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Comparing a conventional and a spring-and-loop with clip traction method of endoscopic submucosal dissection for superficial gastric neoplasms: a randomized controlled trial (with videos)

Open AccessPublished:October 12, 2020DOI:https://doi.org/10.1016/j.gie.2020.09.049

      Background and Aims

      Several traction methods have sought to overcome the technical difficulties of endoscopic submucosal dissection (ESD). However, traction direction has remained limited in most of these methods, with lack of clarity about the optimal method and traction direction for gastric ESD. A spring-and-loop with clip (SLC) has been developed as a multidirectional traction device. Here, we investigated whether SLC traction-assisted ESD (SLC-ESD) improved procedure-related outcomes compared with conventional ESD (C-ESD) among patients with superficial gastric neoplasms.

      Methods

      This single-center randomized controlled trial included patients with superficial gastric neoplasms undergoing SLC-ESD or C-ESD between October 2018 and December 2019. Using the multidirectional traction function, we set traction vertical to the gastric wall for SLC-ESD. The primary outcome was the median procedure time for gastric ESD.

      Results

      The SLC-ESD and C-ESD groups comprised 40 patients each, and all the enrolled patients underwent the assigned treatment. The median ESD procedure time was significantly shorter in the SLC-ESD group (29.1 minutes) than in the C-ESD group (52.6 minutes; P = .005). SLC had a mean attachment time of 1.82 minutes. En bloc resection was achieved without perforation in all the patients in both groups.

      Conclusions

      Our findings suggest that SLC-ESD reduces gastric ESD procedure time without increasing the risk of perforation and that the vertical direction to the gastric wall is the appropriate traction direction for gastric ESD. (Clinical trial registration number: UMIN 000034533.)

      Graphical abstract

      Abbreviations:

      C-ESD (conventional endoscopic submucosal dissection), ESD (endoscopic submucosal dissection), SLC (spring-and-loop with clip)

      Introduction

      Endoscopic submucosal dissection (ESD) is a minimally invasive treatment for superficial GI neoplasms with little metastatic potential.
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      It enables en bloc resection of superficial lesions that are difficult to resect by EMR, thereby facilitating accurate pathologic assessment and a lower recurrence rate.
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      Advantage of endoscopic submucosal dissection compared with EMR for early gastric cancer.
      However, gastric ESD is not universally applied because it is technically difficult and requires a long procedure time.
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      Endoscopic submucosal dissection for early gastric cancer: results and degrees of technical difficulty as well as success.
      ,
      • Nagata S.
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      Influential factors in procedure time of endoscopic submucosal dissection for gastric cancer with fibrotic change.
      Although various traction methods have been developed to overcome these difficulties,
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      A new technique for endoscopic submucosal dissection for early gastric cancer using an external grasping forceps.
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      A new traction device for facilitating endoscopic submucosal dissection (ESD) for early gastric cancer: the “medical ring.”.
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      Suture pulley countertraction method reduces procedure time and technical demand of endoscopic submucosal dissection among novice endoscopists learning endoscopic submucosal dissection: a prospective randomized ex vivo study.
      traction direction is limited in most.
      We are aware of no randomized controlled trials showing any traction method reducing gastric ESD procedure time compared with conventional ESD (C-ESD). The clip-with-line traction method, which is one of the most popular methods, failed to reduce procedure time compared with C-ESD in a multicenter randomized controlled trial.
      • Yoshida M.
      • Takizawa K.
      • Suzuki S.
      • et al.
      Conventional versus traction-assisted endoscopic submucosal dissection for gastric neoplasms: a multicenter, randomized controlled trial (with video).
      The problem appeared centered on the fact that the traction direction of the clip-with-line method was limited to the oral side via the cardia, indicating that the most appropriate traction direction for gastric ESD needs to be assessed.
      A spring-and-loop with clip (SLC; Sakamoto-Osada clip; Zeon Medical, Tokyo, Japan) has been developed as a traction device for ESD, with the great advantage that it can provide traction in any direction (Fig. 1).
      • Sakamoto N.
      • Osada T.
      • Shibuya T.
      • et al.
      The facilitation of a new traction device (S-O clip) assisting endoscopic submucosal dissection for superficial colorectal neoplasms.
      ,
      • Sakamoto N.
      • Osada T.
      • Shibuya T.
      • et al.
      Endoscopic submucosal dissection of large colorectal tumors by using a novel spring-action S-O clip for traction (with video).
      In recent retrospective studies using propensity score matching analysis, SLC traction-assisted ESD (SLC-ESD) reduced gastric ESD procedure time compared with C-ESD.
      • Hashimoto R.
      • Hirasawa D.
      • Iwaki T.
      • et al.
      Usefulness of the S-O clip for gastric endoscopic submucosal dissection (with video).
      ,
      • Nagata M.
      Internal traction method using a spring-and-loop with clip (S–O clip) allows countertraction in gastric endoscopic submucosal dissection.
      However, such research is potentially subject to bias introduced by unobserved differences. This necessitates a randomized controlled trial to evaluate the superiority of SLC-ESD compared with C-ESD for the treatment of superficial gastric neoplasms. We hypothesized that traction vertical to the gastric wall is most appropriate for gastric ESD and that this would be possible using the multidirectional traction function of the SLC. Despite being designed for use in colorectal ESD, we have developed a new application of SLC for gastric ESD.
      • Nagata M.
      Internal traction method using a spring-and-loop with clip (S–O clip) allows countertraction in gastric endoscopic submucosal dissection.
      ,
      • Nagata M.
      Modified attachment method using an S–O clip for gastric endoscopic submucosal dissection.
      Figure thumbnail gr1
      Figure 1The spring-and-loop with clip (SLC; S-O clip; Zeon Medical, Tokyo, Japan) has a 5-mm long spring and a 4-mm long nylon loop at one side of the clip claws. It is attached to the lesion with the loop attached to the gastric wall by a regular hemoclip, allowing spring extension to provide traction for the lesion according to Hook’s law. The spring of the SLC can be extended to about 80 mm, which may be used regardless of the lesion location. Traction direction can be controlled depending on anchor site.
      In this study, we present the results of a randomized controlled trial in which we investigated whether SLC-ESD improved procedure-related outcomes compared with C-ESD among patients with superficial gastric neoplasms.

      Methods

      Study design and ethics

      This prospective, single-center (Shonan Fujisawa Tokushukai Hospital, Kanagawa, Japan), parallel 2-arm, open-label, randomized controlled trial was designed to compare the procedure-related outcomes between SLC-ESD and C-ESD when treating superficial gastric neoplasms. The trial was approved by our institutional review board (Mirai Iryo Research Center; Tokyo, Japan), registered in the University Hospital Medical Information Network (registration number: UMIN 000034533) in October 2018 (before trial initiation), and conducted according to the Declaration of Helsinki. All participants provided written informed consent for this study before enrollment.

      Endpoints

      The primary endpoint was ESD procedure time. Secondary endpoints were as follows: dissection speed, en bloc resection, perforation, post-ESD bleeding, other adverse events, histologic assessment, and SLC-related factors (SLC attachment time, number of SLC application, SLC slip-off, SLC-related damage to the specimen, SLC breakage, and successful removal of the anchor clip).

      Definitions

      The general ESD-related details were defined as follows. ESD procedure time (minutes) was defined as the time from the first injection to completed dissection, including the SLC attachment time. Dissection speed (mm2/min) was defined as the specimen area divided by the ESD procedure time. The length (mm) of the longer axis and the shorter axis of the resected specimen was measured after pinning on a board, and specimen size was defined as the longest axis length of the resected specimen. Specimen area (mm2) was calculated using the ellipse formula: specimen area = ([shorter axis length]/2) × ([longer axis length)]/2) × 3.14. Lesion location (ie, upper, middle, or lower third of the stomach) and position (ie, greater curvature, lesser curvature, posterior wall, or anterior wall of the stomach) were defined according to the Japanese classification of gastric carcinoma.
      Japanese Gastric Cancer Association
      Japanese classification of gastric carcinoma: 3rd English edition.
      En bloc resection was defined as the removal of the neoplastic area in a single piece without using a snare. Complete resection was defined as en bloc resection with pathologically negative margins at both the horizontal and vertical cut ends. Perforation was diagnosed by endoscopy or the presence of free air shown on a radiograph. Post-ESD bleeding was defined as that requiring endoscopic intervention to achieve hemostasis.
      The specific SLC-related details were defined as follows. SLC attachment time was defined as the time from the appearance of the clip applicator on the monitor to completing the anchoring of the SLC loop on the gastric wall. If SLC reattachment was performed, the time required for reattachment was included in SLC attachment time. SLC-related damage to the specimen was defined as any tear or split of the specimen caused by traction force. SLC breakage was defined as the loss of spring elasticity. Removal of the anchor clip was deemed successful when it had been pulled from the gastric wall and extracted out of the body.
      Endoscopic position during submucosal dissection was defined as the position only during the submucosal dissection, except for during submucosal injection and mucosal incision, wherein the position was classified as a forward or retroflexed endoscopic position.

      Participants

      We included patients meeting the following criteria: age 20 to 94 years; no gastrectomy or reconstructive surgery of the gastric tube for esophageal cancer; Eastern Cooperative Oncology Group performance status range 0 to 2; written informed consent by the patient; histopathologically proven gastric adenoma or carcinoma by forceps biopsy before ESD; and carcinoma with the lowest chance of lymph node metastasis according to Japanese guidelines.
      • Ono H.
      • Yao K.
      • Fujishiro M.
      • et al.
      Guidelines for endoscopic submucosal dissection and endoscopic mucosal resection for early gastric cancer.
      The following carcinomas were therefore included: (1) clinically intramucosal (cT1a) differentiated carcinomas of any size, without ulceration (scar); (2) cT1a differentiated carcinomas, ≤30 mm in size, with ulceration (scar); and (3) cT1a undifferentiated carcinomas, ≤20 mm in size, without ulceration (scar).
      • Ono H.
      • Yao K.
      • Fujishiro M.
      • et al.
      Guidelines for endoscopic submucosal dissection and endoscopic mucosal resection for early gastric cancer.
      Patients were excluded if they were pregnant or if pregnancy was possible, if they were lactating, or if they were deemed ineligible for a specific reason.

      Randomization

      Patients were enrolled and randomly assigned to either SLC-ESD or C-ESD in a 1:1 allocation ratio; computer-based block randomization was performed with a block size of 4 and without stratification. Mirai Iryo Research Center (Tokyo, Japan) managed the randomization and data collection, and we had no access to the randomization codes. The operator (M.N.) and the patients were not blind to treatment group assignment.

      Sample size

      The sample size was calculated based on the ESD procedure time. In our pilot study, the mean ESD procedure time of the SLC-ESD group was 40 minutes shorter than that of the C-ESD group, with a common standard deviation of 59 minutes for the 2 groups. To ensure a power of 80% with a 5% 2-sided error, we required 70 participants. Therefore, the final sample was planned to include 80 participants to allow for a dropout rate of about 10%.

      Setting of gastric ESD

      All ESD procedures were performed by a single endoscopist (M.N.) who had experience of >750 ESD procedures, including >50 SLC-ESD procedures at the beginning of the trial. Patients were hospitalized and treated under intravenous sedation. Blood tests and radiographs were performed on the day after ESD to diagnose adverse events. A single-channel endoscope (GIF-Q260J; Olympus) with a straight transparent hood (Olympus) was used for all ESD procedures. Carbon dioxide (CO2) insufflation was used to extend the stomach, with an overtube (TOP, Tokyo, Japan) used to reduce the risk of aspiration; if leakage occurred due to repeated belching, a leak cutter (TOP) was attached to the overtube to maintain a distended stomach. A straight-needle-type electrosurgical knife (KD-650L, DualKnife; Olympus) and hemostatic forceps (FD-412LR, CoagrasperG; Olympus) were used with an electrosurgical generator (VIO300D; ERBE Elektromedizin GmbH, Tübingen, Germany), and a mixture of 0.4% hyaluronic acid (MucoUp; Boston Scientific, Marlborough, Mass, USA) and saline solution in a 1:1 ratio was injected.

      C-ESD procedure

      The C-ESD procedure did not include the traction method, underwater technique,
      • Nagata M.
      Usefulness of underwater endoscopic submucosal dissection in saline solution with a monopolar knife for colorectal tumors (with videos).
      ,
      • Nagata M.
      Underwater endoscopic submucosal dissection in saline solution using a bent-type knife for duodenal tumor.
      the pocket creation method,
      • Miura Y.
      • Hayashi Y.
      • Lefor A.K.
      • et al.
      The pocket-creation method of ESD for gastric neoplasms.
      or any other special technique. After submucosal injection, a partial mucosal incision was performed around the lesion before dissecting the submucosa to make a mucosal flap. A circumferential mucosal incision was then made, and the submucosa under the lesion was dissected completely.

      Basics of SLC-ESD in stomach

      For the SLC-ESD procedure, we selected traction vertical to the gastric wall, using the multidirectional traction function of the SLC device with a modified attachment method.
      • Nagata M.
      Internal traction method using a spring-and-loop with clip (S–O clip) allows countertraction in gastric endoscopic submucosal dissection.
      ,
      • Nagata M.
      Modified attachment method using an S–O clip for gastric endoscopic submucosal dissection.
      SLC and anchor clips could be delivered to the stomach via the accessory channel of the endoscope, and the withdrawal of the endoscope during SLC attachment was not required. All procedures not specific to SLC were conducted as in the description of the C-ESD procedure.
      After circumferential mucosal incision, the easier endoscopic position for performing submucosal dissection was selected from the forward or retroflexed endoscopic position. The shape of the stomach differs from person to person. Hence, similar to C-ESD, the use of the forward or retroflexed endoscopic position in SLC-ESD was case dependent even if the lesion site was similar. Moreover, the position, either forward or retroflexed endoscopic, that was easier to utilize when approaching the lesion parallel to the gastric wall was selected. This approach could facilitate a safe and efficient submucosal dissection because perforation could be prevented even when the electrosurgical knife was placed deep into the submucosa. If both positions had similar degrees, the forward endoscopic position was chosen because it was less likely to cause interference between the endoscope and the spring. If the forward endoscopic position was selected, the SLC was attached to the oral side of the lesion. If the retroflexed endoscopic position was selected, the SLC was attached to the anal side of the lesion.
      After the SLC attachment to the lesion, the spring-and-loop part of the SLC basically fell in the direction of gravitational force. If the loop fell under the mucosa because of gravity, it may be difficult to hook the loop using the anchor clip. Therefore, the SLC was attached to the lesion where the loop of the SLC came over the mucosa, which made it easy to hook the loop using the anchor clip. The clip part of the SLC occasionally fell during submucosal dissection and obstructed the field of vision. In such a situation, the clip part of the SLC was utilized for turning over the mucosal flap similar to that in the clip flap method.
      • Yamamoto K.
      • Hayashi S.
      • Nakabori T.
      • et al.
      Endoscopic submucosal dissection using endoclips to assist in mucosal flap formation (novel technique: "clip flap method").
      After resection, the anchor clip was removed with forceps, and the specimen, SLC, and anchor clip were extracted.

      SLC-ESD procedure in the forward endoscopic position

      The SLC-ESD procedure was performed in the forward endoscopic position as follows (Fig. 2; Video 1, available online at www.giejournal.org). The endoscope rarely interfered with the spring (Fig. 2A). As above, the traction direction was selected to be vertical to the gastric wall (Fig. 2B), and the anchor site was marked by the electrosurgical knife. The SLC was then attached to the oral side of the lesion so that the loop came over the mucosa (Fig. 2C). The loop of the SLC was subsequently anchored to the gastric wall by the regular clip in the forward endoscopic position (Fig. 2D). Spring extension provided sufficient submucosal visualization and tension (Fig. 2E). Damage to the specimen due to SLC rarely occurred because spring elasticity prevented excessive traction force (Fig. 2F).
      Figure thumbnail gr2
      Figure 2Spring-and-loop with clip traction-assisted endoscopic submucosal dissection (SLC-ESD) in the forward endoscopic position for a flat elevated lesion (14 mm) located at the anterior wall of the middle gastric body (, available online at www.giejournal.org). A, The endoscope rarely interferes with the spring in the forward endoscopic position. B, Forward endoscopic view in planning the SLC attachment procedure. If the spring of the SLC is extended in the direction of the yellow arrow, traction vertical to the gastric wall is obtained. C, The SLC (white arrow) is attached to the oral side of the lesion in the direction that the loop comes over the mucosa to make it easy to hook the loop by the anchor clip. D, The loop of the SLC is anchored on the gastric wall by the regular clip in the forward endoscopic position. E, Extension of the spring vertical to the gastric wall provides sufficient submucosal visualization and tension. F, Resected specimen stained with indigo carmine. Complete en bloc resection is achieved without damage to the specimen.

      SLC-ESD procedure in the retroflexed endoscopic position

      The SLC-ESD procedure was performed in the retroflexed endoscopic position as follows (Fig. 3; Video 2, available online at www.giejournal.org). It was necessary to prevent interference between the endoscope and spring by devising an SLC attachment procedure (Fig. 3A). It was possible for the endoscope to interfere with the spring, which may cause it to stretch excessively, thereby decreasing the traction force due to loss of elasticity (Fig. 3B). First, the movement of the endoscope axis during submucosal dissection was confirmed using a practice swing of the endoscope (Fig. 3C). Second, the spring extension direction was selected to be vertical to the gastric wall, avoiding interference between the endoscope axis and the spring simultaneously. The place where the extension line of the traction direction met the gastric wall was marked as the anchor site with an electrosurgical knife. The positional relationship between the endoscope axis, spring extension direction, and gastric wall was then checked (Fig. 3D). Third, the SLC was attached at the anal edge of the lesion where the loop came over the mucosa (Fig. 3E). Fourth, the loop was anchored by the regular clip, and the spring was stretched in the planned direction. For this step, the forward endoscopic position was preferred because poor maneuverability meant that it could be difficult to perform anchoring procedures in the retroflexed endoscopic position. Fifth, the endoscopic position was changed to the retroflexed position after passing through the space between the spring and gastric wall to ensure the positional relationship in step 2 (Fig. 3F). The spring extension allowed for efficient submucosal dissection with sufficient submucosal visualization and tension (Fig. 3G), avoiding interference between the endoscope and the spring (Fig. 3H).
      Figure thumbnail gr3
      Figure 3Spring-and-loop with clip traction-assisted endoscopic submucosal dissection (SLC-ESD) in the retroflexed endoscopic position for a flat elevated lesion (18 mm) located at the posterior wall of the middle gastric body (, available online at www.giejournal.org). A, It is necessary to prevent interference between the endoscope and spring by devising an SLC attachment procedure. B, The endoscope can interfere with the SLC spring and stretch it, resulting in a loss of elasticity and traction force. C, The movement of the endoscope axis during submucosal dissection in the retroflexed endoscopic position is confirmed using a practice swing of the endoscope. The electrosurgical knife emerges from the 7 o’clock side of the screen. Hence, in this situation, the endoscope axis and tip move along with the white arrows and yellow arrows, respectively. D, Retroflexed endoscopic view for planning the SLC attachment procedure to prevent interference between the endoscope and SLC spring. The white arrow represents the endoscope axis and the yellow arrow indicates the direction in which the spring will be extended, based on 2 conditions: (1) where the practice swing of the endoscope confirmed that the endoscope axis did not come during submucosal dissection, and (2) vertical to the gastric wall. The white circle shows the marking dot for the anchor site, the yellow dot represents the GC side of the yellow arrow, and the blue dot represents the LC side of the yellow arrow. Note the positional relationship in which the endoscope axis is at the yellow dot side of the yellow arrow. E, Retroflexed endoscopic view after SLC attachment (white arrow) to the anal side of the lesion. Note that the loop comes over the mucosa, which makes it easy to hook the loop by the anchor clip in the forward endoscopic position. F, Forward endoscopic view after anchoring the loop of the SLC. The spring (yellow arrow) is stretched in the direction planned in D. The yellow dot represents the GC side of the yellow arrow. The blue dot represents the LC side of the yellow arrow. The endoscopic position is going to change to the retroflexed position after passing through the yellow dot side of the yellow arrow so as to be in the positional relationship confirmed in D. This prevents interference between the endoscope and spring. G, The spring extension (yellow arrow) vertical to the gastric wall allows proper submucosal visualization and sufficient submucosal tension. H, Even if the endoscope axis rotates widely in the retroflexed endoscopic position, interference between the endoscope and spring is avoidable. AW, Anterior wall; GC, greater curvature; LC, lesser curvature; PW, posterior wall.

      Statistical analysis

      We performed all statistical analyses in R version 3.5.2 (R Foundation for Statistical Computing, Vienna, Austria), analyzing categorical variables with the Fisher exact test and continuous variables with either the Mann-Whitney U test or the Student t test. Differences between variables were considered statistically significant for P values <.05. Subgroup analyses for gastric ESD procedure time were performed by lesion location and size. Data are reported as medians and interquartile range (IQR), unless stated otherwise. Finally, we performed multiple regression analysis to identify the factors associated with gastric ESD procedure time. Previous reports have demonstrated that ESD procedure times can be increased by technical difficulties associated with lesions located at the upper and middle third of the stomach, positioned at the greater curvature of the stomach, with ulcerative lesions, and lesions covering a large area.
      • Imagawa A.
      • Okada H.
      • Kawahara Y.
      • et al.
      Endoscopic submucosal dissection for early gastric cancer: results and degrees of technical difficulty as well as success.
      ,
      • Nagata S.
      • Jin Y.F.
      • Tomoeda M.
      • et al.
      Influential factors in procedure time of endoscopic submucosal dissection for gastric cancer with fibrotic change.
      ,
      • Ahn J.Y.
      • Choi K.D.
      • Choi J.Y.
      • et al.
      Procedure time of endoscopic submucosal dissection according to the size and location of early gastric cancers: analysis of 916 dissections performed by 4 experts.
      ,
      • Ono S.
      • Kato M.
      • Nakagawa M.
      • et al.
      Outcomes and predictive factors of "not self-completion" in gastric endoscopic submucosal dissection for novice operators.
      We therefore included these factors, together with the resection method (SLC-ESD or C-ESD), age, and sex as explanatory variables. To approximate the gastric ESD procedure time and specimen area to a normal distribution, the common logarithmic conversion value was used for these factors.

      Results

      Study population

      Figure 4 shows the flowchart of patient enrollment. During the study period, we evaluated the eligibility of 87 patients with superficial gastric neoplasms referred to our department. We excluded 2 patients who refused to participate, 3 who were diagnosed out of indication for ESD according to the Japanese guidelines, and 2 with difficulty of transfusion in an emergency for individual reasons. This achieved our target of enrolling 80 patients, who were randomly assigned to the SLC-ESD group (n = 40) or the C-ESD group (n = 40). All enrolled patients underwent their assigned treatment and were included in the analyses.
      Figure thumbnail gr4
      Figure 4Flowchart of patient enrollment. Patients with superficial gastric neoplasms (SGNs) were randomly assigned to undergo spring-and-loop with clip traction-assisted endoscopic submucosal dissection (SLC-ESD) or conventional endoscopic submucosal dissection (C-ESD). ∗Three patients diagnosed out of indication for ESD according to the Japanese guidelines were excluded. ∗∗Two patients with difficulty of transfusion in an emergency for individual reason were excluded.

      Overall outcomes

      The SLC-ESD and C-ESD groups had similar baseline characteristics (Table 1), but some differences existed in treatment outcomes (Table 2). The median ESD procedure time was significantly shorter in the SLC-ESD group (29.1 minutes; IQR, 19.2-57.7 minutes) than in the C-ESD group (52.6 minutes; IQR, 38.9-79.8 minutes) (P = .005). The median dissection speed was also significantly faster in the SLC-ESD group (25.5 mm2/min; IQR, 17.4-33.9 mm2/min) than in the C-ESD group (16.5 mm2/min; IQR, 11.9-21.6 mm2/min) (P < .001). However, no significant differences were found in the rates of en bloc resection, post-ESD bleeding, perforation, or other adverse events.
      Table 1Baseline characteristics of the patients who underwent SLC-ESD or C-ESD for a superficial gastric neoplasm
      SLC-ESD (n = 40)C-ESD (n = 40)
      Age (years), mean (SD)75.3 (8.4)74.6 (8.4)
      Sex, male/female30 (75)/10 (25)29 (72.5)/11 (27.5)
      Lesion size, mm
       Mean (SD)15.9 (10.3)15.7 (10.4)
       Median (IQR)12.0 (9.0-19.0)14.0 (8.8-20.3)
       Range5.0-48.01.4-45.0
      Lesion location
       Upper7 (17.5)6 (15)
       Middle19 (47.5)19 (47.5)
       Lower14 (35)15 (37.5)
      Lesion position
       Greater curvature10 (25)7 (17.5)
       Lesser curvature19 (47.5)15 (37.5)
       Anterior wall6 (15)7 (17.5)
       Posterior wall5 (12.5)11 (27.5)
      Morphology
       Depressed (0-IIc, 0-III)19 (47.5)24 (60)
       Flat (0-IIb)1 (2.5)2 (5)
       Protruded (0-I, 0-IIa)20 (50)14 (35)
      Histology
       Adenoma6 (15)7 (17.5)
       Differentiated adenocarcinoma34 (85)30 (75)
       Undifferentiated adenocarcinoma0 (0)3 (7.5)
      Values are n (%) unless otherwise indicated.
      SLC-ESD, Spring-and-loop with clip traction-assisted endoscopic submucosal dissection; C-ESD, conventional endoscopic submucosal dissection; SD, standard deviation; IQR, interquartile range.
      Table 2Comparison of procedure-related outcomes with SLC-ESD and C-ESD for superficial gastric neoplasms
      SLC-ESD (n = 40)C-ESD (n = 40)P value
      ESD procedure time, minutes
       Median (IQR)29.1 (19.2-57.7)52.6 (38.9-79.8).005
      P < .05.
       Mean (SD)42.9 (31.7)61.7 (38.3).019
      P < .05.
       Range10.4-125.113.6-217.3
      Dissection speed, mm2/min
       Median (IQR)25.5 (17.4-33.9)16.5 (11.9-21.6)<.001
      P < .05.
       Mean (SD)28.1 (14.4)17.5 (7.9)<.001
      P < .05.
       Range9.0-66.65.8-40.4
      Specimen size, mm
       Median (IQR)34 (29-39)35 (30-44).931
       Mean (SD)36.1 (9.2)37.0 (10.8).705
       Range22-6122-67
      Depth.415
       Mucosa
      Intramucosal cancers and adenomas are included in this category.
      33 (82.5)34 (85)
       Submucosa (<500 μm)1 (2.5)3 (7.5)
       Submucosa (≥500 μm)6 (15)3 (7.5)
      Presence of ulceration7 (17.5)7 (17.5)1
      En bloc resection40 (100)40 (100)NA
      Complete resection36 (90)39 (97.5).359
      Adverse events
       Post-ESD bleeding2 (5)3 (7.5)1
       Perforation00NA
       Others00NA
      Values are n (%) unless otherwise indicated.
      SLC-ESD, Spring-and-loop with clip traction-assisted endoscopic submucosal dissection; C-ESD, conventional endoscopic submucosal dissection; IQR, interquartile range; SD, standard deviation; NA, not applicable.
      P < .05.
      Intramucosal cancers and adenomas are included in this category.

      SLC-related factors

      SLC-related factors for the SLC-ESD group are shown in Table 3. The mean SLC attachment time was 1.82 minutes, and the mean number of SLC applications was 1.15. SLC slip-off was only observed once, and this was due to rough attachment. Reattachment was required in 6 patients to add traction force (3 times), because of failure to attach the SLC (2 times), and because of slip-off (1 time). Another SLC was used for reattachment in these 6 patients. In all cases, no SLC-related specimen damage or SLC breakage occurred, and anchor clips were removed successfully and without adverse events.
      Table 3SLC-related factors
      Attachment time, minutes
       Mean (SD)1.82 (0.75)
       Median (IQR)1.45 (1.16-1.95)
       Range0.82-4.25
      Application (n), mean (SD)1.15 (0.36)
      Reattachment6 (15)
      Slip-off1 (2.5)
      Damage to specimen0 (0)
      Breakage0 (0)
      Successful removal of anchor clip40 (100)
      Values are n (%) unless otherwise indicated.
      SLC, Spring-and-loop with clip; SD, standard deviation; IQR, interquartile range.

      Endoscopic position during submucosal dissection

      Table 4 shows the endoscopic position during submucosal dissection. Overall, the forward endoscopic position was selected more often than the retroflexed endoscopic position in SLC-ESD, whereas the forward endoscopic position was selected at the same frequency as the retroflexed endoscopic position in C-ESD. For lesions in the upper and middle third of the stomach, there was a tendency to select the forward endoscopic position for SLC-ESD, whereas the retroflexed endoscopic position was selected more frequently for C-ESD. For lesions in the lesser curvature, the forward endoscopic position was selected significantly more often in SLC-ESD than in C-ESD.
      Table 4Endoscopic position during submucosal dissection
      SLC-ESD (n = 40)C-ESD (n = 40)P value
      Total27/1320/20.173
      Lesion location
       Upper4/32/4.592
       Middle11/88/11.517
       Lower12/210/5.390
      Lesion position
       Greater curvature6/46/1.338
       Lesser curvature13/64/11.037
      P < .05.
       Anterior wall6/05/2.462
       Posterior wall2/35/61
      Values are number (forward endoscopic position/retroflexed endoscopic position) unless otherwise indicated.
      SLC-ESD, Spring-and-loop with clip traction-assisted endoscopic submucosal dissection; C-ESD, conventional endoscopic submucosal dissection.
      P < .05.

      Subgroup analysis

      Table 5 shows the results of the subgroup analyses for ESD procedure time by lesion location and size. The median ESD procedure time for lesions located at the upper- and middle-third of the stomach and for those measuring ≤20 mm in size was significantly shorter in the SLC-ESD group than in the C-ESD group.
      Table 5Subgroup analysis comparing ESD procedure time by lesion location and size
      SLC-ESD (n = 40)C-ESD (n = 40)P value
      NumberMedian (interquartile range)NumberMedian (interquartile range)
      Lesion location
       Upper, middle2639.4 (26.0-64.3)2558.3 (51.9-90.1).005
      P < .05.
       Lower1422.8 (16.9-34.0)1536.2 (27.4-47.6).146
      Lesion size
       ≤20 mm3226.2 (17.5-43.9)3047.4 (33.0-58.3)<.001
      P < .05.
       >20 mm893.8 (76.4-107.7)1094.7 (55.7-107.4)1
      SLC-ESD, Spring-and-loop with clip traction-assisted endoscopic submucosal dissection; C-ESD, conventional endoscopic submucosal dissection.
      P < .05.

      Multivariate analysis

      Multiple regression analysis was reliable (F statistic; P < .001) and had little multicollinearity (all variance inflation factors, <1.1). The results indicated that resection method, lesion location, ulceration, and specimen area were independently associated with ESD procedure time (Table 6).
      Table 6Multiple regression analysis for factors associated with gastric ESD procedure time
      Variablesβ95% CIP value
      Resection method (SLC-ESD or C-ESD)−0.333−0.275 to −0.118<.001
      P < .05.
      Lesion location (U, M, or L)0.13250.113-0.275<.001
      P < .05.
      Lesion position (GC or others)−0.1192−0.171-0.025.1418
      Ulceration (positive or absence)0.25330.090-0.303<.001
      P < .05.
      Specimen area1.24070.636-1.027<.001
      P < .05.
      Age0.0759−0.002-0.008.2706
      Sex (male or female)0.0966−0.021-0.160.1294
      β, Standardized regression coefficient; CI, confidence interval; SLC-ESD, spring-and-loop with clip traction-assisted endoscopic submucosal dissection; C-ESD, conventional endoscopic submucosal dissection; U, upper third of the stomach; M, middle third of the stomach; L, lower third of the stomach; GC, greater curvature of the stomach.
      P < .05.

      Discussion

      The purpose of the present study was to investigate whether SLC-ESD improves procedure-related outcomes in comparison with C-ESD among patients with superficial gastric neoplasms. We demonstrated that SLC-ESD reduced the gastric ESD procedure time without increasing the risk of adverse events. Multiple regression analysis indicated that the resection method (SLC-ESD or C-ESD) was independently associated with ESD procedure time. The mean SLC attachment time was 1.82 minutes, which may be reasonable for clinical practice.
      Although many traction methods have been developed for ESD, little attention has been given to the optimal traction direction. The terms traction and countertraction are used interchangeably in the published literature, with little consideration given to traction direction. Moreover, the subtle distinction between these words results in the potential for confusion.
      • Uppal D.S.
      • Wang A.Y.
      Traction-assisted endoscopic submucosal dissection in the esophagus: should we all be flossing?.
      Traction can be roughly classified into 3 categories (ie, vertical, proximal, and distal) based on the direction against the GI wall and the endoscope tip (Fig. 5).
      Figure thumbnail gr5
      Figure 5Differences in the effects of traction direction during submucosal dissection. A, Vertical traction. This can provide proper submucosal visualization and sufficient tension of submucosa. B, Proximal traction. This can provide sufficient tension for the submucosal dissection plane. However, if the tip of the endoscope cannot be parallel to the gastric wall, it can be difficult to approach the submucosal layer, even with proximal traction. C, Distal traction. This can cause the submucosal dissection plane to fall distally as submucosal dissection advances and can cause misrecognition of the layer, resulting in cutting into the muscle layer or mucosa. D, Diagonally proximal traction. The distance between the SLC attachment site and the anchor site becomes longer than that of vertical traction. Although the distance between the SLC attachment site and the anchor site decreases as submucosal dissection advances, this long-distance helps prevent the attenuation of traction force due to spring shrinkage (eg, Hooke’s law). SLC, Spring-and-loop with clip.
      We selected vertical traction for SLC-ESD in this study (Fig. 5A), which opened the mucosal cutting edge and improved submucosal visualization while providing adequate submucosal tension. Therefore, vertical traction allows submucosal dissection under the direct view of the submucosa, even when stable deployment of the mucosal flap using the endoscope tip is challenging to perform because of severe submucosal fibrosis, gravity, wide movement of the lesion caused by the patient’s respiration, and difficulties in accessing the lesion. If it is difficult to access the lesion with a standard endoscope for anatomic reasons, a multibending endoscope (GIF-2TQ260M; Olympus), which has 2 bent sites at its tip, makes it easier to close the lesion and deploy the mucosal flap with the endoscope tip.
      • Hamada K.
      • Horikawa Y.
      • Koyanagi R.
      • et al.
      Usefulness of a multibending endoscope in gastric endoscopic submucosal dissection.
      However, not every facility has a multibending endoscope because it is a special device. In such a situation, vertical traction may help address the issue.
      By contrast, proximal traction can provide sufficient tension in the submucosal dissection plane (Fig. 5B) and may be effective for esophageal ESD because the endoscope tip is parallel to the esophageal wall and can easily access the submucosa without vertical traction. Indeed, the clip-with-line method allows for adequate proximal traction in esophageal ESD, effectively reducing the procedure time compared with C-ESD in a recent multicenter randomized controlled trial.
      • Yoshida M.
      • Takizawa K.
      • Nonaka S.
      • et al.
      Conventional versus traction-assisted endoscopic submucosal dissection for large esophageal cancers: a multicenter, randomized controlled trial (with video).
      However, proximal traction cannot always be effective in gastric ESD. If the tip of the endoscope cannot be parallel to the gastric wall, it may be difficult to approach the submucosal layer with proximal traction. In addition, distal traction may cause the submucosal dissection plane to fall distally, making the procedure difficult in some cases (Fig. 5C). Vertical traction may therefore be most appropriate for gastric ESD based on our findings that it reduced the ESD procedure time and increased the dissection speed without increasing the risk of adverse events after SLC-ESD.
      In a recent multicenter randomized controlled trial, the clip-with-line method did not reduce the procedure time for gastric ESD compared with C-ESD in the total population, but it did for lesions located at the greater curvature of the upper and middle third of the stomach.
      • Yoshida M.
      • Takizawa K.
      • Suzuki S.
      • et al.
      Conventional versus traction-assisted endoscopic submucosal dissection for gastric neoplasms: a multicenter, randomized controlled trial (with video).
      These results seem reasonable because the traction direction of the clip-with-line method is limited to the oral side via the cardia in gastric ESD, making it anatomically difficult to provide vertical traction unless the lesion is located at the greater curvature. Moreover, the clip-with-line method can result in distal traction when submucosal dissection is performed in the retroflexed endoscopic position, which is common for gastric ESD. By contrast, the SLC can facilitate vertical traction regardless of the lesion location. However, the efficacy of the SLC method may depend on the lesion location. According to a subgroup analysis, the procedure time of SLC-ESD in the upper and middle third of the stomach was significantly shorter than that of C-ESD. In the lower third of the stomach, no significant difference was found between the 2 procedures. This result could be attributed to 2 reasons. First, ESD in the lower third of the stomach is basically easier than that in the upper and middle third of the stomach.
      • Imagawa A.
      • Okada H.
      • Kawahara Y.
      • et al.
      Endoscopic submucosal dissection for early gastric cancer: results and degrees of technical difficulty as well as success.
      ,
      • Kim S.J.
      • Choi C.W.
      • Nam H.S.
      • et al.
      Factors associated with conversion to snare resection during gastric endoscopic submucosal dissection.
      Second, the lumen in the lower third of the stomach is generally narrower than that in the upper and middle third of the stomach. Hence, the distance between the SLC attachment site and the anchor site is challenging to maintain, thereby shortening spring extension and causing lower traction force. This occurs because Hooke’s law dictates that the traction force exerted by the spring is proportional to the spring extension. Therefore, in terms of lesion location, SLC-ESD may be effective in the upper and middle third of the stomach.
      Despite our generally promising results, SLC-ESD was not associated with a reduction in the ESD procedure time for lesions >20 mm. Although this result may be due to the inclusion of few lesions measuring >20 mm, we cannot exclude the possibility that the benefit of SLC is limited by lesion size. Generally, as submucosal dissection advances, the distance between the SLC attachment site and the anchor site decreases, meaning that the traction force of SLC gradually weakens as the spring shortens. Therefore, submucosal dissection can complete before the traction force becomes insufficient if the lesion size is small but cannot complete if the lesion size is large. Three cases required reattachment of the SLC due to reduced traction force in this study, of which 2 measured >20 mm and 1 measured approximately 20 mm. A similar trend was also observed in our previous study.
      • Nagata M.
      Internal traction method using a spring-and-loop with clip (S–O clip) allows countertraction in gastric endoscopic submucosal dissection.
      For larger lesions, increasing the distance between the SLC attachment site and the anchor site by selecting diagonally proximal traction rather than vertical traction may help maintain the traction force during submucosal dissection (Fig. 5D). It has been reported that the mean tumor size of superficial gastric neoplasms indicated for ESD is 18 mm.
      • Akintoye E.
      • Obaitan I.
      • Muthusamy A.
      • et al.
      Endoscopic submucosal dissection of gastric tumors: A systematic review and meta-analysis.
      Nevertheless, further studies are needed to investigate the efficacy of SLC-ESD for large lesions.
      The cost-effectiveness of the procedure should be considered. SLC-ESD requires 1 SLC and 1 regular hemoclip (ZP-CH, Zeon Medical) as an anchor clip, which costs ¥5000 and ¥750 (U.S.$50 and U.S.$7.5, at an exchange rate of ¥100 = U.S.$1), respectively. The SLC-ESD group demonstrated approximately 45% reduction of the median ESD procedure time. Hence, SLC-ESD may be advantageous in terms of cost. With consideration of cost-effectiveness and the outcomes of the subgroup analysis, we recommend SLC-ESD particularly for lesions in the upper and middle third of the stomach and those measuring ≤20 mm.
      Currently, SLC is sold only in Japan. However, it will be sold under the name “Countertraction CLIP” in Asian countries in the future. In countries where the SLC is not available, other traction devices that allow the traction direction to be controlled vertical to the GI wall might be used as an alternative. Such traction devices include ring thread,
      • Mori H.
      • Kobara H.
      • Nishiyama N.
      • et al.
      Novel effective and repeatedly available ring-thread counter traction for safer colorectal endoscopic submucosal dissection.
      multiloop,
      • Suzuki Y.
      • Tanuma T.
      • Nojima M.
      • et al.
      Multiloop as a novel traction method in accelerating colorectal endoscopic submucosal dissection.
      double clip and rubber band,
      • Jacques J.
      • Charissoux A.
      • Bordillon P.
      • et al.
      High proficiency of colonic endoscopic submucosal dissection in Europe thanks to countertraction strategy using a double clip and rubber band.
      and clip-band devices,
      • Ge P.S.
      • Aihara H.
      A novel clip-band traction device to facilitate colorectal endoscopic submucosal dissection and defect closure.
      which uses a thread or a band instead of a spring. However, these devices are usually utilized in colorectal ESD. Thus, their efficacy and feasibility in gastric ESD are unclear. There is a risk of specimen laceration when the endoscope interferes with a thread or a band because their elasticity might be lower than that of the SLC’s spring. Regardless of the device used, the modified attachment method, as described in the section on “SLC-ESD procedure in the retroflexed endoscopic position,” should be adopted to prevent interference between the endoscope and the traction device in the retroflexed endoscopic position.
      It is important to minimize interference between the endoscope and the traction device to avoid excessive force at the site of traction device attachment, which could cause it to slip-off. In peroral traction methods, interference between the endoscope and the traction device due to friction is unavoidable in the narrow spaces where the traction device passes, such as the pharynx, esophagus, and cardia. The slip-off rate of clips when using the clip-with-line method has been reported to be 13.2%.
      • Yoshida M.
      • Takizawa K.
      • Suzuki S.
      • et al.
      Conventional versus traction-assisted endoscopic submucosal dissection for gastric neoplasms: a multicenter, randomized controlled trial (with video).
      In this scenario, SLC-ESD can avoid interference between the endoscope and spring by the modified attachment of the SLC, thereby reducing the risk of SLC slip-off. In the current study, for example, the SLC slip-off rate was only 2.5%.
      This study has several limitations. First, we could not blind the operator to treatment group allocation, which could have led to performance bias. However, it is reassuring that the median procedure time for C-ESD was comparable with the time we previously reported.
      • Nagata M.
      Internal traction method using a spring-and-loop with clip (S–O clip) allows countertraction in gastric endoscopic submucosal dissection.
      Performing both ESD procedures at the same site also helped to mitigate this issue. Second, a modified attachment method is needed to use SLC for gastric ESD and requires some experience. In this study, a single operator who has extensive experience in both SLC-ESD and C-ESD performed all procedures. Further study should focus on investigating the feasibility of SLC-ESD for novice operators.
      In conclusion, we conducted the first randomized controlled trial to determine whether SLC-ESD improves procedure-related outcomes compared with C-ESD when treating superficial gastric neoplasms. We demonstrated that SLC-ESD effectively reduced the gastric ESD procedure time without increasing the risk of adverse events. We also showed that the mean SLC attachment time was only 1.82 minutes with our approach. This indicates that SLC-ESD in the vertical direction may be reasonable for use in clinical practice.

      Supplementary data

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