Introduction: Programmed death-ligand 1 (PD-L1) expression as measured by immunohistochemistry (IHC) has been employed to predict the efficacy of anti-PD-1/PD-L1 therapy. Nevertheless, heterogeneous PD-L1 expression represents a challenge for the selection of patients for anti-PD-1/PD-L1 therapy. Methods: PD-L1 expression using clone 22C3 in 76 resected non-small-cell lung cancer and paired nodal metastases was assessed and classified according to the proportion of immunostained tumour cells using cutoff values of 1%, 5%, and 50%. Results: The concordance rates for PD-L1 expression between primary and metastatic lymph nodes (N1) at these cutoff values were 67.7% (21/31) (Kappa value: 0.455, p<0.000), 60.0% (15/25) (Kappa value: 0.668, p<0.000), and 62.5% (5/8) (Kappa value: 0.497, p<0.000). In 36 paired N1 lymph nodes and N2 lymph nodes, 54.5% (6/11) (Kappa value: 0.625, p<0.000) of cases of PD-L1 expression were coincident at cutoffs of 1%. If stratified by adenocarcinoma and squamous cell carcinoma, 87.5% (14/16) (Kappa value: 0.830, p<0.000) of cases at the 1% cutoff and 46.7% (7/15) (Kappa value: 0.324, p<0.000) of cases at the 1% cutoff were coincident. Conclusion: The results of this study demonstrate that the concordance of PD-L1 expression between primary tumour and nodal metastases is low in non-small-cell lung cancer but is high in adenocarcinoma. Our results also suggest that PD-L1 expression in either lymph nodes or tumour tissues does not predict survival. PD-L1 detection in metastatic lymph nodes is not a suitable replacement for PD-L1 detection in the primary lesion.

AimsTo assess the incidence and risk of arterial and venous thromboembolic events (ATEs and VTEs) associated with antivascular endothelial growth factor (VEGF) agents, including VEGF receptor-tyrosine kinase inhibitors and VEGF monoclonal antibodies, in advanced non-small-cell lung cancer (NSCLC) patients.MethodsWe performed a broad search of PubMed for relevant trials. Prospective randomized trials evaluating therapy with or without anti-VEGF agents in patients with advanced NSCLC were included for analysis. Data on VTEs and ATEs were extracted. The overall incidence, Peto odds ratio (Peto OR), and 95% confidence intervals (CIs) were pooled according to the heterogeneity of included trials.ResultsA total of 13,436 patients from 23 trials were included for analysis. Our results showed that anti-VEGF agents significantly increased the risk of developing high-grade ATEs (Peto OR: 1.44, 95% CI: 1.00–2.07, P=0.048), but not for all-grade ATEs (Peto OR: 0.94, 95% CI: 0.56–1.59, P=0.82) compared with controls. Additionally, no increased risk of all-grade and high-grade VTEs (Peto OR: 0.94, 95% CI: 0.67–1.31, P=0.71 and Peto OR: 0.95, 95% CI: 0.73–1.22, P=0.67, respectively) was observed in advanced NSCLC patients receiving anti-VEGF agents.ConclusionThe use of anti-VEGF agents in advanced NSCLC patients significantly increased the risk of high-grade ATEs, but not for VTEs. Clinicians should be aware of the risk of severe ATEs with administration of these drugs in advanced NSCLC patients.

Gentamicin can lead to cochlear hair cells associated ototoxicity by inducing apoptosis and oxidative stress, which can be alleviated by baicalin, one flavonoid extracted from the root of Scutellaria baicalensis. The role of baicalin in protecting gentamicin-induced hearing loss is unclear. Interference with oxidative stress was investigated in this study using House Ear Institute-Organ of Corti1 (HEI-OC1) cells, which were simultaneously treated with baicalin (0-400 μM) and gentamicin (0.2 or 1 mM). MTT was used to assay cell viability and apoptosis was detected with Annexin V-fluorescein isothiocyanate staining. The production of reactive oxygen species was indicated by 2,7-dichlorofluorescein diacetate fluorescence intensity and mitochondrial depolarization was assayed by JC1-mitochondrial membrane potential assay. Poly(ADP-ribose) polymerase (PARP), cleaved-caspase 3 and cleaved-PARP expression were analyzed with western blot. Baicalin improved the viability of HEI-OC1 cells and significantly reduced the oxidative stress and mitochondrial depolarization compared with the gentamicin treatment group. Gentamicin treatment increased the activation of PARP and caspase-3, while such an increase could be downregulated by baicalin. Baicalin attenuates gentamicin-induced cochlear hair cells ototoxicity, and such inhibition may be mediated by the regulation of reactive oxygen species production, mitochondrial depolarization, and caspase-3 and PARP activation.

Mitochondria play a vital role in maintaining cellular homeostasis. In recent years, studies have found that mitochondria have an important role in the occurrence and development of tumors, and targeting...