The Value of Complete Blood Count For The Prognosis Analysis of Esophageal Squamous Cell Carcinoma

Objective To investigate the value of complete blood count in predicting the survival rate of patients with esophageal squamous cell carcinoma. study. The relevant clinical data were collected by the medical record system, and the patients were followed up by the hospital medical record follow-up system. The follow-up outcome was death. The survival time of all patients was obtained. The survival curve was established using the cut-off value of each index obtained by ROC curve. The Cox proportional hazards regression analysis model and nomogram were established to predict the survival prognosis of esophageal squamous cell carcinoma. The role of each index in the prognosis of patients with esophageal squamous cell carcinoma was studied


Background
Malignancy is a major public health problem in the world. According to the 2019 global cancer data report, esophageal cancer incidence and mortality rank the 7th and 6th in all cancer incidence and mortality worldwide, respectively [1] . According to the histological type, esophageal cancer can be divided into two categories: Esophageal Squamous Cell Carcinoma (ESCC), Esophageal Adenocarcinoma (EAC), ESCC is mainly seen in Asia, accounting for about 90%, EAC is mainly seen in Europe, accounting for about 70% -80% [2] [3] , esophageal cancer is mainly in middle-aged and elderly people, the early clinical manifestations are mainly dysphagia, burning sensation under the sword, weight loss and other atypical symptoms, the later can be manifested as progressive dysphagia, so the early symptoms are easy to miss the diagnosis, most of the diagnosis is advanced, the ve-year survival rate is only 10-20% [4] [5] , although its surgical methods and management have great progress, but the prognosis of patients has no signi cant change, how to evaluate the prognosis of patients has important clinical signi cance for clinicians and patients, can help clinicians to change the treatment plan, and improve the survival con dence of patients.
Over the past few decades, it has been con rmed that depth of invasion, lymph node metastasis, TNM stage, and various other factors [6] are important factors affecting the prognosis of esophageal cancer, and an increasing number of experiments in recent years have demonstrated that in ammation is associated with the survival of malignant tumors. Complete blood count (CBC) is one of the most common clinical laboratory tests, and absolute counts of neutrophils, lymphocytes, and monocytes re ect the in ammatory response and the overall immune status of the body. Peripheral blood prognostic in ammatory markers include Neutrophil to Lymphocyte ratio (NLR), Neutrophil to Monocyte ratio (NMR), Lymphocyte to Lymphocyte ratio (LMR), Red blood cell distribution width (RDW) and Blood cell distribution width (PDW), which have been demonstrated to be closely related to the prognosis of various cancers [6] [7] . In clinical laboratory, because blood routine examination is mandatory for patients, and the cost is low, experimental data is relatively easy to obtain. Therefore, it is of great clinical signi cance to predict and analyze the prognosis of patients with esophageal cancer by using the results of routine blood tests.

Method
Source of data This retrospective study was approved by the Ethics Committee of Cancer Hospital A liated to Xinjiang Medical University. All cases of esophageal cancer were diagnosed by pathological results. A total of 3587 cases of ESCC were initially admitted and diagnosed in Cancer Hospital A liated to Xinjiang Medical University from January 2010 to December 2017. All patients with ESCC were staged according to the 8th edition of TNM staging issued by the American Joint Committee on Cancer (AJCC). Experienced oncologists performed pathological TNM staging according to pathological diagnosis. In order to exclude potential bias such as infection and infectious disease, we excluded white blood cell count ≥ 20 x 10 9 /L. Of these, 2503 were male and 1084 were female. The mean age was 63.4 years for men and 64.3 years for women. The results of the rst routine blood test performed on their initial admission were also collected, all tests were performed in the same institutional laboratory, assessed and the patients were followed up by the hospital case follow-up system, and the follow-up outcome was patient death to obtain the survival time of all patients.

Statistical Analysis
The area under the curve (AUC) was calculated by receiver operating characteristic curve (ROC) and the optimal cut-off value for continuous variables was calculated. Survival curves were compared using the Kaplan-Meier method and the Log-Rank test. In addition, univariate and multivariate analyses were performed using Cox proportional hazards regression analysis models to assess the impact of multiple covariates on survival outcomes, and nomograms were generated with Cox regression coe cients and validated. For all analyses, P < 0.05 was de ned as signi cant. Statistical analysis was performed using SPSS version 26.0 (SPSS, Chicago, IL) and the RMS package in R language.

The Critical Value of Each Detection Index
The ROC curve was used to nd out whether each test item has a suitable critical value to predict the death outcome of patients, and then to demonstrate the signi cance of each index in the prognosis. NLR, NMR, LMR and PDW were the quantitative indexes related to death outcome. The ROC curve and related statistical results of each index are shown in Fig. 1 and Table 1.

Survival Analysis Results Of Signi cance Test Indicators
The survival curve was used to analyze the signi cance of gender, age and ve quantitative indicators related to the death outcome of patients with esophageal cancer in judging the prognosis of patients with esophageal squamous cell carcinoma. The results are shown in Fig. 2. From Fig. 2, it can be seen that there was no signi cant difference in gender, NMR, LMR, RDW and PDW survival (P > 0.05); the survival time of age < 60 years group and NLR < 3.52 group was signi cantly higher than that of age ≥ 60 years group and NLR ≥ 3.52 group (P < 0.05), and the diagnostic e cacy of NLR (ACU: 0.700) was signi cantly higher than other items.

4.univariate And Multivariate Cox Regression Analysis Of Various Indicators
Using univariate Cox regression analysis to calculate the value of gender, age, each quantitative index, tumor location, depth of invasion, lymph node metastasis and stage for the prognosis of ESCC patients (Table 3), respectively, it could be found that age (< 0.001), NLR (< 0.001), RDW (= 0.020), depth of invasion (< 0.001), lymph node metastasis (< 0.001) and stage (< 0.001) were prognostic factors for esophageal cancer; using multivariate Cox regression analysis, it could be found that age (< 0.001), NLR (< 0.001), depth of invasion (< 0.001), lymph node metastasis (< 0.001) and stage < 0.001 were independent risk factors for the prognosis of esophageal cancer; in the group aged ≥ 60 years, the risk of death increased 1.   (Fig. 3). It can predict the probability of death for patients with ESCC.

Discussion
The incidence of esophageal cancer is high in the world. Each year, there are about 580,000 new cases diagnosed worldwide, and about 510,000 people die of esophageal cancer every year. In China, nearly 300,000 patients with esophageal cancer die each year, accounting for more than 50% of the global deaths of esophageal cancer [8]. Now it is generally recognized that in ammation plays an increasingly important role in the development of tumors, and its mechanism may be: in ammation releases cytokines and upregulates transcription factors, leading to the generation and accumulation of a large number of oxygen free radicals, which can cause DNA damage and breakage in parenchymal cells, including stem cells, overexpression of proto-oncogenes, loss of function of tumor suppressor genes and upregulation of genes that promote the cell cycle, leading to abnormal cell proliferation, thereby interfering with the stability of the body's microenvironment, thereby accelerating tumor growth, invasion, metastasis and other processes, affecting the prognosis of tumors [9] [10]. Many reports have shown that LMR, NLR and NMR, PDW, RDW as in ammatory indicators, are closely related to the prognosis of a variety of diseases and can be used as prognostic factors in a variety of malignant tumors [7] [11] [12] .
In this study, we investigated the prognosis of in ammatory indicators in blood routine for esophageal squamous cell carcinoma. Survival curve analysis showed that age < 60 years and NLR < 3.52 patients had survival; univariate Cox regression analysis model showed that RDW (≥ 13.85%) and NLR (≥ 3.52) groups were risk factors for the prognosis of esophageal squamous cell carcinoma, which was the same as most studies; compared with NLR (≥ 3.52), HR was 1.  [19] et al. also did a metaanalysis and concluded that low LMR could predict the poor prognosis of esophageal cancer. In this study, PDW and LMR were not considered to be related to the prognosis of esophageal cancer (P > 0.05), which may be different from the cut-off values of LMR and PDW in the included studies. The criteria and methods for determining cut-off values vary among institutions; a suitable cut-off value cannot be proposed by statistical analysis. This may affect the results and lead to an inevitable potential bias. This may limit the use of NLR, LMR, RDW, PDW in clinical practice and even lead to distinct conclusions, therefore, de ning NLR, LMR, RDW, PDW requires a standard, uniform cutoff. In the present study, we attempted to establish a predictive nomogram based on prognostic factors of blood routine to predict survival prediction. We believe that our model is a simple and easy tool for both physicians and patients and can be used to estimate the survival rate of esophageal cancer patients in the case of initial diagnosis.
Several limitations should be acknowledged in the current study. First, the current study is a retrospective study, although it is a large sample, but other potential diseases affecting in ammatory cannot be completely ruled out; second, excessive uncontrollable factors of laboratory test results of blood cell count-related indicators and excessive variation of indicators lead to its limited role in the judgment of clinical prognosis. Therefore, this study aimed at the expression level of peripheral blood cells in patients with esophageal cancer and explored the relationship between a variety of in ammatory indicators and the prognosis of esophageal cancer, in order to provide new ideas for the prognosis of esophageal cancer. Similarly, we also expect to have a more scienti c and rigorous prospective study to verify in the future.

Declarations Authors'contributions
The author read and approved the nal manuscript.

Competing interests
The author declares that he has no con ict of interests.
Ethics approval and consent to participate The study was approved by Ethics Committee of Xinjiang Medical University.
The study con rming that informed consent was obtained from all subjects or, if subjects are under 16, from a parent and/or legal guardian.