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.

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.

Background: Positive fluid balance and tissue fluid accumulation are associated with adverse outcomes in sepsis. Vascular endothelial growth factor (VEGF) increases in sepsis, promotes vascular permeability, and may affect tissue fluid accumulation and oxygenation. We used near-infrared spectroscopy (NIRS) to estimate tissue hemoglobin (Hb) oxygenation and water (H₂O) levels to investigate their relationship with serum VEGF levels. Material and methods: New-onset severe sepsis patients admitted to the intensive care unit were enrolled. Relative tissue concentrations of oxy-Hb ([HbO₂]), deoxy-Hb ([HbR]), total Hb ([HbT]), and H₂O ([H₂O]) were estimated by near-infrared spectroscopy (NIRS) for three consecutive days and serum VEGF levels were measured. Comparisons between oliguric and non-oliguric patients were conducted and the correlations between variables were analyzed. Results: Among 75 eligible patients, compared with non-oliguric patients, oliguric patients were administrated more intravascular fluids (median [IQR], 1926.00 [1348.50–3092.00] mL/day vs. 1069.00 [722.00–1486.75] mL/day, p < 0.001) and had more positive daily net intake and output (mean [SD], 1,235.06 [1303.14] mL/day vs. 313.17 [744.75] mL/day, p = 0.012), lower [HbO₂] and [HbT] over the three-day measurement (analyzed by GEE p = 0.01 and 0.043, respectively) and significantly higher [H₂O] on the third day than on the first two days (analyzed by GEE p = 0.034 and 0.018, respectively). Overall, serum VEGF levels were significantly negatively correlated with [HbO₂] and [HbT] (rho = − 0.246 and − 0.266, p = 0.042 and 0.027, respectively) but positively correlated with [H₂O] (rho = 0.449, p < 0.001). Subgroup analysis revealed a significant correlation between serum VEGF and [H2O] in oliguric patients (rho = 0.532, p = 0.003). Multiple regression analysis determined the independent effect of serum VEGF on [H₂O] (standardized coefficient = 0.281, p = 0.038). Conclusions: In severe sepsis, oliguria relates to higher positive fluid balance, lower tissue perfusion and oxygenation, and progressive tissue fluid accumulation. Elevated serum VEGF is associated with worsening tissue perfusion and oxygenation and independently affects tissue fluid accumulation.

Background: Studies have indicated that individuals taking aspirin have a reduced risk of cancers and have also established chemo-preventive benefit of aspirin in colorectal cancer. However, research on the association between aspirin use and the survival in patients with lung cancer has revealed inconsistent results. In this study, we investigated the effect of aspirin use on the survival of inoperable non-small cell lung cancer (NSCLC) patients. Methods: We identified a cohort of 38,842 patients diagnosed with NSCLC between 2000 and 2012 using the Taiwan’s National Health Insurance Research Database and used propensity score matching to reduce possible confounding factors. In total, 9864 patients (4932 matched pairs) were included in the matched cohort. Aspirin exposure was analyzed to identify a possible association with mortality in patients with inoperable NSCLC. Time-dependent Cox regression models were used to calculate the hazard ratios (HRs) and the 95% confidence intervals (95% CIs) that corresponded with aspirin exposure. Results: A total of 4979 patients used aspirin at the time of diagnosis of NSCLC. The median overall survival (OS) of the aspirin users was 1.73 (interquartile range, 0.94–3.53) years compared with the 1.30 (interquartile range, 0.69–2.62) years of the non-aspirin users. The Cox proportional hazard model with the time-dependent covariate revealed that aspirin use was associated with a significantly longer OS (HR: 0.83, 95.0% CI: 0.80–0.86). After controlling the sociodemographic characteristics (age, sex, income, and level of urbanization) and lung cancer treatments by propensity score matching, the aspirin users still had a significantly longer OS than the non-aspirin users (HR: 0.79, 95.0% CI: 0.75–0.83). Conclusion: Aspirin use is associated with a longer OS in patients with inoperable NSCLC, suggesting that aspirin has a potential anticancer effect. These results warrant further randomized clinical trials to evaluate the actual role of aspirin in the treatment of NSCLC patients.

We aimed to quantify Soft Mist Inhalers (SMI) delivery to spontaneous breathing model and compare with different adapters via endotracheal tube during mechanical ventilation or by manual resuscitation. A tiotropium SMI was used with a commercial in-line adapter and a T-adapter placed between the Y-adapter and the inspiratory limb of the ventilator circuit during mechanical ventilation. The SMI was actuated at the beginning of inspiration and expiration. In separate experiments, a manual resuscitator with T-adapter was attached to endotracheal tube, collecting filter, and a passive test lung. Drug was eluted from collecting filters with salt-based solvent and analyzed using high-performance liquid chromatography. Results showed the percent of SMI label dose inhaled was 3-fold higher with the commercial in-line adapter with actuation during expiration than when synchronized with inspiration. SMI with T-adapter delivery via ventilator was similar to inhalation (1.20%) or exhalation (1.02%), and both had lower delivery dose than with manual resuscitator (2.80%; p = 0.01). The inhaled dose via endotracheal tube was much lower than inhaled dose with spontaneous breathing (22.08%). In conclusion, the inhaled dose with the commercial adapter was higher with SMI actuated during expiration, but still far less than reported spontaneous inhaled dose.