Predictors for Achieving Textbook outcomes after endoscopic resection of giant submucosal tumors in the esophagus and cardia

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We aim to investigate the predictors of TO for giant SMTs with a long diameter ≥ 7 cm, or a transverse diameter ≥ 3.5 cm. Methods A retrospective review was conducted for endoscopic resection of consecutive patients with giant SMTs in the esophagus and cardia between July 2017 and February 2022 at a tertiary referral center. TO was mainly defined as absences of major adverse events, piecemeal resection, and prolonged hospital stay. Clinicopathologic, procedural characteristics, adverse events, and follow-up outcomes were analyzed. Results A total of 109 patients who completed endoscopic resection were analyzed. The median long and transverse diameter of the tumors were 7.5 cm (range, 4–15 cm) and 4 cm (range, 1.5-7 cm), respectively. The en bloc resection rate was 78.9%. Transverse diameter < 4.5 cm and regular shape were independent predictors for TO. Major adverse events (mAEs) occurred in 14 patients (12.8%). Long diameter ≥ 9 cm and piecemeal resection were significantly associated with mAEs. During a median follow-up of 33.5 months, there was no tumor recurrence or metastasis. Conclusions Giant esophageal or cardia SMTs with a long diameter < 9 cm and transverse diameter < 4.5 cm indicated a safe and credible outcome for endoscopic resection. giant submucosal tumors esophagus cardia STER EFTR Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Large SMTs in the esophagus and cardia often require resection because of clinical symptoms or the risk of malignancy. Nevertheless, since a considerable number of these tumors are benign, thoracoscopic surgery is traditionally recommended as a minimally invasive approach[ 1 ]. Recently, endoscopic treatments including endoscopic submucosal excavation (ESE), submucosal tunneling and endoscopic resection (STER), and endoscopic full-thickness resection (EFTR) have been an optimized minimal-invasive alternatives to surgery as safe and effective approaches for upper gastrointestinal SMTs less than 5cm in length[ 2 – 4 ]. These techniques provide definitive histologic diagnosis and offer a minimally invasive therapeutic approach. Previously, our study exhibited high en bloc resection rates of 90.6% and 88.2%, respectively, regarding STER for esophageal or cardia SMTs with a long diameter of ≤ 5 cm and ≤ 7 cm[ 2 , 5 ]. However, endoscopic resection for giant esophageal or cardia SMTs remains challenging, with limited data regarding the feasibility and safety of this approach for SMTs of considerable size. Under such circumstances, the quality of endoscopic resection was not evaluated, let alone the outcomes comparison with surgery. Textbook outcome (TO) reflecting the surgical quality better by assessments of the orchestration of adverse events, mortality, readmission, hospital stay instead of single indicator[ 6 ]. TO was a outcome-oriented conception, and a representative of safety of operation. To date, no TO assessment were not evaluated and the predictors were largely unknown in the context of endoscopic resections of giant SMTs. Thus, we aim to differentiate giant SMTs suitable for endoscopic resection by assessed the TO and calculated its predictors in an alternative to surgery. We aim to investigate the quality of endoscopic resection for esophageal or cardia SMTs with a long diameter ≥ 7 cm, or a transverse diameter ≥ 3.5 cm, by assessments of the TO and its predictors. We hope this outcome-oriented study and conclusions provides can help the endoscopists to differentiate candidate of qualified endoscopic resections by pre-operative indictors of giant SMTs. Methods Patients Between July 2017 and February 2022, a total of 110 patients with giant SMTs in the esophagus and cardia were included in this study, which was conducted at the Endoscopy Center of Zhongshan Hospital, Fudan University, Shanghai. Endoscopic ultrasonography (EUS) or computed tomography (CT) was performed preoperatively to evaluate the size, layer of origin, shape, growth pattern, anatomic location, and proximity to important neighboring structures. The inclusion criteria for enrollment were as follows: (1) Giant esophageal or cardia SMTs that had a long diameter ≥ 7 cm, or a transverse diameter ≥ 3.5cm. (2) Patients with typical or atypical symptoms requested aggressive treatment. (3) SMTs that originated from the myenteric plexus layer. The endoscopic treatment in a patient who had previously undergone an unsuccessful STER was failed once again, as it led to the rupture of both the esophagus and trachea. The patient was transferred to surgery and underwent tracheal repair, esophageal diversion, and retrosternal colon interposition graft 3 months later. The remaining 109 patients were included in this study for further analysis (Fig. 1 ). The study was approved by the Institutional Review board of Zhongshan Hospital (No. B2021-864R), in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients. Procedure All patients were under general anesthesia with endotracheal intubation. Prophylactic antibiotics were administered 30 minutes before the procedure. CO2 was used for insufflation during the procedure. The procedure was performed by endoscopists with experience of more than 300 cases of ESD, ESE, EFTR or POEM. The selection of techniques by the endoscopists was based on careful consideration of factors including the anatomic location, size, layer of origin, and growth pattern of the tumors. STER was selected as the preferred therapeutic approach for the majority of patients with SMTs located at the esophagus. Details of the standard STER procedure were reported in our previous publications[ 2 ]. Generally, the procedure consisted of main steps: (1) submucosal injection and mucosal incision 3–5 cm orally to the proximal margin of the SMT; (2) submucosal tunneling ended at 1 to 2 cm distal to the tumor; (3) dissection of the SMT; (4) extraction of the mobilized SMT. The entrance of the submucosal tunnel was enlarged in cases where the resected tumor exceeded the mucosotomy; (5) closure of the mucosal incision (Fig. 2 ). EFTR was primarily employed for patients with giant irregular SMTs positioned at the cardia originated from the deep muscularis propria extended extraluminally. The procedure was performed as previously described and included following steps[ 7 ]: (1) marking of the lesion border; (2) incision of the mucosa and submucosal layers surrounding the SMT; (3) dissection of the SMT from the surrounding muscularis propria. Endoclip or dental floss traction was used as needed. (4) extraction of the tumor; (5) closure of the defect by endoclips or endoloop suturing. When the defect could not be successfully closed, a fully covered esophageal was employed (Fig. 3 ). ESE was performed for patients with SMTs circumferentially surrounding the cardia originated from the superficial muscularis propria. The ESE procedure was similar as ESD[ 7 ]. (1) marking of the lesion border; (2) submucosal injection and mucosal incision; (3) submucosal and muscularis dissection to separate the tumor from the surrounding tissues; (4) extraction of the tumor; (5) closure of the defect by endoclips or endoloop suturing. Postoperative management Patients were routinely observed in hospital for at least 2 days. Clinical symptoms such as chest pain, dyspnea, hematemesis or melena, and abdominal pain were carefully observed. Vital signs were monitored every six hours, and blood tests were conducted daily during the first three postoperative days (POD). Patients were kept fasted for 24 h after the procedure, after which they were allowed to consume a liquid diet if remained asymptomatic on POD2. If patients showed symptoms such as ongoing chest pain, dyspnea, or a persistent high fever (≥ 38.5°C), which may suggest potential adverse events, immediate endoscopy and/ or CT scan were conducted. To assess mucosa continuity and detect any leakage, either an endoscopic examination or a contrast swallow radiography was carried out. Upon achieving asymptomatic oral intake, patients were discharged from the hospital and advised to adhere to a soft diet regimen for at least 1 week. Histopathology The size and shape of each removed specimen were examined. A tumor with an oval or globular shape was defined as a tumor with regular shape. Specimens were then fixed in 10% formalin, embedded with paraffin, and sectioned for pathological examination. Tumor pathology was assessed through hematoxylin and eosin staining as well as immunohistochemical staining. Risk classification of the gastrointestinal stromal tumors (GISTs) was performed according to the revised National Institutes of Health grading system[ 8 ]. Outcome definitions Since no TO criteria was put forward in the field of endoscopic resection. We proposed the TO in our study was satisfied in the absences of major adverse events (mAEs), the prolonged hospital stays, the mortality within 30 days, the readmission within 30 days, and recurrences. Prolonged hospital stay was defined hospital stay of 8-day or longer, double of the median. Major adverse events were defined as ICU admission, interventional postoperative procedure, or blood transfusion. The spectrum of mAEs included severe pneumothorax or pleural effusion necessitating depression or drainage, delayed bleeding requiring blood transfusion or endoscopic hemostasis, severe leakage resulting in fistula formation, severe infection, and esophageal stenosis. Minor adverse events included mild pneumothorax or pleural effusion without intervention, and inconsequential febrile episode. Mild subcutaneous or mediastinal emphysema and the had minimal clinical impact, and was thus not regarded as adverse events in this study. The tumor location was categorized based on their position in relation to the incisor teeth, along the esophagus. Tumors located 16 to 24 cm, 24 to 32 cm, and 32 cm to cardia from the incisors were classified as upper, middle and lower esophageal lesions, respectively. An en bloc resection was defined as the removal of a tumor in one piece with an intact capsule. The occurrence of fragmentation during extraction was not regarded as piecemeal resection. Follow-up All patients underwent standard endoscopy and CT scans at 3, 6, and 12-month intervals during the first year after the initial procedure to monitor wound healing and identify any signs of residual or recurrent tumor. Subsequently, patients were followed yearly. Data collection and statistical analysis Clinicopathological, endoscopic, and follow-up data were collected and analyzed. Normally distributed measurement values were expressed as mean and standard deviation, whereas non-normally distributed measurement values were expressed as median, interquartile range, and total range. The risks for piecemeal resection, prolonged procedure time, and major adverse events were assessed by univariate and multivariate logistic regression analyses. Variables that exhibited a p-value less than 0.1 during the univariate analysis were included in multivariate analysis, from which only variables with a p-value below 0.05 were reported. Statistical differences between groups were assessed by means of Chi square analysis for categorial data and by 2 independent samples t-test. All statistical analyses were performed with R software (version 4.2.3). Results Clinicopathologic characteristics In this study, endoscopic procedure was attempted in 110 patients. Of these, one procedure in a patient who had previously undergone an unsuccessful STER was failed once again, as it led to the rupture of both the esophagus and trachea. The patient was transferred to surgery and underwent tracheal repair, esophageal diversion, and retrosternal colon interposition graft 3 months later. Finally, 109 patients with giant SMTs in the esophagus and cardia were analyzed (Table 1). The mean age of the patients was 41.8 ± 10.9 years and the male-to-female ratio was 69:40. Most patients were asymptomatic (n = 78, 71.6%), while 31 patients with typical symptoms (28.4%) presented with dysphagia, choking, and odynophagia. The median long and transverse diameter of the tumors were 7.5 cm (interquartile range (IQR), 6–9 cm; range, 4–15 cm) and 4 cm (IQR, 3–4 cm; range, 1.5-7 cm), respectively. Among all SMTs, 26 had regular shape (23.9%) and 83 had irregular shape (76.1%). Tumor location included 4 in the upper (3.7%), 34 in the middle (31.2%), 28 in the lower esophagus (25.7%) and 43 in the cardia (39.4%). All 109 SMTs originated from the MP layer, including 35 with extraluminal growth pattern (32.1%). Tumor histopathology results revealed 100 leiomyomas (91.7%), 5 GISTs (4.6%), 2 schwannomas (1.8%), and 2 bronchogenic cysts (1.8%). According to the National Institutes of Health grading system, 3 GISTs were categorized into intermediate-risk group and 2 were categorized into high-risk group. As for procedures, 77 patients underwent STER (70.6%), 10 underwent ESE (9.2%) and 22 underwent EFTR (20.2%) (Table 2). Ninety-six lesions were closed using endoscopic or endoloop suturing (88.1%). Fully covered self-expanding metal stents were applied in 13 (11.9%) patients. Predictors of textbook outcomes The Textbook outcomes was achieved in over 70% cases (Table 2). The piecemeal resection rate was 12.8%. The prolonged hospital stay happened in 16 patients but there were not any 30-day readmission cases or deaths. A total of 14 patients underwent major adverse events, a vast of which was pneumothorax effusion. The en bloc resection rates for tumors with transverse diameter ≥ 4.5 cm and < 4.5 cm were 76.5% and 92%, respectively (P = 0.053, Supplementary table 1). Furthermore, multivariate logistic analyses revealed the SMTs with a transverse diameter less than 4.5 cm, instead of long diameter, was an independent protective factor of TO (odds ratio [OR] 0.27; 95% confidential interval [CI] 0.10–0.68, P = 0.006, Table 3). Another protective factor was the regular shape of the giant SMT (OR 0.14; 95% CI 0.02–0.56; P = 0.01). Other parameters, including the patient’s age, gender, chief complain, the location, growth pattern, and long diameter of SMT, and procedures related disposal were not demonstrated to indicate a disappointing outcome. In another words, a shaped SMT with a transverse diameter less than 4.5 cm, was more likely to earn an en bloc resection, as well as a safe and sound outcome. Adverse events Among the compositions of TO, adverse event was a heavy concern of the medical quality and the major ones were listed in Table 4. The incidences of major and minor adverse events were 12.8% and 43.1%, respectively (Table 2 and Table 4). A long diameter of the tumor ≥ 9 cm and piecemeal resection were risk factors for mAEs (Table 5). The incidence of mAEs in patients who underwent EFTR was higher than those who underwent STER (18.2% vs 10.3%), but the difference was not statistically significant (Supplementary table 2). Pneumothorax and pleural effusion occurred in 58 patients (53.2%), twelve (11.0%) of whom requiring thoracic decompression or drainage were regarded as major Pneumothorax and pleural effusion. One patient experienced delayed intratunnel bleeding on POD5, which was successfully stanched by endoscopic hemostasis. Three patients had esophageal-pleural fistula because of delayed barrier failure (Fig. 4 ). These patients received thoracic drainage with negative pressure aspiration and enteral nutrition. Gastroscopy was forwarded into the thoracic cavity through the esophageal fistula for debridement, and a gastric tube was inserted through the mucosal defects for drainage. Subsequent gastroscopy and CT scan revealed a progressive reduction of the residual cavity and a gradual healing of the mucosal defects. All three patients recovered and were discharged in one month. Follow-up gastroscopy 3 months later revealed no abnormalities. Two patients developed infectious adverse events. One patient with a cardia SMT encountered intratunnel inflammation and abdominal abscess on POD4 after STER. The entry of the tunnel was reopened, allowing for insertion of a gastric tube to facilitate drainage. Additionally, percutaneous peritoneal drainage was performed for the abdominal abscess. The patient was kept nil per os and received total enteral nutrition. Finally, this patient recovered and was discharged on POD 20. One patient with a lower esophageal SMT complained of recurrent high fever and a productively cough with a foul odor 1 month after EFTR. CT scan revealed a right lung abscess and encapsulated pleural effusion. The patient underwent thoracic drainage and recovered within 2 weeks. One patient with a tumor encompassing 3/4 circumstance of the cardia developed delayed esophageal stenosis 1 month after ESE. Endoscopic balloon dilation was performed and the patient resumed a regular diet after the procedure. Another risk factor of mAE was piecemeal resection, bearing a four-time hazzard than well-shaped ones (OR 4.54, 95%CI 1.01–19.56, P = 0.04). In this study, the median procedure time was 90 minutes (IQR, 60-130 min; range, 30-300 min). However, prolonged procedure time (> 120min) was not indicated as a predictor of mAE. Follow-up Among the 109 patients with giant esophageal or cardia SMTs treated by endoscopic resection, all patients had a follow-up period more than one year. The overall median follow-up period was 33.6 months (IQR, 23.5–47.4 months; range, 15.4–70.4 months). Two of the five patients with GISTs classified as high-risk received Imatinib treatment. The other three patients were closely monitored without any additional treatments. All of the 109 patients were free from local recurrence and distant metastasis. Discussion Large esophageal or cardia SMTs are more likely to be symptomatic and demanding for endoscopists[ 9 ]. The utilization of endoscopic resection as a minimally invasive approach facilitates both histological diagnosis and clinical treatment. However, the indication for endoscopic resection of SMTs remains a matter of concern. Previous studies mostly focused on small SMTs not exceeding 5 cm in length[ 10 – 12 ]. Recent advancements in the field have brought forward preliminary studies and case reports that highlight the viability of endoscopic resection as a potential approach for SMTs > 5 cm in size[ 5 , 13 – 15 ]. However, the textbook outcomes for those giant SMTs were not summarized, and the revelation of its predictors may help endoscopist distinguish the SMTs safe and appropriate for endoscopist resection. In this study, we retrospectively reviewed data from 109 patients who underwent endoscopic resection for esophageal or cardia SMTs with a long diameter ≥ 7 cm, or a transverse diameter ≥ 3.5 cm at our center. The TO was achieved in 70.6% patients, with a fair en bloc resection rate and mAE-free rate both at 87.2%. Most of SMTs with piecemeal resection were leiomyomas, which were considered acceptable for piecemeal resection[ 7 ]. One GIST and one bronchus cyst underwent piecemeal resection, but no residual tumor or recurrence was observed during close follow-up. Instead of the long diameter, transverse diameter was critical for en bloc resection for giant esophageal or cardia SMTs. It was more difficult and time-consuming to resect tumors with large transverse diameter (Supplementary table 1). As a result, endoscopic resection of tumors with transverse diameter ≥ 4.5 cm could end with unsatisfactory outcomes and might be considered for surgery. Moreover, irregular shape was a risk factor for piecemeal resection, which was consistent with our previous study[ 2 ]. However, it did not contribute to prolonged procedure time or major adverse events. We recommend that when dealing with giant irregular SMTs, it is crucial to conduct preoperative EUS or CT evaluation, ensure adequate preparation, and performed by an experienced endoscopist. In our experience, the long diameter exhibits the other considerable magnitude concerning the outcomes. In this study, the maximum long diameter of the tumor for en bloc resection can reach up to 15 cm. However, long diameter ≥ 9 cm was a risk factor for major adverse events instead of TO. Thus, we concluded it was safe and effective for endoscopic resection of giant esophageal or cardia SMTs with a long diameter < 9 cm and transverse diameter < 4.5 cm. Additionally, SMTs with a long diameter 4.5 cm could be confronted with problems like mild adverse events or prolonged hospital stay. Endoscopic resection of giant esophageal or cardia SMT can exhibit several adverse events. In the present study, major adverse events occurred in 14 patients (12.8%), including 7 simple mass pleural effusion with or without pneumothorax requiring thoracic drainage, 3 esophageal-fistula with mass pleural effusion, two infectious adverse events, 1 delayed intratunnel bleeding and 1 esophageal stenosis. Tumors with long diameter ≥ 9 and piecemeal resection were risk factors for major adverse events. All adverse events were managed conservatively. Esophageal-pleural fistula was a severe adverse event. Esophageal stent can be prophylactic inserted to maintain the lumen integrity and prevent extraluminal soilage. In the management of esophageal-pleural fistula, the therapeutic interventions included debridement of the fistula cavity through the gastroscopy, insertion of gastric tube into the fistula cavity alongside thoracic drainage to eliminate the infection, fasting and gastric decompression to prevent further contamination, enteric nutrition, and endoscopic suture to close the esophageal wound. The majority of esophageal or cardia SMTs consist of leiomyomas, while GISTs account for less than 1% of cases in the esophagus[ 16 ]. In this study, two patients with high-risk GISTs characterized by mitotic rate > 10/50 HPF and piecemeal resection received Imatinib treatment. Meanwhile, the remaining three patients classified as intermediate-risk were closely monitored without any additional treatments. Notably, no local recurrence or distant metastasis were detected in any of the patients during close follow-up. Our study had several limitations. It was performed in a tertiary referral center by experienced endoscopists. As these procedures are very technically demanding, we recommend operators with experience of more than 300 cases of ESD, ESE, EFTR or POEM. Another limitation is the study’s retrospective design. A prospective and randomized study comparing endoscopic resection with other medical approaches for giant esophageal or cardia SMTs should be performed to validate the observed results in the future. In summary, our data suggest that endoscopic resection deserved a satisfactory outcome for giant esophageal or cardia SMTs under some context. Transverse diameter ≥ 4.5 cm and irregular shape are risk factors for textbook outcomes. Endoscopic resection for tumors with a long diameter ≥ 9 cm is also feasible, but associated with a relatively high risk of mAEs. In the opposite, a giant well-shaped SMT with a transverse diameter < 4.5 cm and a long diameter ≥ 9 cm was a worth a try for endoscopic resection for fat chance of textbook outcomes. Further large-scale prospective studies are necessary to fully assess the efficacy and safety of endoscopic resection with conventional treatments. Declarations Financial support: This study was supported by grants from the National Natural Science Foundation of China (8200062), Major Project of Shanghai Municipal Science and Technology Committee (23ZR1445500), Yangfan program of Shanghai Municipal Science and Technology Committee (21YF1440100), and Outstanding Youth Foundation of Zhongshan Hospital, Fudan University (202ZSYQ12). Author’s contributions: Planning and conducting the study: Wei Su, Yun Wang, Haihan Xu, Ji-Yuan Zhang, Sheng-Li Lin, Ping-Hong Zhou. Collecting data: Hu Hao, Quan-Lin Li, Yun-Shi Zhong, Yi-Qun Zhang, Wei-Feng Chen. Analyzing and interpreting data: Yun Wang, Haihan Xu, Xi-Guo, Fang, Ji-Yuan Zhang. Drafting manuscript: Yun Wang, Sheng-Li Lin, Ping-Hong Zhou. Final approval of manuscript: all Conflicts of interest: The authors disclose no conflicts. References Shin, S., et al., Enucleation of esophageal submucosal tumors: a single institution's experience. Ann Thorac Surg, 2014. 97 (2): p. 454-9. Chen, T., et al., Long-term Outcomes of Submucosal Tunneling Endoscopic Resection for Upper Gastrointestinal Submucosal Tumors. Ann Surg, 2017. 265 (2): p. 363-369. Zhai, Y.Q., et al., Endoscopic submucosal excavation and endoscopic full-thickness resection for gastric schwannoma: five-year experience from a large tertiary center in China. Surg Endosc, 2020. 34 (11): p. 4943-4949. Ponte Neto, F.L., et al., Endoscopic resection of esophageal and gastric submucosal tumors from the muscularis propria layer: submucosal tunneling endoscopic resection versus endoscopic submucosal excavation: A systematic review and meta-analysis. Surg Endosc, 2021. 35 (12): p. 6413-6426. Chen, T., et al., Submucosal Tunneling Endoscopic Resection vs Thoracoscopic Enucleation for Large Submucosal Tumors in the Esophagus and the Esophagogastric Junction. J Am Coll Surg, 2017. 225 (6): p. 806-816. Kolfschoten, N.E., et al., Focusing on desired outcomes of care after colon cancer resections; hospital variations in 'textbook outcome'. Eur J Surg Oncol, 2013. 39 (2): p. 156-63. Lu, J., et al., Endoscopic management of upper gastrointestinal submucosal tumors arising from muscularis propria. J Clin Gastroenterol, 2014. 48 (8): p. 667-73. Joensuu, H., Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol, 2008. 39 (10): p. 1411-9. Nishida, T., et al., Submucosal tumors: comprehensive guide for the diagnosis and therapy of gastrointestinal submucosal tumors. Dig Endosc, 2013. 25 (5): p. 479-89. Onimaru, M., et al., Clinical outcomes of per-oral endoscopic tumor resection for submucosal tumors in the esophagus and gastric cardia. Dig Endosc, 2020. 32 (3): p. 328-336. Gong, W., et al., Preliminary experience of endoscopic submucosal tunnel dissection for upper gastrointestinal submucosal tumors. Endoscopy, 2012. 44 (3): p. 231-5. Lv, X.H., C.H. Wang, and Y. Xie, Efficacy and safety of submucosal tunneling endoscopic resection for upper gastrointestinal submucosal tumors: a systematic review and meta-analysis. Surg Endosc, 2017. 31 (1): p. 49-63. Tan, Y. and D. Liu, En bloc submucosal tunneling endoscopic resection for a giant esophageal leiomyoma. Gastrointest Endosc, 2015. 82 (2): p. 399. Maydeo, A., et al., Submucosal tunneling and endoscopic resection of a large, esophageal leiomyoma. Gastrointest Endosc, 2015. 82 (5): p. 954. Kumbhari, V., et al., Submucosal tunneling endoscopic resection of a giant esophageal leiomyoma. Gastrointest Endosc, 2015. 81 (1): p. 219-20. Hu, S., et al., Gastrointestinal stromal tumors (GISTs) arising in uncommon locations: clinicopathologic features and risk assessment of esophageal, colonic, and appendiceal GISTs. Mod Pathol, 2022. 35 (4): p. 554-563. Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Supplementarytables.docx table1.docx table2.docx Table3.docx Table4.docx Table5.docx Cite Share Download PDF Status: Published Journal Publication published 05 Sep, 2025 Read the published version in Digestive Diseases and Sciences → Version 1 posted Editorial decision: Revision requested 14 Jul, 2025 Reviews received at journal 14 Jul, 2025 Reviewers agreed at journal 29 Jun, 2025 Reviews received at journal 24 Jun, 2025 Reviewers agreed at journal 20 Jun, 2025 Reviewers invited by journal 18 Jun, 2025 Editor assigned by journal 17 Jun, 2025 Submission checks completed at journal 14 Jun, 2025 First submitted to journal 14 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6892379","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":473219869,"identity":"ea67b99d-6215-48f2-8dcf-b3890e519756","order_by":0,"name":"Wei Su","email":"","orcid":"","institution":"Zhongshan Hospital, Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Su","suffix":""},{"id":473219870,"identity":"df4dbf18-36b7-4209-8900-e37013fa3d51","order_by":1,"name":"Yun Wang","email":"","orcid":"","institution":"Zhongshan Hospital, Fudan 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University","correspondingAuthor":false,"prefix":"","firstName":"Ping-Hong","middleName":"","lastName":"Zhou","suffix":""},{"id":473219880,"identity":"cbe01e3c-6fca-4338-bd36-7a889c96a937","order_by":11,"name":"Sheng-Li Lin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzElEQVRIiWNgGAWjYFACHjApw8DOfODAhx8kaOFhYGZLPDizhzQtPMaHOdiI0CDff/bg48I9h3nkm3k+HAbqlOcXO4BfC+OMvGTjGc8O8xgc5t1wuMCCwXDm7AT8WpgleMykeQ4AtTADtczgYUgwuE1ACxv/GfPfIC1Ahz04zMNGhBYehhwzZpAWBjAiRouERI4x0GHpQL+wGQADWYKwX+T7zxh+5jlgLSff3vz4w4cfNvL80gS0QEEz3FailINAHdEqR8EoGAWjYAQCAAzyPgo4wg48AAAAAElFTkSuQmCC","orcid":"","institution":"Zhongshan Hospital, Fudan University","correspondingAuthor":true,"prefix":"","firstName":"Sheng-Li","middleName":"","lastName":"Lin","suffix":""}],"badges":[],"createdAt":"2025-06-14 07:08:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6892379/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6892379/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10620-025-09377-1","type":"published","date":"2025-09-05T15:57:32+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":85176071,"identity":"3e43e3f3-d0bd-4128-858b-312aeadf55ed","added_by":"auto","created_at":"2025-06-23 06:34:17","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":137204,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the study profile. STER, submucosal tunneling and endoscopic resection; EFTR, endoscopic full-thickness resection; ESE, endoscopic submucosal excavation.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6892379/v1/00191b37018b80b480a30335.png"},{"id":85175512,"identity":"abd972ef-9008-4e32-9ebb-e4a58c52d1b5","added_by":"auto","created_at":"2025-06-23 06:26:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":265254,"visible":true,"origin":"","legend":"\u003cp\u003eSubmucosal tunneling and endoscopic resection for a giant submucosal tumor in the middle esophagus. (A) Endoscopic view of the tumor. (B) The mucosal entry established. (C) the submucosal tumor exposed and dissected using the submucosal tunnel technique. (D) Endoscopic view of the submucosal tumor and tumor bed after the tumor was removed. (E) The mucosal entry closed using endoclips. (F) The size of the tumor was 9.5 × 4.5 cm.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6892379/v1/5471d224c3f97820414c364f.png"},{"id":85175521,"identity":"7fce024e-f1a1-4b91-a18f-4560276ba2e9","added_by":"auto","created_at":"2025-06-23 06:26:18","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":284448,"visible":true,"origin":"","legend":"\u003cp\u003eEndoscopic full-thickness resection (EFTR) for a giant submucosal tumor in the esophagogastric junction (EGJ). (A) Endoscopic view of a ring-like tumor surrounding the EGJ. (B) Mucosa incision. (C) Submucosal dissection deep to the adventitia to enucleate the tumor. (D) Endoscopic view of the tumor bed after the tumor was removed. (E) Replacement of a fully covered esophageal stent for the EFTR defect. (F) The size of the tumor was 15.0 × 4.5 cm.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-6892379/v1/ca1bfc5bfe2c52b296ab7dee.png"},{"id":85175531,"identity":"59395e2f-ad7c-465b-9c57-d50bdcb35170","added_by":"auto","created_at":"2025-06-23 06:26:18","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":498731,"visible":true,"origin":"","legend":"\u003cp\u003eManagement of an esophageal-pleural fistula after endoscopic full-thickness resection (EFTR). (A) Endoscopic view of the esophageal-pleural fistula on postoperative day (POD) 5. (B) Endoscopic debridement of the residual cavity. (C) A gastric tube inserted into the fistula through the mucosal defect. (D) Endoscopic view of the shrinking fistula on POD 23. (E) Endoscopic view of the healed esophageal wound on POD 27. (F) Endoscopic view of the esophageal scar 6 months after EFTR.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6892379/v1/cd636cd2bf0ded476617b0b8.png"},{"id":90827958,"identity":"7c5b075f-ab72-47b4-84fd-c675d61d05bf","added_by":"auto","created_at":"2025-09-08 16:04:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1974755,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6892379/v1/38f682da-c425-4746-8049-60559a34edd8.pdf"},{"id":85176070,"identity":"7eac26b8-b436-4a22-98ef-c23a549b2d27","added_by":"auto","created_at":"2025-06-23 06:34:17","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":21472,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6892379/v1/58cc9373a9fb57946c92480c.docx"},{"id":85176072,"identity":"bdecb701-6066-41f6-b0f3-fad69b4bcb9f","added_by":"auto","created_at":"2025-06-23 06:34:17","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":80402,"visible":true,"origin":"","legend":"","description":"","filename":"table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6892379/v1/8682a2547fd47ad4204a816a.docx"},{"id":85176073,"identity":"8a6ccf48-6311-4ca3-b168-0d4d4877d8a1","added_by":"auto","created_at":"2025-06-23 06:34:17","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":150961,"visible":true,"origin":"","legend":"","description":"","filename":"table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-6892379/v1/9fcba9928fd8d28495bc1e6b.docx"},{"id":85175535,"identity":"941b7ca0-1ee9-4803-a8a7-9d3b95304f0d","added_by":"auto","created_at":"2025-06-23 06:26:19","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":156684,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-6892379/v1/bac830c2ea1dc02b9d717ec8.docx"},{"id":85175520,"identity":"ffc40288-8e8d-4cc5-a326-16ec277a5f99","added_by":"auto","created_at":"2025-06-23 06:26:18","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":459366,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.docx","url":"https://assets-eu.researchsquare.com/files/rs-6892379/v1/838c868e991d5f5ec4e380ce.docx"},{"id":85176078,"identity":"1adc997d-64fe-43e5-bbfc-c23f3cbdbdab","added_by":"auto","created_at":"2025-06-23 06:34:18","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":155496,"visible":true,"origin":"","legend":"","description":"","filename":"Table5.docx","url":"https://assets-eu.researchsquare.com/files/rs-6892379/v1/fceb83368bea90778e5ff95c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Predictors for Achieving Textbook outcomes after endoscopic resection of giant submucosal tumors in the esophagus and cardia","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLarge SMTs in the esophagus and cardia often require resection because of clinical symptoms or the risk of malignancy. Nevertheless, since a considerable number of these tumors are benign, thoracoscopic surgery is traditionally recommended as a minimally invasive approach[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecently, endoscopic treatments including endoscopic submucosal excavation (ESE), submucosal tunneling and endoscopic resection (STER), and endoscopic full-thickness resection (EFTR) have been an optimized minimal-invasive alternatives to surgery as safe and effective approaches for upper gastrointestinal SMTs less than 5cm in length[\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. These techniques provide definitive histologic diagnosis and offer a minimally invasive therapeutic approach. Previously, our study exhibited high en bloc resection rates of 90.6% and 88.2%, respectively, regarding STER for esophageal or cardia SMTs with a long diameter of \u0026le;\u0026thinsp;5 cm and \u0026le;\u0026thinsp;7 cm[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, endoscopic resection for giant esophageal or cardia SMTs remains challenging, with limited data regarding the feasibility and safety of this approach for SMTs of considerable size. Under such circumstances, the quality of endoscopic resection was not evaluated, let alone the outcomes comparison with surgery.\u003c/p\u003e \u003cp\u003eTextbook outcome (TO) reflecting the surgical quality better by assessments of the orchestration of adverse events, mortality, readmission, hospital stay instead of single indicator[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. TO was a outcome-oriented conception, and a representative of safety of operation. To date, no TO assessment were not evaluated and the predictors were largely unknown in the context of endoscopic resections of giant SMTs. Thus, we aim to differentiate giant SMTs suitable for endoscopic resection by assessed the TO and calculated its predictors in an alternative to surgery.\u003c/p\u003e \u003cp\u003eWe aim to investigate the quality of endoscopic resection for esophageal or cardia SMTs with a long diameter\u0026thinsp;\u0026ge;\u0026thinsp;7 cm, or a transverse diameter\u0026thinsp;\u0026ge;\u0026thinsp;3.5 cm, by assessments of the TO and its predictors. We hope this outcome-oriented study and conclusions provides can help the endoscopists to differentiate candidate of qualified endoscopic resections by pre-operative indictors of giant SMTs.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003e Between July 2017 and February 2022, a total of 110 patients with giant SMTs in the esophagus and cardia were included in this study, which was conducted at the Endoscopy Center of Zhongshan Hospital, Fudan University, Shanghai. Endoscopic ultrasonography (EUS) or computed tomography (CT) was performed preoperatively to evaluate the size, layer of origin, shape, growth pattern, anatomic location, and proximity to important neighboring structures. The inclusion criteria for enrollment were as follows: (1) Giant esophageal or cardia SMTs that had a long diameter\u0026thinsp;\u0026ge;\u0026thinsp;7 cm, or a transverse diameter\u0026thinsp;\u0026ge;\u0026thinsp;3.5cm. (2) Patients with typical or atypical symptoms requested aggressive treatment. (3) SMTs that originated from the myenteric plexus layer.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe endoscopic treatment in a patient who had previously undergone an unsuccessful STER was failed once again, as it led to the rupture of both the esophagus and trachea. The patient was transferred to surgery and underwent tracheal repair, esophageal diversion, and retrosternal colon interposition graft 3 months later. The remaining 109 patients were included in this study for further analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe study was approved by the Institutional Review board of Zhongshan Hospital (No. B2021-864R), in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eProcedure\u003c/h3\u003e\n\u003cp\u003eAll patients were under general anesthesia with endotracheal intubation. Prophylactic antibiotics were administered 30 minutes before the procedure. CO2 was used for insufflation during the procedure. The procedure was performed by endoscopists with experience of more than 300 cases of ESD, ESE, EFTR or POEM. The selection of techniques by the endoscopists was based on careful consideration of factors including the anatomic location, size, layer of origin, and growth pattern of the tumors.\u003c/p\u003e \u003cp\u003eSTER was selected as the preferred therapeutic approach for the majority of patients with SMTs located at the esophagus. Details of the standard STER procedure were reported in our previous publications[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Generally, the procedure consisted of main steps: (1) submucosal injection and mucosal incision 3\u0026ndash;5 cm orally to the proximal margin of the SMT; (2) submucosal tunneling ended at 1 to 2 cm distal to the tumor; (3) dissection of the SMT; (4) extraction of the mobilized SMT. The entrance of the submucosal tunnel was enlarged in cases where the resected tumor exceeded the mucosotomy; (5) closure of the mucosal incision (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eEFTR was primarily employed for patients with giant irregular SMTs positioned at the cardia originated from the deep muscularis propria extended extraluminally. The procedure was performed as previously described and included following steps[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]: (1) marking of the lesion border; (2) incision of the mucosa and submucosal layers surrounding the SMT; (3) dissection of the SMT from the surrounding muscularis propria. Endoclip or dental floss traction was used as needed. (4) extraction of the tumor; (5) closure of the defect by endoclips or endoloop suturing. When the defect could not be successfully closed, a fully covered esophageal was employed (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e ESE was performed for patients with SMTs circumferentially surrounding the cardia originated from the superficial muscularis propria. The ESE procedure was similar as ESD[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. (1) marking of the lesion border; (2) submucosal injection and mucosal incision; (3) submucosal and muscularis dissection to separate the tumor from the surrounding tissues; (4) extraction of the tumor; (5) closure of the defect by endoclips or endoloop suturing.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003ePostoperative management\u003c/h3\u003e\n\u003cp\u003ePatients were routinely observed in hospital for at least 2 days. Clinical symptoms such as chest pain, dyspnea, hematemesis or melena, and abdominal pain were carefully observed. Vital signs were monitored every six hours, and blood tests were conducted daily during the first three postoperative days (POD). Patients were kept fasted for 24 h after the procedure, after which they were allowed to consume a liquid diet if remained asymptomatic on POD2. If patients showed symptoms such as ongoing chest pain, dyspnea, or a persistent high fever (\u0026ge;\u0026thinsp;38.5\u0026deg;C), which may suggest potential adverse events, immediate endoscopy and/ or CT scan were conducted. To assess mucosa continuity and detect any leakage, either an endoscopic examination or a contrast swallow radiography was carried out. Upon achieving asymptomatic oral intake, patients were discharged from the hospital and advised to adhere to a soft diet regimen for at least 1 week.\u003c/p\u003e \n\u003ch3\u003eHistopathology\u003c/h3\u003e\n\u003cp\u003eThe size and shape of each removed specimen were examined. A tumor with an oval or globular shape was defined as a tumor with regular shape. Specimens were then fixed in 10% formalin, embedded with paraffin, and sectioned for pathological examination. Tumor pathology was assessed through hematoxylin and eosin staining as well as immunohistochemical staining. Risk classification of the gastrointestinal stromal tumors (GISTs) was performed\u003c/p\u003e \u003cp\u003eaccording to the revised National Institutes of Health grading system[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eOutcome definitions\u003c/h3\u003e\n\u003cp\u003eSince no TO criteria was put forward in the field of endoscopic resection. We proposed the TO in our study was satisfied in the absences of major adverse events (mAEs), the prolonged hospital stays, the mortality within 30 days, the readmission within 30 days, and recurrences. Prolonged hospital stay was defined hospital stay of 8-day or longer, double of the median. Major adverse events were defined as ICU admission, interventional postoperative procedure, or blood transfusion. The spectrum of mAEs included severe pneumothorax or pleural effusion necessitating depression or drainage, delayed bleeding requiring blood transfusion or endoscopic hemostasis, severe leakage resulting in fistula formation, severe infection, and esophageal stenosis. Minor adverse events included mild pneumothorax or pleural effusion without intervention, and inconsequential febrile episode. Mild subcutaneous or mediastinal emphysema and the had minimal clinical impact, and was thus not regarded as adverse events in this study.\u003c/p\u003e \u003cp\u003eThe tumor location was categorized based on their position in relation to the incisor teeth, along the esophagus. Tumors located 16 to 24 cm, 24 to 32 cm, and 32 cm to cardia from the incisors were classified as upper, middle and lower esophageal lesions, respectively. An en bloc resection was defined as the removal of a tumor in one piece with an intact capsule. The occurrence of fragmentation during extraction was not regarded as piecemeal resection.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eFollow-up\u003c/h2\u003e \u003cp\u003eAll patients underwent standard endoscopy and CT scans at 3, 6, and 12-month intervals during the first year after the initial procedure to monitor wound healing and identify any signs of residual or recurrent tumor. Subsequently, patients were followed yearly.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData collection and statistical analysis\u003c/h3\u003e\n\u003cp\u003eClinicopathological, endoscopic, and follow-up data were collected and analyzed. Normally distributed measurement values were expressed as mean and standard deviation, whereas non-normally distributed measurement values were expressed as median, interquartile range, and total range. The risks for piecemeal resection, prolonged procedure time, and major adverse events were assessed by univariate and multivariate logistic regression analyses. Variables that exhibited a p-value less than 0.1 during the univariate analysis were included in multivariate analysis, from which only variables with a p-value below 0.05 were reported. Statistical differences between groups were assessed by means of Chi square analysis for categorial data and by 2 independent samples t-test. All statistical analyses were performed with R software (version 4.2.3).\u003c/p\u003e\n"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eClinicopathologic characteristics\u003c/h2\u003e\n \u003cp\u003eIn this study, endoscopic procedure was attempted in 110 patients. Of these, one procedure in a patient who had previously undergone an unsuccessful STER was failed once again, as it led to the rupture of both the esophagus and trachea. The patient was transferred to surgery and underwent tracheal repair, esophageal diversion, and retrosternal colon interposition graft 3 months later. Finally, 109 patients with giant SMTs in the esophagus and cardia were analyzed (Table\u0026nbsp;1). The mean age of the patients was 41.8\u0026thinsp;\u0026plusmn;\u0026thinsp;10.9 years and the male-to-female ratio was 69:40. Most patients were asymptomatic (n\u0026thinsp;=\u0026thinsp;78, 71.6%), while 31 patients with typical symptoms (28.4%) presented with dysphagia, choking, and odynophagia.\u003c/p\u003e\n \u003cp\u003eThe median long and transverse diameter of the tumors were 7.5 cm (interquartile range (IQR), 6\u0026ndash;9 cm; range, 4\u0026ndash;15 cm) and 4 cm (IQR, 3\u0026ndash;4 cm; range, 1.5-7 cm), respectively. Among all SMTs, 26 had regular shape (23.9%) and 83 had irregular shape (76.1%). Tumor location included 4 in the upper (3.7%), 34 in the middle (31.2%), 28 in the lower esophagus (25.7%) and 43 in the cardia (39.4%). All 109 SMTs originated from the MP layer, including 35 with extraluminal growth pattern (32.1%). Tumor histopathology results revealed 100 leiomyomas (91.7%), 5 GISTs (4.6%), 2 schwannomas (1.8%), and 2 bronchogenic cysts (1.8%). According to the National Institutes of Health grading system, 3 GISTs were categorized into intermediate-risk group and 2 were categorized into high-risk group. As for procedures, 77 patients underwent STER (70.6%), 10 underwent ESE (9.2%) and 22 underwent EFTR (20.2%) (Table 2). Ninety-six lesions were closed using endoscopic or endoloop suturing (88.1%). Fully covered self-expanding metal stents were applied in 13 (11.9%) patients.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003ePredictors of textbook outcomes\u003c/h2\u003e\n \u003cp\u003eThe Textbook outcomes was achieved in over 70% cases (Table\u0026nbsp;2). The piecemeal resection rate was 12.8%. The prolonged hospital stay happened in 16 patients but there were not any 30-day readmission cases or deaths. A total of 14 patients underwent major adverse events, a vast of which was pneumothorax effusion.\u003c/p\u003e\n \u003cp\u003eThe en bloc resection rates for tumors with transverse diameter\u0026thinsp;\u0026ge;\u0026thinsp;4.5 cm and \u0026lt;\u0026thinsp;4.5 cm were 76.5% and 92%, respectively (P\u0026thinsp;=\u0026thinsp;0.053, Supplementary table 1). Furthermore, multivariate logistic analyses revealed the SMTs with a transverse diameter less than 4.5 cm, instead of long diameter, was an independent protective factor of TO (odds ratio [OR] 0.27; 95% confidential interval [CI] 0.10\u0026ndash;0.68, P\u0026thinsp;=\u0026thinsp;0.006, Table\u0026nbsp;3). Another protective factor was the regular shape of the giant SMT (OR 0.14; 95% CI 0.02\u0026ndash;0.56; P\u0026thinsp;=\u0026thinsp;0.01). Other parameters, including the patient\u0026rsquo;s age, gender, chief complain, the location, growth pattern, and long diameter of SMT, and procedures related disposal were not demonstrated to indicate a disappointing outcome. In another words, a shaped SMT with a transverse diameter less than 4.5 cm, was more likely to earn an en bloc resection, as well as a safe and sound outcome.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eAdverse events\u003c/h2\u003e\n \u003cp\u003eAmong the compositions of TO, adverse event was a heavy concern of the medical quality and the major ones were listed in Table\u0026nbsp;4. The incidences of major and minor adverse events were 12.8% and 43.1%, respectively (Table\u0026nbsp;2 and Table\u0026nbsp;4). A long diameter of the tumor\u0026thinsp;\u0026ge;\u0026thinsp;9 cm and piecemeal resection were risk factors for mAEs (Table\u0026nbsp;5). The incidence of mAEs in patients who underwent EFTR was higher than those who underwent STER (18.2% vs 10.3%), but the difference was not statistically significant (Supplementary table 2).\u003c/p\u003e\n \u003cp\u003ePneumothorax and pleural effusion occurred in 58 patients (53.2%), twelve (11.0%) of whom requiring thoracic decompression or drainage were regarded as major Pneumothorax and pleural effusion. One patient experienced delayed intratunnel bleeding on POD5, which was successfully stanched by endoscopic hemostasis.\u003c/p\u003e\n \u003cp\u003eThree patients had esophageal-pleural fistula because of delayed barrier failure (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). These patients received thoracic drainage with negative pressure aspiration and enteral nutrition. Gastroscopy was forwarded into the thoracic cavity through the esophageal fistula for debridement, and a gastric tube was inserted through the mucosal defects for drainage. Subsequent gastroscopy and CT scan revealed a progressive reduction of the residual cavity and a gradual healing of the mucosal defects. All three patients recovered and were discharged in one month. Follow-up gastroscopy 3 months later revealed no abnormalities.\u003c/p\u003e\n \u003cp\u003eTwo patients developed infectious adverse events. One patient with a cardia SMT encountered intratunnel inflammation and abdominal abscess on POD4 after STER. The entry of the tunnel was reopened, allowing for insertion of a gastric tube to facilitate drainage. Additionally, percutaneous peritoneal drainage was performed for the abdominal abscess. The patient was kept nil per os and received total enteral nutrition. Finally, this patient recovered and was discharged on POD 20. One patient with a lower esophageal SMT complained of recurrent high fever and a productively cough with a foul odor 1 month after EFTR. CT scan revealed a right lung abscess and encapsulated pleural effusion. The patient underwent thoracic drainage and recovered within 2 weeks.\u003c/p\u003e\n \u003cp\u003eOne patient with a tumor encompassing 3/4 circumstance of the cardia developed delayed esophageal stenosis 1 month after ESE. Endoscopic balloon dilation was performed and the patient resumed a regular diet after the procedure.\u003c/p\u003e\n \u003cp\u003eAnother risk factor of mAE was piecemeal resection, bearing a four-time hazzard than well-shaped ones (OR 4.54, 95%CI 1.01\u0026ndash;19.56, P\u0026thinsp;=\u0026thinsp;0.04). In this study, the median procedure time was 90 minutes (IQR, 60-130 min; range, 30-300 min). However, prolonged procedure time (\u0026gt; 120min) was not indicated as a predictor of mAE.\u003c/p\u003e\n \u003cp\u003eFollow-up\u003c/p\u003e\n \u003cp\u003eAmong the 109 patients with giant esophageal or cardia SMTs treated by endoscopic resection, all patients had a follow-up period more than one year. The overall median follow-up period was 33.6 months (IQR, 23.5\u0026ndash;47.4 months; range, 15.4\u0026ndash;70.4 months). Two of the five patients with GISTs classified as high-risk received Imatinib treatment. The other three patients were closely monitored without any additional treatments. All of the 109 patients were free from local recurrence and distant metastasis.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eLarge esophageal or cardia SMTs are more likely to be symptomatic and demanding for endoscopists[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The utilization of endoscopic resection as a minimally invasive approach facilitates both histological diagnosis and clinical treatment. However, the indication for endoscopic resection of SMTs remains a matter of concern. Previous studies mostly focused on small SMTs not exceeding 5 cm in length[\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Recent advancements in the field have brought forward preliminary studies and case reports that highlight the viability of endoscopic resection as a potential approach for SMTs\u0026thinsp;\u0026gt;\u0026thinsp;5 cm in size[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, the textbook outcomes for those giant SMTs were not summarized, and the revelation of its predictors may help endoscopist distinguish the SMTs safe and appropriate for endoscopist resection.\u003c/p\u003e \u003cp\u003eIn this study, we retrospectively reviewed data from 109 patients who underwent endoscopic resection for esophageal or cardia SMTs with a long diameter\u0026thinsp;\u0026ge;\u0026thinsp;7 cm, or a transverse diameter\u0026thinsp;\u0026ge;\u0026thinsp;3.5 cm at our center. The TO was achieved in 70.6% patients, with a fair en bloc resection rate and mAE-free rate both at 87.2%. Most of SMTs with piecemeal resection were leiomyomas, which were considered acceptable for piecemeal resection[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. One GIST and one bronchus cyst underwent piecemeal resection, but no residual tumor or recurrence was observed during close follow-up. Instead of the long diameter, transverse diameter was critical for en bloc resection for giant esophageal or cardia SMTs. It was more difficult and time-consuming to resect tumors with large transverse diameter (Supplementary table 1). As a result, endoscopic resection of tumors with transverse diameter\u0026thinsp;\u0026ge;\u0026thinsp;4.5 cm could end with unsatisfactory outcomes and might be considered for surgery. Moreover, irregular shape was a risk factor for piecemeal resection, which was consistent with our previous study[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, it did not contribute to prolonged procedure time or major adverse events. We recommend that when dealing with giant irregular SMTs, it is crucial to conduct preoperative EUS or CT evaluation, ensure adequate preparation, and performed by an experienced endoscopist.\u003c/p\u003e \u003cp\u003eIn our experience, the long diameter exhibits the other considerable magnitude concerning the outcomes. In this study, the maximum long diameter of the tumor for en bloc resection can reach up to 15 cm. However, long diameter\u0026thinsp;\u0026ge;\u0026thinsp;9 cm was a risk factor for major adverse events instead of TO. Thus, we concluded it was safe and effective for endoscopic resection of giant esophageal or cardia SMTs with a long diameter\u0026thinsp;\u0026lt;\u0026thinsp;9 cm and transverse diameter\u0026thinsp;\u0026lt;\u0026thinsp;4.5 cm. Additionally, SMTs with a long diameter\u0026thinsp;\u0026lt;\u0026thinsp;9 cm and transverse diameter\u0026thinsp;\u0026gt;\u0026thinsp;4.5 cm could be confronted with problems like mild adverse events or prolonged hospital stay.\u003c/p\u003e \u003cp\u003eEndoscopic resection of giant esophageal or cardia SMT can exhibit several adverse events. In the present study, major adverse events occurred in 14 patients (12.8%), including 7 simple mass pleural effusion with or without pneumothorax requiring thoracic drainage, 3 esophageal-fistula with mass pleural effusion, two infectious adverse events, 1 delayed intratunnel bleeding and 1 esophageal stenosis. Tumors with long diameter\u0026thinsp;\u0026ge;\u0026thinsp;9 and piecemeal resection were risk factors for major adverse events. All adverse events were managed conservatively. Esophageal-pleural fistula was a severe adverse event. Esophageal stent can be prophylactic inserted to maintain the lumen integrity and prevent extraluminal soilage. In the management of esophageal-pleural fistula, the therapeutic interventions included debridement of the fistula cavity through the gastroscopy, insertion of gastric tube into the fistula cavity alongside thoracic drainage to eliminate the infection, fasting and gastric decompression to prevent further contamination, enteric nutrition, and endoscopic suture to close the esophageal wound.\u003c/p\u003e \u003cp\u003eThe majority of esophageal or cardia SMTs consist of leiomyomas, while GISTs account for less than 1% of cases in the esophagus[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In this study, two patients with high-risk GISTs characterized by mitotic rate\u0026thinsp;\u0026gt;\u0026thinsp;10/50 HPF and piecemeal resection received Imatinib treatment. Meanwhile, the remaining three patients classified as intermediate-risk were closely monitored without any additional treatments. Notably, no local recurrence or distant metastasis were detected in any of the patients during close follow-up.\u003c/p\u003e \u003cp\u003eOur study had several limitations. It was performed in a tertiary referral center by experienced endoscopists. As these procedures are very technically demanding, we recommend operators with experience of more than 300 cases of ESD, ESE, EFTR or POEM. Another limitation is the study\u0026rsquo;s retrospective design. A prospective and randomized study comparing endoscopic resection with other medical approaches for giant esophageal or cardia SMTs should be performed to validate the observed results in the future.\u003c/p\u003e \u003cp\u003eIn summary, our data suggest that endoscopic resection deserved a satisfactory outcome for giant esophageal or cardia SMTs under some context. Transverse diameter\u0026thinsp;\u0026ge;\u0026thinsp;4.5 cm and irregular shape are risk factors for textbook outcomes. Endoscopic resection for tumors with a long diameter\u0026thinsp;\u0026ge;\u0026thinsp;9 cm is also feasible, but associated with a relatively high risk of mAEs. In the opposite, a giant well-shaped SMT with a transverse diameter\u0026thinsp;\u0026lt;\u0026thinsp;4.5 cm and a long diameter\u0026thinsp;\u0026ge;\u0026thinsp;9 cm was a worth a try for endoscopic resection for fat chance of textbook outcomes. Further large-scale prospective studies are necessary to fully assess the efficacy and safety of endoscopic resection with conventional treatments.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFinancial support:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by grants from the National Natural Science Foundation of China (8200062), Major Project of Shanghai Municipal Science and Technology Committee (23ZR1445500), Yangfan program of Shanghai Municipal Science and Technology Committee (21YF1440100), and Outstanding Youth Foundation of Zhongshan Hospital, Fudan University (202ZSYQ12).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthor\u0026rsquo;s contributions:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePlanning and conducting the study: Wei Su, Yun Wang, Haihan Xu, Ji-Yuan Zhang, Sheng-Li Lin, Ping-Hong Zhou. Collecting data: Hu Hao, Quan-Lin Li, Yun-Shi Zhong, Yi-Qun Zhang, Wei-Feng Chen. Analyzing and interpreting data: Yun Wang, Haihan Xu, Xi-Guo, Fang, Ji-Yuan Zhang. Drafting manuscript: Yun Wang, Sheng-Li Lin, Ping-Hong Zhou. Final approval of manuscript: all\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest:\u003c/strong\u003e The authors disclose no conflicts.\u0026nbsp;\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eShin, S., et al., \u003cem\u003eEnucleation of esophageal submucosal tumors: a single institution\u0026apos;s experience.\u003c/em\u003e Ann Thorac Surg, 2014. \u003cstrong\u003e97\u003c/strong\u003e(2): p. 454-9.\u003c/li\u003e\n\u003cli\u003eChen, T., et al., \u003cem\u003eLong-term Outcomes of Submucosal Tunneling Endoscopic Resection for Upper Gastrointestinal Submucosal Tumors.\u003c/em\u003e Ann Surg, 2017. \u003cstrong\u003e265\u003c/strong\u003e(2): p. 363-369.\u003c/li\u003e\n\u003cli\u003eZhai, Y.Q., et al., \u003cem\u003eEndoscopic submucosal excavation and endoscopic full-thickness resection for gastric schwannoma: five-year experience from a large tertiary center in China.\u003c/em\u003e Surg Endosc, 2020. \u003cstrong\u003e34\u003c/strong\u003e(11): p. 4943-4949.\u003c/li\u003e\n\u003cli\u003ePonte Neto, F.L., et al., \u003cem\u003eEndoscopic resection of esophageal and gastric submucosal tumors from the muscularis propria layer: submucosal tunneling endoscopic resection versus endoscopic submucosal excavation: A systematic review and meta-analysis.\u003c/em\u003e Surg Endosc, 2021. \u003cstrong\u003e35\u003c/strong\u003e(12): p. 6413-6426.\u003c/li\u003e\n\u003cli\u003eChen, T., et al., \u003cem\u003eSubmucosal Tunneling Endoscopic Resection vs Thoracoscopic Enucleation for Large Submucosal Tumors in the Esophagus and the Esophagogastric Junction.\u003c/em\u003e J Am Coll Surg, 2017. \u003cstrong\u003e225\u003c/strong\u003e(6): p. 806-816.\u003c/li\u003e\n\u003cli\u003eKolfschoten, N.E., et al., \u003cem\u003eFocusing on desired outcomes of care after colon cancer resections; hospital variations in \u0026apos;textbook outcome\u0026apos;.\u003c/em\u003e Eur J Surg Oncol, 2013. \u003cstrong\u003e39\u003c/strong\u003e(2): p. 156-63.\u003c/li\u003e\n\u003cli\u003eLu, J., et al., \u003cem\u003eEndoscopic management of upper gastrointestinal submucosal tumors arising from muscularis propria.\u003c/em\u003e J Clin Gastroenterol, 2014. \u003cstrong\u003e48\u003c/strong\u003e(8): p. 667-73.\u003c/li\u003e\n\u003cli\u003eJoensuu, H., \u003cem\u003eRisk stratification of patients diagnosed with gastrointestinal stromal tumor.\u003c/em\u003e Hum Pathol, 2008. \u003cstrong\u003e39\u003c/strong\u003e(10): p. 1411-9.\u003c/li\u003e\n\u003cli\u003eNishida, T., et al., \u003cem\u003eSubmucosal tumors: comprehensive guide for the diagnosis and therapy of gastrointestinal submucosal tumors.\u003c/em\u003e Dig Endosc, 2013. \u003cstrong\u003e25\u003c/strong\u003e(5): p. 479-89.\u003c/li\u003e\n\u003cli\u003eOnimaru, M., et al., \u003cem\u003eClinical outcomes of per-oral endoscopic tumor resection for submucosal tumors in the esophagus and gastric cardia.\u003c/em\u003e Dig Endosc, 2020. \u003cstrong\u003e32\u003c/strong\u003e(3): p. 328-336.\u003c/li\u003e\n\u003cli\u003eGong, W., et al., \u003cem\u003ePreliminary experience of endoscopic submucosal tunnel dissection for upper gastrointestinal submucosal tumors.\u003c/em\u003e Endoscopy, 2012. \u003cstrong\u003e44\u003c/strong\u003e(3): p. 231-5.\u003c/li\u003e\n\u003cli\u003eLv, X.H., C.H. Wang, and Y. Xie, \u003cem\u003eEfficacy and safety of submucosal tunneling endoscopic resection for upper gastrointestinal submucosal tumors: a systematic review and meta-analysis.\u003c/em\u003e Surg Endosc, 2017. \u003cstrong\u003e31\u003c/strong\u003e(1): p. 49-63.\u003c/li\u003e\n\u003cli\u003eTan, Y. and D. Liu, \u003cem\u003eEn bloc submucosal tunneling endoscopic resection for a giant esophageal leiomyoma.\u003c/em\u003e Gastrointest Endosc, 2015. \u003cstrong\u003e82\u003c/strong\u003e(2): p. 399.\u003c/li\u003e\n\u003cli\u003eMaydeo, A., et al., \u003cem\u003eSubmucosal tunneling and endoscopic resection of a large, esophageal leiomyoma.\u003c/em\u003e Gastrointest Endosc, 2015. \u003cstrong\u003e82\u003c/strong\u003e(5): p. 954.\u003c/li\u003e\n\u003cli\u003eKumbhari, V., et al., \u003cem\u003eSubmucosal tunneling endoscopic resection of a giant esophageal leiomyoma.\u003c/em\u003e Gastrointest Endosc, 2015. \u003cstrong\u003e81\u003c/strong\u003e(1): p. 219-20.\u003c/li\u003e\n\u003cli\u003eHu, S., et al., \u003cem\u003eGastrointestinal stromal tumors (GISTs) arising in uncommon locations: clinicopathologic features and risk assessment of esophageal, colonic, and appendiceal GISTs.\u003c/em\u003e Mod Pathol, 2022. \u003cstrong\u003e35\u003c/strong\u003e(4): p. 554-563.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"giant submucosal tumors, esophagus, cardia, STER, EFTR","lastPublishedDoi":"10.21203/rs.3.rs-6892379/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6892379/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground and Aims:\u003c/h2\u003e \u003cp\u003eEndoscopic resection for submucosal tumors (SMTs) in the esophagus and cardia is challenging with hazards of adverse events and the exploration of its achieving textbook outcome (TO) was unknown. We aim to investigate the predictors of TO for giant SMTs with a long diameter\u0026thinsp;\u0026ge;\u0026thinsp;7 cm, or a transverse diameter\u0026thinsp;\u0026ge;\u0026thinsp;3.5 cm.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA retrospective review was conducted for endoscopic resection of consecutive patients with giant SMTs in the esophagus and cardia between July 2017 and February 2022 at a tertiary referral center. TO was mainly defined as absences of major adverse events, piecemeal resection, and prolonged hospital stay. Clinicopathologic, procedural characteristics, adverse events, and follow-up outcomes were analyzed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 109 patients who completed endoscopic resection were analyzed. The median long and transverse diameter of the tumors were 7.5 cm (range, 4\u0026ndash;15 cm) and 4 cm (range, 1.5-7 cm), respectively. The \u003cem\u003een bloc\u003c/em\u003e resection rate was 78.9%. Transverse diameter\u0026thinsp;\u0026lt;\u0026thinsp;4.5 cm and regular shape were independent predictors for TO. Major adverse events (mAEs) occurred in 14 patients (12.8%). Long diameter\u0026thinsp;\u0026ge;\u0026thinsp;9 cm and piecemeal resection were significantly associated with mAEs. During a median follow-up of 33.5 months, there was no tumor recurrence or metastasis.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eGiant esophageal or cardia SMTs with a long diameter\u0026thinsp;\u0026lt;\u0026thinsp;9 cm and transverse diameter\u0026thinsp;\u0026lt;\u0026thinsp;4.5 cm indicated a safe and credible outcome for endoscopic resection.\u003c/p\u003e","manuscriptTitle":"Predictors for Achieving Textbook outcomes after endoscopic resection of giant submucosal tumors in the esophagus and cardia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-23 06:26:12","doi":"10.21203/rs.3.rs-6892379/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-07-14T23:38:24+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-14T16:37:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"296968492675223321190336976981688127926","date":"2025-06-30T02:40:13+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-24T20:21:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"80475470257085534914750027387785208328","date":"2025-06-20T14:09:35+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-18T13:29:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-17T23:56:08+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-14T08:02:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Digestive Diseases and Sciences","date":"2025-06-14T06:59:48+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"8abe0bac-8ed5-4d8e-8048-c9b65285ea66","owner":[],"postedDate":"June 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-08T16:00:23+00:00","versionOfRecord":{"articleIdentity":"rs-6892379","link":"https://doi.org/10.1007/s10620-025-09377-1","journal":{"identity":"digestive-diseases-and-sciences","isVorOnly":false,"title":"Digestive Diseases and Sciences"},"publishedOn":"2025-09-05 15:57:32","publishedOnDateReadable":"September 5th, 2025"},"versionCreatedAt":"2025-06-23 06:26:12","video":"","vorDoi":"10.1007/s10620-025-09377-1","vorDoiUrl":"https://doi.org/10.1007/s10620-025-09377-1","workflowStages":[]},"version":"v1","identity":"rs-6892379","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6892379","identity":"rs-6892379","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}