The evaluation of study on the prognostic significance of preoperative F-SIRI in patients with hepatocellular carcinoma showed that preoperative F-SIRI was independently related to the prognosis of patients, with higher risk of recurrence / metastasis and poorer prognosis in patients with higher preoperative F-SIRI level. F-SIRI, a new parameter established by combining FIB and peripheral blood neutrophil, monocyte and lymphocyte counts, is yet not reported its application in prognosis evaluation in China.
There is a consensus that cancer-related inflammation is an important marker of cancer[8–10]. As more and more evidence showed, local and systemic inflammatory response, plays an important role in promoting tumor growth, deterioration and metastasis, is closely related to the long-term prognosis of patients. Neutrophils can down-regulate the immune function of host cells against cancer cells, thus play an important role in inflammatory response; As the key factor of anti-tumor immunity, lymphocytes participated in the humoral cellular immune process can inhibit the proliferation and metastasis of tumor; while the tumor associated macrophages produced by monocytes can secrete a variety of cytokines such as metalloproteinases after the stimulation of chemokines to the tumor, so play a role in promoting angiogenesis. SIRI, as a new inflammatory index proposed in recent years, is calculated by the counts of neutrophils, monocytes and lymphocytes in peripheral blood. SIRI as an independent predictor of postoperative recurrence and survival in patients with pancreatic cancer, Qi et al. [11] first proposed, it can be more predictive than NLR and LMR. Liu et al. [12]evaluated the application value of SIRI in the prognosis of patients undergoing radical gastrectomy. The results show that as an independent influencing factor of DFS and OS, SIRI is closely related to tumor size, TNM stage and lymphatic invasion. Xu et al. [6]suggested that preoperative SIRI is a reliable predictor of postoperative survival in patients with liver cancer. Therefore, SIRI can also predict the prognosis of tumor.
Other studies also said that hypercoagulable state of blood is related to the occurrence and development of malignant tumor[13, 14]. Abnormal hypercoagulable state of blood can promote the proliferation and invasion of tumor to help the immune escape of tumor. FIB, as a typical coagulation factor, plays an important role in the process of coagulation. Firstly, besides hepatocytes, it can also be synthesized endogenous by cancer cells[15]. Then, fibrinogen can be directly combined with certain growth factors, such as transforming growth factor-B (TGF-B), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) family to regulate the growth of cancer cells[15, 16]. Also, it is believed that inflammation is involved in the progression of tumor, and fibrinogen is a kind of p-globulin which belongs to pro-inflammatory protein and may lead to the elevation of various inflammatory cytokines[17, 18]. Next, increased fibrinogen can enhance cell migration and invasion by regulating the expression of vimentin and cadherin, and by inducing epithelial mesenchymal transition (EMT)[19]. In addition, fibrin helps platelets adhere to tumor cells, while platelets promote more fibrin to gather around tumor cells by forming thrombin. They are promoting each other to protect tumor cells from natural killer cell toxicity. Even tumor cells prefer to adhere to fibrinogen rather than platelets[20]. [21, 22] It has been recognized that high levels of fibrinogen receptors are expressed in some tumor cells, including intercellular adhesion molecule 1 (ICAM-1) and α5, β1, α3, and β3 integrator. Therefore, fibrinogen promotes the bridge connection between platelets and circulating tumor cells (CTC), helping platelets adhere to tumor cells. With the formation of this matrix barrier, carbon tetrachloride escapes from the natural killer cell-induced elimination. It promotes cell migration by providing a matrix for tumor cell migration and by interacting with adhesion molecules and integrins. Fibrinogen can also mediate endothelial cell adhesion to carbon tetrachloride through ICAM-1. On the other hand, Palumbo et al. (2000)[23] proved that the metastatic potential of circulating tumor cells depends to a large extent on fibrinogen, and showed a therapeutic strategy focusing on hemostatic factors to control solid tumor metastasis.
On the other hand, some study [24] found that increased FIB involves with poor prognosis of gastric cancer patients. Yu et al. [25] indicated that Hyper FIBemia is closely related to tumor progression as an independent factor for poor prognosis of cancer patients. Li et al.[26] showed that increased FIB in peripheral blood is an independent risk factor for survival and prognosis of patients with multiple myeloma. These results suggest that FIB may be a predictor of tumor prognosis.
Based on previous studies, we propose a new parameter F-SIRI, which combined FIB and SIRI to better predict the prognosis of HCC patients. This study shows that F-SIRI is correlated with tumor diameter, but not with TNM stage, which may be that lymph node metastasis mainly reflects the aggressive behavior of tumor, but not inflammatory response, therefore requires further research. Survival analysis showed that F-SIRI was associated with DFS and OS in HCC patients. The 5-year DFS and OS rates of patients with higher F-SIRI level were lower; in addition, Cox regression analysis indicated that F-SIRI was an independent predictor of DFS and OS in HCC patients, which was consistent with Gao et al. [27]. Therefore, F-SIRI as a new indicator of inflammatory response can be used to predict the prognosis of patients with hepatocellular carcinoma.
Based on previous studies, we propose a new parameter F-SIRI, which combined FIB and SIRI to better predict the prognosis of HCC patients. This study shows that F-SIRI is correlated with tumor diameter, but not with TNM stage, which may be that lymph node metastasis mainly reflects the aggressive behavior of tumor, but not inflammatory response, therefore requires further research. Survival analysis showed that F-SIRI was associated with DFS and OS in HCC patients. The 5-year DFS and OS rates of patients with higher F-SIRI level were lower; in addition, Cox regression analysis indicated that F-SIRI was an independent predictor of DFS and OS in HCC patients, which was consistent with Gao et al. [18]. Therefore, F-SIRI as a new indicator of inflammatory response can be used to predict the prognosis of patients with hepatocellular carcinoma.
Some limitations in this study: (1) the median follow-up time of 35 months is not enough to fully accumulate the number of deaths, so inevitably affect the stability of the results;(2) Cox regression model did not collect and control all confounding factors although the collected confounding factors were corrected as far as possible;(3) The study only preliminarily discuss the prognostic value of F-SIRI for HCC patients, but not compare with FIB, NLR and SIRI, thus needs further study.