Different prognostic role of EGFR mutation according to the IASLC histological grade in patients with resected early-stage lung adenocarcinoma.

AIMS: The prognostic role of EGFR mutations remains controversial. We aimed to evaluate the prognostic role of EGFR mutation in consideration of the IASLC histological grade in patients with resected early-stage lung adenocarcinoma. METHODS AND RESULTS: A total of 3297 patients with stages I-IIA resected lung adenocarcinoma who had had EGFR mutation tests between January 2014 and December 2019 at the Samsung Medical Center, Seoul, Korea were included. Recurrence-free survival (RFS) was compared by EGFR mutation status (EGFR-M+ versus EGFR-WT) and IASLC histological grade (G1, G2 and G3). Cox proportional hazards models were used to estimate the adjusted HRs (aHRs) and 95% confidence intervals (CIs). RESULTS: Compared to the EGFR-WT group, the EGFR-M+ group had a significantly lower proportion of G3 tumour (16 versus 33%, P < 0.001). During a median follow-up of 41.4 months, 376 patients experienced recurrence. After adjusting for histological grade, the aHR for recurrence comparing the EGFR-M+ to the EGFR-WT was 1.30 (95% CI = 1.04-1.62, P = 0.022). The EGFR-M+ group had a significantly lower 5-year RFS than the EGFR-WT group among G3 patients (58.4 versus 71.5%, P < 0.001), but not among G1 and G2 patients. CONCLUSIONS: EGFR mutation status was associated with a risk of recurrence after consideration of the IASLC histological grading, especially in G3 tumours. The results of this study would be useful for developing a new staging system and identifying a subset of patients who may benefit from adjuvant targeted therapy.

Effects of dexmedetomidine on inflammatory mediators after tourniquet-induced ischemia-reperfusion injury: a randomized, double-blinded, controlled study.

BACKGROUND: Tourniquet use during total knee arthroplasty (TKA) produces ischemia-reperfusion injury (IRI), with systemic release of inflammatory cytokines and reactive oxygen species upon tourniquet release. We conducted a randomized, placebo-controlled, double-blind trial to examine whether dexmedetomidine (DEX) as an adjunct during general anesthesia in patients undergoing unilateral TKA could attenuate the rise in inflammatory cytokines and oxidative stress. METHODS: Sixty-eight patients were randomized to either the control or DEX group. DEX was administered at a loading dose of 0.5 µg/kg, followed by an infusion of 0.4 µg/kg/h. We measured serum levels of malondialdehyde (biomarker of oxidative stress) and proinflammatory cytokines (interleukin-6 [IL-6] and tumour necrosis factor-α [TNF-α]) preinduction (baseline), 60 and 90 min post-tourniquet release. We also assessed hemodynamics, intraoperative remifentanil consumption, and postoperative pain scores and analgesic consumption. RESULTS: Malondialdehyde was higher than baseline after tourniquet release in both groups (P≤0.001), but the levels were similar between groups at all times. TNF-α was significantly higher than baseline at 60 min post-tourniquet release only in the control group (P=0.009). Serum IL-6 increased significantly above baseline at 60 and 90 min post-tourniquet release in both groups (P<0.001). At 90 min, IL-6 was significantly lower in the dexmedetomidine group than in the control group (P=0.049). Remifentanil consumption, heart rate, and pain scores were significantly lower in the dexmedetomidine group. CONCLUSIONS: Our results suggest that dexmedetomidine as an adjunct to general anesthesia attenuated the rise in proinflammatory cytokines, providing protective effects in tourniquet-induced IRI.

Comparison of the laryngeal mask airway supreme and the i-gel in paralysed elderly patients: A randomised controlled trial.

BACKGROUND: The laryngeal mask airway supreme (LMA-S) and i-gel are both popular second-generation supraglottic airway devices that have been widely studied in surgical patients, but their differences in clinical performance in the elderly are not clear. OBJECTIVE: We compared the efficacy and safety of the LMA-S and i-gel in anaesthetised and paralysed elderly patients. DESIGN: A randomised study. SETTING: Single-centre trial, study period January 2014 from to October 2016. PATIENTS: One hundred and six elderly patients who underwent urological or orthopaedic surgery with an expected duration less than 2 h. INTERVENTION: Patients were allocated to either the LMA-S (n = 53) or i-gel (n = 53) group. All insertions were performed in a standardised manner according to the manufacturers' instructions. MAIN OUTCOME MEASURES: Our primary endpoint was the rate of successful insertion at the first attempt. The adequacy of positive pressure ventilation and airway sealing, fibreoptic laryngoscopy grades and stability of airway maintenance during anaesthesia were also assessed. RESULTS: Although the rate of successful insertion at the first attempt was similar between the two groups (94.3 vs. 82.7%, P = 0.072), more patients required device manipulation during insertion with the LMA-S than the i-gel (42.3 vs. 18.9%, P = 0.011). Good fibreoptic laryngoscopy grades were significantly more common with the i-gel than the LMA-S (79.3 vs. 55.8%, P = 0.042), and peak inspiratory pressures were lower in the i-gel group both immediately after insertion and at the end of surgery. Leak pressures were significantly higher in the i-gel group than the LMA-S group, both immediately after insertion and at the end of surgery (25.8 vs. 23.0, P = 0.036; and 28.1 vs. 23.7, P < 0.001, respectively). CONCLUSION: Both the LMA-S and i-gel were used successfully and safely in elderly patients. However, the i-gel demonstrated better airway sealing than the LMA-S at insertion and during maintenance of anaesthesia. TRIAL REGISTRATION: NCT02026791 at clinicaltrial.gov.

Colon-targeted delivery of solubilized bisacodyl by doubly enteric-coated multiple-unit tablet.

A doubly enteric-coated multiple-unit tablet (DET) of bisacodyl (BD) was formulated to selectively deliver the stimulant laxative to the large intestine. Solubilized BD in surfactants was adsorbed into the porous carrier and primarily coated with different combinations of pH-sensitive polymers (Eudragit S and Eudragit L) and time-dependent release polymer (Eudragit RS). BD-loaded granules were compressed into tablets and coated again with pH-sensitive polymers (Eudragit S:Eudragit L=1:1). The multiple-unit tablet was optimized with respect to the granular coating compositions (Eudragit S:Eudragit L:Eudragit RS=5:1:4) and coating level (12.5%), and coating level on the tablet (25%), by evaluating in vitro release profile in continuous dissolution medium. Drug release from the optimized tablet was effectively retarded in the simulated gastric and small intestinal fluids (below 7%), but profound drug liberation was attained in the colonic fluid (over 50%). On the other hand, drug release from the marketed product (Dulcolax®, Boehringer Ingelheim Pharma), a reference drug, in the gastric and small intestinal fluids was reached to 30%, while that in the colonic fluid was only 7%. In an in vivo efficacy study in loperamide-induced constipated rabbits, a remarkable recovery in fecal secretion was observed in the DET-treated group 24h post-dosing, compared to vehicle-treated (p<0.05) and the marketed product-treated groups (p<0.05). Moreover, pharmacokinetic evaluation in the constipated rabbits revealed that the DET system significantly lowered the systemic exposure compared with the marketed product (p<0.05), by hindering drug release in the upper intestine, a preferential absorption site. Therefore, the novel colon-targeted delivery system may be an alternative for boosting pharmacological responses in the colon, while diminishing the intestinal irritation and/or systemic adverse effect of the stimulant laxative.

Tailoring the Composition of Bio-oil by Vapor-Phase Removal of Organic Acids.

Selective removal of organic acids from biomass pyrolysis vapors was demonstrated. A broad adsorbent range was tested with CaCO3 showing the best selectivity. Extensive material characterization demonstrated that the acid removal occurred through monolayer adsorption on CaCO3. Adsorbent regeneration was achieved by in situ heat treatment of the postreaction adsorbent where the adsorbed acid was converted into a ketone. The mitigation of the loss of other products was achieved by using surface modified CaCO3 materials, resulting in a significant improvement in the selectivity toward organic acid removal. The surface modification appeared to lead to formation of a metal-carboxylate intermediate consisting of both acetate and carbonate groups. Acetate group on the CaCO3 surface resulted in the suppression of side reactions. Generally, a higher acid removal was accompanied with a greater loss of other compounds, which could be tuned by using CaCO3 with different surface modification.

Positioning of double-lumen tubes based on the minimum peak inspiratory pressure difference between the right and left lungs in short patients: a prospective observational study.

BACKGROUND: Peak inspiratory pressures (PIPs) during one-lung ventilation (OLV) have served as a clinical marker that could indirectly verify the proper positioning of double-lumen tubes (DLTs). Patients of short stature are highly susceptible to initial DLT malpositioning. OBJECTIVES: We investigated the usefulness of positioning left-sided DLTs using minimum PIP differences between the right and left lungs by comparing with the previously used method of auscultation without fibreoptic bronchoscopy (FOB). We also evaluated the difference in PIPs between the two lungs during OLV after the DLT was ideally positioned with FOB examination. DESIGN: Prospective, observational study. SETTING: A university hospital. PATIENTS: One hundred and two female patients of short stature (≤160  cm). INTERVENTIONS: Verification of DLT position was conducted by three sequential steps: auscultation; minimising the difference in PIP during each OLV; and verifying the resulting position by FOB. MAIN OUTCOME MEASUREMENTS: Fibreoptic bronchoscopic view results of DLT position followed by the position adjustment using the minimum PIP difference method. RESULTS: Repositioning the DLT using the minimum PIP difference led to clinically successful positioning of the DLT in 88% of patients and a more ideal placement of the tube than auscultation alone (69.6 vs. 11.8%, P <0.001). Additionally, the ideal position of DLTs verified by FOB showed that PIP differences were zero or ±1  mmHg in 93% of patients. CONCLUSION: Positioning the DLT based on the minimum PIP difference between the right and left lungs as a supplementation to routine auscultation serves as an easy and reliable method for DLT positioning and may improve the accuracy of DLT positioning as an adjuvant to FOB in short patients. TRIAL REGISTRATION: Clinicaltrial.gov identifier: NCT01533012.

Identification of novel anti-angiogenic factors by in silico functional gene screening method.

Angiogenesis, the formation of new blood vessels out of pre-existing capillaries, occurs in a variety of pathophysiological conditions, and is regulated by a balance of angiogenic activators and inhibitors. To identify novel angiogenic factors, we developed a gene screening method by combining the prediction analysis of transcription factor (TF) binding site and the chromosomal localization analysis. First, we analyzed the promoter sequences from known angiogenesis-related factors using the MATINSPECTOR program in TRANSFAC database. Interestingly, we found that the binding site of LMO2 complex is highly conserved in the promoter regions of these factors. Second, we analyzed chromosome loci based on the hypothesis that angiogenesis-related factors might be co-localized in a specific chromosomal band. We found that angiogenesis-related factors are localized in specific 14 chromosomal bands including 5q31 and 19q13 using AngioDB and LocusLink database mining. From these two approaches, we identified 32 novel candidates that have the LMO2 complex binding site in their promoter and are located on one of 14 chromosomal bands. Among them, human recombinant troponin T and spectrin markedly inhibited the neovascularization in vivo and in vitro. Collectively, we suggest that the combination of the prediction analysis of TF binding site and the chromosomal localization analysis might be a useful strategy for gene screening of angiogenesis.