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M. Inoue



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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): M. Inoue

      • 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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    O12 - Lung Cancer Biology II (ID 87)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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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): M. Inoue

      • 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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    O13 - Limited Resections (ID 101)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Surgery
    • Presentations: 1
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      O13.03 - Survival of 1963 lobectomy-tolerable patients who underwent limited resection for cStage I non-small cell lung cancer (ID 1030)

      10:50 - 11:00  |  Author(s): M. Inoue

      • Abstract
      • Presentation
      • Slides

      Background
      Although the standard operation for lung cancer is lobectomy, precise preoperative diagnosis of the “very early” lung carcinomas may identify patients that can be treated by limited resection. Previous reports on limited resection included patients who were not candidates for lobectomy. The survival of non-small cell lung cancer (NSCLC) patients who were fit for lobectomy and underwent limited resection has not been studied in a large enough scale.

      Methods
      A nationwide multi-institutional project collected clinical data of patients who underwent limited resection (segmentectomy or partial resection) for clinical T1-2N0M0 non-small cell lung carcinoma, who were 75 years old or younger at the time of operation and were considered fit for lobectomy by the physician. Overall and disease free survival, freedom from recurrence were analyzed and factors affecting survival or recurrence were identified.

      Results
      The median age of 1963 patients was 63 years. The mean maximal diameter of the tumor was 1.4 ± 0.6 cm. The overall and recurrence free survival after limited lung resection was 93.7 % and 90.4 % at 5 years, respectively. The recurrence free proportion and local recurrence free proportion were 93.3 % and 98.4 % at 5 years, respectively. Prognostic factors in overall survival were pathologically proven lymph node metastasis, interstitial pneumonia, male gender, older age, complications (cardiac disease, diabetes etc.), radiological invasive cancer, and multiple lesions. The consolidation/tumor ratio on CT of ≤ 0.25 predicted good outcome especially in cT1aN0M0 disease. Prognosis and recurrence was not affected by the method of limited resection (segmentectomy (n=1225) or partial resection (n=738)).

      Conclusion
      If the patient was 75 years old or younger and was judged fit for lobectomy, the result of limited resection for cStage I NSCLC was excellent and was not inferior to the reported result of lobectomy for small sized NSCLC. The radiological noninvasive carcinomas rarely recur and are especially good candidates for limited resection.

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    P1.15 - Poster Session 1 - Thymoma (ID 189)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Thymoma & Other Thoracic Malignancies
    • Presentations: 1
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      P1.15-004 - Relationship of therapeutic results with immunohistochemical findings in thymic carcinoma cases (ID 1016)

      09:30 - 09:30  |  Author(s): M. Inoue

      • Abstract

      Background
      A thymic carcinoma is a thymic epithelial neoplasm that has a large number of malignant features as compared to a thymoma. Since a thymic carcinoma is presented with locally advanced disease or distant metastasis, unresectable cases are frequently encountered at diagnosis, thus systemic chemotherapy is a key treatment strategy. Although cisplatin-based chemotherapy is usually administered for such cases, an optimal regimen has not been established. To determine a prognostic indicator for chemotherapy in patients with thymic cancer we evaluated the expressions of excision repair cross complementing-1 (ERCC1), class III β-Tubulin (TubIII), ribonucleotide reductase M1 (RRM1), and thymidylate synthase (TS)/orotate phosphoribosyltransferase (OPRT), which have been reported as possible indicators of the anticancer activity of cisplatin, taxanes, gemcitabine, and 5-fluorouracil drugs such as S-1, respectively.

      Methods
      Thymic carcinoma tissue samples obtained from 15 patients who underwent surgery or core-needle biopsy procedures between 1996 and 2007 at Osaka University Hospital were used. Immunohistochemical analysis was utilized to determine the expressions of ERCC1, TubIII, RRM1, TS, and OPRT in thymic cancer specimens, then the relationship between expression levels and clinical course were examined in a retrospective manner.

      Results
      Twelve males and 3 females (median age, 60.3 years) were studied. The histological subtype was squamous cell carcinoma in 10, small cell carcinoma in 2, large-cell neuroendocrine carcinoma in 2, and carcinoid in 1, while Masaoka classification was stage III in 4, IVa in 4, and IVb in 7. Surgical resection was performed as initial treatment in 8 patients. Chemotherapy, mainly platinum-based combinations, was administered in 12, including 6 who received combined radiotherapy. The median number of administered regimens and cycles were 2 (range, 1-9) and 7 (range, 2-44), respectively, for each patient. The response rate/disease-control rates following first- and second-line treatments were 83%/92% and 56%/78%, respectively. In 6 patients treated with gemcitabine, 3 tumors with a low expression of RRM1 showed a good response, whereas 2 of 3 tumors with a high expression of RRM1 showed a progressive disease response. S-1 was administered to 1 patient, which successfully suppressed tumor progression, and the specimen from that case demonstrated a low expression of TS and high expression of OPRT. We were able to obtain biopsy specimens before and resected tumors after treatment from 5 patients, in which the expressions of ERCC1, Tub III, and RRM1 were increased after treatment in 4, 3, and 4, respectively. Our results suggest that sensitivity to chemotherapy is lowered with additional courses in thymic carcinoma patients. The median survival was 36 months, while the 1-, 3-, and 5-year survival rates were 81.9%, 55.5%, and 23.1%, respectively.

      Conclusion
      First-line chemotherapy with platinum compounds may be effective treatment for patients with thymic cancer, while new drugs such as gemcitabine and S-1 might be useful in some cases. Prospective multi-institutional studies are required to ascertain the effectiveness of immunohistochemical evaluation used as a screening test for selecting the optimum chemotherapy regimen for thymic cancer patients.

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    P3.07 - Poster Session 3 - Surgery (ID 193)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P3.07-016 - Clinical Impact of Postoperative Cardio-pulmonary Complications on Long-term Outcome in Lung Cancer Patients (ID 1494)

      09:30 - 09:30  |  Author(s): M. Inoue

      • Abstract

      Background
      Postoperative cardiopulmonary complications represent a major source of morbidity and mortality in the acute phase after lung cancer surgery. However, clinical impacts of postoperative cardiopulmonary complications on long-term outcome were not well studied. The objective of this study was to investigate the effects of postoperative cardiopulmonary complications in the acute phase on cardiovascular and respiratory events in the chronic phase after lung cancer surgery.

      Methods
      From a prospective single-institution database of 496 consecutive patients who underwent a lung cancer surgery between August 2008 and December 2011, we retrospective analysed medical charts of all patients with curative surgery for non-small cell lung cancer. Patients with limited surgery (n=32) and postoperative mortality (n=4) were excluded from the analysis. The remaining 460 patients were analysed for the incidence of cardiovascular and respiratory events in the chronic phase after surgery. Results were compared between the patients with and without postoperative cardiopulmonary complications in the acute phase.

      Results
      Postoperative cardiopulmonary complications were identified in 90 (20%) patients; these patients included more advanced patients with pathological stage IB-III compared to those without cardiopulmonary complications (60% vs. 48%; p < 0.05). There were significantly higher cardiovascular and respiratory events in those with postoperative cardiopulmonary complications than those without (Table 1, 14% vs. 4%; p < 0.001). Also, there was significantly higher incidence of cancer recurrence in those with postoperative cardiopulmonary complications than those without (27% vs. 20%; p < 0.05).

      Table 1. Cardiovascular and respiratory events in the chronic phase for the patients with and without postoperative cardiopulmonary complications in the acute phase after lung cancer surgery.
      Variables With cardiopulmonary complications (N=90) Without cardiopulmonary complications (N=370) P Value
      All events 13 (14%) 14 (4%) <0.001
      Cardiovascular events 7 (8%) 7 (2%)
      Acute heart failure 3 1
      Arrhythmias 1 2
      Coronary artery disease 0 3
      Peripheral vascular disease 2 0
      Cerebrovascular disease 1 1
      Respiratory events 6 (7%) 7 (2%)
      Pneumonia 5 6
      Acute respiratory distress syndrome 0 1
      Chronic respiratory failure 1 0

      Conclusion
      Postoperative cardiopulmonary complications in the acute phase were associated with the incidence of cardiovascular and respiratory events in the chronic phase after lung cancer surgery. It is important for those with postoperative cardiopulmonary complications to be careful about not only cancer recurrence but also cardiovascular and respiratory events in the long-term period.