This study found that FPR, NLR/PA, PDW/PLT are associated with the survival and prognosis of patients, and are independent risk factors for the prognosis of bladder cancer. Our findings indicate the potential importance of combining clinicopathological features with FPR, NLR/PA and PDW/PLT to evaluate the prognosis of bladder cancer.
Fibrinogen is a multifunctional protein that affects many cellular processes in tumorigenesis and metastasis. Fibrinogen is one of the most common components of extracellular matrix, which connects to tumor cells. Fibrinogen generates proliferation signals by acting as a scaffold for binding growth factors such as FGF-2 and VEGF. Growth factor binding promotes cell adhesion, proliferation and migration during angiogenesis and tumor cell growth . In addition, cancer cells can synthesize and secrete additional endogenous fibrinogen, high FIB can promote the synthesis of IL-6 and change the nature of leukocyte infiltration, and stimulate T cells and B cells to promote chronic inflammatory response [19–21].
Immune cells play an important role in occurrence, development and metastasis of tumors. Neutrophils can interact with tumor cells and secrete cytokines and chemokines, thus promoting tumor proliferation, angiogenesis and metastasis . It has been reported that neutrophils can secrete vascular endothelial growth factor (VEGF) into the circulation, and VEGF is essential for tumor angiogenesis, metastasis and drug resistance. On the other hand, the role of lymphocytes is mainly to inhibit the occurrence and development of tumor through tumor immune monitoring and tumor cell clearance. At the same time, neutrophils in the tumor microenvironment can also work with lymphocytes to reduce the anti-tumor effect of activated T cells [23, 24]. Therefore, increased NLR can represent neutropenia and lymphopenia, which reflects the imbalance of immune response.
Malnutrition often occurs in patients with malignant tumors. Serum prealbumin is a negative acute phase protein synthesized by the liver, which is often used to evaluate the nutritional status of patients with malignant tumors [25, 26]. Serum prealbumin is a stable tetramer composed of four identical subunits synthesized by liver. Each subunit contains 127 amino acid residues with a relative molecular weight of 61000. It is named after the migration position before albumin in electrophoresis. The content of prealbumin in normal people's serum is very little, and its half-life in vivo is only 1.9D, which is involved in the transport and regulation of vitamin A and thyroxine. At the same time, prealbumin also has thymic activity, which can enhance the body's immunity by promoting lymphocyte maturation, and has potential anti-tumor effect [27–31].
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 malignant tumor and the clinical results studied. Platelets are rich in PDGF, transforming growth factor-β and platelet-derived endothelial growth factor. These platelet-derived growth factors are usually produced in large quantities by cancer cells and contribute to their development [32, 33]. Thrombocytosis is associated with reduced survival in patients with a variety of tumor types, including rectal cancer, lung cancer, renal cancer, gastric cancer, ovarian cancer, brain cancer, endometrial cancer, pancreatic cancer, and breast cancer. Elevated platelets promote cancer progression and metastasis by shielding circulating tumor cells from immune surveillance and killing . For bladder cancer, the increased expression of platelet-derived endothelial growth factor is significantly correlated with the tumor progression of bladder cancer .
PDW is a more specific marker of platelet activation, because it will not increase due to platelet swelling, and it is also a method to measure platelet heterogeneity caused by megakaryocyte heterogeneity demarcation . A high value of this index indicates the presence of 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 megakaryocytes . The cause of poor prognosis in patients with high PDW/PLT is unclear. Inflammation may be the link between PDW/PLT and survival. There is a strong link between inflammation and cancer [37, 38]. Various pro-inflammatory cytokines are up-regulated with the progress of tumor, and promote the maturation of heterologous megakaryocytes, leading to the production and release of immature platelets with various characteristics and sizes into the circulatory system to meet the growing demand of tumor . However, further studies are needed to better understand the causes of poor prognosis of bladder cancer patients with high PDW/PLT.
In this study, we combined these three indicators to evaluate the prognosis of patients with bladder cancer, and the relationship between preoperative FPR, NLR/PA and PDW/PLT and the patients’ OS and PFS. We can find that the prognosis of low FPR group is better than that of high FPR group, the prognosis of low NLR/PA group is better than that of high NLR/PA group, and the prognosis of low PDW/PLT group is better than that of high PDW/PLT group. Further stratified analysis showed that the group with low FPR, low NLR/PA and low PDW/PLT had the best prognosis, while the group with high FPR, high NLR/PA and high PDW/PLT had the worst prognosis. Cox regression analysis showed that TMN stage, grade, FPR, NLR/PA and PDW/PLT were statistically significant. At the same time, in order to avoid the influence of these factors, we included these five factors into the multivariate analysis. Finally, we found that the grade, FPR, NLR/PA and PDW/PLT are independent factors affecting the prognosis of patients with bladder cancer. That is, for patients with bladder cancer, the smaller the FPR value, the smaller the NLR/PA value, the smaller the PDW/PLT value, and the lower the grade, the longer the OS and PFS. At the same time, we found that at least 20 patients had at least one relapse, and 52 patients with NMIBC finally developed into MIBC. This is consistent with the characteristics of multicentric growth, easy recurrence and progression of bladder cancer, and also reflects the positive clinical significance of this study. Based on the results of Cox regression analysis, we drew a nomogram and carried out internal verification, so as to have a more accurate judgment on the prediction of 3-year and 5-year survival rate of bladder cancer patients, which also has a certain practical significance for the development of clinical treatment. In the internal validation, the c-index of the nomogram is 0.8140(95%CI 0.7577–0.8703), so the prediction model has good accuracy.
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 lead to bias in data selection and analysis. Despite these limitations, this study is still the first to reveal that elevated FPR, NLR/PA and PDW/PLT are predictors of poor prognosis in patients with bladder cancer.