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T. Tsujimura



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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. Tsujimura

      • 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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    P2.01 - Poster Session 2 - Cancer Biology (ID 145)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.01-005 - Diagnostic application of 9p21 Homozygous and Heterozygous Deletion Detected by Fluorescence in Situ Hybridization (FISH) and p16 Real-Time PCR in Malignant Mesothelioma (ID 1162)

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

      • Abstract

      Background
      Background: Detection of homozygous deletion of the 9p21 locus, the site of the CDKN2A/p16 gene, is useful in differentiating reactive mesothelial hyperplasia (RMH) from malignant pleural mesothelioma (MPM) in pleural effusion cytology, biopsy specimens, and surgical specimens. However, the cutoff value for 9p21 FISH varies. Furthermore, 9p21 FISH reveals not only homozygous deletion, but also heterozygous deletion, in MPM tissue samples, and only two studies have evaluated heterozygous deletion. The aim of this study was to establish a FISH cutoff value for 9p21 homozygous deletion and apply it to a clinical diagnosis. In addition, we investigated the significance of 9p21 heterozygous deletion in MPM.

      Methods
      Design: Ninety-five histopathological (49 MPM + 47 RMH) and 35 cytological (15 MPM + 20 RMH) cases were studied. Cutoff values were evaluated as mean + 3SD based on the results of RMH 9p21 FISH. The copy number of the p16 gene was analyzed in 22 MPM tissue samples and 17 RMH by real-time PCR, using RSP6 as a control gene, and samples were divided into three groups (1.0: no deletion, 0.5: one allele deletion, and 0: two allele deletions). Methylation-specific PCR (MSP) was performed in two heterozygous deletion dominant cases. Overall survival was evaluated using Kaplan-Meier survival analysis and log-rank test.

      Results
      Results: In MPM, 44/49 (90%) cases were homozygous deletion-positive (>10% cutoff value), and 12/49 (24%) cases were heterozygous deletion-positive (>46.6% cutoff value) by p16 FISH. None of RMH cases were deletion-positive in tissue samples. Real-time PCR was performed for 22 cases of MPM and 17 cases of RMH. The p16 copy number in RMH was 0.83-1.28 (average 1.06). In MPM, 16/22 (73%) revealed a two-allele deletion pattern for p16. Two cases of homozygous deletion-negative MPM by FISH also had no deletion pattern by real-time PCR. One case of heterozygous deletion-dominant MPM (over 55%) revealed a two-allele deletion of p16 by real-time PCR, and two cases showed a one-allele deletion of p16. These cases had no methylation by MSP. In 25 cases of MPM for which follow-up was available, the overall survival rate was significantly lower in homozygous deletion-positive MPM (21/25 cases) than homozygous deletion-negative MPM (4/25 cases) (p= 0.01).

      Conclusion
      Conclusion: 9p21 FISH was useful for differentiating MPM from RMH, and p16 homozygous deletion in MPM has the potential to be a prognostic factor. Moreover, a combination of p16 FISH, p16 real-time PCR and MSP is useful for discriminating heterozygous deletion from homozygous deletion in MPM. The presence of heterozygous deletion suggest the possibility of a p16-independent tumorgenesis pathway in MPM.