Journal Thoracic Oncology

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Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017 time was 22.5 months (range 3-149 months). The duration of survival depends on histological type of primary tumor (21 months for patients with bone or soft tissue sarcoma and 46 months for patients with epithelial tumors). The survival time appeared to be shorter for patients with bilateral process than unilateral but the difference was not statistically significant (23 and 48 months, respectively, p=0.25). Conclusion: The development of distant metastases is associated with extremely poor survival of patients with sarcomas and epithelial tumors. Based on our observation we suggest that some patients with multiple lung metastases can benefit from aggressive surgical treatment. The controlled, prospective, large-scale clinical studies are required to further assess impact of surgical treatment on survival of these patients. Keywords: laser, lung metastases, Surgery Conclusion: The measurement of pCRP+pCEA together represents an accurate and easy to perform tool useful in differentiating between benign and malignant PE, and should be suggested in all cancer patients requiring PE analysis. Keywords: C-reactive protein, malignant pleural effusion, lung metastases, Pleural CEA POSTER SESSION 2 – P2.05: RADIOTHERAPY Biology – TUESDAY, DECEMBER 6, 2016 POSTER SESSION 2 – P2.04: MESOTHELIOMA/THYMIC MALIGNANCIES/ESOPHAGEAL CANCER/OTHER THORACIC MALIGNANCIES ESOPHAGEAL CANCER AND OTHER MALIGNANCIES – TUESDAY, DECEMBER 6, 2016 P2.04-054 PLEURAL CEA AND C-REACTIVE PROTEIN IN PATIENTS WITH LUNG METASTASES AND MALIGNANT PLEURAL EFFUSION. A PROSPECTIVE CASE-CONTROL STUDY Franco Lumachi 1 , Paolo Ubiali 2 , Renato Tozzoli 3 , Alessandro Del Conte 4 , Stefano Basso 2 1 Department of Surgery, Oncology & Gastroenterology, University of Padua, School of Medicine, Padova/Italy, 2 Department of Surgery, General Surgery, S. Maria Degli Angeli Hospital, Pordenone/Italy, 3 Department of Laboratory Medicine, Clinical Pathology Laboratory, S. Maria Degli Angeli Hospital, Pordenone/Italy, 4 Medical Oncology, S. Maria Degli Angeli Hospital, Pordenone/Italy Background: Malignant pleural effusion (PE) is common cancer patients, and may require invasive investivations. The aim of this study was to evaluate the diagnostic utility of pleural carcinoembryonic antigen (pCEA) and pleural C-reactive protein (pCRP) assay in cancer patients with PE. Methods: We prospectively measured both pCEA and pPCR in 41 consecutive patients with a history of cancer and PE (cases). Controls were 41 age- and sex-matched patients with confirmed benign PE. There were 52 (63.4%) men and 39 (47.6%) women, with an overall median age of 71 years (range 40-88 years). Results: The age (p=0.943) and male-to-female ratio (p=0.254) did not differ significantly between groups. pCEA (34.9±104.8 vs. 1.5±1.3 ng/mL; p
Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017 by flow cytometry. Colony formation assay was performed to determine the radiosensitivity. Sphere formation assay in serum-free medium was performed to evaluate the self-renewal capacity. γH2AX foci were analyzed by immunofluorescence. The monoclonal antibody of CACNA2D1 was applied alone or combined with radiation to CACNA2D1+ cells and colony formation and sphere formation assays were performed to determine its effect on CACNA2D1+ cells. Results: CACNA2D1+ cells had higher sphere-forming efficiency, and were resistant to radiation compared with CACNA2D1- cells. In unsorted cells the CACNA2D1+ percentage was enhanced after radiation. These data suggest CACNA2D1+ NSCLC cells are relatively radio-resistant. Knockdown of CACNA2D1 in CACNA2D1-high A549 enhanced radiosensitivity, while overexpression of CACNA2D1 in CACNA2D1-low PC9 and H1975 reduced radiosensitivity, suggesting CACNA2D1 converts the radio-resistance. The number of γH2AX foci increased after radiation, and decreased more rapidly in CACNA2D1-overexpression cells than control group. Moreover, in CACNA2D1- overexpression cells, the baseline phosphorylation level of CHK2 and ATM was higher than control group, and were more activated after radiation, suggesting CACNA2D1 overexpression resulted in an increase in the DNA damage repair capacity. The monoclonal antibody of CACNA2D1 had a synergetic effect with radiation to block self-renewal of CACNA2D1+ A549 cells. The antibody also enhanced radiosensitivity in CACNA2D1+ cells in colony formation assay. Conclusion: CACNA2D1 marks radio-resistant cancer stem-like cells in NSCLC. CACNA2D1 converts resistance to radiation, partially by enhancing the DNA damage repair efficiency. The monoclonal antibody of CANCA2D1 enhances the radio-sensitivity of CACNA2D1+ cells, suggesting its potential to improve the treatment outcome when combined with radiation on NSCLC. Keywords: CACNA2D1, NSCLC, Cancer stem cell, radio-resistance POSTER SESSION 2 – P2.05: RADIOTHERAPY BIOLOGY – TUESDAY, DECEMBER 6, 2016 P2.05-003 PIK3CA MUTATION IS ASSOCIATED WITH INCREASED LOCAL FAILURE IN LUNG STEREOTACTIC BODY RADIATION THERAPY (SBRT) Natalie Lockney 1 , T. Jonathan Yang 1 , Kelly Panchoo 1 , Daphna Gelblum 1 , Ellen Yorke 2 , Andreas Rimner 1 , Abraham Wu 1 1 Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York/NY/United States of America, 2 Medical Physics, Memorial Sloan Kettering Cancer Center, New York/NY/United States of America Background: Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway has been associated with radioresistance. It is unclear whether such mutations also confer suboptimal local control for patients who receive lung stereotactic body radiation therapy (SBRT). Our objective was to examine whether mutations in the EGFR/AKT/PIK3CA signaling pathway are associated with local failure (LF) after lung SBRT. Methods: We retrospectively reviewed 134 patients who underwent SBRT to primary or metastatic lung lesions from 2007-2015 for whom molecular testing data was available for EGFR, AKT, and PIK3CA genes. For tumors of lung origin (n=122), molecular testing data was included from the lung tumor. For metastatic tumors to the lung (n=12), molecular testing data from either a primary or metastatic tumor site was used. Association between clinical factors, including molecular mutation status, and LF was evaluated with Cox regression analysis. The Kaplan-Meier method was used to assess differences in LF rates based on PIK3CA mutation status. Results: The most common histology was adenocarcinoma (90%) among all tumors. Six patients (4%) had PIK3CA mutation, 31 patients (23%) had EGFR mutation, and one patient (0.7%) had AKT mutation. Median lesion size was 2.0 cm (range, 0.6–5.6 cm), median dose was 48 Gy (range 30–70 Gy), and median number of fractions was 4 (range, 3–10). Median follow-up was 20 months (range, 0.2–70 months). LF was observed for 16 patients (12%). Median time to local failure was 15 months (range, 7–31 months). On univariate analysis, PIK3CA mutation presence was associated with LF (HR 5.3 [95% CI 1.1-25.0], p=0.03), while tumor histology (adenocarcinoma vs. other), tumor size (≤2cm vs. >2cm), primary tumor site (lung vs. other), and EGFR or AKT mutation presence were not. By multivariate analysis, PIK3CA mutation trended toward association with LF (HR 5.0 [95% CI 1.0-25.3], p=0.051). At one year, probability of LF in lesions with PIK3CA mutations was 12.4% vs. 5.7% in lesions without mutations (p=0.02). Lesions with PIK3CA mutations were associated with a decreased time to LF (mean 17.9 months [95% CI 12.7–23.2 months]) compared to those without PIK3CA mutation (mean 58.6 months [95% CI 52.6–64.7 months]). Conclusion: We explored EGFR/AKT/PI3KCA pathway mutations and found that patients with PIK3CA mutations are at higher risk for LF after lung SBRT. Due to the limitation of small numbers, this data needs to be validated in a larger patient cohort. Nonetheless, this is a novel finding and hypothesis-generating for future studies. Keywords: Radioresistance, local failure, PIK3CA, Stereotactic body radiation therapy POSTER SESSION 2 – P2.05: RADIOTHERAPY BIOLOGY – TUESDAY, DECEMBER 6, 2016 P2.05-004 ABT-737, A BH3 MIMETIC, ENHANCES THERAPEUTIC EFFECT OF IONIZING RADIATION IN MURINE LUNG CANCER MODEL Jung Mo Lee 1 , Yoon Soo Chang 1 , Eun Young Kim 2 1 Department of Internal Medicine, Yonsei University College of Medicine, Seoul/ Korea, Republic of, 2 Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul/Korea, Republic of Background: Radiotherapy is one of the main treatment modalities of lung cancer, but its effectiveness is often hampered because of dose dependent radiation toxicity. Aberration of apoptotic pathway after irradiation is another mechanism attenuating therapeutic effect of radiation. ABT-737, a ‘first-in-class’ of BH3 mimetics, disrupts the BCL-2/BAK complex and initiates BAK-dependent intrinsic apoptotic pathway. In this study, we sought that ABT-737 is able to maximize the therapeutic effects of radiation in experimental animal models. Methods: Kras:p53 fl/fl double mutant mice were obtained by genotyping of offspring from LSL Kras G12D and p53 fl/fl mouse. Lung cancer was induced by inhalation of 5 X 10 7 PFU AdCre viral particles at 8 weeks age. After 12 (± 2) weeks of inhalation, the mice were randomized and treated with either vehicle or ABT-737 (50 mg/kg, i.p., daily) for 3 days. Then mice underwent microCT and were irradiated in the left lung at a dose of 20 Gy using X-rad 320. In 2 weeks, 2 nd round microCT was performed and lungs were harvested for histological analysis. Results: When the changes in the expression of pro-apoptotic and anti-apoptotic molecules after 20 Gy of irradiation were evaluated by immunoblotting, the decrease of BCL2-like 11 (BCL2L11) was most prominent in the irradiated lung. The tumor area was decreased in the irradiated lung of both vehicle and ABT-737 pretreated mice and inhibitory effect was remarkable when the mice were pretreated with ABT-737. Disputed tumor structure with apoptotic bodies were most frequently observed in the irradiated lung of ABT-737 pretreated mice. To quantify the apoptotic effect of this combination, immunohistochemical analysis against activated caspase-3 was performed. Counts of activated caspase-3 were significantly higher in the irradiated lung with ABT-737 pretreatment, suggesting ABT-737 possesses radiosensitizing property. Conclusion: Decrease of BCL2L11 expression in the irradiated lung is one of prominent findings, which might compromise therapeutic effect of radiation. Pretreatment of ABT-737 enhanced anti-tumor effect of ionizing radiation in Kras:p53 fl/fl lung cancer model, suggesting BH3 mimetics would be a good candidate of radiosensitizer in lung cancer. Further studies are warranted for identification of optimal dosing and schedule of this combination treatment. Keywords: apoptosis, radiosensitizer, BH3 mimetics, ABT-737 POSTER SESSION 2 – P2.05: RADIOTHERAPY BIOLOGY – TUESDAY, DECEMBER 6, 2016 P2.05-005 MECHANISM OF RADIOTHERAPY IN REDUCTION/DELAY OF T790M-MEDIATED EGFR TKI RESISTANCE Yasi Xu 1 , Shirong Zhang 1 , Bing Xia 2 , Lucheng Zhu 3 , Shenglin Ma 4 1 Center for Translational Medicine, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou/China, 2 Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou/China, 3 Department of Radiation Oncology, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou/China, 4 Department of Oncology, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou/China Background: EGFR T790M mutation accounts for more than 50% of acquired resistance to TKI. In pre-clinical, EGFR-TKI resistant cells with T790M exhibited enhanced sensitivity to radiation, suggesting the potential of radiotherapy in reduction and delay of T790M-mediated EGFR TKI resistance. Methods: Under different radiotherapy dose and times, we use droplet digital PCR to observe the emerging time of T790M and its proportion during chronic exposure to gefitinib in TKI-sensitivity cell lines, and to evaluate the anti-tumor effect of early radiation combined with gefitinib in xenograft model with different proportion of T790M. Furthermore, we performed miRNA microarray to screen miRNAs differentially expressed in the paired NSCLC gefitinib-sensitivity cell lines and gefitinib resistant cell lines and find potential molecular markers of T790M mutation. Results: Our data showed radiation combined with gefitinib delayed the occurrence of EGFR T790M mutation compared to gefitinib alone in T790M wildtype (TKI-sensitive) cell line and it also reduced the T790M mutation abundance in de novo T790M mutation (TKI-resistant) cell line. The phenomena was also confirm in mice xenograft model. In addition, our results showed TKI-resistant (induced T790M mutation) cells had higher radiosensitivity than TKI-sensitive cells. miRNA array showed miR-1275 was the one of the most significantly elevated miRNAs in TKI-resistant cells. Knockdown of miRNA-1275 significantly decreased the radiosensitivity of TKI-resistant cells. Western blot showed Copyright © 2016 by the International Association for the Study of Lung Cancer S541
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