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Walter Weder
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MS 08 - Novel Treatment for Mesothelioma (ID 530)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Mesothelioma
- Presentations: 1
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MS 08.01 - Today's Challenges in MPM Care (ID 7675)
15:45 - 16:00 | Presenting Author(s): Walter Weder
- Abstract
- Presentation
Abstract not provided
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P1.02 - Biology/Pathology (ID 614)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.02-005 - Solving the Interfering Problem of Tissue Embedding OCT Compound in Activity Based Multiplex Profiling of Tyrosine Kinase Substrates (ID 9485)
09:30 - 09:30 | Author(s): Walter Weder
- Abstract
Background:
The analysis of clinically relevant human tissue preserved in optimal cutting temperature (OCT) medium with activity based proteomic approaches are promising for the discovery of novel druggable disease biomarkers for the diagnosis, prognosis and prediction of response to therapeutic interventions. Nonetheless, and for many different proteomic approaches, there are important signal interferences observed in the presence of the OCT compound.
Method:
We tested activity based multiplex profiling tyrosine kinase substrates in a large batch of neoplastic and non-neoplastic lung resection specimen embedded with or without OCT. Since January 2003 we collected fresh frozen matched pairs from malignant adenocarcinoma and non-neoplastic lung biopsies. In 2007, we started to embedded all our samples in OCT. We obtained all clinical characteristics of 47 patients with early TNM stage 1 lung adenocarcinoma. We observed significant differences in overall phosphorylation levels and searched for reasons explaining such a large effect.
Result:
We ruled out the implication of either short versus long storage time after sample extraction or of nonhomogeneous batch processing of samples. We documented that the clear downward shift in overall phosphorylation levels coincided with the introduction of OCT as an improved embedding medium for resection specimen. For all the kinomes extracted, we developed a corrective procedure where a median centering was performed on the values of each peptide, separately for the with or without OCT samples.
Conclusion:
We applied corrective filtering of data to the multiplex profiling approach of well characterised tyrosine kinase substrates obtained in lung resection specimen embedded with or without OCT. With the OCT correction parameters applied, the quantitation of molecular prognosis signature based on tyrosine kinase activity differences found in lung adenocarcinoma resection specimens may result in the identification of novel targets for future anti-lung cancer therapies.
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P1.02-015 - Comparison of Study Models of Lung Cancer (ID 9318)
09:30 - 09:30 | Author(s): Walter Weder
- Abstract
Background:
Lung cancer is the most prominent cancer in human with high mortality rate. Although chemo-radiation therapies have been improved, the patient survival is still poor. Thus, not only developing therapeutic medications, but also biomarkers of early diagnosis have been desired. Several models of primary lung cancer research are in use, however, systematic evaluation and characterization of models are required to have suitability and relevance based on study aims. To provide research environment for lung cancer, we reappraise relevant models for lung cancer.
Method:
Three concepts of primary lung cancer models were evaluated: (I) Urethane induced lung tumor. (II) Cell line induced tumor model via intravenous (iv) or subcutaneous (sc) injection. (III) ex vivo 3D primary cell culture model. 20 weeks after urethane injection, the animals were harvested to analyze tumor incidence and tumor immunity. Lewis Lung Carcinoma (LLC) cell line was employed for the orthotopic development of lung tumor in 2 weeks after the injection. Hanging drop method was used for the 3D culture of primary cells from LLC sc induced tumor. Immunohistochemistry (IHC) of proliferation markers (pH3 and Ki67), tumor immunity (CD4, CD8, B220, F4/80, NKp46, and PDL-1) were performed for a finer characterization of tumors.
Result:
Urethane and iv injection of LLC cell line developed heterogeneously distributed tumors in lung. sc injection stably developed single tumor nodule. 3D cultured primary cells formed spheroids within 5 days. IHC revealed that all tumors were consistently proliferating with less extend in urethane and 3D model. F4/80[+ ]cells and CD4[+] cells infiltrated into tumors significantly more than CD8[+], B220[+], or NKp46[+] cells. T cell populations (CD4[+] and CD8[+]) were much more prominent in LLC iv model than other models. Interestingly the expression of PDL-1 was found only in 3D model.
Conclusion:
The urethane-induced primary lung tumor is reliable with a high rate of development, but needs longer time period to develop tumor compared to iv and sc models. iv injection model develops lung tumor in the original location. With relatively more convenience, sc model allows the analysis of tumor without adjacent tissue bias. 3D primary cell culture model enable for conferring characterization of individual tumor and strategic design of therapy, namely personalized medicine. 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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P1.09 - Mesothelioma (ID 695)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.09-009 - Evaluation of a Combined MicroRNA-Clinical Score as Prognostic Factor for Malignant Pleural Mesothelioma (ID 9245)
09:30 - 09:30 | Author(s): Walter Weder
- Abstract
Background:
In 2015, a 6-microRNA signature (miR-Score, Kirschner et al 2015) was demonstrated to show high prognostic accuracy in a series of surgical specimens (with and without induction chemotherapy) from patients with malignant pleural mesothelioma. In-depth analysis of matching pre- and post-chemotherapy tissue specimens has recently shown that a refined 2-miR-Score appears more suitable for use in diagnostic chemo-naïve specimens (Kirschner et al, WCLC 2016). Here, in addition to continued validation, we also aimed to further improve the prognostic accuracy by combining the 2-miR-Score with known clinical prognostic factors.
Method:
Binary logistic regression modelling was used to build a combined score consisting of the 2-miR-Score and the clinical prognostic factors age (<60 years vs >60 years at diagnosis), gender and histological subtype (epithelioid vs non-epithelioid). In addition, microRNA analysis (RT-qPCR) was performed in an additional 33 pairs of chemo-naïve (diagnostic biopsy) and chemo-treated (EPP) specimens. Accuracy of the investigated scores in predicting a good prognosis (>20 months survival post-surgery) was evaluated by ROC curve analysis.
Result:
Combining the refined 2-miR-Score with the clinical prognostic factors histological subtype and age at diagnosis, increased the overall accuracy of the 2-miR-Score in both chemo-naïve diagnostic (AUC=0.80; 95% CI: 0.65-0.95) and post-chemotherapy (AUC=0.86; 95% CI: 0.73-0.98) specimens. Addition of gender as clinical prognostic factor, did not result in further increases, hence this factor was not included in the combined score. Investigation of an additional set of 33 matched pairs of chemo-naïve and post-chemotherapy tissue samples, confirmed the improved prognostic accuracy of the combined score, with AUCs of 0.76 (95% CI: 0.59-0.92) and 0.79 (95% CI: 0.64-0.95) for chemo-naïve and post-Chemotherapy specimens, respectively. Furthermore, addition of the clinical factors resulted in an increase in specificity of the prognostic score from previously 55-65% to now 65-75%, while keeping sensitivities at the previous levels of 75-85%. Importantly, the combined microRNA-clinical Score did not only outperform the 2-miR-Score, but also the clinical factors alone.
Conclusion:
This validation has confirmed the prognostic potential of the novel 2-miR-Score. Furthermore, addition of known clinical prognostic factors was shown to result in a combined Score with increased prognostic accuracy. In addition to continued validation, in currently ongoing analyses we are also investigating combining the 2-miR-Score with our previously proposed multimodality prognostic score (MMPS; Opitz et al 2015).
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P1.17 - Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies (ID 703)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.17-016 - Immunohistochemical Markers as Prognostic Factors in Malignant Thymic Epithelial Tumors (ID 10338)
09:30 - 09:30 | Author(s): Walter Weder
- Abstract
Background:
Thymic epithelial tumors (TET) are rare neoplasms with inconsistent treatment strategies. When researching for molecular pathways to find new therapies, the correlation between specific molecular markers and outcome has been rarely investigated. The aim of this study was to investigate the correlation between survival, metastatic potential and invasiveness of aggressive subtypes of TET and immunohistochemical markers.
Method:
We performed retrospective analysis on patients with WHO type B2/B3 mixed type thymoma (MT), thymoma type B3 (B3) and thymic carcinoma (TC) who underwent surgery from 1998 to 2013. Overall survival (OS), disease-free survival (DFS), progression-free survival (PFS) and metastasis-free survival (MFS) were examined. Tumor specimens were stained using a tissue microarray (TMA) (CD117, CD5, p63, p40, p21, p27, p53, Bcl-2, Ki67, podoplanin, synaptophysin, PTEN and Pax8). Invasive behavior of primary tumors and the presence of extrathoracic metastases were assessed.
Result:
In 23 patients included into this study (four MT, ten B3, nine TC), we found (I) p21 expression in the cytoplasm significantly correlated with a decrease of OS (P=0.016), PFS (P=0.034) and MFS (P=0.005); (II) MFS was significantly shorter when the combination of p21-low p27-low p53-high was present (P=0.029); and (III) nuclear p27 (P=0.042), Ki-67 (P=0.024) and podoplanin (P=0.05) expression correlated with the presence of extrathoracic metastases.
Conclusion:
The main finding of this study is that cytoplasmic p21 expression negatively influences the outcome of malignant TETs and correlates with metastatic activity. Additionally, selected immunohistochemical markers correlate with the distant metastatic potential of TETs. These results may contribute to the stratification of diagnosis and improvement of treatment strategies for thymic malignancies.
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-036 - The Expression Pattern of CD26/DPP4 in Human Lung Cancer (ID 9319)
09:30 - 09:30 | Author(s): Walter Weder
- Abstract
Background:
Lung cancer is the leading cause of death among cancers. Despite improved surgical and novel radiation improvements, the overall prognosis remains poor. CD26/dipeptidyl peptidase 4 (DPP4) is a ubiquitously expressed transmembrane exopeptidase on the cell surfaces of many different cells including malignancies of breast, colon, and mesothelioma. Phase I data in mesothelioma with a specific antibody showed tolerability in mesothelioma patients.Our group found previously that the activity of CD26/DPP4 of lung adenocarcinoma (Adeno-CA) patients is four times higher than in normal tissue and the inhibition of CD26/DPP4 decreased the growth of lung tumors in experimental models. These data prompted us to analyze the expression of CD26/DPP4 in samples from lung cancer patients to unravel the role of CD26/DPP4 as a biomarker for lung cancer and a target for inhibition to reduce lung cancer burden. burden.
Method:
To identify CD26/DPP4 by immunohistochemistry (IHC), we tested four antibodies from Abcam, R/D systems, and Cell signaling technology on multi-organ tissue micro array (TMA) and human lung Adeno-CA cell lines (A549, H460, Gon8, Mai9) derived from advanced stage (IV) of human Adeno-CA. We selected the antibody from Cell signaling technology against CD26/DPP4. For the analysis of CD26/DPP4 by IHC in lung cancer samples, TMAs constructed from non-small cell lung cancer patients were used. The cohort consisted of 475 patients (Adeno-CA: 223; Squamous carcinoma: 252). The intensity of the staining was scored from 0 to 3 in a blinded manner. To quantify CD26/DPP4 in the supernatant of human lung Adeno-CA cell lines in vitro, ELISA was performed.
Result:
IHC scores revealed that Adeno-CA expresses significantly more CD26/DPP4 compared to squamous carcinoma (p<0.0001). Consistent with our previous findings, early stage cancer (IA) scores significantly higher than other stages IIB (p=0.0012), IIIA (p=0.0019), and IV (p=0.02) among Adeno-CA samples. We could not find CD26/DPP4 expression on human Adeno-CA cell lines by IHC, but the secretion of the protein in supernatant stays high (A549: 20pg/ml; H460: 161pg/ml; Gon8: 74pg/ml; Mai9: 648pg/ml).
Conclusion:
CD26/DPP4 expression was significantly higher at early stages of Adeno-CA samples when compared to advanced stages, supporting our previous findings. From the human cell line data, we suggest that advanced cancer secretes CD26/DPP4 more actively than early stage cancers. CD26/DPP4 seems to be a substantial target for inhibition of human Adeno-CA.
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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-056 - SAKK 16/14 – Perioperative Anti-PD-L1 Antibody Durvalumab in Patients with Stage IIIA(N2) Non-Small Cell Lung Cancer (NSCLC) (ID 7902)
09:30 - 09:30 | Author(s): Walter Weder
- Abstract
Background:
Improving the outcome of locally advanced non-small cell lung cancer (NSCLC) is one of the major challenges in thoracic oncology. SAKK substantially contributed to establish a standard of care for patients with stage III NSCLC: The trial SAKK 16/96 established neoadjuvant chemotherapy with three cycles of cisplatin and docetaxel. The randomized trial SAKK 16/00 showed no benefit by adding radiotherapy as third treatment modality to chemotherapy and surgery. Our results consistently showed a 5-year overall survival (OS) of 37%. However, it seems very difficult to further improve the OS by conventional therapies.
Method:
This is a single-arm phase II clinical trial designed to evaluate the addition of perioperative immunotherapy with the anti-PD-L1 antibody durvalumab to the previously established standard of care for stage IIIA(N2) patients, which is based on the trials SAKK 16/96 and SAKK 16/00. Eligible patients with WHO performance status 0-1 and age of 18-75 years must have pathologically proven NSCLC stage IIIA(N2) (T1-3 N2 M0) according to the 7th edition of the TNM classification, irrespective of histological subtype, genomic aberrations or PD-L1 expression status. Tumor tissue has to be available for the mandatory translational research. Patients whose tumor is deemed resectable at diagnosis receive three cycles of chemotherapy with cisplatin 100 mg/m[2 ]and docetaxel 85 mg/m[2] every three weeks followed by two cycles of durvalumab 750 mg every two weeks. Following surgery, patients will be treated with durvalumab 750 mg every two weeks for 12 months. Patients with R1/R2 resection and patients with extracapsular spread of mediastinal lymph node metastases may undergo standard radiotherapy prior to adjuvant treatment with durvalumab. The primary endpoint of the trial is event-free survival at 12 months. Secondary endpoints include OS, objective response, nodal down-staging, complete resection, pattern of recurrence and toxicity. Additionally, a large translation research program accompanies the trial investigating potential predictive biomarkers of anti-PD-L1 therapy.
Result:
Section not applicable
Conclusion:
Section not applicable
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P3.09 - Mesothelioma (ID 725)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.09-010 - 18 Years Single Center Experience of Surgical Resection of Malignant Pleural Mesothelioma After Induction Chemotherapy (ID 10010)
09:30 - 09:30 | Author(s): Walter Weder
- Abstract
Background:
Surgical resection of malignant pleural mesothelioma is discussed controversially. Using our data from nearly 2 decades of single center experience, and focusing on the shift from extrapleural pneumonectomy (EPP) to (extended) pleurectomy/decortication ((e)P/D) we compared the peri- and longterm outcomes of EPP and (e)P/D after induction chemotherapy.
Method:
In a retrospective analysis (September 1999 - June 2016) of our prospective database of mesothelioma patients 196 patients received mentioned multimodality therapy: 149 treated with EPP, 34 with eP/D and 13 with P/D. Major morbidity was defined as bleeding necessitating reoperation, patch failure, chylothorax, empyema, bronchopleural fistula (BPF), pulmonary embolism and acute respiratory distress syndrome (ARDS).
Result:
Both groups did not differ significantly in pT stage, hisotype, but in age and lymph node stadium. Overall 30-day and 90-day mortality were 4% and 8%, respectively. However, patients treated with (e)P/D the 30- and 90-day mortality was 0. Major morbidity was not significantly different between both groups with 37% (EPP) and 23% ((e)P/D), respectively. Patient’s characteristics, freedom from recurrence (FFR) and overall survival (OS) are demonstrated in figure 1.Figure 1
Conclusion:
Multimodality treatment with radical surgery is perfromed safely, (e)P/D known as the less invasive procedure than EPP, shows a longer OS whilst having a shorter FFR.
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P3.16 - Surgery (ID 732)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.16-046 - Pneumonectomy After Induction/Neoadjuvant Treatment for NSCLC: Morbidity, Mortality and Long-Term Survival (ID 9562)
09:30 - 09:30 | Author(s): Walter Weder
- Abstract
Background:
To compare the effects of neoadjuvant/induction chemotherapy or chemoradiation on morbidity, mortality, and long-term survival in patients with locally advanced NSCLC undergoing pneumonectomy.
Method:
All pneumonectomies following neoadjuvant treatment performed for NSCLC between 2000 and 2016 were retrospectively reviewed. The study included 162 patients (28 females; median patient age, 55.4 years [range, 31–73]). Neoadjuvant treatment consisted of chemotherapy in 115 patients (71%, group I) and chemoradiation in 47 patients (29%, group II). Chemotherapy was cisplatin-based, and 2–6 cycles of treatment were completed. Radiotherapy was administered sequentially (dose, 45–60 Gy). Surgery was performed 3–6 weeks after neoadjuvant treatment. Both groups were assessed for 90-day mortality, morbidity, and long-term survival.
Result:
Right pneumonectomy was performed in 60 (37%) patients, and the procedure was completed in a standard manner in 64.2% of the patients. Morbidity was observed in 27.7% of the patients (27,8% in group I; 27.6% in group II,p=0.98). The incidence of bronchopleural fistula was 4.3% (4.2% in group I; 4.3% group II). The 90-days mortality rate was 3.1% (5 patients in group I, 0 in group II,p=0.17). The mortality rates for right and left pneumonectomy were 3.3 (2/60 patients) and 3% (3/102 patients), respectively (p=0.61). The 5-year survival rates were 46.2% in group I and 54.2% in group II, (P = 0.16).
Conclusion:
Pneumonectomy after neoadjuvant chemotherapy or chemoradiation appears to be safe with an acceptable morbidity, mortality, and long-term survival. Chemoradiation did not improve long-term survival compared to chemotherapy despite comparable 90-day mortality and postoperative morbidity.
