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N. Yoshimoto



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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-037 - Transforming growth factor-β1 genetic polymorphisms relate to erlotinib induced diarrheaTransforming growth factor-β1 genetic polymorphisms relate to erlotinib induced diarrheaTransforming growth factor-β1 genetic polymorphisms relate to erlotinib induced diarrhea (ID 2681)

      09:30 - 09:30  |  Author(s): N. Yoshimoto

      • Abstract

      Background
      Rash, liver dysfunction, diarrhea and pneumonitis are known as adverse events of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Transforming growth factor-β1 (TGF-β1) is a cytokine and acts as an anti-proliferative factor in normal epithelial cells and epithelial-mesenchymal transition (EMT) with invasion and metastasis in cancer cells. TGF-β1 mediated Smad activation caused EMT, and activation of the EGFR. TGF-β1-mediated EGFR activation was abolished by EGFR suppression or extracellular EGF depletion pathway. TGF-β1 genotypes are associated with serum level of TGF-β1. It has been hypothesized that TGF-β1 genotypes may be implicated in clinical outcomes of EGFR-TKIs.

      Methods
      Patients were identified through a query of patient information for subjects enrolled in the Medical Information System in Osaka City University Hospital between January 1999 and February 2012. The associations between three genetic polymorphisms of TGF-β1 (C-509T, T869C, and G915C) and adverse events of erlotinib and gefitinib have been studied. Genomic DNA was extracted from peripheral blood or formalin-fixed and paraffin-embedded tissues. TGF-β1 genotypes were determined using RT-PCR method. The primers were designed to amplify the target fragments of TGF-β1 rs1800469, rs1800471, and rs1982073, respectively. In order to identify the risk factors for the adverse events, gender, age, stage and three genetic polymorphisms of TGF-β1 were selected and estimated for their potential confounding effects on rash, diarrhea, and liver dysfunction by multivariate analysis. Unconditional logistic regressions were used to compute the odds ratios (ORs) and their 95% confidence intervals (CIs). All analyses were two-sided, and p values of less than 0.05 were considered statistically significant. This study was approved by the ethics committee of Osaka City University (approval number, 1700).

      Results
      A total of 255 patients received gefitinib, and 75 patients received erlotinib. In the gefitinib group, the rates of rash, diarrhea, and liver dysfunction of grade 1 or more were 66.7%, 26.0% and 48.5%, respectively. In the erlotinib treatment group, the rates of rash diarrhea, and liver dysfunction of grade 1 or more were 84.1%, 43.5% and 33.3%, respectively. The C-509T consisted of TT in 26.6%, CT or CC in 73.3% of patients (n=289), respectively. The T869C consisted of CC in 26.1%, TC or TT in 73.9% of patients (n=272), respectively. The G915C consisted of GG in 100% of (n=313) patients. TT of the C-509T and CC of the T869C were significantly associated diarrhea of grade 1 or more in erlotinib group (OR 0.21, 95% confidence interval [CI] 0.054-0.72, p < 0.001, and OR 0.21, 95% CI 0.05-0.73, p = 0.014, respectively). No associations were observed between TGF-β1 genotypes and any adverse events in gefitinib group.

      Conclusion
      Minor alleles of TT of the C-509T and CC of the T869C were associated with erlotinib induced diarrhea. These alleles are generally associated with high level of TGF-β1 in serum. The increase level of TGF-β1 may be a risk factor for mucosal damage of the gastrointestinal tract in patients treated with erlotinib.

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    P3.03 - Poster Session 3 - Technology and Novel Development (ID 152)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.03-003 - The relationship between fresh macroscopic appearance of tissue specimen by CT guided biopsy and its clinicopathological feature in 58 patients with NSCLC. (ID 2688)

      09:30 - 09:30  |  Author(s): N. Yoshimoto

      • Abstract

      Background
      The CT-guided lung needle biopsy is a well-established and safety technique for diagnosis. A biopsy specimen often had loose connection and broke to tiny pieces before formalin fixation. Tumor invasion often involves the epithelial-mesenchymal transition (EMT) during which cells lose the lateral attachments to their neighbors and become more motile. The hypothesis is the fresh macroscopic appearance of specimens may relate pathological features and predict clinical features in patients with lung cancer.

      Methods
      The correlations between fresh macroscopic appearance of specimens and pathological findings or clinical outcomes were examined in patients who underwent CT-guided lung needle biopsy in our institution between May 2009 and May 2013. The intensity of fiber stained Azan staining (0, 1+, 2+, and 3+) and the percentage of positive cells (<1%, <25%, <50%, <75, and >75%) were assessed. The score of each case was multiplied to give a final score and the fibrosis was finally classified as low (<200) or high (>200). Comparisons of variables were performed by using Fisher exact tests.

      Results
      A total of 93 (86.1%) of 108 patients had adequate samples for diagnosis. The mean nodule diameter was 26 mm (range 4-75mm). CT findings revealed only three of 93 lesions showed ground-glass opacity, and all of them were in tight connection group. Macroscopically, 21.3% (n=23) specimens had loose connection, and 78.7% (n=85) specimens had tight connection. In loose connections, 73.9% (n=17) diagnosed as malignant and 26.1% (n=6) as benign, with sensitivity of 77.3%, specificity of 100%, and accuracy of 78.3%. In tight connections, 75.3% (n=64) as malignant and 24.7% (n=21) as benign, with sensitivity of 86.5%, specificity of 100%, and accuracy of 88.2%. There were 58 NSCLC samples, including 30 well or moderate (w/d or m/d), and 8 poorly differentiated (p/d) adenocarcinomas (Ad), 7 w/d or m/d, and 6 p/d squamous cell carcinomas (Sq), and 7 undifferentiated carcinoma. In 58 samples, 20.7% (n=12) specimens had loose connection and 79.3% (n=46) specimens had tight connection. In Azan staining, the tight connection group had 32 samples of high and 14 of low scores with the mean score of 213.6, and the loose connection group had 4 of high and 8 of low scores with the mean score of 118.6. The tight connection group had significantly higher scores than the loose connection group (p=0.042). The patients with loose connection had significantly higher rate of distant metastasis than those with tight connection (58.3% vs 21.7%, p=0.028). The median survival times are not reached in both groups.

      Conclusion
      Macroscopically loose connection specimens can afford to provide adequate amount of samples for diagnosis with sensitivity of 77.3%, and this appearance was negatively correlated with amount of fiber. Furthermore, the patients with loose connection tissue were associated with distal metastasis. The loose connection specimens may represent the status of EMT acquisition which is induced tumor initiation, growth, and metastasis. These findings suggest that the macroscopic appearance of tissue specimens obtained from CT guided biopsy can be an effective evaluation for prediction of metastasis in patients with NSCLC.