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Gouji Toyokawa



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    OA 13 - Immuno-Biology (ID 677)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      OA 13.06 - Co-Expression of IDO1 and PD-L1 Indicates More Aggressive Features of Lung Adenocarcinoma (ID 9672)

      11:00 - 12:30  |  Author(s): Gouji Toyokawa

      • Abstract
      • Presentation
      • Slides

      Background:
      Indoleamine 2, 3-dioxygenase 1 (IDO1) serves as an immunosuppressive effector and it is closely related to the prognosis in several types of cancer. We herein aim to elucidate the clinicopathological features and prognoses in patients with IDO1-expressing lung adenocarcinoma, and especially, show its correlation with the expression of programmed cell death-ligand 1 (PD-L1).

      Method:
      The expressions of IDO1 and PD-L1 proteins in 427 patients with surgically resected primary lung adenocarcinoma were evaluated by immunohistochemical analyses and any associations identified between IDO1 and the clinicopathological features, the prognosis and co-expression of IDO1 with PD-L1 were investigated. The expressions of IDO1 and PD-L1 at the protein and mRNA levels in lung adenocarcinoma cell lines were examined by an Enzyme-Linked Immuno Sorbent Assay, flow cytometry, and reverse transcription and real-time PCR analysis, respectively.

      Result:
      IDO1 was expressed in 260 patients (60.9%) at a 1% cut-off and in 63 patients (14.8%) at a 50% cut-off, respectively. PD-L1 was positive for 145 patients (34.0%). A ultivariate analysis showed IDO1 positivity (1% cut-off) to be significantly associated with a higher tumor grade, the presence of vascular invasion, and the expression of PD-L1. IDO1 and PD-L1 proteins were co-expressed in 123 patients (28.8%), and the patients whose tumor expressed both proteins exhibited significantly higher malignant traits than those whose tumor expressed only one protein or none. According to a multivariate analysis, the co-expression of both proteins was significantly associated with a shorter disease-free survival and overall survival. The expressions of IDO1 and PD-L1 in lung adenocarcinoma cell lines were elevated by treating them with interferon-γ and transforming growth factor-β.Figure 1



      Conclusion:
      The findings of this study suggest that the co-expression of IDO1 and PD-L1 may indicate more aggressive features of lung adenocarcinoma. Combination therapy targeting both of these proteins may therefore improve the clinical outcomes in patients with lung adenocarcinoma.

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    P1.07 - Immunology and Immunotherapy (ID 693)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 3
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      P1.07-002 - The Expression of PD-L1 Protein as a Prognostic Factor in Lung Squamous Cell Carcinoma (ID 7345)

      09:30 - 16:00  |  Author(s): Gouji Toyokawa

      • Abstract
      • Slides

      Background:
      Programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway-targeted immunotherapy has become the standard option of care in the management of lung cancer. The expression of the PD-L1 protein in lung cancer is expected to be a prognostic factor or to predict the response to PD-1-blocking antibodies. However, the association between PD-L1 positivity and the clinicopathological features and patient outcomes in lung squamous cell carcinoma (SCC) remains unclear because the definitive cut-off value for the expression of PD-L1 protein remains to be established.

      Method:
      The expression of PD-L1 protein in 205 surgically resected primary lung SCC patients was evaluated by immunohistochemistry with the antibody clone SP142. We generated a histogram to show the proportion of PD-L1-positive carcinoma cells as described in the figure below, and set the cut-off values as 1%, 5%, 10% and 50%. Moreover, we examined the proliferative capacity of these tumors using Ki-67 immunohistochemistry.Figure 1



      Result:
      The samples from 106 (51.7%), 72 (35.1%), 61 (29.7%) and 37 (18.0%) patients were positive for the expression of PD-L1 protein at cut-off values of 1%, 5%, 10% and 50%, respectively. Fisher’s exact test showed that, for almost all of the factors, PD-L1 positivity was not associated with the clinicopathological features with any of the four cut-off values. Univariate and multivariate survival analyses revealed that the PD-L1-positive patients only had a poorer prognosis than the PD-L1-negative patients at the 1% cut-off value. The Ki-67 labeling index in the PD-L1-positive patients was higher than that in the PD-L1-negative patients.

      Conclusion:
      The expression of PD-L1 protein was associated with a poor prognosis in lung SCC patients. The 1% cut-off value for PD-L1 might become a better predictive marker than the other cut-off values, and notably, even minimal expression of PD-L1 protein may have a negative prognostic significance.

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      P1.07-014 - Association of Preoperative Serum CRP with PD-L1 Expression in NSCLC: A Comprehensive Analysis of Systemic Inflammatory Markers (ID 8909)

      09:30 - 16:00  |  Author(s): Gouji Toyokawa

      • Abstract
      • Slides

      Background:
      Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have been approved as a standard therapy for metastatic non-small cell lung cancer (NSCLC). Although PD-L1 expression serves as a predictive biomarker for the efficacy of immunotherapy, there are no established biomarkers to predict the expression of PD-L1. The inflammatory markers C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) were recently shown to predict the efficacy of nivolumab for NSCLC patients. Therefore, here we investigated the potential association of PD-L1 expression with systemic inflammatory markers, including CRP, NLR, lymphocyte-monocyte ratio and platelet-lymphocyte ratio.

      Method:
      We retrospectively examined tumor PD-L1 expression in 508 surgically resected primary NSCLC cases by immunohistochemical analysis (cut-off value: 1%). The association of PD-L1 expression with preoperative systemic inflammatory markers was assessed by univariate and multivariate analyses. We generated a PD-L1 association score (A-score) from serum CRP level (cut-off value: 0.3 mg/dl) and smoking status to predict PD-L1 expression.

      Result:
      Among the total 508 patients, 188 (37.0%) patients were positive for PD-L1 expression at the 1% cut-off value and 90 (17.5%) had elevated serum CRP level. Multivariate logistic regression revealed that that PD-L1 positivity was significantly associated with advanced stage, the presence of vascular invasion and high serum CRP level (P=0.0336, 0.0106 and 0.0018, respectively). Though not significant, smoking history tended to be associated with PD-L1 protein expression (P=0.0717). There was no correlation with other inflammatory markers. Smoking history with elevated CRP level (A-score: 2) was strongly associated with PD-L1 protein expression (odds ratio: 5.18, P<0.0001), while it was inversely associated with EGFR mutation (odds ratio: 0.11, P<0.0001).

      Conclusion:
      Our results indicate that among all systemic inflammatory markers examined, serum CRP level could be a helpful biomarker for PD-L1 expression that is easily determined and available worldwide.

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      P1.07-044d - Positive Conversion of the PD-L1 Expression after Treatments with Chemotherapy and Nivolumab (ID 8693)

      09:30 - 16:00  |  Author(s): Gouji Toyokawa

      • Abstract

      Background:
      Programmed death-ligand 1 (PD-L1) expression serves as a predictive biomarker for the efficacy of immune checkpoint inhibitors. Some concern exists regarding the analysis of the PD-L1 expression, specifically with respect to the type of samples, i.e. archival or fresh tumor samples. Some studies reported about the conversion of PD-L1 with treatment; however, there were few reports about detailed clinical course of that. In this translational study, we investigated alternation of the PD-L1 expression in non-small cell lung cancer (NSCLC) before and after chemotherapy and nivolumab.Programmed death-ligand 1 (PD-L1) expression serves as a predictive biomarker for the efficacy of immune checkpoint inhibitors. Some concern exists regarding the analysis of the PD-L1 expression, specifically with respect to the type of samples, i.e. archival or fresh tumor samples. Some studies reported about the conversion of PD-L1 with treatment; however, there were few reports about detailed clinical course of that. In this translational study, we investigated alternation of the PD-L1 expression in non-small cell lung cancer (NSCLC) before and after chemotherapy and nivolumab.

      Method:
      We retrospectively examined the PD-L1 expression in the resected specimen and in the re-biopsy specimen patients with NSCLC by an immunohistochemical analysis. Re-biopsy was performed if disease progression was observed during the treatment.

      Result:
      Four patients were performed re-biopsy after the treatment. Of those, three patients showed positive conversion of the PD-L1 expression. The first case was a 76-year-old male smoker with postoperative recurrence of lung adenocarcinoma. The PD-L1 expression was negative in the resected specimen; however, after the treatment (first-line: platinum-based pemetrexed; second-line: nivolumab; third-line treatment: docetaxel), a re-biopsy of the recurrence lesion (axillary lymph node) showed a positive PD-L1 expression (expression of the tumor-cell membrane [TCM]: 25%). The second case was a 60-year-old male smoker who was diagnosed with carcinosarcoma. Approximately 36.2 months after the first-line (carboplatin+paclitaxel+bevacizumab), second-line (cisplatin+S-1+RTx [60Gy/30Fr.]), third-line (docetaxel), and fourth-line treatments (nivolumab), a relapse of the pulmonary lesion was observed. The PD-L1 expression was negative in the resected archival specimen; however, a re-biopsy of the pulmonary lesion showed a high PD-L1 expression (expression of TCM: 60%). The third case was a 70-year-old male smoker with postoperative recurrence of lung adenocarcinoma. Although the resected specimen showed weak positivity of the PD-L1 expression (expression of TCM: 5%), after the treatment (first-line: platinum-based pemetrexed; second-line: docetaxel; third-line: gemcitabine+navelbine; forth-line: nab-paclitaxel; fifth-line treatments: nivolumab) and palliative radiotherapy (30Gy) for rib metastasis, a re-biopsy of the rib metastasis showed a stronger positive PD-L1 expression (expression of TCM: 30%).

      Conclusion:
      The current three cases are the suggestive cases of the positive conversion of PD-L1 expression after the treatment including nivolumab, suggesting that PD-L1 expression must be assessed in not only the resected specimen but also in the re-biopsied ones, even if PD-L1 protein is not observed in the archival sample. However, whether or not the treatment-induced PD-L1 expression reflects the efficacy of immunotherapy should be clarified.

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    P2.05 - Early Stage NSCLC (ID 706)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Early Stage NSCLC
    • Presentations: 1
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      P2.05-017 - Prognostic Impact of the Clinical T Descriptor in the Eighth Edition of the TNM Staging System of Non-Small Cell Lung Cancer (ID 9494)

      09:30 - 16:00  |  Author(s): Gouji Toyokawa

      • Abstract
      • Slides

      Background:
      The diameter of the solid part of the tumor in a computed tomography (CT) image determines the clinical T descriptor of the new TNM staging system in non-small cell lung cancer (NSCLC). The purpose of this study was to investigate the appropriateness of the clinical T descriptor (cT) in respect to postoperative prognosis.

      Method:
      This retrospective study included consecutive patients who underwent complete resection in Oita University Hospital between 2006 and 2014 and those who underwent complete resection in Kyushu University hospital between 2003 and 2012. The complete clinical data of 1061 NSCLC patients were available for prognostic analyses. The whole tumor size (TS) in diameter and solid-part size (SPS) in diameter were measured by the thin-section CT image before surgery. The tumors with SPS/TS ratio (STR) = 0, those with 0 < STR < 100, and those with STR = 100 were defined as pure ground glass tumors (GGT), part-solid tumors (PST), and solid tumors (ST), respectively. The survival curves were estimated according to the Kaplan-Meier method and were assessed by the log-rank test.

      Result:
      The tumors included 809 adenocarcinomas (Ad), 197 squamous cell carcinomas, 31 large cell carcinomas, 18 adeno-squamous cell carcinomas, and 6 other types of tumor. The 5-year survival rate of patients according to the new cT descriptor (version 8) were cTis, 97.6%; cT1mi, 90.7%; cT1a, 87.8%; cT1b, 81.5%; cT1c, 72.8%; cT2a, 69.6%; cT2b, 55.6%; cT3, 55.0%; and cT4, 23.4%. In analyses of Ad patients, the 5-year survival rate of patients according to the whole tumor size were >0 -10 mm, 89.9%; >10 -20 mm, 89.1%; and >20 -30 mm, 84.1%, and that according to the solid part size were 0mm, 97.6%; >0 -10 mm, 91.9%; >10 -20 mm, 84.8%; and >20 -30 mm, 80.8%. The new cT descriptor predicted patient prognosis more effectively than the old cT descriptor of whole tumor size. Postoperative 5-year survivals of the GGT, PST and ST of Ad patients were 97.6%, 89.0%, and 76.3%, respectively (P<.0001). In analyses of the small-size PST (≤ 3 cm), the new cT descriptor did not adequately predict patient prognosis (P=.458).

      Conclusion:
      The new cT descriptor is a better prognostic indicator than the old cT descriptor in NSCLC. However, patients with small-size PST had a significantly better prognosis than those with ST Ad. Additionally, the new cT descriptor failed to adequately predict the prognoses of the patients with small size PST adenocarcinoma.

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    P2.09 - Mesothelioma (ID 710)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Mesothelioma
    • Presentations: 1
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      P2.09-005 - The C-reactive Protein/Albumin Ratio is a Novel Significant Prognostic Factor in Patients with Malignant Pleural Mesothelioma (ID 7375)

      09:30 - 16:00  |  Author(s): Gouji Toyokawa

      • Abstract
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) is a devastating neoplasm. However, some patients show a good response to chemotherapy or multidisciplinary therapy. It is therefore important to investigate the factors that can be used to select patients who will benefit from such treatment. The C-reactive protein/albumin ratio (CAR) has been used to predict the prognosis in other diseases. The aim of this study was to elucidate the prognostic utility of the CAR in MPM patients.

      Method:
      The data of 83 patients, who were treated with surgery, chemotherapy, or multidisciplinary therapy at National Kyushu Cancer Center between 1995 and 2015, were analyzed in the present study. The CAR was calculated as C-reactive protein value divided by albumin value using the results of blood examination just prior to starting the treatments. A cut-off value of CAR was set to 0.58 according to the receiver operating characteristics (ROC) curve for 1-year-survival.

      Result:
      Thirty of the 83 (36.1%) patients were classified into the high CAR group. Twenty-seven (32.5%) and 56 (67.5%) patients underwent surgery and only chemotherapy, respectively. The ROC curve showed that the CAR had good diagnostic ability with 78.9% sensitivity and 68.0% specificity (AUC=0.761). A high CAR group was significantly correlated with advanced clinical stage (III/IV) (p=0.002) and chemotherapy alone (p=0.005). The high CAR group had significantly poorer overall survival (OS) (p<0.001) and disease or progression free survival (DFS/PFS) (p<0.001). The clinical stage and the CAR were independent predictive factors for the OS (I/II and III/IV, p=0.008; ≤0.58 and >0.58, p=0.034, respectively). The clinical stage and the CAR were also independent predictive factors for the DFS/PFS (I/II and III/IV, p=0.031; ≤0.58 and >0.58, p=0.019, respectively). In the subgroup analysis of the patients who underwent only chemotherapy, the high CAR group showed significantly poorer OS and DFS/PFS compared with the low CAR group (p=0.002 and p<0.001, respectively). However, the difference in OS and DFS/PFS of the patients who underwent surgery was not apparent between the high and low CAR groups (p=0.061 and p=0.187, respectively).

      Conclusion:
      The CAR was an independent predictor of a poor prognosis in the MPM patients. The high CAR group showed a significantly poorer prognosis in patients with MPM treated by only chemotherapy. This score provides useful information for selecting patients who will benefit from treatment, especially chemotherapy. These findings should be validated in further prospective studies.

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    P3.16 - Surgery (ID 732)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Surgery
    • Presentations: 2
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      P3.16-003 - The Clinical Significance of Immune-Nutritional Parameters in Surgically Resected Elderly Patients with Non-Small Cell Lung Cancer (ID 7403)

      09:30 - 16:00  |  Author(s): Gouji Toyokawa

      • Abstract
      • Slides

      Background:
      The world’s population is rapidly aging, and the age of patients with lung cancer will increase as well. The prognostic nutritional index (PNI), controlling nutritional status (CONUT), and the geriatric nutritional risk index (GNRI) are useful parameters for evaluating immune-nutritional status. We aimed to perform a multicenter retrospective study to investigate the correlations of these immune-nutritional parameters with postoperative comorbidities or surgical outcomes of elderly patients with non-small cell lung cancer (NSCLC).

      Method:
      We selected 272 consecutive patients with NSCLC aged >75 years treated from January 2005 to December 2012 and evaluate three preoperative immune-nutritional parameters as potential predictive factors of postoperative comorbidities or as prognostic factors for surgically resected elderly patients with NSCLC.

      Result:
      Both PNI and GNRI as well as sex and preoperative respiratory comorbidities, were significantly associated with postoperative comorbidities (P =0.0287, 0.0443, 0.0191 and 0.0177, respectively). Multivariate analyses showed that preoperative GNRI (P = 0.0161) as well as sex (P < 0.0001), preoperative serum carcino embryonic antigen levels (P = 0.0128), preoperative serum cytokeratin 19 fragment levels (P = 0.0125), pleural invasion (P = 0.0214) and lymphatic vessel invasion (P = 0.0165) significantly affected overall survival (OS). Abnormal GNRI was significantly associated with histology (P = 0.0419) and outcome (P =0.0077). In Kaplan–Meier analysis of OS by preoperative GNRI, the abnormal GNRI group had significantly shorter OS than the normal GNRI group (5-year OS, 45.15% vs. 64.10%, P = 0.0007, log-rank test). CONUT score did not have any correlation with postoperative comorbidities or surgical outcome.

      Conclusion:
      Preoperative GNRI is a novel preoperative predictor of postoperative comorbidities as well as a prognostic factor that may identify high-risk elderly patients with NSCLC.

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      P3.16-033 - Significance of Spread through Air Spaces in Resected Pathological Stage I Lung Adenocarcinoma (ID 9182)

      09:30 - 16:00  |  Presenting Author(s): Gouji Toyokawa

      • Abstract

      Background:
      Spread through air spaces (STAS) is a novel invasive pattern of lung cancer, which spreads within air spaces beyond the edge of the main tumor, but not necessarily accompanying stromal invasion. In the current study, we investigated the significance of STAS in patients with pathological stage I adenocarcinoma.

      Method:
      STAS was assessed in a total of 276 patients with resected pathological stage I adenocarcinoma. STAS was classified as either no STAS, low STAS (1-4 single cells or clusters of STAS), or high STAS (≥5 single cells or clusters of STAS) using a 20x objective and a 10x ocular lens. We evaluated the association between STAS and the clinicopathological characteristics and postoperative survivals.

      Result:
      Among 276 patients, 123 (44.6%), 48 (17.4%) and 105 (38.0%) were classified as having no, low and high STAS, respectively. Fisher’s exact test demonstrated that positivity for STAS was significantly associated with a larger radiological tumor diameter (P=0.008), a higher consolidation/tumor ratio (P<0.001), a higher maximum standard uptake value (P<0.001), a pathologically larger tumor size (P=0.004), the presence of pleural invasion (P=0.027) and a histologically invasive type (P<0.001), while STAS was not significantly associated with epidermal growth factor receptor mutations or programmed death ligand-1 expression (P=0.129 and P=0.872, respectively). Patients with the STAS had significantly shorter recurrence-free and overall survivals than those without (P<0.001 and P=0.002, respectively). According to a multivariate analysis, positivity for STAS remained an independent prognostic parameter for both the recurrence-free and overall survivals.

      Conclusion:
      STAS was associated with clincopathologically invasive features and was predictive of a worse survival. Figure 1