The prognostic impact of preoperative platelet distribution width-to-platelet count ratio in patients with bladder cancer

Background Preoperative platelet distribution width-to-platelet count ratio (PDW/PLT) has been discussed about its prognostic value in several malignancies, whereas its role in bladder cancer remains unclear. In this study, we attempt to investigate the relationship between the PDW/PLT and the prognosis of patients with bladder cancer. Patients and Methods The clinical data of 115 cases of bladder cancer treated in urology from January 2009 to August 2014 were analyzed retrospectively. The best critical value of PDW/PLT was 0.09965 determined by ROC curve. The patients were divided into low PDW/PLT group and high PDW/PLT group. After 5 years of follow-up, survival was observed, and the clinicopathological data of patients were statistically analyzed. Kaplan Meier method and log rank test were used for single factor survival analysis, and Cox regression analysis was used for multiple factors survival analysis. independent risk factor for tumor The of PDW/PLT can significantly reduce OS and PFS in patients with bladder cancer. Conclusions PDW/PLT is an independent prognostic factor in patients with bladder cancer, and it is related to the clinicopathological characteristics. It has a certain value in evaluating the prognosis of patients with bladder cancer.


Introduction
Bladder cancer is the most common malignant tumor of urinary system. The American Cancer Society predicts that the number of new cases and deaths of bladder cancer in 2019 will be 80470 and 17670 respectively (1). In recent years, the incidence and mortality of bladder cancer in China are also increasing (2). In the management of bladder cancer patients, postoperative tumor recurrence and progression is an important clinical end point (3,4). The traditional TNM staging system can predict the prognosis of bladder cancer. However, in patients with similar TNM stage, there was significant difference in clinical outcome (5). Although in Europe and the United States, molecular diagnostic tests can be used to obtain more prognostic information and help guide clinical treatment, they cannot be used in routine clinical practice due to their high cost. Therefore, it is very important to identify the low-cost biomarkers which can be easily obtained by routine blood cell count.
Recent clinical and experimental evidence support that platelets play multiple roles in the progression of malignant tumors. Platelet is a key factor in tumor growth, metastasis and cancer-related thrombosis (6), such as endometrial cancer, gastric cancer, pancreatic cancer, etc. (7)(8)(9). Recent studies have found that platelet-related markers, such as the ratio of platelets to lymphocytes, are more significant prognostic factors in patients with bladder cancer (10).
Larger platelets store more granules and receptors, and adhere faster than smaller platelets. Therefore, the activity of platelets is more accurately expressed by their size than by counting (11)(12)(13). The ratio of platelet distribution width to platelet count is a commonly used measurement of platelet size and an alternative indicator of platelet activation (14). The ratio of platelet distribution width to platelet count has a significant prognosis in breast cancer patients (15), but its clinical significance in bladder cancer is not clear. Therefore, the purpose of this study is to evaluate the relationship between the ratio of preoperative platelet distribution width to platelet count and the prognosis of patients with bladder cancer.

Clinical data
The clinical data of bladder cancer patients admitted to the urology department of Exclusion criteria: ①patients with positive postoperative pathological margin; ②patients with history of blood system, autoimmune diseases and other malignant tumors; ③patients with chronic obstructive pulmonary disease, heart failure, coronary heart disease, highrisk hypertension and other factors affecting postoperative recovery; ④patients with longterm radiation contact history and neoadjuvant chemotherapy before operation; ⑤patients with serious complications during perioperative period; ⑥Non urothelial tumor; ⑦antibiotics, anticoagulants, hormones and other factors have an impact on the blood test results in the near future. 115 patients were included in the study, including 93 males and 22 females. The average age was (68.5 ± 11.4) years.

Research methods
Through the medical record management system of our hospital, the last blood routine examination and the corresponding clinical pathological data were collected. The platelet distribution width, platelet count and PDW/PLT were recorded. The ROC curve of the relationship between PDW/PLT and postoperative tumor progression was established, and the Yoden index was calculated. The PDW/PLT corresponding to the maximum value was selected as the best dividing point, and the patients were divided into high PDW/PLT group and low PDW/PLT group. Postoperative OS and PFS were used as survival analysis indexes to compare the clinicopathological data and survival differences between the two groups.
At the same time, the single factor and multi factor Prognosis of the patients were analyzed.

Follow up
The follow-up methods were outpatient reexamination, readmission medical record and

Statistical Analysis
SPSS 22.0 statistical software was used to process the data. Using ROC curve, the maximum value of Yoden index is selected as cut off value of PDW/PLT. The measurement data is expressed by (X±S), the comparison is expressed by t test, the counting data is expressed by % and the comparison is tested by χ2 test or Fisher's exact probability method. For OS and PFS, Kaplan Meier method and log rank test were used. Factors with statistical significance in single factor analysis were included in the multivariate Cox proportional risk regression model. The difference of P<0.05 was statistically significant.

Relationship between PDW/PLT and tumor progression
ROC curve of the relationship between preoperative PDW/PLT and tumor progression in 115 patients is shown in Figure 1. The optimal cut off value of PDW/PLT determined by ROC curve was 0.09965. According to whether PDW/PLT ≤ 0.09965 before operation, the patients were divided into low PDW/PLT group (n = 94) and high PDW/PLT group (n = 21).

Comparison of OS and PFS between the two groups
The tumor progression rates of the low PDW/PLT group and the high PDW/PLT group were 57.4% (54 / 94), 71.4% (15 / 21), respectively, and the median PFS was 85 months and 71 months, respectively. However, due to the relatively small number of patients included in the study, there was no statistical difference between the two groups, while the OS of the low PDW/PLT group was significantly higher than that of the high PDW/PLT group, the difference was statistically significant (P < 0.05), as shown in Figure 2.

Relationship between PDW/PLT and clinicopathological data
PDW/PLT was only related to the age of patients, but not to gender, TNM stage, grade, lymph node metastasis and other factors. The difference was not statistically significant.

Cox regression analysis
The statistically significant risk factors of single factor analysis were gradually included in Cox regression analysis. The results showed that grading, lymph node metastasis, PDW/PLT ≤ 0.09965 were independent risk factors affecting the postoperative progression time of bladder cancer patients, as shown in Table 3. This study found that PDW/PLT was associated with survival and was an independent risk factor for the prognosis of bladder cancer. Our findings suggest the potential importance of combining clinicopathological features with PDW/PLT to assess the prognosis of bladder cancer.
Although there are many recent studies on the clinical significance of activated platelets in cancer, the range of available data is still limited by the type of cancer and the clinical results studied. Platelet is rich in TGF-β and PDGF. These platelet-derived growth factors are usually produced in large quantities by cancer cells and contribute to their development. Thrombocytopenia is associated with reduced survival in patients with a variety of tumor types, including colorectal, lung, kidney, stomach, ovarian, brain, endometrial, pancreatic and breast cancers. Elevated platelets promote cancer progression and metastasis by shielding circulating tumor cells from immune surveillance and killing (16). For bladder cancer, the increased expression of platelet-derived endothelial growth factor is significantly related to the tumor progression of bladder cancer (17).
PDW is a more specific marker of platelet activation, because it will not increase due to platelet swelling (18) , and it is also a method to measure platelet heterogeneity caused by megakaryocyte heterogeneity delineation (19). The high value of this index indicates that there are both mature and immature cells in the circulation. This means that the increase of PDW may be accompanied by abnormal thrombosis and / or the result of heterogeneous boundary of megakaryocyte (20). The causes of poor prognosis in patients with high PDW/PLT are not clear. Inflammation may be a link between PDW/PLT and survival. There is a strong link between inflammation and cancer (21). All kinds of proinflammatory cytokines are up-regulated with the development of tumor, and at the same time, they promote the maturation of allomegakaryocytes, leading to the production and release of immature platelets with various characteristics and sizes into the circulatory system, so as to meet the growing needs of tumor (22). However, further research is needed to better understand the causes of poor prognosis of bladder cancer patients with high PDW/PLT. This study also has some limitations, including single center design and relatively small sample size. At the same time, this is a retrospective study, which may also lead to data selection and analysis deviation. Despite these limitations, this study is still the first to reveal that the increase of PDW/PLT indicates the poor prognosis of bladder cancer patients.

Conclusion
Although there are some limitations in this study, the data clearly show that the increase of preoperative PDW/PLT measurement is an unfavorable prognostic factor for bladder cancer patients. It is necessary to further study the mechanism of PDW/PLT in bladder cancer. This work was supported financially by grants from the Nantong Science and technology plan fund (MS22019010).

Availability of data and materials
The datasets used or analyzed during the present study are available from the corresponding author on reasonable request.

Authors' contributions
JCW, HFX and XLW designed the study. MDG and HJ analyzed and interpreted the patient data. JCW was a major contributor in writing the manuscript. JJS, XLW, JFZ analyzed and interpreted the patient data. All authors read and approved the final manuscript.

Ethics approval and consent to participate
The study was approved by The Ethics Committee of the Tumor Hospital Affiliated to Nantong University (Nantong, China). Written informed consent was obtained from all individual participants included in the study.

Patient consent for publication
Not applicable.

Figure 2
Comparison of OS curves between the two groups