Gastric cancer originates from the epithelial cells of the gastric mucosa, and it poses a significant health challenge due to its aggressive nature, propensity for invading adjacent organs, such as the esophagus, pancreas, and liver, and high incidence of lymph node and distant metastasis [16, 17]. Moreover, gastric cancer is the second-most common malignant tumor in China, and it constitutes approximately half of the global number of gastric cancer cases, with an upward trend [18]. Despite advancements in surgical techniques, total gastrectomy remains the primary treatment for advanced gastric cancer in clinical practice [19,20,21]. However, the postoperative recurrence rate remains unacceptably high, at 40% to 80%, with a dismal five-year survival rate of less than 10% [22,23,24]. Postoperative recurrence is a major contributor to the poor prognosis of gastric cancer patients. Therefore, vigilant monitoring of postoperative recurrence, early detection, and timely intervention are of paramount importance in extending patient survival [25, 26]. Notably, the influence of chemotherapy, targeted therapy, and immunotherapy drugs on imaging may lead to delayed diagnosis or inaccurate assessments, which affects the clinical evaluation of tumor recurrence. Therefore, it is imperative to identify a convenient, cost-effective, sensitive, and precise method for monitoring postoperative recurrence following total gastrectomy in gastric cancer patients. Although tumor markers have greater sensitivity in diagnosing tumor recurrence than other approaches, such as medical imaging, the quest for a biochemical marker with high sensitivity and specificity for the diagnosis of postoperative recurrence of gastric cancer remains elusive.

Previous studies detected PG I expression in gastric cancer tissues using immunohistochemistry [27, 28]. To determine whether gastric cancer cells directly secreted PG I or PG II, we investigated PG I and PG II levels in ascites collected from recurrent gastric cancer patients and in the culture supernatant of gastric cancer cells derived from these ascites. The results unequivocally indicated substantial levels of PG I and PG II and provided direct evidence that these metastatic gastric cancer cells secreted significant quantities of PG I and PG II. This result serves as a foundational cornerstone for the use of PG I and PG II as robust diagnostic indicators for postoperative biochemical recurrence of GC following total gastrectomy, which is analogous to the clinical value of serum thyroglobulin in predicting biochemical recurrence of papillary thyroid carcinoma following total thyroidectomy [15].

Therefore, we analyzed serum PG I and PG II concentrations in follow-up GC patients after total gastrectomy and examined their relationship with biochemical recurrence. The serum concentrations of PG I and PG II were notably increased in patients with recurrent gastric cancer post-total gastrectomy, and PG II demonstrated a particularly substantial elevation compared to PG I. This result may be attributed to the fact that non-recurrent patients who have undergone total gastrectomy often maintain a relatively high baseline level of serum PG I (< 27 ng/mL), which suggests that tissues beyond the gastric mucosa contribute to PG I secretion. Conversely, non-recurrent patients who undergo total gastrectomy tend to exhibit very low levels of serum PG II (< 1 ng/mL).

The secretion of PG I and PG II are closely linked to the anatomical location of the stomach, but whether the elevated presence of PG I and PG II in recurrent gastric cancer patients also correlate with the site of the primary lesion was not known. Therefore, we performed a comprehensive investigation to determine whether the increased levels of PG I and PG II in recurrent gastric cancer patients were associated with the location of the primary tumor. Our findings revealed intriguing patterns. There was a notable increase in serum PG I level in patients who experienced recurrence following surgery for tumors located in the gastric fundus and body. Conversely, there was no significant alteration in PG II levels. Patients who experienced recurrence after surgery for tumors located in the cardia and sinus demonstrated a marked increase in serum PG II levels, but PG I levels remained relatively stable. This observation suggested that the type of PG secreted by metastatic cancer cells was significantly associated with the primary lesion tissue location. However, notably, a considerable number of recurrent patients exhibited simultaneous increases in PG I and PG II. This finding underscores the heterogeneity and complexity of the biological behavior of gastric cancer tissue cells. This finding also supports the importance of simultaneously assessing both markers when diagnosing the biochemical recurrence of gastric cancer.

To further substantiate the link between biochemical recurrence and serum PG levels, we performed a longitudinal follow-up study of three patients. Our observations revealed a discernible pattern. Patients who remained recurrence-free after surgery consistently maintained low serum PG levels. In stark contrast, individuals who experienced recurrence exhibited a progressive increase in serum PG I and/or PG II levels. This dynamic observation supports the hypothesis that postoperative biochemical recurrence in gastric cancer patients who have undergone total gastrectomy may exhibit increased blood levels of PG I and/or PG II.

In our pursuit of clinical efficacy assessment, we used ROC curve analysis to establish optimal cutoff values. A cutoff value of 26.93 ng/mL for PG I and 0.96 ng/mL for PG II yielded results that were characterized by high specificity and sensitivity in the evaluation of postoperative biochemical recurrence in gastric cancer patients who underwent total gastrectomy. PG-I exhibited an AUC of 0.77, and PG-II had an AUC of 0.90, which supported its distinctiveness primarily in clinical efficacy. Notably, the combination of both markers achieved an impressive AUC of 0.97. These findings suggest that PG I and PG II function as exceptional biological markers for the early diagnosis of biochemical recurrence of GC following total gastrectomy. Traditional tumor markers, such as CEA, CA19-9, and CA72-4, also demonstrate commendable sensitivity in detecting biochemical recurrence in GC patients who underwent total gastrectomy [9]. However, these indicators are not highly specific or sensitive. Therefore, PG I and PG II may compensate for this deficiency due to their tissue-oriented secretion characteristics.

Although the physiological role of PG as a digestive enzyme has been recognized for many years, previous research, dating back more than three decades [29], was constrained by the limitations of the detection methods at that time, such as radioimmunoassay (RIA). These methodological constraints primarily hindered the study of PG for the diagnosis of gastric cancer biochemical recurrence, and there were no parallel investigations into the relevance of PG II. The clinical value of PG I and PG II in diagnosing postoperative biochemical recurrence in GC patients who have undergone total gastrectomy has not received the attention it deserves in clinical practice.

In the present study, we investigated the clinical value of PG in the diagnosis of biochemical recurrence among GC patients who have undergone total gastrectomy. However, this study has certain limitations. It does not provide a comprehensive clarification on the types of gastric cancer cells secreting PG, and whether all types of gastric cancer cells secrete PG is not known. The identification of recurrent patients in the present study relied on traditional indicators, including clinical data, pathological findings, and imaging studies, as opposed to the comprehensive follow-up data. Therefore, there may be a subset of recurrent patients with subtle clinical presentations that remained unconfirmed, which could affect the sensitivity of the evaluation. This factor partially explains the suboptimal sensitivity and false positives of PG in the non-recurrence group.

Another limitation is that this study was a retrospective study performed at a single institution, and it included a relatively modest number of patients who experienced recurrence. In conclusion, this investigation contributes valuable dynamic monitoring tools and molecular evaluation indicators for the early diagnosis of postoperative biochemical recurrence in GC patients who have undergone total gastrectomy. After obtaining the basic levels of PG I and PG II in follow-up patients, the monitoring of dynamic changes in PG I and PG II may allow for effective management of postoperative biochemical recurrence.