Overall response to first-line tyrosine kinase inhibitor and second-line chemotherapy is predictive of survival outcome in epidermal growth factor receptor-mutated adenocarcinoma.

BACKGROUND: First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for the treatment of lung adenocarcinoma with an EGFR-sensitizing mutation, but resistance is inevitable. Chemotherapy is widely used in the second-line setting. The outcome following this treatment scheme has not been thoroughly evaluated. METHODS: From 2007 to 2011, consecutive patients with mutated EGFR receiving first-line TKI and second-line chemotherapy were retrospectively reviewed. The overall response was categorized into double responder, single responder and double nonresponder. RESULTS: Following this treatment scheme, baseline Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (HR 0.60; 95% CI 0.37-0.98; p = 0.041) and double responder (HR 0.24; 95% CI 0.07-0.78; p = 0.018) were independent predictors of overall survival. Absence of pleural metastasis independently predicted the response to first-line TKI (OR 2.60; 95% CI 1.13-5.99; p = 0.025). In TKI responders, ECOG performance status 0-1 before chemotherapy (OR 4.95; 95% CI 1.15-21.28; p = 0.006), an exon 19 deletion (OR 4.74; 95% CI 1.30-17.21; p = 0.018) and progression-free survival (PFS) on first-line TKI (OR 1.02; 95% CI 1.01-1.09; p = 0.049) independently predicted the response to second-line chemotherapy. A moderate linear relationship (Pearson's r = 0.441; p = 0.001) existed between the PFS of this treatment scheme in TKI responders. CONCLUSION: The status of double responder to first-line TKI and second-line chemotherapy was predictive of improved survival in EGFR-mutated adenocarcinoma.

Removal of endobronchial malignant mass by cryotherapy improved performance status to receive chemotherapy.

Although malignant endobronchial mass (MEM) has poor prognosis, cryotherapy is reportedly a palliative treatment. Clinical data on postcryotherapy MEM patients in a university-affiliated hospital between 2007 and 2011 were evaluated. Survival curve with or without postcryotherapy chemotherapy and performance status (PS) improvement of these subjects were analyzed using the Kaplan-Meier method. There were 59 patients (42 males), with median age of 64 years (range, 51-76, and median performance status of 2 (interquartile range [IQR], 2-3). Postcryotherapy complications included minor bleeding (n = 12) and need for multiple procedures (n = 10), while outcomes were relief of symptoms (n = 51), improved PS (n = 45), and ability to receive chemotherapy (n = 40). The survival of patients with chemotherapy postcryotherapy was longer than that of patients without such chemotherapy (median, 534 versus 106 days; log-rank test, P = 0.007; hazard ratio, 0.25; 95% confidence interval, 0.10-0.69). The survival of patients with PS improvement postcryotherapy was longer than that of patients without PS improvement (median, 406 versus 106 days; log-rank test, P = 0.02; hazard ratio, 0.28; 95% confidence interval, 0.10-0.81). Cryotherapy is a feasible treatment for MEM. With better PS after cryotherapy, further chemotherapy becomes possible for patients to improve survival when MEM caused dyspnea and poor PS.

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).

High Transcriptional Activity and Clinical Correlations in Eosinophils of Patients with Late-Onset Asthma.

Background: The immunological features of eosinophils in early-onset asthma (EOA) differ from those in late-onset asthma (LOA). Clinical trials of anti-interleukin-5 (IL-5) treatment for severe eosinophilic asthma showed a better response for LOA patients than EOA patients. We wonder if the transcriptional activity of activated eosinophils was different in EOA and LOA. Methods: Eosinophils obtained from well-controlled EOA and LOA patients and normal subjects were compared in terms of the mRNA expression of activation-related genes and specific markers related to cell functions in eosinophils activated by IL-5 or IL-17. The correlation between mRNA expression and clinical features and lung function was further analyzed. Results: The transcriptional expression of most genes was higher in activated eosinophils from LOA patients than in those from EOA patients and normal subjects. After IL-17 stimulation, the expression of certain genes was higher in atopic EOA patients than in non-atopic EOA patients. Similar observation was noted in obese EOA patients. After IL-5 stimulation, the transcriptional expression of most genes in eosinophils from LOA patients was negatively correlated with indicators of lung function. These correlations were less pronounced in EOA patients: After IL-17 stimulation, some genes in EOA patients were negatively correlated with post-bronchodilator changes in lung function. Conclusion: This study describes differences in the transcriptional active patterns of eosinophils and their correlation to atopy and obesity by age of onset. High transcriptional activity in activated eosinophils and a negative correlation to lung function indicate the importance of eosinophils in the pathogenesis of LOA.

Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study.

BACKGROUND: Findings from the phase 3 FLEX study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival, compared with cisplatin and vinorelbine alone, in the first-line treatment of EGFR-expressing, advanced non-small-cell lung cancer (NSCLC). We investigated whether candidate biomarkers were predictive for the efficacy of chemotherapy plus cetuximab in this setting. METHODS: Genomic DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue of patients enrolled in the FLEX study was screened for KRAS codon 12 and 13 and EGFR kinase domain mutations with PCR-based assays. In FFPE tissue sections, EGFR copy number was assessed by dual-colour fluorescence in-situ hybridisation and PTEN expression by immunohistochemistry. Treatment outcome was investigated according to biomarker status in all available samples from patients in the intention-to-treat population. The primary endpoint in the FLEX study was overall survival. The FLEX study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT00148798. FINDINGS: KRAS mutations were detected in 75 of 395 (19%) tumours and activating EGFR mutations in 64 of 436 (15%). EGFR copy number was scored as increased in 102 of 279 (37%) tumours and PTEN expression as negative in 107 of 303 (35%). Comparisons of treatment outcome between the two groups (chemotherapy plus cetuximab vs chemotherapy alone) according to biomarker status provided no indication that these biomarkers were of predictive value. Activating EGFR mutations were identified as indicators of good prognosis, with patients in both treatment groups whose tumours carried such mutations having improved survival compared with those whose tumours did not (chemotherapy plus cetuximab: median 17·5 months [95% CI 11·7-23·4] vs 8·5 months [7·1-10·8], hazard ratio [HR] 0·52 [0·32-0·84], p=0·0063; chemotherapy alone: 23·8 months [15·2-not reached] vs 10·0 months [8·7-11·0], HR 0·35 [0·21-0·59], p<0·0001). Expression of PTEN seemed to be a potential indicator of good prognosis, with patients whose tumours expressed PTEN having improved survival compared with those whose tumours did not, although this finding was not significant (chemotherapy plus cetuximab: median 11·4 months [8·6-13·6] vs 6·8 months [5·9-12·7], HR 0·80 [0·55-1·16], p=0·24; chemotherapy alone: 11·0 months [9·2-12·6] vs 9·3 months [7·6-11·9], HR 0·77 [0·54-1·10], p=0·16). INTERPRETATION: The efficacy of chemotherapy plus cetuximab in the first-line treatment of advanced NSCLC seems to be independent of each of the biomarkers assessed. FUNDING: Merck KGaA.

Interaction Between CD34+ Fibrocytes and Airway Smooth Muscle Promotes IL-8 Production and Akt/PRAS40/mTOR Signaling in Asthma.

Background: The circulating progenitor cells of fibroblasts (fibrocytes) have been shown to infiltrate the airway smooth muscle compartment of asthma patients; however, the pathological significance of this discovery has yet to be elucidated. This study established a co-culture model of airway smooth muscle cells (ASMCs) and fibrocytes from asthmatic or normal subjects to evaluate innate cytokine production, corticosteroid responses, and signaling in ASMCs. Methods: CD34+ fibrocytes were purified from peripheral blood of asthmatic (Global Initiative for Asthma treatment step 4-5) and normal subjects and cultured for 5∼7 days. In a transwell plate, ASMCs were co-cultured with fibrocytes at a ratio of 2:1, ASMCs were cultured alone (control condition), and fibrocytes were cultured alone for 48 h. Measurements were obtained of interleukin-8 (IL-8), IL-6, IL-17, thymic stromal lymphopoietin, and IL-33 levels in the supernatant and IL-33 levels in the cell lysate of the co-culture. Screening for intracellular signaling in the ASMCs after stimulation was performed using condition medium from the patients' co-culture (PtCM) or IL-8. mRNA and western blot analysis were used to analyze AKT/mTOR signaling in ASMCs stimulated via treatment with PtCM or IL-8. Results: Compared with ASMCs cultured alone, IL-8 levels in the supernatant and IL-33 levels in the ASMCs lysate were significantly higher in samples co-cultured from asthmatics, but not in those co-cultured from normal subjects. Corticosteroid-induced suppression of IL-8 production was less pronounced in ASMCs co-cultured with fibrocytes from asthma patients than in ASMCs co-cultured from normal subjects. ASMCs stimulated using PtCM and IL-8 presented elevating activated AKT substrate PRAS40. Treatment with IL-8 and PtCM increased mRNA expression of mTOR and P70S6 kinases in ASMCs. Treatment with IL-8 and PtCM also significantly increased phosphorylation of AKT and mTOR subtract S6 ribosomal protein in ASMCs. Conclusion: The interaction between ASMCs and fibrocytes from asthmatic patients was shown to increase IL-8 and IL-33 production and promote AKT/mTOR signaling in ASMCs. IL-8 production in the co-culture from asthmatic patients was less affected by corticosteroid than was that in the co-culture from normal subjects. Our results elucidate the novel role of fibrocytes and ASMCs in the pathogenesis of asthma.

Overall Survival Improvement in Patients with Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer and Bone Metastasis Treated with Denosumab.

The impact of an initial skeletal-related event (SRE) and denosumab adjuvant treatment on the survival outcome of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients with bone metastasis remains unclear. This retrospective study included 400 metastatic EGFR-mutated NSCLC patients. Among 190 bone metastasis patients, 61 had initial SREs and 73 received denosumab. We analyzed patient characteristics, SRE-free survival (SRE-FS), and overall survival (OS). In metastatic EGFR-mutated NSCLC, bone metastasis was associated with a poorer OS (21.7 vs. 33.0 months; p < 0.001). Bone metastasis patients with initial SREs at diagnosis had an even shorter OS, compared with those without initial SRE (15.4 vs. 23.6 months; p = 0.026). Denosumab reduced SRE incidence (hazard ratio (HR) 0.57 (95% confidence interval (CI) 0.34−0.94; p = 0.027) and was associated with improved OS (26.6 vs. 20.1 months; p = 0.015). A multivariate analysis demonstrated that denosumab treatment was correlated with a lower incidence of SRE (HR 0.61 (95% CI 0.37−0.98); p = 0.042) and better OS (HR 0.60 (95% CI 0.41−0.88); p = 0.008). In subgroup analyses, denosumab prolonged SRE-FS (HR 0.36 (95% CI 0.19−0.79); p = 0.009) in patients without initial SREs and was related to a better OS (25.3 vs. 12.9 months; p = 0.016) in patients with initial or pre-existing SREs. Osteonecrosis of the jaw was diagnosed in two patients (2.74%) receiving denosumab. Our study confirmed the association between initial SREs and a worse outcome and provided novel evidence of the survival benefit of denosumab for EGFR-mutated NSCLC patients with bone metastasis.

Depressive symptoms during the first chemotherapy cycle predict mortality in patients with advanced non-small cell lung cancer.

PURPOSE: Depressive symptoms are commonly experienced by cancer patients, especially those with advanced disease. The link between depression and survival outcome in cancer patients has received increasing attention. The purpose of this study was to determine, after adjusting the known covariates, whether the depressive symptoms during the first cycle of chemotherapy can predict the mortality of patients with advanced non-small cell lung cancer (NSCLC). METHODS: Patients with stage III or IV NSCLC were recruited from a large teaching hospital located in northern Taiwan. Depressive symptoms were assessed during the first cycle of chemotherapy using the Hospital Anxiety and Depression Scale-Depression subscale. A cut-off of 7/8 was used to categorize patients into depressed and non-depressed groups. All patients were followed up until the end of the study. The follow-up time ranged from 10 to 30 months. RESULTS: The study sample consisted of 90 NSCLC patients. Twenty patients (22.2%) were categorized as depressed. The median survival time in the depressed group was significantly shorter than that of the non-depressed group (11.83 vs. 24.47 months, P = 0.017). After controlling for demographic and clinical factors, depressive symptoms remained significantly (p = 0.023) associated with a shorter survival time. Compared to the non-depressed group, the depressed group had twice the risk of death (HR = 2.18, 95% CI = 1.11 to 4.28). CONCLUSION: The finding supports that depressive symptoms at the early phase of treatment can predict shorter survival in patients with advanced NSCLC.

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/m(2) 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/m(2) on days 1 and 8 every 3 weeks) or pemetrexed (500 mg/m(2) 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.

Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial.

BACKGROUND: Use of cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has the potential to increase survival in patients with advanced non-small-cell lung cancer. We therefore compared chemotherapy plus cetuximab with chemotherapy alone in patients with advanced EGFR-positive non-small-cell lung cancer. METHODS: In a multinational, multicentre, open-label, phase III trial, chemotherapy-naive patients (>or=18 years) with advanced EGFR-expressing histologically or cytologically proven stage wet IIIB or stage IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio to chemotherapy plus cetuximab or just chemotherapy. Chemotherapy was cisplatin 80 mg/m(2) intravenous infusion on day 1, and vinorelbine 25 mg/m(2) intravenous infusion on days 1 and 8 of every 3-week cycle) for up to six cycles. Cetuximab-at a starting dose of 400 mg/m(2) intravenous infusion over 2 h on day 1, and from day 8 onwards at 250 mg/m(2) over 1 h per week-was continued after the end of chemotherapy until disease progression or unacceptable toxicity had occurred. The primary endpoint was overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00148798. FINDINGS: Between October, 2004, and January, 2006, 1125 patients were randomly assigned to chemotherapy plus cetuximab (n=557) or chemotherapy alone (n=568). Patients given chemotherapy plus cetuximab survived longer than those in the chemotherapy-alone group (median 11.3 months vs 10.1 months; hazard ratio for death 0.871 [95% CI 0.762-0.996]; p=0.044). The main cetuximab-related adverse event was acne-like rash (57 [10%] of 548, grade 3). INTERPRETATION: Addition of cetuximab to platinum-based chemotherapy represents a new treatment option for patients with advanced non-small-cell lung cancer. FUNDING: Merck KGaA.

Respiration-averaged CT for attenuation correction in non-small-cell lung cancer.

PURPOSE: Breathing causes artefacts on PET/CT images. Cine CT has been used to reduce respiratory artefacts by acquiring multiple images during a single breathing cycle. The aim of this prospective study in non-small-cell lung cancer (NSCLC) patients was twofold. Firstly, we sought to compare the motion artefacts in PET/CT images attenuation-corrected with helical CT (HCT) and with averaged CT (ACT), which provides an average of cine CT images. Secondly, we wanted to evaluate the differences in maximum standardized uptake values (SUV(max)) between HCT and ACT. METHODS: Enrolled in the study were 80 patients with NSCLC. PET images attenuation-corrected with HCT (PET/HCT) and with ACT (PET/ACT) were obtained in all patients. Misregistration was evaluated by measurement of the curved photopenic area in the lower thorax of the PET images for all patients and direct measurement of misregistration for selected lesions. SUV(max) was measured separately at the primary tumours, regional lymph nodes, and background. RESULTS: A total of 80 patients with NSCLC were included. Significantly lower misregistrations were observed in PET/ACT images than in PET/HCT images (below-thoracic misregistration 0.25+/-0.58 cm vs. 1.17+/-1.17 cm, p<0.001; lesion misregistration 1.38+/-2.10 vs. 3.10+/-4.09, p=0.013). Significantly higher SUV(max) were noted in PET/ACT images than in PET/HCT images in the primary tumour (p<0.001) and regional lymph nodes (p<0.001). Compared with PET/HCT images, the magnitude of SUV(max) in PET/ACT images was higher by 0.35 for the main tumours and 0.34 for lymph nodes. CONCLUSION: Due to its significantly reduced misregistration, PET/ACT provided more reliable SUV(max) and may be useful in treatment planning and monitoring the therapeutic response in patients with NSCLC.

Sleep disturbances and quality of life in lung cancer patients undergoing chemotherapy.

This study described the sleep disturbances of 115 lung cancer patients undergoing their fourth cycle of chemotherapy and examined the impact of sleep disturbances on quality of life and functional performance status while controlling for pain, depression, fatigue, and dyspnea. Sleep disturbance and quality of life were assessed by the Pittsburg Sleep Quality Index (PSQI), and European Organization for Research and Treatment Quality of Life Questionnaire-Cancer 30 (EORTC), respectively. Data were also collected on covariates of sleep disturbance: performance status, pain, fatigue, depression and dyspnea. Patients' mean PSQI global scores for days with chemotherapy (6.86+/-3.83) and for days without chemotherapy (6.23+/-3.47) were both higher than the cut-off of 5, indicating poor quality of sleep during the fourth cycle of chemotherapy. After controlling for covariates, sleep disturbance was significantly associated with impaired cognitive function (EORTC) and poorer functional status. Our results suggest that clinicians should routinely assess sleep problems in lung cancer patients.

High efficacy of erlotinib in Taiwanese NSCLC patients in an expanded access program study previously treated with chemotherapy.

PURPOSE: Erlotinib is the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) which has demonstrated a survival benefit in non-small-cell lung cancer (NSCLC) patients. An open label phase II study was conducted in Taiwanese patients with NSCLC to evaluate its efficacy. METHODS: Patients with proven stage IIIB/IV NSCLC who had received at least one line of standard chemotherapy or radiotherapy were enrolled into this study. All patients were given oral erlotinib, 150mg/day till disease progression. RESULTS: From May 2005 to July 2006, 300 patients were entered from 14 hospitals in Taiwan. This analysis was based on 299 patients who received at least one dose of erlotinib. The best response rates were a 29% partial response and 44% stable disease in 273 patients who had response data available. Non-smoking (p=0.033), adenocarcinoma/BAC (p=0.0027), female (p=0.0013), aged less than 65 years (p=0.0115), stage IV (p=0.0492), patients with skin rash (p=0.0216), and a higher grade of skin rash (p=0.003) were significantly correlated with response to treatment. Skin rash was a common adverse event (any grade: 84%, Gr 3-4: 16%). The median time to disease progression was 5.6 months. Cox regression model for progression free survival showed patients most at risk of early progression were males of low performance status having squamous cell carcinoma. CONCLUSIONS: This was the largest multicenter prospective clinical study of NSCLC in Taiwan. The results demonstrated the excellent response rates, time-to-progression and overall survival of erlotinib in a large population of Taiwanese NSCLC patients who had been previously treated with chemotherapy or radiotherapy.

S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: the role of RELB.

BACKGROUND: Monocytic myeloid-derived suppressor cells (MDSCs), particularly the S100A9+ subset, has been shown initial clinical relevance. However, its role in EGFR-mutated lung adenocarcinoma, especially to EGFR-tyrosine kinase inhibitor (EGFR-TKI) is not clear. In a clinical setting of EGFR mutated lung adenocarcinoma, a role of the MDSC apart from T cell suppression was also investigated. RESULTS: Blood monocytic S100A9+ MDSC counts were higher in lung cancer patients than healthy donors, and were associated with poor treatment response and shorter progression-free survival (PFS). S100A9+ MDSCs in PBMC were well correlated to tumor infiltrating CD68+ and S100A9+ cells, suggesting an origin of TAMs. Patient's MDMs, mostly from S100A9+ MDSC, similar to primary alveolar macrophages from patients, both expressed S100A9 and CD206, attenuated EGFR-TKI cytotoxicity. Microarray analysis identified up-regulation of the RELB signaling genes, confirmed by Western blotting and functionally by RELB knockdown. CONCLUSIONS: In conclusion, blood S100A9+ MDSC is a predictor of poor treatment response to EGFR-TKI, possibly via its derived TAMs through activation of the non-canonical NF-κB RELB pathway. METHODS: Patients with activating EGFR mutation lung adenocarcinoma receiving first line EGFR TKIs were prospectively enrolled. Peripheral blood mononuclear cells (PBMCs) were collected for MDSCs analysis and for monocyte-derived macrophages (MDMs) and stored tissue for TAM analysis by IHC. A transwell co-culture system of MDMs/macrophages and H827 cells was used to detect the effect of macrophages on H827 and microarray analysis to explore the underlying molecular mechanisms, functionally confirmed by RNA interference.

Correction: S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: the role of RELB.

[This corrects the article DOI: 10.18632/oncotarget.24146.].

The concentration-dependent chemokine release and pro-apoptotic effects of neutrophil-derived alpha-defensin-1 on human bronchial and alveolar epithelial cells.

Defensins play a pivotal role in antimicrobial reactions, inflammatory responses, wound repair, and specific immunity. In inflammatory and infectious lung diseases, alpha-defensins are released from recruited neutrophils, and modulate a variety of lung cell functions. We found that human bronchial and alveolar epithelial cells treated with low and moderate concentrations (5 and 10 micro g/ml) of purified neutrophil-derived alpha-defensin-1 secreted more interleukin (IL)-8 and monocyte chemoattractant protein (MCP)-1 in a dose- and time-dependent manner. Under moderate and high concentrations (10 and 20 micro g/ml) of alpha-defensin-1, we observed typical apoptotic changes in the lung epithelial cells after stimulation for 24 h. Furthermore, alpha-defensin-1 triggered lung cell detachment in a time- and dose-dependent manner at moderate and high concentrations. Prior to the detachment, caspase-3 activity significantly increased. On confocal laser microscopy, rapid translocation of alpha-defensin-1 to the endoplasmic reticulum (ER) was noted. These findings suggest that neutrophil-derived alpha-defensin-1 has pro-inflammatory and apoptotic effects in human bronchial and alveolar epithelial cells, which are concentration-dependent and may be associated with ER activity.

Revisit of 1997 TNM staging system--survival analysis of 1112 lung cancer patients in Taiwan.

BACKGROUND: There is neither a nation-wide nor a large-scale, multi-institutional lung cancer database available for stage-by-stage survival analysis in Taiwan at present. METHODS: Using the data element provided by the International Association for the Study of Lung Cancer, the Taiwan Lung Cancer Society initiated a project to include native lung cancer patients into a global database. A total of 1112 Taiwan lung cancer patients treated in 7 medical centers were enrolled. RESULTS: In small cell lung cancer, patients with ipsilateral pleural effusion had a survival between those with locoregional disease alone and those with distant metastasis; however, the difference was not statistically significant (P = 0.204). In non-small cell lung cancer, tumor size had significant survival influence for patients as a whole (P < 0.001) but it did not support the further division of stage IA according to tumor size (P = 0.122). The survival was compatible in stage IIIB and IV patients and therefore, the survival impact of pleural effusion cannot be determined. In patients with pIIIA-N2 disease, those who had station 8 nodal metastasis had inferior survival (P = 0.020) and station 5 superior survival (P = 0.010). In patients with distant metastasis, bone, liver, or distant lymph node metastasis predicted an inferior survival (all P values < 0.05). CONCLUSIONS: The present study provides for comparison in this area a stage-by-stage reference for the survival of lung cancer patients. Some factors other than current TNM descriptors need to be further investigated in constructing the next version of the staging system.

Domiciliary positive expiratory pressure improves pulmonary function and exercise capacity in patients with chronic obstructive pulmonary disease.

BACKGROUND/PURPOSE: This study assessed how positive expiratory pressure (PEP) affected pulmonary function, functional capacity, and subjective cough difficulty in individuals with chronic obstructive pulmonary diseases (COPD). METHODS: This was a prospective, randomized, controlled study. Subjects were recruited from an outpatient department at a university hospital. Thirty-two patients with COPD were allocated to either PEP + FET (forced expiratory technique) group (n = 16) or FET only group (n = 16). Subjects in PEP + FET and FET groups were in a clinically stable condition before and during the study. Subjects in the PEP + FET group received PEP breathing using a mouth adjunct to FET, and the FET group was administered FET for 4 weeks only. Patients received weekly follow-up during the study period. Pulmonary function, 6-minute walk tests, and subjective cough difficulty scores were measured before and after the 4-week interventions. RESULTS: Subjects in the PEP + FET group had a significantly increased diffusing capacity (DLCO) compared to preintervention (p < 0.05) and after intervention in the FET group (p < 0.05). DLCO significantly increased in the PEP + FET group from 18.0 +/- 7.3 to 20.1 +/- 7.2 mL/min/mmHg. The 6-minute walking distance (6MWD) also increased significantly from 516.8 +/- 94.1 to 570.6 +/- 60.4 m in the PEP + FET group (p < 0.001) after intervention, compared to that for the FET group (p < 0.05). Additionally, the PEP + FET group had significantly lower cough difficulty scores compared to those at baseline and in the FET group. CONCLUSION: Four-week PEP therapy as an adjunct to FET further enhanced DLCO and 6MWD, and reduced cough difficulty compared to FET only in COPD patients with mucus hypersecretion.

The efficacy of 40 mg versus dose de-escalation to less than 40 mg of afatinib (Giotrif) as the first-line therapy for patients with primary lung adenocarcinoma harboring favorable epidermal growth factor mutations.

The choice of a first-line therapy for lung cancer is a crucial decision that can impact the survival as well as the quality of life of a patient. Inhibitors of epidermal growth factor receptor (EGFR) such as afatinib, erlotinib, and gefitinib have previously been used to treat non-small cell lung cancer harboring favorable EGFR mutations. Although afatinib has greater efficacy than other EGFR inhibitors, adverse events related to its use can result in the discontinuation of the therapy. In this study, we compared the therapeutic efficacy in lung cancer patients of a regimen of 40 mg/day of afatinib with that of a lower dose regimen of <40 mg/day resulting either from a lower starting dose of 30 mg/day or dose adjustment. Seventy-nine patients were treated with 40 mg/day and 67 received de-escalated doses of <40 mg/day. There was no significant difference in the clinical characteristics of the two groups except that the proportion of patients with a body weight of 50 kg or more was greater in the 40 mg/day group. Otherwise, there were no significant differences between the two groups in the average time to treatment failure (TTF), the rates at which the administration of a second-line therapy was necessary, or the frequency and severity of adverse events. Overall, these results suggest that it is possible to calibrate the dosage of afatinib to suit individual patient parameters such as low body weight, and that such calibration can be advised based on the given patient's individual experience of the drug.

Six-month nocturnal nasal positive pressure ventilation improves respiratory muscle capacity and exercise endurance in patients with chronic hypercapnic respiratory failure.

BACKGROUND/PURPOSE: This study was designed to investigate the effects of 6 months of nocturnal nasal positive pressure ventilation (NNPPV) on respiratory muscle function and exercise capacity in patients with chronic respiratory failure. METHODS: A prospective, randomized, controlled design was used. Twenty-nine patients with chronic respiratory failure were enrolled and allocated to either the NNPPV (n = 14) or control group (n = 15). Patients in the NNPPV group received bi-level positive pressure ventilation via nasal mask for 6 consecutive months. Arterial blood gas, respiratory muscle assessment and 6-minute walk test (6MWT) were performed before and after the 6-month NNPPV intervention. Respiratory muscle function was assessed using the variables of maximal inspiratory pressure (Pimax), maximal expiratory pressure (Pemax), and maximum voluntary ventilation (MVV). RESULTS: Subjects in the NNPPV group showed a significant improvement in blood gas exchange and increased 6-minute walk distance (6MWD) compared to baseline and the control group. The 6MWD was significantly increased from 257.1 +/- 114.1 to 345.2 +/- 109.9 m (34.3%) in the NNPPV group. NNPPV also significantly improved MVV and Pimax relative to baseline. MVV was significantly increased from 19.2 +/- 6.5 to 22.3 +/- 7.1 L/min (16.1%) in the NNPPV group (p < 0.05). Furthermore, there was a significant correlation between the magnitude of MVV improvement and 6MWD change. CONCLUSION: The 6-month NNPPV treatment significantly decreased the partial pressure of carbon dioxide and improved daytime respiratory muscle function, thus contributing to exercise-capacity increase in patients with chronic respiratory failure.