Ting Yu Lin

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 www.clinicaltrials.gov (NCT 01204307).

Feasibility of Bispectral Index-Guided Propofol Infusion for Flexible Bronchoscopy Sedation: A Randomized Controlled Trial

Objectives 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. Methods 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. Results 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. Conclusions 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

Bispectral Index in Evaluating Effects of Sedation Depth on Drug-Induced Sleep Endoscopy.

OBJECTIVE To evaluate the effect of sedation depth on drug-induced sleep endoscopy (DISE). METHODS Ninety patients with obstructive sleep apnea (OSA) and 18 snorers underwent polysomnography and DISE under bispectral index (BIS)-guided propofol infusion at two different sedation levels: BIS 65-75 (light sedation) and 50-60 (deep sedation). RESULTS For the patients with OSA, the percentages of velopharynx, oropharynx, hypopharynx, and larynx obstructions under light sedation were 77.8%, 63.3%, 30%, and 33.3%, respectively. Sedation depth was associated with the severity of velopharynx and oropharynx obstruction, oropharynx obstruction pattern, tongue base obstruction, epiglottis anteroposterior prolapse and folding, and arytenoid prolapse. In comparison, OSA severity was associated with the severity of velopharynx obstruction, severity of oropharynx obstruction, and arytenoid prolapse (odds ratio (95% confidence interval); 14.3 (4.7-43.4), 11.7 (4.2-32.9), and 13.2 (2.8-62.3), respectively). A good agreement was noted between similar DISE findings at different times and different observers (kappa value 0.6 to 1, respectively). A high percentage of arytenoid prolapse (46.7% among the patients with OSA under light sedation) was noted. CONCLUSIONS Greater sedative depth increased upper airway collapsibility under DISE assessment. DISE under BIS-guided propofol infusion, and especially a level of 65-75, offers an objective and reproducible method to evaluate upper airway collapsibility. Some findings were induced by drug sedation and need careful interpretation. Specific arytenoid prolapse patterns were noted for which further investigations are warranted. CLINICAL TRIALS REGISTRATION http://www.clinicaltrials.gov, identifier: NCT01100554. COMMENTARY A commentary on this article appears in this issue on page 965.

Low-dose weekly docetaxel is as tolerable as pemetrexed in previously treated advanced non-small-cell lung cancer.

Objectives: Docetaxel and pemetrexed have been validated as therapeutics for previously treated advanced non-small-cell lung cancer (NSCLC), but tolerability is a concern for standard treatment with docetaxel administered once every 3 weeks (tri-weekly 75-mg/m2 schedule). We conducted this retrospective study to compare the efficacy and toxicity of weekly low-dose docetaxel versus tri-weekly pemetrexed for previously treated advanced NSCLC. Methods: Consecutive patients who received low-dose single docetaxel (30 mg/m2 on days 1 and 8 every 3 weeks) or pemetrexed (500 mg/m2 every 3 weeks) at a single university-affiliated hospital following failure of previous treatment were retrospectively reviewed. Their outcomes and toxicity profiles were determined. Results: 179 patients were included between 2005 and 2008 (docetaxel, n = 79; pemetrexed, n = 100). Both groups had similar hematologic (16.5 vs. 15.0%; p = 0.84) and non-hematologic (20.3 vs. 24%; p = 0.55) toxicities. After controlling for confounding factors, docetaxel remained superior to pemetrexed for progression-free survival (median 4.0 vs. 2.4 months; hazard ratio 0.64; 95% CI 0.47–0.87; p = 0.005) and overall survival (median 15.0 vs.8.5 months; hazard ratio 0.54; 95% CI 0.38–0.77; p <0.001). Conclusion: Although this study showed that weekly low doses of docetaxel were as tolerable as pemetrexed for previously treated advanced NSCLC, a prospective design is needed to confirm this finding.

Associated bone mineral density and obstructive sleep apnea in chronic obstructive pulmonary disease

Background Osteoporosis is an important issue for patients with chronic obstructive pulmonary disease (COPD). Worse systemic inflammation and reduced exercise capacity have been reported in COPD patients with obstructive sleep apnea (OSA), implying that OSA may be an independent factor for osteoporosis in COPD patients. Methods A total of 66 patients with bone mineral density (BMD) and polysomnography results from a previous COPD cohort (January 2008 to January 2013) were retrospectively enrolled. Clinical characteristics such as medication, pulmonary function, BMD, and results of polysomnography were analyzed. Results The BMD in those with OSA was significantly lower than in those without OSA (−1.99±1.63 versus −1.27±1.14, P=0.045). In univariate analysis, body mass index, forced expiratory volume in 1 second, percentage of predicted value, incremental shuttle walk test, apnea–hypopnea index, and oxygen desaturation index (ODI) were significantly associated with BMD. After multivariate linear regression analysis, the ODI was still an independent factor for BMD. In addition, smaller total lung capacity is significantly associated with higher ODI and lower BMD, which implies that lower BMD might cause severer OSA via decreased total lung capacity. Conclusion OSA may be an independent factor for BMD in patients with COPD, which implies a possible vicious cycle takes place in these patients.

Chronic cough and obstructive sleep apnoea in a sleep laboratory-based pulmonary practice

BackgroundObstructive sleep apnoea (OSA) has recently been identified as a possible aetiology for chronic cough. The aim of this study was to compare the incidence of chronic cough between patients with and without OSA and the impact of continuous positive airway pressure (CPAP) treatment in resolving chronic cough.MethodsPatients referred to the sleep laboratory from January 2012 to June 2012 were retrospectively enrolled. Clinical data, treatment course and resolution of chronic cough were analysed. Specifically, gastro-oesophageal reflux (GERD), upper airway cough syndrome, asthma, apnoea-hypopnoea index and the impact of CPAP treatment on chronic cough were assessed.ResultsA total of 131 patients were reviewed. The incidence of chronic cough in the OSA group was significantly higher than the non-OSA group (39/99 (39.4%) vs. 4/32 (12.5%), p = 0.005). Both GERD and apnoea-hypopnoea index were significantly associated with chronic cough in univariate analysis. After multivariate logistic regression, GERD was the only independent factor for chronic cough. Moreover, the resolution of chronic cough was more significant in the OSA patients with CPAP treatment compared with those not receiving CPAP treatment (12/18 (66.7%) vs. 2/21 (9.5%), p = 0.010).ConclusionThe incidence of chronic cough was significantly higher in the OSA patients. In addition, CPAP treatment significantly improved chronic cough. Therefore, OSA may be a contributory factor to chronic cough.

The safety and efficacy of alfentanil-based induction in bronchoscopy sedation: A randomized, double-blind, controlled trial

Background: Alfentanil in combination with propofol produces a synergistic sedative effect in patients undergoing flexible bronchoscopy (FB). However, the use of this combination is controversial due to the risk of cardiopulmonary depression. The aim of this study was to evaluate the proper induction regimen of alfentanil in propofol target-controlled infusion for FB sedation. Methods: One hundred seventy-three patients were assigned randomly into 5 regimens: Group 1 and 2, alfentanil 2.5 and 5 &mgr;g/kg, respectively, immediately before propofol administration; Group 3 and 4, alfentanil 2.5 and 5 &mgr;g/kg, respectively, 2 minutes before propofol administration; and Group 5, propofol administration alone to achieve the observer assessment of alertness and sedation scale 3∼2. The bronchoscopists, physicians in charge of sedation, and patients were blind to the regimens. Adverse events, drug dose, induction, procedure and recovery time, cough severity, and propofol injection related pain were recorded. Results: The patients in groups 2 and 4 required a lower dose of propofol (P = 0.031 and 0.019, respectively) and shorter time (P = 0.035 and 0.010) than group 5 for induction. Patients in group 2 experienced more hypoxemia than those in group 5 during induction (P = 0.031). The physician in charge of sedation scored a lower severity of cough in the patients in group 4 than in groups 3 and 5. There were no differences in terms of propofol injection related pain among the groups. Conclusion: Alfentanil 5 &mgr;g/kg given immediately before propofol infusion cannot be recommended. Further study is required to define conclusions about alfentanil 2.5 and 5 &mgr;g/kg because of the low power rating of subgroup in the present study.

Capnography monitoring the hypoventilation during the induction of bronchoscopic sedation: A randomized controlled trial

We hypothesize that capnography could detect hypoventilation during induction of bronchoscopic sedation and starting bronchoscopy following hypoventilation, may decrease hypoxemia. Patients were randomized to: starting bronchoscopy when hypoventilation (hypopnea, two successive breaths of at least 50% reduction of the peak wave compared to baseline or apnea, no wave for 10 seconds) (Study group, n = 55), or when the Observer Assessment of Alertness and Sedation scale (OAAS) was less than 4 (Control group, n = 59). Propofol infusion was titrated to maintain stable vital signs and sedative levels. The hypoventilation during induction in the control group and the sedative outcome were recorded. The patient characteristics and procedures performed were similar. Hypoventilation was observed in 74.6% of the patients before achieving OAAS < 4 in the control group. Apnea occurred more than hypopnea (p < 0.0001). Hypoventilation preceded OAAS < 4 by 96.5 ± 88.1 seconds. In the study group, the induction time was shorter (p = 0.03) and subjects with any two events of hypoxemia during sedation, maintenance or recovery were less than the control group (1.8 vs. 18.6%, p < 0.01). Patient tolerance, wakefulness during sedation, and cooperation were similar in both groups. Significant hypoventilation occurred during the induction and start bronchoscopy following hypoventilation may decrease hypoxemia without compromising patient tolerance.