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M. Sonobe



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    MO04 - Lung Cancer Biology I (ID 86)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO04.07 - Chronic lung injury by constitutive expression of AID leads to focal alveolar regeneration and cancer (ID 116)

      16:55 - 17:00  |  Author(s): M. Sonobe

      • Abstract
      • Presentation
      • Slides

      Background
      Activation-induced cytidine deaminase, AID, is an enzyme required for somatic hypermutation and class-switch recombination which diversify immunoglobulin genes and causes DNA mutations and strand breaks. Uncontrolled expression of AID is cytotoxic. AID transgenic mice invariably develop lung lesions morphologically similar to human atypical adenomatous hyperplasia (AAH), which can be a precursor of bronchioloalveolar carcinoma. About 10 % of these mice develop visible lung tumor including adenocarcinoma. However, the relationship between this mouse AAH-like lesion (MALL) and lung cancer is unclear. In the present study, we examined MALLs to elucidate their characteristics and involvement in lung cancer.

      Methods
      p53, KRAS, and EGFR mutation status in each laser-microdissected MALL were analyzed. The expression of airway epithelial cell markers and lung alveolar regeneration markers in MALLs were investigated by immunohistochemistry. Apoptosis assay were performed in murine lungs. For cell proliferation assay, AID Tg mice were received a daily intraperitoneal injection of 1 mg 5-ethynyl-2’-deoxyuridine (EdU) for 7 days. Then, mice were studied 1 day (day 1) or 3 weeks (day 20) after the last injection.

      Results
      We found mutations of p53 in 10.5% of MALLs (4/38), but no mutations of KRAS and EGFR. In immunohistochemistry, MALLs were partially positive for SP-C (lung alveolar type II cell-specific marker), but negative for CC-10 (clara cell-specific marker) and podoplanin (lung alveolar type I cell-specific marker). Frequency of apoptotic cells among lung alveolar wall cells was significantly higher in AID transgenic mice than in wild type mice. Moreover, frequency of Edu-positive MALL decreased significantly at day 20 compared to that at day 1. The expressions of p63, cytokeratin 5/14, and E-cadherin/Lgr6, the recently described markers of lung alveolar regeneration, were observed in MALLs.

      Conclusion
      Based on these observations, we speculate that MALL is a regenerating tissue compensating for alveolar epithelial cell loss caused by AID-induced genotoxic stress. AID expression in such regenerating tissue should predispose cells to malignant transformation by its mutagenic activity. AID transgenic mice could be a mouse model that may provide the link between lung regeneration after injury and the development of lung cancer.

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    O13 - Limited Resections (ID 101)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Surgery
    • Presentations: 1
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      O13.03 - Survival of 1963 lobectomy-tolerable patients who underwent limited resection for cStage I non-small cell lung cancer (ID 1030)

      10:50 - 11:00  |  Author(s): M. Sonobe

      • Abstract
      • Presentation
      • Slides

      Background
      Although the standard operation for lung cancer is lobectomy, precise preoperative diagnosis of the “very early” lung carcinomas may identify patients that can be treated by limited resection. Previous reports on limited resection included patients who were not candidates for lobectomy. The survival of non-small cell lung cancer (NSCLC) patients who were fit for lobectomy and underwent limited resection has not been studied in a large enough scale.

      Methods
      A nationwide multi-institutional project collected clinical data of patients who underwent limited resection (segmentectomy or partial resection) for clinical T1-2N0M0 non-small cell lung carcinoma, who were 75 years old or younger at the time of operation and were considered fit for lobectomy by the physician. Overall and disease free survival, freedom from recurrence were analyzed and factors affecting survival or recurrence were identified.

      Results
      The median age of 1963 patients was 63 years. The mean maximal diameter of the tumor was 1.4 ± 0.6 cm. The overall and recurrence free survival after limited lung resection was 93.7 % and 90.4 % at 5 years, respectively. The recurrence free proportion and local recurrence free proportion were 93.3 % and 98.4 % at 5 years, respectively. Prognostic factors in overall survival were pathologically proven lymph node metastasis, interstitial pneumonia, male gender, older age, complications (cardiac disease, diabetes etc.), radiological invasive cancer, and multiple lesions. The consolidation/tumor ratio on CT of ≤ 0.25 predicted good outcome especially in cT1aN0M0 disease. Prognosis and recurrence was not affected by the method of limited resection (segmentectomy (n=1225) or partial resection (n=738)).

      Conclusion
      If the patient was 75 years old or younger and was judged fit for lobectomy, the result of limited resection for cStage I NSCLC was excellent and was not inferior to the reported result of lobectomy for small sized NSCLC. The radiological noninvasive carcinomas rarely recur and are especially good candidates for limited resection.

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    P3.19 - Poster Session 3 - Imaging (ID 181)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P3.19-005 - Quantitative CT predicts histological tumor invasiveness: analysis on 211 lesions of cT1N0M0 lung adenocarcinoma (ID 1500)

      09:30 - 09:30  |  Author(s): M. Sonobe

      • Abstract

      Background
      Biological behavior of small lung adenocarcinoma differs in each patient. High intensity area of the tumor on single slice of chest CT has been reported as a prognostic factor in several studies. However, because single slice is obviously insufficient to utilize all of the information on CT images of a tumor, we applied 3- dimensional volumetric evaluation for whole tumor volume. Our study aims to predict lymph node metastasis and tumor invasiveness by means of preoperative quantitative CT for lung cancer patients.

      Methods
      From January 2011 to November 2012, 236 lesions of cT1N0M0 lung adenocarcinoma were surgically resected in our institute. Among them, total 211 lesions of 193 patients were included in this study (Age: 67.2±9.5 male/female: 94/99). We analyzed preoperative CT images of 211 lesions of resected cT1N0M0 lung adenocarcinoma retrospectively. All patients were subjected to helical scanning using sections 1mm or less thick during one breath hold. We applied threshold of -800 and -300 Hounsfield units (HU) within those CT data, calculated the tumor volume, and then, integrated them with clinico-pathological information. We defined the area -300HU and over as “solid tumor volume” and between -800 to-301 HU as “GGO tumor volume”. Spearman’s rank test was utilized for statistical analyses.

      Results
      We divided those lesions into 3 groups by solid tumor volume; less than 0.25cm[3] (n=61), 0.25 to 1.5cm[3] (n=72), and over 1.5cm[3] (n=78). Solid tumor volume correlated with histological tumor invasiveness; less than 0.25cm[3], p1to3 (0, 0%) ly1 (0, 0%) v1 (0, 0%); 0.25 to 1.5cm[3], p1to3 (6, 77%) ly1 (1, 1%) v1 (1, 1%); over 1.5cm[3], p1to3 (14, 19%) ly1 (4, 6%) v1 (14, 19%), (p<0.01, p=0.03, p<0.01, respectively). Pathological tumor differentiation was also investigated; less than 0.25cm[3], well (34, 56%) moderate (26, 43%) poor (1, 2%); 0.25 to 1.5cm[3], well (17, 22%) moderate (57, 73%) poor (4, 5%); over 1.5cm[3], well (8, 11%) moderate (51, 71%) poor (13, 18%) (p<0.01). Lymph node metastases were found in none (0%) of solid tumor volume less than 0.25cm[3], in 2 (3%) with 0.25 to 1.5cm[3], in 6 (8%) with over 1.5cm[3] (p=0.01). Moreover we calculated the proportion of solid tumor volume / (solid tumor volume + GGO tumor volume) as “solid tumor ratio”. We divided those lesions into 2 groups by solid tumor ratio; 0.3 or less (n=123), and over 0.3 (n=88). Solid tumor ratio also correlated with histological tumor invasiveness; 0.3 or less, p1to3 (0, 0%) ly1 (0, 0%) v1 (0, 0%); over 0.3, p1to3 (20, 23%) ly1 (5, 6%) v1 (15, 17%). (p<0.01, p<0.01, p<0.01, respectively) Strikingly, lymph node metastases were found in none (0%) of solid tumor ratio 0.3 or less, but in 8 (9%) with over 0.3. (p<0.01)

      Conclusion
      Both tumor volume -300HU and over “solid tumor volume” and “solid tumor ratio” significantly correlated with tumor invasiveness. Preoperative quantitative CT is probably useful for predicting tumor invasiveness and lymph node metastases, and, as a result, effectively selecting operative procedure for cT1N0M0 lung cancer whether lobectomy or segmentectomy is applicable.