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K. Kondo



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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 - 12:00  |  Author(s): K. Kondo

      • 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)

      10:30 - 12:00  |  Author(s): K. Kondo

      • 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)

      10:30 - 12:00  |  Author(s): K. Kondo

      • 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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    P2.12 - Poster Session 2 - NSCLC Early Stage (ID 205)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.12-022 - A feasibility study of postoperative adjuvant chemotherapy with fluoropyrimidine S-1 in patients with stage II-IIIA non-small cell lung cance (ID 3352)

      09:30 - 16:30  |  Author(s): K. Kondo

      • Abstract

      Background
      S-1 is an orally active combination of tegafur, gimeracil and oteracil in a molar ratio of 1:0.4:1. We conducted a feasibility study of S-1 as postoperative adjuvant chemotherapy in patients with curatively resected pathologically stage II-IIIA non-small cell lung cancer (NSCLC).

      Methods
      Patient eligibility required compliance with the following criteria: histologically proved NSCLC; pathologic stage II-IIIA (according to the Union for International Cancer Control 6th edition) after complete resection; no previous treatment except for surgery; age >=20 and <80 years; performance status (PS) 0 or 1; no organ dysfunction; no concurrent malignancy; and written informed consent. Chemotherapy comprised 9 courses (4-week administration, 2-week withdrawal) of S-1 at 80-120 mg per day according to body surface area and renal function. The primary end point was the completion rate of scheduled adjuvant chemotherapy. Secondary end points were safety, overall survival and relapse-free survival. From November 2007 through December 2010, 24 patients were enrolled in this trial.

      Results
      Patient characteristics were as follows: median age of 68 (range: 49-79); male/female: 16/8; surgical procedure lobectomy/pneumonectomy: 21/3; pathologic stage IIA/IIB/IIIA: 8/6/10; and histologic type adenocarcinoma/squamous cell carcinoma/other: 19/4/1. Three patients were censored due to the disease recurrence, and the completion rate of 9 courses was calculated to be 42.9% (9/21). Completion rate of more than 70% of scheduled 9 courses was 61.9% (13/21). Most common adverse events were grade 1 or 2 anorexia (54.2%) or fatigue (20.8%), which were reasons of discontinuation of S-1 administration. Although grade 3 elevated total bilirubin (4.2%) and pneumonitis (4.2%) were observed, no grade 4 or 5 adverse events occurred. Overall and relapse-free survival rates at 3 years were 69.5% and 51.1%, respectively. Patients who completed more than 70% of scheduled 9 courses showed better relapse-free survival than 70% uncompleted patients (p=0.01).

      Conclusion
      Postoperative administration of S-1 seems feasible with few severe adverse events as adjuvant chemotherapy for patients with curatively resected pathologically stage II-IIIA NSCLC.

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    P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.05-015 - Positron-emission tomography-computed tomography with the glucose analogue [18F] fluorodeoxyglucose in orthotopic implantation SCID mouse model of lung cancer (ID 2619)

      09:30 - 16:30  |  Author(s): K. Kondo

      • Abstract

      Background
      In vivo evaluation is essential for development of lung cancer treatment. However, the subcutaneous xenograft models are not closely reproducing microenvironment of lung cancer. Although orthotopic implantation SCID mouse model of lung cancer presents lymphatic metastasis to mediastinum or pleuritis carcinomatosa with progression of disease, it has been difficult to evaluate the efficacy of treatment without sacrifice of model mouse. Positron-emission tomography-computed tomography (PET-CT) with the glucose analogue [18F] fluorodeoxyglucose (FDG) has been recently applied for evaluating tumor response to anticancer therapy. We have evaluated the utility of FDG PET-CT in orthotopic implantation SCID mice model of lung cancer.

      Methods
      Animals: 6 weeks male SCID mice (n=12). Cell line: Ma44-3 cloned from Ma44 (human squamous cell lung cancer cell line). Under sufficient anesthesia, mice were placed in the left lateral decubitus position. A 1-cm transverse incision was made in the right lateral skin just below the inferior border of the scapula. After intercostal muscles were exposed, 2 x 10[6] tumor cells/ml with 400 μg/ml Matrigel® was injected into the right lung in a volume of 10 μl (2.0x10[4 ]cells) of medium. Four or 5 days after implantation (6 mice on day 4 and other 6 mice on day 5), the SCID mice were examined with FDG PET-CT and mice whose lung tumors were identified were randomized to treatment group and control group. Treatment group mice received intraperitoneal injection of cisplatin (7mg/kg) on day 6 after implantation. All mice were examined with FDG PET-CT on day 8 and 13 after implantation. Tumor volume and maximal standardized uptake value (SUV max) of the lung tumor were calculated for all mice. All SCID mice were sacrificed on day 13 after implantation for histopathologic analysis.

      Results
      Six mice whose lung tumors were identified at the first FDG PET-CT were randomized to treatment group (n=3) and control group (n=3). The average growth rates (day 13 versus day 5 or 6) of tumor volume and SUV max of the treatment group were 144% and 108%, respectively, whereas the average growth rates of tumor volume and SUV max of the control group were 1470% and 271%, respectively.

      Conclusion
      Tumor growth and inhibition were evaluated by FDG PET-CT in orthotopic implantation SCID mice model of lung cancer. This in vivo evaluation system is useful for development of lung cancer treatment.

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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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      P3.07-042 - Prophylactic landiolol administration can prevent atrial fibrillation after lobectomy? (ID 3062)

      09:30 - 16:30  |  Author(s): K. Kondo

      • Abstract

      Background
      It is said that atrial fibrillation(Af) after lobectomy is seen in about 20%, sometimes difficulty in postoperative management. Landiolol is very short acting selective β1-blocker. It is reported that landiolol have the usefullness of not only treatment for Af, but also the prevention of Af after lobectomy. We had randamized control study about preventation of Af after lobectomy or more.

      Methods
      We divided into control group and landiolol administration group for patients to perform lobectomy or more. The patients of administration group are subjected prophylactic landiolol to 24hr continuous infusion from the start of surgery at 5γ. We analysed the 93 cases with informed consent in this clinical trial from June 2010 to April 2013. Finally, 2cases dropped out because of changing operative procedure for dissemination of lung cancer.

      Results
      45 cases is in landiolol administration group and 46 cases is in control group of 91 cases. Postoperative Af was occurred 10 cases. But, there were no occurrence of Af during landiolol infusion. 9 cases of 10 cases had Af during the 3days after surgery. The data is following: (administration group, control group) Event of Af=(6,4), postoperative days of Af=(1.5, 3.), age(years-old)=(70±8.7, 66.3±9.4), gender(M:F)=(25:20, 29:17), pasthistory of Af=(0, 5), operative site(R:L)=(29:16, 31:15), bleeding=(286±463ml, 212±308ml), operation time=(290±86min,272±87min), in-out balance in operation=1816±827ml, 1414±732ml), the rate of concomittant use of epidural anethesia=(91%:95%), operatibe approach(open:VATS)=(6:39, 10:36), operative procedure(lobectomy:bilobectomy:pneumonectomy)=(45:0:0, 40:3:3), upper mediastinal LN disection rate=(67%, 63%), #7 LN disection rate=(73%, 70%). Adverse effect of landiolol is hypotension(BP<80) in 3 cases(7%) and bradycardia(HR<60) in 1 case.

      Conclusion
      Landiolol administration group had more occurrence of postoperative Af, compared to control group. Considering the incidence of Af is high up to 3days after surgery, only 24hr continuous administration can not suppress Af after stopping infusion. β- action, by exciting sympathetic nerve, is important for the occurrence of postoperative Af. β- action is inhibited by landiolol during administration, for positive feedback, β-receptor are upregulation. It is thought that Af occurrence after stopping landiolol is increasing in administration group than control group, because the β-agonist binds to the upregulated receptor. It is possible that turned out to be different result, if prophylactic landiolol administration would continue until 3days after surgery, for Af is high up to 3days after surgery.