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Y. Nakanishi

Moderator of

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    O12 - Lung Cancer Biology II (ID 87)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Biology
    • Presentations: 8
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      O12.01 - Prospective isolation of human lung stem/progenitor cells and their role in the initiation of lung cancer (ID 1716)

      10:30 - 10:40  |  Author(s): C.E. Weeden, K. Viitaniemi, G. Ramm, J. Ciciulla, I. Bertoncello, M. Asselin-Labat

      • Abstract
      • Presentation
      • Slides

      Background
      Cells of origin of cancers acquire the first genetic aberration(s) that lead to tumourigenesis. An understanding of the cell of origin in different subtypes of lung cancer could allow earlier detection of malignancies and more effective treatment. Stem or progenitor cells are likely tumour initiating cells due to both their longevity, allowing for accumulation of genetic lesions, and their capacity for renewal. This study aims to isolate human lung progenitor subpopulations based on their differential expression of cell surface markers to evaluate their role as the cell of origin of the different subtypes of lung cancer.

      Methods
      Single cell suspensions were generated from adjacent normal tissue of patients undergoing lung cancer resection. Epithelial cells were immediately separated based on their expression of cell surface markers by fluorescence activated cell sorting (FACS). The progenitor cell capacity of epithelial cell subsets was then assessed using an in vitro colony forming assay. Subsets with progenitor activity were analysed for their expression of differentiated lung cell markers both before and after colony formation.

      Results
      We have identified a sort strategy that allows for enrichment of basal cells, Clara cells, type I and II pneumocytes from fresh human lung tissue as shown by qPCR and electron microscopy data. The basal cell and type II pneumocyte subpopulations consistently formed colonies in vitro - cell types that have previously shown progenitor activity in the mouse lung. The Clara cell and type I cell compartment did not consistently form colonies. Basal and type II cells formed phenotypically distinct colonies when cultured in a three-dimension matrix that expressed different lung specific markers (p63, SP-C…) as shown by RT-PCR analysis and immunofluorescence staining.

      Conclusion
      This study has demonstrated the prospective isolation of four epithelial cell subsets from fresh human lung tissue for the first time and confirmed the progenitor activity of basal cells and type II cells in the human lung. We are currently comparing the genetic profile of these human lung progenitor cells with the genetic profile of molecular subtypes of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) using next generation sequencing. Future studies aim to transform lung progenitor cells with genetic alterations common in NSCLC and SCLC to further establish their role as cells of origin of these cancers.

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      O12.02 - Pathway Analysis of Gene Expression Profiles that Distinguish Persistent from Regressive Bronchial Dysplasia Indicate Synergistic Role for Polo-Like Kinase 1 (PLK1) and Epoxide Hydrolase 3 (EPHX3) in Malignant Progression. (ID 3334)

      10:40 - 10:50  |  Author(s): D.T. Merrick, M.G. Edwards, W. Franklin, M. Sugita, Y. Miller, M. Friedman, L. Dwyer-Nield, M. Tennis, K. Choo, G. Hickey, T. Kennedy, A. Van Bokhoven, L. Heasley, F.R. Hirsch, P.A. Bunn, M. Geraci, R.L. Keith, R. Nemenoff

      • Abstract
      • Presentation
      • Slides

      Background
      160,000 Americans die from lung cancer annually and the prognosis for invasive lung cancer is poor. Prevention of cancer represents an approach with high potential for significant reduction in mortality. Bronchial dysplasia (BD) is a precursor lesion of squamous cell carcinoma (SCC) of the lung, and persistent BDs represent a high risk subset of these lesions. Genomic instability is an important process underlying malignant progression. Gene expression microarray analyses were used to identify potential mediators of genomic instability in persistent BD and study their activity in these high risk lesions. Two genes, PLK1, which abrogates G2-M checkpoint DNA damage repair, and EPHX3, which converts tobacco smoke derived pro-carcinogens to mutagens, were selected for further analysis.

      Methods
      Sixty-three frozen baseline biopsies were classified into persistent/progressive BD, regressive BD , progressive non-dysplasia and stable non-dysplasia groups according to the presence or absence of BD on follow-up biopsies. H&E staining was performed on frozen sections to confirm histology, and RNA was harvested for global gene expression microarray analysis. Intergroup comparisons employed ANOVA statistical analysis with a false discovery rate of 10% to identify differentially expressed genes associated with persistence and gene expression alterations related to baseline histology used Spearman correlation coefficient cutoff of r= +/- 0.5. A pathway analysis (Ingenuity) using the persistence related genelist was performed to identify active pathways associated with persistence of BD. Validational studies were performed by quantitative RT-PCR in cell lines established from persistent and regressive bronchial sites. Inhibitors of persistence associated enzymes were used in tissue culture based assays of cellular proliferation.

      Results
      Gene expression analyses support the unique biological nature of persistent BD. Intergroup comparisons showed significant numbers of differentially expressed genes only in the comparisons of persistent BD with regressive BD (318 genes) or stable non-dysplasia (6254 genes). 831 genes showed differential expression associated with increasing baseline dysplastic grade regardless of outcome. While approximately half of these genes also differentiated persistent from regressive BD, the presence of numerous persistence related genes that are independent of histology further substantiates the unique high risk nature of persistent BD. A pathway analysis revealed “mitotic roles of PLKs” as having the most significant association with persistence. Quantitative RT-PCR using cultures of 8 persistent BD and 6 regressive BD validated increased expression in persistent BD of PLK1 (2.77X, p=0.002) and EPHX3 (2.36X, p=0.081). Using a classification of dysplastic specimens as high or low expressers of PLK1 and/or EPHX3 (high > mean), we found a significant direct relationship with increased level of outcome diagnosis score: low expression of both genes (2.58); high expression of only one gene (3.60); and high expression of both (5.06). The baseline diagnosis did not differ between groups. Culture of the SCC cell line H2009 with EPHX inhibitor revealed a non-significant trend toward decreased proliferation (80.4% vs untreated).

      Conclusion
      Gene expression data confirms the biologically distinct nature of persistent BD. PLK1 and EPHX3 overexpression demonstrate a cooperative effect in respect to increased outcome histology suggesting a potential role for these enzymes in persistence/progression of BD via promotion of genomic instability.

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      O12.03 - Pseudogenes as miRNA sponges in non-small cell lung cancer (ID 3455)

      10:50 - 11:00  |  Author(s): G.L. Stewart, K.S. Enfield, S. Lam, W.L. Lam

      • Abstract
      • Presentation
      • Slides

      Background
      Lung cancer is the most common cause of cancer death worldwide, with a five-year survival of less than 15%. This poor therapeutic outcome is largely due to complex molecular backgrounds as well as typically late stage at diagnosis, with most patients presenting with unresectable local tumours or metastatic disease. While mutations of driver genes is a well known mechanism of tumorigenesis, approximately half of all non-small cell lung cancer (NSCLC) tumours harbour no known actionable oncogenic drivers, emphasizing the need to explore alternative mechanisms. New sequencing technologies have allowed investigation of previously unexplored areas of the genome and revealed that several classes of non coding RNAs (ncRNAs), those with no protein product, are involved in tumourigenesis, emphasizing the need for further exploration and study. MicroRNAs (miRNAs) have emerged as major players in lung carcinogenesis, displaying both oncogenic and tumor suppressive functions through translational inhibition of genes containing miRNA target sequences. Pseudogenes are non-coding relatives of protein-coding genes that contain a high degree of sequence similarity with their parent genes, thus sharing many of the same miRNA target sequences. As a result, when overexpressed, a pseudogene can function as a miRNA "decoy" protecting its parent gene from miRNA-mediated translational inhibition. DNA copy number (CN) alterations (gain of oncogenes/loss of tumour suppressors), is a major molecular mechanism driving cancer. Like protein coding genes, CN alterations can influence ncRNA expression levels, and several pseudogenes have been reported to be deregulated at the CN level in other cancer types. We hypothesize that pseudogenes of lung cancer-related genes are deregulated at the CN level in NSCLC.

      Methods
      Global CN profiles for 83 lung adenocarcinomas, and 12 squamous cell carcinomas, as well as paired adjacent non-malignant tissues were generated on the Affymetrix SNP 6.0 array. Frequencies of DNA CN alterations were assessed at candidate pseudogene loci (gain>2.3 copies, loss<1.7 copies). Candidate pseudogenes (1) have a parent gene that has been previously reported to play a role in cancer biology, (2) are expressed in human tissue, and (3) share at least one conserved miRNA binding site with its parent gene.

      Results
      Several pseudogenes for OCT4 (octamer-binding transcription factor 4), an early embryonic transcription factor, were found to be frequently gained (46.9-34.9%), and could protect OCT4 from miRNA-mediated translational inhibition. Additionally, pseudogenes for E2F3 (E2F Transcription Factor 3), a potent cell cycle regulator, as well as those for the well known lung cancer oncogene BRAF, were found to have high frequencies of CN alteration (36.1%, and 19.2%, respectively). These high frequencies of alteration suggest that these pseudogenes play an important role in NSCLC.

      Conclusion
      These results suggest that pseudogenes are clonally selected for at the DNA level, and pseudogene-mediated protection of oncogenic transcripts from miRNA-mediated translational inhibition may represent a novel mechanism of oncogenicity in NSCLC. Analyses of pseudogene expression and corresponding parent gene protein level in cell models will yield insight into how this class of ncRNA affects tumourigenesis, potentially leading to improvements in early detection, diagnosis, and treatment.

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      O12.04 - DISCUSSANT (ID 3896)

      11:00 - 11:15  |  Author(s): K. Sutherland

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      O12.05 - Defining the role of ZEB1 in the pathogenesis of non-small cell lung cancer (NSCLC) using immortalized human bronchial epithelial cells (HBECs) (ID 1139)

      11:15 - 11:25  |  Author(s): J.E. Larsen, J.K. Osborne, A. Augustyn, J.P. Sullivan, M. Sato, L. Girard, A.F. Gazdar, J.D. Minna

      • Abstract
      • Presentation
      • Slides

      Background
      To study the role of common lung cancer mutations in transforming lung epithelial cells in an appropriate cellular context we used cdk4/hTERT-immortalized normal HBECs. We developed an isogenic series of HBECs by introducing genetic manipulations representing common lung cancer mutations (such as p53, KRAS[V12], cMYC, and LKB1). This defined in vitro system allows characterization of specific tumorigenic contributions as well as identification of acquired changes, likely representing tumor acquired vulnerabilities and novel therapeutic targets (Mol Cancer Res 2013). One acquired change observed with oncogenic transformation of HBECs is a spontaneous epithelial-to-mesenchymal transition (EMT), an important biologic process in cancer. This study sought to characterize the role of EMT in driving tumorigenesis in HBECs and, in turn, lung cancer to identify novel therapeutic targets.

      Methods
      Genetic manipulations were introduced into cell lines using siRNA/shRNA or over-expression constructs. Tumorigenicity was measured using in vitro (anchorage-dependent and -independent colony formation, proliferation, migration and transwell Matrigel invasion assays) and in vivo (subcutaneous or intravenous injection into NOD/SCID mice) methods. Genome-wide mRNA expression data from five independent datasets was obtained either in-house using Illumina HumanHT-12v4 BeadChips or from publicly available databases.

      Results
      Analysis of EMT-promoting transcription factors in our isogenic series of oncogenically-manipulated HBECs found ZEB1 expression highly correlated with mesenchymal-like HBECs. Functional studies confirmed ZEB1 was a significant driver of tumorigenic phenotypes in both oncogenic HBECs and human lung cancer cell lines where loss of ZEB1 resulted in decreased colony formation, migration and invasion in vitro and subcutaneous tumor growth and intravenous colonization in vivo. A set of ZEB1-associated genes was identified from analyzing five independent mRNA microarray datasets comprising both cell lines and lung adenocarcinomas. From this gene set we found ZEB1 directly represses ESRP1 by binding to its promoter, which leads to increased mesenchymal splicing of the ESRP1 target CD44. The mesenchymal isoform of CD44, CD44s, conferred a CD44[hi] flow cytometry profile which, in turn, could be used to select for a highly tumorigenic subpopulation in partially transformed HBECs. To identify candidate ZEB1-activated targets we screened ZEB1-upregulated genes in a siRNA invasion assay. Several genes including PMP22 and CD70 could phenocopy ZEB1 where siRNA-mediated loss of expression led to decreased invasiveness in multiple NSCLC cell lines. CD70 (also called TNFSF7, tumor necrosis factor ligand superfamily member 7) may represent a prime therapeutic target for anti-metastatic growth in lung cancer. The ligand for CD27, it is involved in immune regulation, upregulated in some cancers and is being studied as a potential target for antibody therapeutics. Importantly, an anti-CD70 monoclonal antibody inhibited invasion of NSCLC cell lines comparably to siCD70 and siZEB1.

      Conclusion
      We demonstrate in vitro models of defined oncogenic HBEC transformation provide an invaluable tool to study lung cancer progression where EMT is an important mediator. ZEB1 is spontaneously expressed with malignant transformation of HBECs and is a significant driver of oncogenic progression in both HBECs and NSCLC cells. Identification of CD70 and PMP22 as downstream targets of ZEB1 may represent novel therapeutic targets for lung cancer.

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      O12.06 - Hedgehog/Gli Promotes Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (ID 2091)

      11:25 - 11:35  |  Author(s): H. Li, D. Yue, T.H. Tseng, D.M. Jablons, T. Cheng, B. He, M.J. Mann

      • Abstract
      • Presentation
      • Slides

      Background
      A majority of non-small cell lung cancer (NSCLC) patients are diagnosed with metastatic phenotypes. Epithelial-to-Mesenchymal Transition (EMT), characterized by loss of epithelial markers, such as E-cadherin, is suggested to be involved in the metastatic process. In addition, aberrant activation of the Hedgehog-Gli(Hh/Gli) signaling pathway is implicated in various cancers, including NSCLC. We hypothesize that the Hh/Gli signaling pathway may regulate EMT in NSCLC, and inhibition of Hh/Gli pathway may provide a novel strategy to treat NSCLC and prevent metastasis.

      Methods
      Tumor tissues of 324 NSCLC patients were analyzed by immunohistochemistry for Gli and E-cadherin expression. Mechanistic studies were carried out in four NSCLC cell lines, A549, H1666, H2170 and H1703. Our lab has developed a novel small molecule Gli inhibitor (Gli-I )that effectively suppresses lung cancer in vitro and in vivo. Gli-I and a Smoothened inhibitor vismodegib were applied to suppress Hh/Gli signaling, while Hh protein was utilized to stimulate the pathway. Upon different treatments, EMT phenotypes were evaluated by wound healing assays and 3D cell invasion assays. Expression of EMT markers was measured by immunofluorescent staining and western blot at protein levels, as well as quantitative RT-PCR at mRNA levels.

      Results
      Our results demonstrated elevated Gli expression in 78% of NSCLC patient tissues. Gli expression was reversely correlated with E-Cadherin in patient tissues and culture cell lines. Inhibition of Hh signaling reduced cell migration and invasion, while stimulation of Hh signaling promoted EMT phenotypes. Specifically, Gli-I significantly suppressed cell proliferation, migration and invasion more effectively than vismodegib. Furthermore, mechanistic studied showed Hh/Gli signaling may regulate EMT through suppressing E-Cadherin.

      Conclusion
      Our results suggested that SHh/Gli signaling promotes cell proliferation and EMT, leading to NSCLC cell invasion and metastasis. Inhibition of Hh/Gli signaling by a novel Gli inhibitor Gli-I suppresses cell proliferation and invasion. Our novel Gli inhibitor holds the promise to provide an effective therapeutics to treat NSCLC and prevent metastasis.

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      O12.07 - Pulmonary fibroblasts increase EMT signaling and decrease sensitivity to chemotherapy in non-small cell lung cancer cells via TGF-beta and IL-6 signaling (ID 265)

      11:35 - 11:45  |  Author(s): Y. Shintani, A. Abulaiti, T. Kimura, S. Funaki, T. Nakagiri, M. Inoue, N. Sawabata, M. Minami, E. Morii, M. Okumura

      • Abstract
      • Presentation
      • Slides

      Background
      The tumor microenvironment is a key factor in tumor progression. A specific subset of stromal cells, termed cancer associated fibroblasts (CAFs), modulate the behavior of adjacent cancer cells by secreting various growth factors and cytokines. The purpose of this study was to clarify the roles of transforming growth factor (TGF)-β and interleukin (IL)-6 in the communication between CAFs and non-small-cell lung cancer (NSCLC) cells.

      Methods
      Fibroblasts obtained during surgical exploration were co-cultured with human lung adenocarcinoma cell lines. We defined fibroblasts obtained from tumors as CAFs and those from normal lung tissue as lung normal fibroblasts (LNFs). Immunohistochemistry was used to examine the fibroblast distribution, as well as TGF-β and IL-6 expression in 60 tumor specimens obtained from patients with NSCLC after undergoing induction chemotherapy or chemoradiotherapy (ITx).

      Results
      The expression levels of myofibroblast markers were higher in CAFs than LNFs after 5 passages in the absence of continuing interaction with carcinoma cells, and we used at least 2 pairs of those CAFs and LNFs in the following experiments. Conditioned medium (CM) from both types of fibroblasts induced epithelial mesenchymal transition (EMT) and acquisition of cancer stemness in lung cancer cells (A549 and NCI-H358), indicating it to be biologically active. Phenotypic changes of cancer cells by CM from CAFs were greater than those induced by CM from LNFs. These CAF-induced changes were inhibited by addition of the TGF-β inhibitor SB431542 or IL-6 receptor neutralizing antibody (IL6-R-Ab). The concentrations of TGF-β1 and IL-6 were higher in CM from CAFs as compared to that from LNFs. Subcutaneous co-injection of lung cancer cells and CAFs in mice enhanced tumor growth when compared with cancer cells alone, which was attenuated by administration of SB431542 or IL-6R-Ab. These findings suggested that CAFs may be more activated in our experimental system as compared to LNFs, and stimulate tumor progression via TGF-β and IL-6 signaling. In addition, decreased expression of epithelial markers and upregulation of mesenchymal markers were detected in surgically resected specimens after ITx as compared with biopsy specimens obtained before treatment. The disease-free survival rate of patients with EMT marker-positive tumors was significantly lower than that of those with EMT marker-negative tumors, indicating that EMT changes are associated with insensitivity to ITx. Furthermore, an increased diffuse distribution pattern of SMA-positive activated fibroblasts was significantly correlated with the expression of EMT markers. Also, though SMA-stained fibroblasts expressed IL-6 in the surgical specimens, TGF-β was expressed in cancer cells as well as CAFs after ITx. Together, our results suggest that tumor stromatic tissues including CAFs increase in response to ITx, while CAFs secrete TGF-β and IL-6, inducing EMT in cancer cells.

      Conclusion
      The TGF-β and IL-6 axis induces EMT and stimulates tumor progression, while TGF-β and IL-6 may play roles to contribute to communication between CAFs and NSCLC cells for tumor progression. Targeting CAFs as a therapeutic strategy against cancer is an intriguing concept that would benefit from further study.

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      O12.08 - DISCUSSANT (ID 3897)

      11:45 - 12:00  |  Author(s): J. Minna

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    G02 - Global Lung Cancer Coalition (GLCC) Session: Deserve Better - Expect Better: Advocating for Better Outcomes for Lung Cancer Patients (ID 15)

    • Event: WCLC 2013
    • Type: Other Sessions
    • Track: Nurses
    • Presentations: 1
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      G02.3 - Clinicians as Advocates: Raising Public Awareness of Lung Cancer - The West Japan Oncology Group Experience (ID 441)

      16:52 - 17:08  |  Author(s): Y. Nakanishi

      • Abstract
      • Presentation
      • Slides

      Abstract
      Background: In Japan and Asian countries, patient advocacy has not been popular to citizens and government, especially in patients with lung cancer compared to USA and EU countries. Therefore, a few clinicians had played a role as advocate instead of cancer survivors group or governments. Clinicians as advocates have a certain advantage to give professional information by themselves, with trained communication skill about bad news, and to use medical resources which is involved to medical society for lung cancer or hospital. West Japan Oncology Group (WJOG), non-profit organization which was established in 2000 by volunteer oncologists, has the mission to conduct and support multi-center clinical co-operative study for cancer and to provide the information about lung cancer, the importance and necessity of clinical study for standard treatment widely, therefore to contribute improving social welfare. Methods: To achieve the mission of WJOG, we carried out open lecture in city hall in major city every year and published lecture recordings in newspaper as well DVD video distribution. In another way, we planed to publish the guideline book for the patients with lung cancer and revised in five years interval. The board of directors determined the plan and the guideline editors committee was organized by WJOG member in March, 2006. The committee edited constitution, drafting, plan, writing as an enterprise in 2006, and 2011. Questions and answers style was adopted in accordance to previous US guidebook . Results: In these 12 years, 27 times of open lecture were held and medical specialists for oncology, novelists with cancer, representative or president of organization for patients advocacy, and etc gave lecture and discussed with patients. Nearly two to eight hundred people had participated in each meeting, occupied by most women and senior citizens. The questionnaire survey to participant revealed satisfaction for lecture and expectation for next meeting. The contents of lecture appeared full page in the Asahi which has a large circulation of almost 8 million (the second position in the world) as well as DVD-video was distributed widely to institute participating to our study and patients for the purpose of providing larger citizens with useful information. Furthermore WJOG official web site show the detail of each lecture in Japanese because Japanese patients with lung cancer are old and difficult to read English web site. Last year, second edition guideline book for patients was edited which consists of 118 questions and answers with full color 200 pages, as well posted to the WJOG website. GLCC international quantitative survey in 2010 showed that Japan is one of the countries with the greatest proportion of adults who think lung cancer is the biggest killer Conclusions: It seems that patient advocacy is developed to be more popular through open lecture, newspaper, web site and guideline book even in Japan. This method may be one of the ways to raise public awareness of lung cancer in Asian countries.

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    MO03 - Thymic Malignancies (ID 123)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO03.10 - A multicenter prospective study of carboplatin and paclitaxel for advanced thymic carcinoma: West Japan Oncology Group 4207L (ID 987)

      11:25 - 11:30  |  Author(s): Y. Nakanishi

      • Abstract
      • Presentation
      • Slides

      Background
      Thymic carcinoma (TC) is a rare malignant tumor originated within the thymus gland and is associated with a poor prognosis, differing from thymoma which is the most common type of thymic malignant neoplasm. No results of clinical trials focusing on TC have been reported. This single-arm study evaluated carboplatin and paclitaxel (CbP) in previously untreated patients (pts) with advanced TC.

      Methods
      Pts with Masaoka’s stage III to IVb TC, ECOG PS 0 to 1, and more than 20 years old were eligible. The study treatment consisted of carboplatin (AUC 6) and paclitaxel (200 mg/m2) every 3 weeks for a maximum of 6 cycles. The primary endpoint was objective response rate (ORR) by extramural assessment. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. All pts were followed-up until 24 months (mo) after last enrollment. Based on the SWOG 2-stage design, the planned sample size of 40 pts was determined to reject the ORR of 20% under the expectation of 40% with a power of 0.85 and a type I error of 0.05.

      Results
      From May 2008 to November 2010, 40 pts were enrolled from 21 centers. Of 39 evaluable for analysis, the median age was 62 years (range, 36–84); 23/16 males/females; 3/10/26 with Masaoka’s stage III/IVa/IVb; 9/11/19 with squamous cell carcinoma/poorly differentiated neuroendocrine carcinoma/other types. The median number of cycles was 6. There was 1/13 complete/partial responses with an ORR of 36% (95% confidence interval [CI], 21-53%; P = 0.031). The median PFS was 7.5 mo (6.2-12.3 mo) while OS did not reach the median value. The 1-year and 2-year survival rates were 85% (95% CI, 69-93%) and 71% (95% CI, 54-83%), respectively. Major adverse event was grade 3-4 neutropenia in 34 pts (87%). Two cases (5%) of grade 3 febrile neutropenia, neuropathy, and arthralgia were observed, respectively. There was no treatment-related death.

      Conclusion
      CbP showed high efficacy in advanced TC. Our results established that CbP, one of the standard treatments for non-small cell lung cancer, also serves as a key chemotherapy regimen for TC.

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    MO24 - NSCLC - Chemotherapy III (ID 110)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO24.11 - A prospective multicenter observational study of chemotherapy induced nausea and vomiting in lung cancer patients (ID 862)

      11:30 - 11:35  |  Author(s): Y. Nakanishi

      • Abstract
      • Presentation
      • Slides

      Background
      Chemotherapy-induced nausea and vomiting (CINV) is one of the major causes to deteriorate patient’s quality of life. Therefore, it is important to assess the current status of CINV nationwide for the appropriate treatment method to manage CINV. For this purpose, prospective multi-center observational study was performed in Japan.

      Methods
      Between 2011/Apr and 2012/Dec, 458 lung cancer patients who underwent systemic chemotherapy with high (HEC) or moderate emetogenic agents (MEC) were registered and the data in 429 patients were analyzed. CINV status was assessed in acute phase (within 24 hours from chemotherapy start) and late phase (after 24 hours) separately. Multivariate analysis was performed to clear the predictive factors in patient background for CINV.

      Results
      Patient background was as follows; median age 65, 318 male and 111 female patients, 190 patients treated with HEC and 239 with MEC. In acute phase, nausea and vomiting were observed in 5.6% (HEC 6.8%, MEC 4.6%) and 1.2 % (HEC 0.5%, MEC 1.7%) of all patients, respectively. In late phase, nausea and vomiting were observed in 40.1% (HEC 46.3%, MEC 35.2%) and 9.6 % (HEC 7.9%, MEC 10.9%) of all patients, respectively. The frequency of nausea in late phase is significantly higher in HEC than that in MEC. The predictive factors for nausea were a younger age in female patients, and younger age, no drinking history, decreased hemoglobin in male patients. The prediction of CINV by physician was relatively poor in late phase vomiting.

      Conclusion
      In this study, the current status of CINV and antiemetic therapy in lung cancer patients in Japan were elucidated. CINV was frequently observed in late phase and the appropriate management for late emesis is needed according to the guideline.

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    O09 - General Thoracic Surgery (ID 100)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Surgery
    • Presentations: 1
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      O09.02 - Clinicopathological characteristics and surgical results of lung cancer patients aged up to 50 years: the Japanese Lung Cancer Registry Study 2004 (ID 83)

      16:25 - 16:35  |  Author(s): Y. Nakanishi

      • Abstract
      • Presentation
      • Slides

      Background
      Since the incidence of lung cancer death increases from 50 years-old, the surgical results of young lung cancer patients remains unclear.

      Methods
      Seven hundred and four patients with lung cancer, aged up to 50 years, were enrolled from among the 11,663 patients registered in the Japanese Lung Cancer Registry Study 2004, and their clinical data were compared with those of 10959 patients older than 50 years.

      Results
      In the young/old groups, pneumonectomy was performed in 5.7%/3.2%; adjuvant therapies were given preoperatively in 10.4%/4.7% (p<0.001) and postoperatively in 31.4%/24.5% (p<0.001). The proportions of patients with p-stage IIIA and adenocarcinoma histology were higher in the young group. The 5-year overall survival rate (5Y-OS) was 94.8%/86.2% for p-stage IA (p<0.001), 87.0%/73.2% for p-stage IB (p=0.001), 61.0%/61.6% for p-stage IIA (p=0.595), 71.0%/48.4% for p-stage IIB (p=0.003), 49.6%/39.4% for p-stage IIIA (p=0.020), and 80.0%/24.8% for p-stage IIIB (p=0.012); it was 83.5%/80.7% for females (p=0.106) and 75.1%/62.3% for males (p<0.001) in the young/old groups. The postoperative survival was significantly better with all operative procedures in the young group. The 5Y-OS after recurrence was better in the young group (17.9%, p=0.016). In the young group, the 5Y-OS was better in females (83.5%) than in males (75.1%, p=0.002), and for patients with adenocarcinoma (80.3%) than for those with squamous cell carcinoma (68.5%, p=0.013). Age up to 50 years was identified as an independent prognostic factor on multivariate analysis. Figure 1

      Conclusion
      The postoperative survival in lung cancer patients aged up to 50 years was better than that in patients older than 50 years.

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    P2.22 - Poster Session 2 - Epidemiology, Etiology (ID 167)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P2.22-001 - Japanese Nation Wide Lung Cancer Registries conducted by the Japanese Joint Committee of Lung Cancer Registry (JJCLCR) (ID 66)

      09:30 - 09:30  |  Author(s): Y. Nakanishi

      • Abstract

      Background
      The Japanese Joint Committee of Lung Cancer Registry (JJCLCR) is jointly established by the Japan Lung Cancer Society, the Japanese Respiratory Society, the Japanese Association for Chest Surgery and the Japan Society for Respiratory Endoscopy, conducting Japanese nation-wide registries of lung cancer patients

      Methods
      In 1999, 2004 and 2009, registries were conducted for surgical patients in 1994, 1999 and 2004, respectively. In 2002, both surgical and non-surgical (non-biased) patients in 2002 were registered with a follow up period of 3 years or more. In 2012, a registry has been conducted for non-surgical patients in 2012 with a follow up period of 3 years. In 2016, surgical patients in 2010 will be registered. These registries were observationally assessed.

      Results
      Registries for surgical cases in 1994, 1999 and 2004 which were conducted in 1999, 2004 and 2009 revealed the trend of increase in mean age, rates of female, the aged, small sized lesion, adenocarcinoma and stage I, and that of decrease in the rate of perioperative death. Furthermore proposals for TNM classification were stated as peer reviewed papers- invasion to visceral pleura, chest wall and fat tissue in the mediastinum for T factor. In addition, status of N2 disease were assessed resulting in that highly selected cases (3.8%) were subjected to surgery or surgery-included multimodal therapy with a 5-year survival rate of 30.1% in cN2/pN2-Stage IIIA and it was better than previous registries. Registry for surgical and non-surgical patients in 2002 revealed that stage-specific prognosis was within a range similar to other reports and stage, gender, surgery and performance status were independent prognostic indicator of both non-small and small cell lung cancer. Registry of non-surgical cases in 2012 was conducted and greater than 8,000 cases were registered. In this study, status of usage of FDG-PET scan for staging, EGFR gene mutation and individual therapy were, and prognosis of patients will be registered. In up-coming registry for surgical cases in 2010 which will be performed in 2016, new parameters- the size of tumor regarding non-invasive regions in adenocarcinoma (ground grass opacity in computed tomography), quantitative assessment of lymph node metastasis (the number of metastasized lymph node) as a prognostic indicator, which may be assessed as factors of TNM classification in the future. Besides, the TNM classification will be revised in 2016 according to the proposal from IASLC staging project, to which the JJCLCR offered data of 47,306 cases (approximately 25% of whole world wide cases) from the recent 4 registries.

      Conclusion
      The JJCLCR conducted nation-wide lung cancer registry in Japan, revealing the condition of the treatment of lung cancer and contributing to the TNM staging program.

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    P3.09 - Poster Session 3 - Combined Modality (ID 214)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P3.09-007 - Update data of biomarker analysis of WJOG4107 (A randomized phase II trial of adjuvant chemotherapy with S-1 versus CDDP+S-1 for resected stage II-IIIA non-small cell lung cancer (NSCLC)) (ID 1504)

      09:30 - 09:30  |  Author(s): Y. Nakanishi

      • Abstract

      Background
      We conducted a randomized phase II trial for patients with resected stage II-IIIA NSCLC comparing postoperative oral S-1 (80 mg/m2/day for consecutive 2 weeks q3w for 1 year) (S) (N=100) or cisplatin (CDDP) (60 mg/m2 day1) plus oral S-1, (80 mg/m2/day for 2 weeks) q3w for 4 cycles (PS)(N=100). We reported that disease free survival rate at 2 years (DFS@2) (95% confidence interval: CI), a primary endpoint, was 66 (55-74) % for S and 58 (48-67)% for PS. Here, we report the preliminary results of preplanned biomarker analysis, a co-primary endpoint, to identify molecules whose expression is significantly associated with patient outcome.

      Methods
      　cDNA extracted from macro-dissected formalin-fixed paraffin-embedded specimens were available for 197/200 patients. Thirty-one genes including those whose expressions have been potentially associated with　CDDP (e.g. ERCC1, XRCC1, BRCA1, GSTpi, HMG1, TBP) or fluorouracil (FU) sensitivity (TS, DHFR, DPD, UMPS, UPP1) were measured by QGE analysis (MassArray, Sequenom, CA). Additional analysis are being performed to assess ERCC1 isoform expression with an isoform-specific TaqMan probe (Applied Biosystems, CA). The expression of each gene was dichotomized according to its median value.

      Results
      Molecules such as ERCC1 and GSTpi whose expression have been previously associated with CDDP sensitivity did not emerge as predictive markers (P=0.7908, 0.6406, respectively). We quantitated ERCC1 by isotype (202 and 204 cannot be distinguished). There was a trend in patients with high 201 or 202/204, CDDP/S-1 was worse than S-1.

      Conclusion
      Quantitation of ERCC1 by isotype may define a patient subset that would benefit from postoperative platinum therapy.