| Background and objectivesA connection between inflammation and cancer has been long suspected. Increasing basic experimental and epidemiological studies have paid more and more attentions on the contact. The researches have established that many tumors occur in association with chronic inflammation stimulation and persistent inflammation accelerates the development of cancer. Hepatocellular carcinoma (HCC) is one clear example of inflammation-related cancer. This study aims to compare the value of systemic inflammation and hepatic inflammation-related markers on predicting the long-term outcomes of patients with HCC after curative resection and further to develop a postoperative inflammation-based prognostic score model. Then we performed the literature-based meta-analysis to evaluate the prognostic value of systemic inflammatory markers. Furthermore, exploring the relationship between intratumoral inflammatory/immune cells and clinicopathological features, microvessel density (MVD), proliferation index (Ki-67), the recurrence and death risk is also the goal of the current study.Methods1. From Jan 1th 2004 to Dec 31th 2010,401 cases with HBV-associated HCC who underwent curative resection in the PLA general hospital as initial therapy were included in the study. The effects of clinicopathological factors, systemic inflammatory markers (NLR, PLR, PNI) and hepatic inflammatory markers (APRI, GGT/ALT) on predicting the long-term outcomes of patients with HCC were investigated by Kaplan-Meier univariate analysis. The factors which were showed significant in the univariate analysis were further included into the Cox proportional hazard model in order to identify the independent prognostic factor associated with OS. The postoperative prognostic score model was constructed from inflammation markers found to be significant in the multivariate analysis. ROC curve analysis was performed to compare the prognostic significance of preoperative inflammation-based prognostic score model versus that of AJCC 7th TNM Staging.2. The original articles which were published in PubMed, Embase and Web of Science databases until Dec 31th,2015 were the primary source of the current research. Studies which meet with proposed inclusion and exclusion criteria would be selected into the meta-analysis to evaluate the prognostic value of systemic inflammatory markers including NLR, PLR and PNI in HCC. STATA 12.0 was used to data analysis and consolidation. Heterogeneity was tested and evaluated by Cochran’s Q statistic method. According to the results of Heterogeneity test, the effective models were chosen in order to combine the corresponding effect measures. Meta-analysis was performed by HR/OR and their 95% CI as effect measure.3. The infiltrations of CD8* T lymphocytes, CD 15’neutrophils and CD68+ macrophages in the tumor microenvironment were assessed by immunohistochemistry in tissue microarray containing 234 HCC patients. Correlations between CD8+ T lymphocytes, neutrophils, macrophages and clinicopathologic features, CD34+ MVD, Ki-67 were also analyzed. The impact of CD8+ T lymphocytes density, CD 15+ neutrophils density and CD68+ macrophages density on the OS and DFS were evaluated by Kaplan-Meier and Cox regression analysis.Results1. In the multivariate Cox model, only the serum AFP (P=0.009), ALT(P=0.001), tumor differentiation (P=0.030), maximum size of tumors (P=0.001), TNM Stage (P=0.000), PNI (P=0.047), GGT/ALT (P=0.005) were independently prognostic factors. The risk of death in high GGT/ALT group is 1.629 times higher than in low group. The risk of death in high PNI group is only 0.732 times compared to the low group. We then established a novel prognostic score based on PNI and GGT/ALT. The case whose PNI value was less than or equal to 48.50 and GGT/ALT was greater than or equal to 1.52 was marked with score 1 respectively. Conversely, the case whose PNI value was greater than 48.50 and GGT/ALT was less than 1.52 was given a score of 0 respectively. Finally, patients were stratified into 3 risk groups (Score was 0,1 and 3 respectively) and the median OS were 47.0,86.6,111.8 months from low to high group (P=0.000). The novel preoperative inflammation-based prognostic score was superior (area under the curve [AUC],0.659) to 7th TNM Stage (AUC,0.600) though no statistically significant difference was observed (P= 0.1036).2. A total of 6008 patients from 27 studies,1215 patients from 6 studies and 926 patients from 4 studies were included to evaluate the association between NLR, PLR, PNI and clinical outcome of HCC accordingly. The summary results showed that NLR was a negative predictor for its OS with HR of 1.61(95%CI:1.36-1.91,P<0.001) and 2.16 (95%CI:1.73-2.71, P<0.001) for DFS. High PLR indicated poor OS significantly (HR=1.55,95%CI:1.06-2.29,P=0.025), but had no impact on DFS (P=0.222). Low levels of PNI was a negative prognostic marker in patients with HCC including OS (HR=2.12, 95%CI:1.67-2.7, P<0.001) and DFS (HR=1.69,95%CI:1.02-2.8, P=0.043).3. The infiltrations of CD 15+ neutrophils and CD68+ macrophages in the tumor microenvironment were independently risk factors in predicting DFS and OS of patients with HCC. However, CD8+ T lymphocyte had no prognostic value. The risk of recurrence and death in CD 15+ neutrophils group is 1.639 times (95%CI:1.207-2.226; P=0.002) and 1.987 times (95%CI:1.459-2.705;P=0.000) higher than in low group respectively. The risk of recurrence and death in CD68+ macrophages group is only 0.520 times (95%CI: 0.380-0.712; P=0.000) and 0.468 times (95%CI:0.342-0.639; P=0.000) lower than in low group respectively. In addition, the distribution density of CD 15+ neutrophils and CD68+ macrophages in the tumor microenvironment was significantly associated with MVD, but not related to Ki-67.Conclusions1. This study demonstrates that PNI (a systemic inflammation marker) and GGT/ALT (a hepatic inflammation marker) are independent risk factors in predicting OS of patients with HBV-associated HCC after curative hepatectomy. We have validated a novel and simple inflammation-based prognostic score model combing the systemic and hepatic inflammation marker that is suitable feasible and low cost for the preoperative evaluation of prognosis in patients with HBV-associated HCC.2. High level of NLR and low PNI are potential prognostic biomarkers in HCC. High PLR is independently associated with unfavorable OS, but has no significant relationship with DFS. The results about PLR remained to be further confirmed by large-scale studies. Detection of systemic inflammatory markers before treatment may contribute to predict the prognosis of HCC patients.3. The high density of CD15+ neutrophils and low CD68+ macrophages in the tumor microenvironment are independent and unfavorable prognostic factors for HCC patients. Targeting neutrophils and macrophages may be a new potential tumor immunotherapy. |
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