Methods: Triptolide's inhibition of cell viability was detected by sulforhodamine B (SRB) assay. Cell cycle was measured by flow cytometry and cell apoptosis was assessed by flow cytometry and western blot. Expression of β-catenin was analyzed by western blot and immunofluorescence (IF). The anti-tumor effects of triptolide were determined using a subcutaneous in-vivo model. Cell proliferation and apoptosis were evaluated by immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, respectively. The expression level of p-p70S6K and p-GSK-3α/β was evaluated by western blot and IHC.
Results: Triptolide inhibited cell proliferation, induced S-phase cell cycle arrest and apoptosis in taxol-resistant A549 (A549/TaxR) cells. Moreover, intraperitoneal injection of triptolide resulted in a significant delay of tumor growth without obvious systemic toxicity in mice. Additionally, triptolide reversed epithelial-mesenchymal transition (EMT) through repression of the p70S6K/GSK3/β-catenin signaling pathway.
Conclusions: Our study provides evidence that triptolide can reverse EMT in taxol-resistant lung adenocarcinoma cells and impairs tumor growth by inhibiting the p70S6K/GSK3/β-catenin pathway, indicating that triptolide has potential to be used as a new therapeutic agent for taxol-resistant lung adenocarcinoma.
Methods: We searched PubMed-MEDLINE, Embase and Scopus, from inception to 20 Sep 2019, and reviewed major conferences' abstracts, for randomised controlled trials of ICI in advanced-stage NSCLC (Stage IIIB or IV) without EGFR mutation that reported hazard ratios (HRs) stratified by geographical region including the region "Asia" or "East Asia". The primary outcome measures were overall survival (OS) and progression-free survival (PFS). The pooled HR and its 95% confidence interval (CI) for OS and PFS in East Asians and non-East Asians were calculated using a random effect model and the difference compared using an interaction test.
Results: A total of 5,465 patients from 7 randomised controlled trials involving CTLA-4 and/or PD-1/L1 inhibitors were included, with 1,740 (32%) East Asians and 3,725 (68%) non-East Asians. ICI was associated with an improvement in OS and PFS for both East Asian (OS HR, 0.74; 95% CI, 0.65-0.85; PFS HR, 0.56; 95% CI, 0.40-0.79) and non-East Asian patients (OS HR, 0.78; 95% CI, 0.72-0.85; PFS HR, 0.69; 95% CI, 0.56-0.85), with no significant difference between the two groups (Pinteraction=0.55 for OS; Pinteraction=0.33 for PFS). Subgroup analyses showed a statistically significant superior PFS (but not OS) for East Asians than non-East Asians in trials that used immune checkpoint inhibitor in the first-line treatment (Pinteraction=0.02). No significant regional difference was found in further subgroups of pure ICI and combination of ICI with chemotherapy.
Conclusions: There is no significant difference in response to ICI between East Asians and non-East Asians with advanced stage NSCLC, and the statistically significant subgroup difference in PFS in the first line use of ICI may not be clinically significant.
METHODS: Retrospective review of consecutive rEBUS bronchoscopy performed with a 6.2 mm conventional bronchoscope navigated via manual bronchial branch reading technique over 18 months.
RESULTS: Ninety-eight target lesions were included. Median lesion size was 2.67 cm (IQR 2.22-3.38) with 96.9% demonstrating positive CT bronchus sign. Majority (86.7%) of lesions were situated in between the third and fifth airway generations. Procedure was performed with endotracheal intubation in 43.9% and fluoroscopy in 72.4%. 98.9% of lesions were successfully navigated and verified by rEBUS following the pre-planned airway road map. Bidirectional guiding device was employed in 29.6% of cases. Clinical diagnosis was secured in 88.8% of cases, majority of which were malignant disease. The discrepancy between navigation success and diagnostic yield was 10.1%. Target PPL located within five airway generations was associated with better diagnostic yield (95.1% vs. 58.8%, P
METHODS: In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival.
RESULTS: The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%).
CONCLUSIONS: Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation-positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125 .).