Benign and malignant uptake in the postoperative diagnosis of gastrointestinal tumors: a comparative study of ⁶⁸Ga-FAPI-04 and ¹⁸F-FDG

Introduction

Gastrointestinal (GI) cancer is among the top ten cancers in terms of global incidence and mortality rates, accounting for 26% of all cancer cases and 35% of cancer-related deaths worldwide (1). Surgical resection remains the most commonly used treatment for patients with esophageal cancer (EC), gastric cancer (GC), and colorectal cancer (CRC) (2). Due to the high metastasis rate and low rate of radical resection, postoperative recurrence is common among patients with GI tumors (3). Therefore, early and accurate assessment of disease progression after surgery is crucial (4). However, the physiological uptake of fluorine-18 fluorodeoxyglucose (¹⁸F-FDG) in the GI tract and its high uptake in inflammatory lesions may affect the postoperative diagnosis. In addition, ¹⁸F-FDG imaging has a poor imaging effect on low-metabolic tumors.

Cancer-associated fibroblasts (CAFs) are key components of the tumor stroma and play a critical role in cancer invasion and metastasis within the tumor microenvironment (5). Fibroblast activation protein (FAP) is overexpressed in the CAFs of most epithelial tumors (6,7). Several studies have shown that the radio-tracer gallium-68-labeled fibroblast activation protein inhibitor-04 (⁶⁸Ga-FAPI-04) has higher sensitivity in diagnosing primary GI tumors (8,9), liver metastases (10,11), peritoneal metastases (12), and bone metastases (13), with minimal expression in healthy organs (5,14) than does ¹⁸F-FDG. Compared to the conventional glucose analog ¹⁸F-FDG, FAP inhibitors (FAPIs) have emerged as excellent PET probes for accurately detecting a wide range of cancers, gaining significant attention in the field.

Although FAPI expression is extremely rare in normal tissues, some cases still exhibit high uptake in nonmalignant sites, such as the joints (15), muscles (16), uterus (17), and pancreas (18) [maximum standardized uptake value (SUVmax) >2.5]. In our work, we observed a notably high ⁶⁸Ga-FAPI-04 uptake (SUVmax =11.97) in a case of benign pancreatic ductal adenoma. Based on these observations, we conducted a retrospective study comparing the diagnostic efficiency of ¹⁸F-FDG positron emission tomography-computed tomography (PET/CT) and ⁶⁸Ga-FAPI-04 PET-magnetic resonance imaging (PET/MRI) for the postoperative evaluation of GI cancers. We further investigated and compared the uptake of benign and malignant lesions postsurgery. Additionally, we generated receiver operating characteristic (ROC) curves to further compare and analyze the diagnostic efficacy of the two radiotracers.

We hypothesized that ⁶⁸Ga-FAPI-04 PET/MRI is more effective than is conventional ¹⁸F-FDG PET/CT in diagnosing postoperative malignant lesions in GI tumors, with more prominent radiotracer uptake and superior diagnostic performance. However, for other lesions, both benign and malignant lesions demonstrate high uptake with ⁶⁸Ga-FAPI-04. Therefore, for accurate diagnosis, clinicians should combine FAPI data with other indicators to avoid misdiagnosis. Optimal results can be achieved through long-term experience. We present this article in accordance with the STARD reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-670/rc).

Methods

Participants

This retrospective clinical investigation was carried out at the First Affiliated Hospital of Anhui Medical University from February 2023 to June 2023. A total of 16 participants were enrolled based on a comprehensive evaluation integrating imaging findings, clinical assessments [including age and Karnofsky performance status (KPS) score], and pathological results. The study protocol received approval from the Institutional Review Board (IRB) of the First Affiliated Hospital of Anhui Medical University (ethics No. PJ2022-05-09) and this study was registered in ClinicalTrials.gov (identifier: NCT06270394). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. All participants provided their written informed consent prior to their enrollment in the study. The inclusion criteria were as follows: (I) surgical treatment; (II) postoperative histopathological confirmation of GI malignancy; and (III) no history of other tumors. Due to the relatively long scanning time of PET/MRI, the exclusion criteria were set as follows: (I) age 75 years or older; (II) implantation of ferromagnetic objects; (III) a KPS score of 80 or lower; and (IV) claustrophobia. On this basis, these patients were required to have both ⁶⁸Ga-FAPI-04-avid benign lesions and malignant lesions to enable comparison. For all patients, the median interval from GI cancer surgery to the postoperative surveillance scan that identified suspected recurrence was 15.5 months (range, 1 month to 7 years). Prior to ¹⁸F-FDG PET/CT scanning, 6 patients had undergone biopsies; however, all biopsies were performed ≥6 weeks before the ¹⁸F-FDG PET/CT scan to minimize inflammatory interference. The detailed flowchart of the study design is presented in Figure 1.

Figure 1 Flowchart of patient selection. ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; ⁶⁸Ga-FAPI-04, ⁶⁸gallium-labeled fibroblast activation protein inhibitor 04; CT, computed tomography; GI, gastrointestinal; KPS, Karnofsky performance status; MRI, magnetic resonance imaging; PET, positron emission tomography.

Preparation of ⁶⁸Ga-FAPI-04 and ¹⁸F-FDG

With reference to Lindner et al.’s (19) pioneering work on ⁶⁸Ga-FAPI-04 targeting FAP, radiotracer synthesis in this study was performed as follows: For generator elution, a ⁶⁸Ge/⁶⁸Ga generator was eluted with 3.0 mL of 0.1 M hydrochloric acid solution. For the reaction setup, the eluate was mixed with 20 µg of FAPI precursor (≥98% purity; molecular weight 872.91; Huayi Isotope Co., Changshu, China) and 375 µL of 1.25 M sodium acetate buffer. For radiolabeling, the reaction mixture was incubated at 95 ℃ for 10 minutes in a thermostatic heating block. In purification, the crude product was passed through an activated Sep-Pak light ¹⁸C cartridge (Shanghai Xintuo Trading Co., Ltd., Shanghai, China). The radiolabeled tracer retained on the Sep-Pak light ¹⁸C cartridge was eluted with 0.8 mL of 80% ethanol and filtered through a 0.2-µm microporous filter membrane (Pall Corporation, Port Washington, NY, USA) to remove impurities, yielding the final product. ⁶⁸Ga-FAPI-04 was formulated in house at the First Affiliated Hospital of Anhui Medical University under current good manufacture practices-compliant conditions. For comparison, ¹⁸F-FDG was directly sourced from Nanjing Jiangyuan Andico Positron Research and Development Co., Ltd. (Nanjing, China). The product underwent rigorous purification prior to clinical use, with a radiochemical purity >95% being achieved, as confirmed by high-performance liquid chromatography.

PET/MRI and PET/CT imaging

¹⁸F-FDG PET/CT and ⁶⁸Ga-FAPI PET/MRI scans were independently performed by two certified nuclear medicine technologists. The injection of ⁶⁸Ga-FAPI-04 was carried out after the completion of ¹⁸F-FDG metabolism in the body. The interval between ¹⁸F-FDG PET/CT and ⁶⁸Ga-FAPI-04 PET/MRI examinations was no more than 4 days. The PET/MRI scan was conducted with a SIGNA PET/MRI scanner (GE HealthCare, Chicago, IL, USA) with a coil configuration of one specialized head-neck coil and two flexible body coils. Patients did not need to fast before the examination. ⁶⁸Ga-FAPI-04 (1.85–3.7 MBq/kg) was injected intravenously, and imaging was performed approximately 40 minutes after injection. A step-scan acquisition mode was used. Acquisitions were corrected for respiratory motion through the application of respiratory gating. The scan covered a range from the top of the head to the upper thigh and had a duration of 60±10 minutes. Multiparametric MRI sequences, including T1-weighted imaging (T1WI) (echo time =15–25 ms and repetition time =300–600 ms) and T2-weighted imaging (T2WI) (echo time =80–130 ms and repetition time >2,000 ms) of the head, neck, chest, abdomen, and pelvis, were acquired. The PET reconstruction was carried out with the ordered subsets expectation maximization, time-of-flight, and point-spread function algorithms, with 2 iterations, 28 subsets, a 440×440 matrix, and a 5-mm Gaussian filter. For routine PET/CT imaging, the standard ¹⁸F-FDG PET/CT protocol was implemented under a dedicated clinical workflow within 4 days prior to the ⁶⁸Ga-FAPI-04 PET/MRI examination.

In this study, we deliberately used both PET/MRI and PET/CT instead of only PET/CT. The reason we chose PET/MRI as the scanning modality for the expected group is mainly due to its practical advantages. PET/MRI has an integrated imaging function and can synergistically combine the results of T1WI, T2WI, diffusion-weighted imaging (DWI), and the apparent diffusion coefficient (ADC) obtained from MR scans. This enables a more accurate and detailed assessment of the benign or malignant nature of lesions. The reduced radiation dose associated with PET/MRI was also an important consideration, especially for patients who may require multiple imaging sessions over time. The comparison of these two modalities was applied to improve the overall validity and reliability of our research results. However, precisely because we used two types of equipment, cross-modality standardization was necessary when we conducted semiquantitative parameter comparisons. The specific methods are described in the section “Semiquantitative image analysis and cross-modality standardization” below.

Imaging analysis

Image interpretation and follow-up validation

Two nuclear medicine physicians with ≥10 years of experience and no access to clinical data (CT, MRI, endoscopic findings, or pathological results) independently interpreted ⁶⁸Ga-FAPI-04 PET/MRI and ¹⁸F-FDG PET/CT images from the syngo.via MM Oncology toolset (Siemens Healthineers, Erlangen, Germany) under blinded conditions. The image interpretation focused on identifying benign and malignant lesions at the anastomotic site, lymph nodes, and other organs, with diagnostic outcomes systematically recorded. In cases of uncertain examination results or disagreements between the two parties, a third clinician with more than 5 years of experience in nuclear medicine conduct an appraisal and analysis to avoid subjectivity.

After scanning, each patient was followed up for at least 1 year. During this period, a benign lesion was defined as a nonmalignant pathological biopsy result, stable imaging findings (CT/MRI), or a lesion that did not respond to systemic chemotherapy and showed no progression 1 year after the end of treatment. Conversely, a malignant lesion was confirmed by gastroscopy/pathological examination or imaging studies demonstrating disease progression. In this study, a true positive was defined as a situation in which the actual lesion was malignant, and the physician, through blinded interpretation of ¹⁸F-FDG PET and ⁶⁸Ga-FAPI-04 PET images, also diagnosed it as malignant. A false positive was defined as a scenario in which the actual lesion was benign, but the physician diagnosed it as malignant. A true negative was defined as a scenario in which actual lesion was benign, and the physician also diagnosed it as such. A false negative was defined as a scenario in which the actual lesion was malignant, yet the physician diagnosed it as benign. In the qualitative image interpretation, we compared the sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of ¹⁸F-FDG PET/CT and ⁶⁸Ga-FAPI-04 PET/MRI in the diagnosis of benign and malignant lesions.

It is worth noting that the patient data we collected were postoperative and that the patients had already experienced surgical trauma. Pathological analysis is an invasive examination. Therefore, for some small benign lesions that have little impact on the body and show no obvious symptoms or signs of malignancy, clinicians will comprehensively consider and not recommend invasive pathological examinations to avoid causing unnecessary harm to patients. Moreover, some lesions in deep-seated parts of the body, such as retroperitoneal lesions, are inherently difficult to explore through pathological means. Thus, except for the sites that suggested recurrence or metastasis in routine examinations of postoperative patients, for which we conducted pathological examinations as clinically required, we determined the lesions' status through imaging or endoscopic follow-up. Only lesions with definitive results were retained, while lesions with indeterminate results were excluded from the study.

Semiquantitative image analysis and cross-modality standardization

The region of interest (ROI) was manually delineated by experienced operators. We used syngo.via software within the MM Oncology toolset to automatically compute the SUVmax, which serves as a crucial parameter for quantifying the radiotracer uptake in the lesions.

SUVmax values were automatically generated via syngo.via MM Oncology; however, direct comparison between PET/CT and PET/MRI SUVmax was precluded due to the inherent differences in imaging principles, acquisition protocols, and attenuation correction algorithms. To address this, target-to-background ratios (TBRs) were calculated (10,20). More specifically, the target-to-muscle ratio (TBR-M) was calculated as follows: TBR-M = lesion SUVmax/muscle SUVmax; the target-to-aorta ratio (TBR-A) was calculated as follows: TBR-A = lesion SUVmax/descending aorta SUVmax; the target-to-liver ratio (TBR-L) was calculated as follows: TBR-L = lesion SUVmax/liver SUVmax. These semiquantitative metrics enabled cross-modality comparison while preserving lesion-specific uptake characteristics.

Plotting of the ROC curve

A comparison was made between the diagnostic efficacy of two tracers, ¹⁸F-FDG and ⁶⁸Ga-FAPI-04, with reference to anastomotic sites, lymph nodes, and other lesions, based on various parameters, including SUVmax, TBR-M, TBR-A, and TBR-L. The indicators included area under the curve (AUC), 95% confidence interval (CI), P value, cutoff value, sensitivity, and specificity, which provided comprehensive data for evaluating the diagnostic performance of the two tracers at different lesion sites.

Statistical analysis

Statistical analysis was performed via SPSS 26.0 software (IBM Corp., Armonk, NY, USA). The qualitative study included the diagnostic attributes of ¹⁸F-FDG PET/CT and ⁶⁸Ga-FAPI-04 PET/MRI, including sensitivity, specificity, accuracy, PPV, and NPV. When comparing the above-mentioned diagnostic attributes using a row × column contingency table for binary categorical variables, we used the Chi-squared test when the total number of lesions was ≥40 and the minimum theoretical frequency (T) was ≥5. When the total number of lesions was ≥40 and at least one theoretical frequency met the condition of 1≤ T <5, the corrected Chi-squared test was applied. When the total number of lesions was less than 40 or the minimum theoretical frequency in at least one cell was less than 1, the Fisher exact probability method was used.

In the semiquantitative analysis of the two tracers, the arrays that conformed to the normal distribution are represented by the mean ± standard deviation, while those that did not conform to the normal distribution are represented by the median ± interquartile range. For determining whether there were differences in TBR-M, TBR-A, and TBR-L between the two tracers, ¹⁸F-FDG and ⁶⁸Ga-FAPI-04, for benign and malignant anastomotic sites, lymph nodes, and other lesions, we used the paired t-test for data that conformed to a normal distribution, while the Wilcoxon rank-sum test was used for data that did not conform to a normal distribution. When comparing the uptake differences of the same tracer between benign and malignant lesions, since the imaging were are the same, we used the SUVmax directly for comparison. Given that the samples were different, the independent two-sample t-test was applied to the data that followed a normal distribution, while the Mann-Whitney test was used for the data that did not follow a normal distribution. The P value of the ROC curve was automatically calculated via GraphPad software version 8.0.2 (Dotmatics, Boston, MA, USA).

Color-coding of ¹⁸F-FDG and ⁶⁸Ga-FAPI-04 uptake in benign and malignant lesions

We selected three representative patients with both benign and malignant lesions at the anastomotic site, lymph nodes, and other organs. Except for the known conventional physiological uptake of ¹⁸F-FDG, the areas with a SUVmax of radioactive uptake greater than 2.5 were marked with colors. For ⁶⁸Ga-FAPI-04, the malignant areas were marked red and the benign areas were marked blue. For ¹⁸F-FDG, the malignant areas were marked green and the benign areas were marked yellow (Figures 2-4).

Figure 2 A 61-year-old male patient 2 years after esophageal cancer surgery. Whole-body MIP images of ¹⁸F-FDG PET and ⁶⁸Ga-FAPI-04 PET (A); axial ¹⁸F-FDG PET/CT fusion images at the level of the anastomotic site (B) and the kidneys (C); axial ⁶⁸Ga-FAPI-04 PET/MRI fusion images at the level of the anastomosis (D) and the kidneys (E); gastroscopy findings at the time of examination (F) and one month later (G). (A) MIP image comparison, with physiological uptake excluded, demonstrating color-coded lesion areas where SUVmax >2.5. The right image shows [I] the fusion of malignant lesions (anastomosis and surrounding peritoneum) between ⁶⁸Ga-FAPI-04 PET (red area) and ¹⁸F-FDG PET (blue area) and [II] the fusion of benign lesions (joints, esophagus, kidney, and peritoneum) between ⁶⁸Ga-FAPI-04 PET (green area) and ¹⁸F-FDG PET (yellow area). On ¹⁸F-FDG PET, both the malignant anastomotic metastasis (B, blue arrow) (SUVmax 2.78) and the benign kidney disease (C, yellow arrow) (SUVmax 2.66) had a smaller extent and lower uptake as compared to ⁶⁸Ga-FAPI-04 PET [(D, red arrow) anastomotic metastasis: SUVmax 9.25; (E, green arrow) benign kidney disease: SUVmax 10.91]. At that time, gastroscopy did not show any obvious abnormalities at the anastomosis (F). Gastroscopy follow-up 1 month later confirmed the recurrence at the esophagogastric anastomosis (G). The uptake in the left kidney was determined to be a benign lesion through imaging follow-up for 7 months and tumor marker tests. The color bar on the left side of the image (0.0-7.0) provides a unified and reliable visual reference for the color/radioactivity concentration in Images A/B/C/D/E, ensuring consistent quantitative standards and avoiding misjudgment caused by different color scales. ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; ⁶⁸Ga-FAPI-04, ⁶⁸gallium-labeled fibroblast activation protein inhibitor 04; CT, computed tomography; FAPI, fibroblast activation protein inhibitor; MIP, maximum intensity projection; MRI, magnetic resonance imaging; SUVmax, maximum standardized uptake value; PET, positron emission tomography.

Figure 3 A 74-year-old female patient 11 months after gastrectomy. Whole-body MIP images of ¹⁸F-FDG PET and ⁶⁸Ga-FAPI-04 PET (A); axial ¹⁸F-FDG PET/CT fusion images at the level of the mediastinum (B) and uterus (C); axial ⁶⁸Ga-FAPI-04 PET/MRI fusion images at the level of the mediastinum (D) and uterus (E); axial T1WI (F) and T2WI (G) MRI images at the level of the mediastinum. (A) MIP image comparison, with physiological uptake excluded, demonstrating color-coded lesion areas with SUVmax >2.5. The right image demonstrates [I] fusion of malignant lesions (posterior mediastinal and retroperitoneal lymph nodes) between ⁶⁸Ga-FAPI-04 PET (red area) and ¹⁸F-FDG PET (blue area), with [II] ⁶⁸Ga-FAPI-04 PET (green area) indicating physiological uptake in a normal gastrointestinal tract and uterus and ¹⁸F-FDG PET (yellow area) indicating inflammatory lymph nodes in the mediastinum and bilateral hilar regions. The uterus also demonstrates a normal physiological uptake on ¹⁸F-FDG PET (yellow area). On ¹⁸F-FDG PET, the posterior mediastinal metastatic lymph node [(B) blue arrow; SUVmax 10.35] demonstrated smaller lesion extent and mildly lower radiotracer uptake compared to its appearance on ⁶⁸Ga-FAPI-04 PET [(D) red arrow; SUVmax 10.73]. Physiological uptake was observed in the normal uterus on ¹⁸F-FDG PET [(C) yellow arrow; SUVmax 2.59], which also showed significantly lower uptake relative to the ⁶⁸Ga-FAPI-04 PET study [(E) green arrow; SUVmax 9.21]. Additionally, ¹⁸F-FDG PET showed intense uptake in multiple mediastinal/bilateral hilar inflammatory lymph nodes [(B) yellow arrows; SUVmax 9.25]. MRI confirmed posterior mediastinal lymph nodes with hypointensity on T1WI (F, red arrow) and hyperintensity on T2WI (G, red arrow), consistent with metastatic involvement. The color bar on the left side of the image (0.0-7.0) provides a unified and reliable visual reference for the color/radioactivity concentration in Images A/B/C/D/E, ensuring consistent quantitative standards and avoiding misjudgment caused by different color scales. ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; ⁶⁸Ga-FAPI-04, ⁶⁸gallium-labeled fibroblast activation protein inhibitor 04; CT, computed tomography; FAPI, fibroblast activation protein inhibitor; MIP, maximum intensity projection; MRI, magnetic resonance imaging; PET, positron emission tomography; SUVmax, maximum standardized uptake value; T1WI, T1-weighted imaging; T2WI, T2-weighted imaging.

Figure 4 A 53-year-old female patient 12 years after gastric cancer resection. Whole-body MIP images of ¹⁸F-FDG PET and ⁶⁸Ga-FAPI-04 PET (A); axial ¹⁸F-FDG PET/CT fusion images at the level of the pancreatic tail (B) and uterine adnexa (C); axial ⁶⁸Ga-FAPI-04 PET/MRI fusion images at the level of the pancreatic tail (D) and uterine adnexa (E); pathological images of HE-stained biopsy specimens from the uterine adnexa, at 150× magnification (F, G). (A) MIP image comparison, with physiological uptake excluded, demonstrating color-coded lesion areas where SUVmax >2.5. The right image shows a [I] malignant lesion fusion (bilateral ovarian metastases) between ⁶⁸Ga-FAPI-04 PET (red area) and ¹⁸F-FDG PET (blue area), with [II] ⁶⁸Ga-FAPI-04 PET (green area) showing a benign lesion (pancreatic tail) and no obvious uptake (SUVmax <2.5) on ¹⁸F-FDG PET. Both the benign pancreatic tail lesion [(B) yellow arrow; SUVmax 1.87] and right ovarian metastasis [(C) blue arrow; SUVmax 5.84] exhibited smaller lesion extent and lower radiotracer uptake on ¹⁸F-FDG PET than on ⁶⁸Ga-FAPI-04 PET [(D) green arrow; pancreatic tail: SUVmax 11.97; (E) red arrow; right ovarian metastasis: SUVmax 8.93]. Subsequent pathological confirmation revealed right ovarian metastasis (F,G), while a 1-year follow-up CT confirmed the pancreatic tail lesion as benign intraductal papilloma. The color bar on the left side of the image (0.0-7.0) provides a unified and reliable visual reference for the color/radioactivity concentration in Images A/B/C/D/E, ensuring consistent quantitative standards and avoiding misjudgment caused by different color scales. ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; ⁶⁸Ga-FAPI-04, ⁶⁸gallium-labeled fibroblast activation protein inhibitor 04; CT, computed tomography; HE, hematoxylin-eosin; MIP, maximum intensity projection; MRI, magnetic resonance imaging; PET, positron emission tomography; SUVmax, maximum standardized uptake value.

Results

A total of 16 patients were finally included in this study (age 61.00±6.08 years; 11 males and 5 females). All participants underwent both ¹⁸F-FDG PET/CT and ⁶⁸Ga-FAPI-04 PET/MRI within 4 days of one another. Among these patients, 15 (15/16, 93.75%) had developed other metastases. Based on the 1-year follow-up results in this comparative study, including pathological findings, gastroscopy, and follow-up CT/MRI, we identified 3 cases of anastomotic recurrence, 23 benign anastomotic sites, 49 lymph node metastases, 22 benign lymph nodes, 25 other metastases, and 22 benign other lesions. Focal high uptake of ⁶⁸Ga-FAPI-04 (SUVmax >7.00) was observed in the benign anastomotic sites of two participants, the benign lymph nodes of four participants, and the benign pancreas of three participants, which could have easily led to misdiagnosis. All patients were followed up for 1 year until July 2024. This study was conducted to discern the uptake pattern of ⁶⁸Ga-FAPI-04 and to compare it with that of the traditional ¹⁸F-FDG. The basic information of all patients is shown in Table 1.

Analysis of the anastomotic site

Comparison of the diagnostic performance of the two tracers for anastomotic sites

There were no statistically significant differences in the sensitivity, specificity, accuracy, PPV, or NPV between the two imaging agents for the detection of recurrent anastomotic sites (P=0.40, P=0.53, P=0.24, P=0.30, and P=0.23, respectively) (Table 2). However, this does not imply that ⁶⁸Ga-FAPI-04 has no potential advantages in the diagnosis of postoperative anastomotic sites. The result of no statistical difference could have been due to the relatively small number of anastomotic recurrence cases we collected. It is widely known that anastomotic sites produce the nonspecific uptake of ¹⁸F-FDG during healing, affecting the diagnosis. In the detection of anastomotic sites, the specificity of the ⁶⁸Ga-FAPI-04 detection group (17/23, 73.91%) was slightly higher than that of the ¹⁸F-FDG group (14/23, 60.87%) (P=0.35); meanwhile, the false-positive rate in the ⁶⁸Ga-FAPI-04 detection group (6/23, 26.09%) was slightly lower than that of the ¹⁸F-FDG group (9/23, 39.13%) (P=0.35). ⁶⁸Ga-FAPI-04 should have the ability to produce a low misdiagnosis rate, but the difference was not statistically significant in this study.

Semiquantitative comparison of the two tracers for recurrent anastomotic sites

As listed in Table 3, for recurrent anastomotic sites, the mean ± standard deviation values of the TBR-M, TBR-A, and TBR-L for ⁶⁸Ga-FAPI-04 were all higher than those of ¹⁸F-FDG; however, only the difference in TBR-M was statistically significant (5.44, 1.03 vs. 2.61, 1.91; P=0.04).

In the cases we examined (Figure 2), the anastomotic recurrence and the metastatic infiltration of the surrounding peritoneum showed much higher uptake and a much larger imaging range in the ⁶⁸Ga-FAPI-04 PET imaging than in the ¹⁸F-FDG PET imaging. The gastroscopy at that time did not show anastomotic recurrence, but the gastroscopy 1 month later revealed anastomotic recurrence. The patient’s pathological type was moderately-to-poorly-differentiated adenocarcinoma, indicating that the characteristic of ⁶⁸Ga-FAPI-04 targeting CAFs makes it more sensitive to early recurrence and has the potential to be applied to the individualized monitoring of high-risk patients.

Semiquantitative comparison of the two tracers in normal anastomotic sites

The lower part of Table 3 compares the measurement results of ¹⁸F-FDG and ⁶⁸Ga-FAPI-04 tracers in terms of TBR-M, TBR-A, and TBR-L in benign anastomotic sites. Specifically, regarding TBR-L, the measurement value of ⁶⁸Ga-FAPI-04 was higher than that of ¹⁸F-FDG (2.41±2.02 vs. 0.97±0.37), and a significant difference was observed between the two (P=0.002). In terms of TBR-M and TBR-A, statistical tests showed no significant differences between ⁶⁸Ga-FAPI-04 and ¹⁸F-FDG (P=0.36 and P=0.16, respectively).

ROC curve analysis for the diagnostic performance of ¹⁸F-FDG and ⁶⁸Ga-FAPI-04 in anastomotic site detection

For anastomotic site detection, the SUVmax parameter of ¹⁸F-FDG yielded an AUC of 0.725, with a sensitivity of 100% but a specificity of only 60.87%, and a P value of 0.214, which was not statistically significant. The SUVmax parameter of ⁶⁸Ga-FAPI-04 performed excellently, with an AUC of 0.957, a sensitivity of 100%, a specificity of 95.65%, and a P value of 0.012, which was statistically significant. Under the TBR-M, TBR-A, and TBR-L parameters, ⁶⁸Ga-FAPI-04 also demonstrated higher AUCs and several P values with statistical significance, indicating its superior performance in anastomotic site diagnosis as compared to ¹⁸F-FDG.

Analysis of lymph nodes

Comparison of the diagnostic performance of the two tracers for lymph nodes

The detection sensitivity of ⁶⁸Ga-FAPI-04 PET/MRI for malignant lymph nodes reached 100% (43/43), which was significantly higher than that of ¹⁸F-FDG PET/CT, which was 90.70% (39/43) (P=0.04). Meanwhile, the specificity of ⁶⁸Ga-FAPI-04 PET/MRI was 84.00% (21/25), nearly double that of ¹⁸F-FDG PET/CT (11/25, 44.00%) (P=0.003), indicating that this technique has a significant advantage in reducing false positives. The overall diagnostic accuracy of ⁶⁸Ga-FAPI-04 PET/MRI was 94.12% (64/68), which was 20.59 percentage points higher than that of ¹⁸F-FDG PET/CT (50/68, 73.53%) (P=0.001), suggesting its higher reliability in clinical decision-making. Among the positive results of ⁶⁸Ga-FAPI-04 PET/MRI, 91.49% (43/47) were true positives, which was significantly higher than the 73.58% (39/53) of ¹⁸F-FDG (P=0.02). In this study, the negative results of ⁶⁸Ga-FAPI-04 PET/MRI completely excluded malignancy (100%), while ¹⁸F-FDG had a 26.67% risk of missed diagnosis (P=0.02).

Semiquantitative comparison of the two tracers for metastatic lymph nodes

After GI tumor surgery, the analysis of semiquantitative parameters related to lymph nodes was conducted to further understand the performance of different tracers in evaluating the status of lymph nodes. For metastatic malignant lymph nodes, there were significant differences in the TBR-M, TBR-A, and TBR-L measured by ¹⁸F-FDG and ⁶⁸Ga-FAPI-04 (all P values <0.0001). The TBR-M, TBR-A, and TBR-L values produced by ⁶⁸Ga-FAPI-04 were 5.06±2.03, 5.66±2.68, and 5.61±3.28, respectively, which were all significantly higher than those of ¹⁸F-FDG, which were 3.26±2.03, 2.96±1.71, and 2.18±1.26, respectively.

Semiquantitative comparison of the two tracers in normal and inflammatory lymph nodes

In terms of inflammatory lymph nodes, there was a significant difference in TBR-M between ¹⁸F-FDG and ⁶⁸Ga-FAPI-04 (P=0.007). The TBR-M of ¹⁸F-FDG was 4.75±4.45, which was higher than the 2.23±2.59 of ⁶⁸Ga-FAPI-04. However, there were no significant differences in TBR-A or TBR-L between the two (P=0.10 and P=0.91). The TBR-A and TBR-L of ¹⁸F-FDG were 1.87±0.80 and 1.34±0.60, respectively, while those ⁶⁸Ga-FAPI-04 were 1.52±1.42 and 1.31±1.34, respectively.

These results indicate that ⁶⁸Ga-FAPI-04 has obvious semiquantitative parameter advantages over ¹⁸F-FDG in differentiating metastatic malignant lymph nodes after GI tumor surgery. In the evaluation of inflammatory lymph nodes, the two tracers were different in terms of TBR-M but similar in terms of TBR-A and TBR-L.

ROC curve analysis for the diagnostic performance of ¹⁸F-FDG and ⁶⁸Ga-FAPI-04 in lymph node detection using

The lymph node detection results revealed that both ¹⁸F-FDG and ⁶⁸Ga-FAPI-04 exhibited high AUC values for the SUVmax, TBR-A, and TBR-L parameters, with ⁶⁸Ga-FAPI-04 showing statistically significant P values below 0.0001. Additionally, ⁶⁸Ga-FAPI-04 demonstrated a high sensitivity of 95.92% for the SUVmax parameter, surpassing the sensitivity of 73.47% observed with ¹⁸F-FDG. For the TBR-M parameter, the AUC of ⁶⁸Ga-FAPI-04 was 0.863, significantly higher than the 0.532 AUC of ¹⁸F-FDG, highlighting the superior overall diagnostic performance of ⁶⁸Ga-FAPI-04 in lymph node detection.

Analysis of other lesions

Comparison of the diagnostic performance of the two tracers for other benign and malignant lesions

Table 2 shows that in terms of sensitivity, the detection sensitivity of ¹⁸F-FDG PET/CT for other metastatic lesions (17/25, 68.00%) was lower than that of ⁶⁸Ga-FAPI-04 PET/MRI (24/25, 96.00%), representing a significant difference (P=0.03). This result indicates that ⁶⁸Ga-FAPI-04 PET/MRI has a higher detection ability than does ¹⁸F-FDG PET/CT in identifying other metastatic lesions and can effectively reduce the risk of missed diagnosis. Meanwhile, the specificity of ¹⁸F-FDG PET/CT was 70.83% (17/24), while the specificity of ⁶⁸Ga-FAPI-04 PET/MRI was only 4.17% (1/24), and the difference between the two was highly statistically significant (P<0.0001). This suggests that ¹⁸F-FDG PET/CT has a relative advantage in discriminating other lesions as nonmetastatic (normal tissue or benign lesions), while ⁶⁸Ga-FAPI-04 PET/MRI has a higher false-positive rate.

In terms of accuracy, the overall diagnostic accuracy of ¹⁸F-FDG PET/CT was 69.39% (34/49), while that of ⁶⁸Ga-FAPI-04 PET/MRI was 51.02% (25/49), representing a significant difference (P=0.0005). This shows that ¹⁸F-FDG PET/CT has higher reliability than does ⁶⁸Ga-FAPI-04 PET/MRI in comprehensively judging the metastatic status of other lesions. In terms of PPV, the true-positive proportion of positive results of ¹⁸F-FDG PET/CT was 70.83% (17/24), while that of ⁶⁸Ga-FAPI-04 PET/MRI was 51.06% (24/47), which was not a significant difference (P=0.11). In terms of NPV, the true-negative proportion of negative results of ¹⁸F-FDG PET/CT is 68.00% (17/25), while that of ⁶⁸Ga-FAPI-04 PET/MRI is 50.00% (1/2), also not representing a significant difference (P>0.99).

In summary, ⁶⁸Ga-FAPI-04 PET/MRI demonstrated a significant sensitivity advantage in detecting other metastatic lesions after GI tumor surgery but has a low specificity and is prone to false-positive results; meanwhile, ¹⁸F-FDG PET/CT performs better in terms of specificity and accuracy. Different from that of ¹⁸F-FDG, the false-positive uptake of ¹⁸F-FDG often indicates metabolically active inflammatory areas or physiological uptake in the intestine, without actual lesions. In contrast, the false-positive uptake of ⁶⁸Ga-FAPI-04 can reveal benign lesions, such as intraductal papilloma of the pancreas. If used rationally, ⁶⁸Ga-FAPI-04 can provide superior diagnostic performance in both benign and malignant lesions.

Semiquantitative comparison of the two tracers for other metastases

Table 3 shows the comparison of semiquantitative parameters of the two tracers, ¹⁸F-FDG and ⁶⁸Ga-FAPI-04, in the evaluation of other metastases of GI tumors, indicating significant differences.

The measured values of ⁶⁸Ga-FAPI-04 were all significantly higher than those of ¹⁸F-FDG, including TBR-M (3.72±4.06 vs. 8.61±15.24, P=0.0002), TBR-A (3.46±2.16 vs. 6.08±3.45; P<0.0001), and TBR-L (2.53±1.86 vs. 8.48±5.33; P<0.0001).

Overall, the outstanding performance of ⁶⁸Ga-FAPI-04 in these three semiquantitative parameters strongly implies that it has a stronger affinity for other metastatic lesions of GI tumors and can more efficiently accumulate at the metastatic sites, presenting higher uptake signals than ¹⁸F-FDG in the images. Thus, ⁶⁸Ga-FAPI-04 has obvious potential advantages over ¹⁸F-FDG in detecting other metastases of GI tumors and is likely to help more accurately detect and locate other metastatic foci.

Naturally, these differences in parameters may be the result of various factors such as tumor biological characteristics and the microenvironment of the lesions. Although ⁶⁸Ga-FAPI-04 produced remarkable results in terms of semiquantitative parameters, in actual clinical application, its specificity and other factors need to be comprehensively considered to prevent the interference of false-positive results.

Semiquantitative comparison of the two tracers in other benign lesions

Table 4 shows the comparison of the semiquantitative parameters of the two tracers, ¹⁸F-FDG and ⁶⁸Ga-FAPI-04, in the evaluation of benign lesions after GI tumor surgery, revealing significant differences between the two.

The measured values of ⁶⁸Ga-FAPI-04 were all significantly higher than those of ¹⁸F-FDG in terms of TBR-M (2.35±1.80 vs. 6.66±3.25; P<0.0001), TBR-A (1.43±0.65 vs. 6.39±2.93; P<0.0001), and TBR-L (7.77±4.53 vs. 1.04±0.44, P<0.0001). These results may imply that ⁶⁸Ga-FAPI-04 has a stronger binding ability to certain targets in postoperative benign lesion tissues, thus producing a higher uptake level than ¹⁸F-FDG in imaging. The higher TBR values suggest that ⁶⁸Ga-FAPI-04 may more effectively distinguish these lesions from the surrounding normal tissues.A comparison of all semiquantitative parameters is provided in Figure 5 and Tables 3,4.

Figure 5 It compares the uptake differences of ¹⁸F-FDG and ⁶⁸Ga-FAPI-04 in benign and malignant lesions across different semiquantitative parameters. Comparison of semiquantitative parameters (TBR-M, TBR-A, and TBR-L) of malignant lesions (A-C) on ¹⁸F-FDG and ⁶⁸Ga-FAPI-04. Comparison of semiquantitative parameters (TBR-M, TBR-A, and TBR-L) of benign lesions (D-F) on ¹⁸F-FDG and ⁶⁸Ga-FAPI-04. Comparison between benign and malignant lesions with the same tracer (G-I). *, P<0.05; **, P<0.01; ***, P<0.001; ****, P<0.0001; ns, no significance. ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; ⁶⁸Ga-FAPI-04, ⁶⁸gallium-labeled fibroblast activation protein inhibitor 04; SUVmax, maximum standardized uptake value; TBR-A, target-to-aorta ratio; TBR-L, target-to-liver ratio; TBR-M, target-to-muscle ratio.

ROC curve analysis for the comparison of the diagnostic performance between ¹⁸F-FDG and ⁶⁸Ga-FAPI-04 in detecting other lesions

In the detection of other types of metastasis, ¹⁸F-FDG yielded high AUC values for the SUVmax, TBR-A, and TBR-L parameters, with P values less than or equal to 0.0001, indicating statistical significance for these parameters. The sensitivity for the SUVmax parameter reached 100%. In contrast, ⁶⁸Ga-FAPI-04 exhibited lower AUC values than ¹⁸F-FDG for these parameters, with most P values not reaching statistical significance, and its sensitivity and specificity were relatively suboptimal. This suggests that based on the cases we collected, ¹⁸F-FDG outperforms ⁶⁸Ga-FAPI-04 in detection of other types of metastasis.

All ROC curve-related results are shown in Figure 6 and Table 5.

Figure 6 ROC curves for semiquantitative parameters used to differentiate between benign and malignant lesions. ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; ⁶⁸Ga-FAPI-04, ⁶⁸gallium-labeled fibroblast activation protein inhibitor 04; AUC, area under the curve; ROC, receiver operating characteristic; SUVmax, maximum standardized uptake value; TBR-A, target-to-aorta ratio; TBR-L, target-to-liver ratio; TBR-M, target-to-muscle ratio.

Discussion

In this preliminary clinical trial, we used ¹⁸F-FDG and ⁶⁸Ga-FAPI-04 to evaluate malignant and benign lesions in postoperative patients with GI tumors as confirmed by histopathology or follow-up. In the diagnosis of malignant lesions (including anastomotic sites, lymph nodes, and other metastases) after GI tumor surgery, ⁶⁸Ga-FAPI-04 exhibited higher sensitivity than did ¹⁸F-FDG, with a significant increase in uptake. ROC analysis showed that ⁶⁸Ga-FAPI-04 outperformed ¹⁸F-FDG in diagnosing these postoperative lesions. Specifically, ⁶⁸Ga-FAPI-04 PET imaging revealed that cancer lesions at the anastomotic sites (P=0.0008) and lymph nodes (P<0.0001) had significantly higher uptake than did nonmalignant lesions; however, in other lesions, there was no significant difference in uptake between benign and malignant lesions (P=0.82).

As a well-established imaging agent, ¹⁸F-FDG plays a key role in the diagnosis and staging of GI tumors, effectively assessing treatment efficacy by facilitating the observation of changes in tumor cell uptake (21,22). However, ¹⁸F-FDG is not without limitations, including false-positive uptake in inflammatory lesions and physiological uptake during anastomotic healing (23,24). CAFs are closely linked to tumor cell invasion, angiogenesis, and growth, and their presence often indicates poor prognosis (25). Compared to ¹⁸F-FDG, ⁶⁸Ga-FAPI-04, which targets CAFs, shows no significant physiological uptake in the brain, liver, or GI tract, providing more distinct imaging of malignant GI tumors (26,27), even detecting low-metabolism lesions that ¹⁸F-FDG fails to visualize (28). However, research indicates that ⁶⁸Ga-FAPI-04 shows high uptake in certain benign lesions, such as pancreatic benign lesions (29), arthritis (30,31), and postmyocardial infarction chronic inflammation (32), and our results are in line with this. In our study, the SUVmax reached as high as 11.97 (Figure 4D), with extremely high imaging uptake. Although these benign lesions have no direct connection with postoperative GI tumors, the coexistence of both is quite common. Given that sites with high uptake are generally metastatic or recurrent lesions, the high uptake in benign diseases does not conform to the general perception. As a consequence, it has the potential to interfere with the diagnosis of postoperative metastasis in GI tumors. For benign lesions, the uptake of ¹⁸F-FDG in inflammatory lymph nodes within the mediastinum and bilateral lung hilar regions is typically higher than that of ⁶⁸Ga-FAPI-04. Conversely, in other benign lesions such as intraductal papillary neoplasms of the pancreas, arthritis, postmyocardial infarction fibrosis, and senile obsolete uterus, the uptake of ⁶⁸Ga-FAPI-04 is generally more pronounced than is ¹⁸F-FDG. Despite both tracers demonstrating uptake in benign areas, ⁶⁸Ga-FAPI-04 exhibited a particularly prominent uptake pattern.

Our findings indicate that the false-positive uptake associated with ¹⁸F-FDG commonly stems from physiological uptake, wound healing processes, and inflammatory lesions (33). In contrast, false-positive uptake of ⁶⁸Ga-FAPI-04 is often linked to specific pathologies, including pancreatic ductal adenomas and postmyocardial infarction fibrosis. In the context of clinical practice, incorporating the patient’s comprehensive medical history, tumor marker data, other imaging characteristics, and the clinician’s specialized knowledge can significantly enhance the diagnostic utility of ⁶⁸Ga-FAPI-04. For example, the high uptake of ⁶⁸Ga-FAPI-04 caused by myocardial fibrosis can be easily distinguished, as myocardial tumors are extremely rare, which is a matter of medical common sense.

Unlike previous studies that focused on primary and metastasis tumors (34), our study concentrated on postoperative changes in GI tumors. The addition of the ROC curve and critical value calculations greatly enriched the quantitative indicators. Besides the known uptake in joints (30,31) and uteri of older adults (17), we, for the first time, have also identified benign uptake of fibrosis in renal failure. As experienced clinicians continue to deepen their understanding of disease features and enhance their clinical judgment, ⁶⁸Ga-FAPI-04 is expected to play a more prominent role in clinical practice.

We further found that in the patients included in our study, during anastomotic recurrence, ⁶⁸Ga-FAPI-04 showed widespread uptake and a high TBR. We speculate that this might be due to the presence of high fibrous matrix components around the anastomotic sites caused by invasion of the peritoneum, which is crucial for the early postoperative detection of anastomotic recurrence.

In the in-depth study of anastomotic sites, we obtained a series of valuable findings. In their study on anastomotic sites, Li et al. (35) reported that “both tracers (⁶⁸Ga-FAPI-04 and ¹⁸F-FDG) displayed high NPVs in identifying anastomotic recurrence, with ⁶⁸Ga-FAPI-04 exhibiting higher sensitivity than ¹⁸F-FDG”, which is consistent with the results of our study. Moreover, an interesting phenomenon was observed in this study. The uptake of ⁶⁸Ga-FAPI-04 in normal postoperative anastomotic sites was slightly higher at 3 months than at 6 months (3.51±1.17 vs. 1.42±0.35; P=0.002). Additionally, the SUVmax of ⁶⁸Ga-FAPI-04 in normal anastomotic sites showed a decreasing trend over time following surgery. The correlation was automatically calculated with GraphPad software v. 8.0.2. Statistical analysis indicated that this downward trend was moderately correlated with postoperative time, with a relatively high degree of confidence (r=−0.51; P=0.01). This result suggests that the uptake of ⁶⁸Ga-FAPI-04 in normal anastomotic sites exhibited a decreasing trend over the 6-month postoperative follow-up, which may be used as a diagnostic reference. The mechanism underlying this phenomenon may be as follows: early in anastomotic healing, excessive fibrosis leads to a high uptake of ⁶⁸Ga-FAPI-04, whereas, after 6 months after surgery, the uptake gradually decreases due to collagen fiber remodeling.

More importantly, previous research in this area (35) has not explicitly addressed the comparison between abdominal wall anastomotic sites and other types of anastomotic sites. In this study, we revealed that the absorption rate of abdominal wall anastomotic sites was significantly higher than that of esophagogastric anastomotic sites, esophageal-GI anastomotic sites, GI anastomotic sites, and intestinal-intestinal anastomotic sites (P=0.0005, P=0.05, P=0.008, and P=0.005, respectively). Distinguishing abdominal wall anastomotic sites from other anastomotic sites represents the key contribution of our study.

The issue of radiation dose generated by nuclear medicine examinations has long attracted public attention. Currently, a biological dose of less than 100 mSv is defined as low-dose radiation (36). Although the radiation dose of ¹⁸F-FDG is within the safe range, a portion of individuals remain hesitant to exposure and may even refuse related medical procedures, displaying excessive concern regarding radiation hazards. In this context, ⁶⁸Ga-FAPI-04 provides unique advantages. The radioactive dose used for its examination is almost half of that of conventional ¹⁸F-FDG, which undoubtedly provides a safer and more reliable option for clinical application.

Certain limitations to this study should be addressed. First, we adopted a single-center, retrospective design. This is primarily due to the strict inclusion criteria. Patients with postoperative GI tumors were required to undergo ¹⁸F-FDG PET/CT after clinical recurrence, followed by ⁶⁸Ga-FAPI-04 PET/MRI within 4 days, and to have complete histopathological or follow-up data. Additionally, each patient was required to have both ⁶⁸Ga-FAPI-04-positive benign lesions and ⁶⁸Ga-FAPI-04-positive malignant lesions for benign-malignant comparison after ⁶⁸Ga-FAPI-04 PET/MRI, which further reduced the sample size. For recurrent anastomotic sites, restrictions to small sample size were further compounded by the low recurrence rate at such sites, as surgery remains the primary and more effective treatment modality. Second, this experiment did not strictly limit the pathological types of digestive tract tumors, which might have led to deviations in research results, which may fail to comprehensively and accurately reflect the application value of ⁶⁸Ga-FAPI-04 PET/MRI in various digestive tract tumors. Third, due to the dual limitations of ethics and technical conditions, it was impossible to biopsy all lesions with FAPI uptake; therefore, we could only rely on long-term follow-up observations to determine the benign and malignant nature of the lesions. To maximize the diagnostic accuracy, the diagnostic work in this study should be carried out in collaboration with senior clinicians. In addition, to deeply and comprehensively characterize the uptake pattern of ⁶⁸Ga-FAPI-04 in benign and malignant lesions, further large-scale, multicenter studies are urgently needed. Despite these shortcomings, this study nonetheless provides a novel perspective and valuable reference for the application of ⁶⁸Ga-FAPI-04 in the diagnosis of postoperative lesions of GI tumors and is expected to provide strong support and a reference for subsequent research and clinical practice.

Conclusions

In this study comparing ¹⁸F-FDG PET/CT and ⁶⁸Ga-FAPI-04 PET/MRI for the retrospective assessment of GI cancers, ⁶⁸Ga-FAPI-04 PET/MRI showed significantly better performance than did ¹⁸F-FDG PET/CT in detecting recurrent anastomotic sites and lymph node metastases, with higher sensitivity, specificity, accuracy, PPV, and NPV, as well as more distinguishing semiquantitative parameters and ROC characteristics. This could be attributed to the physiological uptake of ¹⁸F-FDG at the anastomotic site and its susceptibility to inflammatory uptake in hilar lung lymph nodes. In contrast, ⁶⁸Ga-FAPI-04 remains unaffected by metabolism, thereby conferring it with high diagnostic efficiency. However, for other lesions, ⁶⁸Ga-FAPI-04 PET/MRI had high sensitivity but very low specificity, resulting in low accuracy, while ¹⁸F-FDG PET/CT had better performance in differentiating other benign and malignant lesions according to ROC analysis. ¹⁸F-FDG PET/CT remains the preferred imaging method for metastatic diseases in current clinical practice. This is because ⁶⁸Ga-FAPI-04 is taken up in many nonmalignant sites, such as in cases of benign pancreatic tumors, arthritis, postmyocardial infarction fibrosis, and the uterus of older adults. Clinicians should consider these differences when selecting imaging modalities and may need to combine other clinical information. For example, benign lesions are often flocculent and extensive in scope, while malignant lesions are characterized by localness and invasiveness. Through this approach, the advantages of ⁶⁸Ga-FAPI-04 in the postoperative diagnosis of GI tumors can be fully utilized.

Acknowledgments

We acknowledge and thank all participants of this study. Additionally, we are grateful to The First Affiliated Hospital of Anhui Medical University for providing technical support and the National Natural Science Foundation of China (No. 81801736) for financial assistance.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-670/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-670/dss

Funding: This work was supported by the National Natural Science Foundation of China (No. 81801736).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-670/coif). All authors report that this research was funded by the National Natural Science Foundation of China (No. 81801736). The authors have no other 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 protocol received approval from the Institutional Review Board (IRB) of the First Affiliated Hospital of Anhui Medical University (ethics No. PJ2022-05-09). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. All participants provided their written informed consent prior to their enrollment in the study.

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