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T. Nakano



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    P1.01 - Poster Session 1 - Cancer Biology (ID 143)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.01-025 - Apoptosis-Related Gene Transcription in Human A549 Lung Cancer Cells via A<sub>3 </sub>Adenosine Receptor (ID 2157)

      15:06 - 15:20  |  Author(s): T. Nakano

      • Abstract

      Background
      Extracellular adenosine induces apoptosis in a variety of cancer cells via diverse signaling pathways. The present study investigated the mechanism underlying adenosine-induced apoptosis in A549 human lung cancer cells.

      Methods
      MTT assay, TUNEL staining, flow cytometry using propidium iodide and annexin V-FITC, real-time RTPCR, Western blotting, monitoring of mitochondrial membrane potentials, and assay of caspase-3, -8, and -9 activities were carried out in A549 cells, and the siRNA to silence the A~3 ~adenosine receptortargeted gene was constructed.

      Results
      Extracellular adenosine induces A549 cell apoptosis in a concentration(0.01-10 mM)-dependent manner, and the effect was inhibited by the A~3~ adenosine receptor inhibitor MRS1191 or knocking-down A~3~ adenosine receptor. Like adenosine, the A~3~ adenosine receptor agonist 2-Cl-IB-MECA also induced A549 cell apoptosis. Adenosine increased expression of mRNAs for Puma, Bax, and Bad, disrupted mitochondrial membrane potentials, and activated caspase-3 and -9 in A549 cells, and those adenosine effects were also suppressed by knocking-down A~3~ adenosine receptor.

      Conclusion
      Adenosine induces A549 cell apoptosis by upregulating expression of Bax, Bad, and Puma, to disrupt mitochondrial membrane potentials and to activate caspase-9 followed by the effector caspase-3, via A~3~ adenosine receptor.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P1.14-012 - Activation of mTOR signal pathway is associated with prolonged survival in malignant pleural mesothelioma patients (ID 2715)

      09:30 - 09:30  |  Author(s): T. Nakano

      • Abstract

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

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

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

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

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    P2.14 - Poster Session 2 - Mesothelioma (ID 196)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P2.14-005 - Assessment of postoperative complications after the first all Japan multi-institutional trial of induction chemotherapy followed by extrapleural pneumonectomy for malignant pleural mesothelioma (ID 1517)

      09:30 - 09:30  |  Author(s): T. Nakano

      • Abstract

      Background
      The first all Japan multi-institutional trial was completed to evaluate the feasibility of induction chemotherapy using pemetrexed plus cisplatin, followed by extrapleural pneumonectomy (EPP) and postoperative hemithoracic radiation in patients with resectable malignant pleural mesothelioma (MPM). The main results were presented at the ASCO 2013. In this study, we especially reviewed major postoperative complications and mortality of patients who underwent EPP and determined the risk factors responsible for adverse outcomes.

      Methods
      From 2008 to 2010, 42 patients with MPM were enrolled in this study. Thirty-nine patients received planed chemotherapy. Thirty-three patients proceeded to EPP, which was completed in 30 patients. These patients were candidates in this study. Major complications were defined by grade 3, 4, 5 events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Treatment-related death was defined as any death occurring within 84 days after operation. Logistic regression analysis was performed on preoperative variables for major adverse outcomes.

      Results
      A total of 17 institutions in Japan with certified specialists in oncology, surgery and radiation therapy participated in this trial. Thirty patients (29 male, 1 female; median age of 66 years, range 43–74) completed EPP (14 right-sided and 16 left-sided), and macroscopic complete resection was accomplished in all patients. Histology of the tumors was epithelial in 22, biphasic in 4, sarcomatous in 1, and others in 3. Median operation time and blood loss were 437 minutes (range, 335-655) and 1461 gram (range, 390-4530), respectively. Major postoperative complications developed in 73.3% of the patients, and treatment-related death occurred in 4 patients (13.3%), which causes were cardiac herniation (n = 1), ARDS (n = 2), bronchial fistula and ARDS (n = 1). There were no significant predictors for major postoperative complications and treatment related death in both univariate and multivariate analysis.

      Conclusion
      We cannot find the predictor of major adverse events and treatment related death in MPM patients treated with induction chemotherapy followed by EPP. Although that is why sample size is small, we also recognize that multimodality treatment including EPP for MPM has more than 10% mortality and should be included in a prospective trial at specialized centers.