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J. Yoshida



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    OA07 - Lymph Node Metastases and Other Prognostic Factors for Local Spread (ID 376)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Surgery
    • Presentations: 1
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      OA07.05 - Prognostic Impact of Pleural Lavage Cytology (PLC): Significance of PLC after Lung Resection (ID 5801)

      14:20 - 15:50  |  Author(s): J. Yoshida

      • Abstract
      • Presentation
      • Slides

      Background:
      We previously reported the prognostic significance of pleural lavage cytology (PLC) in patients undergoing surgery for non-small-cell lung cancer (NSCLC). Based on a larger cohort of more than 3500 NSCLC patients, which is the largest ever reported from a single institution in the literature, we evaluated the prognostic impact of PLC on survival and recurrence.

      Methods:
      From January 1993 to July 2015, 3671 patients underwent R0 surgical resection for NSCLC at our institution and PLC results before (pre-) and after (post-) lung resection were both available. The cytological evaluation was classified into 3 categories: negative (-), suggestive (±), positive (+). We excluded 77 patients whose PLC results were suggestive, and 3594 patients were analyzed. The impact of PLC results on survival and recurrence was evaluated with conventional clinicopathological factors.

      Results:
      The overall survival (OS) of pre-PLC (+) patients was significantly inferior to that of pre-PLC (-) patients. However, the 5-year OS rate of pre-PLC (+) patients was 43%, which was significantly better than that of patients with pleural dissemination (11%). In the following analyses, we divided the patients into 3 groups according to pre/post- PLC results as follows: Pre (-)/ post (-), Group A (n=3461); pre (+)/ post (-), Group B (n=43); and post (+), Group C (n=87). Statistically significant difference was not observed between Groups A and B in OS or in recurrence-free survival (RFS) (p=1.00, 0.28, respectively). However, there were significant differences in OS and RFS between Groups B and C (p=0.01 and p=0.02), and between Groups A and C (p<0.01 and p<0.01), respectively. In univariate and multivariate analyses of clinicopathological factors including post-PLC results to identify prognosticators for OS, post-PLC(+) (hazard ratio (HR) =2.20, p<0.01), older age (≥65 years; HR=1.95, p<0.01), smoking history (+) (HR=1.48, p<0.01), elevated serum CEA level (>5.0 mg/dL; HR=1.28, p<0.01), pathological(p)T≥2 (HR=1.28, p<0.01), pN≥1 (HR=1.48, p<0.01), pStage≥II (HR=1.51, p<0.01), pl(+) (HR=1.43, p<0.01), ly(+) (HR=1.32, p<0.01), and v(+) (HR=1.53, p<0.01) were found to be significant independent unfavorable prognosticators.

      Conclusion:
      The prognostic impact of pre-PLC was moderate and not prohibiting lung resection. Post-PLC was shown to be a strong independent prognostic factor. Its impact on survival of NSCLC patients was very strong, and therefore should be incorporated in the future TNM classification.

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    OA15 - Sublobar Resections for Early Stage NSCLC (ID 396)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Surgery
    • Presentations: 1
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      OA15.01 - Limited Resection Trial for Pulmonary Sub-solid Nodules: Case Selection Based on High Resolution CT: Outcome at Median Follow-up of 105 Months (ID 4454)

      16:00 - 17:30  |  Author(s): J. Yoshida

      • Abstract
      • Presentation
      • Slides

      Background:
      The objective of this study is to confirm limited resection efficacy as radical surgery in patients with minimally invasive lung cancer as indicated by high-resolution (HR) computed tomography (CT), and to confirm intraoperative cytology as a negative margin indicator and reliable margin non-recurrence predictor.

      Methods:
      Enrollment required patients with a tumor ≤ 2 cm in diameter, diagnosed or suspected as a clinical T1N0M0 carcinoma in the lung periphery based on a CT scan. They had to have a HRCT scan indicating a sub-solid nodule with tumor disappearance ratio; TDR ≥ 0.5. (TDR = 1- DM/DL; DM: maximum tumor diameter on mediastinal settings, DL: maximum tumor diameter on lung settings). Patients unfit for lobectomy and systematic lymph node dissection were excluded. We performed a wedge or segmental resection. The used stapling cartridges were washed with saline, which was cytologically evaluated. If cytology was cancer positive, additional margin was resected, and cytologic examination repeated. If the second exam was positive, a routine lobectomy and systematic lymph node dissection was performed. We aimed at enrolling 100 patients. The primary endpoint is 10-year local recurrence free survival rate.

      Results:
      This prospective study started in November 2003, and 101 patients were enrolled in 6 years. Of them, 99 were eligible for analysis. The mean age was 62 years (range: 30-75), and 60 were women. There were 11 Noguchi type A tumors, 54 type B tumors, 26 type C tumors, one type D tumor, one malignant lymphoma, 3 hyperplastic lesions, and 3 inflammatory fibroses. None of the 93 malignant nodules showed any vessel invasion. Although no positive cytology results were obtained, pathologically positive margin was reported after surgery in one type C patient. He later underwent a routine lobectomy and systematic lymph node dissection. There was no clear correlation between tumor size, TDR, and Noguchi subtype. No mortality occurred, but one patient developed postoperative pneumothorax and pneumonia, and another hemorrhagic gastric ulcer. With a median follow-up period of 105 months (range: 72−129) as of June 2016, there have been no recurrences, but one patient died for unspecified cause.

      Conclusion:
      We have repeatedly warned that delayed cut-end recurrence is possible following limited resection even for small sub-solid lung cancers. So far, however, HRCT scans appear to predict non- or minimally invasive sub-solid lung cancers with high reliability, warranting limited resection as curative surgery in this cohort. Intraoperative cytology reliably indicated negative margins and seems to predict freedom from local recurrence.

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    P1.07 - Poster Session with Presenters Present (ID 459)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      P1.07-037 - Clinicopathological Significance of Cancer Stem-Like Cell Markers in High-Grade Neuroendocrine Carcinoma of the Lung (ID 4993)

      14:30 - 15:45  |  Author(s): J. Yoshida

      • Abstract

      Background:
      Over the past decade, cancer stem cells or cancer stem-like cells (CSLCs) have been identified in various tumors. However, few studies have examined the significance of CSLC marker expression in high-grade neuroendocrine carcinoma (HGNEC). This study aimed to evaluate the clinicopathological significance of CSLC markers in high-grade neuroendocrine carcinoma (HGNEC) of the lung, including small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC).

      Methods:
      We retrospectively studied patients who underwent surgical resection of SCLC (n = 60) and LCNEC (n = 45) to analyze their clinicopathological profiles and the immunohistochemical expression of putative CSLC markers (Caveolin, Notch, CD44, CD166, SOX2, ALDH1, and Musashi1). Staining scores for these markers in tumor cells were calculated by multiplying the percentage of positive tumor cells per lesion by the staining intensity level (0, 1, and 2); a score of ≥ 10 represented positive expression.

      Results:
      There was a difference between SCLC and LCNEC with respect to both SOX2 (55 vs. 27 %, p = 0.003) and CD166 (27 vs. 47 %, p = 0.034) expression. ALDH1 expression was equally observed in SCLC and LCNEC (67 vs. 73 %, p = 0.46), and patients with ALDH1-positive HGNEC had significantly worse recurrence-free survival (RFS) and overall survival (OS) rates than those with ALDH1-negative HGNEC (5-year RFS: 39 vs. 67 %, p = 0.009; 5-year OS: 50 vs. 79 %, p = 0.021). A multivariate analysis revealed that positive ALDH1 expression was an independent unfavorable prognostic factor with respect to both RFS and OS.

      Conclusion:
      The differences in the expression profiles of CSLC markers might reflect morphological differences between SCLC and LCNEC. Positive ALDH1 expression in lung HGNEC was associated with an unfavorable patient prognosis, which suggested that ALDH1-positive tumor cells might be future therapeutic targets for the treatment of lung HGNEC.

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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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      P1.08-062 - The Short and Long-Term Outcomes of Completion Pneumonectomy Compared with Primary Pneumonectomy (ID 5828)

      14:30 - 15:45  |  Author(s): J. Yoshida

      • Abstract

      Background:
      Completion pneumonectomy has been reported to be high morbidity and mortality procedure in lung cancer patients. However, we sometimes have no choice but to apply this procedure for the patients who developed secondary lung cancer in the remaining lung after lung resection, local recurrence, or postoperative complication. In this study, we investigated the short and long-term outcomes of completion pneumonectomy compared with primary pneumonectomy in our single institution.

      Methods:
      Between January 1997 and December 2014, 243 patients who underwent pneumonectomy in our institution were enrolled in this study. Retrospectively, we investigated the postoperative complication, short and long-term outcomes of the patients who underwent completion pneumonectomy (CP) and primary pneumonectomy (PP). CP was defined as pneumonectomy in patients with previous lung resection conducting a hilar manipulation.

      Results:
      Thirty-three patients (14%) of 243 patients underwent CP. CP was performed for 28 malignant tumors and 5 benign diseases. Postoperative severe complication (CTCAE Grade3 or more) occurred in 36% of CP group and 12% of PP group (p<0.01).Especially, bronchopleural fistula (BPF) was more likely to occur in patients undergoing CP (PP 5% vs CP 15%, p=0.03). The incidence of BPF in PP group was related to the side of procedure (right 70% versus left 30%, p=0.01), but those in CP group was not related (right 60% versus left 40%, p=0.57). In the patient with BPF after CP, Bronchial stump coverage was performed in 2 of 5 patients undergoing the right-side procedure, not performed in other 3 of 5 patients (2 left-side and 1 right-side). The 30-day mortality for CP group (9%) was a significantly higher compared with PP group (2%, p=0.04). However, the 90-day mortality (PP 5% vs CP 12%, p=0.14) and the overall survival (PP 47% vs CP 52%, p=0.44 ) were not significant difference between the two groups.

      Conclusion:
      Postoperative morbidity and 30-days mortality rates in CP were higher than those in PP group, but the long-term survival of CP is acceptable compared with PP group. The incidence of left-side BPF is similar to right-side in CP group in this study. It will be also necessary to take preventive procedure against BPF (bronchial stump coverage) in left-side CP.

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    P3.01 - Poster Session with Presenters Present (ID 469)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P3.01-024 - Drastic Morphological and Molecular Differences between Lymph Node Micrometastatic Tumors and Macrometastatic Tumors of Lung Adenocarcinoma (ID 5894)

      14:30 - 15:45  |  Author(s): J. Yoshida

      • Abstract
      • Slides

      Background:
      The expansion of micrometastatic tumors to macrometastatic ones is thought to be tightly regulated by several microenvironmental factors. The aim of this study was to elucidate the morphological and phenotypical differences between micrometastatic and macrometastatic tumors.

      Methods:
      We first examined the morphological characteristics of 66 lymph node (LN) micrometastatic tumors (less than 2 mm in size) and 51 macrometastatic tumors (more than 10 mm in size) in 42 lung adenocarcinoma cases. Then, we evaluated the expression level of E-cadherin, S100A4, ALDH1, and Geminin in cancer cells and the number of smooth muscle actin (SMA), CD34, and CD204 (+) stromal cells in the primary tumors, matched micrometastatic tumors, and macrometastatic tumors (n = 34, each).

      Results:
      Tumor budding reflects the process of EMT, and stromal reactions were observed more frequently in macrometastatic tumors (P < 0.001). E-cadherin staining score for the micrometastatic tumors was significantly higher than that for the primary tumors (P < 0.001). In contrast, the E-cadherin staining score for the macrometastatic tumors was significantly lower than that for the micrometastatic tumors (P = 0.017). As for the stromal cells, the numbers of SMA (+) fibroblasts, CD34 (+) microvessels, and CD204 (+) macrophages were significantly higher for the macrometastatic tumors and primary tumors than for the micrometastatic tumors (P < 0.001, all).

      Conclusion:
      The present study clearly showed that dynamic microenvironmental changes (e.g., EMT-related changes incancer cells and structural changes in stromal cells) occur during the growth of micrometastases into macrometastases.

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