Risk of Ophthalmic Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) -induced adverse events (AEs) have been reported affecting almost all human organs. However, studies about ocular AEs are few. A meta-analysis was performed to evaluate the risks of ICI-related ophthalmic AEs compare to chemotherapy.Methods: Eligible studies were selected from phase II/III randomized controlled trials investigating ICIs. The data were analyzed by R software and Stata. RESULTS: Odds ratio of treatment-related AE (trAEs) and nonspecific ophthalmic trAEs (NS-trAEs) were lower for PD-1/PD-L1 inhibitors than chemotherapy (OR 0.44, p < .05; OR 0.28, p < .001; OR 0.18, p < . 05; OR: 0.18, p < .001respectively). Compared with monotherapy, PD-1 plus CTLA-4 inhibitors increased the risks of immune-related AEs (irAEs) (OR 4.52, p < .01); ICIs plus chemotherapy increased the risks of trAEs and irAEs (OR 2.82, p < .001; OR 3.63, p < .05 respectively). CONCLUSIONS: PD-L1/PD-1 inhibitors had lower risks of trAEs and NS-trAEs than chemotherapy; Compared with monotherapy, combination therapy had higher risks of ophthalmic trAEs and irAEs. ABBREVIATION: PD-1: programmed cell death protein 1; PD-L1: programmed cell death protein ligand 1; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; ICI: immune checkpoint inhibitor; AE: adverse event; trAE: treatment-related adverse event;irAE: immune-related adverse events; NS-trAE: nonspecific ophthalmic treatment-related adverse event; RCT: randomized controlled trials; PFS: progression-free survival; OS: overall survival; ORR: objective response rate; MM: melanoma; NSCLC: non-small cell lung cancer; SCLC: small cell lung cancer; HNSCC: head-neck squamous cell carcinoma; PICOL: patient, intervention, comparison, and outcome; Versus: VS; Chem: chemotherapy; 95%CI: 95% confidence interval; FEM: fixed-effects model; REM: random-effects model; NA: not applicable; MeSH: medical subject heading.

Rictor Activates Cav 1 Through the Akt Signaling Pathway to Inhibit the Apoptosis of Gastric Cancer Cells.

BACKGROUND: Rapamycin-insensitive companion of mammalian target of rapamycin (Rictor) protein is a core subunit of mammalian target of rapamycin complex 2, and is associated with cancer progression. However, the biological function of Rictor in cancer, particularly its clinical relevance in gastric cancer (GC) remains largely unknown. METHODS: Rictor expression and its association with clinicopathologic characteristics in GC were analyzed by immunohistochemistry. Effect of Rictor and Caveolin-1 (Cav 1) on GC cells apoptosis was evaluated via overexpression experiment in vitro. Mechanisms of Rictor and Cav 1 in GC were explored through overexpression and knockdown, by immunofluorescence and western blot analyses. RESULTS: Rictor was upregulated in GC, and mainly located in the cytoplasm of cancer cells. Moreover, higher Rictor levels were associated with worse prognosis. Rictor could inhibit GC cell apoptosis and promote cell growth in vitro. The results of immunofluorescence revealed that Cav 1 localized in GC cell membrane but did not co-localize with Rictor. Further, Rictor regulated apoptosis-related proteins, long non-coding RNAs and also activated cellular signaling, thereby positively regulating Cav 1 expression. This effect was attenuated by the Akt inhibitor ly294002. Cav 1 did not significantly affect the ability of Rictor to inhibit tumor cell apoptosis. CONCLUSIONS: Rictor is upregulated in GC and associated with worse prognosis. It inhibits tumor apoptosis and activates Cav 1 through the Akt signaling pathway to inhibit the apoptosis of GC cells. Rictor is, therefore, a promising prognostic biomarker and possible therapeutic target in GC patients.