Clips for closure of full-thickness defects

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1 Contents lists available at ScienceDirect 2 3 4 5 6 journal homepage: www.techgiendoscopy.com/locate/tgie 7 8 9 10 11 12 13 n 14 Q1 Alireza Sedarat, MD 15 Interventional Endoscopy Services, Division of Digestive Diseases, University of California Los Angeles, West Los Angeles Veterans Affairs Medical Center, Los Angeles, California 16 17 18 19 a r t i c l e in fo a b s t r a c t 20 Article history: The ability to close a full-thickness defect of the gastrointestinal wall is a key step in performance of full21 Received 16 March 2015 thickness resection and translumenal procedures. This step perhaps represents the greatest hurdle in 22 Accepted 20 June 2015 overcoming the barriers to making full-thickness resection a common therapeutic endoscopic procedure. 23 There are many devices and methods that have been developed for closure of an iatrogenic defect, but 24 through-the-scope and over-the-scope clips are most widely available. This article reviews the literature Keywords: 25 Perforation and methods of using clips for full-thickness defect closure. 26 Clips & 2015 Published by Elsevier Inc. 27 Hemoclips Endoclips 28 Through-the-scope clips 29 Over-the-scope clips 30 Endoscopic full-thickness resection 31 67 32 68 33 69 34 70 a nonoperative means to manage endoscopic perforation is 1. Introduction 35 71 increasingly accepted as a viable strategy in selected cases. More 36 72 recently, other novel methods of clip deployment have been Closure of a full-thickness defect of the gastrointestinal (GI) 37 73 commercially available. The most widely known is an over-thetract is one of the most ambitious and necessary goals for the 38 74 scope (OTS) clipping device that offers the ability to capture more advancement of therapeutic GI endoscopy. The ability to easily and 39 75 tissue. This article reviews the literature and techniques of TTS clip reliably close a full-thickness defect (defined as disruption of the 40 76 and OTS clip (OTSC) application for closure of full-thickness defects GI wall through the muscularis propria layer) represents a major 41 77 of the GI tract. gap that remains between the therapeutic endoscopist and the 42 78 surgeon. Closure of a full-thickness defect is crucial to the endo43 79 scopic management of iatrogenic perforation, natural orifice trans44 80 lumenal surgery (NOTES), and endoscopic full-thickness resection 2. Overview: Types of clips and closure methods 45 81 (EFTR). The endoscopic through-the-scope (TTS) clip (variously 46 82 called clip, endoclip, or hemoclip) has been around since the 1970s 2.1. TTS clips 47 83 [1], became more accepted in general practice only within the last 48 84
15 years, primarily for mechanical hemostasis [2], and is now a TTS clips are available from at least 3 different manufacturers 49 common tool in the armamentarium of the endoscopist. Initially (Figure 1). Availability varies by country and newer versions are in F1 85 50 86 designed for hemostasis, the clip has been adapted to a variety of development. The next generation of TTS clips promise to offer 51 87 endoscopic scenarios, including perforation and fistula managegreater capacity, reliable rotation, and ease of use in difficult 52 88 ment, securing devices (stents and feedings tubes), fluoroscopic anatomy or scope positions. In the first description of NOTES, 53 89 markers [3], to aid in biliary cannulation [4], traction assistance for Kalloo et al [7] used standard available TTS clips to close the 54 90 endoscopic submucosal dissection [5], and for the focus of this gastrotomy of the porcine model. The TTS clip remains the most 55 91 review closure of intentional full-thickness defects of the GI wall. intuitive, most familiar, and most widely available method of 56 92 In 1993 the first report of clip closure of a perforation was defect closure. There is at least one comparative study showing 57 93 published after removal of a leiomyoma [6]. Clip deployment as superior histologic healing of TTS clips compared with T-tags [8]. 58 94 The major drawback of TTS clips is the unreliability of the 59 95 closure and the heterogeneity of outcomes in studies. For full60 The author reports no direct financial interests that might pose a conflict of 96 thickness resection to become an accepted standard therapy, 61 interest in connection with the submitted manuscript. 97 n closure of the defect must be at least as reliable as a surgeon’s Correspondence to: 952 6th St, Apt B, Santa Monica, California 90403. 62 98 suture. TTS clips, especially early generation versions, do not E-mail addresses: [email protected], [email protected] 63 99 64 http://dx.doi.org/10.1016/j.tgie.2015.06.001 100 65 0049-0172/& 2015 Published by Elsevier Inc. 101 66

Techniques in Gastrointestinal Endoscopy

Clips for closure of full-thickness defects

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102 103 104 105 106 W 107 E 108 B 109 4 110 C 111 / 112 F 113 P 114 O Fig. 1. A sample of currently available TTS clips; left to right: Boston Scientific 115 Q10 Resolution, Olympus QuickClip 2 long, Olympus QuickClip Pro, and Cook Instinct. 116 117 reliably oppose the entire GI wall. This is primarily due to an 118 inability to reliably grasp and maintain long-term opposition of 119 anything deeper than the mucosa or superficial submucosa. 120 F2 Furthermore, the ability to grab deeper layers may vary depending 121 on the wall thickness of the organ. Though generally considered 122 easy to use and intuitive, the ability to close large defects or those 123 with significant bleeding or edema easily and efficiently has been 124 questioned. An important variant of extralumenal access, the submucosal 125 126 tunnel, deserves special attention. Submucosal endoscopy is per127 formed by expanding the submucosal space with a fluid cushion, 128 incising the mucosal layer, entering and dissecting through a 129 submucosal tunnel, and performing the procedure desired at an 130 area geographically removed by a few centimeters from the 131 mucosal entry point. This has been applied to NOTES, per-oral 132 endoscopic myotomy, EFTR, and subepithelial tumor resection. The 133 major advantage is that the submucosal tunnel offsets the mucosal 134 defect and the muscular defect from one another; this flap allows 135 for a “safety valve” to aid in closure and minimize extralumenal 136 contamination. In general, the mucosal defect is closed by appli137 cation of TTS clips (though OTSCs and endoscopic suturing have 138 also been used effectively). In this case, TTS clips are well suited 139 and effective because only mucosal closure is needed. As this 140 method of translumenal access is unique, it deserves its own 141 discussion and would not be considered for the purposes of this 142 review. The technique of TTS clip application is well known to most 143 144 endoscopists. The closed clip is passed through the instrument 145 channel into the field of view and the jaws are opened. The jaws 146 (either through manipulation of the endoscope tip or by rotation 147 of the clip apparatus) are oriented perpendicular to the axis of the 148 defect. Suction of air may allow for better tissue capture by 149 collapsing the lumen. The clip is closed to appose tissue and 150 deployed. Currently available clips allow for multiple opening and 151 closing maneuvers before firing. Some manufacturers have devel152 oped improved ability to rotate the clip axis for improved 153 orientation. Multiple clips are applied side-to-side akin to interrupted 154 155 suture closure until the defect is closed. Consistent with surgical 156 principles of sutured enterotomy closure, serial clip application in 157 a line that is perpendicular to the long axis of the lumen may 158 result in superior closure [9]. Depending on the size and shape of 159 the defect and the relative size of the opened jaw, closure typically 160 starts at the periphery of the defect and progress is made toward 161 the center to systematically close the defect. Firing the first clip 162 just lateral to the incision (ie, on uncut, normal mucosa) may help 163 tent the mucosal defect and make subsequent clip application 164 from the periphery easier and more effective. Though the size of 165 the defect that can be closed with clips is generally limited by the 166 opening size of the jaw, this limitation can be partially overcome 167 with this systematic method.

168 169 170 OTSCs were designed to overcome the limitations of TTS clips 171 for a more reliable full-thickness closure. The clip results in a 172 compression closure of the defect. The major drawback is that 173 there is an upper limit of defect closure of approximately 20 mm 174 for a single clip owing to the size of the cap and clip deployment 175 mechanism. Although side-by-side application of multiple clips has been reported (see animal experiments referenced later), it is Q4 176 177 less well studied. The dominant OTSC on the market is manufac178 tured by Ovesco Endoscopy (Tubingen, Germany). 179 The OTS has important technical limitations in applicability. The 180 assembled OTSC device on the tip of the endoscope is bulky and may 181 be difficult to pass beyond the oropharynx, upper esophageal 182 sphincter, or through narrowed or tortuous anatomy. Application of 183 the clip in retroflexion, around tight turns, or other difficult anatom184 ical situations may be challenging or impossible. Additionally, a single 185 clip is fairly expensive, though when compared to deployment of 186 multiple TTS clips the cost may be comparable. As shown in Figure 2, 187 there are 3 types of Ovesco OTSC: “atraumatic” (blunt teeth, primarily 188 designed for hemostasis), traumatic (with short sharp teeth designed 189 for defect closure), and “gastric closure” (with longer teeth designed 190 for improved tissue grip for full-thickness closure and NOTES 191 applications). Because of the strength of OTSCs, they may be difficult 192 (though not impossible [10-14]) to remove once deployed. 193 The technique of OTSC requires some training but is easy to 194 learn and is akin to endoscopic band ligation of esophageal varices. 195 The endoscope is removed to affix a cap with a preloaded open 196 OTSC over the tip that is linked with a thread to the firing handle. The endoscope with the preloaded cap and clip is advanced to the Q5 197 defect. Using suction, tissue graspers, or tissue anchor the edges to Q6 198 199 be apposed are drawn into the cap, and the handle is rotated to fire 200 the clip. 201 A different manufacturer (Padlock-G clip, Aponos Medical, 202 Kingston, NH) has developed an OTSC that works on a similar 203 principle as that of the Ovesco OTSC. The major difference is that it 204 is a circumferential clip that delivers uniform radial compression 205 when deployed. The device is preloaded on a cap that is affixed to 206 the tip of the endoscope. The deployment mechanism is through a 207 thumb-fired handle that runs on outside the endoscope. Though 208 data are limited, animal models show feasibility of full-thickness 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 W 225 226 E 227 B 228 4 C 229 230 / 231 F 232 P Fig. 2. A sample of different sizes and versions of the Ovesco OTSC. O 233 2.2. OTS clips

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234 closure [15,16]. There are no comparative studies of the different 235 OTSCs. Because of a larger body of data, for the purposes of this 236 review, references to the OTSC are to the Ovesco device. 237 238 3. Variations of technique 239 240 3.1. Cut first or close first? 241 242 There are 2 general approaches to EFTR. Perhaps most familiar 243 is the approach to resect a tumor and subsequently close the 244 defect with a chosen method. This method is intuitive and allows 245 for the most freedom in lesion resection, but may hamper closure 246 owing to bleeding and edema following resection. Furthermore, if 247 closure becomes difficult or prolonged, the peritoneal cavity is 248 subject to prolonged exposure of lumenal contents and potentially 249 higher infectious complications. There are also concerns of tumor 250 seeding into the peritoneum or adjacent structures if closure is 251 difficult or delayed or if the specimen falls out of the lumen. The 252 other method seeks to secure closure first followed by resection. 253 This is akin to surgical wedge resection of the stomach using a 254 stapling device. The major advantage is that lumenal closure is 255 obtained without peritoneal exposure and possibly decreases the 256 risk of complications. 257 By necessity, TTS clip closure involves a “resect first” approach. 258 Other closure modalities (such as endoscopic flexible staplers and 259 others) use the “close-first” approach. The OTSC closure provides 260 the potential to “close first” and this has led to a dedicated EFTR 261 device by the manufacturer (full-thickness resection device 262 [FTRD], Ovesco) based on the OTSC. 263 264 3.2. Loop and clip combinations 265 266 In an attempt to overcome the limitations of TTS clips, endo267 loops have been used in a variety of ways to reinforce the clip 268 closure for larger defects. Usually, a double-channel gastroscope is 269 preloaded with a TTS clip in one channel and an endoloop in the 270 other. Outside the patient the endoloop can be captured in the 271 jaws of the clip and both devices pulled into the channels to 272 preload the instrument before inserting the gastroscope. The TTS 273 clip with the endoloop is affixed to the defect and additional clips 274 are placed to anchor the endoloop to the defect edge. The 275 endoloop is then closed and deployed, resulting in drawing and 276 tightly apposing the edges of the defect. In another variation, TTS 277 clips are used to close the defect as much as possible and then an 278 endoloop is used to ensnare the deployed clips. The endoloop is 279 similarly closed to draw all the clips and the defect together. 280 Additional looping can be performed to reinforce the closure 281 or form a pseudopolyp of captured tissue at the defect closure 282 site. Variations of this theme have been described for EFTR in 283 humans without a preferred or dominant approach yet emerging 284 285 Q7 (discussed later). Similar methods using multiple loops, metal rings, or other 286 attachment devices have been described but not used in EFTR in 287 humans [17-20]. Other variations (described in animal models of 288 NOTES) preapply the loop (or loops) with TTS clips to the mucosa 289 before the transmural incision [21,22]. 290 291 292 3.3. Endoscopic omental patching 293 294 Following the example of the omental patch (also known as 295 Graham patch) for surgical treatment of perforated peptic ulcers, 296 endoscopists have described drawing the omentum into a full297 thickness defect to assist in closure, especially when the defect is 298 too large to close completely with clips alone [23,24,42]. This has 299 been variously termed omental patching, omentoplasty,

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omentopexy, and omental plugging. Suction, forceps, or the clips themselves are used to pull omentum into the defect. The omental tissue is then affixed circumferential to the defect edges with TTS clips. The defect edges themselves may or may not be apposed. This technique has been applied to humans for EFTR of gastric subepithelial tumors (discussed later). 3.4. OTSC and EFTR integrated device The ability of the OTSC to more reliably achieve full-thickness compression closure and the potential advantages of a “close-first” approach have led to the evolution of snare resection of tissue above the deployed OTSC from a freehand snare or using an EMR cap [43,44,71,72] (discussed later) into a dedicated EFTR device (FTRD, Ovesco). The FTRD system has been described in animals [45,46], and in a limited series of humans [73,74]. A prospective trial of the FTRD device in colonic lesions (difficult adenomas, early cancers, and subepithelial tumors) is currently recruiting participants (Clinicaltrials.gov id NCT02362126). The system consists of a cap with an opened OTSC and an over-the-endoscope sleeve that contains a channel for the snare. The snare runs on the outside of the scope with the assistance of the sleeve and is prelooped into the cap. Using tissue grasping devices or suction or both, the lesion is drawn into the cap, clipped, and snare resected in a single step. The device is not yet approved for use in the United States.

4. The experimental NOTES and EFTR experience Much of the fund of knowledge for the development of EFTR developed out of the experimental work performed to develop NOTES. In particular, much of what we know about durability and reliability of different closure methods comes from ex vivo and in vivo experimental animal models that were searching for the optimal NOTES closure method. Most of these models focused on creating a defect in the GI wall (usually stomach or colon models) using balloon dilation to allow passage of the endoscope. This is advantageous for NOTES because stretching rather than incising the gastrotomy or colotomy access point may allow for easier closure after the NOTES procedure is performed owing to the natural contraction of the muscle layer providing some degree of closure and tissue apposition. During EFTR, on the contrary, the defect is usually incised with electrocautery (eg, with a knife or snare) and there is conceptually a more complete disruption of the muscle layer, which may be more challenging to close completely. Along these lines, the gastrotomy or colostomy is generally dilated no more than 15-20 mm; thus, the applicability of these data for closure of EFTR defects greater than 2 cm becomes further limited. In parallel with the NOTES experience, experimental work has also been done for iatrogenic perforation closure and along with a growing number of published series of human experiences with perforation closure it has contributed to what we know about the feasibility and potential success of clip closure for EFTR [25]. Most of the data (with a few notable exceptions, as discussed later) has focused on the stomach and colon; there are probably organspecific considerations and results that may not be relevant to applications in the esophagus or small bowel. Finally, much of the early animal model data focus on leak pressures (air or fluid depending on experimental design) and these results may or may not translate into the same behavior in vivo (eg, leak pressure cutoffs may be too stringent or not reflective of risk of infectious complications such as abscess formation). There are some survival studies focusing on clinical outcome and histologic healing, but they are of relatively short term. As a result, the experience of experimental NOTES closure may be limited or not applicable when considering effective EFTR closure, especially for large

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resections, in humans. Nonetheless, there are important lessons that are to be considered from the NOTES experience. 4.1. TTS clips Although the initial animal and human experience in NOTES using endoclips seemed promising [7,26], it generally became clear that TTS clips could not be universally used and would not satisfy the American Society of Gastrointestinal Endoscopy/Society of American Gastrointestinal and Endoscopic Surgeons NOTES White Paper [27] mandate for effective and reliable closure comparable to that of surgery. A comparative study of different TTS clips showed what endoscopists intuitively knew: not all clips are created equal. In this early porcine survival study, only one of the 3 brands of clips was retained after 4-5 weeks [28]. Conceivably, a clip with a longer retention would be more appropriate for defect closure as premature dislodgement could result in devastating delayed complications. It should be noted that in this article and in most of the published data of clip closure, earlier versions of clips were used; whether or not these data are applicable to currently available clips is unknown. In recent years, manufacturers have introduced different TTS clips with larger capacity jaws; these may provide longer retention times and possibly deeper tissue apposition, but they have not been formally tested or compared head-to-head for closure applications. A comparative ex vivo trial to evaluate optimal gastric closure methods found that clips had inferior air leak pressures compared with the experimental prototype and hand-sewn closure. Importantly, clip closure appeared more difficult and variable in length (15-60 minutes compared with o 5 minutes for the other methods) [29]. The same group performed another experiment comparing additional methods in both the colon and the stomach of ex vivo models. In the stomach models, clip closure provided superficial apposition on histologic analysis (mucosal and some seromuscular closure) and inferior leak pressures to other methods. Interestingly, in the colon model, although the thickness of closure was still histologically limited (mucosal and some seromuscular closure), leak pressures were surprisingly strong despite lack of serosal closure [30]. This along with the extensive animal work by Raju et al [31] of iatrogenic colon perforations, which showed effective and leak-proof closure with TTS clips, suggests that the colon may be more amenable to effective closure with clips compared with the stomach. This may be related to the thinner wall of the colon or the ability to capture more of the muscle layer. These studies seem to indicate that future considerations and studies of EFTR and closure methods should be organ specific. Another group compared 7 gastric closure methods and found the leak pressures for the TTS clips to be noninferior in comparison to surgical closure [32]. The same group later published a followup study that showed similar leak pressure with the OTSC compared to their prior TTS clip data [33]. On the contrary, a subsequent randomized controlled live pig survival trial of TTS clips vs OTSCs by a different group showed inferiority of closure and higher infectious complications with TTS clips [34]. In a systematic review comparing the methodologies and outcomes of various gastrotomy closure methods, the authors acknowledge the lack of standardization and homogeneity, the variable methods to determine adequate closure, and inconsistent outcomes with some studies showing no or minimal complications and some showing severe infectious complications with TTS clip closure [35]. These studies highlighted the variability of clip performance, the critical need for live animal survival analysis, and the need for further study. Limited models in the esophagus have been published and suggest adequate but potentially suboptimal TTS clip closure. A

comparison between TTS clips and a suture system showed adequate sealing of the defect in the porcine esophagus but histologic superficial closure with discontinuation of the muscular layer with clip closure compared with complete healing with sutured closure [36]. In contrast with the studies quoted earlier, another experimental model by the same group concluded that TTS clip closure was faster than thorascopic sutured closure and an endoscopic suturing system with comparable survival outcomes (though mortality and infection complications were actually worse in the non-TTS clip groups, this did not reach statistical significance) [37]. Notably, in contrast with other experimental models, the transmural disruption in these esophageal models was made by electrosurgical incision instead of balloon dilation. The effect of these data was that investigators sought (and continue to seek) better alternatives to TTS clips for closure. It should be reiterated that since these experimental models have been published, improved clip designs have become commercially available; these have not yet been tested formally for defect closure to see if there is a difference in outcome compared to previous clip models. 4.2. OTS clips Investigators have evaluated the OTS clip for closure of perforations and NOTES access sites. This was driven by the reliable fullthickness serosal-to-serosal apposition and relatively quicker application time for the OTSC. In the survival porcine randomized trial referenced earlier [34], investigators found mean times for closure significantly smaller with the OTSC compared with the TTS clip (8.5 vs 31.5 minutes, respectively) and a wide range of closure times with TTS clips (8-88 minutes). This is similar to the experience other investigators have had with the TTS clip: closing an edematous, bleeding, or large defect with TTS clips can be difficult, inconsistent, and time consuming with elevated chance of failure to close [38,39]. Interestingly, the same group compared the OTSC with open surgical repair and found better air leak pressures with the OTSC (though this did not reach statistical significance) [40]. In a slightly different experimental model, the OTSC was used to close defects created on an ex vivo model with a surgical scalpel and was found to be effective in both the stomach (5-20 mm defects) and the colon (10-30 mm defects) compared with historical surgical suture data [41]. In another interesting study of nonsurvival and survival animals comparing TTS clips, omentoplasty, and OTSCs for gastrotomy closure, OTSCs had superior leak pressures and OTSCs and omentoplasty had similar and superior histologic healing compared with TTS clips [42]. These studies have established the OTSC as a viable consideration for fullthickness closure and worthy of further consideration. There is an emerging body of literature describing experimental animal experience in EFTR. The recent animal experiments dedicated to EFTR (rather than NOTES access models) with clip closure have employed the OTSC rather than TTS clips. In a nonsurvival porcine study of a grasp and snare model of colonic EFTR, investigators found inadequate closure using the OTSC alone but improved closure success and fewer complications in the subset of animals where OTSC closure was preceded by endoloop ligation. In addition to supporting a “close-first” approach, this study highlighted important limitations of OTSC closure. As noted earlier, previous studies closed defects up to
18-20 mm. In this study, defects up to 27 mm were closed effectively. Larger defects could sometimes be closed with 2 serially placed OTSCs but often resulted in lumen obstruction [43]. Following the paradigm of the “close-first” approach, the OTSC deployment system has been modified to incorporate snare resection. In a porcine survival study of a prototype of this method 2-cm colonic EFTR was performed successfully in 7 of 8 animals

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with good clinical and histologic closure outcomes. In 2 subjects, more than one clip was required; one of these animals was sacrificed owing to lumen obstruction from the additional clip [44]. This prototype became the basis of a commercially available dedicated EFTR device based on the OTSC (FTRD, Ovesco), which has been tested in animal models of gastric subepithelial tumors [45] and colon EFTR [46]. In an experiment to test a mechanical counter-traction device to overcome limitations of lumen deflation after EFTR, investigators evaluated closure of large (40-50 mm) simulated gastric tumors in a survival canine model. After resection, the large defect was closed with multiple serial OTSCs. All resections were complete and survival animals did well without complications and with good closure on follow-up endoscopy. This study challenges the upper limit of EFTR defect closure with OTSC and shows feasibility and safety of multiple side-to-side OTSCs in the colon [47]. In contrast, a canine survival study by the same group comparing OTSC closure to a prototype suturing system of large (5 cm) gastric EFTR defects resulted in infectious complications and deaths in the OTSC arm [48]. These important experiments highlight the potential superiority of the OTSC and the potential limitations of TTS clips. Despite these exciting data, the OTSC has not been a panacea. The upper size limit of resection that can be closed with OTSC has not been definitively defined and the efficacy and safety of multiple OTSCs for larger defects need further study. In some publications, incomplete OTS closure, immediate or delayed failure, and significant infectious complications have been reported in nonsurvival and survival animal models [35].

5. Human experience with EFTR Building on the experimental models and clinical experience of NOTES, iatrogenic perforation closure, and animal EFTR there is a growing body of literature describing EFTR of tumors in humans in a variety of locations of the GI tract. Most of the human data in this nascent field are descriptive series without a large body of comparative data.

5.1. Esophagus and GE junction Compared with other GI sites, there are fewer published reports of EFTR in the esophagus and gastroesophageal junction (GEJ). Most series in esophageal and GEJ EFTR have employed a submucosal tunnel technique with the mucosal entry site closed by TTS clips with good outcomes (termed “STER”: submucosal tunneling and endoscopic resection) [49-51]. The published attempts at resection without a submucosal tunnel have been primarily attempts at preserving the muscular layer without true full-thickness resection. A case series of 4 patients with GEJ leiomyoma showed feasibility of resection in this challenging location (though without complete transection of the muscular layer) with successful closure with TTS clips [52]. A series of 31 subepithelial tumors resected by “endoscopic muscular dissection” without intentional EFTR included 14 esophageal lesions and 7 cardia lesions. Defects were closed with TTS clips; 2 perforations (esophagus and cardia) recognized postprocedurally were treated with covered esophageal stent placement [53]. Though pure EFTR of the esophagus is a potentially feasible approach, clip closure (TTS or OTS) may be more difficult owing to limited space. The consequences of failed closure in the mediastinum and thorax are potentially more serious than in the peritoneum; this has limited EFTR without a submucosal tunnel in this location.

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5.2. Gastric subepithelial tumors Much of the human experience in EFTR has been in gastric SETs. A number of descriptive case series have emerged, primarily from China and Germany, showing the feasibility of a variety of approaches. After descriptions of dissection of tumors off the muscular layer without full-thickness resection using techniques similar to endoscopic submucosal dissection (variously called enucleation, endoscopic muscular dissection, or endoscopic submucosal excavation) [54-56], including TTS clip closure of transmural perforations during the resection attempt [57,58], investigators started to pursue EFTR. Zhou et al [59] published a series of 26 patients with successful “cut-first” EFTR of gastric SETs (primarily gastrointestinal stromal tumor [GIST] and leiomyoma) with successful TTS clip or omental patch clip closure of all cases and without complications. Wang et al described a series of 109 patients with gastric stromal tumors o 4 cm who underwent EFTR. After informed consent, patients chose between a surgical and an endoscopic approach; 66 were treated with endoscopic resection. Endoscopic closure was performed using a combination of an adapted nylon ring and TTS clips. Operative time, hospital costs, and bleeding complications for the endoscopy group were significantly lower but there were less full-thickness resections and more wound disruptions and localized peritonitis in this group [60]. Huang et al [61] followed this with a series of 69 patients with gastric SETs resected by 3 different methods depending on size. EFTR using a “cut-first” approach was performed on 13 patients with tumors 42 cm and defects were closed with TTS clips or omental flap clip closure with good clinical outcomes. Feng et al described their series of 48 patients with gastric SETs up to 4.8 cm (mean ¼ 1.59 cm, mostly GISTs) resected by EFTR. The defects were closed with TTS clips in all cases. This group reported the number of clips used and stratified this to size of the lesion. Though not statistically significant, there was a trend of higher number of clips with a larger tumor (mean ¼ 6.96 clips for tumors o1 cm up to mean ¼ 12 clips for tumors 4 3 cm) [62]. There are relatively limited descriptions of the OTSC closure for EFTR in the stomach. A series of 8 patients included 2 carcinoid tumors of the stomach that were successfully removed using the “close-first” approach with the OTSC [63]. In a prospective series of 20 patients with gastric SETs o 3 cm, 14 were resected endoscopically with and without laparoscopic control using a “cut-first” approach. The OTSC was used in 7 patients (including 6 recognized transmural resections) and TTS clip in 1 patient (owing to inability to pass the OTSC system beyond the epiglottis). There were no complications reported [64]. A mixed series of 17 patients included 2 stomach SETs (1 carcinoid and 1 “scattered spleen tissue”); a “close-first” approach was employed and no complications were reported [65]. In addition to the omental patch and TTS clip-loop combination approaches in the aforementioned studies, many of the recent series of EFTR in the stomach have focused on other effective TTS clip closure variants. Shi et al described a series of 20 patients with gastric SETs (up to 3 cm, mean ¼ 1.47 cm in size) who underwent EFTR with successful closure using TTS clip and endoloop combination [66]. Zhang et al [67] published a similar but slightly modified TTS clip-endoloop closure approach of 30 gastric SETs (mostly GIST, mean tumor size 1.9 cm) without complications. Ye et al described another variation in 50 cases of GISTs and leiomyomas. EFTR was successful in 50 of 51 patients (one was converted to laparoscopy after the tumor fell into the peritoneum) and TTS clip and endoloop combination was effective for closure without complications [68]. These authors concluded that the use of the TTS clip-loop combination was easier and more reliable than

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TTS clips alone, though this has not been formally compared in a head-to-head manner. 5.3. Colon There are human descriptions of EFTR in the colon for early cancer [69-72], difficult-to-resect adenomatous polyps [65,73,74], and neuroendocrine tumors [65,75]. A larger mixed series of patients that included 14 with colorectal lesions underwent successful EFTR in all but one; closure was with the OTSC [65]. Most of these have used a “close-first” approach (and some have also successfully employed the FTRD, Ovesco, discussed earlier). In contrast with the stomach, much of the human descriptions of EFTR in the colon have used the OTSC, but there is at least one series showing some feasibility with TTS clips for EFTR in the colon. A series of 19 patients with colonic SETs less than 3 cm underwent EFTR; one tumor was converted to laparoscopic resection owing to attachment to an extralumenal organ. Complete closure was performed in all of the remaining 18 patients: 2 of the 18 with TTS clips alone and 8 of the 18 with TTS clip and endoloop combination. Of these patients 3 had complications and were managed nonoperatively. Pathologic diagnoses were mostly leiomyoma and GIST [76]. 5.4. Small bowel Limited experience exists with small bowel EFTR and the published data are on duodenal neuroendocrine tumors, mostly closed with OTSC [63,65]. A very early description of EFTR was a small series by Suzuki and Ikeda [77] in 2001; 2 rectal and 1 duodenal carcinoid were resected using a “close-first” approach with endoscopic band ligation and metal loop ligation before snare resection; TTS clip was used to complete closure. More work is needed for small bowel EFTR and it is a particularly appealing option for small duodenal neuroendocrine tumors.

6. Conclusions With increasing comfort in endoscopic management of iatrogenic perforation and the knowledge gained from the prior NOTES experience, EFTR is evolving as a viable minimally invasive technique to treat carefully selected GI neoplasms. The key step is a reliable, secure, and efficient means of defect closure. Feasibility of approaches using both the TTS clips and OTSCs has been demonstrated in animal models of EFTR and in emerging human data, but the optimal method has not been established. There are limitations to the TTS clip that limit its universal applicability to defect closure. The OTSC seeks to overcome these limitations, but is not a perfect solution. Further studies, including long-term comparative trials, are needed with clips and with other closure devices to allow this field to mature in clinical practice.

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