Prognostic value of combined lymphocyte-to-monocyte ratio and cancer antigen 724 in patients with proximal gastric cancer residing in extremely cold regions

1 Introduction

Gastric cancer remains one of the five most commonly diagnosed cancers worldwide and ranks as the fourth leading cause of cancer-related mortality^[1]. Due to the often subtle or absent symptoms in its early stages, many patients are diagnosed only after the disease has progressed. Although radical resection followed by adjuvant chemotherapy has become the standard treatment for gastric cancer, a significant proportion of patients still experience recurrence and metastasis, resulting in poor longterm survival outcomes^[2].

In recent years, the incidence of distal gastric cancer has declined in many Western countries, whereas the incidence of proximal gastric cancer has continued to rise^{[3, 4, 5]}. Studies have shown that proximal and distal gastric cancers exhibit distinct biological behaviors and clinical characteristics, with proximal tumors associated with a poorer prognosis^[6]. Because of its higher malignancy and worse outcomes, proximal gastric cancer requires individualized treatment strategies and reliable prognostic biomarkers to support clinical decision-making.

At present, the TNM staging system remains the most widely utilized tool for assessing prognosis and guiding treatment in gastric cancer^[7]. However, TNM staging alone may be insufficient for accurate prognostic evaluation, particularly in patients with proximal gastric cancer. To enhance prognostic stratification and complement existing staging systems, researchers have explored a variety of additional predictive indicators.

Among these, systemic inflammatory responses have been recognized as important contributors to tumor development and progression. Recent studies have highlighted several readily measurable inflammatory markers derived from routine blood tests that are associated with gastric cancer prognosis. These include the lymphocyte-to-monocyte ratio (LMR)^[8], the hemoglobin, albumin, lymphocyte and platelet (HALP) score^[9], and the glucose-to-lymphocyte ratio^[10]. In addition, tumor markers are widely used in clinical practice to evaluate recurrence risk and long-term outcomes.

In extremely cold regions, environmental and lifestyle factors such as climate conditions, dietary habits, and cultural practices may influence the epidemiology and prognosis of gastric cancer. Notably, the consumption of high-salt and pickled foods— commonly seen in cold climates—has been identified as a significant risk factor for gastric cancer^[11]. In this study, we focused on patients from a cold climate region diagnosed with proximal gastric cancer. Our objective was to investigate the prognostic value of preoperative hematological markers, including LMR and cancer antigen 724 (CA724), in order to improve prognostic assessment and support the development of personalized treatment strategies for these patients.

2 Patients and methods

A total of 313 patients diagnosed with gastric fundus cancer who underwent gastrectomy at Harbin Medical University Cancer Hospital between January 2014 and December 2017 were retrospectively enrolled in this study. The inclusion criteria were as follows: (1) residency in extremely cold regions for an extended period; (2) no chemotherapy and/or radiotherapy prior to surgery; (3) primary tumor located in the gastric fundus; (4) no history of other malignant tumors; and (5) survival for at least one month postoperatively. Demographic data, preoperative laboratory findings, surgical records, and pathological characteristics were systematically collected. Staging was classified according to the 8th edition of the TNM classification by the UICC/AJCC. The study was approved by the Ethics Committee of Harbin Medical University (2019-164-R) and conducted in accordance with the Declaration of Helsinki. All patients included in this study have signed written informed consent.

3 Results

3.3 AUC values for LMR, CA724, and LMR + CA724 scores

ROC curve analysis was used to determine the optimal cutoff values for the LMR and cancer antigen 724 (CA724), which were 2.31 and 3.7478, respectively. Based on these thresholds, patients were categorized into high and low groups for each marker.

Patients with LMR ≥ 2.31 and CA724 < 3.7478 were assigned a score of 0 in the LMR + CA724 scoring system. Patients with LMR < 2.31 and CA724 ≥ 3.7478 were assigned a score of 2. All other patients were assigned a score of 1. According to this scoring system, 85 patients (27.2%) were scored as 0, 163 patients (52.1%) as 1, and 65 patients (20.7%) as 2.

The area under the curve (AUC) values for predicting overall survival were as follows: (1) LMR: 0.576 (95 percent confidence interval [CI] = 0.510-0.641), (2) CA724: 0.594 (95 percent CI = 0.530-0.657), (3) LMR + CA724: 0.646 (95 percent CI = 0.5900.702).

These results suggest that the combined LMR + CA724 score demonstrated superior prognostic accuracy compared to either marker alone (Fig. 1).

Fig. 1

ROC curves of LMR, CA724, and LMR + CA724 score for predicting overall survival. ROC, Receiver operating characteristic; LMR, lymphocyte-to-monocyte ratio

3.4 Survival analysis of LMR + CA724 score

Survival analysis demonstrated that patients in the low LMR group had a significantly poorer prognosis compared to those in the high LMR group. Similarly, patients with high CA724 levels experienced worse outcomes than those with low CA724 levels. When stratified by the LMR + CA724 score, patients in the score 2 group exhibited the worst overall survival compared to those in the score 0 and score 1 groups (Fig. 2).

Fig. 2

Kaplan-Meier survival curves based on LMR, CA724, and LMR + CA724 score. LMR, lymphocyte-to-monocyte ratio

3.6 Subgroup analysis

To further evaluate the prognostic value of the LMR + CA724 score in patients with gastric fundus cancer, survival analyses were conducted across several clinically relevant subgroups. These included stratification by pTNM stage (I + II versus III + IV), Borrmann classification (Borrmann type IV versus non-Borrmann type IV), and histological differentiation (high to moderate differentiation, poorly differentiated adenocarcinoma, and signet-ring cell carcinoma).

The results showed that, except in the Borrmann type IV subgroup, patients with an LMR + CA724 score of 2 consistently exhibited significantly worse overall survival compared to those with scores of 0 or 1 (all P < 0.05). Although statistical significance was not reached in the Borrmann type IV subgroup, the median survival time for patients with an LMR + CA724 score of 2 was markedly shorter than that of patients with scores of 1 and 0 (4.6 months versus 21.8 months versus 19.8 months, respectively), indicating a clear trend toward poorer outcomes (Fig. 3).

Fig. 3

Subgroup analysis of combined scoring

(A) Stage I-II; (B) Stage III-IV; (C) Non-Borrmann IV; (D) Borrmann IV; (E) High-moderately differentiated; (F) Poorly differentiated; (G) Low adhesion cancer.

3.8 Prognostic nomogram for OS in proximal gastric cancer

Based on the results of multivariate analysis, four independent prognostic indicators, pTNM stage, Borrmann classification, histological type, and the LMR + CA724 score, were incorporated into a prognostic nomogram to predict overall survival in patients with proximal gastric cancer. The area under the curve (AUC) of the nomogram was 0.817, indicating strong predictive accuracy. Additionally, both the decision curve analysis and the calibration plot demonstrated the model's clinical utility and consistency in predicting survival outcomes (Fig. 4).

Fig. 4

Prognostic nomogram for overall survival and corresponding calibration and decision curve analyses

(A) Nomogram predicting 5-year survival; (B) ROC analysis of nomogram predicting 5-year mortality rate; (C) Decision curve analysis of nomogram; (D) calibration curve of nomogram.

4 Discussion

Over the years, the intricate relationship between inflammation and cancer has played a critical role in guiding the prevention and treatment of inflammation-related malignancies such as liver and gastric cancers^{[12, 13]}. Inflammatory markers including the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) have been extensively investigated in various malignancies, offering practical prognostic insight for clinicians^{[14, 15]}. Likewise, tumor markers such as CA724 have demonstrated diagnostic and prognostic value in multiple clinical settings^[16].

In this study, which focused on patients with proximal gastric cancer residing in extremely cold regions, Cox univariate analysis identified only the LMR and CA724 as statistically significant prognostic indicators. Based on this finding, these two markers were combined to develop the LMR + CA724 score. To the best of our knowledge, this is the first investigation of the prognostic significance of the preoperative LMR + CA724 score in this specific patient population. Our results show that an elevated preoperative LMR + CA724 score is associated with a poorer prognosis. Furthermore, subgroup analyses revealed that this score effectively stratifies patient outcomes across different TNM stages, Borrmann classification groups, and histological subtypes.

The prognostic impact of LMR may be explained by the role of lymphocytes and monocytes in tumor immunity and progression. Lymphocytes contribute to antitumor activity through cytotoxic effects and immune surveillance. Tumor-infiltrating lymphocytes can induce apoptosis in tumor cells, and growing evidence supports the role of lymphocytes as essential cellular components in immune-mediated tumor suppression^{[17, 18]}. A reduction in lymphocyte count may impair immune responses, in part by promoting the release of immunosuppressive cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β)^[19]. Conversely, monocytes play a pro-tumorigenic role. They are actively recruited to the tumor microenvironment in response to tumor-derived signals such as CCL5, and can differentiate into tumor-associated macrophages (TAMs), which suppress immune surveillance and facilitate tumor growth, invasion, and metastasis^{[20, 21, 22, 23]}. The LMR thus reflects a balance between antitumor immunity and tumor-promoting inflammation, making it a reliable prognostic indicator across multiple malignancies^{[24, 25]}. CA724 is a high-molecular-weight, mucin-like glycoprotein that is upregulated in gastrointestinal, reproductive, and pulmonary malignancies. It is widely used in clinical practice for the diagnosis, monitoring, and prognostic evaluation of gastrointestinal cancers^{[26, 27]}.

In this study, the combined LMR + CA724 score demonstrated a higher AUC than either LMR or CA724 alone, indicating superior prognostic accuracy for patients with proximal gastric cancer. Furthermore, this score functioned as an independent prognostic factor. Clinically, patients with elevated LMR + CA724 scores should be monitored closely and may benefit from more aggressive postoperative adjuvant chemotherapy and follow-up.

Nonetheless, several limitations must be acknowledged. First, this was a single-center, retrospective study, which may introduce selection and reporting biases. Future studies should aim to use multicenter, prospective designs to improve the generalizability of these findings. Second, although OS is a widely accepted endpoint, this study lacked sufficient data on disease-free survival (DFS), which limited our ability to assess long-term recurrence risk. Therefore, additional prospective studies with comprehensive clinicopathological and survival data are needed to validate and refine the utility of the LMR + CA724 score.

5 Conclusion

In this study of patients with proximal gastric cancer from a cold climate region, we identified that the preoperative combination of the lymphocyte-to-monocyte ratio and CA724 (LMR + CA724) serves as a robust and independent predictor of overall survival. Elevated LMR + CA724 scores were significantly associated with worse outcomes across diverse clinical subgroups. This combined score offers a practical and cost-effective tool to support individualized prognostic assessment and guide treatment planning. Future multicenter, prospective studies are warranted to confirm these findings and further establish the clinical applicability of the LMR + CA724 score in gastric cancer management.