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The Significance of Fibrinogen in Combination with the Neutrophil to Lymphocyte Ratio in Predicting the Prognosis of Patients with Gastric Cancer

Objective To investigate the significance of fibrinogen (Fib) in combination with the neutrophil to lymphocyte ratio (NLR) in predicting the prognosis of patients with gastric cancer. Methods The preoperative peripheral blood-related indicators of 281 gastric cancer patients were reviewed retrospectively, and the differences in relationship indicators between the survival and death groups were compared and analyzed. The COX regression analysis and Kaplan–Meier Curve (K-M) were used to assess the prognostic significance of Fib combined with NLR in patients with gastric cancer. Results ① The difference between the survival and death groups of patients with gastric cancer was statistically significant in the high and low Fib and NLR levels (X2=6.868 and 17.051, respectively, all P <0.01).② The correlation between Fib and NLR was remarkable (r=0.266, P=0.000).③ The F-NLR classifications showed statistically significant difference between the survival and death groups for gastric cancer patients (X2=20.200, P=0.000).④ Except for Fib and the middle/low classification of F-NLR, which was P<0.05, and the rest were all P<0.01. There was a substantial statistical difference between F-NLR classifications, Fib and NLR.⑤ F-NLR was found to be a predictive factor of death in patients with gastric cancer in COX regression analysis (P=0.000).⑥Patients with F-NLR scores of “0”, “1” and “2” had 5-year survival rates of 92.6%, 64.0% and 47.2%, respectively, and 3-year survival rates of 92.6%, 74.3% and 51.9%, respectively (all P=0.000). Conclusion The combination of Fib and NLR (F-NLR) improves the accuracy of prognosis in patients with gastric cancer.


Grouping Methods
Patients were divided into the death group (including deterioration and death, a total of 47 cases) and the survival group (all cases except for deterioration and death, a total of 234 cases) for comparative analysis.
Taking the death group as the state variable, the ROC curve was drawn, and the area under the curve was 0.647, as shown in Figure 1. According to the curve graph, NLR=1.82 was selected as the best cut-off point. At this time, the corresponding Youden index was the largest, with the corresponding sensitivity of 93.6% and the specificity of 36.9%. Based on this, 281 gastric cancer patients were divided into high NLR level (>1.82) and low NLR level (≤1.82). Palaj et al found that fibrinogen level higher than 3.5g/L was significantly related to poor overall survival rate in gastric cancer patients. 11 Yamamoto et al found that the RFS and OS of the high fibrinogen level were significantly lower than those of the normal fibrinogen level in gastric cancer patients, with a cutoff value of 3.5 g/L. 12 Referring to the above references, we took the value of 3.5g/L as the cut-off value, and divided the patients into high Fib level (>3.5g/L) and low Fib level (≤3.5g/L).
Patients were divided into three F-NLR scoring classifications. High Fib (>3.5g/L) and high NLR (>1.82), with a score of 2, were the high F-NLR classification. High Fib (>3.5g/L) or high NLR (>1.82), with a score of 1, was the middle F-NLR classification. If there was no abnormality, the score was 0, which was the low F-NLR classification.
Statistical Analysis SPSS 23.0 software was used for statistical analysis. ROC was used to compare the sensitivity and specificity of NLR levels for predicting prognosis. Chi-square test was used to compare the counting data. T-test, F-test and H-test were used to compare the measurement data. The correlation was analyzed by Pearson. SNK-q test was used to compare the mean

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between groups. Cox proportional hazard regression model was used to evaluate the prognostic factors, and Kaplan-Meier method was used to draw the survival curve. P<0.05 was regarded as a statistically significant difference.

The Relationship Between Fib, NLR and Clinical Characteristics and Hematology
The specific results are shown in Table 1.
As can be seen from Table 1, the high and low Fib levels of different groups, age, preoperative bleeding, blood transfusion, NLR, Fib, Hb, WBC, NE, MO, platelet (PLT), C-reactive protein (CRP), albumin (ALB), C-reactive protein/ albumin ratio (CAR), prealbumin (PA) and C-reactive protein to prealbumin ratio (CPR) were statistically significant. Comparative analysis of specific hematological indicators in high and low Fib levels revealed that the values of Hb, ALB and PA in low level Fib were significantly higher than those in high level Fib, while the values of NLR, Fib, WBC, NE, MO, PLT, CRP, CAR and CPR in low level Fib were significantly lower than those in high level Fib. The other indicators, including gender and lymphocyte (LY), were not statistically significant.
It can also be seen from Table 1 that the high and low NLR levels of different groups, gender, NLR, Fib, WBC, NE, LY, MO, CRP, CAR and CPR were statistically significant. Comparative analysis of specific hematological indicators between high and low levels of NLR in patients with gastric cancer revealed that the LY value of low NLR level was significantly higher than that of high NLR level, while the values of NLR, Fib, WBC, NE, MO, CRP, CAR and CPR in low NLR level were significantly lower than those in high NLR level. There was no statistical significance in other indicators including age, preoperative bleeding, blood transfusion, Hb, PLT, ALB and PA.

Results of Correlation Analysis
As seen above, Fib, NLR and related indicators have statistical differences. The analysis results of Fib, NLR and Hb, WBC, PLT, CRP, ALB and PA are shown in Table 2.

The Relationship Between F-NLR and Clinical Characteristics and Hematology
The specific results are shown in Table 3.
After F and H-tests, all the above-mentioned sample averages were statistically significant, except PLT. The SNK-q test was used to compare the means between classifications, and the specific results are shown in Table 4.
It can be seen from Table 4 that the values of Fib, NLR and WBC were different among three classifications. There were differences in CRP, CAR, PA and CPR between high classification and low classification, and between high classification and middle classification. But there was no difference between middle classification and low classification and above-mentioned indicators. There were differences in Hb and ALB between high classification and middle classification, but there was no difference between high classification and low classification, and between middle classification and low classification.

Cox Regression Analysis Results of Various Indicators
The specific results are shown in Table 5.

F-NLR and Survival Curve Analysis
The survival rates of patients were calculated by the Kaplan-Meier method, and the specific results are shown in Figure 2. It was found that the 5-year survival rates of patients with F-NLR scores of "0", "1" and "2" were 92.6%, 64.0% and 47.2%, respectively (P=0.000). The 3-year survival rates were 92.6%, 74.3% and 51.9%, respectively (P=0.000). In the patients with F-NLR scores of "0" and "1", the median survival time could not be obtained due to the fact that the median time of the statistics had not yet arrived. Only the median survival time of patients in score "2" was 52 months (P=0.000).

Discussion
Studies have shown that NLR and Fib are significantly related to the prognosis of gastric cancer, and can be used as potential indicators of the prognosis of gastric cancer patients.
Inflammatory response and immune status play an important role in the occurrence and development of tumors. NLR, as an indicator reflecting systemic inflammatory response and immune status, was one of the independent risk factors for predicting the prognosis of gastric cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cholangiocarcinoma and other malignant tumors. 13 NLR could reflect the relative balance of neutrophils and lymphocytes in tumor microenvironment, and the increase of NLR indicated the change of tumor microenvironment. 14 There was a correlation between preoperative high NLR and high lymph node metastasis in patients with gastric cancer, 15 and the incidence of lymph node metastasis in gastric cancer patients was higher than that in normal patients. 16 Patients in the high NLR level were in a state of high inflammatory reaction, with low individual immunity and decreased antitumor immune function, suggesting a poor prognosis. 17,18 Our results also showed that NLR was an independent prognostic factor for gastric cancer patients (P=0.004). However, we found that the high and low NLR levels had no obvious relationship with age, preoperative bleeding, blood transfusion, Hb, ALB, PA and other indicators, suggesting that NLR could not fully reflect the clinical and hematological characteristics of gastric cancer patients, so it might not have a certain influence on the prognosis.

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The preoperative Fib level could predict the prognosis of patients with gastric cancer to a certain extent, and it was expected to provide further diagnosis and treatment directions for patients who had undergone surgery and chemotherapy. 19 We found that Fib had obvious correlation with age, preoperative bleeding, blood transfusion, as well

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as Hb, WBC, ALB, PA, CAR and CPR in addition to gender, indicating that Fib had great significance in judging the prognosis of patients with gastric cancer. Our results showed that Fib was significant in univariate analysis, but not in multivariate analysis. This may be related to our limited sample size. However, other studies have shown that Fib is an independent factor affecting the prognosis. For example, Yu et al 20 showed that Fib was positively correlated with the progression and metastasis of gastric cancer, and Fib was an independent risk factor, which could be used to predict the survival of gastric cancer patients.
Recently, F-NLR has been used as a new indicator to explore its relationship with tumor prognosis. Huang et al 8 confirmed that the preoperative F-NLR score was a valuable prognostic indicator for patients with early-stage resectable non-small cell lung cancer. Kijima et al 9 reported that the F-NLR score was expected to be a predictor of the efficacy and prognosis of patients with advanced esophageal squamous cell carcinoma undergoing esophagectomy. Liu et al 10 demonstrated that the F-NLR score independently predicted the prognosis of patients undergoing radical gastric cancer surgery. Yamamoto et al 6 pointed out that the prognosis of patients with high F-NLR score may be worse than those with relatively low F-NLR score. F-NLR could increase the adverse effects of Fib or NLR alone, and finally increased its application in predicting tumor progression. 21 We analyzed the relationship between F-NLR and clinical and hematological indicators of gastric cancer patients, and found that in addition to PLT, there were significant correlations with gender, age, preoperative bleeding, blood transfusion and prognosis, as well as Hb, WBC, ALB, PA, CAR, CPR and other indicators. F-NLR can be used as a good indicator to judge the prognosis of gastric cancer patients.
Further analysis showed that the difference between the survival and death groups of gastric cancer patients was statistically significant with F-NLR classifications (X 2 =20.200, P=0.000). F-NLR was a prognostic factor of death in patients with gastric cancer (P=0.000). The 5-year survival rates of patients with F-NLR scores of "0", "1" and "2" were 92.6%, 64.0% and 47.2% respectively, and the 3-year survival rates were 92.6%, 74.3% and 51.9% respectively, all of which had a P value of 0.000, suggesting that F-NLR was significantly related to the patient survival rate. According to the above relationship between F-NLR and clinical features and hematology, as well as the results of prognosis analysis, it was showed that F-NLR could effectively judge the prognosis of gastric cancer.
In conclusion, F-NLR is related to the prognosis of gastric cancer patients, and may provide an important reference for the early diagnosis and treatment of cancer patients. Since the cut-off values set by NLR for predicting prognosis are different in different tumors, even in the same tumor, the cut-off value of NLR as an indicator for predicting the prognosis of gastric cancer patients remains to be further explored. [22][23][24][25][26][27][28] Our study also has potential limitations. It is a retrospective analysis with a limited sample size, and this study does not include advanced patients. The results may be biased. We will unify the diagnostic criteria and parameter indicators, strict the inclusion and exclusion criteria of patients, and expand the number of cases in combination with multi-center to further clarify the significance of fibrinogen combined with neutrophil to lymphocyte ratio (F-NLR) on the prognosis of patients with gastric cancer.