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N. Ikeda
Moderator of
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SC25 - The Role of Surgeons in Multimodality Clinical Trials (ID 349)
- Event: WCLC 2016
- Type: Science Session
- Track: Surgery
- Presentations: 5
- Moderators:N. Ikeda, G. Stamatis
- Coordinates: 12/07/2016, 11:00 - 12:30, Strauss 2
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SC25.01 - Trial Design for Multimodality Treatment of NSCLC (ID 6705)
11:00 - 11:20 | Author(s): D. Jones
- Abstract
- Presentation
Abstract not provided
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SC25.02 - Quality of Resection in Induction and Adjuvant Clinical Trials (ID 6706)
11:20 - 11:40 | Author(s): E. Vallieres
- Abstract
- Presentation
Abstract not provided
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SC25.03 - Quality of Centers and Patient Inclusion (ID 6707)
11:40 - 12:00 | Author(s): J.G. Edwards
- Abstract
- Presentation
Abstract not provided
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SC25.04 - The Importance of Cooperation: The Essen Experience (ID 6708)
12:00 - 12:20 | Author(s): W. Eberhardt
- Abstract
- Presentation
Abstract not provided
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SC25.05 - Multimodality Trials: The Chinese Experience (ID 6898)
12:20 - 12:30 | Author(s): K. Chen
- Abstract
- Presentation
Abstract not provided
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Author of
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-082 - The Feasibility of Cell-Free DNA Sequencing for Mutation Detection in Non–Small Cell Lung Cancer Was Detemined by Tumor Volume (ID 6001)
14:30 - 14:30 | Author(s): N. Ikeda
- Abstract
Background:
Targeted therapeutics such as tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) have recently been introduced into clinical practice for individuals with NSCLC positive for actionable mutations of EGFR or ALK fusions, respectively. Molecular profiling that is able to predict the response to such drugs has thus become an important therapeutic strategy, allowing selection of the most appropriate treatment for individual patients.
Methods:
Matched lung cancer tissue and serum specimens were collected from 150 patients who underwent surgery at Tokyo Medical University Hospital from January 2013 to July 2014. All tissue samples were stored at –80°C until analysis. Tumor DNA and cfDNA samples were subjected to analysis with next-generation sequencing (NGS) panels for mutation detection.
Results:
All tumor DNA samples were successfully sequenced with the Ion Proton platform. The median read number per amplicon was 15,632. We identified TP53 mutations in 58 cases (38.7%); EGFR mutations in 56 (37.3%); KRAS mutations in 15 (10.0%); CTNNB1 mutations in 7 (4.7%); ERBB2, PIK3CA, BRAF, and PTEN mutations in 3 each (2.0%); and ERBB4, MET, ALK, FGFR2, NRAS, AKT1, and FBXW7 mutations in 1 each (0.7%). No mutation was detected in 22.0% (33/150) of the samples. Serum cfDNA was extracted for all 150 patients, with a median yield (copy number) of 4936 (range, 572 to 373,658). A total of 149 of the 150 (99.3%) cfDNA samples were successfully sequenced with the Ion Proton platform, with sequencing failure being due to an insufficient read number per amplicon in the one unsuccessful case. The median read number per amplicon for the 149 successfully sequenced cfDNA samples was 33,982.
Conclusion:
These results suggested that detection of mutations in cfDNA of patients with disease at stage IA or IB or at T2a or lower is difficult, and that the feasibility of mutation detection with cfDNA may depend on the T factor rather than the N factor. Tumor volume in the cfDNA mutation–positive group was significantly greater than that in the cfDNA mutation–negative group (159.1 ± 58.0 versus 52.5 ± 9.9 cm[3], p = 0.014). The maximum tumor diameter calculated at diagnosis was also larger in the cfDNA mutation–positive group than in the cfDNA mutation–negative group (5.3 ± 0.7 versus 4.1 ± 0.3 cm, p = 0.050). These results suggested that tumor volume is a determining factor for the feasibility of mutation detection with cfDNA.
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P1.03 - Poster Session with Presenters Present (ID 455)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.03-022 - Possibility of FDG-PET Predicting the Clinicopathological Characteristics and Prognosis of Lung Adenocarcinoma: Multicenter Study (ID 5799)
14:30 - 14:30 | Author(s): N. Ikeda
- Abstract
Background:
This multicenter study aimed to investigate the relationship of standardized uptake value (SUV) on [18F]-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) and the clinicopathological characteristics of lung adenocarcinomas, and if it can be a predictor of prognosis of those patients.
Methods:
A total of 870 patients of adenocarcinoma patients received FDG-PET preoperatively and underwent curative resection with systematic lymph node dissection. The relationship among histological characteristics, pathological staging, prognosis, and SUV on FDG-PETmax was retrospectively examined.
Results:
The pathological stages of the cases were IA 526, IB 182, IIA 62, IIB 27, IIIA 67, IIIB 1, and IV 5, respectively. Pathological N1 (n = 60) and N2 (n = 58) cases showed a significantly higher SUVmax than N0 (n = 752) (9.15 ± 7.13 and 8.58 ± 6.14 vs 3.23 ± 4.16). Cases with pathological tumor invasiveness such as lymphatic, vascular or pleural infiltration showed a significantly higher SUVmax than cases with no invasiveness. (Ly negative; n=687, 2.76±3.59 vs Ly positive; n=183, 7.67±6.23, and v0; n=641, 2.18±2.58 vs v1 or 2; n=229, 8.30±6.23. p<0.001, respectively) The areas under the receiver operating characteristic curve for SUVmax used to predict the relapse-free survival was 2.9 (p < 0.001) in adenocarcinoma. The 3-year relapse-free survival was 97%/66% (SUVmax lower/ higher than 2.9) in adenocarcinoma. SUVmax was parallel to the aggressive nature based on histological subtypes (AIS +MIA; n=76, 0.51±0.58, Lepidic + Papillary + Acinar; n=686, 3.52±4.12, and Solid + Micropapillary; n=84, 8.52±6.67), which was statistically significant. (p<0.001 respectively)
Conclusion:
SUVmax of the primary tumor reflected the biological malignancy of lung adenocarcinomas. SUVmax is also useful for predicting pathological stage and prognosis. Multimodality treatment might be recommended in cases of high UVmax.
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P1.04 - Poster Session with Presenters Present (ID 456)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Pulmonology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.04-015 - Clinical Application of Virtual Navigated Bronchial Intervention (ID 4996)
14:30 - 14:30 | Author(s): N. Ikeda
- Abstract
Background:
Removal of endobronchial tumor is considered the first treatment of choice to improve respiratory status to dilate and maintain the airway. In patients with inoperable tumors we frequently regard endoscopic treatment as the first treatment of choice, but the indications and decisions regarding the method require careful consideration. We reported the indications and efficacy of virtual navigated bronchial intervention for the treatment of bronchial tumors. To select safer and precisely approach for patients with bronchial tumors, we evaluate virtual navigated bronchial intervention using a high-speed 3-dimensional (3D) image analysis system, Synapse Vincent (Fuji Photo Film Co., Ltd., Tokyo, Japan).
Methods:
We set out to clarify, based on retrospective evaluation of routine work-up data in our charts and patient treatment data, the efficacy of virtual navigated bronchial intervention for the treatment of different types of bronchial tumors, yet representative of the spectrum of conditions we encounter, in order to provide a guide to techniques available in interventional bronchology for obstructive lesions. All computed tomography (CT) must satisfy several conditions necessary to analyze images by Synapse Vincent. Synapse Vincent provides more information not only concerning tumor size and shape, but also whether the tumor invades surrounding tissue and the extent of airway and vessel involvement. Constructed images are displayed on a monitor, which can be utilized for deciding the simulation and interventional strategy and for navigation during interventional manipulation.
Results:
In these cases, Synapse Vincent was used to determine the best planning of virtual navigated bronchial intervention. The feasibility and safety of Synapse Vincent in performing useful preoperative simulation and navigation of interventional procedures lead to the safer, more precise, and less invasive for the patient, and easy to construct an image, depending on the purpose, in 5-10 minutes using Synapse Vincent. Moreover, if the lesion is in the parenchyma or sub-bronchial lumen, it helps to perform simulation with virtual skeletal subtraction to estimate potential lesion movement. By using virtual navigated system for simulation, bronchial intervention was performed with no complications safely and precisely.
Conclusion:
Preoperative simulation using virtual navigated bronchial intervention reduces the surgeon’s stress levels, particularly when highly skilled techniques are needed to operate on lesions. This task, including interventional simulation and navigation both pre- and during manipulation, could lead to greater safety and precision. These technological instruments should be helpful for bronchial intervention procedures, and are also excellent devices for educational training.
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P1.05 - Poster Session with Presenters Present (ID 457)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.05-051 - Safety and Compliance Data of the Phase III Study of Adjuvant Chemotherapy in Completely Resected P-Stage I Non Small Cell Lung Cancer: JCOG0707 (ID 3877)
14:30 - 14:30 | Author(s): N. Ikeda
- Abstract
Background:
Post-operative UFT (tegafur/uracil) has been shown to prolong survival of Japanese patients (pts) with completely resected, pathological (p-) stage I (T1> 2 cm) non small cell lung cancer (NSCLC). This trial aimed at estimating the efficacy of S-1 (tegafur/gimeracil/oteracil) compared to UFT as adjuvant therapy in this population.
Methods:
Eligible pts had undergone complete resection with lymph node dissection for p-stage I (T1-2N0M0, T1> 2 cm, by 5[th] Edition UICC TNM) NSCLC, within 56 days of enrollment. Pts were randomized to receive either oral UFT 250mg/M2/d for 2 years (Arm A), or oral S-1 80mg/M2/d for 2 weeks followed by 1 week of rest, for 1 year (Arm B). The initial primary endpoint was overall survival (OS). Based upon the results of monitoring in Jun. 2013, which showed the combined OS of the 2 arms better than expected (4-year OS of 91.6% vs. presumed 5-year OS of 70-76.5%), the study was judged to be underpowered. The study protocol was amended so that the primary endpoint was relapse-free survival (RFS). With a calculated sample size of 960, this study would detect the superiority of Arm B over Arm A with power 79% and a one-sided type I error of 0.05, assuming the 5-year RFS of 75% in Arm A and the hazard ratio of 0.75.
Results:
From Nov. 2008 to Dec. 2013, 963 pts were enrolled: median age 66 (range: 33 to 80), male 58%, adenocarcinoma 80%, p-T1/T2 46%/54%. Only 2 pts received pneumonectomy. All pts had completed protocol therapy. >Grade 3 toxicities (hematologic/nonhematologic) were observed in 15.9 (1.5/14.7) % in Arm A, and in 14.6 (3.6/11.9) % in Arm B, respectively. In Arm A, 59.5% of the pts completed protocol therapy, and 70.7% received UFT for >1 year, which was comparable to prior studies. In Arm B, 54.7% completed protocol therapy, and 69.9% received S-1 for > 6 months. There were 4 cases of on-protocol deaths, probably of cardio-vascular origin: 1 in Arm A and 3 in Arm B. Based on the 2[nd] interim analysis in Sep. 2015, the data and safety monitoring committee recommended the follow-up of pts without unmasking of treatment arms. Estimated combined 2-year OS and RFS were 97.3% and 89.6%, respectively.
Conclusion:
Both post-operative adjuvant therapies were feasible, with similar compliances. Main results will be available in 2019.
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P1.08 - Poster Session with Presenters Present (ID 460)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.08-034 - Prognostic Impact of EGFR Mutation in Patients with Surgically Resected Lung Adenocarcinoma; Analysis about Subtypes of EGFR Mutations (ID 6031)
14:30 - 14:30 | Author(s): N. Ikeda
- Abstract
Background:
Epidermal growth factor receptor (EGFR) gene mutations have an important role for predicting the prognosis in advanced or recurrent lung cancer patients. However, the significance of EGFR mutation as a prognostic factor for survival after complete resection remains controversial. The aim of this study is to evaluate the impact of mutational status in patients with surgically resected lung adenocarcinoma.
Methods:
We retrospectively investigated the data of 414 patients (pts) with p-stage I-IIIA adenocarcinoma who underwent completely tumor resection in our hospital from 2009 to 2013. Overall survival (OS), disease-free survival (DFS) , and clinico-pathological factors affecting these factors were evaluated.
Results:
There were 202 males and 212 females (median age, 67 years). In total, 270 (65%), 66 (16%) and 78 pts (19%) had p-stageI, II and IIIA disease respectively. In all 210 pts (51%) with EGFR mutation were detected. Eighty-six pts (21%) had exon 19 deletion (19 del) and 113 pts (27%), exon 21 mutation (L858R). Among 414 pts, 131 pts (31%) had lung cancer recurrence. The median follow-up period was 38.6 months. p-stageI mutant/wild:145/125, II:24/42, and IIIA:41/37. The 3-year survival rates of p-I-II and IIIA mutant/wild were 96.8%/92.1% and 81.6%/61.8% respectively. The median survival time of p-stageIIIA mutant was 80.5 months, and those of others were not reached. The 3-year DFS of p-I-II and IIIA mutant/wild were 78.3%/69.2% and 27.1%/45.1%, respectively. There were no significant difference in OS and DFS at each p-stage despite the EGFR mutational status. Compared to the wild type, the p-IIIA mutant group had a poor DFS. conversely, compared to wild type, the p-I mutant group showed a favorable DFS. According to the subtypes of EGFR mutation, there were no significant differences among EGFR subtypes, but pts with 19del tended to have the worst DFS. In subgroup analysis of 131 pts with recurrence, 3-year survival rate of p-I-II and IIIA mutant/wild were 92.0%/75.8% and 80.8%/45.6% respectively. Pts with p-IIIA mutant showed significantly favorable OS than those of wild type (p=0.014) as well as with p-I-II wild type. Although OS was not significantly different among the subtypes of EGFR mutation, pts with 19del showed statistically better prognosis than shown by the wild type (p=0.038).
Conclusion:
EGFR status was an independent prognostic factor in pts with surgically resected lung adenocarcinoma. Particularly, EGFR exon 19 deletion might be the strongest predictive factor of poor DFS and good OS in resected lung adenocarcinoma.
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-084 - Linker-Phosphorylated Smad2 and STAT3 Induce Resistance to Tyrosine Kinase Inhibition in Lung Cancer (ID 6092)
14:30 - 14:30 | Author(s): N. Ikeda
- Abstract
Background:
Cancer-associated inflammation develops resistance to the epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancers (NSCLCs) harboring oncogenic EGFR mutations. The molecular mechanisms how the cytokines produced and activated in the tumor microenvironment such as transforming growth factor-β (TGF-β) and IL-6 regulate EGFR-TKI resistance remain largely unknown.
Methods:
To determine the mechanisms how Smad-mediated TGF-β signaling and STAT3-mediated IL-6 signaling regulate sensitivity and resistance to gefitinib, we treated HCC827 adenocarcinoma cell line harboring an oncogenic deletion within the EGFR (delE746-A750) with gefitinib, an activin receptor-like kinase5 (ALK5) inhibitor, EW-7197 and/or IL-6.
Results:
IL-6 and a TGF-β antagonist, EW-7197 synergized to suppress gefitinib-induced apoptosis of HCC827. Treatment with gefitinib induced interaction between unphosphorylated Smad2 and STAT3 in cytoplasm. IL-6 and/or EW-7197 significantly upregulated phosphorylation of Smad2 linker region. Linker-phosphorylated Smad2 at serine 245 and 255 residues interacted with phosphorylated STAT3 at tyrosine 705 and serine 727 residues to suppress gefitinib-induced apoptosis of HCC827. In contrast with Smad2, IL-6 and EW-7197 synergized to downregulate the expression of Smad3.
Conclusion:
Our data suggest that inhibition of phosphorylation of Smad2 linker region and STAT3 could prevent EGFR-TKI resistance in NSCLCs.
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P2.02 - Poster Session with Presenters Present (ID 462)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.02-017 - A Clinical Outcome of Resected Small-Sized Non-Small Cell Lung Cancer 1 cm or Less in Diameter with N2 Lymph Node Metastasis (ID 5573)
14:30 - 14:30 | Author(s): N. Ikeda
- Abstract
Background:
The detection of small-sized (≤ 1cm) non-small cell lung cancer (NSCLC) has increased with the development of high-resolution computed tomography. The reported 5-year survival rate of T1a (≤ 2cm) N0M0 patients is more than 80%, and that of p-T1a (≤ 2cm) N2M0 patients has also steadily improved.
Methods:
Between 1991 and 2011, a total of 917 patients with small-sized (≤ 2cm) NSCLC underwent curative pulmonary resection with systematic lymph node dissection at Tokyo Medical University Hospital and Tokyo Medical University Ibaraki Medical Center. We retrospectively evaluated their postoperative clinical outcomes and survival rates. Survival was analyzed using the Kaplan-Meier method and log-rank test.
Results:
There were 46 (5.0%) patients with mediastinal lymph node metastasis in pT1a (≤ 2cm). And there were 6 (0.6%) patients with pT1a (≤ 1cm) N2M0. The histological types were 3 cases of adenocarcinoma, 2 case of squamous cell carcinoma, and one large cell carcinoma. The respectively status of lymph node metastasis was single station in 2 cases and multiple station in 4 cases. Skip lymph node metastasis was observed in 2 cases. There were 26 cases (56.5%) that were upstaged from clinical diagnosis in pT1a (≤ 2 cm) N2M0 patients. There was one upstaging case from cT1a (≤ 1 cm) N0M0 to pT1a (≤ 2 cm) N2M0. The median overall survival period and 5-year survival of patients in pT1 (≤ 2 cm) N2M0 was 52.1 months and 45%. And patients with pT1a (≤ 1 cm) N2M0 has 29.8 months and 0% (3 year overall survival rate was 33.3%). The recurrence rate was 71.7% (5/6) and disease free survival was 13.2 months.
Conclusion:
This study showed that 5.0% of small-sized (≤ 2 cm) NSCLC had N2 disease and 0.6% of T1a (≤ 1 cm) NSCLC has pN2. Moreover, 56.5% of small-sized (≤ 2 cm) NSCLC was upstaged from clinical diagnosis to pathological diagnosis. The patients with pT1a (≤ 1 cm) N2M0 had worse survival data than the patients with pT1a (≤ 2 cm) N2M0. We recommend systematic lymph node dissection for local treatment as well as accurate diagnosis. As multiple mediastinal node metastases showed an unfavorable prognosis, surgery combined with systematic treatment is recommended.
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P3.01 - Poster Session with Presenters Present (ID 469)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 3
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.01-024 - Drastic Morphological and Molecular Differences between Lymph Node Micrometastatic Tumors and Macrometastatic Tumors of Lung Adenocarcinoma (ID 5894)
14:30 - 14:30 | Author(s): N. Ikeda
- Abstract
Background:
The expansion of micrometastatic tumors to macrometastatic ones is thought to be tightly regulated by several microenvironmental factors. The aim of this study was to elucidate the morphological and phenotypical differences between micrometastatic and macrometastatic tumors.
Methods:
We first examined the morphological characteristics of 66 lymph node (LN) micrometastatic tumors (less than 2 mm in size) and 51 macrometastatic tumors (more than 10 mm in size) in 42 lung adenocarcinoma cases. Then, we evaluated the expression level of E-cadherin, S100A4, ALDH1, and Geminin in cancer cells and the number of smooth muscle actin (SMA), CD34, and CD204 (+) stromal cells in the primary tumors, matched micrometastatic tumors, and macrometastatic tumors (n = 34, each).
Results:
Tumor budding reflects the process of EMT, and stromal reactions were observed more frequently in macrometastatic tumors (P < 0.001). E-cadherin staining score for the micrometastatic tumors was significantly higher than that for the primary tumors (P < 0.001). In contrast, the E-cadherin staining score for the macrometastatic tumors was significantly lower than that for the micrometastatic tumors (P = 0.017). As for the stromal cells, the numbers of SMA (+) fibroblasts, CD34 (+) microvessels, and CD204 (+) macrophages were significantly higher for the macrometastatic tumors and primary tumors than for the micrometastatic tumors (P < 0.001, all).
Conclusion:
The present study clearly showed that dynamic microenvironmental changes (e.g., EMT-related changes incancer cells and structural changes in stromal cells) occur during the growth of micrometastases into macrometastases.
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P3.01-028 - Comparison of Touch Imprint Cytology and Section Histopathology in the Diagnostic of the Small Peripheral Lung Tumors (ID 5997)
14:30 - 14:30 | Author(s): N. Ikeda
- Abstract
Background:
There have been some reports on transbronchial biopsy (TBB) through endobronchial ultrasonography with a guide sheath (EBUS-GS) for diagnostic sampling of small-sized tumors which showing ground-glass opacity (GGO) on chest CT. However, technique such as EBUS-GS is limited in their ability to diagnose such small lung tumors. The discussion about the cytological features of small tumors with GGO in detail is necessary. We evaluated about the association of the cytological features with the histological examination using the surgically resected specimen. 140 patients, age between 23–86 years old, who showed clinical and radiological signs of peripheral lung tumors below 3.0cm in diameter, underwent surgical resection at our institution between 2013 and 2015.
Methods:
Imprints or touch preparation and squash smears preparation were prepared from the unfixed, fresh sample in 140 cases. Papanicolaou's stain was employed in all cases. To make the squash smears preparation, the slides are drawn apart away from each other, in the direction of the long axis of the slide. Tissue fragments taken from surgical specimen were fixed with 10% neutral buffered formalin and stained with hematoxylin and eosin (H&E).
Results:
By histological examination (in the 140 cases), the diagnostic of lung cancer was given with the establishing of the histological type. In 110 cases (78.6%) of the cases diagnosed as adenocarcinoma, in 21 cases (15%) squamous cell carcinoma, in 4cases (2.9%) was neuroendocrine tumors, and one case each of adenosquamous carcinoma, pleomorphic carcinoma and pleomorphic sarcoma. In 84 of the 110cases (76.3%), the result of imprint cytological examination was adenocarcinoma. In the 110 pathological diagnosed as adenocarcinoma cases, 52 patients (47.2%) are below 2.0cm in size. Tumor stamps of small sized adenocarcinoma are characterized by moderate cellularity and are composed of atypical cells arranged in small flat sheets. The nuclei are generally round, slightly hyperchromatic with small nucleoli.
Conclusion:
Our data indicate the fact that the cytological examination on stamps from surgical material offers a very high percentage of positive results, close to the histological one. But in the tumor size less than 1.0cm, the establishing of the histological type of lung cancer is more difficult by cytological examination. Despite this, the cytology may be extremely useful in diagnose of the small peripheral tumors. The cytological characteristics of small peripheral adenocarcinoma were little reference to the differentiation at the cellular level. Our findings indicated that the presence of several nucleoli and granular chromatin densely are the factors of adenocarcinoma.
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P3.01-035 - Nicotine Enhances Hepatocyte Growth Factor-Mediated Lung Cancer Cell Migration (ID 3860)
14:30 - 14:30 | Author(s): N. Ikeda
- Abstract
Background:
Cigarette smoking not only promotes lung carcinogenesis, but it has also been demonstrated to promote the progression of lung cancer. Despite nicotine being a major component of cigarette smoke, it is not carcinogenic when acting alone. Instead, it is believed to function as a tumor promoter that stimulates the processes of invasion and metastasis. In the present study we aimed to determine the effect of nicotine on the migratory activity of lung cancer cells.
Methods:
The effect of nicotine on the migration of lung cancer A549 cells was evaluated by a wound healing assay. Hepatocyte growth factor (HGF) was used as a pro‑migratory stimulus. During several of the experiments, specific inhibitors of α7‑nicotine acetylcholine receptor (α7‑nAchR), phosphoinositide kinase‑3 (PI3K) and extracellular signal‑related kinase (ERK)1/2 were included. The phosphorylation levels of Akt and ERK1/2 were examined using a cell‑based protein phosphorylation assay.
Results:
Nicotine did not induce cell migration by itself, but it instead promoted HGF‑induced cell migration (Figure). The effects of nicotine were inhibited by the pretreatment of the cells with the α7‑nAchR inhibitor, methyllycaconitine, and the PI3K inhibitor, LY294002. The mitogen‑activated protein kinase/ERK kinase kinase inhibitor exerted modest, but non‑significant inhibitory activity on the effect of nicotine. Nicotine did not induce Akt phosphorylation by itself, but instead promoted the HGF‑induced phosphorylation of Akt. It was also observed that nicotine had no effect on ERK1/2 phosphorylation.Figure 1
Conclusion:
These results indicate that nicotine, when alone, does not have a pro‑migratory function, but instead enhances responsiveness to the pro‑migratory stimulus emitted by HGF. This study provides an insight into the mechanism of tumor promotion by demonstrating that nicotine and α7‑nAchRs act in synergy with the HGF‑induced PI3K/Akt signaling pathway, increasing the sensitivity of lung cancer cells to HGF, and thereby promoting cell migration, a vital step in invasion and metastasis.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-013 - Combination Therapy of Oncolytic Herpes Simplex Virus Type 1 with Erlotinib in a Human Lung Cancer Xenograft Model (ID 5848)
14:30 - 14:30 | Author(s): N. Ikeda
- Abstract
Background:
Despite the development of a number of new targeted therapies, lung cancer remains the leading cause of cancer-related death worldwide. The use of oncolytic herpes simplex virus type 1 (HSV-1) has been shown to be an effective therapeutic approach for a variety of cancer in preclinical models. A third generation oncolytic HSV-1, G47Δ, is currently used in multiple clinical trials in Japan.
Methods:
In this study, we evaluated the efficacy and safety of G47Δ when used in combination with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in lung cancer xenograft models in mice. Human lung cancer cell line A549 subcutaneous tumor-bearing mice were treated with G47Δ and erlotinib, each alone or in combination, and effects on tumor volume were determined. The toxicity was evaluated by body weight changes.
Results:
In this subcutaneous tumor model, combination therapy resulted in the inhibition of tumor growth without toxicity to a greater extent than that using each agent alone.
Conclusion:
These findings suggest that combination therapy of G47Δ and erlotinib may be a new treatment strategy against human lung cancer.
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SC08 - IASLC- ESTS Joint Symposium: The Borderline Patient (ID 332)
- Event: WCLC 2016
- Type: Science Session
- Track: Pulmonology
- Presentations: 1
- Moderators:J. Kuzdzal, H. Hoffmann
- Coordinates: 12/05/2016, 16:00 - 17:30, Hall C7
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SC08.04 - SABR Versus Surgery (ID 6631)
17:00 - 17:20 | Author(s): N. Ikeda
- Abstract
- Presentation
Abstract:
In recent years, the number of early stage lung cancers has enormously increased and this tendency is more prominent in octogenarians. Both curability and non-inavasiveness should be required for such situation. Surgery is the standard treatment for early stage lung cancer and VATS lobectomy or sublobar resection have been routinely performed for selected patients to maintain performance status[1)]. Especially, the indication of sublobar resection is considered to be related to the aggressive nature of tumors, thus several studies by HRCT findings and PET-CT were performed to predict the invasive nature as well as clinical stage. In JCOG 0201, 545 case who received lobectomy and mediastinal lymph node dissection due to stage I NSCLC were enrolled prospectively. Pathological non-invasive cancer (both vascular and lymphatic invasion negative) was evaluated by the consolidation/tumor ratio on preoperative HRCT. Adenocarcinoma <2.0 cm with <0.25 consolidation to the maximum tumor diameter (35 patients, 12.1%) revealed pathological non-invasiveness in 98.7% (95% CI: 93.2–100.0%), and this criterion could be used for radiological early lung cancer[2)]. The prognostic study of cases enrolled in JCOG0201 revealed that 5 year OS and RFS survivals of the entire patients were 90.6% and 84.7%, respectively. The 5-year OS of radiologic early and invasive adenocarcinomas were 97.1% and 92.4%, respectively (p=0.259). If the consolidation/tumor ratio lower than 0.5 in cT1a-b was used as a cutoff, the 5-year OS of radiologic early (121 patients, 22.2%) was 96.7% and invasive adenocarcinomas, 88.9% (p<0.01)[3)]. Based on the criteria of radiologic early cancer obtained by JCOG0201, randomised phase 3 trial to evaluate non-inferiority in OS of segmentectomy compared to lobectomy (JCOG0802)[4)]. The maxSUV of the primary tumor on PET/CT could be used as a prognostic marker of early stage lung cancer. Analyses of 610 resected stage IA adecocarcinoma showed that maxSUV and GGO ratio cutoffs to predict recurrence were 2.9 and 25%, respectively. They were also related to nodal metastasis, histological tumor invasiveness and recurrence. The 5-year RFS of cases with maxSUV <2.9 (n=456) was 95%, while cases with maxSUV>2.9 (n=154), 72% (p<0.001)[5)]. Surgical management of early stage lung cancer should be selected by based on the tumor size, GGO ratio and maxSUV to predict the biological malignancy of each case. Streotactic ablative radiotherapy (SABR) has attained importance for efficacy and safety for the treatment of early cancers located in the peripheral lung. There are two representative randomised phase 3 trial (STARS and ROSEL) to compare SABR and surgery. Eligible patients of these studies were T1-2a (<4cm) N0M0 and a total of 58 cases were registered (31 received SABR and 27, surgery). The combined analysis of these two studies revealed that 3 year OS in SABR (95%) was superior to that of surgery (79%) (p=0.037) and RFS at 3 years was similar; 86% in SBRT and 80% in surgery (p=0.54). Only 10% of cases in SBRT group suffered grade 3 toxicity but 44% of surgery group developed grade 3 and 4 toxicities. The pooled analysis of the two studies showed SBRT had similar treatment efficacy to that of surgery in spite of the small sample size[6)]. Japan Clinical Oncology Group evaluated the efficacy and safety of SBRT for operable/inoperable T1N0M0 patients (JCOG 0403). A total of 164 patients (100 inoperable and 64 inoperable) were treated by 48 Gy. The 3 year OS was 59.9% in inoperable patients and 76.5% in operable patients[7)]. Investigations into the effectiveness of SABR for operable patients as well as the optimal indication, dose and fraction should be clarified by prospective manner. SABR has become a radical treatment for inoperable stage I lung cancer. In addition, if operable cases treated by SABR in JCOG0403 show favorable outcome, further comparable trial of SABR versus less invasive surgery should be warranted. References 1) Committee for Scientific Affairs The Japanese Association for Thoracic Surgery, Thoracic and cardiovascular surgery in Japan during 2013 : Annual report by the Japanese Association for Thoracic Surgery. Gen Thorac Cardiovasc Surg.2015;63:670-701. 2) Suzuki K, Koike T, Asakawa T, et al.: A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan Clinical Oncology Group 0201). J Thorac Oncol 2011;6:751-756 3) Asamura H, Hishida T, Suzuki K, et al. Radiographically determined noninvasive adenocarcinoma of the lung: Survival outcomes of Japan Clinical Oncology Group 0201 J Thorac Cardiovasc Surg 2013;146:24-30 4) Nakamura K, Saji H, Nakajima R, et.al. A Phase III Randomized Trial of Lobectomy Versus Limited Resection for Small-sized Peripheral Non-small Cell Lung Cancer (JCOG0802/WJOG4607L) Jpn J Clin Oncol 2010;40:271–274 5) Uehara H, Tsutani Y, Okumura S, et al. Prognostic Role of Positron Emission Tomographyand High-Resolution Computed Tomography in Clinical Stage IA Lung Adenocarcinoma Ann Thorac Surg 2013;96:1958–1965 6) Chang JY, Senan S, Paul MA et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: A pooled analysis of two randomized trials. Lancet Oncol 2015;16:630–637. 7) Nagata Y, Hiraoka M, Shibata T, et al. Prospective trial of stereotactic body radiation therapy for both operable and inoperable T1N0M0 non-small cell lung cancer: Japan Clinical Oncology Group Study JCOG0403. Int J Radiat Oncol Biol Phys 2015;93;989-996.
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