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I. Yoshino



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    MO03 - Thymic Malignancies (ID 123)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 3
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      MO03.01 - Outcome of surgical treatment for thymic epithelial tumors based on the nationwide retrospective database of 3033 patients in Japan (ID 2284)

      10:30 - 10:35  |  Author(s): I. Yoshino

      • Abstract
      • Presentation
      • Slides

      Background
      Thymic epithelial tumor, consisting of thymoma, thymic carcinoma and thymic neuroendocrine carcinoma, is a relatively rare neoplasm, and there is not a satisfying consensus in the treatment strategy. Because of lack of TNM staging system and global consensus on pathological classification, global research in these research has been difficult. To participate in movement of establishing the global database, Japanese Association for research of the Thymus (JART) conducted the project of Japanese nation-wide database in 2012.

      Methods
      Patients undergoing surgical treatment during 20 years between 1991 and 2010 in Japan were collected from 32 institutes. 3182 patients were first enrolled, but after exclusion of cases with insufficient information, 3033 cases remained for analysis finally.

      Results
      1435 patients (44%) were male, and 1595 were female (not identified in 3 patients). The age at operation was 13 to 88 years (mean 57 years old). Pathological diagnosis was thymoma in 2505 patients (Type A: 203, Type AB: 710, Type B1: 599, Type B2: 669, Type B3: 329), thymic carcinoma in 381 patients (Squamous cell carcinoma: 223, neuroendocrine carcinomas 66), and unclassified or unknown in 147 patients. According to Masaoka staging system, 1063 patients were in stage I, 1084 were in stage II, 477 in stage III, 197 in stage IVA, 57 in stage IVB (undetermined in 155 patients). Complete resection was achieved in 2753 patients (92%), subtotal resection (mass reduction of more than 80%) in 157 patients (5%), partial resection including biopsy in 86 patients (unknown in 37 patients). 249 patients were alive with tumor. 316 patients were dead during the observation period, and 161 patients died from tumor. Among 2557 patients who underwent complete resection (R0), 269 patients (10.5%) had tumor recurrence. In the patients who underwent complete or subtotal resection, 10-year overall survival rate was 89% in thymoma, 56% in squamous cell carcinoma, 30% in non-squamous thymic carcinoma, 72% in well-differentiated neuroendocrine carcinoma and 29% in poorly-differentiated neuroendocrine carcinoma. According to Masaoka stage, 10-year overall survival rate was 94% in stage I, 93% in stage II, 74% in stage III, 59% in stage IVA and 44% in stage IVB. In thymoma patients who underwent complete resection, recurrence-free survival rate at 10 years was 96% in type A, 99% in type AB, 92% in type B1, 80% in type B2, 72% in type B3. By Cox’ proportional hazard model, involvement of the mediastinal pleura (p=0.01), involvement of the lung (p=0.01), pleural dissemination (p=0.0009), distant metastasis (p=0.01) and WHO histological subtype (p<0.0001) were found to be independent factors for tumor recurrence after complete resection, while nodal metastasis, intrapericardial dissemination, involvement of pericardium, pulmonary artery, SVC, brachiocephalic vein, aorta, or brachiocephalic artery were not.

      Conclusion
      Japanese nation-wide database revealed the oncological difference among thymoma, thymic carcinoma and thymic neuroendocrine carcinoma. In thymoma, involvement of pleura and lung, pleural dissemination, distant metastasis and WHO histological classification were significant factors of tumor recurrence. These results are supposed to contribute to clinical practice for tumor treatment as well as establishment of global TNM classification.

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      MO03.02 - Surgical Outcome of Patients with Stage III Thymoma in the Japanese Nationwide Database (ID 2842)

      10:35 - 10:40  |  Author(s): I. Yoshino

      • Abstract
      • Presentation
      • Slides

      Background
      Stage III thymoma has a variety characteristics in terms of involved organs, complex surgery and multimodal strategy, and a careful consideration is required in choices of treatments. Recently the Japanese Association for Research on the Thymus (JART) conducted a nationwide large cohort analysis for thymic epithelial tumors. The aim of this study is to clarify clinical characteristics and therapeutic outcome of patients who underwent surgical resection for stage III thymoma using this database.

      Methods
      Clinical data of 3,033 thymic epithelial tumor patients of 1991 to 2010 were collected rom 32 Japanese institutes. Medical information registered included patients’ characteristics, types of surgery, pathological diagnosis, perioperative therapy, and clinical outcomes were registered. In this study, stage III thymoma patients who underwent surgery were extracted from the database, and retrospectively analyzed for clinical characteristics and surgical outcome.

      Results
      A total of 340 records of patients were analyzed in this study, which comprised 186 males (54.7%) and 153 females (45.0%), 83 (24.4%) with myasthenia gravis, 42 (12.4%) with induction chemotherapy, 18 (5.3%) with preoperative radiotherapy, and 29 (8.5%) with adjuvant chemotherapies. WHO histologic types comprised 16 A (4.7%), 40 AB (11.8%), 47 B1 (13.8%), 118 B2 (34.7%) and 97 B3 (28.5%). Involved organs were lung in 209 (61.4%), pericardium in 167 (49.1%), chest wall in 7 (2.1%), phrenic nerve in 88 (25.9%) and great vessels in 134 (39.4%). Completeness of resection was R0 in 268 (78.8%), R1 in 35 (10.3%) and R2 in 20 (5.9%). Complications were observed in 85 (25.0%) including arterial fibrillation, phrenic nerve palsy, bleeding and crisis of myasthenia gravis, and 30-day mortality rate was 1.8% (6 cases). Tumor recurrence was experienced in 96 (28.2%), and 39 (11.5%) died during the observation. Overall and disease-free 10-year survival rates were 81.0% and 56.7%, respectively. Involved organs except for chest wall, completeness of resection or myasthenia gravis did not affect the survivals. Number of involved organs (1 vs. >2) and tumor length (<7cm vs. >7cm) affected disease-free survival but not overall survival. Among factors suggested to affect overall survival by univariate analyses such as male, surgical complication, WHO histologic type B1-3, chest wall invasion, induction treatments, and recurrence, independent adverse predictors were revealed by a multivariate analysis to be male (p=0.031, HR=2.47), induction chemotherapy (p=0.034, HR=2.39), postoperative complication (p=0.018, HR=2.41) and recurrence of disease (p=0.041, HR=2.15). Of 96 patients with recurrence, 47 patients who underwent salvage resection showed better prognosis than 49 patients who did not (p=0.009).

      Conclusion
      This nationwide registry study exhibited favorable surgical outcome in Japanese patients with stage III thymoma. Effectiveness of multimodal treatments need to be further investigated in prospective controlled trials.

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      MO03.04 - Analysis of lymphatic metastases of thymic epithelial tumors on Japanese database (ID 3196)

      10:45 - 10:50  |  Author(s): I. Yoshino

      • Abstract
      • Presentation
      • Slides

      Background
      Thymic epithelial tumors sometimes metastasize to lymph nodes (LNs). The frequency of lymph node metastasis, the pattern of node metastasis and the relationship between prognosis and node metastasis are still unclear.

      Methods
      We registered patients with thymic epithelial tumors who had undergone resection between 1991 and 2010 from 29 institutes in Japan by the Japanese Association for Research on the Thymus (JART). We investigated the collected data according to the site of lymphatic metastasis. Yamakawa-Masaoka's paper (Cancer 1991;68:1984–7.) tentatively classified the N factor to 3 groups: metastasis to anterior mediastinal lymph nodes around the thymus were defined as N1, metastasis to intrathoracic lymph nodes other than anterior mediastinal lymph nodes as N2, and metastasis to extrathoracic lymph nodes as N3.

      Results
      The rate of lymphatic metastasis in thymoma was 1.75% (44 cases of 2508). Most of metastatic nodes were located in anterior mediastinal lymph nodes (N1, 78%). There is a significant difference of overall survival between thymomas with LN metastasis and those without LN metastasis (p<0.0001, 10-year survival: 89.8% vs 63.6%). Thymomas with N1 metastasis showed a good prognosis than those with other node metastasis, although there is no significant relationship (5-year survival: 64.4% vs 52.5%). The rate of lymphatic metastasis in thymic carcinoma including thymic carcinoid was 22% (84 cases of 380). Most of metastatic nodes were located in anterior mediastinal lymph nodes (N1, 69%). There is a significant difference of overall survival between thymic carcinomas with LN metastasis and those without LN metastasis (p<0.0001, 10-year survival: 59.5% vs 18.4%). Thymic carcimomas with N1 metastasis showed good prognosis than those with other node metastases, although there was no significant relationship (5-year survival: 55.5% vs 27.5%).

      Conclusion
      The rate of lymphatic metastasis in thymoma and thymic carcinoma was 1.75% and 22%, respectively. Both tumors frequently metastasized to the anterior mediastinal nodes. There was a significant difference of overall survival between tumors with LN metastasis and without LN metastasis in both tumors. And both tumors with N1 metastasis showed good prognoses than those with other node metastases, although there was no significant relationship. We think that it may be reasonable to consider the anterior mediastinal lymph node group (N1) to be a primary lymph node of thymic epithelial tumor.

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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): I. Yoshino

      • 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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    P1.07 - Poster Session 1 - Surgery (ID 184)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P1.07-001 - The impact of combined pulmonary fibrosis and chronic obstructive pulmonary disease on long-term survival after lung cancer surgery (ID 121)

      09:30 - 09:30  |  Author(s): I. Yoshino

      • Abstract

      Background
      The purpose of this study was to determine the impact of pulmonary fibrosis on postoperative complications and on long-term survival after surgical resection in lung cancer patients with chronic obstructive pulmonary disease.

      Methods
      A retrospective chart review was conducted of 380 patients with chronic obstructive pulmonary disease who had undergone pulmonary resection for lung cancer at Chiba University Hospital between 1990 and 2005. The definition of chronic obstructive pulmonary disease was a preoperative forced expiratory volume in one second /forced vital capacity ratio of less than 70%; pulmonary fibrosis was defined as obvious bilateral fibrous change in the lower lung fields, confirmed by computed tomography. Statistical comparisons were carried out between the groups, and multiple logistic regression analysis was used to evaluate for independent risk factors for decreased survival.

      Results
      Pulmonary fibrosis was present in 41 patients (10.8%) with chronic obstructive pulmonary disease; the remaining 339 patients (89.2%) did not have pulmonary fibrosis. The preoperative forced vital capacity and forced expiratory volume in one second were significantly lower in patients in the group with pulmonary fibrosis than in the group without (p < 0.05). Acute lung injury and home oxygen therapy were significantly more common in the pulmonary fibrosis group; however, the 30-day mortality was similar between the groups. The cumulative survival at 3 and 5 years was 53.6% and 36.9% in the pulmonary fibrosis group and 71.4% and 66.1% in the non-pulmonary fibrosis group (p = 0.0009). The group without pulmonary fibrosis had significantly better survival, due to a lower rate of cancer recurrence. Increased age, decreased body mass index, advanced pathologic stage and the existence of pulmonary fibrosis were identified as independent risk factors for decreased survival.

      Conclusion
      Pulmonary fibrosis is a risk factor for decreased survival after surgical treatment in lung cancer patients with chronic obstructive pulmonary disease.

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    P2.07 - Poster Session 2 - Surgery (ID 190)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P2.07-011 - A pilot study on the effects of perioperartive administration of the neutrophil elastase inhibitor, Sivelestat, to non-small cell lung cancer patients with preoperative risk factors of acute respiratory distress syndrome after pulmonary resection (ID 1217)

      09:30 - 09:30  |  Author(s): I. Yoshino

      • Abstract

      Background
      Postoperative acute respiratory distress syndrome (ARDS) is a recognized complication of pulmonary resection. ARDS following lung resection has a miserable prognosis, with overall hospital mortality rates over 25%. Previous studies demonstrated that there were risk factors of ARDS after pulmonary resection including age, chronic obstructive pulmonary disease (COPD), interstitial pneumonia, concurrent cardiac disease, prior therapy, remaining lung perfusion, duration of operation, increased blood loss and so on. Neutrophils and neutrophil elastase (NE) are believed to play a key role in the endothelial injury and increased vascular permeability characteristic of ARDS. Sivelestat sodium hydrate is a selective NE inhibitor and has been shown to improve respiratory status in cases of ARDS. It has not been well known whether or not NE inhibitors are beneficial for prevention of ARDS after lung resection.

      Methods
      We conducted a pilot study to investigate the efficacy of perioperative administration of sivelestat sodium hydrate to prevent postoperative ARDS in 34 non-small cell lung cancer (NSCLC) patients who had the various preoperative risk factors of the incidence of ARDS after pulmonary resection in Chiba University between 2009 and 2011. They received sivelestat sodium hydrate (5mg/kg/day) intravenously for 7 days starting at the beginning of operation.

      Results
      The patient demographics were as follows: median age, 68 years of age (range 47 to 83 years), male/female ratio, 31/3, clinical stage I/II/III, 9/6/19. The histology was adenocarcinoma (n =19), squamous cell carcinoma (n=10) and others (n =5). Risk factors of ARDS included induction chemotherapy (n=3), induction chemoradiotherapy (n=17), interstitial pneumonia (n=10), COPD (n=3) and medical history of ARDS (n=1). All 34 patients underwent complete resection. The operations included 2 partial resections, 31 lobectomies, and 1 pneumonectomy. Of the 31 patients who received lobectomy, bronchial or arterial plasty was performed in 9 patients. The postoperative mortality rate was 2.9%. One patient died of heart failure on the nineth postoperative day. There was no incidence of ARDS after pulmonary resection in all patients.

      Conclusion
      Perioperative administration of sivelestat sodium hydrate can be beneficial to prevent postoperative ARDS in NSCLC patients. Prospective studies are required.

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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): I. Yoshino

      • 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): I. Yoshino

      • 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.

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    P3.21 - Poster Session 3 - Diagnosis and Staging (ID 171)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P3.21-008 - Effective Diagnosis of Postoperative Mediastinal Recurrence of Lung Cancer by Endobronchial Ultrasound-guided Transbronchial Needle Aspiration (ID 2057)

      09:30 - 09:30  |  Author(s): I. Yoshino

      • Abstract

      Background
      Diagnosis of postoperative recurrence of lung cancer usually depends on radiologic examinations. However, the diagnostic yield of radiological examination is limited and it often times show false-positive result. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is well accepted modality for the pre-operative lymph node staging in patients with lung cancer; however, the efficacy of diagnosis for post-operative recurrence still remains unclear. In this study, usefulness of EBUS-TBNA pathologic confirmation of regional node metastasis was investigated in comparison with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET).

      Methods
      The patients who were suspected to have lymph node recurrence by routine chest CT follow-up after radical surgery for lung cancer were retrospectively investigated, and diagnostic yields of FDG-PET and EBUS-TBNA for the recurrence were compared. The cut-off value for positive results by PET was standard uptake value (SUV max) more than 2.5. Rapid on-site cytological evaluation was performed during the procedure of EBUS-TBNA for convenience and pathological diagnosis was employed by independent pathologist. A dedicated 22-gauge needle was used for TBNA. Final decision of presence of nodal recurrence was made based on pathological findings of cancer recurrence for EBUS-TBNA sample, and that of absence of the recurrence was made based on radiologic follow-up for more than 6 month.

      Results
      A total of 40 patients were eligible for this study. The mean duration between thoracotomy and EBUS-TBNA was 23.5 months, and the median follow-up period after EBUS-TBNA was 21.8 months. Diagnostic sensitivity, specificity and accuracy of EBUS-TBNA was 100% for each whereas those of FDG-PET were 95.8%, 12.5%, and 62.5%, respectively. 24 patients with metastatic lymph node confirmed by EBUS-TBNA showed significantly unfavorable prognosis than 16 patients with negative result by EBUS-TBNA (p=0.024). 22 out of the 24 patients who diagnosed as recurrence received anti-cancer treatments properly. 14 patients with positive results by FDG-PET but negative by EBUS-TBNA were determined as negative (false positive) since no deterioration of the nodal status was confirmed by radiological follow-up. Pathological findings of these false-positive lymph nodes showed 12 anthracosis and 2 non-specific granuloma.

      Conclusion
      Minimally-invasive diagnosis by EBUS-TBNA should be indicated when regional lymph node recurrence is suspected since radiologic modalities frequently recognize benign lesions as positive. The accurate diagnosis by EBUS-TBNA reduces fertile cancer treatment and improves patient management. Figure 1