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W. Weder
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MINI 14 - Pre-Clinical Therapy (ID 119)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:L. Fernandez-Cuesta, A.F. Gazdar
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2c-3c
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MINI14.14 - Suppression of Lung Cancer Growth by CD26/DPP4 Inhibitor (ID 1546)
10:45 - 12:15 | Author(s): W. Weder
- Abstract
- Presentation
Background:
Lung cancer is the most prominent cause of death among cancers, accounting for 1.38 million deaths worldwide annually. In spite of improved treatment in surgery, chemo- and radiation therapy, the five year survival is poor, being 69% for stage Ia and <5% for stage IV. The cure rates of current therapies are disappointing and did not significantly prolong long term survival. Surfactant protein (SP) in lung determines not only function of the organ, but also inflammatory reaction in an infectious condition. Recently Nishioka et al. showed that stimulated SP production in the orthotopic models of human lung cancer recruits inflammatory, type I macrophages in the tumor which decreased the size of the tumor. Also, Stephan et al. found increased productions of SPs in rat by CD26/DPP4 inhibitor treatment or CD26-/- animal. In our previous work, we found the activity of CD26/DPP4 of lung cancer from patients was four times higher than normal lung tissue from same patients (n=38). Therefore, we tested if pharmacological CD26/DPP4 inhibitor (Vildagliptin) inhibits lung cancer growth in various animal models.
Methods:
Mouse lung cancer cell line (Lewis Lung Carcinoma (LLC)) and human lung adenocarcinoma cell line, H460, were used to develop syngeneic (C57BL6: n=8) or xenogeneic (CD1-nude: n=20) tumor models by sc. injection. Tumor growth was represented by wet weight of tumor mass at harvest (4 weeks). BALB/c mouse strain (n=12) was used to induce lung cancer by Urethane (1g/kg) ip. Urethane injected mice were harvested 5 months after ip. Vildagliptin treatment was given in drinking water (0.2 mg/ml: 50mg/kg day) during the experimental course. Tumor nodules were counted macroscopically under surgical microscope. For histological assessment, HE, TUNEL, immunohistochemistry (IHC) of CD31, Ki67, CD3, Nkp46, and F4/80 were performed. The expression of surfactant protein C (SP-C) was detected by western blotting.
Results:
Vildagliptin treatment significantly reduced the size of tumor developed by lung cancer cell line injection (p<0.05 for both). Tumor induced by Urethane ip. in BALB/c mice was less incident by Vildagliptin treatment (40%: 2/5 mice) than control (100%: 7/7) group. The number of tumor nodule per mouse was also significantly reduced by Vildagliptin compared to control (p<0.05). Beside tumor weight, there was no difference in HE, TUNEL stain, and IHCs of CD31, Ki-67, CD3, and Nkp46. However we found significantly increased numbers of macrophages (F4/80) in the tumors induced by lung cancer cell line injection (p<0.05 for both) along with increased expression of SP-C in lung cancer cell lines in vitro.
Conclusion:
Inhibition of CD26/DPP4 by Vildagliptin decreased lung cancer growth in the models of mouse and human lung cancer cell lines and increased infiltrating macrophages within tumors. Furthermore, there was increased expression of SP-C by Vildagliptin treatment found in lung cancer cell lines. This finding suggests that surfactant production in lung cancer is induced and potentially activates macrophages against lung cancer by CD26/DPP4 inhibitor, Vildagliptin.
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MS 11 - New Approaches to Combined Modality Therapy for Stage III Disease (ID 29)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:D. Jablons, J.P. Van Meerbeeck
- Coordinates: 9/08/2015, 14:15 - 15:45, 605+607
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MS11.02 - Future Role of Surgery (Timing, Patient Selection, and New Techniques) (ID 1897)
14:15 - 15:45 | Author(s): W. Weder
- Abstract
- Presentation
Abstract:
The optimal management of locally advanced NSCLC is discussed controversially and depends from various aspects including the extend of N2 disease and/or T-stage as well as the patients risk profile and preference and the institutional experience. Therefore existing guidelines need a balanced modification during the tumorboard taking into account the different aspects relevant for the patient’s outcome and hence to define the best individualized treatment. Due to the lack of fully convincing randomized trials and the diversity of phase II studies and especially the heterogeneity of the study population, it is not surprising that the available evidence is interpreted differently and discussed controversially. Survival data may differ widely between studies and an explanation is often elusive. Patient selection is among other factors the key for differences in outcome. Unfortunately N2 disease is often imprecisely described. Several authors have proposed that N2 disease should be divided into subgroups. The question, whether N2 disease is resectable, cannot be answered easily in borderline situations since several co-founding factors play a role. The question includes at least four different aspects. The first aspect is resectability. The surgeon has to answer if the affected lymph nodes are completely removable. This question is a prerequisite and is typically answered by analysing images especially the CT or PET/CT by an experienced surgeon. The second and even more critical aspect relates to the question if local resection is useful for the patient since N2 disease may be the tip of an iceberg and indicate more than just locally advanced disease and rather a disease with systemic spread of tumor cells to other organs. The third aspect is the response rate of the tumor and mediastinal lymph nodes to neoadjuvant chemo- or chemo-radiotherapy. Finally the fourth consideration has to take into account the risk benefit ratio for the patient regarding the treatment. It is relevant for the decision making to evaluate to what risk the patient is exposed when a lobectomy or pneumonectomy is performed after neoadjuvant therapy. There are subgroups in stage IIIA (N2) which can be defined in which treatment recommendations are agreed among most oncologists, surgeons and radiotherapists. Microscopic N2 found unexpectedly during surgery and a radical resection of the tumor as well of the lymph nodes is possible and tolerated by the patient, surgery should be completed and adjuvant therapy is recommended. On the other hand in cases of bulky multilevel N2 at initial diagnosis and especially persistent after neoadjuvant therapy, surgery is not generally indicated since the patient will not experience a profit. The main controversy occurs in cases with initially diagnosed N2 disease at either a single or in some adjacent stations but surgically resectable. These patients are recommended to undergo neoadjuvant chemo- or chemo-radiotherapy followed by surgery most cases but direct surgery followed by adjuvant treatment is justified in single station N2 without extranodal disease. Definitive chemo-radiotherapy is reserved for those who are not completely resectable or with a high perioperative mortality. In general, these patients require a lobectomy with a complete mediastinal lymphadenectomy. In locally advanced stages, many surgeons still prefer to do these operations though a thoracotomy and in only a smaller percentage of patients can be operated minimal invasively by VATS. The invasiveness of the approach (VATS or open) is in any case of less importance than the completeness of the resection. Pneumonectomy should be avoided whenever possible and reconstructive techniques with bronchial-and or vascular reconstructions (sleeve resections) should be considered. These techniques can be done safely, even after induction chemo-or chemoradiotherapy. However, there are clear situation, when a pneumonectomy is necessary to achieve a complete resection and this should be considered, when the patient tolerates it functionally. Treatment of patients with locally advanced lung cancer is a challenge and requires the expertise of specialists from each discipline who respect the benefit and limitations of each individual technique in order to define the best individual treatment.
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ORAL 14 - Biology 2 (ID 112)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:T. Nakano, P. Baas
- Coordinates: 9/07/2015, 16:45 - 18:15, 702+704+706
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ORAL14.05 - Intracavitary Cisplatin-Fibrin After Resection of Malignant Pleural Mesothelioma (ID 1165)
16:45 - 18:15 | Author(s): W. Weder
- Abstract
Background:
Local tumor recurrence is very frequent after resection of malignant pleural mesothelioma (MPM). Intracavitary chemotherapy has been shown to be a promising approach to improve local tumor control. Here, we present the results of a phase-I-dose-escalation trial with intracavitary application of cisplatin-fibrin after surgical tumor resection.
Methods:
Altogether 12 patients (75% IMIG stage III-IV) were treated with 4 different dose levels of cisplatin (11, 22, 33 and 44mg/m[2] body surface area (BSA)). Eight patients of 22, 33 and 44mg/m[2] groups received previous induction treatment with intravenous cisplatin/pemetrexed. Cisplatin-fibrin was sprayed on the surface of chest wall, diaphragm, mediastinum and lung after pleurectomy/decortication (P/D). Blood was taken before surgery and at several time points after the treatment. Tissue sampling was conducted before and at 90 minutes after the administration. Cisplatin levels were measured by inductively coupled plasma sector field mass spectrometry.
Results:
Serum cisplatin kinetics and AUC0-120 are depicted in figure 1. Induction intravenous chemotherapy contributed to >50% of total serum cisplatin levels compared to cisplatin-fibrin (figure 1B). The median AUC0-24 of the 3 patients in the highest dose level (44mg/m[2]BSA) including predoses from induction chemotherapy reached 23h*µg/g, which is still below the suggested renal toxicity risk level, 25h*µg/g (Royer 2008). Our serum cisplatin AUC levels stayed far below levels reported after intrapleural perfusion (approx. 89h*µg/g (Ried 2013)). Local cisplatin concentration in tissues varied from 12-133 (median: 36.5µg/g) and did not seem to be dose dependent. No dose limiting toxicity due to cisplatin was observed. Major morbidity was observed in 4 patients (33%). 30day- and 90day-mortality was 0%. The median follow up after surgery was 11 months (range: 5-28 months). In 8 patients receiving 11, 22, 33 mg/m[2]BSA, relapse was detected after a median freedom from recurrence (FFR) of 8 months (95% confidence interval (CI): 1-14 months). In three patients with early IMIG stage (I and II), no sign of relapse was observed at 28, 8 and 6 months after the treatment (11, 44, 44 mg/m[2]BSA, respectively). The last patient (44mg/m[2]BSA) with IMIG stage III tumor currently shows no sign of recurrence at 5 months after surgery. Figure 1
Conclusion:
The administration of intracavitary cisplatin-fibrin as high as 44mg/m[2]BSA is safe after P/D, also in combination with induction chemotherapy. Tissue cisplatin concentration was high whereas no dose limiting toxicity due to systemic distribution was detected. A confirmation of the safety and efficacy of the highest dosage, 44 mg/m[2]BSA, in a phase II trial is warranted.
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ORAL 37 - Novel Targets (ID 146)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:S.S. Ramalingam, E. Thunnissen
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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ORAL37.05 - Prevalence and Clinical Association of MET Gene Amplification in Patients with NSCLC: Results from the ETOP Lungscape Project (ID 444)
16:45 - 18:15 | Author(s): W. Weder
- Abstract
Background:
The reported prevalence of MET gene amplification in non-small cell lung cancer (NSCLC) varies from 0-21% and clinical correlations are emerging slowly. In a well-defined NSCLC cohort of the ETOP Lungscape program, we explore the epidemiology, the natural history of MET amplification and its association with MET overexpression, overall survival (OS), relapse-free survival (RFS) and time to relapse (TTR).
Methods:
Resected stage I-III NSCLC, identified based on the quality of clinical data and FFPE tissue availability, were assessed for MET gene copy number (GCN) and expression analysis using silver in-situ hybridization (SISH) and immunohistochemistry (IHC), respectively, on TMAs (MET and centromere-specific probes; anti total c-MET antibody, clone SP44; Ventana immunostainer). MET amplification was defined as MET/centromere ratio ≥2 with average MET GCN ≥4, high MET GCN at two levels as ≥median CGN and ≥5 (irrespective of amplification) and MET IHC+ as 2+ or 3+ intensity in ≥50% of tumor cells. Sensitivity analysis to define the amplification’s thresholds was also performed. All cases were analysed at participating pathology laboratories using the same protocol, after successful completion of an external quality assurance (EQA) program.
Results:
Currently 2709 patients are included in the Lungscape iBiobank (median follow-up 4.8 years, 53.3% still alive). So far, 1547 (57%) have available results for MET GCN with amplification detected in 72 (4.7%; 95%CI: 3.6%, 5.7%) and high MET GCN (≥5) in 65 (4.2%; 95%CI: 3.2%, 5.2%). The median value of average MET GCN per cell is 2.3. IHC MET expression is available for 1515 (98%) of these cases, 350 (23%) of which are MET IHC positive [170 cases (49%) 3+, 180 (51%) 2+]. The median age, for the cohort of 1547 patients, is 66.2 years, with 32.8% women, and 13.5%, 29.7%, 54% never, current, former smokers, respectively. Stage distribution is: IA 23.6%, IB 24.6%, IIA 17%, IIB 12.1%, IIIA 20.9%, IIIB 1.8%, while 52.7%, are of adenocarcinoma and 40.0% of squamous histology. MET amplification and high MET GCN (≥5) are not significantly associated with any histological tumor characteristics or stage (multiplicity adjusted alpha: 0.005). High MET GCN (≥2.3) is less frequent in current smokers (38.3% vs. 55.6% for former or non-smokers, p<0.001). MET amplification and high MET GCN are significantly associated with IHC MET positivity (p<0.001 in all cases). MET amplification is present in 9.7% of IHC MET+ vs 3.1% of IHC MET- patients and high MET GCN (≥5) in 8.6% of IHC MET+ vs 2.8% of IHC MET- patients. MET amplification ranges from 0 to 16% between centers, while high MET GCN (≥5) and (≥2.3) from 0% to 12%, and 11.8% to 98.9%, respectively. MET amplification and both levels of high MET GCN are not associated with OS, RFS or TTR.
Conclusion:
The preliminary results for this large, predominantly European, multicenter cohort demonstrate that MET amplification assessed by SISH prevails in 4.7% of NSCLC, is associated with strong MET expression, and has no influence on prognosis. The large inter-laboratory variability in GCN despite EQA efforts may highlight a critical challenge of MET SISH analysis in routine practice.
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ORAL 40 - Biology 1 (ID 154)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:C. Brambilla, R. Bueno
- Coordinates: 9/09/2015, 16:45 - 18:15, 702+704+706
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ORAL40.06 - Sarcomatoid Differentiation During Progression of Malignant Pleural Mesothelioma (ID 1161)
16:45 - 18:15 | Author(s): W. Weder
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is a highly aggressive tumour with a high local recurrence rate and often a poor prognosis despite multimodal treatment. We evaluated the prognostic impact of morphological and immunohistochemical changes in sequential biopsies obtained from patients with MPM during disease progression.
Methods:
Tissue microarrays were constructed from paraffin-embedded tissue samples of 36 MPM patients (26 epithelioid, 6 biphasic and 4 sarcomatoid) taken before induction-chemotherapy, during surgery and at the time point of tumour recurrence. Immunohistochemical staining for calretinin, cytokeratin 5/6 (CK5/6) and Wilm’s tumor-1 (WT-1) as well as the biomarkers mesothelin, osteopontin, and fibulin-3 was performed, and staining intensity and percentage of positively stained tumour cells scored semi-quantitatively. The results were correlated with clinico-pathological characteristics of the patients including overall survival (OS). To determine the prognostic value of the markers at the different time points, a multivariate analysis including all factors that were significant in univariate analysis was performed.
Results:
In 28% of patients with epithelioid or biphasic MPM, a transition towards biphasic or sarcomatoid growth pattern during disease progression was observed (Figure 1). This dedifferentiation was associated with significantly decreased immunoreactivity for WT-1 (p=0.03), calretinin (p=0.005), mesothelin (p=0.01) as well as a shorter OS (p=0.04). Figure 1 Overall, patients with epithelioid or biphasic MPM in the diagnostic biopsy had a significantly better OS (29 months; 95% confidence interval (CI): range 27-32 months) in comparison to patients with sarcomatoid MPM (5 months; 95% CI: 3-7 months) (p<0.0005). On multivariate analysis, male gender (p=0.04) and high fibulin-3 (p=0.02) in the pre-chemotherapy samples were found to be associated independently with shorter OS.
Conclusion:
In patients with epithelioid or biphasic MPM, high fibulin-3 expression in pretreatment samples and gender are independent predictors of shorter OS. In up to one third of patients disease progression is accompanied by sarcomatoid differentiation, suggesting that factors such as molecular alterations involved in epithelial-to-mesenchymal transition (EMT) are contributing to disease course and clinical outcome. Alternatively, induction chemotherapy might contribute to this transition by promoting selection and outgrowth of therapy resistant tumor cells. Eventually, the different tumor biology of this subgroup of patients may be taken into account for the consideration of alternative patient handling.
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P1.05 - Poster Session/ Prevention and Tobacco Control (ID 215)
- Event: WCLC 2015
- Type: Poster
- Track: Prevention and Tobacco Control
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.05-004 - Smoking Prevention Intervention with School Classes at a University Hospital by Thoracic Surgeon and Pulmonologist (ID 901)
09:30 - 17:00 | Author(s): W. Weder
- Abstract
Background:
Smoking prevention in schoolchildren with the aim to inform and prevent smoking initiation has been widely studied and has shown variable results. Interventions provided by physicians in a hospital setting have been rarely reported. Here we show the feasibility and gain of knowledge of our smoking prevention project in a hospital setting.
Methods:
Interventions performed from November 2009 - December 2014 were evaluated. Overall 790 children participated in our preventive intervention. A 7-item questionnaire was provided to the school classes (Grades 6 to 10) before and after a two-hour smoking prevention intervention consisting of anatomical models, oral presentations, videos, patient interviews and hands-on lung function tests. The goal was to show the anatomical and physiological basics as well as age-based information about the harms of smoking. During the intervention the children have been motivated to be actively involved. Class selection has been performed for groups of children in a highly vulnerable phase of age before smoking initiation.
Results:
The baseline questionnaire was completed by 768 children, the one after intervention by 719. The knowledge about which organs are affected by smoking increased from 7.1-99.3% to 64.5-99.5% (p<0.01). While only 58.9% knew that only a minority of people is able to quit smoking successfully, 96.3% answered the question correctly after intervention (p<0.001). Prior to the intervention only 75.6% believed that minor tobacco consumption is not damaging which increased to 87.8% after the teaching session (p<0.05). Smoking hookah was believed to be less harmful than cigarettes by 32.2% of children decreasing to 8.3% after the intervention (p<0.001).
Conclusion:
Information on health effects provided by lung specialists in the hospital leads to a statistically significant increase in knowledge as assessed by a short questionnaire. The intervention is feasible and well received. This kind of interventions might help to prevent schoolchildren from smoking in a highly vulnerable phase of age.
