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K. Kajiura



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    P1.02 - Poster Session with Presenters Present (ID 454)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-081 - The Relationship of CDH3 Expression and DNA Methylation in Thymic Epitherial Tumors (ID 5929)

      14:30 - 15:45  |  Author(s): K. Kajiura

      • Abstract
      • Slides

      Background:
      The genome wide sequence and microarray has performed flourishingly for major cancer specimen in recent day. However, thymic epithelial tumor(TET) was rare tumor comparatively, there are few reports about epigenetic alternation in TET. Cadherin-3, also known as P-cadherin, is a protein encoded by the CDH3 gene. This study was aimed at identifying the relationship DNA methylation and gene expression of CDH3 gene in TET, especially B3 thymoma and thymic cancer.

      Methods:
      A)DNA methylation 1) DNA were extracted fresh frozen samples of B3 thymoma and thymic cancer, diagnosed as squamous cell carcinoma. These samples collected from the patients, diagnosed as TET, underwent surgery at Tokushima university from 1990 to 2016. 2) DNA was treated by bisulfite conversion. 3) DNA methylation level was measured by infinium methylation assay(Human Methylation 450K DNA Analysis Kit ; Illumina) exhaustively. 7 cases of thymic cancer and 8 cases of B3 thymoma applied this assay. 4) The methylation levels of CpG sites were calculated as β-values (β = Intensity (methylated)/intensity (methylated + unmethylated) by applying default settings of the GenomeStudio Software's DNA methylation module (Illumina). Analysis of this methylation assay used by R package. B) Immunostaining Immunostaining was performed Envision method. It was used Anti-pan-Cadherin antibody (ab16505), dilution 1300 times as first antibody. DAKO Chemomate EnVsion kit was used as second antibody.

      Results:
      CDH3 had 2 CpG islands. 450K methylation assay set 5 CpG sites on first CpG island as promoter region. (CpG sites:B3 thymoma averageβ-values : thymic cancer averageβ-values : p-value by t-test)=(cg0900242 : 0.07±0.08 : 0.45±0.05 : 2.7×10[-7]), (cg07061260 : 0.21±0.21 : 0.55±0.09 : 3.3×10[-3]), (cg00748373 : 0.19±0.20 : 0.45±0.07 : 0.01), (cg06575065 : 0.28±0.18 : 0.50±0.07 : 0.02), (cg27417609 : 0.35±0.21 : 0.59±0.09 : 0.02). Immunostaining specimen were classified by scoring system measured by stain intensity and stain expanding. It was classified 2points;strong, 1point;weak, 0point;none, in stain intensity. It was classified 3points;diffuse(>80%), 2point;moderate(50-80%), 1point;focal(20-50%), 0point;none(<20%) in stain stain expanding. Expression rate(stain intensity point and stain expanding point) defined more than 4point as expression promotion. Expression promotion rate is 0% in B3 thymoma and 75% in thymic cancer.

      Conclusion:
      DNA methylation of CDH3 was increasing and P-cadherin protein expression was increasing in thymic cancer compared to B3 thymoma.

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    P1.03 - Poster Session with Presenters Present (ID 455)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Radiology/Staging/Screening
    • Presentations: 1
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      P1.03-030 - FDG-PET/CT Might Be a Predictor for Residual Disease in Advanced NSCLC after Chemoradiotherapy (ID 6299)

      14:30 - 15:45  |  Author(s): K. Kajiura

      • Abstract
      • Slides

      Background:
      The standard treatment for locally advanced non-small-cell lung cancer (NSCLC) is chemoradiotherapy (CRT), some patients are considered for trimodality therapy represented by concurrent CRT followed by surgical resection. However, there is no validated clinical predictor for surgical resection after CRT. In the present study, we analyzed that the correlation between SUVmax of FDG-PET/CT in pre/post CRT and treatment effect.

      Methods:
      22 patients with advanced NSCLC underwent CRT in Tokushima University Hospital between February 2006 to March 2016. we reviewed the medical records of 22 patients to obtain information on age, gender, histological type, clinical stage, adverse events, reduction ratio of tumor, SUVmax of FDG-PET/CT in pre/post CRT. Radiographic response was assessed by Modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Toxicities were assessed according to the National Cancer Institute Common Toxicity Criteria (NCI-CTCAE).

      Results:
      Patient characteristics were as follows: average age of 65; male/female: 21/1, histologic type adenocarcinoma/squamous cell carcinoma/other: 14/5/3; clinical stage IB/IIB/IIIA: 1/3/18. Chemotherapy were platinum doublets regimen in almost cases. The average amounts of radiotherapy were 42Gy. The response rate was 29%. The number of PR/SD were 10/22 in RECIST. The adverse events were following: G2;11(50%), G3;8(36%), G4;5(23%). 2cases stopped treatment because of adverse events. Operative procedure were followings: lobectomy/bilobectomy/pneumonectomy: 17/2/3. The complication rate of operation was 27.2%, however, there was no hospital death. Overall survival was 69.7±10.3 months. Relapse free survival was 64.5±12.3 months. Pathological Complete Response(pCR) was recognized in 10cases(45.5%). The 4cases in 10cases of pCR got recurrence as distant metastasis, without local recurrence. The SUVmax decreasing rate was 69.8% in CRT. The SUVmax decreasing rate was 79% in the patients of pCR(n=5), however, this decreasing rate was 65% in not pCR(n=7, p=0.059). All cases of pCR indicated the SUVmax decreasing rate was more than 70%.

      Conclusion:
      The pCR were recognized in 10/22(45/5%) cases, underwent CRT. The treatment response in localregion was good in all cases. The SUVmax decreasing rate was more than 70% in all pCR cases.

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    P1.08 - Poster Session with Presenters Present (ID 460)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Surgery
    • Presentations: 1
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      P1.08-005 - Stratification of pStage I Lung Adenocarcinoma by the Scoring System Based on Prognostic Factors (ID 5168)

      14:30 - 15:45  |  Author(s): K. Kajiura

      • Abstract
      • Slides

      Background:
      In Stage I lung cancer, tumor size and PL factors are only reflected by the TNM staging system. However, other clinicopathological factors have the potential to influence recurrence and prognosis, especially in pStage I lung adenocarcinoma. This study aimed to evaluate prognostic factors, and to thereby stratify pStage I lung adenocarcinoma patients.

      Methods:
      A total of 203 patients who underwent curative resection for Stage I invasive adenocarcinoma, from 2006 to 2013, were retrospectively reviewed. [18]F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) was performed in 194 patients and the maximum standardized uptake value (SUVmax) of the tumor was calculated. Invasive adenocarcinoma was classified into 3 predominant subtypes (lepidic, papillary and others) according to the IASLC/ATS/ERS classification. The associations between various clinicopathological factors and recurrence were evaluated, and disease-free survival (DFS) was analyzed.

      Results:
      Twenty-eight patients had recurrent disease during the follow-up period (mean; 59.3±25 months). Univariable analysis showed male gender, smoking history >20 pack-years, BMI≦20, CEA>5ng/ml, T classification, tumor size>20mm, predominant histologic subtype (lepidic, papillary, others), pleural invasion, vascular invasion, and SUVmax>3.0 to be significantly associated with worse DFS. On multivariable analysis, tumor size>20mm (P=0.006), papillary predominant (P=0.023), other predominant (P=0.008), and SUVmax>3.0 (P=0.008) were extracted as independent prognostic factors associated with worse DFS. Predictive variables were scored as follows; tumor size>20mm (1 point), papillary predominant (1 point), other predominant (2 points) and SUVmax >3.0 (1 point). Patients were classified into 3 risk groups (low-risk; 0-2, intermediate-risk; 3, high-risk; 4) according to their aggregate scores. The 5-year DFS rate was 91% in the low-risk group, 55% in the intermediate group and 36% in the high-risk group. The 5-year DFS rates during the same period in our institute were 88% in pStage IA, 69.5% in pStage IB, 53% in pStage II, and 38% in pStage IIIA patients. Therefore, the DFS rate in the intermediate-risk group was comparable to that of pStage II, and the DFS rate in the high-risk group was comparable to that of pStage IIIA.

      Conclusion:
      In Stage I lung adenocarcinoma, tumor size, SUVmax and histologic subtypes were suggested to be prognostic factors. This scoring system may predict the groups, such as patients with pStage II and IIIA, requiring platinum based post-operative chemotherapy.

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    P2.04 - Poster Session with Presenters Present (ID 466)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      P2.04-052 - Promoter Hypermethylation of DNA Mismatch Repair Gene hMLH1 of Lung Cancer in Chromate-Exposed Workers (ID 6112)

      14:30 - 15:45  |  Author(s): K. Kajiura

      • Abstract
      • Slides

      Background:
      Although it is known that chromium is an important inhaled carcinogen for lung cancer, there are few reports about genetic effects of chromium in oncogenic process. Our previous studies revealed that chromate lung cancer frequently had microsatellite instability (MSI), and that MSI was associated with the loss of expression of MLH1, which is one of the essential DNA mismatch repair proteins. Inactivation of MLH1 due to promoter methylation causes high level of microsatellite instability in hereditary nonpolyposis colorectal cancer (HNPCC). Therefore, we hypothesized that loss of expression of MLH1 in chromate lung cancer is caused by MLH1 promoter methylation similar to HNPCC. In the present study, we analyze DNA methylation of MLH1 promoter regions in chromate and non-chromate lung cancers and clarify whether methylation of MLH1 has the influence on MLH1 protein expression and MSI.

      Methods:
      Thirty-three tumor samples from chromate workers with lung cancer and thirteen tumor samples from lung cancer patients without chromate exposure (non-chromate group) were obtained. DNA was extracted from chromate and non-chromate lung cancer and bisulfite pyrosequencing was used to examine DNA methylation levels of MLH1 promoter regions. MSI, MLH1 protein expression of these tumor samples have been investigated in our previous studies.

      Results:
      High methylation levels of MLH1 promoter regions were found in 42.4% (7/33) of chromate lung cancers and 15.4% (2/13) of non-chromate lung cancers. Methylation rates of MLH1 promoter region and the grade of MSI were related to positive correlation in chromate lung cancers. Immunohistochemistry for MLH1 was performed in 24 chromate lung cancer, High methylation of MLH1 was found in 27.3% (3/11) of tumors with repression of MLH1 protein and 4.3% (1/13) of tumors with normal expression of MLH1 protein.

      Conclusion:
      According to the present data, DNA methylation of MLH1 promoter regions might contribute to loss of expression of MLH1 protein and MSI. We speculate that in addition to genetic changes, epigenetic events have emerged in chromium carcinogenesis.

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