Background/Aims: Systemic inflammatory response (SIR) is widely considered as a preoperative risk factor for hepatocellular carcinoma (HCC) outcomes. The neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR), two of the prognostic indices, have been investigated in post-therapeutic recurrence and survival of HCC. Here, we quantify the prognostic value of these two biomarkers and evaluate their consistency in different HCC therapies. Methods: A systematic review of electronic database of the Web of Science, Embase, PubMed and the Cochrane Library was conducted to search for associations between the NLR and PLR in the blood and clinical outcomes of HCC. Overall survival (OS) and recurrence-free survival (RFS) were the primary outcomes, and hazard ratios (HRs) and 95% confidence intervals (95% CIs) were explored as effect measures. Subgroup analyses were performed to explore the heterogeneity of different therapies. Results: A total of 24 articles comprising 6318 patients were included in the meta-analysis. Overall, the pooled outcomes revealed that a high NLR before treatment predicted a poor OS (HR: 1.54, 95% CI: 1.34 to 1.76, p<0.001) and poor RFS (HR: 1.45, 95% CI: 1.16 to 1.82, p=0.001). Moreover, an increased PLR predicted a poor OS (HR: 1.63, 95% CI: 1.34 to 1.98, p<0.001) and earlier HCC recurrence (HR: 1.52, 95% CI: 1.21 to 1.91, p<0.001). In addition, both the NLR and PLR were identified as independent risk factors for predicting OS and RFS in HCC patients in a subgroup analysis of different treatment types, including curative or palliative therapy; however, these results were not found in the sorafenib subgroup due to limited clinical research. Conclusion: An increased NLR or PLR indicated poor outcomes for patients with HCC. The NLR and PLR may be considered as reliable and inexpensive biomarkers for making clinical decisions regarding HCC treatment.

Mesenchymal stem cells (MSCs) have been reported to exert therapeutic effects on immunoregulation, tissue repair, and regeneration from the bench to the bedside. Increasing evidence demonstrates that extracellular vesicles (EVs) derived from MSCs could contribute to these effects and are considered as a potential replacement for stem cell‐based therapies. However, the efficacy and underlying mechanisms of EV‐based treatment in hepatic ischemia‐reperfusion injury (IRI) remain unclear. Here, we demonstrated that human umbilical cord MSC‐EVs (huc‐MSC‐EVs) could protect against IRI‐induced hepatic apoptosis by reducing the infiltration of neutrophils and alleviating oxidative stress in hepatic tissue in vivo. Meanwhile, huc‐MSC‐EVs reduced the respiratory burst of neutrophils and prevented hepatocytes from oxidative stress‐induced cell death in vitro. Interestingly, we found that the mitochondria‐located antioxidant enzyme, manganese superoxide dismutase (MnSOD), was encapsulated in huc‐MSC‐EVs and reduced oxidative stress in the hepatic IRI model. Knockdown of MnSOD in huc‐MSCs decreased the level of MnSOD in huc‐MSC‐EVs and attenuated the antiapoptotic and antioxidant capacities of huc‐MSC‐EVs, which could be partially rescued by MnSOD mimetic manganese (III) 5,10,15,20‐tetrakis (4‐benzoic acid) porphyrin (MnTBAP). In summary, these findings provide new clues to reveal the therapeutic effects of huc‐MSC‐EVs on hepatic IRI and evaluate their preclinical application.—Yao, J., Zheng, J., Cai, J., Zeng, K., Zhou, C., Zhang, J., Li, S., Li, H., Chen, L., He, L., Chen, H., Fu, H., Zhang, Q., Chen, G., Yang, Y., Zhang, Y. Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate rat hepatic ischemia‐reperfusion injury by suppressing oxidative stress and neutrophil inflammatory response. FASEB J. 33, 1695–1710 (2019). http://www.fasebj.org

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Background: There is growing evidence that the systemic immune-inflammation index (SII), a novel prognostic biomarker based on peripheral lymphocyte, neutrophil, and platelet counts, is associated with poor prognosis for several tumors. However, the prognostic value of SII in patients with hepatocellular carcinoma (HCC) who undergo liver transplantation (LT) remains unclear. The aim of this study was to determine the correlation between SII and prognosis in these patients. Methods: This retrospective study involved 150 patients with HCC who underwent LT within the Hangzhou criteria. The optimal cut-off value was determined by receiver-operating characteristic (ROC) curve analysis to stratify the patients into those with a high SII and those with low SII. The Kaplan-Meier method and the Cox proportional hazards model were used to evaluate the prognostic value of SII. Finally, we calculated the area under the ROC curve to compare the prognostic power of SII, platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and monocyte-to-lymphocyte ratio (MLR). Results: Patients were divided into high SII (≥ 226) and low SII (< 226) groups. Five-year overall survival (OS) was lower in the high SII group than in the low SII group (56.1% vs. 82.4%, p = 0.002). SII ≥ 226 × 109/L, maximum tumor size> 5 cm, microvascular invasion, and poor differentiation were independent prognostic factors for OS. However, SII did not predict 5-year recurrence-free survival (high vs. low SII: 64.1% vs. 78.4%, p = 0.073). The area under the ROC curve was greater for SII than for PLR, NLR, and MLR. Conclusions: Preoperative SII may be a powerful prognostic biomarker in patients with HCC who undergo LT within the Hangzhou criteria. SII is superior to PLR, NLR, and MLR for prediction of OS in these patients.