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T. Mizuno



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    P1.07 - Poster Session 1 - Surgery (ID 184)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P1.07-021 - The risk factor of late recurrence in patients with completely resected non-small cell lung cancer (ID 1542)

      09:30 - 16:30  |  Author(s): T. Mizuno

      • Abstract

      Background
      Recurrences in patients with completely resected non-small cell lung cancer (NSCLC) rarely occur more than 5 years after operation. Various follow-up programs for postoperative patients are recommended in each guideline. The purpose of this study is to clarify the risk factor of late recurrence and to determine which patients might benefit from routine computed tomography (CT) follow-up more than 5 years after operation.

      Methods
      Between January 1995 and December 2006, 1,437 consecutive patients with NSCLC underwent pulmonary resections at our institution. Of these, 617 patients remained recurrence-free for 5 years after resection. We retrospectively analyzed the clinicopathological features of these patients. Disease free survival (DFS) was defined as endpoint and was analyzed using Cox proportional hazards model. Variables for univariate analysis were as follows: age, gender, smoking history, carcinoembryonic antigen, operative procedure, pathological type, pathological stage, and pleural lavage cytology (PLC).

      Results
      At the median follow-up time of 7.5 years, 20 patients (3.2%) developed late recurrence more than 5 years after resection. Distant metastasis occurred in 15 patients and locoregional recurrence occurred in 5 patients (Table 1). There were 3 patients (15%) with positive PLC in late recurrence group and 7 patients (1.2%) in recurrence free group. In univariate analysis, only PLC was significant. In a multivariate analysis, PLC was a significant predictor of late recurrence. The Hazard ratio (HR) for positive PLC in comparison to negative PLC was 5.75 (95% CI 1.16–19.26; p=0.04)Figure 1.

      Conclusion
      PLC is a strong independent factor for late recurrence. Patients with positive PLC might be good candidates for routine chest CT more than 5 years after resection.

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    P1.16 - Poster Session 1 - Other Thoracic Malignancies (ID 186)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Thymoma & Other Thoracic Malignancies
    • Presentations: 1
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      P1.16-002 - Histological impact of primary tumor on indication of repeated pulmonary metastasectomy (ID 1346)

      09:30 - 16:30  |  Author(s): T. Mizuno

      • Abstract

      Background
      Lung is one of the most common metastatic sites from malignances. Although efficacy of pulmonary metastasectomy (PM) has been reported recently, the prevalence has not been enough among thoracic surgeons. Moreover, beneficial effects of repeated PMs for longer survivals have been poorly evaluated. The aims of this study are to examine the efficacy of repeated PMs (Re-PM) for re-recurred diseases and evaluate the histological impact of the primary tumor on the treatment.

      Methods
      We retrospectively reviewed 263 patients who underwent PMs for various malignancies from 1996 through 2011. These factors below were evaluated; age, gender, origin of primary tumors, disease free interval (DFI) to the first PM, surgical procedure of PM, number of resected tumors, frequency of PMs, DFI after the first PM, overall survival after the first PM and prognosis.

      Results
      Among 263 patients, 166 were male, and 98 were female. The median age was 60 years old (range: 7-85). Origins of primary tumors were following; 91 colorectum, 54 bone and soft tissue, 22 head and neck, 20 adnexa uteri, 17 urinary tract, 14 testis (germ cell tumor), 45 others. Mean number of resected nodules at the first PM was one, and the maximum was 19. Wedge resections were performed most frequently in 159 patients (60%), lobectomies in 69 (26%), segmentectomies in 32 (12%), and bilobectomies in 5 (2%). Re-PMs were indicated in 47 patients (18%). Among them, while the prevalence of Re-PM was 20% (18/91) in colorectal cancer patients, that is as high as 37% (20/54) in bone and soft tissue sarcoma patients. Estimated five-year survival rate of the whole patients was 50.6%. And that of patients without recurrence, with Re-PM and without Re-PM were 92.9, 58.5 and 14.5%, respectively. In univariate analyses, sublober resection of the first PM, DFI and presence of complete resection at the first PM were significant favorable factors for overall survival. In the multivariate analysis, sublober resection and presence of complete resection at the first PM were revealed to be the independent prognostic factors.

      Conclusion
      The large portion of Re-PM patients had colorectal cancer, or bone and soft tissue sarcoma as their primary tumor. Re-PM may improve the survival of selected patients who experienced re-recurrence in lung after PM. Primary tumor of bone and soft tissue sarcoma were the most applicable histology for Re-PM.

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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P2.18-008 - Transformation to sarcomatoid carcinoma in ALK-rearranged adenocarcinoma which developed acquired resistance to crizotinib and received subsequent chemotherapies (ID 1723)

      09:30 - 16:30  |  Author(s): T. Mizuno

      • Abstract

      Background
      Non-small-cell lung cancers (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement are highly sensitive to the ALK kinase inhibitor crizotinib, but drug resistance invariably emerges. Morphological transformation from adenocarcinoma to SCLC represents one acquired resistance mechanism to epidermal growth factor receptor tyrosine kinase inhibitors. We present the case of transformation to sarcomatoid carcinoma in ALK-rearranged adenocarcinoma which developed acquired resistance to crizotinib.

      Methods
      not applicable

      Results
      A 32-year-old man presented with cough and bloody sputum. Computed tomography (CT) showed a mass in the S6 segment and diffuse consolidation throughout the lower lobe of the left lung. Transbronchial lung biopsy revealed adenocarcinoma with lymphangiosis. Immunohistochemistry (IHC) showed ALK protein expression and break-apart fluorescent in-situ hybridization (FISH) showed ALK gene rearrangement. First-line chemotherapy with cisplatin and docetaxel was started. After tumor progression, the patient was enrolled in the clinical trial and was allocated to the pemetrexed arm. Subsequently, he was enrolled in other trial to receive crizotinib in July 2011. After partial response was observed, a nodule in the S9 segment developed to 2cm in February 2012, and crizotinib was discontinued. CT scans performed after 4 cycles of carboplatin and gemcitabine showed a mixed response, with improvements in lymphadenopathy and lymphangiosis but progression of the mass in S9. CT-guided core-needle biopsy revealed ALK-positive atypical cells but it was impossible to distinguish histological types because of degeneration and necrosis. Thereafter, carboplatin, paclitaxel, and bevacizumab were administered, but the same mixed response was observed. The mass in S9 increased rapidly and reached 7 cm.  Left lower lobectomy was performed. The primary tumor in S6 was diagnosed as adenocarcinoma positive for thyroid transcription factor (TTF)-1 immunostaining, whereas the tumor in S9 was TTF-1-negative sarcomatoid carcinoma. ALK was positive with IHC in both tumors, and FISH revealed high-level gene amplification of the ALK fusion gene only in the sarcomatoid carcinoma. Reverse transcriptase polymerase chain reaction revealed the same variant of echinoderm microtubule-associated protein like 4-ALK (E13; A20) and it indicated that these tumors have the same origin. Moreover, in the sarcomatoid carcinoma, DNA sequencing revealed no additional resistance point mutations from ALK exon 20 to exon 23. Brain metastases occurred 2 months after pulmonary resection and he underwent brain surgery. The tumor was diagnosed as sarcomatoid carcinoma. Ten days later, he died due to exacerbation of lymphangiosis To discuss potential epithelial-to-mesenchymal transition (EMT), we performed E-cadherin and keratin staining as epithelial markers, and vimentin staining as a mesenchymal marker in 4 specimens. The specimens were pre-crizotinib specimen in S6, surgical specimen in S6, rebiopsied specimen in S9 after carboplatin and gemcitabine, and surgical specimen in S9. Rebiopsied specimen in S9 was unevaluable for IHC staining because of degeneration and necrosis. All of the 3 evaluable specimens showed positive expression of vimentin and only surgical specimen in S9 showed negative of epithelial markers.

      Conclusion
      The transformation from adenocarcinoma to sarcomatoid carcinoma could be interpreted as kind of EMT. This transformation might represent a novel acquired resistance mechanism to crizotinib, although there is another possibility that subsequent chemotherapies induced this transformation.

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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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      P2.19-010 - The association between baseline clinical-radiological characteristics and growth of pulmonary nodules with ground-glass opacity (ID 1729)

      09:30 - 16:30  |  Author(s): T. Mizuno

      • Abstract

      Background
      Pulmonary nodules with ground-glass opacity (GGO) are frequently encountered. We previously reported that, based on natural history of 108 pulmonary nodules that were 3 cm or less and had 50 % or more GGO component, these nodules should be followed for at least 3 years to accurately evaluate lesion growth. However, it remains unclear whether all GGOs should be followed for as long as 3 years. To establish reasonable follow-up plan, it would be useful to if we could predict which of GGO lesions tend to grow by any of clinical-radiographic characteristics. The purpose of this study was to clarify which baseline clinical and radiological characteristics were associated with growth of these nodules.

      Methods
      We retrospectively studied patients between 1999 and 2013 with pulmonary nodules that met the following criteria: (1) lesion diameter of ≤ 3 cm, (2) GGO proportion of ≥ 50%, and (3) observation without treatment in the prior 6 months. We evaluated the changes in lesion size on serial computed tomography. Two endpoints, “Time to 2-mm growth” and “2-mm growth incidence”, were analyzed using Cox proportional hazards and logistic regression models, respectively.Variables for univariate analysis were as follows: age; gender; smoking history; past history of lung cancer; lesion multiplicity; lesion diameter; and solid proportion. Factors for which p-value was < 0.05 in univariate analysis, as well as past history of lung cancer which was reported as a predictor in previous reports, were included in multivariate analysis. To strictly define “no growth”, we excluded lesions which had been observed for less than 3 years in logistic regression analyses.

      Results
      120 pulmonary lesions in 67 patients fulfilled inclusion criteria. At the median observation period of 4.2 years, 34 lesions had become larger by 2mm or more, whereas the remaining 86 had persisted without changing in size. Smoking history and initial lesion diameter were statistically significant in both regression and time-to-event analyses. In terms of time to 2mm growth, hazard ratio (HR) for smoking history was 3.67 (P < 0.01). Compared to those ≤ 1 cm, HRs for 1.1–2 cm and 21-3 cm lesions were 2.23 (P = 0.08) and 5.08 (P = 0.04), respectively. In contrast, odds ratio (OR) for the likelihood of 2mm growth for smoking history was 6.51 (P < 0.01), and OR for lesion diameter of 1.1–3 cm in comparison to ≤ 1 cm was 4.06 (P = 0.02).

      Conclusion
      Smoking history and initial lesion diameter are significantly associated with the growth of these nodules. These results suggested that closer follow up of larger size GGO in smoking patients be recommended.