Hepatotoxicity in patients with solid tumors treated with PD-1/PD-L1 inhibitors alone, PD-1/PD-L1 inhibitors plus chemotherapy, or chemotherapy alone: systematic review and meta-analysis.

BACKGROUND: This meta-analysis examined the risk of hepatotoxicity in patients with solid tumors who received a PD-1/PD-L1 inhibitor alone, a PD-1/PD-L1 inhibitor plus chemotherapy, or chemotherapy alone. METHODS: Potentially eligible studies were identified by searches of Embase and PubMed. All included studies were randomized controlled trials (RCTs) that examined patients with solid tumors who received a PD-1/PD-L1 inhibitor and/or chemotherapy. RESULTS: We included 20 clinical trials (11,634 patients). Thirteen trials compared PD-1/PD-L1 inhibitor monotherapy with chemotherapy. These two groups had similar risk for elevated markers of hepatotoxicity (based on analysis of all marker grades and high marker grades), although the PD-1/PD-L1 inhibitor group had an elevated relative risk (RR) of elevated aspartate aminotransferase (AST; RR = 2.13, 95% CI = 1.04 to 4.36, P = 0.04) when considering high grades alone; however, this disparity was not significant for comparisons of the pembrolizumab and nivolumab subgroups with the chemotherapy group. Compared with chemotherapy, PD-1/PD-L1 inhibitors increased the risk of all-grade hepatitis (RR = 5.85, 95% CI = 1.85 to 18.46, P < 0.01), and high-grade hepatitis (RR = 5.66, 95% CI = 1.58 to 20.27, P < 0.01). Seven other studies compared PD-1/PD-L1 inhibitor plus chemotherapy with chemotherapy alone. The combined treatment led to a higher risk for all-grade hepatitis (RR = 2.14, 95% CI = 1.29 to 3.55, P < 0.01) and high-grade hepatitis (RR = 5.24, 95%CI = 1.89 to 14.52, P < 0.01), but these groups had similar risk for all-grade and high-grade elevated markers of hepatotoxicity. CONCLUSIONS: Relative to chemotherapy alone, PD-1/PD-L1 inhibitors with or without chemotherapy increased the risk of all-grade and high-grade hepatitis, but generally did not increase the risk of elevated blood markers of hepatotoxicity.

Risk of Pneumonitis and Pneumonia Associated With Immune Checkpoint Inhibitors for Solid Tumors: A Systematic Review and Meta-Analysis.

Background: We performed a systematic review and meta-analysis to evaluate the risk of pneumonitis and pneumonia associated with immune checkpoint inhibitors (ICIs) for solid tumors. Methods: The following keywords were used in searching the Embase and PubMed database: pneumonitis, pneumonia, and immune checkpoint inhibitors. The data was analyzed by using the R software and Metafor package. Results: Among 3,436 studies, 23 randomized clinical trials (RCTs) met our selection criteria which included data from 12,876 patients. Compared with chemotherapy, PD-1 inhibitors showed significant increase in grade 1-5 and grade 3-5 pneumonitis (RR, 5.17, 95% CI: 2.82-9.47, p < 0.001; RR, 4.14, 95% CI: 1.82-9.42, p < 0.001), but not in pneumonia. PD-L1 inhibitors showed significant increase in grade 1-5 pneumonitis and pneumonia (RR, 3.25, 95% CI: 1.61-6.57, p < 0.001; RR, 2.11, 95% CI: 1.20-3.70, p < 0.001). There was no significant difference in any grade pneumonitis and pneumonia in cytotoxic T lymphocyte-associated protein 4 (CTLA4) inhibitors subgroup. Programmed cell death protein 1 (PD-1) inhibitor (nivolumab and pembrolizumab) both showed significant increase in grade 1-5 pneumonitis, and pembrolizumab specially tended to increase grade 3-5 pneumonitis. (RR, 5.64 95% CI: 1.94-16.38, p < 0.001). Compared with PD-1 inhibitor (nivolumab) or CTLA-4 inhibitor (ipilimumab) monotherapy, PD-1 inhibitor, and CTLA-4 inhibitor (nivolumab plus ipilimumab) combination therapies showed significant increase in grade 1-5 and grade 3-5 pneumonitis (RR 3.47, 95%CI:1.76-6.83, p < 0.001; RR 3.48, 95%CI: 1.10-11.02, p < 0.001). Conclusions: PD-1/PD-L1 inhibitors treatment could increase the risk of all-grade pneumonitis. CTLA4 inhibitor ipilimumab treatment alone could not increase the risk of pneumonitis but could augment the risk of pneumonitis in PD-1/PD-L1 inhibitor treated patients. There was no significant increase in the risk of pneumonia after either PD-1/PDL-1inhibitor or CTLA4 inhibitor treatment alone or in combination.

Serum level of co-expressed hub miRNAs as diagnostic and prognostic biomarkers for pancreatic ductal adenocarcinoma.

Background: Sensitive and specific non-invasive biomarkers are urgently needed in order to improve the survival of patients with pancreatic ductal adenocarcinoma (PDAC), which is the fourth leading cause of cancer-related death. We aim to identify serum hub miRNAs as potential diagnostic and prognostic biomarkers for PDAC. Methods: A total of 2578 serum miRNA expression data from 88 PDAC patients and 19 healthy subjects were downloaded from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA) was constructed and significant modules were extracted from the network by WGCNA R package. Network modules and hub miRNAs closely related to PDAC were identified. The prognostic value of hub miRNAs was assessed by Kaplan-Meier overall survival analysis. Results: Two modules strongly associated with PDAC were identified by WGCNA, which were labeled as turquoise and brown respectively. Within each module, twenty hub miRNAs were found. At the functional level, turquoise module was mainly associated with tumorigenesis pathways such as P53 and WNT signaling pathway, while the brown module was mostly related to the pathways of cancer such as RNA transport and MAPK signaling pathway. Utilizing overall survival analyses, five "real" miRNAs were able to stratify PDAC patients into low-risk and high-risk groups. Conclusions: The association of specific Hub miRNAs with the development of pancreatic cancer was established by WGCNA analysis. Five miRNAs (mir-16-2-3p, mir-890, mir-3201, mir-602, and mir-877) were identified as potential diagnostic and prognostic biomarkers for PDAC.