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Mikio Okazaki



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    MA20 - Thymic Tumors: From Molecular to Clinical Results and New Challenges in Other Rare Thoracic Tumors (ID 149)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 1
    • Now Available
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      MA20.11 - Surgical Treatment for Metastatic Lung Tumors from Sarcomas of Soft Tissue and Bone (Now Available) (ID 2391)

      11:30 - 13:00  |  Author(s): Mikio Okazaki

      • Abstract
      • Presentation
      • Slides

      Background

      Sarcoma is one of the refractory malignant tumors and often develops pulmonary metastasis. The purpose of this study was to evaluate the impact of surgical resection for metastatic lung tumors from sarcomas of soft tissue and bone retrospectively.

      Method

      Between 2006 and 2015, we had a total of 158 patients with metastatic lung tumors from soft-tissue and bone sarcomas who underwent pulmonary metastasectomy for the first time. In total, 265 surgical procedures were performed in Okayama University Hospital in this period. We analyzed the age, sex, site of primary lesion, histology, extent of primary tumors at the initial diagnosis, extent of pulmonary metastases at the first pulmonary metastasectomy, presence or absence of local recurrence and/or extrapulmonary metastases with or before pulmonary metastases, operative procedures, size of the largest lesions resected, maximum number of the resected tumors, postoperative complications, and the prognosis at the end of 2018.

      Result

      Average number of resected tumors per intervention was 4.0 (range 1-19). These sarcoma patients consisted of 36 males and 122 females, and their average age was 53.7 years (range 14-88 years). Leiomyosarcoma was the most common histological subtype (n = 92, 58.2%) and uterus was the most common location of the primary disease (n = 71, 44.9%). Operative procedures were composed of 202 partial resections, 35 segmentectomies with or without partial resections, 26 lobectomies with or without partial resections, 1 pneumonectomy, and 1 basal segmental auto-transplantation after pneumonectomy. The postoperative complications were limited, showing that pulmonary metastasectomies for sarcomas are acceptable. Overall 3-year survival after the first pulmonary metastasectomy was 50.6%. In univariate analysis, the survival was significantly better for the group with disease-free interval of more than 2 years from the date of the initial treatment for primary disease until the date of diagnosis for the first pulmonary metastasis, the one who underwent pulmonary resections three times or more, and the one in which size of the largest resected lesion was 20 mm or less. Those factors significant in univariate analysis were all significant in multivariate analysis.

      Conclusion

      Surgical resections for metastatic lung tumors from sarcomas of soft tissue and bone were performed without major complications, indicating the acceptable feasibility. If disease-free interval is more than 2 years and the size of the largest resected lesion is less than 20 mm, patients may maximally benefit from pulmonary resection. In order to increase the opportunities of pulmonary resections, we should preserve the lung parenchyma as much as possible when performing pulmonary metatstasectomy, resulting in the better survival.

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    P1.03 - Biology (ID 161)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.03-16 - Anti-Tumor Effect of Pan-RAF Inhibitor in NSCLC Cells Harboring BRAF Mutation (Now Available) (ID 1206)

      09:45 - 18:00  |  Author(s): Mikio Okazaki

      • Abstract
      • Slides

      Background

      BRAF mutation occurs in 0.5-3% of lung adenocarcinoma and acts as an oncogenic driver. Dabrafenib (BRAF inhibitor) combined with trametinib (MEK inhibitor) has shown substantial antitumor effect in patients with non-small-cell lung cancer (NSCLC) harboring BRAF V600E mutation. However, in patients with NSCLC harboring BRAF non-V600E mutation, there are few reports of effective targeted therapy. LY3009120, a newly discovered pan-RAF inhibitor, showed strong anti-tumor effect in BRAF-mutant cancers, such as melanoma, colorectal and pancreatic cancers in preclinical studies. In this study, we evaluated the anti-tumor effect of LY3009120 in BRAF-mutant NSCLC cells.

      Method

      We examined the sensitivity of LY3009120 against normal bronchial cells BEAS-2B which ectopically overexpressing wild-type or mutant BRAF. Human cDNAs encoding full-length BRAF (wild-type and its variants V600E and G469V) were inserted into the pIDT-SMART (C-TSC) vector, pCMViRTSC. In addition, we treated four BRAF-mutant NSCLC cell lines, one BRAF-mutant colorectal cancer cell line, and one KRAS-mutant cell line with LY3009120. The type of BRAF mutation consisted of V600E, L597V, G469A, and G466V. We determined cell proliferation by MTS assay and calculated the IC50 values. We also performed Western blotting to investigate downstream signaling pathways.

      Result

      BEAS-2B cells ectopically overexpressing wild-type BRAF or mutants (V600E and G469V) showed constitutive auto phosphorylation of BRAF and activation of downstream signaling by Western blotting. The IC50 values in BRAF mutant cell lines ranged from 9.4nM to 1,193nM, which suggests strong anti-tumor effect of LY3009120. This effect was observed regardless of the type of BRAF mutation, including non-V600E mutation. On the other hand, LY3009120 did not show anti-tumor effect in KRAS-mutant cell (IC50 value, 6,948nM). LY3009120 suppressed the phosphorylation of downstream MEK and ERK activation in BRAF-mutant cell lines by Western blotting.

      Conclusion

      LY3009120 showed strong anti-tumor effect in NSCLC cells harboring BRAF mutation regardless of the type of mutation, suggesting that LY3009120 can be a promising therapeutic option in the treatment of NSCLC harboring BRAF mutation.

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    P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.16-35 - The Prognostic Impact of Sarcopenia on the Clinical Outcome of Thoracic Surgery for Non-Small Cell Lung Cancer in Elderly Patients (ID 1544)

      09:45 - 18:00  |  Author(s): Mikio Okazaki

      • Abstract
      • Slides

      Background

      The elderly patients who undergo surgery for non-small cell lung cancer (NSCLC) is increasing in Japan whereas they are at high risk for surgery because of weakness of physical strength and increased comorbidity. Skeltal muscle depletion, referred to as sarcopenia, has recently been identified as a risk factor of poor clinical outcomes after surgery in the patients with various malignancies including NSCLC. We investigated the impact of sarcopenia on the clinical outcome of thoracic surgery for NSCLC in elderly patients.

      Method

      We enrolled 259 patients over 65 years old with NSCLC who underwent pulmonary resection (lobectomy or segmentectomy) without any induction treatment before surgery in our hospital during 2012 to 2015. Sarcopenia was assessed by the psoas muscle mass index (PMI, cm2/m2) using the computed tomography imaging at the third lumbar vertebra level before surgery. Postoperative complications, which were observed within 30days after surgery, were classified according to Clavien-Dindo classification. Overall survival (OS) was evaluated by the Kaplan-Meier method with log-rank test (univariate analyses) and by the cox proportional hazard model (multivariate analyses).

      Result

      Median age was 73 years old (65 - 92). One hundred fifty-five (60%) patients were male. Two hundred nine (81%) patients were cStage0 or I. Fifty-seven (22%) patients were squamous cell carcinoma (SCC). Postoperative pneumonia, arrhythmia, and delirium were observed in 17 (7%), 35 (14%) and 17 (7%) patients, respectively. Median follow-up was 48.7 months (range 3.0 – 79.6). Using the cutoff values as previously reported, 179 (69%) and 80 (31%) patients were diagnosed as sarcopenic and non-sarcopenic, respectively. Male and ever smoker were significantly more frequent in the sarcopenic patients than the non-sarcopenic patients (P < 0.001 and P = 0.018, respectively). The sarcopenic patients showed the trend of high incidence of Postoperative complications, however, there was no significant difference in OS between the sarcopenic and non-sarcopenic patients. Next, we performed the subgroup analysis to elucidate the prognostic factors only in the elderly sarcopenic patients. Among 179 sarcopenic patients, multivariate analysis including statistically significant factors in the univariate analysis revealed that the patients with restrictive lung disease, advanced cStage, postoperative pneumonia and delirium were inferior in OS [Hazard Ratio, 11.1, 3.6, 5.3 and 4.6; 95% confidence interval, 1.6 to 68.1, 1.1 to 13.0, 1.4 to 20.0 and 1.1 to 16.5; P= 0.011, 0.037, 0.017 and 0.041], suggesting the importance of the intensive perioperative management to avoid complications.

      Conclusion

      Perioperative complications are significantly associated with the prognosis of the sarcopenic elderly patients with NSCLC. Intensive perioperative management is mandatory for NSCLC patients with sarcopenia to improve the clinical outcome after thoracic surgery.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-82 - Lung Cancer in Lung Transplant Recipients (Now Available) (ID 2334)

      10:15 - 18:15  |  Author(s): Mikio Okazaki

      • Abstract
      • Slides

      Background

      Long-term immunosuppression is considered to increase the chance of developing malignancy, which is one of the leading causes of death after organ transplantation. Lung cancer in lung transplant recipients can originate from de-novo occurrence, transplanted donor’s lung and progression/recurrence of the recipient’s lung cancer. We conducted a survey of lung cancer in lung transplant recipients in our institution and report the case series.

      Method

      All 189 recipients who underwent lung transplantation (97 brain-dead donor lung transplantation, 90 living donor lobar lung transplantation, 2 hybrid lung transplantation) since October 1998 until December 2018 at Okayama University Hospital were retrospectively reviewed.

      Result

      Lung cancer was diagnosed in 4/189 (2.1%) of 16/189 (8.5%) all malignant diseases, in lung transplant recipients with a median follow-up of 4.5 years. Whereas de novo lung cancer occurred in one patient, patient-baring lung cancer was histologically detected in resected lung in three patients, leading to progression after transplantation in the two recipients. One recipient who had a previous history of lung cancer with over 5-year disease free period, experienced no recurrence afterword. All three recipients who had advanced lung cancer died relatively early from the diagnosis of lung cancer, regardless of cancer treatment.

      Lung cancer in lung transplant recipients could be difficult to detect by radiological screening and biopsy due to severely deteriorated lung condition, especially in idiopathic interstitial pneumonitis. Additionally, recipients with advanced lung cancer seem to have poor prognosis.

      Case Underlying disease Occurrence LTx - Lung cancer Degree of progression Treatment/Prognosis
      #1 LAM De novo 10 years Chest wall invasion Right pneumonectomy (10 months)chemotherapy (9 months)death
      #2 IIP Resected recipient’s lung 15 months Mediastinal lymph-nodes Lymph-node resection (10 months) death
      #3 IIP Resected recipient’s lung 3 months Pleural Dissemination chemotherapy (6 months)death
      #4 BO Resected recipient’s lung nil nil

      nil

      LAM: lymphoangioleiomyomatosis IIP: idiopathic interstitial pneumonitis BO: bronchiolitis obliterans LTx: lung transplant

      Conclusion

      Lung cancer in lung recipients should be screened carefully ever since listing for transplantation.

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