Comparison between Submucosal Tunneling Endoscopic Resection and Endoscopic Submucosal Dissection for Prepyloric Submucosal Tumors: A Case-Matched Controlled Study

Objectives Endoscopic submucosal dissection (ESD) has become a well-established treatment method for gastric submucosal tumors (SMTs). However, there existed some challenges to perform ESD for prepyloric SMTs on account of the special location. Recently, submucosal tunneling endoscopic resection (STER) provided a novel option for prepyloric SMTs. This study aimed to make a comprehensive comparison between prepyloric STER (P-STER) and ESD for the treatment of prepyloric SMTs. Methods Patients with prepyloric SMTs undergoing P-STER treatment between January 2016 and October 2021 were retrospectively reviewed and individually matched at 1 : 1 ratio with those with ESD treatment according to lesion size, lesion location, pathologic diagnosis, lesion origin, and surgery date, forming P-STER and ESD group, respectively. A sample size of 12 patients was collected for each group. Treatment outcomes including resection time, en bloc resection rate, complete resection rate, and postoperative hospital stay as well as occurrence of complications were evaluated. Results Compared with ESD group, P-STER group got shorter resection time (52.50 minutes for ESD group vs. 38.67 minutes for P-STER group, P = 0.001), shorter postoperative hospital stay (7.00 day for ESD group vs. 5.50 day for P-STER group, P = 0.008), and lower rate of postoperative abdominal pain (50.00% for ESD group vs. 8.33% for P-STER group, P = 0.025). No complication was encountered in P-STER group, whereas one patient with postoperative bleeding was found in ESD group. Conclusions For the treatment of prepyloric SMTs, P-STER appeared to be a more effective endoscopic technique compared with ESD, although further randomized controlled trials were warranted.


Introduction
To date, endoscopic submucosal dissection (ESD) is a wellaccepted method for removing the gastric submucosal tumors (SMTs) in China [1][2][3]. However, to a certain extent, it is time-consuming and difficult to perform ESD for prepyloric SMTs given the special location. First, the prepyloric SMTs were often perpendicular to the resection knife under endoscopy, increasing the risk of muscularis propria (MP) damage and operation difficulty. Second, the postoperative wound tended to involve the pylorus ring, which might affect the function of pyloric sphincter. Therefore, in 2017, we first introduced the prepyloric submucosal tunneling endoscopic resection (P-STER) for a case of SMT [4]. P-STER technique has the potential to lower the operation time and difficulty by establishing a submucosal tunnel, which can slow down the diffusion of the submucosal liquid cushion and provide a clear vision for endoscopic resection; moreover, the integrity of mucosa above postoperative wound can decrease the influence of the possible gastric-wall defect (GWD) and pylorus ring involvement. However, the studies confirming the safety, effectiveness, and advantages of P-STER for SMTs are lacking. The aim of this study, therefore, was to report the outcomes from P-STER, and compare the efficiency between P-STER and ESD for treating prepyloric SMTs.

Gastroenterology Research and Practice
Hospital. Informed consent was obtained for all patients described. Between January 2016 and October 2021, a total of 54 patients undergoing P-STER or ESD for prepyloric SMT in our hospital. Patient-related and procedurerelated data were retrieved from a prospectively maintained database. The inclusion criteria were as follows: (1) patients diagnosed as prepyloric SMTs based on postoperative pathology diagnosis; (2) patients ≥18 years old. The exclusion criteria were as follows: (1) patients under clinical follow-up for less than six months or loss of follow-up. Of note, the choice of ESD or P-STER as the treatment of prepyloric SMT was depended on the operation habits of endoscopists.
2.2. P-STER and ESD Procedure. Endoscopic ultrasonography (EUS) was routinely performed to determine the lesion origin. Patients were maintained in the left lateral position, and general anesthesia was administered using mechanical ventilation. All procedures were carried out by three experienced endoscopists with experience with over 300 ESD cases and 300 STER cases. ESD procedure was carried out using the following steps: marking-injection-circumferential incision-submucosal dissection. Of note, the post-ESD wound was closed using metal clips if the GWD occurred during the procedure.
The P-STER procedure was carried out as follows: (1) Several milliliters of a mixture solution (100 mL saline + 2 mL indigo carmine + 1 mL epinephrine) was injected 3-4 cm proximal to the prepyloric SMTs with an injection needle (NM-4L-1, Olympus; Figures 1(a), 1(b), and 1(c)); (2) an inverted T incision as described previously was made as the tunnel entrance [5] (Figure 1(d)); (3) a tunnel was created between the mucosal and MP layer with the triangular knife and the tunnel ended at 1 cm distal to the prepyloric SMTs (Figures 1(e) and 1(f)); (4) an insulation-tip knife (KD611L, IT2, Olympus), a triangular knife, or a snare (ASM-1-S or ASJ-1-S, Cook, Limerick, Ireland) was used to remove the prepyloric SMT after it was completely exposed (Figures 1(g) and 1(h)); and (5) the incision was closed with clips (HX-610-135, Olympus) after examination of the tunnel (Figure 1(i)). Of note, the endoscopists could chose the full-thickness resection of MP if the lesion originated from the MP layer. The specimen was routinely pinned at a rubber plate for size measurement followed by fixing into formalin for histopathological evaluation.
Moreover, the snare could be used to remove the lesion at the discretion of the endoscopists in both the ESD and P-STER procedures, if operation difficulty was encountered in the final stage of the procedure.

Postoperative Treatments and Follow-Up.
Patients in study were observed closely after P-STER or ESD treatment for complications, including perforation, bleeding, and abdominal infection. Corresponding treatment was given once complications were encountered. Patients were kept fasting for 2 days after the procedure, and a liquid diet was followed for an additional 1 day if no complications or postoperative abdominal pain occurred. Diet was gradually restored to normal from the fourth day. Patients would be discharged on the fifth day if there were no complications or postoperative abdominal pain observed, otherwise the hospital discharge would be delayed at the discretion of the endoscopists. Postoperative medications mainly included proton pump inhibitor (PPI) and antibiotics. PPI, including esomeprazole (20 mg, twice a day), rabeprazole (20 mg, once a day), and so on, was required for at least 2 weeks. In terms of antibiotics, levofloxacin, sulperazon, or other thirdgeneration cephalosporin could be administrated. All the 24 patients with prepyloric SMTs involved in this study were arranged with endoscopic follow-up in the local hospital or our hospital in April 2022.

Outcomes and
Definitions. Flowchart of the study was shown in detail in Figure 2. In this study, treatment outcomes were analyzed between the P-STER and ESD groups, including en bloc resection, complete resection, GWD, resection time, residue, recurrence, postoperative bleeding, postoperative abdominal pain, postoperative hospital stay, and followup time. Resection time was recognized as the time from the submucosal injection in STER procedure or marking in ESD procedure to the withdrawn of endoscopy. Complete resection was defined as the entire removal of lesion in one piece with negative margins. Recurrence meant that the tumor was found again in the original location or location within 1 cm of the original location within the following 6 months postoperatively. Postoperative bleeding was defined as emergence of melena or hematemesis. Postoperative abdominal pain referred to the obvious abdominal pain lasting more than 6 hours, and the pain medications could be prescribed if necessary. Prepyloric SMTs were defined as the SMTs within 3 cm from the pylorus ring.

Statistical Analysis.
Comparisons between the two groups were assessed by paired sample t-test for continuous variables and the chi-squared for categorical variables. Wilcoxon signed-rank test was used when equal variances were not figured out. Between January 2016 and October 2021, 13 patients with prepyloric SMTs were treated with P-STER in our hospital. Those patients were matched with patients with ESD at a 1:1 ratio according to lesion size (±0.5 cm), lesion location, pathologic diagnosis, lesion origin, and surgery date (±2 years). One out of thirteen patients with prepyloric SMTs undergoing P-STER was excluded because of the failure of lesion location matching with the ESD group ( Figure 2). Two-sided P-value <0.05 was considered as statistical significance. Parametric data are presented as means.
Nonparametric data are expressed as medians.

Baseline Characteristics of Patients.
The baseline characteristics of the 24 patients in this study (12 patients for each group) was depicted in Table 1. There was no significant difference observed in age, gender, lesion size, pathology results, distance from pylorus ring, lesion location, lesion origin, and the appearance under EUS between the two groups studied (P > 0:05).

Comparison of Treatment
Outcomes between P-STER and ESD Groups. As shown in Table 2, the standard P-STER and ESD treatment outcomes were successfully operated in all the 12 patients, respectively. Among the treatment outcomes, there were no significant difference observed in the usage frequency of the snare during the procedure, GWD, recurrence, postoperative bleeding, and follow-up time (P = 0:386, 0:414, 1:000, 0:307, and 0:065, respectively). Only one patient was found with postoperative bleeding in ESD group, and conservative treatment was given. The en-bloc resection was successfully achieved in all the 12 patients in the P-STER and ESD groups respectively. The complete resection appeared to be increased in the P-STER group relative to the ESD group; although, there was no statistical significance [11/12 (91.67%) vs. 9/12 (75.78%), P = 0:273]. Of the four patients without complete resection, two were ectopic pancreas, and the other two were gastrointestinal stromal tumors (GISTs) (G1). No recurrence was found during the follow-up for these four patients without complete resection. More importantly, the P-STER group exhibited a significantly less operation time (52.50 minutes for ESD group vs. 38.67 minutes for P-STER group, P = 0:001), shorter postoperative hospital stay (7.00 day for ESD group vs. 5.50 day for P-STER group,

Discussion
The diagnosis for gastric SMTs are various, including nonneoplastic lesions, benign neoplasms, and potentially and overtly malignant tumors [6]. The nature of the gastric SMTs cannot be determined based on its endoscopic image alone; moreover, a standard endoscopic forceps biopsy typically fails to obtain material adequate for diagnosis [7]. The emergence of ESD made it possible to resect, en bloc, even large mucosal and submucosal lesions [8][9][10]. In addition, ESD has become a well-established treatment and diagnosis method for gastric SMTs. However, there existed some challenge to conduct ESD for prepyloric SMTs because of the special location. Hence, in 2017, we reported a case of P-STER for a prepyloric SMT.
The present study compared the treatment results of P-STER and ESD for prepyloric SMTs, and showed that patients who received a P-STER underwent a faster operation (Table 2). During the procedures for ESD for prepyloric SMTs, the diffusion of the submucosal liquid cushion was quickly after the circumferential incision, and the approximate vertical angle between the resection knife and MP layer could not be changed. Therefore, ESD for prepyloric SMTs was time-consuming. In comparison, in P-STER procedures, the submucosal injection solutions could be retained in the submucosal layer for a longer time, and the vertical angle between the resection knife and MP layer could be changed by the submucosal liquid cushion; moreover, the submucosal tunnel could provide a clear operation vision for the submucosal dissection. For the foregoing reasons, compared with ESD, P-STER presented a faster operation efficiency. What is more, in ESD procedures, the postoperative wound always involved the pylorus ring (Figure 1(j)), which might affect the function of pyloric sphincter. In contract, in the P-STER procedures, the retained mucosa above the wound might protect the pylorus ring from damage.
On the other hand, the P-STER group exhibited a lower rate of postoperative abdominal pain and shorter postoperative hospital stay, compared with that of the ESD group. As shown in Table 2, the occurrence rate of GWD in P-STER and ESD group were 58.33% (7/12) and 41.67% (5/7), respectively. In the P-STER group, the mucosa above the surgical wound was retained during and post the procedure, which could protect the wound and abdominal cavity from the irritation of gastric juice. In contract, in the ESD group, the gastric juice and gas could enter the abdominal cavity more easily during the procedure if the GWD occurred, and the postoperative wound would be irritated by the 6 Gastroenterology Research and Practice gastric acid if no metal clips were used to close the wound. Therefore, compared with the P-STER group, the patients in the ESD group suffered a higher rate of postoperative abdominal pain, leading to a longer postoperative hospital stay. Of note, the four patients without complete resection did not receive additional treatments given the postoperative pathologic diagnosis (two were ectopic pancreas and two were G1 GISTs).
The main limitation of this study was that it was designed as a retrospective study. Second, the sample size of this study was small (n = 12 for each group) since P-STER was a novel application for prepyloric SMTs in recently. Third, there may be some bias in the choice of treatment strategy according to the operation habits of endoscopists in this study. Moreover, this study relied on reports from a tertiary referral center, and could mean that the results from this study may not be representative of findings from other hospitals. However, to the best of our knowledge, this study first reported the comparison results between P-STER and ESD for prepyloric SMTs.
In conclusion, compared with ESD, we found that P-STER appears to produce a higher operation efficacy. However, further randomized controlled trials were warranted.

Data Availability
Data supporting this research article are available from the corresponding author or first author on reasonable request.

Disclosure
Drs. Wengang Zhang, Jiafeng Wang, Ningli Chai, and Enqiang Linghu have no conflicts of interest or financial ties to disclose.

Conflicts of Interest
The author(s) declare(s) that they have no conflicts of interest.

Authors' Contributions
Wengang Zhang and Jiafeng Wang analyzed the data and wrote the manuscript. Enqiang Linghu and Ningli Chai performed the procedures. Wengang Zhang and Jiafeng Wang are co-first authors.