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M.A. Hoda
Moderator of
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OA15 - Sublobar Resections for Early Stage NSCLC (ID 396)
- Event: WCLC 2016
- Type: Oral Session
- Track: Surgery
- Presentations: 8
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OA15.01 - Limited Resection Trial for Pulmonary Sub-solid Nodules: Case Selection Based on High Resolution CT: Outcome at Median Follow-up of 105 Months (ID 4454)
16:00 - 16:10 | Author(s): J. Yoshida, G. Ishii, K. Nagai, T. Hishida, K. Aokage, M. Tsuboi, H. Ito, T. Yokose, H. Nakayama, K. Yamada
- Abstract
- Presentation
Background:
The objective of this study is to confirm limited resection efficacy as radical surgery in patients with minimally invasive lung cancer as indicated by high-resolution (HR) computed tomography (CT), and to confirm intraoperative cytology as a negative margin indicator and reliable margin non-recurrence predictor.
Methods:
Enrollment required patients with a tumor ≤ 2 cm in diameter, diagnosed or suspected as a clinical T1N0M0 carcinoma in the lung periphery based on a CT scan. They had to have a HRCT scan indicating a sub-solid nodule with tumor disappearance ratio; TDR ≥ 0.5. (TDR = 1- DM/DL; DM: maximum tumor diameter on mediastinal settings, DL: maximum tumor diameter on lung settings). Patients unfit for lobectomy and systematic lymph node dissection were excluded. We performed a wedge or segmental resection. The used stapling cartridges were washed with saline, which was cytologically evaluated. If cytology was cancer positive, additional margin was resected, and cytologic examination repeated. If the second exam was positive, a routine lobectomy and systematic lymph node dissection was performed. We aimed at enrolling 100 patients. The primary endpoint is 10-year local recurrence free survival rate.
Results:
This prospective study started in November 2003, and 101 patients were enrolled in 6 years. Of them, 99 were eligible for analysis. The mean age was 62 years (range: 30-75), and 60 were women. There were 11 Noguchi type A tumors, 54 type B tumors, 26 type C tumors, one type D tumor, one malignant lymphoma, 3 hyperplastic lesions, and 3 inflammatory fibroses. None of the 93 malignant nodules showed any vessel invasion. Although no positive cytology results were obtained, pathologically positive margin was reported after surgery in one type C patient. He later underwent a routine lobectomy and systematic lymph node dissection. There was no clear correlation between tumor size, TDR, and Noguchi subtype. No mortality occurred, but one patient developed postoperative pneumothorax and pneumonia, and another hemorrhagic gastric ulcer. With a median follow-up period of 105 months (range: 72−129) as of June 2016, there have been no recurrences, but one patient died for unspecified cause.
Conclusion:
We have repeatedly warned that delayed cut-end recurrence is possible following limited resection even for small sub-solid lung cancers. So far, however, HRCT scans appear to predict non- or minimally invasive sub-solid lung cancers with high reliability, warranting limited resection as curative surgery in this cohort. Intraoperative cytology reliably indicated negative margins and seems to predict freedom from local recurrence.
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OA15.02 - Survival Outcomes in Sublobar Resection for Clinical T1N0M0 Non-Small Cell Lung Cancer: Wedge Resection or Segmentectomy (ID 4710)
16:10 - 16:20 | Author(s): A.K. Kobayashi, R. Ishikawa, M. Takao, A. Shimamoto, A. Ito, H. Shimpo
- Abstract
- Presentation
Background:
Lobectomy remains the standard treatment for early-stage non-small cell lung cancer (NSCLC).In practice, however, sublobar resection has been selectively offered for patients with clinical Stage IA NSCLC as curative treatment. To seek optimal surgical procedure for early stage lung cancer, we carried out retrospective analyses of 2122 patients who had undergone limited resection for c-T1N0M0 NSCLC from 26 institutions of Japanese association for chest surgery.
Methods:
A total of 1963 patients with lobectomy tolerance were eligible for survival analysis. We retrospectively categorized patients of these nodules on numbers of criteria for CT findings; scores were added according to the dominance of ground glass appearance (GGA); >75% = 0, <75% =1, and size of tumor; T1a =0, T1b =1. Statistical analyses were carried out using propensity-matching and Kaplan-Myer with log-rank testing.
Results:
We analyzed 1:1 matched 731 patients for segmentectomy and wedge resection with propensity matching.The overall survival (OS) for score 0 group was 90.2% in segmentectomy (n=419) and 94.7% in wedge resection (n=451) (p=0.0351). The disease free survival (DFS) for score 0 group was 90.2% in segmentectomy and 92.7% in wedge resection (p=0.0645). The OS for score 1 group was 93.6% in segmentectomy (n=278) and 80.4% in wedge resection (n=246)(P<0.001)(Fig. 1). The DFS for score 1 group is 94.1% in segmentectomy and 75.3% in wedge resection (P<0.001). The OS for scores 2 was 79.1% in segmentectomy (n=34) and 69.2% in wedge resection (n=34) (p=0.109). The DFS for score 2 group was 87.0% in segmentectomy and 58.1% in wedge resection (p=0.581). Figure 1
Conclusion:
This study showed that GGA dominant T1a may be treated by wedge resection where possible. The consolidation dominant T1b did not benefit from sublobar resection. In patients with GGA dominant T1b or consolidation dominant T1a, anatomical segmentectomy with curative intension may provide better prognosis.
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OA15.03 - Comparison of Prognosis between Lobectomy and Sublobar Resection for Clinical Stage I Non-Small Cell Lung Cancer with Interstitial Lung Disease (ID 4063)
16:20 - 16:30 | Author(s): Y. Tsutani, T. Mimura, Y. Kai, M. Ito, Y. Handa, N. Tsubokawa, K. Misumi, H. Hanaki, Y. Miyata, M. Okada
- Abstract
- Presentation
Background:
The prognosis after standard lobectomy for non-small cell lung cancer (NSCLC) with interstitial lung disease (ILD) is poor. This study aimed to compare the prognosis after lobectomy and sublobar resection for early NSCLC with ILD.
Methods:
Among 794 consecutive patients with clinical stage I NSCLC who underwent complete resection, 107 patients with ILD on high-resolution computed tomography (HRCT), which was defined according to the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association classification, were identified.
Results:
Overall survival (OS) was significantly worse for patients with possible usual interstitial pneumonia (UIP) or UIP pattern than those with inconsistent with UIP pattern (3-year OS, 64.5% vs. 82.1%, respectively; P = 0.031). No significant difference existed in OS between lobectomy and sublobar resection for all patients with ILD (3-year OS, 67.1% vs. 81.9%, respectively; P = 0.14). Although in patients with inconsistent with UIP pattern, OS was similar between lobectomy and sublobar resection groups (3-year OS, 81.1% vs. 83.6%, respectively; P = 0.87), OS was better for patients who underwent sublobar resection than lobectomy in patients with possible UIP or UIP patterns (3-year OS, 81.0% vs. 50.5%, respectively; P = 0.069). Multivariate Cox analysis demonstrated that preoperative diffusing capacity of the lung for carbon monoxide (P = 0.018), not the surgical procedure (P = 0.14), was an independent prognostic factor for OS.
Conclusion:
Sublobar resection can be an alternative choice for clinical stage I NSCLC with ILD especially for UIP or possible UIP patterns on HRCT.
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OA15.04 - Discussant for OA15.01, OA15.02, OA15.03 (ID 7090)
16:30 - 16:45 | Author(s): S.B. Watzka
- Abstract
- Presentation
Abstract not provided
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OA15.05 - Anatomical Pulmonary Segmentectomy and Sub-Sebmentectomy for Lung Cancer Using the Novel Fluorescence Technique with Vitamin B2 (ID 5305)
16:45 - 16:55 | Author(s): R. Waseda, Y. Tatsuzawa, I. Matsumoto, H. Takemura
- Abstract
- Presentation
Background:
The identification of an accurate segment is essential for successful anatomic pulmonary segmentectomy. We have previously developed a new fluorescence technique using a PDD endoscope system[TM] and vitamin B2 for identification of pulmonary segments in animal experiments. In this study, we applied this technique clinically to examine the efficacy and safety in anatomical pulmonary segmentectomy and sub-segmentectomy for pulmonary malignancies.
Methods:
Our technique requires two key instruments, a PDD endoscope system[TM](KARL STORZ GmbH and Co., Tuttlingen, Germany) as a fluorescence sensing device and vitamin B2 solution as a fluorescent substance. 17 patients with small lung nodules were enrolled in this study. Regarding our surgical technique, after identification of the target segmental or sub-segmental bronchus, vitaminB2 solution is injected via the bronchus. The target segment is identified as a fluorescent segment with the PDD endoscope system[TM]. The identified segment is resected with an electric cautery, stapling devices, or combination of them. In case patient’s lung has severe abnormal change such as emphysema or fibrosis, another technique is indicated. After ligation of the target segmental or sub-segmental artery, vitaminB2 solution is systemically administrated with intravenous injection. The target segment is identified as a defect of fluorescence with the PDD endoscope system[TM]. Following outcomes were collected; success rate of identifying the pulmonary segments, pathological evaluation of dissection margin, duration of chest drainage, and perioperative complications.
Results:
A total of 18 procedures were performed using this technique. Performed segmentectomy or sub-segmentectomy were as follows; Right S1, S2, S3, S2a+3b, S6, S9, Left S1+2, S3, S4+5, S6, S8a+9b, S9+10. Resected nodules were 14 primary lung cancers, 1 MALT-lymphoma, 1 metastatic lung cancer, and 2 benign lung nodules. Histology of primary lung cancer was adenocarcinoma in all 14 cases. Pathological stage of lung cancer was 12 stageIA (pT1a; 10, pT1b; 2), 1 stageIIA (pT1aN1), and 1 stageIIIA (pT1aN2). The success rate of identifying pulmonary segments was 100%. Dissection of segmental border was performed with only electric cautery in 12 procedures, and with both of electric cautery and stapling device in 6 procedures. In all cases, no cancer cells were found on the resection margin pathologically. Mean drainage time was 1.7 days (1-4 days). Regarding perioperative complications, veno-vagal reflex was occurred after systemic injection of vitaminB2 in one case, and 1 delayed pneumothorax was found in one case.
Conclusion:
Our novel fluorescence technique involving a PDD endoscope system[TM] and vitaminB2 allowed performing accurate and safe pulmonary segmentectomy and sub-segmentectomy.
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- Abstract
- Presentation
Background:
Although the confirmation of an appropriate resection margin from the tumor is crucial for reducing the risk of local recurrence after lung segmentectomy for pulmonary malignancies, there has been no method of measurement. We established a novel approach for performing segmentectomy by using an infrared thoracoscopy with transbronchial instillation of indocianine green (ICG), and improved this method by adding an advanced computer technology via lung volume analyzer for obtaining an appropriate resection margin.
Methods:
Preoperatively, each patient underwent multislice enhanced computed tomography (CT) using 320-slice scanners for pulmonary angiography and virtual bronchoscopy, and to create several virtual segmentectomies by using Volume Analyzer Synapse VINCENT (Fujifilm co., Tokyo, Japan). We measured the shortest distance from the tumor to the resection margin in each simulated segmentectomy and selected the most appropriate area of sublobar resection based on the adequate resection margin of approximately 2 cm from the tumor. We prospectively performed segmentectomy in 17 patients and compared between simulated distance and actual distance measured from the specimen.
Results:
The average number of created patterns of virtual segmentectomy in each case was 4.1 ± 1.0. The mean distance of resection margin in selected virtual segmentectomy was 19.3 ± 9.7 mm. On the other hand, actual shortest distance in resected specimen was 25.4 ± 8.1 mm, which was significantly longer than simulated distance (p=0.027). There was no tumor recurrence in all patients.
Conclusion:
Lung volume analyzer was an excellent tool for selecting an ideal area of sublobar resection with an appropriate resection margin.
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- Abstract
- Presentation
Background:
The standard surgical treatment of stage I non-small cell lung cancer is anatomical lobectomy. However, in some cases, small peripheral lung cancer (≤2cm) is treated by sublobar resection. The purpose of this study was to define the necessity of completion lobectomy when the tumor was revealed as non-small cell lung cancer with pleural invasion or lymphovascular invasion after sublobar resection.
Methods:
We retrospectively reviewed 271 consecutive patients who underwent curative resection for stage I non–small cell lung cancer of 2 cm or less. We analyzed clinicopathological findings and survival between two groups with either invasion-positive tumor (tumor with visceral pleural invasion or lymphovascular invasion) or invasion-negative tumor (tumor without visceral pleural invasion and lymphovascular invasion): sublobar resection group and lobectomy group.
Results:
Except for age and pulmonary function, there were no differences in clinocopathological characteristics between sublobar resection group and lobectomy group with invasion-positive tumor or invasion-negative tumor. There was no difference in the 5-year recurrence-free survival rate between two groups in the invasion-positive tumor and invasion-negative tumor (78.9% vs 79.8%; p=0.928, 80.2% vs 85.4%; p=0.505). In the multivariate analysis, only number of dissected lymph nodes was a significant recurrence-related factor of stage I invasive-positive non-small cell lung cancer (hazard ratio 0.914, 95% confidence interval 0.845-0.988, p=0.023). Sublobar resection was not a risk factor for recurrence.
Conclusion:
The survival between sublobar resection group and lobectomy group in small (≤2cm) non-small cell lung cancer with visceral pleural invasion or lymphovascular invasion were not different. Completion lobectomy is not necessary in small lung cancer after sublobar resection whether the tumor has visceral pleural invasion or lymphovascular invasion.
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OA15.08 - Discussant for OA15.05, OA15.06, OA15.07 (ID 7091)
17:15 - 17:30 | Author(s): W. Zhong
- Abstract
- Presentation
Abstract not provided
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Author of
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IA05 - The Practical Use of the TNM Classifications for Thoracic Cancers (ID 291)
- Event: WCLC 2016
- Type: Interactive Session
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:H. Asamura, C. Herold
- Coordinates: 12/06/2016, 11:00 - 12:30, Hall C7
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IA05.02 - Mesothelioma Cases (ID 6525)
11:30 - 11:50 | Author(s): M.A. Hoda
- Abstract
- Presentation
Abstract:
Malignant pleural mesothelioma (MPM) is a highly lethal malignancy arising from the serosal lining of the pleural cavity [1]. In up to 80% of patients, asbestos is considered to contribute to the development of this tumor within about 20 to 40 years of exposure time [2]. The incidence of MPM is expected to increase dramatically over the next few decades. It has been estimated that 250 000 people will die of MPM in Europe in the next three decades, and 2500–3000 new cases are diagnosed each year in the USA [3]. The macroscopic appearance of MPM depends on disease stage. In early stage MPM, the cancer presents as multiple small nodules on the surface of both pleural linings. In advanced stages, the multiple small nodules form a tumor plate which surrounds the lung like a cage and in most cases invades the lung parenchyma, diaphragm and pericardium [4]. The establishment of the pathological diagnosis of MPM and the classification in three main histological subtypes (namely epitheloid, biphasic and sarcomatoid) is important and has an impact on therapy and prognosis. Epitheloid MPM is more therapy responsive and associated with better outcome compared to biphasic and sarcomatoid histotypes. Other very important simple prognostic factors for MPM are disease stage and lymph node involvement. Therefore an adequate staging of MPM patients is crucial for therapy decision-making. The currently widely used staging system is the one according to International Mesothelioma Interest Group (IMIG) established in 1996 [5]. Based on the TNM (tumor-node-metastasis) system for malignant tumors, this staging system describes: the extent and size of the primary tumor, lymph node involvement and distant metastases. By the different TNM descriptors, MPM can be classified and summarized in four different tumor stages (IMIG I-IV). Patients suffering from stage I-III are considered for surgery within multimodality protocols, while palliative systemic or local treatment is indicated for stage IV in accordance with the current classification. Butchart et al. [6]proposed in 1976 an alternative staging system, referred to as the Butchart Staging. Contrary to the IMIG system (based on lung cancer staging) the Butchart system is particularly set up for MPM. Therefore, several differences between both staging systems exist. However, the IMIG in collaboration with the International Association for the Study of Lung Cancer (IASLC) have proposed a new T, N and M descriptors for in the forthcoming 8[th] edition of the TNM classification for MPM with significant changes to the 7[th] TNM edition and proposals have been very recently published [7-9]. With regard to the T descriptor, a fusion of both, clinical and pathological T1a and T1b into a T1 was recommended [7]. Regarding the N descriptor, a summary of the clinical and pathological N1 and N2 categories into a single category with the classification into ipsilateral, intrathoracic nodal metastases (N1) was proposed [8]. No changes have been recommended for the M descriptor in the 8[th] edition of the TNM [9]. In this presentation, 4 patient cases of different stages of MPM patients will be presented and the newly proposed TNM descriptors and IMIG staging will be applied. Cases and changes in the staging system will be discussed together with the attending audience in an interactive manner. After the presentation, the participants will be able to understand and practically apply the forthcoming changes in the TNM system for staging of MPM patients. 1. Whitaker, D., J.M. Papadimitriou, and M.N. Walters, The mesothelium and its reactions: a review. Crit Rev Toxicol, 1982. 10(2): p. 81-144. 2. Lanphear, B.P. and C.R. Buncher, Latent period for malignant mesothelioma of occupational origin. J Occup Med, 1992. 34(7): p. 718-21. 3. Peto, J., et al., The European mesothelioma epidemic. Br J Cancer, 1999. 79(3-4): p. 666-72. 4. Rudd, R.M., Malignant mesothelioma. Br Med Bull, 2010. 93: p. 105-23. 5. Rusch, V.W., A proposed new international TNM staging system for malignant pleural mesothelioma from the International Mesothelioma Interest Group. Lung Cancer, 1996. 14(1): p. 1-12. 6. Butchart, E.G., et al., Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura. Experience with 29 patients. Thorax, 1976. 31(1): p. 15-24. 7. Nowak, A.K., et al., The IASLC Mesothelioma Staging Project: Proposals for Revisions of the T descriptors in the forthcoming Eighth edition of the TNM classification for pleural mesothelioma. J Thorac Oncol, 2016. 8. Rice, D., et al., The IASLC Mesothelioma Staging Project: Proposals for Revisions of the N Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Pleural Mesothelioma. J Thorac Oncol, 2016. 9. Rusch, V.W., et al., The IASLC Mesothelioma Staging Project: Proposals for the M Descriptors and for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Mesothelioma. J Thorac Oncol, 2016.
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OA02 - Novel Targets and Biomarkers in Malignant Pleural Mesothelioma (ID 369)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:L.E. Raez, M. Jakopovic
- Coordinates: 12/05/2016, 11:00 - 12:30, Stolz 2
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OA02.03 - Circulating Fibroblast Growth Factor 18 is Elevated in Malignant Pleural Mesothelioma Patients - A Multi-Institutional Study (ID 5988)
11:20 - 11:30 | Author(s): M.A. Hoda
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is a rare but devastating malignancy. Despite the search for new promising treatment approaches, the outcome for most MPM patients remains dismal. Therefore, the identification of novel biomarkers is urgently needed in order to identify patients with a better prognosis and to support personalized therapeutic decisions. In our previously published study, we were able to show that fibroblast growth factor 18 (FGF18) is overexpressed in MPM tissue specimens and cell models. The objective of this study was the evaluation of FGF18 as a circulating biomarker in MPM.
Methods:
Plasma was collected from 107 MPM patients at the time of diagnosis or before surgical resection. Samples were included from the Medical University of Vienna, University Hospital Center in Zagreb and from The Concord Repatriation General Hospital and Strathfield Private Hospital in Sydney. Samples from 49 healthy volunteers and from 8 patients with non-malignant pleural diseases served as controls. Circulating FGF18 was measured by enzyme-linked immunosorbent assay and correlated to clinical, pathologic and radiologic parameters.
Results:
Plasma FGF18 level was significantly elevated in MPM patients vs. healthy controls (P<0.0001). A slight increase of circulating FGF18 level was also detected in patients with pleuritis or fibrosis (vs. control, P=0.0067). Sarcomatoid (n=7) morphology was associated with high FGF18 levels when compared to the epithelioid (n=77) histology (P=0.0064). Importantly, MPM patients presenting with FGF18 levels below the median had a significantly longer overall survival when compared to those with high FGF18 levels (median survival 625 versus 382 d, P=0.0038). Data on multivariate analysis, disease-free survival, correlation with other biomarkers and tumor volume will be presented at the conference.
Conclusion:
Our findings reveal that FGF18 is a promising blood-derived candidate biomarker in MPM. Furthermore FGF18 may support the histological classification of MPM and the identification of MPM patients with poor prognosis. .
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OA07 - Lymph Node Metastases and Other Prognostic Factors for Local Spread (ID 376)
- Event: WCLC 2016
- Type: Oral Session
- Track: Surgery
- Presentations: 1
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OA07.01 - Incidence, Local Distribution and Impact of pN2 Skip Metastasis in Patients Undergoing Curative Resection for NSCLC (ID 4177)
14:20 - 14:30 | Author(s): M.A. Hoda
- Abstract
- Presentation
Background:
Background: The presence of N2 lymph node (LN) involvement has strong impact on therapy and prognosis in non-small cell lung cancer (NSCLC). N2 LN metastasis may occur by skipping N1 LN stations (N2skip-met). We aim to analyze incidence, local distribution and impact of N2skip-mets in a large cohort of patients undergoing curative resection for NSCLC.
Methods:
Methods: A retrospective non-interventional singe-center cohort study was conducted, assessing all patients undergoing curative resection for NSCLC between 2006 and 2013 at our institution by reviewing medical charts. Incidence of N2skip-mets among these patients was the primary endpoint. Subsequent secondary correlation of clinical parameters was performed using uni- and multivariate logistic and cox regression models.
Results:
Results: In total, 1110 patients were enrolled, with the following pathological LN status: 789 (71%) pN0, 211 (19%) pN1, 105 (9.5%) pN2, 5 (0.5%) pN3. Histological subtype was: adenocarcinoma, n=675 (61%); squamous cell carcinoma, n=309 (28%); other, n=126 (11%). Incidence of N2skip was 55% (47/105). N2skip-mets occurred more frequently in right sided tumors (odds ratio (OR) 2.14, p=0.058) and patients with adenocarcinoma (vs. other, OR 1.54, p=0.19). Presence of N2skip-mets did not correlate with tumor size (ROC, area under curve (AUC) 0.44, p=0.32). Strikingly, presence of N2skip-mets was significantly increased in smokers (OR 3.5, 95% CI 1.38-8.83, p=0.006). Moreover, patients with N2skip-mets were more likely to develop subsequent brain mets (OR 4.13, p=0.06). Overall- and recurrence free survival will be presented at the conference.
Conclusion:
Conclusion: N2skip-mets occur in a high number of patients with N2 disease, with distinct differences in clinicopathologic features. Considering the results of this study, subclassification of N2 disease as recently proposed by the IASLC may have clinical impact in patients with resectable NSCLC.
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-026 - Activin A is Associated with Poor Prognosis and Promotes Metastatic Growth in Small Cell Lung Cancer (ID 5888)
14:30 - 14:30 | Author(s): M.A. Hoda
- Abstract
Background:
Small cell lung cancer (SCLC) is a devastating malignancy characterized by resistance to therapy and poor clinical outcome. Therefore, identification of novel therapeutic strategies and non-invasive biomarkers that facilitate early detection and predict prognosis is urgently needed. Expression of the growth factor activin A (ActA), a member of the TGF beta superfamily, is deregulated in a number of malignancies. However, to date there is no data on the role of ActA in SCLC.
Methods:
In a cohort of SCLC patients (n=79) and in sex- and age-matched controls (n=66), plasma levels of ActA were measured by ELISA. The diagnostic value of plasma ActA was evaluated by ROC curve analysis. The mRNA and protein expression levels of ActA were analyzed in SCLC cell lines by qRT-PCR and by ELISA, respectively, and one of the cell lines with low baseline ActA expression was transfected with ActA and a control vector. The effect of ActA overexpression on the in vivo growth of SCLC cells was investigated in an orthotopic xenograft model.
Results:
Increased plasma ActA levels were found in patients with SCLC (vs. controls) and ActA levels were elevated in a TNM stage-dependent manner. Moreover, high ActA levels were associated with significantly shorter overall survival and multivariate analysis revealed that plasma ActA concentration is an independent negative prognostic factor in this patient cohort. With an area under the curve of 0.81 (95% CI: 0.74-0-0.88), circulating ActA was identified as a useful biomarker for the diagnosis of SCLC. Expression of ActA in SCLC cell lines was detected in vitro. Furthermore, ActA overexpression increased the metastatic capacity of SCLC cells in our xenograft model.
Conclusion:
Our findings suggest that the measurement of circulating ActA can support the diagnosis and staging of SCLC and, moreover, that it can help to predict the clinical outcome. We also conclude that ActA has a role in the aggressive behavior of this tumor type and that its potential therapeutic relevance needs to be further investigated.
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P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 3
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-002 - Inducible Changes in Cell Morphology and Gene Expression Reflecting the Histological Subtypes of Mesothelioma (ID 5405)
14:30 - 14:30 | Author(s): M.A. Hoda
- Abstract
Background:
Malignant pleural mesothelioma (MPM) represents an aggressive malignancy with dismal prognosis and limited therapeutic options. MPM occurs in three main histological subtypes: epithelioid, sarcomatoid and biphasic, which are characterized by differences in morphological growth pattern, aggressiveness and patient prognosis. However, the mechanisms and causes responsible for the different cell morphologies are poorly understood. Epithelial-mesenchymal transition (EMT) has been implicated in cancer progression and chemoresistance, but its role in MPM is not well understood. Fibroblast growth factor (FGF) signals promote cell growth, survival and aggressiveness in several tumors including mesothelioma. Aim of this study was to characterize growth factor-induced, EMT-like changes with respect to the MPM histological subtypes.
Methods:
Morphological and behavioral changes of treated cell models were analyzed by morphometry, immunoblotting and functional assays. Alterations in gene or microRNA expression were evaluated via qPCR and array hybridization. Pathway enrichment analysis was based on KEGG.
Results:
In several cell lines established from biphasic MPM, treatment with FGF2 and EGF induced morphological changes reminiscent of EMT and aggressive behavior such as scattering, increased migration, proliferation and invasiveness. Inhibition of the fibroblast growth factor receptors (FGFR) or the MAPK axis via small-molecule inhibitors could prevent these changes and, in cell lines with sarcomatoid-like shape, reverse scattering and induce a more epithelioid morphology. Comparable results were obtained using an engineered FGFR1 enabling contactless activation via blue light. Analyses of genes and microRNAs regulated by FGF2 or EGF showed an overlap with previously established EMT markers but also identified several novel potential markers such as MMP1, ESM1, ETV4, PDL1, ITGA6 or BDKRB2. Blocking the FGFR or MAPK pathways resulted in the opposite regulation of these genes. Inhibition of MMP1 via siRNAs or pharmacological inhibitors prevented FGF2-induced scattering and invasiveness. In unsupervised clustering, the gene expression profiles of solvent- or cytokine-treated cells were associated with those of epithelioid and sarcomatoid MPM, respectively. Immunohistochemistry showed an association of MMP1 as well as phospho-ERK with the sarcomatoid part of tissue specimens from biphasic tumors. Pathway enrichment analysis of differentially expressed genes as well as the targets of altered microRNAs after FGF2 treatment showed that the regulated genes are assigned to categories important for cell growth and aggressive behavior.
Conclusion:
Our data characterize FGFR-mediated signals as important players in MPM aggressiveness and the morphological and behavioral plasticity of mesothelioma cells, leading to a better understanding of the link between the MPM histological subtypes and their influence on patient outcome.
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P3.03-006 - Optical Control of Growth Factor Receptors to Advance Signal Transduction Research and Drug Screening (ID 5358)
14:30 - 14:30 | Author(s): M.A. Hoda
- Abstract
Background:
Growth factor receptors are central elements of signal transduction pathways and increasingly important targets for anticancer drugs. In recent years naturally occurring light sensitive protein domains (LSPDs) from different kingdoms of life have been used to generate genetically encoded chimeric signalling molecules that can be activated reversibly and with spatiotemporal precision by light. The development of such optogenetic tools has led to a plethora of new discoveries in the neurosciences but has received comparably little attention in cancer research - partly due to a lack of appropriate tools. Our aim was therefore to generate synthetic growth factor receptors that can be activated with light and allow fine-tuned control of growth factor-associated signal transduction pathways.
Methods:
To generate receptor tyrosine kinases (RTKs) that can be optically activated (Opto-RTKs), intracellular domains of RTKs were fused to LSPDs of the light-oxygen voltage (LOV) family from various species. The resulting chimeric receptors were tested for light-dependent activation of signal transduction by reporter gene assays, immunoblotting and various cell biological tests assessing DNA synthesis, epithelial mesenchymal transition (EMT) and angiogenesis.
Results:
Three of the tested LOV domains enabled light-dependent receptor dimerisation and activation of the corresponding signal transduction pathways when fused to the intracellular domains of FGFR1, EGFR, RET, c-Met or ROS1. Opto-RTKs enabled stringent control of the MAPK, PI3K and PLCγ pathways. Signal activation could be spatially confined to illuminated regions of culture plates and signals rapidly subsided after cessation of illumination. Light was able to replace FGF2 for the induction of cell proliferation and EMT in mesothelioma cells and VEGF for the stimulation of angiogenic sprouting in endothelial cells. Moreover, Opto-RTKs enabled light-assisted screening for small molecule inhibitors of EGFR, FGFR1 and the orphan RTK ROS1.
Conclusion:
Our optogenetic approach allows light-mediated control of growth factor receptors representing clinically relevant drug targets. Opto-RTKs enable dissection of dynamic signals with increased spatiotemporal resolution and open new possibilities for drug screening. Transfer of the design principle to additional membrane receptors is ongoing.
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P3.03-046 - Prognostic Fibrinogen/Leucocyte Score at Diagnosis Predicts Survival and Benefit from Multimodality Treatment in MPM (ID 4179)
14:30 - 14:30 | Author(s): M.A. Hoda
- Abstract
Background:
The aim of this study was to identify and validate prognostic and predictive biomarkers in a large cohort of patients with malignant pleural mesothelioma (MPM).
Methods:
We performed a retrospective chart review, including all patients with histologically confirmed MPM, treated at two specialized centers between 1994 and 2014. The effect of different clinical and pathological characteristics and laboratory values on outcome was investigated by using uni- and multivariate logistic and cox regression models.
Results:
Two-hundred ninety-one patients were enrolled (222 males and 69 females). Main histological subtype was epitheloid (n=199, 68%). Multimodality treatment, defined as macroscopic complete resection combined with chemotherapy and/or radiation therapy and/or intracavitary treatment, was performed in 134 (46%) patients. Median overall survival (OS) was 17.7 months from diagnosis. In the multivariate cox regression model, leucocyte count at diagnosis (continuous, hazard ratio (HR) 1.087, p=0.04), fibrinogen at diagnosis (continuous, HR 1.002, p=0.002), histological subtype (epitheloid vs. non-epitheloid, HR 0.064, p=0.006) and age (continuous, HR 1.035, p=0.001) remained as independently significant co-factors influencing OS. ROC curve analyses for predicting 1-year survival revealed an area under the curve (AUC) of 0.72 (p=0.001) for fibrinogen and 0.65 (p=0.001) for leucocytes. Dichotomizing fibrinogen and leucocytes at the median values (550 mg/dl and 8 G/l) revealed a sensitivity of 0.65 and 0.55 and a specificity of 0.69 and 0.61 for predicting 1-year survival, respectively. Combining dichotomized fibrinogen/leucocytes to an inflammation based prognostic score (none, one or both elevated) significantly influenced 1-year survival (p<0.001) and OS (score 0 vs. I, p=0.005; I vs. II, p=0.03). When introducing to the multivariate cox regression model, the fibrinogen/leucocytes score remained as independently prognostic for OS (I vs. O, HR 1.48, p=0.02; II vs. 0, HR 2.26, p<0.001). Strikingly, a significant predictive interaction between the fibrinogen/leucocytes score and treatment modality was observed (p<0.001).
Conclusion:
The inflammation based fibrinogen/leucocytes score predicts OS independently from sex, age, stage, subtype and treatment modality. Multimodality treatment including surgery increases survival selectively in patients with low fibrinogen/leucocytes score.
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P3.04 - Poster Session with Presenters Present (ID 474)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.04-003 - Incidence and Outcome of Female Patients with Previous Breast Cancer Undergoing Curative Resection for Lung Cancer (ID 4178)
14:30 - 14:30 | Author(s): M.A. Hoda
- Abstract
Background:
Due to recent improvements in breast cancer (BC) therapy and outcome, female patients with BC may be at higher risk of developing secondary malignancies such as lung cancer (LC). The aim of this study is to evaluate the incidence and outcome of previous BC in female patients with resectable lung cancer.
Methods:
A retrospective non-interventional singe-center cohort study was conducted, assessing all female patients undergoing curative resection for LC between 2006 and 2013 at our institution by reviewing medical charts. Follow-up will be completed in September 2016. Incidence of previous BC among these patients was the primary endpoint. Subsequent secondary correlation of clinical parameters was performed using uni- and multivariate logistic and cox regression models.
Results:
Allover, 463 female patients with LC were identified. The incidence of previous BC was 8.6% (40/463). Mean age was 64.1 years (SD ± 11.5) and was not different between patients with LC and LC/BC. Main histological LC subtype was adeno-carcinoma (64%; squamous cell, 23%; other, 13%). Stage (TNM-7) distribution was: I, 64.5%; II, 22%; III, 12.5%. Lobectomy was the preferred anatomical resection and mean hospital stay was 8.3 days. Complication rate was 7.6%. Recurrence free and overall survival will be presented at the conference. There were no statistical differences between patients with LC/BC and LC with regard to main clinical parameters and short term outcome.
Conclusion:
Due to improvements in breast cancer therapy, a reasonably number of patients developing subsequent lung cancer is observed. Short-term outcome of patients with LC/BC is similar to those with LC.
