In addition to lowering tumor stage and raising the likelihood of curative resection, NAC for GC also eliminates early micrometastases and improves patient survival.[12, 13] Despite the widespread acceptance of NAC in the treatment of progressive GC, a clinical trial found that the rate of patients achieving pathological complete remission (TRG = 0) after receiving NAC was only 10%.[14] Therefore, it is critical to screen for patients who are sensitive to NAC. We analyzed the clinicopathological characteristics and multisystem serological parameters of GC patients and discovered that PDW, ADA, Urea, and cT stage were independent factors influencing the prediction efficacy of NAC, which we used to construct a nomogram of NAC efficacy. The advantages of this nomogram are its low cost, simple operation and wide applicability in clinical applications.
PDW is an important indicator used to assess platelet morphology and activation that measures the variability of platelet volume in the blood.[15, 16] It has been demonstrated that tumor cells can directly activate platelets through G protein-coupled receptor signaling.[17] Therefore, it was discovered that PDW was higher in tumor patients than in the general population for a number of cancers.[16, 18–23] It has been found that TGF-β released from platelet activation prevents tumor cell DNA from being damaged, creates chemoresistance in cancer cells, and encourages tumor cell metastasis.[24, 25] By increasing the sensitivity of chemotherapy, the use of TGF-β inhibitors can promote cancer cell division outside of the G1/S phase.[26] Furthermore, it was discovered in Chen H's study that activated platelet-derived TGF-β could stimulate PI3K/Akt and MEK/Erk signaling in pancreatic cancer cells, hence reducing the sensitivity of chemotherapy.[27] This explains why patients with high PDW levels are less likely to benefit from NAC. Similar results have been reported in breast cancer.[28]
The primary function of ADA is in the metabolism of adenosine, which can hydrolyze and deamination adenosine to produce inosine and dideoxyinosine. Because tumors typically experience hypoxia and necrosis, resulting in a large release of adenosine,[29, 30] they cause a compensatory increase in ADA as well.[31] Thus, in a number of tumors, it has been discovered that ADA is higher in tumor patients than in healthy individuals.[32, 33] The effective anti-tumor immune response is inhibited when the accumulated adenosine binds to adenosine receptors, promoting the proliferation and activation of bone Marrow-Derived Suppressor Cells (MDSCs) and regulatory T cells (Treg cells).[33] The ability of NAC to destroy tumors is compromised in this immunosuppressive microenvironment. Additionally, elevated serum ADA levels indicate rapid malignancy, more lymph node metastasis, and fast malignancy.[34] The effectiveness of NAC will be impacted by local hypoxia and a significant buildup of inflammatory factors in the tumor microenvironment
The body produces urea through the urea cycle in the liver, which is then fused in the blood and primarily by glomerular filtration. Urea was found to be an independent influential factor in predicting the efficacy of NAC in GC in this study. Patients with higher pre-treatment serum Urea levels were more likely to achieve efficacy in GC NAC. However, the underlying mechanism is still not clear. Studies have shown that patients using the drug with low levels of Urea are more likely to develop liver damage early in treatment.[35] Furthermore, liver dysfunction has been identified as a risk factor for a poor prognosis in large cohort studies.[36] Therefore, NAC therapy may be less effective for patients with low urea levels since they may be more likely to experience hepatic impairment. Similar results have been reported in breast cancer patients.[37]
This study discovered that the cT stage had a separate bearing on predicting NAC's effectiveness. The disease is frequently more severe in these patients, and a higher cT stage signifies deeper tumor involvement. Local hypoxia of the tumor and large accumulation of inflammatory factors in the tumor microenvironment can influence the efficacy of NAC. However, the study observation is that the clinical stage of the tumor was not a valid predictor of NAC efficacy. This could be attributed to the fact that the accuracy of enhanced CT examination in determining the cN stage is about 70%,[38, 39] leading to errors in the determination of tumor staging by imaging physicians.
The effect of tumors on the human body is not limited to local tissues and organs, and to some extent, the progress of tumors and the prognosis of patients can be determined by analyzing serological indicators of different human systems. this study finally screened out four independent influencing factors: PDW, ADA, Urea, and cT stage through multivariate regression analysis, which has great advantages in developing new Nomogram prediction model. First, the nomogram created in this study fills a gap in the predictive models that exist for the effectiveness of NAC in treating GC. Second, to construct the current nomogram, radiological features taken from portal phase CT and some clinical signs are primarily used.[4–7] Nonetheless, these radiological features are not easily accessible to clinical practitioners, and the resulting Nomogram is difficult to develop for general use. The nomogram developed in this study was primarily based on common serological indicators and the cT stage of GC patients before treatment. In clinical work, these common parameters are simple and economical to obtain. Thirdly, the correlation between these indicators and NAC for GC was analyzed more comprehensively with a total of 74 clinical parameters being included in this study, covering all routine serological indicators. Moreover, no studies have included parameters such as PDW, ADA, and Urea as predictors in the field of predicting the efficacy of GC NAC. Finally, the consistency index of the Nomogram prediction model developed in this study is greater than that of the previous model (C-index is 0.923), reflecting superior rectification and clinical practicability in verification and evaluation. Although the results of the current study differ from those of some other studies, this variation may be attributed to the different criteria for evaluating the efficacy of NAC. Whereas in other studies only TRG = 0 was included in the group with the efficacy of NAC, the current study included patients with TRG ≤ 2 as well [4].
The study has some shortcomings as well. First, it is a retrospective study introducing selection bias. Second, it has a relatively small sample size and is conducted in a single race. Therefore, a larger sample size is required to make the results more accurate and solid. Finally, the nomogram constructed in this study lacks external validation and will be further evaluated in a multicenter study.