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Comparison of endoscopic full-thickness resection and cap-assisted endoscopic full-thickness resection in the treatment of small (≤1.5 cm) gastric GI stromal tumors

  • Author Footnotes
    ∗ Drs Yang, Ni, and Jiang contributed equally to this article.
    Jinping Yang
    Footnotes
    ∗ Drs Yang, Ni, and Jiang contributed equally to this article.
    Affiliations
    Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Jiangsu, China
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  • Author Footnotes
    ∗ Drs Yang, Ni, and Jiang contributed equally to this article.
    Muhan Ni
    Footnotes
    ∗ Drs Yang, Ni, and Jiang contributed equally to this article.
    Affiliations
    Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu, China
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  • Author Footnotes
    ∗ Drs Yang, Ni, and Jiang contributed equally to this article.
    Jingwei Jiang
    Footnotes
    ∗ Drs Yang, Ni, and Jiang contributed equally to this article.
    Affiliations
    Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu, China
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  • Ximei Ren
    Affiliations
    Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu, China
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  • Tingting Zhu
    Affiliations
    Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu, China
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  • Shouli Cao
    Affiliations
    Department of Gastroenterology, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Shandong, China
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  • Shahzeb Hassan
    Affiliations
    Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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  • Ying Lv
    Affiliations
    Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu, China
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  • Xiaoqi Zhang
    Affiliations
    Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu, China
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  • Yongyue Wei
    Correspondence
    Yongyue Wei, Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
    Affiliations
    Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
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  • Lei Wang
    Correspondence
    Lei Wang, The Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, Jiangsu, China.
    Affiliations
    Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu, China
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  • Guifang Xu
    Correspondence
    Reprint requests: Guifang Xu, 1 Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, No. 321 Zhongshan Road, Nanjing 210008, Jiangsu, China.
    Affiliations
    Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Jiangsu, China

    Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu, China
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  • Author Footnotes
    ∗ Drs Yang, Ni, and Jiang contributed equally to this article.
Open AccessPublished:November 01, 2021DOI:https://doi.org/10.1016/j.gie.2021.10.026

      Background and Aims

      With the increasing incidence of small GI stromal tumors (GISTs), endoscopic full-thickness resection (EFTR) and cap-assisted EFTR (EFTR-C) have been suggested as 2 effective resection methods. We aimed to compare the outcomes of EFTR and EFTR-C for the treatment of small (≤1.5 cm) gastric GISTs.

      Methods

      This retrospective study included 67 patients who underwent EFTR and 46 patients who underwent EFTR-C at Nanjing Drum Tower Hospital. Clinicopathologic features, adverse events (AEs), and outcomes were compared between the 2 groups. Univariate and multivariate linear and logistic regressions were used to analyze the effects of the procedure on the therapeutic outcomes of patients and adjusted for covariates in the multivariate analysis.

      Results

      The tumor size in the EFTR group tended to be larger (P = .005). The resection time in the EFTR-C group was shorter than that in the EFTR group (38.3 ± 20.7 minutes vs 15.0 ± 11.8 minutes, P < .001), which retained statistical significance with adjustment for the covariates (adjusted mean difference, 22.2; 95% confidence interval, 15.0-29.4; P < .001). The R0 resection rate of the EFTR group was 94.0% and of the EFTR-C group 97.8% (P = .355). The EFTR-C group was superior to the EFTR group in terms of perioperative therapeutic outcomes, AEs, and postoperative recovery. No recurrence occurred in the EFTR and EFTR-C groups.

      Conclusions

      EFTR-C was found to be the preferable technique for small (≤1.5 cm) gastric GISTs with shorter operation times, lower AEs, faster postoperative recovery, and shorter hospitalization times as compared with EFTR.

      Abbreviations:

      AE (adverse event), CI (confidence interval), EFTR (endoscopic full-thickness resection), EFTR-C (cap-assisted endoscopic full-thickness resection), FTRD (full-thickness resection device), GIST (GI stromal tumor), WBC (white blood cell)
      GI stromal tumor (GIST) is the most common mesenchymal tumor of the GI tract and can be benign or malignant in biologic behavior.
      • Li J.
      • Ye Y.
      • Wang J.
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      Chinese consensus guidelines for diagnosis and management of gastrointestinal stromal tumor.
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      Comparative clinical features and short-term outcomes of gastric and small intestinal gastrointestinal stromal tumours: a retrospective study.
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      • Bumming P.
      • Meis-Kindblom J.M.
      • et al.
      Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden.
      GISTs with a diameter <2 cm are defined as small GISTs. Small GISTs with high incidence are usually asymptomatic and typically found incidentally. Kawanowa et al
      • Kawanowa K.
      • Sakuma Y.
      • Sakurai S.
      • et al.
      High incidence of microscopic gastrointestinal stromal tumors in the stomach.
      reported that among 100 patients with gastric cancer who underwent total gastrectomy, up to 35% had small GISTs. Miettinen et al
      • Miettinen M.
      • Sobin L.H.
      • Lasota J.
      Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up.
      found that of all GISTs they examined, 40.6% (717/1765) were small GISTs. Although most small GISTs are clinically benign or inert, those with high mitotic counts may exhibit aggressive behavior.
      • Coe T.M.
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      Population-based epidemiology and mortality of small malignant gastrointestinal stromal tumors in the USA.
      ,
      • Pang T.
      • Zhao Y.
      • Fan T.
      • et al.
      Comparison of safety and outcomes between endoscopic and surgical resections of small (</= 5 cm) primary gastric gastrointestinal stromal tumors.
      The latest guidelines have no consensus on the treatment of GISTs with a diameter <2 cm.
      • Li J.
      • Ye Y.
      • Wang J.
      • et al.
      Chinese consensus guidelines for diagnosis and management of gastrointestinal stromal tumor.
      ,
      • Demetri G.D.
      • von Mehren M.
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      NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors.
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      • Casali P.G.
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      • et al.
      Gastrointestinal stromal tumours: ESMO-EURACAN clinical practice guidelines for diagnosis, treatment and follow-up.
      The Chinese Society of Clinical Oncology (CSCO)
      • Li J.
      • Ye Y.
      • Wang J.
      • et al.
      Chinese consensus guidelines for diagnosis and management of gastrointestinal stromal tumor.
      and National Comprehensive Cancer Network (NCCN)
      • Demetri G.D.
      • von Mehren M.
      • Antonescu C.R.
      • et al.
      NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors.
      indicate that complete surgical resection is the main treatment for symptomatic or asymptomatic patients with high-risk EUS features. For patients with GISTs (<2 cm) and without high-risk EUS features, endoscopic monitoring can be considered every 6 to 12 months. European Society for Medical Oncology (ESMO)
      • Casali P.G.
      • Abecassis N.
      • Aro H.T.
      • et al.
      Gastrointestinal stromal tumours: ESMO-EURACAN clinical practice guidelines for diagnosis, treatment and follow-up.
      recommends that small GISTs should be resected once diagnosed.
      Considering the high cost of long-term monitoring of patients with small GISTs and the risk of enlargement and metastasis, some experts believe that a small GIST should be treated with surgery or endoscopic treatment once identified under endoscopy.
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      • Sun C.
      • Wang J.
      • et al.
      Efficacy and safety of endoscopic submucosal dissection in treating gastric subepithelial tumors originating in the muscularis propria layer: a single-center study of 144 cases.
      Laparoscopic surgery and traditional surgery are still the standard for the treatment of GISTs.
      • Wakamatsu K.
      • Lo M.E.
      • Szomstein S.
      • et al.
      Feasibility of laparoscopic resection of gastrointestinal stromal tumor of the stomach.
      With the development of endoscopic technology and the improvement of equipment technology, endoscopic resection is widely used to remove GISTs <5 cm.
      • Marcella C.
      • Sarwar S.
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      • et al.
      Efficacy and safety of endoscopic treatment for gastrointestinal stromal tumors in the upper gastrointestinal tract.
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      • et al.
      Endoscopic resection of gastric gastrointestinal stromal tumors.
      Compared with surgical operation, endoscopic treatment has the advantages of being minimally invasive, permitting shorter hospital stays, and having lower costs. Therefore, endoscopic resection could be an attractive alternative treatment for patients with small GISTs.
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      Endoscopic submucosal dissection for treatment of gastric subepithelial tumors (with video).
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      • Kim H.
      • et al.
      Endoscopic versus surgical resection of GI stromal tumors in the upper GI tract.
      Endoscopic full-thickness resection (EFTR) has been used to resect GISTs that grow outside the cavity and/or close to the serous membrane. Many studies have shown that EFTR is a relatively safe, easy, and feasible method for removing GISTs originating from the muscularis propria.
      • Schlag C.
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      • et al.
      Endoscopic full-thickness resection with defect closure using an over-the-scope clip for gastric subepithelial tumors originating from the muscularis propria.
      Cap-assisted EFTR (EFTR-C) is an improved method to remove the tumor quickly and completely, with few adverse events (AEs) and associated perforations that are easy to repair under endoscopy. Compared with other endoscopic treatment methods, EFTR-C is less time-consuming, easy to manage postoperatively, and does not require special endoscopic equipment.
      • Tada M.
      • Inoue H.
      • Yabata E.
      • et al.
      Feasibility of the transparent cap-fitted colonoscope for screening and mucosal resection.
      • Yang D.H.
      • Park Y.
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      • et al.
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      • Dan X.
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      Efficacy and safety of multiband mucosectomy versus cap-assisted endoscopic resection for early esophageal cancer and precancerous lesions: a systematic review and meta-analysis.
      Nonetheless, the safety, effectiveness, and feasibility of EFTR and EFTR-C remain controversial. For the treatment of small gastric GISTs, it is not clear whether EFTR-C has significant advantages over traditional EFTR. This study aimed to compare the outcomes of EFTR and EFTR-C to elucidate any potential advantages of either method for the treatment of small gastric GISTs.

      Methods

      Study population

      Inclusion criteria were patients diagnosed with GIST by histopathologic evaluation, lesion location in the stomach, use of EFTR or EFTR-C as an operative method, and no age or sex limitations. Exclusion criteria were localized GIST with a pathologic maximum diameter >1.5 cm, presence of distant metastasis, presence of other malignant tumors or multiple-organ failure, severe mental disorders and uncooperative patients, coagulation dysfunction or combined bleeding disorders, surgery failures, and incomplete data. Following these criteria, we retrospectively analyzed cases of GISTs diagnosed at the Nanjing Drum Tower Hospital affiliated with Nanjing University Medical School from May 2012 to January 2020.
      One hundred thirteen patients were recruited into this study. Patients were then classified according to the method of endoscopic resection: 67 in the EFTR group and 46 in the EFTR-C group (Fig. 1). All patients who underwent endoscopic resection were evaluated before the operation with a medical history review, laboratory examination, CT, electrocardiography, endoscopy, and EUS. For tumor characteristics, we evaluated the size, growth pattern, level of origin, location, internal echocardiogram, and presence or absence of distant metastasis. Preoperatively, patients who underwent endoscopic resection were told to avoid taking aspirin or other anticoagulants 1 week before the surgery.
      Figure thumbnail gr1
      Figure 1Flowchart for patient selection and grouping. GIST, GI stromal tumor; EFR, endoscopic full-thickness resection; EFR-C, cap-assisted endoscopic full-thickness resection.
      All patients signed an informed consent form for the operation and were informed of the risks associated with the operation. The Medical Ethics Committee of Nanjing Drum Tower Hospital approved this retrospective cohort study.

      Endoscopic full-thickness resection

      All EFTR procedures were conducted by tracheal intubation with the patient under general anesthesia, and vital signs were continuously monitored throughout the process. Carbon dioxide insufflators were used in all operations. All procedures were performed by experienced endoscopists. A dual knife (KD-650 L; Olympus Optical Co Ltd, Tokyo, Japan) was used to determine the lesion area, and a mixture of .9% saline solution containing epinephrine (1:10,000) and indigo carmine dye was injected into the submucosal layer of the lesion area. Initially, the dual knife made a circumferential incision at the lesion. Subsequently, an insulated-tip knife (KD-610 L; Olympus Optical Co Ltd) was used to peel off the submucosa piece by piece. Then, the dual knife was used to dissect the GIST from the muscularis propria to the serous membrane; the serous membrane was cut along the edge of the tumor with an insulated-tip knife, resulting in an “artificial perforation.” After the tumor was completely resected, suction was used to suck part of the tumor into the cap, and the tumor was removed with an endoscope. The endoscope was placed into the stomach cavity again to carefully observe whether there was bleeding from the wound. If there was bleeding, the bleeding was stopped with hot forceps. Then, the wound was sealed with titanium clips (Fig. 2).
      Figure thumbnail gr2
      Figure 2A-F, Representative images of endoscopic full-thickness resection for small gastric GI stromal tumors. G, Hematoxylin and eosin staining (orig. mag. ×40). H, Immunohistochemistry showed that CD117 was present in most tumor cells (orig. mag. ×40).

      Cap-assisted EFTR

      All patients underwent intubation and resection under propofol anesthesia. A transparent cap (D-206-05; Olympus) was installed at the front end of the Q26OJ endoscope, and a snare (SD-221U-25; Olympus) was placed in the transparent cap. This helped with targeting the lesion and attracting the lesion into the transparent cap. Specifically, the snare tightened the base of the lesion, and the lesion was subsequently excised by high frequency. The tumor, including the muscularis propria and serosal layers, was resected, and perforation of the stomach wall was visible. After the tumor was completely resected, suction was used to suck part of the tumor into the cap, and the tumor was removed with an endoscope. The endoscope was placed into the stomach cavity again to carefully observe whether there was bleeding from the wound. If there was bleeding, the bleeding was stopped with hot forceps. Then, the wound was sealed with titanium clips (Fig. 3).
      Figure thumbnail gr3
      Figure 3A-F, Representative images of cap-assisted endoscopic full-thickness resection for small gastric GI stromal tumors. G, Hematoxylin and eosin staining (orig. mag. ×40). H, Immunohistochemistry showed that CD117 was present in most tumor cells (orig. mag. ×40).

      Pathology assessment

      Specimens were fixed with formalin, blocked with paraffin, and subsequently sectioned. The location, size, surgical margin, mitosis, and depth of the tumors were appropriately recorded. Using the 2008 National Institutes of Health classification, we based risk assessment on the size, location and number of mitoses per 50 high-power field.
      • Joensuu H.
      Risk stratification of patients diagnosed with gastrointestinal stromal tumor.
      When the tumor was resected en bloc and the lateral and basal edges of the tumor were free, the tumor was considered to be completely removed.
      • Shi Q.
      • Zhong Y.S.
      • Yao L.Q.
      • et al.
      Endoscopic submucosal dissection for treatment of esophageal submucosal tumors originating from the muscularis propria layer.
      Immunohistochemical staining was used to distinguish GISTs from other stromal tumors. CD117 and DOG-1 are sensitive indicators for the diagnosis of GISTs, whereas the high positive expression rate of CD34 can also be used as a diagnostic marker. Although the positive expression rate of SMA, DES, S-100, and so on are low, these markers can help in making the diagnosis when there is negative expression of DOG-1 and CD117.

      Outcome measures and AEs

      Operation time was defined as the time from entering the endoscope to exiting the endoscope. Resection time was defined as the time from the start of the submucosal injection to complete closure of the defect. En-bloc resection was defined as complete removal of the tumor fiber capsule, with no tumor remaining under endoscopy. Active bleeding was identified when the intraoperative visual field was affected, surgical treatment was required, and hemoglobin was significantly decreased (>2 mg/dL). Pneumoperitoneum was identified when liver dullness disappeared and/or in the absence of drum sounds after the operation. Delayed bleeding was defined as active bleeding from postoperative ulcers. Peritonitis was described as the presence of symptoms of tenderness, rebound pain, and peritoneal tension when combined with the abdominal CT examinations of patients. Preoperative white blood cell (WBC) counts and neutrophil percentages were measured on the second morning of admission. Postoperative WBC counts and neutrophil percentages were measured 24 hours after the procedure. Postoperative temperature was taken within 24 hours after the procedure, and fever was defined as a body temperature greater than 37.3°C. The time to first liquid diet was the time from endoscopic removal to liquid food. The postoperative length of hospital stay was defined as the period from resection to discharge. Survival time was defined as the date of operation to the date of follow-up.

      Postoperation follow-up

      All patients underwent telephone follow-up at 1 month after endoscopic treatment. In the first year after the initial procedure, all patients underwent standard endoscopic re-examinations at 3, 6, and 12 months after the procedure to assess whether there was any residual tumor or recurrence. Within 3 years thereafter, endoscopic surveillance was limited to once a year. It was also recommended to assess distant metastasis by abdominal CT every year. Furthermore, moderate- or high-risk patients were recommended to take imatinib and undergo endoscopic monitoring.

      Statistical analysis

      Data were analyzed using SPSS version 23.0 software (Chicago, Ill, USA). Continuous variables are summarized by mean ± standard deviation and were compared using a t test between groups. Categorical variables are summarized by frequency and percentage and were compared using the χ2 test or the Fisher exact test. Linear or logistic regression was used to analyze the effect of EFTR-C versus EFTR on therapeutic outcomes without or with adjustment for covariates; the results from the regression model were reported as b and 95% confidence interval (CI) for continuous outcomes and as odds ratio and 95% CI for binary outcomes. The baseline covariates with P < .1 in the comparison between EFTR-C and EFTR were selected as potential confounders and adjusted in the regression models. Univariate and multivariate linear regression models were used to further investigate the association between procedure method and operation time with adjustment for potential confounding variables. The confounders in model I were selected based on their associations with the outcomes of a change in effect estimate of more than 10%. The model II confounders included all demographics and clinicopathologic characteristics. A P < .05 was considered statistically significant, unless otherwise stated.

      Results

      Comparison of demographics and clinicopathologic characteristics

      One hundred thirteen patients were included in the study, of which 63 (55.8%) were men. EFTR and EFTR-C were performed on 67 and 46 patients with small gastric GISTs, respectively. Mean patient age was 57.7 ± 9.9 years (range, 26-78). There was no significant difference in sex, age, preoperative WBC count, preoperative neutrophil percentage, mitotic count, or concomitant diseases between the EFTR and EFTR-C groups.
      The gastric location of the tumors for both groups was as follows: fundus (76.1%), corpus (14.2%), antrum (6.2%), and cardiac (3.5%). We used preoperative EUS to determine that 108 tumors originated from the muscularis propria (95.6%) and 5 tumors originated from the submucosa (4.4%). Between the 2 groups, the tumor growth pattern of 92 patients showed intraluminal growth (81.4%), 9 patients showed extraluminal growth (8.0%), and 12 patients showed intraluminal and extraluminal growth (10.6%). Overall, 112 patients (99.1%) were of very low risk and 1 (.9%) was of high risk, according to the 2008 National Institutes of Health classification. However, mean tumor size, as measured under microscopy, was larger in the EFTR group (1.1 ± .3 cm; range, .3-1.5) compared with the EFTR-C group (.9 ± .4 cm; range, .2-1.5 cm; P = .005).
      Median follow-up time was 38.9 ± 28.1 months (range, 4-96) in the EFTR-C group and 31.3 ± 25.5 months (range, 6-86) in the EFTR group. Follow-up results showed no recurrence or metastasis, and only 1 patient died of lymphoma (Table 1).
      Table 1Comparison of demographics and clinicopathologic characteristics
      All (n = 113)Endoscopic full-thickness resection (n = 67)Cap-assisted endoscopic full-thickness resection (n = 46)P value
      Sex.803
       Male50 (44.2)29 (43.3)21 (45.7)
       Female63 (55.8)38 (56.7)25 (54.3)
      Age, y57.7 ± 9.958.6 ± 9.856.4 ± 10.0.255
      Hypertension24 (21.2)16 (23.9)8 (17.4).407
      Diabetes5 (4.4)3 (4.5)2 (4.3).974
      Preoperative white blood cell count, 109/L4.9 ± 1.34.9 ± 1.34.9 ± 1.3.607
      Preoperative neutrophil percentage54.6 ± 8.255.3 ± 8.353.7 ± 8.1.213
      Location.489
       Cardiac4 (3.5)2 (3.0)2 (4.3)
       Fundus86 (76.1)49 (73.1)37 (80.4)
       Corpus16 (14.2)10 (14.9)6 (13.0)
       Antrum7 (6.2)6 (9.0)1 (2.2)
      Layer of origin n.006
       Submucosa5 (4.4)05 (10.9)
       Muscularis propria108 (95.6)67 (100.0)41 (89.1)
      Tumor growth pattern.936
       Intraluminal growth92 (81.4)54 (80.6)38 (82.6)
       Extraluminal growth9 (8.0)6 (9.0)3 (6.5)
       Intraluminal and extraluminal growth12 (10.6)7 (10.4)5 (10.9)
      Size under microscopy, cm1.0 ± .31.1 ± .3.9 ± .4.005
      Mitotic count, no. per 50 high-power fields1.8 ± 1.72.0 ± 1.91.6 ± 1.4.457
      National Institutes of Health risk category
       Very low risk112 (99.1)66 (98.5)46 (100.0)
       High risk1 (.9)1(1.5)0
      Survival outcome112 (99.1)67(100. 0)45(97. 8)
      Follow-up time, mo35.8 ± 27.238.9 ± 28.131.3 ± 25.5.148
      Values are n (%) or mean ± standard deviation.

      Comparison of intraoperative therapeutic outcomes

      Intraoperative outcomes are shown in Table 2. The en-bloc resection rate of the 2 groups was 100%. No significant differences were observed in the pneumoperitoneum and suture methods (P > .05). The R0 resection rate of the EFTR group was 94.0% and of the EFTR-C group 97.8% (P = .355). Five patients were found to have incomplete resection under microscopy, 4 from the EFTR group and 1 from the EFTR-C group. They all had the microscopic presence of tumor cells at the resection margins. Most defects (109) were closed by titanium clip, with only 4 closed by purse-string suture. The number of titanium clips for sutures was significantly lower in the EFTR-C group (5.0 ± 2.0) than in the EFTR group (6.4 ± 2.8; P = .004). The incidence rate of using a heat clamp to stop bleeding was significantly lower in the EFTR-C group (10.9%) than in the EFTR group (65.7%; P < .001) (Fig. 4B). No lesion had tumor rupture, active bleeding, or surgical intervention. Moreover, the incidence of pneumoperitoneum was 13.4% in the EFTR group and 6.5% in the EFTR-C group.
      Table 2Comparison of intraoperative therapeutic outcomes


      Outcome
      SummaryUnivariateCovariates adjusted
      EstimatesP valueEstimatesP value
      Operation time, minMean ± SDb (95% CI)b (95% CI)
       EFTR55.5 ± 25.4Ref.Ref.
       EFTR-C41.0 ± 16.6–14.5 (–22.9 to –6.2)<.001–11.8 (–20.8 to –2.7).012
      Resection time, minMean ± SDb (95% CI)b (95% CI)
       EFTR38.3 ± 20.7Ref.Ref.
       EFTR-C15.0 ± 11.8–23.3 (–29.9 to –16.6)<.001–22.2 (–29.4 to –15.0)<.001
      Tumor rupture0
      Suture with titanium clipn (%)
       EFTR63 (94.0)
       EFTR-C46 (100.0)
      No. of titanium clips for sutureMean ± SDb (95% CI)b (95% CI)
       EFTR6.4 ± 2.8Ref.Ref.
       EFTR-C5.0 ± 2.0–1.4 (–2.4 to –.5).004–1.3 (–2.3 to –.2).019
      Active bleeding0
      Pneumoperitoneumn (%)OR (95% CI)OR (95% CI)
       EFTR9 (13.4)Ref.Ref.
       EFTR-C3 (6.5).4 (.1-1.8).251.4 (.1-1.9).261
      Heat clamp to stop bleedingn (%)OR (95% CI)OR (95% CI)
       EFTR44 (65.7)Ref.Ref.
       EFTR-C5 (10.9).1 (.0-.2)<.001.1 (.0-.2)<.001
      R1 resectionn (%)OR (95% CI)OR (95% CI)
       EFTR4 (6.0)Ref.Ref.
       EFTR-C1 (2.2).4 (.0-3.2).355.2 (.0-1.8).140
      Adjusted for layer of origin and size under microscopy. b represents the adjusted mean difference between EFTR and EFTR-C.
      OR, Odds ratio; CI, confidence interval; EFTR, endoscopic full-thickness resection; EFTR-C, cap-assisted endoscopic full-thickness resection; SD, standard deviation.
      Figure thumbnail gr4
      Figure 4A, Kaplan-Meier curves were used to illustrate time to resection completion and compare the time to resection completion between cap-assisted endoscopic full-thickness resection and endoscopic full-thickness resection. B, Comparison of using a heat clamp to stop bleeding according to procedure method. EFR, Endoscopic full-thickness resection; EFR-C, cap-assisted endoscopic full-thickness resection.
      The operation time was significantly longer in the EFTR group as compared with that in the EFTR-C group (55.5 ± 25.4 minutes vs 41.0 ± 16.6 minutes; b = 14.5; 95% CI, 6.2-22.9; P < .001). The resection time was also significantly shorter in the EFTR-C group as compared with that in the EFTR group (38.3 ± 20.7 minutes vs. 15.0 ± 11.8 minutes; b = 3.3; 95% CI, 16.6-29.9; P < .001) (Fig. 4A). After adjusting for layer of origin and size under microscopy, the differences in operation time (b = 11.8; 95% CI, 2.7-20.8; P = .012) and resection time (b = 22.2; 95% CI, 15.0-29.4; P < .001) between the 2 groups retained statistical significance.
      Sensitivity analyses for the model retained statistical significance for EFTR-C versus EFTR with resection time by adjusting for baseline variables, including sex, tumor growth pattern, size under microscopy, layer of origin, heat clamp to stop bleeding, suture method, and number of titanium clips in sutures (b = 19.5; 95% CI, 11.4-27.6; P < .001) (Supplementary Table 1, available online at www.giejournal.org) or with additional adjustment for age, hypertension, diabetes, location, and mitotic count (b = 19.7; 95% CI, 11.3-28.0; P < .001) (Supplementary Table 2, available online at www.giejournal.org).

      Comparison of postoperative AEs

      The postoperative WBC counts and neutrophil percentages were 6.3 ± 1.7 and 69.7 ± 9.3 in the EFTR-C group, respectively, which were significantly lower than those in the EFTR group (WBC count, 8.6 ± 3.3; neutrophil percentage, 78.5 ± 7.7; P < .001). The postoperative fever rate was significantly lower in the EFTR-C group (13.0%) than in the EFTR group (58.2%; P < .001). With adjustment for layer of origin and size under microscopy, they were still significantly different between the 2 groups (Table 3). In addition, no patient had delayed bleeding, and only 1 patient in the EFTR group encountered peritonitis without surgical intervention.
      Table 3Comparison of postoperative adverse events


      Outcome
      SummaryUnivariateCovariates adjusted
      EstimatesP valueEstimatesP value
      Postoperative white blood cell count, 109/LMean ± SDb (95% CI)b (95% CI)
       EFTR8.6 ± 3.3Ref.Ref.
       EFTR-C6.3 ± 1.7–2.3 (–3.3 to –1.2)<.001–2.1 (–3.3 to –1.0)<.001
      Postoperative neutrophil percentageMean ± SDb (95% CI)b (95% CI)
       EFTR78.5 ± 7.7Ref.Ref.
       EFTR-C69.7 ± 9.3–8.8 (–11.9 to –5.6)<.001–8.0 (–11.4 to –4.6)<.001
      Antibioticsn (%)OR (95% CI)OR (95% CI)
       EFTR51 (76.1)Ref.Ref.
       EFTR-C12 (26.1).1 (.0-.3)<.001.1 (.1-.3)<.001
      Postoperative antibiotic, daysMean ± SDb (95% CI)b (95% CI)
       EFTR3.0 ± 2.5Ref.Ref.
       EFTR-C.9 ± 1.7–2.2 (–3.0 to –1.3)<.001–1.9 (–2.8 to –1.0)<.001
      Postoperative fevern (%)OR (95% CI)OR (95% CI)
       EFTR39 (58.2)Ref.Ref.
       EFTR-C6 (13.0).1 (.0-.3)<.001.1 (.0-.3)<.001
      Delayed bleeding0
      Peritonitisn (%)
       EFTR1 (2.3)
       EFTR-C0
      Adjusted for layer of origin and size under microscopy. b represents the adjusted mean difference between EFTR and EFTR-C.
      OR, Odds ratio; CI, confidence interval; SD, standard deviation; EFTR, endoscopic full-thickness resection; EFTR-C, cap-assisted endoscopic full-thickness resection; —, .

      Comparison of hospital postoperative recovery

      As shown in Table 4, the time to first liquid diet in the EFTR-C group (1.7 ± 1.1 days) was significantly shorter than that in the EFTR group (2.4 ± 1.5 days; P < .001). The postoperative length of hospital stay (EFTR-C vs EFTR, 2.9 ± 1.5 vs 4.1 ± 1.9 days; P < .001) and total days spent in the hospital (EFTR-C vs EFTR, 5.8 ± 2.0 vs 7.4 ± 2.3; P < .001) in the EFTR-C group were also shorter than those in the EFTR group. The differences remained statistically significant after adjusting for the layer of origin and size under microscopy.
      Table 4Comparison of hospital postoperative recovery


      Outcome
      SummaryUnivariateCovariates adjusted
      EstimatesP valueEstimatesP value
      Time to first liquid diet, daysMean ± SDb (95% CI)b (95% CI)
       EFTR2.4 ± 1.5Ref.Ref.
       EFTR-C1.7 ± 1.1–.7 (–1.2 to –.2).005–.6 (–1.1 to –.0).037
      Postoperative length of hospital stay, daysMean ± SDb (95% CI)b (95% CI)
       EFTR4.1 ± 1.9Ref.Ref.
       EFTR-C2.9 ± 1.5–1.1 (–1.8 to –.5)<.001–1.1 (–1.8 to –.3).004
      Total days in hospitalMean ± SDb (95% CI)b (95% CI)
       EFTR7.4 ± 2.3Ref.Ref.
       EFTR-C5.8 ± 2.0–1.6 (–2.4 to –.7)<.001–1.5 (–2.4 to –.6).001
      Adjusted for layer of origin and size under microscopy. b represents the adjusted mean difference between EFTR and EFTR-C.
      OR, Odds ratio; CI, confidence interval; SD, standard deviation; EFTR, endoscopic full-thickness resection; EFTR-C, cap-assisted endoscopic full-thickness resection; —, .

      Discussion

      The safety of endoscopic methods, including endoscopic submucosal dissection, endoscopic submucosal excavation, EFTR, and submucosal tunneling endoscopic resection, for the treatment of small GISTs has previously been confirmed. Among these, EFTR is more suitable to resect small GISTs when the tumor originates from the muscularis propria.
      • Park J.J.
      Long-term outcomes after endoscopic treatment of gastric gastrointestinal stromal tumor.
      • Ye L.P.
      • Zhang Y.
      • Luo D.H.
      • et al.
      Safety of endoscopic resection for upper gastrointestinal subepithelial tumors originating from the muscularis propria layer: an analysis of 733 tumors.
      • Bialek A.
      • Wiechowska-Kozlowska A.
      • Pertkiewicz J.
      • et al.
      Endoscopic submucosal dissection for treatment of gastric subepithelial tumors (with video).
      • Joo M.K.
      • Park J.J.
      • Kim H.
      • et al.
      Endoscopic versus surgical resection of GI stromal tumors in the upper GI tract.
      In recent years EFTR-C has been popularized and used on a large scale; however, no studies have yet focused on comparing the differences between EFTR and EFTR-C.
      In this study, we found that both EFTR and EFTR-C achieved a high histologic complete resection rate and were safe for treating small gastric GISTs. However, the operation time and resection time were markedly shorter in the EFTR-C group than in the EFTR group. Of note, we used linear regression analysis to further clarify the association between the procedure method and resection time. Additionally, EFTR is a derivative technology of endoscopic submucosal dissection (the most common AEs of endoscopic operations are perforation and bleeding).
      • Schurr M.O.
      • Baur F.
      • Ho C.N.
      • et al.
      Endoluminal full-thickness resection of GI lesions: a new device and technique.
      ,
      • Schurr M.O.
      • Baur F.E.
      • Krautwald M.
      • et al.
      Endoscopic full-thickness resection and clip defect closure in the colon with the new FTRD system: experimental study.
      Gastric GISTs are mostly located in the fundus of the stomach, which is rich in vascular networks. The EFTR procedure is more complex, so the incidence rate of using a heat clamp to stop bleeding was significantly higher in the EFTR group (EFTR vs EFTR-C, 65.7% vs 10.9%; P < .001). Considering that EFTR uses a dual knife to peel off the lesions, during the dissection process, the separated blood vessels need to be pretreated to avoid bleeding with a heat clamp. Active bleeding sites can also be controlled with a heat clamp. The wound was larger in the EFTR group, so bleeding was more common than in the EFTR-C group during the operation. As previously reported, EFTR and EFTR-C can easily perforate the digestive tract during surgery.
      • Guo J.
      • Liu Z.
      • Sun S.
      • et al.
      Endoscopic full-thickness resection with defect closure using an over-the-scope clip for gastric subepithelial tumors originating from the muscularis propria.
      ,
      • von Renteln D.
      • Rösch T.
      • Kratt T.
      • et al.
      Endoscopic full-thickness resection of submucosal gastric tumors.
      ,
      • Huang L.Y.
      • Cui J.
      • Wu C.R.
      • et al.
      Endoscopic full-thickness resection and laparoscopic surgery for treatment of gastric stromal tumors.
      All lesions in this study underwent iatrogenic perforation to achieve an R0 resection rate, but the perforated wound could easily be visualized and repaired endoscopically with titanium clips without an increase in serious procedure-related AEs. Most published studies also confirmed that iatrogenic perforations can be successfully managed by endoscopic methods.
      • Shi Q.
      • Chen T.
      • Zhong Y.S.
      • et al.
      Complete closure of large gastric defects after endoscopic full-thickness resection, using endoloop and metallic clip interrupted suture.
      • Qiao Z.
      • Ling X.
      • Zhu J.
      • et al.
      Therapeutic application of purse-string sutures with nylon loops and metal clips under single-channel endoscopy for repair of gastrointestinal wall defects.
      • Kobara H.
      • Mori H.
      • Nishiyama N.
      • et al.
      Over-the-scope clip system: a review of 1517 cases over 9 years.
      • Kato M.
      • Takeuchi Y.
      • Yamasaki Y.
      • et al.
      Technical feasibility of line-assisted complete closure technique for large mucosal defects after colorectal endoscopic submucosal dissection.
      • Tian X.
      • Shi B.
      • Chen W.Q.
      Modified endoscopic full-thickness resection of gastric stromal tumor originating from the muscularis propria layer.
      Our previous studies demonstrated that the endoscopic treatment, including EFTR, of gastric GISTs (≤5 cm) was safe and cost-effective, along with having advantages of better perioperative outcomes and lower costs compared with laparoscopic or surgical resection.
      • Pang T.
      • Zhao Y.
      • Fan T.
      • et al.
      Comparison of safety and outcomes between endoscopic and surgical resections of small (</= 5 cm) primary gastric gastrointestinal stromal tumors.
      ,
      • Zhao Y.
      • Pang T.
      • Zhang B.
      • et al.
      retrospective comparison of endoscopic full-thickness versus laparoscopic or surgical resection of small (</= 5 cm) gastric gastrointestinal stromal tumors.
      Nonetheless, research comparing the outcomes of EFTR and EFTR-C is sparse. We used postoperative fever, postoperative WBC count, and postoperative neutrophil percentage as indicators of postoperative inflammation. Data from our center showed that the incidence of postoperative inflammation in the EFTR-C group was significantly lower than that in the EFTR group. Moreover, no serious AEs, such as GI bleeding or abdominal abscess, were found. Only 1 patient had peritonitis in the EFTR group, which resolved without surgical intervention. The perioperative AEs of endoscopic treatment were all controllable because our lesions were all small. Importantly, the EFTR-C group showed a significant advantage over the EFTR group in terms of total days spent in hospital. There were also significant differences in postoperative recovery between the 2 groups according to our research results. In summary, both EFTR and EFTR-C were relatively safe in terms of perioperative outcomes. Nevertheless, the EFTR-C group was superior to the EFTR group in terms of operation time, resection time, postoperative recovery, and reduced incidence rate of heat clamp hemostasis.
      The median follow-up time was 35.8 ± 27.2 months in all patients. There was no recurrence, metastasis, or death from GISTs, including 5 cases with an R1 resection. This finding is similar to previous studies.
      • Pang T.
      • Zhao Y.
      • Fan T.
      • et al.
      Comparison of safety and outcomes between endoscopic and surgical resections of small (</= 5 cm) primary gastric gastrointestinal stromal tumors.
      ,
      • Zhao Y.
      • Pang T.
      • Zhang B.
      • et al.
      retrospective comparison of endoscopic full-thickness versus laparoscopic or surgical resection of small (</= 5 cm) gastric gastrointestinal stromal tumors.
      ,
      • Dematteo R.P.
      • Lewis J.J.
      • Leung D.
      • et al.
      Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival.
      Currently, there is insufficient evidence that the R1 resection rate is related to worse overall survival for low-risk GISTs.
      • Demetri G.D.
      • von Mehren M.
      • Antonescu C.R.
      • et al.
      NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors.
      Pang et al
      • Pang T.
      • Zhao Y.
      • Fan T.
      • et al.
      Comparison of safety and outcomes between endoscopic and surgical resections of small (</= 5 cm) primary gastric gastrointestinal stromal tumors.
      suggested that reoperation may not be needed if a low-risk GIST is completely removed with endoscopy, including tumors with an R1 resection. Therefore, we recommended that patients with an R1 resection should be monitored closely under endoscopy and CT. No recurrence or metastasis was observed during the follow-up period. However, considering the slow progression of small gastric GISTs, long-term follow-up data with a large number of cases are necessary to further confirm the safety and effectiveness of EFTR and EFTR-C.
      This study showed that EFTR-C was the preferable technique for small (≤1.5 cm) gastric GISTs compared with EFTR. However, in our center EFTR-C is limited in that it is only suitable for small (≤1.5 cm) gastric GISTs because of size of the transparent cap. Gastric GISTs mostly originate in the muscularis propria (not only the lesion but also the serosal layer should be sucked into the cap). We considered that the maximal size of the lesion should be smaller than the diameter of the cap to achieve an R0 resection rate with EFTR-C. Many similar studies have reported that the maximum tumor size to resect is limited by the transparent cap.
      • Yang D.H.
      • Park Y.
      • Park S.H.
      • et al.
      Cap-assisted EMR for rectal neuroendocrine tumors: comparisons with conventional EMR and endoscopic submucosal dissection (with videos).
      ,
      • Mahadev S.
      • Vareedayah A.A.
      • Yuen S.
      • et al.
      Outcomes of a hybrid technique using EMR and endoscopic full-thickness resection for polyps not amenable to standard techniques (with video).
      According to clinical practice in our center, EFTR-C en-bloc resection may not be achieved if the maximum diameter of the tumor is >1.5 cm. With the endoscopic technology of EFTR, the diameter of GISTs has increased continuously by endoscopic resection.
      • Pang T.
      • Zhao Y.
      • Fan T.
      • et al.
      Comparison of safety and outcomes between endoscopic and surgical resections of small (</= 5 cm) primary gastric gastrointestinal stromal tumors.
      ,
      • Zhao Y.
      • Pang T.
      • Zhang B.
      • et al.
      retrospective comparison of endoscopic full-thickness versus laparoscopic or surgical resection of small (</= 5 cm) gastric gastrointestinal stromal tumors.
      The treatment of small GISTs is also controversial, as questions remain regarding whether small GISTs (<2 cm) need to be treated. However, with the popularity of endoscopy, an increasing number of small GISTs have been accidentally discovered. Frequent endoscopic monitoring, histologic specifications, or the possibility of tumor growth can become burdensome for patients. Some guidelines suggest resection, even for small GISTs, because the potential for progression and metastasis is great.
      • Blackstein M.E.
      • Blay J.Y.
      • Corless C.
      • et al.
      Gastrointestinal stromal tumours: consensus statement on diagnosis and treatment.
      In clinical practice, patients often have a strong preference to remove the lesion. Overall, endoscopic resection is a better choice than surgery.
      • Pang T.
      • Zhao Y.
      • Fan T.
      • et al.
      Comparison of safety and outcomes between endoscopic and surgical resections of small (</= 5 cm) primary gastric gastrointestinal stromal tumors.
      and endoscopic submucosal dissection and its related technologies are too complicated and difficult to perform for small GISTs, especially in the fundus of the stomach. In contrast, EFTR-C is simple to operate, easy to master, has a short operation time, and has a high complete resection rate. Traditional endoscopic methods can be selected for GISTs >1.5 cm.
      In addition, EFTR with a full-thickness resection device (FTRD; Ovesco Endoscopy, Tübingen, Germany) is a novel and feasible method for resection of mucosal and submucosal lesions in Western countries.
      • Mahadev S.
      • Vareedayah A.A.
      • Yuen S.
      • et al.
      Outcomes of a hybrid technique using EMR and endoscopic full-thickness resection for polyps not amenable to standard techniques (with video).
      ,
      • Brand M.
      • Reimer S.
      • Reibetanz J.
      • et al.
      Endoscopic full thickness resection vs. transanal endoscopic microsurgery for local treatment of rectal neuroendocrine tumors—a retrospective analysis.
      Its operating steps are different from the 2 endoscopic methods introduced in our study, and our 2 methods create artificial perforations. FTRD can complete closure of the wall by applying an over-the-scope clip before snare excision and reduce AEs, especially perforation.
      • Hajifathalian K.
      • Ichkhanian Y.
      • Dawod Q.
      • et al.
      Full-thickness resection device (FTRD) for treatment of upper gastrointestinal tract lesions: the first international experience.
      ,
      • Meier B.
      • Schmidt A.
      • Glaser N.
      • et al.
      Endoscopic full-thickness resection of gastric subepithelial tumors with the gFTRD-system: a prospective pilot study (RESET trial).
      Hajifathalian et al
      • Hajifathalian K.
      • Ichkhanian Y.
      • Dawod Q.
      • et al.
      Full-thickness resection device (FTRD) for treatment of upper gastrointestinal tract lesions: the first international experience.
      suggested that FTRD is a relatively safe and effective option for endoscopic resection of appropriate upper GI tract lesions, including subepithelial lesions, with a 68 % R0 resection rate. In addition, 21% of patients reported mild to moderate AEs. However, the R0 resection rate was less than that in the EFTR-C group. In our study, the R0 resection rate was 95.6%. The operative technique of FTRD is not difficult. Additionally, the price of FTRD in China is 309.6 U.S. dollars and is not covered by medical insurance. Compared with EFTR-C, the cost of FTRD is higher. For the above reasons, the FTRD method is not widely used in the treatment of small GISTs (≤1.5 cm) in China. In fact, FTRD is not even available in our center.
      There are several limitations of our research study. First, this was a single-center and retrospective study at a tertiary endoscopic center in Jiangsu Province. Hence, there might have been some potential selection bias, despite robust univariate and multivariate analyses with adjustments for covariates. Second, the median follow-up time, 35.8 ± 27.2 months, was not long enough in our study. The shortest follow-up time was only 4 months. We believe that with further follow-up, the results will be more accurate and credible. Third, the sample size was relatively small, with only 113 cases. Thus, large-scale data are necessary for verification.
      In conclusion, endoscopic resection is safe and effective for gastric GISTs <1.5 cm, especially with an experienced endoscopic team. EFTR-C is preferable for small (≤1.5 cm) GISTs with the advantages of fewer AEs, quicker operation time, shorter hospitalization time, and faster postoperative recovery when compared with EFTR. However, large-scale studies are recommended to further verify our data.

      Appendix

      Supplementary Table 1Univariable regression analysis for resection time
      Variablesb (95% Confidence interval)P value
      Method
       EFTR-CReference
       EFTR23.3 (16.6-29.9)<.001
      Sex
       MaleReference
       Female–6.6 (–14.4 to 1.1).095
      Age.1 (–.2 to .5).468
      Hypertension3.9 (–5.6 to 13.3).428
      Diabetes2.9 (–16.0 to 21.8).765
      Location
       CardiacReference
       Fundus–10.3 (–30.7 to 10.1).325
       Corpus–4.6 (–26.9 to 17.8).690
       Antrum–4.6 (–26.9 to 17.8).298
      Tumor growth pattern
       Intraluminal growthReference
       Extraluminal growth3.1 (–11.2 to 17.4).669
       Intraluminal and extraluminal growth11.9 (–.6 to 24.5).065
      Size under microscopy10.1 (–1.2 to 21.4).082
      Layer of origin
       SubmucosaReference
       Muscularis propria21.2 (2.7-39.7).027
      Mitotic count, no. per 50 high-power fields–1.3 (–3.6 to 1.0).263
      Heat clamp to stop bleeding15.0 (7.7-22.4)<.001
      Suture method
       Titanium clipReference
       Purse-string suture39.6 (19.8-59.3)<.001
      No. of titanium clips for suture1.8 (0.4-3.3).016
      b represents the adjusted mean difference between EFTR and EFTR-C.
      EFTR, Endoscopic full-thickness resection; EFTR-C, cap-assisted endoscopic full-thickness resection.
      Supplementary Table 2Multivariable regression models evaluating the association between method and resection time
      MethodCrudeModel IModel II
      b (95% CI)P valueb (95% CI)P valueb (95% CI)P value
      EFTR-CReferenceReferenceReference
      EFTR23.3 (16.6-29.9)<.00119.5 (11.4-27.6)<.00119.7 (11.3-28.0)<.001
      Model I: sex; tumor growth pattern, size under microscopy, layer of origin, heat clamp to stop bleeding, suture method, number of titanium clips of suture. Model II: sex, age, hypertension, diabetes, location, tumor growth pattern, size under microscopy, layer of origin, mitotic count, heat clamp to stop bleeding, suture method, number of titanium clips of suture. b represents the adjusted mean difference between EFTR and EFTR-C.
      CI, Confidence interval; EFTR, endoscopic full-thickness resection; EFTR-C, cap-assisted endoscopic full-thickness resection.

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