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Background: The comparative efficacies of different generation tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR)‐mutated advanced non‐small cell lung cancer (NSCLC) remain largely unknown. Moreover, whether one EGFR‐TKI confers superior survival remains unclear, especially in East Asians. We conducted a network meta‐analysis (NMA) comparing the survival outcomes of East Asian patients with advanced NSCLC treated with first‐line EGFR‐TKIs. Methods: The NMA included observational real‐world evidence studies on adult patients with EGFR‐mutated advanced NSCLC who received first (gefitinib and erlotinib), second (afatinib), or third (osimertinib) generation EGFR‐TKIs as frontline therapy. Studies were identified through an online bibliographic search of Medline articles in the PubMed, SCOPUS, Web of Science, and Cochrane Library databases. Results: For overall survival (OS), afatinib had significantly better hazard ratios (HRs) than osimertinib (HR: 0.46, 95% confidence interval [CI]: 0.23–0.91), gefitinib (HR: 0.56, 95% CI: 0.43–0.72), and erlotinib (HR: 0.71, 95% CI: 0.54–0.92). For progression‐free survival (PFS), afatinib had significantly better HRs than gefitinib (HR: 0.45, 95% CI: 0.36–0.56) and erlotinib (HR: 0.63, 95% CI: 0.49–0.81). Moreover, afatinib was most likely to achieve the longest OS (81.3%), followed by erlotinib (13%), osimertinib, and gefitinib. Furthermore, afatinib was most likely to achieve the longest PFS (48.3%), followed by osimertinib (34.9%) and erlotinib. Conclusions: This real‐world evidence shows that afatinib confers better survival than other first‐line EGFR‐TKIs in East Asian patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

Background: Despite the well‐established efficacies of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung cancer (NSCLC), there is limited real‐world evidence comparing their effectiveness according to patients' clinical characteristics. This network meta‐analysis (NMA) compared survival outcomes among first‐line EGFR‐TKIs in different subgroups of East Asian patients with advanced NSCLC. Methods: This NMA included real‐world observational studies reporting outcomes with TKIs in patients aged >65 years, with baseline brain metastasis, with different Eastern Cooperative Oncology Group (ECOG) statuses, or with different common EGFR mutation types. Results: In patients with the EGFR L858R mutation, afatinib resulted in significantly longer progression‐free survival (PFS) than erlotinib (hazard ratio [HR]: 0.59, 95% confidence interval [CI]: 0.46–0.75) and gefitinib (HR: 0.41, 95% CI: 0.32–0.53). Similarly, in patients with the EGFR Del19 mutation, afatinib and erlotinib resulted in significantly longer PFS than gefitinib (HR: 0.48 with 95% CI: 0.33–0.71 and HR: 0.54 with 95% CI: 0.36–0.80, respectively). Moreover, afatinib resulted in significantly longer PFS than gefitinib in patients with brain metastasis (HR: 0.53, 95% CI: 0.33–0.87) or ECOG status 0–1 (HR: 0.37, 95% CI: 0.23–0.59). Conclusion: This NMA suggests that afatinib results in similar PFS to erlotinib and superior PFS than gefitinib in patients with Del19 mutant NSCLC, aged ≥65 years, with ECOG scores of 0–1, and with baseline brain metastasis. [ABSTRACT FROM AUTHOR]

Exposure to BTEX has been suggested to be a potential risk factor for asthma,[[1], [3]] a heterogeneous disease with unclear etiology, but its individual risk for adult asthma and its phenotypic clusters remains unclear. An hourly grid-scale model was utilized to estimate the residence-based ambient air BTEX levels and the time-lag effect (lag-0, lag-1, lag-2, lag-3, lag-4, and lag-5) on the daily asthma ERVs and outpatient visits. Abbreviations 2,4-DPMA N -acetyl- S -(2,4-dimethylbenzene)- l -cysteine 4-HNE 4-hydroxynonenal BMA N -acetyl- S -(benzyl)- l -cysteine BTEX benzene, toluene, ethylbenzene, and xylene C1P ceramide-1-phosphate ERV emergency room visit HEL N -(hexanoyl)-lysine LC-MS liquid chromatography-tandem mass spectrometry NHIRD National Health Insurance Research Database PGA phenylglyoxylic acid PMA N -acetyl- S -phenyl- l -cysteine RR relative risk S1P sphingosine-1-phosphate SL sphingolipid VOCs volatile organic compounds In a combined population-based and case-control study, exposure to benzene, toluene, ethylbenzene, and xylene (BTEX), particularly benzene, concomitant with increased oxidative stress and sphingolipid dysregulation, posed a significant, but differential, risk for current asthma, its severity, and phenotypic clusters. [Extracted from the article]

Background: The aim of the study was to assess programmed death‐ligand‐1 (PD‐L1) expression in different histological types and gene mutation status of patients with non‐small cell lung cancer (NSCLC). Methods: A total of 4062 pathology‐confirmed lung cancer patients were retrospectively screened at Kaohsiung Chang Gung Memorial Hospital from November 2010 to June 2017. There were 699 NSCLC patients with confirmed PD‐L1 expression level retrospectively enrolled for analysis. Results: There was a trend of higher PD‐L1 expression in squamous cell carcinoma and adenosquamous cell carcinoma than in adenocarcinoma (p = 063). Significant higher PD‐L1 expression in EGFR wild‐type was noted (p < 0.001). No significant differences in PD‐L1 expression were found between ALK wild‐ and mutant types, but there seem was a trend of high PD‐L1 level noted in ALK mutation patients (p = 0.069). In EGFR mutation patients, a higher time to treatment failure (TTF) duration was observed in no PD‐L1 expression (p = 0.011). Longer tumor tissue storage time correlated with lower PD‐L1 expression in lung cancer (p < 0.001 for linear trend). Conclusions: There were a trend or significant differences in PD‐L1 expression between different histological types in NSCLC, different EGFR and ALK status, and different tumor tissue storage time. A higher survival benefit was observed in no PD‐L1 expression than with PD‐L1 expression in adenocarcinoma, EGFR and ALK mutation patients. We recommend that PD‐L1 assay should be performed as early as possible if tissue is available. [ABSTRACT FROM AUTHOR]

Purpose To investigate the survival benefit with first/second generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) and osimertinib in different treatment sequences. Methods: We retrospectively screened 3807 patients diagnosed with cancer between 2013 and 2019 at Kaohsiung Chang Gung Memorial Hospital. In total, 76 patients with EGFR T790M mutation who received osimertinib after re‐biopsy or liquid biopsy were enrolled for the analysis. Results: The median progression‐free survival (PFS), median overall survival (OS), and median OS2 of the 76 patients were 11.93, 66.53, and 29.57 months, respectively. A significant difference was observed in the disease control rate between those who received osimertinib treatment after chemotherapy (group A) and those who received osimertinib immediately following EGFR‐TKI therapy (group B) (34 [94.4%] vs. 31 [77.5%], p = 0.036). In addition, chronic obstructive pulmonary disease tended to be a poor prognostic factor for PFS and OS. Conclusion: This real‐world analysis revealed that previous chemotherapy could affect the treatment outcomes of patients with non‐small cell lung cancer treated with osimertinib. Osimertinib treatment following first/second generation EGFR‐TKI treatment or chemotherapy resulted in improved survival benefit. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is a syndrome leading to chronic intermittent hypoxia, and the up-regulation of toll-like receptors (TLR) 2 and 6 on peripheral blood cells has been reported. We hypothesized that DNA methylation in TLR2 and TLR6 genes may play a role in the development of OSA and its excessive daytime sleepiness (EDS) phenotype. DNA methylation over 28 cytosine-phosphate-guanine (CpG) sites of the TLR2 promoter region and 3 CpG sites of the TLR6 gene body, and their protein expressions were measured by using pyrosequencing and ELISA methods in 18 heathy subjects (HS) and 58 patients with severe OSA (divided into 18 non-EDS and 40 EDS group). Patients with severe OSA had higher DNA methylation levels over five CpG sites (#1, #2, #3, #25 and #28) and lower DNA methylation levels over CpG site #18 of the TLR2 promoter region, higher DNA methylation levels over two CpG sites (#1 and #3) of the TLR6 gene body, and higher protein expressions of TLR6 than HS. The CpG site #2 of the TLR6 gene body was hypermethylated in severe OSA patients with EDS. Both DNA methylation levels over CpG site #1 of the TLR6 gene body and protein expressions of TLR6 were reduced after more than 6 months of nasal CPAP treatment in seven selected patients. Aberrant DNA methylation of the TLR2 promoter region and TLR6 gene body are associated with the consequence of severe OSA and its EDS phenotype. [ABSTRACT FROM AUTHOR]

In the pre-tyrosine kinase inhibitors (TKIs) era, non-small cell lung cancer (NSCLC) patients with de novo bone metastases had a worse prognosis than those without. However, whether (EGFR)-TKIs affect the outcomes of EGFR mutant NSCLC patients with de novo bone metastases has not been well studied thus far. We retrospectively studied the effect of EGFR mutation status and first-line EGFR-TKIs on patient outcomes and created a survival scoring system for NSCLC patients with de novo bone metastases. This retrospective study evaluated 1510 NSCLC patients diagnosed between November 2010 and March 2014. Among these patients, 234 patients had de novo bone metastases. We found that 121 of these 234 patients (51.7%) had positive EGFR mutation tests, and a positive EGFR mutation test significantly affected overall survival (OS) (EGFR mutant: 15.2 months, EGFR wild type: 6.5 months; p < 0.001). Other prognostic factors significant in the multivariable analysis for NSCLC with de novo bone metastases included Eastern Cooperative Oncology Group performance status (PS) (OS; PS 0–2: 11.2 months, PS 3–4: 4.9 months; p = 0.002), presence of extraosseous metastases (OS; with extraosseous metastases: 8.8 months, without extraosseous metastases: 14.0 months; p = 0.008), blood lymphocyte-to-monocyte ratio (LMR) (OS; LMR > 3.1: 17.1months, LMR ≤ 3.1: 6.9months; p < 0.001). A positive EGFR mutation status reversed the poor outcomes of NSCLC patients with de novo bone metastases. A simple and useful survival scoring system including the above clinical parameters was thus created for NSCLC patients with de novo bone metastases. [ABSTRACT FROM AUTHOR]

Microparticles (MPs) are substantially increased in patients with operable stage non-small cell lung cancer (NSCLC) prior to lung resection surgery. This study tested the hypothesis that there is a decrease in MPs after surgical intervention. Between March 2012 and January 2015, 33 patients who had operable stage NSCLC were consecutively and prospectively enrolled into the study. Additionally, 31 healthy subjects who were consecutively enrolled in the study period served as age- and gender-matched controls. Circulating MPs (EDAc-MPs, EDAp-MPs, PDAc-MPs, PDAp-MPs) were measured by flow cytometry once in control subjects and twice (i.e., prior to and three months later after surgical intervention) in NSCLC patients. Compared with control subjects, these four types of circulating MPs were significantly higher in NSCLC patients prior to operation (all P < 0.005), but did not differ among the controls and NSCLC patients at 3 months after surgery (all P > 0.2). Additionally, a receiver operating characteristic curve (ROC) showed that these four types of MPs were significantly valuable predictors for detecting early stage NSCLC (all P < 0.004). Circulating MPs which were remarkably increased in the operable stage of NSCLC prior to surgery were substantially decreased 3 months later after surgery. These findings show that circulating MPs might be an accessory biomarker for monitoring those of NSCLC after receiving lung resection surgery. [ABSTRACT FROM AUTHOR]

Background: Antacid treatments decrease the serum concentrations of first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), although it is unknown whether antacids affect clinical outcomes. As cerebrospinal fluid concentrations of TKIs are much lower than serum concentrations, we hypothesized that this drug-drug interaction might affect the prognosis of patients with de novo brain metastases. Materials and Methods: This retrospective study evaluated 269 patients with EGFR-mutant non-small cell lung cancer (NSCLC) who had been diagnosed between December 2010 and December 2013, and had been treated using first-line first-generation EGFR-TKIs. Among these patients, we identified patients who concurrently used H2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) as antacids. Patients who exhibited >30% overlap between the use of TKIs and antacids were considered antacid users. Results: Fifty-seven patients (57/269, 21.2%) were antacid users, and antacid use did not significantly affect progression-free survival (PFS; no antacids: 11.2 months, H2RAs: 9.4 months, PPIs: 6.7 months; p = 0.234). However, antacid use significantly reduced overall survival (OS; no antacids: 25.0 months, H2RAs: 15.5 months, PPIs: 11.3 months; p = 0.002). Antacid use did not affect PFS for various metastasis sites, although antacid users with de novo brain metastases exhibited significantly shorter OS, compared to non-users (11.8 vs. 16.3 months, respectively; p = 0.041). Antacid use did not significantly affect OS in patients with bone, liver, or pleural metastases. Conclusion: Antacid use reduced OS among patients with EGFR-mutant NSCLC who were treated using first-line first-generation EGFR-TKIs, and especially among patients with de novo brain metastases. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress is known to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Evidence suggests that leukocytes mitochondria DNA (mtDNA) is susceptible to undergo mutations, insertions, or depletion in response to reactive oxidative stress (ROS). We hypothesize that mtDNA copy number is associated with the development of COPD. Methodology/Principal Findings: Relative mtDNA copy number was measured by a quantitative real-time PCR assay using DNA extracted from peripheral leukocytes. MtDNA copy number of peripheral leukocytes in the COPD group (n = 86) is significantly decreased compared with non-smoker group (n = 77) (250.3± 21.5 VS. 464.2± 49.9, P<0.001). MtDNA copy number in the COPD group was less than that in the healthy smoking group, but P value nearly achieved significance (250.3± 21.5 VS. 404.0± 76.7, P = 0.08) MtDNA copy number has no significance with age, gender, body mass index, current smoking, and pack-years in COPD group, healthy smoker group and no smoker group, respectively. Serum glutathione level in the COPD group is significantly decreased compared with healthy smoker and non-smoker groups (4.5± 1.3 VS. 6.2± 1.9 and 4.5± 1.3 VS. 7.1±1.1 mU/mL; P<0.001 respectively). Pearson correlation test shows a significant liner correlation between mtDNA copy number and serum glutathione level (R = 0.2, P = 0.009). Conclusions/Significance: COPD is associated with decreased leukocyte mtDNA copy number and serum glutathione. COPD is a regulatory disorder of leukocytes mitochondria. However, further studies are needed to determine the real mechanisms about the gene and the function of mitochondria. [ABSTRACT FROM AUTHOR]

Background: Patients with early-stage lung cancer who have a high baseline lymphocyte-to-monocyte ratio (LMR) have a favorable prognosis. However, the prognostic significance of LMR in patients with advanced-stage EGFR-mutant non-small cell lung cancer (NSCLC) receiving first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has not been established. We conducted a retrospective analysis to investigate the influence of LMR on clinical outcomes including progression-free survival (PFS) and overall survival (OS) in EGFR-mutant patients with NSCLC. Materials and Methods: Of 1310 lung cancer patients diagnosed between January 2011 and October 2013, 253 patients receiving first-line EGFR-TKIs for EGFR-mutant NSCLC were included. The cut-off values for baseline and the 1-month-to-baseline ratio of LMR (MBR), determined by using receiver operating characteristic curves, were 3.29 and 0.63, respectively. Patients were divided into 3 prognostic groups: high LMR and MBR, high LMR or MBR, and low LMR and MBR. Results: The mean patient age was 65.2 years, and 41% were men. The median PFS and OS were 10.3 and 22.0 months, respectively. The PFS in patients with high LMR and MBR, high LMR or MBR, and low LMR and MBR were 15.4, 7.1, and 2.0 months, respectively (p < 0.001), whereas the OS were 32.6, 13.7, and 5.1 months, respectively (p < 0.001). Conclusion: A combination of baseline and trend of LMR can be used to identify patients with a high mortality risk in EGFR-mutant NSCLC patients receiving first-line EGFR-TKIs. [ABSTRACT FROM AUTHOR]

The Lipid A moiety of endotoxin potently activates TLR-4 dependent host innate immune responses. We demonstrate that Lipid-A mediated leukotriene biosynthesis regulates pathogen-associated molecular patterns (PAMP)-dependent macrophage activation. Stimulation of murine macrophages (RAW264.7) with E. coli 0111:B4 endotoxin (LPS) or Kdo2-lipid A (Lipid A) induced inflammation and Lipid A was sufficient to induce TLR-4 mediated macrophage inflammation and rapid ERK activation. The contribution of leukotriene biosynthesis was evaluated with a 5-lipoxygenase activating protein (FLAP) inhibitor, MK591. MK591 pre-treatment not only enhanced but also sustained ERK activation for up to 4 hours after LPS and Lipid A stimulation while inhibiting cell proliferation and enhancing cellular apoptosis. Leukotriene biosynthesis inhibition attenuated inflammation induced by either whole LPS or the Lipid A fraction. These responses were regulated by inhibition of the key biosynthesis enzymes for the proinflammatory eicosanoids, 5-lipoxygenase (5-LO), and cyclooxygenase-2 (COX-2) quantified by immunoblotting. Inhibition of leukotriene biosynthesis differentially regulated TLR-2 and TLR-4 cell surface expression assessed by flow cytometry, suggesting a close mechanistic association between TLR expression and 5-LO associated eicosanoid activity in activated macrophages. Furthermore, MK591 pre-treatment enhanced ERK activation and inhibited cell proliferation after LPS or Lipid A stimulation. These effects were regulated in part by increased apoptosis and modulation of cell surface TLR expression. Together, these data clarify the mechanistic association between 5-lipoxygenase activating protein-mediated leukotriene biosynthesis and 5-LO dependent eicosanoid metabolites in mediating the TLR-dependent inflammatory response after endotoxin exposure typical of bacterial sepsis. [ABSTRACT FROM AUTHOR]

Nutritional status could affect clinical outcomes in critical patients. We aimed to determine the prognostic accuracy of the modified Nutrition Risk in Critically Ill (mNUTRIC) score for hospital mortality and treatment outcomes in patients with severe community-acquired pneumonia (SCAP) compared to other clinical prediction rules. We enrolled SCAP patients in a multi-center setting retrospectively. The mNUTRIC score and clinical prediction rules for pneumonia, as well as clinical factors, were calculated and recorded. Clinical outcomes, including mortality status and treatment outcome, were assessed after the patient was discharged. We used the receiver operating characteristic (ROC) curve method and multivariate logistic regression analysis to determine the prognostic accuracy of the mNUTRIC score for predicting clinical outcomes compared to clinical prediction rules, while 815 SCAP patients were enrolled. ROC curve analysis showed that the mNUTRIC score was the most effective at predicting each clinical outcome and had the highest area under the ROC curve value. The cut-off value for predicting clinical outcomes was 5.5. By multivariate logistic regression analysis, the mNUTRIC score was also an independent predictor of both clinical outcomes in SCAP patients. We concluded that the mNUTRIC score is a better prognostic factor for predicting clinical outcomes in SCAP patients compared to other clinical prediction rules. [ABSTRACT FROM AUTHOR]

Body mass index (BMI) influences the prognosis of patients with non-small cell lung cancer (NSCLC), including both early-stage and late-stage NSCLC patients that are undergoing chemotherapies. However, earlier research on the relationship between BMI and survival in patients taking epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) yielded contradictory results. These publications either had a limited number of patients or were getting TKIs in various lines of therapy, which might explain why the outcomes were contradictory. As a result, we undertook retrospective study to examine the effect of BMI on survival outcomes in patients with advanced EGFR mutant NSCLC receiving first-line EGFR-TKIs. We also compared the findings to those with wild-type EGFR. Between November 2010 and March 2014, 513 patients with advanced NSCLC were enrolled in the study. According to the adjusted BMI cut-off point for Asia, 35 out of 513 (6.8%) patients were underweight (BMI < 18.5 kg/m2), whereas 197 (38.4%) were overweight (BMI > 24 kg/m2). Overweight patients with wild-type EGFR exhibited longer progression-free survival (4.6 vs. 2.1 months, p = 0.003) and overall survival (OS) (8.9 vs. 4.3 months, p = 0.003) than underweight patients. Overweight patients with EGFR mutations had a longer OS than normal-weight patients (23.0 vs. 20.2 months, p = 0.025). Bodyweight reduction was related to a shorter OS in both the mutant EGFR patients (17.1 vs. 30.5 months, p < 0.001) and the wild-type EGFR patients (7.8 vs. 18.7 months, p < 0.001). In conclusion, advanced stages NSCLC patients with a lower BMI and early weight loss had a worse outcome that was independent of EGFR mutation status. [ABSTRACT FROM AUTHOR]

Dual open‐slot antennas were integrated in the metal back case and metal frame of a tablet computer for long‐term evolution applications. The single feed dual excitation source antennas were sufficiently narrow (2 mm) for installation between the metal frame and metal back case of the tablet computer. Each antenna had two open‐slot radiators (slot 1 and slot 2) with embedded filter circuits to enable wideband (699‐906 and 1710‐2690 MHz) operation required for LTE applications. The filter circuit values were adjusted to make the impedance more smooth and excite the desired modes. The proposed multiple‐input‐multiple‐output antennas were installed lengthwise on the long sides of the tablet and facing in operate directions. In this configuration, the user hand grip did not interfere with antenna performance, and isolation was improved (> 20 dB). The operating mechanism of the proposed antenna with matching circuits is described in detail. The effects of the user hand grip and the embedded display panel are also discussed. [ABSTRACT FROM AUTHOR]

Background: Adult asthma is phenotypically heterogeneous with unclear aetiology. We aimed to evaluate the potential contribution of environmental exposure and its ensuing response to asthma and its heterogeneity., Methods: Environmental risk was evaluated by assessing the records of National Health Insurance Research Database (NHIRD) and residence-based air pollution (particulate matter with diameter less than 2.5 micrometers (PM 2.5 ) and PM 2.5 -bound polycyclic aromatic hydrocarbons (PAHs)), integrating biomonitoring analysis of environmental pollutants, inflammatory markers and sphingolipid metabolites in case-control populations with mass spectrometry and ELISA. Phenotypic clustering was evaluated by t-distributed stochastic neighbor embedding (t-SNE) integrating 18 clinical and demographic variables., Findings: In the NHIRD dataset, modest increase in the relative risk with time-lag effect for emergency (N=209 837) and outpatient visits (N=638 538) was observed with increasing levels of PM 2.5 and PAHs. Biomonitoring analysis revealed a panel of metals and organic pollutants, particularly metal Ni and PAH, posing a significant risk for current asthma (ORs=1.28-3.48) and its severity, correlating with the level of oxidative stress markers, notably Nε-(hexanoyl)-lysine (r=0.108-0.311, p<0.05), but not with the accumulated levels of PM 2.5 exposure. Further, levels of circulating sphingosine-1-phosphate and ceramide-1-phosphate were found to discriminate asthma (p<0.001 and p<0.05, respectively), correlating with the levels of PAH (r=0.196, p<0.01) and metal exposure (r=0.202-0.323, p<0.05), respectively, and both correlating with circulating inflammatory markers (r=0.186-0.427, p<0.01). Analysis of six phenotypic clusters and those cases with comorbid type 2 diabetes mellitus (T2DM) revealed cluster-selective environmental risks and biosignatures., Interpretation: These results suggest the potential contribution of environmental factors from multiple sources, their ensuing oxidative stress and sphingolipid remodeling to adult asthma and its phenotypic heterogeneity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Nutritional status could affect clinical outcomes in critical patients. We aimed to determine the prognostic accuracy of the modified Nutrition Risk in Critically Ill (mNUTRIC) score for hospital mortality and treatment outcomes in patients with severe community-acquired pneumonia (SCAP) compared to other clinical prediction rules. We enrolled SCAP patients in a multi-center setting retrospectively. The mNUTRIC score and clinical prediction rules for pneumonia, as well as clinical factors, were calculated and recorded. Clinical outcomes, including mortality status and treatment outcome, were assessed after the patient was discharged. We used the receiver operating characteristic (ROC) curve method and multivariate logistic regression analysis to determine the prognostic accuracy of the mNUTRIC score for predicting clinical outcomes compared to clinical prediction rules, while 815 SCAP patients were enrolled. ROC curve analysis showed that the mNUTRIC score was the most effective at predicting each clinical outcome and had the highest area under the ROC curve value. The cut-off value for predicting clinical outcomes was 5.5. By multivariate logistic regression analysis, the mNUTRIC score was also an independent predictor of both clinical outcomes in SCAP patients. We concluded that the mNUTRIC score is a better prognostic factor for predicting clinical outcomes in SCAP patients compared to other clinical prediction rules.

We intended to develop a scoring system to predict mechanical ventilator dependence in patients who survive sepsis/septic shock with respiratory failure. This study evaluated 251 adult patients in medical intensive care units (ICUs) between August 2013 to October 2015, who had survived for over 21 days and received aggressive treatment. The risk factors for ventilator dependence were determined. We then constructed a ventilator dependence (VD) risk score using the identified risk factors. The ventilator dependence risk score was calculated as the sum of the following four variables after being adjusted by proportion to the beta coefficient. We assigned a history of previous stroke, a score of one point, platelet count less than 150,000/μL a score of one point, pH value less than 7.35 a score of two points, and the fraction of inspired oxygen on admission day 7 over 39% as two points. The area under the curve in the derivation group was 0.725 (p < 0.001). We then applied the VD risk score for validation on 175 patients. The area under the curve in the validation group was 0.658 (p = 0.001). VD risk score could be applied to predict prolonged mechanical ventilation in patients who survive sepsis/septic shock.

We investigated whether circulating microparticles (MPs) could serve as prognostic biomarkers in non-small cell lung cancer (NSCLC) patients. We enrolled 25 control subjects and 136 NSCLC patients categorized into disease-progression (DP, n=42) and disease-control (DC, n=94) groups. Flow cytometric analysis showed that levels of four types of circulating microparticles (EDAc-MPs, EDAp-MPs, PDAc-MPs and PDAp-MPs) were higher in the study patients than the control subjects ( P < 0.04). DP patients showed poor initially performance status and more non-adenocarcinomas than DC patients. DC patients showed more EGFR mutations and poorer performance to targeted therapy than DP patients ( P < 0.01). Three months after therapy, the levels of all four types of circulating MPs were lower in DC than DP patients ( P < 0.02), and were comparable to the levels in control subjects. In addition, the levels of circulating MPs after 3 months accurately predicted one-year prognostic outcomes ( P < 0.05). This study showed that circulating MPs are valuable prognostic biomarkers in advanced NSCLC patients., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interests.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are first-choice treatments for advanced non-small-cell lung cancer patients harboring EGFR mutations. Although EGFR mutations are strongly predictive of patients' outcomes and their response to treatment with EGFR-TKIs, early failure of first-line therapy with EGFR-TKIs in patients with EGFR mutations is not rare. Besides several clinical factors influencing EGFR-TKI efficacies studied earlier such as the Eastern Cooperative Oncology Group performance status or uncommon mutation, we would like to see whether semi-quantify EGFR mutation gene expression calculated by 2 -ΔΔct was a prognostic factor in EGFR-mutant non-small cell lung cancer patients receiving first-line EGFR-TKIs. This retrospective study reviews 926 lung cancer patients diagnosed from January 2011 to October 2013 at the Kaohsiung Chang Gung Memorial Hospital in Taiwan. Of 224 EGFR-mutant adenocarcinoma patients, 148 patients who had 2 -ΔΔct data were included. The best cutoff values of 2 -ΔΔct for in-frame deletions in exon 19 (19 deletion) and a position 858 substituted from leucine (L) to an arginine (R) in exon 21 (L858R) were determined using receiver operating characteristic curves. Patients were divided into high and low 2 -ΔΔct expression based on the above cutoff level. The best cutoff point of 2 -ΔΔct value of 19 deletion and L858R was 31.1 and 104.7, respectively. In all, 92 (62.1%) patients showed high 2 -ΔΔct expression and 56 patients (37.9%) low 2 -ΔΔct expression. The mean age was 65.6 years. Progression-free survival of 19 deletion mutant patients with low versus high expression level was 17.07 versus 12.04 months (P = 0.004), respectively. Progression-free survival of L858 mutant patients was 13.75 and 7.96 months (P = 0.008), respectively. EGFR-mutant lung adenocarcinoma patients with lower EGFR gene expression had longer progression-free survival duration without interfering overall survival.

Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) readministration to lung cancer patients is common owing to the few options available. Impact of clinical factors on prognosis of EGFR-mutant non-small cell lung cancer (NSCLC) patients receiving EGFR-TKI readministration after first-line EGFR-TKI failure and a period of TKI holiday remains unclear. Through this retrospective study, we aimed to understand the impact of clinical factors in such patients., Methods: Of 1386 cases diagnosed between December 2010 and December 2013, 80 EGFR-mutant NSCLC patients who were readministered TKIs after failure of first-line TKIs and intercalated with at least one cycle of cytotoxic agent were included. We evaluated clinical factors that may influence prognosis of TKI readministration as well as systemic inflammatory status in terms of neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR). Baseline NLR and LMR were estimated at the beginning of TKI readministration and trends of NLR and LMR were change amount from patients receiving first-Line TKIs to TKIs readministration., Results: Median survival time since TKI readministration was 7.0 months. In the univariable analysis, progression free survival (PFS) of first-line TKIs, baseline NLR and LMR, and trend of LMR were prognostic factors in patients receiving TKIs readministration. In the multivariate analysis, only PFS of first-line TKIs (p < 0.001), baseline NLR (p = 0.037), and trend of LMR (p = 0.004) were prognostic factors., Conclusion: Longer PFS of first-line TKIs, low baseline NLR, and high trend of LMR were good prognostic factors in EGFR-mutant NSCLC patients receiving TKI readministration.

Microparticles (MPs) are substantially increased in patients with operable stage non-small cell lung cancer (NSCLC) prior to lung resection surgery. This study tested the hypothesis that there is a decrease in MPs after surgical intervention. Between March 2012 and January 2015, 33 patients who had operable stage NSCLC were consecutively and prospectively enrolled into the study. Additionally, 31 healthy subjects who were consecutively enrolled in the study period served as age- and gender-matched controls. Circulating MPs (EDAc-MPs, EDAp-MPs, PDAc-MPs, PDAp-MPs) were measured by flow cytometry once in control subjects and twice (i.e., prior to and three months later after surgical intervention) in NSCLC patients. Compared with control subjects, these four types of circulating MPs were significantly higher in NSCLC patients prior to operation (all P < 0.005), but did not differ among the controls and NSCLC patients at 3 months after surgery (all P > 0.2). Additionally, a receiver operating characteristic curve (ROC) showed that these four types of MPs were significantly valuable predictors for detecting early stage NSCLC (all P < 0.004). Circulating MPs which were remarkably increased in the operable stage of NSCLC prior to surgery were substantially decreased 3 months later after surgery. These findings show that circulating MPs might be an accessory biomarker for monitoring those of NSCLC after receiving lung resection surgery.

Among epidermal growth factor receptor (EGFR) mutation status unknown nonsmall cell lung cancer (NSCLC) patients, those with higher carcinoembryonic antigen (CEA) level are more likely to response to EGFR-tyrosine kinase inhibitors (TKIs) because they tend to have mutant epidermal growth factor receptor (EGFR). However, patients with higher CEA also have more tumor burden. With the above paradoxical evidence, it is prudent to understand the prognostic significance of baseline CEA in patients with EGFR-mutant NSCLC treated with first-line EGFR-TKIs. The clinical significance of the trend in CEA after treatment and the impact of CEA normalization during EGFR-TKI therapy are also unknown and potentially important. A total of 241 patients who received first-line EGFR-TKIs were included. As to baseline CEA, patients were divided into normal, low, and high baseline CEA by cut point determined by receiver operating characteristic curves. As to CEA responses, patients were divided into 3 groups accordingly to their amount of CEA change after taking TKIs. In group A, 1-month follow-up CEA level decreased more than 35% with nadir CEA normalization; in group B, 1-month follow-up CEA level decreased more than 35% without nadir CEA normalization; and in group C, 1-month follow-up CEA level decreased less than 35% or increased. Patients with higher baseline CEA levels had shorter progression-free survival (PFS) and overall survival (OS) (CEA > 32 vs 5-32 vs <5  ng/mL, PFS = 8.8 vs 11.3 vs 14.4 months, respectively, P < 0.001; OS = 17.8 vs 22.0 vs 27.9 months, respectively, P = 0.01). For trend and CEA normalization in groups A, B, and C, PFS was 14.3, 10.6, and 7.1 months, respectively (P < 0.001); OS was 29.7, 20.0, and 16.2 months, respectively (P < 0.001). Baseline, trend, and normalization of CEA levels are potential prognostic markers for patients with EGFR-mutant advanced NSCLC treated with first line EGFR-TKIs., Competing Interests: The authors have no conflicts of interest to disclose.

Obesity is considered to be a major contributing factor to obstructive sleep apnea (OSA); however, there is limited evidence with regard to gender predominance. We analyzed 2345 patients (339 females) in correlation with body mass index (BMI) and OSA severity. Male AHIs were significantly higher than female AHIs in each BMI group. As the BMI increased, the AHI increased in both males and females, and this trend was more obvious in males. For BMI-matched male and female patients with OSA, the severity of OSA was higher in males. As BMI increased, the severity of OSA increased more obviously in males. Our findings suggest that increased body fat contributes to the pathogenesis of OSA more in males than in females and that obesity plays a more significant role in contributing to OSA in male patients.

Objectives: This study aimed to identify the independent biomarkers and clinical factors that could predict ICU mortality and 6-month outcomes in relatively healthy patients with severe pneumonia and acute respiratory distress syndrome (ARDS)., Patients and Methods: We prospectively enrolled patients with severe pneumonia-related ARDS that required mechanical ventilation. Patients were excluded if they were unable to take care of themselves. Several biomarkers and clinical factors were evaluated prospectively on day 1 and day 3 after ICU admission. All biomarkers and clinical factors were collected for analysis., Results: 56 patients were enrolled in this study. We determined that the initial appropriate antibiotics use was an independent clinical factor and day 1 high-mobility group protein B1 (HMGB1) concentration was an independent biomarker for ICU mortality. Interestingly, we also found that a low day 1 albumin level was an independent biomarker for predicting patient life dependence 6 months after a pneumonia event., Conclusion: Patients with severe pneumonia and ARDS requiring mechanical ventilation experience high rates of ICU mortality or disability, even if they were quite healthy before. Initial appropriate antibiotics use and day 1 level of HMGB1 were independent factors for predicting ICU mortality. Day 1 albumin level was predictive of 6-month patient life dependence.

Background: Endothelial-derived microparticles (EDMPs) and platelet-derived microparticles (PDMPs) have been reported to be increasing in various diseases including malignant diseases. Here, we investigated whether these MPs may be useful biomarkers for predicting lung cancer (LC) disease status, cell type, or metastasis., Methods and Results: One hundred and thirty LC patients were prospectively enrolled into the study between April 2011 and February 2012. Flow cytometric analysis demonstrated that the circulating levels of platelet-derived activated MPs (PDAc-MPs), platelet-derived apoptotic MPs (PDAp-MPs), endothelial-derived activated MPs (EDAc-MPs), and endothelial-derived apoptotic MPs (EDAp-MPs) were significantly higher in LC patients than in 30 age- and gender-matched normal control subjects (all P < 0.05). Additionally, circulating level of PDAc-MPs was significantly lower (P = 0.031), whereas the circulating levels of the other three biomarkers did not differ (all P > 0.1) in early stage versus late stage LC patients. Furthermore, the circulating levels of the four types of MPs did not differ among patients with different disease statuses (i.e., disease controlled, disease progression, and disease without treatment, i.e., fresh case) (all P > 0.2) or between patients with or without LC metastasis (all P > 0.5). Moreover, only the circulating level of EDAp-MPs was significantly associated with the different cell types (i.e., squamous cell carcinoma, adenocarcinoma, and small cell carcinoma) of LC (P = 0.045)., Conclusion: Circulating MP levels are significantly increased in LC patients as compared with normal subjects. Among the MPs, only an increased level of EDAp-MPs was significantly associated with different LC cell types.

Objectives: To determine risk factors associated with ventilator dependence in patients with ventilator-associated pneumonia (VAP)., Study Design: A retrospective study was conducted at Chang Gung Memorial Hospital, Kaohsiung, from January 1, 2007 to January 31, 2008., Methods: This study evaluated 163 adult patients (aged ≥ 18 years). Eligibility was evaluated according to the criterion for VAP, Sequential Organ Failure Assessment (SOFA) score, Acute Physiological Assessment and Chronic Health Evaluation II (APACHE II) score. Oxygenation index, underlying comorbidities, septic shock status, previous tracheostomy status, and factors related to pneumonia were collected for analysis., Results: Of the 163 VAP patients in the study, 90 patients survived, yielding a mortality rate of 44.8%. Among the 90 surviving patients, only 36 (40%) had been weaned off ventilators at the time of discharge. Multivariate logistic regression analysis was used to identify underlying factors such as congestive cardiac failure (P = 0.009), initial high oxygenation index value (P = 0.04), increased SOFA scores (P = 0.01), and increased APACHE II scores (P = 0.02) as independent predictors of ventilator dependence. Results from the Kaplan-Meier method indicate that initial therapy with antibiotics could increase the ventilator weaning rate (log Rank test, P < 0.001)., Conclusions: Preexisting cardiopulmonary function, high APACHE II and SOFA scores, and high oxygenation index were the strongest predictors of ventilator dependence. Initial empiric antibiotic treatment can improve ventilator weaning rates at the time of discharge.

The Global initiative for Chronic Obstructive Lung Disease (GOLD) staging has widely used in the stratification of the severity of COPD, while BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index was proven superior to FEV1 in predicting mortality, exacerbation and disease severity in patients with COPD. Clinical COPD Questionnaire (CCQ), a questionnaire with ten items categorized into three domains (symptoms, functional state and mental state) was developed to measure health status of COPD patients. However, little is known about the relationship between CCQ score and BODE index. We performed a prospective study with the inclusion of 89 patients who were clinically stable after a 6-week-therapy for COPD symptoms comparing their health status assessed by CCQ, BODE index and GOLD staging. We found that the total CCQ score was correlated with BODE score (P < 0.001) and GOLD staging (P < 0.001); of three CCQ domains, the functional status correlated the most with BODE index (rS = 0.670) and GOLD staging (rS = 0.531), followed by symptoms (rS = 0.482; rS = 0.346, respectively), and mental status (rS = 0.340; rS = 0.236, respectively). Our data suggest that CCQ is a reliable and convenient alternative tool to evaluate the severity of COPD.

Although many parameters were investigated about weaning and mortality in critical patients in intensive units, no studies have yet investigated predictors in prolonged mechanical ventilation (PMV) patients following successful weaning. A cohort of 142 consecutive PMV patients with successful weaning in our respiratory care center was enrolled in this study. Successful weaning is defined as a patient having smooth respiration for more than 5 days after weaning. The results showed as follows: twenty-seven patients (19%) had the reinstitution within 14 days, and 115 patients (81%) had the reinstitution beyond 14 days. Renal disease RIFLE-LE was associated with the reinstitution within 14 days (P = 0.006). One year mortality rates showed significant difference between the two groups (85.2% in the reinstitution within 14 days group versus 53.1% in the reinstitution beyond 14 days; P < 0.001). Kaplan-Meier analysis showed that age ≥70 years (P = 0.04), ESRD (P = 0.02), and the reinstitution within 14 days (P < 0.001) were associated with one-year mortality. Cox proportional hazards regression model showed that only the reinstitution within 14 days was the independent predictor for mortality (P < 0.001). In conclusion, the reinstitution within 14 days was a poor predictor for PMV patients after successful weaning.

Background: Ventilator-associated pneumonia (VAP) contributes to high mortality, prolonged intensive care unit (ICU) stay and increased costs of health care. Reports of early predictors of death in patients with VAP are rare. Our study was designed to determine early predictors of poor outcome in patients with VAP., Methods: A total 838 patients with nosocomial lower respiratory tract infection in a tertiary medical center from January, 2004 to June, 2006 were retrospectively reviewed. Forty-two patients had VAP and were enrolled in the study. The age, sex, underlying diseases, including hypertension, diabetes mellitus, chronic obstructive pulmonary disease, end-stage renal disease, congestive heart failure/coronary artery disease, and collagen vascular disease, diagnosis at admission, Acute Physiological Assessment and Chronic Health Evaluation II score (APACHE II score), Clinical Pulmonary Infection Score (CPIS), time between intubation and ICU admission, time between intubation and development of VAP, risk factors for multi-drug resistant pathogens, time to adequate therapy, initial antibiotics regimen, bacterial cultures, mortality rate from VAP, 28-day mortality rate and in-hospital mortality rate were compared between the mortality group and non-mortality group., Results: The VAP, 28-day and in-hospital mortality rates were 23.8% (10/42), 40.5% (17/42) and 50% (21/42), respectively. The APACHE II score (p=0.002) and CPIS (p=0.048) at the onset of VAP, inadequate initial antibiotics treatment (p=0.007) and concomitant bacteremia (p=0.008) were the only parameters which were significantly different between groups. The independent risk factors for VAP mortality in multivariable analysis were the APACHE II score at the onset of VAP (p=0.018), inadequate initial antibiotics treatment (p=0.032) and concomitant bacteremia (p=0.034). An APACHE II score>27 at VAP onset was an independent and early predictor of the mortality. (ROC AUC: 0.841; Sensitivity: 70%; Specificity: 90.6%; p=0.001)., Conclusion: A high APACHE II score (>27) at VAP onset was an independent and early predictor of mortality due to VAP.

Aim: To identify risk factors predictive of intensive care unit (ICU) mortality in patients with ventilator-related pancreatitis. The clinical outcomes of patients with ventilator-related pancreatitis were compared with those of patients with pancreatitis-related respiratory failure as well as controls., Methods: One hundred and forty-eight patients with respiratory failure requiring mechanical ventilation and concomitant acute pancreatitis were identified from a prospectively collected dataset of 9108 consecutive patients admitted with respiratory failure over a period of five years. Sixty patients met the criteria for ventilator-related pancreatitis, and 88 (control patients), for pancreatitis-related respiratory failure., Results: Mortality rate in ventilator-related pancreatitis was comparable to that in ICU patients without pancreatitis by case-control methodology (P = 0.544). Multivariate logistic regression analysis identified low PaO(2)/FiO(2) (OR: 1.032, 95% CI: 1.006-1.059, P = 0.016) as an independent risk factor for mortality in patients with ventilator-related pancreatitis. The mortality rate in patients with ventilator-related pancreatitis was lower than that in patients with acute pancreatitis-related respiratory failure (P < 0.001)., Conclusion: We found that low PaO(2)/FiO(2) was an independent clinical parameter predictive of ICU mortality in patients with ventilator-related pancreatitis.