Predictive Value of F-SIRI in Prognosis of Patients with Hepatocellular Carcinoma after Radical Hepatectomy

Background: Objective to evaluate the predictive value of preoperative brinogen and systemic inammatory response index (F-SIRI) in the prognosis of patients with hepatocellular carcinoma after radical hepatectomy. Methods: the clinical data of 298 patients with hepatocellular carcinoma who underwent surgery and conrmed by postoperative pathology in our hospital from January 2015 to December 2017 were retrospectively analyzed. The F-SIRI score was calculated according to FIB and SIRI data of peripheral blood. The relationship between F-SIRI score and clinicopathological characteristics was analyzed. The survival analysis was performed by Kaplan Meier method, Cox regression analysis was used to analyze the prognostic factors. Results: preoperative F-SIRI score was correlated with tumor diameter, FIB and SIRI (P<0.05), but not with age, gender, TNM stage and other clinical features (P>0.05). There were signicant differences in the 5-year DFS rate and OS rate among patients with different preoperative F-SIRI scores(P<0.05); Cox regression analysis showed that preoperative tumor diameter, alpha fetoprotein level and F-SIRI score were independent predictors of DFS in patients with HCC (P< 0.05), while preoperative tumor diameter, ALB and F-SIRI score as independent predictors of OS (P<0.05). Conclusion: preoperative F-SIRI is an independent prognostic factor in patients with HCC after radical hepatectomy, with poor prognosis in patients with high level of F-SIRI.


Background
According to GLOBOCAN 2018 data [1], there were 841080 new cases of liver cancer in the world in 2018, including 596574 male cases. There were 244506 cases of liver cancer in women. The incidence rate of global liver cancer is 11.0/10 million, and the standardized incidence rate in the world is 9.3/10 million. Liver cancer has become the sixth most common cancer in the world and the fourth leading cause of cancer death in the world and half of new cases of liver cancer occur in China every year. Therefore, we are actively looking for more effective treatment as lacking reliable prognostic indicators to guide clinical treatment decisions. Tumor -related in ammatory response, as an obvious feature of malignant tumor, plays an important role in the occurrence and development of malignant tumor [2]. Fibrinogen (FIB), a glycoprotein secreted by hepatocytes, as a key regulator of coagulation system, plays an important role in coagulation, cell adhesion and systemic in ammatory response. Increased brinogen level occurs in a variety of malignant tumors, including liver cancer, which is signi cantly correlated with tumor progression, invasion, distant metastasis and low survival rate [3,4]. Peripheral blood cells, including neutrophils, lymphocytes and monocytes, are common indicators of in ammatory response. In addition, a variety of new in ammatory factors can be used to predict the prognosis of patients with malignant tumors, such as neutrophil / lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), as well as the new prediction model (F-NLR) established by FIB and NLR showing good prediction effect in the prognosis evaluation of patients with resectable gastric cancer [5]. In recent years, systemic in ammatory response index (SIRI) based on peripheral blood neutrophil, monocyte and lymphocyte counts has been considered as a predictor of the prognosis of liver cancer [6]. Therefore, we propose a prognostic index based on preoperative FIB and SIRI (F-SIRI) to explore whether it can accurately predict the survival and prognosis of patients with hepatocellular carcinoma. Subject And Method 1.1 Subject 298 patients with hepatocellular carcinoma who were received by our hospital from January 2015 to December 2017 were selected, including 251 males and 47 females, with an age of (52.6 ± 10.8) years old. Inclusive criteria: (1) conducted radical hepatectomy; (2) con rmed hepatocellular carcinoma according to postoperative pathology; (3) The preoperative laboratory data included FIB and SIRI data; (4) The clinical and follow-up data were complete. Exclusion criteria: (1) patients received chemotherapy before operation; (2) Patients with severe acute and chronic infection; (3) Patients with severe hematological diseases; (4) Patients with other malignant tumors; (5) whose data missing.
1.2 Observation Index and De nition of F-SIRI SIRI = neutrophil count × Monocyte count / lymphocyte count. According to the instructions of the instrument, the normal range of plasma FIB is 2.0 ~ 4.0g/L, which is de ned as Hyper-FIBemia when higher than 4.0g/L, so 4.0g/L as the preoperative FIB critical value [7]. The critical value of SIRI was 0.9 by using the method of maximum determined rank statistics, which is a high expression when higher than 0.9. Based on the expression level of FIB and SIRI, the F-SIRI score was calculated. The score standard: FIB ≤ 4.0g/l is 0, and > 4.0g/l is 1; The score of SIRI ≤ 0.9 is 0, and the score of SIRI > 0.9 is 1; The sum of FIB and SIRI scores is F-SIRI score.

Follow-up
The patients were followed up by outpatient and telephone, with every 3 months in the rst two years and once every six months after the operation, till to December 2020 or the patient died, with the median follow-up time of 35 (6-75) months. Overall survival (OS) time refers to the time from the beginning of the day after surgery to the end of the patient's death or follow-up. Disease free survival (DFS) is de ned as the time from the day after surgery to the end of local recurrence / distant metastasis or follow-up.

Statistical Methods
SPSS20.0 software was used for statistical analysis. The count data were compared by χ 2 test; The measurement data were expressed by the mean value ± standard deviation (x ± s), the comparation was tested by t-test; survival curve was draw according to Kaplan-Meier method, and Log-rank test was performed for comparison between groups; Cox regression model was used for multivariate survival analysis. P < 0.05 refers to signi cant difference.

Discussion
The evaluation of study on the prognostic signi cance 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 in ammation is an important marker of cancer [8][9][10]. As more and more evidence showed, local and systemic in ammatory 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 in ammatory 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 in ammatory 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] rst 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 in uencing 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, brinogen can be directly combined with certain growth factors, such as transforming growth factor-B (TGF-B), broblast 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 in ammation is involved in the progression of tumor, and brinogen is a kind of p-globulin which belongs to pro-in ammatory protein and may lead to the elevation of various in ammatory cytokines [17,18]. Next, increased brinogen can enhance cell migration and invasion by regulating the expression of vimentin and cadherin, and by inducing epithelial mesenchymal transition (EMT) [19]. In addition, brin helps platelets adhere to tumor cells, while platelets promote more brin 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 brinogen rather than platelets [20]. [21,22] It has been recognized that high levels of brinogen receptors are expressed in some tumor cells, including intercellular adhesion molecule 1 (ICAM-1) and α5, β1, α3, and β3 integrator. Therefore, brinogen 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 brinogen, 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 re ects the aggressive behavior of tumor, but not in ammatory 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 in ammatory 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 re ects the aggressive behavior of tumor, but not in ammatory 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 in ammatory 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.

Conclusion
In conclusion, this study preliminarily shows that F-SIRI can be used to predict prognosis as an independent in uencing factor for HCC patients after radical hepatectomy. The Survival Curve of Patients with Different F-SIRI Scores