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Y. Hasegawa
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P3.03 - Chemotherapy/Targeted Therapy (ID 719)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.03-013 - Identification of Proteasomal Catalytic Subunit PSMA6 as a Therapeutic Target for Lung Cancer through a Pooled shRNA Screen (ID 8867)
09:30 - 09:30 | Author(s): Y. Hasegawa
- Abstract
Background:
Recent advances in high-throughput genetic analysis revealed that single lung cancer cells harbour a number of genetic and epigenetic changes. Nevertheless, findings from cancer epidemiology and the experimental models of the multi-step lung carcinogenic process, which were developed by our group and others, suggested that only a handful of changes are ‘drivers’ whereas others are only ‘passengers’. Thus, it is very important to identify those that truly contribute to the oncogenic properties of cancer cells by performing functional screening. To this end, we performed screening with a pooled shRNA library in search for genes that are critical for the survival and/or proliferation of lung cancer cells using a lung cancer cell line.
Method:
NCI-H460 cell line was used for semi-genome-wide dropout viability analysis using a pooled shRNA library that targeted 5,043 genes. Two Cdk4/hTERT-immortalised normal human bronchial epithelial cell lines, HBEC3 and HBEC4 were used as controls. Pathway analysis was done using NIH-DAVID. Microarray gene expression analysis was done using Illumina Human WG-6 v3.0 Expression BeadChip for 163 non-small cell lung cancer (NSCLC) cell lines and 59 normal control cell lines. DNA copy number analysis with array CGH was done for 108 NSCLC cell lines. Proteasome activity was measured using a 20S proteasome activity assay kit. 20 pairs of resected lung cancer and matched normal lung samples were used for immunohistochemistry of PSMA6. Cell growth was evaluated by WST-1 colorimetric proliferation assay. Cell cycle analysis was done using FACS for cells stained with propidium iodide.
Result:
shRNA screening targeting 5,043 genes in NCI-H460 identified 51 genes as candidates for therapeutic targets. Pathway analysis revealed that the 51 genes were enriched for the five pathways, including ribosome, proteasome, RNA polymerase, pyrimidine metabolism and spliceosome pathways. We focused on the proteasome pathway that involved six candidate genes because its activation has been demonstrated in diverse human malignancies, including lung cancer. Microarray expression and array CGH data showed that PSMA6, a proteasomal subunit of a 20S catalytic core complex, was highly expressed in lung cancer cell lines, with recurrent gene amplifications in some cases. Therefore, we further examined the roles of PSMA6 in lung cancer. Silencing of PSMA6 induced apoptosis or G2/M cell cycle arrest in cancer cell lines but not in an immortalised normal lung cell line.
Conclusion:
Our data suggested that PSMA6 serves as an attractive target with a high therapeutic index for lung cancer.
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P3.09 - Mesothelioma (ID 725)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.09-006 - Preoperative Six-Minute Walk Distance and Desaturation in Patients with Malignant Pleural Mesothelioma (ID 8762)
09:30 - 09:30 | Author(s): Y. Hasegawa
- Abstract
Background:
Surgery for malignant pleural mesothelioma (MPM) is an invasive procedure associated with high morbidity. MPM often invades adjacent structures such as the chest wall, diaphragm, and mediastinum. Therefore, pulmonary functions and levels of physical fitness are reduced in advanced MPM. The aim of this study was to characterize preoperative exercise capacity and relate it to pulmonary functions, oxygenation, and postoperative outcomes in patients with MPM.
Method:
A retrospective study was conducted on 18 patients with MPM who were scheduled to undergo extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D) followed by postoperative rehabilitation at Nagoya University Hospital from July 2012 to April 2016 (Institutional Review Board approval No. 2015-0413). To estimate preoperative exercise capacity, 6-min walk test (6MWT) and oxygen saturation of a peripheral artery (SpO~2~) during the 6MWT were assessed. Grades III and IV of the Clavien-Dindo classification were defined as major postoperative complications.
Result:
The age was 65.8 ± 6.4 years. Preoperative 6-min walk distance (6MWD) was 465.9±96.7 m. Minimum SpO~2~ ranged from 86% to 97%. The 6MWD significantly correlated with inspiratory capacity (r=0.507, P<0.05) and % of predicted value of diffusing capacity of the lung for carbon monoxide (%DL~CO~) (r=0.470, P<0.05). The minimum SpO~2~ during 6MWT significantly correlated with % of predicted values of vital capacity (r=0.619, P<0.01) and total lung capacity (r=0.493, P<0.05) and postoperative days of extubation (r=-0.495, P<0.05). The preoperative partial pressure of oxygen in arterial blood significantly correlated with %DL~CO~ (r=0.505, P<0.05). There was a total of 13 major postoperative complications (8 respiratory failure, 2 pneumonia, 1 empyema, 1 atrial fibrillation, and 1 prolonged air leak) in 6 patients. There was no in-hospital death or death within 30 days after surgery. The incidence of major complications was significantly associated with longer stays in intensive care unit (3.3±1.8 vs. 1.7±1.0 days, P<0.05) and hospital (54.2±31.2 vs. 12.3±3.2 days, P<0.05) but not with preoperative physical status or pulmonary functions. Stays in hospital after EPP (n=7) were significantly longer than those after P/D (n=11) (median 28 vs. 12 days, P=0.01) but there was no significant difference in incidence of major complications between the EPP and P/D groups.
Conclusion:
Our results indicate that the 6MWT is a convenient and useful field test to assess preoperative physical status in patients with MPM. Future studies with a larger cohort are required to elucidate risk factors for postoperative morbidity and mortality.
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P3.16 - Surgery (ID 732)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.16-010 - Preoperative Six-Minute Walk Distance Is Associated with Complications of Pneumonia after Lung Resection (ID 8147)
09:30 - 09:30 | Author(s): Y. Hasegawa
- Abstract
Background:
Postoperative pulmonary complications such as pneumonia are significant negative predictors of short- and long-term survival after thoracic surgery. A preoperative cardio-pulmonary function is known as a predictor for postoperative pulmonary complications in patients with lung cancer. However, little is known about the relationship between preoperative exercise capacity and complication of pneumonia after lung resection. The 6-min walk distance (6MWD) measured by the 6-min walk test (6MWT) is a simple, safe, and inexpensive field test that can be used to evaluate the functional exercise capacity. We examined the association between preoperative 6MWD and development of postoperative pneumonia.
Method:
A retrospective study was conducted on patients with malignant lung tumors who were scheduled to undergo lung resection at Nagoya University Hospital from January 2014 to December 2015 (Institutional Review Board approval No. 2015-0413). Preoperative pulmonary function tests and 6MWT were assessed. A logistic regression model and receiver operating characteristic (ROC) curves were used to analyze clinical variables and compare the performance on 6MWD and percentages of predicted values of forced expiratory volume in 1 s (%FEV~1~) and diffusion capacity of the lung for carbon monoxide (%DLco).
Result:
The data from a total 321 patients including 283 with primary lung cancer and 38 with metastatic lung tumors were analyzed. Preoperative 6MWD significantly correlated with age, FEV~1~, forced vital capacity (FVC), %DLco, and serum albumin level. Pneumonia developed in 13 patients (4.0%) and the 6MWD of patients with pneumonia was significantly lower than that of patients without (413.9±89.0 vs. 495.2±93.2 m, p=0.002). Incidences of smoking history and comorbidity of COPD and interstitial lung disease were significantly higher and %FEV~1~, FEV~1~/FVC, %DLco, and serum albumin level were significantly lower in patients with pneumonia than in those without. Length of hospital stay after surgery was significantly longer in patients with pneumonia than in those without (30.4±29.6 vs. 7.4±7.0 days, p<0.001). In ROC analysis, 6MWD ≤450 m was a threshold for predicting postoperative pneumonia with 69.2% sensitivity and 71.1% specificity. A 6MWD ≤450 m, %FEV~1~ <80%, %DLco <80%, serum albumin <3.5 g/dL, and blood loss during surgery >200 g were significantly associated with development of postoperative pneumonia in a logistic model adjusted by age, sex, and primary lung cancer.
Conclusion:
Preoperative 6MWD is associated with development of pneumonia after lung resection for malignancies. Preoperative 6MWT is a useful screening tool in patients with primary and metastatic lung tumors.
