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H. Nishiguchi



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    P1.01 - Poster Session 1 - Cancer Biology (ID 143)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 2
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      P1.01-021 - Class III beta-tubulin expression in non-small cell lung cancer as a predictive marker for paclitaxel. (ID 2627)

      14:10 - 14:24  |  Author(s): H. Nishiguchi

      • Abstract

      Background
      Paclitaxel is one of the key drugs used in chemotherapy for the non-small cell lung cancer (NSCLC). Anti-microtubule agents, such as paclitaxel, stabilizes the microtubule polymer and prevents their breakdown. Data from the metastatic study suggest high tumor class III beta-tubulin (TUBB3) expression is a determinant of insensitivity to paclitaxel. To clarify whether TUBB3 is a true predictive marker for chemotherapy with paclitaxel, chemosensitivity was examined using an in vitro drug sensitivity assay.

      Methods
      Initially, 12 specimens were obtained to analyze the dose-response curve and to measure the median effective dose 50 (ED50) in the histoculture drug response assay (HDRA). The HDRA was perfomed for paclitaxel at several concentrations (minimum 0 μg/ml ,maximal 256μg/ml), in order to analyze the dose-response curves for individual patients. The value that was obtained from HDRA were directly applied for non-linear least square analysis using a formula of simplified dose-response curve. Subsequently, 41 surgically resected NSCLC specimens were applied to the HDRA and inhibition ratio at the concentration of 25μg/ml paclitaxel (IR25) was measured. H-scores were calculated by immunohistochemical staining. The patients comprised 26 male patients and 15 female patients. Mean age was 72±6.8. The specimens examined were 24 adenocarcinomas 17 squamous cell carcinomas.

      Results
      The mean (±SD) slope factor, ED50 and maximal response was 11.7±6.5, 24.6±7.73 μg/ml and 87.4±6.15% respectively. And the mean H-score was 50; (20-140). Among 12 specimens whose dose-response curve was obtained, the ED50 was higher than 25μg/ml in 5 (Resistant group) and lower in 7 (Sensitive group). The median H-score was significantly (p=0.0076) higher in Resistant group (240) than in Sensitive group (10). The mean IR25 was 53.8±26.6%. The median H-score in the specimens with IR25 above 50% (60, n=15) was significantly (p=0.0337) higher than that in specimens with IR25 under 50% (35, n=26).

      Conclusion
      Tumors with high TUBB3 levels exhibited chemoresistance to paclitaxel than tumors with low TUBB3 levels. HDRA revealed that TUBB3 expression is a true predictive factor for the response of paclitaxel in NSCLC.

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      P1.01-022 - Calbindin-D28k expression is correlated with the organotropism of lung cancer adrenal metastasis. (ID 946)

      14:24 - 14:38  |  Author(s): H. Nishiguchi

      • Abstract

      Background
      Lung cancer easily metastasizes to multiple organs, such as bone, lung, brain, liver, and adrenal gland. The frequency of the distant metastasis usually appears to be dependent on the volume of each target organ. However, metastasis to the adrenal gland is frequently observed in spite of its small volume. We hypothesized that some organotropic mechanisms exist in lung cancer adrenal metastasis. We applied microarray analysis to find the gene expression influencing organotropism of lung cancer adrenal metastasis.

      Methods
      Human lung adenocarcinoma cell lines PC-14, A549, and VMRC-LCD were used. Cell were cultured for 7 days on the fresh tissue slice of athymic mouse (Balb/c-nu/nu) adrenal gland. After that, proliferated cancer cells were collected from the surface of adrenal gland and cultured in the flask again. This process was repeated up to 5 times. This procedure was also applied to the other organs, which were lung, kidney, bone, and muscle, at the same time. Then the conditioned cells from each organ were obtained. Microarray analysis was applied to these cells including original cells in order to detect specific gene alteration in each organ. Expressions of 28869 genes were evaluated in each cell using microarray analysis. Gene expressions of conditioned cells obtained from each organ were compared with original cells. The genes with expression altered 1.5 fold or more were regarded as significant. Adrenal gland specific alterations were checked using unpaired t-test. The values P<0.05 were regarded as significant.

      Results
      Adrenal gland metastasis specific alteration was observed in 76 genes. There were 59 genes with increased expressions and 17 genes with decreased expressions. The same statistical analysis was applied to lung, liver, kidney, bone, and muscle, too. We detected 22 genes as lung metastasis specific alterations, 212 with liver, 25 with kidney, 141 with bone, and 27 with muscle. The most change in adrenal grand was increased expression of calbindin-D28k. Calbindin-D28k has anti-apoptotic properties. These properties may suppress steroid induced apoptosis and promote adrenal metastasis in lung cancer. In vitro evaluation revealed that proliferation of original PC-14 cells was inhibited by 1,4, 16, 64 µg/ml of dexamethasone in the dose-dependent manner. On the other hand, proliferation of PC-14 cells obtained from adrenal grand was not inhibited by dexamethasone in all concentrations.

      Conclusion
      Microarray analysis was applied to find the gene expression influencing organotropism of lung cancer adrenal metastasis. Our study results detected 76 genes as the candidates. Calbindin-D28k seemed to regulate lung cancer adrenal metastasis.

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    P2.19 - Poster Session 2 - Imaging (ID 180)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P2.19-011 - Compensation of vital capacity of residual lobes after lung resection in patients with lung cancer (ID 2493)

      09:30 - 09:30  |  Author(s): H. Nishiguchi

      • Abstract

      Background
      Major lung resection may induce expansion of the remaining lung, accompanied by some gain in the function of this lung. Pulmonary function studies have been performed in thoracotomy patients mainly for the purpose of predicting postoperative morbidity and mortality. Lobectomy is the standard operative procedure for lung cancer. However, the impact of this compensatory response of the residual lobes remains unclear, because spirometry cannot evaluate pulmonary function of individual lobe as single units.

      Methods
      Thirty-one patients who underwent lobectomy were included in this study. They were consisted of 15 males and 16 females, and 67 years old in average. Surgical procedures were 30 lobectomies and 1 bilobectomy. Chest CT scans at inspiratory and expiratory levels were performed at the same time using 40-slice MDCT (Brilliance 40, Philips, Netherlands). Scan conditions were 120 kV, ≤ 250 mAs, 0.5 sec./rotation, 32x1.25 configuration, pitch 0.906, and 5 sec. scan time. We then calculated the volume of individual lobes using graphic workstation (Virtual Place Lexus 1.0, AZE, Japan). Voxels with -215 HU or less were regarded as the air in the lung. VC of each lobe (VCL) was calculated as lobar volume at the inspiratory level subtracted by lobar volume at the expiratory level. This CT volumetry was performed before and 1 year after surgery.

      Results
      VCLs of the residual lobes in the operated side were 1.01±0.47L before surgery, and significantly (p=0.0094) increased to 1.22±0.74L after surgery. There was 22.3±43.6% gain in VCL of the lobes in the operated side after surgery compared with that before surgery. However, there was no significant difference (p=0.7040) in VCLs of the lobes in the unoperated side between before (1.71±0.71L) and after (1.69±0.63L) surgery. The rate of compensatory response of VCL of the residual lobes in the operated side was significantly (p=0.0002) correlated with the percentage of the VCL of the resected lobes. Statistical analysis revealed that the rate of compensatory response (%) could be calculated as the ratio of VCL in resected lung (%) before surgery multiplied by the constant of 1.556.

      Conclusion
      The compensatory response in pulmonary function after lobectomy appeared to occur only in the lobes in the operated side. The rate of this functional gain was significantly correlated with the ratio of the VCL in the resected lobes. These data may provide more precise prediction of postoperative lung function in patients who underwent lung 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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      P3.19-016 - Fast Fourier transform analysis for the contour of pulmonary nodules. (ID 2641)

      09:30 - 09:30  |  Author(s): H. Nishiguchi

      • Abstract

      Background
      Differential diagnosis of primary lung cancer and metastatic lung tumor before surgery is important. However, histological diagnosis using bronchofiberscopy is often difficult in these small peripheral lung nodules. It appears to be useful to diagnose pulmonary nodules using chest CT. As already known, primary lung cancer presents complicated appearance in chest CT. Contour of primary lung cancer is expressed using the words such as undulated, irregular, and spiculated. Contrary, metastatic lung tumor usually shows simple round shadow. These characteristics are used for the differential diagnosis of tumors. However, we often meet tumors with borderline complexity that we are not able to clearly classify. Chest CT finding is expressed by words at the diagnosis. Therefore, it is difficult to standardize or compare the diagnostic properties. Numerical evaluation of complexity of tumor outline results in the quantitative evaluation of tumor shape and may help the standardization of diagnosis of pulmonary nodules on chest CT. Malignant pulmonary tumors basically show round appearance. Therefore, complexity of tumor outline is to be expressed by the deviation from a circle. And the extent of deviation can be expressed numerically. The array data set of the deviation is to be regarded as the composition of various kinds of waves. Fast Fourier transform (FFT) analysis is suitable to evaluate these components of the wave data. In this study, we performed the quantitative analysis for the complexity of tumor outline of both primary lung cancer and metastatic lung tumor utilizing FFT analysis. And then we evaluated the usefulness and adequacy of our evaluation method.

      Methods
      Sequential cases of 72 histologically proven primary lung cancers (Group PL) and 54 metastatic lung tumors (Group MT) were included. The diameters of tumors in groups PL and MT were 18.9±7.4 mm and 12.2±6.1 mm, respectively. The outline of each tumor on chest CT images was described using polar coordinates, and converted to rectangular coordinates, yielding wave data of the tumor outline. The FFT was then used to analyze the wave data. The complexity index (Cxi) was defined as the sum of the amplitude of all harmonics over a fundamental frequency.

      Results
      The Cxi was higher (P <0.0001) for group PL (10.3±6.7 mm) than for group MT (3.2±2.4 mm), and it was correlated with tumor diameter in both groups: PL (r =0.667, P <0.0001) and MT (r = 0.809, P <0.0001). The cut-off equation “Cxi = 0.127 DT + 2.23” provided the highest diagnostic accuracy for distinguishing Group PL from Group MT such as a sensitivity of 95.8%, a specificity of 81.5%, and an accuracy of 89.7%.

      Conclusion
      Complexity of outline of the pulmonary nodules can be evaluated quantitatively using FFT analysis. This analytical procedure was designed from the beginning as it can be equipped on the graphic workstation, and we are now starting to develop it. This analytical method will help the diagnosis of primary lung cancer. FFT analysis appears useful for quantification of complexity of the tumor outline.