on the feasibility of introducing EGFR testing into New Zealand for Maori lung cancer patients as an example of the complexity of timelines between research and clinical practice

      Methods
      Aims of this mixed method study included exploring clinicians' and patients’ views on EGFR testing, which was not routinely available in New Zealand at that time.

      Results
      Between the time of the research proposal being written and the 12-month study completed and findings published, the landscape changed dramatically, with an emerging national focus on access to both EGFR testing and tyrosine kinase inhibitors. The time line for the project and key findings are presented alongside the evolving research, international and national guidelines for molecular testing and implementation of EGFR testing. We suggest how these developments may influence the implementation of future molecular testing such as ALK testing, which remains sporadic in New Zealand.

      Conclusion
      The translation of scientific discoveries to research findings to clinical practice guidelines is convoluted and complex rather than orderly and sequential. This case of EGFR testing provides lessons for the translation of other scientific discoveries, which may significantly improve the care of lung cancer patients

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      P1.18-011 - Is Visceral Pleural Invasion Significant Prognostic Factor in Lung Cancer Patients with Ground Glass Opacity on Thin-Section CT Scan? (ID 1919)

      A. Hattori, K. Suzuki, T. Matsunaga, Y. Tsushima, K. Takamochi, S. Oh

      • Abstract

      Background
      Due to the recent amendment of lung cancer staging by the IASLC committee, pathological visceral pleural invasion (VPI) has been considered as a new prognostic factor and even pT1a-b lung cancers is included in pT2a, if the tumors have VPI. Basically, lung cancers with VPI are often revealed in patients with radiologically “pure-solid” appearance on thin-section CT scan. On the other hand, controversies still remain with regard to the prognostic significance of VPI in patients with radiologically early lung cancer with ground glass opacity (GGO) predominance.

      Methods
      Between 2004 and 2012, among 543 patients with surgically resected pN0 non-small cell lung cancer less than 30mm in diameter, 466 patients that revealed radiologically “part-solid” and “pure-solid” appearance on thin-section CT scan were retrospectively reviewed. Pure-solid tumors were defined as a tumor constructed only by consolidation without GGO, whereas part-solid tumors were defined as a focal nodular opacity that contained both consolidation and GGO on thin-section CT scan. Several clinicopathological factors were evaluated to elucidate the prognostic factors for each group using a multivariate analysis. Survivals for each group were calculated by Kaplan-Meier estimation.

      Results
      Among 466 eligible lung cancers, 209 (45%) were pure-solid and 237 (55%) were part-solid nodule on thin-section CT scan. In the group with pure-solid nodule, 128 patients were men and 81 were women with average age of 67 years. VPI was found in 79 (38%) patients. Based on a multivariate analysis, VPI, maximum tumor diameter and CEA level were significant prognostic factors in patients with pure-solid nodule (p=0.0071, 0.0278, 0.0314). The 5-year survival in patients with VPI (-) (81.3%) was significantly greater than that in VPI (+) (70.1%) (p=0.0051). While the group with part-solid nodule included 97 men and 140 women with average age of 66 years. VPI was found in 24 (10%) of the patients with part-solid nodule, however, it was not a significant prognostic factor in these lesions (p=0.4697). Furthermore, the 5-year survival in patients with VPI (-) was 94.9%, whereas that with VPI (+) was 85.6% (p=0.3798).

      Conclusion
      It is no doubt regarding the prognostic significance of visceral pleural invasion in patients with radiologically pure-solid lung cancer. On the other hand, even pleural invasion may not participate in the prognosis in patients with part-solid lung cancers. Thus, upgrading of TNM staging system and administration of postoperative chemotherapy due to pleural factor should be carefully considered in lung cancer patients with GGO predominance.

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      P1.18-012 - Thyroid transcription factor (TTF-1) negative lung adenocarcinomas will be wild type for epidermal growth factor receptor (EGFR) mutations. (ID 2036)

      M.J. Fidler, N. Somaiah, E. Garrett-Mayer, X. Huang, K. Chirai, C. Sherman, A. Wahlquist, K. Danenberg, T. Hensing, P. Bonomi, G.R. Simon

      • Abstract

      Background
      TTF-1 is expressed in approximately 70% of adenocarcinomas (ACs) of the lung. EGFR mutations are present in 13-15% of unselected patients with AC in the United States and national guidelines suggest initiating first line EGFR tyrosine kinase inhibitors in this population. Both high TTF1 expression and EGFR mutations are associated with terminal respiratory unit (TRU) type ACs, female sex, never-smoking status and longer survival. We hypothesized that TTF-1 negative AC would have a high probability of being negative for EGFR mutations.

      Methods
      Microdissected formalin-fixed paraffin-embedded tumors from 693 patients with NSCLC were analyzed for EGFR mutations by allele-specific PCR in a pilot data set to test the hypothesis (pilot cohort). TTF-1 status was documented as positive, negative or not reported. Negative predictive value (NPV) for a range of true prevalences of EGFR mutation (1%-50%) was estimated using a Bayesian modeling approach. To further corroborate the hypothesis, a separate validation cohort of patients treated with erlotinib at two academic affiliated institutions with known TTF1 and EGFR mutation status was studied using the same modeling approach (validation cohort).

      Results
      301 patients with documented ACs and known TTF-1 status were included in the pilot cohort. In this population enriched to have EGFR mutations, EGFR mutations were present in 224 specimens (74%). Only 2 of the 224 specimens that were positive for EGFR mutations were negative for TTF-1 expression yielding a sensitivity of 99.1% (95% confidence interval (CI) 96.8-99.9%). For prevalence rates of EGFR mutations of 13% and 15%, the estimated NPV are 99.5% (95% credible interval (CRI) 98.6%-99.9%) and 99.4% (98.4%-99.9%), respectively. Data from 211 patients comprised the validation cohort. With an 11% rate of EGFR mutations, the estimated NPV was 92% (95% CRI - 73%-99%). For true EGFR mutation rates of 13% and 15%, using the data from the validation cohort, the estimated NPVs were 97% (95% CRI 92%-99%) and 96% (95% CRI 91%-99%), respectively. Figure 1. estimated NPVby true prevalence of EGFR mutation for both datasets Figure 1

      Conclusion
      An overwhelming majority of Lung ACs that are TTF-1 negative will be negative for EGFR mutations. These findings may be useful in avoiding delay of chemotherapy initiation in TTF-1 negative patients with newly diagnosed non-small cell lung cancer.

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      P1.18-013 - Extracting High quality RNA from FFPE samples for gene expression studies (ID 2092)

      J. Weiss, H. Do, P.A. Russell, G. Wright, A. Dobrovic

      • Abstract

      Background
      The use of targeted therapies in the treatment of non-small cell lung cancer is still limited to a relatively small fraction of patients. Chemotherapy remains the mainstay of treatment for most patients today. So far, the best predictors for chemotherapeutic success are based on the expression of certain nucleotide metabolism genes or DNA damage response and repair related genes. However, the samples available for study most commonly comprise FFPE samples, which are characterised by a high degree of RNA fragmentation or degradation.

      Methods
      To address this problem, we have developed a protocol to reliably extract reasonable-quality RNA from FFPE samples. The protocol includes pathology review of the FFPE block, removal of a 2mm core, followed by RNA extraction. Next, the total RNA amount is quantified and a small proportion is accessed for fragmentation e.g. by TapeStation technology and/or a multiplex RT-PCR to determine the amount and size of amplifiable templates. We then assessed the extracted total RNA by various RNA based methodologies.

      Results
      To this end, we prepared core punches from 118 different lung adenocarcinomas and successfully extracted sufficient amounts of total RNA (> 50ng /ul in a 20ul elution) from 111 of the cores (average is 307ng/ul ranging from 53ng to 1.1ug/ul). Fragmentation assessment of 26 of these RNAs showed that all samples contained sufficient amounts of fragments with at least >100 nt. We first tested single gene expression by RT-qPCR. Of 26 samples tested, 24 samples showed robust amplification of a 161 bp fragment of the TBP housekeeping mRNA. We next assessed our RNA using gene expression analysis by NanoString®. We interrogated 150ng total RNA from 10 samples for the expression levels of 45 genes. Data analysis showed robust expression values and no quality control problems in all samples. Finally, we tested whether the RNA was of sufficient quality for next-generation RNA sequencing. We used 100 and 50 bp paired end sequencing on un-size-selected RNA, and 100 bp paired end sequencing after one round of size selection. On average, we obtained 23 million reads per sample, of which 70% mapped to reference sequences after either extensive read clipping or size selection.

      Conclusion
      In conclusion, our extraction protocol enables us to reliably extract total RNA from FFPE samples, which can be used for single-gene expression by RT-qPCR and gene expression of limited gene sets by NanoString® technology. However, the amount of samples and genes tested here were not sufficient to allow identification significant differences between samples, but shows the possibility to use the RNA extracted following our extraction protocol. RNAseq, however, poses a larger problem. The amount of mapped reads is significantly lower compared to high quality RNA from e.g. fresh frozen material or cell lines. The reason for these problems and possible solutions remain elusive. Overall, we present a simple and fast way to accurately extract RNA from FFPE material and show that after QC, single or small gene panels can successfully be assessed. However, large-scale sequencing efforts remain problematic and further optimization is needed.

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      P1.18-014 - An analysis of mRNA and long non-coding RNA (lncRNA) expression during the progression from pre-invasive lesions (PL) to invasive squamous cell carcinoma (SqCC) of the bronchus. (ID 2251)

      A. Koper, L. Joseph, J.R. Gosney, K.M. Kerr, M. Evison, P. Crosbie, M. Lindsay, R. Booton

      • Abstract

      Background
      Lung cancer is a common disease, with a poor 5-year survival rate often attributed to late diagnosis where curative treatment is uncommon. SqCC account for ~40% of non-small cell lung cancer (NSCLC) that possess a clinically detectable preinvasive phase. Intervention following early diagnosis of NSCLC using low-dose CT and autofluorescence bronchoscopy can significantly reduce mortality. PL are histological changes of bronchial epithelium that can be classified into squamous metaplasia (M), mild dysplasia (MID), moderate dysplasia (MOD), severe dysplasia (SD), carcinoma in-situ (CIS). They are found with varying prevalence, in high-risk cohorts such as smokers or individuals exposed to occupational carcinogens. MID and MOD are more frequently identified but only a minority progress to a SqCC. SD and CIS more commonly progress to SqCC but this is not universal.

      Methods
      The natural history of PL is not sufficiently understood. In order to address this, we have used exon arrays to profile mRNA and lncRNA levels in total RNA samples derived from formalin fixed wax embedded bronchial biopsies subject to laser microdissection. Three thoracic pathologists (KK, JG, LJ) reviewed all biopsies and agreed the morphological classification. We will report changes in differential expression of mRNA and lncRNA levels when we compare the transcriptome profiles of 5 categories of PL (M, miD, moD, sD, CIS) and 2 categories of SqCC (node negative and node positive), with those of matched normal bronchial epithelial cells. We believe this analysis provides an unprecedented insight into the molecular events that drive progression towards invasive malignancy, and may aid the identification of novel tools for the management of early squamous cell lung cancer.

      Results
      not applicable

      Conclusion
      not applicable

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      P1.18-015 - Screening for ALK-rearranged NSCLC in selected cases using immunohistochemistry followed by FISH and RT-PCR testing of tumours with increased ALK protein expression in a routine clinical diagnostic setting (ID 2838)

      A.M. Quinn, J. Harris, S. Huang, P. Bishop, A. Paiva-Correia, W. Newman, F. Blackhall, A. Wallace, D. Nonaka

      • Abstract

      Background
      The diagnosis of anaplastic lymphoma kinase (ALK) gene rearrangement in non small cell lung cancer (NSCLC) has acquired therapeutic significance, subsequent to the established response of ALK-rearranged tumours to crizotinib therapy. General recommendations on NSCLC ALK testing will be published later this year by the National Institute for Health and Care Excellence. In advance of this, patients were prospectively screened for ALK-rearranged NSCLC at the Christie Hospital, Manchester, U.K. from May 2012 to May 2013.

      Methods
      Pulmonary adenocarcinomas were selected for testing by ALK immunohistochemistry (IHC) based the presence of any of the following clinicopathologic features associated with ALK rearrangement; never smoker, light ex-smoker, age less than 50 years, signet ring/goblet cell morphology. IHC was performed with the 5A4 clone (Novocastra) according to the European Thoracic Oncology Platform protocol. All IHC-positive cases (intensity score 1+, 2+ or 3+) were tested for ALK rearrangement by both fluorescent in situ hybridisation (FISH) and reverse transcriptase polymerase chain reaction (RT-PCR). FISH analysis using the Abbott Molecular LSI ALK Dual Colour Break Apart Probe required a minimum of 15% of (at least 100) tumour cells with gene rearrangement for a positive diagnosis. RT-PCR testing was employed to detect EML4-ALK fusion transcripts using a series of primers located in EML4 exons 1 to 22, a reverse primer located in ALK exon 20 (Sanders et al., 2011;204:45-52) and sample RNA extracted from a single 40 µM section. Amplified products were Sanger sequenced to establish the fusion variant present.

      Results
      Ninety-one specimens were screened by ALK IHC and of these, 13 demonstrated positive staining. FISH and RT-PCR results were concordant (with the exception of one RT-PCR negative case which failed FISH testing) and 9 cases were diagnosed with ALK-rearrangement (9.9%). The majority of the EML4-ALK fusion transcripts were of variant 1 type (77.8%), with just two subtypes diagnosed as variant 3 (22.2%). The median time from referral for FISH/RT-PCR to the issue of reports was 5 working days.

      Table 1. Summary of clinicopathological features, IHC, FISH and RT-PCR results of cases positive for ALK protein staining on IHC. (ACA =adenocarcinoma)
      Case Age Sex Sample type Histology IHC H-score FISH % + RT-PCR Final ALK diagnosis EGFR mutation
      1 84 F Node excision ACA, signet ring cells 170 55 E13;A20 variant 1 + -
      2 59 M Lung resection ACA, solid with hepatoid cells 190 77 E13;A20 variant 1 + -
      3 56 M Pleural effusion ACA, hepatoid cells 240 64 E13;A20 variant 1 + -
      4 46 M Node biopsy Adenosquamous 300 64 E6;A20 variant 3 + -
      5 64 M Pleural biopsy ACA, solid with hepatoid cells 300 48 E13;A20 variant 1 + -
      6 60 F Node aspirate ACA, signet ring and hepatoid cells 300 66 E13;A20 variant 1 + -
      7 41 F Node biopsy ACA, hepatoid cells 300 71 E13;A20 variant 1 + -
      8 40 M Pleural biopsy ACA, solid with hepatoid cells 300 58 E6;A20 variant 3 + -
      9 65 F Node aspirate ACA, signet ring and hepatoid cells 300 45 E13;A20 variant 1 + -
      10 54 M Pleural effusion ACA 20 5 Negative - -
      11 52 F Pericardial effusion ACA 10 Failed Negative - -
      12 49 F Pleural fluid ACA 35 0 Negative - +
      13 70 F Lung resection ACA, solid with hepatoid cells 54 9 Negative - Unknown

      Conclusion
      In keeping with reported findings ALK-rearranged NSCLC was found in 9.9% of selected adenocarcinomas. Although FISH/RT-PCR was not carried out on IHC-negative cases in this group, the application of IHC as a screening method appears to be a cost-effective means of highlighting ALK-rearranged tumours. RT-PCR testing of formalin-fixed, paraffin-embedded tissue is feasible in the clinical diagnostic setting, and may have an important role in the determination of specific variants detected by IHC.

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      P1.18-016 - The association between size and histology in discarded intrapulmonary lymph nodes (LN) from non-small cell lung cancer (NSCLC) resection specimens: can we select nodes for examination by their size? (ID 2996)

      R.U. Osarogiagbon, R. Ramirez, C.G. Wang, L.E. Miller, X. Yu, M. Smeltzer

      • Abstract

      Background
      Pathologic nodal staging is the most important prognostic factor in resected NSCLC, but LN yields are low. A median of 3 N1 nodes are examined in US lung resection specimens, though fastidious examination yields a median of 11 N1 LN. A bias towards examination of larger nodes may cause understaging when small LN with metastasis are missed. We examined the size and histologic characteristics of LN material retrieved during a fastidious redissection of discarded lung cancer resection specimens.

      Methods
      Prospective study of lobectomy specimens discarded after completion of the routine pathology examination. A fastidious redissection protocol was used to retrieve all grossly LN-like material for histologic examination, irrespective of size. The Wilcoxon-Mann-Whitney test was used to compare the materials with and without metastasis.

      Results
      1094 LN-like materials retrieved from 112 resection specimens: 345 (32%) were not LN on histologic examination (including 11 satellite metastatic nodules); 749 (68%) were LN, of which 71 (9%) had metastasis. The distribution of size and histology is shown (Figure). The median size (range) of the non-LN, LN without metastasis, and LN with metastasis was: 4.0 (0.9 - 20); 6.0 (1.0 - 27), 12.0 (1.0 - 27) mm (p<.0001, for all comparisons). Twenty-six patients (23%) had LN with metastasis (see histogram). In 4 patients, LN with metastasis were smaller than LN without metastasis.Figure 1Figure 2

      Conclusion
      Despite the statistically significant tendency for LN with metastasis to be larger than those without metastasis, there was broad size distribution overlap. Furthermore, a third of materials that grossly appeared to be LN were not, though some were satellite metastatic nodules. This probably contributes to the relatively low LN yield in routine examinations. LN size is not a reliable means of distinguishing between those with and without metastasis. The protocol for gross N1 LN retrieval should be modified to facilitate a more thorough routine examination.

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      P1.18-017 - The prevalence of micrometastasis (MM) in discarded intrapulmonary lymph nodes (LN) in resected non-small cell lung cancer (NSCLC). (ID 3000)

      R.U. Osarogiagbon, S. Sareen, C.G. Wang, R. Ramirez, L.E. Miller, J. Rodriguez, R. Eisenberg, S. Suster, I.I. Wistuba

      • Abstract

      Background
      44% of pN0 NSCLC resection patients die within 5 years. We recently showed 12% of pN0 NSCLC resection specimens have discarded LN with metastasis on H&E microscopy. ACOSOG Z0040 demonstrated the prognostic impact of immunohistochemistry positive (IHC+) LN MM. In this report, we investigated the prevalence of IHC+ LN MM in patients with and without H&E + LN metastasis in discarded lung resection specimens.

      Methods
      Using a fastidious redissection special pathology examination (SPE) protocol, we retrieved LN from discarded NSCLC resection specimens after the routine pathology examination (RPE). All retrieved LN were examined for metastasis by H&E light microscopy. We matched 26 patients with 1 or more H&E+ LN (irrespective of whether detected on RPE or SPE) with 28 patients without detectable nodal metastasis. Fresh sections were cut from all retrieved LN tissue blocks of these 54 patients and stained with AE1/AE3 immunostain (Dako) at an independent institution. All slides were examined independently by pathologists at two different institutions, and discordant reports resolved at a consensus review session. The prevalence of IHC positivity was determined from the final consensus of pathologists.

      Results
      Figure 1

      Conclusion
      Micrometastatic disease is evident in a significant proportion of the LN retrieved from discarded NSCLC resection specimens, further extending the potential clinical implications of incomplete LN examination. IHC+ nodes were not found in LN from patients with H&E negative disease after fastidious examination by SPE. The survival implications of these findings will be investigated in future clinical trials.

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      P1.18-018 - Diagnosis of lung cancer: performance of pre-operative procedures in clinical practice correlated with characteristics of the tumor. (ID 3086)

      M.T. Almodovar, C. Matos, F. Santos, F. Cunha, S. Esteves, J. Duro Da Costa

      • Abstract

      Background
      Recent treatments for advanced non-small cell carcinoma (NSCLC) have increased the demand for accurate diagnosis of NSCLC rendered by histology or cytology. However precise classification is not always possible

      Methods
      We investigated the performance characteristics of preresection procedures for diagnosis of NSCLC Database was searched for resected NSCLCs during 2008-2011 with corresponding preresection cytology and/or biopsy cases. The pre-resection diagnoses were correlated with resection diagnosis considering the type of bronchoscopic or transthoracic procedure, size, location of tumor in bronchoscopy and distance from thoracic wall in transthoracic cases. Pathologic data were reviewed by two pathologists and TAC by two pulmonologists. Pathology of resection was categorized as adenocarcinoma- AD, squamous cell- SQ, adenosquamous carcinoma (ADSQ), and large cell carcinoma-LCC. The bronchoscopy (BF) procedures- bronchial biopsy BB, distal biopsy DB, bronchial washing (BW), bronchial brushing (BBr), endobronchial/transbronchial biopsy (ETBX), and trans-thoracic procedures (TT)—transthoracic fineneedle aspiration(TT-FNA) and transthoracic needlecore biopsy(TT-NCB) were identified. Sensitivity of procedures was determined taking surgical pathology as reference; 95% confidence intervals were estimated by Wilson method. Agreement was evaluated using Cohen’sKappa. Univariate and multivariate logistic regression was used to evaluate factors possibly associated with absence of pre-surgery tumor diagnosis and lack of agreement in the subset with pre-surgical diagnosis.

      Results
      A total 189 patients were included, with 538 previous diagnostic procedures. The distribution for diagnosis was 105 AD, 48 SQ, 9 ADSQ, and 17 LC. Median (Max-Min) size of the tumor was 27mm (10-25). Median (Max-Min) distance from the thoracic wall was 7 mm (0 – 50). Procedures sensibility were: all 69% (63% - 76%), , TT 57% (46%-66,5%) , TT-NCB 71%, TT-FNA 33%,BF 54% (47%-62%)BB 63%, DB 54%, ETBX 32%, BBR 22%, BW 12%. The 131 patients in the subset with pre-surgery diagnosis agreement between pre and post-surgical diagnosis was: all procedures k=0,54, TT k=0,69, TT-NCB k=0,69, TT-FNA k=0,34, BF k=0,69, BB 0,59, DB k=0,73, ETBX k=0,80, BBR k=0,57, BW k=0,51. Concordance by histology was all procedures- AD 82%, SQ 78%; TT - AD85%, SQ 67%; NCB- AD 93%,SQ 75%; TT-FNA AD 78%, SQ 50%; BF AD 81%, SQ 87%; BB AD 82%,SQ 86; DB AD 100%, SQ 90%; ETBX 88% SQ 100%; BBR AD 79%, SQ 38%; BW AD 67%, SQ 60%. From factors possibly associated with diagnosis sensibility only the size of the tumor, in TT ODD 5% by additional mm (p=0,001), in BF ODD 3% (p=0, 0038) was significantly associated in univariated and multivariated analysis. From the factors possibly associated with agreement between pre-surgical and surgical diagnosis only the size of tumor in PATT was significantly associated in univariated and multivariated analysis.

      Conclusion
      All procedures had a substantial to almost perfect agreement in diagnosis of non-small-cell lung cancer subtype. Broncoscopy had 69% sensibility, lower than literature maybe because only operable tumors were considered, influenced by tumor size and an agreement in diagnosis independent of all factors considered. Transthoracic procedures had a sensibility lower than literature with substantial agreement influenced by tumor size. Broncoscopy was better in squamous-cell diagnosis and transthoracic procedures in adenocarcinoma maybe due to location in lung

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      P1.18-019 - Micropapillary Histology Is Associated with Occult Lymph Node Metastasis (pN2) in Patients with Clinically N2-Negative (cN0/N1) Lung Adenocarcinoma (ID 3232)

      Y. Yeh, J. Nitadori, K. Kadota, C.S. Sima, N.P. Rizk, V.W. Rusch, W.D. Travis, P.S. Adusumilli

      • Abstract

      Background
      Among patients with lung adenocarcinoma staged as N2-negative in the mediastinum by PET/CT scan, up to 16% will have occult N2 metastasis (pN2) detected on mediastinoscopy or surgical resection. We investigated the association between histologic subtyping (according to the newly proposed IASLC/ATS/ERS classification) and occult lymph node metastasis in patients with unsuspected N2 disease.

      Methods
      We performed a retrospective review of 297 patients with lung adenocarcinoma (≤2 cm, 51%; >2 cm, 49%) who underwent surgical resection and mediastinal nodal dissection from 2007 to 2009. Mediastinal lymph node disease was assessed preoperatively by FDG-PET/CT scan. Histologic subtyping was performed according to the newly proposed IASLC/ATS/ERS classification.

      Results
      Ninety-three percent of patients had N0 disease, and 7% had N1 disease, as detected by preoperative PET/CT scan. Of the 297 patients, 32 (10.8%) had occult N2 metastasis identified by pathologic examination (9.7% of patients with cN0 disease, 25% of patients with cN1 disease). On univariate analysis, SUVmax of the primary tumor >4 (p=0.001), predominant histologic subtype (p=0.001), presence or absence of lepidic pattern (p<0.001), micropapillary pattern (p=0.009), and solid pattern (p=0.011) were associated with pN2 disease. On multivariate analysis, presence of lepidic pattern (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.14-0.77; p=0.011), presence of micropapillary pattern (OR, 2.58; 95% CI, 1.13-5.92; p=0.025), and SUVmax of the primary tumor >4 (OR, 2.44; 95% CI, 1.03-5.79; p=0.042) were significantly associated with occult N2 metastasis.

      Conclusion
      Micropapillary histology and primary tumor SUVmax >4 on FDG-PET/CT were independently associated with occult N2 metastasis.

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      P1.18-020 - Molecular Alterations in Advanced Lung Cancer: Genomic Sequencing in a Community Profiling Program of the Sarah Cannon Research Institute (SCRI) (ID 3357)

      S. Liang, T. Bauer, P. Chandra, Z. Ma, D. Haynes, J. Prescott, D. Stults, S. Jones, J. Hainsworth, J. Infante, H. Burris, D. Spigel

      • Abstract

      Background
      In October 2012, SCRI launched a genomic sequencing program at a single community clinical research center in middle Tennessee to explore molecular alterations with proven or potential therapeutic significance for patients (pts) with advanced solid and hematologic tumors. Herein we report the findings from the lung cancer cohort tested to date.

      Methods
      Biospecimens from pts with advanced lung cancer (ECOG ≤ 2) who consented to molecular profiling were tested by Next-Generation Sequencing (NGS) with 1000X average coverage in a CLIA/CAP-certified laboratory. Oncogenic hotspot mutations in 35 genes were tested (copy number variation and translocation were not tested). Results were reported to the treating physician within 12 days of receipt of suitable tissue, and were used to inform treatment decisions. Molecular profiling results were stored in a database to enable correlation with clinical outcomes.

      Results
      As of May 31 2013, a total of 594 tumor samples were profiled, 143 (24%) of which were from pts with lung cancer. 23% (33/143) of the lung samples were inadequate for assay. Of the 110 lung samples with sufficient tissue, 47 (43%) were found to have at least 1 identifiable mutation: 30 (27%) single mutations and 17 (16%) multiple mutations. The mutation frequency by histology was adenocarcinoma 63% (34/54 pts), squamous 19% (4/21 pts), large cell 67% (4/6 pts), and small-cell 8% (1/13 pts). The most frequent mutations from this 35-gene panel were KRAS and EGFR (18% and 14%, respectively). Other genetic alterations identified included STK11 6%, MET 5%, RUNX1 4%, FGFR3 3%, BRAF 2%, MEK1 2%, PIK3CA 2%, WT1 1%, SMO 1%, KIT 1%, GNAS 1% and FGFR4 1%.

      Breakdown of KRAS and EGFR Mutations
      Gene Codons Tested Mutation Codons Detected Number of Mutations % of Detected Mutations
      KRAS 12, 13, 61, 146 12 19 95%
      61 1 5%
      EGFR 709-719, exon 19 deletion, 768-790, exon 20 insertion, 833, 858-861 769 2 13%
      796 1 7%
      833 1 7%
      852 1 7%
      858 3 20%
      Deletion 7 40%
      Insertion 1 7%

      Conclusion
      This program confirms the feasibility of molecular profiling in the community setting to assist medical oncologists in treatment decisions for pts with lung cancer, including enrollment in clinical trials.

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      P1.18-021 - Retrospective analysis of the prevalence of NSCLC driver mutations in unselected samples. (ID 3365)

      W. Saliba, L. Corrales-Rodriguez, R. Albadine, D. Soulieres, X. Weng, I. Gorska, M. Audet, D. Tran-Thanh, B. Fan, M. Tehfe, M. Florescu, N. Blais

      • Abstract

      Background
      Much of the recent improvement in lung cancer outcomes owes to the advent of the Lung Cancer Mutation Consortium. We aimed to assess thequality of the pathologic specimens and to study the prevalence of each of the most clinically relevant driver mutations in a non-referred population with non-squamous, non-small cell lung cancer (NS-NSCLC) treated in a tertiary center in the province of Quebec characterized by a high prevalence of smokers (25% of adult population).

      Methods
      Consecutive patients with pathologically proven NS-NSCLC diagnosed or treated in our institution between January 2006 and June 2009 inclusively were accrued. Patients whose diagnosis is based uniquely on a positive cytology or whose diagnostic material was not available were excluded. Specimens were tested for ALK translocations (by IHC and FISH), for EGFR mutations in exons 19 and 21 by PCR (fragment analysis and qPCR) and for mutations in KRAS codons 12 and 13 by PCR-RFLP. ALK-FISH and ALK-IHC results were analyzed in a blinded manner.

      Results
      A total of 1017 consecutive patients were screened. We excluded 209 patients who had only cytologic material, 55 patients who had no residual material and 197 patients who had insufficient tissue. Analysis was possible on 556 patients. The median age of the analyzed population was 64 years and male gender frequency was 45.5%. Compared to our entire cohort, metastatic cases were significantly under-represented in the analyzed population 27.3% vs. 79.1% for local disease (p<0.0001). The distribution according to stage and year of diagnosis along with that related to overall eligible population as well as the percentage of each of the 3 driver mutations status in the specimens analyzed so far are shown in the table below:

      Local disease analyzable / overall Loco-regional analyzable / overall Metastatic analyzable / overall Total analyzable / overall
      2006 - 2007 188/227 (82.8%) 66/147 (44.9 %) 55/207 (26.6 %) 311/583 (53.3 %)
      2008 - Mid 2009 161/214 (75.2%) 50/96 (52.1 %) 36/126 (28.6 %) 247/436 (56.7 %)
      Total 349/441 (79.1%) 116/243 (47.7%) 91/333 (27.3 %) 556/1017 (54.7 %)
      Mutation results: Local disease positive/total analyzed Loco-regional positive/total analyzed Metastatic positive/total analyzed Total positive/total analyzed
      KRAS codon 12 76/216 (35.2%) 20/55 (36.4%) 17/54 (31.5%) 113/325 (34.8%)
      KRAS codon 13 7/216 (3.2%) 2/55 (3.6%) 2/54 (3.7%) 11/325 (3.1%)
      KRAS mutated 83/216 (38.4%) 22/55 (40%) 19/54 (35.2%) 124/325 (37.9%)
      EGFR exon 19 11/128 (8.6%) 2/42 (4.8%) 4/39 (10.3%) 17/209 (8.1%)
      EGFR exon 21 6/128 (4.7%) 3/42 (7.1%) 1/39 (2.6%) 10/209 (4.8%)
      EGFR mutated 17/128 (13.3%) 5/42 (11.9%) 5/39 (12.8%) 27/209 (12.9%)
      ALK-FISH 2/264 (0.8%) 0/90 (0%) 1/69 (1.4%) 3/423 (0.7%)
      ALK – IHC* 1/277 (0.4%) 0/97 (0%) 1/75 (1.3%) 2/453 (0.4%)
      *One ALK-FISH positive case was IHC negative on repeated testing.

      Conclusion
      Our study shows that adequate tumor sampling is a challenge when performing retrospective molecular biology studies, creating a bias of adequate tissue availability in favor of more localized stages of disease. Nonetheless, our study shows a lower percentage of EGFR/ALK mutations and a higher percentage of KRAS mutations than that reported by the LCMC and other groups. This may be related to the non-selected, regional distribution and smoking habits of our study population. Prospective studies on the molecular diagnosis of NS-NSCLC will refine epidemiologic features of the different genetic subtypes of this disease.

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      P1.18-022 - The natural history of bronchial pre-invasive disease (ID 3433)

      J. Brown, G. Hardavella, B. Carroll, M. Falzon, N. Navani, J. George, S. Janes

      • Abstract

      Background
      Bronchial pre-invasive lesions represent the earliest stages of the stepwise progression of squamous carcinogenesis, they predominantly affect the large airways and are readily detectable using autofluoresence bronchoscopy (AFB) however very little is known about the natural history of these lesions and no randomised data exists to determine whether intervention before progression to invasion improves outcome.

      Methods
      A total of 94 patients with bronchial dysplasia were enrolled into an on-going surveillance cohort at University College London Hospital running prospectively since 1999. Lesions were biopsied longitudinally and kept under regular surveillance with AFB and low dose annual CT scanning until resolution or progression to invasive disease occurred. Retrospective analysis of lesional destiny was undertaken to determine the proportions of progressive vs. regressive lesions that occur in low grade dysplasia (LGD- squamous metaplasia, mild and moderate dysplasia) vs. high grade dysplasia (HGD- severe dysplasia (SD) and carcinoma-in-situ). A lesion was considered to have progressed/ regressed if it crossed between groups (LGD, HGD, invasive cancer).

      Results
      A total of 117 separate lesions that were biopsied on more than one occasion were identified of which 61 were HGD and 56 LGD. Of the low grade lesions 54/56 (96%) regressed or remained static, 1 (2%) progressed to CIS and 1 (2%) to invasive carcinoma both of these lesions progressed from moderate dysplasia. Of the high grade lesions there were 13 SD and 48 CIS, overall 35/61 (57%) of HGD progressed to invasive cancer 9/61 (15%) regressed and 17/61 (28%) remained static. There was a trend toward higher progression to cancer (62% vs 56%) and lower rates of regression (8% vs. 17%) for SD versus CIS in the HGD cohort although the numbers are too small to be statistically significant (see fig. 1). In the HGD group median time to invasion was 9.5 months (range 3-49), static lesions were documented to have remained as such for a median of 17 months (range 4-60). Figure 1

      Conclusion
      In our cohort we see very few lesions following the traditional stepwise progression and LGD remains relatively indolent. There is a significant proportion of HGD that progresses to invasive cancer and further studies are required to test the role of endobronchial intervention to prevent progression and to determine the most efficacious modality of treatment.

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    P1.19 - Poster Session 1 - Imaging (ID 179)

    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 15
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      P1.19-001 - Inhaled Cisplatin Displayed with the CytoViva Technique in Stage II Non-Small Cell Lung Cancer Patients (ID 160)

      P. Zarogoulidis, D. Sparopoulou, K. Darwiche, D. Spyratos, J.F. Turner, W. Hohenforst-Schmidt, H. Huang, Q. Li, L. Krauss, R. Browning, K. Zarogoulidis

      • Abstract

      Background
      Lung cancer therapies during the last decade are targeting the genome of cancer cells. However, investigating the gene pathways of tumor has the disadvantage so far that mutations are found in a limited number of patients therefore limiting the production of targeting therapies. Novel routes for administering lung cancer therapies have been investigated for decades. Aerosol therapies for several systematic diseases and systemic infections have been introduced in the market for a decade. One of the main issues of aerosol therapies has been the investigation of the deposition of a drug compound throughout the systematic circulation and lymph node circulation. Until now none of the published studies have efficiently displayed the deposition of a chemotherapy pharmaceutical within the lymph node tissue.

      Methods
      The CytoViva[®] technique can be summarized to the following information. Optical and hyperspectral images along with hyperspectral data were captured utilizing a research grade optical microscope equipped with the CytoViva[®] advanced darkfield illumination system, dual mode fluorescence module and integrated hyperspectral imaging system. This integrated system builds hyperspectral image files via “push broom” method, enabling the creation of a high signal to noise spectral image file. Subsequent image analysis delineates the reflectance spectral response of the sample elements in each nanoscale pixel of the image file.

      Results
      Figure 1 First picture represents an optical image lymph node station 7 after inhaled cisplatin. Second image represents spectral image of lymph node station 7 red areas represent the cisplatin diffusion within the tissue. Third image spectral library of inhaled cisplatin (90minutes after aerosol cisplatin administration, 40mg) The concentration 90 minutes after the aerosol cisplatin administration (40mg) was 2.09 μg/g Pt. in lymph node station 7 as measured with biochemistry techniques in a second patient.

      Conclusion
      We have efficiently presented data correlating at the same time local deposition with diffusion of aerosol cisplatin and concentration within lymphnodes. Using an optical technique and a biochemistry technique. Aerosol chemotherapy is an efficient method of treatment and further investigation is warranted with or without additional carriers added to the drug formulation.

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      P1.19-002 - An open-label, single arm trial to evaluate the predictive value of perfusion CT and early radiologic response to cisplatin (C) gemcitabine (G) and bevacizumab (B) in patients (pts) with advanced or metastatic non-squamous non-small cell lung cancer (nsNSCLC). (ID 723)

      N. Reguart, P. Arguis, M. Sanchez, N. Viñolas

      • Abstract

      Background
      Classically the evaluation of response in oncology has been based in comparing pre and post treatment tumour volume by means of studying changes in the diameter lesions. The introduction of new targeted drugs creates the need of a different evaluation of tumours and their response to treatment. Functional imaging techniques that are able to study in vivo physiological processes of tissues and tumours have lately acquired more importance. The dynamic techniques may be more appropriate for assessing response to antiangiogenic drug, such as B, whose mechanism of action appears to focus on the normalization of the tumor vasculature. Preliminary studies have demonstrated significant and very early changes in flow, blood volume and tumor perfusion with therapy. These techniques could be useful to select patients those that are going to respond to drugs with an early evaluation of response by means of functional imaging

      Methods
      IMPACT is an open-label, single arm phase II study to evaluate the predictive value and early radiologic response or perfusion CT in pts diagnosed with unresectable advanced, metastatic or recurrent nsNSCLC treated with C, G and B. Pts receive B (7.5 mg/kg IV on d1), C (80 mg/m2 on d1) and G (1250 mg/m2 on d1 and 8) up to 6 cycles of 21 d. Pts with no evidence of progression of disease continue to receive single-agent B 7.5 mg/Kg on d1 every 21 d until progression or unacceptable toxicity. Primary endpoint is to assess basal results and early tumour response (at day +7) in terms of blood flow (BF), blood volume (BV), time to enhancement peak (TTEP) and permeability (P) as compared to Objective Response Rate (ORR) in terms of RECIST at d42. Secondary objectives include to assess tumour response (at d42) in terms of BF, BV, TTEP and P as compared to ORR at d42, to assess basal results in terms BF, BV, TTEP and P as compared to PFS and OS, to assess tumour response (at d7 and d42) in terms of BF, BV, TTEP and P to PFS and OS, to describe the safety profile using NCI-CTC AE and efficacy in the subgroup of adenocarcinoma. Planned sample size is 20 pts.

      Results
      not applicable

      Conclusion
      not applicable

    • +
      • Abstract

      Background
      PET-CT is a standard investigation to stage the mediastinum in non-small cell lung cancer when radical management is planned. The absence or presence of mediastinal lymph node involvement on PET-CT informs surgical selection (with or without further nodal sampling). The clinical utility of PET-CT in carcinoid tumours is uncertain as its test performance at identifying mediastinal lymph node disease in these tumours is as yet undefined with such tumours being rare and FDG avidity often considered to be variable or low. As such, it is argued whether PET-CT serves the same purpose in selecting patients for radical management in carcinoid tumours as it does with other non-small cell lung cancers. The aim of this study was to determine the test performance of PET-CT for mediastinal lymph node staging of pulmonary carcinoid tumours by collating a multicentre database.

      Methods
      We collated retrospective data from 7 institutions by performing a search on pathological databases for a consecutive series of patients who underwent thoracic surgery for a carcinoid tumour from Nov 1999 - Jan 2013. Preoperative PET-CT staging reports (prior to surgery with lymph node dissection) were obtained from patients’ records and compared against the reference standard of pathologic results obtained from lymph node dissection, and test performance reported using sensitivity and specificity.

      Results
      From Nov 1999 - Jan 2013, a total of 247 patients from 7 institutions underwent surgery for a carcinoid tumour with a corresponding preoperative PET-CT scan. The mean age of the patients was 61 (SD 15) and 84 were male (34%). The pathologic sub-type was typical carcinoid in 217 patients (88%) and atypical carcinoid in 30 patients (12%). The mean SUV uptake in the primary tumour was 4.8 (SD 4). Results from lymph node dissection were obtained in 213 patients. PET-CT reported uptake at mediastinal lymph nodes in 19 patients, of which only 3 were positive on subsequent pathology. Pathological results, from lymph node dissection carried out in 213 patients at the time of surgery, found 8 patients with mediastinal lymph node positive disease, of which only 3 had been picked up in preoperative PET-CT staging. The calculated sensitivity and specificity of PET-CT to identify mediastinal lymph node disease was 38% (95% CI 8-76%) and 93% (88-96%) respectively.

      Conclusion
      In non-small cell lung cancer, preoperative PET-CT is used for nodal and distant staging to assist in the selection of patients for radical treatment. British Thoracic Society guidelines for the radical management of patients with lung cancer recommend “radical treatment without further mediastinal lymph node sampling if there is no significant uptake in normal sized mediastinal lymph nodes on PET-CT scanning”. In carcinoid tumours, our results of the largest cohort to date suggest that PET-CT has a poor sensitivity but good specificity for the presence of mediastinal lymph node metastases in the staging of pulmonary carcinoid tumours. Therefore lymph node metastases cannot accurately be ruled out in carcinoid tumours with a negative PET-CT. If treatment decisions are based on the N2 status, invasive mediastinal staging should be undertaken in carcinoid tumours.

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      P1.19-004 - Evaluation of a cloud-based solution for local imaging evaluations in clinical trials for lung cancer (ID 1362)

      N. Aragane, N. Kobayashi, E. Bonnard, C. Charbonnier, J. Yamamichi, H. Mizobe, S. Kimura

      • Abstract

      Background
      Background: Clinical trials for determination of anti-cancer effects of chemotherapeutic agents are key for developing new strategies for cancer treatment. In most trials, primary endpoints are provided by imaging evaluations. Regulatory authorities have been recommending an Independent Central Review (ICR) with several readers to mitigate potential biases resulting from variance between investigator sites in clinical trials. Based on recent publications promoting site -based evaluation as imaging endpoint, they currently investigate an alternative to ICR. The goal of this study is to evaluate a cloud-based paradigm implementing software solutions and services that standardize the imaging evaluations among international investigator sites.

      Methods
      Methods: Ten lung cancer patients, who received epidermal growth factor receptor-tyrosine kinase inhibitor and for which chest CT scans were available at three time points from baseline to progression, were retrospectively selected. CT scans were evaluated according to the RECIST 1.1 criteria by two oncologists (Saga University) and one radiologist (Nice University Hospital) independently, through a cloud-based software solution named LMS (Lesion Management Solutions, MEDIAN Technologies), which offers reviewing tools and lesion segmentation algorithms. Such system was hosted on the data center (Canon IT Solutions, Japan) and used by readers and data managers (Canon and MEDIAN Technologies) for de-identification, quality control and centralization of the images and their evaluations. The study compared response evaluations between readers and analyzed the reasons for discordances.

      Results
      Results: Readers with different medical training and education, working at distant locations were able to reliably perform radiological evaluations using the same cloud-based system. Between the oncologists and the radiologist, a discordance rate of 35 % (14/40 evaluations) was observed when considering RECIST overall response (CR, PR, SD, PD) at all time points. Precisely, 6 and 8 evaluations were discordant at time point 1 and 2, respectively. . Half of discordances (7/14) were explained by a difference in the selection of target lesions. There were 3 /14 discordances due to a difference in lesion segmentation. The different segmentations occurred when the lesions were adjacent to mediastinum or pleura, where limits of lesions are not very contrasted.

      Conclusion
      Conclusion: The study shows the feasibility of imaging evaluation based on cloud services for clinical studies involving multiple international sites. Centralization of data made possible the on-going monitoring of evaluations through specialized services reducing variability among sites. Analysis of discordances between readers identified areas of improvement for cloud-based services such as a consensus process for target selection at baseline and the development of segmentation tools to standardize management of measurable lesions.

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      P1.19-005 - Computer-aided lung nodule analysis focused on ground glass opacity and consolidation on thin-section computed tomography. (ID 1447)

      E. Yamada, K. Aokage, H. Ohmatsu, T. Miyoshi, Y. Matsumura, T. Hishida, J. Yoshida, K. Nagai

      • Abstract

      Background
      Ground-glass opacity (GGO) component in a nodule on thin-section computed tomography (TSCT) often corresponds to a lepidic growth pattern of adenocarcinoma. In contrast, solid attenuation or consolidation on TSCT corresponds to invasive components. Many researchers reported consolidation tumor ratio (CTR; defined as the ratio of the size of solid attenuation to the maximum tumor dimension) was a reliable parameter in predicting tumor invasiveness. However, it has been pointed out that inter-/intra-observer variability in CTR measurement is a major problem in precise and reproducible evaluation of tumor characteristics. The aim of this study was to determine the optimal CT settings to reproducibly diagnose GGO and consolidation areas on TSCT by using an imaging software.

      Methods
      We reviewed preoperative TSCT images of the patients undergoing surgical resection for T1 lung adenocarcinoma in our institution between 2005 and 2009. The TSCT images were obtained without contrast enhancement and reconstructed in 1.0 or 2 mm thickness, using several CT systems. The imaging software colored GGO areas with cut-off CT levels of -800, -700 and -600 HU. Consolidation areas were colored with cut-off CT levels of -300, -200 and -100 HU. These GGO/consolidations identified by the software were compared with those visually determined by the consensus of the 4 authors (EY, KA, YM, HO). The 4 authors scored the correspondence between visual evaluation and software identification according to the cut-off levels. The scores were summarized to determine the optimal cut-off CT levels.

      Results
      We have reviewed 20 patients so far. Figure 1 shows a TSCT image and software-yielded image showing good correspondence with each other of GGO and consolidation areas. The best score was obtained when the cut-off level was -700 HU for GGO and -200 HU for consolidation. Figure1. Figure 1

      Conclusion
      Although based on a small cohort, we found optimal cut-off CT levels to identify GGO and consolidation areas using an imaging software. We need to analyze more cases, but this image analysis method is promising in determining CTR reproducibly.

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      P1.19-006 - Predictors of nodule malignancy in the Danish Lung Cancer Screening Trial (DLCST) (ID 2172)

      Z. Saghir, A. Dirksen, J.H. Pedersen

      • Abstract

      Background
      Pulmonary nodules are detected more frequently than ever in both clinical and screening settings. Timely and correct suspicion of malignancy is of great importance in the subsequent management of the nodules. We present data on pulmonary nodule growth and participants baseline characteristics to determine predictors of malignancy.

      Methods
      In DLCST, 4,104 current and former smokers, with a history of at least 20 pack years and age between 50-70 years, were randomized to either five annual multi-slice low-dose CT screenings or no screening. All participants had an annual visit to the screening clinic where lung function tests and questionnaires concerning health, lifestyle, smoking habits etc. were performed. The scans were read by two chest radiologists who recorded the location and size of any nodules. Nodules of diameters between 5-15 mm were considered indeterminate, and rescanned after three months. Participants with nodules larger than 15 mm were referred to diagnostic workup, as were those with growing nodules. Lung cancer was diagnosed by pathological evaluation. Using volumetric software solid and nonsolid/partsolid nodules were segmented and followed. Only visually correct segmented nodules that were present more than one year were included. Doubling times of mass, volume and diameter from the first to the last record of the nodule were calculated. We performed logistic regression analysis with malignancy as the outcome and baseline characteristics, nodule type and growth measurements as explanatory variables.

      Results
      975 nodules in 618 participants were included. 31 nodules (3%) were diagnosed as lung cancers. 10(33%) of the malignant nodules were nonsolid/partsolid. Fig. 1 shows histograms of growth measurements. Fig. 2 show the logistic regression analysis. In both cases FEV1 and Mass Doubling Times predicted malignancy significantly.Figure 1Figure 2

      Conclusion
      Growth rates measured by volumetric software and FEV1 are powerful predictors for malignancy when a pulmonary nodule is present in a low dose chest CT scan.

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      P1.19-007 - Prediction of pleural adhesion during video-assisted thoracopic surgery in lung cancer patients (ID 2175)

      K.N. Jin, H. Moon, Y.W. Sung, H. Seo

      • Abstract

      Background
      Pleural adhesions increase the risk of lung injury and lead consequent prolonged air-leak or conversion to open thoracotomy. We aimed to find the clinical or image predictor for pleural adhesion during video-assisted thoracoscopic surgery (VATS) in lung cancer patients.

      Methods
      Eighty-nine consecutive patients who underwent VATS for lung cancer were included. We retrospectively investigated operative records and clinical information including age, gender, smoking history, body mass index (BMI), forced expiratory volume in 1 second (FEV1), and forced vital capacity (FVC). Pleural adhesion was categorized into 5 grades; none, minimal, moderate (requiring adhesiolysis during VATS with 30 minute or less), severe (requiring adhesiolysis with 30 minute or longer), and very severe (near total involvement of the hemithorax). Advanced adhesion was defined as the presence of moderate or severe or very severe adhesion. Two radiologists blinded to clinical information performed visual analysis for image characteristics of chest CT in consensus. The presence of parenchymal band or calcified granuloma or pleural retraction around the tumor was determined. Severity of emphysema or interstitial fibrosis was assessed as 5 grades (none, trivial, mild, moderate, and severe). The extent of bronchiectasis or pleural thickening or pleural calcification or extrapleural fat thickening was evaluated as 3 grades (none, localized, and extensive).

      Results
      Pleural adhesion was found in 51 subjects (57.3 %) including 15 (16.9 %) minimal, 18 (20.2 %) moderate, 16 (18.0 %) severe, 2 (2.2 %) very severe adhesion. Male gender and current smoker was 66 subject (74.2 %) and 60 (67.4 %), respectively. Mean age was 64.6 ± 10.4 years-old. Mean value of FEV1 and FVC was 2.4 ± 0.6 ml (range; 0.7-3.9) and 3.4 ± 0.8 ml (range; 1.3-5.0), respectively. Tumor size was 3.1 ± 1.5 cm. Parenchymal band, calcified granuloma, pleural retraction was found in 41.6 %, 27 %, and 44.9 %, respectively. Most subjects had no (49.4 %) or minimal (23.6 %) emphysema. Mild, moderate, and severe emphysema was found in 18.0 %, 7.9 %, and 1.1 %, respectively. Most patients have no bronchiectasis (86.5 %) and no interstitial fibrosis (89.9 %). Localized and extensive bronchiectasis was found in 12.4 % and 1.1 %, respectively. Trivial and moderate interstitial fibrosis was found in 6.7 % and 3.4 %. Localized and extensive pleural thickening was found in 10.1 % and 1.1 %, respectively. Localized and extensive pleural calcification was found in 4.5 % and 1.1 %, respectively. Both localized and extensive extrapleural fat thickening was found in 5.6 %. In univariate analysis, male gender (P = 0.013), age (P = 0.21), FEV1 (P < 0.001), tumor size (P = 0.003) were significant predictors of advanced adhesion. Among the image characteristics, severity of emphysema was a significant predictor of advanced adhesion in univarite analysis (coeffient of 1.83, P = 0.007). Multivariate analysis revealed that independent predictor for advanced pleural adhesion was only FEV1 (coefficient of 0.13, P < 0.001).

      Conclusion
      Severity of emphysema and FEV1 might enhance the prediction of pleural adhesion during VATS in lung cancer patients.

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      P1.19-008 - Clinicoradiological evaluation of surgically resected pulmonary pleomorphic carcinoma (ID 2742)

      A. Nishida, H. Abiru, H. Hayashi, M. Uetani, T. Iida, T. Hayashi, K. Matsumoto, T. Tsuchiya, N. Yamasaki, T. Nagayasu, K. Ashizawa

      • Abstract

      Background
      Pulmonary pleomorphic carcinoma is rare and aggressive subtype of non-small cell lung cancer, with a dual-cell component of spindle and/or giant cells, and of epithelial cells. The objective of this retrospective study was to assess the clinicoradiological characteristics and surgical outcome of this tumor.

      Methods
      Data were retrospectively examined for 25 patients who had undergone surgical resection for pulmonary pleomorphic carcinoma. Epithelial components of the pleomorphic carcinoma were as follows: 13 adenocarcinoma (52%), 3 squamous cell carcinoma (12%) and 2 large cell carcinoma (8%). 7 tumors (28%) were composed only of spindle and giant cells.

      Results
      21 patients (84%) were male. 19 patients (76%) were smokers. Of the 14 symptomatic patients (56%), 7 had cough, 5 had hemoptysis, 1 had back pain and 1 had fatigue. The size of the tumor ranged from 1.9 to 10.1cm (mean 5.2cm). The tumors were located peripherally in 21 patients (84%). Calcification within the tumor was visible in only one patient. The margin of the tumors was well defined in 24 patients (96%). Notch, spiculation and pleural indentation of the tumors were observed in 14, 8 and 6 patients respectively. The tumors were inhomogeneously enhanced in 20 patients (80%) on contrast-enhanced CT. Low attenuation areas on contrast-enhanced CT were found to correspond to areas of necrosis in pathologic specimens. Surrounding area of ground-glass attenuation was seen in 14 patients (56%). Among them, hemorrhagic foci were observed in the pathologic specimens in 5 patients. Invasion of chest wall, diaphragm, other lobes of the lung and SVC was noted in 7, 2, 2, 1 patients, respectively. In addition, 6 patients had pleural invasion. The median length of the follow-up examinations was 46 months (range, 2.3–153.5 months). The 5-year overall survival rate was 30%. Patients with tumors invading the parietal pleura, chest wall, diaphragm, and other lobes of the lung had significantly worse overall survival (P=0.027). The subtype of epithelial components did not affect prognosis. Figure 1

      Conclusion
      The CT features of pulmonary pleomorphic carcinoma were well-defined and lobulated tumor located peripherally with inhomogeneous enhancement. Peritumoral areas of ground-glass attenuation are associated with tumoral hemorrhage in some cases. Pleomorphic carcinoma carried a poor prognosis, even when completely resected. The lung cancer comprised of at least 10 % of spindle and/or giant cells is suggested to have an aggressive malignant behavior.

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      P1.19-009 - Differences in proliferation of tumor cells in ground-glass opacity lesions on computed tomography for primary non-small cell lung cancer (ID 2801)

      G. Nishii, K. Takahashi, Y. Hirami

      • Abstract

      Background
      Ground-glass opacities (GGOs) on computed tomography (CT) represent a distinctive finding for nodules of bronchioloalveolar carcinoma that are generally stable or growing very slowly due to a low degree of malignancy. Therefore, small GGOs are often followed conservatively. However, some GGO nodules undergo clear enlargement during follow-up. The present study aimed to define the clinical features of GGO with potentially high degree of malignancy.

      Methods
      Among patients who underwent surgery for non-small cell carcinoma between June 2010 and April 2013 in our hospital, all 28 patients with GGO or mixed GGO nodules who had been prospectively evaluated with high-resolution computed tomography (CT) were enrolled in this study. Immunohistochemical studies using MIB-1 antibody to evaluate cell proliferation were performed using specimens obtained from GGO parts of 6 pure GGO and 22 mixed GGO nodules. A high-proliferation group was defined as cases showing >10% positive cells. The following clinical parameters were assessed: sex; age; smoking history; tumor size; tumor shape; tumor contour; ratio of consolidation area to whole area of tumor; and density of GGO. Correlations between high-proliferation status and clinical parameters were analyzed using Fisher’s exact probability test.

      Results
      Median frequency of positive cells by immunohistochemistry for MIB-1 was 9% (range, 1-42%) and the high proliferation group comprised 10 cases (35.7%). This group correlated significantly with high-density GGO, defined as showing a difference >400 Hounsfield units between the GGO field and adjacent lung field (P=0.038), and tended to correlate with tumor diameter >20 mm (P=0.095).

      Conclusion
      Density of GGO lesions correlates with proliferation of tumor cells. This clinical feature appears likely to allow differentiation of high-risk patients with GGO lesions.

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      P1.19-010 - Prognostic Value of FDG-PET-based Metabolic Tumor Volume<br /> in Conjunction with Mathematical Classifiers<br /> in Non-small Cell Lung CancerPatients (ID 2983)

      Y. Jiang, J. Wang, B. O'Brien-Penney, Y. Pu

      • Abstract

      Background
      The TNM staging system for prognostication in non-small cell lung cancer (NSCLC) is less than satisfactorily accurate. Previous research suggests that FDG-PET-based metabolic tumor volume (MTV) may be an independent prognostic marker in NSCLC when used in Cox-regression models. This study was to determine the potential prognostic utility of FDG-PET-based MTV used in mathematical classifiers for prognostication of NSCLC.

      Methods
      A consecutive cohort of 328 NSCLC patients (156 males, 172 females) with histologic confirmation and FDG-PET scans was identified for retrospective analysis. MTV measurements were made on baseline 18F-FDG PET/CT scans of the primary tumor (MTV~T~), metastatic lymph nodes (MTV~N~), and metastatic tumors (MTV~M~). Whole-body MTV (MTV~WB~) was defined as the sum of MTVs of primary tumor, metastatic lymph nodes, and metastatic tumors (MTV~WB~ = MTV~T~ + MTV~N~ + MTV~M~). A semi-automated 3D contouring program was used for obtaining the MTVs. Patient survival was determined from cancer registry data, and known survival length of living and lost-to-follow-up (i.e., censored) patients was recorded. Patient survival was determined at one year (189 survived, 129 did not) and two years (127 survived, 186 did not) after baseline FDG-PET scan, and survival status was known for most censored patients except for ten at one year and 15 at two years. Linear discriminant analysis classifiers were constructed on data of patient age, gender, histology, TNM stage, and MTVs. Cross-validation was done as follows: to predict a patient's survival status, a classifier was trained on data of all other patients of known survival status and not on the patient in question. Areas under receiver operating characteristic (ROC) curve (AUC), analogous to C concordance statistics, were compared statistically.

      Results
      The median patient age was 68.3 years and patient distribution by stage was 46 stage IA, 43 stage IB, 19 stage IIA, 18 stage IIB, 52 stage IIIA, 39 stage IIIB, and 111 stage IV. Median follow-up of living and lost-to-follow-up patients was 58 months and death confirmation was known in 249 (88.4%) patients. For one-year survival, the AUC (± standard error) value of the classifier based on age, gender, histology, and stage was 0.77±0.026 and that of the classifier based on age, gender, histology, stage, and MTVs was 0.82±0.023 (p < 0.01). For two-year survival, the corresponding AUC values were 0.75±0.028 and 0.79±0.026, respectively (p < 0.02). The AUC values were similar for classifiers based on age, gender, histology and MTVs and for classifiers based on age, gender, histology, and stage (p > 0.5). These results were consistent with previous results of statistically significantly better prognostic ability of multivariate Cox-regression models of MTV~WB~ compared with models not including MTV~WB~, after adjusting for age, gender, histology, treatment options, and whole-body tumor SUV~max~.

      Conclusion
      FDG-PET-based metabolic tumor volume can potentially increase prognostic accuracy for NSCLC patients beyond that of the TNM staging system at one and two years, and mathematical linear classifiers can potentially be used as an alternative to Cox-regression models for estimating survival probability.

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      P1.19-011 - Correlation between the tumor size measured by using chest radiograph and CT chest comparison to the pathologic size (ID 3037)

      T. Hantrakul, J.-. Euathrongchit, Y. Wannasopha, N. Lertprasertsuke, S. Saeteng, A. Tantraworasin

      • Abstract

      Background
      The size of the tumor is an important prognostic factor in cancer patient. It is ultimately based on the pathologic measurement of gross specimen from surgical resection. However, the preoperative tumor size could be determined by direct measurement of palpable superficial lesion or radiologic imaging such as chest radiograph or computed tomography (CT) in both lung window setting and mediastinal window setting. To our knowledge, there is no definite method to measure tumor’s size on radiographic imaging, moreover, the correlation between pulmonary tumor size measured by using radiographic imaging and pathologic size has not been studied in Thailand yet. The Northern Thailand Thoracic Group (NT-TOG) would like to determine the correlation between tumor size measured by using chest radiograph and CT chest comparison to the pathological tumor size.

      Methods
      After institutional review board approval, the retrospectively analytic cross sectional study from pathological records of all patients who underwent surgery in Chiang Mai University Hospital were reviewed. All cases that achieved CT imaging in the department of radiology were included. Finally 60 pulmonary tumors were collected to measure their sizes on chest radiograph and 98 pulmonary tumors were gather to measure their sizes on mediastinal and lung window sets and compared to the pathological sizes. The location of the tumor and histological cell type were recorded. Data analysis was performed using STATA software to find out the correlation between sizes that had been measured on chest radiograph and on CT images comparison to the tissue pathologic size.

      Results
      The tumor locations were common in the RUL and LUL. Adenocarcinoma was the most common histological type, followed by squamous cell carcinoma and metastasis respectively. The mean radiologic tumor sizes on chest radiograph, CT using mediastinal and lung window settings were 4.8 cm, 4.8 cm and 5.1 cm in maximal diameters, respectively. The mean pathologic tumor size was 4.7 cm in maximal diameter. The mean errors of chest radiographic measurement, CT measurement using mediastinal and lung window settings were 0.25 cm, 0.04 cm and 0.41 cm, respectively. The error of tumor size measured by using CT in mediastinal window setting was statistically significant less than that of using lung window setting (p<0.001). There was a statistically significant difference between tumor size measured by using CT in mediastinal window setting and pathologic tumor size (p<0.001). Predicted tumor size was calculated by using the equation “calculated tumor size (cm) = 1+(0.78xtumor size on CT in mediastinal window (cm)).

      Conclusion
      Although there is a statistically significant difference between CT measurement and pathologic tumor size, the tumor size measured by using CT in mediastinal window setting is seemly more accurate than in lung window setting or chest radiograph.

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      P1.19-012 - The Quality Of Consolidation In Part Solid Nodule Could Be A Predictor Of Survival (ID 3253)

      T. Ichikawa, K. Suzuki, T. Matsunaga, Y. Tsushima, S. Oh, K. Takamochi

      • Abstract

      Background
      The size of consolidation on thin-section computed tomography (CT) has been one of the most important preoperative prognostic factors in resected lung cancer. On the other hand, few reports mentioned the nature of consolidation as prognostic factor.

      Methods
      A retrospective study was conducted on 617 lung cancers of clinical stage IA which were resected between 2009 and 2012. Thin-section CT scans were available for all cohorts, which were reviewed by authors. Moreover authors divided lung cancers into three categories: ground glass opacity (GGO), part solid and pure solid. 235 cases are part solid nodule. We classified these 235 part solid lung cancers into two groups: homogeneous or heterogenous. The relationship between these consolidation statuses were evaluated using the chi-square test and Fisher’s exact test. The medical record of each patient was examined for investigating following clinicopathological factors: age, gender, smoking status (pack-year smoking), preoperative serum carcinoembryonic antigen (CEA), SUV max of the primary tumor on positron emission tomography (PET), pathological pleural, vascular, and lymphatic invasion. P-value <0.05 was considered statically significant.

      Results
      Ninety pts (38.3%) had homogeneous consolidation. There were 32 (35.6%) , and 56 (38.6%) men, 6 (14.6%), and tumor having 3 or more SUV max on PET was found in 6 (14.6%), 5 (10.4%), respectively. Based on univariate analysis, age, gender, and pack-year smoking were not statistically significant differences. In homogeneous consolidation group, 2 patients have nodal metastasis, however nodal metastasis were not observed in scattered consolidation group. (P=0.023) Vascular invasive was frequently found in homogeneous consolidation group. (P=0.04)

      Conclusion
      This result of our study shows that the quality of consolidation in part solid lung cancer could be the prognostic factor.

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      P1.19-013 - FDG-PET/CT differ Bronchial NETs from hamartomas (ID 3363)

      O. Grundberg

      • Abstract

      Background
      Bronchial NET:s account for approximately 1% of all lung cancers and usually require surgical removal. Hamartoma is a benign tumor not necessary to treat. The two conditions may have a very similar radiological appearance when studied by chest x-ray or CT, especially when the bronchial NET has a peripheral location. The objective was to assess if integrated FDG PET-CT examination could contribute to the decision-making process.

      Methods
      The material consists of 119 consecutively operated patients at our Centre during the Period of October 2005 to February 2012, where the Diagnosis (pathologically confirmed) either was Hamartoma or bronchial NET. Retrospective analysis of the Patient Charts and Radiology were performed. Out of these 119 cases, 58 hamartomas and 38 bronchial NET:s had been subject to FDG-PET-CT. All examinations were reviewed by one single radiologist/nuclear medicine physician. SUV-values were measured as well as morphological characteristics were assessed.

      Results
      Of the 38 Bronchial NET:s, 23 were peripheral and 8 central according to radiological appearance. Mean SUVmax of the Bronchial NET:s was 3.5 ( range 0–7.5). 6 Bronchial NET:s did not show any FDG-uptake. Mean SUVmax of the hamartomas was 0.77 (range 0.0–3.7). 31 of the hamartomas (61%) showed no FDG-uptake.

      Conclusion
      Although peripheral Bronchial NET:s may be indistinguishable to hamartoma at CT, the two conditions differ in FDG-PET appearance. Thus, it may be possible to avoid unnecessary thoracotomy when a peripheral solid lesion shows absence of FDG-uptake.

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      P1.19-014 - Stage survival for lung cancer staged by PET/CT, EUS FNA and/or EBUS TBNA (ID 3371)

      M. Krasnik, A. Mellemgaard

      • Abstract

      Background
      The seventh edition of the TNM classification of lung cancer was based on the 67.725 patients from 19 countries treated by all modalities between 1990 and 2000. There was no information about how the c TNM and pTNM was determined and there were probably differences in the preoperative staging methods. At Gentofte University Hospital diagnostic work-up and staging procedures included PET / CT, EUS FNA and EBUS TBNA early on after the introduction of these technologies. The purpose of the project was to evaluate the survival after lung cancer surgery in patients who were diagnosed and staged by PET / CT, EUS FNA and / or EBUS TBNA and to compare survival with the results from the IASLC's staging project.

      Methods
      All patients in the period 1.1.2005 to 12.1.2012 who had had PET / CT, EUS FNA and / or EBUS TBNA leading to a diagnosis of non small cell lung cancer before surgery were included in the project The date of surgery and the date of death if any were recorded. Survival was measured from the date of surgery and was calculated by the Kaplan-Meier method. cTNM and the methods by which the diagnosis and stage was determined was included in the analysis.

      Results
      In this period, 4090 lung cancer patients were diagnosed and staged at Gentofte University Hospital.1187 were staged by PET CT, EUS FNA and/or EBUS TBNA and of these 791 were operated. Over all, survival based on cTNM for patients staged at Gentofte University Hospital was on the same level level as found in the the IASLC's analysis for pTNM. In particular, the survival curves for cTNM stage IA, IB and IIIA found in this material appears to be identical with those found in the Stage survicalIASLC's project for the same pTNM stages. For example, the 3-year survival for the cIA in our study was 84% where the IASLC's pIA was 83% and cIIIA in our study was 32% while the IASLC's pIIIA was 37% The cTNM IIIB in our material shows a better survival than IASLC pTNM IIIB (33% vs 14%) There were too few patients in stages IIA and IIB for any meaningful conclusion.

      Conclusion
      As the treatment regime is based on the cTNM, it is important that it is as accurate as possible. Thus, concordance between cTNM and pTNM should ideally be very high. Using new technologies, the concordance at our institution has increased to the current level of 95%. It is therefore not surprising that the survival of the various cTNM stages in our study are similar to the survival curves from IASLCs staging project.

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      P1.19-015 - Clinical application of thin section chest CT with computer-aided detection system for the detection of small metastatic nodules in pulmonary metastasectomy. (ID 3428)

      H. Kim, C.H. Kang, J.M. Goo, I.K. Park, Y.T. Kim

      • Abstract

      Background
      It is important to identify possible metastatic nodule prior to metastasectomy, in order to perform complete resection. Thin section chest CT (TSCT) can detect small metastatic nodules more accurately than conventional chest CT. Conventional CT is known to miss metastatic nodules that are manually palpable by up to 40%. Reported sensitivity of helical CT cannot exceed 90%, also. We adopted TSCT and applied computer-aided detection (CAD) system for the search of small metastatic nodules to improve the detection power of TSCT.

      Methods
      From March 2009 to February 2013, 333 patients were referred to thoracic surgeon for pulmonary metastasectomy. TSCT with CAD was performed in every candidate for pulmonary metastasectomy. Every nodule detected by TSCT and CAD was annotated by radiologists and the whole map and annotation numbers of nodules were reported before operation. Intraoperatively, bi-manual palpation in open metastasectomy and finger palpation in video assisted thoracoscopic surgery (VATS) were used to detect the nodules. Only operations with complete available data were included in the study and 251 operations from 239 patients were analyzed.

      Results
      A total of 1021 nodules were identified by TSCT with CAD, while 115 nodules (11.3%) were additionally detected by CAD. Among the annotated nodules, 742 nodules were palpable during operation. Including intraoperatively detected 49 nodules, a total of 824 nodules were resected. Of 527 pathologically proven malignant nodules, 518 (62.9%) nodules were metastatic lesions. Among metastatic lesions, 496 were detected by TSCT (95.8%), 9 by CAD (1.7%) and 13 by manual palpation (2.5%). Also, 11 metastatic nodules were no palpated during operation but resected according to the annotation on CT. The overall sensitivity of thin section chest CT with CAD was 97.5%. Though overall specificity of TSCT with CAD was very low as 12.1% because that of radiologist’s reading was 14.2%, specificity only for CAD was 45.6%.

      Conclusion
      TSCT could detect small subcentimetre nodules and CAD enabled detecting additional small nodules. With help of TSCT with CAD, even the metastatic nodules, which were not palpable during operation, could successfully be resected. Furthermore, TSCT with CAD could detect tiny nodules with rather high specificity compare to radiologist’s reading only. Although the number of true metastatic nodules was small and several metastatic nodules were undetected, the TSCT with CAD system increased the detection sensitivity and would be helpful in complete metastasectomy.

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    P1.20 - Poster Session 1 - Early Detection and Screening (ID 172)

    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 11
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      P1.20-001 - Early lung cancer detection programme - its impact on activity of the local thoracic surgery department (ID 74)

      T. Grodzki, J. Alchimowicz, J. Wójcik, B. Kubisa, J. Pieróg, A. Kozak, N. Wójcik

      • Abstract

      Background
      The impact of massive early lung cancer detection program on patients` profile and surgical activity of the local thoracic surgery department is analyzed.

      Methods
      Early lung cancer detection program was conducted in a single city of 400000 inhabitants from 2008 till 2011. Enrollment criteria included both sexes aged 55-65 years with history of 20 pack-years of tobacco smoking. All detected lesions were followed up in accordance with IELCAP protocols. All cases requiring surgery were referred to a single local thoracic surgery department serving for the population of appr. 2 million people. Following data were analyzed: number of NSCLC detected and resected, number of stage I resected patients, histology, type of surgery.

      Results
      15020 patients were screened (39.5% of the population of people aged 55-65 in our city). 6240 pulmonary lesions were detected, majority (59%) smaller than 5mm. 445 lesions (7.1%) were bigger than 15mm. 182 patients (2.9% of all detected lesions) were referred to the local thoracic surgery. Overall 925 NSCLC were resected at our department in 2008-2011. 232 (25%) of them were stage I. Number of pneumonectomies was 166 (18%). Dominant histology was squamous cell (52%) 247 metastatic lesions were resected in the same period. The early detection group delivered 77 NSCLC resections (8.3% of all resections). 53/77 (69%) were stage I (significant difference versus the entire group). Number of pneumonectomies was 2/77 (2.5%, significant difference vs entire group). Dominant histology was adenoca (50%). 33 metastatic lesions (13.3% of all metastases resections) were treated surgically. 15 small cell lung cancer were diagnosed and referred for chemotherapy. 33 metastatic lesions were resected, too.

      Conclusion
      The patients with NSCLC detected by the early lung cancer detection programme are treated surgically in earlier stages in comparison to the entire population of patients referred to our department. They require pneumonectomy significantly less frequently than the entire group.

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      P1.20-002 - Elevated Inflammatory Markers Could be Useful In Early Diagnosing And Monitoring Lung Cancer (ID 1365)

      I. Yucel, Y. Kemal, B. Yılmaz, G. Demirag, K. Ekiz, F. Teker, E. Kut

      • Abstract

      Background
      Background: Lung cancer is still the first leading cause of cancer death worldwide, and late diagnosis is a major obstacle to improving lung cancer outcomes. Tumor inflammation and immunology are recently identified as enabling cancer characteristics and play important roles in tumor progression and metastasis. Recently, elevated preoperative or pretreatment neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio(PLR) and mean platelet volume (MPV) detected in peripheral blood were identified as independent prognostic factors associated with poor survival in various cancers, including colon cancer, esophageal cancer, gastric cancer and breast cancer. These markers are highly repeatable, inexpensive and widely available. The aim of this study is to examine whether MPV, NLR and PLR could be useful inflammatory markers for differentiating lung cancer from healthy controls; also to determine the relation between these markers and other prognostic factors and histopathologic subgroups.

      Methods
      Methods: Retrospectively eighty-one lung cancer patients and 81 age-sexes matched healthy subjects included into the study. Patients with hypertension, hematological and renal disease, heart failure, chronic infection, hepatic disorder and other cancer were excluded from the study. The preoperative or pretreatment blood count data was obtained from the recorded computerized database.

      Results
      Results: NLR and PLR values were significantly higher in lung cancer patients compared to healthy subjects.( NLR: 4.42 vs 2.45 p=0.001, PLR: 245.1 vs. 148.2 p= 0.002) MPV values were similar in two study groups (7.7 vs. 7.8). On the other hand we did not find statistically significant relationship between these markers ( MPV, NLRand PLR) and histopathologic subgroups, TNM stages, grade, OS and PFS (all p>0.05).

      Conclusion
      Conclusion: Our data suggests that NLR and PLR values may be used as easily and available biomarkers for early diagnosis of lung cancer, but needs more large prospective studies to predict patients outcome.

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      P1.20-003 - Lung Cancers Detected Using Low-dose CT Screening: Results of an Eight-year Observational Study (ID 1779)

      M. Kusumoto, R. Kakinuma, H. Asamura, K. Tsuta, T. Tsuchida, T. Tamura, G. Ishii, K. Nagai

      • Abstract

      Background
      To evaluate lung cancers detected using low-dose CT screening between February 2004 and March 2012.

      Methods
      The number of screenees analyzed in the observational study was 12,116. Screenees were classified into three groups based on their smoking index (SI): SI ≥ 600, SI < 600, and never-smokers. Overall, 147 lung cancers in 132 cases treated at the National Cancer Center Hospital and the National Cancer Center Hospital East were evaluated according to the smoking index. Adenocarcinomas were evaluated based on the following classification: group A (adenocarcinoma in situ and minimally invasive adenocarcinoma), and group B (invasive adenocarcinoma). Statistical analyses were performed using the chi-square test.

      Results
      The ages of the patients with lung cancer ranged between 42 and 85 years (mean, 61 years). Thirty-two of the 2989 male screenees (1.48%) and 2 of the 149 female screenees (1.34%) in the SI≥600 group, 22 of the 2989 male screenees (0.74%) and 10 of the 796 female screenees (1.26%) in the SI<600 group, and 16 of the 2148 male screenees (0.74%) and 50 of the 3878 female screenees (1.29%) in the never-smoker group were diagnosed as having lung cancer. Among the 147 lung cancers, 8 lesions (5.4%) did not present as nodules and instead appeared as a partial thickening of the bulla wall, a funicular-like shadow, a pneumonia-like shadow, etc. Among the remaining 139 lung cancers, 35 lesions (25.2%) presented as pure ground-glass nodules (GGNs), 64 lesions (46%) presented as part-solid nodules, and 40 lesions (28.8%) presented as solid nodules. The histology of the lung cancers was adenocarcinoma in 132 cases (89.8%), squamous cell carcinoma in 8 cases (5.4%), small cell carcinoma in 3 cases (2%), adenosquamous carcinoma in 1 case (0.7%), carcinoid tumor in 2 cases (1.4%), and NSCLC in 1 case (0.7%). The disease stages were as follows: IA, 127 (86.4%); IB, 11 (7.5%); IIA, 2 (1.4%); IIB, 1 (0.7%); IIIA, 3 (2.0%); and IIB, 3 (2.0%). Among the 147 cancers, the number of incident cases was 8 in the SI≥600 group (median follow-up period, 3.1 years), 3 in the SI<600 group (median follow-up period, 2.9 years), and none in the never-smoker group (median follow-up period, 3.0 years). Lung cancer cases in smokers (including ex-smokers) occurred predominantly in men (male, 54; female, 12), while lung cancer cases in never-smokers occurred predominantly in women (female, 50; male, 16) (P < 0.0001). The number of adenocarcinomas in smokers (including ex-smokers) was 29 in group A and 24 in group B, while the number of adenocarcinomas in never-smokers was 42 in group A and 23 in group B (P = 0.274). In the never-smoker group, the number of adenocarcinomas in men was 7 in group A and 9 in group B, while the number of adenocarcinomas in women was 35 in group A and 14 in group B (P < 0.05).

      Conclusion
      The number of invasive adenocarcinomas was not statistically different between smokers (including ex-smokers) and never-smokers. Never-smokers should also be a target population of CT lung cancer screening. Adenocarcinoma may be overdiagnosed among female never-smokers.

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      P1.20-004 - UK lung Cancer Screening trial (UKLS): Base line data (ID 1796)

      J.K. Field, A. Devaraj, D.R. Baldwin, J. Holemans, N. Screaton, M. Ledson, R.C. Rintoul, A. Nair, J.R. Gosney, D. Rassl, K.M. Kerr, S. Duffy, D.H. Hansell

      • Abstract

      Background
      Lung Cancer causes over 35,000 UK deaths per year: early detection by CT screening has been shown to reduce mortality in the USA by 20%.

      Methods
      UKLS is a pilot randomised controlled trial, screening individuals at a high risk of developing lung cancer (>5% over 5yrs) with low-dose CT. UKLS is population-based, approaching people of 50-75yrs identified through local primary care records and using a validated lung cancer risk prediction model to identify high risk individuals from the target group (Raji Annals of Int. Med 2012). We report observations made from the initial recruitment to the trial. 250,000 individuals were approached in Liverpool and Cambridgeshire, 30% responded positively to the first questionnaire. 4000 individuals were recruited and randomised to receive either a low-dose CT scan or usual care. All CTs were double read according to UKLS protocol. Nodules were reported as category 1, 2, 3 or 4 depending on size and volume (Baldwin et al. Thorax 2011). Participants with category 4 nodules (>500mm3) were referred to the lung cancer multi-disciplinary team (MDT) for further workup. Individuals with a category 3 nodule (50-500 mm3) underwent a repeat CT within 3 months, whereas category 2 nodules (15-50mm3) were followed up at 12 months. The trial is currently in follow-up and some participants are still in the 3 and 12 month phases.

      Results
      1991 high risk UKLS participants underwent baseline CT by June 2013. 1044/1991(52.4%) individuals had nodules requiring further imaging or work-up. 79/1991 (4.0%) had nodules which required referral to the MDT clinics at the pilot sites for further workup. At this time 31/1991(1.6%) had a prevalent lung cancer. 27/31 lung cancers (87.1%) were non-small cell lung cancer and 25/31 lung cancers (80.6%) were Stage I or II (based on pathological staging or clinical staging where the pathology staging was not available).

      Conclusion
      UKLS has already demonstrated 1.6% prevalence, utilising the LLP risk prediction model to identify high risk individuals, which compares favourably with the NELSON and other European trials. The Pilot UKLS is due to provide an interim report in 2014.

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      P1.20-005 - Comparison between Chest Radiography, Chest Tomosynthesis and Computed Tomography to Detect Pulmonary Nodules: A Phantom study and clinical experience. (ID 2327)

      J.-. Euathrongchit, T. Kattipathanapong, Y. Wannasopha, S. Ua-Apisitwong, S. Saeteng, K. Jirapong, N. Lertprasertsuke, A. Tantraworasin

      • Abstract

      Background
      It is true that treatment in the early stage of lung cancer provides the best benefit, so many researchers have actively sought a good screening test for early detection. Although, chest radiography (CXR) is commonly used for evaluating patient with pulmonary disease. There are some limitations in early detection small nodule. Computed Tomography (CT) can easily solve this problem. However, the disadvantages of the CT are high cost and high radiation dose. Recently, there is a new technique called digital tomosynthesis, which can reconstruct sectional images at arbitrary depths by collecting a number of projection images at different angles using a digital detector. The overlapping anatomy of the section images is much less than the standard projection radiograph. Currently, many articles have presented the benefits of DT. The learning curve for interpretation of the technology is also important. The purpose of this study is to find the detection rate of nodule by using CXR, chest digital tomosynthesis (CDT) and CT examination with phantoms and preliminary clinical application in Maharaj Nakorn Chiang Mai hospital.

      Methods
      After institutional review broad approval, in-house chest phantom was made from acrylic, plaster and catheters. The plastic beads, diameter size 1-2 mm., 3-4 mm., 5-6 mm., 7-8 mm. and 9-10 mm. were implanted to represent pulmonary nodules in a phantom. None to 20 nodules were randomly embedded in each model and photographed by digital chest radiograph (CXR), chest digital tomosynthesis (CDT) and chest computed tomography (CT). Two thoracic radiologists were blinded to review and label nodules on each image. Percentage of nodular detection in each study was calculated and compared between each other. After gain experience from phantom study, CDT was preliminary applied to the surgical cases for preoperative evaluation.

      Results
      There were 332 nodules in the 34 phantom-models. Nodule detection rate from each modality was 75.3% of CXR, 91.0% of CDT and 98.8% of CT, respectively. CT could detect all nodules, which were larger than 3 mm in diameter. There were over 90 % of detected nodules from CDT that diameter were larger than 5mm. Percentages of nodular detection of CDT and CT were not statistically significant difference in 5-10 mm sized nodules. Poor nodular detection areas on CXR were mediastinal and hilar regions, while on CDT was costophrenic sulcus. Clinical examinations were shown.

      Conclusion
      CT showed the highest percentage of nodular detection, followed by CDT and digital CXR, respectively. The percentage of detection in nodules size 5 – 10 mm between CT and CDT was not statistically significant difference.

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      P1.20-006 - Non-invasive Detection of Lung Cancer from Cells in Sputum Using Cell-CT™ (ID 2624)

      A. Nelson, M. Meyer, T. Neumann, J. Hayenga, R. Katdare, C. Presley, B. Hawthorne, D. Steinhauer, T. Bell, S. Spring, A. Tourovskaia, F. Patten, G. Pawlick, T. Colgan, D. Wilbur, D. Johnson, N. Peled, R.W. Aye, P. Zarogoulidis, J. Chien

      • Abstract

      Background
      Cell-CT is a fully-automated, single-cell analysis system that has been developed to enable non-invasive screening for lung cancer. We report the results of a pilot clinical study using Cell-CT for lung cancer detection from patient sputum, including the determination of criteria that define specimen adequacy, the detection of abnormal cells in adequate specimens (sensitivity), and the detection of normal cells (specificity), performed automatically or further enhanced with human evaluation.

      Methods
      Twenty-seven patients with biopsy-confirmed lung cancer produced spontaneous-cough sputa (three morning-pooled) that were fixed, stained with hematoxylin following mucus dissolution, then enriched for epithelial cells using the method of fluorescence-activated cell sorting. The specimens were analyzed using Cell-CT, which computes 3D digital images of single cells through tomographic reconstruction with isometric, sub-micron resolution (see figure). The 3D cell images were automatically interrogated to measure morphometric biosignatures for lung cancer. 3D feature measurements were combined to produce two probabilistic scores: one that identifies abnormal cell candidates (moderate, marked dysplasia, and cancer) and another that identifies normal bronchial epithelial cells to determine specimen adequacy. 3D images of the abnormal cell candidates were transmitted to a workstation for cytopathologist confirmation and final diagnosis, using a custom computer interface (Surveyor™). Figure 1

      Results
      Based on a stringent criterion for determining specimen adequacy, 12 of the 27 sputum specimens (or roughly 50%) were deemed adequate. In the adequate specimens, abnormal cells were automatically detected, correctly classified, and confirmed in 11 of the 12 cases. This result is statistically significant and demonstrates that the Cell-CT can achieve an abnormal cell detection rate for lung cancer cells in sputum nearing 92% sensitivity. The area under the receiver operator characteristic curve (aROC) for abnormal cell detection is 0.99 (see figure). We can estimate the specificity for normal specimens by examining the rate of correct normal cell detection and classification. With the detection of 9,683 normal cells, seven were falsely classified as abnormal (false positives). However, following human evaluation using Surveyor, the resulting specimen specificity was essentially 100%.

      Conclusion
      This first important study of Cell-CT shows there are sufficient abnormal cells in adequate, spontaneous sputa to achieve high-sensitivity lung cancer detection rates without false positives. The power of 3D single-cell morphometry supports the future potential impact of a non-invasive, sputum-based lung cancer screening test.

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      P1.20-007 - Low-Dose Computed Tomographic Screening in Healthy Adults at Low Risk for Lung Cancer (ID 2661)

      C.A. Yi, K.S. Lee, M. Shin, Y.Y. Cho, K.E. Shin, Y. Choi

      • Abstract

      Background
      The benefit of low-dose CT screening was proved by showing reduced mortality from lung cancer in persons at high risk for lung cancer. We evaluated the effect of low-dose CT screening in healthy adults at low risk for lung cancer.

      Methods
      From January 2006 through December 2008, we retrospectively enrolled 13,085 symptom-free healthy adults who underwent three annual screenings with either low-dose CT (6,256 persons) or chest radiography (6,829) for regular check-ups. They were divided into groups at high risk (≥30 pack-year smoking and ≥ 55 years), intermediate risk (≥20 pack-year smoking and ≥ 50 years), or low risk (<20 pack-year smoking). Data were collected on numbers of screening detected lung cancer and survival from screening detected lung cancer that occurred through December 31, 2012.

      Results
      The rate of positive screening test was 53.2% with low-dose CT and 13.1% with radiography. A total of 98.2% of the positive screening results in CT group and 97.9% in radiography group were false positive results. CT screening increased the number of screening detected lung cancers in the less than high risk population (multivariable-adjusted odds ratio (OR) 4.75, 95% confidence interval (CI) 2.56 to 8.82, P <.001), but not in high risk population (OR 1.23, CI 0.38 to 3.93, P =.730). In the less than high risk population CT screening detected lung cancers were all adenocarcinomas and were more frequently part-solid or non-solid nodules (P=.008). The stage of CT screening detected lung cancer more commonly in IA disease (76.1% in CT vs. 20% in radiography, P <.001) and the survival of CT screening detected lung cancer was consistently better than radiography screening detected lung cancers in the less than high risk population (multivariable-adjusted hazard ratio (HR) 0.08, CI 0.01 to 0.60, P =.014), in the less than intermediate risk population (HR 0.07, CI 0.01 to 0.66, P =.021), and in the low risk population (HR 0.07, CI 0.01 to 0.69, P =.023).

      Conclusion
      CT screening in low risk population detected more number of stage IA adenocarcinomas which area more frequently part-solid or nonsolid nodules, as compared with chest radiography or with CT in high risk population. The survival of CT screening detected lung cancer was better than that of chest radiography detected lung cancers in the lower risk population.

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      P1.20-008 - Health Care costs in the Randomized Controlled Danish Lung Cancer CT Screening Trial. (ID 2741)

      J.F. Rasmussen, V. Siersma, J.H. Pedersen, B. Heleno, S. Zaghir, J. Brodersen

      • Abstract

      Background
      Low dose computerized tomography (CT) screening for lung cancer can reduce mortality but it is currently unclear whether CT screening is cost effective. Denmark is a small country (5.3 mio. inhabitants) with a uniform and a public health care system covering all inhabitants. The unique civil registration system allows a linking of all health care expenses to the individual person. The objective of this study is to evaluate the direct healthcare costs generated by a randomized lung cancer CT screening trial in Denmark.

      Methods
      Methods: A Registry study nested in the Danish lung cancer screening trial (DLCST), involving 4104 participants, current or former heavy smokers, aged 50–70 years. Participants were randomized to five annual low dose CT scans or usual care during 2004 – 2010. Total healthcare costs and utilization data for the primary and the secondary healthcare sector, were retrieved from public registries, covering the period from randomization until September 2011

      Results

      Table 1. Cumulative relative health care costs in the diagnostic groups compared with the control group in the DLCST, shown as the multiplicative factor the costs on average differ from the costs in the control group.
      Annual costs were significantly higher in the screening group compared with the control group (p<0.001), but when cost of CT-scans was excluded, there was no longer a significant difference (p=0.52). Analyses according to diagnostic groups showed that annual costs were 10.57 times higher for the true-positive and 1.67 times higher for the false-positive group compared with the control group (Table 1).

      Conclusion
      Lung cancer CT screening increases overall healthcare costs compared with no screening, equivalent to the costs of the CT-screening scans. Overall healthcare costs were higher for the true-positive and false-positive groups than for the control group, even when excluding CT-screening scan costs. This increase was outweighed by the larger true-negative group who had reduced, but not statistically significant, costs compared with the control group (Table 1 and Figure 1). .Figure 1

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      P1.20-009 - New potential marker for the diagnosis of lung cancer: Hyaluronan. (ID 3087)

      M.P. Rangel, V.K. De Sa, E.R. Parra, V.L. Capelozzi

      • Abstract

      Background
      HA concentration is elevated in several cancers, but there is no data regarding its concentration in the sputum of lung cancer patients. In this study, we examined the HA concentrations in tissue and sputum samples and its impact on the screening and diagnosis of lung cancer patients.

      Methods
      Hyaluronic Acid (HA) was examined in lung cancer tissue of 14 patients through immunohistochemistry using a HA-probe. The analysis was performed using ImageProPlus 7.0. The HA concentration in sputum samples of 90 lung cancer patients, 25 COPD patients and 15 healthy controls was also analyzed. All the patients and healthy controls selected underwent a sputum induction. Sputum samples were incubated with urea 7M at 60[o]C and afterwards incubated with a proteolytic enzyme. The levels of HA were measured by a noncompetitive ELISA-like fluorometric assay.

      Results
      It was observed a different expression pattern of HA in squamous cell carcinomas vs. adenocarcinomas specimens (p<0.05). In sputum, a significant different concentration pattern of HA was found among lung cancer, COPD and healthy individuals (p<0.001; Fig1A). Equally significant was the difference between HA in the sputum from lung cancer and healthy volunteers (p<0.001), as well as lung cancer and COPD patients (p=0.002). ROC curve between lung cancer and healthy volunteers furnished an area of 0.821 (0.727–0.915). Assuming a cut off value of 31,44ng/mg, the specificity was 100% and the sensitivity was 51% (Fig1B). ROC curve to distinguish COPD patients from lung cancer patients showed an area of 0.698 (0.600-0.797) and the cut off value of 48.3ng/mg presented 100% of specificity and 33% of sensitivity (Fig1C). Figure 1

      Conclusion
      The results presented suggest a promising role of HA in the developing and progression of lung cancer and its concentration in the sputum as a novel diagnostic marker for differentiating normal from lung cancer patients.

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      P1.20-010 - A Prospective Study of Annual CT Screening for Lung Cancer in HIV Smokers (ID 3367)

      A. Hulbert, C. Hooker, D.C. Li, M.D. Teran, S. Cox, T. Brown, K. Horton, J. Wrangle, E. Fishman, K. Pelowski, B. Lee, C. Sam, S. Tsai, E. Welthe, B. Mudge, G. Pridham, J. Keruly, R. Moore, J. Herman, R. Brown, M.V. Brock

      • Abstract

      Background
      Of all the non-AIDS associated malignancies, lung cancer is the most deadly because of its advanced stage of presentation. Within the HIV population, the incidence of non-small cell lung cancer (NSCLC) is estimated to be 2-4 times that of the general population. Despite this growing burden of NSCLC in HIV-infected smokers, no data exist regarding early detection of lung cancer in this population since screening trials, such as the U.S. National Lung Cancer Screening Trial, excluded HIV-infected participants. Preliminary data have highlighted the ineffectiveness of chest x-rays in diagnosing lung cancer early, and waiting for HIV-positive individuals to develop symptoms is misguided. These facts provide a compelling argument for the use of helical CT as a screening tool for lung cancer in HIV-infected patients.

      Methods
      From 2006-2013, a prospective feasibility study was conducted to determine the prevalent and incident CT detection rates in HIV-infected smokers of lung cancer. The secondary objective was to determine if CT screening could change the stage distribution of HIV lung cancer to that of an early stage disease. Annual CT screening was conducted for lung cancer in current or former smokers over age 25 years old with ≥20 pack-years history and a confirmed HIV diagnosis. To determine markers of lung cancer risk, we also analyzed from trial participants, clinical data, sera, and CT scans using quantitative, densitometry imaging as an estimate of emphysema, and compared these variables to similar parameters from 130 HIV patients at our institution with known lung cancer.

      Results
      Of the 224 individuals enrolled, 72% were males, 90% African-Americans, 9.5% Caucasian, and 0.5% Hispanic. The median age was 48 years and the median number of smoking pack-years was 34. No prevalent lung cancers were detected by CT screening and only lung cancer was found on incident screening. There were no interim diagnoses of lung or extrapulmonary cancers. Eighteen deaths occurred but none were cancer-related. Of 29 nodules detected at baseline screening, fifteen were further imaged, five biopsied, but none progressed to cancer at study end. Emphysema was commonly observed and its heterogeneity across the entire lung as measured by CT densitometry was significantly higher in HIV subjects with lung cancer than in those without (p≤0.01). On multivariate regression, increased age, higher smoking pack-years, low CD4 nadir, and increased heterogeneity of emphysema on quantitative CT imaging were all significantly associated with lung cancer in HIV individuals.

      Conclusion
      This pilot feasibility study is the world’s first reported annual lung cancer CT screening trial in HIV-positive smokers. During 4 years of CT screening of 224 HIV subjects with a median age of 48 years, only one incident lung cancer was found. This suggests that until the median age of the worldwide HIV population increases, the ability of annual CT screening to detect lung cancers in HIV-infected smokers will be low. Immunologic and radiographic differences that exist between HIV patients with and without lung cancer may serve as biomarkers of lung cancer risk.

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      P1.20-011 - Retrospective Study of Lung Cancer Screening. (ID 3372)

      Y. Morishige, S. Oh, T. Maeyashiki, S. Uchida, T. Ichikawa, R. Tachi, M. Fukui, T. Matsunaga, Y. Tsushima, K. Takamochi, K. Suzuki

      • Abstract

      Background
      The lung cancer screening in Japan is only chest radiography now. But in 2011, the national lung screening trial research team was reported reduced lung-cancer mortality with low-dose computed tomographic screening. We studied lung cancer patients about a difference of a screening type, for example radiography and computed tomography.

      Methods
      From January 2008 through May 2013, we performed the operation of 1344 lung cancer patients. In those patients, 1018 patients were proved the type of screening.

      Results

      symptom radiography CT
      pt 146 340 378
      age 64±1 64±0.7 67±0.5
      cStage IA 50 199 296
      IB 22 66 42
      IIA 18 25 6
      IIB 15 13 8
      IIIA 25 21 12
      IIIB 6 4 2
      IV 7 3 1
      pStage IA 35 155 259
      IB 18 57 53
      IIA 12 31 13
      IIB 16 23 11
      IIIA 41 50 30
      IIIB 6 4 1
      IV 12 7 4
      The number of patients by symptom, radiography and computed tomography are 146 (14%), 340 (33%) and 378 (37%), respectively. The rate of clinical stage I (789, 78%) are 72 (7%), 265 (26%), 338 (33%), respectively. The rate of pathological stage I (672, 66%) are 53 (5%), 212 (21%), 312 (31%), respectively. On the other hand, the rate of clinical III are 31 (3%), 25(2%), 14 (1%), respectively. The rate of pathological III are 47 (5%), 54 (5%), 31 (3%), respectively. The difference of between clinical stage I and screening type are 0.000, 0.813, and 0.000, respectively. The difference of between pathological stage I and screening are 0.000, 0.081, and 0.000, respectively.

      Conclusion
      In the group of symptom and radiography, there are a lot of advanced lung cancer patients, while in the group of computed tomography, we can detect a lot of early lung cancer patients. Computed tomography is better than the other screening about the detecting lung cancer. We should use a computed tomography in screening of lung cancer.

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    P1.21 - Poster Session 1 - Diagnosis and Staging (ID 169)

    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 9
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      P1.21-001 - Cancer Diagnosis in the Acute Setting (CADIAS): a study on behalf of the London Cancer Alliance (ID 86)

      T. Benepal, T. Newsom-Davis, C. Hughes, L. Forbes

      • Abstract

      Background
      The United Kingdom has poorer cancer survival rates than other comparable countries (EUROCARE and International Cancer Benchmarking Partnership studies). Furthermore, for some cancers stage at diagnosis is more advanced; largely explained by differences in one-year survival, a marker of later diagnosis. In 2012, the National Cancer Intelligence Network published a report as part of National Awareness and Early Diagnosis Initiative, Routes to Diagnosis. The key findings were that 24% of newly diagnosed cancer patients in England presented as emergencies. Tumour types most likely to present in this way included lung (39%). Emergency new cancer presentations were more likely in older patients and those from a more deprived background, and the relative one-year survival was significantly lower across nearly all tumour types. However, little is known about the reasons why so many patients present acutely with a potentially delayed diagnosis. Factors that lead to delayed diagnosis have been associated with the patient, the doctor and the healthcare system. Previous research in the area has been restricted by separating primary and secondary care, and data on the patient experience is limited. The CADIAS study is designed to examine the whole diagnostic pathway and consider improvements across all three domains.

      Methods
      This National Cancer Research Network approved study recruits patients who present to hospital as an emergency with a new diagnosis of lung or colorectal cancer. Data are collected from three sources, the patient, primary care and secondary care. The study aims to understand the whole diagnostic pathway; from first recognising a symptom to emergency presentation in secondary care, including the role of primary care; map the patient, clinical and organisational factors that contribute to an emergency new cancer diagnosis; and suggest ways to improve outcomes by identifying gaps in service provision and any opportunities to diagnose cancer earlier. Six hospitals within the London Cancer Alliance will aim to recruit 250-300 patients into the study (Chelsea and Westminster, Lewisham, Croydon, Hillingdon, St. Georges and Gyus and St. Thomas'). A small pilot study was conducted to confirm the feasibility of the recruitment methods and data collection tools, specifically the use of patient interviews across a relatively large scale and with a group of potentially unwell participants. This part of the study, which included research nurse training, was designed by the Promoting Early Cancer Presentation team at Kings College London.

      Results
      Data analysis of 9 patients and of the 1st cohort of nurse training demonstrated that the methods used and data collected is of the required quality and standard to open the study to full recruitment. CADIAS is now open across the remaining hospital sites and, at the time of abstract submission, a total of 19 patients had been enrolled.

      Conclusion
      Understanding the factors which contribute to an estimated 39% of lung cancer patients presenting as an emergency is key to improving cancer services and outcomes. This study brings the patient story together with data from primary care and secondary care to present a rich picture of this type of presentation and identifying any opportunities to diagnose cancer earlier.

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      P1.21-002 - A survey of EGFR mutation frequency and testing practices in Asia Pacific (ID 1213)

      Y. Yatabe, K.M. Kerr, A. Utomo, R. Pathmanathan, V.K. Tran, X. Du, T. Chou, M..L.D. Enriquez, G.K. Lee, J. Iqbal, S. Shuangshoti, R. McCormack, T. Mok

      • Abstract

      Background
      The efficacy of EGFR TKIs in EGFR mutation-positive NSCLC patients has led to a need for accurate, timely EGFR mutation testing worldwide. Although EGFR mutation testing has been adopted by many laboratories in Asia, accurate data are lacking on the proportion of NSCLC patients tested in each country, and the most commonly used testing methods. The objectives are to investigate the practice of EGFR mutation analysis in Asian Pacific countries and document the prevalence of routine testing in this population.

      Methods
      This is a retrospective database survey of records from NSCLC patients tested for EGFR mutations from 1 January 2011 to 1 January 2012 at participating sites across the Asia Pacific region. The majority of eligible hospitals/laboratories that participated had performed ≥ 100 EGFR mutation tests during that period. Accessible patient records were used to complete an online questionnaire, with data being stored in a central database. Primary objectives were to determine the number of NSCLC patients tested for EGFR mutations and the rate of EGFR mutation positivity: overall, by histological subtype, and by demography. Other variables included the number of NSCLC cases diagnosed, EGFR mutation testing methods used, and tumour sample characteristics and processing. The proportion of EGFR mutation-positive patients and 95% CI were calculated; other variables will be summarized descriptively. An interim analysis has been conducted using data collected from more than 18,000 newly diagnosed NSCLC patients at 29 sites.

      Results
      The data from surveyed sites indicates that the overall proportion of NSCLC patients tested for EGFR mutations was 31.9% (95% CI 31.2-32.6%), with an EGFR mutation positivity rate of 40.2% (95% CI 39.1-41.4%) overall, ranging from 28.7% to 53.4% (Table). Additional data on demographic and histological subgroups and current testing practices (methods, sample types, sample preparation) will be presented. [*: Wilson score confidence interval. **: Note that the sites from Vietnam (one site) and Philippines (one site) did not test ≥ 100 patients. N.D.: No data.]

      Table: Proportion of Patients Tested and EGFR Mutation Rates at Participating Sites
      Country Total number of newly diagnosed NSCLC patients Proportion of patients tested, % (95% CI*) EGFR mutation positivity, % (95% CI*)
      Total 18,050 31.9 (31.2-32.6) 40.2 (39.1-41.4)
      Japan 2,379 64.8 (62.9-66.7) 30.2 (28.0-32.6)
      China 12,086 18.3 (17.6-19.0) 38.1 (36.3-39.9)
      Taiwan 2,530 52.9 (50.9-54.8) 53.4 (50.7-56.0)
      Hong Kong 399 31.1 (26.7-35.8) 49.2 (40.6-57.9)
      Malaysia 357 98.6 (96.8-99.4) 45.7 (40.6-51.0)
      Thailand 249 57.8 (51.6-63.8) 45.1 (40.6-49.8)
      Vietnam** 50 100.0 (92.9-100.0) 36.0 (24.1-49.9)
      Philippines** N.D. Not Known 38.9 (29.5-49.2)
      Indonesia N.D. Not Known 28.7 (20.8-38.2)

      Conclusion
      The data collected in this survey indicate that, in 2011, testing practices varied widely across the region, despite the well-known high incidence of the mutation. The data provide an insight into these practices and provide a reference platform on which to compare and build on for the future of EGFR mutation testing and molecular diagnosis of NSCLC in Asia Pacific.

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      P1.21-003 - Impact on stage migration in lung cancer from 6th to 7th edition of TNM a study conducted at two hospitals in Nepal. (ID 1448)

      S.C. Acharya, R. Pun, A. Karn, B. Acharya, B.D. Poudel, M.K. Piya

      • Abstract

      Background
      Lung cancer is the leading cause of cancer related morbidity and mortality in both the sexes in Nepal. It accounts for 15.4 % of total cancer as per hospital based Cancer Registry in Nepal. Patient usually present with stage III (55%) or IV (34%) disease. With the revision of Lung cancer staging system by International Association of the study of Lung Cancer (IASLC) and adoption of this Seventh edition of staging system by American Joint Comitte on Cancer (AJCC) in 2010, we tried to make an attempt and to recognize how many percentages of patients will upstage and downstage with comparison to the sixth edition of staging system.

      Methods
      This retrospective cross-sectional observational study was conducted at Department of Radiotherapy and Oncology, Bir Hospital and National Hospital and Cancer Research Centre, Nepal. We reviewed the record of the entire registered, histologically diagnosed lung cancer patient in these two centers during the year 2012. Total of 151 patient’s record were analyzed and restaged using both sixth and the seventh edition of staging system. The data were recorded and evaluated.

      Results
      Male preponderance observed with 63% of the cases and female of 37%. The mean age group was 63.93 years with the youngest being 31 years and the eldest with 83 years of age. The total patients in the different stage with seventh edition observed are IB 2(1%0, IIA 6(4%), IIB (8%), IIIA 59(39%), IIIB 24(16%), and IV 52 (34%. Stage migration was seen in 15.23 % of the total cases. Most prominent was downstage from IIIB to IIIA which accounts for the 7% of all the cases. This downstage is due to the Tumor size >7cm and a separate tumor nodule in the same lobe which elaborates T3 of the seventh edition. Next prominent stage migration noticed was due to categorization of pleural fluid cytology as M1a in seventh edition, which cause a total of 4% of cases to be upstaged from IIIB to IV, which in fact this may further increase. The entire patients presented with pleural effusion have not undergone cytological evaluation because in most of these cases T4 disease was due to invasion and or satellite nodule along with the pleural effusion so effusion was ignored as per 6[th] edition. Rest patient were downstage from T4 to T3 and T3 to T2, which is due to the sub categorization of the tumor by size.

      Conclusion
      In this cohort of patients, there was downstaging from IIIB to IIIA and upstaging from IIIB to IV because of revised TNM classification. Thus, we feel that a prospective larger study is required as it will further allow us to explain the prognosis and the survival pattern based on the staging system and we strongly recommend to have detailed staging and a routine pleural fluid cytology in the patient with pleural effusion before initiation of the treatment.

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      P1.21-004 - Profiling the clinical and diagnostic pathway of Epidermal Growth Factor Receptor (EGFR) mutant Non-Small Cell Lung Cancer (NSCLC) in Ireland (ID 1455)

      J. Naidoo, S. Noonan, M.Y. Teo, Y.S. Rho, J. Clince, K. Gately, C. O'Brien, T. O'Grady, E. Kaye, P.G. Morris, K. O'Byrne, O.S. Breathnach

      • Abstract

      Background
      The presence of an EGFR mutation in NSCLC provides prognostic and therapeutic information for patients and clinicians. This study investigates the clinical behaviour of EGFR mutant (MT) versus EGFR wild-type (WT) NSCLC in an Irish cohort of patients. Differences in the pattern of presentation, metastasis and diagnostic methods between patients with EGFR-MT and WT tumours are poorly characterised. In this retrospective study, we investigated these parameters, variations in EGFR mutation type and resultant impact on overall survival (OS).

      Methods
      Patients with EGFR-MT NSCLC were identified from a National Multi-Institutional database. Patient demographics, diagnostic and clinical data were collected by review of medical records. From the database, EGFR-WT controls matched for age, gender and stage were identified and used as a comparator group. Fisher’s exact and Mann-Whitney tests were used to compare variables between groups. Cox model was used to examine the effect of mutation type on OS.

      Results
      We identified 416 patients with NSCLC. Forty (10%) patients had EGFR-MT positive tumours, of which data were available on 35 (87%) patients. Among patients with EGFR-MT tumours, median age was 64 (range 35-89), 29 (83%) were female, 34 (97%) patients had adenocarcinoma, and 1 (3%) patient had adenosquamous carcinoma. Twelve (34%) patients had resected disease, and 23 (66%) had metastatic disease. At median follow up of 12.8 months, 3 (25%) patients with localised EGFR-MT disease recurred, 0 (0%) of EGFR-WT recurred. There were no significant differences in the pattern of disease between EGFR MT and WT in terms of central/peripheral localisation of primary lesion, or sites of metastasis such as the lung, liver, adrenal gland, bone or brain (p=1.0). Patients with EGFR-MT disease were more likely to be diagnosed via transbronchial biopsy (n=16, 47%) than EGFR-WT (n= 4, 11% p<0.01.) Patients with EGFR-WT disease were more likely to be diagnosed via endobronchial ultrasound/fine needle aspiration (FNA) (n= 21, 58%. p<0.01.) Among those with EGFR-MT disease, 19 (54%) patients had tumours which harboured Exon 19 deletions, and 6 (17%) harboured L858R mutations. The remaining mutations comprised L861Q, V689M and deletions in Exons 18, 20 and 21. Among patients with stage IV disease at diagnosis, the median OS was 20.9 months and 7.3 months for EGFR-MT and EGFR-WT disease respectively (p=0.16.) The median OS for patients who underwent resection was not reached in either group.

      Conclusion
      There were no significant differences in patterns of presentation and metastasis between patients with EGFR-MT and WT tumours in this cohort. Patients with EGFR mutations were more likely to be detected by transbronchial biopsy compared to patients with WT disease, who were diagnosed more commonly by FNA. Possible explanations for this include institutional preferences or ease of tissue acquisition. In this cohort, the most common mutations in EGFR were Exon 19 deletion or L858R. The likelihood of mutation detection might be improved with the inclusion of a full EGFR mutational analysis.

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      P1.21-005 - Multiple primary malignancies in patients with lung cancer: clinical features and prognosis (ID 2074)

      S. Kim, S.J. Lee, Y.J. Ryu, J.H. Lee, J.H. Chang

      • Abstract

      Background
      BACKGROUNDS: The development of multiple synchronous primary malignancies in an individual is uncommon and unfortunate, but the frequency is increasing. The metachronous cancers will appear more commonly as cancer patients live longer lives. OBJECTIVES: The aim of this study was to determine clinical features, organ location, and prognosis in patients with multiple primary malignancies (MPM) including lung cancer.

      Methods
      METHODS: Following a retrospective review of clinical data, 101 patients with MPM including lung cancer confirmed with a histopathological diagnosis between 2002 and 2012 were enrolled in a tertiary referral hospital.

      Results
      RESULTS: The median age was 67 years (interquartile range (IQR), 61-73 years) at lung cancer diagnosis, and 66 (65%) patients were male. The most common histologic type of lung cancer was adenocarcinoma (47%), and 5 patients (5%) were diagnosed with triple cancers. In a total 56 metachronous cancer (55%), the median time between lung cancer and other cancer was 47.1 months (IQR 23.6-72.1 months) and 20 had lung cancer diagnosed before the occurrence of other primary cancers. The synchronous tumors were in 45 of 101 (46%). The most frequent cancers accompanying lung cancer were urogenital malignancies (30%) followed by gastrointestinal tract (28%) and thyroid malignancies (17%). Median survival duration calculated from the diagnosis of the first cancer was 33 months in the lung cancer first patients, 11 months in the other cancer first patients and 1.5 months in synchronous patients (p ≤ 0.001) with median follow up of 12.2 months. The factors of significantly associated with the survival of MPM were adenocarcinoma; histologic type of lung cancer (p = 0.010), the initial intensive treatments of lung cancer (p ≤ 0.001), non-smoker (p = 0.045) and operable lung cancer stage (p = 0.049) using Kaplan–Meier method with the log-rank test.

      Conclusion
      CONCLUSION: The synchronous tumors showed worse outcomes compared with those of the metachronous tumors including lung cancer. Despite multiple primary malignancies in patients with lung cancer, the influence of effective anticancer therapies that improve the survival, and the prognostic factors including the histologic type, staging, and smoking status were similar to the known factors of lung cancer.

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      P1.21-006 - Diagnostic value of CT fluoroscopy-guided transbronchial biopsy in endobronchially invisible and transthorasically inaccessible nodule/mass of the lung (ID 2408)

      E. Yilmaz, A. Akkoclu, A. Alpaydin, A. Gulsen, N. Sahin, F. Sever

      • Abstract

      Background
      To evaluate the usefulness of transbronchial needle biopsy (TBNB) under computed tomography fluoroscopy (CTF) for pulmonary nodule/mass that is invisible at bronchoscopy and not suitable for biopsy using transthoracic approach.

      Methods
      The study included 23 patients (14 men, 9 women and mean age of 57 years) with pulmonary mass/nodule on computed tomography (CT) scans. In all patients, there was no an endoluminal lesion at bronchoscopy previously carried out and transthoracic biopsy was considered to be inappropriate owing to location of the lesion and/or presence of serious emphysema with abnormal pulmonary function test result. The procedure was done in a CT room with a monitor faced to the radiologist, while performing the broncoscopy by a bronchoscopist. CT fluoroscopic real-time scans were used to confirme that the tip of the bronchoscopic needle was exactly inside of the pulmonary target lesion. After the biopsy performed under CTF guidance, the obtaining samples were examined histopathologically.

      Results
      Figure 1 CTF-guided transbronchial biopsy samples were adequate for definitive diagnosis in 19 (83%) patients and inadequate in 4 (17%) patients. Inadequate results were caused by inability to reach the lesion as seen on CTF scans. 15 nodules/masses were diagnosed as malignant, 4 as benign. For malignant lesions, the final diagnoses were adenocarcinoma (n=5), small cell lung cancer (NSCLC) (n=4), non-NSCLC of undetermined cell type(n=2), epidermoid carcinoma (n=2), lymphoma (n=1) and sarcoma (n=1). Among the benign lesions, specific diagnoses were obtained in 2 (%50) patients. Mild to moderate hemoptysis occurred in 4 (17%) patients.

      Conclusion
      CT fluoroscopy-guided transbronchial biopsy is an effective and safe method to obtain the diagnosis of the lung lesion. It seems to be particularly valuable with a real-time guidance in pulmonary nodule/mass which is invisible at bronchoscopy and inappropriate for transthoracic biopsy.

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      P1.21-007 - Usefulness of Computed Tomography Guided Percutaneous Transthoracic Biopsies in Diagnosing Thoracic Malignancies - Experience from a State Hospital in Malaysia (ID 2648)

      C.K. Ong, L. Pereirasamy, K. Raj, I. Ali

      • Abstract

      Background
      Computed tomography (CT) guided percutaneous transthoracic biopsy is a minimally invasive procedure that has been widely accepted as an effective, safe and feasible alternative for diagnosis of thoracic lesions. It guides therapeutic decisions, avoiding surgical biopsies in many clinical settings. The diagnosis sensitivity rate for malignant lung lesions was high (88-95%). The study was conducted to evaluate the diagnostic accuracy and complications of CT guided percutaneous transthoracic biopsies of suspected malignant pulmonary lesions.

      Methods
      Retrospective study involving all consecutive patients who underwent diagnostic CT guided percutaneous biopsies of suspected thoracic malignancies on dual slice CT equipment between Jan 2010 and December 2012. Percutaneous core needle biopsies were performed using a 16 / 18 / 20G Temno trucut automatic cutting needle under CT guidance. After the biopsy, a CT slice through the area of biopsy was performed to determine the presence of significant bleeding or pneumothorax. The samples were sent for the histological analysis. Evaluation included clinical data, pathologic results and therapeutic consequences. Statistical analysis of factors related to patient characteristics, lung lesions and biopsy technique was performed to determine possible contribution to the occurrence of pneumothorax.

      Results
      A total of 204 patients (143 males; 61 females) with mean age of 59.5 ± 14.0 years were included in the study. Mean diameter of lung lesion was 44.4 ± 14.5 mm. Mean depth of lung lesion was 14.4 ± 6.9 mm. Biopsies samples were adequate in 198 patients (97.1%) and inadequate in 6 patients (2.9%). Percutaneous transthoracic biopsy had an overall diagnostic accuracy of 93.6%. For malignant lesions, biopsy was positive in 161 patients (sensitivity of 97.6%) and for benign lesions, in 30 patients (sensitivity of 76.9%). Pneumothorax was observed in 30 patients (14.7%) and only 3 of them (1.5%) required a chest drain. The significant risk factors for pneumothorax were lesion depth >20 mm (p<0.0001), pathology type (malignant; p<0.0001), larger needle size (p<0.0001), number of passes >2 (p=0.001), lesion size <30 mm (p=0.009). There were no haemothoraces or major bleeding complications. However, post-interventional local hemorrhages were observed in 9 patients (4.4%) and hemoptysis was reported in 2 patients.

      Conclusion
      Percutaneous transthoracic CT guided biopsies of lung lesions were an effective procedure in the diagnosis of malignant lung lesions. Our study also shows that CT-guided needle biopsy is relatively safe, with only 1.5% of pneumothorax requiring chest drain and no major bleeding complications observed.

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      P1.21-008 - Accuracy of nodal staging in early stage NSCLC in the modern era of PET-CT, EBUS-TBNA and multidisciplinary team approach (ID 2745)

      T. Saghaie, K. Tonga, P. Bui, C. Bui, L. Morgan, P. Flynn, B. Ng

      • Abstract

      Background
      Accurate staging of NSCLC remains the most important step in predicting outcome. It has been proposed that PET-CT, as an addition to conventional work up, allows for more accurate pre operative detection of stage IIIa and IIIb disease. On the other hand, it appears to have limitations in reliably staging nodal involvement in early stage NSCLC. We aimed to compare pre-operative nodal staging (PET-CT and/or EBUS-TBNA findings) with post-operative histopathological results to determine the accuracy of PET- CT in a multi-disciplinary team setting.

      Methods
      This was a prospective, observational study of consecutive patients discussed through Nepean Lung Cancer MDT that underwent surgical resection for NSCLC from Jan 2010 until Feb 2013. PET-CT parameters of all patients, including FDG uptake in primary lesion(s) as well as hilar and mediastinal lymph nodes, were compared with post operative histopathology of the primary lesions and resected lymph nodes. Pre-operative nodal staging based on PET-CT +/- EBUS-TBNA was compared with post-operative histopathological staging. A PET-CT SUV (max) of equal or more than 2.5 was considered positive.

      Results
      74 patients (mean age 69 years, range 47-86, 45 M ) underwent surgical resection with lymph node dissection for NSCLC (65 lobectomies, 5 bi-lobectomies, 2 wedge resections and 2 pneumonectomies). The most common malignancy in this group was Adenocarcinoma (39 [52.7%]) followed by Squamous Cell Carcinoma (25 [33.7%]) and undifferentiated large cell carcinoma (10 [13.5%]). Most patients were post-operatively confirmed to be in early stages (32 stage I and 26 stage II) with other patients in stage III (12 IIIa and 1 IIIb) and stage IV (3). In 47% of cases, PET-CT nodal staging was concordant with final histopathological results. There was discordance in 39/74 cases with PET-CT being more likely to upstage (30/74) than to downstage (9/74) the mediastinum. Symmetrical FDG uptake in hilar lymph nodes was common amongst upstaged cases. Anthracosis/silicosis was reported in lymph node histopathology of 16/74 (%21.6) patients, with 8 upstaged by PET-CT. Overall, sensitivity of PET-CT mediastinal staging in our cohort was 31.25% with a specificity of 70.5%. This translates into accuracy of 70.2%. In 7 cases, EBUS-TBNA was performed to establish nodal staging. One case of micro-metastasis, confirmed on post-operative histopathology, was not detected on EBUS-TBNA.

      Conclusion
      Nodal staging by PET-CT in early stage NSCLC has reasonable specificity but poor sensitivity, tending to upstage rather than downstage. Benign inflammatory processes affecting intra-thoracic lymph nodes such as anthracosis/silicosis may cause false positive PET-CTs. Nodal staging based only on PET-CT is inadequate and discussion through a multidisciplinary panel as well as minimally invasive investigations such as EBUS-TBNA is recommended. This is consistent with current international guidelines.

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      P1.21-009 - Reliability of transthoracic fine needle aspiration and core needle biopsy for the diagnosis of pulmonary mucinous adenocarcinoma (ID 2759)

      H.Y. Lee, H.Y. Lee, J. Han, O.J. Kwon, K.S. Lee

      • Abstract

      Background
      In case of mucinous adenocarcinoma (MA), cytologic atypia is usually mild to moderate and can be absent in some cases, creating a diagnostic pitfall in recognizing MA in small tissue biopsy and cytology specimens. Specific diagnosis of mucinous subtype in small tissue n FNA is important because it is considered an invasive neoplasm until proven otherwise, and it carries a worse prognosis for its aggressive behavior with frequent multicentricity and intrapulmonary metastatic spread. The purpose of this study was to evaluate the diagnostic accuracy of transthoracic fine needle aspiration (FNA) or core needle biopsy (CNB) of MA of the lung.

      Methods
      We retrospectively reviewed a consecutive series of 184 patients who underwent curative operation for MA. Among those patients, 105 patients underwent pre-operative percutaneous FNA (n= 34) or CNB (n= 79). Eight patients underwent both FNA and CNB for the same tumors. Diagnostic accuracies of FNA and CNB for MA were evaluated, and the contribution of various clinicopathologic parameters to subtyping accuracy was analyzed.

      Results
      Diagnostic accuracies of FNA and CNB in determining malignancy were 67.6% and 87.3%, respectively. 20.6% and 59.5% were successfully diagnosed as MA through FNA and CNB, respectively. Univariate analysis implicated type of procedure and prominent growth pattern of mucinous adenocarcinoma as significant factors for successful pathologic diagnosis. Figure 1

      Conclusion
      CNB of diagnosis of MA is feasible and accurate. Our data support the suitability of small biopsy specimens for the new therapeutic paradigms even in mucinous adenocarcinoma.

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    P1.22 - Poster Session 1 - Epidemiology, Etiology (ID 166)

    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 12
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      P1.22-001 - An Nickel Workers Cohort Study in China (Jinchuan Cohort)-the Largest Nickel Population in World (ID 95)

      Y. Bai, A. Yang, H.Q. Pu, J. He, T. Zheng, M. Dai, W.Y. Zhang, Q. Wang, N. Cheng

      • Abstract

      Background
      Nickel is one of the most widely distributed and used metals in the world. Exposure to nickel compounds can result in a variety of adverse effects on human health. The China Nickel Workers Cohort Study (Jinchuan cohort) is estimated to include more than 50 000 nickel workers.

      Methods
      Since 2011, all staff and workers have been eligible for a medical examination every 2 years, and these workers who participated in the medical examination will be in-person interviewed with a standardized and structured questionnaire with trained interviewers and will be included in the Jinchuan cohort study. The medical examination includes a comprehensive physical examination, biochemical examination, epidemiologic survey and collection of biological samples. The Jinchuan cohort has the largest data set from a cohort of nickel exposed workers with both questionnaire and laboratory-based information and the exposure and disease information will be updated every 2 years through the biannual survey and medical examination.

      Results
      The comprehensive epidemiological and biological data will permit the evaluation of a number of hypotheses concerning the health effects of nickel exposure. The unique repository of blood samples including blood cell, plasma, and serum collected at the time the epidemiology survey will provide a population-based platform to examine biological indicators that closely correlate with nickel exposure and illness by using molecular epidemiologic methods. All of the cryopreserved blood samples are being stored in cryogenic tubes for future studies.

      Conclusion
      We are conducting the first occupational epidemiological study of nickel exposure in China among over 50 000 workers Comprehensive physical and biochemical examinations, an epidemiologic survey, and collection of biologic samples from workers are being used to evaluate the relationship between nickel exposure, cancer, and other health outcomes The cohort will be followed every two years with a repeat medical examination to update exposure and outcome information

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      P1.22-002 - Non-small cell lung cancer in young patients: Clinicopathological features (ID 670)

      U. Coskun, Y. Gunaydin, A. Ulas, O. Balakan, M. Inanc, A. Inal, M. Gumus, R. Davutoglu, N. Alkis, M. Benekli

      • Abstract

      Background
      Non-small cell lung cancer (NSCLC) is the most common cancer worldwide. NSCLC is strongly related to age. Its incidence increases with advancing age and the median age at diagnosis is 70 years. Less than 5% of all NSCLC is seen before 40 years of age. Furthermore, young patients have different characteristics compared with older patients. In this study, the clinical features of patients less than 40 years of age were analyzed.

      Methods
      Medical records of patients diagnosed as having NSCLC between March 2000 and March 2013 were retrospectively examined in 17 institutions of Anatolian Society of Medical Oncology. Epidemiological data such as age, gender and smoking history was collected. Additionally, histological subtype, ECOG performance status, stage, number of organ metastasis, presence of cranial metastases were analyzed.

      Results
      A total of 210 patients were evaluated. Median age was 35 years (range, 18-40). The majority of the patients were males (148 males and 62 females). There were 120 patients with a history of smoking. Seventy-eight patients were non-smokers and twelve were unknown. Majority of the patients (64%) had stage IV disease at presentation. Most of the patients had good performance status. Half of these patients had two or more organ metastasis (53%). Cranial metastases were detected in 55 patients. Adenocarcinoma was the most common histological subtype (57%). Other subtypes were squamous cell carcinoma (20%) and unclassified (20%). In stage IV disease, adenocarcinoma was more frequent (64%). There was no association between histopathologic subtype and smoking history. Median overall survival (OS) of the entire cohort was 15.1 months. Median OS was similar to the literature data (stage II: 45.8 months, IIIA: 44.4 months, IIIB: 21.1 months and stage IV: 9.9 months).

      Conclusion
      Adenocarcinoma was more common in the younger patients. These patients had advanced disease and good performance status at presentation. However, survival was not better than older patients based on historical literature data.

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      P1.22-003 - Lung Cancer Survival in Southern Tasmania (ID 684)

      K. See, N. Harkness, C. Hunter

      • Abstract

      Background
      Lung cancer incidence and mortality are high in Tasmania; Incidence Mortality Australia (AIHW 2007) 43/100 000 34/100 000 Tasmania (Cancer Registry 2007) 58/100 000 54/100 000 There is limited published data looking at 5 year survival for primary Non-Small Cell Lung Cancer (NSCLC) particularly from Australian cohorts.

      Methods
      Local clinical practice information was collected in a prospective database. Cases presented at a multidisciplinary lung cancer meeting over a 24 month period (April 2006 -March 2008) were analysed. Patients with NSCLC were identified (n=181). Survival data was obtained for all NSCLC cases (n=181/181) via hospital and general practitioner records as well as the Registry of Births, Deaths and Marriages. Lung cancer stage was based on the 6[th] edition IASLC TNM classification. Mortality data and survival times were calculated according to clinical stage.

      Results
      Five year survival was 10.5% (19/181) for all stages of NSCLC. Stratified by stage, 5 year survival was: Stage I 25% (13/52), Stage II 25% (3/12), Stage III 6% (3/52), and Stage IV 0% (0/65). Overall median survival was 7 months and when stratified by stage was: 30 months for Stage I, 5.5 months for Stage II, 9.1 months for Stage III and 3 months for stage IV disease. Patients who underwent surgical resection with curative intent had a 60% 5 year survival (13/22) which is in keeping with other published Australian data.

      Conclusion
      The five year survival rates for Stage II, III and IV NSCLC were comparable with that of internationally published cohorts. In contrast, all-cause mortality rates for Stage I NSCLC appear higher than expected however rates of surgical cure are in keeping with published data.

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      P1.22-004 - Pathologic subgroup analysis in patients who were diagnosed as non-small cell lung carcinoma and analysis of its effect together with basic demographic and clinical characteristics of patients on survival parameters. (ID 1673)

      C. Karadeniz, F. Köse, H. Mertsoylu, A.A. Beşen, S. Muallaoğlu, A. Sezer, O. Ozyilkan

      • Abstract

      Background
      Lung cancer is the most common cause of cancer-related deaths in the world. In the last decades, the patients with adenocarcinoma histology have been increasing, although we don’t know the exact reason, and now constitute most common histological subgroup of Non-small Lung Carcinoma (NSCLC).Main aim of this study is analysis of histological subgroup of NSCLC, changing of histological subgroupsover time and its effect on survival parameters.

      Methods
      We analyzed 493 NSCLC patients those who were followed at our department between January 2006 and December 2011. Basic demographic and clinical characteristics such as stage of disease, initial diagnostic tests including invasive procedures, immunohistemochemical methods to clarify the histopathological subgroups, treatment protocols together with survival parameters were recorded retrospectively.

      Results
      Included were 493 patients with a median age of 60 years (35-102). There were 426 men (86.4%)and 67 women(13.6%)446 (90.5%) patients had a history of cigarette smoking. The percentage of female patients in whole group had been increased over timenonsignificantly(p=0.24). We found that adenocarcinoma was most common histopathological diagnosis (44.9%). Better performance status, early diagnosis, and adenocarcinoma histology exhibit statistically significant effect on overall survival with p values of (p=0.003,p=0.054, p=0.006), respectively. Statistical analysis showed that overall survival and TTF-1 positivity were significantly increased over time in the study with p values of (p=0.011) and (p=0,001) respectively. We also found that TTF-1 positivity was higher in female gender (p=0.005). Additionally,we were not able to show significant effects of basic demographic and clinical characteristicsof the patients such as age, TTF-1 positivity and primary localization of tumor on overall survival (p>0.05).

      Conclusion
      Our study showed that adenocarcinoma is the dominant histology of NSCLC in Turkey and the percentage of female patients in NSCLC and overall survival in NSCLC had been increased significantly over time.Patient and tumor characteristics, such as histological shifting to adenocarcinoma over time, that we found during our study is compatible with literature.

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      P1.22-005 - A Prospective, Molecular Epidemiological Study of EGFR Mutations in Asian Patients with Advanced Non-Small-Cell Lung Cancer with Adenocarcinoma Histology (PIONEER study) - China Subset Analysis (ID 2241)

      Y. Shi, J. Li, S. Zhang, M. Wang, S. Yang, N. Li, G. Wu, W. Liu, G. Liao, K. Cai, L. Chen, M. Zheng, P. Yu, X. Wang, Y. Liu, Q. Guo, L. Nie, J. Liu, X. Han

      • Abstract

      Background
      PIONEER (A molecular ePIdemiOlogy study in Asian patients with advanced NSCLC of adEno histology to assess EGFR mutation status; NCT01185314) was a multinational prospective epidemiological study planned to investigate EGFR mutation frequency in patients from Asia with newly diagnosed advanced lung adenocarcinoma (ADC) and the influence of demographic and clinical factors on EGFR mutation frequency. Here we report analysis results for the subset of patients from China.

      Methods
      Patients were aged ≥20 years, with treatment naïve stage IIIB/IV lung ADC. The primary objective was assessment of overall EGFR mutation frequency. The secondary endpoints included investigation of the correlation between EGFR mutation status and demographic and clinical factors and attrition rates of EGFR mutation testing. The acquisition, preparation, and processing of tumor material was performed in line with the routine clinical practice of the participating hospital laboratories. Tumor EGFR mutation status was determined in central labs using amplification refractory mutation system (ARMS)-based EGFR mutation detection kit (Scorpion ARMS IVD2, Qiagen, Crawley, UK). 29 mutations were detectable by this method across Exons 18, 19, 20, and 21.

      Results
      747 patients were registered in 17 investigational sites in China (50.4% of the overall study population). 46.9% of the patients were female, mean age was 58 years (range 17-83), and 56.4% were never-smokers. 72.4% (541/747) of the samples used for mutation testing were primary tumor. Sample locations include lung (73.5%), local lymph nodes (10.3%), distant lymph nodes (6.3%), pleural effusion (2.5%), pleura (2.0%), and others. sample types include image-guided core biopsy (29.7%), bronchoscopic biopsy (24.1%), incisional biopsy(12.7%), cytology and others. The median time interval taken from order to report of mutation test was 16 days with a range from 3 days to 62 days. EGFR mutation status was successfully evaluated in 741 patients: 372 (50.2%) were mutation positive, 369 (49.8%) were mutation negative. Smoking status and pack years had a statistically significant association with presence of EGFR mutation, but even in regular smokers, the mutation frequency was 35.3%. 12 patients provided both histology and cytology samples. Among these 11 had concordant EGFR mutations status and 1 had mutation results that did not match.

      Conclusion
      Locations and types of the samples used for EGFR mutation testing were various in clinical practice. The overall EGFR mutation frequency in clinically unselected Chinese ADC was 50.2%. Smoking status and pack years had a statistically significant association with presence of EGFR mutation.

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      P1.22-006 - The impact of sex hormone-binding globulin levels on thromboembolic events at cancer patients with adenocarcinoma (ID 2410)

      M. Bozkurt

      • Abstract

      Background
      Thromboembolic events (TE) are common complication of cancer, may lead to mortality and detoriate quality of life. The most common malignancies associated with TE’s are adenocarcinomas and the mechanism needs to be elucidated.Several studies suggest that increased risk of TE’s with hormonal contraceptives is mediated through the sex hormone-binding globulin levels (SHBG). The aim of this study is to investigate if the SHBG level is associated with TE’s in cancer patients with adenocarcinoma.

      Methods
      We compared the SHBG levels in 45 patients with TE and 23 patients without TE, all of them cancer with adenocarcinoma histology. A p value of less than 0.05 was considered statistically significant.

      Results
      Sixty eight patients, aged between 37-80, are evaluated. Thirty five women. There was no statistical significant relationship for age and gender between TE and non-TE groups. AT TE group, 20 (44%) had distal lower extremity (DLE) deep venous thrombosis (DVT), 17 (38%) had PE and the rest includes 4 central/proximal DVT (9%), 4 central venous catheter-related DVT (9%). Frequencies of histopathology for TE and non-TE group were; colorectal cancer 20 (30 %), gastric cancer 13 (20 %), pancreatic cancer 11(16%), breast 10 (%14), Lung 6 (9 %), and other (prostatic 3, hepatobiliary 2, unknown primary 2 and ovarian 1) 8 (%11). There was no difference between SHBG levels with TE group (mean±SD; 59±41) and non-TE group (60±49)( student’s t test; p=0.98).

      Conclusion
      SHBG levels do not play any role in the mechanism of cancer- related thrombosis in patients with adenocarcinoma.

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      P1.22-007 - The prevalence of epidermal growth factor receptor (EGFR) mutation in non-small non-squamous lung cancer in UAE (a single institute experience in the middle east) (ID 2463)

      H. Jaafar, K. Quasmeh, M. Jaloudi

      • Abstract

      Background
      Epidermal growth factor receptor (EGFR) is a trans-membrane protein it belongs to the ErbB-family, its activity includes transmitting of growth factor signaling from the surface of cells into the cells and activates the enzyme tyrosine kinase, triggering reactions that cause the cells to grow and multiply. EGFR has an impact on malignant cells development in various tumors, affecting their proliferation, apoptosis, motility and angiogenesis. In NSCL cancer EGFR-protein mutations in exons 18–21 results in constant hyper-activation of downstream pro-survival signaling pathways, independent from any external receptor stimulation. Approximately 10% of US patients and 35% in East Asia patients show EGFR mutation of which, almost 90% of these mutations are exon 19 deletions or exon 21 l858r point mutations. EGFR has been identified as an important therapeutic target for the treatment. Purpose: To evaluate the prevalence of EGFR mutations in the diagnosed cases of NSCLC in our hospital, which deals with approximately 80% of lung cancer cases in UAE and to compare it with other geographic and ethnic groups.

      Methods
      Methods: A retrospective analysis of all non-small non-squamous lung ca cases that had EGFR testing was performed. LAB 21 in UK was used for the EGFR mutation testing. A total of 50 tumor blocks were sent to the laboratory. The test could not be performed on one case. Out of the remaining 49 patients, 13 (26%) were female and 36 (74%) were male. Open biopsy by either lymph node excision, pleuroscopy, open lung biopsy or craniotomy were the tissue source for the EGFR analysis in 23 patients while only 15 had enough tissue from one procedure (bronchoscopy or guided biopsy).

      Results
      Results: EGFR mutation was identified in 18/49 (37%) patients. of the 18 patient, who had EGFR mutation, 10 (56%) patients had exon 19 mutation, 6 (33%) patients had exon 21 deletion and 2 (11%) patient had double mutation. in those two patients with double mutation, one had mutation in exons 19 and 21 and the other had mutation in exons 18 and 20. No significant difference was observed in EGFR-mutations among the gender of patients, 35% in men and 38% in women. Analysis of ethnicity and prevalence of EGFR-mutation showed a significant difference between Arabs (15 of 32 / 46%) and non-Arabs (3 of 17 / 18%). in the Arabian cohort with EGFR mutations 8 out of 22 patients (36 %) had a smoking history and 7 out of 10 (70%) were documented as non (never)-smoker.

      Conclusion
      Conclusion: Local prevalence of EGFR mutation was found to be 37% among all the ethnic groups, which is in line with the incidence in Asian population but the Prevalence of EGFR mutations in Arabs was (46%). it is to be stressed here that testing for EGFR mutations should be considered for all patients with non-small non squamous cell lung cancer at diagnosis, regardless of clinical characteristics. This strategy can warrant the prompt use of EGFR tyrosine kinase inhibitors to promote the practice of personalized medicine.

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      P1.22-008 - Identifying evidence-practice gaps in lung cancer and priority setting with clinicians in NSW, Australia. (ID 2518)

      N.M. Rankin, T. Shaw, D. McGregor, P. Butow, J. Young, K. White, J. Phillips, S. Pearson, J. Simes, R. O'Connell, E. Stone, D. Barnes

      • Abstract

      Background
      Implementation Science has emerged over the past 20 years to highlight a fundamental problem in health care: that knowledge about optimal care is not applied in clinical practice. A ‘gap analysis’ is an initial research activity undertaken when quantifying the gap between existing knowledge and clinical practice. The purpose of this presentation is to describe outcomes of a gap analysis conducted in lung cancer and priority setting focus groups held with oncology health professionals. This research is being conducted by Sydney Catalyst, a Translational Cancer Research Centre that brings together teams of clinicians and researchers from more than 20 member organisations across NSW, Australia, for the purpose of facilitating rapid translation of scientific evidence into clinical practice and policy.

      Methods
      A systematic approach was used to examine the evidence across the lung cancer patient journey. Data sources included international and national clinical practice guidelines, systematic reviews and meta-analyses, and research from peer reviewed publications, including population-based patterns of care studies and data linkage studies. We also conducted a descriptive analysis of data from clinical cancer registries and administrative databases used in the local setting of Sydney and regional NSW, Australia, to determine what gaps were locally relevant. All data sources were reviewed and synthesised to create the list of evidence-practice gaps. The gaps are presently being tested in three focus groups in urban and regional cancer services in NSW, Australia. Focus group participants include specialists in lung and thoracic oncology, medical, nursing, allied health and supportive care health professionals. The purpose of these focus groups is to conduct a priority setting exercise, where clinicians can rate the relevance of gaps to the local context and agree on which gaps should first be addressed in any subsequent research projects.

      Results
      Seven evidence-practice gaps were identified across the patient journey (from initial presentation and diagnosis through to palliative care). We analysed 2008 data from one local hospital for all lung cancer patients (N=329) and found that local patterns of care appear to be consistent with those previously observed in a NSW patterns of care study. This assists in demonstrating that gaps identified at the population level are also present in local health care settings and strengthens a rationale for developing collaborative lung cancer specific research projects that engage clinicians and researchers. The analysis and outcomes of focus groups will be presented, along with a critical appraisal of the gap analysis methodology and show how this approach in lung cancer is relevant to other tumour groups and health conditions.

      Conclusion
      A gap analysis enables researchers and clinicians to identify where deficiencies exist between published research evidence and optimal patient care. By drawing together and synthesizing data from multiple sources of evidence, identifying gaps and setting priorities with local health professionals, we believe we can address the goal of more rapidly translating evidence into practice.

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      P1.22-009 - Mesothelioma in Australia 2012: Data from the new Australian Mesothelioma Registry (ID 2553)

      L. Huang, B. Armstrong, E. Macfarlane, M.R. Sim, F. De Crespigny, A. Anderson, N.V. Zandwijk, A.W. Musk, V. Dalton, C. Scott, A. Ratchford, P. Laws

      • Abstract

      Background
      Australia has the highest incidence rates of malignant mesothelioma in the world. The exact mechanism of mesothelioma development is only partly understood, however it has been linked to occupational and increasingly, non-occupational exposures to asbestos. The Australian Mesothelioma Registry (AMR) was established to collect incidence and mortality data on all cases of mesothelioma in Australia, including detailed information on asbestos exposure. The Australian Mesothelioma Registry completed its second full year of data collection on cases from 1 July 2010.

      Methods
      The AMR compiles notifications from state/territory cancer registries. Clinicians may be requested to advise if their patients are suitable for recruitment to the asbestos exposure component. Consenting participants are assessed for past asbestos exposure by The Monash Centre for Occupational and Environmental Health, after completing a job and residential history questionnaire and telephone interview using OccIDEAS, an online exposure assessment tool.

      Results
      More than 600 cases of mesothelioma have been notified to the Registry for 2011. At 30 June 2013, 619 diagnoses of mesothelioma had been reported to the AMR for 2012. Exposure assessments collected within the AMR framework will provide information not previously available. Data will be presented for 2012, the second calendar year of data collection, in addition to results for the exposure assessment component.

      Conclusion
      AMR information has the potential to provide an accurate assessment of sources of asbestos exposure currently contributing to causing newly diagnosed mesothelioma in Australia. The AMR is a national resource for researchers and may assist in preventing mesothelioma in the future.

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      P1.22-010 - Goddard classification is associated with clinical characteristics in patients with COPD and advanced NSCLC. (ID 2726)

      K. Matsuura, T. Kimura, T. Nakai, N. Yamamoto, G. Tamagaki, S. Mitsuoka, Y. Tochino, K. Asai, S. Kudoh, K. Hirata

      • Abstract

      Background
      Chronic obstructive pulmonary disease (COPD) is a frequent complication seen in 24.9% in patients with lung cancer. In practice, a decreased respiratory function due to COPD influences to decision of treatment. The airway obstruction is assessed by the Global Initiative for obstructive lung disease (GOLD) classification. On the other hand, Goddard classification is a method for evaluating the emphysema using CT images. The respiratory function of an advanced lung cancer has various modifications such as tumor airway obstruction or atelectasis. The hypothesis is that in patient with COPD and advanced lung cancer patients, GOLD classification may not correspond to the Goddard classification. We evaluated the associations of clinical characteristics with Goddard classification as well as GOLD classification.

      Methods
      Between May 2007 and April 2012, the pre-treatment respiratory function was assessed for patients diagnosed at Osaka City University Hospital as non-small cell lung cancer stage IIIB or IV without EGFR gene active mutations. FEV/FVC% less than 70% were diagnosed for COPD. GOLD and Goddard classification were evaluated. Two doctors independently determined the Goddard classification, and the final score was adopted from the average of two scores. The association of clinical characteristics with Goddard classification as well as GOLD classification was performed by fisher exact test. An univariate analysis was performed to evaluate the prognosis by COX regression method. In multivariate analysis, histology, stage, number of cigarette smoking, and FEV/FVC% were performed to evaluate the prognosis by COX regression selected variable method (stepwise method).

      Results
      A total of 67 patients were enrolled with median age of 70 (49-81). GOLD classification showed normal (n=32), mild (stage I/II, n=30), and moderate (stage III, n=5) airflow obstructions. There was no severe COPD (stage IV) patient. In GOLD classification, no-significant associations of clinical characteristics were observed such as lobe site of primary lesion (p=0.84), tumor histology (p=0.21), gender (p=0.17), and cigarette smoking (p=0.42). Goddard classification showed non (score zero, n=12), mild (score <8, n=32), and moderate-severe (score 8-20, n=23) emphysema findings. In Goddard classification, there were significant associations of clinical characteristics in tumor histology of squamous cell carcinoma (p=0.010), male (p=0.031), and number of cigarette smoking (p=0.020). Univariate analyses showed neither GOLD nor Goddard classification was associated with overall survival. In multivariate analysis, FEV/FVC% was not associated with overall survival.

      Conclusion
      As compared with Goddard classification, the distribution of GOLD classification shift relatively mild direction. Therefore, there is no-significant association of clinical characteristics in GOLD classification, and Goddard classification was significant association of squamous cell carcinoma, male, and cigarette smoking. Surprisingly, the FEV/FVC% did not become a prognostic factor for NSCLC received chemotherapy. The severity of COPD might not influence outcome of chemotherapy in advanced NSCLC.

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      P1.22-011 - Assessment of the accuracy and reliability of health related behavioural data obtained from patient-reported surveys (PRS) compared with electronic patient records (EPR) in lung cancer patient population (ID 2948)

      P.R. Palepu, C. Brown, O. Espin-Garcia, G. Joshi, L. Eng, J. Ramanna, S. Cuffe, S. Keshavjee, T. Waddell, G.E. Darling, A. Pierre, K. Yasufuku, M. De Perrot, M. Cypel, W. Xu, G. Liu

      • Abstract

      Background
      Cigarette smoking, alcohol consumption and presence of co morbidities are important factors that affect health status and mortality in patients diagnosed with lung cancer. While the gold standard for presence or absence of co-morbidities is EPR, the gold standard for obtaining accurate data pertaining to health-related behaviours is by PRS. The purpose of this study is to ascertain, whether in the absence of patient self-reported data, health related behavioural data pertaining to cigarette smoking and alcohol consumption abstracted from EPR provides an accurate and reliable surrogate.

      Methods
      731 lung cancer patients completed a PRS pertaining to information on their lifetime tobacco use, alcohol consumption and whether or not they had been diagnosed with certain co-morbid conditions. Relevant smoking, alcohol consumption and co-morbidity data was collected independently from EPR. Kappa coefficient analysis was used to assess the agreement.

      Results
      Results can be seen in Table 1. Ever/never status for smoking showed almost perfect agreement (k=0.95) between PRS and EPR and surpassed all other health behavioural measures and all co-morbidity agreement values. The calculation of pack-years from EPR and PRS showed substantial agreement (k=0.77); However, categorizing the smoking status into current/ former / never, resulted in only moderate agreement (k=0.47). Alcohol ever/ never status agreement was moderate (0.44) with high sensitivity (0.90) but low specificity (0.50). The lung related co-morbidities like emphysema (k=0.41) and chronic bronchitis (k=0.28) showed fair agreement but with substantial missing data through EPR.

      Table 1
      Health Behaviour N Missing Data in EPR Agreement (k) 95% CI (P value) Se Sp
      Smoking (E/N) 709 0 0.95 (0.79, 0.89) 0.995 0.94
      Smoking (Pkyrs)* 606 81(11%) 0.77 P<0.0001
      Smoking (C/F/N)** 705 4(0.5%) 0.47 (0.41, 0.51)
      Alcohol (E/N) 575 150(20.5%) 0.44 (0.36, 0.52) 0.9 0.5
      Comorbidity
      Emphysema 589 126(17.2%) 0.41 (0.33, 0.49) 0.41 0.95
      Chronic Bronchitis 601 94(12.8%) 0.28 (0.19, 0.37) 0.39 0.88
      *Spearman correlation coefficient
      **Weighted kappa

      Conclusion
      In the absence of PRS data, EPR provides a reliable surrogate for ever/ never smoking status and moderately reliable for lifetime smoking exposure in this lung cancer population. However current/ former/ never smoking status and ever/ never alcohol status cannot be reliably ascertained from medical records. Missing EPR data related to smoking pack years, alcohol consumption and lung co-morbidities is concerning and suggests more systematic or synoptic reporting by physicians would improve opportunities for research

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      P1.22-012 - Continuous exposure to chrysotile asbestos can cause transformation of human mesothelial cells via HMGB1 and TNF-α signaling. (ID 3478)

      F. Qi, G. Okimoto, S. Jube, A. Napolitano, H. Pass, R. Laczko, R.M. Demay, G. Khan, M. Tiirikainen, C. Rinaudo, A. Croce, H. Yang, G. Gaudino, M. Carbone

      • Abstract

      Background
      Background: Malignant mesothelioma is strongly associated with asbestos exposure. Among asbestos fibers, crocidolite is considered the most and chrysotile the least oncogenic. Chrysotile accounts for >90% of asbestos used worldwide but its capacity to induce malignant mesothelioma is still controversial.

      Methods
      Methods: Human mesothelial cells were exposed to crocidolite or chrysotile for a period of 48hr or 5 weeks, either in the presence of TNF–α or human macrophages in a co-culture system mimicking the process of recruitment and activation of inflammatory cells to sites of fiber deposition, which leads to the carcinogenesis of mesothelioma. Functional studies, as well as whole-genome wide expression profiling were performed to compare the molecular mechanisms and the carcinogenic potential of chrysotile and crocidolite.

      Results
      Results: We found that chrysotile and crocidolite exposures have similar effects on human mesothelial cells. Morphological and molecular alterations suggestive of epithelial-mesenchymal transition, such as E–cadherin down-regulation and β–catenin phosphorylation followed by nuclear translocation, were induced by chrysotile and crocidolite. Gene expression profiling data detected High-Mobility Group Box-1 protein (HMGB1) as a key regulator of the transcriptional alterations induced by both chrysotile and crocidolite. Crocidolite and chrysotile induced differential expression of 57 out of 28,869 genes interrogated by oligo-nucleotide microarrays and 13 were HMGB1 targeted genes. Crocidolite-induced gene alterations were sustained, while chrysotile effects returned to background levels in five weeks. Similarly, HMGB1 release in vivo progressively increased for 10 or more weeks following crocidolite exposure, while returned to background levels eight weeks from chrysotile exposure.

      Conclusion
      Conclusion: Our results show that chrysotile has the capacity to induce, in HM, molecular changes associated to MM development similar to those induced by crocidolite, but these changes are short lasting. The data suggest that HMGB1 and TNF–α are key mediators of these processes for both crocidolite and chrysotile. However a continuous administration of chrysotile was required for inducing sustained HMGB1 levels. These data support the hypothesis that the different bio-persistence of the two asbestos fibers influences their biological activities.

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    P1.23 - Poster Session 1 - Tobacco Control, Prevention and Chemoprevention (ID 162)

    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 3
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      P1.23-001 - The real role of health care professionals in providing smoking cessation counselling among lung cancer patients: preliminary data (ID 1051)

      S. Vallone, S. Demichelis, S. Rapetti, B. Crida, E. Gobbini, M.V. Pacchiana, S. Novello

      • Abstract

      Background
      According to the World Health Organization, one hundred million deaths were caused by tobacco in the 20th century and the expectation for 2030 is equal to 10 million deaths. Lung cancer is the leading cause of cancer death and in the United States cigarette smoking is responsible for an estimated 90% of all lung cancers. About 50% of lung cancer patients are current smokers at the time of diagnosis and 11 to 48% of all smokers continue to smoke. Parsons et al. in a review of 10 studies suggest that smoking cessation after early stage lung cancer diagnosis improves prognostic outcomes and, despite evidences that smoking cessation is related with more effective treatment, reduced chemotherapy and radiotherapy toxicities and a better prognosis, the belief prevails that treating tobacco dependence is less important than the other therapeutic approaches.

      Methods
      122 lung cancer patients referring to the Thoracic Oncology Unit of the S. Luigi Hospital in Orbassano – Italy (31% of the total number of patients referring to this center in this period of time) were prospectively and sequentially evaluated from 02/01/2013 to 30/05/2013. In order to collect data, a dedicated 15 question-anonymous survey was developed with the aim to understand if smoker or former smoker patients had received information by health professionals, about smoking cessation before or after the diagnosis, which reaction they had and which actions were adopted for quitting smoking.

      Results
      The median age of participants was 65 years or more, 75% were men, 25% women. 27% were smokers, 73% former smokers. Among active smokers, most patients (87.8%) reduced the number of cigarettes after being diagnosed. 45.4% of patients report not to have received information on smoking cessation by the healthcare professionals and among patients who received it, the majority (84.2%) declared a good or very good ability of health workers to understand the difficulty of quitting smoking. About 76% considers positively the action of health care providers and a little percentage reports a warning and paternalistic attitude of them. 67.7% of patients who attempted to quit smoking, state the sudden termination as the most effective measure, more than the gradual reduction of cigarettes. Analyzing anti-smoking techniques or therapies adopted, most patients declare not to resort to such methods: only 25% started using electronic cigarettes, 5.5% has used a nicotine replacement treatment, 4.1% is attending an antismoking clinic.

      Conclusion
      The analysis of the study results underline that most lung cancer patients are interested in smoking cessation programs and although many of them receive advice and assistance by healthcare workers, the recourse to the use of techniques, drugs or access to specific clinic is very low. In Italy there are few centers offering counseling for smoking cessation, while in UK, Norway and Netherlands innovative interventions are available and oncology nurses are essential in the identification of and intervention with patients who struggle with this dependence. This is a pivotal experience and other Italian and Spanish centers are already been involved in the questionnaire collection to get more complete and heterogeneous results

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      P1.23-002 - A randomized controlled trial of brief counselling intervention and audio materials for smoking cessation in a low-dose CT screening study (ID 2959)

      H.M. Marshall, I.A. Yang, L. Passmore, E.M. McCaul, R. Bowman, K.M. Fong

      • Abstract

      Background
      Smoking cessation is a highly cost-effective health intervention. Embedding a smoking cessation program within a lung cancer screening program may significantly enhance the cost-effectiveness of screening. Smokers enrolling in Low-dose CT screening studies are motivated to quit but the best strategy to aid smoking cessation is not yet defined.

      Methods
      Population: smokers enrolled in a LDCT screening study, age 60-74years, with >=30 pack-year smoking history. Smokers could enrol at any time during the LDCT study. Intervention: single face-to-face counselling session on the day of attendance for LDCT screening plus audio cessation advice (on mp3 player) plus written quit materials. The individualised counselling session was given by a thoracic physician using motivational interview techniques. Control: written quit materials only. Outcome: point prevalence self-reported smoking cessation at 1 year, confirmed with exhaled CO measurement (ECO) where available; ≥10ppm level indicating non-abstinence.

      Results
      Fifty-four participants were randomized (control group n=26, intervention group n=28). There were no statistically significant differences between groups in age, sex, pack-years smoking, baseline CT scan findings, nicotine dependence score, self-belief in ability to quit (on a scale of 1-5, higher score indicating stronger belief) or education level although the intervention group reported a higher number of cigarettes smoked per day (table 1). Baseline LDCT scans were reported as positive if one or more non-calcified nodules >=4mm diameter were detected. The mean duration of interview was 26 minutes. Overall, ten participants (18.6%) reported smoking cessation (five had ECO confirmation and five did not have ECO testing); two patients (3.7%, one from each group) had missing data and were assumed to be continuing smokers; the remainder reported continued smoking. There was no difference in self-reported cessation between the intervention and control groups (17.8% vs 19.2% respectively).

      Table 1
      Control Intervention p value
      Women 10 10 ns
      Men 16 18 ns
      Education Up to High School 13 13 ns
      Teriary 13 15 ns
      Age, years, mean 64 64 ns
      Age started smoking, years 16 17 ns
      Cigarette consumption per day, n 23 30 0.03
      Pack years smoking, mean 61 64 ns
      FEV1 % predicted, mean 92 90 ns
      Fagerstrom nicotine dependence score, mean 4.9 5.2 ns
      Baseline CT Scan report Negative 12 10 ns
      Positive 14 18 ns
      Self-belief in ability to quit 3.7 3.4 ns

      Conclusion
      The 18% quit rate in this study is higher than reported background rates however the brief intervention provided did not increase quit rates above that of the control group. Smokers in this study reported moderate to high levels of nicotine dependence with extensive smoking histories, and, although motivated to quit, may require more intensive assistance to support smoking cessation.

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      P1.23-003 - Health care costs of patients with Non Small Cell Lung Cancer related to smoking in the National Cancer Institute of Mexico (ID 3100)

      O. Arrieta, R. Quintana, F. Corona, E. Correa, J. Zinser, D. De La Mata, A. Mohar, G. Ahumada, L.M. Reynales

      • Abstract

      Background
      Smoking is a public health problem in Mexico and the world, the economic impact in developing countries have not been fully documented. In our country there is a direct relationship between smoking and the 10 leading causes of death in adults. The purpose of this study was to estimate the direct costs of medical care for lung cancer attributable to the tobacco habit in the National Cancer Institute of Mexico (INCan).

      Methods
      The study was conducted at the National Cancer Institute of Mexico (INCan) during 2009. Costs were estimated from the perspective of services supplier based on the Cost of Illness method. An expert panel developed a diagnostic-therapeutic guide which integrated infrastructure, human resources, technology and health services provided at INCan. Costs were valued in Mexican pesos using an exchange rate of 1USD=13.0659 pesos.

      Results
      297 incident cases of any type of Non Small Cell Lung Cancer during 2009 were analyzed. The annual average cost attributable to smoking per patient was 84,189 USD regardless of clinical stage. The 96% of the annual cost corresponded to stage IV. The annual total cost of Non Small Cell Lung cancer associated to tobacco habit at the INCan was 18, 807,354.8 USD. Figure 1

      Stage [+] Anual total cost Anual total cost due to tobacco *
      LC I 45,787.2 30,219.5
      LC II 76,244.7 50,321.5
      LC III 928,261.2 612, 652.4
      LC IV 27,445,699.0 18,114,161.3
      Total 28,495,992.1 18,807,354.8
      Currency: USA dollar, 1 dollar = 13.0659 mexican pesos Exchange according to Banco de México(Banxico) information [+] Estructure established by the Lung Cancer experts of the INCan and the CIE-10 2009. *Obtained with tobacco attributable fraction of LC, calculated for national IMSS; 0.66. Reynales et al.

      Conclusion
      Health care costs for Non Small Cell Lung Cancer attributable to smoking represent an important and high cost to the INCan and the health sector of Mexico. These costs could be avoided if all the provisions of the Agreement-framework of the World Health Organization for tobacco control were implemented in our country.