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Y. Ishikawa

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    MS10 - Beyond Lung Cancer - The Pathology of Intra-Thoracic Mimics (ID 27)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Pathology
    • Presentations: 4
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      MS10.1 - Metastases to Lung and Differential Diagnosis (ID 501)

      14:00 - 15:30  |  Author(s): K.F. To

      • Abstract
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      Abstract not provided

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      MS10.2 - Salivary Gland Tumours and Lymphoepithelioma-Like Carcinoma (ID 502)

      14:00 - 15:30  |  Author(s): L. Chirieac

      • Abstract
      • Presentation
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      Abstract not provided

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      MS10.3 - Pleural Neoplasms (ID 503)

      14:00 - 15:30  |  Author(s): S. Klebe, D.W. Henderson

      • Abstract
      • Presentation
      • Slides

      Abstract
      Pleural neoplasms may be difficult to diagnose because they must be distinguished from metastatic malignancy involving the pleura, and from benign reactive processes causing pleural thickening. In contrast to primary lung neoplasms, primary pleural neo­plasms are uncommon, with secondary involvement being more frequent. A correct diagnosis is important, so that appropriate therapy can be delivered. Also, the diagnosis may affect the pateint’s prospects for compensation. The most common primary pleural neoplasm is mesothelioma, but compared to lung tumours even mesotheliomas are relatively rare. Mesotheliomas exhibit a wide variety of histologic patterns, which may be confused with other neo­plasms. Here we consider those other pleural lesions that must be differen­tiated from mesothelioma. Secondary Malignant Neoplasms Affecting the Pleura Secondary neoplasms represent the most common malignancy affecting the pleura, with lung carcinoma being the most common, followed by metastatic breast cancer, malignant lymphoma, (including Hodgkin and non-Hodgkin malignant lymphomas). Metastatic carcinomas of ovarian or gastric origin, malignant melanoma and sarcomas account for only a small percentage of cancer-associated pleural disease (about 5%). Some of these may show diffuse infiltration of the pleura in a pattern indistinguishable from pleural malignant mesothelioma macroscopically and radiologically. The majority of such so-called pseudomesotheliomatous neoplasms originate from the lung, but metastases from kidney, thyroid gland, larynx, stomach and cutaneous malignant melanoma as well as various sarcomas, including malignant phyllodes tumor, have also been described. Renal cell carcinoma (RCC) and amelanotic malignant melanoma may also metastasize to the pleura. RCCs with a sarcomatoid pattern can present a diagnostic problem. Labelling for RCC-related markers such as CD10 can also be seen in mesotheliomas and in sarcomatoid RCCs, the other RCC markers may be negative: correlation with imaging studies is imperative. Rare cases of sarcoma metastatic to the pleura may mascerade as mesothelioma and comprehensive clinical history is of highest imprtance. Other Neoplasms Arising in the Pleura Thymoma Affecting the Pleura Thymoma may spread into the pleura from an anterior mediastinal thymoma, but primary pleural thymomas are described and can present as localised masses or with diffuse pleural thickening. The concept of primary pleural thymoma has become accepted, but only about 25–30 cases have been reported to date. Spindle Cell Neoplasms Synovial sarcoma of the pleura Both biphasic and monophasic synovial sarcomas (SySa) are characterized by a distinctive t(X;18) chromosomal translocation and the production of the resultant alternative fusion genes, SYT-SSX1 or SYT-SSX2. SySa are well recognised as primary intrathoracic neoplasms in the pleura, where they can be confused with biphasic or sarcomatoid mesothelioma, carcinosarcoma /spindle cell carcinoma, or a biphasic pulmonary blastoma. Clinical features, immunohistochemistry and electron microscopsy are of limited usefulness and it is the detection of the t(X;18) chromosomal translocation and expression of the resultant SYT-SSX1 or SYT-SSX2 that is diagnostic of SySa. This can be done by FISH, but PCR is more sensitive and we consider molecular analysis of t(X;18) to be mandatory for discrimination between a genuine pleural SySa versus a biphasic or monophasic mesothelioma with histological appearances that mimic SySa. Solitary Fibrous Tumors (SFTs) Of Pleura Solitary fibrous tumors (SFTs) are uncommon localized spindle-cell fibroblastoid neoplasms. They most commonly arise in relation to the visceral pleura (~80%) or the parietal pleura, but they can occur in the mediastinum, lung parenchyma or related to pericardium or diaphragm. Terms such as submesothelial fibroma, fibrous mesothelioma and localized fibrous tumor have been used as synonyms in the past. Localized fibrous tumor might be the best term, because multiple simultaneous tumours have been described but 'SFT' is well established. Thoracic SFTs can vary greatly in size abd have a peak incidence between the 4[th] and 6[th] decade. SFTs are often incidental findings in asymptomatic patients, and the radiologic appearances may suggest the diagnosis, but a biopsy is always required. Symptoms can be related to the size and site of the tumor with compression of surrounding tissues. The histology ranges from the 'patternless pattern' of Stout to 'herringbone', cellular, myxoid and hemangiopericytic or angiofibromatoid areas. The mitotic index may be useful to predict malignant behaviour. Desmoid Tumors of the Pleura Desmoid tumors in the region of the chest wall are well recognized and can impinge upon the parietal pleura, but primary desmoid tumors of the pleura and lung are extremely rare. Benign and Malignant Nerve Sheath Tumors Neoplasms that have histologic and immunohistochemical features of nerve sheath tumors can occur as primary tumours in the pleural cavity. Benign ones typically show Verocay bodies and Antoni A and B areas. When malignant, these cells can cause major diagnostic confusion. Immunohistochemical staining with neural markers such as S100 protein is helpful to confirm a neurogenic origin. Inflammatory Myofibroblastic Tumors Inflammatory pseudotumors (plasma cell granuloma; inflammatory myofibroblastic tumor) may occasionally involve the pleura. They consist of of a proliferation of spindle cells with varying numbers of inflammatory cells, with prominene of plasma cells. Current thinking favours the concept that these are neoplastic lesions with the capacity in some cases for multicentricity, angioinvasion and metastasis (especially in older patients in whom IHC for anaplastic lymphoma kinsae (ALK) is negative). Epithelioid Hemangioendothelioma of the Pleura Epithelioid hemangioendothelioma is a malignant angioformative neoplasm, where the neoplastic endothelial cells are epithelioid and sometimes quite bland in appearance. The pattern in H&E-stained sections may be virtually indistinguishable from mesothelioma, and both may label for thrombomodulin and in some cases, cytokeratins. Labelling for endothelial markers such as CD31, CD34 or factor VIII-RAG aids in the diagnosis. Pleuropulmonary Blastoma Pleuropulmonary blastomas are rare in the pleura and mostly occur in early childhood. Tumours consist of primitive cells underneath an epithelium with a cambium layer-like appearance as seen in sarcoma botryoides. Rhabdomyoblasts may be found and anaplastic sarcomatous elements, such as embrynal rhabdomyosarcoma, fibrous sarcoma, chondrosarcoma and undifferentiated sarcoma, may be present. Pleural Lymphomas Primary pleural lymphomas are rare, with primary effusion lymphoma (PEL) and pyothorax-associated lymphoma being the most common. In our experience, most cases of pleural lymphoma represent secondary spread in cases of previously-diagnosed extrapleural lymphoma.

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      MS10.4 - Pulmonary Sarcomas (ID 504)

      14:00 - 15:30  |  Author(s): I. Petersen

      • Abstract
      • Presentation
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      Abstract not provided

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    MO10 - Molecular Pathology II (ID 127)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      MO10.09 - DISCUSSANT (ID 3985)

      16:15 - 17:45  |  Author(s): Y. Ishikawa

      • Abstract
      • Presentation
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      Abstract not provided

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    MO13 - SCLC I (ID 118)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO13.08 - A pilot study of adjuvant chemotherapy with irinotecan and cisplatin for completely resected high grade pulmonary neuroendocrine carcinona (Large cell neuroendocrine carcinoma and small cell lung cancer) (ID 1562)

      10:30 - 12:00  |  Author(s): Y. Ishikawa

      • Abstract
      • Presentation
      • Slides

      Background
      Large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) are recognized as high grade neuroendocrine carcinoma (HGNEC) of the lung. In patients with completely resected HGNEC, platinum-based adjuvant chemotherapy may be considered. However, the optimum chemotherapy regimen has not been determined. We conducted a multicenter single-arm phase II trial to evaluate irinotecan and cisplatin in postoperative adjuvant chemotherapy for HGNEC patients.

      Methods
      Patients with completely resected stage I- IIIA HGNEC received 4 cycles of irinotecan (60 mg/m[2], day 1, 8, 15) plus cisplatin (60 mg/m[2], day 1). This regimen was repeated every 4 weeks. Other eligibility criteria included ECOG PS 0–1, age 20, and <75 years old, adequate organ function, and no prior chemotherapy or radiotherapy. Patients with UGT1A1 polymorphisms (homozygous for *6 or *28, or simultaneously heterozygous *6 and *28), associated with irinotecan-related severe toxicity, were excluded. The primary endpoint was the rate of completion of chemotherapy (defined as underwent 3 or 4 cycles), and secondary endpoints were 3-year relapse free survival (RFS), rate of 3-year survival and toxicities.

      Results
      Forty patients were enrolled between September 2007 and April 2010. Patients’ characteristics were as follows: median age (range) 65 (45-73) years; male 85%; ECOG-PS 1 60%; LCNEC 57% and SCLC 43%; stage IA/IB/IIB/IIIA 32/35/8/5%; 95% received lobectomy. The rate of completion of chemotherapy was 83% (90% C.I.; 71-90%). The rate of overall survival at 3 years was estimated at 81%, and of RFS at 3 years was 74%. The rates of overall survival and RFS at 3 years were 86% and 74% among 23 LCNEC patients, and 74%, 76% among 17 SCLC patients, respectively. Nineteen patients (48%) experienced grade 3 or 4 neutrophils, but only five patients (13%) developed febrile neutropenia. Two patients (5%) developed grade 3 diarrhea, and 4 patients (10%) had grade 3 nausea. No treatment related deaths were observed in this study. All 40 specimens were also diagnosed as HGNEC at pathological central review among 7 pathologists. There were two specimens that showed the difference in between institutional diagnosis and central pathological diagnosis.

      Conclusion
      The combination of irinotecan and cisplatin as postoperative adjuvant chemotherapy was feasible and possibly efficacious for resected HGNEC.In Japan, a randomized phase III trial is ongoing to evaluate adjuvant chemotherapy of irinotecan and cisplatin, compared with etoposide and cisplatin, for completely resected HGNEC.

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    MO26 - Anatomical Pathology II (ID 129)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      MO26.05 - DISCUSSANT (ID 3989)

      10:30 - 12:00  |  Author(s): Y. Ishikawa

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    O17 - Anatomical Pathology I (ID 128)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      O17.03 - Morphological and Mucin profile of lung adenocarcinoma harboring driver mutation (ID 2523)

      10:30 - 12:00  |  Author(s): Y. Ishikawa

      • Abstract
      • Presentation
      • Slides

      Background
      Recent advantages of molecular study reveal several subsets of lung adenocarcinoma (AdCa) with specific genetic alterations of receptor tyrosine kinase (RTK), including EGFR, ALK, RET and ROS, which are dramatically responding to targeted inhibitors for activating RTK. The goal of this study is to evaluate the correlation between genetic alteration and histologic phenotype of lung AdCa, including cell type characteristics and mucin phenotype.

      Methods
      319 surgically resected lung Ad CA was examined genetic alterations of EGFR by Cycleave or direct sequencing, ALK by FISH and immunohistochemistry and KRAS by PCR-RFLP and direct sequencing methods. Resected materials were reviewed detail histologic findings, using HE-stained slides of whole tumor. A histologic predominant subtype of AdCa, based on a new IASLC/ATS/ERS classification, and nuclear grading were evaluated. The mucin phenotype of AdCa was evaluated by Immunohistochemical staining, including muc1, muc2, muc5ac and muc6. The correlation between genetic alteration and histologic phenotypes was examined.

      Results
      Genetic alterations of this study were 150 EGFR, 44 ALK, 9 KRAS and 116 wild-type. EGFR mutated AdCa had 55.4% lepidic- (lep), 40% papillary- (pap), 2.6% of acinar- (aci) and 2% of solid- (sol) predominant subtypes. ALK AdCa had 20.5% of lep, 36.4% pap, 18.2% aci, 22.7% sol and 2.3% micropapillary predominant subtypes. Kras mutated AdCa were 44.4% pap, 33.3% aci and 22.2% sol. All wild type AdCa were 35.3% of lep, 53.4% pap, 5.2% aci- and 6% sol. Presence of mucin producing cells was observed in 4.7, 90.9, 66.7, and 26.7% of EGFR, ALK, KRAS and wild type AdCa, respectively. EGFR and ALK showed lower nuclear grade compared to KRAS. IHC examination revealed ALK AdCa was positive for muc1, but negative for muc2, 5ac and 6, in contrast to wild type /EGFR AdCa which were positive for muc1, sometimes for muc2, muc 5ac and/or muc6.

      Conclusion
      In summary, the most common histologic phenotype of EGFR AdCa was lepidic-predominant, non-mucin producing with low nuclear grade; ALK AdCa was papillary, mucin producing with low nuclear grade, and KRAS was papillary, mucin producing with high nuclear grade. The predominant subtype-based classification of AdCa showed an incomplete correlation to a genetic abnormality. Cell type characteristics, including mucin phenotype, would be useful to predict the genetic alteration of lung AdCa, in addition to the predominant subtype which is architecture-based assessment.

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    P2.01 - Poster Session 2 - Cancer Biology (ID 145)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.01-007 - Distinct characteristics of small cell lung cancer (SCLC) correlate with central or peripheral origin - microarray analysis of snap frozen tissue samples. (ID 1383)

      09:30 - 16:30  |  Author(s): Y. Ishikawa

      • Abstract

      Background
      We previously reported that SCLC distinct characteristics by primary tumor location (central type or peripheral type) and TTF-1 expression. Peripheral type and/or TTF-1 expression were predictive factors of poor prognosis in SCLC. In this study, we examined whether or not SCLC distinct characteristics of gene expression by primary tumor location, using microarray analysis of snap frozen tissue samples.

      Methods
      Fourteen SCLC, diagnosed from biopsies and/or surgical materials, for which snap frozen tissue samples were available, were collected during 2004-2011 from Japanese patients. We evaluated the location of primary tumor (central or peripheral) by CT at diagnosis. Total RNAs from the snap frozen fresh tissue sample of the surgically resected SCLC (n=14, central type:3, peripheral type:11) were used to prepare cDNAs, which were hybridized to the Whole genome Human 60K Microarray chips (Agilent Technologies Inc, Tokyo, Japan). Data normalization, log transformation, statistical analysis, gene ontology (GO) analysis, and pattern study were performed with GeneSpring GX12 (Agilent Technologies Inc, Tokyo, Japan) and Ingenuity Pathway Analysis software, with the stringency of P < 0.01 and a < 2-fold change by moderated t-test corrected with Bonferroni multiple testing.

      Results
      There were a total of 31551 genes scored as differentially expressed between groups. A total of 833 genes were identified that differed significantly in expression: 424 genes were upregulated and 409 genes were downregulated in peripheral type compared with central type. Interestingly, upregulated gene analysis revealed that peripheral type SCLC had increased levels of neuroendocrine genes such as NCAM, Synaptophysin (SYN), Chromogranin A (CGA), Gastrin-releasing peptide (GRP), ASCL1, and TTF-1. Subsequently, GO and network analysis revealed that most of upregulated genes in peripheral group were related to neuron functions. Hierarchical cluster analysis clearly distinguished between central type and peripheral type.

      Conclusion
      SCLC had a distinct gene expression profile from tumor location and had higher expression of genes associated with neural function in peripheral SCLC. Defining gene expression profiles by tumor location may help elucidate distinct characteristics of SCLC between central type and peripheral type.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-020 - Sorafenib in patients with RET fusion-positive non-small cell lung cancer (ID 1717)

      09:30 - 16:30  |  Author(s): Y. Ishikawa

      • Abstract

      Background
      RET fusions were recently identified in non-small cell lung cancer (NSCLC) and considered to be a druggable target of NSCLC. There are several small molecules which can potentially inhibit RET kinase activity. Among them, sorafenib, sunitinib and vandetanib are clinically available, and sorafenib is the most promising agent which showed potent anti-RET activity (the IC50 against RET is 0.0059-0.047 μM) in preclinical studies. However, it is difficult to evaluate the efficacy of this agent in RET-positive NSCLC in large clinical trials, because RET-positive NSCLC makes up only 1% to 2% of NSCLC cases. Therefore, we conducted a pilot study to evaluate the efficacy and feasibility of sorafenib treatment in a small number of patients with RET fusion-positive NSCLC.

      Methods
      Eligible patients had advanced or recurrent NSCLC, were more than 20 years old, had undergone treatment with one or more previous chemotherapy regimens, had an ECOG performance status (PS) 0–2, adequate organ function and provided informed consent. The RET fusion gene was confirmed by a split FISH assay. Patients received 400 mg of sorafenib orally twice daily. The treatment was continued until disease progression or unacceptable toxicity.

      Results
      From March 2012 to April 2013, three patients were enrolled. The first patient was a 62-year-old female who had stage IV NSCLC and had received three prior chemotherapy regimens (pemetrexed with cisplatin, docetaxel and erlotinib) and two courses of palliative radiation (thorax and whole brain) before being enrolled this study. The second patient was a 38-year-old male who had recurrence after thoracic surgery and had received two prior chemotherapy regimens (pemetrexed with cisplatin and docetaxel) and whole brain radiation before enrolling this study. The third patient was a 75-year-old female who had recurrence after thoracic surgery and had received one prior chemotherapy regimen (Docetaxel). The pathological diagnoses were adenocarcinoma in two patients and NSCLC not otherwise specified in one patient. Their tumors did not demonstrate any EGFR mutations or ALK fusion. The RET partner genes were KIF5B in two patients and unknown in one patient. All three patients were treated with sorafenib at 400 mg orally twice daily. Unfortunately, there was no response. The best responses to sorafenib in the patients were PD, SD and SD. In the third patient, sorafenib treatment was continued for over seven weeks. The most common toxicities were hand-foot syndrome, hypertension and diarrhea. The third patient needed a dose reduction to 400 mg once daily due to grade 3 hand-foot syndrome.

      Conclusion
      Sorafenib seems to have some efficacy for the RET fusion-positive NSCLC, but no dramatic response was observed.

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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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      P2.18-010 - Copy number changes in chromosome 2p are unique events among ALK fusion positive lung adenocarcinomas (ID 1805)

      09:30 - 16:30  |  Author(s): Y. Ishikawa

      • Abstract

      Background
      ALK fusion is a unique gene transversion detected among lung adenocarcinomas. It emerged as a target for cancer therapy, but little is known how this genomic abnormality is created. To unveil the underlying mechanisms leading to gene fusion, we compared the genomic structures of the two groups using SNP-array allelokaryotyping analysis.

      Methods
      35 ALK fusion positive and 95 ALK fusion negative cases were involved in this study. Immunohistochemical staining and multiplex RT-PCR was employed for screening and confirmation. Chromosome 2p were closely examined using SNP-array based allelokaryotyping.

      Results
      Copy number changes of the regions including ALK and EML4 were detected among ALK fusion positive tumors (10/35, 29%) in contrast with ALK fusion negative tumors (0/95, 0%). In other words, the genomic regions unnecessary to constitute each fusion gene variants were deleted in ALK fusion positive tumors. And some of them showed copy number gain of fusion gene. In addition, clustered genomic number changes within 2p were more frequently encountered in ALK fusion positive tumors compared with fusion negative ones.

      Conclusion
      Copy number changes within the genomic region including EML4 and ALK are particular findings in ALK fusion positive tumors. In addition, genomic structure of the short arm of chromosome 2 was more unstable than ALK fusion negative tumors. We speculate that clustered chromosomal rearrangements of the short arm of chromosome 2 contribute to EML4-ALK gene fusion.

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    P3.02 - Poster Session 3 - Novel Cancer Genes and Pathways (ID 149)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.02-002 - Identification of CpG island methylator phenotype predicts the prognosis of small cell lung cancer (ID 42)

      09:30 - 16:30  |  Author(s): Y. Ishikawa

      • Abstract

      Background
      Small cell lung cancer (SCLC) accounts for 13-15% of new lung cancer cases in worldwide and has the poor therapeutic outcomes with a median survival of just over one year. A CpG island methylate phenotype (CIMP) is well known as a methylator phenotype with characteristic promoter DNA methylation alterations, in colorectal cancers, glioblastoma and breast cancers, although there has been no report about any CIMP of SCLC. We investigated whether DNA methylation profiles can provide useful molecular subtyping of SCLC in terms of etiology and prognosis of SCLC.

      Methods
      We analyzed 28 fresh frozen samples from pure SCLC patients and 13 noncancerous lung tissues. All patients underwent surgical lung resection at the Cancer Institute Hospital, nine patients among them were treated with chemotherapy before surgery. After genomic DNA was treated with sodium bisulfite, bisulfite-converted genomic DNA was analyzed using Illumina’s Infinium HumanMethylation27 BeadChip. And, total RNA was extracted from twenty-five SCLC tumor samples and mRNA expression of these samples were analyzed by Agilent’s SurePrint G3 Human CGH Microarray. Next, we matched these two data sets by Gene Symbol, and identified fifty-five most differentially methylated CpG sites (corresponding to 46 genes) with a FDR p value cut off of 0.05. Gene ontology analysis was performed using DAVID Bioinformatics Resources.

      Results
      We selected a total of 1741 most differentially methylated CpG sites (s.d. > 0.20) across the 28 SCLC tumor tissues in each DNA methylation platform, after an elimination of the probes related with the X- and Y- chromosome. Unsupervised hierarchical clustering of methylation data from SCLC samples reveals two major subgroups with different prognosis: the 5 years disease-free interval (DFI) rate of patients in cluster 1 (11.1%) was lower than that of patients in cluster 2 (61.57%) (p = 0.001). By multivariate analysis for DFI, both postoperative chemotherapy and cluster 1 were a significant prognostic factor (p = 0.002 and 0.002; respectively). Next, among 1220 genes with methylation and expression data both available, the CpG sites were ranked on the basis of the spearman’s correlation coefficient between cluster 1 and cluster 2 into an ascending order. Finally, we identified that fifty-five CpG sites were nagetively correlated and found that apoptosis pathway was a most differentially expressed.

      Conclusion
      By comprehensive DNA methylation profiling, two distinct subgroups with different molecular and clinical phenotype were identified to evoke a CIMP of SCLC. We found some promoter markers in the apoptosis pathway could make a difference between the two groups, and we hope that our data can contribute to provide a useful resource for the construction of therapeutic strategy and the development of a new chemotherapeutic agent.

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    P3.07 - Poster Session 3 - Surgery (ID 193)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P3.07-011 - Prognostic and predictive factors for recurrence-free survival in patients with completely resected pN2 non-small cell lung cancer (ID 1001)

      09:30 - 16:30  |  Author(s): Y. Ishikawa

      • Abstract

      Background
      The role of surgical resection remains controversial for pathologic N2 (pN2) non-small cell lung cancer (NSCLC). The objective of our study was to determine the prognostic and predictive factors for recurrence-free survival (RFS) in patients with completely resected pN2 NSCLC.

      Methods
      Between 1990 and 2009, 2439 patients with NSCLC underwent curative surgical resection at the Cancer Institute Hospital. Of these patients, 311 (12.8%) were diagnosed as having pN2 NSCLC. Surgical resection was performed in 79, 71, 70, and 91 patients in 1990–1994, 1995–1999, 2000–2004, and 2005–2009, respectively. Overall survival (OS) and RFS were calculated using the Kaplan-Meier method, and survival outcomes were assessed using the log-rank test. Univariate and multivariate Cox proportional hazards models were used to identify factors influencing RFS.

      Results
      The patient population comprised 199 male and 112 female patients, with ages ranging from 16 to 84 years (median, 61.4). Lobectomies or bilobectomies were conducted in 263 cases, and pneumonectomies were performed in 48 cases. For the entire cohort, 5-year OS and 5-year RFS rates were 46% and 24%, respectively. The median follow-up time was 44 months. OS and RFS rates were 34% and 23% in 1990–1994, 42% and 34% in 1995–1999, 45% and 20% in 2000–2004, and 59% and 20% in 2005–2009, respectively. The recent improvement in OS was remarkable, whereas the RFS rate did not improve. Multivariate analysis identified 4 independent predictors for poor RFS: multiple-zone mediastinal lymph node metastasis (hazard ratio [HR], 1.551; P = .002), ipsilateral intrapulmonary metastasis (HR, 1.038; P = .002), tumor size > 30 mm (HR, 1.007; P = .046), and clinical N1 or N2 stage (HR, 1.039; P = .041). Patients were grouped according to the number of risk factors for poor RFS. Patients with none of the identified risk factors had an RFS rate of 32%, those with 1–2 factors had an RFS rate of 25%, and those with 3–4 factors had an RFS rate of 7% (P < .001).Figure 1

      Conclusion
      In patients with surgically resected pN2 NSCLC, OS tended to improve in recent years, whereas RFS was fairly constant over the study period. The overall prognosis of patients with surgically resected pN2 NSCLC remains poor. However, prognosis is considerably better in those patients with fewer risk factors. Accordingly, surgical resection could be beneficial in select patients.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-010 - Patterns of relapse and prognosis after crizotinib therapy failure in ALK+ Non-small cell lung cancer (ID 983)

      09:30 - 16:30  |  Author(s): Y. Ishikawa

      • Abstract

      Background
      Although crizotinib which is a first-in-class oral ALK inhibitor shows dramatic response and prolonged PFS in patients with ALK(+) NSCLC, most of the patients relapsed within one year. However, patterns of relapse, prognosis, and outcome of further therapy after crizotinib failure have not been well examined.

      Methods
      We identified patients at our hospital with ALK(+) NSCLC who received and failed in crizotinib therapy.

      Results
      There were 20 patients (11 females and 9 males, with a median age 48 years). ALK fusion gene was confirmed by IHC and/or FISH (17 patients IHC+/FISH+, 3 patients FISH+). The median treatment duration of crizotonib was 4.5 months (range, 1.1-18.6 months) and the median overall survival (OS) after discontinued on crizotinib was 4.8 months; 13 patients died. At the time when crizotinib was discontinued, 2 patients (10%) had progressive disease (PD) at the primary site of disease (local recurrence), 18 patients (90%) had PD of distant metastasis and one patient had PD at both the primary site and distant metastasis. PD in CNS was observed in 9 patients. Re-biopsies after failure of criztotinib were performed in 3 patients. Two secondary mutation were identified in 2 of 3 pts (L1196M (n = 1) and G1269A (n = 1). Eleven of 20 patients received additional chemotherapy (7 cytotoxic chemotherapies and 4 ALK-inhibitor). Two of 7 patients who received cytotoxic chemotherapy (included docetaxel, S-1, cisplatin+pemetrexed+bevacizumab and carboplatin+pemetrexed) after crizotinib had PR (28.5%).

      Conclusion
      After crizotinib therapy failure, PD most commonly occurred at distant metastasis especially CNS in ALK+ NSCLC patients. Cytotoxic chemotherapy after crizotinib failure provide only minimum responses. A New effective therapeutic strategy after failure of crizotinib is necessary in ALK+ NSCLC patients.