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Purpose: We performed this systematic review and meta-analysis to assess the incidence of fatal adverse events that were associated with the use of programmed cell death ligand 1 (PD-L1) inhibitors, to describe them and to statistically depict factors that were associated with these events. Method: PubMed, Embase, and Cochrane Library were completely searched based on the following terms or relevant Medical Subject Heading ones: "atezolizumab", "durvalumab", "avelumab", and "cemiplimab". Results: A total of 26 eligible studies were identified, incorporating 6,896 unique participants. The overall incidence was 1.24% (95% CI: 0.93–1.65%). The incidence and odds were higher in patients with non-squamous non-small cell lung cancer (NSCLC) than those with urothelial carcinoma [(2.25 vs. 0.85, p = 0.04), (odds ratio [OR]: 2.69; 95% CI: 1.04–6.97, p = 0.04)], higher in the middle-aged group than the young group [(1.74 vs. 0.89, p = 0.01), (OR: 2.13; 95% CI: 1.26–3.61, p = 0.01)], and higher in the trial phase I than the trial phase II [(1.76 vs. 0.60, p = 0.01), (OR: 0.31; 95% CI: 0.13–0.75, p = 0.01)]. Notably, the trial phase I had a higher incidence than trial phase II or III following regulating for cancer types and average age (OR: 0.28; 95% CI: 0.11–0.71, p = 0.01, OR: 0.48; 95% CI: 0.24–0.95, p = 0.04, respectively). In terms of organ-specific fatal adverse events, interstitial lung disease (ILD) was frequently documented. A variety of respiratory system-related fatal adverse events were recorded, including but not limited to pneumonia and respiratory failure. As for organ-unspecific fatal adverse events, substantial cases of sepsis and neutropenia were recorded. Conclusion: This study firstly provided a comprehensive incidence and the spectrum of fatal adverse events associated with PD-L1 inhibitors, and identified three potential susceptible factors of that, yielding a capability for clinicians to distinguish high-risk populations from relatively low-risk ones, and facilitating to improve the safety of PD-L1 inhibitors broadly used in the clinical setting. [ABSTRACT FROM AUTHOR]

Background: Aberrant expression of microRNAs (miRNAs) in non-small-cell lung cancer (NSCLC) has been reported. Dysregulation of miRNAs exerts tumor-suppressing or tumor-promoting actions on the pathology and biological behaviors of NSCLC. miR-612 is associated with many types of human cancer; however, the expression, potential roles, and regulatory mechanisms of miR-612 in NSCLC remain unclear. Material and methods: Here, the expression level of miR-612 in NSCLC tissue specimens and a panel of cell lines were evaluated by RT-qPCR. Cell-Counting Kit 8, flow cytometry, Transwell migration and invasion, and in vivo tumor growth assays were performed to determine the functional role of miR-612 in malignant phenotypes of NSCLC cells. The molecular mechanism underlying the tumor-suppressive roles of miR-612 in NSCLC was investigated. Results: miR-612 was expressed at low levels in NSCLC, and low miR-612 expression was significantly correlated with TNM stage and lymph node metastasis. NSCLC patients with low miR-612 expression had shorter overall survival rate than those with high levels. Exogenous miR-612 expression decreased proliferation, migration, and invasion, and promoted apoptosis of NSCLC cells in vitro. miR-612 upregulation hindered NSCLC tumor growth in vivo. Bromodomain-containing protein 4 (BRD4) was confirmed as a direct target gene of miR-612 in NSCLC cells. BRD4 was obviously overexpressed in human NSCLC tissues and inverse correlated with miR-612 expression. Inhibition of BRD4 expression simulated the tumor-suppressive functions of miR-612 overexpression in NSCLC cells. Reintroduction of miR-612 expression abrogated the miR-612-mediated suppressive effects on NSCLC cells. BRD4 upregulation inhibited activation of the PI3K/Akt pathway in NSCLC cells in vitro and in vivo. Conclusion: This study supports the first evidence that miR-612 exerts tumor-suppressive roles in the aggressive behaviors of NSCLC cells in vitro and in vivo through direct targeting BRD4 and deactivating the PI3K/Akt pathway. Thus, miR-612 might be a promising target for anticancer therapies in patients with NSCLC. [ABSTRACT FROM AUTHOR]