Comparing Clinical Outcomes of Tiotropium/Olodaterol, Umeclidinium/Vilanterol, and Indacaterol/Glycopyrronium Fixed-Dose Combination Therapy in Patients with Chronic Obstructive Pulmonary Disease in Taiwan: A Multicenter Cohort Study.

Background: Long-acting beta-agonists (LABA) and long-acting muscarinic antagonists (LAMA) combination therapy improved lung function and health-related quality-of-life and reduced exacerbation rates and dyspnea in symptomatic chronic obstructive pulmonary disease (COPD) patients. We compared the real-world effects of three fixed-dose LABA/LAMA combinations for COPD in Taiwan. Methods: This multicenter, retrospective study evaluated 1-year outcomes after LABA/LAMA combination therapy in patients with symptomatic COPD. Exacerbations and symptoms of COPD, lung functions, and therapy escalation were compared among patients using tiotropium/olodaterol, umeclidinium/vilanterol and indacaterol/glycopyrronium. Propensity score matching (PSM) was applied to balance the baseline characteristics. Results: Data of 1,617 patients were collected. After PSM, time to first moderate-to-severe COPD exacerbation was comparable among three groups, while the annualized rates of the exacerbation (episodes/patient/year) in patients receiving tiotropium/olodaterol (0.19) or umeclidinium/vilanterol (0.17) were significantly lower than those receiving indacaterol/glycopyrronium (0.38). COPD-related symptoms were stable over the treatment period, and there was no significant difference in the changes of symptom scores including CAT and mMRC among three groups at the end of the study period. Conclusion: This study presented valuable real-world outcome in terms of exacerbation and treatment response of COPD patients treated with fixed-dose LABA/LAMA regimens in Taiwan. The annualized rates of moderate-to-severe exacerbation in patients receiving tiotropium/olodaterol or umeclidinium/vilanterol were significantly lower than those receiving indacaterol/glycopyrronium, though the time to first moderate-to-severe exacerbation was similar among different fixed-dose LABA/LAMA combinations.

Virtual Screening and In Vitro Evaluation of PD-1 Dimer Stabilizers for Uncoupling PD-1/PD-L1 Interaction from Natural Products.

Genetic mutations accumulated overtime could generate many growth and survival advantages for cancer cells, but these mutations also mark cancer cells as targets to be eliminated by the immune system. To evade immune surveillance, cancer cells adopted different intrinsic molecules to suppress immune response. PD-L1 is frequently overexpressed in many cancer cells, and its engagement with PD-1 on T cells diminishes the extent of cytotoxicity from the immune system. To resume immunity for fighting cancer, several therapeutic antibodies disrupting the PD-1/PD-L1 interaction have been introduced in clinical practice. However, their immunogenicity, low tissue penetrance, and high production costs rendered these antibodies beneficial to only a limited number of patients. PD-L1 dimer formation shields the interaction interface for PD-1 binding; hence, screening for small molecule compounds stabilizing the PD-L1 dimer may make immune therapy more effective and widely affordable. In the current study, 111 candidates were selected from over 180,000 natural compound structures through virtual screening, contact fingerprint analysis, and pharmacological property prediction. Twenty-two representative candidates were further evaluated in vitro. Two compounds were found capable of inhibiting the PD-1/PD-L1 interaction and promoting PD-L1 dimer formation. Further structure optimization and clinical development of these lead inhibitors will eventually lead to more effective and affordable immunotherapeutic drugs for cancer patients.

Metformin Prolongs Survival in Type 2 Diabetes Lung Cancer Patients With EGFR-TKIs.

Background: Metformin use reportedly reduces cancer risk and improves survival in lung cancer patients. This study aimed to investigate the effect of metformin use in patients with diabetes mellitus (DM) and lung cancer receiving epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. Methods: A nationwide, population-based cohort study was conducted using the Taiwan National Health Insurance Research Database. From January 1, 2004, to December 31, 2012, a total of 373 metformin and 1260 non-metformin lung cancer cohorts with type 2 DM and EGFR-TKI treatment were studied. Results: Metformin use was significantly associated with a reduced risk of death (hazard ratio: 0.73, 95% confidence interval [CI]: 0.62-0.85, P < .001), as well as a significantly longer median progression-free survival (9.2 months, 95% CI: 8.6-11.7, vs 6.4 months, 95% CI: 5.9-7.2 months, P < .001) and median overall survival (33.4 months, 95% CI: 29.4-40.2, vs 25.4 months, 95% CI: 23.7-27.2 months, P < 0.001). Conclusions: In conclusion, metformin may potentially enhance the therapeutic effect and increase survival in type 2 DM patients with lung cancer receiving EGFR-TKI therapy.

Real-world effectiveness of medications on survival in patients with COPD-heart failure overlap.

The appropriate treatment for patients with coexistent chronic obstructive pulmonary disease (COPD) and heart failure (HF) remains unclear. Data from the Taiwan National Health Insurance Research Database was used for this retrospective cohort study. Patients diagnosed with both diseases between 1997 and 2012 were enrolled as the COPD-heart failure overlap cohort. Patients were categorized as non-users and users of specific COPD and HF medications. Medication prescriptions in each 3-month and 1-year period served as time-dependent covariates. The primary endpoint was cumulative survival. The validation study confirmed the accuracy of definitions of COPD (94.0% sensitivity) and HF (96.3% sensitivity).The study included 275,436 patients with COPD-heart failure overlap, with a mean follow-up period of 9.32 years. The COPD-heart failure overlap cohort had more medical service use and higher mortality than did the COPD alone cohort. Use of inhaled corticosteroid (ICS)/long-acting ß2 agonist (LABA) combinations, long-acting muscarinic antagonist (LAMA), angiotensin receptor blockers (ARBs), ß blockers, aldosterone antagonists, and statins reduced mortality risk compared with non-use. Sensitivity and subgroup analyses confirmed the consistency and robustness of results.ICS/LABA combinations, LAMA, ARBs, ß blockers, aldosterone antagonists, and statins use was associated with a lower mortality risk in patients with COPD-heart failure overlap.

Use of ICS/LABA Combinations or LAMA Is Associated with a Lower Risk of Acute Exacerbation in Patients with Coexistent COPD and Asthma.

BACKGROUND: Based on current guidelines, more research is urgently needed to guide appropriate treatment for patients with asthma-chronic obstructive pulmonary disease (COPD) overlap. OBJECTIVE: The objective of this study was to investigate medication effects on acute exacerbation in patients with coexistent COPD and asthma. METHODS: Using Taiwan's National Health Insurance Research Database, we conducted a nationwide population-based study to evaluate medication effects in patients with COPD and asthma. Patients diagnosed with both asthma and COPD between 1997 and 2012 were enrolled as the COPD + asthma cohort. The primary endpoint was acute exacerbation. The definitions of COPD and asthma were validated. The validation study confirmed the accuracy of definitions of COPD (86.2% sensitivity) and asthma (92.0% sensitivity). RESULTS: The study included 251,398 patients with COPD + asthma and 514,522 patients with COPD alone, with a mean follow-up period of 9.85 years. After adjustment, hazard ratios (HRs) for long-acting muscarinic antagonist (LAMA) and inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) combinations were lower (time-dependent model, 1 year: LAMA, HR 0.51, 95% confidence interval [CI] 0.49-0.54; ICS/LABA combinations, HR 0.61, 95% CI 0.60-0.62; all P < .0001) than were those for LABAs or ICSs in patients with COPD and asthma. CONCLUSIONS: The use of LAMA or ICS/LABA combinations was associated with a lower risk of acute exacerbation in patients with COPD and asthma in this study.

Danshen improves survival of patients with advanced lung cancer and targeting the relationship between macrophages and lung cancer cells.

In traditional Chinese medicine, Salvia miltiorrhiza Bunge (danshen) is widely used in the treatment of numerous cancers. However, its clinical effort and mechanism in the treatment of advanced lung cancer are unclear. In our study, the in vivo protective effort of danshen in patients with advanced lung cancer were validated using data from the National Health Insurance Research Database in Taiwan. We observed in vitro that dihydroisotanshinone I (DT), a bioactive compound in danshen, exerts anticancer effects through many pathways. First, 10 µM DT substantially inhibited the migration ability of lung cancer cells in both macrophage and macrophage/lung cancer direct mixed coculture media. Second, 10 µM DT repressed the phosphorylation of signal transducer and activator of transcription 3 (STAT3), the protein expression of S-phase kinase associated protein-2 (Skp2), and the mRNA levels of STAT3-related genes, including chemokine (C-C motif) ligand 2 (CCL2). In addition, 10 µM DT suppressed the macrophage recruitment ability of lung cancer cells by reducing CCL2 secretion from both macrophages and lung cancer cells. Third, 20 µM DT induced apoptosis in lung cancer cells. Furthermore, DT treatment significantly inhibited the final tumor volume in a xenograft nude mouse model. In conclusion, danshen exerts protective efforts in patients with advanced lung cancer. These effects can be attributed to DT-mediated interruption of the cross talk between lung cancer cells and macrophages and blocking of lung cancer cell proliferation.

In silico-based identification of human α-enolase inhibitors to block cancer cell growth metabolically.

Unlimited growth of cancer cells requires an extensive nutrient supply. To meet this demand, cancer cells drastically upregulate glucose uptake and metabolism compared to normal cells. This difference has made the blocking of glycolysis a fascinating strategy to treat this malignant disease. α-enolase is not only one of the most upregulated glycolytic enzymes in cancer cells, but also associates with many cellular processes or conditions important to cancer cell survival, such as cell migration, invasion, and hypoxia. Targeting α-enolase could simultaneously disturb cancer cells in multiple ways and, therefore, is a good target for anticancer drug development. In the current study, more than 22 million chemical structures meeting the criteria of Lipinski's rule of five from the ZINC database were docked to α-enolase by virtual screening. Twenty-four chemical structures with docking scores better than that of the enolase substrate, 2-phosphoglycerate, were further screened by the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties prediction. Four of them were classified as non-mutagenic, non-carcinogenic, and capable of oral administration where they showed steady interactions to α-enolase that were comparable, even superior, to the currently available inhibitors in molecular dynamics (MD) simulation. These compounds may be considered promising leads for further development of the α-enolase inhibitors and could help fight cancer metabolically.

Incidence and risk factors of depression after diagnosis of lung cancer: A nationwide population-based study.

This study aimed to explore the incidence and risk factors of depression after lung cancer diagnosis. Using the Taiwan National Health Insurance Research Database (NHIRD), incidences and risk factors of depression in lung cancer and nonlung cancer cohorts were analyzed.From 1998 to 2006, a total of 22,125 patients were included in each matched cohort of lung cancer and nonlung cancer patients from NHIRD. The incidence of depression was higher in the lung cancer cohort than in the nonlung cancer cohort (1545.8 vs 1366.6 per 100,000 person-years). An increased risk of depression was observed in the lung cancer cohort [adjusted hazard ratio (aHR): 1.16, 95% confidence interval (95% CI): 1.01-1.34, P = .0377]. In lung cancer patients, age ≤50 years (aHR: 2.72, 95% CI: 2.02-3.66, P < .0001), age 50 to 69 years (aHR: 2.34, 95% CI: 1.87-2.94, P < .0001), female gender (aHR: 1.50, 95% CI: 1.26-1.80, P < .0001), coronary artery disease (CAD) (aHR: 1.40, 95% CI: 1.08-1.82, P = .0113), and operation (aHR: 1.78, 95% CI: 1.46-2.16, P < .0001) were associated with an increased risk of depression. In addition, higher incidences of emergency room (ER) visit (4.76 vs 2.82, per person-year) and admission (5.73 vs 4.33, per person-year) were observed in lung cancer patients with depression than those without depression.Our results showed that early surveillance and intervention of depression should be advocated after a diagnosis of lung cancer.

Nutritional supplementation in patients with chronic obstructive pulmonary disease.

Malnutrition in patients with chronic obstructive pulmonary disease (COPD) is associated with cachexia, sarcopenia, and weight loss, and may result in poorer pulmonary function, decreased exercise capacity, and increased risk of exacerbations. Providing nutritional supplementation is an important therapeutic intervention, particularly for severely ill COPD patients with malnutrition. Higher calorie intake through nutritional supplementation significantly increases body weight and muscle strength, and improves quality of life in malnourished COPD patients. Difficulties may be experienced by these COPD patients, who are struggling to breathe and eliminate CO2 from the lungs, resulting in dyspnea, hypercapnia, hypoxia, and respiratory acidosis, which exacerbates muscle loss through oxidative stress and inflammatory responses. To overcome these problems, nutritional supplements should aim to reduce metabolic CO2 production, lower respiratory quotient, and improve lung function. Several studies have shown that high-fat supplements produce less CO2 and have lower respiratory quotient value than high-carbohydrate supplements. In addition, high-fat supplements may be the most efficient means of providing a low-volume, calorie-dense supplement to COPD patients, and may be most beneficial to patients with prolonged mechanical ventilation where hypercapnia and malnutrition are most pronounced. Further studies are required to investigate the optimal nutritional supplements for COPD patients according to their disease severity.

Effects of hydroxyethyl starch resuscitation on extravascular lung water and pulmonary permeability in sepsis-related acute respiratory distress syndrome.

OBJECTIVE: Hydroxyethyl starch (HES) has greater volume expansion effect and longer intravascular persistence than crystalloids. HES also decreases microvascular permeability and capillary leakage by biophysically plugging endothelial leaks, exerting an anti-inflammatory effect, and decreasing activation of endothelial cells. The aim of our study was to determine whether medium molecular weight HES (pentastarch) resuscitation in the early stage of acute respiratory distress syndrome (ARDS) simultaneously increases cardiac output without worsening pulmonary edema and whether it attenuates pulmonary vascular permeability. DESIGN: Prospective observational study. SETTING: Twenty-bed medical intensive care unit of a tertiary medical center. PATIENTS: Twenty patients with early-stage ARDS. INTERVENTION: Volume expansion with a 500-mL infusion of 10% pentastarch (HES 200/0.5) at a rate of 10 mL/kg/hr. MEASUREMENTS AND MAIN RESULTS: Baseline hemodynamics including systemic and pulmonary artery blood pressures, central venous pressure, pulmonary artery occlusion pressure, and cardiac output were obtained from an online HP Component Monitoring System and a pulmonary artery catheter. Intrathoracic blood volume (ITBV), global end-diastolic volume, extravascular lung water (EVLW), and pulmonary vascular permeability (EVLW/ITBV) were measured with a PiCCOplus monitor. Hemodynamic measurements were repeated immediately and 2, 4, and 6 hours after volume expansion. Pentastarch loading significantly increased central venous pressure, pulmonary artery occlusion pressure, pulmonary arterial pressures, and cardiac output. Pulmonary mechanics, venous admixtures, and EVLW values remained unchanged throughout the study. EVLW/ITBV significantly decreased immediately after the pentastarch infusion. CONCLUSIONS: In patients with early ARDS, pentastarch resuscitation significantly improved their hemodynamics and cardiac output without worsening pulmonary edema and pulmonary mechanics. It even attenuated pulmonary vascular permeability.

Mercury vapor inhalation from Chinese red (Cinnabar).

INTRODUCTION: Acute inhalation of mercury fumes or vapors is a rare but frequently fatal cause of acute lung injury. This report describes a rare cause of mercury inhalation from Chinese red. CASE REPORT: An 87-year-old male inhaled the vapors from heating Chinese red (Cinnabar, mercury sulphide) intended to treat his foot ulceration. He subsequently developed acute lung injury (progressive dyspnea and acute respiratory failure) that was treated with mechanical ventilation. DMPS (2,3-Dimercapto-1-propanesulfonic acid) and penicillamine were used as chelating agents, and methylprednisolone pulse therapy was used to treat his pulmonary disease. Despite being extubated once, the patient eventually died from profound hypoxemia. CONCLUSION: A rare case of mercury intoxication was due to inappropriate use of an alternative medicine, Chinese red. This case serves as a reminder of the toxicity of the noxious gas from this substance and the importance of being familiar with alternative medicines.