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Introduction: Endothelial cell (EC) activation may increase systemic vascular permeability caused an extravasation of water (EVLW) in sepsis with acute respiratory distress syndrome (ARDS). The correlation of thrombin and EVLW in sepsis and ARDS hasn’t addressed.Methods Septic patients with ARDS were prospectively enrolled during 2014 and 2016, and EVLW and serum thrombin on day 1 and 3 were measured and compared between those with survival and non-survival. Additionally, morphologic change of human umbilical vein endothelial cells (HUVECs) with serum from patients with high and low EVLW was conducted.Results Twenty-seven patients were enrolled and the baseline characters including age, gender, APACHE II, prior 24hrs fluid balance, BMI, and shock status were similar between survivors and non-survivors. But day 1 EVLW was higher in non-survivor (27.5 ± 8.4 vs. 22 ± 6.5 ml/kg, p = 0.049). EVLW of survivor was improved from day 1 to day 3 (22 ± 6.5 vs. 11 ± 3.8 ml/kg, p = 0.0001), but it did not improve in non-survivor (27.5 ± 8.4 vs. 28 ± 6.7 ml/kg, p = 0.89). Thrombin level of survivor significantly improved (1.03 ± 0.55 vs. 0.87 ± 0.25 U/ml, p = 0.04) but it did not improve in non-survivor (1.97 ± 0.75 vs. 2.2 ± 0.75 U/ml, p = 0.07) from day 1 to day 3. EVLW and thrombin revealed a positive correlation (r2 = 0.71, p Conclusion The level of EVLW and thrombin correlated positively and may impact the survival of these patients. Thrombin inhibitor may act as a novel valuable approach for preventing endothelial hyper-permeability and provides the rational basis for the use of this kind of drug in patients with severe sepsis and ARDS.

RationaleSevere asthma and chronic obstructive pulmonary disease (COPD) share common pathophysiological traits such as relative corticosteroid insensitivity. We recently published three transcriptome-associated clusters (TACs) using hierarchical analysis of the sputum transcriptome in asthmatics from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort comprising one Th2-high inflammatory signature (TAC1) and two Th2-low signatures (TAC2 and TAC3).ObjectiveWe examined whether gene expression signatures obtained in asthma can be used to identify the subgroup of patients with COPD with steroid sensitivity.MethodsUsing gene set variation analysis, we examined the distribution and enrichment scores (ES) of the 3 TACs in the transcriptome of bronchial biopsies from 46 patients who participated in the Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease COPD study that received 30 months of treatment with inhaled corticosteroids (ICS) with and without an added long-acting β-agonist (LABA). The identified signatures were then associated with longitudinal clinical variables after treatment. Differential gene expression and cellular convolution were used to define key regulated genes and cell types.Measurements and main resultsBronchial biopsies in patients with COPD at baseline showed a wide range of expression of the 3 TAC signatures. After ICS±LABA treatment, the ES of TAC1 was significantly reduced at 30 months, but those of TAC2 and TAC3 were unaffected. A corticosteroid-sensitive TAC1 signature was developed from the TAC1 ICS-responsive genes. This signature consisted of mast cell-specific genes identified by single-cell RNA-sequencing and positively correlated with bronchial biopsy mast cell numbers following ICS±LABA. Baseline levels of gene transcription correlated with the change in RV/TLC %predicted following 30-month ICS±LABA.ConclusionSputum-derived transcriptomic signatures from an asthma cohort can be recapitulated in bronchial biopsies of patients with COPD and identified a signature of airway mast cells as a predictor of corticosteroid responsiveness.

Introduction The clinical features of patients with metastatic epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma receiving first-line therapy based on erlotinib combined with bevacizumab are unclear. Here, we sought to analyze the clinical features of this patient group. Methods Data were analyzed for the period from January 2015 to August 2019 for 49 patients with metastatic EGFR-mutated lung adenocarcinoma receiving first-line erlotinib-and-bevacizumab combination therapy from the Linkou and Kaohsiung Chang Gung Memorial Hospitals. Results The combination of erlotinib and bevacizumab showed an 83.7% objective response rate and a 97.9% disease control rate. The median progression-free survival (PFS) and overall survival (OS) were 22.0 [95% CI (19.7–22.33)] and 47.6 [95% CI (38.87–56.37)] months, respectively, for all patients. The secondary EGFR-T790M mutation rate in the patients with acquired resistance to the combination was 72.4%. No predictive factor associated with the appearance of secondary EGFR-T790M mutations was found. The most frequent adverse event (AE) caused by the combination therapy was dermatitis (100%), and most of the AEs were manageable and grades 1 and 2. Conclusion Erlotinib combined with bevacizumab is an effective and safe therapy for untreated metastatic EGFR-mutated lung adenocarcinoma. The combination does not alter secondary EGFR-T790M mutations in patients with acquired resistance and is feasible in real-world clinical practice. Graphic Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s40487-021-00152-6.

Immune checkpoint inhibitors (ICIs) are the standard treatment for non-small-cell lung cancer (NSCLC). We assessed the clinical prognostic factors in NSCLC patients receiving atezolizumab as a second- or later-line (2L+) treatment. Data were retrospectively collected for NSCLC patients treated with atezolizumab from July 2017 to June 2019 at six medical centers in Taiwan. Clinical characteristics, treatment course and responses of patients were recorded. A total of 128 NSCLC patients received 2L+ atezolizumab, and the outcomes included a response rate of 10.2%, median progression-free survival (mPFS) of 3.5 months, and median overall survival (mOS) of 10.7 months. Eleven patients who had received osimertinib treatment before atezolizumab had a shorter mPFS (2.3

The aim of this retrospective study was to investigate the tolerability and survival outcomes of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment in patients with a performance status ≥ 2. The data for 517 patients treated with EGFR-TKIs between January 2011 and January 2018 at a regional hospital in northern Taiwan were analyzed. Clinical and pathological features were collected, and univariate as well as multivariable analyses were undertaken to identify potential prognostic factors. The overall objective response rate, median progression-free survival (PFS), and median overall survival (OS) were 56.3%, 11.4 months, and 15.3 months, respectively. The mutation status (exon 19 deletion), locally advanced disease, dose adjustment, and the lack of liver and pleural metastasis were independent and favorable prognostic factors for PFS. Age < 60 years, mutation status (exon 19 deletion), dose adjustment, and lack of lung, liver, and no pleural metastasis were independent and favorable prognostic factors for OS. GFR-TKIs demonstrated acceptable efficacy and safety in the current cohort. Dose adjustment was identified as an independent prognostic factor for both PFS and OS, regardless of which EGFR-TKIs were used. The current research provided novel evidence of the clinical prescription of frontline EGFR-TKIs for EGFR-mutated lung adenocarcinoma patients with a PS score ≥2.

Background Concurrent chemoradiotherapy (CCRT) is an optimal recommended treatment for stage III non‐small cell lung cancer (NSCLC). Herein, we aimed to investigate the efficacy and safety of oral vinorelbine plus cisplatin with concomitant radiotherapy for stage III NSCLC. Methods This prospective, open‐label, single‐arm, observational cohort study was performed between January 2010 and September 2016. Patients were treated with two cycles of chemotherapy with 60 mg/m2 intravenous cisplatin on day 1 and 50 mg/m2 oral vinorelbine on days 1, 8, and 15; radiotherapy was administered concurrently from day 1 when chemotherapy was initiated. A total dose of 66–70 Gy radiotherapy was delivered in daily fractions of 2 Gy for 6.5–7 consecutive weeks. The tumor response was assessed after completing concomitant treatment. Results A total of 58 patients were enrolled and analyzed; 31 patients had stage IIIA NSCLC and 27 had stage IIIB NSCLC. After induction CCRT, 31 patients achieved an objective response (complete response in one and partial response in 30; the response rate was 53.4%). The median progression‐free survival was 6.73 months (95% confidence interval [CI], 5.42–7.91), duration of response was 12.30 months (95% CI, 5.59–19.01), and overall survival was 24.83 months (95% CI, 19.26–30.21). No treatment‐related mortality was observed, and neutropenia was the most common grade 3 and 4 treatment‐related toxicity (11 patients; 18.9%). Conclusions CCRT with the weekly regimen of oral vinorelbine plus triweekly cisplatin was effective and safe for stage III NSCLC.

Early-stage NSCLC (stages I and II, and some IIIA diseases) accounts for approximately 30% of non-small cell lung cancer (NSCLC) cases, with surgery being its main treatment modality. The risk of disease recurrence and cancer-related death, however, remains high among NSCLC patients after complete surgical resection. In previous studies on the long-term follow-up of post-operative NSCLC, the results showed that the five-year survival rate was about 65% for stage IB and about 35% for stage IIIA diseases. Platinum-based chemotherapy with or without radiation therapy has been used as a neoadjuvant therapy or post-operative adjuvant therapy in NSCLC, but the improvement of survival is limited. Immune checkpoint inhibitors (ICIs) have effectively improved the 5-year survival of advanced NSCLC patients. Cancer vaccination has also been explored and used in the prevention of cancer or reducing disease recurrence in resected NSCLC. Here, we review studies that have focused on the use of immunotherapies (i.e., ICIs and vaccination) in surgically resectable NSCLC. We present the results of completed clinical trials that have used ICIs as neoadjuvant therapies in pre-operative NSCLC. Ongoing clinical trials investigating ICIs as neoadjuvant and adjuvant therapies are also summarized.

Second primary cancer is prevalent in patients with gastrointestinal (GI) cancer, for which lung cancer is the most common and associated with high lethality. Image screening for lung cancer was proved to be effective in early diagnosis and lower mortality. However, trials of screen for lung cancer generally excluded patients with a previous diagnosis of malignancy. The study aimed to investigate the outcome of second primary lung cancer and the factor that improve survival in patients with hepato-GI cancer. A total of 276 patients with secondary lung cancer were found among 3723 newly-diagnosed lung cancer patients diagnosed in Chang Gung Memorial Hospital, between 2010 and 2014. Patients’ clinical characteristics, stages and survival were recorded and analyzed. The patients were separated into 2 groups: Group I was defined as lung cancer detected in original primary cancer clinic and group II patients defined as lung cancer detected in other medical places. Sixty-nine cases with primary GI-hepatic and secondary lung cancer were diagnosed (42 (60.8%) in Group I and 27 (39.1%) in Group II). Although both groups had comparable primary cancer stages and treatment, more patients in Group I than Group II were diagnosed as early stage lung cancer (stage I-II: 40.5% vs 11.1%; P = .023). Group II had larger lung tumor sizes than Group I (4.7 vs 3.5 cm; P = .025). Group I showed better 5-year overall survival than Group II (P = .014, median survival: 27 vs 10 months). Among Group II, only 37% had received image follow up in clinic compared with 67% of Group I cases (P = .025). Patients with chest image follow up in clinics also had better 5-year overall survival (P = .043). GI-hepatic cancer was the most common primary malignancy in the lung cancer cohort. Patients had better survival outcome when secondary lung cancer was diagnosed in original primary cancer clinic. Chest image screening strategy may contribute better survival in secondary lung cancer due to detection at an earlier stage.

Background and aim Appropriate sedation is important to the success of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). Dexmedetomidine is a sedative agent that operates via the α2 adrenergic agonist, which provides sleep-like sedation with little respiratory suppression. This study compared the efficacy and safety of dexmedetomidine sedation with propofol in cases of EBUS-TBNA. Methods Patients requiring EBUS-TBNA were randomly assigned dexmedetomidine sedation (D, n=25) or propofol sedation (P, n=25). Vital signs, diagnostic yield and the bispectral index (BIS) were recorded throughout the bronchoscopic procedure and recovery period. The tolerance and cooperation of the patients were evaluated using questionnaires. Measurements and results The lowest mean arterial blood pressure in group D (79.2±9.9 versus 72.5±12.9 mmHg, p=0.049) exceeded that in group P, the lowest heart rate was lower (60.9±10.2 versus 71.4±11.8 beats·min−1, p=0.006) and the mean BIS during sedation was significantly higher (84.1±8.3 versus 73.6±5.7, p, Compared to propofol sedation for EBUS-TBNA, dexmedetomidine provided patients lighter sedation with lower heart rates and less decrease in blood pressure. The recovery times, hypoxaemia, cooperation and diagnostic yield in the two groups were similar. https://bit.ly/33qgEj3

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is the standard first-line therapy for metastatic lung adenocarcinoma harboring sensitive EGFR mutations. Tumor surface programmed death-ligand 1 (PD-L1) is expressed in some metastatic EGFR-mutated lung adenocarcinoma, but its impact on the efficacy of EGFR-TKIs is unclear. We retrospectively investigated 117 untreated metastatic lung EGFR mutated adenocarcinoma patients with a PD-L1 immunohistochemistry test. The PD-L1 expression level was classified by tumor proportion scores (TPS). Forty-five patients had negative expression (TPS &lt, 1%), 45 had a weak expression (TPS 1&ndash, 49%), and 27 had a strong expression (&ge, 50%). All patients recruited in this study received EGFR-TKIs as a first-line therapy. No significant differences were observed for objective response rates (68.9% versus 62.2% versus 73.1%, p = 0.807) and median time to treatment failure (TTF) (12.17 versus 13.17 versus 11.0 months, p = 0.443) of first-line EGFR-TKIS among the three groups of patients (negative versus weak versus strong). The median overall survival was 21.27 versus 20.63 versus 19.43 months among the three groups of patients (p = 0.77). Our results demonstrated that PD-L1 did not affect the efficacy of first-line EGFR-TKIs in metastatic EGFR mutated lung adenocarcinoma. Thus, EGFR-TKIs are suggested as the preferred clinical therapy for these patients, despite their PD-L1 levels.

BACKGROUND: Sputum analysis in asthmatic patients is used to define airway inflammatory processes and might guide therapy. OBJECTIVE: We sought to determine differential gene and protein expression in sputum samples from patients with severe asthma (SA) compared with nonsmoking patients with mild/moderate asthma. METHODS: Induced sputum was obtained from nonsmoking patients with SA, smokers/ex-smokers with severe asthma, nonsmoking patients with mild/moderate asthma (MMAs), and healthy nonsmoking control subjects. Differential cell counts, microarray analysis of cell pellets, and SOMAscan analysis of sputum analytes were performed. CRID3 was used to inhibit the inflammasome in a mouse model of SA. RESULTS: Eosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in patients with SA compared with MMAs. Forty-two genes probes were upregulated (>2-fold) in nonsmoking patients with severe asthma compared with MMAs, including IL-1 receptor (IL-1R) family and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NRLP3) inflammasome members (false discovery rate

// Chien-Ying Liu 1, 2 , Chih-Liang Wang 1, 2 , Shih-Hong Li 1 , Ping-Chih Hsu 1 , Chih-Hung Chen 1 , Ting-Yu Lin 1, 2 , Chih-Hsi Kuo 1, 2 , Yueh-Fu Fang 1, 2 , How-Wen Ko 1 , Chih-Teng Yu 1, 2 , Tai-Yun Yang 1, 2 and Cheng-Ta Yang 1, 2 1 Division of Pulmonary Oncology, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan 2 School of Medicine, Chang Gung University, Taoyuan, Taiwan Correspondence to: Cheng-Ta Yang, email: yang1946@cgmh.org.tw Keywords: afatinib, dose de-escalation, epidermal growth factor mutations, lung adenocarcinoma, therapeutic efficacy Received: January 12, 2017 Accepted: March 22, 2017 Published: June 27, 2017 ABSTRACT 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

Background Malignant endobronchial mass (MEM) has poor prognosis, cryotherapy is reportedly to diagnose MEM, however, the therapeutic role of cryotherapy impacts on survival has not be well addressed. Methods Cohort data on post-cryotherapy MEM patients in a university-affiliated hospital between 2007 and 2012 were evaluated. Factors that impact survival of these subjects were analyzed using multivariate regression analysis. Results During study period, 67 patients (47 males), with median age was 63 years (range, 50–77 and median performance status of 2 (inter-quartile range [IQR], 2–3). Twenty-five had primary lung squamous cell carcinoma, 14 primary had lung adenocarcinoma, seven had metastatic colon adenocarcinoma, four had sarcoma, four had non-small cell lung cancer, four had small cell lung cancer, three had large cell carcinoma, two had lymphoma, one had muco-epidermoid carcinoma, two had esophageal squamous cell carcinoma, and one had metastatic renal cell carcinoma. MEM were observed as follows: 15 at the trachea, 14 at the left main bronchus, 12 at the right main bronchus, 12 at the right upper lobe bronchus, five at the right intermediate bronchus, three at the right lower lobe bronchus, three at the left upper lobe bronchus, two at the left lower lobe bronchus, and one at the right middle lobe bronchus Post-cryotherapy complications included minor bleeding (n = 14) and need for multiple procedures (n = 12); outcomes were relief of symptoms (n = 56), improved performance status (n = 49) and ability to receive chemotherapy (n = 43). After controlling for other variables, performance status improved after cryotherapy (odds ratio [OR] 3.7; p = 0.03; 95% confidence interval [CI] 1.2~10.7) and ability to receive chemotherapy (OR 4.3; p = 0.02; 95% CI 1.4~13.7) remained significant survival factor. Patients who received chemotherapy and cryotherapy had better survival than patients who received only cryotherapy (median, 472 vs. 169 days; log-rank test, p = 0.02; HR 0.37; 95% CI 0.16–0.89). Conclusion Cryotherapy could be useful management of MEM by flexible bronchoscopy. The performance status after cryotherapy improved and caused further chemotherapy possible for the study patients and thereby, improved survival. However, the mechanism in detail of cryotherapy improve survival should be explored in the future.

The efficacy of afatinib in combination with bevacizumab in untreated advanced epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma is currently unclear. We sought to investigate the efficacy of this combination through a multicenter observational analysis. Data for 57 patients with advanced EGFR-mutated lung adenocarcinoma who received afatinib combined with bevacizumab as first-line therapy at the Chang Gung Memorial Hospitals in Linkou and Kaohsiung and Taipei Tzu Chi Hospital from May 2015 to July 2019 were analyzed. The objective response rate and disease control rate of afatinib combined with bevacizumab therapy were 87.7% and 100%, respectively. In all patients, the median progression-free survival (PFS) and overall survival (OS) were 23.9 (95% confidence interval (CI) (17.56&ndash, 29.17)) and 45.9 (95% CI (39.50&ndash, 53.60)) months, respectively. No statistical significance between exon 19 deletion and L858R mutations was noted in PFS or OS. The most frequent adverse events (AEs) were diarrhea (98.2%) and dermatitis (96.5%), and most AEs were grade 2 or lower and manageable. The combination of afatinib and bevacizumab is an effective therapy for untreated advanced EGFR-mutated lung adenocarcinoma with acceptable safety. Future prospective studies focusing on this combination for untreated advanced EGFR-mutated lung adenocarcinoma are warranted.

Background: Precision medicine of asthma requires understanding of its heterogeneity and molecular pathophysiology. Aim: Three sputum-derived transcriptomic clusters (TACs) were previously identified [Kuo at al. Eur Respir J.2017, 49] in the U-BIOPRED cohort: TAC1 consisting of T2 high patients with eosinophilia, TAC2 with neutrophilia and inflammasome activation and TAC3, a more heterogeneous cluster with mostly paucigranulocytic patients. We further refine TAC3. Methods: Gaussian mixture modelling for model-based clustering was applied to sputum gene expression of 104 asthmatic participants from the adult cohort to substructure TAC3. Gene set variation analysis (GSVA) was used to explore the enrichment of gene signatures across the TACs. Results: We again produce the three TACs (TAC1 N=23, TAC2 N=24) but TAC3 was further split into two groups (TAC3a N=28, TAC3b N=29), distinguished by distinct neutrophils and macrophages density and enrichment of IL13 stimulation, inflammasome activation and OXPHOS gene signatures (Figure), as well as IL-4 and LPS-stimulated macrophage gene signatures. However, there were no distinguishing clinical features. Conclusion: Identification of sub-structure of sputum TACs, particularly of TAC3, will help towards improved targeted therapies.

In vitro models have demonstrated immune-modulating effects of bevacizumab (BEV). Combinations of an EGFR tyrosine kinase inhibitor (TKI) with BEV improve progression-free survival (PFS) in patients with EGFR-mutated lung adenocarcinoma. How BEV confers this clinical effect and the underlying mechanisms of its effect are not clear.A total of 55 patients with stage 4 EGFR-mutated lung adenocarcinoma were enrolled. Myeloid-derived suppressor cells (MDSCs), type 1 and type 2 helper T cells, and cytotoxic T lymphocytes were analyzed by flow cytometry. Clinical data were collected for analysis.In all, 25 patients received EGFR TKI and BEV combination therapy (the BEV/TKI group) and 30 patients received EGFR TKI monotherapy (the TKI-only group). The BEV/TKI group had longer PFS (23.0 versus 8.6 months [p = 0.001]) and, in particular, better intracranial control rates (80.0% versus 43.0% [p = 0.03]), a longer time to intracranial progression (49.1 versus 12.9 months [p = 0.002]), and fewer new brain metastases (38.0% versus 71.0% [p = 0.03]) than the TKI-only group did. The BEV/TKI group had a lower percentage of circulating MDSCs (20.4% ± 6.5% before treatment versus 12.8% ± 6.6% after treatment, respectively [p = 0.02]), and higher percentages of type 1 helper T cells (22.9% ± 15.3% versus 33.2% ± 15.6% [p0.01]) and cytotoxic T lymphocytes (15.5% ± 7.2% versus 21.2% ± 5.6% [p0.01]) after treatment, changes that were not seen in the TKI-only group. Pretreatment percentage of MDSCs was correlated with PFS, with this correlation attenuated after BEV/TKI treatment. Percentage of MDSCs was also associated with shorter time to intracranial progression.Combining a EGFR TKI with BEV extended PFS and protected against brain metastasis. Those effects were probably due to the reduction of circulating S100A9-positive MDSCs by BEV, which leads to restoration of effective antitumor immunity. Our data also support the rationale for a BEV-immune checkpoint inhibitor combination.

Background The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) eventually fails in treating advanced lung adenocarcinoma harboring sensitive EGFR mutations because of acquired resistance. In clinical practical setting, platinum-doublet chemotherapy has been frequently performed after failure of first-line EGFR-TKIs. The efficacy of different regimens was compared. Methods From January 2012 to December 2013, 160 patients with mutated EGFR receiving first-line EGFR-TKIs and second-line chemotherapy were analyzed retrospectively. Sixty-eight patients received pemetrexed-based therapy and among them, 61 were in combination with cisplatin. Ninety-two patients received non-pemetrexed-based therapy and among them, 79 were combined with cisplatin. Results The progression-free survival of first-line EGFR-KI was 9.0 and 8.6 months for pemetrexed and non-pemetrexed treatment groups respectively (HR: 0.9146, 95% CI: 0.6656 to 1.257, P =0.5818). The median progression-free survival (PFS) of second-line therapy was 8.3 and 5.6 months for pemetrexed and non-pemetrexed treatment groups respectively (HR: 0.4217, 95% CI: 0.2952 to 0.6025, P =0.0001). The median overall survival (OS) after first-line EGFR-TKIs was 16.9 and 10.3 months for pemetrexed and non-pemetrexed groups respectively (HR: 0.5160, 95% CI: 0.3381 to 0.7873, P =0.0021). For those receiving pemetrexed continuous maintenance therapy, there was 18.7 months of survival after first-line EGFR-TKI, compared to 11.1 months for those without maintenance (HR: 0.4012, 95% CI: 0.2577 to 0.6247, P Conclusion The efficacy of pemetrexed was superior to other chemotherapeutic agents in second line treatment for patients with lung adenocarcinoma harboring sensitive EGFR mutations after first-line EGFR-TKI therapy. Continuous maintenance pemetrexed therapy also improved the PFS and OS.

Chronic obstructive pulmonary disease (COPD) airways are characterised by thickening of airway smooth muscle, partly due to airway smooth muscle cell (ASMC) hyperplasia. Metabolic reprogramming involving increased glycolysis and glutamine catabolism supports the biosynthetic and redox balance required for cellular growth. We examined whether COPD ASMCs show a distinct metabolic phenotype that may contribute to increased growth. We performed an exploratory intracellular metabolic profile analysis of ASMCs from healthy nonsmokers, healthy smokers and COPD patients, under unstimulated or growth conditions of transforming growth factor (TGF)-β and fetal bovine serum (FBS). COPD ASMCs showed impaired energy balance and accumulation of the glycolytic product lactate, glutamine, fatty acids and amino acids compared to controls in unstimulated and growth conditions. Fatty acid oxidation capacity was reduced under unstimulated conditions. TGF-β/FBS-stimulated COPD ASMCs showed restoration of fatty acid oxidation capacity, upregulation of the pentose phosphate pathway product ribose-5-phosphate and of nucleotide biosynthesis intermediates, and increased levels of the glutamine catabolite glutamate. In addition, TGF-β/FBS-stimulated COPD ASMCs showed a higher reduced-to-oxidised glutathione ratio and lower mitochondrial oxidant levels. Inhibition of glycolysis and glutamine depletion attenuated TGF-β/FBS-stimulated growth of COPD ASMCs. Changes in glycolysis, glutamine and fatty acid metabolism may lead to increased biosynthesis and redox balance, supporting COPD ASMC growth., A metabolic shift in airway smooth muscle cells of COPD patients may support their increased growth and survival http://ow.ly/XVkb30eUTLJ

Background: Severe asthma and COPD share pathophysiologic traits such as chronic airflow obstruction, exacerbations and corticosteroid insensitivity. Aim: To examine whether there are common mechanisms through a molecular approach. Methods: Three transcriptomic-associated clusters (TACs) were described from a hierarchical analysis of sputum transcriptomics of U-BIOPRED cohort: TAC1=High T-2; TAC2= inflammasome; TAC3= Mitochondrial OXPHOS [Kuo at al. Eur Respir J.2017, 49, in press]. Using gene set variation analysis (GSVA), we examined the distribution of the 3 TACs in the transcriptome of bronchial biopsies from the GLUCOLD cohort (GSE36221). Results: Bronchial biopsies at baseline showed a wide range of expression of the 3 TACs, with a significant inverse correlation between ES TAC3 and ES TAC1 but a positive correlation between TAC3 and TAC2. After combined inhaled corticosteroids (ICS) and LABA, ES of TAC1 was significantly reduced at 6 and 30 months, but TAC2 and TAC3 ES were not affected. Conclusions: Mitochondrial dysfunction is present in COPD as previously reported, and that the expression of the 3 asthma-derived TACs in COPD indicate potential overlap of molecular pathways. As predicted, TAC1 is the only signature suppressed by ICS. Severe asthma and COPD may share common pathways.

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.

Objectives: To present the complications of Ultraflex Self-Expandable Metallic Stents (SEMSs) applied in patients with benign tracheobronchial diseases. Methods: Eighty patients received 124 SEMSs were retrospectively reviewed in a tertiary hospital. Results: The baseline characteristics of patients received SEMS implantation including age (mean + standard deviation: 62.5 + 14.8 years), gender (male, 60.5%), smoking (46.8%), forced expiratory volume in first one second (FEV1) (mean + standard deviation, 0.92 +0.41 L/s), follow-up days after SEMS implantation (median (interquartile range); 457 (131 - 897)) and covered SEMS (33.9%) were listed. Symptoms improved after SEMS implantation among 95 patients (76.6%). Time to complications developed was 236 (median; interquartile range, 59 - 672) days. The overall complication rate was 41.9% after SEMS implantation. The complications included SEMS migration (6.5%), granuloma (19.3%) and SEMS fracture (16.1%). Successful management rates of SEMS migration, granuloma and SEMS fracture were up to 100%, 83.3%, and 85% respectively. Conclusions: Patients received SEMS implantation due to benign conditions had poor lung function and were old. The complication rate in patients with benign conditions was high after longer follow-up period, however, successful management achieved in most patients with complications.