Introduction
Endoscopic full-thickness resection (EFTR) is considered one of the less invasive
endoluminal surgeries for gastric neoplasms such as gastrointestinal stromal tumours
(GISTs) [1]
[2]
[3]. However, it has several technical issues that are difficult to address. For example,
conventional EFTR involves intentional perforation to resect a lesion in a full-layered
manner, which can cause air leakage and deflation of the stomach, and management of
the endoscope in a collapsed stomach is difficult owing to poor endoscopic visualisation.
Furthermore, secure endoscopic closure of a wall defect after resection is technically
demanding, particularly in a deflated stomach. Various closure methods have been proposed
so far [4]
[5]
[6]; however, most of these methods are still in development, and hence, have been infrequently
introduced in a clinical setting.
Endoscopic resection with submucosal tunnelling has been indicated for intraluminally
growing submucosal tumours in the esophagus or stomach [7]
[8]
[9]. However, this technique innately involves enucleation surgery without adequate
safety margins; therefore, unexpected injury of the capsule around the tumor can occur,
which might cause tumour seeding through the seromuscular defect.
To avoid these drawbacks in conventional EFTR and the endoscopic enucleation technique,
we developed a novel EFTR approach termed third-space EFTR. With this novel approach,
lesions can be removed transorally in a full-thickness manner without collapse of
the stomach or a decrease in endoscopic visualization. The current study aimed to
demonstrate the feasibility and safety of third-space EFTR in ex vivo and in vivo
porcine survival models.
Methods
Settings
The ex vivo study included three porcine stomachs isolated from pigs used for food.
After rinsing the insides of the stomachs with tap water, they were set in a training
kit for endoscopic submucosal dissection (ESD). In addition, endoscopic instruments
were prepared for ESD and endoscopic hand suturing (EHS), as described elsewhere [10]
[11]. A simulating lesion approximately 3 cm in diameter was created in each stomach
by simply placing mucosal markings.
The in vivo porcine survival study was performed after obtaining approval from the
institutional review board of our animal laboratory. The study included four live
pigs weighing approximately 20 kg. Under general anaesthesia, third-space EFTR was
performed as mentioned below. As in the ex vivo study, a gastric lesion was created
in each of the pigs. After completion of the procedure, on waking up, the pigs were
allowed to drink water and eat soft food on postoperative day (POD) 1, followed by
normal food on POD 2. We administered 0.5 g of cefazolin sodium hydrate which was
intramuscularly injected just before the procedure and 0.5 g of cefalexin with diet
from postoperative Day 1 until Day 3. Proton pump inhibitor was not administered perioperatively.
The pigs were carefully monitored thereafter. On POD 7, they were endoscopically observed
and killed for autopsy.
Third-space EFTR
Third-space EFTR involved several endoscopic procedures ([Fig. 1]). First, a circumferential mucosal incision was made around the lesion using the
DualKnife (KD-650-L; Olympus Co. Ltd, Tokyo, Japan) after submucosal injection, and
then the submucosa on the lateral side was undermined to enlarge the submucosal space.
Second, a submucosal tunnel 3 to 4 cm in length was created on the proximal side of
the lesion by removing the proximal mucosa with the ESD technique and suturing the
lateral mucosa with the EHS technique in the shape of a tunnel or by simply using
the per-oral endoscopic myotomy (POEM) technique [12]. Third, the mucosa surrounding the lesion was linearly sutured using the EHS technique,
with the lesion extruded towards the outside. Fourth, submucosal dissection was performed
around the lesion through the submucosal tunnel to broaden the “third space” around
the lesion until the endoscope could smoothly approach the muscular layer around the
lesion. Fifth, a seromuscular incision was made circumferentially to remove the lesion,
and it was transorally retrieved through the submucosal tunnel. The procedure was
completed with entry site closure using the EHS technique or clipping.
Fig. 1 Schema of third-space endoscopic full-thickness resection a The procedure is initiated by a circumferential mucosal incision of the lesion and
an approach to undermine the surrounding submucosal layer, followed by the creation
of a submucosal tunnel 3 to 4 cm in length on the proximal side of the lesion. b The surrounding mucosa is tightly sutured using the endoscopic hand suturing technique,
with the lesion everted towards the outside of the stomach. c Through the submucosal tunnel, the seromuscular layer around the everted lesion is
circumferentially resected under counter-traction created by the clip-and-string technique.
d The lesion is retrieved through the submucosal tunnel and the mouth (the tunnel may
be broadened according to lesion size). e The procedure is completed with entry site closure of the submucosal tunnel. (Illustration:
Isamu Shinohara and Kazunori Honjoh)
Outcome measures
As technical outcomes, completeness of the procedure, achievement of R0 resection
and procedure duration were investigated in both the ex vivo and in vivo studies.
Furthermore, the amount of intraoperative bleeding, occurrence of intraoperative and
postoperative adverse events (AEs), 1-week survival, existence of anastomotic leakage
at POD 7, post mortem gross findings in the abdominal cavity, and histological findings
at the surgical site were assessed in the in vivo study.
Results
Ex vivo study
A submucosal tunnel was created by suturing both edges of the mucosal defect at the
proximal side. The procedure was successfully completed with R0 resection using only
the DualKnife ([Table 1]). Mean duration of the procedure was 124.3 ± 11.6 minutes. In addition, mean maximum
sizes of the mucosal and serosal sides were 32 mm and 34 mm, respectively.
Table 1
Ex vivo study details.
|
Cases
|
Location
|
Circumference
|
Procedure completeness
|
R0 resection
|
Total procedural time (min)
|
Time for hand suturing (min)
|
Mucosal size (mm × mm)
|
Serosal size (mm × mm)
|
1-week survival
|
|
Ex vivo 1
|
M
|
Post
|
Completed
|
Yes
|
112
|
48
|
30 × 20
|
40 × 20
|
|
|
Ex vivo 2
|
M
|
Less
|
Completed
|
Yes
|
135
|
48
|
40 × 25
|
38 × 22
|
|
|
Ex vivo 3
|
M
|
Ant
|
Completed
|
Yes
|
126
|
53
|
25 × 24
|
25 × 23
|
|
|
In vivo 1
|
N
|
Post
|
Completed
|
Yes
|
157
|
40
|
30 × 25
|
25 × 12
|
Alive
|
|
In vivo 2
|
M
|
Gre
|
Completed
|
Yes
|
110
|
38
|
35 × 32
|
23 × 8
|
Alive
|
|
In vivo 3
|
M
|
Ant
|
Completed
|
Yes
|
112
|
34
|
20 × 16
|
15 × 9
|
Alive
|
|
In vivo 4
|
M
|
Post
|
Completed
|
Yes
|
166
|
24
|
40 × 40
|
30 × 25
|
Alive
|
Min, minutes; post, posterior wall; less, lesser curvature; ant, anterior wall; gre,
greater curvature.
In vivo survival study
This study included four pigs. In the first two pigs, a submucosal tunnel was created
in the same
manner as in the ex vivo study. However, the suture site on the roof of the tunnel
partially
tore because of pressure from the endoscope at the seromuscular incision in the first
pig. The
damage was intraoperatively repaired with repeated EHS, and there were no issues.
Therefore, the
tunnel was created using the POEM technique in the latter two pigs. The procedure
was completed
in all pigs. Snaring resection was conducted in the first three cases. However, R0
resection
failed in the third pig owing to blind resection by snaring because the lesion moved
to the
distal side from the endoscope as we proceeded with the incision due to lack of counter-traction
and the accurate incision line became difficult to recognize. Therefore, in the fourth
pig,
counter-traction was utilized by pulling the proximal edge of the lesion using the
clip-with-string technique [13], which led to optimal and successful en-bloc resection using only the DualKnife
([Fig. 2], [Video 1]). Mean duration of the procedure was 136.3 ± 29.4 minutes ([Table 1]). In addition, mean maximum sizes of the mucosal and serosal sides were 31 mm and
23 mm, respectively. In all cases, no severe bleeding occurred, and minor bleeding
events were stopped spontaneously or by coagulation with the tip of the electrocautery
knife.
Fig. 2 Images of third-space endoscopic full-thickness resection in an in vivo porcine model.
a A mucosal incision around a simulating lesion is completed circumferentially. Subsequently,
submucosal dissection beneath the surrounding mucosa is partially performed to widen
the submucosal space. b A submucosal tunnel 3 to 4 cm in length is created at the proximal side of the lesion.
The oral side of the lesion is seen through the tunnel. c The mucosal layer around the lesion is closed using the endoscopic hand suturing
technique, with the lesion buried. d The buried lesion is visible in the “third space” through the submucosal tunnel.
e A seromuscular incision is performed while pulling the lesion with a clip and string.
f After retrieval of the lesion transorally, the entry site of the submucosal tunnel
is closed. g A mucosal plane of the resected specimen. h A serosal plane. Full-thickness resection is achieved with a pure endoscopic procedure.
Video 1 Third-space endoscopic full-thickness resection. Third-space endoscopic full-thickness
resection involves a circumferential mucosal incision, submucosal tunnelling at the
proximal side, a mucosal closure, and a seromuscular incision in the third space.
After retrieval of the specimen, the procedure is completed with entry site closure.
Pneumoperitoneum was inevitable in all cases; however, vital signs were stable during
the procedure, therefore, no abdominal puncture was required. All the pigs survived
without severe AEs. Endoscopy on POD 7 showed no anastomotic leakage in all the pigs
([Fig. 3a]). A small amount of ascites with a localized abscess at the wall defect was observed.
There was no fistula owing to firm attachment of the greater omentum ([Fig. 3b], [Fig. 3c]). Histologically, granulomatous tissue bridged the wall defect with attachment of
the omentum ([Fig. 3 d]). There was no apparent transmural communication. These changes were found in all
pigs and no apparent differences were observed.
Fig. 3 Gross and histological findings on postoperative Day 7. a Endoscopic findings. The resection scar and entry site are closed. b Serosal side of the operated site. The seromuscular defect is covered with the greater
omentum (arrow). c Inside of the operated site. No apparent fistula is seen. d Histology of the anastomotic site. A granulomatous change with massive fibrotic tissue
is seen. The greater omentum is patched to the seromuscular defect (arrowhead).
Discussion
In our two consecutive animal studies, we successfully demonstrated that third-space
EFTR was feasible and safe. With this technique, which does not involve direct perforation
and therefore does not involve deflation of the lumen, secure and optimal full-layered
resection is expected endoscopically, without a decrease in endoscopic visualization
and a subsequent decrease in endoscopic maneuverability. Accordingly, this technique
may be a secure and minimally invasive endoscopic option for transorally retrievable
submucosal tumors.
The three main components of third-space EFTR are mucosal incision and suturing, tunnelling
and seromuscular incision. Initiation of mucosal suturing before the seromuscular
incision is important to avoid full-layer perforation. Submucosal tunnelling is necessary
to approach the lesion for the seromuscular incision after mucosal suturing and to
avoid deflation of the lumen [14]. When compared with conventional EFTR, third-space EFTR additionally requires submucosal
tunnelling, and it is mandatory to overcome the drawbacks of conventional EFTR.
When compared with endoscopic enucleation [7]
[8]
[9], third-space EFTR enables removal of the lesion in a full-thickness manner without
exposure of the tumor surface. Particularly for a GIST, injury of the capsule around
the tumor should be avoided owing to the possibility of tumor cell seeding. In this
technique, it is possible to resect the lesion without causing injury to the capsule;
however, care should be taken to avoid unintentional rupture of the capsule. Furthermore,
submucosal dissection around the entire tumor surface is not required with this technique.
Therefore, this technically demanding phase in endoscopic enucleation can be skipped,
and the procedural time can be reduced. Obviously, this technique should not be used
to treat ulcerated GISTs or early adenocarcinomas because neoplastic cells are already
exposed in these lesions and therefore risk of peritoneal seeding may arise by performing
this transluminal technique.
In clinical settings, we may have to be careful to prevent damage to the suture site
in the seromuscular incision because, unlike the simulating lesions which are flat,
SMTs are large and bulging and might lead to tearing of the suture site due to a narrow
working space. Adequate undermining of the submucosal layer and sufficient enlargement
of the third-space may be important for a successful procedure in human cases.
Furthermore, ways to treat and avoid massive bleeding in the abdominal space remain
a major concern in clinically introducing this procedure. Although we have fortunately
not encountered massive bleeding from larger vessels, we may have to be careful not
to unintentionally cut larger vessels by taking a short step in the seromuscular incision
under clear visualization or by using a scissors-type knife.
Suture-and-cut techniques with the over-the-scope clip can be promising in terms of
simplicity and accessibility [15] when the target lesions are small enough. The current technique can target larger
lesions, as the resection line can be optimally designed without size limitations
of clips or electrocautery snares.
The current study had several limitations. First, it was preclinical with a small
number of porcine stomachs. Based on the results in our animal studies, a further
clinical study should be performed to investigate the feasibility of third-space EFTR.
Second, the current technique leaves a seromuscular defect intact. Although the in
vivo study demonstrated 1-week survival of the pigs and previous clinical studies
[1]
[2]
[3] have demonstrated the safety of conventional EFTR, which was accompanied by only
mucosal closure, the safety of the current technique should be confirmed in clinical
settings. Otherwise, seromuscular closure with an available technique [4]
[5]
[6] or a new approach should be considered. Third, it is unclear whether the current
technique can be applied to various locations in the stomach, as the technique was
performed for optimal lesions in this study. Although we are optimistic about application
of the current technique to various locations considering that ESD or other advanced
endoscopic surgeries can be performed irrespective of the location, the feasibility
of this technique should be confirmed in other locations. Fourth, suturing by the
EHS technique has not been available worldwide so far, which makes the technique a
little less reproducible.
Conclusion
In conclusion, third-space EFTR was found to be feasible and safe in porcine models.
This reliable EFTR technique can be applied to per-orally retrievable gastric submucosal
tumors in a full-thickness manner with adequate surgical margins. A further clinical
study is expected in the future.
