IJGII Inernational Journal of Gastrointestinal Intervention

pISSN 2636-0004 eISSN 2636-0012


home All Articles View

Review Article

Int J Gastrointest Interv 2020; 9(2): 42-52

Published online April 30, 2020 https://doi.org/10.18528/ijgii200007

Copyright © International Journal of Gastrointestinal Intervention.

Third space endoscopy: Current evidence and future development

Alex Qinyang Liu and Philip Wai Yan Chiu *

Division of Upper GI and Metabolic Surgery, Department of Surgery, Prince of Wales Hospital, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China

Correspondence to:* Division of Upper GI and Metabolic Surgery, Department of Surgery, Prince of Wales Hospital, Faculty of Medicine, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, N.T., Hong Kong, China.
E-mail address: philipchiu@surgery.cuhk.edu.hk (P.W.Y. Chiu).

Received: February 19, 2020; Revised: April 23, 2020; Accepted: April 24, 2020

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Therapeutic endoscopy has evolved tremendously over the past decades and the development of submucosal endoscopy opens the third space for treatment of gastrointestinal diseases. This review focused on the recent development in third space endoscopy, with introduction of its development from peroral endoscopic myotomy (POEM) to beyond. Two recent randomized trials comparing POEM against pneumatic dilation and laparoscopic Heller myotomy (LHM) demonstrated significantly better relief of dysphagia for POEM compared to pneumatic dilation, while POEM achieved similar outcomes compared to LHM. Apart from achalasia, third space endoscopy is now developed to manage spastic esophageal motility disorders, esophageal diverticular diseases, gastroparesis, and Hirschsprung’s disease. Subepithelial tumors can also be resected through tunneling and endoscopic full-thickness resection. In future, third space endoscopy will be one of the major areas in development of diagnostic and therapeutic endoscopy using novel imaging technologies and therapeutic devices.

Keywords: Peroral endoscopic myotomy, Peroral endoscopic tumor resection, Submucosal endoscopy, Submucosal tunneling endoscopic resection, Third space endoscopy

In the past 70 years, rapid advancement in endoscopy has crucial impact on the management of gastrointestinal (GI) diseases.1 Today, endoscopy represents the standard of practice for diagnosis and treatment of pathologies within the GI lumen. Traditionally, endoscopic interventions have been confined to within the lumen, which is known to endoscopists as “the first space”.2 From first polypectomy for treatment of colorectal polyp in 1969 by Dr. Shinya,3 endoluminal interventions have seen tremendous progress with more aggressive techniques for endoscopic resections like endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD).4,5

Imbued with visionary imagination, pioneers in endoscopy aimed to perform “No Scar” flexible endoscopic surgery within the peritoneal space. Natural orifice transluminal endoscopic surgery (NOTES), which began in 2004 with the idea of transgastric peritoneoscopy,6 had been mostly a proof of concept development in transvaginal and transgastric procedures.7 Nevertheless, endoscopic exploration into the peritoneal space, the “second space”2 of endoscopy, has paved way to the development of important technical advances in the field. One particularly important technique designed for safe breaching of the GI wall, submucosal tunneling, was first described in porcine models by Sumiyama et al8 in 2007. The submucosal endoscopy with mucosal flap safety valve (SEMF) technique opened a novel submucosal world for endoscopic intervention. Pasricha et al9 conducted a preclinical research on submucosal endoscopic myotomy in animal models using the principles of SEMF. Inoue and colleagues performed the first human peroral endoscopic myotomy (POEM) for management of achalasia in 2008.10 The same group published the world’s first series of POEM for treatment of achalasia in 17 patients,11 demonstrating POEM as an effective and safe treatment, unleashing a decade of innovation and research in submucosal endoscopy—the third space for endoscopy.

In this review, we will look into the current state and future perspective of submucosal endoscopy, also known as “third space endoscopy” amongst other names such as “submucosal endoscopy” or “submucosal endoscopic surgery”.2 These procedures are based on endoscopically creating the third space, i.e., submucosal space, between the muscularis mucosa and the muscularis propria, while keeping the mucosal flap intact thus enabling intervention up to the muscularis propria level or further into the mediastinum or peritoneum12,13 while preventing GI luminal content leak. Latest evidence on third space endoscopic procedure such as POEM, submucosal tunnel endoscopic resection (STER), and endoscopic full-thickness resection (EFTR) will be covered, based on literature search on PubMed/MEDLINE and EMBASE with keywords including: third space endoscopy; submucosal endoscopy; peroral endoscopic myotomy; STER; and EFTR. All types of articles including prospective randomized trial, case control studies, retrospective cohort studies and case series as well as systematic reviews and meta-analysis were included in this review.

ESD14 is the first endoscopic procedure that involved direct visualization and dissection at the submucosal space. Its development was to overcome limitations of EMR in achieving en-bloc resection of neoplasia larger than 20 mm. Today, ESD is well established and extensively applied15 for treatment of esophageal superficial squamous cell carcinoma (SCC), gastric superficial neoplastic lesions,16 and early colorectal neoplasia. Systematic reviews and meta-analyses showed that ESD obtained high en-bloc resection rates, high histological complete resection rates, and lower recurrence rates for esophageal superficial SCC15 as well as superficial gastric neoplastic lesions.1719

Achalasia is the most common primary esophageal motility disorder characterized by failure of lower esophageal sphincter (LES) relaxation and esophageal aperistalsis. Over the past decade, POEM was successfully translated from a clinical novelty into an established treatment option for achalasia patients,20 with clinical studies confirming the its efficacy (Fig. 1). Table 1 summarized the currently available reviews which pooled outcomes from case series of POEM, which reported high clinical success and reasonable safety profile.2126

Table 1 . Summary of the Results of Systematic Reviews on Clinical Outcomes of Peroral Endoscopic Myotomy (POEM).

AuthorSearch periodStudies includedNo. of casesPOEM operative time (min)*Clinical successComplication (%)Mean follow-up duration (mo)GERD (%)
Barbieri et al (2015)212010–201316551156 (42–112)93% as defined by clinically relevant improvement in dysphagiaAdverse event (14)613
Talukdar et al (2015)222005–2014191,045NASignificant reduction in Eckardt score overall effect size (Z) of –7.95 (P < 0.0001)Bleeding (1.0)6.510.9
Mediastinal emphysema (5.2)
Perforation (2.3)
Pleural effusion (17.4)
Pneumonia (9.9)
Pneumoperitoneum (16.2)
Pneumothorax (8.7)
Subcutaneous emphysema (21.8)
Akintoye et al (2016)23Up to 2014271,73388 ± 697% as defined by Eckardt score < 3Bleeding (0.6)8.815
Esophageal perforation (0.3)
Mucosal injury (9.4)
Pleural effusion (9.5)
Pneumoperitoneum (13)
Pneumothorax (5.4)
Subcutaneous emphysema (11)
Crespin et al (2017)24Up to February 2015191,310NA89.4% defined as Eckardt score < 3 in all studies except one using Eckardt score < 4Mucosal perforation (9.0)11.1NA
Pleural effusion (10.1)
Pneumonia (7.9)
Pneumoperitoneum (16.9)
Pneumomediastinum (4.4)
Pneumothorax (5.3)
Subcutaneous emphysema (10.0)
Andolfi and Fisichella (2019)252008–201820449NA95.8% defined by relevant clinical improvement of dysphagiaNA20.9NA
Li et al (2019)26Up to November 20171037366.7 (17.9–220)92.9% defined as Eckardt score ≤ 3Mediastinal emphysema (5.6)30.010.2
Mucosal perforation (7.2)
Pneumothorax (1.9)
Pneumoperitoneum (5.6)
Subcutaneous emphysema (4.0)
Others (4.0)

GERD, gastroesophageal reflux disease; NA, not available..

*Values are presented as median (range) or mean ± standard deviation..

Figure 1. Peroral endoscopic myotomy for treatment of achalasia. (A) Mucosal incision in anterior approach using Triangle Tip knife. (B) Development of submucosal tunnel from esophagus to gastric cardia. (C) Selective inner circular myotomy starting from esophageal side. (D) Selective inner circular myotoy extending to the tigh gastroesophageal junction. (E) Closure of mucosal incision using endoclips. (F) Complete closure of the mucosal incision using endoclips.

Compared to conventional treatments including endoscopic pneumatic dilatation and laparoscopic Heller myotomy (LHM), POEM has the advantage of achieving the definitiveness of myotomy without surgical incisions. Recent randomized trial provided quality clinical evidence in comparing the outcomes of POEM to the established endoscopic and surgical treatments. Ponds et al27 conducted a prospective randomized trial comparing POEM against pneumatic dilatation for patients with achalasia. Among 133 patients randomized to either treatment, those treated by POEM had significantly higher rate of relief of dysphagia compared to pneumatic dilatation at 24 months after treatment (92% vs 54%; p < 0.01). Werner et al28 conducted a randomized controlled trial (RCT) comparing POEM against LHM plus Dor’s fundoplication, recruiting 112 patients in the POEM arm and 109 patients in the LHM arm. Clinical success (defined as Eckardt score ≤ 3) at 2-year follow-up was noted to be 83.0% in POEM group and 81.7% in LHM plus fundoplication group (p = 0.007 for non-inferiority). The POEM group had shorter procedure time by 13.81 minutes (95% confidence interval [CI], 6.26–21.36). There was no difference between the two groups in terms improvement of LES integrated relaxation pressure or the Gastrointestinal Quality of Life index. Another recent RCT by Moura et al29 compared POEM against LHM, recruiting 20 patients into either arm. The study noted no statistically significant difference between the two groups in terms of Eckardt score, height of barium contrast column, LES pressure, and adverse events rate at 1 year, with the POEM group having significant shorter operative time (95.7 vs 218.7 minutes, p < 0.001).

However, gastroesophageal reflux disease (GERD) after POEM remains a significant sequela after POEM, affecting range of 10.2% to 15% of patients23,26 in the systematic reviews summarized in Table 1. The incidence of GERD was especially higher in Western series compared to those in Asia, up to 72.2% in one study.30 This phenomenon was reproduced in the aforementioned randomized trials, with POEM arm more likely to develop reflux esophagitis than the pneumatic dilatation arm (41% vs 7%, p = 0.002),27 LHM arm (64.6% vs 11.1%, p = 0.002),29 or LHM with Dor’s fundoplication arm (44% vs 29%; odds ratio, 2.00; 95% CI, 1.03–3.85)28 respectively. In view of such outcome, there are now novel attempts of adding endoscopic transperitoneal partial fundoplication to the standard POEM (POEM + F) in order to minimize GERD complications. A case series of 21 patients31 has demonstrated its technical feasibility, with no major adverse events noted. POEM + F describes an anterior fundoplication technique and is better suitable with anterior POEM, and might not be suitable in patients with prior POEM due to submucosal fibrosis.31 Further studies are needed for assessment on postoperative GERD symptoms, as well as the durability of the fundoplication wrap.

Apart from functional disorders, submucosal endoscopy emerged as a therapeutic option for subepithelial tumors (SETs) of the GI tract.32,33 Recently, SETs are increasingly diagnosed, one of the major reasons is due to the increasing performance of diagnostic endoscopy. SETs of the GI tract include a spectrum of different pathologies arising from subepithelial tissues, including gastrointestinal stromal tumor (GIST), leiomyoma, lipoma, schwannoma, as well as ectopic pancreas. Peroral endoscopic tumor resection (POET)13 and submucosal tunneling endoscopic resection (STER) had been reported for treatment of SETs in esophagus, gastroesophageal junction and stomach. The technique of POET/STER evolved from POEM with similar initial steps of submucosal tunneling development, while the mucosal entrance would be closer to the submucosal tumor (SMT) (Fig. 2). The dissection should be performed over lateral side of the submucosal tumor, and a submucosal space should be developed distal to the tumor prior to complete dissection at the muscularis propria so as to allow space for tumor manipulation. For most of the procedures, there would be a bridge into the adventitial layer or the serosa upon dissection at the base of tumor over muscularis propria, while keeping integrity of mucosa avoided a full thickness perforation (Fig. 2).

Figure 2. Submucosal tunnel endoscopic resection for treatment of subepithelial tumors at the cardia of stomach. (A) Development of submucosal tunnel after mucosal incision over distal esophagus to approach subepithelial tumor at gastric cardia. (B) Identification of proximal margin of the subepithelial tumor within submucosal tunnel. (C) Dissection around the lateral border of the gastric subepithelial tumor using dual knife. (D) Further dissection at the inferior border of gastric subepithelial tumor over the adherent part at muscularis propria. (E) Endoscopic retrieval of the subepithelial tumor using net. (F) Complete closure of the mucosal incision at the esophageal side with endoclips.

Two systematic reviews34,35 summarizing the results of current observational studies on STER were shown in Table 2. Majority of the SETs resected were leiomyoma, accounting for 76.9% of all lesions based on 28 observation studies.35 The results demonstrated high clinical efficacy of STER with excellent complete resection rates ranging from 97.5% to 99.8%, and high en-bloc resection rates from 94.6% to 92.1%. No tumor recurrence was reported in follow-up period ranging from 1 to 32 months. Subcutaneous emphysema with or without pneumomediastinum was the commonest encountered complication with a pooled prevalence of 14.8% (95% CI, 10.5–20.5) from 17 studies, and this complication commonly occurred for STER performed over the esophagogastric junction. Most of the emphysema were managed conservatively36; Chen et al37 reported that only 10% of STERs required intervention for complications. Risk factors for STER-related complications33,37 included overlying ulcerated mucosa,37 SETs with irregular borders,36 tumor involvement with deep portion of muscularis propria layer,38 long procedure time, and insufflation with air.37

Table 2 . Summary of Systematic Reviews on Clinical Outcomes of Submucosal Tunnel Endoscopic Resection (STER) for Treatment of Subepithelial Tumors.

AuthorSearch periodStudies includedNo. of casesFollow-up duration (mo)Mean tumor size (cm)Mean operative time (min)Complete resection rate (%)En-bloc resection rate (%)Tumor recurrence (%)Complication
Jain et al (2017)34Up to February 201616 studies:
-4 prospective
-9 retrospective
-3 case reports
703 patients1–322.1 (0.6–5.5)Esophageal or EGJ lesions: 120.1 (15–365)99.892.10272 adverse events (37.0%)
-Air leak: 1 (0.1%)
-Bleeding: 6 (0.8%)
-Chest pain: 4 (0.5%)
-Esophageal diverticulum: 2 (0.2%)
-Esophageal pleural fistula: 1 (0.1%)
-Mucosal injury/laceration: 4 (0.5%)
-Perforation: 17 (2.3%)
-Pneumomediastinum: 16 (2.2%)
-Pneumoperitoneum: 19 (2.6%)
-Pneumothorax: 44 (6.0%)
-Subcutaneous emphysema: 101 (13.7%)
-Subphrenic infection: 1 (0.1%)
-Thoracic/pleural effusion: 56 (7.6%)
736 lesions:
-465 esophageal
-146 EGJ
-125 gastric
Gastric lesions: 86.7 (25–320)
Lv et al (2017)35Up to November 201528 studies:
-8 prospective
-20 retrospective
1,041 patients7.1 (1.9–18.0)*1.9 (0.5–7)55.897.594.60263 adverse events
-Bleeding: 8
-Perforation: 18 (5.6%)
-Pneumoperitoneum: 42 (6.8%)
-Pneumothorax: 48 (6.1%)
-Subcutaneous emphysema and pneumomediastinum: 147 (14.8%)
1,085 lesions:
-712 esophageal
-95 EGJ
-141 cardia
-137 gastric

Values are presented as mean (range)..

EGJ, esophagogastric junction..

*Median of mean follow-up (range)..

While the performance of STER avoided full thickness perforation through preservation of mucosa, the dissection is usually close to the tumor border, with difficulty confirming dissection completeness during the procedure.39 This contributes a significant risk of incomplete resection to submucosal tumor especially for GIST. In difficult cases, the close margins of dissection could cause injury to tumor capsule and potentiate tumor seeding. EFTR could achieve better en-bloc resection and avoid the risks of bridging of tumor capsule during STER. The technique of EFTR can be classified into three approaches (Fig. 3)40: (1) non-tunneled exposed EFTR; (2) tunneled-exposed EFTR; and (3) non-exposed EFTR. The term “exposed” refers to any temporary exposure of the GI tract lumen to the peritoneal cavity. Exposed EFTR involved creation and closure of luminal defects during the resection, which can be subdivided into tunneled and non-tunneled exposed EFTR. Tunneled-exposed EFTR is similar to STERs, and closure of the mucosal flap entry site after complete full thickness resection will suffice. Exposed non-tunneled EFTR is performed with a similar approach as ESD with dissection around the submucosal tumor first at the submucosal layer, then the tumor is completely resected through the muscularis propria to serosa to achieve en-bloc resection (Fig. 4). In exposed EFTR, closure of luminal defect is achieved by either clips application, clip and loop technique,41 endoscopic suturing devices,42,43 and prototype endoscopic staplers.44 One of the major difficulties for exposed non-tunnel EFTR is to achieve safe closure of the defect upon which the luminal insufflation would be compromised upon complete resection of tumor. Our technique utilized tumor retraction with clip and line so as to minimize gas leakage during dissection, and luminal closure with overstitch endoscopic suturing.

Figure 3. Illustrations on different types of endoscopic full-thickness resection (EFTR). (A) Exposed non-tunnelled EFTR. 1: Direct incision from mucosa, submucosa to muscularis propria. 2: Complete resection of the subepithelial tumor. 3: Closure of mucosal incision with clips or overstitch. (B) Exposed tunnelled EFTR. 1: Development of submucosal tunnel proximal to the subepithelial tumor. 2: Dissection of subepithelial tumor within the submucosal tunnel with full thickness dissection to peritoneal cavity. 3: Closure of the mucosal entrance after complete dissection of the subepithelial tumor with endoclips. (C) Non-exposed EFTR with full-thickness resection device (FTRD). 1: Endoscopic localization of the subepithelial tumor and assessment of the tumor size fitting with FTRD device. 2: Aspiration of the subepithelial tumors using suction or tissue retraction device within the distal attachment cap, followed by application of the over-the-scope clip for complete closure of the gastrointestinal wall before resection. 3: Complete full thickness resection of the subepithelial tumor with snare. Data from the article of Liu et al (Surg Endosc. 2013;27:4354-9).36
Figure 4. Endoscopic full-thickness resection for treatment of gastric gastrointestinal stromal tumor (GIST). (A) Gastric GIST located at posterior wall of cardia. (B) Half circumferential mucosal incision distal to the GIST. (C) Extending the submucosal dissection to muscularis propria. (D) Full-thickness incision over muscularis propria into peritoneal cavity. (E) Retraction of the submucosal GIST using clip and string technique, and exposure of serosal margin of the GIST. (F) Full-thickness closure using overstitch suturing device.

Non-exposed EFTR avoids full thickness perforation by retracting the segment containing the target lesion into the lumen, allowing approximation and fixation of two serosal surfaces before resection.40,45 One of the advances in achieving non-exposed EFTR is the development of a full-thickness resection device (FTRD) which combines resection and closure by the over-the-scope clip (OTSC) device. FTRD achieved EFTR through grasping and pulling of target lesion into the transparent hood, followed by deployment of OTSC to close approximate GI wall prior to resection of the lesion above the clip.46 FTRD is limited by the size of specimen achieved and the size of the device which hindered its deployment in narrowed part of the GI tract. Non-exposed EFTR does not utilize principles of third space endoscopy, therefore it will not be further covered in this review. We identified 11 retrospective cohort studies reporting short and mid-term outcomes of exposed EFTR of gastric SMTs, as summarized in Table 3.4757 Majority of the resected SMTs were confirmed to be GIST histologically. While the sample size of each series is still small, the published data demonstrated high complete resection rate (90.3%–100%). There were very few major complications with 15 cases of GI bleeding events (3.6%) and 3 cases of perforation (0.07%) on pooled analysis. Abdominal distention and discomfort from the pneumoperitoneum after EFTR resulting upon full thickness resection was up to 20%.50 Postoperative fever amenable to conservative management was also between 0% to 17% (5 out of 30), likely from intraoperative peritoneal contamination as sub-group analysis demonstrated a correlation between lower incidence of postoperative fever and shorter operative time.54 The size of resected gastric SMTs ranged from 0.6 to 6.0 cm, and endoscopists reported technical difficulties of EFTR for both extremes of sizes. Small SMTs < 0.5 cm are difficult to identify, while large SMTs create issues of difficult closure of large luminal defect, longer operative time and inability of specimen retrieval per orally.54

Table 3 . Summary of Cohort Studies on Clinical Outcomes of Endoscopic Full-Thickness Resection (EFTR) of Treatment of Gastric Subepithelial Tumors.

AuthorStudy periodNo. of patientsClosure methodMean tumor size (cm)Mean operative time (min)Complete resection rate (%)Follow-up duration (mo)Tumor recurrence rateComplication
Zhou et al (2011)47July 2007 to January 200926Metallic clips2.8 (1.2–4.5)105 (60–145)1008 (6–24)No lesion residual or recurrenceNone of the studied patients had peritonitis or abdominal abscess.
Ye et al (2014)48January 2009 to December 201251Clips with endoloop2.4 (1.3–3.5)*52 (30–125)*98.022.4 (1–48)*No residual tumor or tumor recurrenceNo patients had severe complications, such as massive bleeding, delayed bleeding, peritonitis, or gastrointestinal tract leakage.
Feng et al (2014)49November 2009 to October 201248Metallic clips1.59 (0.50–4.80)59.72 (30–270)10011.8 (2–48)No recurrenceNo post-EFR complication, such as bleeding and peritonitis, was observed.
Huang et al (2014)50January 2010 to September 201335Metallic clips2.8 (2.0–4.5)90 (60–155)1006 mo for all patientsNo residual lesion, no recurrenceNo gastric bleeding, peritonitis or abdominal abscess occurred
Yang et al (2015)51June 2012 to April 201441-35 patients with metallic clips1.63 ± 0.5978.82 ± 46.44100Not applicableNot assessedNo severe complications such as peritonitis, digestive tract hemorrhage, or local infection
-6 patients with the over-the-scope clip, i.e., OTSC system
Guo et al (2015)52October 2013 to March 201423OTSC system1.21 (0.6–2.0)40.5 (16–104)1003 (1–6)No residual lesion, no recurrenceNo postoperative bleeding or perforation
Schmidt et al (2015)53January 2007 to February 201431-29 patients, with the Plicator suturing device2.05 (0.8–4.8)60.0 (39–229)90.37.1 (0–58)No recurrence-12 (38.7%) bleeding
-2 patients with the GERDX suturing device-3 (9.6%) perforations
Lu et al (2016)54January 2013 to March 201562Metallic clips0.6–6.025–18098.41–24No recurrenceNo peritonitis
Shi et al (2017)55April 2014 to February 201568Metallic clips with endoloops2.6 (2.0–3.5)41 (23–118)1007 (3–13)No residual tumor, no recurrence-1 (1.5%) Mallory–Weiss syndrome
-1 (1.5%) delayed bleeding
Duan et al (2018)56April 2011 to May 201628Metallic clips1.53 ± 0.763.3 ± 24.410022.8 ± 18.4No recurrence-1 (3.6%) delayed bleeding
Shichijo et al (2019)57January 2016 to December 20188-3 clip-and-endoloop purse-string suturing2.0 (1.0–3.5)*67.5 (50–166)*100% En-bloc resection, but 5/8 (62.5%) had indeterminate resection margins histologicallyNot applicableNot assessedNo ≥ CTCAE grade 2 adverse events
-2 simple endoclipping
-1 OTSC system

Values are presented as mean (range) or mean ± standard deviation..

EFR, endoscopic full-thickness resection; OTSC, over-the-scope clip; CTCAE, Common Terminology Criteria for Adverse Events (ver. 5.0; released on 2017)..

*Median (range)..

Oncologically, these cohort studies demonstrated no significant residual tumor or rate of local recurrence upon re-assessment endoscopy in short-term follow-up. In terms of long-term outcome of endoscopic resection of gastric GIST, two recent series with median follow-up period of 36 months and 57 months reported low recurrence of 1.7% (1 out of 60 patients)58 and 0% (0 out of 225 patients)59 respectively.

Apart from gastric lesions, EFTR has also been applied to lesions in other parts of the GI tract. However, full thickness resection in esophagus, duodenum, and colorectal tract presents greater challenges in closing large defects with higher incidence of leaks,60 therefore current data on exposed EFTR are lacking. In these regions, FTRD offered a technically less demanding approach with encouraging results of clinical success in achieving non-exposed EFTR.6163 A 2019 multicenter study of 114 patients receiving EFTR with FTRD for colorectal lesion reported lateral and deep R0 resection up to 90% and 92%, respectively,46 with 11% experiencing adverse clinical events (only 1 patient with major bleeding and 1 patient with perforation).

Submucosal tunnel opened the third space for development of novel procedures. Apart from POEM for treatment of achalasia, numerous innovative procedures had been developed for treatment of GI diseases. These procedures included G-POEM for gastroparesis, D-POEM for esophageal diverticulum, Z-POEM for Zenker’s diverticulum, per rectal endoscopic myotomy for Hirschsprung disease.

With the establishment of POEM in achalasia management, the next logical step is to expand its indication to other spastic esophageal disorders (SED) include type III achalasia, diffuse esophageal spasm (DES), and nutcracker/Jackhammer esophagus. While these disorders vary in manometric findings and pathophysiology, with the former two associated with loss of neural inhibition and the latter caused by cholinergic activation,64 they share similar symptomology of dysphasia, regurgitation, and chest discomfort. By adjusting length and location of myotomy,10 POEM achieved high clinical success of treatment of these disorders as demonstrated in a meta-analysis of 8 observational studies.64 POEM achieved high clinical success rates of 92%, 88%, and 72% and adverse events rate of 11%, 14%, and 16% for treatment of type III achalasia, DES, and Jackhammer esophagus respectively. A more recent meta-analysis65 demonstrated a promising pooled clinical success rate of 89.6% for SEDs. However, both meta-analyses could only include a paucity of cases of DES and Jackhammer esophagus due to the lower disease incidence. Further prospective studies with higher case volume and longer-term outcomes should be conducted to confirm the effectiveness of POEM for these motility disorders.

Third space endoscopy allowed endoscopic approach to treatment of esophageal diverticular diseases through creation of submucosal tunnel and dissection at the septum between the diverticulum and muscularis propria. The common types of esophageal diverticulum included Zenker’s diverticulum, mid esophageal diverticulum and epiphrenic diverticulum. Treatment of esophageal diverticulum focused on relief of symptoms caused by both the pulsion diverticulum and the underlying motility disorder. Zenker’s diverticulum is an acquired pulsion type diverticulum at the Killian triangle over pharyngo-esophagus.66 Conventional treatment for Zenker’s diverticulum included diverticulectomy, diverticulopexy, diverticular inversion with or without myotomy, cricopharyngeal myotomy as well as endoscopic septotomy.67 Recently, third space endoscopy was reported as a novel approach to achieve septotomy through a submucosal tunnel. The approach was named as submucosal tunneling for endoscopic septum division (STESD) or otherwise Z-POEM.6872 This approach avoided direct incision into the septum, and theoretically allowed endoscopists to achieve a higher rate of complete septotomy. The submucosal tunnel enabled non-exposure of the cut-edge of the septotomy and preventing leakage or perforation after the procedure. The same principles and techniques of Z-POEM can be applied for treatment of diverticulum in mid-esophagus and epiphrenic area, the procedure named as diverticular POEM (D-POEM). D-POEM achieved complete septal dissection without risk of perforation and achieved high symptomatic relief.70 The largest reported multi-center retrospective study involves 75 patients who received Z-POEM for Zenker’s diverticulum73 with high clinical success rate of 92% in relieving dysphagia, and a low adverse event rates of 6.7% (1 bleeding, 4 perforations). A separate cohort of patients with mid-esophageal diverticula and epiphrenic diverticula by the same group74 also demonstrated good efficacy and safety for D-POEM. There was no long term adverse events reported for the 25 patients after D-POEM in a 12-month follow-up study.75

The principles of POEM and third space endoscopy were applied to treatment of gastroparesis, which is caused by incoordinate peristalsis of antrum and relaxation of pylorus.76 The etiology of gastroparesis can be divided into iatrogenic (usually caused by surgical trauma to vagal nerve), diabetes and idiopathic. For gastroparesis caused by uncoordinated relaxation of pylorus, therapeutic options mostly targeted at pyloric myotomy and release the spastic contraction. In 2013, Khashab et al77 performed the first human case of gastric POEM (G-POEM), also known as peroral endoscopic pyloromyotomy (POEP or POP). The technique of G-POEM is very similar to POEM with the myotomy focused on the muscular ring of pylorus. Numerous small-scale case series subsequently reported the safety and efficacy of G-POEM for treatment of gastroparesis.7883 The first meta-analysis84 pooled 196 cases of G-POEM from seven observational studies. These patients included those with refractory gastroparesis not responsive to medical therapy or with persistent symptoms of more than 6 months. It was found that the clinical success rate was 82%, with statistically significantly improved gastric emptying 2 to 3 months postoperatively. Twelve adverse events (6.1%) were reported, with capnoperitoneum being the most common one. It was interesting to note that the underlying etiology of gastroparesis does not affect the clinical success of G-POEM. A more recent meta-analysis85 comparing G-POEM (332 patients pooled from 11 studies) with surgical pyloroplasty (375 patients from 7 studies) also demonstrated comparable rate of clinical success (75.8%) and low adverse event rate (11%) in the G-POEM group when compared to surgical pyloroplasty. Follow-up of 16 patients in 14.5 months shows a promising long-term clinical efficacy of 81.6%.86

Another exciting development in third space endoscopic myotomy is the extension of submucosal endoscopic myotomy to the lower GI tract. Hirschsprung’s disease is characterized by aganglionosis of Auerbach and Meissner plexuses starting from the rectum and extending proximally, resulting in a functional obstruction.87 After the initial description of per-anal endoscopic myotomy in a porcine model,88 Bapaye et al89 performed the first successful per-rectal endoscopic myotomy (PREM) in an 24-year-old adult patient with Hirschsprung’s disease. The same group published case reports of successful PREM in a pediatric patient (8 years old)90 and an infantile patient (2 years old).91 With more evidence, the same technique can perhaps be expanded to manage other lower GI motility disorders such as hypertensive anal sphincter and sphincter dyssynergia.

Submucosal endoscopy may serve as a novel approach to treatment of GERD. Electrostimulation of the LES aimed to its functionality for treatment of refractory GERD, and clinical studies demonstrated significant improvement in symptomatic relief for GERD.92 Third space endoscopy for the implantation of stimulation leads93 or even devices94 in the LES was tested in porcine models for electrostimulation therapy. In future, further refinements in the device and the techniques will lead to clinical trial on submucosal endoscopic electrostimulation therapy for treatment of GERD.

Wagh and Draganov95 described peroral endoscopic tunneling for restoration of the esophagus (POETRE) in 4 patients with complete esophageal obstruction. In this procedure, submucosal dissection was performed in the fibrotic obstructed segment followed by guidewire-assisted insertion of esophageal stent, enabling easier traverse of longer segments of completely obstructed esophagus (> 3 cm).

While most of the procedures covered are therapeutic in nature, the technique of submucosal endoscopy also offers a safer means for natural orifice transluminal endoscopy compared to its earlier forms.6 The mucosal safety valve technique enables safe access into mediastinum or peritoneal cavity via the esophagus, stomach or even colons, with feasibility demonstrated in animal models as well as human case series.8,96,97 With further development, third space endoscopy has the potential to replace laparoscopy for staging of malignancies.

Third space endoscopy is an evolving field with on-going innovative development. The submucosal space allowed endoscopists to perform novel therapeutic procedures for GI tract for a variety of disease spectrum ranging from functional/motility disorders to malignancies. Nevertheless, the current clinical evidence lacks sufficient sample size and high-quality randomized trials. Given the procedures’ novelty, long term efficacy and safety data is also deficient. Further research and follow-up studies is warranted to better understand third space endoscopy, and establish it as an integral part of clinical care in this new age of endoscopy.

  1. Hunt R. A brief history of endoscopy. Gastroenterology. 2001;121:738-9.
  2. Khashab MA, Pasricha PJ. Conquering the third space: challenges and opportunities for diagnostic and therapeutic endoscopy. Gastrointest Endosc. 2013;77:146-8.
    Pubmed CrossRef
  3. Wolff WI, Shinya H. Polypectomy via the fiberoptic colonoscope. Removal of neoplasms beyond reach of the sigmoidoscope. N Engl J Med. 1973;288:329-32.
    Pubmed CrossRef
  4. Tada M, Shimada M, Yanai H, Arima K, Kanda M, Okazaki Y, et al. New technique of gastric biopsy. Stomach Intest. 1984;19:1107-16.
  5. Inoue H, Fukami N, Yoshida T, Kudo SE. Endoscopic mucosal resection for esophageal and gastric cancers. J Gastroenterol Hepatol. 2002;17:382-8.
    Pubmed CrossRef
  6. Kalloo AN, Singh VK, Jagannath SB, Niiyama H, Hill SL, Vaughn CA, et al. Flexible transgastric peritoneoscopy: a novel approach to diagnostic and therapeutic interventions in the peritoneal cavity. Gastrointest Endosc. 2004;60:114-7.
    Pubmed CrossRef
  7. Khashab MA, Kalloo AN. NOTES: current status and new horizons. Gastroenterology. 2012;142:704-10.
    Pubmed CrossRef
  8. Sumiyama K, Gostout CJ, Rajan E, Bakken TA, Knipschield MA. Transesophageal mediastinoscopy by submucosal endoscopy with mucosal flap safety valve technique. Gastrointest Endosc. 2007;65:679-83.
    Pubmed CrossRef
  9. Pasricha PJ, Hawari R, Ahmed I, Chen J, Cotton PB, Hawes RH, et al. Submucosal endoscopic esophageal myotomy: a novel experimental approach for the treatment of achalasia. Endoscopy. 2007;39:761-4.
    Pubmed CrossRef
  10. Inoue H, Maydeo A. Peroral endoscopic myotomy (POEM) opens the door of third-space endoscopy. Endoscopy. 2019;51:1010-2.
    Pubmed CrossRef
  11. Inoue H, Ikeda H, Yoshida A, Onimaru M, Sato H, Minami H, et al. Peroral endoscopic myotomy for esophageal achalasia. Video J Encycl GI Endosc. 2013;1:94-5.
  12. Maydeo A, Dhir V. Third-space endoscopy: stretching the limits. Gastrointest Endosc. 2017;85:728-9.
    Pubmed CrossRef
  13. Holmstrom AL, Aadam AA, Hungness ES. Submucosal endoscopy. Tech Gastrointest Endosc. 2018;20:211-7.
  14. Saito Y, Fujii T, Kondo H, Mukai H, Yokota T, Kozu T, et al. Endoscopic treatment for laterally spreading tumors in the colon. Endoscopy. 2001;33:682-6.
    Pubmed CrossRef
  15. Pimentel-Nunes P, Dinis-Ribeiro M, Ponchon T, Repici A, Vieth M, De Ceglie A A, et al. Endoscopic submucosal dissection: European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy. 2015;47:829-54.
    Pubmed CrossRef
  16. Japanese Gastric Cancer Association Association. Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer. 2017;20:1-19.
    Pubmed KoreaMed CrossRef
  17. Park YM, Cho E, Kang HY, Kim JM. The effectiveness and safety of endoscopic submucosal dissection compared with endoscopic mucosal resection for early gastric cancer: a systematic review and metaanalysis. Surg Endosc. 2011;25:2666-77.
    Pubmed CrossRef
  18. Lian J, Chen S, Zhang Y, Qiu F. A meta-analysis of endoscopic submucosal dissection and EMR for early gastric cancer. Gastrointest Endosc. 2012;76:763-70.
    Pubmed CrossRef
  19. Facciorusso A, Antonino M, Di Maso M M, Muscatiello N. Endoscopic submucosal dissection vs endoscopic mucosal resection for early gastric cancer: a meta-analysis. World J Gastrointest Endosc. 2014;6:555-63.
    Pubmed KoreaMed CrossRef
  20. Chiu PW, Wu JC, Teoh AY, Chan Y, Wong SK, Liu SY, et al. Peroral endoscopic myotomy for treatment of achalasia: from bench to bedside (with video). Gastrointest Endosc. 2013;77:29-38.
    Pubmed CrossRef
  21. Barbieri LA, Hassan C, Rosati R, Romario UF, Correale L, Repici A. Systematic review and meta-analysis: efficacy and safety of POEM for achalasia. United European Gastroenterol J. 2015;3:325-34.
    Pubmed KoreaMed CrossRef
  22. Talukdar R, Inoue H, Nageshwar Reddy D D. Efficacy of peroral endoscopic myotomy (POEM) in the treatment of achalasia: a systematic review and meta-analysis. Surg Endosc. 2015;29:3030-46.
    Pubmed CrossRef
  23. Akintoye E, Kumar N, Obaitan I, Alayo QA, Thompson CC. Peroral endoscopic myotomy: a meta-analysis. Endoscopy. 2016;48:1059-68.
    Pubmed CrossRef
  24. Crespin OM, Liu LWC, Parmar A, Jackson TD, Hamid J, Shlomovitz E, et al. Safety and efficacy of POEM for treatment of achalasia: a systematic review of the literature. Surg Endosc. 2017;31:2187-201.
    Pubmed CrossRef
  25. Andolfi C, Fisichella PM. Meta-analysis of clinical outcome after treatment for achalasia based on manometric subtypes. Br J Surg. 2019;106:332-41.
    Pubmed CrossRef
  26. Li H, Peng W, Huang S, Ren Y, Peng Y, Li Q, et al. The 2 years' long-term efficacy and safety of peroral endoscopic myotomy for the treatment of achalasia: a systematic review. J Cardiothorac Surg. 2019;14:1.
    Pubmed KoreaMed CrossRef
  27. Ponds FA, Fockens P, Lei A, Neuhaus H, Beyna T, Kandler J, et al. Effect of peroral endoscopic myotomy vs pneumatic dilation on symptom severity and treatment outcomes among treatment-naive patients with achalasia: a randomized clinical trial. JAMA. 2019;322:134-44.
    Pubmed KoreaMed CrossRef
  28. Werner YB, Hakanson B, Martinek J, Repici A, von Rahden BHA BHA, Bredenoord AJ, et al. Endoscopic or surgical myotomy in patients with idiopathic achalasia. N Engl J Med. 2019;381:2219-29.
    Pubmed CrossRef
  29. Moura ET, Farias GF, Coutinho LM, Delgado A, de Moura DT DT, Nasi A. A randomized controlled trial comparing peroral endoscopic myotomy (POEM) versus laparoscopic Heller myotomy with fundoplication in the treatment of achalasia. Gastrointest Endosc. 2019;89(6 Suppl 1):AB84.
  30. Chiu PW, Inoue H, Rösch T. From POEM to POET: applications and perspectives for submucosal tunnel endoscopy. Endoscopy. 2016;48:1134-42.
    Pubmed CrossRef
  31. Inoue H, Ueno A, Shimamura Y, Manolakis A, Sharma A, Kono S, et al. Peroral endoscopic myotomy and fundoplication: a novel NOTES procedure. Endoscopy. 2019;51:161-4.
    Pubmed CrossRef
  32. Wong VWY, Goto O, Gregersen H, Chiu PWY. Endoscopic treatment of subepithelial lesions of the gastrointestinal tract. Curr Treat Options Gastroenterol. 2017;15:603-17.
    Pubmed CrossRef
  33. Dellatore P, Bhagat V, Kahaleh M. Endoscopic full thickness resection versus submucosal tunneling endoscopic resection for removal of submucosal tumors: a review article. Transl Gastroenterol Hepatol. 2019;4:45.
    Pubmed KoreaMed CrossRef
  34. Jain D, Desai A, Mahmood E, Singhal S. Submucosal tunneling endoscopic resection of upper gastrointestinal tract tumors arising from muscularis propria. Ann Gastroenterol. 2017;30:262-72.
    Pubmed KoreaMed CrossRef
  35. Lv XH, Wang CH, Xie Y. Efficacy and safety of submucosal tunneling endoscopic resection for upper gastrointestinal submucosal tumors: a systematic review and meta-analysis. Surg Endosc. 2017;31:49-63.
    Pubmed CrossRef
  36. Liu BR, Song JT, Kong LJ, Pei FH, Wang XH, Du YJ. Tunneling endoscopic muscularis dissection for subepithelial tumors originating from the muscularis propria of the esophagus and gastric cardia. Surg Endosc. 2013;27:4354-9.
    Pubmed CrossRef
  37. Chen T, Zhang C, Yao LQ, Zhou PH, Zhong YS, Zhang YQ, et al. Management of the complications of submucosal tunneling endoscopic resection for upper gastrointestinal submucosal tumors. Endoscopy. 2016;48:149-55.
    Pubmed CrossRef
  38. Ye LP, Zhang Y, Mao XL, Zhu LH, Zhou X, Chen JY. Submucosal tunneling endoscopic resection for small upper gastrointestinal subepithelial tumors originating from the muscularis propria layer. Surg Endosc. 2014;28:524-30.
    Pubmed CrossRef
  39. Chiu PWY, Yip HC, Teoh AYB, Wong VWY, Chan SM, Wong SKH, et al. Per oral endoscopic tumor (POET) resection for treatment of upper gastrointestinal subepithelial tumors. Surg Endosc. 2019;33:1326-33.
    Pubmed CrossRef
  40. Aslanian HR, Sethi A, Bhutani MS, Goodman AJ, Krishnan K, Lichtenstein DR, et al. ASGE guideline for endoscopic full-thickness resection and submucosal tunnel endoscopic resection. VideoGIE. 2019;4:343-50.
    Pubmed KoreaMed CrossRef
  41. Ryska O, Martinek J, Filipkova T, Dolezel R, Juhasova J, Motlik J, et al. Single loop-and-clips technique (KING closure) for gastrotomy closure after transgastric ovariectomy: a survival experiment. Wideochir Inne Tech Maloinwazyjne. 2012;7:233-9.
    Pubmed KoreaMed CrossRef
  42. Rothstein R, Filipi C, Caca K, Pruitt R, Mergener K, Torquati A, et al. Endoscopic full-thickness plication for the treatment of gastroesophageal reflux disease: a randomized, sham-controlled trial. Gastroenterology. 2006;131:704-12.
    Pubmed CrossRef
  43. Mori H, Kobara H, Fujihara S, Nishiyama N, Rafiq K, Oryu M, et al. Feasibility of pure EFTR using an innovative new endoscopic suturing device: the double-arm-bar suturing System (with video). Surg Endosc. 2014;28:683-90.
    Pubmed CrossRef
  44. Kaehler G, Grobholz R, Langner C, Suchan K, Post S. A new technique of endoscopic full-thickness resection using a flexible stapler. Endoscopy. 2006;38:86-9.
    Pubmed CrossRef
  45. Takizawa K, Knipschield MA, Gostout CJ. Submucosal endoscopy as an aid to full-thickness resection: pilot study in the porcine stomach. Gastrointest Endosc. 2015;81:450-4.
    Pubmed CrossRef
  46. Andrisani G, Soriani P, Manno M, Pizzicannella M, Pugliese F, Mutignani M, et al. Colo-rectal endoscopic full-thickness resection (EFTR) with the over-the-scope device (FTRD®): a multicenter Italian experience. Dig Liver Dis. 2019;51:375-81.
    Pubmed CrossRef
  47. Zhou PH, Yao LQ, Qin XY, Cai MY, Xu MD, Zhong YS, et al. Endoscopic full-thickness resection without laparoscopic assistance for gastric submucosal tumors originated from the muscularis propria. Surg Endosc. 2011;25:2926-31.
    Pubmed CrossRef
  48. Ye LP, Yu Z, Mao XL, Zhu LH, Zhou XB. Endoscopic full-thickness resection with defect closure using clips and an endoloop for gastric subepithelial tumors arising from the muscularis propria. Surg Endosc. 2014;28:1978-83.
    Pubmed CrossRef
  49. Feng Y, Yu L, Yang S, Li X, Ding J, Chen L, et al. Endolumenal endoscopic full-thickness resection of muscularis propria-originating gastric submucosal tumors. J Laparoendosc Adv Surg Tech A. 2014;24:171-6.
    Pubmed CrossRef
  50. Huang LY, Cui J, Lin SJ, Zhang B, Wu CR. Endoscopic full-thickness resection for gastric submucosal tumors arising from the muscularis propria layer. World J Gastroenterol. 2014;20:13981-6.
    Pubmed KoreaMed CrossRef
  51. Yang F, Wang S, Sun S, Liu X, Ge N, Wang G, et al. Factors associated with endoscopic full-thickness resection of gastric submucosal tumors. Surg Endosc. 2015;29:3588-93.
    Pubmed KoreaMed CrossRef
  52. Guo J, Liu Z, Sun S, Liu X, Wang S, Ge N, et al. Endoscopic full-thickness resection with defect closure using an over-the-scope clip for gastric subepithelial tumors originating from the muscularis propria. Surg Endosc. 2015;29:3356-62.
    Pubmed KoreaMed CrossRef
  53. Schmidt A, Bauder M, Riecken B, von Renteln D D, Muehleisen H, Caca K. Endoscopic full-thickness resection of gastric subepithelial tumors: a single-center series. Endoscopy. 2015;47:154-8.
    Pubmed CrossRef
  54. Lu J, Jiao T, Li Y, Zheng M, Lu X. Facilitating retroflexed endoscopic full-thickness resection through loop-mediated or rope-mediated countertraction (with videos). Gastrointest Endosc. 2016;83:223-8.
    Pubmed CrossRef
  55. Shi D, Li R, Chen W, Zhang D, Zhang L, Guo R, et al. Application of novel endoloops to close the defects resulted from endoscopic full-thickness resection with single-channel gastroscope: a multicenter study. Surg Endosc. 2017;31:837-42.
    Pubmed CrossRef
  56. Duan TY, Tan YY, Wang XH, Lv L, Liu DL. A comparison of submucosal tunneling endoscopic resection and endoscopic full-thickness resection for gastric fundus submucosal tumors. Rev Esp Enferm Dig. 2018;110:160-5.
    Pubmed CrossRef
  57. Shichijo S, Uedo N, Yanagimoto Y, Yamamoto K, Kono M, Fukuda H, et al. Endoscopic full-thickness resection of gastric gastrointestinal stromal tumor: a Japanese case series. Ann Gastroenterol. 2019;32:593-9.
    Pubmed KoreaMed CrossRef
  58. Yu C, Liao G, Fan C, Yu J, Nie X, Yang S, et al. Long-term outcomes of endoscopic resection of gastric GISTs. Surg Endosc. 2017;31:4799-804.
    Pubmed CrossRef
  59. Zhang Y, Mao XL, Zhou XB, Yang H, Zhu LH, Chen G, et al. Long-term outcomes of endoscopic resection for small (≤ 4.0 cm) gastric gastrointestinal stromal tumors originating from the muscularis propria layer. World J Gastroenterol. 2018;24:3030-7.
    Pubmed KoreaMed CrossRef
  60. Cai M, Zhou P, Lourenço LC, Zhang D. Endoscopic full-thickness resection (EFTR) for gastrointestinal subepithelial tumors. Gastrointest Endosc Clin N Am. 2016;26:283-95.
    Pubmed CrossRef
  61. Bauder M, Schmidt A, Caca K. Endoscopic full-thickness resection of duodenal lesions-a retrospective analysis of 20 FTRD cases. United European Gastroenterol J. 2018;6:1015-21.
    Pubmed KoreaMed CrossRef
  62. Schmidt A, Beyna T, Schumacher B, Meining A, Richter-Schrag HJ, Messmann H, et al. Colonoscopic full-thickness resection using an over-the-scope device: a prospective multicentre study in various indications. Gut. 2018;67:1280-9.
    Pubmed CrossRef
  63. Albrecht H, Raithel M, Braun A, Nagel A, Stegmaier A, Utpatel K, et al. Endoscopic full-thickness resection (EFTR) in the lower gastrointestinal tract. Tech Coloproctol. 2019;23:957-63.
    Pubmed CrossRef
  64. Khan MA, Kumbhari V, Ngamruengphong S, Ismail A, Chen YI, Chavez YH, et al. Is POEM the answer for management of spastic esophageal disorders? A systematic review and meta-analysis. Dig Dis Sci. 2017;62:35-44.
    Pubmed CrossRef
  65. Chandan S, Mohan BP, Chandan OC, Jha LK, Mashiana HS, Hewlett AT, et al. Clinical efficacy of per-oral endoscopic myotomy (POEM) for spastic esophageal disorders: a systematic review and meta-analysis. Surg Endosc. 2020;34:707-18.
    Pubmed CrossRef
  66. Sato H, Takeuchi M, Hashimoto S, Mizuno KI, Furukawa K, Sato A, et al. Esophageal diverticulum: new perspectives in the era of minimally invasive endoscopic treatment. World J Gastroenterol. 2019;25:1457-64.
    Pubmed KoreaMed CrossRef
  67. Yuan Y, Zhao YF, Hu Y, Chen LQ. Surgical treatment of Zenker's diverticulum. Dig Surg. 2013;30:207-18.
    Pubmed CrossRef
  68. Li QL, Chen WF, Zhang XC, Cai MY, Zhang YQ, Hu JW, et al. Submucosal tunneling endoscopic septum division: a novel technique for treating Zenker's diverticulum. Gastroenterology. 2016;151:1071-4.
    Pubmed CrossRef
  69. Brieau B, Leblanc S, Bordacahar B, Barret M, Coriat R, Prat F, et al. Submucosal tunneling endoscopic septum division for Zenker's diverticulum: a reproducible procedure for endoscopists who perform peroral endoscopic myotomy. Endoscopy. 2017;49:613-4.
    Pubmed CrossRef
  70. Balassone V, Pizzicannella M, Biasutto D, Di Matteo FM FM. Submucosal per-oral endoscopic myotomy for a large Zenker's diverticulum with use of a hydrodissector knife and an over-the-scope clip closure. VideoGIE. 2018;3:373-4.
    Pubmed KoreaMed CrossRef
  71. Hajifathalian K, Dawod Q, Saumoy M, Kahaleh M. Submucosal tunneling endoscopic septum division for treatment of Zenker's diverticulum. Endoscopy. 2018;50:E340-1.
    Pubmed CrossRef
  72. Hernández Mondragón OV OV, Solórzano Pineda MO MO, Blancas Valencia JM JM. Zenker's diverticulum: submucosal tunneling endoscopic septum division (Z-POEM). Dig Endosc. 2018;30:124.
    Pubmed CrossRef
  73. Yang J, Novak S, Ujiki M, Hernández Ó, Desai P, Benias P, et al. An international study on the use of peroral endoscopic myotomy in the management of Zenker's diverticulum. Gastrointest Endosc. 2020;91:163-8.
    Pubmed CrossRef
  74. Yang J, Zeng X, Yuan X, Chang K, Sanaei O, Fayad L, et al. An international study on the use of peroral endoscopic myotomy (POEM) in the management of esophageal diverticula: the first multicenter D-POEM experience. Endoscopy. 2019;51:346-9.
    Pubmed CrossRef
  75. Maydeo A, Patil GK, Dalal A. Operative technical tricks and 12-month outcomes of diverticular peroral endoscopic myotomy (D-POEM) in patients with symptomatic esophageal diverticula. Endoscopy. 2019;51:1136-40.
    Pubmed CrossRef
  76. Arts J, Holvoet L, Caenepeel P, Bisschops R, Sifrim D, Verbeke K, et al. Clinical trial: a randomized-controlled crossover study of intrapyloric injection of botulinum toxin in gastroparesis. Aliment Pharmacol Ther. 2007;26:1251-8.
    Pubmed CrossRef
  77. Khashab MA, Stein E, Clarke JO, Saxena P, Kumbhari V, Chander Roland B B, et al. Gastric peroral endoscopic myotomy for refractory gastroparesis: first human endoscopic pyloromyotomy (with video). Gastrointest Endosc. 2013;78:764-8.
    Pubmed CrossRef
  78. Shlomovitz E, Pescarus R, Cassera MA, Sharata AM, Reavis KM, Dunst CM, et al. Early human experience with per-oral endoscopic pyloromyotomy (POP). Surg Endosc. 2015;29:543-51.
    Pubmed CrossRef
  79. Gonzalez JM, Vanbiervliet G, Vitton V, Benezech A, Lestelle V, Grimaud JC, et al. First European human gastric peroral endoscopic myotomy, for treatment of refractory gastroparesis. Endoscopy. 2015;47(Suppl 1):E135-6.
    Pubmed CrossRef
  80. Mekaroonkamol P, Li LY, Dacha S, Xu Y, Keilin SD, Willingham FF, et al. Gastric peroral endoscopic pyloromyotomy (G-POEM) as a salvage therapy for refractory gastroparesis: a case series of different subtypes. Neurogastroenterol Motil. 2016;28:1272-7.
    Pubmed CrossRef
  81. Khashab MA, Ngamruengphong S, Carr-Locke D, Bapaye A, Benias PC, Serouya S, et al. Gastric per-oral endoscopic myotomy for refractory gastroparesis: results from the first multicenter study on endoscopic pyloromyotomy (with video). Gastrointest Endosc. 2017;85:123-8.
    Pubmed CrossRef
  82. Xue HB, Fan HZ, Meng XM, Cristofaro S, Mekaroonkamol P, Dacha S, et al. Fluoroscopy-guided gastric peroral endoscopic pyloromyotomy (G-POEM): a more reliable and efficient method for treatment of refractory gastroparesis. Surg Endosc. 2017;31:4617-24.
    Pubmed CrossRef
  83. Malik Z, Kataria R, Modayil R, Ehrlich AC, Schey R, Parkman HP, et al. Gastric per oral endoscopic myotomy (G-POEM) for the treatment of refractory gastroparesis: early experience. Dig Dis Sci. 2018;63:2405-12.
    Pubmed CrossRef
  84. Aghaie Meybodi M M, Qumseya BJ, Shakoor D, Lobner K, Vosoughi K, Ichkhanian Y, et al. Efficacy and feasibility of G-POEM in management of patients with refractory gastroparesis: a systematic review and meta-analysis. Endosc Int Open. 2019;7:E322-9.
    Pubmed KoreaMed CrossRef
  85. Mohan BP, Chandan S, Jha LK, Khan SR, Kotagiri R, Kassab LL, et al. Clinical efficacy of gastric per-oral endoscopic myotomy (G-POEM) in the treatment of refractory gastroparesis and predictors of outcomes: a systematic review and meta-analysis using surgical pyloroplasty as a comparator group. Surg Endosc. ; doi: 10.1007/s00464-019-07135-9. [Epub ahead of print].
    Pubmed CrossRef
  86. Xu J, Chen T, Elkholy S, Xu M, Zhong Y, Zhang Y, et al. Gastric peroral endoscopic myotomy (G-POEM) as a treatment for refractory gastroparesis: long-term outcomes. Can J Gastroenterol Hepatol. 2018;2018:6409698.
    Pubmed KoreaMed CrossRef
  87. Pini Prato A A, Gentilino V, Giunta C, Avanzini S, Parodi S, Mattioli G, et al. Hirschsprung's disease: 13 years' experience in 112 patients from a single institution. Pediatr Surg Int. 2008;24:175-82.
    Pubmed CrossRef
  88. Wang L, Cai Q, Fan C, Ren W, Yu J. A new potential method per anus endoscopic myotomy for treatment of internal anal sphincter achalasia. Gastrointest Endosc. 2013;77(5 Suppl 1):AB451.
  89. Bapaye A, Wagholikar G, Jog S, Kothurkar A, Purandare S, Dubale N, et al. Per rectal endoscopic myotomy for the treatment of adult Hirschsprung's disease: first human case (with video). Dig Endosc. 2016;28:680-4.
    Pubmed CrossRef
  90. Bapaye A, Bharadwaj T, Mahadik M, Ware S, Nemade P, Pujari R, et al. Per-rectal endoscopic myotomy (PREM) for pediatric Hirschsprung's disease. Endoscopy. 2018;50:644-5.
    Pubmed CrossRef
  91. Bapaye A, Mahadik M, Korrapati SK, Nemade P, Pujari R, Date S, et al. Per rectal endoscopic myotomy (PREM) for infantile Hirschsprung's disease. Endoscopy. 2018;50:S74.
  92. Kim SE, Soffer E. Electrical stimulation for gastroesophageal reflux disease: current state of the art. Clin Exp Gastroenterol. 2016;9:11-9.
    Pubmed KoreaMed CrossRef
  93. Banerjee R, Pratap N, Kalpala R, Reddy DN. Effect of electrical stimulation of the lower esophageal sphincter using endoscopically implanted temporary stimulation leads in patients with reflux disease. Surg Endosc. 2014;28:1003-9.
    Pubmed CrossRef
  94. Hajer J, Novák M, Rosina J. Wirelessly powered endoscopically implantable devices into the submucosa as the possible treatment of gastroesophageal reflux disease. Gastroenterol Res Pract. 2019;2019:7459457.
    Pubmed KoreaMed CrossRef
  95. Wagh MS, Draganov PV. Per-oral endoscopic tunneling for restoration of the esophagus: a novel endoscopic submucosal dissection technique for therapy of complete esophageal obstruction. Gastrointest Endosc. 2017;85:722-7.
    Pubmed CrossRef
  96. Lee CK, Lee SH, Chung IK, Lee TH, Lee SH, Kim HS, et al. Human diagnostic transgastric peritoneoscopy with the submucosal tunnel technique performed with the patient under conscious sedation (with video). Gastrointest Endosc. 2010;72:889-91.
    Pubmed CrossRef
  97. Takizawa K, Brahmbhatt R, Knipschield MA, Bingener J, Gostout CJ. Transcolonic peritoneoscopy by using submucosal endoscopy with mucosal flap for the detection of peritoneal bead targeting in the porcine survival model: a feasibility and effectiveness study. Gastrointest Endosc. 2014;79:127-34.
    Pubmed CrossRef