Routine mucosal closure with a detachable snare and clips after endoscopic submucosal dissection for gastric epithelial neoplasms: a randomized controlled trial.

Abstract

The aim of this study was to determine whether the routine closure of mucosal defects after endoscopic submucosal dissection (ESD) can enhance mucosal healing and reduce ESD-associated bleeding.
Patients with gastric epithelial neoplasias and no obvious submucosal invasion were prospectively enrolled. Mucosal defects were left untreated in the control group. In the study group, mucosal closure was attempted with a 2-channel endoscope, a detachable snare, and clips. All participants received a second-look endoscopy the day after ESD, and coagulation therapy was administered to patients with visible vessels and active bleeding points.
Fifty-two patients were enrolled in the study, and 26 patients were assigned to each group. Complete mucosal defect closure occurred in 16 patients (61%) in the study group; incomplete closure occurred in 8 patients (31%) in the study group, and failed closure occurred in 2 patients (8%). Coagulation therapy at the second-look endoscopy was performed more often in the control group than in the study group (31% vs 4%, p=0.024). There were no significant differences in the incidence of immediate or delayed bleeding or in the two-week decrease in hemoglobin between the groups. The prevalence of open ulcers after 8 weeks was significantly lower in the study group than in the control group (18% vs 43%, p=0.012).
Routine mucosal closure after ESD supports earlier healing of artificial ulcers. A larger-scale trial is necessary to determine whether mucosal closure can reduce ESD-associated bleeding.

Full text

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ORiginal Article
Gut and Liver, Vol. 5, No. 4, December 2011, pp. 454-459
Routine Mucosal Closure with a Detachable Snare and Clips after
Endoscopic Submucosal Dissection for Gastric Epithelial Neoplasms: A
Randomized Controlled Trial
Bo-In Lee*, Byung-Wook Kim*, Hyung-Keun Kim†, Hwang Choi*, Jeong-Seon Ji*, Sun-Mee Hwang*, Young-Seok Cho†,
Hiun-Suk Chae†, and Kyu-Yong Choi‡
*Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary’s Hospital, The Catholic University of Korea College of
Medicine, Incheon, †Division of Gastroenterology, Department of Internal Medicine, Uijeongbu St. Mary’s Hospital, The Catholic University
of Korea College of Medicine, Uijeongbu, and ‡Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary’s Hospital, The
Catholic University of Korea College of Medicine, Seoul, Korea
Background/Aims: The aim of this study was to determine
whether the routine closure of mucosal defects after endo-
scopic submucosal dissection (ESD) can enhance mucosal
healing and reduce ESD-associated bleeding. Methods:
Patients with gastric epithelial neoplasias and no obvious
submucosal invasion were prospectively enrolled. Mucosal
defects were left untreated in the control group. In the study
group, mucosal closure was attempted with a 2-channel
endoscope, a detachable snare, and clips. All participants
received a second-look endoscopy the day after ESD, and
coagulation therapy was administered to patients with vis-
ible vessels and active bleeding points. Results: Fifty-two
patients were enrolled in the study, and 26 patients were
assigned to each group. Complete mucosal defect closure
occurred in 16 patients (61%) in the study group; incomplete
closure occurred in 8 patients (31%) in the study group,
and failed closure occurred in 2 patients (8%). Coagulation
therapy at the second-look endoscopy was performed more
often in the control group than in the study group (31% vs
4%, p=0.024). There were no significant differences in the
incidence of immediate or delayed bleeding or in the two-
week decrease in hemoglobin between the groups. The
prevalence of open ulcers after 8 weeks was significantly
lower in the study group than in the control group (18% vs
43%, p=0.012). Conclusions: Routine mucosal closure after
ESD supports earlier healing of artifi cial ulcers. A larger-scale
trial is necessary to determine whether mucosal closure can
reduce ESD-associated bleeding. (Gut Liver 2011;5:454-459)
Correspondence to: Byung-Wook Kim
Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary’s Hospital, The Catholic University of Korea College of Medicine,
665 Bupyeong-dong, Bupyeong-gu, Incheon 403-720, Korea
Tel: +82-32-280-5052, Fax: +82-32-280-5987, E-mail: gastro@catholic.ac.kr
Received on February 22, 2011. Revised on March 30, 2011. Accepted on April 10, 2011.
pISSN 1976-2283 eISSN 2005-1212 http://dx.doi.org/10.5009/gnl.2011.5.4.454
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Key Words: Stomach neoplasms; Endoscopic submucosal
dissection; Closure
INTRODUCTION
The development of endoscopic submucosal dissection (ESD)
has enabled the en bloc resection of larger gastrointestinal
neoplasms.1,2 However, ESD-associated complications such as
perforation and bleeding are still serious considerations. Some
studies have shown that postoperative bleeding occurs in ap-
proximately 6% to 16% of patients after gastric ESD.3-5 While
surgeons almost always approximate and close surgical wounds
after surgery, a mucosal defect remains following gastric ESD.
Such defects may be associated with complications such as
bleeding.
Mucosal closure with clips is not always feasible, especially
for larger defects after ESD.6 However, we have shown that larg-
er mucosal defects can be closed with a two-channel endoscope,
a detachable snare, and clips.7 Other researchers have used a
comparable method to close mucosal defects after colorectal en-
doscopic mucosal resection (EMR).8
This study was performed to determine whether the routine
closure of mucosal defects after ESD with a detachable snare
and clips can enhance mucosal healing, shorten hospital stays,
and reduce ESD-associated complications.

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Lee BI, et al: Mucosal Closure after Endoscopic Resection 455
MATERIALS AND METHODS
1. Study subjects
This randomized controlled trial was carried out at Incheon
St. Mary’s Hospital, The Catholic University of Korea in
Incheon, Korea between January 2008 and August 2009. The
protocol was approved by the Institutional Review Board. Eli-
gible patients had gastric epithelial neoplasias (noninvasive low
grade dysplasia, noninvasive high grade dysplasia, or invasive
neoplasia without obvious submucosal invasion).9 The depth of
invasion was estimated primarily by gross findings. Endoscopic
ultrasonography (EUS) was performed when the depth of inva-
sion could not be assessed by gross findings only. All biopsy
specimens from the body and antrum were stained using the
Warthin-Starry method to identify Helicobacter pylori infection
at the preoperative endoscopy.
Patients were excluded from the study if they had received
anticoagulant, or had a coagulation disorders, end-stage renal
disease, severe cardiopulmonary disorder, or undifferentiated
cancer. Patients were also excluded if they were scheduled to
receive ESD for multiple gastric lesions or a locally recurrent le-
sion after a previous EMR or ESD. Patients were also excluded
if a clip was applied to control profuse bleeding or to close an
obvious or impending perforation during the procedure. Pa-
tients with neoplasia at the cardia, fundus, or upper one third
of corpus were not included because mucosal closure with a
detachable snare and clips often cannot be performed at those
locations.
Antiplatelet agents, including aspirin, were stopped one week
before ESD and were then withdrawn for three weeks under the
supervision of the cardiologist or neurologist.
2. ESD
All ESD procedures were performed by one physician (B.W.
Kim). During the procedure, patients were under conscious se-
dation with midazolam (0.05 mg/kg) and pethidine (50 mg); ad-
ditional doses were given according to the physician’s instruc-
tions.
A conventional gastroscope (GIF-Q240X; Olympus, Tokyo,
Japan) fitted with a transparent distal attachment (D-201-11304;
Olympus) was used for the ESD procedures. The margin of the
tumor was determined by gross findings and indigocarmine
chromoscopy. Circumferential markings were generated with
argon plasma coagulation, effect 2 (ARCO 3000; Söring GmbH,
Quickborn, Germany), 0.5 cm from the margin of the tumor. Af-
ter a mixture of 0.9% normal saline and 0.0005% epinephrine
was injected into the submucosal layer, a precut was made out-
side the marking with a hook knife (KD-620LR; Olympus) and
an Endocut-I current (effect 1, duration 3, interval 3; VIO300D;
ERBE Elektromedizin GmbH, Tübingen, Germany). Submucosal
dissection was performed mainly with a hook knife and a forced
coagulation current (effect 2, 40 W). A coagrasper (FD-410LR;
Olympus) and a soft coagulation current (effect 7, 80 W) was
primarily used to control bleeding.
ESD was performed as extensively as possible for complete
removal of the lesion. When extreme difficulty was encountered
during the submucosal dissection for any reason (e.g., severe
fibrosis or profuse bleeding), snaring with an Endocut-Q current
was allowed for the final excision.
The size of the resected specimen/mucosal defect was mea-
sured with a 3-cm flexible linear probe, and the area was esti-
mated using the formula to calculate the area of an ellipse (1/4×ϖ
×major axis×minor axis).
3. Mucosal closure
Patients were randomly assigned to either a study group or
a control group; attempts were made to close mucosal defects
in the study group, and these defects were left untreated in the
Fig. 1. Mucosal closure with a de-
tachable snare and clips after endo-
scopic submucosal dissection. (A) A
mucosal defect remains after ESD.
(B) A detachable snare is deployed
on the mucosal defect through a
working channel, and a rotating
clip-fixing device with a long clip
is inserted through the other work-
ing channel. (C) The wire of the
detachable snare is placed between
both legs of the clip. (D) The clip is
applied to the edge of the mucosal
defect. (E) Another clip is applied
to the opposite side of the mucosal
defect in the same manner. (F) The
snare is squeezed gently, and the
mucosal defect is approximated. (G)
Additional clips are applied to close
the defect. (H) The defect is closed
completely.

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456 Gut and Liver, Vol. 5, No. 4, December 2011
control group. Mucosal closure was performed with a double
channel endoscope (GIF-2T200; Olympus), a detachable snare
(HX-20Q; Olympus), and clips (HX-610-090L; Olympus) (Fig. 1).7
‘Complete closure’ occurred when no submucosa or muscle was
apparent after the closure (Fig. 2). ‘Incomplete closure’ occurred
when the mucosal defect was still visible after the procedure but
had clearly decreased in size. ‘Failed closure’ occurred when the
size of the mucosal defect could not be decreased using the pro-
cedure.
4. Post-ESD protocol
Following the ESD procedure, pantoprazole (40 mg) was ad-
ministered intravenously once a day for 3 days and then given
to the patients orally. All participants received a second-look
endoscopy on the day after ESD; during this endoscopy, dehis-
cence of the mucosal closure was assessed, particularly in the
study group. Visible vessels or active bleeding was treated with
a coagrasper and soft coagulation as described above.
Patients who did not receive coagulation therapy at the
second-look endoscopy were allowed to eat a light meal the day
after ESD. Those who did receive coagulation therapy were al-
lowed to eat a light meal the day after the therapy. All patients
were discharged from the hospital the day after oral intake was
allowed unless they showed any signs or symptoms of com-
plications (i.e., significant changes in vital signs, persistent ab-
dominal pain, or tarry stools). Hemoglobin levels were checked
daily during admission and a follow-up check was performed
at the outpatient department 2 weeks after ESD. Pantoprazole
was maintained for 6 weeks, and a follow-up endoscopy was
performed 8 weeks after ESD.
5. Assessment
All specimens were fixed with formalin, cut into 2-mm slices
and examined. Histological assessment was performed accord-
ing to the Vienna classification of gastrointestinal epithelial
neoplasia.9
‘Complete submucosal dissection’ occurred when the lesion
could be cut off without snaring. ‘En bloc resection’ was defined
as a single-piece resection of the entire lesion where the rim of
the artificial ulcer was tumor-free after ESD. ‘Histologic com-
plete resection’ occurred when no neoplasia could be observed
histologically in the lateral or deep margin of the resected speci-
men.
Immediate bleeding was defined as either a hemodynamic
change or a necessary blood transfusion during or within 24
hours of the procedure. Delayed bleeding was defined as bleed-
ing requiring transfusion or endoscopic hemostasis, or as a 2
g/dL or more decrease in hemoglobin concentration after 24
hours.
The ESD procedure time was measured from the insertion of
the endoscope to its withdrawal and included the mucosal clo-
sure.
At the follow-up endoscopy 8 weeks after ESD, a closed ulcer
was defined when complete epithelialization was achieved and
no exudation or fibrin was observed.
6. Statistical analysis
A chi-square (χ2) test was used to compare the sex ratio and
the prevalence of H. pylori infection between the control and
study groups. Fisher’s exact test was used to compare the fol-
lowing variables between the two groups: recent use of anti-
platelet agents, tumor location, the rate of complete submucosal
dissection, en bloc resection and histologic complete resection,
final histology, the frequency of coagulation therapy at the
second-look endoscopy, and the incidence of immediate and
delayed bleeding. Fisher’s exact test was also used to examine
the prevalence of open ulcers at 8 weeks after ESD in relation to
Fig. 2. The mucosal defect at the gastric angle is closed completely
with a detachable snare and clips.
Table 1. Baseline Characteristics of the Control and Study Group
CharacteristicControl group Study group p-value
Sex
Male
Female
19 (73)
7 (27)
63.9±6.8
18 (69)
8 (31)
63.2±7.8
1.000
Age, yr
Recent use of
antiplatelet agents
H. pylori infection
Location
Body
Angle
Antrum
Pyloric ring
0.720
0 (0)1 (4)1.000
18 (70) 17 (65) 0.768
8 (31)
3 (11)
13 (50)
2 (8)
7 (27)
1 (4)
18 (69)
0 (0)
0.324
Data are presented as mean±SD or number (%).

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Lee BI, et al: Mucosal Closure after Endoscopic Resection 457
the completeness of mucosal closure in the study group.
The Student’s t-test was used to compare age, procedure time,
and decrease in hemoglobin 2 weeks following ESD. A Wilcox-
on rank sum test was used to compare the area of the resected
specimen, the area of the mucosal defect, procedure time per
area of resected specimen, and duration of stay in the hospital
between the control and study groups. The area of the mucosal
defect that could be closed completely was also compared with
the area that could not be closed completely using a Wilcoxon
rank sum test.
A p-value of 0.05 was used to denote significance. SPSS ver-
sion 12.0 (SPSS Inc., Chicago, IL, USA) was used for all statisti-
cal calculations.
RESULTS
Fifty-two patients were enrolled in the study; 26 patients
were randomly assigned to each group. EUS was performed in
13 patients (25%), and all the lesions were confined within the
mucosal layer. There were no significant differences in sex, age,
recent use of antiplatelet agents, or prevalence of H. pylori in-
fection between the 2 groups. There was also no significant dif-
ference in the location of the neoplasia between the groups (Table
1). A second-look endoscopy was performed in all patients. A
follow-up endoscopy was performed 8 weeks after ESD in 81%
(21/26) of the control group patients and 85% (22/26) of the
study group patients.
There were no significant differences in the area of the re-
sected specimen or the mucosal defect between the control and
study groups. A snare was used at the final stage of dissection
in one case in each group. En bloc resection was performed
in all cases, whereas histologic complete resection was not
achieved in one case in the study group.
Among the control group, 11 (42%) patients had invasive
Table 2. Results of ESD between the Control and Study Group
VariableControl group Study group p-value
Area of resected specimen, median (range), cm2
Area of mucosal defect, median (range), cm2
Complete submucosal dissection
En bloc resection
Histologic complete resection
Final histology
Noninvasive low grade neoplasia
Noninvasive high grade dysplasia
Intramucosal carcinoma
10.3 (2.8–27.0)
14.1 (5.9–30.0)
25 (96)
26 (100)
26 (100)
7.7 (3.1–24.0)
11.0 (4.5–37.7)
25 (96)
26 (100)
25 (96)
0.164
0.213
1.000
–
1.000
11 (42)
4 (16)
11 (42)
6 (23)
6 (23)
14 (54)
0.344
Data are presented as median (range) or number (%).
ESD, endoscopic submucosal dissection.
Table 3. Mucosal Closure and Related Outcomes between the Control and Study Group
Variable Control group Study group p-value
Procedure time, mean±SD, min
Elapsed time for mucosal closure, median (range), min
Procedure time/area of resected specimen, median (range), min/cm2
Mucosal closure, n (%)
Complete
Incomplete
Failed
Coagulation therapy at the second-look endoscopy, n (%)
Immediate bleeding, n
Delayed bleeding, n (%)
Hb decrease 2 wk after ESD, mean±SD, g/dL
Hospital stay, median (range), day
Open ulcer until 8 wk after ESD, n (%)
58.4±26.6
-
4.6 (2.0–26.0)
62.2±20.0
14.4 (7.4–32.1)
6.8 (2.9–22.0)
0.562
-
0.026
-
16 (61)
8 (31)
2 (8)
1 (4)
0
1 (4)
0.0±0.9
3 (2–4)
2 (9)
–
8 (31)
0
0 (0)
0.3±0.7
4 (3–13)
9 (43)
0.024
–
1.000
0.273
0.000
0.016
Hb, hemoglobin level; ESD, endoscopic submucosal dissection.

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458 Gut and Liver, Vol. 5, No. 4, December 2011
neoplasia, whereas 14 (54%) patients presented this condition in
the study group. However, there was no case with submucosal
invasion in either group (Table 2).
Although there was no significant difference in the overall
procedure time between the control and study groups, there was
a significant difference in the procedure time per area of re-
sected specimen (Table 3). Among the study group, the mucosal
defect could be closed completely in 16 cases (61%) and incom-
pletely in 8 cases (31%). Mucosal closure failed in 2 cases (8%)
because the mucosal edge where the clip was applied tore when
the snare was squeezed. Among the study group, the median
area of the mucosal defect that could be closed completely was
10.1 cm2 (range, 4.5 to 23.0); the median area of the defect that
could be closed incompletely or could not be closed was 14.5
cm2 (range, 8.2 to 37.7; p=0.053).
At the second-look endoscopy, dehiscence occurred in 3
(19%) of the 16 patients whose mucosal defects had been closed
completely. The area of dehiscence was enlarged in 3 (38%) of
the 8 patients with incompletely closed mucosal defects. Eight
patients in the control group received coagulation therapy for
visible vessels or bleeding, while only one study group patient
required coagulation therapy (31% vs 4%, p=0.024).
No patients experienced immediate bleeding. One patient in
the control group developed acute pancreatitis after ESD that
was resolved with conservative care. Delayed bleeding occurred
in one study group patient 10 days after ESD; this patient’s
mucosal defect had been closed completely and the closure
showed no dehiscence at the second-look endoscopy. However,
an emergency endoscopy revealed complete dehiscence of the
closure and black stigmata on the ulcer base. There was no sig-
nificant difference in the 2-week hemoglobin decrease between
the control and study groups. The length of stay in the hospital
was significantly shorter in the study group than in the control
group (median 3 days, 2 to 4 vs. 4 days, 3 to 13; p=0.000).
There was a significant difference in the prevalence of open
ulcers 8 weeks after ESD between the control and study groups
(43% vs 18%, p=0.012). However, in the study group, no sig-
nificant relationship was observed between the prevalence of
open ulcers 8 weeks after ESD and the completeness of mucosal
closure (complete closure 8% vs incomplete closure 14% vs
failed closure 0%; p=1.000).
One or two clips remained in 9 patients (41%) from the study
group and no tumor recurrence was observed within 8 weeks
after ESD in either the control or study groups.
DISCUSSION
We hypothesized that immediate closure of the artificial ul-
cer by ESD would decrease exposure of the submucosal vessels
to gastric acid, pepsin, and mechanical stimuli and, therefore,
would decrease ESD-associated bleeding. However, this study
failed to confirm that routine mucosal closure after ESD can
reduce ESD-associated bleeding. Only one case of bleeding (2%)
occurred among 52 ESD procedures; this rate is much lower
than the bleeding rates reported in other studies.3-5 It is well
known that proton pump inhibitors (PPIs) effectively prevent
bleeding from the ulcer created after ESD,10,11 and in this study,
a standard dose of pantoprazole was given to all participants
intravenously for 3 days and then orally for 6 weeks. Coagula-
tion therapy at the second-look endoscopy might also decrease
bleeding rates in this study, although there is some debate over
whether a second-look endoscopy after gastric ESD can contrib-
ute to the prevention of delayed bleeding.4 In addition, patients
with a high risk of bleeding (i.e., those who received antico-
agulation therapies, who have coagulation disorders, end stage
renal disease, severe cardiopulmonary disease, or who required
the application of clips to control profuse bleeding during sub-
mucosal dissection) were excluded from the study; these exclu-
sions may have decreased the bleeding rate observed in the
study. Small numbers of the subjects in each group is another
limitation of the study.
Active bleeding or visible vessels were infrequently observed
in the study group at the second-look endoscopy, and therefore,
coagulation therapy was rarely necessary. However, stigmata
might be covered by the mucosal closure in the study group.
Finally, there was no significant difference in the incidence of
immediate or delayed bleeding or in the hemoglobin decrease
between the groups.
It is not conclusive that mucosal closure shortened hospital
stay even though the duration was significantly shorter in the
study group than in the control group. Patients who received
coagulation therapy were allowed a meal 1-day later than those
who did not, therefore the result of the second-look endoscopy
might play as a primary determinant of hospital stay. In addi-
tion, the patient who developed acute pancreatitis in the control
group was admitted for 13 days.
However, the present study did demonstrate that mucosal
closure after ESD facilitated healing of the artificial ulcer. When
the continuity of the mucosal epithelium of the gastrointestinal
tract is disrupted, a process called ‘restitution’ occurs as viable
epithelial cells migrate from areas adjacent to the injured sur-
face to re-establish a barrier to the noxious substances within
the lumen.12,13 Approximation with a detachable snare and clips
is comparable to restitution because the process forces the mi-
gration of the mucosal layer to the artificial ulcer and reseals
the barrier.
The prevalence of open ulcer 8 weeks after ESD in the control
group seems to be higher than those in other studies.14,15 This
may be because H3 stage ulcers were considered as open ulcers
in this study and PPI was discontinued 2 weeks before a follow
endoscopy.
One potential concern is that mucosal closure after ESD could
conceal local recurrence of the tumor. However, there is cur-
rently no evidence that mucosal closure delays the detection of