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G. Ishii



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    MINI 19 - Surgical Topics in Localized NSCLC (ID 138)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
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      MINI19.02 - Mediastinal Nodal Involvement in Patients with Clinical Stage I Non-Small-Cell Lung Cancer - Possibility of Rational Lymph Node Dissection - (ID 2320)

      16:45 - 18:15  |  Author(s): G. Ishii

      • Abstract
      • Presentation
      • Slides

      Background:
      Recent developments of radiological examinations have been able to bring more accurate information about the biological malignancy of primary tumors in non-small cell lung cancer (NSCLC). The aim of this study is to elucidate the optimal candidate of lobe-specific selective lymph node dissection (LND) that reduces the extent of mediastinal LND according to clinical information including radiological evaluation of primary tumor on thin-section computed tomography (TSCT) and tumor location in clinical(c)-stage I NSCLC patients.

      Methods:
      Eight hundred and seventy-six patients with c-stage I NSCLC (adenocarcinoma and squamous cell carcinoma), who underwent complete surgical resection between January 2003 and December 2009 were included in this study. For all tumors, we obtained the maximum dimension of the tumor (tumor) and solid component (consolidation) using a lung window level setting from the TSCT scan images, and estimated the consolidation-to-tumor ratio (C/T ratio) for each tumor. We elucidated the lymph node metastatic incidence and distribution according to the primary tumor lobe location and extracted the associated clinicopathological factors with mediastinal lymph node involvement.

      Results:
      The patients included 490 men and 386 women, with a median age of 66 years old. The radiological findings were ground glass opacity (GGO)-predominant (C/T ratio ≤ 0.5) in 134 patients and solid-predominant (C/T ratio > 0.5) in 742 patients. There were 744 adenocarcinoma cases and 132 squamous cell carcinoma cases, and the incidences of mediastinal lymph node metastasis were 9.9% in adenocarcinoma cases and 4.5% in squamous cell carcinoma cases, respectively. There were no cases with hilar and mediastinal lymph node metastasis in GGO-predominant tumors. There was no significant association of clinical factors with subcarinal lymph node metastasis in right upper-lobe and left upper-division lung adenocarcinoma. In 257 bilateral lower-lobe lung adenocarcinomas, a total of 32 cases (12.5%) were positive for mediastinal lymph node metastasis, and seven cases (2.7%) were negative for subcarinal lymph node metastasis but positive for upper mediastinal lymph node metastasis (mediastinal skip metastasis). An elevated preoperative serum carcinoembryonic antigen (CEA) level (p < 0.001) showed only a significant association with upper mediastinal lymph node metastasis in the patients with bilateral lower-lobe primary lung adenocarcinoma.

      Conclusion:
      It would be acceptable to perform selective LND in patients with c-stage I NSCLC with GGO-predominant tumor. Elevated serum CEA was associated with upper mediastinal lymph node involvement in lower-lobe primary lung adenocarcinoma with radiologically solid-predominant tumor. We should be careful when applying selective LND to patients with solid-predominant tumor, especially located in the lower lobe.

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    MINI 36 - Imaging and Diagnostic Workup (ID 163)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Screening and Early Detection
    • Presentations: 1
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      MINI36.01 - Three-Dimensional Quantitative Computed Tomography Evaluation of Pulmonary Adenocarcinoma Using Image-Analysis Software (ID 772)

      18:30 - 20:00  |  Author(s): G. Ishii

      • Abstract
      • Slides

      Background:
      Several 2-dimensional computed tomography (CT)-based evaluation methods of small-sized lung adenocarcinomas have been reported as predictors of the disease invasiveness. They include the ratio of the maximum diameter of consolidation to the maximum entire tumor diameter (C/T ratio), tumor shadow disappearance rate on mediastinal window images (TDR), and visual estimation of the ratio of ground-glass opacity area (GGO-R). However, these measurements can be poorly reproducible due to possible inter-observer discrepancy, and can be unrepresentative because measuring is done only on one section of a lesion. We have developed a 3-dimensional quantitative entire-nodule evaluation method using novel image-analysis software. The aim of this study is to compare the new method to these 2-dimensional evaluation methods as a predictor of small-sized invasive lung adenocarcinomas.

      Methods:
      There were 101 consecutive patients with clinical stage IA adenocarcinoma of the lung who underwent complete resection between 2002 and 2005 at our institution, excluding patients undergoing preoperative treatment and those with multiple lung nodules or with a past history of other cancers. Of them, 75 had a nodule separated from the chest wall and mediastinum depicted on preoperative thin section CT scan without contrast enhancement, and they were the subject of this study. The reconstruction interval of the CT scans was 0.2mm and the reconstructed slice thickness was 0.5mm. The image analysis software recognizes a nodule as a collection of cubic voxels. Ground glass opacity (GGO) was defined as the area of increased attenuation in the lung with preservation of the bronchial and vascular margins. As the average CT value of pulmonary arteries on non-contrast-enhanced CT was 50 Hounsfield Unit (HU), we measured the percentage of the voxels over 50 HU in a nodule to identify voxels representing solid component, and the percentage was defined as R-50. Invasive cancer was defined as a nodule with pathological lymphatic permeation, vascular invasion or node involvement. The correlation between invasive lung cancer and clinicopathological factors, including the image findings (C/T ratio, TDR, GGO-R and R-50) was evaluated using multivariate analysis. The areas under the curve (AUC) of receiver operating characteristics curves were compared among the image evaluation methods.

      Results:
      There were 17 invasive cancers. C/T Ratio, TDR, GGO-R and R-50 were independent predictors of invasive lung cancers (p<0.01). R-50 was equivalent in AUC to the other evaluation methods (AUC: R-50, 0.807; C/T Ratio, 0.800; TDR, 0.809; GGO-R, 0.792, respectively).

      Conclusion:
      Our new 3-dimensional quantitative evaluation method using image-analysis software had invasive cancer predictability similar to the other 2-dimensional evaluation methods. As this method enables entire-tumor evaluation quantitatively and objectively, it should be more reproducible and reliable than the conventional methods.

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    P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 2
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      P1.04-009 - Max Collapse and Fibrosis below 5 cm Predict the Prognosis of pT1 Lepidic Predominant Adenocarcinoma (ID 2605)

      09:30 - 17:00  |  Author(s): G. Ishii

      • Abstract

      Background:
      According to the International Association for the Study of Lung Cancer , American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) classification, lepidic predominant pattern in pT1 lung adenocarcinoma is divided into adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic predominant invasive adenocarcinoma (LPIA) by using new diagnostic criteria. However the new criteria have many item to diagnose MIA. So we simply classified the pT1 lepidic predominant adenocarcinoma by using only collapse and fibrosis below 5cm as invasive component, and we evaluated prognosis of MIA.

      Methods:
      A total of 231 patients treated for pT1 lepidic predominant lung adenocarcinoma by complete resection at National cancer center hospital east, Chiba, Japan from January 2003 to December 2010 were assessed. We excluded multiple tumor and mucinous invasive adenocarcinoma from the analysis. We classified 187 patients into AIS, MIA, LPIA, according to the IASLC/ATS/ERS classification. The MIA was defined as group A. In the LPIA, we defined invasive component as collapse and fibrosis 5 cm below, and reclassified into MIA and LPIA. Reclassified MIA and LPIA were defined as Group B and C respectively. We analyzed the prognosis of these patients retrospectively.

      Results:
      AIS, Group A, Group B, Group C were 52 (22.5%), 29 (12.5%), 39 (16.9), 111 (48.1%) respectively. Positive lymphatic invasion and, or vascular invasion and, or pleural invasion in Group A, Group B, Group C were 0 (0%), 4 (1.2%), 24 (21.6%) respectively. There are significant difference in 5-year recurrence free survival (5y-RFS) between Group A and B (5y-RFS rate 100% versus 88.1%; p = 0.022), and Group A and C (5y-RFS rate 100% versus 88.1%: p = 0.046).

      Conclusion:
      Max collapse and fibrosis below 5 cm correlated with the prognosis of pT1 lepidic predominant adenocarcinoma. Max collapse and fibrosis below 5cm is more simpl and easy method to measure invasive component than the new IASLC/ATS/ERS classification. This method may have potential to diagnose MIA instead of the IASLC/ATS/ERS classification.

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      P1.04-055 - Fibroblast-Dependent Cancer Cell Invasion: Analysis of Cancer-Associated Fibroblasts That Remodel the Extracellular Matrix (ID 2633)

      09:30 - 17:00  |  Author(s): G. Ishii

      • Abstract
      • Slides

      Background:
      Cancer-associated fibroblasts (CAFs) communicate with cancer cells and play important roles in cancer invasion. We previously reported that local invasion of cancer cells was frequently observed in lung adenocarcinoma patients with podoplanin(PDPN)-expressing CAFs. However, the underlying mechanisms of this phenomenon have remained unclear.

      Methods:
      We established a novel collagen invasion assay model in which cancer cells and CAFs were co-cultured; we analyzed the mechanisms governing how cancer cell invasion was promoted by PDPN(+)CAFs.

      Results:
      By observing the dynamic movement of both CAFs and cancer cells in the collagen matrix, we found that PDPN(+)CAFs invaded the matrix to a greater extent, with more cancer cells invading within the “tracks” created by the CAFs, compared with control CAFs. The knockdown of PDPN in CAFs decreased the invasion of both the CAFs and the cancer cells. PDPN(+)CAFs displayed a higher RhoA activity, and treatment with a ROCK inhibitor cancelled the increased invasion ability of PDPN(+)CAFs and subsequently decreased the number of invaded cancer cells. After intravenous injection in the mouse tail vein, PDPN(+)CAFs invaded and promoted cancer cell invasion into the lung parenchyma, compared with control CAFs. Among the patients with lung adenocarcinoma, we observed some cases with PDPN(+)CAFs at the invasive front of the tumor. These cases predominantly exhibited pleural invasion of cancer cells, known as pathological invasiveness.

      Conclusion:
      Our results indicated that PDPN(+)CAFs were tumor-promoting CAFs that lead and enhance the local invasion of cancer cells, suggesting that the invasion activity of CAFs themselves could be rate-determining for cancer cell invasion. For analysis of fibroblast-dependent cancer cell invasion, we established single-cell derived clones from primarily cultured CAFs and conduct further investigation.

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    P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P2.04-064 - Microenvironmental Factor of Primary Lung Adenocarcinoma Which Predicts the Effectiveness of Chemotherapy in Patients with Recurrences (ID 815)

      09:30 - 17:00  |  Author(s): G. Ishii

      • Abstract
      • Slides

      Background:
      The influence of microenvironmental factors on the effectiveness of chemotherapy is being increasingly recognized. Stromal cells in cancer tissue, such as tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), have been shown to influence tumor progression. The associations of CD204-positive cells, which represent an M2 phenotype of TAMs, and podoplanin-positive CAFs, which represent a subpopulation of CAFs with a tumor-promoting phenotype, with a poor prognosis have been identified in patients with lung adenocarcinoma, but whether these associations are involved in the response to chemotherapy remains unknown. The purpose of this study was to investigate the relationships between cancer cell and stromal cell phenotypes in primary tumors and the progression-free survival (PFS) of recurrent lung cancer patients who received platinum-based chemotherapy.

      Methods:
      We retrospectively analyzed 87 postoperative recurrent lung adenocarcinoma patients treated with platinum-based chemotherapy. The expressions of drug resistance-related proteins including BCRP, Ezrin and ALDH1 in cancer cells, the number of CD204-positive TAMs, and the presence of podoplanin-positive CAFs in the primary tumor were examined. The relationships between the immunohistochemical staining results of primary tumors and the PFS after receiving chemotherapy were also analyzed.

      Results:
      Among the clinicopathological factors of primary tumors, only an advanced pathological stage was significantly associated with a shorter PFS. As for immunohistochemical staining, no significant relationships were found between the PFS and the expression of BCRP, Ezrin, or ALDH1. The number of CD204-positive TAMs was not associated with the PFS. The presence of podoplanin-positive CAFs, identified in thirty (34%) of 87 samples, was significantly associated with a shorter PFS (median PFS: 5.1 vs. 7.8 months, P=0.028), but was not significantly associated with a shorter overall survival (median survival time: 18.1 vs. 23.7 months, P=0.156). A multivariate analysis revealed a tendency of podoplanin-positive CAFs to be correlated with a shorter PFS (P=0.087).

      Conclusion:
      The presence of podoplanin-positive CAFs in the primary tumor could be a predictor of a shorter PFS in recurrent lung adenocarcinoma patients who received chemotherapy. These findings suggest that stromal-cell derived factors should be incorporated into predictions of the effectiveness of chemotherapy.

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