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chemistry showed positive CK7, negative CK20, focally positive CEA and negative TTF-1. ..... Case A man, 63 years old was admitted with cough, dyspnoea, and fever ..... patients. Methods Demographic and clinical information of Malaysian patients whose .... incongruity in the pharynx and swelling under the jaw. Biopsy ...
Respirology (2012) 17 (Suppl. 2), 80–100

doi: 10.1111/j.1440-1843.2012.02296.x

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PULMONARY METASTASIS FROM MALIGNANT DEGENERATION OF A BENIGN GIANT CELL TUMOR: A CASE REPORT AND REVIEW OF THE LITERATURE JG SISON-SAN LUIS, AD WANG, EHM WANG Department of Internal Medicine, Section of Pulmonary Medicine, Manila Doctors Hospital, Philippines Tumors that metastasize are considered malignant by definition. Benign neoplastic lesions, on the other hand, rarely, if ever, metastasize. We report the first locally known and interesting case of a 31 year old female who presented with a left pelvic mass with a histologic diagnosis of a benign Giant Cell Tumor (GCT); which eventually spread to the lungs with malignant degeneration, five years after diagnosis and treatment with tumor embolization and radiotherapy of the primary site. GCT of the bone is a benign but potentially aggressive lesion. The Western literature has described the potential of the tumor for local recurrence and metastasis, by as yet unclear mechanisms, but without undergoing sarcomatous transformation. Such occurrence is considered rare. Unlike prior reports published in the Western literature, histologically malignant transformation of the pulmonary metastases was documented in our patient. Because of its rarity, very little is known about the long-term outcome, the risk factors for metastasis and the best treatment for pulmonary metastases arising from benign GCT of the bone. Our patient succumbed to acute respiratory failure due to the rapidly increasing size of the pulmonary mass and attendant complications of massive pleural effusion, pneumonia and possible pulmonary embolism. Our report intends to raise local awareness for the potential for extra-skeletal spread of benign GCT of the bone, which necessitates close follow up and monitoring. We also hope to contribute to the better appreciation of the natural history of this tumor. Prompt recognition and resection of the metastatic lesion may be required to control tumor spread. References 1. Osaka S. Sugita Yoshida, et al. Clinical and immunohistochemical characteristics of benign giant cell tumor of bone with pulmonary metastases: case series. J Orthop Surg 2004. 12:55–62. 2. Takeuchi A., Wang E, et al. The prognostic factors of recurrent GCT: a cooperative study by the Eastern Asian Musculoskeletal Oncology Group. J Orthop Sci 2011. 16:192–202.

CHARACTERISTICS OF LUNG CANCER PATIENTS AT CIPTO MANGUNKUSUMO NATIONAL HOSPITAL Z AMIN Division of Pulmonology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Cipto Mangunkusumo Hospital, Indonesia Background Lung cancer is the leading cause of cancer deaths in both men and women. In the United States in 2010, 157,300 people were projected to die from lung cancer, which is more than the number of deaths from colon and rectal, breast, and prostate cancer combined. While secondary lung cancers are found in 20–55% of patients dying of various malignancies. Cipto Mangunkusumo National Hospital as the top referral hospital in Indonesia had managed various cases of carcinoma including lung cancer. As the referral hospital, it needs epidemiology and characteristic descriptions of the patients. Aim To obtain characteristics of patients with lung cancer treated at Cipto Mangunkusumo National Hospital. Methods Retrospective study that was based on data reported in Chest meetings being held by Pulmonology division of Internal Medicine at Cipto Mangunkusumo National Hospital from January 2007 until December 2008. Results A total of 84 cases of lung cancer consist of 68 cases of primary lung cancer and 16 cases of secondary lung cancer. On patients with primary lung cancer, more than half of patients were female (67.7%) and mostly more than forty years old. Thirty two patients showed no data of smoking history that it was only obtained 55% of patients with smoking history. Cough became the most common respiration symptoms found (69%). Ronchi and lymphadenopathy were two most common signs observed and pleural effusion as most common complication with percentage of 42%. On histopathologic examination, adenocarcinoma had highest number of tumor type found by 37%. While on secondary lung cancer, 81% of patients were female and half of patients were more than 40 years old. Ninety four per cent of patients showed no data of smoking history. There was no patient with smoking history. Secondary lung cancer most commonly was originated from breast cancer (25%), followed by thyroid cancer (18.75%), cervical cancer (12.5%), and others (6.25% each). Conclusion Characteristics of patients observed in this study are similar, except sex, with another characteristics mentioned in literatures or other studies in developed or developing countries. Key Words Lung cancer, primary lung cancer, secondary lung cancer.

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GENETICALLY ENGINEERED ONCOLYTIC MEASLES VIRUS EFFECTIVELY TARGETS AND KILLS NON-SMALL CELL LUNG CANCER STEM CELLS H INOUE1,2, K YASUNARI1, Y MATSUMURA1, S MIYAMOTO1, A SAKAMOTO1, K NOSAKI1,2, K TAKAYAMA2, Y NAKANISHI2, K TANI1 1 Division of Molecular and Clinical Genetics, Medical Institute of Bioregulation, Kyushu University, Japan, and 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Japan Accumulating evidences suggest that Cancer Stem Cells (CSCs) play a critical role in cancer development, chemo- and radio-resistance, and seemingly initiation of metastasis. Development of novel cancer therapies targeting CSCs therefore offers great promise for cancer treatment. Here, we demonstrated that newly developed oncolytic measles virus Edmonston strain genetically engineered by replacing the N, P, and L genes with those of the wild-type MV strain (MV-NPL) elicited more enhanced oncolytic activity against human NonSmall Cell Lung Cancer (NSCLC) Stem Cells (NSCLC-CSCs) while sparing human normal lung cells, compared with the parental MV. Our results of in vitro pan-caspase inhibition assays showed that caspase-dependent apoptosis substantially contributed to the oncolysis of NSCLC-CSCs by MV-NPL, despite their higher expression levels of anti-apoptotic protein of both XIAP and Mcl-1 in NSCLC-CSCs. In addition, combination use of MV-NPL with PI3K inhibitor synergized the oncolytic effects by MV-NPL. Furthermore, consecutive intratumoral MV-NPL administrations into subcutaneous NSCLC-CSCs xenografts preestablished in athymic mice significantly inhibited the outgrowth of NSCLCCSCs without severe side effects. Altogether, this study opens the perspective that MV-NPL may have value as a novel oncolytic virotherapy for NSCLC patients resistant to conventional therapies.

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RETROSPECTIVE ANALYSIS OF PEMETREXED IN THE TREATMENT OF NON-SMALL CELL LUNG CANCER M SHIMADA1, T KITAZAKI1, M FUKUDA1, K HASHIGUCHI1, D OGAWARA2, H YAMAGUCHI3, N TOMONAGA4, H SODA5, Y NAKAMURA1, S KOHNO1 1 Department of Respiratory Medicine, The Japanese Red Cross Nagasaki Genbaku Hospital, Japan, 2Department of Internal Medicine, Nagasaki Goto Chuoh Hospital, Japan, 3Second Department of Internal Medicine, Nagasaki University School of Medicine, Japan, 4Department of Internal Medicine, Nagasaki Prefecure Shimabara Hospital, Japan, and 5Department of Respirology, Sasebo General Hospital, Japan Background Pemetrexed is a multitargeted antifolate that inhibits the enzymes involved in folate metabolism and DNA synthesis. In May 2009, pemetrexed was approved as a treatment of advanced non-small cell lung cancer in Japan. Patients and Methods We retrospectively analyzed the efficacy and toxicity in patients with non-small cell lung cancer treated with pemetrexed between May 2009 and August 2011. Results One hundred forty-two cases were evaluated. Patients characteristics were 52 males/90 females, median age 67 (range, 33–85), and 133 adenocarcinoma/5 squamous/3 large. The patients treated with single were 84, plus cisplatin 22, and plus carboplatin 34. As 1st lines were 46, 2nd 27, and 3rd ∼ 69. The response rate, disease control rate, and overall survival were 20.0%, 64.8%, and 15.8 months, respectively. The G3/4 toxicities were mainly neutropenia (34.3%), and other adverse events included anemia, anorexia, malaise, rash, nausea, vomiting, and elevations of transaminase. Conclusion Pemetrexed provides both good tolerability and survival.

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PHASE II TRIAL OF ERLOTINIB IN PATIENTS WITH ADVANCED NON-SMALL-CELL LUNG CANCER HARBORING EPIDERMAL GROWTH FACTOR RECEPTOR MUTATIONS: ADDITIVE ANALYSIS OF PHARMACOKINETICS OF ERLOTINIB A FUKUSHIMA1, K MOTOSHIMA2, M SHIMADA1, T KITAZAKI1, M FUKUDA1, K HASHIGUCHI1, S NAGASHIMA2, K SANO3, Y NAKAMURA2, S KOHNO2 1 Respiratory Medicine, Japanese Red-Cross Nagasaki Genbaku Hospital, Japan, 2Second Department of Internal Medicine, Nagasaki University School of Medicine, Japan, and 3Department of Drug Metabolism and Disposition, Meiji Pharmaceutical University, Japan Introduction We conducted a phase II trial of erlotinib in patients with advanced Non-Small Cell Lung Cancer (NSCLC) harboring Epidermal Growth Factor Receptor (EGFR) mutations. In addition, we evaluated the relationship between the plasma concentration of it and the efficacy of it. Methods Previously treated but EGFR-tyrosine kinase inhibitors naïve patients with advanced NSCLC harboring EGFR mutations were enrolled. Erlotinib was given at 150 mg once a daily until disease progression. The primary end point was Objective Response Rate (ORR). Plasma trough levels of erlotinib were measured on Days 2 (D2) and 8 (D8) by high-performance liquid chromatography. Results A total of 29 patients were enrolled from September 2008 to January 2011. ORR was 61.5% (95% confidence interval [CI] 40.57–79.8) of 26 assessable patients. The median Progression Free Survival (PFS) and Overall Survival (OS) were 6.3 months and 16.9 months, respectively. Skin rash was observed in 24 patients but most of them were grade 1 or 2. Grade 2 pneumonitis was observed in one patient. We collected blood samples from 17 patients. The median PFS of the high and low D8/D2 ratio group was 11.2 months and 5.6 months, respectively (p = 0.0439, hazard ratio = 3.318, 95% CI, 1.033–10.65). Conclusions Erlotinib showed a comparative ORR and acceptable toxicity profile for the patients with NSCLC harboring EGFR mutations, the response as the primary end point did not reach the predetermined threshold level, though. D8/D2 ratio of plasma trough level might be predictive factor in PFS of erlotinib.

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INVASIVE MUCINOUS PREDOMINANT ADENOCARCINOMA PRESENTING AS DIFFUSE CONSOLIDATION IN A 38-YEAROLD MALE: A CASE REPORT SK TAN Fellow-in-Training, Section of Pulmonary Medicine, Department of Internal Medicine, Philippine General Hospital, Philippines Background Bronchioloalveolar Carcinoma (BAC) accounts for 2–14% of all lung cancers. Both pathologic and clinical aspects of this carcinoma are the subject of debate. In the 2004 WHO classification, three histologic subtypes of BAC were recognized. Mixed mucinous and non-mucinous subtype is the rarest of the three. Diffuse disease, consisting of multiple bilateral nodules or consolidations, is observed in about 30% of BAC patients and is associated with a worse prognosis than the localized disease. Last February 2011, International Association for the Study of Lung Cancer (IASLC) published the latest classification of lung adenocarcinoma. IASLC recommends using invasive mucinous adenocarcinoma for mucinous BAC and adenocarcinoma with lepidic pattern for non-mucinous BAC. We report an unusual case of invasive mucinous predominant adenocarcinoma presenting as diffuse consolidation in a 38-year-old male. Clinical Case A 38-year-old non-smoker male sought consult for chronic cough and chest pain. Decrease breath sounds were noted on both mid to bases. The rest of the physical examination was unremarkable. Chest radiograph showed bilateral pulmonary masses vs. consolidation (Figure 1). Computed tomography of the chest showed consolidations in both lungs with minimal sparing of both apices, anterior segment of the right upper lobe and left lung base; aerated lungs show reticulonodular densities with tree in a bud pattern; small to slightly enlarged mediastinal and hilar lymph nodes. Computed tomography guided aspiration biopsy of the pulmonary masses were done showing benign bronchial epithelial cells, histiocytes and few lymphocytes; negative for malignant cells. Lung tissue was also negative for acid fast bacilli. Repeat biopsy was contemplated. Patient had two hospital admissions for pneumonia. Patient succumbed to death after 5 months from first consult. Autopsy showed invasive mucinous predominant adenocarcinoma (formerly mixed mucinous and non-mucinous BAC pattern). Immunohistochemistry showed positive CK7, negative CK20, focally positive CEA and negative TTF-1. Conclusion This case illustrates BAC can be a differential diagnosis in a patient presenting with diffuse consolidation. Recognition of this presentation will hasten work-up for prognostication and possible treatment.

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DIAGNOSTIC VALUE AND PROGNOSTIC SIGNIFICANCE OF PLEURAL C-REACTIVE PROTEIN IN LUNG CANCER WITH MALIGNANT PLEURAL EFFUSIONS KE HWANG, HR KIM, ET JEONG Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, Korea Objectives It is still often difficult for clinicians to confirm Malignant Pleural Effusions (MPE). C-Reactive Protein (CRP), acute-phase protein, has been implicated in various inflammatory and advanced malignant states. Increased serum CRP levels have been shown in associated with independent prognostic factor for survival in patients with advanced lung cancer. However, only few studies have focused on the role of CRP in pleural effusions. This study aimed to evaluate the diagnostic value of pleural CRP to discriminate lung cancer with MPE from benign effusion and its prognostic role in lung cancer patients with MPE. Patients and Methods Pleural effusion samples were collected from patients with MPE (68 lung cancers; 12 extrathoracic tumors), and from 68 with various benign conditions (31 with pneumonia; 37 with tuberculosis). Concentrations of pleural (p) and serum (s) CRP were measured by Enzyme-Linked Immunosorbent Assay (ELISA). The expression profile of CRP in pleural fluid, and its association with survival were investigated. Results P-CRP levels correlated with s-CRP levels (P = 0.0028). The area under the ROC curve (AUC) of p-CRP (0.86) in their diagnostic accuracy to differentiate lung cancer with MPE from benign pleural effusion was greater than those of s-CRP (0.77). High p-CRP expression was significantly correlated with shorter overall survival (P = 0.0001). In a multivariate Cox regression analysis, p-CRP was independent prognostic factor significantly associated with overall survival (P = 0.0001). The relative risk of overall survival for lung cancer patients with high p-CRP was 3.909 (95% CI, 2.000–7.639). Conclusions P-CRP is superior to s-CRP in determining the pleural fluid etiology. Quantitive assay of CRP in pleural effusion might be useful complementary test both in diagnosis and prognosis for lung cancer patients with MPE.

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TUMOR SUPPRESSOR GENE RBM5 DELIVERED BY ATTENUATED SALMONELLA INHIBITS LUNG ADENOCARCINOMA BY INDUCING APOPTOSIS K WANG1, C SHAO2,3, LJ ZHAO3 1 Department of Respiratory Medicine, The Second Affiliated Hospital of Jilin University, China, 2Department of Digestive Medicine, China-Japan Union Hospital of Jilin University, China, and 3Department of Pathophysiology, Norman Bethune College of Medicine of Jilin University, China Background RBM5 (RNA-Binding Motif protein 5, also named H37/LUCA15) gene from chromosome 3p21.3 has been demonstrated to be tumor suppressor. Current researches in vitro confirm that RBM5 can suppress the growth of lung adenocarcinoma cells by inducing apoptosis. There is still no effective model in vivo, however, to deeply investigate the effect and molecular mechanism of RBM5 on lung adenocarcinoma. Methods We established the transplanted tumor model on BALB/c nude mice using A549 cell line. The mice were treated with the recombinant plasmids (pcDNA3.1 and pcDNA3.1-RBM5), carried by attenuated Salmonella, for getting the overexpression of RBM5 in tumor tissues. RBM5 overexpression was confirmed by immunohistochemistry staining. H&E staining was performed to observe the histological performance on plasmids treated A549 xenografts. Apoptosis was assessed by the TUNEL staining with a TUNEL detection kit. Apoptosis-regulated genes were detected by Western blot. Results We successful established the lung adenocarcinoma animal model in vivo. The growth of tumor xenografts was significantly retarded on the mice treated with pcDNA3.1-RBM5 carried by attenuated Salmonella compared to that on mice treated with pcDNA3.1. Overexpression of RBM5 enhanced the apoptosis in tumor xenografts. Furthermore, the expression of Bcl-2 protein was decreased significantly, while the expression of BAX, TNF-α, cleavedcaspase3, cleaved-caspase3, cleaved-caspase8, cleaved-caspase9 and cleaved-PARP proteins was significantly increased in the pcDNA3.1-RBM5 treated mice as compared to that in the control mice. Conclusion In this study, we established a novel animal model set up in BALB/c nude mice treated with attenuated Salmonella as a vector carrying plasmids to determine RBM5 function in vivo, and concluded that RBM5 inhibited tumor growth in mice by inducing apoptosis. The study suggests that although RBM5’s involvement in the death receptor–mediated apoptotic pathway remains to be in depth investigated, RBM5-mediated growth suppression, at least in part, employs regulation of mitochondrial apoptotic pathways.

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REBIOPSY OF NON-SMALL CELL LUNG CANCER PATIENTS WITH ACQUIRED RESISTANCE TO EGFR-TKI: COMPARISON BETWEEN T790M MUTATION-POSITIVE AND -NEGATIVE POPULATIONS A HATA Division of Integrated Oncology, Institute of Buomedical Research and Innovation, Japan Background The secondary Epidermal Growth Factor Receptor (EGFR) mutation T790M accounts for approximately half of acquired resistances to EGFR-Tyrosine Kinase Inhibitors (TKI). A recent report has demonstrated the presence of T790M predicts a favorable prognosis and indolent progression, compared to the absence of T790M after TKI failure. However, rebiopsy to confirm T790M status can be challenging due to limited tissue availability and procedural feasibility, and little is known regarding the differences among patients with or without T790M. Methods We investigated 73 patients harboring EGFR sensitive mutations who had undergone rebiopsy to confirm the emergence of T790M after TKI failure. The peptide nucleic acid-locked nucleic acid PCR clamp method was used in EGFR mutational analyses. Patient characteristics (age, gender, smoking history, performance status, EGFR mutation site, initial TKI, response to initial TKI, line of initial TKI, progression-free survival with initial TKI, and biopsy site) and Postprogression Survivals (PPS) after initial TKI failure, were retrospectively compared in patients with and without T790M. Results We identified T790M in 2 (10%) of 21 Central Nervous System (CNS) (19 cerebrospinal fluid and 2 brain tissue) specimens, and in 20 (38%) of 52 other lesions (25 lung tissue, 24 pleural effusion, and 3 lymph node) (p = 0.0225). Other characteristics had no statistical association with the detection of T790M. Median PPS in patients with T790M was 34.0 months, and in those without T790M, 14.5 months (p = 0.0038). Although none of our patients received TKIs continuously after initial failure, 56 (77%) patients were re-administered TKIs. Regardless of T790M status, PPS in patients with TKI re-administration (23.4 months) was significantly longer than without readministration (10.4 months) (p = 0.0085). Conclusions The emergence of T790M in CNS is rare compared with other lesions. Patients with T790M after TKI failure have significantly better prognosis than those without T790M. The effectiveness of TKI re-administration or continuous administration beyond progression is suggested after initial TKI failure.

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A PHASE II STUDY OF S-1 FOR PREVIOUSLY UNTREATED ELDERLY PATIENTS WITH ADVANCED NON-SMALL CELL LUNG CANCER N TOMONAGA1, T IKEDA2, M TOMONAGA1, A KINOSHITA1, M FUKUDA3, T KASAI4, M FUKUDA5, Y NAKAMURA2, M OKA6, S KOHNO2 1 Nagasaki Prefecture Shimabara Hospital, Japan, 2Second Department of Internal Medicine, Nagasaki University Hospital, Japan, 3Japanese Red Cross Nagasaki Atomic Bomb Hospital, Japan, 4Devision of Thoracic Oncology, Department of Medical Oncology, Tochigi Cancer Center, Japan, 5 National Hospital Organization Nagasaki Medical Center, Japan, and 6 Division of Respiratory Diseases, Department of Medicine, Kawasaki Medical School, Japan Background S-1, a novel oral fluoropyrimidine, is active in the treatment of Non-Small Cell Lung Cancer (NSCLC). However, there is no sufficient data of S-1 for elderly NSCLC patients. In the present study, we determined the efficacy and toxicity of S-1 for previously untreated elderly patients with advanced NSCLC. Patients and Methods Eligibility criteria were no prior chemotherapy, StageIIIB without any indications for radiotherapy or IV, NSCLC patients, performance status 0–1, age >70, and adequate hematological, hepatic, and renal function. Patients received the oral administration of S-1 (40 mg/m2 twice a day) for 28 consecutive days. This schedule was repeated every 6 weeks. Primary end-point was the assessment of tumor response rate measured by RECIST criteria. Results 32 patients were enrolled and 31 patients evaluable for toxicity and response. Male/Female: 24/8; median age 80 (71–88); Path: adeno 24 (75%); squamous 6 (19%); Pleomorphic ca 1 (3%); NSCLC unclassified 1 (3%). The median treatment cycles was 2 (1–11). Evaluation of responses were 0CR, 7PR, 14SD, 10PD and 1NE (response rate 22.6%), and the median survival time was 10.0 months. Grade 3/4 toxicities in first cycle included: leukopenia (1/0), anemia (2/0), thrombocytopenia (1/2), neutropenia (1/1), nausea (1/0), diarrhea (1/0), and 1 febrile neotropenia. Conclusions In elderly patients with previously untreated advanced NSCLC, S-1 appears to be well tolerated and demonstrates encouraging activity.

© 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology

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HDL-CHOLESTEROL IS REDUCED IN ADVANCED STAGE LUNG CANCER PATIENTS WITH WEIGHT LOSS ˘ LU1, O BILGI1, R GÖRÜR2, A ÖZGÜN1, B KARAGÖZ1, L EMIRZEOG T TUNÇEL1, T IS¸ITMANGIL2 1 Department of Medical Oncology, GATA Haydarpasa Training Hospital, Turkey, and 2Department of Thoracic Surgery, GATA Haydarpasa Training Hospital, Turkey Background and Aim Lipids play roles in several biological functions such as cell growth, division, and membrane stabilization in normal and cancer cells. There has been also interest in the relation of serum lipid levels and cancer in various studies. Epidemiological studies have demonstrated that high total cholesterol level is associated decreased cancer incidence. On time of diagnosis, HDL-cholesterol levels are reduced in lung cancer patients. We investigated the relation between lipid profile and weight loss in advanced stage lung cancer patients. Material and Methods Forty-eight advanced stage lung cancer patients and 20 healthy subjects were included in the study. SCLC patients had extensive stage disease and NSCLC patients were stage IIIB and IV. All of study patients and control subjects were smoker and non-obese. Serum lipid profile, total protein, albumin, Erythrocyte Sedimentation Rate (ESR) and clinical data were recorded. Results Lower HDL-cholesterol levels detected in advanced stage lung cancer patients. Serum total cholesterol, total protein, and albumin levels were also lower in cancer patients than controls. Serum LDL-cholesterol measurements were not different between patients and healthy subjects. However, ESR is higher in patients than controls. Twenty-four patients had weight loss. Total cholesterol, HDL-cholesterol, and LDL-cholesterol levels were lower in the patients with than without weight loss. However, total cholesterol, HDLcholesterol, and LDL-cholesterol levels were not different between lung cancer patients without weight loss and control subjects. In lung cancer patients, serum HDL-cholesterol level was correlated with inversely ESR; directly with serum albumin level. Discussion Although the weak association between HDL-cholesterol and cancer has been reported and the effect of HDL-cholesterol in carcinogenesis has been discussed, we not found difference in lipid profiles of lung cancer patients without weight loss. We consider that the reduction of lipid levels may be related to cancer cachexia. Moreover, serum albumin level and ESR, indirectly markers of inflammation, were correlated with HDL-cholesterol. It is known that inflammation reduce HDL-cholesterol. The cause of coincidence between reducing HDL-cholesterol and cancer may be inflammatory process. Further studies that investigate the clinical signification of reduced HDLcholesterol and other lipids are necessary.

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A RETROSPECTIVE ANALYSIS OF 128 CASES OF PULMONARY MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA IN CHINA Q YU, Q CHEN Department of Gerontology, Xiangya Hospital, Central South University, China To investigate the clinical characteristic, imaging features, treatment and prognosis of Pulmonary Mucosa-Associated Lymphoid Tissue (p-MALT) lymphoma of Chinese people. We searched Chinese CNKI, WANFANG and VIP databases from January 1, 1980 to December 31, 2011 to identify p-MALT lymphoma, and made an analysis and summary. 128 cases were included. There were 71 men and 57 women, aged from 25–87 years old. The most frequent symptoms were expectoration (46.1%), chest distress (21.1%), chest pain (20.3%), fever (18.8%), dry cough (14.8%), tachypnea (14.1%) and 20.3% had no symptoms. The main imaging manifestations were nodule or mass (57.8%), pneumonia (43.8%). The major diagnosis ways were surgery (55.5%) and CT-guided biopsy (33.5%). The primary treatments were operation (41.3%), chemotherapy (27.9%) and operation combined with chemotherapy (18.3%). From this retrospective analysis, we find that pulmonary mucosa-associated lymphoid tissue lymphoma is a rare disease and tends to occur in old males. The main characteristics were non-specific clinic manifestations, atypical kinds of imaging features, non-unified treatment and better prognosis after treatment. This is the largest retrospective study of p-MALT lymphomas in China. According to this study, doctors can have a deeper understanding of p-MALT and a lower rate of diagnosis and treatment.

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STUDY ON BENZO(A)PYRENE-INDUCED EPITHELIALMESENCHYMAL TRANSITION IN LUNG ADENOCARCINOMA A549 CELLS AND ITS UNDERLYING MECHANISM MX XIE1, Q CHEN1, HB PENG1, SY HE2, CP HU1 1 Department of Geriatric Medicine, Department of Respiratory, Xiangya Hospital of Central South University, China, and 2Department of Biochemistry and Molecular Biology, University of South China, China

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CYTOKERATIN 19 FRAGMENT (CYFRA 21-1) PREDICTS THE EFFICACY OF EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR)-TYROSINE KINASE INHIBITOR IN NON-SMALL CELL LUNG CANCER HARBORING EGFR MUTATION T KOSUKE Interrate of Medical Oncology, IBRI, Japan Background Epidermal Growth Factor Receptor (EGFR) gene mutation is independently associated with a favorable response in Non-Small Cell Lung Cancer (NSCLC) patients receiving EGFR-Tyrosine Kinase Inhibitors (TKI), regardless of gender or smoking history. However, recent reports have indicated that squamous cell carcinoma patients harboring EGFR mutations show a significant worse response to EGFR-TKIs than adenocarcinoma patients. We hypothesize that serum cytokeratin 19 fragment (CYFRA 21-1) is associated with efficacy of EGFR-TKIs in EGFR mutated NSCLC patients. Methods We retrospectively screened 160 NSCLC patients harboring EGFR mutations who received either gefitinib or erlotinib between 1992 and 2011. Patients were screened for clinical characteristics, efficacy of EGFR-TKI, and tumor markers (CEA/CYFRA 21-1) at initial diagnosis. Results Out of 160 eligible patients treated with EGFR-TKIs, 77 patients with high CYFRA 21-1 level (>2 ng/ml) showed statistically shorter ProgressionFree Survival (PFS) than 83 patients with normal CYFRA 21-1 level (median PFS 7.5 vs 13.3 months, p < 0.001). No significant difference in PFS was observed between high CEA group (>5 ng/ml) and normal CEA group (median PFS 8.6 vs 11.2 months, p = 0.242). Multivariate analysis revealed that high CYFRA 21-1 level is independently associated with PFS (HR 1.35; p = 0.002) as well as squamous cell carcinoma (HR 1.40; p = 0.020) and poor performance status (HR 2.63; p = 0.003). No statistically significant difference in Overall Survival (OS) was observed between high CYFRA 21-1 group and normal group (median OS 24.8 vs 39.1 months, p = 0.104). Conclusions High CYFRA 21-1 level patients have significantly shorter PFS. CYFRA 21-1 is a predictive marker of EGFR-TKI treatment in EGFR mutated NSCLC patients.

Background Benzo[a]pyrene (B[a]P), a major human carcinogen in combustion products of cigarette smoke, is metabolically activated into DNA-reactive metabolites and promoted lung tumor development. Our study aims to explore the role of B[a]P in tumor cell metastasis and proliferation by modulating Twist1, a key transcription factor in metastasis-related process named Epithelial-Mesenchymal Transition (EMT) in human lung adenocarcinoma A549 cells. Methods Human lung adenocarcinoma A549 cells were treated with 1 μmol/L B[a]P in DMSO for 4 weeks. After 4 weeks of incubation, different index indicating EMT process were examined between B[a]P group, DMSO group and control group at different time points. Cell morphology was observed by an inverted microscopy. Cell migration was evaluated by transwell and wound-healing assay. Protein levels of epithelial phenotypic marker Ecadherin, as well as mesenchymal phenotypic markers including vimentin, N-cadherin and Twist1 were analyzed by Western blot; mRNA levels were assessed by RT-PCR. The cellular localization and expression of E-cadherin and vimentin was observed using a laser scanning confocal microscope. After silencing Twist1 by Twist1 specific shRNA named pGCsilencerTM-Twist1shRNA, EMT index mentioned above were reassessed. Results After 4 weeks of incubation with B[a]P, A549 cells underwent morphological alteration from epithelial to mesenchymal spindle cells. Accordingly, cells acquired highly migratory abilities. N-cadherin, vimentin and Twist1 were highly expressed, whereas E-cadherin expression was scant both at mRNA and protein levels. E-cadherin expression was decreased while vimentin was increased both mainly in the cytoplasm. After Twist1 was successfully suppressed, cellular morphology were reversed from mesenchymal to epithelial polygonal shape; cell migration ability was refrained compared to B[a]P group without Twist1 suppression. Expression of previous elevated EMT markers such as N-cadherin, vimentin were downregulated to a certain extent, while E-cadherin expression was restored both in mRNA and protein levels. Conclusion Based on our research, we can confirm that B[a]P can induce EMT in human lung adenocarcinoma A549 cells. Twist1 participates in and promotes the process of EMT induced by B[a]P. Supported by Research Funds from the Education Department of Hunan Province, the Science and Technology Agency, Environment Protection Agency of Changsha.

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THE RISK AND BENEFIT OF CHEMOTHERAPY IN PATIENTS WITH STAGE IV NON-SMALL LUNG CANCER PRE-EXISTING INTERSTITIAL LUNG DISEASE

CLINICAL SIGNIFICANCE OF INCIDENTAL THYROID NODULES IDENTIFIED ON LOW-DOSE CT FOR SCREENING OF LUNG CANCER

K TAKAMURA1,2, H ASAHINA2, S OIZUMI2, Y FUJITA2, T KOJIMA2, T HARADA2, Y KAWAI2, T SASAKI2, M YAMAMOTO2, H DOSAKA-AKITA2, H ISOBE2, M NISHIMURA2 1 First Department of Medicine, Obihiro-Kosei General Hospital, Japan, and 2 Hokkaido Lung Cancer Clinical Study Group, Japan

JH LEE1, YH KIM2, JC LEE1 1 Department of Pulmonary and Allergy Medicine, Jeju National University Hospital, Korea, and 2Department of Pulmonary and Critical Care Medicine, Kyung Hee University Hospital, Korea

Background Chemotherapy (Cx) may cause the acute deterioration of Interstitial Lung Disease (ILD), sometimes called as Acute Exacerbation (AE). However, little is known about its risk and prognostic significance in stage IV Non-Small Cell Lung Cancer (NSCLC) Patients (pts) with pre-existing ILD. Methods A total of 242 subjects (6.9% of all) were retrospectively identified to have pre-existing ILD by Computed Tomography (CT) from a sum of 3524 lung cancer pts at 8 institutions during 2004 to 2009. CT images of all the eligible pts were centrally reviewed. We conducted the subgroup analysis of 62 pts with stage IV NSCLC to elucidate the role of Cx. Univariate and multivariate analyses were performed using a Cox proportional hazard model to examine the potential role of any prognostic factors for Overall Survival (OS). Results Pts’ characteristics were: male/female = 53/9; median age (range) = 72 (42–85) yrs.; smoking status: ever/never = 56/6; Performance Status: 0/1/2/3/4 = 9/29/12/9/3; Histology: adeno/squamous/other = 37/15/10; CT pattern: Usual Interstitial Pneumonia (UIP)/non-UIP = 30/32; extent of normal lung on baseline CT: 10–50%/60–90% = 43/19; pre-existing emphysema: yes/ no = 47/15. Cx administration: yes/no = 41/21. AE occurred in 15 of 62 pts (24%), leading to the 10 pts’ death due to AE. AE occurred significantly more in pts with Cx than those without (13 of 41 pts vs. 2 of 21 pts, p = 0.041). The Median Survival Time (MST) of all pts was 159.5 days (95% CI, 93 to 187). There was no significant difference between the MST of pts with and without AE; 125 (95% CI, 62 to 184) days with AE and 172 (95% CI, 93 to 204) days without AE (p = 0.42), while the pts with Cx significantly lived longer than pts without Cx; 179 (95% CI, 98 to 242) days vs. 48.5 (95% CI, 26 to 126) days, respectively. Multivariate analysis revealed that only Cx (HR: 0.47, 95% CI: 0.24–0.90, p = 0.031) was significantly associated with OS. Conclusions Cx significantly increased the risk of AE in stage IV NSCLC pts with pre-existing ILD. On the other hand, Cx contributed to better prognosis in these pts.

Background Incidental thyroid nodules are defined as newly identified thyroid nodules encountered during imaging study2. Low-dose CT for screening of lung cancer often detects on incidental thyroid nodules. However, there have been few reports that have examined for incidental thyroid nodules being identified on chest low-dose CT1,2. We investigated the prevalence of incidental thyroid nodules and their risk for malignancy. We also evaluated the features of clinical characteristics and scans of CT for differentiating between benign and malignant thyroid nodules. Methods We retrospectively reviewed the medical records of patients undergoing low-dose CT scans for screening of lung cancer without history of previous thyroid disease. The clinical characteristics, outcomes, and the CT findings of subjects were analyzed. Results Among enrolled 1941 patients undergoing low-dose CT, 55 (2.8%) showed incidental thyroid nodules. Seven (12.7%) of these were proven malignancy. The positive and negative predictive value of low-dose CT for detection of malignant thyroid nodule were 12.7% and 99.3%, respectively. The considerable factors for the low-dose CT features of malignant thyroid nodules were mean attenuation value more than 55 and densly calcification. (respectively, p = 0.036 and p = 0.048). Sex, age, location of nodule, longest diameter, AP/T (Anterior-Posterior/Transverse) ratio, margin, hypodense density, any punctuate calcifications, and thyroid enlargements showed no difference between benign and malignant thyroid nodules. In multivariable analyses, mean attenuation value above 55 showed a statistical significance between both groups. (p = 0.048). Conclusion Incidental thyroid nodules were detected on 2.8% of patients undergoing low-dose CT. Of these, 12.7% were revealed malignancy. Mean attenuation value more than 55 was considered as a only predictive factor of malignant thyroid nodule for CT features. For patients undergoing low-dose CT, careful assessment for thyroid glands as well as pulmonary lesions should be performed. References 1. Yoon DY, Chang SK, Choi CS, et al. The prevalence and significance of incidental thyroid nodules identified on computed tomography. J Comput Assist Tomogr 2008;32:810–815. 2. Ahmed S, Horton KM, Jeffrey RB, Jr., et al. Incidental thyroid nodules on chest CT: Review of the literature and management suggestions. AJR Am J Roentgenol 2010;195:1066–1071.

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PRIMARY PULMONARY NON-HODGKIN T CELL LYMPHOMA: A CASE REPORT AN ROSYID, RY MELIANA Department of Pulmonology and Respiratory Medicine, Medical Faculty of Airlangga University, Soetomo Hospital, Indonesia Background Primary Pulmonary Lymphoma (PPL) is rare case and T cell type more extremely rare. Patients with Primary Pulmonary Lymphoma characteristics are difficult to diagnose because its growth slow (with a tendency to relapse), the clinical and radiological finding were not specific. Primary Pulmonary Non-Hodgkin T cell Lymphoma have bad prognostic. Case A man, 63 years old was admitted with cough, dyspnoea, and fever since 2 weeks before. There are multiple right coli nodule and swelling of neck. Peripheral bloods smear with normal limit and increase of Lactate Dehidrogenase (LDH) serum. Chest radiography suggested lung mass. CT scan thorax found solid mass with irregular border edge at central of right lung through the mediastinal that cause atelectasis right upper lobe. Fiber optic bronchoscopy found intra luminary mass at right upper lobe and we performed forceps biopsy. We found para aorta nodule from abdomen ultra sound graphic. Histology finding of right coli nodule and FNAB CT Guiding mass are non-Hodgkin Lymphoma. Immune histochemistry of intra luminary mass is Pancytokeratin negative, CD45 Positive, CD20 Negative. We diagnosed this patient as Primary Pulmonary Lymphoma T-cell type. We performed chemotherapy CHOP for this patient. Discussion Most PPL arise from the Mucosa-Associated Lymphoid Tissue (MALT) of the bronchus. T cell type is extremely rare. Clinical and radiological of PPL is similar with lung mass. Increasing of LDH is tumor marker for Lymphoma. Histopathology followed by immune histochemistry is the gold standard for diagnosing mass. PPL can cause several of complication and it also metastases to other organ. Chemotherapy is one of modality for PPL treatment. Summary We report herein a 63-year-old man who was found to have a primary pulmonary non-Hodgkin lymphoma with T-cell type and we performed chemotherapy. References 1. Kara M, Özkan M, Sak SD, Kuzu I, Kavukçu S. Primary Pulmonary nonHodgkin Lymphoma. J Ankara Med School 2002; 24(4): 201–206. 2. Shin CH, Paik SH, Park JS, Kim HK, Park SI, Cha JG, Koh ES. Primary Pulmonary T-Cell Lymphoma: a Case Report. Korean J Radiol. 2010 Mar– Apr; 11(2): 234–238.

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DIAGNOSTIC PROBLEM A WOMAN WITH RADIOLOGIC FINDINGS A MASS ON LEFT LUNG WITH THE NODULES IN RIGHT AXILLA AND RADICULOPHATY SINISTRA: A CASE REPORT T BUDISATRIO, W LAKSMI Department of Pulmonology and Respiratory Medicine, Medical Faculty of Airlangga University, Indonesia Background Pneumonia which resolves slowly after appropriate antibiotic therapy can be problematic. It can vary depending on the infecting organism and the host immune status. Slowly resolving pneumonia infrequently simulate cancer, and their differentiation, based on imaging findings, can sometimes be difficult. A specific diagnosis is necessary for the initiation of appropriate therapy. Case A woman, 43 years old with a chief complaint of bloody cough, accompanied by shortness of breath and fever. Patients also complained of pain in the left leg and nodules in the right axilla. Patients had undergone multiple FAM operations at right and left breast. Laboratory findings showed leukocytosis, granulositosis accompanied by anemia and hypoalbuminemia. Thoracic CT scan showed a solid enhancing mass in the inferior lobe of the left lung. FNAB CT Guiding which performed two times gives the results of the inflammatory process. Sputum culture showed growth of Streptococcus viridians. Sputum cytology obtained negative results. FOB examination found elliptical narrowing and intraluminar mass in left bronchus, with BAL fluid culture obtained growth of Pseudomonas aeroginosa bacteria and forceps biopsy showed suppuratif chronic inflammation. Serial chest X-ray still showed similar radiological picture. EMG impression denoted nerve root compression of left preganglioner L5-S1 causing radiculopati sinistra. Lumbosacral MRI gave the results of malignant marrow replacement in the corpus region of S1 and S2 until left side of the os sacrum with the results of FNAB showed a malignant tumor. FNAB nodules in the right axilla showed an overview infitrating ductal carcinoma, while open biopsy at the same place denoted Hodgkin’s lymphoma. Review biopsy of vertebrae L 5-S1 also suggested a Hodgkin’s lymphoma. Result Antibiotics administration according to culture results gave clinical improvement, although radiologic picture remains the same. Radiotherapy serial on the damage site of the spine also given to this patients. Chemotherapy is planned to inhibit the development of Hodgkin’s lymphoma. Conclusion We already reported a patient with slow-resolving pneumonia with similar description of malignancy accompanied with Hodgkin’s lymphoma and Radiculopathy Sinistra. Reference 1. Jayaprakash B, Varkey V, Anithakumari K. Etiology and Clinical Outcome of Non-Resolving Pneumonia in a Tertiary Care Centre. JAPI, vol 60, 2012, pages 20–23.

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THE POLYMORPHISM OF PLK1 GENE IN LUNG CANCER AND THE INHIBITS ON A549 CELLS BY PLK1 SIRNA FL LIU2, Y ZHOU1, CX BAI2, KJ YING1 1 Department of Respiratory Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, China, and 2Department of Respiratory Medicine, Zhongshan Hospital, Fudan University, China Background PLK1 was positively correlated with the formation and development of lung cancer, so the inhibiting of PLK1 gene expression by SiRNA interference technique may be a new method to treat lung cancer. However, to ensure the specific inhibitory effect of SiRNA, it is very important to choose a target gene sequence. Methods At first, we find out the possible polymorphism of PLK1 gene in lung cancer cells and 30 lung cancer tissues through sequence-based testing. And then, we design a SiRNA targeting PLK1 mRNA away from the unstable region of PLK1, transfect it into A549 cells. Use Real-Time PCR and Westernblot to investigate the effect of siRNA on VEGF gene expression, then use MTT method and FCA to investigate the effect of SiRNA-mediated PLK1 gene silencing on proliferation and apoptosis of human adenocarcinoma cells A549. Results The ORF of PLK1 gene of A549, NCI-H446, and SK-MES-1 has no mutation, but the its expression of the first three cell lines are significantly higher than BEAS-2B. The rate of SNP in 30 lung cancer tissues is 1/30, but the relationship between the SNP and the lung cancer is still unclear. And this SNP is a heterozygous mutation. We designed a SiRNA targeting 606–627 site of PLK1 gene fragment. The results of Real-Time PCR and Western-blot suggest that our SiRNA can effectively decrease the expression of PLK1 gene in A549 cells (P < 0.05), and the results of MTT and FCA method suggest that the depletion of PLK1 mediated by SiRNA can significantly inhibit the proliferation of A549 (70.72%), and also induce it apoptosis (14.94%). Conclusions Our research indicated that there may be some transcription or post-transcription regulation affecting the expression of PLK1 gene; Although, one heterozygous mutation was found in a lung cancer tissue, and it probably located on the recessive alleles, we still should make sure that the 1114 site is not in the SiRNA targeting region; The SiRNA we designed to target PLK1 can effectively decrease the expression of PLK1 gene in A549 cells, and the inhibition ratio is higher than it repotted in the previous literature; The depletion of PLK1 mediated by SiRNA can significantly inhibit the proliferation of A549, and can also induce its apoptosis. It implies that PLK1 SiRNA can be possibly used as a method to treat lung cancer, and it can also support the fact that the excessive expression of PLK1 gene relates to the formation and the development of lung cancer.

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CLINICAL SIGNIFICANCE OF RACK1 IN LUNG ADENOCARCINOMA AND ITS EFFECT IN METASTASIS OF A549 CELL Y GAO, Q CHEN, X CHEN, CP HU Department of Geriatric Medicine, Department of Respiratory, Xiangya Hospital of Central South University, China Background RACK1, which could bind PKC and regulate ribosomal translation, was proved to act as a major promoter in certain cancers. Our study intended to systematically analyze the prognosis and clinicopathological features of lung adenocarcinoma by concerning the expression of RACK1 in clinical samples, and to investigate the change of metastasis ability of lung adenocarcinoma A549 cell after RACK1 interference and its brief mechanism. Methods 92 human lung adenocarcinoma samples and clinical data were gathered by the agreement of the patients and ethics committee. The immunohistochemistry was applied to examine the expression of RACK1 in 92 samples. Further analysis of disease-free/over-all survival tests, corelationship test and risk factors test were investigated by Kaplan-Meier analysis, Log-rank test, Spearman analysis and Uni/Multi-Variate analysis associated with RACK1 expression. Human lung adenocarcinoma cell A549 were transfected with RACK1 shRNA plasmids and the interference efficiency was validated. Transwell migration/invasion assay, wound healing assay and cytoskeleton immunofluorescence were studied. The downstream molecules which regulated by RACK1, including Snail, E-Cadherin, N-Cadherin, Vimentin and MMP-9, was examined by Western-blot. Results The median survival time of RACK1 high expression group was significantly lower than the RACK1 low expression group in over-all survival test and disease-free survival test. And the expression of RACK1 was significantly correlated with TNM staging and lymph node metastasis. High expression of RACK1 is an independent risk factor of the poor prognosis of lung adenocarcinoma. shRNA1 plasmids was proved to have greatest interference efficiency, which inhibited the abilities of migration and invasion of A549 by the investigations of transwell migration/invasion assay and wound healing assay. Furthermore, cytoskeleton changes of A549RACK1-shRNA1 cell, including irregular shape and structural disorder, was examined by immunofluorescence. The expression of Snail, N-Cadherin, Vimentin and MMP-9 was significantly decreased in A549RACK1-shRNA1 cell. Meanwhile the expression of E-Cadherin was significantly elevated. Conclusion RACK1 high expression predicted poor prognosis and correlated with TNM staging and lymphnode metastasis in human lung adenocarcinoma. And it is an independent risk factor of the poor prognosis of human lung adenocarcinoma. RACK1 could also facilitate metastasis of lung adenocarcinoma A549 cell through a series of downstream genes. Key Words RACK1, lung adenocarcinoma, metastasis and invasion, clinicopathological factors, prognosis. Supported by Research Funds from the Education Department of Hunan Province, the Science and Technology Agency, Environment Protection Agency of Changsha.

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FORCED EXPIRATORY VOLUME IN ONE SECOND AND SEVERITY OF EMPHYSEMA AS PROGNOSTIC FACTORS IN ADVANCED NON-SMALL CELL LUNG CANCER JH LEE1, Y KIM2, S LEE1, YJ RYU1, JH CHANG1 1 Department of Internal Medicine, School of Medicine, Ewha Womans University, Korea, and 2Department of Radiology, School of Medicine, Ewha Womans University, Korea Background Both of reduced lung function and emphysema are important risk factors for lung cancer and increases surgical risk in patients with operable stages of lung cancer. The aim of this study was to investigate whether low Forced Expiratory Volume in one second (FEV1) and/or severity of emphysema are prognostic facotors in patients with advanced lung cancer. Methods Data were retrospectively collected from patients with Non-SmallCell Lung Cancer (NSCLC) of stage IIIB or IV and available spirometry at diagnosis of lung cancer. They had been diagnosed as having advanced NSCLC between December 2002 and December 2008 in a tertiary referral hospital. We excluded patients without available follow-up record and with pleural effusion and/or obstruction of lobar bronchus with atelectasis, which can make it hard for a radiologist to measure exact lung volume. Chest CT scans were performed on all patients at full inspiration using a 16-multi detector CT scanner (Somatom Sensation; Siemens Medical System, Forchheim, Germany). Images of the whole lung were extracted automatically and the attenuation coefficient of each pixel was calculated. The cutoff level between normal lung density and Low-Attenuation Areas (LAA) was defined as −950 Hounsfield Units. To evaluate pulmonary emphysema quantitatively, the total lung volume and the volume of LAA were automatically measured using a volume data set on a computer workstation (Rapidia 3D version 2.8; Infinitt Health Care, Seoul, Korea), and the percentage volume of LAA (%) was calculated as (volume of LAA)/(total lung volume)×100 (%). Emphysema is defined as having LAA% of more than 10%. Results Among a total of 65 patients, 58 died as of January 2012. Their mean age was 66 years; 49 (75%) were male. Mean FEV1 was 2.01 L (83% of predicted). Thirty two patients (49%) had adenocarcinom. In a multivariate analysis using Cox regression model, independent prognostic factors were adenocarcinoma (hazard ratio [HR] = 0.294, 95% confidence interval [CI]: 0.156–0.551, p < 0.001), FEV1 less than 50% of predicted (HR = 5.471, 95% CI: 1.989–15.048, p = 0.001), and male gender (HR = 2.608, 95% CI: 1.270– 5.356, p = 0.009). Conclusions Reduced FEV1, but not emphysema severity, is an important prognostic factor in advanced NSCLC.

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DETECTION OF DIFFERENTIALLY EXPRESSED CANCER DRUG TARGETS GENES REGULATED BY RBM5 IN HUMAN LUNG ADENOCARCINOMA CELLS USING PCRARRAY J ZHANG, P LI, K WANG, H LIANG Department of Respiratory Medicine, Second Hospital, Jilin University, China Background RBM5 (previously referred to as g15, LUCA-15, and H37) is an RNA-binding protein that has the ability to modulate apoptosis and a putative tumor suppressor gene for lung cancer. RBM5 may serve as a biomarker with the ability to predict a response to cisplatin and corelate with EGFR and KRAS in lung cancer. We aimed to identify the Cancer Drug Targets Genes expression profiles regulated by RBM5 using PCRarray. This study provides foundation for further study on RBM5 and gene therapy in lung cancer. Methods The A549 cells were transfected with a pcDNA3-RBM5 plasmid and an empty vector pcDNA3.0. RNA was isolated using TRIZOL® Reagent (Invitrogen), and assesed RNA yield and quality. The First Strand cDNA was Synthesised using SuperScript. III Reverse Transcriptase (Invitrogen) kit. Two X SuperArray PCR master mix (SABiosciences, Cat. No. PAHS-507) was used in real time PCR reactions. The fold-change of genes expression profile was calculated between groups as ΔΔCt Methods. Results RBM5 mRNA and protein expression in A549 cells transfected with RBM5 plasmid increased significantly compared with that of the empty vetor control (P < 0.01). Gene expression profiles from RBM5/A549 cells were compared to pcDNA3 A549 cells. Selected genes had to be up- or downregulated at least two-fold in PCR arrays. Seven genes (including HRAS) were found to be significantly upregulated and 23 genes (including Kras and EGFR) were significantly downregulated in RBM5-overexpressing cells. Conclusion Many of the Cancer Drug Targets Genes are modulated by RBM5. Our findings suggest that there may be clinical utility for ectopic RBM5 as an gene therapy target. This work was funded by the National Natural Science Foundation of China (No. 81071919 and No. 30971315) and the Science & Technology Development Planning Project of Jilin Province (No. 200905147).

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REVERSAL EFFECT OF RBM5 ON CHEMORESISTANCE TO CISPLATIN IN HUMAN LUNG ADENOCARCINOMA CELLS IN VITRO AND IN VIVO P LI, J ZHANG, GP MENG, YQ HAO Department of Respiratory Medicine, Second Hospital, Jilin University, China Background Increasing RBM5 levels inhibit tumor cell growth and promote apoptosis. In this study, we investigated the role of RBM5 in the cisplatin resistance observed in human lung non-small cell lung cancer cells and in tumor-bearing mice. Methods RBM5 mRNA and protein expression in the A549 and A549/DDP cells was analyzed by semi-quantitative RT-PCR and western blot. The A549/ DDP cells were then transfected with a pcDNA3-RBM5 plasmid, prior to treatment with cisplatin. Twenty-four nude mice were implanted with A549/DDP cells before randomization into the following treatment groups: control; cisplatin only; RBM5 only; RBM5 + cisplatin. Tumor volume was assessed. Semiquantitative RT-PCR and western blot analyses were performed to confirm the expression of RBM5 mRNA or protein, respectively. MTT assays were used to evaluate chemosensitivity to cisplatin. Apoptosis was assessed by DAPI nuclear staining and flow cytometric analysis with an Annexin-V-FITC apoptosis kit. Cleaved caspase-3 and cleaved caspase-9 were detected by western blot. Results The expression of RBM5 mRNA and protein was significantly reduced in the A549/DDP cells compared with the A549 cells. Exogenous expression of RBM5 by the pcDNA3-RBM5 resensitized the response of A549/ DDP to cisplatin, resulting in a significant increase in tumor-suppressing activity induced by cisplatin. The decrease in tumor volume when compared to RBM5 and cisplatin treated animals was obvious. We also found that the RBM5-enhanced chemosensitivity was associated with activation of caspase-9 and the downstream marker caspase-3 in vitro and in vivo. Conclusion Our results demonstrate that RBM5 may serve as a biomarker with the ability to predict a response to cisplatin. It may also act as a prognostic indicator in lung cancer patients. The pcDNA3.0-RBM5 up-regulated the expression of RBM5, promoted apoptosis and reversed resistance to cisplatin in cisplatin-resistant A549/DDP cells. There may be clinical utility for ectopic RBM5 such as enhancing and resensitizing nonresponders to cisplatin. This work was funded by the National Natural Science Foundation of China (No. 81071919 and No. 30971315) and the Science & Technology Development Planning Project of Jilin Province (No. 200905147).

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KU80 OVEREXPRESSION IS ASSOCIATED WITH CISPLATIN RESISTANCE IN NON-SMALL CELL LUNG CANCER AND TARGETED INHIBITION OF KU80 ENHANCES THE ACTIVITY OF CISPLATIN IN A549/DDP CELLS MY XU, QS MA, P LI, J ZHANG Department of Respirtory Medicine, Second Hospital, Jilin University, China Background Ku80 protein is involved in DNA double-strand break repair, V(D)J recombination and chemoresistance. We investigated Ku80 expression and its correlation with cisplatin resistance and prognosis in Non-Small Cell Lung Cancer (NSCLC) patients. Then, we investigated the role of Ku80 in the cisplatin-induced resistance and the reversal of drug resistance by targeted reduction Ku80 in human lung adenocarcinoma cell. Methods Tumor specimens from 79 patients with operable NSCLC were obtained from 2005 to 2009. Among these patients, 58 patients have been treated with at least three cycles of cisplatin-based chemotherapy. Ku80 protein expression was examined by immunohistochemistry and Western blot on the tumor samples and a cultured A549/DDP cell line, respectively. Cell survival and apoptosis were determined by MTT and TUNEL, respectively. Results 62.50% (20/32) cisplatin-resistant tumors showed high Ku80 expression levels, while 19.23% (5/26) cisplatin-sensitive tumors showed high Ku80 expression levels (p < 0.01). Univariate analysis indicated that overall survival and disease-free survival were significantly better in NSCLC patients with low vs those with high Ku80 expression levels (p < 0.01). Treatment with cisplatin resulted in a dose-dependent increase in Ku80 protein expression in A549 cells, and Ku80 siRNA effectively inhibited Ku80 expression. Ku80 siRNA significantly enhanced sensitivity of A549/DDP cells to cisplatin, associated with increased cell apoptosis. Conclusions Our results indicate that Ku80 is a new promising target for the combination of cisplatin-based chemotherapy in NCSLC patients.

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DIAGNOSTIC ACCURACY OF US-GUIDED TRANSTHORACIC BIOPSY FOR PERIPHERAL THORACIC LESIONS M FUKUSUMI, Y HAMAMOTO, T IBE, S TAKEOKA, K WAKUDA, A MOURI, M KAMIMURA Pulmonology Department, National Hospital Organization Disaster Medical Center, Japan Background and Aim We evaluated a diagnostic rate of Ultrasonography (US)-guided transthoracic biopsy for peripheral thoracic lesions, which have a number of advantages over Computed Tomography (CT)-guided biopsy, including easy approach and no radiation exposure1. Method We investigated the 33 cases with peripheral thoracic lesions in which US-guided transthoracic biopsy was underwent from December 2010 to May 2012. CT-guided transthoracic biopsy was performed in the peripheral thoracic lesions in 18 cases from June 2009 to November 2010, and diagnostic rate and complications were compared. Results In US-guided transthoracic biopsy group, the median diameter was 45.0 mm (14.8–107 mm). The diagnosis was made in 29 lesions (88%), including 21 lung cancers, one malignant mesothelioma, one sarcoma, one metastatic cancer, one plasma cell myeloma, one thymoma, one tuberculoma, and one lung abscess. In four cases, in which the diagnosis were not made, two were proven to be lung cancer and metastatic cancer by surgical biopsy, the other two were diagnosed as lung cancers by CT-guided transthoracic biopsy. Two patients developed post biopsy pneumothorax, two developed post biopsy hemoptysis, and one developed post biopsy empyema. On the other hand, the median diameter of the 18 lesions in CT-guided transthoracic biopsy group was 39.3 mm (14–88.5 mm). The diagnosis was made in 16 lesions (89%), including 16 lung cancers. In two cases, in which the diagnosis were not made, one was proven to be a lung cancer by surgical biopsy, the other one was diagnosed as a lung cancer by CT-guided transthoracic biopsy again five months after. One patient developed post biopsy pneumothorax. Conclusion US-guided transthoracic biopsy, with a real-time visualization of biopsy needle in the lesions, appears to be a safe and effective procedure for diagnosis of peripheral thoracic lesions. Reference 1. Wei-Yu Liao, et al. US-guided Transthoracic Cutting Biopsy for Peripheral Thoracic Lesions Less than 3 cm in Diameter. Radiology 2000;217:685– 691.

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EFFICACY AND SAFETY OF PEMETREXED FOR NONSMALL CELL LUNG CANCER PATIENTS WITH IDIOPATHIC INTERSTITIAL PNEUMONIA M KATO, F TAKAHASHI, R KOYAMA, K MURAKI, R KO, I KOBAYASHI, A MURAKAMI, Y HOSHIKA, T SHYUKUYA, R OHASHI, N SHIMADA, A SAKURABA, K TAKAHASHI Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Japan Background In clinical practice, advanced non-small cell lung cancer (NSCLC) patients with idiopathic Interstitial Pneumonia (IIP) have been carefully treated with cytotoxic chemotherapy. The efficacy and safety of chemotherapy regimen in NSCLC patients with IIP are unknown. Pemetrexed (PEM) is one of the important anticancer drugs for advanced NSCLC, and the incidence of acute lung injury induced by PEM was reported to be 2 percent. In this study, we investigated the efficacy and safety of PEM treatment in NSCLC patients with IIP. Method The medical records of NSCLC patients with or without IIP treated with PEM alone at Juntendo University Hospital between April 2009 and March 2012 were retrospectively reviewed. Patients with squamous cell lung cancer were excluded from this study. Result 77 non-squamous NSCLC patients treated with PEM alone were analyzed. 14 patients were diagnosed as having IIP before treatment (designated as IIP group), and 63 patients did not complicate with IIP (non-IIP group). There were no significant differences in gender, median age, and the median number of the administered cycles between these two groups. PEM alone was administered as second or third line chemotherapy in the majority of patients in both groups. The response rate and the disease control rate were 7.1% and 28.6% in IIP group, and 7.9% and 14.3% in non-IIP group. There were no patients with Complete Response (CR) in both groups. Median Progression Free Survival (PFS) of IIP group and non-IIP group were 20.9 weeks and 28.9 weeks, respectively (p = 0.09 N.S.). 2 patients developed Acute Lung Injury (ALI) and died in IIP group, although there was no patient with ALI in non-IIP group. The treatment was discontinued due to adverse events in 4 patients (28.6%) in IIP group, and 15 patients (23.8%) in non-IIP group. Conclusion Our results indicated that the incidence of PEM-related ALI was significantly higher in SCLC patients with IIP than those with non-IIP (15.3% vs 0%, P = 0.03). PEM must be carefully administered when treating NSCLC patients with IIP. However, further investigations in large scale study are necessary.

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NOTCH-1 CONTRIBUTES TO EGFR-TKI ACQUIRED RESISTANCE IN NON-SMALL CELL LUNG CANCER M XIE1, L ZHANG2, F XU2 1 China State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, China, and 2State Key Laboratory of Oncology in Southern China and Department of Medical Oncology, Sun Yat-sen University Cancer Center, China Background Although some cancers are initially sensitive to EGFR Tyrosine Kinase Inhibitors (TKIs), resistance invariably develops. Recent studies have shown that Notch signal is associated with drug resistance. However, the exact mechanism of Notch during acquisition of resistance to EGFR-TKI in human lung cancer remains unclear. Methods Western blot, Immunofluorescence assay were used to analyze the expression level of Notch signaling and Epithelial-Mesenchymal Transition (EMT) markers in parental and Gefitinib-resistant PC9 and NCI-H1650 cells. Molecular manipulations (silencing or overexpression) were performed to investigate the effect of Notch-1 on EMT and sensitivity to gefitinib. In addition, cancer cells isolated from malignant pleural effusion of lung cancer patients were analyzed for the expression of Notch-1 and EMT markers by qPCR. The effect of Notch inhibitor MRK003 in combination with Gefitinib was tested in murine lung cancer xenograft model. Results Notch-1 was highly upregulated in Gefitinib acquired resistant lung cancer cells. More importantly, Notch-1 contributed to the acquisition of EMT phenotype, which was critically associated with acquired resistance to Gefitinib. Silencing of Notch-1 using siRNA resulted in Mesenchymal-Epithelial Transition (MET), consistent with impaired invasion and anchorage-independent growth of lung cancer and re-sensitization to gefitinib in acquired resistant NSCLC cells. In clinical samples, a trend of increased Notch-1 with downregulation of epithelial marker and up-regulation of mesenchymal markers was shown in Gefitinib acquired resistant lung cancer. Finally, Gefitinib treatment of Balb/c nu/nu with acquired resistant lung cancer xenografts in combination with Notch inhibitor MRK003 resulted in effective tumor growth retardation. Conclusion Notch-1 might play a novel role in acquired resistance to gefitinib, which could be reversed by inhibiting Notch-1.

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IDENTIFYING RISK FACTORS FOR REFRACTORY FEBRILE NEUTROPENIA IN PATIENTS WITH LUNG CANCER M FUJITA, T MATSUMOTO, T HIROTA, S TAKEDA, R HIRANO, J UCHINO, T HARADA, K WATANABE Department of Respiratory Medicine, Fukuoka University Hospital, Japan Background The evidence concerning the development of Febrile Neutropenia (FN) in patients with solid tumors remains insufficient. In the present study, we searched for predictive factors for the failure of the initial antimicrobial agents used for FN in patients with lung cancer. Methods Sixty FN patients treated in our ward from June of 2005 to May of 2011 were retrospectively analyzed. The definition of FN, and the response to antimicrobial agents was determined by the Japanese guidelines. We divided the FN patients into two groups by their response to the initial antimicrobial agents. Next, the characteristics of the two groups were compared. Results and Conclusion The Multinational Association of Supportive Care in Cancer (MASCC) score1 did not differ between the two groups. The nonresponder group demonstrated significant elevation of the serum C-Reactive Protein (CRP) level. A multivariate analysis demonstrated that a CRP level higher than 10 mg/dl is an independent risk factor for the failure of initial antimicrobial agents for febrile neutropenia with lung cancer (OR, 11.0; 95% CI, 1.635–74.5). When the CRP score was added to the MASCC score1, the scoring system could more precisely predict the failure of initial antimicrobial agents in patients with lung cancer who developed FN. Reference 1. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patient with cancer:2010 update by the Infection disease society of America. Clin Infect Dis 2011; 52;e56–93.

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CHARACTERISTICS OF LUNG CANCER DIAGNOSED WITH LOW DOSE CHEST CT SCREENING

EPIDERMAL GROWTH FACTOR RECEPTOR MUTATIONS IN LUNG ADENOCARCINOMA IN A MULTIETHNIC POPULATION

SH CHOI1, CH LEE2, SY KWON1 1 Department of Internal Medicine, National University Hospital Healthcare System Gangnam Center, Korea, and 2Department of Diagnostic Radiology, National University Hospital Healthcare System Gangnam Center, Korea

CK LIAM1, MI A. WAHID2, P RAJADURAI3, YK CHEAH4, TSY NG4 1 Department of Medicine, Faculty of Medicine, University of Malaya, Malaysia, 2Beacon International Specialist Centre, Petaling Jaya, Malaysia, 3 Monash University, Bandar Sunway, Malaysia, and 4University Putra Malaysia, Serdang, Malaysia

Background Role of chest CT in early diagnosis of lung cancer is controversial now in terms of mortality reduction and possible harms of overdiagnosis and unnecessary radiation exposure. Also, the clinical characteristics of lung cancer on CT screening are not well known despite some studies. Methods This study included 15,615 Korean adults who received low dose chest CT for lung cancer screening in part of health checkup program in Healthcare system Gangnam center from Oct 2003 to June 2010. Patients of lung cancer diagnosed on screening were reviewed retrospectively about clinical parameters such as sex, smoking, and final pathology and staging. Results 35 lung cancer patients occurred. Lung cancer detection rates were 0.22% (crude annual incidence rate 61.0/100,000/year). Male and female ration was 6:4. 18 of 35 lung cancers occurred in high-risk groups (>20 packyear smoking) and 17 in low risk group (ex-smokers and non-smokers). 76% of lung cancers were less than 3 cm (90%, intrapleural group >95%. Conclusion Bevacizumab is capable of suppressing angiogenesis and tumorigenesis. In vivo, the ways of bevacizumab administration can affect the inhibitory effect on NSCLC tumor growth, and intrapleural injection is relatively more effective than intraperitoneal and intravenous routes.

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THE NEUTROPHIL TO LYMPHOCYTE RATIO AS AN INDEPENDENT PROGNOSTIC FACTOR IN NON-SMALL CELL LUNG CANCER HARBORING K-RAS MUTATION EY KIM, SK KIM, J CHANG, YS CHANG Department of Internal Medicine, Yonsei University College of Medicine, Korea Background Inflammation promotes cancer development and progression. The Neutrophil to Lymphocyte Ratio (NLR) is a simple biomarker that reflects systemic inflammatory responses and predicts patients’ survival in many types of cancers, including lung cancer. In this study, we investigated the prognostic value of NLR in patients with Non-Small Cell Lung Cancer (NSCLC) harboring K-ras mutation. Methods From June 2005 to June 2012, a total of 81 patients with NSCLC harboring K-ras mutation in codon 12 or 13 were identified and enrolled. Clinicopathological information was obtained from electronic medical records. NLR was calculated by dividing the neutrophil count value by the number of lymphocytes during the period of initial evaluation. Predictive factors for Progression-Free Survival (PFS) and Overall Survival (OS) were calculated using Kaplan-Meier Estimator and Cox proportional hazards model. Results The mean value of NLR was 3.36 ± 2.59 (range: 0.64–13.39). The OS of the patients with high NLR (≥3.36) was significantly shorter than that of the patients with low NLR ( 0.05). We made a comparison between direct sequencing and MEL in 50 cases whose EGFR gene type had been tested by MEL and mutant-enriched PCR, and found that the mutations detection rate was 22.0% (11/50) by directing sequencing, which was significantly lower than by MEL [50.0%(25/50)] (χ2 = 12.07, p < 0.05). Conclusions We suggest that the blood-based mutant-enriched liquid chip assay has the ability to provide the most direct and valuable guidance for clinicians to make decision on EGFR TKIs (gefitinib) therapy in the advanced NSCLC patients. Reference 1. He C, Liu M, Zhou C, et al. Detection of epidermal growth factor receptor mutations in plasma by mutant-enriched PCR assay for prediction of the response to gefitinib in patients with non-small-cell lung cancer. Int. J. Cancer, 2009,125:2393–2399. Supported by An Education Bureau of Guangzhou Research Fund.

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CLINICAL CORRELATION OF EGFR PROTEIN OVEREXPRESSION WITH HISTOLOGICAL GROWTH PATTERN: A PRELIMINARY REPORT

RETROSPECTIVE MULTICENTER SURVEY FOR MANAGEMENT FOLLOWING PROGRESSION DISEASE WITH GEFITINIB IN NON-SMALL CELL LUNG CANCER

MA ABD RAHMAN1, NS BAKAR1, NKM KORNAIN1, WAW YAACOB2, WHWAN MOHAMAD1, MA MOHD ZIM1, TS ISMAIL1, AI ISMAIL1 1 Faculty of Medicine, Universiti Teknologi MARA, Malaysia, and 2Hospital Selayang, Malaysia

Y FUTAMURA1, T SAWA1, T HASEGAWA1, A HORIBA1, T ISHIGURO1, T YOSHIDA1, J SHINDOH2, T ABE2, Y OHNO3, N FUNAGUCHI3, S SATOH4, T OGURI4, O TAGUCHI5, M MORISE6, Y HASEGAWA6 1 Division of Respiratory Medicine and Oncology, Gifu Municipal Hospital, Japan, 2Ogaki Municipal Hospital, Japan, 3Department of Respiratory Medicine, Gifu University, Japan, 4Department of Medical Oncology, Nagoya City University, Japan, 5Department of Respiratory Medicine, Mie University, Japan, and 6Department of Respiratory Medicine, Nagoya University, Japan

Background Amplification of Epidermal Growth Factor Receptor (EGFR) is associated with strong staining in Immunohistochemistry (IHC) and solid histological growth pattern. To date, there has been no report which correlates EGFR protein over-expression and histological growth pattern and clinical staging among Malaysian patients. Methods Details were obtained from electronic records of confirmed diagnosis of the lung adenocarcinoma in Hospital Selayang. The demographic details employed include age, gender, race and smoking history. The eligible archived samples were sectioned and treated according to DAKO (Agilent Technologies Company) protocols of IHC staining for EGFR. Immunoreaction was defined positive when at least 10% of tumor cells stained. Results Fifty two patients were included in the study. There were 30 males and 22 females. Distributions among races are 48.1% (25) Malay, 46.2% (24) Chinese and 5.8% (3) Indian. Median age was 60.5 at diagnosis. Number of non smoker was 23 (44.2%), of smoker 19 (36.5%) and unrecorded smoking history was 10 (19.2%). All smokers were male while six male along with seventeen females were non smokers and gender proportion for unrecorded smoking history was equal. Histological diagnoses were obtained from twenty two bronchial biopsies (42.3%), thirteen pleural biopsies (24.3%), eight radiologically guided lung biopsies (15.4%) and nine cytological specimens (17.3%). Only thirty four samples were eligible for EGFR immunohistochemical staining after exclusion of nine samples due to very little tumor cells and nine were only cytological samples. Microscopically, twenty seven out of 34 adenocarcinoma cases shown predominantly solid growth pattern. Meanwhile, the rest were five predominantly glandular patterns and two predominantly papillary patterns. Five out of 34 cases (14.7%) were positive for EGFR staining. All five EGFR+ stained the solid component. Among the five cases EGFR+ tumors, two stained on both membrane and cytoplasm, two stained on cytoplasm only and one stained on membrane only. Conclusion There is fair correlation between EGFR+ from IHC and solid histological growth pattern of the adenocarcinoma. However, study on correlation between histological growth pattern on biopsy versus resected specimen and correlation between biopsy histological growth pattern with clinical staging at diagnosis with bigger number of samples are recommended.

Background Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) is effective in patients with activating EGFR mutations, and median time to progression in such patients is generally up to 12 months. Usually, treatment with EGFR-TKI is terminated when Disease Progression (PD) is confirmed, while acute exacerbation after the withdrawal of EGFR-TKI has been reported. To investigate current clinical management beyond PD with gefitinib, multicenter survey was conducted in Japan. Methods All patients with EGFR mutation-positive non-small cell lung cancer confirmed PD in the treatment of gefitinib in 2010, were included in this survey to evaluate patients characteristics, progression free survival with gefitinib, selection of regimen beyond PD and response rate. Result From the six participating institute, 64 cases (median age 69 years old, exon19 in 37 cases, exon18 in 25 cases, another type in 4 cases respectively) had been enrolled. Gefitinib has been used as first line in 35 cases, as second line in 25 cases, as 3rd line or more in 6 cases. Progression free survival was 13 months, and overall survival was 33 months. In PFS and OS, there is no difference between first line and second line use with gefitinib. Response rate shows good efficacy in patients with good performance status. Beyond PD, gefitinib administration was continued in 9 cases (including additional combined therapy in 4 cases), and erlotinib was switched in 15 cases while platinum doublet in 2 cases, another monotherapy in 19 cases respectively. Response rate was shown 22.2% in gefitinib, 26.7% in erlotinib even beyond PD. Conclusion In the patients with active EGFR mutation, it is confirmed that antitumor effectiveness is recognized in patients who continues to be treated under EGFR-TKI after progression of gefitinib.

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CLINICAL FEATURES OF 322 ELDERLY PATIENTS WITH NONSMALL CELL LUNG CANCER−IMPLICATION OF THE CLINICAL BENEFIT OF ERLOTINIB FOR THOSE WITH MUTATIONNEGATIVE EGFR∼ K HIRAI, H YOKOUCHI, H MINEMURA, S SEKINE, K OSHIMA, K KANAZAWA, Y TANINO, T ISHIDA, M MUNAKATA Department of Pulmonary Medicine, Fukushima Medical University, Japan Background Recent increasing of the morbidity and mortality of elderly patients with lung cancer offer the prompt improvement and development of the treatments for this cohort. It has been important to select optimal strategies against those patients especially with non-small cell lung cancer who received chemotherapy. A Japanese phase III trial (WJTOG9904) demonstrated favorable clinical outcome by docetaxel monotherapy over vinorelbine, while a recent French phase III trial (IFCT-0501) revealed superiority of platinum doublet (carboplatin plus weekly paclitaxel) to monotherapy (gemcitabine or vinorelbine) in overall survival. However, it is still undermined whether platinum doublet or monotherapy is optimal for the elderly patients (over 75 years old) with non-small cell lung cancer due to the relative higher toxicity of the platinum doublet therapy. Aim To investigate the clinical features of the elderly patients especially with advanced (IIIB and IV) non-small cell lung cancer stratified by treatment modalities, thereby clarify the prognosis and its related factors. Methods We retrospective reviewed 322 patients with non-small cell lung cancer from January 2007 to March 2012. Results Average age was 79.5 (75–94). There were 241 males and 81 females, 71 Non-smokers and 172 (53.4%) adenocarcinomas. Active EGFR mutation ratio was 23.5%. Clinical stage IA/IB/IIA/IIB/IIIA/IIIB/IV (TMN ver.7) was 69/36/12/15/24/31/73. Eighty-nine (66.9%) patients with clinical stage IA-IIB underwent surgery, while 47 (45.2%) patients with clinical stage IIIB and IV selected chemotherapy. There were 29 patients who received platinum doublet (D) and 17 patients who underwent monotherapy (M). Average age was statistically higher in the patients with D than those with M (78.9 years vs 76.3 years, respectively: p < 0.001). There was no statistically significant difference between two groups in both PFS (D: 6.8 months vs M: 4.7 months, p = 0.251) and OS (D: 12.6 months vs M: 12.1 months, p = 0.936). There were more patients negative for EGFR mutation in D (D: 24 pts versus M: 6 pts: p < 0.01). Erlotinib was initiated for 10 patients with D and 4 patients with M after progression of each treatment. There was a tendency of more toxicities in D group. Conclusion The results of OS and toxicity profile in our subjects suggested that monotherapy should be selected for the elderly patients (over 75 years old) with advanced non-small cell lung cancer. Moreover, erlotinib as a second line therapy might contribute the Post Progression Survival (PPS) of those patients even with mutation-negative EGFR.

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LOCATION AND HISTOLOGICAL PATTERN OF LUNG CARCINOMA AMONG BANGLADESHI SMOKERS AM MAHMUD, R SULTANA, MA HOSSAIN, KS BENNOOR, MR HASSAN Department of Respiratory Medicine, National Institute of Diseases of Chest and Hospital, Bangladesh Background Smoking has definite role on location as well as on histological pattern of lung cancer. Lung tumor which arises in association with smoking exposure tends to occur in upper lobe, with typical upper and lower ration being roughly 2.5:1. The main objective of the study was to assess the relationship of cigarette smoking with the location and histological pattern of lung cancer and to observe recent histological trend of lung cancer both in smokers and nonsmokers in Bangladesh. This cross-sectional study was conducted from July 2007 to June 2008. Methods 98 histologically proven primary lung cancer cases were included in the study. Among them 87 (88.7%) of the cases were maleand 11 (11.2%) of the cases were female, most of the patients were between 50–65 years age. To see the location of tumour, CT scan of chest and Fibre-optic bronchoscopy was done. For histopathology bronchial biopsy brushing and BAL was taken. CT guided FNAC was also performed. Results It was observed that 41.8% of the patients were current smokers, 40.8% were past smokers and 17.2% non-smokers. Mean duration of smoking was 27.5 ± 11.8 years and mean pack-years of smoking was 32.8 ± 21.2. Among smokers upper lobe tumour was 94.1% and lower lobe tumour (56.7%) and among non-smokers upper lobe tumour was 5.9% and lower lobe tumour 43.3%. The difference was statistically significant. Analysis of histological pattern with location of tumour revealed squamous cell and small cell carcinoma were more common in upper lobe (97.7%) than lower lobe (2.3%). The incidence of squamous cell carcinoma is higher among smokers (33.3%) than non smokers (5.9%). It was also observed from the study that more mean pack-year of smoking was related to squamous cell and small cell carcinoma and more time since quitting was related to adenocarcinoma of lung. Conclusion Upper lobe tumour is more common in smokers and Squamous cell carcinoma and small cell lung cancer are more predominant in upper lobe than lower lobe. Age at starting of smoking duration and pack-years of smoking, time since quitting smoking and type of smoking all has definite role on lung cancer histology.

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SERUM CARCINOEMBRYOGENIC ANTIGEN (CEA) LEVEL IN NON SMALL CELL LUNG CANCER PATIENTS IN ADAM MALIK GENERAL HOSPITAL MEDAN, INDONESIA N SOEROSO, L SOEROSO, T SYAFIUDDIN Department of Pulmonology and Respiratory Medicine, School of Medicine Universitas Sumatera Utara, Adam Malik General Hospital Medan, Indonesia Background Increased of Carcinoembryogenic Antigen (CEA) levels often found in lung cancer patients especially histologically adenocarcinoma and large cell cancer type, but also could found benign and malignant tumors and slight increase of CEA levels found in the smoker. CEA is use for evaluation of therapy whether after operation, chemotherapy or radiotherapy and also detecting of recurrence of adenocarcinoma. The aim of this study is to obtain characteristic of serum Carcinoembryogenic Antigen (CEA) levels in Non Small Cell Lung Cancer Patients in Adam Malik General Hospital, Medan, Indonesia. Methods This study is a descriptive with a retrospective approach, where the data was taken from the secondary data. This study was conducted in Department of Pulmonology and Respiratory Medicine in Adam Malik General Hospital in January 2010 until Mei 2012. Results One hundred sixty seven (167) samples were determined in study. This study showed Non Small Cell Lung Cancer patients was obtained 85.62% are males, 38.32% age 51–60 years old and 90.41% had history of smoking. Farmers is the most job that we found about 37.12%. Race was Batak about 49.1%. The largest number of clinical manifestation that was found shortness of breath which are about 43.71%. In Non Small Cancer patients in this study we found Histogically Adenocarcinoma about 56.8%, 37.12% in Squamous cell carcinoma and Large Cell about 5.98%. Stage in NSCLC patients was Stage IIIB about 54.8%. Increased of CEA levels more the 3 ng/ml was found about 63.4% in NSCLC patients. And there is significant difference between serum CEA levels with cytology/histopathology in NSCLC patients (p = 0.048). Conclusions The result of this study showed there was significant difference between increased of serum CEA levels with cytology/histopathology in Non Small Cell Lung Cancer patients. Key Words Characteristic, serum CEA level, non small cell lung cancer patients, cytology, histopathology.

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CHARACTERISTICS OF LUNG CANCER PATIENTS IN ADAM MALIK GENERAL HOSPITAL MEDAN, INDONESIA

CLINICAL ANALYSIS OF COMBINED PULMONARY FIBROSIS AND EMPHYSEMA COMPLICATED WITH LUNG CANCER

N SOEROSO, HM SARAGIH, P HASIBUAN, AS WAHYUNI Department of Pulmonology and Respiratory Medicine, School of Medicine Universitas Sumatera Utara, Adam Malik General Hospital Medan, Indonesia

A TAKIGAMI, M BANDO, H YAMASAWA, M OOHATA, Y MIZUSHINA, M NAKAYAMA, N MATO, Y SUGIYAMA Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Japan

Background Lung cancer is the leading cause of cancer-related mortality not only in the United States but also around the world. The most important risk factor for lung cancer is tobacco. Any action that prevents cigarette smoking initiation or promotes cessation among dependent smokers is a step to preventing lung cancer. Only about 15% of lung cancers are discovered when they are still localized. Prevention and early detection of lung cancer have proven difficult. The aim of this study is to obtain the characteristics of patients with lung cancer who are being treated in Adam Malik General Hospital Medan, Indonesia. Methods This research is a descriptive study with a retrospective approach, where the data was taken from the secondary data. Result Three hundred twenty lung cancer patients were determined in Adam Malik Medan general hospital from January 2007 until December 2010, 201 patients fulfill the inclusion criteria which are patients who have been definitively diagnosed with lung cancer (cytology/histopathology). In lung cancer patients was obtained; 86.1% are males, 40.8% aged ≤60 years old and 87.6% had history of smoking. Male patients who are smokers are about 96% where 72% of them are active smokers when they were diagnosed with lung cancer. Female patients who are non-smokers are about 84%. The largest number of clinical manifestation that was found was shortness of breath which are about 49.2%, chest X-Ray revealed mass about 42.3%, adenocarcinoma was found about 57.3% patients with 54.8% of them were identified as stadium III B. Conclusion From the result of this research, lung cancer patients are mostly found in males aged 60 and above with a large number of them are smokers, which require some effective approach to reduce the prevalence of the smokers so that the number of the lung cancer patient can be reduced. Key Words Characteristics, lung cancer, smoking, adenocarcinoma.

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PHASE II TRIAL OF CARBOPLATIN AND PEMETREXED AS FIRST-LINE CHEMOTHERAPY FOR NON-SQUAMOUS NONSMALL CELL LUNG CANCER AND CORRELATION BETWEEN THE EFFICACY/TOXICITY AND SINGLE NUCLEOTIDE POLYMORPHISMS ASSOCIATED WITH PEMETREXED METABOLISM: HOT0902 Y FUJITA, K KANAZAWA, T ISHIDA, S FUJIUCHI, T HARADA, M HARADA, K TAKAMURA, I KINOSHITA, Y KATSUURA, O HONJO, T KOJIMA, S OIZUMI, H ISOBE, H AKITA, M MUNAKATA, M NISHIMURA Hokkaido Lung Cancer Clinical Study Group, Japan Background The importance of biomarkers is increasing in individualized treatment strategy for cancer patients. We evaluated the efficacy and safety of carboplatin and pemetrexed in Japanese patients with non-squamous NonSmall Cell Lung Cancer (NSCLC), and Single Nucleotide Polymorphisms (SNPs) associated with pemetrexed metabolism were also analyzed to investigate their relationship with efficacy or toxicity. Methods Eligible patients had a performance status 0 or 1, aged from 20 to 74 years, chemotherapy-naïve stage IIIB/IV non-squamous NSCLC, and adequate organ function. Patients received carboplatin (AUC = 5) and pemetrexed (500 mg/m2) every 3 weeks. More than 3 cycles was considered as completion of treatment. Peripheral blood was drawn for SNPs analyses of Thymidylate Synthase Gene (TYMS) and Methylenetetrahydrofolate Reductase Gene (MTHFR) in patients with consent for the biomarker study. Results Forty-one patients (28 men, 13 women; median age 63 years, range 43–73), with 39 adenocarcinomas and 2 large cell carcinomas, were enrolled and SNPs were analyzed in 37 patients. The median follow-up time was 16.1 months and the median number of treatment cycle was 4 (range 1–6). The completion rate was 80.5% (33 patients). All patients were assessable for response; the overall Response Rate (RR) was 36.6% and Disease Control Rate (DCR) was 85.4%. Median Progression-Free Survival (PFS) and Overall Survival (OS) were 4.6 months (138 days: 95% C.I.; 107–168) and 16.1 months (483 days: 95% C.I.; 180–786), respectively. Grade 3 or 4 hematologic toxicities included anemia (34.1%), neutropenia (29.3%), leukopenia (19.5%) and thrombocytopenia (17.1%). Grade 3 or 4 non-hematologic toxicities included anorexia (7.3%) and nausea (4.9%). No treatment-related death was observed. Although the SNPs had no relation to RR, PFS, OS nor hematologic toxicity, the variable number of tandem repeat (VNTR) of the TYMS significantly correlated with anemia (p = 0.047) and thrombocytopenia (p = 0.038). Conclusion The efficacy of this regimen seems even better than previously reported, and with acceptable toxicities. VNTR of the TYMS may be a predictive factor of anemia and thrombocytopenia associated with this regimen.

Background Combined Pulmonary Fibrosis and Emphysema (CPFE) might increase the risk of lung cancer, and acute exacerbation of CPFE often occurs after lung cancer surgery or chemotherapy. The aim of this study was to investigate clinical characteristics of CPFE patients complicated with lung cancer. Methods We retrospectively reviewed 54 CPFE patients, and 29 of 54 CPFE patients had lung cancer. All patients met the imaging of criteria for CPFE described previously by Cottin et al. They had a checkup at our hospital between September 2005 and April 2012. Results The mean age of the patients was 68.1 ± 7.2 years. Twenty-five of the 29 patients were male and almost all patients were heavy smokers (59.5 ± 32.0 pack-years) except for one patient. Mean percent predicted vital capacity (%VC), forced expiratory volume in one second (FEV1.0)/forced vital capacity (FVC), and percent predicted diffusing capacity of the lung for carbon monoxide (DLco)/VA were 98.6 ± 10.9%, 70.6 ± 9.1%, and 69.7 ± 18.1%, respectively. Squamous cell carcinoma was the most frequent cell type (53.6%), followed by adenocarcinoma (28.6%) and small cell carcinoma (17.8%). Lung cancer frequently developed in the lower lobe and 69.3% of the squamous cell carcinomas were located in the periphery of the lower lobe. Stage IIIB and IV lung cancers were defined as advanced stage disease, and 16 of the 29 lung cancer patients with CPFE were diagnosed as advanced stage. Twelve patients underwent surgery. Nine patients died over the study period. Causes of death were lung cancer death (n = 6), respiratory failure (n = 2), and other cancer death (n = 1). Acute exacerbation occurred in two patients and one patient was treated by corticosteroid. Of the four patients with respiratory failure after lung cancer surgery, two patients died of acute exacerbation and pulmonary embolization with pneumothorax. Conclusion Lung cancer in IPF patients tended to occur in the lower lobe, and it in CPFE patients also tended to occur in the lower lobe. As respiratory failure including acute exacerbation sometimes occurred during treatment, it is important to inform patients and their families of the risk of the treatment before starting treatment.

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THE EFFECTIVENESS OF ACUPUNCTURE FOR FATIGUE SEVERITY IN PATIENTS WITH LUNG CANCER: PILOT STUDY SC LEE1, DS HYUN1, SW SHIM1, JD KIM2, HJ GYUN2, KC KIM1 1 Department of Internal Medicine, Catholic University of Daegu School of Medicine, Korea, and 2Daegu Hanny University, Korea Background Lung cancer is the first of causes of cancer deaths in the world. Fatigue has been reported as a common, serious and painful symptom in patient with cancer and 60–80% of patients with advanced cancer appear to moderate or severe fatigue. Effectiveness and safety of acupuncture treatment (that is one of the treatment modality of oriental medicine) to improve fatigue in patients with lung cancer were evaluated. Methods The patients diagnosed as lung cancer with their own activities, at least three weeks or more passed after surgery or chemotherapy or radiotherapy for the lung cancer and fatigue scores (Fatigue Severity Scale, FSS) over three point were enrolled in this study. The acupuncture treatments for fatigue were performed twice a week for 4 weeks by verified method as oriental medicine. Differences of FSS were checked before and after acupuncture treatments, the adverse event and safety after treatment were evaluated. Results Patients included in this study were eight men (88.9%) and a woman (11.1%). The mean age was 66.22 ± 7.93 years, and the mean value of smoking history was 30.67 ± 27.26 pack-year. The cellular types of lung cancer were three adenocarcinomas (33.3%), four squamous cell carcinomas (44.4%) and two small cell lung cancers (22.2%). The stages of lung cancer were a IA (11.1%), a IIA (11.1%), three IIIA (33.3%), a IIIB (11.1%) and three IV (33.3%). FSS, which is a index of effectiveness was significantly decreased from 4.92 to 3.74 before and after acupuncture treatment (p = 0.012). There was neither statistically significant adverse reaction nor hematologic abnormality. Conclusion The acupuncture treatment for fatigue improvement in patients with lung cancer might be safe and effective. However studies involving larger number of patient would be needed.

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DYNAMIC CHANGES OF REGULATORY T LYMPHOCYTES AND REGULATORY B LYMPHOCYTES AFTER FIRST LINE CHEMOTHERAPY IN PERIPHERAL BLOOD FROM PATIENTS WITH ADVANCED STAGE LUNG CANCER 1

1

2

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FH DING , DW YANG , ZH MIN , QY HONG , J HU , JX OU , FL LIU , D ZHANG1, JB ZHOU1, YL SONG1, XD WANG1,2, CX BAI1 1 Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, China, and 2Biomedical Research Center, Zhongshan Hospital, Fudan University, China Background Lung cancer is currently the leading cause of cancer-related mortality worldwide. Approximately 70% of lung cancer patients are diagnosed in advanced stages. Chemotherapy remains the mainstay of treatment for advanced stage lung cancer patients. Long-term survival for patients with advanced stage disease is still limited. Thus both early diagnosis and additional effective adjuvant therapy are urgently needed to fight lung cancer. Intratumoral and circulating regulatory T cells (Tregs) have been demonstrated crucial in the pathogenesis of lung cancer. However, there is limited knowledge on the alterations of regulatory B cells (Bregs). We here investigated dynamic alterations of peripheral circulating Tregs and Bregs in patients with advanced stage lung cancer undergoing first line chemotherapy to reveal the relationship between regulatory lymphocytes and its clinical implications. Methods 30 patients with advanced stage lung cancer, 6 with AECOPD, 6 with high risk of lung cancer and 6 healthy volunteers were enrolled for this study. Frequencies of peripheral Tregs and Bregs were measured by flow cytometry with antibodies against CD4, CD25, CD127, CD19 and IL-10 before 1st, 2nd and 3rd cycle of chemotherapy. Then, clinical informatics including chemotherapy responsiveness of lung cancer patients was achieved through Digital Evaluation Score System (DESS) for the assessment of disease severity. Results Level of circulating CD4+CD25+CD127low Tregs and CD19+IL10hi Bregs in advanced stage lung cancer patients was significantly lower than that in healthy donors and patients with COPD before chemotherapy, but was increased after chemotherapy. The dynamic trend of Tregs and Bregs is consistent. Conclusion Frequencies of peripheral Tregs and Bregs in advanced stage lung cancer patients increased after chemotherapy. These results suggest that immunotherapy targeting on Tregs and Bregs in combination with chemotherapy may bring benefit to patients with advanced stage lung cancer. Supported by National Basic Research Program of China [Grants 2012CB933304].

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TREATMENT OUTCOMES IN ELDERLY WITH ADVANCEDSTAGE NON-SMALL CELL LUNG CANCER TCC TAM, JCM HO, MKY WONG, WM WONG, JKL WANG, JCM LAM, MMS LUI, WK LAM, MSM IP, DCL LAM Department of Medicine, The University of Hong Kong, Hong Kong Background Lung cancer remains the top cause of cancer morbidity and mortality in the world. Therapeutic clinical trials seldom focused on elderly lung cancer subjects. Although the identification of Epidermal Growth Factor Receptor (EGFR) gene mutations could predict clinical efficacy of Tyrosine Kinase Inhibitor (TKI), molecular testing for predictive biomarkers are not always possible due to tissue availability or financial constraints. The overall therapeutic decision remains a clinical one for a significant proportion of elderly patients with advanced stage lung cancer but no known EGFR mutation status. Aims To compare the outcome of different drug treatment modalities in Progression-Free Survival (PFS), Overall Survival (OS) and adverse effect profile for elderly with advanced-stage Non-Small Cell Lung Cancer (NSCLC), and to identify any clinical parameter that could predict treatment outcomes. Method Clinical records of patients aged 70 years or above with Stage III or IV NSCLC, who have received either chemotherapy or Tyrosine Kinase Inhibitor (EGFR-TKI) in the Department of Medicine, Queen Mary Hospital from 2003 to 2009, were reviewed. A group of gender- and histology-matched subjects aged below 70 were identified as controls. Results 56 elderly patients (age ≥ 70) were included. The median age at diagnosis was 73 years (70–83 years). The proportion of NSCLC, adenocarcinoma (AD) and squamous cell carcinoma (SCC) were 21.4%, 48.2% and 16.1% respectively. 60.7% of patients received only one line of treatment. Median PFS was 10 months (IQR 5 to 15 months) and the OS was 19 months (IQR 11 to 31 months). Baseline performance status (PS) was the only predictor of improved PFS (p = 0.042) and OS (p = 0.002). Age was not a significant prognostic factor, and there was no difference in survival between the upfront chemotherapy group and the TKI group. Conclusion In elderly subjects with advanced stage NSCLC without known EGFR mutation status, use of EGFR-TKI and chemotherapy resulted in comparable survival benefits and rates of treatment-related adverse effects. Age was not predictive of worse treatment outcome in advanced stage NSCLC patients. The baseline performance status of the patient should be taken into consideration in the therapeutic decision in elderly subjects with NSCLC.

© 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology