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1.  Tumor-associated macrophages in stage IIIA pN2 non-small cell lung cancer after neoadjuvant chemotherapy and surgery 
Purpose: Most of the patients with stage IIIA pN2 non-small cell lung cancer (NSCLC) develop recurrence after surgery. It is not clear whether post neoadjuvant chemotherapy tumor-associated macrophages is associated with recurrence. Patients and Methods: Stage IIIA pN2 NSCLC patients underwent cisplatin/docetaxel neoadjuvant chemotherapy and surgery were retrospectively enrolled. Immunohistochemical staining of CD68 was used to identify macrophages in surgical resected stored tissues. Results: The objective response rate of cisplatin/docetaxel was 68%, overall median disease-free survival (DFS) was 13.1 months and median overall survival (OS) 36.8. months. Multiple Cox regression analysis showed low total macrophage numbers and mediastinal lymph nodes downstaging were independent factors for longer DFS, whereas high islet/stromal macrophages ratio was an independent facto for OS. In patients downstaged to pN0, low total macrophage numbers was also associated with longer DFS. Conclusions: Low total macrophage number is an independent factor for better DFS in pN2 stage IIIA NSCLC patients receiving neoadjuvant chemotherapy and surgical resection, which association was kept in those downstaged to pN0. Further studies are warrant to confirm the predictive role of TAMs and their potential causative role in tumor recurrence.
PMCID: PMC4212933  PMID: 25360223
Lung cancer biology; immunochemistry; immunology
2.  CD14+S100A9+ Monocytic Myeloid-derived Suppressor Cells and Their Clinical Relevance in Non–Small Cell Lung Cancer 
Rationale: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of myeloid cells that suppress T-cell immunity in tumor-bearing hosts. Their clinical relevance remains unclear.
Objectives: To identify subtypes of myeloid-derived suppressor cells in patients with non–small cell lung cancer (NSCLC) and their clinical relevance.
Methods: CD11b+CD14− and CD11b+CD14+ cells, determined and phenotyped by fluorescence-activated cell sorter analysis, in the peripheral blood mononuclear cells (PBMCs) of treatment-naive patients with advanced NSCLC were correlated with clinical data. T-cell activation in response to CD3/CD28 costimulation was determined by carboxy-fluorescein diacetate succinimidyl ester (CFSE) staining and ELISA analysis of IFN-γ. The percentage of CD11b+CD14+S100A9+ cells in PBMCs was correlated with and tested as a predictor for treatment response in a cohort of patients prospectively receiving first-line cisplatin-based chemotherapy.
Measurements and Main Results: Patients with NSCLC had a significantly higher ratio of CD11b+CD14+ cells than healthy subjects, which was correlated with poor performance status and poor response to chemotherapy. The depletion of these cells in the PBMC reversed the suppression of CD8+ and CD4+ T cells. Isolated CD11b+CD14+ cells suppressed CD8+ T-cell proliferation and IFN-γ production, and the former effect was attenuated by the inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine hydrochloride, arginase inhibitor N-hydroxy-nor-l-arginine (nor-NOHA), and blocking antibodies for IL-4Rα+ and IL-10. CD11b+CD14+ cells were monocyte-like, expressing CD33+, CD15−/low, IL-4Rα+, and S100A9+ and producing iNOS, arginase, and several cytokines. The ratio of S100A9+ cells positively correlated with the suppressive ability of the CD11b+CD14+ cells, was associated with poor response to chemotherapy, and predicted shorter progression-free survival.
Conclusions: CD14+S100A9+ inflammatory monocytes in patients with NSCLC are a distinct subset of MDSCs, which suppress T cells by arginase, iNOS, and the IL-13/IL-4Rα axis. The amount of these inflammatory monocytes is associated with poor response to chemotherapy.
Clinical trial registered with (NCT 01204307).
PMCID: PMC4132576  PMID: 22955317
non–small cell lung cancer; myeloid-derived suppressor cell; S100A9; cancer immunity
3.  Feasibility of Bispectral Index-Guided Propofol Infusion for Flexible Bronchoscopy Sedation: A Randomized Controlled Trial 
PLoS ONE  2011;6(11):e27769.
There are safety issues associated with propofol use for flexible bronchoscopy (FB). The bispectral index (BIS) correlates well with the level of consciousness. The aim of this study was to show that BIS-guided propofol infusion is safe and may provide better sedation, benefiting the patients and bronchoscopists.
After administering alfentanil bolus, 500 patients were randomized to either propofol infusion titrated to a BIS level of 65-75 (study group) or incremental midazolam bolus based on clinical judgment to achieve moderate sedation. The primary endpoint was safety, while the secondary endpoints were recovery time, patient tolerance, and cooperation.
The proportion of patients with hypoxemia or hypotensive events were not different in the 2 groups (study vs. control groups: 39.9% vs. 35.7%, p = 0.340; 7.4% vs. 4.4%, p = 0.159, respectively). The mean lowest blood pressure was lower in the study group. Logistic regression revealed male gender, higher American Society of Anesthesiologists physical status, and electrocautery were associated with hypoxemia, whereas lower propofol dose for induction was associated with hypotension in the study group. The study group had better global tolerance (p<0.001), less procedural interference by movement or cough (13.6% vs. 36.1%, p<0.001; 30.0% vs. 44.2%, p = 0.001, respectively), and shorter time to orientation and ambulation (11.7±10.2 min vs. 29.7±26.8 min, p<0.001; 30.0±18.2 min vs. 55.7±40.6 min, p<0.001, respectively) compared to the control group.
BIS-guided propofol infusion combined with alfentanil for FB sedation provides excellent patient tolerance, with fast recovery and less procedure interference.
Trial Registration
ClinicalTrials. gov NCT00789815
PMCID: PMC3223212  PMID: 22132138

Results 1-3 (3)