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B. Passlick
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MINI 21 - Novel Targets (ID 133)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:B.P. Levy, D.S. Tan
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 2a-3b
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MINI21.01 - Purinergic Signaling in NSCLC - First in Vivo Data and Potential Therapeutic Targets (ID 166)
16:45 - 16:50 | Author(s): B. Passlick
- Abstract
- Presentation
Background:
Purines are well known as intracellular sources for energy but also act as extracellular signaling molecules. In the last decade there has been a growing interest in the therapeutic potential of purinergic signaling for cancer treatment. The effects carried out depend on the concentration, expressed pattern of purinergic receptors and general dynamics of synthesis and degradation. In this study we analyze different purines and purinergic receptors in bronchoalveolar lavage (BAL) of patients with non-small-cell lung cancer (NSCLC) to provide further insight on their relevance in the tumor microenvironment.
Methods:
In this prospective clinical trial we enrolled 27 patients with NSCLC and 16 patients with chronic obstructive pulmonary disease (COPD) without signs of malignancy. The study was approved by our local ethics committee and registered as a clinical trial in the German Registry for Clinical Trials (DRKS-ID: DRKS00005415). BAL was performed using flexible bronchoscopes. The bronchoscope was wedged into a subsegment were the tumor was present and a total of 300 ml sterile saline was instilled. The BAL-fluid (BALF) was recovered by gentle aspiration. Purines (ATP, ADP, AMP, Adenosine and Inosine) were analyzed using fluorescence/luminescence based assays. Expression of purinergic receptors and Ectonucleotidases in NSCLC (P2X1, P2X4, P2X7, P2Y1, P2Y2, P2Y4, P2Y6, P2Y12, P2Y13, P2Y14, CD39, CD73) were analyzed using qPCR.
Results:
Patients with NSCLC have significantly lower ATP and ADP concentrations in BALF than patients with COPD without signs of malignancy (p=0.006 and p=0.009). Inosine concentrations however are higher in patients with malignant disease (p=0.01). In the subgroup-analysis of metastasized versus non-metastasized tumors receptor-analysis revealed a higher expression of P2X4 (p=0.07), P2X7 (p=0.0008) and P2Y1 (p=0.009) as well as of the ectonucleotidase CD39 (p=0.007). Analysis of the purine metabolites in the respective groups showed no statistically significant differences. Furthermore there is a positive correlation of the proportion of macrophages in differential cell count in BAL with the expression of P2X7 (r=0.53, p=0.02).
Conclusion:
Previous data suggests pro-inflammatory, zytotoxic and thus anti-neoplastic effects of Adenosine-Triphosphate (ATP) and ADP. Also it has been shown that low ATP concentrations in the tumor microenvironment can lead to enhanced proliferation of tumor cells. In this first in vivo study on purinergic signaling in lung cancer we find lower concentrations of ATP and ADP in samples from NSCLC patients compared to COPD without signs of malignancy in accordance with these findings. Furthermore in aggressive, metastasized NSCLC we find a higher expression of the ectonucleotidase CD39. This enzyme degrades ATP and ADP to Adenosin and has previously been shown to hence induce immune escape in malignant disease. Furthermore we demonstrate elevated expression of P2X4, P2X7 and P2Y1 in the tumor microenvironment of metastasized NSCLC compared to non-metastasized tumors. This suggests a role of these receptors in tumor metastasis, however the exact mechanisms remain unclear. To further illustrate these interactions we are currently initiating a study to identify purinergic receptors in NSCLC tumor cells from pathologic specimen. With this knowledge future translational studies can be conducted to potentially provide new therapeutic targets.
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ORAL 35 - Surgical Approaches in Localized Lung Cancer (ID 155)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:M. de Perrot, J. Mitchell
- Coordinates: 9/09/2015, 16:45 - 18:15, 601+603
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ORAL35.08 - Discussant for ORAL35.05, ORAL35.06, ORAL35.07 (ID 3375)
18:01 - 18:11 | Author(s): B. Passlick
- Abstract
- Presentation
Abstract not provided
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P2.02 - Poster Session/ Treatment of Localized Disease – NSCLC (ID 210)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.02-034 - Induction Therapy with Intercalated TKI and Chemotherapy in NSCLC with Activating EGFR Mutation in Stages II-IIIB: NeoIntercal (ID 2255)
09:30 - 09:30 | Author(s): B. Passlick
- Abstract
Background:
EGFR TKI treatment is standard of care in patients with metastasized NSCLC carrying an activating EGFR mutation. 1[st] and 2[nd] generation agents lead to response rates of up to 70% in metastatic EGFRM+ NSCLC. Recently, new light has been shed on intercalated regimens of chemotherapy and TKI have shown improved PFS as well as OS in the metastatic setting in an unselected Asian population (Wu et al. 2013 The Lancet Oncology 14 (8): 777-86). Response is a predictor of PFS and OS in limited and locally advanced NSCLC. Chemotherapy induction alone leads to pCR rates of no more than 15%. No data have been generated for induction therapy including EGFR TKI in EGFRM+ NSCLC. Four cases treated in one center have demonstrated the feasibility and tolerability of an intercalated induction therapy concept (Lüers et al. 2013 Abstract WCLC).
Methods:
Therefore, NeoIntercal a single arm phase II study has been initiated in 9 centers in Germany. In a first step, patients with stage II to IIIB staged according to local standards will be screened for EGFR mutations by a ring certified pathologist. EGFRM+ patients will receive gefitinib 250 mg / die p.o. on d-12 to -1 (d1 = first day of first cycle of chemotherapy) followed by 3 cycles of taxane and platinum containing chemotherapy with intercalated gefitinib on d4-d20 of each cycle. After 2 cycles, restaging CT is performed and patients are scheduled to undergo surgery during the 4[th] or 5[th] week of the last cycle of CTx-gefitinib. Pathologic response rate is the primary endpoint. If more than 30% of patients achieve pCR (regression grades IIB and III according to Junker) in the mediastinal lymph nodes, it is planned to additionally enroll 28 patients in the 2[nd] part of the study. Secondary endpoints include OS, PFS, relapse rate and pattern, toxicity and feasibility. A liquid biopsy project is included in the study to correlate EGFR mutation status from tumor biopsy results with ctDNA plasma analysis. Furthermore, therapy effects will be monitored by liquid biopsy.
Results:
Study preparation and recruitment of clinical trial centers is nearly completed and the enrollment of the first patient is planned for 3Q2015. An interim analysis will be performed approximately 12 months after enrollment initiation with data from 21 patients. Should the interim analysis be positive and an additional 28 patients are included, the study is scheduled to end in approximately 2019 after a follow up period of 24 months.
Conclusion:
According to our knowledge, NeoIntercal is the first study in the neoadjuvant setting with curative intent applying an intercalating combination of chemotherapy and targeted therapy. The NeoIntercal study group believes that this study will potentially contribute to the improvement of EGFRM+ NSCLC therapy.
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P2.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 225)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.08-018 - The Impact of the Resection Margin on Recurrence and Survival in Bronchopulmonary Carcinoids (ID 2411)
09:30 - 09:30 | Author(s): B. Passlick
- Abstract
Background:
Complete surgical resection is the treatment of choice in bronchopulmonary carcinoids. Previously published data showed no inferiority of sublobar versus lobar resection. Data on the extent of resection margins are lacking, thus we aimed to analyze resection margins in pulmonary carcinoids and correlated them with survival and recurrence.
Methods:
We retrospectively analyzed 85 patients that underwent surgery for atypical (AC) or typical (TC) pulmonary carcinoids. Patient charts were reviewed and clinicopathologic and survival data was collected. Pathology reports were reviewed for length of resection margins.
Results:
The median follow-up period was 42.3 months (range 0.3 - 172.2). There was no statistically significant difference in disease-free survival (DS) when comparing resection margins ≤2 mm to >2 mm (p=0.93, Hazard Ratio (HR)=1.7). When looking at AC alone, a worse DS can be seen if the resection margin was smaller than 2 mm (p=0.06, HR=15.8). In AC likelihood of recurrence was higher when the resection margin was ≤1 cm (Odds ratio=5.1, p=0.28). In TC this tendency was not present (Odds ratio=1.2, p=1).
Conclusion:
There is a trend towards a worse prognosis and higher likelihood of recurrence in smaller resection margins in AC in contrast to TC. Due to low sample size no definitive statements can be made based on this study, however respective data on these rare tumors cannot be drawn from tumor databases. The resection margin is the most critical issue for the treating surgeon and any information on this topic is of highest importance to the field.
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P3.02 - Poster Session/ Treatment of Localized Disease – NSCLC (ID 211)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.02-027 - Surgical Salvage Resection for Local Recurrence after Stereotactic Body Radiotherapy for Primary and Metastatic Lung Tumors (ID 2600)
09:30 - 09:30 | Author(s): B. Passlick
- Abstract
Background:
Stereotactic body radiation therapy (SBRT) is an alternative to surgery for the treatment of early stage lung cancer or solitary metastasis in high-risk individuals. The aim of the study was to identify patients that underwent surgical resection as a salvage therapy for local recurrences following SBRT.
Methods:
In a single institution prospective database patients that underwent SBRT for early-stage NSCLC or pulmonary metastatic tumors were identified over 5 years. Patients that underwent surgical salvage resection for local recurrences after SBRT were analyzed for clinicopathological data and outcome.
Results:
In 4/188 (2.1%) patients salvage surgery was performed for local recurrences after SBRT within a median period of 14.5 months. SBRT was performed with a total dosage of 35 Gy in 3 and 37.5 Gy in 1 patient. No perioperative mortality occurred after salvage resection, and complete resection was achieved in all cases. Histopathology demonstrated viable tumor cells accompanied by fibrosis and necrosis in all resected specimens.
Conclusion:
Salvage surgery should be considered in operable patients after lung SBRT for primary and metastatic tumors as viable tumor can be expected. It can be performed safely in appropriate candidates that need to be identified in a multidisciplinary setting. Further analysis of larger series could further clarify true incidence of local recurrences after SBRT and selection criteria for salvage surgery in this challenging group of patients.
