Geriatric Nutritional Risk Index is an effective prognostic predictor for metastatic/recurrent or unresectable esophageal cancer receiving immunotherapy

Introduction

Esophageal cancer (EC) is a prevalent malignant tumor of the gastrointestinal tract, particularly in China, where its incidence and mortality rates are significantly high (1-3). In contrast to Western countries, squamous cell carcinoma represents the predominant histological subtype of EC in China (4,5). Due to the lack of prominent symptoms during the early stages of the disease, a majority of patients receive their diagnosis at intermediate or advanced stages. Even if surgical intervention is performed for tumor resection, it does not yield curative effects, resulting in a high occurrence rate of postoperative metastasis and recurrence (6,7). Some patients are ineligible for surgical removal due to the tumor’s location being inaccessible or an advanced stage of disease progression; consequently, they may only have radiotherapy (RT) and/or chemotherapy (CT) as treatment options with a poor prognosis (8-10). The advent of immune checkpoint inhibitors (ICIs) has revolutionized the conventional treatment approach for EC. The findings from numerous clinical studies have already validated the remarkable efficacy of ICIs in EC; however, there is variability in patients’ responses to treatment (11,12). Programmed cell death ligand 1 (PD-L1) expression is considered an effective biomarker that can predict the prognosis of immunotherapy for EC. However, this requires molecular level testing, which increases the economic burden on patients (13-15). Therefore, investigating indicators associated with the effectiveness of ICIs based on readily available clinical features of patients will have practical implications in clinical settings.

Dysphagia is a prominent symptom of esophageal squamous cell carcinoma (ESCC), and the resulting malnutrition can significantly impact patients’ quality of life. Numerous studies have reported a close association between nutritional status and prognosis in various types of cancer (16,17). Serum albumin serves as a reliable biochemical marker that directly reflects patients’ nutritional status (18-20). Additionally, the body mass index (BMI), determined by height and weight, can provide valuable insights into patients’ overall physical condition (21). The Geriatric Nutritional Risk Index (GNRI), derived from these two indicators, has been demonstrated to be an effective prognostic indicator for cancers. It not only correlates with the occurrence of surgical complications but also predicts patients’ survival outcome (22-25). Patients with metastatic or recurrent ESCC not only experience the burden of the disease itself, but also encounter adverse reactions such as radiation-induced esophagitis and CT-related appetite suppression, leading to a prevalent state of malnutrition in these individuals (26). However, there is currently insufficient exploration on the association between nutritional status and tumor response as well as overall survival (OS) following ICIs treatment for ESCC.

The primary objective of this study was to evaluate the prognostic significance of GNRI, as well as Tumor Node Metastasis (TNM) stage, previous treatments, ICI modalities, and distant organ metastasis in patients with metastatic/recurrent or unresectable ESCC receiving ICIs. Subsequently, we analyzed the combined predictive value of PD-L1 expression and GNRI for tumor objective response rate (ORR) and OS in patients with unresectable ESCC who received ICIs as their first-line treatments. These findings underscore the substantial importance of GNRI in predicting patients’ prognosis following immunotherapy. We present this article in accordance with the REMARK reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-722/rc).

Methods

Patients

The retrospective study included patients with ESCC who had experienced postoperative metastasis or recurrence, as well as those with unresectable lesions who received ICIs at The First People’s Hospital of Yancheng from July 2019 to March 2023. The inclusion criteria were as follows: (I) histopathologically confirmed ESCC; (II) receiving ICIs for more than 2 cycles. The exclusion criteria were as follows: (I) incomplete pre-immunotherapy clinical examination data; (II) unclear prior treatment history; (III) absence of imaging examination to confirm distant metastasis presence; and (IV) patients who had undergone neoadjuvant immunotherapy. Ultimately, a total of 677 patients were included in this study. Among them, 234 patients experienced postoperative metastasis or recurrence. Postoperative metastasis included both regional lymph node metastasis and distant metastasis to organs such as the lungs and liver, while local recurrence was defined as the reappearance of esophageal tumors at the original site. Additionally, 443 patients were deemed unresectable due to extensive tumor invasion, substantial lymph node involvement, or severe cardiopulmonary comorbidities. The patient enrollment flowchart is illustrated in Figure 1. This study was approved by the Ethics Committee of The First People’s Hospital of Yancheng (No. 2021-K-100) and adhered to the principles of the Helsinki Declaration (as revised in 2013). Informed consent forms were obtained from all patients who provided tissue samples for testing, while other patients were exempt as only their historical clinical data were respectively collected.

Figure 1 Patient screening flowchart. ICI, immune checkpoint inhibitor; ESCC, esophageal squamous cell carcinoma.

Clinical data collection

This study gathered baseline demographic and disease-related data from patients to identify factors influencing the prognosis of immunotherapy. The demographic data included gender, age, height, weight, and BMI. The disease-related data consisted of Eastern Cooperative Oncology Group performance status (ECOG PS) score, tumor location, tumor length, tumor differentiation, T and N classification, distant organ metastasis, previous treatments, ICI modalities, and ICI agents.

Definition of GNRI

The calculation methodology for GNRI has been delineated in our prior research (27), with the specific formula outlined as follows:

Formen:Idealbodyweight(kg)=height(cm)−100−{[height(cm)−150]÷4}Forwomen:Idealbodyweight(kg)=height(cm)−100−{[height(cm)−150]÷2.5}[1]

GNRI=[1.489×albumin(g/L)]+{41.7×[actualbodyweight(kg)]÷[idealbodyweight(kg)]}[2]

When the actual body weight exceeds the ideal body weight, we set actual body weight/ideal body weight to 1.

Immunohistochemistry (IHC) analysis

A subset of patients was selected from the cohort to evaluate the expression levels of PD-L1 in their endoscopic biopsy tissues. The inclusion criteria were as follows: (I) patients with unresectable lesions who received immunotherapy as first-line treatment; (II) patients who had not undergone any prior anticancer therapies; (III) patients who completed a minimum of four cycles of immunotherapy; (IV) patients with measurable lesions as defined by the Response Evaluation Criteria in Solid Tumor (RECIST version 1.1) criteria (28). Ultimately, 45 patients satisfied the inclusion criteria. Specimens for PD-L1 testing were obtained from residual tissue samples collected at the time of initial diagnosis. Formalin-fixed, paraffin-embedded (FFPE) blocks of these tissues were retrieved from the pathology department and prepared for IHC. The experimental procedure was conducted as follows: firstly, the tissue sections were dewaxed using xylene and subsequently rehydrated through a gradient of ethanol-water mixture. Next, antigen retrieval of the tissue sections was performed by subjecting them to high temperature in a microwave with sodium citrate buffer (pH 6.0). Once the antigen-retrieval solution cooled to room temperature, the tissue sections were washed with distilled water and incubated with a 5% bovine serum albumin (BSA) solution for 1 hour to block non-specific binding sites. Subsequently, the tissue sections were washed three times with phosphate buffer solution (PBS) and then incubated overnight at 4 ℃ with the primary antibody anti-PD-L1 (E1L3N, AmoyDx, Xiamen, China). The following day, any unbound primary antibody was rinsed off before incubating with the secondary antibody (AS014, ABclonal, Wuhan, China). Thorough cleaning of the sections using PBS followed this step, after which 3,3’-diaminobenzidine (DAB) staining was carried out for 5 minutes and subsequent rinsing with running water was done to stop the reaction. Hematoxylin staining and hydrochloric acid alcohol differentiation procedures were then performed. Finally, dehydration, transparency treatment, and sealing of the slices were carried out. The IHC results were independently assessed by two pathologists, and in case of discordance, a collaborative evaluation was conducted to achieve a final consensus. The combined positive score (CPS) for PD-L1 represents the proportion of PD-L1-positive cells among tumor cells, lymphocytes, and macrophages.

Treatment

All patients were administered ICI therapy with anti-programmed cell death 1 (PD-1) delivered intravenously every three weeks. For patients receiving combination therapy with CT, the regimens primarily consisted of abraxane, paclitaxel, 5-fluorouracil, S-1, or capecitabine, either as monotherapy or in conjunction with platinum-based agents. In cases where immunotherapy was combined with RT, the radiation dose was determined based on the target lesion and typically ranged from 50 to 66 Gy, delivered in fractions of 1.8 to 2.0 Gy per session, five times weekly.

Evaluation of tumor response

The assessment of tumor response was conducted in accordance with the RECIST 1.1, based on the changes observed in target lesions before and after treatment, which are categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). The ORR is defined as the proportion of patients who achieve a best response of CR or PR among all evaluable cases.

Follow-up

All patients were contacted via telephone, and the final follow-up was on June 12, 2024. OS was defined as the duration from the initial administration of immunotherapy until either death or the last follow-up. At the end of the final follow-up, 423 patients had deceased, while 254 remained alive. The duration of follow-up for all patients ranged from 0.13 to 54.6 months, with a median survival time of 14.8 months.

Statistical analysis

The statistical analysis was conducted using the Statistical Package for Social Sciences version 30.0 (SPSS Inc., Chicago, IL, USA), while data visualization was performed using GraphPad Prism 9 software (GraphPad Software Inc., San Diego, CA, USA). The cut-off value of GNRI was determined by time-dependent receiver operating characteristic (ROC) curves. Pearson’s Chi-squared test was utilized to evaluate the association between GNRI and clinical-pathological parameters, as well as to compare disparities in ORR among different groups. Survival differences among various groups were assessed using the Kaplan-Meier method and Log-rank test. Univariate and multivariate analyses were carried out employing the Cox proportional hazards model. A P value <0.05 was considered statistically significant.

Results

Baseline characteristics of the patients

The study included a total of 677 patients, with their baseline characteristics detailed in Table 1. Within the entire patient cohort, the male-to-female ratio was 2.24:1, and the mean age was 70.2±8.03 years. Among the group of individuals who had previously undergone surgery (n=234), clear classification according to TNM stage was achieved; however, for those with unresectable disease (n=443), TNM staging remained unknown. Out of all the patients included in the study, distant organ metastasis was observed in 247 patients prior to the initiation immunotherapy. Additionally, 428 individuals received immunotherapy as their primary treatment modality, while others had previously undergone CT, RT, or chemoradiotherapy (CRT). With regard to the specific immunotherapy approaches employed, ICI monotherapy was administered to a total of 92 patients, while ICI combined with CT was utilized for a larger cohort of 324 patients. Furthermore, ICI in combination with RT or CRT was given to 97 and 164 patients respectively. The baseline characteristics of the metastatic/recurrent and unresectable subgroups are detailed in Tables S1,S2, respectively.

Correlation between GNRI and patients’ clinical pathological parameters

The GNRI was stratified into high and low groups based on the cut-off value determined by the time-dependent ROC curve, which was set at 91.5. A comprehensive analysis was conducted to investigate the correlation between GNRI and clinical pathological parameters in all patients, as well as in the two subgroups of metastatic/recurrent and unresectable patients (Table S3). The findings revealed a significant association between GNRI and BMI, as GNRI incorporates both height and weight measurements. Besides that, GNRI exhibited a significant correlation with the ECOG PS score, indicating that nutritional status substantially influences patients’ physical condition. Moreover, an elevated prevalence of low GNRI was observed in patients with distant organ metastasis, suggesting a potential correlation between malnutrition and the occurrence of distant metastasis. Furthermore, there was a higher proportion of patients with low GNRI who received ICI monotherapy, indicating that malnourished patients have reduced tolerance for CT and RT. In the subgroup of postoperative metastasis or recurrence, GNRI was found to be correlated not only with BMI but also with the tumor location. However, in the subgroup of unresectable disease, GNRI showed associations with BMI, distant organ metastasis, and ICI modalities.

Survival analysis based on GNRI

The Kaplan-Meier analysis revealed that the median survival time for patients with low GNRI was 8.23 months, whereas those with high GNRI had a significantly longer median survival time of 22.1 months (P<0.001, Figure 2A). In the subgroup of postoperative metastasis or recurrence, individuals with low GNRI exhibited a median survival time of 8.43 months, while those with high GNRI had a median survival time of 16.03 months (P=0.003, Figure 2B). Among the unresectable subpopulation, patients with low GNRI demonstrated a median survival time of 8.1 months compared to 22.9 months for those with high GNRI (P<0.001, Figure 2C). These findings indicate that patients with favorable nutritional status, regardless of metastatic/recurrent disease or unresectable status, exhibit prolonged OS following immunotherapy.

Figure 2 Overall survival between different GNRI groups. Survival analysis stratified by GNRI in all patients (A), a subgroup of postoperative metastasis or recurrence (B), and a subgroup of unresectable disease (C). GNRI, Geriatric Nutritional Risk Index.

Prognostic value of GNRI in various subgroups

The impact of GNRI was further explored through survival analysis conducted on subgroups of patients, stratified by factors such as gender, age, and tumor location. The results demonstrated that GNRI played a significant protective role in OS across nearly all subgroups, particularly among patients receiving immunotherapy as first-line treatment [hazard ratio (HR) =0.387, 95% confidence interval (CI): 0.298–0.503]. Notably, higher GNRI levels were associated with significantly prolonged survival durations in patients with ESCC treated with ICIs, highlighting the close relationship between nutritional status and OS (Figure 3). Given that ICI modalities also influence patient prognosis, it is imperative to investigate the predictive value of the GNRI in specific subgroups. The findings demonstrated that a higher GNRI was associated with an improved prognosis across various ICI modalities (Figure 4). Specially, in the metastatic/recurrent subgroup, patients with a higher GNRI experienced significantly prolonged survival when treated with ICIs in combination with CRT (P=0.04, Figure 4D). In the unresectable subgroup, a higher GNRI was associated with a significantly better prognosis for patients receiving ICIs in combination with CT (P<0.001, Figure 4F), RT (P<0.001, Figure 4G), or CRT (P=0.004, Figure 4H).

Figure 3 Survival risk analysis of GNRI across different subgroups. GNRI, Geriatric Nutritional Risk Index; BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group performance status; T, tumor; N, lymph node; CT, chemotherapy; RT, radiotherapy; CRT, chemoradiotherapy; ICI, immune checkpoint inhibitor; CI, confidence interval.

Figure 4 OS stratified according to GNRI in various ICI modalities subgroups. Survival analysis based on GNRI in metastatic/recurrent patients received ICI monotherapy (A), ICI combined with chemotherapy (B), ICI combined with radiotherapy (C) and ICI combined with chemoradiotherapy (D). Survival analysis based on GNRI in unresectable patients received ICI monotherapy (E), ICI combined with chemotherapy (F), ICI combined with radiotherapy (G), ICI combined with chemoradiotherapy (H). OS, overall survival; GNRI, Geriatric Nutritional Risk Index; ICI, immune checkpoint inhibitor; CT, chemotherapy; RT, radiotherapy; CRT, chemoradiotherapy.

Univariate and multivariate analyses

To further elucidate the factors influencing patient survival, both univariate and multivariate analyses were conducted in the entire cohort as well as in subgroups of patients with postoperative metastasis/recurrence and unresectable conditions. The results of univariate analysis in all patients revealed that BMI (P=0.006), ECOG PS score (P<0.001), distant organ metastasis (P<0.001), previous treatments (P<0.001), ICI modalities (P<0.001), ICI agents (P=0.03), and GNRI (P<0.001) were significant factors influencing patient survival. Upon inclusion of these factors in a multivariate analysis, it was found that ECOG PS score (P<0.001), distant organ metastasis (HR =1.793, 95% CI: 1.460–2.202, P<0.001), previous treatments (P=0.003), ICI modalities (P<0.001), and GNRI (HR =0.648, 95% CI: 0.532–0.789, P<0.001) independently predicted OS (Table 2). In the subgroup of patients with postoperative metastasis or recurrence, ECOG PS score (P<0.001), differentiation (P=0.001), distant metastasis (P=0.02), ICI modalities (P=0.001), and GNRI (P=0.04) were identified as independent prognostic factors for patients (Table 3). In the subgroup of patients with unresectable disease, ECOG PS score (P<0.001), tumor length (P=0.02), distant metastasis (P<0.001), previous treatments (P=0.02), ICI modalities (P<0.001), and GNRI (P<0.001) were determined to be independent prognostic factors for patients (Table 4). These findings indicate that maintaining a favorable nutritional status is positively correlated with the prognosis of immunotherapy in both subgroups of patients with metastasis and recurrence or unresectable disease.

Predictive value of GNRI combined with PD-L1 expression

The previous clinical trials have demonstrated that patients with a PD-L1 CPS ≥10 may exhibit significantly prolonged survival after receiving treatment with PD-1 inhibitors. This study aims to further investigate whether the combination of GNRI and PD-L1 expression can enhance predictive performance. The expression of PD-L1 in endoscopic biopsy samples obtained from 45 patients with unresectable ESCC who underwent immunotherapy as their first-line treatment was evaluated. Baseline characteristics of these patients are summarized in Table S4. Pathological evaluations revealed that 16 patients exhibited CPS ≥10, while 29 patients had CPS <10. Representative images depicting the expression of PD-L1 are shown in Figure 5A. The Kaplan-Meier analysis revealed that patients with a PD-L1 CPS <10 exhibited a non-significant trend towards poorer prognosis (P=0.38, Figure 5B). Furthermore, survival analysis based on GNRI groups demonstrated that individuals with low GNRI experienced notably reduced survival durations (P=0.009, Figure 5C). Upon combining PD-L1 CPS and GNRI, it was observed that the median survival time for patients in group I (both low PD-L1 expression and low GNRI) was 9.715 months compared to 22.27 months for those in group II who displayed either high PD-L1 expression or high GNRI levels (P=0.03, Figure 5D). The present finding suggests that the combination of PD-L1 CPS with GNRI can augment the prognostic impact on OS in patients receiving PD-1 inhibitor, as compared to PD-L1 CPS alone.

Figure 5 Predictive performance of GNRI combined with PD-L1 (n=45) (A) Relevant illustrations depicting negative and positive PD-L1 immunostaining. Magnification ×100 (scale bar, 200 µm) and ×400 (scale bar, 50 µm), respectively. (B) Survival analysis grouped by PD-L1 CPS. (C) Survival analysis grouped by GNRI. (D) Survival difference between group I (both low PD-L1 expression and low GNRI) and group II (displayed either high PD-L1 expression or high GNRI). PD-L1, programmed cell death ligand 1; CPS, combined positive score; GNRI, Geriatric Nutritional Risk Index.

Additional observation was carried out to assess the potential impact of GNRI on tumor response. The computed tomography images were evaluated for 45 patients, revealing that one patient achieved CR, 18 achieved PR, 13 had SD, and 13 experienced PD. The ORR was determined to be 42.22%. Upon stratifying patients based on PD-L1 CPS, the findings revealed a significantly higher ORR of 68.75% for those with CPS ≥10 compared to those with CPS <10 (P=0.007, Table 5). Subsequently, upon stratifying patients based on their GNRI levels, it was observed that the ORR was 51.72% for individuals with high GNRI and 25% for those with low GNRI, indicating superior tumor responses in the former group (P=0.08). Furthermore, when combining PD-L1 CPS and GNRI, patients in group I exhibited an ORR of 16.67%, whereas patients in group II demonstrated an ORR of 51.52% (P=0.04). These results underscore the superior predictive value of PD-L1 over GNRI in tumor responses, while their combination can augment the predictive capacity of GNRI regarding response to PD-1 inhibitors.

Discussion

ICIs have been extensively utilized in the treatment of various types of cancer. In China, some patients with ESCC who are not eligible for esophagectomy have achieved effective disease control through the combination of immunotherapy with CT or RT. This represents a significant breakthrough with important implications for the development of standardized treatment protocols for ESCC patients (29-33). Based on abundant clinical evidence, both the National Comprehensive Cancer Network (NCCN) of the United States and the Chinese Society of Clinical Oncology (CSCO) have endorsed PD-1 inhibitors as first-line treatment for EC in patients with locally advanced or metastatic disease. This signifies that immunotherapy has ushered in a new era in the clinical management of EC (34). Therefore, it is essential to search for biomarkers that can predict the efficacy of immunotherapy and to explore combination treatment strategies aiming at enhancing immune responses in order to improve the clinical effectiveness of treatment.

Many patients with ESCC often experience malnutrition due to various complications arising from the disease itself or treatment, such as dysphagia and radiation-induced esophagitis. This nutritional deficiency significantly impacts their tolerance to treatment and prognosis. GNRI is a simple nutritional assessment indicator based on serum albumin, height, and weight. Our previous study has shown that it can effectively predict the OS of patients after RT for ESCC (27), which is consistent with the results reported by Bo et al. (35). Qiu et al. demonstrated the prognostic significance of GNRI in locally advanced ESCC patients undergoing concurrent CRT or RT, establishing GNRI as an independent prognostic factor for patient survival (36). Similar conclusions have been drawn by other studies (37-41). Additionally, Feng et al. reported that in ESCC patients receiving immunotherapy, those with high GNRI exhibited increased pathological complete response (pCR) rates following neoadjuvant immunotherapy, along with reduced postoperative complications and extended OS (42). The present study provides the initial evidence on the prognostic significance of GNRI in predicting survival outcomes following immunotherapy among patients with ESCC who have experienced postoperative metastasis, recurrence, or unresectable disease. To comprehensively assess the prognostic significance of nutritional indicators in immunotherapy for ESCC patients, we further collected additional peripheral blood parameters and evaluated the prognostic value of the Prognostic Nutritional Index (PNI) and the Controlling Nutritional Status (CONUT) score (Figure S1). Consistent with previous literature, our findings indicate that patients with higher PNI exhibit improved prognosis (P<0.001) (43,44), while those with CONUT scores of 0–1 also show extended OS (P<0.001) (45). These results underscore the critical role of nutritional status in influencing the prognosis of ESCC patients undergoing immunotherapy.

To the best of our knowledge, this study represents the largest retrospective analysis to date, investigating the correlation between nutritional markers and the prognosis of ESCC immunotherapy. It not only clearly illustrates the significant predictive value of GNRI in terms of survival for immunotherapy recipients, but also sheds light on the impact of distant organ metastasis, previous treatments, and ICI modalities on patient survival, offering potential insights for future developments in immunotherapy protocols. Moreover, this study further integrated GNRI with PD-L1 expression to evaluate the combined predictive capacity of these factors for tumor response and survival following immunotherapy. Surprisingly, the performance of GNRI in predicting OS may surpass that of PD-L1, while PD-L1 expression excels in predicting tumor response. Therefore, the concurrent utilization of these two indicators can effectively predict both short-term efficacy and long-term outcomes of immunotherapy, thus justifying their clinical promotion and application. Albumin is a key parameter in GNRI, reflecting nutritional status. It supports cell growth, DNA replication, reduces platelet aggregation, and has antioxidant effects. Low serum albumin levels correlate with shortened survival in cancer patients. Mechanistically, pro-inflammatory factors like interleukin-6 (IL-6) and tumor necrosis factor (TNF) reduce hepatocyte albumin synthesis, increase vascular permeability, and lower serum albumin, leading to hypoalbuminemia or cachexia (46). Malnutrition compromises immune function, thereby affecting the efficacy of ICI therapy. However, the relationship between nutritional indicators and PD-L1 expression remains unclear and warrants further investigation.

There are some limitations in this study. Firstly, all the patients included in this study were sourced from a single institution, potentially introducing selection bias. Secondly, due to the retrospective nature of the study, incomplete documentation was found regarding patients’ family history, smoking habits, and alcohol consumption in the previous clinical data; therefore, the influence of these factors on OS could not be analyzed. Furthermore, due to challenges in obtaining tissue samples, only a limited number of patients’ tissues were tested for PD-L1 expression in this study. Therefore, further validation is required to assess the predictive effect of GNRI combined with PD-L1 in a larger population.

Conclusions

ESCC patients with favorable nutritional status demonstrate prolonged survival following immunotherapy, while GNRI serves as an effective prognostic indicator. Furthermore, no distant organ metastasis, utilization of first-line immunotherapy, and the combination of ICI with CRT have all been shown to be associated with improved prognosis. The integration of PD-L1 and GNRI demonstrates significant predictive value for tumor response and OS among patients with ESCC undergoing immunotherapy, warranting its widespread clinical adoption.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the REMARK reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-722/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-722/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-722/prf

Funding: This study was supported by the Jiangsu Province Traditional Chinese Medicine Science and Technology Development Program (No. YB2020079), the Project of National Clinical Research Base of Traditional Chinese Medicine in Jiangsu Province, China (No. JD2023SZX14), the Project of Jiangsu Health Commission (No. Z2022016), and Yancheng Medical Science and Technology Development Program Project (No. YK2021025).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-722/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was approved by the Ethics Committee of The First People’s Hospital of Yancheng (No. 2021-K-100) and adhered to the principles of the Helsinki Declaration (as revised in 2013). Informed consent forms were obtained from all patients who provided tissue samples for testing, while other patients were exempt as only their historical clinical data were respectively collected.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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