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  • WCLC 2015

    16th World Conference on Lung Cancer

    Access to all presentations that occur during the 16th World Conference on Lung Cancer in Denver, Colorado

    Presentation Date(s):
    • September 6 - 9, 2015
    • Total Presentations: 2499

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    MINI 35 - Biology (ID 161)

    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 14
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      MINI35.01 - Genetic Alterations in the Fanconi Anemia Pathway in Lung Cancers (ID 2325)

      W. Duan, L. Gao, K. Dotts, A. Kalvala, B. Aguila, G. Otterson, M. Villalona

      • Abstract
      • Presentation
      • Slides

      Background:
      The FA pathway contains 17 complementation groups, referred to as FA subtypes A, B, C, D1/BRCA2, D2, E, F, G, I, J, L, M, N, O, P, Q and S. Cells with FA deficiency are hypersensitive to DNA damaging agents such as cisplatin and mitomycin C (MMC). Disruptions of the FA pathway may involve epigenetic silencing of the FA-core complex, mutations or deletion of one or several FA genes. Recently we developed a FA triple-staining immunofluorescence (FATSI) method to detect FANCD2 foci formation using formalin fixed paraffin embedded (FFPE) tumor samples. We screened 139 non-small cell lung cancer (NSCL) FFPE tumors for FANCD2 foci formation by FATSI analysis. Based on the FATSI analysis, 104 of 139 tumor samples were evaluable (lack of Ki67 was defined as non-evaluable samples) for FANCD2 foci status. Among 104 evaluable tumors, 23 (22%) were FANCD2 foci negative. However, further investigation and confirmation of the genetic and epigenetic alterations involved in the FANCD2 foci defective tumors is critical for supporting application of this selection process to justify subsequent clinical treatment strategies for cancer patients.

      Methods:
      The aim of the study is to investigate the genetic alterations in the FANCD2 foci defective lung tumors and matching non-tumors. The FANCD2 foci defective tumors were identified with the FATSI method. DNA samples isolated from frozen tumor and matching non-tumor tissues were analyzed with whole exome sequencing. All 17 genes involved in the FA pathway were analyzed.

      Results:
      To investigate the gene involved in disrupting the FA pathway in patient tumors, we applied exome sequencing to 18-paired DNA samples (15 paired foci-negative non-small cell lung tumor and non-tumor frozen tissues, and 3 paired foci-positive non-small cell lung tumor and non-tumor frozen tissues). Among the 15 foci negative tumors, 7 tumors contain 9 somatic mutations including FANCA, FANCC, FANCD2, FANCM, FANCM, FANCP/ SLX4 and FANCS/BRCA1. There was no mutation detected among the three foci positive tumors. Loss of heterozygosity (LOH) events were detected in nine tumors, including one foci positive and eight foci negative tumors. The LOHs occurred in FANCA, FANCD1, FANCD2, FANCM, FANCI, FANCP/SLX4, FANCQ/ERCC4. LOHs on FANCA gene were found in three tumors and LOHs on FANCD2 gene were detected in four tumors including one foci positive tumor.

      Conclusion:
      Based on our preliminary study, 7 of the 15 FANCD2 foci negative lung tumors contained somatic mutation and 8 of the 15 foci negative tumors contained LOHs in the FA genes. A higher frequency of somatic mutation (2 of 7 tumors) and LOHs (3 of 9 tumors) was detected in FANCA gene. In addition, 4 of 9 tumors contained LOHs on FANCD2 indicating the importance of this gene in maintaining FA foci formation. However, we are uncertain if these alterations are functional. Given that FA pathway disruptions may also involve epigenetic silencing of the FA-core complex, plus its collaboration with other proteins, it is necessary to investigate the genetic alteration in the FA associated proteins and promoter methylation status of these genes.

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      MINI35.02 - Inhibitor of Differentiation 1 (Id-1) Gene Silencing Reduces Liver Metastases Formation in a NSCLC Animal Model (ID 2995)

      E. Castanon, I. Lopez, M. Ponz-Sarvise, M. Collantes, M. Ecay, I. Gil-Aldea, C. Rolfo, A. Calvo, I. Gil-Bazo

      • Abstract
      • Presentation
      • Slides

      Background:
      Around 30% of non-small cell lung cancer (NSCLC) patients present LM during the disease course causing a negative clinical impact on survival and quality of life. The expression of certain genes in cancer cells might be crucial for allowing tumor cells to spread to the liver. According to this hypothesis Id1 and Id3 genes, part of the signature that facilitates breast cancer cells to disseminate to the lungs, might be determinant for NSCLC LM development.

      Methods:
      Three cohorts including totally 80 mice were compared; Id1 wild-type C57BL/6 (WT) female mice (n = 40) vs. Id1 knock out (IDKO) female animals (n = 28) vs Id1/Id3 knock out mice (Id1Id3KO) (n = 12). In both groups of mice 500,000 Lewis Lung Carcinoma cells (LLC) Id1 WT (Id1+/+) Id3 WT (Id3+/+), or Id1 homozygously deficient (Id1-/-) and Id3 WT (Id3+/+) or Id1-/- and Id3 heterozygously deficient (Id3+/-) were generated through gene silencing, and intrasplenically injected. Thereafter, both groups of mice were weekly monitored with FDG-micro-positron emission tomography (mPET) scans for LM formation. Animals were sacrificed (and tissues microscopically analyzed) by the time LM were developed and clinical deterioration was evident.

      Results:
      Expression of Id1 in both the host and the tumor cell line injected were independent predictive factors for the presence of LM. In fact, silencing Id1 expression in tumor cells (OR = 0.04; CI 95% 0.2 (0.04-0.9) or knocking down Id1 in the host tissues (OR: 0.2; CI 95% 0.06-0.7), impaired LM presentation. Silencing Id3 seemed not to diminish the risk of LM presentation.

      Conclusion:
      Absence of Id1 expression in the host partially impairs LM presentation. Silencing Id1 in tumor cells diminish the odds of presenting LM. Knocking down Id1 in the host or targeting Id1 in the tumor cell may represent a new approach to prevent LM presentation, and thus, improving the outcome in NSCLC patients.

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      MINI35.03 - N-Myc Downstream Regulated Gene 1(NDRG1) Promotes the Stem-Like Properties of Lung Cancer Cells Through Stabilized C-Myc (ID 996)

      Y. Wang, K. Wang

      • Abstract
      • Presentation
      • Slides

      Background:
      Tumor-initiating cells (TIC) which were defined their ability to generate tumor play a critical role in tumorigenesis and development of lung cancer. However, the mechanism underlying how TICs keep self-renewal needs to be clarified. We investigated the biological function and clinical significance of N-myc downstream regulated gene 1 (NDRG1) in lung TICs.

      Methods:
      Recombinant NDRG1 shRNA lentivirus or NDRG1-overexpressed lentivirus was employed to knock down or reinforce NDRG1 expression respectively. Biological functions of NDRG1 silenced and overexpressed cells were investigated using in vitro and in vivo methods.

      Results:
      NDRG1 was much highly expressed in lung tumor-initiating cells compared with parental lung cancer cells in both human NSCLC cell lines and primary NSCLC cells. Immunohistochemical on the lung cancer tissues showed that NDRG1 was highly expressed. The GSEA analysis showed that patients with increased expression of NDRG1 had a worse survival and prognosis in the analysis of 226 cases of lung cancer specimens. Enhanced expression of NDRG1 promoted stem-like properties of NSCLC cells in A549 and H1975 cells while the knockdown of NDRG1 decreased the expression of iPS factors (OCT4、SOX2、KLF4、C-MYC), the spheres-forming ability in vitro and tumorigenecity and mass of lung cancer H1299 and HCC827 cells in vivo. Furthermore, we revealed that c-Myc was a key molecule of which NDRG1 involved in the self-renewal of TICs. NDRG1 was positively correlated with c-Myc expression. NDRG1 inhibited the ubiquitylation degradation of c-Myc to promote self-renewal of lung TICs through interaction with Skp2. The Interaction between NDRG1 and Skp2 was enforced in lung TICs. Moreover, the distribution of NDRG1 was generally in cellular membrane, cytoplasm and nucleus of lung cancer cells and its nuclear localization was positively regulated by the 79th tyrosine phosphorylation of NDRG1. Phosphorylated NDRG1 at Y79 which was positively regulated by PI3K-AKT pathway increased the expression of c-Myc.

      Conclusion:
      NDRG1 promotes the self-renewal of lung TICs through stabilizing c-Myc by interaction with Skp2. Our study indicates that NDRG1 is one of potential targets for eradication of lung TICs.

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      MINI35.04 - Degradation of FGFR1/Akt/Src/C-Raf/Erk by Arsenic Trioxide and FGFR Inhibitor in Squamous Cell Lung Cancer (ID 747)

      J.C.M. Ho, S.K. Lam

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is one of the top cancer killers. Squamous cell lung carcinoma (SCC) represents the second most common histologic subtype of lung cancer. Arsenic trioxide (ATO) inhibits tumor growth and initiates apoptosis in lung adenocarcinoma and acute promyelocytic leukemia. Fibroblast growth factor receptor (FGFR) amplification has been shown in some SCC. FGFR inhibitor (e.g. PD173074) has been developed to inhibit FGFR.

      Methods:
      The combination effect of ATO and PD173074 (PD) was studied using a SCC cell line (SK-MES-1) with FGFR1 amplification. The effect of ATO and/or PD on cell viability and protein expression was studied by MTT assay and Western blot respectively. Cell cycle analysis, phosphatidylserine externalization and mitochondrial membrane depolarization were monitored by flow cytometry. Proteasome inhibitor (MG-132) was used to study the degradation mechanism. The in vivo effect of ATO and/or PD was investigated with a nude mice xenograft model.

      Results:
      Combination of ATO and PD reduced cell viability along with increased sub-G1 population, phosphatidylserine externalization and mitochondrial membrane depolarization, more significantly than single agents alone. Downregulation of FGFR1, p-Akt, Akt, p-Src, Src, p-c-Raf, c-Raf, Erk and survivin as well as upregulation of cleaved PARP were observed upon ATO and/or PD treatment. MG-132 partially reversed the degradation of Akt, Src, c-Raf and Erk induced by ATO/PD, suggesting the involvement of proteasome degradation system (Fig 1). Nonetheless, the mechanism of FGFR1 downregulation remained unknown. Downregulation of FGFR1, Akt, Src, c-Raf and Erk as well as cleaved PARP elevation induced by ATO and/or PD were confirmed in vivo (Fig 2). Figure 1 Figure 2





      Conclusion:
      Massive protein degradation (FGFR1, Akt, Src, c-Raf and Erk) was induced by ATO and/or PD treatment mainly via proteasomal degradation in a SCC cell line (SK-MES-1) in vitro and in vivo. Potential role of combined ATO with FGFR inhibitor in SCC warrants further exploration.

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      MINI35.05 - Discussant for MINI35.01, MINI35.02, MINI35.03, MINI35.04 (ID 3436)

      M.G. Kris

      • Abstract
      • Presentation

      Abstract not provided

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      MINI35.07 - ATM Mutations in Cancer Cell Lines Predict Higher Mutation Rates and Genetic Instability (ID 1704)

      L.F. Petersen, Y. Shen, A. Fox, J. Laskin, D..G. Bebb

      • Abstract
      • Presentation
      • Slides

      Background:
      Ataxia telangiectasia-mutated (ATM) is a critical first responder in the cell to DNA damage. Individuals lacking ATM are extremely sensitive to DNA-damaging ionizing radiation, and are predisposed to develop cancers. The mechanism for ATM dysfunction in A-T patients, or cancer patients that are ATM-deficient, is unknown. ATM has been sequenced in lung cancer patient samples, but no specific mutation hotspots have been linked with disease development, despite ATM being one of the most mutated genes in lung cancer. Our own quantitative analysis of ATM protein levels in patient samples suggests that expression is lost in 20-25% of cases and that this loss correlates with poor overall survival and increased response to adjuvant chemotherapy treatments. We believe that this may be the result of increased genomic instability within the cancer cells caused by a lack of adequate DNA repair. Given that ATM-deficient cancer cells may have higher genetic instability, and that ATM is so highly mutated in lung cancer, we sought to quantify the relationship between ATM mutations and genomic instability, as measured by total somatic mutations.

      Methods:
      Using data available from the Broad Institute’s Cancer Cell Line Encyclopedia (CCLE), we correlated mutations in ATM and other genes involved with the DNA repair response with the total number of mutations annotated in ~900 cancer cell lines. We also analyzed total mutations per cell line against the functional impact score of single nucleotide variations (SNVs) within ATM. To determine the clinical relevance of the cancer cell line observations, we partnered with the BC Genome Sciences Centre (BCGSC) to perform similar analyses on ~100 whole-genome-sequenced patient samples.

      Results:
      We show that in cell lines across all cancer types, mutations in ATM correlate with a significantly higher number of total mutations. When analyzed by site of origin, the greatest differences in total mutations were found in lung, breast, intestinal, and esophageal cancer cells. We examined additional genes associated with the DNA-repair response, including direct response genes (i.e. ATR, BRCA1&2) and downstream targets (i.e. p53). Only mutations in the direct response genes appeared to associate with total mutations, whereas p53 – while more commonly mutated – did not correlate with higher mutations. In 10 lung cancer patients, one had a truncating mutation and had the second highest number of somatic mutations, and highest among non-smokers.

      Conclusion:
      We have identified a potential relationship between ATM mutation and total somatic mutations in cancer cell lines and patient tumour genomes, which may be indicative of overall genetic instability in these samples. Analysis of the ATM mutations in cell lines and patient samples clearly shows that there are no specific hotspots for mutation in ATM that correlate with increased total mutations. Thus screening for ATM mutations alone may not be sufficient to indicate loss of function or instability. However, this data may prove useful in developing panels of targets to screen as mutation hotspots of instability, and ultimately to help identify patients that may benefit from targeted or modified therapy options based on ATM-deficiency or higher genetic instability.

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      MINI35.08 - Functional Role of Cancer Associated Fibroblasts in Non-Small Cell Lung Cancer Patients (ID 3134)

      R. Navab, J. Hao, M. Pintilier, T. Wang, I. Jurisica, M.S. Tsao

      • Abstract
      • Slides

      Background:
      Cancer-associated fibroblasts (CAFs) are well known to strongly influence tumor development, progression and metastasis. Their characteristics and prognostic role in non-small cell lung cancer (NSCLC) patients have been recognized. However, the functional heterogeneity of CAFs between patients and their genetic basis are less understood.

      Methods:
      Primary cultures of CAFs and noncancer fibroblasts were established from 28 independent resected non-small cell lung cancers and their corresponding non-neoplastic lung parenchyma. Collagen gel contraction, xCELLigence Real-Time Cell Analysis of proliferation and in vivo tumorigenicity were studied to assess the CAF activity. Percent area of desmoplasia among total tumor stroma was used to define high desmoplasia (HD) versus low desmoplasia (LD). Gene expression data on RNA extracted from contracted gels following 8 hours incubation was obtained using Illumina Human HT-12v4 Bead Chips array and was preprocessed and normalized using RMA and values were log2 transformed. Two-fold change cutoff was applied to identify differentially expressed genes in CAF-HD versus CAF-LD.

      Results:
      High desmoplasia correlates with higher ability to contract collagen gel, increased cell proliferation and tumor growth. Microarray gene expression analysis of the 24 CAF cell lines identified 23 genes that were differentially expressed between 12 CAF-HD versus 12 CAF-LD lines and were correlated significantly (p ≤ 0.05) with the gel contraction. 23 differentially gene expression were evaluated in gene expression microarray data (Affymetrix HG-U133 Plus 2 Array) from 181 NSCLC patients. We found 7 out of 23 differential gene expression to be significantly in concordant with the cohort of 181 NSCLC patients. Taking 7 prioritized genes, we have generated physical protein-protein interaction network by quering I2D ver. 3 and visualizing it in NAViGaTOR ver 2.3 (http://ophid.utoronto.ca/navigator). To study the degree of desmoplasia and outcome, we used the cohort of 181 NSCLC patients data set. We observed that desmoplasia appears to be associated with the time to relapse in univariable analysis. The association was far stronger in the adenocarcioma group with significance for both univariable and multivariable analysis.

      Conclusion:
      We provide evidence for a functional heterogeneity of CAFs in NSCLC patients based on the level of desmoplasia in tumor stroma. Furthermore, we develop desmoplasia-specific gene signature that could subgroup CAFs and contribute to their functional heterogeneity.

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      MINI35.09 - Sonic Hedgehog Is Required for Tumor Progression in a Mouse Model of Small Cell Lung Cancer (ID 1103)

      A. Szczepny, S. Jayasekara, A. Mudiyanselage, D.N. Watkins

      • Abstract
      • Slides

      Background:
      Activation of the Hedgehog (Hh) signaling pathway is well documented in many cancers including Small Cell Lung Cancer (SCLC). Whilst it has been shown that Smoothened, the central Hh pathway mediator, is required for the initiation and progression of SCLC in a mouse model, it is unclear what drives activation of this pathway in these tumors. As these tumors commonly express the Sonic Hedgehog (Shh) ligand and lack pathway activating mutations, it was hypothesized that production of the Shh ligand by SCLC cells could be causing cell-autonomous pathway activation and thereby driving tumorigenesis.

      Methods:
      To address this question, we used a well-characterized conditional genetic mouse model of SCLC in which inhalation of recombinant adenovirus expressing Cre can trigger recombination at loxP sites in the airway epithelium. When the virus is administered to mice double homozygous for the conditional p53 and Rb knockout alleles (p53[lox/lox];Rb[lox/lox]), mice develop multiple tumors over 9 months. To define the role of the Shh ligand in the initiation and progression of SCLC in this tumor model, p53[lox/lox];Rb[lox/lox] animals were further crossed with a conditional Shh-overexpressing transgenic mouse (ShhTg). Reciprocally, genetic deletion of Shh was achieved by crossing p53[lox/lox];Rb[lox/lox ]mice with a conditional Shh knockout mouse (Shh[lox]).

      Results:
      Aged cohorts of AdenoCre-infected p53[lox/lox];Rb[lox/lox];ShhTg mice developed more frequent and significantly larger tumors compared to their p53[lox/lox];Rb[lox/lox ]littermate controls, with tumors exhibiting a highly malignant and proliferative phenotype. Conversely, genetic deletion of Shh resulted in a dramatic reduction in tumor size in p53[lox/lox];Rb[lox/lox];Shh[lox/lox] mice compared to littermate controls.

      Conclusion:
      Together, these findings demonstrate that Shh plays a crucial role in driving the progression of SCLC, suggesting that Shh may be a potentially useful therapeutic target.

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      MINI35.10 - Discussant for MINI35.07, MINI35.08, MINI35.09 (ID 3554)

      B.E. Johnson

      • Abstract
      • Presentation

      Abstract not provided

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      MINI35.11 - Mutant ARAF Drives Lung Carcinogenesis Through a Distinct Oncogenic Mechanism (ID 1016)

      L.H. Araujo, J.M. Amann, M. Imielinski, H. Greulich, M. Meyerson, D.P. Carbone

      • Abstract
      • Presentation
      • Slides

      Background:
      We recently identified a novel somatic mutation in ARAF in a lung adenocarcinoma from a patient that demonstrated a remarkable response to sorafenib. The S214C lies in a negative regulatory domain of ARAF, distinct from the catalytic domain mutations commonly found in BRAF. The aim herein was to characterize the biochemical and functional aspects of ARAF S214C.

      Methods:
      ARAF constructs were generated and ectopically expressed in an immortalized bronchial epithelial cell line (BEAS-2B). We evaluated the acquisition of anchorage independence, MEK activation, and cell morphology. COS7 cells were used for co-immunoprecipitation (IP) and kinase assays.

      Results:
      Cells expressing ARAF S214C substantially increased soft agar colony formation relative to vector, wild-type, kinase-dead (D429A), and double-mutant (S214C+D429A) variants. Accordingly, ARAF S214C cells exhibited increased phospho-MEK levels, suggesting that the transforming potential is dependent on its kinase activity. Interestingly, ARAF S214C cells acquired an elongated, fibroblast-like shape, characteristic of MEK-active cells, whereas none of other variants presented this morphology. We also demonstrated that cells expressing ARAF S214C with an additional RAS-binding domain mutation (R52L) or dimerization interface mutation (R362H) lacked MEK activation, showing that RAS binding and RAF-RAF dimerization are essential for activity. To elucidate the role of BRAF and RAF1 as dimerization partners of ARAF S214C, we performed knockdowns of BRAF, RAF1, or both. ARAF S214C-induced MEK activation was not reversed by the BRAF knockdown, however both RAF1 and double knockdowns (BRAF and RAF1) led to loss of MEK activation, suggesting that RAF1 is required. Subsequently, COS7 cells were co-transfected with tagged constructs of ARAF and either BRAF or RAF1, followed by co-IP. We showed that mutant ARAF presents a higher rate of dimerization than wild-type ARAF in the presence of sorafenib. Importantly, sorafenib-induced heterodimers lacked kinase activity, compatible with the clinical response reported.

      Conclusion:
      ARAF S214C demonstrates the in vitro features of a driver oncogene, and also a distinct mechanism of action. This oncogenic process can be successfully suppressed by RAF inhibitors like sorafenib, and could represent a new target for personalized therapy in advanced lung adenocarcinoma. Figure 1 Figure: Summary of the ARAF S214C oncogenic mechanism.



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      MINI35.12 - Stratifin Accelerates Progression of Lung Adenocarcinoma at an Early Stage (ID 506)

      A. Shiba, Y. Kim, M. Noguchi

      • Abstract
      • Presentation
      • Slides

      Background:
      Adenocarcinoma in situ (AIS) of the lung has an extremely favorable prognosis. However, early but invasive adenocarcinoma (eIA) sometimes has a fatal outcome. We had previously compared the expression profiles of AIS with those of eIA showing lymph node metastasis or a fatal outcome, and found that stratifin (SFN, 14-3-3 sigma) was a differentially expressed gene related to cell proliferation (Aya Shiba-Ishii, IJC. 2011). We also found that SFN expression was totally suppressed in normal lung tissue, whereas demethylation of its promoter triggered aberrant SFN overexpression in eIAs in a p53-independent manner (Aya Shiba-Ishii, AJP. 2012). SFN has been linked to cancer most directly, possibly having tissue-specific functions and regulating progression of the cell cycle. Here, we performed an in vivo study to clarify the role of SFN in progression of lung adenocarcinoma.

      Methods:
      We induced stable knockdown of SFN using two individual shRNAs (shSFN). To evaluate the oncogenic activity of SFN, we injected A549-shSFN intrabronchially or intravenously into SCID mice. Additionally, we generated SFN-transgenic mice (Tg-SPC-SFN[+/-]) showing lung-specific expression of human SFN (hSFN) under the control of a tissue-specific enhancer, the SPC promoter. In order to observe the tumorigenic activity of SFN, Tg-SPC-SFN[+/-] and WT ICR mice were intraperitoneally administered 4 mg 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, a pulmonary carcinogen) or saline as a control, and tumorigenicity was assessed for 20 weeks. Lungs of representative mice were periodically examined using animal CT.

      Results:
      Although control A549 cells formed advanced tumors in the lungs of SCID mice after intrabronchial and/or intravenous injection, we also found pleural dissemination in the control group (in 75% after intravenous injection and in 25% after intrabronchial injection). However, A549-shSFN did not form any tumors. Next, we confirmed the lung-specific expression hSFN in Tg-SPC-SFN[+/-] using RT-PCR and IHC. In a chemical carcinogenesis experiment, animal CT revealed several pulmonary tumors in some Tg-SPC-SFN[+/-] from 15 weeks after NNK administration, and at 20 weeks 47.8% of Tg-SPC-SFN[+/-] (11/23) had developed lung tumors, whereas only 11.1% of WT ICR (3/27) had done so (statistically significant). Surprisingly, two of seven Tg-SPC-SFN[+/-] mice (28.6%) developed tumors even though they were not administered NNK. All of the tumors that developed in Tg-SPC-SFN[+/-] lung expressed hSFN abundantly.

      Conclusion:
      Here, we showed that suppression of SFN expression in lung adenocarcinoma A549 cells was significantly reduced in terms of not only lung tumor formation but also metastatic potential. Additionally, it was found that Tg-SPC-SFN[+/-] mice developed lung tumors at a significantly higher rate than control mice after NNK administration. Interestingly, several Tg-SPC-SFN[+/-] mice developed lung tumors without carcinogen. Because these tumors showed high hSFN expression, SFN was thought to facilitate not only tumor progression but also tumor initiation, and to work as an oncogene. Soda et al. found that 100% of Tg-EML4-ALK mice developed hundreds of adenocarcinoma nodules in both lungs within a few weeks after birth (Nature 2007). Although the oncogenic activity of SFN is weaker than that of EML4-ALK fusion kinase, SFN might also have the potential to initiate peripheral-type lung adenocarcinoma.

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      MINI35.13 - Targeting Cancer Stem Cell Factor BMI1 to Sensitize Non-Small Cell Lung Cancer to Chemotherapy and Radiation Therapy (ID 502)

      K.R. Chaudhary, B. Halmos, H. Cheng, J.M. Silva, T.K. Hei, S.K. Cheng

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is known to be the most frequent disease and the leading cause of cancer-related death in men and women worldwide. Despite treatment advances, patient outcomes remain dismal and overall survival at 5 years is only 15%. The resistance mechanisms for concurrent chemoradiation therapy are poorly studied. Cancer stem cells have been proposed to be the driver for many cancers including lung cancer and may be also responsible for therapy resistance.

      Methods:
      We sought therefore to identify therapy resistance pathways in lung cancer by using genome-wide RNAi high-throughput screen via a shRNA viral library pool containing approx. 60,000 individual shRNAs targeting alomost 80% of human genome on a human lung adenocarcinoma cell line (PC9) treated with cisplatin alone, radiation alone and combined radiation and cisplatin.

      Results:
      From the cisplatin and radiation screen, analysis of top 100 potential hits interestingly showed several cancer stem cells markers including Sox, Lrg6, and members of the Hedgehog signaling pathway Patched and Bmi1. FACS analysis showed increased stem cell markers CD133, ABCG2 and CXCR4 expression on PC9 cells treated multiple times with cisplatin and radiation compared to non-treated cells, pointing towards acquired stemness of lung cancer cells after treatmentent and subsequently resistanve to treatment. Further FACS and real time PCR analysis revealed evlevated EMT marker such as CD44 and SNAIL and decreased expression of E-Cadherin and Vementin in treated cells compared to non-treated cells. Cells treated with cisplatin and radiation in combination with PTC-209 showed increased cleaved-PARP staining compared to cells treated with combined chemoradiation. We further determined the effects of Bmi1 on therapy resistance with survival assays by treating PC9 cells with Bmi1 inhibitor PTC-09. MTT cell survival and colonogenic assays was performed by treating PC9 cells with PTC-09 in triplicate and then treated with increasing dosage of cisplatin (0.1, 1 and 10 µM) or X-ray radiation (2, 4 and 6 Gy). Significantly decreased cell survival was observed in PTC-09 treated PC9 cells treated with cisplatin or radiation compared to control and cisplatin or radiation alone treated cells. Further colonogenic assay of PC9 cells treated with 2Gy+1 um cisplatin and increasing dosage of PTC-09 showed significant decrease in the ability of cells to form colonies compared to control.

      Conclusion:
      By performing an unbiased genome wide RNAi screen for therapeutic resistance, we have successfully identified and validated a molecular regulator of cancer stem cell pathway which enabled us to successfully test the revelance of the cancer stem cell model in lung cancer. Our study provides evidence for the concept that targeting cancer stem cells can be therapeutically beneficial. We are further evaluating effect of Bmi1 using CRISPR knock out model and downstream target.

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      MINI35.14 - Microthrombosis Enhances Extravasation via Myeloid Hypoxia-Inducible Factors (ID 94)

      C.E. Evans, A. Prodger, C. Branco-Price, A. Palazon, P. Tyrakis, J. Sim, H. Rundqvist, P. Bendahl, M. Belting, R.S. Johnson

      • Abstract
      • Presentation
      • Slides

      Background:
      Mechanisms that regulate the positive association between thrombosis and pulmonary metastasis are incompletely understood. It was hypothesised that thrombus formation stimulates a hypoxic response, which in turn promotes extravasation. The primary aim was to determine whether thrombosis of the pulmonary microvasculature (T~pm~) increases extravasation via myeloid (neutrophil and macrophage) hypoxia-inducible factor (HIF).

      Methods:
      Pulmonary microthrombosis was induced in wildtype and conditional HIFα knockout mice by administration of intravenous polystyrene microbeads (n=15/group). Murine lung cancer cell extravasation was quantified, and both murine pulmonary and human breast tumors (n=221) were characterised by immunostaining and image analysis.

      Results:
      T~pm~ was induced in wild type mice via tail vein administration of polystyrene microbeads (15μm diameter, 1000/mouse). T~pm~ led to chronological increases in pulmonary HIF1α expression (P=0.01), HIF2α expression (P<0.01), neutrophil infiltration (P<0.05), and macrophage infiltration (P<0.05; 1-5days post-T~pm~ vs. non-thrombosed vehicle controls, n=8/group/time point); these increases were comparable with changes observed following vena cava thrombosis (assessed via image analysis of immunostained tissue throughout). In wild type mice with circulating Lewis lung cancer cells (LLCs, 1million/mouse i/v), T~pm~ led to increases in pulmonary fibrin deposition (P<0.0001), HIF1α expression (P<0.05), HIF2α expression (P<0.05), and LLC extravasation (P<0.0001; 14days post-LLCs vs. non-thrombosed controls, n=15/group). Using conditional HIFα knockout mice (vs. wild type littermates), it was shown that T~pm~-induced increases in pulmonary fibrin deposition and LLC extravasation were dependent upon HIF1α or HIF2α in neutrophils and macrophages; myeloid HIFs were also responsible for T~pm~-induced increases in pulmonary tumour proliferation and vascularisation (n=15/group). In human tumour samples (n=221), fibrin deposition was positively correlated with HIF2α expression (RS=0.22, P<0.001), while increases in HIF2α were associated with reductions in metastasis-free survival (P<0.05).

      Conclusion:
      Thrombus formation in mouse pulmonary microvasculature enhances cancer cell extravasation via neutrophil- and macrophage-specific HIF1α or HIF2α. In human tumours, HIF2α is associated with increased fibrin deposition, and reduced survival. Pulmonary microvascular thrombosis can enhance cancer cell dissemination via myeloid cell-specific HIFs.

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      MINI35.15 - Discussant for MINI35.11, MINI35.12, MINI35.13, MINI35.14 (ID 3555)

      J.W. Goldman

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MINI 36 - Imaging and Diagnostic Workup (ID 163)

    • Type: Mini Oral
    • Track: Screening and Early Detection
    • Presentations: 15
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      MINI36.01 - Three-Dimensional Quantitative Computed Tomography Evaluation of Pulmonary Adenocarcinoma Using Image-Analysis Software (ID 772)

      K. Aokage, K. Hata, H. Ohmatsu, J. Yoshida, G. Ishii, T. Hishida, M. Tsuboi

      • Abstract
      • Slides

      Background:
      Several 2-dimensional computed tomography (CT)-based evaluation methods of small-sized lung adenocarcinomas have been reported as predictors of the disease invasiveness. They include the ratio of the maximum diameter of consolidation to the maximum entire tumor diameter (C/T ratio), tumor shadow disappearance rate on mediastinal window images (TDR), and visual estimation of the ratio of ground-glass opacity area (GGO-R). However, these measurements can be poorly reproducible due to possible inter-observer discrepancy, and can be unrepresentative because measuring is done only on one section of a lesion. We have developed a 3-dimensional quantitative entire-nodule evaluation method using novel image-analysis software. The aim of this study is to compare the new method to these 2-dimensional evaluation methods as a predictor of small-sized invasive lung adenocarcinomas.

      Methods:
      There were 101 consecutive patients with clinical stage IA adenocarcinoma of the lung who underwent complete resection between 2002 and 2005 at our institution, excluding patients undergoing preoperative treatment and those with multiple lung nodules or with a past history of other cancers. Of them, 75 had a nodule separated from the chest wall and mediastinum depicted on preoperative thin section CT scan without contrast enhancement, and they were the subject of this study. The reconstruction interval of the CT scans was 0.2mm and the reconstructed slice thickness was 0.5mm. The image analysis software recognizes a nodule as a collection of cubic voxels. Ground glass opacity (GGO) was defined as the area of increased attenuation in the lung with preservation of the bronchial and vascular margins. As the average CT value of pulmonary arteries on non-contrast-enhanced CT was 50 Hounsfield Unit (HU), we measured the percentage of the voxels over 50 HU in a nodule to identify voxels representing solid component, and the percentage was defined as R-50. Invasive cancer was defined as a nodule with pathological lymphatic permeation, vascular invasion or node involvement. The correlation between invasive lung cancer and clinicopathological factors, including the image findings (C/T ratio, TDR, GGO-R and R-50) was evaluated using multivariate analysis. The areas under the curve (AUC) of receiver operating characteristics curves were compared among the image evaluation methods.

      Results:
      There were 17 invasive cancers. C/T Ratio, TDR, GGO-R and R-50 were independent predictors of invasive lung cancers (p<0.01). R-50 was equivalent in AUC to the other evaluation methods (AUC: R-50, 0.807; C/T Ratio, 0.800; TDR, 0.809; GGO-R, 0.792, respectively).

      Conclusion:
      Our new 3-dimensional quantitative evaluation method using image-analysis software had invasive cancer predictability similar to the other 2-dimensional evaluation methods. As this method enables entire-tumor evaluation quantitatively and objectively, it should be more reproducible and reliable than the conventional methods.

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      MINI36.02 - Newly Detected Solid Nodules at Incidence CT Lung Cancer Screening Rounds: Occurrence and Lung Cancer Probability (ID 1352)

      J.E. Walter, M.A. Heuvelmans, G.H. De Bock, P.A. De Jong, R. Vliegenthart, M. Oudkerk

      • Abstract
      • Slides

      Background:
      Lung cancer screening by low-dose computed tomography (LDCT) is now recommended for high-risk individuals by US guidelines. New nodules detected after initial baseline screening may complicate management. So far, reported results of new nodules have been inconsistent as different definitions were used. The purpose of this study was to determine the occurrence of new solid nodules and their respective lung cancer rate at incidence screening rounds of the Dutch-Belgian Randomized Lung Cancer Screening Trial (NELSON).

      Methods:
      The NELSON trial was approved by the Dutch Ministry of Health. All participants gave written informed consent. In total, 7,557 individuals underwent baseline LDCT screening. Incidence-screening rounds took place after 1, 3 and 5.5 years. This study included participants with solid non-calcified nodules, newly detected after baseline and also in retrospect not present on any previous screen. Lung cancer diagnosis was based on histology, and benignity was based on either histology or a stable size for at least two years. Nodule volume was generated semi-automatically by Lungcare software (Siemens, Erlangen, Germany), and the nodule detection limit was 15mm[3].

      Results:
      During the incidence screening rounds, 1,484 new solid nodules were detected in 949 participants (77% male), with a median age of 59 years (interquartile-range 55-63 years). At the second screening round (1 year after baseline), at least one new solid nodule was present in 4.7% (344/7,295) of participants, and at the third screening round (2 years after the second screening round) additional new nodules were found in 7.1% (491/6,922) of participants. Eventually, a new solid nodule was proven to be lung cancer in 7.9% (75/949) of participants with new solid nodules (77 cancers). A higher number of pack-years smoked increased the risk of a new nodule being cancer significantly (P=0.004). Age and gender distribution were comparable between participants with and without lung cancer detected in a new solid nodule (P=0.236 and P=0.157 respectively). The majority of cancers was diagnosed at stage I (48/77 [62.3%]). Most of the lung cancers were adenocarcinoma (30/77 [39.0%]), squamous cell carcinoma (20/77 [26.0%]) or small cell lung cancer (9/77 [11.7%]).

      Conclusion:
      New solid nodules are common findings in LDCT lung cancer screening and possess a comparably high risk of malignancy. Guidelines may need to consider a more stringent follow-up for new nodules. More research concerning new nodules is necessary to determine a sufficient follow-up strategy and evaluate distinguishing nodule features of benign and malignant new nodules.

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      MINI36.03 - Multi-Nodularity in Baseline CT Lung Cancer Screening and Relationship with Lung Cancer Probability (ID 1392)

      R. Peters, M.A. Heuvelmans, P. De Jong, P. Van Ooijen, M. Oudkerk, G. De Bock, R. Vliegenthart

      • Abstract
      • Slides

      Background:
      Currently, there is little known about prevalence of multi-nodularity in a high risk screening population. Radiologists often find more than one nodule per screenee. Whether the number of lung nodules plays a role in the probability of lung cancer, remains still largely unknown.

      Methods:
      In the Dutch-Belgian randomized lung cancer screening trial (NELSON), launched in 2003, participants were selected with at least one non-calcified nodule at baseline. The NELSON trial was approved by the Ministry of Health and the ethics board of each participating center. All participants gave written informed consent. The per-participant number of baseline nodules was determined. The probability of lung cancer was compared for categories based on the number of baseline nodules, using chi-square testing. Lung cancer diagnosis was confirmed by histology. Nodules were classified as benign if they did not show growth for up to six years after baseline.

      Results:
      3,392 participants (84,4% male, median age 58 years, median pack years 37,9) with 7,258 nodules at baseline CT screening were included. Of these 3,392 screenees, 1,746 (51,5%) had one nodule, 800 (23,6%) had two nodules, 354 (10,4%) had three nodules, 191 (5,6%) had four nodules, and 301 (8,9%) had five or more nodules. The probability of lung cancer was 61/354 (3.5%) in subjects with one nodule, 37/800 (4.6%) in those with two nodules, 17/354 (4.8%) for three nodules, 12/191 (6.3%) for four nodules and 10/301 (3.3%) when a participant had over four nodules (p=NS). In the baseline screening round, 62 subjects had a malignant nodule. Lung cancer diagnosis was made in the nodule with the largest volume in 60/62 (96.8%) cases. Overall, lung cancer was diagnosed in 137/3,392 subjects (4.0%) in whom nodules were found at baseline. Mean nodule count in screened subjects with only benign nodules was 2.1±1.8, compared to 2.3±2.2 in those with a malignant nodule.

      Conclusion:
      At baseline CT lung cancer screening, nearly half of screened participants with lung nodules have more than one lung nodule. Nodule count did not have predictive value in the determination of lung cancer probability in lung cancer screening participants. In the first screening round, of all detected nodules per screenee, lung cancer was detected most frequently in the nodule with the largest volume.

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      MINI36.04 - Automated Measurement of Malignancy Risk of Lung Nodule Detected by Screening Computed Tomography (ID 1737)

      A.J. Ritchie, M. Tammemägi, C. Jacobs, J. Mayo, W. Zhang, H. Roberts, M. Gingras, S. Pasian, L. Stewart, S. Tsai, D. Manos, J.M. Seely, P. Burrowes, R. Bhatia, S. Atkar-Khattra, B. Van Ginneken, M.S. Tsao, S. Lam

      • Abstract
      • Presentation
      • Slides

      Background:
      We have previously reported a practical predictive tool that accurately estimates the probability of malignancy for lung nodules detected at baseline screening LDCT (New Engl J Med. 2013;369:908-17). Manual measurement of nodule dimensions and generation of malignancy risk scores is time consuming and subjected to intra- and inter-observer variability. The goal of this study is to prepare a nodule malignancy risk prediction model based on automated computer generated nodule data and compare it to an established model based on radiologists’ generated data.

      Methods:
      Using the same published PanCan dataset (New Engl J Med. 2013;369:908-17) with the number of lung cancers updated, we prepared a logistic regression model predicting lung cancer using computer-generated imaging data from the CIRRUS Lung Screening software (Diagnostic Imaging Analysis Group, Nijmegen, The Netherlands). Ninety-one of the 2,537 baseline (first) scans were not available or could not be processed by CIRRUS. The remaining 2,446 scans were first annotated by the CIRRUS software. A human non-radiologist reader then accepted/rejected the annotated marks and manually searched the LDCT for nodules missed by CIRRUS or the study radiologist. New nodules found that were not recorded by the study radiologist were reviewed by a subspecialty trained chest radiologist with 14 years experience in lung cancer screening (JM). Nodule morphometric measurements (maximum and mean diameter, volume, mass, density) and total nodule count per scan irrespective of size were automatically generated by the CIRRUS software. The nodule type (nonsolid, part-solid, or solid), nodule description (lobulated, spiculated or well defined) and nodule location (upper versus middle or lower lobe) were manually entered. The variables were evaluated in models as untransformed and natural log transformed variables. Nonlinear relationships with lung cancer were also evaluated. Socio-demographic and clinical history predictors were not included in the model.

      Results:
      Radiologists evaluation identified 8,570 pulmonary nodules of any size in 2063 individuals - 124 nodules in 119 individuals were diagnosed as cancer in follow-up. Based on CIRRUS software annotated marks that were accepted by a human reader, computer analysis identified 11,520 pulmonary nodules in 2174 individuals - 121 nodules in 115 individuals were diagnosed as cancer in follow-up. Thirty-six percent of new nodules found by CIRRUS and/or second human reader were ≥4 mm (mean±SD, 5.9± 3.5 mm). Both the computer generated imaging data model (Model-CIRRUS) and the radiologist generated data model (Model-RAD) demonstrated excellent discrimination and calibration. Their predictive performances were also similar. Comparing Model-CAD to Model-RAD, the AUCs were 0.9537 versus 0.9541, the 90[th] percentile absolute errors were 0.0008 versus 0.0007, and the Brier scores were 0.0093 versus 0.0137. Mean nodule diameter is a better risk predictor than maximum nodule diameter, nodule density or mass.

      Conclusion:
      The predictive performances of computer and radiologist generated data models were similar. The model can be integrated to the CIRRUS Lung Screening software to automatically generate a nodule malignancy risk score to facilitate nodule management recommendation. Supported by the Terry Fox Research Institute, The Canadian Partnership Against Cancer and the BC Cancer Foundation on behalf of the Pan-Canadian Early Detection of Lung Cancer Study Group.

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      MINI36.05 - Computer Vision Tool and Technician as First Reader of Lung Cancer Screening CT (ID 1702)

      A.J. Ritchie, C. Sanghera, C. Jacobs, W. Zhang, J. Mayo, H. Roberts, M. Gingras, S. Pasian, L. Stewart, S. Tsai, D. Manos, J.M. Seely, P. Burrowes, R. Bhatia, S. Atkar-Khattra, B. Van Ginneken, M. Tammemägi, S. Lam

      • Abstract
      • Presentation
      • Slides

      Background:
      The recommendation by the US Preventive Services Task Force to screen high-risk smokers with low-dose computed tomography (LDCT) and the recent decision by the Centers for Medicare and Medicaid Services to fund LDCT screening under the Medicare program mean that LDCT screening will be implemented at the population level in the US and likely in other countries. With the large volume of scans that will be generated, accurate and efficient interpretation of LDCT images is key to providing a cost-effective implementation of LDCT screening to the large at risk population. Objective To evaluate an alternative workflow to identify and triage abnormal LDCT scans in which a technician assisted by Computer Vision (CV) software acts as first reader with the aim to reduce workload, improve speed, consistency and quality of interpretation of screening LDCT scans.

      Methods:
      A test dataset of baseline Pan-Canadian Early Detection of Lung Cancer Study LDCT scans (New Engl J Med. 2013;369:908-17) was used. This included: 136 scans with lung cancers, 556 scans with benign nodules and 136 scans without nodules. The scans were randomly assigned for analysis by the CV software (CIRRUS Lung Screening, Diagnostic Imaging Analysis Group, Nijmegen, The Netherlands). The annotated scans were then reviewed by a technician without knowledge of the diagnosis. The scans were classified by the technician as either normal (no nodules or benign nodules only, potentially not requiring radiologist review) or abnormal (suspicious of malignancy or other abnormality requiring radiologist review). The results were compared with the Pan-Can Study radiologists. Nodules found by CIRRUS but not by the radiologist were reviewed by a subspecialty trained chest radiologist with 14 years experience in lung cancer screening (JM).

      Results:
      The overall sensitivity and specificity of the technician to identify an abnormal scan were: 97.7% (95% CI: 96.3 - 98.7) and 98.0% (95% CI: 89.5 - 99.7) respectively. The technician correctly identified all the scans with malignant nodules. The time taken by the technician to read a scan was 208±120 sec.

      Conclusion:
      A technician assisted by CV software can categorize accurately abnormal scans for review by a radiologist. Pre-screening by a technician and CV software is a promising strategy for reducing workload, improving the speed, consistency and quality of scan interpretation of screening chest CTs. Supported by the Terry Fox Research Institute, The Canadian Partnership Against Cancer and the BC Cancer Foundation on behalf of the Pan-Canadian Early Detection of Lung Cancer Study Group.

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      MINI36.06 - Discussant for MINI36.01, MINI36.02, MINI36.03, MINI36.04, MINI36.05 (ID 3443)

      M. Steliga

      • Abstract
      • Presentation

      Abstract not provided

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      MINI36.07 - Diagnostic Value of Electromagnetic Navigation Bronchoscopy for Peripheral Pulmonary Lesions : A Randomized Controlled Trial (ID 1152)

      S. Jiayuan, Y. Xin, Z. Xin, B. Han

      • Abstract
      • Presentation
      • Slides

      Background:
      Navigational bronchoscope including conventional electromagnetic navigation bronchoscope(ENB) and endobronchial ultrasound(EBUS) with a guide sheath(GS) for transbronchial lung biopsy (TBLB) has improved the diagnostic outcome for peripheral pulmonary lesions (PPLs). However, ENB required the bronchoscope for large diameter of the working channel(>2.6mm) which could limit the deep of the insertion and EBUS-GS could be regarded as the confirmation tool other than navigation system. A new, realtime electromagnetic guidance system for bronchoscopy using a thin bronchoscope(4.0mm) with a GS(1.95mm) for TBLB is a novel method to increase diagnostic yield of PPLs.

      Methods:
      A prospective, open label, two centers, randomized controlled pilot study involves two diagnostic arms: ENB-GS-TBLB and traditional GS-TBLB which was conducted to determine the ability and safety.ENB-GS-TBLB is performed using an electromagnetic navigation system with a GS and an internal locatable guide with diameter of 1.45 mm. Primary outcome was diagnostic yield. Secondary outcomes were yields by total procedure time, the time for finding lesions and the X-ray time using during operation. Complications were also documented.

      Results:
      Of the 86 patients recruited, 81 had a definitive histological diagnosis and were included in the final analysis. The diagnostic yield of the ENB-GS-TBLB (87%) was greater than GS-TBLB (64%; p<0.05). The time for finding lesions of the ENB-GS-TBLB(3min 43s) was significantly less than GS-TBLB(4min 44s; p<0.05). ENB-GS-TBLB was independent of lesion size or lobar distribution. No complications were found in both two groups.

      Conclusion:
      ENB-GS-TBLB seems to be an accurate and safe procedure. It allowed us to improve the diagnostic yield of flexible bronchoscopy in PPLs.

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      MINI36.08 - 18F-FDG PET Imaging Utilization in the National Lung Screening Trial (ID 539)

      V.S. Nair, V. Sundaram, M.K. Gould, S.S. Gambhir, M. Desai

      • Abstract

      Background:
      The National Lung Screening Trial (NLST) showed that chest CT screening for patients at risk for lung cancer reduces lung cancer mortality compared to Chest X-Ray (CXR) screening, but with considerable costs due to a high rate of false positive findings. The use of FDG PET has been advocated as a diagnostic tool to aid clinicians in evaluating nodules that may or may not be cancer, but no investigations to date have ascertained current practice patterns in a large group of patients across the U.S.

      Methods:
      Using data from the NLST, we determined the appropriateness and characteristics of diagnostic FDG PET use in patients with an abnormal finding (defined as a ≥ 4 mm nodule) during lung cancer screening via CT or CXR. Diagnostic FDG PET consisted of either a PET alone or combined PET/CT, which was done prior to a lung cancer diagnosis but after an abnormal finding. Appropriateness was defined as diagnostic FDG PET use for nodules ≥ 8 mm. We used multivariable logistic regression techniques to assess factors associated with diagnostic FDG PET use.

      Results:
      Of 9,964 patients with an abnormal finding during any of the three rounds of screening, 1,206 (12%) had a diagnostic FDG PET scan at 33 different medical centers across the U.S. (Table 1). Forty percent (n = 484) of these scans were recommended by a radiologist as a follow-up for an abnormal finding. Twenty-seven percent (n = 331) were performed for nodules less than 8 mm, and of these 24% (n = 81) were recommended by radiologists. There were no regional differences in PET use across U.S. areas with endemic fungal disease but patients from the Northeast and Southeast were twice as likely as the West to have a PET scan after a positive screen. Older age, nodule size ≥ 0.8 –2.0 cm, upper lobe location and a spiculated nodule border were associated with increased diagnostic FDG PET use.

      Conclusion:
      This is the first study to describe differential FDG PET use across the U.S and by medical specialty. Importantly, PET imaging was used inappropriately for small nodule evaluation in one out of four cases. Future studies should characterize associated costs and whether better adherence to current national guidelines can reduce such costs. Figure 1



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      MINI36.09 - CT-Guided Cutting Needle Lung Biopsy Using 'Liquid Withdraw' Technique: Prominently Reduced Incidence of Pneumothorax (ID 1411)

      R. Li, W. Ren, H. Zhang, L. Wang, B. Liu

      • Abstract
      • Presentation
      • Slides

      Background:
      CT-guided cutting needle lung biopsy is important for the diagnosis of lung cancer. The co-axial method is now widely used. However, co-axial method failed to decrease the incidence of pneumothorax. This study is to investigate whether our new-developed “Liquid withdraw” technique (to inject small amount of lidocaine during withdraw of the needle) can reduce incidence of pneumothorax when combined with co-axial technique. Figure 1 Fig.1.What is liquid withdraw



      Methods:
      From Jan 2013 to Dec 2014, We retrospectively studied 38 CT-guided percutaneous lung biopsy using co-axial and liquid withdraw techniques. The pathologies and complications secondary to biopsy procedure (pneumothorax, bleeding and hemoptysis) were noted. Pneumothorax was graded as mild, moderate, and severe.

      Results:
      37 cases was diagnosed out of 38 biopsies, of which 23 cases were adenocarcinoma (21 patients consented EGFR mutation test, and 15 cases had EGFR mutaions),2 squamous cell carcinoma, 1 non-small cell lung cancer (cannot be further classified after IHC), 1 small-cell lung cancer, 2 primary lung cancer of other types, 5 metastatic lung cancer and 3 benign diseases. 4 cases (10.5%) happened pneumothorax (all were mild pneumothorax),bleeding during biopsy happened in 1 (2.6%) case, 6 cases with a small amount of hemoptysis(15.8%). No infection, tumor implantation or aeroembolism happened. Figure 1 Fig.2. A case of CT-guided cutting needle lung biopsy using “Liquid Withdarw” technique A: The co-axial inducer needle is located at the margin of the lesion B&C:after biopsy, the lidocaine can be seen in the needle passage and no pnemothorax is found.



      Conclusion:
      CT-guided percutaneous lung biopsy using co-axial and liquid withdraw is an accurate, safe,reliable technique. Compared to co-axial technique without liquid withdraw, the incidence of pneumothorax was reduced from approximately 35% to 10.5%. More studies according to liquid withdraw technique will be conducted in our future work.

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      MINI36.10 - Discussant for MINI36.07, MINI36.08, MINI36.09 (ID 3556)

      D. Grunenwald

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI36.11 - Pre-Operative Fine Needle Aspiration (FNA) for Diagnosis of Suspected Early Stage Lung Cancer Reduces Non-Malignant Resection Rate (ID 2124)

      J.A. Barta, C.I. Henschke, R. Flores, D.F. Yankelevitz, C.A. Powell

      • Abstract
      • Presentation
      • Slides

      Background:
      Rates of resection of non-malignant lung nodules suspected pre-operatively to be lung cancer vary widely and are reported to be as high as 40%. Commonly used modalities in the pre-operative workup of new lung nodules suspicious for lung cancer include positron emission tomography (PET), bronchoscopy, and computed tomography (CT)-guided fine needle aspiration (FNA). We evaluated the non-malignant resection rate (NMRR) and the frequency of benign resections among patients with pre-operative FNA in our lung cancer center.

      Methods:
      The study population was identified using databases of the Mount Sinai Departments of Thoracic Surgery and Radiology. Eligible patients included those with a CT-guided FNA and/or surgical resection performed during the 12-month period between July 2013 – July 2014 for known or suspected first primary early stage lung cancer presenting with a lung nodule or mass. Cases were included if patients were >18 years of age with no history of cancer treated within 5 years. Patient data were abstracted from the electronic medical records.

      Results:
      A total of 283 nodules from 264 patients met inclusion criteria. Of these, FNA was performed in 217 (77%) of the 264 patients, with 131 results (60%) categorized as malignant. Similarly, 228 nodules (81%) were PET imaged, and 141 (62%) of these were positive (Standard Uptake Value >2). Sensitivity and specificity of FNA and PET for diagnosis are reported in Table 1. Post-FNA pneumothorax requiring a chest tube occurred in 11/193 FNAs performed at Mount Sinai (6%). Of 208 surgically resected nodules, 27 cases (13.0%) had a non-malignant diagnosis on pathologic examination. The non-malignant resection rate (NMRR) ranged from 0% to 39% by different surgeons and did not correlate with surgical case volume. Among the 142 resections preceded by FNA, 11 (7.7%) were found to have non-malignant pathology. In contrast, among the remaining 66 resections without a pre-operative FNA, 16 (24.2%) were benign (OR 3.81, 95%CI 1.52-9.69; p = 0.001). Figure 1



      Conclusion:
      In this single center retrospective analysis, the overall NMRR was lower than in previously published reports. Furthermore, the NMRR was significantly lower in thoracic operations preceded by a CT-guided FNA compared with those without a pre-operative FNA. Diagnostic accuracy of FNA in this cohort of patients at moderate to high risk for lung cancer is higher than that of PET, with an acceptably low complication rate. These findings suggest that pre-operative diagnostic confirmation by FNA results in a low rate of non-malignant resection.

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      MINI36.12 - Diagnosis of Peripheral Lung Nodules: Cost Analysis of EMB/EBUS Compared to TTNB (ID 254)

      K..A. Lee

      • Abstract
      • Presentation
      • Slides

      Background:
      This analysis compares the cost–effectiveness of radial endobronchial ultrasound (EBUS) and electromagnetic navigation (ENB) to transthoracic needle biopsy (TTNB) to achieve diagnosis of suspicious lung lesions. As more centers develop lung screening and lung nodule clinics, there will be a need for diagnosis of small pulmonary nodules. The National Lung Screening Trial (NLST) showed a probable positive Low Dose Computer Tomography (LDCT) incidence of 25%, indicating the number of patients requiring a diagnostic evaluation will increase. The expectation of increased lung cancer screening due to the Centers of Medicare and Medicaid Services approving coverage for LDCT for eligeable patients, and the American College of Chest Physicians (ACCP) recommendation for improved techniques to diagnose peripheral lung lesions necessitate utilizing clinical and economic assessment tools that support clinical decisions. The study seeks to identify the most cost-effective biopsy protocol to reduce costs, and deliver improved diagnostic accuracy.

      Methods:
      The study reviewed the NLST which enrolled over 50,000 people aged 55–74 years with at least a 30-pack/year smoking history, in fairly good health and non-symptomatic of lung disease. The study found low-dose computed tomography of the chest resulted in a 20% lower mortality from lung cancer compared with those who had chest x-rays. Approximately 25% of the LDCT-screened patients had a positive screen requiring confirmation of the lung lesion. Using an estimate of 5.2 million annual chests CT scans in the USA as a basis for the number of patients seeking a confirmative result before being recommended for surgery for possible benign lung lesions. The cost–effectiveness models employed estimate the direct costs to the hospital and to the patient. Direct costs were calculated using the Medicare Median cost files by Current Procedural Terminology (CPT) code for 2012. Additional costs were added to account for the fee of the procedure room, nursing and clinical support staff, and observation room time. Reimbursement reflects the 2013 Medicare allowable payment exclusive of the geographic adjustment factor. Reimbursement from commercial insurers is constructed upon a conservative multiple of the Medicare allowable. CPT codes subject to the multiple procedure discounts were properly reduced by 50% as they would be for reimbursement purposes for both Medicare and commercial insurance reimbursement.

      Results:
      Modeling 200 representative patients delegated to; TTNB, bronchoscopy, or R-EBUS-/ENB-enabled endobronchial percutaneous (Endo-Perc) when comparing procedure fees, insurance payment and clinical outcomes, the Endo-Perc technique lead to the most cost-effective option to biopsy the lung lesion. The lower adverse event profile of pneumothorax and reduced cost exhibited by the Endo-Perc procedure; resulted in a benefit of $130,464 compared with a loss of $562,863 for TTNB, or a loss of $103,487 for routine bronchoscopy.

      Conclusion:
      The results suggest combining R-EBUS with ENB provides a high-diagnostic yield at a lower cost due to the lower risk of a pneumothorax when compared with transthoracic lung biopsy.

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      MINI36.13 - Quantitative Computed Tomography as Predictor of Cardiopulmonary Complication after Lobectomy for Lung Cancer in COPD Patients (ID 1227)

      Y. Yasuura, T. Maniwa, N. Miyata, R. Shimizu, H. Kayata, H. Kojima, S. Takahashi, M. Isaka, Y. Ohde

      • Abstract
      • Presentation
      • Slides

      Background:
      In lung cancer resection, COPD is a risk factor for postoperative complications. There are few reports about postoperative complications that assume a pictorial emphysematous change an index. We examine a relationship of an emphysematous regional ratio in preoperative CT in patients with COPD who underwent lung cancer resection and cardiopulmonary complication.

      Methods:
      One hundred fifty-nine patients with COPD who underwent lobectomy for lung cancer in our hospital from 2002 to 2011 were retrospectively evaluated in this study. Preoperative factors, including proportion of emphysematous area measured by CT (percentage of low attenuation area: LAA%), and operative factors were analyzed. Cardiopulmonary complications include pyothorax, pneumonia, atelectasis, acute pulmonary injury, chest tube indwelling, O~2~ long supply and arrythmia.

      Results:
      Cardiopulmonary complications were observed among 61 patients (38%). Ages, FEV1.0%, LAA% and amounts of blood lost were significantly relevant to cardiopulmonary complications by univariate analysis. Multivariate analysis indicated that patient’s age and LAA% could be significant independent predictors. Table1.Complications incidence by LAA%

      LAA% N complications:n=61 no complications:n=98 p value
      ~1% 1~10% 10%~ 77 67 15 15(19.5%) 37(55.2%) 9(60.0%) 62(80.5%) 30(44.8%) 6(40.0%) <0.001
      Table2. Operative factors in relation to cardiopulmonary complications
      variables Odds ratio 95%Confidence Interval p value
      Age(>70 years) FEV1.0% GOLD PaO2 LAA%(1%~) blood lost(>150ml) 4.612 1.042 2.044 0.973 5.570 2.073 2.028-10.489 0.973-1.117 0.857-4.876 0.940-1.008 2.302-13.480 0.878-4.894 <0.001 0.242 0.107 0.128 <0.001 0.096


      Conclusion:
      LAA% is useful for predicting cardiopulmonary complications in patients with COPD undergoing lobectomy for lung cancer.In patients with COPD undergoing lobectomy for lung cancer, 70 years of age or older, the LAA% 1% or more of the cases, more careful intraoperative, and postoperative management are required.

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      MINI36.14 - Improving Pathways to Early Lung Cancer Diagnosis: Process Mapping and Qualitative Analysis (ID 746)

      N.M. Rankin, T. Shaw, S. York, D. McGregor, P. Butow, J. Young, K. White, D. Barnes, R. Zielinski, E. Stone

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is one of the most difficult cancers to diagnose in primary care settings. Lung symptomatology alone is a poor indicator of likelihood of diagnosis and in Australia, most primary care practitioners (general practitioners, GPs) will see only one or two lung cancer cases annually. Early diagnosis leads to improved survival with 5-year lung cancer survival much higher in localised disease (30% versus 16% overall). Australia has a mixed public-private model of health services and referral pathways from primary to secondary and tertiary services are based on traditional or informal networks resulting in wide variations in practices. This presentation will report results from diagnostic pathway mapping in lung cancer across three multidisciplinary teams (MDTs) to inform future intervention strategies to reduce variation and improve patient outcomes.

      Methods:
      We conducted process-mapping workshops with each team to identify the barriers to delivering diagnostic and treatment services. We also developed qualitative interview schedules for GPs and patients. We recruited participants through multiple strategies (mail out, personal invitation from the clinical champion) with local ethics approval.

      Results:
      Forty-six lung cancer clinicians and four consumers participated in process mapping workshops across three sites. The resulting process maps highlight health system delays and complexities for patients navigating health services, particularly for those living in regional and rural areas. The provision of specialist services for lung cancer diagnosis varies significantly geographically with potential for patients to be lost to follow up. Twelve GPs completed in-depth qualitative interviews or participated in a focus group to identify barriers and enablers in diagnostic pathways. Qualitative analysis reveals that GPs need tailored information about appropriate referrals to specialist pulmonologists or oncologists at the time of a suspicious lung cancer. For GPs without established referral networks, there can be significant uncertainty about the most appropriate referral pathways. Analysis from qualitative interviews with 20 lung cancer patients and their carers indicates that they perceive their GP as having an advocacy role in coordinating their care across specialists’ appointments and diagnostic investigations. Patients reported that personal contact and networking across clinicians in primary, secondary and tertiary settings was a significant factor in the timeliness of investigations or being referred for treatment. In particular, the urgency or severity of symptoms significantly impacted timeliness in securing appointments for investigative diagnostic tests. Patients reported that GPs willing to coordinate their care played an enabling or facilitating role in their care pathway.

      Conclusion:
      This collaborative project between clinicians and researchers has identified significant barriers and enablers in diagnostic pathways in lung cancer. Primary care practitioners play a significant role in managing patient care and require timely and tailored information about how to refer to a specialist who actively participates in a MDT. We have subsequently developed a protocol to implement a referral decision prompt at the time of CT investigation for those people with a suspicious lung lesion. This prompt will be directed at primary care practitioners and we are currently undertaking a pilot study to examine its feasibility and acceptability.

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      MINI36.15 - Discussant for MINI36.11, MINI36.12, MINI36.13, MINI36.14 (ID 3557)

      K. Garg

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MINI 37 - SCLC Therapy (ID 165)

    • Type: Mini Oral
    • Track: Small Cell Lung Cancer
    • Presentations: 13
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      MINI37.01 - Chk1 Inhibition Enhances Cisplatin Cytotoxicity Regardless of p53 Status in Human Small Cell Lung Cancer Cells (ID 947)

      W. Hsu, S. Hsu, G. Rao, I. Kim, A.T. Alberobello, Y. Wang, G. Giaccone

      • Abstract
      • Presentation
      • Slides

      Background:
      Small cell lung cancer (SCLC) has a poor prognosis and harbors complex genetic alterations including frequent loss-of-function mutations of p53 and Rb, which impair the G1/S checkpoint control. Checkpoint Kinase 1 (Chk1) is a vital serine/threonine specific protein kinase responsible for halting the cell cycle in check after DNA damage. With abrogation of Chk1-mediated cell cycle checkpoint control, cancer cells may enter mitosis with extensive DNA damage leading to mitotic catastrophe and apoptotic cell death. Previous in vitro studies showed that p53 deficient cancer cells benefit from Chk1 inhibition. Here we demonstrate that a combination of Chk1 inhibition and cisplatin causes more growth inhibition and caspase activation in SCLC cell lines compared to cisplatin alone, regardless of p53 status.

      Methods:
      Chk1 inhibition was achieved by siRNA knockdown (Qiagen) and AZD7762 (Selleckchem) in p53 mutant SCLC cell lines (GLC4, NCI-H82) and p53 intact SCLC cell lines (NCI-H128, NCI-H209). Cell viability was measured by Cell-Titer Glo assay (Promega) after 72hrs of drug treatment. Synergism was defined by combination index (CI)>1 using the Chou-Talalay method. Cell cycle analysis was performed by PI staining and detected by FACS. Western blotting and immunofluorescent staining were used to evaluate caspase activation and other signaling proteins.

      Results:
      SCLC cell lines were treated with cisplatin 24hrs at each IC50 dosage after Chk1 siRNA transfection. In GLC4 after 2.5uM cisplatin treatment, cell viabilities of control siRNA-treated and Chk1 siRNA-treated cells were 28% and 10.6% (p=0.006, by paired t-test), respectively. Similar significant reduction of cell viability was observed in 1uM cisplatin-treated NCI-H82 cells (44.6% vs. 29.7%; p=0.0632) and in 3uM cisplatin-treated NCI-H128 cells (62.5% vs. 45.3%; p=0.0155), respectively. More cleaved caspase-2 and caspase-3 were noted in Chk1 knockdown plus cisplatin-treated GLC4 cells than in cisplatin alone. The IC50 (72hrs) of single agent AZD7762 (Chk1 inhibitor) treatment was 240nM, 211nM, 266nM and 215nM in GLC4, NCI-H82, NCI-H128 and NCI-H209 respectively. The combination indexes of AZD7762 and cisplatin (both given at around IC50s) calculated by Chou-Talalay method indicated synergism in all these 4 cell lines. Cell cycle analysis revealed that AZD7762 abrogated cisplatin-induced G2/M arrest in GLC4 and G1 arrest in NCI-H128. Inhibition Chk1 by AZD7762 was associated with reduction of CDC25C and CDC2 phosphorylation. Phospho-Histone H3 (mitotic marker) was increased in AZD7762 and cisplatin combined treatment compared to cisplatin alone in a p53 independent fashion. Intriguingly, inhibition of Chk1 by AZD7762 alone in GLC4 cells activated caspase-2.

      Conclusion:
      Chk1 inhibition both by siRNA knockdown and AZD7762 enhances cisplatin cytotoxicity. The synergism was primarily due to increased apoptosis and abolished cell cycle arrest. Although p53 is frequently mutated in SCLC, growth inhibition was seen in a p53 independent manner. In GLC4, single agent AZD7762 treatment can cause caspase-2 activation through an as yet unidentified mechanism. Our findings suggest that Chk1 is a potential therapeutic target in small cell lung cancer and is synergistic with chemotherapy. The effects of Chk1 inhibitor and its combination with chemotherapy agents in SCLC animal models are currently underway.

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      MINI37.02 - The Novel HSP90 Inhibitor-SN-38 Conjugate (STA-12-8666), Is Highly Active in Preclinical Models of Small Cell Lung Cancer (SCLC) (ID 911)

      Y. Boumber, A. Gaponova, A. Nikonova, A. Deneka, A. Kudinov, M. Kopp, B.L. Egleston, S. Litwin, J.S. Duncan, K. Duncan, H. Borghaei, R. Mehra, D. Proia, E. Golemis

      • Abstract
      • Presentation
      • Slides

      Background:
      Small cell lung cancer (SCLC) is a highly aggressive disease representing 12-13% of all lung cancers, with 5 year survival rate of only 6%. While most patients respond initially to cytotoxic chemotherapies such as irinotecan, etoposide, or carboplatin, resistance rapidly emerges and response to second line agents such as topotecan is limited. In contrast to non-small cell lung cancer, few targetable oncogenes have been identified in SCLC. STA-12-8666 is a small molecule drug, which binds the tumor-concentrated active form of heat shock protein 90 (HSP90), with a cleavable linker attached to SN-38, the active metabolite of irinotecan. Cleavage of the linker within the tumor provides time-release of SN-38 at high local concentration, while significantly limiting drug exposure and toxicity in non-transformed tissue. The goal for this work was to evaluate STA-12-8666 for potential use as a new second line monotherapy, or as adjuvant in the frontline setting for SCLC.

      Methods:
      Three dose levels of STA-12-8666 were evaluated in comparison to irinotecan, ganetespib, carboplatin, etoposide, cisplatin and chemotherapy combinations in 4 independent SCLC xenograft models, including parental and cisplatin-resistant derivative cell lines (SCLC1, SR2), and a patient-derived xenograft (PDX). STA-12-8666 was also evaluated in drug combinations. Intratumoral responses were profiled using a mass spectrometry based approach to evaluate kinase pathway activation, and results confirmed by immunohistochemistry and western blot analysis. Pharmacokinetic analysis was performed to benchmark retention of STA-12-8666 to irinotecan in lung tumors.

      Results:
      In all four models, high dose (150 mg/kg) STA-12-8666 was tolerated without side effects. In most cases, three doses administered at weekly intervals caused complete regression of established tumors, with response durable for > 2 months. Those tumors that regrew were responsive to re-dosing with STA-12-8666, and were subsequently eliminated. Further, STA-12-8666 induced complete or partial regression of tumors that progressed following first or second line treatment with standard of care agents for SCLC. Low dose (50 mg/kg) STA-12-8666 inhibited tumor growth and enhanced the anti-tumor activity of 30 mg/kg carboplatin, resulting in complete tumor regression. Pharmacokinetic and proteomic analysis confirmed STA-12-8666 concentration in tumors, and identified a signature of DNA damage response biomarkers in STA-12-8666-treated tumors that is different from that induced by irinotecan.

      Conclusion:
      The findings that HSP90i-drug conjugate STA-12-8666 is highly active in preclinical models of SCLC (in both frontline and second line settings) support the evaluation of this novel compound in clinical trials.

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      MINI37.03 - Survival after Surgery for pN1 and pN2 Small Cell Lung Cancer: A Comparison with Surgical Treatment of Non-Small Cell Lung Cancer (ID 3100)

      C.J. Yang, D.Y. Chan, B.C. Gulack, P.J. Speicher, M.G. Hartwig, M.F. Berry, B.C. Tong, M.W. Onaitis, T.A. D'Amico, D. Harpole

      • Abstract
      • Presentation
      • Slides

      Background:
      With the advent of modern chemotherapy and radiotherapy, we hypothesize that patients who undergo surgery followed by adjuvant therapy for locally advanced small cell lung cancer (SCLC) may have significantly better long-term survival compared to historical data suggesting 2-year overall survival of 4-20% for patients undergoing surgery for SCLC.

      Methods:
      Prospectively-collected perioperative outcomes and survival data of patients with pathologic T1-3, N1 and (limited) N2 SCLC and non-small cell lung cancer (NSCLC) who underwent complete resection with adjuvant chemotherapy ± radiation and no induction therapy were reviewed from the US National Cancer Data Base from 2003-2011 using Kaplan-Meier method and propensity-score matching. Groups were matched for common prognostic co-variates including year of diagnosis, age, sex, race, education, insurance status, facility type, distance from facility, Charlson/Deyo co-morbidity score, T and N status, tumor size, and tumor location. These prospective data were acquired by certified tumor registrars and include over 70% of cancer diagnoses annually in the U.S.

      Results:
      During the study period, 369 and 12,152 patients underwent complete resection for pathologic T1-3 N1-2 M0 SCLC and pT1-3 N1-2 M0 NSCLC, respectively. Median follow-up time was 43 months. Five-year overall survival was 37% for SCLC pN1 patients and 26% for SCLC pN2 patients (Table). Matched patients with pN1/N2 NSCLC had better 5-year survival compared to patients with pN1/N2 SCLC (Table and Figure). Figure 1 Figure 2





      Conclusion:
      SCLC T1-3 N1-2 patients who undergo complete resection followed by adjuvant chemotherapy ± radiation have 5-year survival greater than 26%. Compared to NSCLC, SCLC patients with N1/N2 disease have worse survival; however, the differences in survival between NSCLC and SCLC patients with N1/N2 disease are much smaller than previously reported. These results support a re-evaluation of the role of surgery in multimodality therapy for locally advanced small cell lung cancer.

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      MINI37.04 - Discussant for MINI37.01, MINI37.02, MINI37.03 (ID 3444)

      M.C. Pietanza

      • Abstract
      • Presentation

      Abstract not provided

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      MINI37.05 - Carfilzomib, Carboplatin and Etoposide for Previously Untreated Extensive-Stage Small Cell Lung Cancer: Initial Results from a Phase 1b/2 Study (ID 3008)

      F. Badin, E. Eskander, H. Harper, A. Chiang, D. Haggstrom, W. Harb, S. Aggarwal, E. Demirhan, W. Fisher

      • Abstract
      • Presentation
      • Slides

      Background:
      Proteasome inhibitors synergize with topoisomerase inhibitors (eg, etoposide), which are frequently used to treat extensive-stage small cell lung cancer (ES-SCLC; Takigawa et al. Anticancer Res 2006;26:1869–76). Results from study PX‑171-007 (NCT00531284) suggest that carfilzomib has activity in relapsed SCLC (Papadopoulos et al. Cancer Chemother Pharmacol 2013;72:861–8), and clinical experience in myeloma suggests that carfilzomib may be added to other agents with limited additive toxicity. Preliminary results are presented from the phase 1b portion of the CFZ004 trial (NCT01987232) intended to determine the maximum tolerated dose (MTD) and safety of carfilzomib with carboplatin and etoposide in patients with previously untreated ES-SCLC.

      Methods:
      Patients received carfilzomib (30-minute intravenous infusion) on days 2, 3, 9, and 10 (20 mg/m[2] [days 2 and 3 of cycle 1]; 20–56 mg/m[2] thereafter) and fixed doses of carboplatin (target area under the concentration-time curve: 5 mg/mL/min) on day 1 and etoposide (100 mg/m[2]) on days 1, 2, and 3 of a 21‑day cycle for up to 6 cycles. Assessment of dose‑limiting toxicities (DLTs) in cycle 1 was used to determine dose escalation up to the MTD or recommended phase 2 dose. Disease response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Patients achieving ≥stable disease (SD) after 6 cycles could receive single-agent carfilzomib until disease progression or unacceptable toxicity.

      Results:
      As of March 31, 2015, 17 patients (median age: 59.0 years) had been treated in the phase 1b portion in 5 dosing cohorts; enrollment in the 56-mg/m[2] cohort is ongoing. Patients initiated a median of 6 cycles of carfilzomib; the median treatment duration was 16.3 weeks. One patient (56-mg/m[2] cohort) experienced a DLT. There were no on-study deaths. Two patients discontinued carfilzomib due to an adverse event (AE; metastatic pain: n=1; decreased neutrophil count: n=1). All-grade AEs were generally consistent with the profiles of the agents under study. Thirteen patients (76.5%) had a grade ≥3 AE; the most common (≥3 patients) were anemia (n=4), neutropenia (n=4), decreased neutrophil count (n=4), and leukopenia (n=3). The preliminary overall response rate (≥partial response) in 14 response-evaluable patients was 57.1%, with 1 complete response (Table 1). All response-evaluable patients achieved ≥SD.

      Conclusion:
      The MTD of carfilzomib with carboplatin and etoposide has not been reached. Patients are showing encouraging responses to treatment, with AEs generally consistent with the profiles of the agents under study. Response data, currently immature, will be updated at the meeting. Table 1. Phase 1b Best Overall Responses per Investigators

      Cohort
      1 2 3 4 5 Total
      CFZ, mg/m[2]
      20/20 (n=5) 20/27 (n=3) 20/36 (n=3) 20/45 (n=3) 20/56 (n=3) (N=17)
      Best overall response, n (%)[a]
      CR 0 1 (33.3) 0 0 0 1 (5.9)
      PR 2 (40.0) 2 (66.7) 3 (100.0) 0 0 7 (41.2)
      SD 3 (60.0) 0 0 2 (66.7) 1 (33.3) 6 (35.3)
      Not evaluable 0 0 0 1 (33.3) 2 (66.7) 3 (17.6)
      Overall response rate (CR+PR), n (%)
      All patients 2 (40.0) 3 (100.0) 3 (100.0) 0 0 8 (47.1)
      Response-evaluable patients 2 (40.0) 3 (100.0) 3 (100.0) 0 0 8 (57.1)
      [a]Per RECIST, v1.1.

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      MINI37.06 - Randomized Phase II Trial of CODE or Amrubicin Plus Cisplatin Chemotherapy after Chemoradiotherapy for Limited-Disease Small Cell Lung Cancer (ID 1033)

      I. Sekine, H. Harada, N. Yamamoto, T. Takahashi, K. Goto, N. Nogami, T. Seto, F. Oshita, H. Okamoto, H. Tanaka, M. Wakabayashi, Y. Ohe

      • Abstract
      • Presentation
      • Slides

      Background:
      Four cycles of etoposide plus cisplatin (EP) concurrently with accelerated hyperfractionation thoracic radiotherapy (AHTRT) is the standard treatment for limited-disease small cell lung cancer (LD-SCLC). The objectives of this study were to evaluate efficacy and toxicities of CODE or amrubicin plus cisplatin (AP) chemotherapy following one cycle of EP and AHTRT in patients with LD-SCLC, and to select the promising arm for subsequent phase III trials.

      Methods:
      Eligibility criteria included patients with previously untreated LD-SCLC with measurable lesion, ECOG PS of 0-1, and 20-70 years of age. Eligible patients received one cycle of EP (etoposide 100 mg/m[2] on days 1-3 and cisplatin 80mg/m[2] on day 1) plus AHTRT (45Gy/ 30 fractions in 3 weeks). Patients who achieved CR, PR or SD were secondarily registered and randomized to receive either 3 cycles of CODE (cisplatin 25 mg/m[2] on days 1 and 8, doxorubicin 40 mg/m[2] on day 1, etoposide 80 mg/m[2] on days 1-3, and vincristine 1 mg/m[2] on 8 every 2 weeks) or 3 cycles of AP (amrubicin 40 mg/m[2] on days 1-3 and cisplatin 60 mg/m[2] on day 1 every 3 weeks). G-CSF was administered on the days when chemotherapy was not administered in CODE, or on day 5 to the day when a neutrophil count exceeded 5,000/µL in AP. Patients with CR after CODE or AP received prophylactic cranial irradiation. The primary endpoint was the one-year progression-free survival (PFS) after the second registration. Tumor responses were assessed with RECIST version 1.1 by the central review committee. A better regimen for phase III trial is determined with a randomized phase II selection design. The sample size was 72 randomized patients to detect >= 10% difference in one-year PFS with a probability of 80%.

      Results:
      From May 2011 to Jan 2014, 85 patients from 28 institutions were registered. After the induction EP plus AHTRT, 75 patients were randomized to CODE (n=39) or AP (n=36). Patient demographics were well balanced between the arms. One patient did not receive CODE and 34 (89%) of the 38 patients received 3 cycles of CODE, whereas 33 (92%) of the 36 patients received 3 cycles of AP. Grade 4 neutropenia, anemia and thrombocytopenia were observed in 47%, 21% and 16% of patients in CODE, and in 78%, 6% and 17% of patients in AP, respectively. Grade 3 non-hematological toxicities with the incidence of 5% or higher included febrile neutropenia (16%), hyponatremia (8%), hypokalemia (5%), fatigue (5%), and anorexia (5%) in CODE, and febrile neutropenia (42%), nausea (11%), anorexia (11%), fatigue (8%), esophagitis (6%) in AP. CR and PR were noted in 13 and 25 patients in CODE, and in 10 and 24 patients in AP, respectively. The median overall survival in the 74 patients was 42.8 months. The one-year PFS (95% CI) was 41.0 (25.7 - 55.8) % in CODE and 54.3 (36.6 - 69.0) % in AP.

      Conclusion:
      The one-year PFS seemed better in AP than in CODE. AP arm is considered to be the test regimen for the subsequent phase III trial.

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      MINI37.07 - PCI Survival Improvement for Extensive Stage SCLC Limited to Patients on Maintenance Systemic Therapy: A Secondary Analysis of CALGB 30504 (ID 861)

      J.K. Salama, L. Gu, X. Wang, J. Bogart, J. Crawford, S. Schild, N. Ready, E. Vokes

      • Abstract
      • Presentation
      • Slides

      Background:
      PCI has become standard of care for extensive stage small cell lung cancer (ES-SCLC) patients. However, one recent randomized study establishing this standard did not require brain imaging prior to enrollment, and another, which did, failed to show a benefit for PCI. CALGB 30504 (Alliance) was a randomized phase II study of sunitinib vs placebo in ES-SCLC patients responding to at least 4 cycles of platinum based therapy requiring baseline brain imaging at enrollment. As this study spanned the introduction of PCI for ES-SCLC, PCI was left to the discretion of the treating team. Therefore, we performed a secondary analysis of CALGB 30504 to determine the impact of PCI on ES-SCLC patients.

      Methods:
      CALGB 30504 was a phase II randomized study in ES-SCLC comparing maintenance sunitinib versus placebo following SD or CR/PR to 4-6 cycles of etopside 100 mg/m[2] d1-3 and either carboplatin AUC=5 or cisplatin 80 mg/m[2] d1 q 21 days. Sunitinib was 150 mg PO d 1 then 37.5 mg PO qd until progression. The primary objective was to determine if maintenance sunitinib would improve PFS, as was recently reported. PCI was recommended at 25 Gy in 2.5 Gy fractions, within 4-6 weeks of chemotherapy, but not required. Sunitinib was to be held 2 days prior, during, and 2 days after the completion of PCI. All statistical analyses were performed by the statisticians at Alliance/CALGB Statistical and Data Center on the platform of SAS (version 9.3; SAS Institution Inc., Cary, North Carolina).

      Results:
      85 patients received maintenance therapy(41placebo, 44 sunitinib). 41 (48%) received PCI, 44 didn’t. All patients and tumor characteristics were balanced between PCI and no-PCI patients. PCI dose was 25 Gy for 31 patients (range: 25-37.5 Gy). Median time to PCI was 21 wks (range: 12-27 wks) from enrollment. For all patients, PCI was associated with an improvement in PFS (median 7.8 vs 6.5 mo HR=0.63 (95% CI: 0.41-0.98), p=0.037), but not OS (median 12.9 vs 13.2 mo, HR=1.01 (95% CI: 0.64-1.62), p=0.955). In placebo patients, there was no PFS or OS difference between patients receiving PCI or not. In patients randomized to sunitinib, PCI conferred a PFS benefit (9.7 vs 6.8 mo, HR=0.49 (95% CI: 0.26-0.92), p=0.024), but not an OS benefit (14.1 vs 13.5 mo, HR=0.85 (95% CI: 0.44-1.66), p=0.636). When restricted to patients who did not receive PCI, there was no difference in survival between sunitinib or placebo patients. In PCI patients, those receiving sunitinib had non-significant improvement in PFS (9.7 vs 6.7 months, HR=0.63 (95% CI: 0.34-1.20), p=0.158) and trended towards an improvement in OS (14.1 vs 10.6 months, HR=0.56 (95% CI: 0.29-1.10), p=0.087), which was magnified and approached significance when crossover patients were excluded (14.1 vs 10.0 mo, HR=0.49 (95% CI: 0.22-1.06), p=0.064).

      Conclusion:
      PFS, and trends for OS improvement were limited to patients receiving the combination of PCI and maintenance sunitinib. Placebo patients did not benefit from PCI. Improved outcomes for ES-SCLC patients with PCI are likely limited to patients who achieve both intracranial and extracranial disease control.

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      MINI37.08 - Pazopanib as Second Line Treatment of Platinum Sensitive SCLC Patients: A Multicenter Phase II Trial of the Hellenic Oncology Research Group (ID 1683)

      A. Kotsakis, V. Karavasilis, S. Agelaki, N. Kentepozidis, S. Peroukidis, E. Samantas, C. Christophyllakis, E.K. Dermitzaki, F. Koinis, G. Fountzilas, V. Georgoulias

      • Abstract
      • Presentation
      • Slides

      Background:
      Pazopanib is a small anti-angiogenic molecule inhibiting the tyrosine kinase of VEGFR‑1, VEGFR‑2, VEGFR‑3, PDGF, and c‑kit. An increased angiogenesis and VEGF expression has been reported in SCLC which is correlated with disease dissemination and poor prognosis. A multicenter phase II study of second line pazopanib in patients with SCLC was conducted.

      Methods:
      Patients with histologically confirmed SCLC who relapsed at least 3 months after the completion of front line VP-16/CDDP chemotherapy (platinum sensitive disease) were enrolled. Eligible patients should have measurable disease and ECOG performance status (PS) 0-2. Treatment consisted of daily p.o. pazopanib 800 mg in cycles of 28 days until disease progression. The primary endpoint was progression-free rate (PFR) at 8 weeks since anti-angiogenic factors are not associated with objective tumor shrinkage.

      Results:
      Thirty seven out of 39 enrolled patients (2 pts are still ongoing) were evaluable for response and toxicity. The median age was 65 years (range 39-82); male=33 pts; PS 0=22 pts; PS 1=15 pts. Eleven (28.2%) patients had only local relapse. The median interval from previous treatment was 5.4 months (3.0-38.2). One (3%) CR, 10 (26%) PR and 10 (26%) SD were documented, for an overall progression free rate (PFR) of 55% (95% CI: 39.4- 71.2%). The median PFS and OS was 3.7 and 10.6 mo, respectively, while the estimated 1-year survival was 58% (median follow up= 18.9 mo). Grade 4 adverse events (AEs) included neutropenia (n=2 pts) and diarrhea (n=2 pts) whereas grade 3 AEs were fatigue (n=4pts), nausea (n=1 pt), diarrhea (n=2 pts), hand-foot syndrome (n=1 pt) and transaminasaemia (n=1 pt). Epistaxis (gr 2) was reported in 3 pts, proteinuria (gr 2) and hypertension (gr 2) in 2 pts each. There were no treatment-related deaths.

      Conclusion:
      Second line treatment with pazopanib of patients with sensitive SCLC, was well-tolerated and resulted in a promising overall survival and disease control rate, including objective responses.

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      MINI37.09 - Discussant for MINI37.05, MINI37.06, MINI37.07, MINI37.08 (ID 3445)

      T.K. Owonikoko

      • Abstract
      • Presentation

      Abstract not provided

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      MINI37.10 - Factors Associated with Severe Pneumonitis for Limited Stage Small Cell Lung Cancer (ID 1714)

      R.U. Komaki, X. Wei, P.K. Allen, E.B. Holliday, A. Farooqi, S.H. Lin, P. Balter, R. Mohan, Z. Liao, J.D. Cox

      • Abstract
      • Presentation
      • Slides

      Background:
      Pneumonitis is a major side effect for the treatment of limited stage small cell lung cancer with concurrent chemotherapy and radiotherapy (CChRT). Prevention is more important than treatment when patients develop grade 3-5 severe pneumonitis (SP). We investigated factors causing SP among patients with limited stage small cell lung cancer (SCLC) treated by CChRT.

      Methods:
      This is a retrospective analysis of 559 patients with limited-stage SCLC treated at a single institution from 1986-2009 with definitive CChRT to a total dose of 45-70 Gray (Gy). Candidate variables included tumor size, year of diagnosis & treatment period (1986-1999 vs. 2000-2009), gender, age, Karnofsky’s Performance Status (KPS), ethnicity, radiation dose, cycles of induction chemotherapy, use of intensity-modulated-radiation-therapy (IMRT) and fractionation. CTCAE v2 before 2003 and CTAE v3 in 2003-2009 were used to evaluate SP Grade 3-5 which were similar. Chi-square test was used for between group comparisons for categorical variables and the median test was used for between group comparisons for continuous variables. Kaplan-Meier estimates were constructed for overall survival (OS), disease-free survival (DFS), local-recurrence-free survival (LRFS), distant metastasis-free survival (DMFS). Analysis was performed using Logistic regression analysis with SP as the primary endpoint.

      Results:
      Of the 559 patients included in this analysis, tumor size was available for 520 patients. Median follow-up was 21.2 months (range 1.2-240.8). Thirty-five (6.2%) patients developed SP (26 Grade-3, 8 Grade-4 & 1 Grade-5). 2D or 3DCRT was used before 2000 and IMRT was usually used for small cell lung cancer in 2000-2009. Univariate analysis (UVA)showed that SP was associated with treatment given in 2000-2009 ( OR 3.93, P<001) ,age ≥ 60 (OR 7.72, P=0.001) ,KPS < 90 (OR 2.22, P=0.02), IMRT (OR 2.3, P= 0.026) and twice daily fractionation( OR 2.38, P=0.03).Induction Chemotherapy reduced SP (OR 0.39, P= 0.023) compared to immediate CChRT. Tumor size (at cut points 3 cm & 5 cm) did not make significant difference regarding SP. Multivariate analysis (MVA) has shown that significantly higher SP was associated with treatment given in 2000-2009 (OR 3.42, P=0.006), age ≥ 60 (OR 7.77, P= 0.001), male (OR 2.12, P=0.047)and twice daily RT (OR 2.45, P=0.026) . OS was significantly reduced among SP group vs. Pneumonitis ≤ Grade 2 (MST 17.9 vs.25 months, P= 0.038) (5-year OS 16 % vs. 27%), respectively. SP were not significantly correlated with DFS, LRFS and DMFS.

      Conclusion:
      Significantly higher SP was seen among patients with limited stage small treated in 2000-2009, age ≥ 60, male and twice daily RT. OS was significantly reduced SP. UVA showed IMRT causing significantly higher SP. MVA did not show IMRT was a significant factor for SP. Tumor size did not show significant difference regarding SP.

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      MINI37.11 - Inter-Observer Variability in Hippocampus Delineation on MRI Scans for Hippocampal Avoidance Prophylactic Cranial Irradiation Trial (ID 2620)

      C. Chen, M. De Ruiter, F. Bartel, F. Vandaele, S. Sunaert, K. De Jaeger, N. Dollekamp, M. Kwint, E. Dieleman, Y. Lievens, D. De Ruysscher, S. Schagen, J. Belderbos

      • Abstract
      • Presentation
      • Slides

      Background:
      Prophylactic cranial irradiation (PCI) is the standard treatment in patients with small-cell lung cancer (SCLC) without progression after chemo-radiotherapy in stage I-III disease and after having a remission after chemotherapy in stage IV. In an international phase III trial (NCT01780675), patients with SCLC are randomised to receive PCI with or without Hippocampal Avoidance (HA). Accurate delineation of the hippocampus is crucial for this trial. In this study we evaluate the hippocampus delineation variability among radiation oncologists in multi-institutions for SCLC patients.

      Methods:
      The left and right hippocampus from 5 randomly selected patients (10 structures) were delineated by 5 radiation oncologists and 2 neuroradiologist in 7 institutions according to the RTOG atlas (http://www.rtog.org/CoreLab/ContouringAtlases/HippocampalSparing.aspx), together with a questionnaire. For each patient, a high resolution 3D inversion recovery T1 weighted MRI-scan was first registered to the planning CT-scan (1mm slicing). The observer then delineated the hippocampus according to the atlas on axial slices of the MRI. The mapped delineations on the CT were then used in dose planning with a 5mm margin. The mean and standard deviation (SD) of 1) volume and 2) range in medio-lateral, superior-inferior and anterior-posterior directions were computed for each structure. The corresponding inter-observer reliability was estimated by the intra-class correlation coefficient (ICC absolute agreement) using a linear mixed model. A median surface was computed and the overall delineation variability per structure was calculated by the root-mean-square (rms) of the local SD per sampled points on the median surface, while the local SD corresponds to the perpendicular distance between each observer and a sampled point.

      Results:
      The standard deviation of the delineated volume per structure varied from 0.14 to 0.48cm3. The corresponding inter-observer reliability (ICC) was 0.19, implying a high variability among the observers. The overall delineation variability per structure varied from 0.6 to 1.0mm. Areas with good agreements were the superior and inferior part of the hippocampus. The difficult area (Fig.1) was in the anterior medial area, close to the amygdala and uncus. The ICC in medio-lateral, superior-inferior and anterior-posterior directions were 0.55, 0.64 and 0.80, respectively. A large spread of the SD of range in medio-lateral direction and the relative low ICC imply that a better instruction, or training is desirable to improve the delineations. Figure 1



      Conclusion:
      There was a substantial variability in hippocampus delineation among the observers. Stricter adherence to the RTOG guidelines and (web-based) training are needed. The implication of the variations on the dose distribution is currently verified.

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      MINI37.12 - Survival Trends of Small Cell Lung Cancer (SCLC) in the United States: A SEER Database Analysis (ID 399)

      K.M. Islam, L. Nawal, P.E. Deviany, T. Anggondowati, A.K. Ganti

      • Abstract
      • Presentation
      • Slides

      Background:
      Small cell lung cancer (SCLC) has poor outcomes. The past thirty years have seen some advances in the management options for SCLC. However the impact of these advances on outcomes in the general population with SCLC is unclear.

      Methods:
      The Surveillance, Epidemiology, and End Result (SEER) registry 18 was used to identify SCLC cases from 1988 to 2011. Patients were classified either limited stage (LS) or extensive stage (ES) disease at diagnosis. Cox regression model was used to compare overall survival after adjustment for confounding covariates.

      Results:
      A cohort of 83,396 SCLC patients was analyzed. A higher proportion of males had ES-SCLC compared to females (72.7% vs. 67.4%; p<0.0001) Males had worse median overall survival (OS) compared to females (LS-SCLC: 10 vs. 12 months, HR: 1.11; 95% CI, 1.08-1.14; ES-SCLC: 6 vs. 7 months; HR: 1.16, 95% CI, 1.14-1.18). A higher proportion of younger patients (≤70 years) compared to older patients (>70 years) had ES-SCLC at diagnosis (70.76 vs. 68.02%; p<0.0001). However, median OS was worse in older patients for both stages (LS-SCLC: 10 vs. 13 months; HR 1.31, 95% CI 1.27-1.34; ES-SCLC: 6 vs. 8 months, HR: 1.19, 95% CI 1.16-1.21). A higher proportion of whites presented with ES-SCLC as compared to blacks or others (70.1% vs. 66.5% and 65.9%; p<0.0001). Blacks had worse median OS compared to whites (LS-SCLC: 10 vs. 11 months; HR: 1.07, 95% CI, 1.02-1.12; ES-SCLC: 6 vs. 7 months, HR: 1.07, 95% CI 1.02-1.12). Compared to the reference period 1993-1997, patients diagnosed with ES-SCLC during the latter time periods had worse OS: 1998-2002 (HR: 1.12; 95% CI, 1.08-1.15), 2003-2007 (HR: 1.23, 95% CI 1.20-1.27) and 2008+ (HR: 1.53, 95% CI, 1.49-1.58). A similar difference was not seen in patients with LS-SCLC, where only the most recent time period 2008+, had a worse survival compared to 1993-1997 period (HR: 1.37, 95% CI, 1.30-1.43).

      Conclusion:
      Females, whites, and younger patients with SCLC had better OS compared to males, blacks and older patients, respectively. Unfortunately, survival from SCLC has not improved significantly and may actually have worsened, during the past 20 years. The reason for this discord between clinical trial evidence and real-world evidence need to be investigated further. Newer treatment approaches are urgently needed for this disease.

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      MINI37.13 - Discussant for MINI37.10, MINI37.11, MINI37.12 (ID 3446)

      N. Murray

      • Abstract
      • Presentation

      Abstract not provided

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    MINI 38 - Biology and Prognosis (ID 167)

    • Type: Mini Oral
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 15
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      MINI38.01 - FAK Inhibitor VS-6063 Targets Mesothelioma Cancer Stem Cells: Rationale for Maintenance Therapy after Conventional Chemotherapy (ID 2710)

      V. Kolev, I. Shapiro, P. Baas, R. Bueno, J. Pachter, D. Weaver

      • Abstract
      • Presentation
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung and peritoneum with median overall survival with standard of care (SOC) chemotherapy only 12 months from diagnosis. This poor prognosis may be attributed at least in part to cancer stem cells (CSCs) that are resistant to chemotherapy and can mediate cancer recurrence and progression. Focal adhesion kinase (FAK) plays an essential role in the survival, self-renewal and tumor-initiating capability of CSCs. The FAK inhibitor VS-6063 (defactinib) is currently being tested in patients with MPM following disease control on standard pemetrexed/platinum chemotherapy (COMMAND, ClinicalTrials.gov NCT01870609).

      Methods:
      An Aldefluor assay, previously validated as a CSC assay (Shapiro et al., 2014), was used to assess the effects of chemotherapy or VS-6063 on CSCs in vitro. Tumor initiating potential of MPM cells after treatment with SOC agents, and VS-6063 alone or in combination with pemetrexed was measured in vivo. CSC marker expression in MPM patient tumor samples was measured by IHC, Q-PCR and RNASeq analysis. Novel CSC markers were validated in an in vivo limiting dilution assay.

      Results:
      Treatment of a human MPM cell line with pemetrexed or cisplatin, the SOC therapy for mesothelioma, resulted in a 6-fold enrichment of ALDH-positive CSCs. In direct contrast, the FAK inhibitor VS-6063 markedly reduced the proportion of CSCs. Control and pemetrexed-treated MPM cells showed robust tumor initiation in vivo, while cells treated with VS-6063 alone or VS-6063 plus pemetrexed had decreased tumor initiating capacity. FAK inhibitor was found to selectively induce apoptosis in CSCs, indicating that the mechanism of their elimination is cell death. In addition to ALDH, several new mesothelioma CSC markers were validated in in vivo limiting dilution assay and their clinical utility was assessed. An increase in CSC markers, including ALDH1, CD133 and CXCR2, was observed in tumor samples from 11 patients following first line pemetrexed-cisplatin chemotherapy. In tumor biopsies from MPM patients treated for 12 days with VS-6063, tumor pFAK (Y397) and expression of CSC markers was reduced. Interestingly, gene expression analysis of these samples revealed an inhibition of CSC pathways after VS-6063 administration. VS-6063 maintained the effect of chemotherapy in patient-derived xenograft (PDX) mouse model. Treatment with pemetrexed/cisplatin resulted in tumor growth inhibition followed by rapid tumor re-growth upon cessation of the treatment. Tumor re-growth was substantially delayed when FAK inhibitor was administered after chemotherapy.

      Conclusion:
      These data provide a strong rationale for the current clinical testing of VS-6063 following treatment with pemetrexed plus platinum to potentially prolong time to progression in patients with mesothelioma.

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      MINI38.02 - BAP1 Inactivation in Mesothelioma Is Highly Prevalent (ID 657)

      M.G. Zauderer, A. Cercek, A. Rimner, V. Rusch, P.S. Adusumilli, G.M. Nash, A. Moreira, J. Hmeljak, M. Ladanyi, L.M. Krug

      • Abstract
      • Presentation
      • Slides

      Background:
      Efforts to elucidate tumorigenic mutations in mesothelioma are essential to advance therapy. Prior efforts to characterize the molecular heterogeneity of this disease have been limited by sample condition and testing platforms. Herein, we describe efforts to prospectively test patients using next-generation sequencing with matched patient germline controls.

      Methods:
      Sequential mesothelioma patients were approached for consent to our IRB protocol NCT01775072 to perform MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), a comprehensive molecular profiling platform based on solution-phase exon capture and next generation sequencing to detect somatic genetic alterations in FFPE tumor specimens. MSK-IMPACT involves hybridization capture and deep sequencing of all protein-coding exons of 341 key cancer-associated genes, including all genes that are druggable by approved therapies or are targets of experimental therapies being investigated in clinical trials at MSKCC.

      Results:
      51 patients with mesothelioma underwent MSK-IMPACT testing (see Table 1). 12 samples had low tumor content. Among 39 samples with reliable results, BAP1 was the most common alteration (46%). Another 3 samples had changes also thought to inactivate BAP1 (2 samples had gene copy number changes just below the cutoff for whole gene deletions and 1 had an inversion of LIMD-BAP1 thought to inactivate BAP1), making the incidence of BAP1 alterations possibly as high as 56%. In 4 samples with sufficient tumor content, no alterations were identified. Table 1

      N=39 (%)
      Gender M/F 26/13 (67/33)
      Primary site of disease * Pleural * Peritoneal * Testicular 32 (82) 6 (15) 1 (3)
      # identified alteration, average 3
      Alterations present in >6% * BAP1 * NF2 * CDKN2Ap16INK4A * SETD2 * CDKN2Ap14ARF * LATS1 * CREBBP * WT1 * CDKN2B * PI3KCA * PBRM1 * TP53 18 (46) 8 (21) 5 (13) 5 (13) 4 (10) 4 (10) 4 (10) 4 (10) 3 (8) 3 (8) 3 (8) 3 (8)


      Conclusion:
      Using MSK-IMPACT, BAP1 inactivation is the most common alteration. Other aberrations previously reported at high frequency were identified but albeit at lower frequencies (NF2 and p16, previously reported as 40% and 75% respectively). For multiple samples with deep coverage, no alterations were identified. The high incidence of BAP1 mutations in this systematic testing makes this pathway ideal for developing and testing targeted therapies.

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      MINI38.03 - Validation of a Specific Missense GTF2I Mutation in More Indolent Thymic Epithelial Tumours (ID 3017)

      S. Gennatas, H. Anbunathan, A. Montero, A.G. Nicholson, S. Popat, A.M. Bowcock

      • Abstract
      • Presentation
      • Slides

      Background:
      Thymic epithelial tumours (TETs) are rare intrathoracic cancers that can be invasive and very difficult to treat. There is currently a huge gap in the understanding of the basic science behind their development as well as great clinical need for development of effective treatments. Recently a missense mutation (T>A, at the same position on chromosome 7, 74146970) was identified in GTF2I at high frequency (78%) in the more indolent type A and AB thymomas. We examined the frequency of this alteration in an independent cohort of well clinically characterized patients from the UK.

      Methods:
      Tumour samples were collected from 94 patients from a single tertiary cardiothoracic centre in the UK, the Royal Brompton & Harefield NHS Foundation Trust (London). These were subject to histological assessment by expert Consultant Histopathologists to confirm the diagnosis and determine tumour abundance. DNA was extracted with Quiagen’s QIAamp DNA FFPE Tissue Kit (Catalogue No. 56404). PCR and Sanger sequencing was performed with semi-nested primers.

      Results:
      We assessed the frequency of the GTF2I mutation in a total of 94 TETs with a tumour abundance of at least 70%. The mean age for all patients was 57 and the male: female ratio was 1:1.25 The GTF2I mutation was seen in 25 of 87 evaluable TETs (29%) and was present more commonly in type A (85%) and AB (46%) thymomas. The frequency decreased to 9% in type B1 (1/11) and 5% in type B2 thymomas (1/19). In our cohort the mutation was not detected in any B3 thymomas or carcinomas, including neuroendocrine tumours or two cases of thymic hyperplasia. Interestingly all AB thymomas with the mutation had a much lower percentage of mutant alleles compared to the majority of the A thymomas. Twenty-three of the 25 patients (92%) with the mutation had Stage I – II disease at presentation and had complete resection of their thymoma.

      Conclusion:
      Our results confirm the presence of the GTF2I mutation at a high frequency in type A and AB thymomas in an entirely different patient cohort. Although the frequency of the mutation in type A thymomas in our cohort is very similar to what was reported originally (85% and 82% respectively) it was lower in the AB thymomas (46% and 74% respectively). Explanations for this include the smaller sample number in our cohort and a higher percentage of the lymphocytic component in our samples than that in the original series. The lower mutation frequency in the B subtypes and carcinomas compared to the original series could be due to the smaller numbers in our cohort. We aim to address these issues by expanding our validation series to over 200 samples. Whole exome and RNA sequencing of TETs is ongoing and will allow us to further confirm and extend this finding.

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      MINI38.04 - BRCA1/OCT1/MAD2L1 Axis Regulates a Bifurcating Apoptotic Pathway Induced by Vinorelbine in Mesothelioma (ID 2675)

      S. Busacca, A.J. Sharkey, D. Waller, A. Nakas, L. O'Regan, K. Kerr, M. Sheaff, A. Fry, D.A. Fennell

      • Abstract
      • Slides

      Background:
      There is currently no licenced second line therapy for mesothelioma patients upon relapse after pemetrexed cisplatin. The vinca alkaloid spindle poison, vinorelbine, exhibits useful activity in mesothelioma, warranting evaluation in a new UK randomised clinical trial, VIM. However the molecular determinants of efficacy are unclear. We have reported that BRCA1 is an essential regulator of vinorelbine-induced apoptosis, and loss of detectable BRCA1 occurs in 39% of mesotheliomas. However the mechanisms governing BRCA1 dependent lethality has been lacking. We have utilized a functional genetic approach to uncover critical genes required for vinorelbine efficacy.

      Methods:
      Apoptosis was analysed by PARP cleavage and caspase 3/7 activity assay. Focused RNAi targeting Caspase 8, BAX and BAK was conducted to delineate critical death activators. Mouse embryonic fibroblasts (MEFs) wild type (WT) or double knockout (DKO) for BAX/BAK cells were also used. MAD2L1 expression was studied by western blot and qRT-PCR. Tumour explants were derived from 10 MPM patients.

      Results:
      Mitochondrial and caspase-8 dependent apoptosis pathways were shown by triple knockdown of BAX, BAK and Caspase 8 to be required to rescue completely from vinorelbine-induced apoptosis. Loss of BRCA1 recapitulated this apoptosis block and was associated with loss of Oct1 dependent MAD2L1 associated transcriptional upregulation. RNAi mediated silencing of MAD2L12 phenocopied BRCA1 loss. In cells selected for resistance to vinorelbine, MAD2L1 failed to upregulate, secondly to constitutive downregulation of BRCA1. Using mesothelioma explants derived at extrapleural decortication, exhibited either marked resistance or sensitivity to vinorelbine induced apoptosis; correlation with regulation of BRCA1/Oct1/MAD2L is ongoing and will be presented.

      Conclusion:
      BRCA1 functions through an Oct1/MAD2L1-dependent activation of both mitochondria dependent and independent pathways to induce apoptosis. This implicates a requirement for a functional spindle assembly checkpoint, with implications for expanding the biomarker repertoire governing vinorelbine efficacy in mesothelioma

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      MINI38.05 - Discussant for MINI38.01, MINI38.02, MINI38.03, MINI38.04 (ID 3449)

      J.P. Van Meerbeeck

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI38.06 - FP1039/GSK3052230 with Chemotherapy in Patients with Fibroblast Growth Factor (FGF) Pathway Deregulated Squamous NSCLC or MPM (ID 2879)

      P. Garrido, I. Delgado, E. Felip, M. Domine, P. Paik, J. Trigo, J. Schellens, S. Gadgeel, H.L. Kindler, P. Lara Jr., S. Orlov, J. Vansteenkiste, E. Levchenko, U. Lassen, S. Viteri, J. Hambleton, K. Baker-Neblett, L. Yan, C. Wang, D. Sedoti, G. Kirby, I. Mitrica, J. Botbyl, D. Morgensztern

      • Abstract
      • Presentation
      • Slides

      Background:
      GSK3052230/FP1039 is a soluble fusion protein with the ECD of FGFR1c linked to the hinge and Fc regions of human IgG1 and acts as a ligand trap by sequestering FGFs involved in tumor growth and angiogenesis. In contrast to small molecule FGFR kinase inhibitors, GSK3052230 spares the hormonal FGF ligands, namely FGF19, 21 and 23. GSK3052230 combined with chemotherapy was efficacious in xenograft models of FGFR1-amplified NSCLC and malignant pleural mesothelioma (MPM) with FGF2 mRNA overexpression. A phase I monotherapy study determined 20mg/kg weekly as the maximum feasible dose (MFD) achieving the desired blood concentration, with no maximum tolerated dose (MTD) reached.

      Methods:
      This study (NCT01868022 funded by GSK) will evaluate the safety and efficacy of GSK3052230 weekly infusion in combination with paclitaxel + carboplatin in previously untreated FGFR1 amplified metastatic sqNSCLC (Arm A), in combination with docetaxel in FGFR1 amplified metastatic sqNSCLC that has progressed after at least 1 line of chemotherapy (Arm B), or in combination with pemetrexed + cisplatin in patients with untreated and unresectable MPM (Arm C). Each arm involves a dose escalation phase utilizing the 3+3 design, followed by an expansion phase up to 30 patients (pts). Key endpoints include the MTD/MFD of GSK3052230 with chemotherapy, safety, response rates and duration.

      Results:
      Thirty-four pts have been dosed with GSK3052230 at dose levels ranging from 5mg/kg to 20mg/kg in combination with chemotherapy across three Arms, n=15 (A), n=6 (B) and n=13 (C). Baseline characteristics: males/females 29/5; mean age 68.5 years; ECOG PS 0 (n=20), 1 (n=13), 2 (n=1). Most common AEs were: Arm A: asthenia, neutropenia; Arm B: neutropenia, diarrhea, rash; Arm C: decreased appetite, nausea, infusion reaction. Infusion reactions were seen in 8/34 (24%) pts (n=3 Grade (Gr)1, n=3 Gr2, n=2 Gr3). Serious AEs included: Arm A- neutropenia (n=4), fatigue (n=1), asthenia (n=1), fever (n=1), respiratory infection (n=1); Arm B- neutropenia (n=1), abdominal pain (n=1); Arm C-bowel perforation/ischemia (n=1), infusion reaction (n=1), elevated creatinine (n=1). No DLTs have been observed in sqNSCLC pts (Arms A and B). Three DLTs were reported in mesothelioma pts (Arm C 20mg/kg): Gr5 bowel perforation/ischemia, Gr4 elevated creatinine levels and Gr3 infusion reaction. MFD for Arm A is determined at 20mg/kg. Dose escalation is ongoing for Arms B and C. Preliminary PK results revealed no drug-drug interactions. At time of data-cutoff, 10 PR were observed among 23 patients evaluable for efficacy (ORR = 43%) and a clinical benefit rate of 78% with two ongoing subjects on study >300 days. Preliminary efficacy is as follows: Arm A (6 PR, 2 SD, 1 PD, 6= not-yet-evaluable (NE)), Arm B (4 SD, 1 PD, 1 NE), and Arm C (3 PR, 3 SD, 3 PD, 4 NE).

      Conclusion:
      GSK3052230 is in general well tolerated in combination with chemotherapy. The MFD for GSK3052230 is 20mg/kg in combination with paclitaxel + carboplatin in first line sqNSCLC patients. Toxicities typically associated with small-molecule FGFR inhibitors, namely hyperphosphatemia and retinal, nail, and skin changes, were not observed. The initial activity and safety profile of GSK3052230 ​warrant further study.

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      MINI38.07 - RITA Enhances Mithramycin-Mediated Growth Arrest and Apoptosis of Malignant Pleural Mesothelioma Cells In-Vitro and In-Vivo (ID 2996)

      M. Rao, V. Shukla, D. Straughan, S. Azoury, P. Feingold, S.M. Atay, Y. Hong, T. Upham, J.A. Hong, M. Zhang, X. Li, R.T. Ripley, D.S. Schrump

      • Abstract
      • Presentation
      • Slides

      Background:
      Malignant pleural mesotheliomas (MPM) are relatively rare tumors for which there are no effective treatment options. Previously we reported that mithramycin (MM) dramatically inhibits growth and tumorigenicity of MPM cells in part via depletion of Specificity Protein 1 (SP1) and activation of p53 signaling. We also demonstrated that 24h MM treatment induces G0/G1arrest and senescence with subsequent apoptosis of MPM cells. The present study was undertaken to examine the effects of RITA (Reactivation of p53 and Induction of Tumor cell Apoptosis- a p53 activator and MDM2 inhibitor) with or without MM in cultured MPM cells in vitro and in vivo.

      Methods:
      NCI-SB-MES1 and NCI-SB-MES7 (MES1 and MES7, respectively) with wild-type p53 were cultured in the presence of mithramycin (24h) and/or RITA (48h). DNA damage, senescence and autophagy were assessed by immunoblot/immunofluorescence analysis of g-H2A-X phosphorylation and foci formation, ß-gal staining, and immunoblot/immunofluorescence analysis of LC3 proteins. Propidium iodide and APO-BrdU techniques were used to determine cell cycle kinetics and quantify apoptosis. qRT-PCR and immunoblot techniques were used to examine signal transduction, cell cycle-related and apoptosis-related protein levels in MPM cells. Murine subcutaneous xenograft models were used to evaluate the combinatorial antitumor effects of RITA and MM in-vivo.

      Results:
      MM treatment (10-100nM x 24h) mediated dose-dependent depletion of SP1 and markedly increased p53 levels in MPM cells; these effects coincided with DNA damage, G0/G1 arrest, senescence and an autophagy phenotype as evidenced by induction of LC3 puncta/proteins and p-AMPK and inhibition of p-S6 kinase. Senescence or autophagy phenotype coincided with up-regulation of CDKN1A, MDM2/TP53INP1, MAPLC3B, and down-regulation of EZH2, SP1/MTOR. RITA (100-1000nM x48h) alone mediated low-level, dose-dependent growth inhibition in MPM cells. However treatment with subtherapeutic doses of MM for 24h followed by RITA for 48h resulted in synergistic growth inhibition and apoptosis in MPM cells, detected by flow cytometry, as well as immunoblot analysis of cleaved PARP and cleaved caspase 3. Sequential intraperitoneal treatment with MM (1mg/kg/week) followed by RITA (2 mg/kg/3d/week) significantly reduced volumes/masses of subcutaneous MES1 xenografts in athymic nude mice.

      Conclusion:
      Sequential mithramycin/RITA treatment significantly reduces mesothelioma tumor burden via induction of apoptosis. These findings provide preclinical rationale for evaluation of this drug regimen in MPM patients.

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      MINI38.08 - Contemporary Analysis of Prognostic Factors in Patients with Unresectable Malignant Pleural Mesothelioma (MPM) (ID 1745)

      A. Bille, M.G. Zauderer, K. Woo, V. Rusch, L.M. Krug

      • Abstract
      • Presentation
      • Slides

      Background:
      The CALGB and EORTC have previously developed prognostic scoring systems for patients with MPM, but these included patients managed surgically and predated the use of pemetrexed. We sought to identify prognostic factors in a contemporary cohort of patients with unresectable MPM.

      Methods:
      We retrospectively reviewed the charts of patients with histologically proven MPM managed non-surgically at MSKCC from 2000-2012. Variables analyzed and correlated with overall survival (OS) included: sex, age at diagnosis, smoking history, asbestos exposure, tumor laterality, initial performance status (PS), tumor histology, clinical TNM, initial PET maximum Standardized Uptake Value (SUVmax), hemoglobin level, platelet, lymphocyte and neutrophil counts, treatment type (chemotherapy and/or radiotherapy), and response to treatment. OS was analyzed by Kaplan-Meier method, and significance (p<0.05) of prognostic factors was analyzed by log-rank test and Cox regression.

      Results:
      191 patients met study criteria: median age 71 years (range 46-90), 147 (77%) male, 128 (67%) epithelioid , 20 (10.5%) biphasic, and 28 (14.6%) sarcomatoid. 34 patients were stage I-II at presentation and 157 (82%) stage III-IV. First line chemotherapy included pemetrexed in 159 (90.3%) patients. Median time from diagnosis to treatment was 1.2 months. With a median follow-up of 13.2 months, median OS for all patients was 13.4 months. By univariate analysis, histology (p<0.001), platelet count (≤450 vs. >450, p<0.001), initial PS, maximum PET SUV (> or ≤8.1, p=0.037) were significant. Clinical staging (I/II vs III/IV) did not correlate with OS (p=0.35). By multivariable analyses, only histology, platelet count and PS were independent prognostic factors. 1-year OS was 69% (95%CI 62%-78%) for epithelioid versus 30% (95%CI 15%-59%) and 29% (95%CI 16%-51%) for biphasic and sarcomatoid tumors, respectively. Patients with PS 0-1 had a 1-year OS of 64% (95%CI 56%-73%) versus 42% (95%CI 31%-57%) for PS 2 or greater. Epithelioid histology, PS 0-1 and elevated neutrophil count at diagnosis were significantly associated with response to first line chemotherapy. Patients with response or stable disease after the first two cycles of chemotherapy had significantly better OS, median OS was 16.8 (95% CI 14.8 – 20.1) versus 6.5 (95% CI 5.4-8.5) months (p<0.001). Patients receiving more than one line of chemotherapy had better OS, median OS 14.2 (95% CI 12.1 – 16.8) versus 8.7 (95% CI 6.6 – 11.0 ) months (p=0.013). There was no significant association between use of radiotherapy and OS (p=0.058), but patients who received radiotherapy showed a 1-year OS of 60.5% vs 44.0% of patients who did not receive radiotherapy.

      Conclusion:
      This analysis in patients with unresectable MPM confirms that some elements of the CALGB and EORTC prognostic scoring systems (platelet count, PS, histology) correlate with OS, and identifies factors (PS, elevated neutrophil count, histology) associated with response to chemotherapy. Our analysis emphasizes the impact of histology and response to first-line chemotherapy on outcomes, but also the lack of predictability with the use of clinical staging.

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      MINI38.09 - The Prognostic Significance of Nodal Metastatic Burden in Survival following Radical Surgery for Malignant Pleural Mesothelioma (ID 2776)

      A.J. Sharkey, A. Nakas, D. Waller

      • Abstract
      • Presentation
      • Slides

      Background:
      The staging of malignant pleural mesothelioma (MPM) remains undetermined. But it is still important for informing prognosis and selection for high risk surgery. The specific lymphatic drainage of the pleura implies that nodal staging based on that used in lung cancer may not be accurate for MPM. We have evaluated an alternative nodal staging strategy.

      Methods:
      We retrospectively analysed the pathology and outcome of 282 patients who survived for over 30 days following radical surgery for MPM: 190 extended pleurectomy decortication(EPD), 92 extrapleural pneumonectomy(EPP). All patients underwent intraoperative systematic nodal dissection. Nodal stations were assigned to all nodes, and patients were staged according to the current UICC system. The status and number of nodes in each station were recorded. Survival was calculated for the standard nodal stages (N0, N1, N2). We derived nodal groups Na, Nb, Nc based on the percentage of sampled nodes containing tumour, irrespective of nodal station: Na = N0, Nb ≤ median %, Nc > median %.

      Results:
      The type of surgery did not influence median survival; EPD 12.3 vs. EPP 14.5 months, p=0.46. The median survival of the standard nodal stages were: N0(113 patients), 16.5 months; N1(13 patients), 13.0 months; N2(156 patients), 11.8 months. There was no significance difference in survival between N1 and N2, p=0.65 but there was between N0 and N1/N2, p=0.04. The median percentage of nodal metastases was 43%. There were significant differences in median survival between Na, Nb and Nc, p=0.03. There were significantly more positive N2 nodes in group Nc (98%), than in group Nb (86%) p=0.001.

      Nodal stage No of patients Median survival (months)
      N0 113 16.5
      N1 13 13.0
      N2 156 11.8
      Na - no metastases 113 16.5
      Nb - 86 13.5
      Nc - > 43% metastases 83 9.9
      Figure 1



      Conclusion:
      There appears to be greater accuracy in a nodal staging system based on the nodal burden of metastases rather than an anatomically based system. There may be less accuracy in nodal staging in lung sparing radical surgery for MPM due to less extensive nodal sampling.

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      MINI38.10 - Discussant for MINI38.06, MINI38.07, MINI38.08, MINI38.09 (ID 3482)

      J.W. Riess

      • Abstract
      • Presentation

      Abstract not provided

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      MINI38.11 - Tumor Volume and Epithelioid Differentiation Are Independent Predictors of Survival in  Malignant Pleural Mesothelioma (ID 2428)

      D. Kircheva, A. Husain, S. Watson, A. Qudsia, A. Durkin Celauro, S. Armato, H.L. Kindler, W.T. Vigneswaran

      • Abstract
      • Presentation
      • Slides

      Background:
      Maximal cyto-reductive surgery with adjuvant therapy provides survival advantage in selected patients with malignant pleural mesothelioma (MPM). Extended pleurectomy and decortication (EPD), a lung sparing procedure, provides an opportunity to measure the tumor volume. We hypothesized that tumor volume is a better predictor of survival than the T and N, because it represents tumor burden more accurately. Currently the significance of epithelioid differentiation in the biphasic histology also remains poorly understood. We report our experience with patients undergoing EPD and the implication of tumor volume and epithelioid differentiation in overall survival.

      Methods:
      We evaluated 116 patients who underwent EPD for MPM. The following variables were assessed: age, gender, histology, tumor volume and pathological T and N stage. The tumor volume of resected specimens was measured using a water displacement method. All histological examinations were performed by a single pathologist, and the percent epithelioid histology was estimated in all patients. A Cox regression model was used to identify significant predictors of survival. Kaplan-Meier was used to summarize overall and subgroup survival.

      Results:
      There were 95 males and 21 females with a median age of 68 years (range 43-88 years). Epithelioid differentiation was 100% in 60 patients, 50-95% in 35 patients, and less than 50% in 21 patients (no patient with pure sarcomatoid histology was included in this report). Mean tumor volume was 642+/- 400ml. Tumor volume was between 100-299cc in 20 patients, between 300-599cc in 37 patients, and >600cc in 54 patients. In 5 patients the volume was not estimated. Six patients (5%) died within 30 days. Two-year survival from EPD was 28%. Median survival was 15.7 months. Percent epithelioid differentiation (p=0.0004) and tumor volume (p=0.001) were significant predictors of survival. T (p=0.05) stage, but not N stage, was a significant predictor of survival. Tumor volume was a predictor of T stage (p=0.05). No relationship between N stage and either tumor volume or histology was observed.

      Conclusion:
      Percent epithelioid differentiation and tumor volume are independent predictors of survival in MPM patients undergoing EPD.

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      MINI38.12 - Multiplex Immunofluorescence Identifies Differences in Immune Microenvironment & Prognostic Biomarkers between Mesothelioma Subtypes (ID 3217)

      T. Seiwert, S. McGregor, C. Shu, I. Feldman, T. Zi, Z. Zuo, A. Khattri, A. Husain, H. Duraid, W.T. Vigneswaran, T.N. Krausz, S. Sathyanarayanan, H.L. Kindler

      • Abstract
      • Presentation
      • Slides

      Background:
      Malignant mesothelioma (MM) is a universally lethal disease, which develops in the pleura, peritoneum, pericardium, and tunica vaginalis. MM is commonly associated with a prominent inflammatory reaction, including extensive macrophage infiltration. Early reports indicate presence of tumor infiltrating lymphocytes (TILs), PD-L1 expression (Kindler et al ASCO 2014), and activity of anti-PD-1 therapy (Alley et al AACR 2015). However, quantitative evaluation of multiple immune markers in a large mesothelioma cohort and evaluation of prognostic and biologic implications has not been reported.

      Methods:
      We performed multiplex immunofluorescence (IF) staining and automated, quantitative density assessments in a clinically annotated cohort of 109 malignant mesotheliomas (58 epithelioid, 43 biphasic, 8 sarcomatoid). Staining for PD-1, PD-L1 (immune checkpoint), FOXP3 (T-regulatory cells), and CD8 (TILs) was performed using a quantitative, multiplex IF system (TissueFax), and a multi-tumor-validated, quantitative StrataQuest analysis algorithm in order to identify specific immune cells and respective densities. Gene expression data (TCGA) was analyzed to confirm individual correlations. Staining for CD206 (macrophages) is ongoing.

      Results:
      PD-L1 density correlated with more aggressive histology, and was highest in sarcomatoid (median density score of 3016), and biphasic (2720) tumors compared with epithelioid tumors (1740). Using a cutoff of 5% PD-L1 density by area 19% of epithelioid, 38% of sarcomatoid, and 44% of biphasic tumors were deemed PD-L1 positive. PD-L1 expression exhibited a bimodal distribution (peaks at both high and low PD-L1 densities). Also with the biphasic tumor cohort expression of PD-L1 correlated with worse outcome (P=0.02), while PD-1 and CD8 did not have prognostic implications (and could not distinguish histologic subtypes). By contrast in epithelioid MM CD8 infiltration density showed a trend towards improved prognosis (P=0.06) (and correlated with PD-1 expression), while PD-L1 expression was not prognostic. Interestingly, PD-1/CD8 and PD-L1 expression did not correlate regardless of histology (R=0.02-0.08), suggesting macrophage-driven PD-L1 expression. Gene expression data supported this hypothesis and staining for M2-related macrophage markers is ongoing. In epithelioid tumors FOXP3 T-regulatory cell density showed a trend towards worse prognosis (P=0.07). In biphasic and sarcomatoid tumors prognosis was poor regardless of FOXP3 expression. Data on stromal versus tumor expression patterns is being processed.

      Conclusion:
      In mesothelioma CD8, PD-1, PD-L1 and FOXP3 are widely expressed, with 19% of epithelioid, and 38-44% of sarcomatoid and biphasic tumors showing elevated PD-L1 density. PD-L1 expression correlates with a worse prognosis by subtype and in the biphasic tumor population. In epithelioid tumors PD-1 may indicate better outcome. PD-1 and PD-L1 expression do not correlate with each other in malignant mesothelioma, which relates to pro-tumorigenic macrophages leading to potentially interferon gamma independent PD-L1 expression.

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      MINI38.13 - Survival Outcomes in Malignant Pleural Mesothelioma Patients Fit for Surgery According to Type of Procedure and Completeness of Resection (ID 2786)

      M. Infante, E. Bottoni, E. Morenghi, P.A. Zucali, D. Rahal, A. Morlacchi, A.M. Ascolese, P. Navarria, A. Testori, E. Voulaz, V. Errico, M. Perrino, M. Scorsetti, M. Alloisio

      • Abstract
      • Presentation
      • Slides

      Background:
      The value of surgical treatment for malignant pleural mesothelioma is still an open question. We analysed a surgical series of MPM patients undergoing surgery for MPM in a single institution

      Methods:
      A retrospective analysis was carried out of all surgical patients treated in our Department from 2000 to February 2015. Selection criteria were age<75, performance status 0-1, non-sarcomatoid histology, pretreatment stage I-III, and fit for major surgery. The procedure of choice was extrapleural pneumonectomy (EPP) until 2010 and radical pleurectomy/decortication (PD) thereafter. Patients that were found to be unresectable underwent palliative pleurectomy. The IMIG system was used for pathological staging, complications were scored based on WHO-derived criteria and the Charlson Co-morbidity Index was used to stratify patients.

      Results:
      Radical surgery was attempted in 163 patients: 91 received EPP, 47 underwent PD (1 with macroscopic residual disease) and 25 a palliative pleurectomy. Their main features and survival outcomes are summarized in table 1. Mean age and Charlson score were higher in PD than in EPP patients. A mixed histology was more prevalent in those who received palliative pleurectomy. Complications were equally frequent after EPP and PD but less frequent after palliative surgery. However, EPP patients had a high frequency of early- and late-occurring (30-600+ days postop) pleural sepsis (p=0.002) that had an unfavorable effect on OS (p=0.035). Induction chemotherapy was associated with better outcomes in PD but not in EPP. At multivariate analysis, epithelial histology (p=0.0419, grade 3+ complications (p=0.001) and Charlson index (p=0.001) were associated with better overall survival (OS). PD was associated with better OS compared with palliative pleurectomy (p=0.05), while EPP was not. Figure 1

      EP (%) P/D (%) R2 (%)
      91 47 25
      Mean Age (95% CI) 60 (58 - 61) 65 (62 - 67) 63 (60 - 66)
      Males 66 (72) 31 (66) 22 (88)
      Trimodal** 28 (30.77) 33 (70.21) 6 (24.00)
      Epithelioid 81 (89.01) 46 (97.87) 20 (80.00)
      p-Stage 0-II 18 (19.8) 18 (38.3) -
      p-Stage III 68 (74.73) 20 (42.55) 2 (8.00)
      p-Stage IV 5 (5.49) 9 (19.15) 21 (92.00)
      Grade 3+ Complications 25 (25.47) 12 (25.53) 2 (8.00)
      30-Day Mortality 3 (3.30) 1 (2.13) -
      Median OS (IQI) 19.0 (9.3 - 35.6) 29.9 (13.7 - 35.2) 13.3 (4.7 - 31.6)
      Median DFS (IQI) 11.5 (7.1 - 21.8) 12.1 (6.4 - 19.2) -
      Title table: Patients' features and survival outcomes in surgical MPM patients * Surgery + either chemo or RT, **induction + Surgery + Postoperative radiotherapy, IQI= Interquartile Interval



      Conclusion:
      EPP does not offer a significant benefit while PD may offer an advantage over palliative pleurectomy. The Charlson index is a major independent prognosticator in patients undergoing surgery for MPM.

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      MINI38.14 - Surgery and Not Radiation Improves Survival in Malignant Pleural Mesothelioma (ID 3168)

      A. Wolf, E. Taioli, M. Camacho-Rivera, A. Kaufman, D. Lee, D. Nicastri, K. Rosenzweig, R. Flores

      • Abstract
      • Presentation

      Background:
      Surgery has a controversial role in the treatment of malignant pleural mesothelioma (MPM) as no trial has demonstrated independent survival benefit of surgery. Likewise, there is lack of consensus regarding the role of radiation in MPM. We evaluated whether cancer-directed surgery and/or radiation independently influenced MPM survival in a large population-based dataset.

      Methods:
      The Surveillance, Epidemiology, and End Results database was explored from 1973 to 2009 to identify all cases of pathologically-proven MPM. Age, sex, race, diagnosis year, stage, cancer-directed surgery, radiation, and vital status were analyzed (chemotherapy data not available). The association between prognostic factors and survival was estimated using a Cox proportional hazards model.

      Results:
      There were 14,228 patients with pathologic diagnosis of MPM. On multivariable analysis, female gender, younger age, localized stage, and cancer-directed surgery were independently associated with longer survival (Table). Survival was longer for patients who underwent surgery or surgery and radiation but not for those who underwent radiation only (Figure).

      Table. Association between Patient and Disease Characteristics and Survival
      Variable Category Adjusted HR (95% CI) *
      Sex Male 1 (Ref)
      Female 0.78 ( 0.75-0.82)
      Race White 1 (ref)
      Black 1.07 (0.98-1.16)
      Other 0.99 (0.89-1.09)
      Age (years) continuous 1.24 (1.22-1.26)
      Stage Localized 1 (ref)
      Regional 1.30 (1.21-1.40)
      Distant 1.34 (1.26-1.42)
      Diagnosis year 1973-1989 1 (ref)
      1990-1994 0.91 (0.85-0.97)
      1995-1999 0.86 (0.81-0.92)
      2000-2004 0.86 (0.81-0.91)
      2005-2009 0.80 (0.75-0.84)
      Therapy No radiation or surgery 1 (ref)
      Radiation only 1.17 (1.10-1.25)
      Surgery only 0.65 (0.62-0.68)
      Radiation and surgery 0.69 (0.63-0.75)
      Figure 1



      Conclusion:
      In this study of 14,228 patients over 36 years, cancer-directed surgery was associated with better survival in MPM, independent of other forms of therapy, including radiation. These data support the role of surgery-based therapy as the cornerstone for treatment in this challenging disease.

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      MINI38.15 - Discussant for MINI38.11, MINI38.12, MINI38.13, MINI38.14 (ID 3558)

      H.I. Pass

      • Abstract
      • Presentation

      Abstract not provided

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    ORAL 41 - Immune Biology, Microenvironment and Novel Targets (ID 159)

    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 8
    • +

      ORAL41.01 - Tumor-Infiltrating B Lymphocytes Characterized by CD79a and MUM1 Independently Predict Outcome in Patients with Non-Small Cell Lung Cancer (ID 485)

      R.N. Fischer, A.H. Scheel, S.I. Rothschild, H.A. Schlößer, J. Wolf, R. Büttner, S. Ansén, M.S. Von Bergwelt-Baildon

      • Abstract
      • Presentation
      • Slides

      Background:
      Tumor-infiltrating lymphocytes play an important role in cell-mediated immune-destruction of cancer cells and tumor growth control. For non-small cell lung cancer (NSCLC) a prognostic role of T cell subtypes, natural killer cells and dendritic cells within the tumor stroma has been described. Here, we studied the role of tumor-infiltrating B cells characterized by CD79a (B-cell antigen receptor complex-associated protein alpha chain) and MUM1 surface expression (Multiple myeloma oncogene 1) in patients with NSCLC. To our knowledge, this study represents the so far largest cohort analyzing the prognostic impact of tumor-infiltrating B-cells.

      Methods:
      B cell infiltration was quantified using immunohistochemistry and antibodies to CD79a (Dako, clone JCB117) and MUM1 (Dako, clone MUM1p) on tissue microarrays (TMA) of paraffin embedded tumor sections. Genetic driver mutations were identified by next-generation sequencing and FISH analysis. SPSS version 20 (IBM Corp.) was used for statistical analysis. Chi-square test, Fisher’s exact test, Kaplan-Meier survival analysis and Cox-regression analysis were used as appropriate.

      Results:
      478 tissue samples from NSCLC patients were available for immunohistochemistry. 65% of patients were male, median age was 66 years. 56% had adenocarcinoma and 39% squamous cell histology. 61% of patients had localized disease (stage I/II), 30% locally advanced disease (stage III) and 6% were diagnosed with stage IV. Frequencies of genomic aberrations are listed in Table 1. CD79a and MUM1 positive cells were detected in 40.8% (195/478) and 40.2% (192/478) of the analyzed NSCLC tissue samples, respectively. B cell infiltration was not associated with clinical or histo-pathological characteristics. MUM1 expression was associated with a significantly prolonged overall survival (median OS 54 vs. 40 months, p=0.025). The expression of CD79a showed a trend towards a better outcome (median OS 49 vs. 40 months, p=0.069). In the multivariate analysis B cell infiltration characterized by CD79a/MUM1 positivity was an independent prognostic marker for survival (p=0.045) as was MUM1 expression (p=0.031). Table 1.

      Genomic aberration Number of patients Frequency
      TP53 mutation 136 28.5%
      KRAS mutation 65 13.6%
      FGFR1 amplification 28 5.9%
      PIK3CA mutation 17 3.6%
      EGFR mutation 12 2.5%
      ALK fusion 4 0.8%
      ERBB2 mutation 4 0.8%
      ERBB2 amplificiation 4 0.8%
      ROS1 fusion 2 0.4%
      BRAF mutation 2 0.4%
      DDR2 mutation 2 0.4%
      FGFR2 mutation 1 0.2%


      Conclusion:
      B cell infiltration characterized by immunohistochemical positivity for CD79a and MUM1 represents an independent prognostic marker in NSCLC. This finding supports the hypothesis of a B cell-mediated anti-tumor immunity.

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      ORAL41.02 - Novel Mechanism of Immune-Tolerance and Cancer Metastasis Due to Aberrant Expression of Natural Killer Immunoglobulin-Like Receptors (KIRs) (ID 2199)

      D.C. Chan, Z. Zhang, D. Zheng, T. Chan, J. Dipaola, B. Warren, M. Berg, K. Horwitz, N. Ahn, L. Lanier, P.A. Bunn, Jr

      • Abstract
      • Presentation
      • Slides

      Background:
      Natural Killer (NK) cells are a major defense to eliminate cancer cells. Cancer cells and metastases may have aberrantly expressed KIRs to prevent killing by NK cells. In addition, platelets may inhibit NK killing of cancer cells. Metastatic cancer cells spread through blood vessels where they constantly interact with platelets by forming tumor microemboli and thereby protected from otherwise rapid elimination from host immune defense cells such as NK cells. Here, using an in vivo model of cancer metastasis in athymic nude mice by directly injecting cancer cells into the blood stream, we study the ability of platelets and KIRs in helping cancer cells to escape from immune surveillance and promote metastasis.

      Methods:
      GFP-luciferase tagged human lung adenocarcinoma cell line, H2122-GL, was further transfected with KIR2DL1 (LL454) plasmids. Stable transformants were enriched by cell sorting. In vivo experimental metastasis were performed in both athymic nude mice and in Nbeal2 knockout and wild type C57 black mice, by tail vein injections of H2122 parental and KIR expressing cells, with and without pre-infusion of human platelets. Levels of tumor cells detected in the lung and other sites were closely monitored by bioluminescence imaging at various time intervals, using an IVIS200 imager.

      Results:
      24 hours after tail vein injection of a million parental H2122-GL, as low as 0.4 million photons were detectable in the lungs of nude mice (n=5), while those mice injected with a same number of H2122-GL-KIR2DL1 cells, they produced 1.85 million photons in the lungs, showing a 4.6 fold increase in accumulation of KIR-expressed cancer cells than those parental cells in the lung. When the nude mice were pre-infused with iv injection of human platelets followed by tail vein injection of parental or KIR-expressed H2122 cells, enhancement up to 7 fold of lung metastases of KIR expressed H2122 were detected relative to the parental cells as early as 24 hours. 5 weeks post injection, an enhancement up to 190 fold in bioluminescence intensity was found with KIR expressed cells relative to the parental cells. Interestingly, the enhancement of lung metastases was abrogated when similar experiments were repeated in the NBeal2 knockout mice, whose platelets were nonfunctional due to defective alpha-granules and deficiency in their cargo, including von Willebrand factor, thrombospondin-1, and platelet factor 4. One hour after tail vein injection, both parental and KIR expressed H2122 cells produced same but low number of lung metastases, indicating that the defective platelets in the ko mice had failed to promote lung metastases. In the wild type mice, significantly more KIR expressed H2122 cells were detected in the lung relative to parental cells. However, as expected, these early lung metastases were rejected later by the host intact immune cells.

      Conclusion:
      Our studies demonstrated that metastatic cancer cells acquire immune-resistance by aberrantly express Natural Killer-Cell Immunoglobulin-like Receptors (KIRs) on their surface and that KIR-expressing cancer cells interact more strongly with platelets leading to significantly increase in NK tolerance and enhancing cancer metastases in pre-clinical models.

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      ORAL41.03 - Myeloid Derived Supressor Cells and Their Clinical Relevance in Non-Small Cell Lung Cancer (ID 2946)

      O. Arrieta Rodriguez, R. Morales-Flores, A. Garcia-Vicente, E. Montes-Servín, F. Salinas-Parra, L. Barrera

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is the leading cause of cancer death worldwide and most of the patients are diagnosed with advanced disease. Myeloid-derived suppressor cells (MDSCs) are major contributors to tumor immune tolerance and targeting them can improve antitumor activity.

      Methods:
      We investigated the CD33[+]CD11b[+]CD66b[+]CD15[+]VEGFR-1[hi] MDSCs frequency in 120 non-small cell lung cancer (NSCLC) treatment-naive patients, with stage IIIB and IV of disease. We analyzed 1-year survival and its prognostic significance in relation to outcome analysis as well as its potential immunosuppression over cytotoxic CD8[+] T lymphocytes. The immunophenotyping of cell population was performed with multiparametric technique by flow cytometry.

      Results:
      We found a significant increase compared with controls in: Percentage of CD33[+]CD14[-]CD11b[+]CD66b[+]CD15[+ ](10.4 ± 5.01% vs. 3.1 ± 1.7% P<0.0001); Mean Fluorescence intensity (MFI) of VEGFR on MDSCs (P<0.001); plasma levels of arginase-1 (P<0.01); arginase-1 enzymatic activity (P<0.05); plasma levels of TGF-β (P<0.0001), IL-10 (P=0.0027) and IL-6 (P<0.0001). On the other hand, we found a significant decrease compared with controls in: Plasma levels of IFN-γ (P<0.0001); CD8[+] T cells (P<0.001); CD8[+]T cells IFN-γ production co-cultured with MDSCs (N=10; P<0.001) and MFI of CD3ζ chain (N=10; P<0.05). The percentage of MDSCs was negatively related to the percentage of CD8[+] T cells in the peripheral blood (N=155, R=-0.3045, P=0.0167). Finally, we found an inverse correlation between circulating MDSCs percentages and overall survival (P=0.09).

      Conclusion:
      Our study provides evidence of an increased pool of CD33+CD11b+CD66b+CD15+VEGFR-1hi MDSCs in the peripheral blood of NSCLC patients. The suppressive effect, of MDSCs on CD8+ T lymphocytes, suggests an important role in mediating immunosuppression in NSCLC that should enable the development of a novel biomarker and thus might represent a potential target for therapeutic intervention.

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      ORAL41.04 - Discussant for ORAL41.01, ORAL41.02, ORAL41.03 (ID 3439)

      N.A. Rizvi

      • Abstract
      • Presentation

      Abstract not provided

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      ORAL41.05 - Targeting Phosphatidylserine-Mediated Immune Suppression Enhances the Efficacy of Immune Checkpoint Blockade in Pre-Clinical Tumor Models (ID 1011)

      R.A. Brekken, B. Freimark, J. Gong, C. Baldwin, V. Nguyen, M. Gray, S. Yin, J. Hutchins, A. Schroit, X. Huang

      • Abstract
      • Presentation
      • Slides

      Background:
      Despite substantial progress, only a subset of cancer patients benefit from blockade of the PD-1 immune checkpoint. Multifocal immune suppression in the tumor microenvironment is the underlying cause for the limited efficacy of immune checkpoint blockade. Persistent immune suppression prevents the development of a robust T cell response to tumor specific antigens that is required for effective downstream immune checkpoint blockade. An underappreciated but significant contributor to immune suppression in tumors is the expression of the membrane phospholipid phosphatidylserine (PS) on the surface of tumor cells and tumor-derived microvesicles. PS is recognized by receptors on immune cells where it triggers the secretion of immune suppressive cytokines, prevents the differentiation of myeloid-derived suppressor cells (MDSCs) and inhibits dendritic cell (DC) maturation; events that prevent a productive anti-tumor T cell response. Bavituximab, a chimeric monoclonal antibody that targets PS and inhibits PS-mediated immunosuppressive signaling, drives immune activation by reducing the levels of MDSCs, by polarizing tumor-associated macrophages towards an M1 phenotype and by promoting the maturation of dendritic cells (DCs).

      Methods:
      The efficacy of bavituximab, anti-PD-1 and combination therapy was evaluated in multiple syngeneic, pre-clinical tumor models. Treatment efficacy was determined by inhibition of tumor growth and by immunophenotyping of spleen and tumor infiltrating leukocytes.

      Results:
      The combination of antibody-mediated PS and PD-1 blockade was significantly more effective in reducing tumor burden and promoting immune activation than single agent therapy. Combination therapy increased tumor infiltration of effector T-cells (Teff), increased the Teff:T regulatory cell ratio in the tumor and enhanced Teff function as determined by IFN-γ, TNFα and granzyme B levels associated with Teff cells in the spleen and tumor. Furthermore combined blockade of PS and PD-1 signaling reduced the level of immune suppressive cells (e.g., MDSCs, M2 macrophages, and Treg) in the tumor microenvironment.

      Conclusion:
      These results raise the possibility that PS blockade with bavituximab can enhance the efficacy of anti-PD-1 therapy even in patients with tumors that are unresponsive to single agent immune checkpoint therapy.

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      ORAL41.06 - Transcriptional Profiling of Distinct Macrophage Subsets in Lung Tumor Microenvironment Reveals Their Functional Heterogeneity (ID 3181)

      J.M. Poczobutt, S. De, V. Yadav, H. Li, J. Kwak, T. Sippel, D. Hanson, T.T. Nguyen, M.C. Weiser-Evans, R. Nemenoff

      • Abstract
      • Slides

      Background:
      Lung cancer is the leading cause of cancer-related deaths in both men and women. While extensive research has focused on genetic mutations in neoplastic epithelial cells, it has now become apparent that cancer progression and metastasis involve complex interactions between cancer cells and the cells of the tumor microenvironment. Myeloid cells of mononuclear phagocyte lineage are a significant component of the tumor microenvironment in lung cancer. Depending on the activation state, myeloid cells have been implicated in tumor – promoting processes such angiogenesis, tissue remodeling and immunosuppression, but also in anti-tumor immunity such as supporting immune surveillance and direct cytotoxicity. The goal of this study was to identify distinct populations of monocyte/macrophage cells and to gain insight into their functions through transcriptional profiling.

      Methods:
      We used an orthotopic immunocompetent mouse model, in which Lewis Lung carcinoma cells, a cell line derived from mouse adenocarcinoma, were injected directly into the left lung lobe of syngeneic C57BL/6 mice. Whole left lung lobes bearing primary tumors were harvested at 2 and at 3 weeks after cancer cell injection, together with lungs from uninjected mice. Tissues were processed into single-cell suspensions and analyzed by multi-color flow cytometry. The flow cytometry strategy employed a combination of myeloid specific surface markers such as CD11b, CD11c, CD64, and SiglecF to identify distinct monocyte/macrophage subpopulations. We recovered these cell populations by flow cytometry-based cell sorting, isolated RNA, and performed transcriptional profiling by RNA-seq. Sequencing data were analyzed by TopHat/Cufflinks/CuffDiff software package and EdgeR. To define the lineage of the isolated cells we correlated their transcriptional profiles to published profiles of immune cells from blood and lung of naïve mice. Further, we used hierarchical clustering and web-based bioinformatic pathway analysis tool to discover functions and pathways enriched in specific myeloid populations.

      Results:
      Based on the combination of myeloid markers and transcriptional profiling, we identified 4 distinct populations of monocyte/macrophage cells: MacA, which represent alveolar macrophages, MacB1, which represent a mixture of dendritic cells and Ly6C- monocytes, MacB2, which represent Ly6C+ monocytes, and MacB3, which represent interstitial/infiltrating macrophages. While the numbers of MacA and MacB1 remain unchanged with cancer progression, MacB2 and MacB3 expand rapidly. Pathway analysis indicated that each population of cells regulates distinct functions in the tumor microenvironment, such as lipid metabolism, cytokine or chemokine secretion, production and remodeling of extracellular matrix, antigen presentation.

      Conclusion:
      These data provide critical insights into the heterogeneous nature and diverse functions of myeloid cells in tumor microenvironment of lung cancer. This study has the potential for development of therapeutics that target specific subsets of myeloid cells that could complement conventional cancer-cell-targeted therapies.

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      ORAL41.07 - The Identification of Therapeutic Targets in Lung Cancer Based on Transcriptomic and Proteomic Characterization of Cancer-Testis Antigens (ID 1555)

      D. Djureinovic, B. Hallström, J.S.M. Mattsson, L. La Fleur, J. Botling, L. Fagerberg, H. Brunnström, S. Ekman, E. Ståhle, H. Koyi, M. Lambe, C. Lindskog, E. Branden, F. Pontén, M. Uhlén, P. Micke

      • Abstract
      • Presentation
      • Slides

      Background:
      Most immunotherapeutic modalities are based on the concept that the immune system can attack targets that are specifically expressed in cancer cells. Cancer testis antigens (CTAs) are a group of genes with a broad expression in cancers including non-small cell lung cancer (NSCLC). In normal tissues the expression of CTAs is restricted to immune privileged organs such as testis and placenta. This limited expression in somatic tissues renders CTAs as a valuable group of genes for the exploration of potential immunotherapeutic targets. The aim of this study was to comprehensively explore the CTA repertoire in NSCLC and to try identifying new CTAs.

      Methods:
      RNA sequencing (RNAseq) was performed on 202 NSCLC samples from a consecutive clinical cohort of surgically resected patients. For the analysis of the comprehensive CTA expression profile in NSCLC we used Cancer Testis (CT) Database containing all genes reported as CTAs in the literature. The NSCLC transcriptome was compared to the normal transcriptome comprising of 22 paired normal lung tissues as well as to 122 samples from 32 different normal human tissues. Corresponding protein expression was evaluated by using immunohistochemistry (IHC) on tissue microarrays (TMAs) containing tumor tissue from the same patients as used in the RNA sequencing.

      Results:
      Of the 276 established CTAs, 155 genes (56%) were restricted to testis and placenta among normal tissues and were identified as CTAs. One third (35%) was expressed in at least one of the 202 individual NSCLC cases and 28 of these genes were previously not reported to be expressed as CTAs in NSCLC. Applying stringent analysis criteria on our RNA sequencing data set we identified 61 genes that were expressed in NSCLC and testis or placenta, but not in other normal tissues. Thus, these genes present potential new CTAs. The specific cancer/testis expression of selected genes (ZNF560, TGIF2LX, TFPI2, HMGB3, TKTL1 and STK31) from this group was confirmed on protein level using IHC. Additional analysis revealed that most CTAs were concurrently expressed in adenocarcinoma and squamous cell carcinoma. The expression of a subset of genes was histology dependent, with predominant expression in adenocarcinoma (e.g. XAGE family members) and in squamous cell carcinoma (e.g. MAGE family members).

      Conclusion:
      Our study provides deep sequencing mRNA expression profiles of the whole CTA repertoire in NSCLC. Several CTAs previously identified in other cancers but not analyzed in NSCLC have been identified on both mRNA and protein level. Additionally, we have identified 61 novel genes as CTAs in NSCLC that previously have not been reported as CTAs and several of these were also confirmed on protein level. This data offers the opportunity to design individual therapy options to target single CTAs or CTA clusters.

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      ORAL41.08 - Discussant for ORAL41.05, ORAL41.06, ORAL41.07 (ID 3440)

      R. Herbst

      • Abstract
      • Presentation

      Abstract not provided

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    ORAL 42 - Drug Resistance (ID 160)

    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 7
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      ORAL42.01 - ALK-Rearranged NSCLC Adaptive Cell Plasticity with Early Onset TGFb2 Mediated Precision Drug Escape through PRC-2 Epigenetic Reprogramming (ID 3111)

      P.C. Ma, L. Yin, W. Zhang, I. Shi, X. Wu, J. Phillips, H. Choi, H. Makishima, D. Lindner, Y. Feng, F. Almeida, J.P. Maciejewski, Y. Saunthararajah, Z. Zhang

      • Abstract
      • Slides

      Background:
      ALK-tyrosine kinase inhibitor (ALKi) is currently the standard precision therapy for advanced ALK(2p23)-rearranged (ALK+) non-small cell lung cancer (NSCLC), often with impressive primary responses. Nonetheless, acquired clinical resistance even in excellent/complete responders still develops ultimately with time; thus hampering long term benefits. Classic tumor rebiopsy studies that deciphered drug-resistance mechanisms focused on the “late phase” resistance at time of clinical progression in treated ALK+ NSCLC. These studies identified diverse pattern of drug-resistance mechanisms, including numerous non-dominant secondary drug-resistant ALK kinase mutations (e.g. C1156Y and L1196M), bypass signaling pathways (e.g. EGFR, KIT signaling), ALK gene amplification, and overexpression of microenvironmental factors (e.g. EGF, TGF-α, HGF). The mechanisms underlying the initial and early emergence of drug-resistance under precision therapy are poorly understood.

      Methods:
      EML4-ALK(+) H3122 and patient-derived ALKi acquired resistant biopsied-lung tumor tissue cells were used to investigate drug-escape mechanisms. Stem cell transcription factors QPCR array and RNA-sequencing profiling were performed on H3122 cells under ALKi up to day 14, compared with untreated and drug-washout controls. MTS cell viability assays using ALKis, in vitro and in vivo tissues QPCR assays, as well as in vivo xenograft IHC analyses were also performed. Patient-derived bronchoscopic biopsied NSCLC tissues (Ma0083) during ALKi resistance was procured and propagated in cell culture in accordance with approved institutional protocols.

      Results:
      We identified that H3122 cells displayed cell plasticity and can escape ALKi’s (TAE-684, crizotinib) remarkably early after precision therapy initiation, with augmented prosurvival signaling via upregulated autocrine TGFβ2 signaling, but not TGFβ1 or β3, as early as day 14 post-treatment. We validated using both in vitro and in vivo models the upregulated cascade of tumoral TGFβ2-HOXB3-mitochondrial priming during adaptive drug-escape. The early onset drug-resistant cells were marked by reversible autocrine TGFβ2-mediated transcriptome reprogramming with reversibly enhanced EMT-ness and cancer stemness. Moreover, RNA-seq findings strongly suggest a “reverse Warburg” cell state during adaptive drug-escape. The adaptive cellular plasticity was verified also in patient-derived bronchoscopic biopsied NSCLC tissues (Ma0083) with ALKi resistance. Interestingly, inhibiting mitochondrial priming using dual BCL-2/BCL-xL BH3-mimetics ABT-263 was effective to suppress early drug-escape, but not with the BCL-2-specific agent ABT-199, suggesting BCL-xL is a key target. Importantly, we also identified upregulated HOXB3 expression correlated with the early adaptive drug-resistance cell state, emerged through dynamic remodeling of EZH2/UTX in the polycomb repressive complex-2 (PRC-2). Deregulated EZH2/UTX epigenetic balance impacted the poised chromatin state of HOXB3 promoter H3K27me3/H3K4me3 histone marks. Early drug-escape cell state was correlated with suppressed EZH2 expression, at mRNA and also protein levels, in both in vitro and in vivo models. Finally, our results showed that specific EZH2 inhibitor GSK126 promoted ALKi drug-resistance, while UTX inhibitor GSK-J4 eradicated ALKi adaptive drug-resistance.

      Conclusion:
      Our study findings provide novel insights into the initial emergence and evolution of ALK precision drug-resistance and highlighted the significance of understanding the role of adaptive tumor cell plasticity in the early drug-escape process with important therapeutic implications. Therapeutic modulation of the coordinated EZH2/UTX balance in the PRC-2 complex can profoundly impact ALKi drug treatment outcome.

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      ORAL42.02 - Qualitative and Quantitative Heterogeniety in Acquiring Resistance to EGFR Kinase Inhibitors in Lung Cancer (ID 572)

      K. Suda, I. Murakami, K. Sakai, H. Mizuuchi, K. Sato, K. Tomizawa, K. Nishio, T. Mitsudomi

      • Abstract
      • Presentation
      • Slides

      Background:
      Acquisition of resistance to EGFR- tyrosine kinase inhibitors (TKIs) is one of important issues in lung cancer researches. Several resistance mechanisms have been identified. However, inter-tumor heterogeneity in acquisition of resistance to EGFR-TKIs is currently unclear.

      Methods:
      Eleven autopsied patients who developed acquired resistance to EGFR-TKI monotherapy were included in this study. All patients harbored activating EGFR mutations (exon 19 deletion or L858R mutation), and developed acquired resistance to EGFR-TKI after initial response to the drug. Details of patient characteristics are summarized in Table 1. The resistance mechanisms of seven patients have been reported in our previous analyses (Suda K, et al. Clin Cancer Res 2010, and Suda K, et al. APLCC 2014). In this study, we analyzed acquired resistance mechanisms in twenty-eight tumor samples obtained from the four additional patients using target sequencing technique by next-generation sequencer.

      Results:
      Among eleven patients, four developed T790M EGFR secondary mutation in all TKI-refractory lesions. One patient developed MET amplification in all TKI-refractory lesions. Three patients harbored both TKI-refractory lesions with T790M mutation and those with MET amplification. The other three patients showed respective resistance mechanisms (Table 1).

      Table 1. Summary of resistant mechanisms in eleven patients.
      Pt. ID Age/Sex Pack-Year Resistant Mechanisms TTF (m)
      C1 57/F 0 T790M or MET 13.8
      C2 48/F 0 T790M or MET 11.0
      C3 58/M 34 MET 14.5
      C4 75/M 0 T790M 43.9
      C5 93/F 0 T790M 14.8
      C6 62/M 26 T790M 9.1
      P1 86/F 0 T790M 10.8
      P2 72/M 27 T790M or MET 3.8
      P3 89/F 0 EGFR loss with MET or Unknown 9.0
      P4 84/F 0 Unknown 22.6
      A1 76/F 0 SCLC transformation or T790M 5.0
      In the target sequence analysis, allele count data were further analyzed in tumor samples with T790M mutation, and we observed diverse T790M/activating EGFR mutation allele ratio ranging from 2 – 51%. In the analysis for time to treatment failure (TTF), we observed longer TTF in patients who developed single resistance mechanism compared with those who developed multiple resistance mechanisms (Fig. 1; p = 0.055). Figure 1



      Conclusion:
      In this study, we observed qualitative heterogeneity and quantitative heterogeneity of T790M allele ratio in acquisition of resistance to EGFR-TKIs in lung cancers. Qualitative heterogeneity in resistance mechanisms would have a correlation with TTF of EGFR-TKIs.

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      ORAL42.03 - Discussant for ORAL42.01, ORAL42.02 (ID 3441)

      L. Heasley

      • Abstract
      • Presentation
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      Abstract not provided

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      ORAL42.04 - Rictor Alterations Elicit Mechanisms of Survival Advantage and Resistance to Targeted Therapy in Non-Small Cell Lung Cancer (NCSLC) (ID 2991)

      D. Ruder, V. Papadimitrakopoulou, L. Shen, R. Herbst, L. Girard, J. Wang, G.M. Frampton, V. Miller, J. Minna, W.K. Hong, I.I. Wistuba, J.G. Izzo

      • Abstract
      • Presentation

      Background:
      Rictor (RPTOR independent companion of MTOR, complex 2) is a highly conserved protein and is a critical component for assembly and functionality of the mTORC2 complex. Alterations of the PI3K/mTOR/AKT pathway are hallmark of many cancer types, underscoring the potential important role of Rictor. The goal of our current study was to characterize the functional consequences of genomic alterations of Rictor in advanced refractory NSCLC. Our preliminary data suggest that Rictor alterations have the potential to, not only signal canonically (via activation of AKT), but also provide cancer cells with alternate, more advantageous oncogenic signaling via non-canonical mechanisms.

      Methods:
      We correlated genomic data (DNA next generation sequencing (NGS), Foundation Medicine, Inc) gene expression profiling, and clinical outcome in the context of the ongoing BATTLE-2 clinical trial of targeted therapies in chemo-refractory NSCLC(198 cases). We further (1) surveyed early stage NSCLC cases(230 cases) in The Cancer Genome Atlas (TCGA) database to perform two-way hierarchical clustering comparing gene expression profiling in amplified vs diploid cases; (2) utilized a single-nucleotide polymorphism array to select Rictor amplified and diploid NSCLC cell lines; (3) assessed Rictor protein and RNA expression by Western blot and qRT-PCR, respectively; (4) performed Rictor knockdown (siRNA), and (5) performed drug sensitivity to targeted therapies by MTS assay.

      Results:
      In the Battle-2 cases, we identified 15% of Rictor alterations (9% gene amplifications, 6.6% mutations, non-concomitant). Among the mutations, 1 was mapped to an N-terminal phosphorylation site, while all others are of unknown significance to date. Rictor alterations were significantly associated with lack of 8-week disease control in the AKTi+MEKi therapeutic arm. In the TCGA we found: (1) 10% Rictor amplifications and 3% mutations; (2) significant correlation between amplification and elevated Rictor gene expression; (3) a putative functional gene expression signature associated with Rictor amplification. In diploid cell lines we found concordance between AKT phosphorylation and activation of other downstream mTORC2 targets (i.e. SGK1 and PKCα), but in Rictor amplified cell lines we witnessed a discordant activation of these pathways. Furthermore, following Rictor knockdown in our amplified cell lines, a significant reduction of colony formation, migratory, and invasive potential was seen in a pathway-differential manner. Thus, suggesting that Rictor amplifications may provide survival advantage in select cancer cells by tipping the signaling balance toward a non-canonical oncogenic pathway (AKT-independent[I1] ).Also in a differential pathway manner, Rictor gene amplification and overexpression contributed to resistance to a number of targeted therapies

      Conclusion:
      Rictor alterations may constitute a potential novel mechanism of targeted therapy resistance via the activation of non-canonical signaling pathways. These alterations could define new molecular NSCLC subtypes with distinct biology that expose unique avenues for therapeutic implication. Ongoing studies are exploring therapeutic vulnerabilities, non-canonical signaling and Rictor mutations.

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      ORAL42.05 - <em>SMARCA4</em>/BRG1 Is a Biomarker for Predicting Efficacy of Cisplatin-Based Chemotherapy in Non-Small Cell Lung Cancer (NSCLC) (ID 849)

      E.H. Bell, A.R. Chakraborty, X. Mo, Z. Liu, K. Shilo, S. Kirste, P. Stegmaier, M. McNulty, N. Karachaliou, R. Rosell, G. Bepler, D.P. Carbone, A. Chakravarti

      • Abstract
      • Slides

      Background:
      Adjuvant platinum-based chemotherapy remains a primary treatment of non-small-cell lung cancer (NSCLC); however, identification of predictive biomarkers is critically needed to improve the selection of patients who derive the most benefit. In this study, we hypothesized that decreased expression of SMARCA4/BRG1, a known regulator of transcription and DNA repair, is a predictive biomarker of increased sensitivity to platinum-based therapies in NSCLC. Moreover, this study also sought to confirm the prognostic role of SMARCA4/BRG1 in NSCLC.

      Methods:
      The prognostic value of SMARCA4 expression levels was tested using a microarray dataset from the Director’s Challenge Lung Study (n=440). Its predictive significance was determined using a gene expression microarray dataset (n=133) from the JBR.10 trial, and RT-PCR data from 69 patients enrolled on the MADe-IT trial and 33 platinum-treated patients from an institutional cohort.

      Results:
      In the Director's challenge study, low expression of SMARCA4 was found to be associated with poor overall survival compared to high and intermediate expression (P = 0.006). Upon multivariate analysis, compared to high, low SMARCA4 expression predicted an increased risk of death and confirmed its prognostic significance (HR=1.75; P=0.002). In the JBR.10 trial, improved five-year disease-specific survival was noted only in patients with low SMARCA4 expression when treated with adjuvant cisplatin/vinorelbine (HR 0.1, P= 0.001 (low); HR 1.1 , P= 0.762 (high)). An interaction test showed significance (P=0.007). In addition, a trend toward improved progression-free survival was noted only in patients with low SMARCA4 receiving a carboplatin- versus a non-carboplatin-based regimen in the MADe-IT trial. Figure 1 Fig1. Low SMARCA4 correlates with improved disease-specific survival with adjuvant cisplatin-based chemotherapy in the JBR.10 trial.



      Conclusion:
      Although decreased expression of SMARCA4/BRG1 is significantly associated with worse prognosis, it is a novel significant predictive biomarker for increased sensitivity to platinum-based chemotherapy in NSCLC patients.

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      ORAL42.06 - Cancer Stem Cells: Targeting Aldehyde Dehydrogenase 1 (ALDH1) as a Novel Strategy in Cisplatin Resistant Non-Small Cell Lung Cancer? (ID 2724)

      L. Mac Donagh, S.G. Gray, K.J. O'Byrne, S. Cuffe, S.P. Finn, M.P. Barr

      • Abstract
      • Presentation
      • Slides

      Background:
      Cisplatin is the backbone of chemotherapeutic treatment of lung cancer. Unfortunately the development of resistance has become a major challenge in the use of this cytotoxic drug. Understanding the mechanisms underlying this resistance phenotype may potentially result in the development of novel agents that may enhance the sensitivity of cisplatin chemotherapy in the clinical setting. The root of this resistance is hypothesized to be due to the presence of a rare cancer stem cell (CSC) population within the tumour that can reform a heterogenic tumour, resulting in recurrence and resistance following cisplatin chemotherapy.

      Methods:
      An isogenic model of cisplatin resistance was established by chronically exposing a panel of NSCLC cell lines (H460, SKMES, H1299) to cisplatin for 12months, thereby creating cisplatin resistant (CisR) sublines and their corresponding age-matched parental (PT) cells. To identify a CSC population within the resistant sublines, PT and CisR cell lines representing the three classifications of NSCLC were stained for ALDH1 using the Aldefluor kit (Stemcell Technologies). ALDH1 positive (+ve) and negative (-ve) subpopulations were isolated and their functional characteristics assessed. Proliferation and survival of ALDH1+ve fractions in response to cisplatin was assessed using BrdU and clonogenic survival assays relative to ALDH1-ve cells. ALDH1 subpopulations were examined for asymmetric division and expression of the human embryonic stem cell markers Nanog, Oct-4, Sox-2, Klf-4 and c-Myc and CD133. To confirm that this ALDH1+ve population is associated with cisplatin treatment, PT and CisR cells were chronically exposed to high dose cisplatin for 2 weeks and stained for ALDH1 and re-assessed for stemness qualities. Apoptosis and clonogenic survival of PT and CisR cells was assessed in response to selective inhibition of ALDH1 using diethylaminobenzaldehyde (DEAB) in combination with cisplatin. Xenograft studies in NOD/SCID mice are currently under investigation to examine the tumourigenic potential of isolated subpopulations of ALDH1.

      Results:
      A significant ALDH1+ve population was detected in CisR sublines, but not in their PT counterparts. Characterisation of the ALDH1+ve subpopulation confirmed enhanced expression of stemness markers, increased resistance and clonogenic survival in response to cisplatin compared to their ALDH1-ve counterparts, and the ability to asymmetrically divide. Chronic cisplatin treatment of the PT cell lines for 2 weeks increased resistance to cisplatin, increased stemness marker expression and induced the emergence of an ALDH1+ve population. Chronic high dose cisplatin treatment significantly expanded the ALDH1+ve population in the CisR cell lines. Importantly, inhibition of ALDH1 activity, with DEAB, decreased the mean cell viability, clonogenic survival capacity and increased cisplatin-induced apoptosis of the CisR cells when used in combination with cisplatin, an effect not seen in the PT cells.

      Conclusion:
      In this study, we have demonstrated the existence of a putative CSC population within our model of isogenic cisplatin resistant cell lines and suggest a role for ALDH1 inhibition as a potential therapeutic strategy in re-sensitizing chemoresistant lung cancer cells to the cytotoxic effects of cisplatin. Further studies will focus on re-purposing of FDA-approved ALDH1 inhibitor, Disulfiram (Antabuse), used in the treatment of chronic alcoholism as a potential combination therapy to prime chemoresistant cells to cisplatin.

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      ORAL42.07 - Discussant for ORAL42.04, ORAL42.05, ORAL42.06 (ID 3442)

      S. Yano

      • Abstract
      • Presentation

      Abstract not provided

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    ORAL 43 - Enhancing Physical Wellbeing in Lung Cancer (ID 168)

    • Type: Oral Session
    • Track: Nursing and Allied Professionals
    • Presentations: 8
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      ORAL43.01 - Guideline for Patient Information on Enhanced Recovery in Thoracic Surgery (ID 185)

      J. Mitchell

      • Abstract
      • Presentation
      • Slides

      Background:
      On behalf of the Thoracic Surgery Group, National Lung Cancer Forum for Nurses The Thoracic Surgery Group is a sub-group of the National Lung Cancer forum for Nurses with a membership of thoracic nurse specialists, lung cancer nurse specialists, research nurses and allied health professional. The objective of the group is to develop links to other health professionals working within the specialism of thoracic surgery to enhance the care and support of patients undergoing surgical procedures for suspected or confirmed thoracic malignancies. The group has previously produced guidelines on supporting patients having lung resection surgery and telephone follow-up following thoracic surgery. Enhanced recovery is an approach to the care of patients undergoing surgery that aims to ensure that patients are in the best possible condition for surgery, have the best possible management during and after their operation, and experience the best post-operative rehabilitation. Patients on enhanced recovery programs are partners in their care pathways. This guideline has been developed, by a multi-professional group, to provide guidance to healthcare professionals involved in providing patient information on enhanced recovery programs.

      Methods:
      Following a literature review and review of practice in UK thoracic surgery centers the group have developed this guidance on the information required by patients undertaking an enhanced recovery program. Guidance is provided about: Thoracic surgery enhanced recovery program information Written patient information Verbal patient information Information about the enhanced recovery pathway Information about thoracic surgery Patient diary Quality assurance and patient information

      Results:
      Central to the enhanced recovery concept is the involvement, empowerment and partnership with the patient. Evidence shows that patients participating in enhanced recovery programs have fewer post-operative complications and reduced rates of readmission. To increase understanding of the enhanced recovery pathway it is vital that patients are provided with relevant information. The aim of this guideline is to support the provision of patient information regarding enhanced recovery programs so that patients are in partnership with healthcare professionals thereby improving patient experience and clinical outcomes. This guideline is based on evidence available and identified best practice in UK thoracic surgical centers.

      Conclusion:
      The guideline is relevant to all thoracic surgery centers that are running or wish to set up an enhanced recovery program, it could also be adapted for other surgical specialties. This guideline is a series of broad statements and where necessary local procedures should be developed to complement the guideline in each clinical area. This document compliments the ‘Guideline for Telephone Follow-up for Patients Undergoing Thoracic Surgery’ and the ‘Guideline to Prepare and Support Patients Undergoing Lung Resection’ also produced by the Thoracic Surgical Group. All of the guidance produce by the group are available on the National Lung Cancer Forum for Nurses (NLCFN) website

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      ORAL43.02 - Which Patients Are Assessed by a Lung Cancer Nurse Specialist: A UK National Lung Cancer Audit Study (ID 1258)

      A. Khakwani, R.B. Hubbard, P. Beckett, D. Borthwick, A.M. Tod, A. Leary, J. White, L.J. Tata

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer nurse specialists (LCNS) are an integral part of the multidisciplinary team, supporting, managing and coordinating of care for people with lung cancer. In the UK the National Institute of Health and Care Excellence (NICE) recommends that all patients have access to a LCNS in a trust, but recent National Lung Cancer Audit (NLCA) reports show that LCNS access varies across England. The aim of this study was to examine how access to a LCNS varies by patient and National Health Service (NHS) trust characteristics.

      Methods:
      We used data on all lung cancer patients in the NLCA first presenting to 150 English NHS trusts between January 1[st] 2007 and December 31[st] 2011. NHS trusts are health care organisations typically 1-3 hospitals collectively covering regional catchment populations. The NLCA collects key clinical information, including LCNS assessment on all individuals with a diagnosis of lung cancer presenting to NHS trusts. Data from 146/150 trusts were successfully linked with the National Cancer Action Team (NCAT) census of the LCNS workforce (number, salary grades) for 2011. Multinomial logistic regression was used to calculate the likelihood of being assessed by a LCNS by patients clinical and LCNS workforce at each trust.

      Results:
      Across 146 NHS trusts there were128,124 patients and 321 LCNSs. LCNS assessment records showed80,113 (62%) patients were assessed, 7,544 (6%) were not assessed, and 40,467 (32%) had missing information on assessment. Missing assessment information was random and not biased to certain types of patients or trust and data completeness increased over the years. Patients (>75 years old), those with poor performance status (i.e. PS 4) and those with comorbidities were less likely to be assessed (adjusted relative risk ratios (RRR) (95% confidence interval) 0.84 (0.75 – 0.93), 0.34 (0.24 – 0.47) & 0.71 (0.63 – 0.79) respectively). There was no difference in assessment rates by socioeconomic groups. Patients who received anti-cancer treatment (surgery, chemotherapy with radiotherapy or chemotherapy alone) were over twice likely to have been assessed by a LCNS compared with those who did not receive treatment 2.09 (1.75 – 2.50), 3.96 (3.11 – 5.04) & 3.45(2.71 – 4.38). Annual LCNS patient caseload did not appear to impact access, but there was an association between assessment and a higher salary grade of the LCNS workforce in a trust (RRR 1.59 (0.86 – 2.92) for trusts with LCNS salary band 7 & 8).

      Conclusion:
      We found variations in access to LCNSs by both patient and trust a feature, which indicates an unmet need for people with lung cancer in England. To meet the needs of all people with lung cancer and the clear targets set out by NICE, we need to expand the current LCNS workforce and ensure that we retain experienced nurses as LCNS are an integral part of the lung cancer team and provide help to people with lung cancer.

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      ORAL43.03 - The Rationale of Exercise in Patients with Inoperable Lung Cancer (ID 2554)

      M. Quist, S. Langer, L. Adamsen, M. Roerth

      • Abstract
      • Presentation
      • Slides

      Background:
      Patients with lung cancer often experience severe physical and psychological symptoms, such as decreased exercise capacity, muscle weakness, compromised health-related quality of life (HRQOL) and increased anxiety and depression levels, as a direct consequence of the disease or the antineoplastic therapy. The main concern of patients with lung cancer is the fear of losing independence and not being able to perform daily activities. In recent years, several studies show that exercise training is safe, feasible and beneficial for patients with inoperable lung cancer. Results have shown increased physical capacity, increases muscle strength and functionality, and reduced anxiety and depression levels.

      Methods:
      This presentation will focus on the rationale of exeicse in patients with inoperable lung cancer and will present results from the EXHALE study, a prospective, clinical and explorative study.

      Results:
      Patients showed significant improvement in physical capacity, functional capacity, muscle strength and “emotional well-being”, as well as a significant reduction in “social well-being” and the level of anxiety. No serious adverse events (SAE) or adverse events (AE) were reported.

      Conclusion:
      This presentation will document that the patients with inoperable lung cancer are able to complete a six-week exercise and relaxation intervention without exercise-related SAE. In addition we can conclude that patients with inoperable lung cancer can increase VO2max, functional capacity (6MWD)and muscle strength significantly. We also found that the intervention significantly reduced the patients’ level of anxiety. The patients did not improve their HRQOL significantly, but we did observe a significant improvement in emotional well-being

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      ORAL43.04 - Discussant for ORAL43.01, ORAL43.02, ORAL43.03 (ID 3447)

      M. Davies

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ORAL43.05 - Development and Evaluation of Health and Wellbeing Events for People Affected by Lung Cancer (ID 891)

      S. Moore, M. Johnson, N. Doyle, B. Quinn, L. Askins, D. Brown, L. Eldridge, M. Evans, R. Hargreaves, B. Hartley, L. Hutton, K. Jones, C. L'Hermenier, J. Vick, T. Wiseman

      • Abstract
      • Presentation
      • Slides

      Background:
      In the UK, Health and Wellbeing Events for people with cancer have developed as part of the National Cancer Survivorship Initiative. They are aimed at supporting people living with and beyond cancer to live as healthy and active lives as possible for as long as possible (Richards et al 2011). They are designed to provide an opportunity for people with cancer and their family members to gain information and support, to help them manage the consequences of cancer and make positive life-style changes where appropriate (NCSI 2013). Early pilot work suggests events of this kind may not only benefit attendees in terms of improved levels of knowledge, confidence and physical and emotional wellbeing, but may also lead to more appropriate use of services, and potentially reduce unplanned consultations and admissions. However, to date, much of this early work has been in the context of breast and urological cancers, and there has been little exploration and evaluation of events aimed specifically at helping people affected by lung cancer (Office for Public Management/Macmillan Cancer Support 2011). The poster will address this knowledge deficit by reporting data from an ongoing collaborative project undertaken at three London NHS Foundation Trusts. The project aims to develop and evaluate a series of Lung Cancer Health and Wellbeing Events. Specifically, data will describe the process of developing and delivering events for people with lung cancer, and identify the perceived feasibility, acceptability and usefulness of these events from the perspective of attendees (patients and their family members/close friends) and professionals involved in organising the events.

      Methods:
      Design: A prospective mixed method service evaluation including; 1) Event attendance rates and demographics (i.e. patient/family member, gender, age, ethnicity), 2) Participants’ perceptions of how useful the events are (using questionnaires administered immediately after the event and at 4-6 weeks), 3) Health professionals’ perceptions of the usefulness and impact of the events (using questionnaires and group discussions), 4) Analysis of the costs and resources required to host the events (e.g. professionals' time, administration and organisation, additional financial expenditure etc). Analysis: Descriptive statistics and qualitative thematic analysis will be used.

      Results:
      The poster will present data from the first two events held in 2015. At the time of writing, intial analysis from the first event suggests that although only a small proportion of patients with lung cancer may choose to attend these kinds of events (7% of 257 invited) , the experience of attendees (patients and family members) is reported as largely positive. For example, 71% (15/21) found the event ‘quite’ or ‘very helpful’ and 91% (20/22) would recommend it to others in a similar situation. Initial feedback from professionals is also positive whilst elucidating the resource required to develop and deliver events.

      Conclusion:
      Health and Wellbeing Events are a recent initiative in the UK to help support people living with and beyond a diagnosis of cancer. This poster will present results of an evaluation of lung cancers-specific events. The findings will indicate their feasibility, acceptability and accessibility to patients and family members, Implications for future service development and delivery will be discussed.

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      ORAL43.06 - Improving Surviorship through Prehabiltiation for Thoracic Cancer Patients (ID 43)

      K.J. Clayton, V. Beattie, J. Roberts, A. McIver, J. Draffen, M. Guerin, D. Hodges, K. Bridges

      • Abstract
      • Presentation
      • Slides

      Background:
      Prognosis for lung cancer is poor, with 5 year survival of 8.8% in men and 11.1% in women. (MCS 2013) It is essential to enhance performance status and timely access to treatment. NICE recommends that patients have access to specialist services from the start of the pathway. This includes the expertise of the Lung CNS (DOH 2011). It is essential that people with a thoracic malignancy have their health and wellbeing maximised before diagnosis and treatment decision to improve outcomes and quality of lie. The Lung CNS’s management of the pathway leads to improved treatment outcomes (NLCA 2013)

      Methods:
      Lung CNS’s have a consensus that pre-diagnosis services are currently ad hoc and inequitable. The NLCFN undertook literature reviews using key words “PREHABILITATION & LUNG CANCER”; this did not identify any significant results. The search was therefore widened to include “PULMONARY DISEASE”. This showed that the most common co morbidity associated with lung cancer was COPD. To understand Lung CNS practice, a short electronic survey was devised and distributed to all NLCFN members.

      Results:
      118 Lung CNS’s responded to the questionnaire (34%). Questions covered current practice with regard to: Symptom control, health promotion, co-morbidity management Availability of assessment tools. Availability of support/pre- rehabilitation services

      Conclusion:
      Following the literature search and questionnaire, the NLCFN devised a prompt checklist. This aide memoire captures key areas of assessments at pre-diagnosis to enable effective referrals to appropriate services which will ultimately improve the patients’ health and wellbeing in preparation for treatment.

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      ORAL43.07 - Performance Status (PS): Is There a Correlation Between Doctor and Patient? (ID 203)

      K.J. Clayton, L. Creech, K. Cannon, S. Iyer, M. Babores

      • Abstract
      • Presentation
      • Slides

      Background:
      PS is a very useful marker which is used to determine suitability for treatment on patients with lung cancer. Previous studies have shown good correlation between PS and survival. To assess the correlation between the Respiratory specialist (consultants and SpRs) and the patient’s own assessment.

      Methods:
      A random selection of patients attending our Rapid Access Lung Clinic were given, prior to the consultation with the doctor, the ECOG guidelines and were asked to score themselves.

      Results:
      50 patients were given the questionnaire but one preferred not to answer it. The results are reflected in the table below:

      Identical score 21 / 50 (42%)
      Patient score higher than doctor 14 / 50 (28%)
      Patient score lower than doctor 4 / 50 (8%)
      Not documented by doctor 11 / 50 (22%)
      from Rapid Access Lung clinic on the same day without a diagnosis of malignancy Out of the patients that scored themselves higher than the doctors, only 2/ 14 gave themselves All the patients that did not have a PS documented by the doctor were discharged a score two points higher.

      Conclusion:
      Although nearly half of the scores between patients and doctors were the same there is a significant number of patients that scores themselves higher than the medical professionals. This is likely to be a combination of the fact that the doctors could be overlooking some co-morbidities and that they are keen to give the patient the best opportunity for treatment.

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      ORAL43.08 - Discussant for ORAL43.05, ORAL43.06, ORAL43.07 (ID 3448)

      B. Ivimey

      • Abstract
      • Presentation

      Abstract not provided

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