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W. Weder

Moderator of

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    PC01 - Pro Con Session: Invasive Mediastinal Staging for N2 Disease (ID 323)

    • Event: WCLC 2016
    • Type: Pro Con
    • Track: Radiology/Staging/Screening
    • Presentations: 4
    • Now Available
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      PC01.01 - Introduction & Vote (ID 6872)

      H. Prosch

      • Abstract
      • Slides

      Abstract not provided

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

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      PC01.02 - Invasive Staging and Restaging (Now Available) (ID 6594)

      C. Dooms

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The aim of mediastinal staging is to exclude with the highest certainty and the lowest morbidity patients with mediastinal nodal disease. The concepts of decision analysis and Bayes’ theorem form the basis for a mediastinal staging strategy. The goal of the clinical staging strategy is to lower the post-test probability sufficiently so that it falls below a testing threshold, which ascertains the clinician that the result is accurate. The ESTS working group considers a rate of unforeseen mediastinal nodal disease at the time of anatomic resection with lymph node dissection less than 10% as acceptable.[1] Contrast-enhanced multi-detector CT (computed tomography) scanning has an excellent spatial resolution but is an imperfect means of staging the mediastinum. A Cochrane review evaluated integrated positron emission tomography (PET) - CT for assessing mediastinal lymph node involvement in NSCLC.[2] The review showed that the accuracy of PET-CT is insufficient to allow management on PET-CT alone, but PET-CT can be used to guide clinicians in the next step (either a biopsy or direct to surgery). The suboptimal specificity of mediastinal lymph nodes positive on PET-CT requires a tissue confirmation. There are conditions where invasive staging is also mandatory despite a normal mediastinum on PET-CT as the prevalence of N2/N3 disease remains significant. These conditions include a primary tumour >3 cm, any central primary tumour, PET/CT hilar N1 disease, or low FDG uptake in the primary tumour.[1] Cervical Mediastinoscopy. A conventional cervical mediastinoscopy through a pretracheal suprasternal incision was introduced in 1959 and for decades considered the gold standard for invasive mediastinal nodal staging. Recently, a very large (N=721 patients; prevalence of mediastinal nodal disease 47 %) retrospective single center study reported on safety and efficacy of cervical mediastinoscopy performed by general thoracic surgeons.[3] There was no mortality, a low perioperative complication rate at 1.3 %, and an unexpected hospital (re)admission rate of 0.46 %. The sensitivity, negative predictive value and post-test probability were 0.90 (95% CI 0.87-0.92), 0.92 (95% CI 0.90-0.94), and 0.09 (95% CI 0.07-0.11), respectively. It is performed under general anesthesia and allows a full mapping of the ipsilateral and contralateral superior mediastinal lymph nodes. Since 1995, the use of video techniques has been introduced leading to video-assisted mediastinoscopy (VAM) clearly improving visualization and teaching. In addition, VAM allows bimanual dissection with possibilities to perform nodal dissection and removal rather than sampling or biopsy. The ESTS working group recommends performing VAM.[1] Endoscopic ultrasonography (EUS) en endobronchial ultrasonography (EBUS). In the last decade, the predominant role of cervical mediastinoscopy has been challenged by EUS and EBUS using a convex probe. When mediastinal nodal staging is required, systematic nodal sampling seems feasible but some primary choices have to be made. At least mediastinal nodal stations 4R, 4L and 7 should be sought. To avoid contamination, the order of sampling should begin at the level of N3 stations followed by N2 stations before N1. There is no evidence to suggest that sampling of all visible nodes in each nodal station is superior to a systematic nodal sampling of the largest measuring ≥5 mm or PET-positive node in each station. It must be stressed that EBUS cannot access the prevascular nodes (station 3a), the subaortic and para-aortic nodes (stations 5 and 6) as well as the paraesophageal and pulmonary ligament nodes (stations 8 and 9). Some of these nodes (stations 8 and 9) can however be reached from the esophagus. Therefore the use of the EBUS scope is extended to an esophageal exploration with EUS-B sampling of stations 4L, 7, 8 and 9. In terms of safety, EBUS and EUS have a low complication or serious adverse event rate of 1.4 and 0.3%, respectively.[4,5] The two staging strategies, surgical staging alone on the one hand and combined EUS/EBUS followed by surgical staging whenever endosonography was negative on the other hand, were compared in a pivotal randomized controlled trial (RCT).[6] It was concluded that invasive mediastinal nodal staging should start with combined linear endosonography, as the trial showed that a staging strategy starting with combined linear endosonography (EUS+EBUS) detected significantly (P=0.02) more mediastinal nodal N2/N3 disease compared to cervical mediastinoscopy alone, resulting in a significantly higher sensitivity of 0.94 (95%CI 0.85-0.98) compared to 0.79 (95%CI 0.66-0.88), respectively.[6] Another RCT suggested that EBUS-TBNA is the preferred primary procedure in combined linear endosonography for mediastinal nodal staging of resectable stage I-III lung cancer.[7] There is no RCT comparing combined EBUS-EUS(-B) to EBUS-TBNA alone for mediastinal nodal staging, but a recent meta-analysis suggested that the combined EBUS-EUS is more sensitive than EBUS-TBNA alone to detect mediastinal nodal disease.[8] The absolute increase in sensitivity of the combined approach compared to EBUS-TBNA alone depends on the quality of the EBUS-TBNA procedure, but published studies suggest an increase in sensitivity up to 10%. Overall, a confirmatory VAM is still warranted for the individual patient with a negative combined linear endosonography as this further lowers the post-test probability. This has been shown within ASTER for patients with clinical N2/3 disease on PET-CT (prevalence of mediastinal nodal disease 63%), as the post-test probability of a negative linear combined endosonography of 20% could be lowered to 5% by adding a cervical mediastinoscopy.[9] A recent prospective cohort study on clinical stage II lung cancer based on N1 disease on imaging (prevalence of mediastinal nodal disease 24%) showed that the post-test probability of a negative endosonography was 19%, which could be lowered to 9% by adding a cervical mediastinoscopy.[10] In conclusion, combined EBUS-EUS(-B) linear endosonography is the standard for initial baseline mediastinal nodal staging, but a VAM is still recommended after a negative (or incomplete) combined linear endosonography. Mediastinal restaging after induction therapy for locally advanced stage III NSCLC is an important prognostic factor. In the context of a 40-50% prevalence of residual mediastinal disease after induction therapy, a first cervical VAM as a restaging technique seems to be the most accurate method for nodal assessment.[1] Overall, limited literature reported a sensitivity and NPV for linear endosonography that is lower than for a first mediastinoscopy.

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      PC01.03 - No Invasive Staging Nor Restaging (Now Available) (ID 6595)

      E. Lim

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      PC01.04 - Discussion & Vote (Now Available) (ID 6873)

      W. Weder

      • Abstract
      • Presentation

      Abstract not provided

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Author of

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    MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA04.10 - Lung Cancer Growth is Suppressed by CD26/DPP4-Inhibition via Enhanced NK Cell and Macrophage Recruitment (Now Available) (ID 6143)

      W. Weder

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is the leading cause of death among cancers. There is broad evidence that immune cells are involved in the growth and development of these malignancies. CD26/DPP4 (dipeptidyl peptidase 4) is a transmembrane glycoprotein, that is constitutively expressed on hematopoetic cells, but also found on lung epithelial and endothelial cells. We found previously that the activity of CD26/DPP4 of lung cancer patients at early stages is four times higher than in normal tissue. Here, we tested if CD26/DPP4-inhibition is able to modulate lung cancer growth in mice.

      Methods:
      An orthotopic lung tumor model was employed by sc. injections of the mouse lung cancer (Lewis Lung Carcinoma (LLC)) and a human lung adenocarcinoma cell line (H460). These were developed in mice C57BL6 (n=18) and CD1-nude mice (n=20) respectively. The CD26/DPP4-inhibitor Vildagliptin was given in drinking water of 50mg/kg daily dose. Tumor growth was evaluated by wet weight of tumor mass at 2 weeks. Histological assessments included TUNEL, immunohistochemistry (IHC) of CD3, B220, F4/80 and NKp46. IL-10, Arginase, IL-12, NKp46, NK1.1, IFN-g, Granzyme, and Perforin 1 were analyzed by RT-PCR. In vitro analysis of surfactant protein (SP) expression in LLC and H460 were performed by western blotting. For a proof of concept, macrophage ablation was performed by clodronate-liposome during Vildagliptin treatment.

      Results:
      Vildagliptin treatment significantly reduced the tumor growth of both, LLC and H460 in mice. IHC showed macrophages (F4/80+) and NK cells (NKp46+) to be significantly increased by Vildagliptin within tumors, while TUNEL stain and IHC of T- and B cell infiltration did not show any difference. Gene expression levels of anti-inflammatory markers (IL-10, and Arginase) were unchanged, while the pro-inflammatory cytokine IL-12 was significantly elevated. The NK cell markers NKp46, NK1.1, IFN-g, Granzyme and Perforin 1 were significantly upregulated within the tumor by Vildagliptin, indicating that inhibition of CD26/DPP4 recruits NK cells into the tumor. Furthermore, we found enhanced SP expressions in lung cancer cell lines by Vildagliptin treatment in vitro. Macrophage ablation with clodronate-liposome in Vildagliptin treated mice reversed the tumor size significantly.

      Conclusion:
      The Inhibition of CD26/DPP4 decreased lung cancer growth in primary models of mouse and human lung cancer and increased inflammatory macrophages and NK cell cytotoxicity within those tumors. Furthermore, an increased expression of SP by Vildagliptin treatment in lung cancer cell lines suggests that surfactant production in lung cancer activates macrophages to fight against lung cancer via the recruitment of macrophages and NK cells.

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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
    • Now Available
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      OA02.03 - Circulating Fibroblast Growth Factor 18 is Elevated in Malignant Pleural Mesothelioma Patients - A Multi-Institutional Study (Now Available) (ID 5988)

      W. Weder

      • Abstract
      • Presentation
      • Slides

      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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    OA22 - Novel Trials and Biomarkers in Malignant Pleural Mesothelioma (ID 403)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 2
    • Now Available
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      OA22.06 - Refinement of the Prognostic miR-Score for Use in Diagnostic Specimens from Chemo-Naïve Malignant Pleural Mesothelioma Patients (Now Available) (ID 5045)

      W. Weder

      • Abstract
      • Presentation
      • Slides

      Background:
      A 6-microRNA signature (miR-Score, Kirschner et al 2015) was previously demonstrated to show high prognostic accuracy in a series of surgical specimens (with and without induction chemotherapy). In the present study we investigated these microRNAs in an independent cohort of MPM patients all treated with induction chemotherapy followed by extrapleural pneumonectomy (EPP). The main focus of the study was to evaluate the possible effects of induction chemotherapy on microRNA expression and to refine and validate the miR-Score for use in chemo-naïve diagnostic specimens.

      Methods:
      We identified a cohort of 120 MPM patients who received chemotherapy followed by EPP between 1999 and 2014 at University Hospital Zurich. At present microRNA analysis (RT-qPCR) has been carried out in 34 pairs of chemo-naïve (diagnostic biopsy) and chemo-treated (EPP) specimens. Paired-samples t-test was employed to determine differences in microRNA expression pre- and post-chemotherapy. Accuracy of the miR-Score in predicting a good prognosis (>20 months survival post-surgery) was evaluated by ROC curve analysis. In addition, binary logistic regression modelling was used to build a refined miR-Score.

      Results:
      Applying the miR-Score to chemo-naïve diagnostic specimens revealed an area under the ROC curve (AUC) of 0.65 (95% CI: 0.46-0.84), and the same analysis on the EPP specimens gave an AUC of 0.57 (95% CI: 0.37-0.77). Therefore, the accuracy of the miR-Score was lower than observed in the previous study. However, pairwise comparison of microRNA expression before and after chemotherapy showed that although not reaching statistical significance, the levels of several microRNAs were lower following induction chemotherapy. We next employed binary logistic regression modelling on microRNA levels in chemo-naïve tissue to determine whether a refined microRNA signature less susceptible to chemotherapy-induced changes could be created. A refined miR-Score consisting of miR-221 and miR-30e, the two microRNAs least affected by chemotherapy, achieved AUCs of 0.77 (95% CI: 0.61-0.94) and 0.80 (95% CI: 0.64-0.96) in diagnostic and EPP specimens, respectively. When applied to samples from the previous study, the refined score resulted in an AUC of 0.72 (95% CI: 0.54-0.90).

      Conclusion:
      This validation and refinement study has shown that the expression of several miR-Score microRNAs appears to be affected by standard chemotherapy. A refined miR-Score was generated which is less susceptible to the effect of chemotherapy and may have prognostic value when applied to diagnostic specimens. Further validation in additional paired samples and investigation of the effect of cisplatin, pemetrexed and gemcitabine on microRNA expression are ongoing.

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      OA22.07 - Correlation of CT Scan Based Tumor Volume Measurement to Actual Resected Tumor Volume - A New T-Factor? (Now Available) (ID 5958)

      W. Weder

      • Abstract
      • Presentation
      • Slides

      Background:
      Tumor volume has been reported to be a valuable prognosticator for malignant pleural mesothelioma (MPM) survival. We wanted to assess the precision of CT scan based preoperatively measured tumor volume when correlated to the actual resected tumor weight and tumor volume after pleurectomy/decortication.

      Methods:
      From 10/2012 – 06/2016 the tumor weight of surgery specimens was measured in 32 patients undergoing macroscopic complete resection by (extended) pleurectomy/decortication ((e)P/D). The median tumor weight of all patients was (n=32) 443g (95-783g). In all patients tumor volume was measured in the CT or PET-CT scans performed before surgery as described previously (Frauenfelder 2011). Tumor volume of the resected specimen was additionally measured in 21 patients. Relations between tumor weight, tumor volume at surgery, CT-volume, cT stage and pT stage were analyzed using Spearman rank correlation.

      Results:
      Median time between CT scan and surgery was 18 days (range 1-48). The analysis revealed a moderate correlation between CT tumor volume and weight (p=0.001, correlation coefficient 0.58, CT volume and tumor volume at surgery showed strong correlation (p=0.001, correlation coefficient 0.65). No significant correlation was observed between cT stage and tumor weight (p=0.1, correlation coefficient 0.31), but a moderate correlation between cT stage and CT volume (p=0.001, correlation coefficient 0.58) as well as specimen volume (p=0.008, correlation coefficient 0.58). There was a moderate correlation of tumor weight with pT stage (p=0.02, correlation coefficient 0.42), but no correlation of CT volume (p=0.1, correlation coefficient 0.31) as well as specimen volume with the pT stage (p=0.2, correlation coefficient 0.32). Figure 1



      Conclusion:
      The correlation between preoperatively assessed CT tumor volume and volume of the resected specimen showed a strong correlation. To assess the prognostic role of CT measured tumor volume a correlation to prognosis has to be performed before implementation as a new T-factor.

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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
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      P1.02-025 - Evaluation of NGS and RT-PCR Methods for ALK Assessment in European NSCLC Patients: Results from the ETOP Lungscape Project (ID 5001)

      W. Weder

      • Abstract

      Background:
      The reported prevalence of ALK rearrangement in NSCLC ranges from 2%-7%, depending on population and detection method. The primary standard diagnostic method is fluorescence in situ hybridization (FISH). Recently, immunohistochemistry (IHC) has also proven to be a reproducible and sensitive technique. Reverse transcriptase-polymerase chain reaction (RT-PCR) has been advocated and most recently the advent of targeted Next-Generation Sequencing (NGS) for ALK and other fusions has become possible. This is one of the first studies comparing all 4 techniques in resected NSCLC from the large ETOP Lungscape cohort.

      Methods:
      96 cases from the ETOP Lungscape iBiobank (N=2709) selected based on any degree of IHC staining (clone 5A4 antibody, Novocastra, UK) were examined by FISH (Abbott Molecular, Inc.; Blackhall, JCO 2014), central RT-PCR and NGS. H-score 120 is used as cutoff for IHC+. For both RT-PCR and NGS, RNA was extracted from the same formalin-fixed, paraffin-embedded tissues. For RT-PCR, primers were used covering the most frequent ALK translocations. For NGS, the Oncomine™ Solid Tumour Fusion Transcript Kit was used, allowing simultaneous sequencing of 70 ALK, RET and ROS1 specific fusion transcripts associated with NSCLC, as well as novel ALK translocations using 5’-3’ ALK gene expression ‘Imbalance Assay’.

      Results:
      NGS provided results for 90 cases, while RT-PCR for 77. Overall, 70 cases have results for all 4 methods, with fully concordant 60 (85.7%) cases (49 ALK-, 11 ALK+). Before employing the ‘Imbalance Assay', in 5 of the remaining 10 cases, NGS differs from the other methods (3 NGS-, 2 NGS+), while in the other 5, NGS agrees with RT-PCR in all, IHC in 2, and FISH in 1. Using the concordant result of at least two of the three methods as true negative/positive, the specificity and sensitivity of the fourth is 96/94/100/96% and 94/94/89/72% for IHC/FISH/RT-PCR/NGS, respectively (incorporating imbalance: NGS sensitivity=83%). Imbalance scores are presented here for 18 NGS- cases: 9 ‘NGS-/FISH+/IHC+’, 9 ‘NGS-/FISH-/IHC-‘. Among the ‘NGS-/FISH+/IHC+’, there is strong evidence of imbalance in 4 cases (score’s range: 0.0144-0.0555), uncertain in 5 (range: 0.0030-0.0087), and no evidence (scores≤0.0004) in the 9 negative cases.

      Conclusion:
      NGS is a useful screening tool for ALK rearrangement status, superior to RT-PCR when RNA yield is limited. When using NGS, it is critically important to integrate the 5’-3’ imbalance assay and to confirm with one or more additional methods in the ‘imbalance’ cases. Data further highlight the possibility of missing actionable rearrangements when only one screening methodology is available.

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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
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      P1.05-057 - Prediction of Early Recurrence in Patients with Stage I and II Non-Small Cell Lung Cancer Using FDG PET Quantification (ID 4872)

      W. Weder

      • Abstract

      Background:
      Although surgical resection remains the optimal treatment for early-stage NSCLC, up to 50% of patients with stage I and II relapse and die within 5 years after curative resection. Therefore prognostic markers are important as these patients might benefit from adjuvant therapy. The goal of this study was to evaluate established PET quantification metrics including: maximal standard uptake volume (SUV~max~), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) as prognostic markers for early recurrence and overall survival in resected early stage lung cancer.

      Methods:
      Between January 2003 and December 2010 182 surgically resected patients with stage I-II NSCLC who underwent 18 F FDG PET/CT less than one month prior to surgery have been evaluated. All patients had at least 5 years of follow-up. Cox proportional hazard model was used to determine the association between variables and survival respectively time to recurrence. For the multivariate analysis the following variables have been included: tumor size on CT, age tumor stage, histology, SUV~max~, TLG (for TLG~42%~ (threshold at 42% SUV~max~) and TLG~2.5 ~(cut-off at SUV 2.5) and MTV~42%~ and MTV~2.5~). To identify high-risk patients we used survival trees.

      Results:
      133 patients were included, 71 with adeno carcinoma, 62 with squamous cell carcinoma. TLG~2.5~ and MTV~2.5~ values have been a significant prognostic factor for recurrence (P<0.0001). Patients with a MTV2.5 above 42 cm[3] had a mean recurrence time of 0.8±0.9 years, while patients with MTV2.5 ≤ 42 cm[3 ]recurred within 2.8±1.3 years. Using the survival tree models TLG~42%~ has been the first choice variable for discriminating high risk patients for DOD (dead of disease) independent from histological type, whereas MTV~2.5~ has been the first choice for DOD in adeno carcinoma patients.

      Conclusion:
      TLG and MTV may be useful prognostic variables in stage I-II NSCLC depending on the tumor type. Using a cut-off at 42 cm[3 ]for early stage adenocarcinoma patients a high risk of recurrence within one year might be identified and adjuvant therapy following surgical resection could improve outcome for those patients.

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    P2.04 - Poster Session with Presenters Present (ID 466)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
    • Now Available
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      P2.04-029 - Primary Pulmonary Sarcoma: Risks and Optimal Surgical Treatment Options (Now Available) (ID 5652)

      W. Weder

      • Abstract
      • Slides

      Background:
      Primary pulmonary sarcoma (PPS) is a rare tumor among malignant lung neoplasms. We aimed to clarify the clinical characteristics and therapeutic outcomes of patients who underwent surgical resection for PPS and to discuss beneficial treatment and surgical options.

      Methods:
      We retrospectively reviewed the records of those who underwent surgical resection for primary pulmonary sarcoma in our institution between 1995 and 2014. Cases only with biopsy were excluded.

      Results:
      Twenty four patients were analyzed. Eighteen were male. Their ages ranged from 18 to 83 years (mean 57). Surgical procedures were pneumonectomy in 10, lobectomy in 11 and wedge resection in 3. Complete resection was achieved in 14. Pathological stage based on the 7th lung cancer TNM classification were stage I in 4, II in 12, III in 2, and IV in 5. Four patients had metastasis in lymph nodes. The pathological grades were G1 in 4, G2 in 5 and G3 in 15. Five patients had postoperative complications. Tumor recurrence was observed in 5. During the observation 12 patients died. 5-year overall survival was 50.1%. Adverse prognostic factors for overall survival were detected as (p=0.001), incomplete resection (p=0.014), advanced pathological stage (p=0.001), higher pathological grade (p=0.028), and tumor size more than 7cm (p=0.044).

      Conclusion:
      Our series of primary pulmonary sarcoma revealed that pneumonectomy, incomplete resection, advanced pathological stage, higher pathological grade, and tumor size were unfavorable factors for long survival. Although complete resection is essential for primary pulmonary sarcoma due to its poor prognosis, it is recommended to avoid pneumonectomy, if possible, and to consider conservative surgical approaches including sleeve lobectomy.

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    P3.01 - Poster Session with Presenters Present (ID 469)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P3.01-053 - Mouse Models of Primary Lung Cancer - A Thorough Evaluation (ID 6176)

      W. Weder

      • Abstract

      Background:
      Lung cancer is the most prominent cancer in human with the highest mortality rate among cancer patients in both genders nowadays. Several models of primary lung cancer research are in use, however, no systematic evaluation of optimal models is available. Here, we assess and reappraise the most robust models of primary lung cancer for their suitability of cancer evolution and targetability for new therapeutics.

      Methods:
      Three models of primary lung cancer were evaluated: (I) Carcinogen (urethane or diethylnitrosamine (DEN)) induced lung cancer model, established via three intraperitoneal (i.p.) injections to BALB/c and C57BL/6 mouse strains. Five and ten months after injections, mice were assessed for tumor incidence. Lewis Lung Carcinoma (LLC) cell line was employed for an orthotopic development of lung tumor in syngeneic mouse. The cell line was injected (II) intravenously (i.v.) or (III) subcutaneously (s.c.) to establish lung tumor models in 14 days. Tumor nodules and tumor necrosis were confirmed by microscopy. Immunohistochemistry (IHC) of markers of proliferation (p-Histone3, inhibitor of differentiation 1 (Id1), and Ki67), immune cells (CD4, CD8, B220, F4/80, and NKp46), vascular structure (CD31), stroma (alpha-actin) were performed for a finer characterization of the tumor.

      Results:
      Ten months after i.p. injections of carcinogens, we found that the urethane model stably induced tumor nodules (90%: 9/10) when compared to DEN (30%: 3/10). BALB/c strain was significantly more susceptible for the urethane induced tumor development compared to C57BL/6 strain. Injection of LLC cell line via i.v. developed diffuse lung tumor without metastasis to other organs. s.c. injection also stably developed single tumor nodule (~500mg). IHC revealed that all tumors were consistently positive for the proliferation markers, and F4/80+ cells and CD4+ cells infiltrated into tumors significantly more than CD8+, B220+, or NKp46+ cells. Heterogeneous distributions of CD31+ cells and alpha-actin+ cells were observed in overall tumor models.

      Conclusion:
      The urethane-induced lung tumor is reliable and reproducible with a high rate of development and seems superior to DEN induced tumor, but need a long time period to develop. In contrast, the i.v. and s.c. tumor models are established within short time ranges. The tumors developed by s.c. enable for the analysis of the tumor only without adjacent tissue bias. The involvement and characteristics of immune cells found within tumors were comparable across all models. Injections by i.v. or s.c. of cell line to mouse can be considered as an alternative yet convenient model to develop various different types of lung cancers.

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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: 2
    • Now Available
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      P3.03-001 - Targeting Cullin Ubiquitin Ligase Leads to Growths Arrest in Malignant Pleural Mesothelioma Cells (Now Available) (ID 5486)

      W. Weder

      • Abstract
      • Slides

      Background:
      Mutation of the tumor suppressor gene NF2 was detected in 30-40% of malignant pleural mesothelioma (MPM) patients. NF2 suppresses tumorigenesis in part by inhibiting Cullin4 ubiquitin ligase. Cullin4A (CUL4A) gene amplification and its’ overexpression has been detected in MPM cell lines and tumors. We hypothesized that cullin4 is a potential treatment target for MPM. Cullins’ activity can be blocked by the inhibition of neddylation, a post-translational modification for cullins. In this study we assessed the efficacy of pevonedistat, an inhibitor of protein neddylation.

      Methods:
      Thirteen MPM cell lines and 3 MPM primary cells grown in monolayer (2D) were employed to assess the efficacy of pevonedistat in vitro compared to normal mesothelial cells, using MTT assay. The expression of cullins was assessed by quantitative real time PCR and western blot. Cell cycle was analyzed by flow cytometry. Four cell lines were cultured in multicellular spheroid (3D) format and measured for viability by acid phosphatase assay.

      Results:
      Five MPM cell lines overexpressing CUL4A are highly sensitive to pevonedistat (figure1). The treatment induced G2 cell cycle arrest and accumulation of cells containing >4N DNA content, representing cells undergoing DNA re-replication. DNA re-replication is known to be mediated by the accumulation of a DNA replication licensing factor, CDT1. Indeed, higher CDT1 accumulation was detected in the sensitive compared to the resistant cell lines. All primary cells showed no CUL4A overexpression compared to normal mesothelial cells, nonetheless 2 of them were sensitive to pevonedistat. Interestingly, these cells exhibited higher levels of neddylated (activated) CUL4A and higher CTD1 accumulation following the treatment. Cells lines overexpressing CUL4A remained sensitive to pevonedistat when grown in 3D spheroids. Figure 1



      Conclusion:
      Inhibition of cullins by pevonedistat induced growth arrest preferentially in MPM cells overexpressing CUL4A in 2D and 3D cultures. The major mechanism seems to be mediated by DNA re-replication induced by CDT1 accumulation.

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      P3.03-044 - Is Toxicity Increased by Adding Intraoperative Chemotherapy to Preoperative Induction Chemotherapy for Mesothelioma Patients? (Now Available) (ID 5945)

      W. Weder

      • Abstract
      • Slides

      Background:
      Intracavitary application of chemotherapy after mesothelioma resection is intended to prevent local recurrence. In the present study, we compared hematological and renal toxicity of patients treated with or without additional intracavitary cisplatin-fibrin after (extended) pleurectomy/decortication ((e)P/D) and previous i.v. induction chemotherapy with cisplatin/pemetrexed (CTX).

      Methods:
      Hemoglobin values, platelet count as well as urea, creatinine, sodium, potassium and magnesium values of 32 patients treated with (e)P/D were compared to the first five patients receiving 44mg/m[2] BSA intracavitary cisplatin-fibrin in our INFLuenCe-Meso phase II trial (www.clinicaltrial.gov NCT01644994). The median time between last cycle of CTX and surgery was 6 weeks (1-14 weeks). The blood values were measured on postoperative day (POD) 1 to 5, 7, 10 and 14 if available. For statistical comparison Mann-Whitney U test was used.

      Results:
      No significant difference between the 2 groups was observed in the preoperative baseline blood samples. On POD3 hemoglobin dropped significantly more in patients with cisplatin-fibrin application (Figure 1A). However, the use of blood transfusion was not significantly different in both groups. Also sodium, potassium (Figure 1B) and magnesium levels were significantly lower in the study patient group. Disorders in electrolytes were however never reflected in clinical symptoms and reached only in 3 patients a CTCAE level ≥3. There was no significant difference in platelet count, urea and creatinine levels. Figure 1



      Conclusion:
      The present analysis shows that additional intracavitary cisplatin-fibrin after eP/D and previous i.v. induction chemotherapy with cisplatin/pemetrexed can lead to electrolyte disorders and drop in hemoglobin concentration. However, none of the mentioned laboratory findings had a clinically significant impact on the patients’ postoperative course.

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    PC01 - Pro Con Session: Invasive Mediastinal Staging for N2 Disease (ID 323)

    • Event: WCLC 2016
    • Type: Pro Con
    • Track: Radiology/Staging/Screening
    • Presentations: 1
    • Now Available
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      PC01.04 - Discussion & Vote (Now Available) (ID 6873)

      W. Weder

      • Abstract
      • Presentation

      Abstract not provided

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    SC08 - IASLC- ESTS Joint Symposium: The Borderline Patient (ID 332)

    • Event: WCLC 2016
    • Type: Science Session
    • Track: Pulmonology
    • Presentations: 1
    • Now Available
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      SC08.02 - Emphysema as a Limiting Factor for Lung Resection: How Far We Can Go? (Now Available) (ID 6629)

      W. Weder

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    WS04 - Mesothelioma Workshop (Ticketed Session) (ID 416)

    • Event: WCLC 2016
    • Type: Workshop
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 12/04/2016, 08:00 AM - 11:00 AM, Stolz 2
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      WS04.03 - Debate - Induction Chemotherapy is Better than Postoperative Adjuvant Therapy for Early Stage Pleural Mesothelioma (Now Available) (ID 6985)

      W. Weder

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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