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Y. Satoh



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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-045 - Validation Study of Postoperative Platinum-based Adjuvant Chemotherapy for Japanese Patients with Completely Resected Pathological StageIIIA Non-small Cell Lung Cancer (ID 2608)

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

      • Abstract

      Background
      In the Japanese Clinical Practice Guideline for Lung Cancer, postoperative platinum-based adjuvant chemotherapy in patients with pathological stage IIIA (p-stage IIIA) non-small cell lung cancer (NSCLC) is recommended (grade B). However, the verification of the effect of adjuvant chemotherapy in Japanese patients is not sufficient. In this study, we aimed to validate the effectiveness of platinum-based adjuvant chemotherapy for p-stage IIIA NCSLC.

      Methods
      Between January 2002 and December 2009, we retrospectively reviewed records of patients with completely resected p-stage IIIA NSCLC in our institution. Exclusion criteria include the patients with oral anticancer drug, tegafur and uracil (UFT), >75 years old, large cell neuroendocrine carcinoma and pleomorphic carcinoma. The primary endpoint of this study was progression-free survival. Cumulative survival curves were estimated with the Kaplan-Meier method and compared with the log-rank test. Multivariable analysis was performed with the Cox proportional hazards regression model to estimate the independent prognostic effect of adjuvant chemotherapy on prognosis by adjusting for confounding factors.

      Results
      Sixty-seven patients (median age, 63 years; 40 men, 27 women) were eligible. 49 patients had adenocarcinoma and 18 had squamous cell carcinoma. 63 patients underwent lobectomy and 4 patients had pneumonectomy. Of the 33 patients with platinum-based adjuvant chemotherapy regimens, 16 had cisplatin plus gemcitabine, 13had carboplatin plus paclitaxel, and 4 had cisplatin plus vinorelbine. Five-year progression-free survival (PFS) and 5-year overall survival (OS) in the adjuvant chemotherapy group versus in surgery alone group were not statistically significant (5-year PFS rates were 28% and 31%, respectively; p = 0.69, and 5-year OS rates were 54% and 40%, respectively; p = 0.10). Multivariate analysis showed that platinum-based adjuvant chemotherapy did not affect patient prognosis significantly (HR, 0.70; 95% CI, 0.37-1.32; p=0.27).

      Conclusion
      Our date showed that platinum-based adjuvant chemotherapy in patients with p-stage IIIA NSCLC did not have such impact on our patient’s prognosis as we could understand in daily medical practice. Although there were some limitations of this study, we feel a strong need for searching more effective chemotherapy regimens or individualized treatment strategies.

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    P3.01 - Poster Session 3 - Cancer Biology (ID 147)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.01-002 - Dendritic Cells Promoted the SDF-1-expressing Premetastatic Niche Formation in Mediastinal Lymph Node Metastasis for Lung Cancer via COX-2-derived PGE<sub>2</sub>-EP3 Signaling. (ID 1400)

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

      • Abstract

      Background
      Lung cancer is the most widespread cause of cancer death in the world. COX-2 derived prostaglandin E~2~ (PGE~2~) is well known to induce tumor growth and metastasis, and thus is associated with a poor prognosis. Lymph node metastasis is also one of the major determinant of the prognosis and is facilitated by lymphangiogenesis, however the precise of the mechanisms is not well understood. In the presenr atudy, we investigated the role of COX-2-derived PGE~2~ on formation of premetastatic niche facilitate the lymph node metastasis in Lung Cancer. Lung cancer is the most widespread cause of cancer death in the world. COX-2 derived prostaglandin E~2~ (PGE~2~) is well known to induce tumor growth and metastasis, and thus is associated with a poor prognosis. Lymph node metastasis is also one of the major determinant of the prognosis and is facilitated by lymphangiogenesis, however the precise of the mechanisms is not well understood. In the presenr atudy, we investigated the role of COX-2-derived PGE~2~ on formation of premetastatic niche facilitate the lymph node metastasis in Lung Cancer.

      Methods
      Male C57BL/6 (6-8 weeks-old, Wild type; WT) and EP3 knockout mice (EP3[-/-]), one of PGE~2~ receptor subtype, were used. Orthotopic intrapulmonary implantation model was made by injecting Lewis Lung Carcinoma (LLC 5.0X10[6] cells/ml) cells into the lung. We estimated the expressions of lymphangiogenic factors, SDF-1/CXCR4, subtypes of EP receptors by immunehistochemical staining, ELISA and real time PCR. The accumulation of immature dendritic cells (iDCs) and regulatory T cells (Tregs) were estimated by immunofluolecent analysis. Furthermore, we estimated the role of iDC on lymph node metastasis by injecting iDCs.

      Results
      The expression of COX-2 and SDF-1, and accumulation of iDCs and Tregs were increased before LLC cell accumulated in lymph node. Compared to vehicle mice, mediastinal lymph node metastasis formations were suppressed with a COX-2 inhibitor (celecoxib, 100mg/kg/day, p.o., P<0.05). Compared to other PGE~2~ subtype receptors, the expression of EP3 receptor was significantly suppressed in celecoxib treated mice (P<0.05). The expression of lymphangiogenesis markers and lymph node metastasis were suppressed in EP3[-/-]. The expression of SDF-1 and accumulations of CD11c[+]DCs and FOXP3[+]Tregs in lymph nodes were significantly suppressed in EP3[-/-] (P<0.05). In vitro study, under PGE~2~ stimulation, the SDF-1 conentration and expression of EP3 in culutured iDCs were significanltly enhanced compared to control. Furthrmore, WT transplanted with EP3[-/-]BM were significantly suppressed mediastinal lymph node metastasis formation compared to WT transplanted with WT mice.

      Conclusion
      These results suggested that premetastatic niche formation in mediastinal lymph node was induced by bone marrow derived immatured dendritic cells via PGE~2~-EP3 signaling by induction of SDF-1-expression. Thus, COX-2 inhibitors, CXCR4 antagonists and/or EP3 antagonists may become one of the options to suppress the lymph node metastasis.

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    P3.02 - Poster Session 3 - Novel Cancer Genes and Pathways (ID 149)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.02-002 - Identification of CpG island methylator phenotype predicts the prognosis of small cell lung cancer (ID 42)

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

      • Abstract

      Background
      Small cell lung cancer (SCLC) accounts for 13-15% of new lung cancer cases in worldwide and has the poor therapeutic outcomes with a median survival of just over one year. A CpG island methylate phenotype (CIMP) is well known as a methylator phenotype with characteristic promoter DNA methylation alterations, in colorectal cancers, glioblastoma and breast cancers, although there has been no report about any CIMP of SCLC. We investigated whether DNA methylation profiles can provide useful molecular subtyping of SCLC in terms of etiology and prognosis of SCLC.

      Methods
      We analyzed 28 fresh frozen samples from pure SCLC patients and 13 noncancerous lung tissues. All patients underwent surgical lung resection at the Cancer Institute Hospital, nine patients among them were treated with chemotherapy before surgery. After genomic DNA was treated with sodium bisulfite, bisulfite-converted genomic DNA was analyzed using Illumina’s Infinium HumanMethylation27 BeadChip. And, total RNA was extracted from twenty-five SCLC tumor samples and mRNA expression of these samples were analyzed by Agilent’s SurePrint G3 Human CGH Microarray. Next, we matched these two data sets by Gene Symbol, and identified fifty-five most differentially methylated CpG sites (corresponding to 46 genes) with a FDR p value cut off of 0.05. Gene ontology analysis was performed using DAVID Bioinformatics Resources.

      Results
      We selected a total of 1741 most differentially methylated CpG sites (s.d. > 0.20) across the 28 SCLC tumor tissues in each DNA methylation platform, after an elimination of the probes related with the X- and Y- chromosome. Unsupervised hierarchical clustering of methylation data from SCLC samples reveals two major subgroups with different prognosis: the 5 years disease-free interval (DFI) rate of patients in cluster 1 (11.1%) was lower than that of patients in cluster 2 (61.57%) (p = 0.001). By multivariate analysis for DFI, both postoperative chemotherapy and cluster 1 were a significant prognostic factor (p = 0.002 and 0.002; respectively). Next, among 1220 genes with methylation and expression data both available, the CpG sites were ranked on the basis of the spearman’s correlation coefficient between cluster 1 and cluster 2 into an ascending order. Finally, we identified that fifty-five CpG sites were nagetively correlated and found that apoptosis pathway was a most differentially expressed.

      Conclusion
      By comprehensive DNA methylation profiling, two distinct subgroups with different molecular and clinical phenotype were identified to evoke a CIMP of SCLC. We found some promoter markers in the apoptosis pathway could make a difference between the two groups, and we hope that our data can contribute to provide a useful resource for the construction of therapeutic strategy and the development of a new chemotherapeutic agent.