The diagnostic efficacy of serum galectin-3 and other markers in papillary thyroid carcinoma

Introduction

Thyroid cancer is a malignant tumor originating from the thyroid follicular epithelium or follicular epithelial cells, and it is also the most common malignancy in the head and neck region (1). Papillary thyroid carcinoma (PTC) is the most common histological subtype and accounts for approximately 85–90% of all thyroid cancers (2).

In recent years, the incidence of thyroid cancer has rapidly increased on a global scale. Thyroid cancer is responsible for 567,000 cases worldwide in 2018, and the global incidence rate in women of 10.2 per 100,000 is three times higher than in men (3). Similarly, according to the National Cancer Registry, thyroid cancer is the fourth most common malignant tumor in women in urban areas of China. The age-standardized incidence rates (ASIRs) of women and men were 15.81 and 5.11 per 100,000 population, respectively in 2016. In women, the ASIR showed a significant increase for thyroid cancer (17.7%) from 2000 to 2016 (4). Thyroid cancer experienced a dramatical increase in incidence among all cancer types, whereas its mortality remained stable, indicating overdiagnosis may play a part with the introduction of new diagnostic techniques.

High-resolution ultrasound, recognized for its convenience, non-invasiveness, and cost-effectiveness, serves as the preferred imaging method for thyroid cancer. It can effectively detect thyroid nodules with a diameter greater than 2 mm, providing detailed information about their boundaries, morphology, and internal structure (5). However, its diagnostic accuracy relies on the clinical expertise of the sonographer. For the preoperative assessment of thyroid nodules’ benign or malignant nature, fine-needle aspiration biopsy (FNAB) emerges as the most sensitive and specific method (6). However, this approach is limited by its invasiveness, cost, inadequate sampling, indeterminate cytology, and operator dependency. Numerous studies indicate that accurately diagnosing benign or malignant thyroid nodules remains a formidable challenge in clinical pathology, with up to 15% of thyroid cancer cases ultimately eluding detection through FNAB (7).

Galectin-3 (beta-galactoside-binding lectin-3, GAL-3), implicated in cell adhesion, is associated with the initiation and progression of tumors (8). Existing research reveals that GAL-3 is absent in normal thyroid tissues but markedly expressed in differentiated thyroid cancer (DTC) tissues (9). Now, GAL-3 has been identified to be a recognized histological marker of PTC and has good specificity in DTC (10). Additionally, numerous studies suggest that GAL-3 plays a role in predicting lymph node metastasis (LNM) in PTC (11).

In the current practice of immunohistochemical diagnosis following the excision of thyroid cancer tissue, GAL-3 and other markers are used combinedly to identify PTC (12). It is also suggested that the combined action of GAL-3 and thyroid peroxidase (TPO) aids in differentiating and diagnosing thyroid tumors (13). Recently, HER2 expression has been linked to the expression of estrogen receptors in thyroid tumor tissue and associated with BRAF^V600E mutation in familial PTC (14). Several studies have shown that immunohistochemical staining for CK19 may assist in the differentiation of the follicular variant of PTC from follicular benign and malignant tumors (15). The marker Ki-67 is an antigen in nucleus, which can perform in cell nuclei through active phases (G1, S, G2, and mitosis) excepting those in the quiescent cells phase (G0). These characteristics make the Ki-67 antigen a highly effective marker for the detection of cells that are rapidly proliferating in both normal and malignant cell populations, such as thyroid, breast, prostate, lung, and other tumors (16). CD56 is a cell surface glycoprotein in which this marker is constitutionally expressed in normal thyroid follicular cells and is preserved in almost all benign thyroid tumor cells. Decreased expression of CD56 has frequently been found in malignant thyroid tumors, especially in PTC (17).

In spite of several studies being done related to the utility of these markers in single as well as in various combinations, a uniform consensus is yet to be reached. GAL-3 accumulating in thyroid cancer tissues has been demonstrated, whereas whether serum GAL-3 and other markers may be used to differentiate PTC from benign thyroid tumors remains unclear. Therefore, our study aims to explore the diagnostic significance of serum GAL-3 and other markers in thyroid cancer, providing insights into the differential diagnosis of PTC and benign thyroid tumors. We present this article in accordance with the STARD reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-320/rc).

Methods

Patients and sample collection

This was a retrospective observational study on thyroid tumors. Data were collected from 260 patients with thyroid tumors admitted to Beijing Tongren Hospital, Capital Medical University, from January 2023 to May 2023. Inclusion criteria were as follows: (I) complete clinical data; (II) no special treatments (e.g., radiotherapy, chemotherapy, hormone replacement therapy, etc.); (II) postoperative pathology confirming PTC or benign thyroid tumor, diagnosis of PTC followed the 5^th edition classification system of the World Health Organization; and (IV) clear pathological staging. Exclusion criteria were as follows: (I) noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP); (II) concurrent other cancers; (III) concurrent kidney diseases; (IV) concurrent other infectious diseases; and (V) concurrent cardiovascular system diseases. The tumor-lymph node-metastasis (TNM) staging followed the 8^th edition classification system of the American Joint Committee on Cancer.

In addition, to assess the serum GAL-3 levels in a population of healthy individuals undergoing normal physical examination, we collected samples from healthy individuals without cardiovascular, liver, kidney, diabetes, thyroid, hypertension, tumor-related conditions, pregnancy, etc.

Prior to surgery, fasting peripheral venous blood samples of 3 mL were collected from all patients and immediately centrifuged at 3,000 rpm for 10 minutes. Clinical biochemical and thyroid function indicators were promptly analyzed. The remaining serum was stored at −80 ℃ for subsequent detection of GAL-3 and other markers, including human epidermal growth factor receptor 2 (HER2), Ki-67, cytokeratin 19 (CK19), TPO, and CD56.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Academic Ethics Committee of Beijing Tongren Hospital, Capital Medical University (approval No. TRECKY2021-131). Informed consent was waived because of the retrospective design of this study.

Detection of clinical biochemical and thyroid function indicators

Beckman AU5811 biochemical analyzer and its corresponding reagents (Beckman Coulter Inc., Brea, CA, USA) were used to measure serum glucose (GLU), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum urea (UREA), and creatinine (CRE).

Beckman DXI800 chemiluminescent immunoassay analyzer and its associated reagents (Beckman Coulter Inc.) were utilized for the detection of thyroid function indicators, including total triiodothyronine (TT3), total thyroxine (TT4), free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), thyroglobulin, thyroglobulin antibody (TG-Ab), and TPO antibody (TPO-Ab).

Detection of GAL-3 and other markers

The serum GAL-3 levels were measured using the Abbott Diagnostics fully automated immunoassay analyzer (I2000SR, Abbott Diagnostics, Chicago, IL, USA) and its corresponding reagents. Other indicators, including HER2, Ki-67, CK19, TPO, and CD56, were assessed using enzyme-linked immunosorbent assay (ELISA). Additionally, serum HER2 and Ki-67 contents were determined using the CUSABIO kits (Wuhan, China), and serum CK19 and TPO levels were measured using the Jianglai kits (Shanghai, China). The determination of serum CD56 content was performed using the ELB kit (Wuhan, China). For the ELISA procedure, 100 µL of serum was added to each well of the enzyme-coated plate, sealed, and incubated at 37 ℃ for 120 minutes. After five washes, 100 µL of enzyme-labeled reagent was added, followed by incubation at 37 ℃ for 60 minutes. After washing, 90 µL of chromogenic agent was added, and the mixture was incubated at 37 ℃ in the dark for 15 minutes. The reaction was terminated by adding 50 µL of stop solution to each well. The absorbance was measured at 450 nm using an enzyme label reader (MB530, Huisong, Shenzhen, China), and the levels of the other markers were calculated using a standard curve.

Statistical analysis

The statistical analysis was conducted using SPSS 22.0 software, and graphing was performed using GraphPad Prism 8.0 software. Normality of the distribution was examined by the Kolmogorov-Smirnov test, and normally distributed metric data were expressed as mean ± standard deviation (SD). Differences between the two groups were compared using independent sample t-tests, while differences among the three groups were assessed using one-way analysis of variance (ANOVA). For skewed distribution measurement data, the median [interquartile range (IQR)] values were used. Comparisons between multiple groups were performed using the Kruskal-Wallis test, and the Mann-Whitney U test was employed to compare differences between two groups. Count data were presented as cases or percentages, and inter-group comparisons were made using the Chi-squared test. Logistic regression analysis was performed to investigate risk factors for PTC. Receiver operating characteristic (ROC) curve analysis was applied to assess the diagnostic value of GAL-3 and other indicators in combination for distinguishing between benign thyroid tumors and PTC, with a higher area under the curve (AUC) indicating better discriminatory ability. Furthermore, DeLong’s test was performed to compare between the AUC of the best single marker and the combined model to validate that the combination offered a significant improvement. A significance level of P<0.05 was considered statistically significant.

Results

Patient characteristics

A total of 260 patients were included, with 165 in the PTC group and 95 in the benign thyroid tumor group based on the postoperative pathological results. Basic patient characteristics were presented in Table 1. No significant differences were found for age (P=0.09) and gender (P=0.85) between the two groups. Among the 165 PTC patients, 121 cases (73.33%) had a tumor diameter greater than 1 cm, 108 cases (65.45%) were solitary, and 57 cases (34.55%) were multifocal. Tumor staging revealed 137 cases (83.03%) in stages 1–2 and 28 cases (16.97%) in stages 3–4. LNM was absent in 90 cases (54.55%) and present in 75 cases (45.45%). Among the 95 patients in the benign thyroid tumor group, 8 cases were benign papillary hyperplasia, 9 cases were thyroid adenoma, and 78 cases were nodular thyroid goiter. The healthy group included 138 individuals, with 79 males and 59 females, aged between 18 and 65 years old (mean age 41.8±9.3 years).

The clinical biochemical tests did not differ between the two groups, including the serum GLU, liver function (ALT, AST), and kidney function (UREA, CRE). Similarly, no significant differences were observed between the two groups in TT3, TT4, FT3, FT4, TSH, and TPO-Ab. However, the benign thyroid tumor group exhibited significantly higher levels of thyroglobulin compared to the PTC group [16.82 (IQR, 5.25–51.32) vs. 8.84 (IQR, 3.05–21.35) ng/mL, P=0.001, respectively] while the PTC group showed significantly higher levels of TG-Ab than the benign thyroid tumor group [0.2 (IQR, 0.1–1.6) vs. 0.0 (IQR, 0.0–0.3) IU/mL, P<0.001, respectively].

Establishment of the reference interval of serum GAL-3 in normal physical examination population

The Kolmogorov-Smirnov test for normality indicated that data of the healthy group were normally distributed (P=0.08). The mean serum GAL-3 level of the healthy group was 8.5±2.7 ng/mL, as shown in Table 2. The 2.5^th percentile [95% confidence interval (CI)] was 3.0 (2.7–3.3) ng/mL, and the 97.5^th percentile (95% CI) was 14.3 (13.4–15.2) ng/mL. Therefore, the reference range for serum GAL-3 in the healthy group was 3.0–14.3 ng/mL. The serum GAL-3 levels in both males and females were found to follow a normal distribution. Although males exhibited higher GAL-3 levels, the difference between male and female GAL-3 levels was not statistically significant (8.7±2.4 vs. 8.1±3.0 ng/mL, P=0.24, respectively).

Results of serum GAL-3 and other markers in PTC and benign thyroid tumor patients

As shown in Table 3, the serum GAL-3 levels in PTC patients were significantly higher than those in patients with benign thyroid tumors [15.6 (IQR, 12.8–18.5) vs. 13.6 (IQR, 11.4–15.2) ng/mL, P=0.045, respectively]. Additionally, serum HER2 and Ki-67 levels in PTC patients were also markedly higher than those in benign tumor patients (P<0.05). However, no significant differences were observed between the two groups in CK19, TPO, and CD56 (P>0.05).

Furthermore, according to the results from the Mann-Whitney U test, serum GAL-3 levels in patients with PTC and benign thyroid tumors were significantly elevated compared to those in normal healthy individuals (Figure 1).

Figure 1 Serum GAL-3 level in patients with PTC, benign thyroid tumor, and healthy population. *, P<0.05; **, P<0.01. GAL-3, galectin-3; PTC, papillary thyroid carcinoma.

Analysis of PTC risk using univariate and multivariate logistic regression

The logistic regression analysis results for patients with PTC are presented in Table 4. The relationships between independent variables (GAL-3, HER2, and Ki-67) and dependent variables (patients with or without PTC) were analyzed. In univariate logistic regression analyses, serum GAL-3 [odds ratio (OR), 1.138; 95% CI: 1.059–1.222; P<0.001], HER2 (OR, 1.145; 95% CI: 1.068–1.227; P<0.001), and Ki-67 (OR, 6.455; 95% CI: 3.506–11.886; P<0.001) were correlated with the presence of PTC. However, in multivariate logistic regression analyses, only serum GAL-3 (OR, 1.134; 95% CI: 1.046–1.228; P=0.002) and Ki-67 (OR, 5.754; 95% CI: 2.947–11.234; P<0.001) were independent risk factors for PTC.

Enhanced efficacy in the combined assessment of GAL-3 and Ki-67 for differential diagnosis of benign thyroid tumors and PTC

To further evaluate the diagnostic efficacy of serum GAL-3 and Ki-67 levels in differentiating benign thyroid tumors and PTC, we employed ROC curve analysis. The results revealed that the area under the ROC curve for GAL-3 in discriminating between benign thyroid tumors and PTC was 0.645 (95% CI: 0.577–0.714; sensitivity, 60.9%; specificity, 76.8%; P<0.001). The AUC for serum Ki-67 in diagnosing benign thyroid tumors and PTC were 0.764 (95% CI: 0.707–0.822; sensitivity, 64.3%; specificity, 81.4%; P<0.001), as shown in Table 5. When two markers were combined for diagnostic purposes, the AUC increased to 0.785 (95% CI: 0.725–0.854), with a sensitivity of 70.6% and specificity of 87.4% (P<0.001) (Figure 2). By the DeLong’s test, the combination of serum GAL-3 and Ki-67 offered a significant improvement.

Figure 2 ROC curve analysis of diagnostic efficacy of GAL-3, Ki-67, and the combination of GAL-3 and Ki-67. AUC, area under the curve; GAL-3, galectin-3; ROC, receiver operating characteristic.

Comparison of serum GAL-3 between PTC patients with and without LNM

Moreover, we investigated the correlation of preoperative serum GAL-3 and LNM in PTC patients. Among the 165 PTC patients, there were 90 cases (54.55%) without LNM and 75 cases (45.45%) with cervical LNM. The results demonstrated that serum GAL-3 of PTC with LNM patients were 16.1 (range, 13.7–18.8) ng/mL, significantly higher than those without LNM 15.0 (range, 12.6–17.1) ng/mL (P=0.03) (Figure 3).

Figure 3 The levels of serum GAL-3 between PTC patients with and without LNM. *, P<0.05. GAL-3, galectin-3; LNM, lymph node metastasis; PTC, papillary thyroid carcinoma.

Comparison of serum GAL-3 between PTC patients with different tumor stages

Among the 165 PTC patients, there were 137 cases (83.03%) in stages T1–2 and 28 cases (16.97%) in stages T3–4. Although serum GAL-3 of PTC in the T1–2 patients [14.1 (range, 11.7–17.2) ng/mL] was slightly lower than those T3–4 patients [16.2 (range, 13.8–20.4) ng/mL], there was no significant difference (P=0.25) (Figure 4).

Figure 4 The levels of serum GAL-3 between PTC patients with different tumor stage. ns, not significant (P>0.05). GAL-3, galectin-3; PTC, papillary thyroid carcinoma; T, tumor.

Discussion

The incidence of thyroid cancer is steadily increasing, with PTC being the most prevalent subtype. However, current laboratory tests lack a reliable indicator for PTC screening. GAL-3, a β-galactoside-binding glycoprotein, has been found to be overexpressed in a variety of cancers and is associated with tumor progression and metastasis, such as adenocarcinoma and squamous cell carcinoma of the lung, laryngeal Carcinoma (18). Additionally, serum GAL-3 can help clinicians screen for salivary gland tumor patients (19). At present, GAL-3 is commonly employed in the pathological diagnosis of thyroid cancer. Consequently, we investigated the feasibility of preoperatively distinguishing between benign and malignant thyroid nodules through the detection of the serum biomarker GAL-3. The results suggest that serum GAL-3 detection holds promise for differentiating between benign and malignant thyroid diseases, and the combined detection of serum GAL-3 and Ki-67 can significantly enhance the diagnostic efficacy of thyroid cancers.

In the assessment of thyroid function markers, including TT3, TT4, FT3, FT4, TSH, and TPO-Ab, no significant differences were observed between the PTC and benign thyroid tumor groups. However, there was a notable elevation in thyroglobulin levels in the benign disease group compared to the PTC group. At present, elevated serum thyroglobulin levels across various thyroid disorders contribute to the consideration by both the European and American Thyroid Associations that preoperative thyroglobulin testing is insensitive and non-specific for thyroid cancer (20,21). Similarly, the 2017 Chinese Expert Consensus on the Clinical Application of Serum Markers in Thyroid Cancer does not recommend using thyroglobulin to differentiate between benign and malignant thyroid tumors (22). Aligned with the conclusions of Lu et al.’s study, our findings also revealed a significant elevation in serum TG-Ab levels in PTC patients compared to those with benign thyroid tumors (23). When the TG-Ab was present in the serum, it maybe interfered with the determination of thyroglobulin, which commonly caused falsely low serum thyroglobulin measurements (24,25). On the contrary, when the level of TG-Ab was very low, the reference significance of thyroglobulin would be greater. So, high level of serum TG-Ab affected the detection of serum thyroglobulin, which led to the decrease of serum thyroglobulin in patients with PTC, compared with the benign thyroid tumor group.

In this study, we preliminarily established a reference range for serum GAL-3 in a normal healthy population, which ranged from 3.0 to 14.3 ng/mL. This range is lower than the serum GAL-3 levels reported in Krintus et al.’s study [2017], where the 97.5^th percentile was noted as 18.1 ng/mL (26). Older age contributed to higher GAL-3 concentrations. In our study, the proportion of older age subjects (≥40 years, 50 out of 138 cases) was similar with Krintus et al.’s study, so this difference may be attributed to the ethnic disparities. Meanwhile, we found higher serum GAL-3 levels in males compared to females. However, there was no significant difference between the genders.

In recent years, there has been a growing body of research on the correlation between serum GAL-3 and PTC. Concordantly with previous studies, we measured elevated serum GAL-3 in PTC patients. And Li et al. [2021] proposed that a combined assessment of serum long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) and GAL-3 could serve for the discrimination of benign and malignant thyroid diseases (27). In Li et al. [2021], the area under the serum GAL-3 curve was 0.817, surpassing our curve’s area. However, it is worth noting that the control group in Li et al. [2021] predominantly comprised patients with thyroid adenomas, while our study mainly featured individuals with nodular thyroid goiters, and the nodule sizes usually exceeded 3 cm.

Consistently with another study, Yu et al. [2020], which suggests a significant difference in serum GAL-3 levels between PTC patients with LNM and those without, our results demonstrated that the level of GAL-3 was highly significant in the serum of LNM patients compared with no metastasis patients (28). GAL-3 can promote chronic activation of K-Ras and differentiation block in malignant thyroid carcinomas (29). GAL-3 acts as a selective intracellular scaffold of K-Ras in the plasma membrane and enhances Ras signaling. Thyroid carcinoma cells strongly expressing GAL-3 showed high levels of K-Ras expression, and K-Ras transmitted strong signals to extracellular signal-regulated kinase. Menachem has also demonstrated that malignant thyroid carcinoma cell proliferation could be inhibited by Ras and GAL-3 inhibitors (30). Moreover, GAL-3 attenuates the apoptosis of human thyroid carcinoma cells through Bax heterodimerization (31). However, because of the small amount of PTC T3–4 patients, no significant difference of serum GAL-3 levels was found between the low and high T-stage groups. Our results also indicated a trend that a higher T-stage would correlate with higher serum GAL-3.

In addition, there was a significant overlap between the reference range of GAL-3 in healthy individuals (3.0–14.3 ng/mL) and the values observed in both the benign thyroid cancer group (median, 13.6 ng/mL; IQR, 11.4–15.2 ng/mL) and the PTC group (median, 15.6 ng/mL; IQR, 12.8–18.5 ng/mL). And the AUC for serum GAL-3 in discriminating between benign thyroid tumors and PTC was only 0.645. While statistically significant, a value (AUC =0.645) was generally considered ‘poor’ for a diagnostic marker. This substantial overlap may be the direct cause of the low AUC of 0.645, so serum GAL-3 was unsuitable for screening PTC, and we suggest limitations in the clinical applicability of GAL-3 as a standalone marker.

Consistent with the result of Wei et al., our findings demonstrated that overall HER2 overexpression was found in PTC. HER2 expression may represent an additional aid to identify a subset of patients who are characterized by a worse prognosis and are potentially eligible for targeted therapy (32). Unfortunately, serum HER2 was not an independent risk factor for PTC through the multivariate logistic regression analyses.

In our study, serum Ki-67 was the best single marker in discriminating between benign thyroid tumors and PTC. Ki-67 is a protein bonded to DNA present in the nucleus, which is linked to growth of cell. Ki-67 has been greater utilized in medications and researches of numerous types of cancer as it is one of the key markers of cell proliferation. Because of the direct linkage between the expressions of Ki-67 marker and tumor cell proliferation or growth, therefore, this marker is used as a marker in routine pathological research. Lindfors et al. investigated the prognostic relevance of a Ki-67 staining index in papillary thyroid cancer and demonstrated that Ki-67 was a predictive factor of PTC patients for disease-free survival (33). So, Ki-67 may be a crucial marker for assessing the aggressiveness of tumors and inflammatory diseases. ROC analysis demonstrated that the high levels of serum GAL-3 and Ki-67 were useful for distinguishing PTC from benign thyroid tumors, and their combination exhibited the best diagnostic efficiency.

Furthermore, we found no significant differences of serum CK19 between the two groups. Makki et al. also discovered no significant difference in serum CK19 levels between PTC and benign tumors (34). Muthusamy et al. revealed that CD56 was expressed in 52/54 (96.3%) of benign specimens and only 24/54 (44.4%) of thyroid cancer specimens, which comprised 31 (57.4%) PTCs (35). However, the number of the PTC group was larger than that of benign thyroid tumor group in our study, there was no difference of serum CD56 between the two groups.

Nevertheless, there were limitations in the study. First, the patient cohort composition suggests a potential for selection bias. The number of cases in the benign group (n=95) was smaller than in the PTC group (n=165). However, benign thyroid tumors are far more common in the general population. Next, we will pay more attention to serum GAL-3 levels in benign thyroid nodules. Secondly, the heterogeneity of benign thyroid tumor group warrants further consideration and clarification. Benign thyroid tumor group was largely composed of nodular thyroid goiter (78 out of 95 cases), a condition with a varied pathological background. The potential impact of this heterogeneity (e.g., co-existing inflammation), which could elevate GAL-3 on marker levels, possibly reduced the observed difference from the cancer group. We should notice this potential impact and select the other benign thyroid tumor group except the nodular thyroid goiter. Thirdly, in this study, we emphasis on the correlation of serum GAL-3 and LNM in PTC patients. Among the LNM patients, we did not distinguish between central (N1a) and lateral neck (N1b) metastasis. Next, we will pay attention to the serum GAL-3 and surgical therapy of PTC, including the N1a and N1b metastasis patients. Finally, it was a single-center, retrospective study with a relatively small sample size, which may be susceptible to selection bias. These problems will be solved by multicenter and prospective studies in the future.

Conclusions

We found that serum GAL-3 levels of PTC patients were significantly higher than those in patients with benign thyroid tumors. The ROC curve analysis revealed that GAL-3 had an AUC of 0.645 for distinguishing between benign thyroid tumors and PTC. When combined with Ki-67, the AUC increased to 0.785. Our results suggest that the combination of GAL-3 and Ki-67 may serve as a useful adjunct to existing diagnostic methods of thyroid cancer, such as ultrasonography and FNAB.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-320/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-320/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-320/prf

Funding: This study was supported by the Abbott Laboratories and Hospital Joint Fund (No. TRECKY2021-131).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-320/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 conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Academic Ethics Committee of Beijing Tongren Hospital, Capital Medical University (approval No. TRECKY2021-131). Informed consent was waived because of the retrospective design of this study.

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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