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Endoscopic full-thickness resection and defect closure in the colon
ORIGINAL ARTICLE: Experimental Endoscopy
Endoscopic full-thickness resection and defect closure in the colon Daniel von Renteln, MD, Arthur Schmidt, MD, Melina C. Vassiliou, MD, MEd, Hans-Ulrich Rudolph, MD, Karel Caca, MD Mannheim, Germany; Montreal, Canada
Background: Endoscopic full-thickness resection (eFTR) is a minimally invasive method for en bloc resection of GI lesions. Objective: The aim of this pilot study was to evaluate the feasibility of a grasp-and-snare technique for eFTR combined with an over-the-scope clip (OTSC) for defect closure. Design: Nonsurvival animal study. Setting: Animal laboratory. Animals: Fourteen female domestic pigs. Interventions: The eFTR was performed in porcine colons using a novel tissue anchor in combination with a standard monofilament snare and 14 mm OTSC. In the first group (n ⫽ 20), closure of the colonic defects with OTSC was attempted after the resection. In the second group (n ⫽ 8), an endoloop was used to secure the resection base before eFTR was performed. Results: In the first group (n ⫽ 20), eFTR specimens ranged from 2.4 to 5.5 cm in diameter. Successful closure was achieved in 9 out of 20 cases. Mean burst pressure for OTSC closure was 29.2 mm Hg (range, 2-90; SD, 29.92). Injury to adjacent organs occurred in 3 cases. Lumen obstruction due to the OTSC closure occurred in 3 cases. In the second group (n ⫽ 8), the diameter of specimens ranged from 1.2 to 2.2 cm. Complete closure was achieved in all cases, with a mean burst pressure of 76.6 mm Hg (range, 35-120; SD, 31). Lumen obstruction due to the endoloop closure occurred in one case. No other complications or injuries were observed in the second group. Limitations: Nonsurvival setting. Conclusions: Colonic eFTR using the grasp-and-snare technique is feasible in an animal model. Ligation of the resection base with an endoloop before eFTR seems to reduce complication rates and improve closure success and leak test results despite yielding smaller specimens. (Gastrointest Endosc 2010;71:1267-73.)
The technique of endoscopic removal of adenomas and early (T1) cancers of the GI tract has evolved substantially since its introduction in the 1970s.1-5 Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have now become widely accepted methods for treatment of premalignant lesions and superficial GI carcinomas. These methods aim to maintain the integrity of the organ wall while achieving complete resection of the
lesions through mucosal resection or submucosal dissection. The colorectum is the portion of the GI tract most frequently affected by tumors, with colorectal adenocarcinoma being the third most common cancer and cause of cancer deaths in the United States.6 Research suggests that the decline of colorectal carcinoma incidence of about 1.5% annually since the 1980s is associated with endoscopic screening and polyp removal.6-9 Endoscopic full-
Abbreviations: eFTR, endoscopic full-thickness resection; EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection; OTSC, over-the-scope clip.
Current affiliations: Department of Gastroenterology, Medizinische Klinik I, Klinikum Ludwigsburg, Ludwigsburg (D.v.R., A.S., K.C.), University Hospital Mannheim, University of Heidelberg, Mannheim (H.-U.R.), Germany; Department of Surgery, Montreal General Hospital, McGill University, Montreal, Quebec, Canada (M.C.V.).
DISCLOSURE: All authors disclosed no financial relationships relevant to this publication. (Research support for this study was provided by Ovesco Endoscopy and Olympus Germany.) Copyright © 2010 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2009.12.056 Received September 20, 2009. Accepted December 17, 2009.
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Reprint requests: Daniel von Renteln, MD, Department of Gastroenterology, Hepatology and Oncology, Klinikum Ludwigsburg, 71640 Ludwigsburg, Germany. If you want to chat with an author of this article, you may contact Dr. von Renteln at [email protected]
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thickness resection (eFTR) may provide a less-invasive alternative to surgery for en bloc resection and may improve the accuracy of histologic assessment compared with ESD. In combination with translumenal lymph node staging, eFTR might be particularly useful in the management of T1sm cancers, with colorectal lesions being the most important clinical target.10-13 Recent animal studies have evaluated eFTR in various areas of the GI tract.10,11,13-23 Most techniques are limited regarding safety and reproducibility, are technically challenging, and require complex or specialized equipment.15,16,19-21 Moreover, a secure and reliable closure technique is of fundamental importance before these procedures can be introduced into the clinical arena. An earlier study demonstrated a “grasp and snare” technique for gastric eFTR to be feasible and efficient, but it did not aim to close the generated defects.22 The purpose of the present study was to evaluate colonic eFTR when using a novel endoscopic anchoring device and to develop a model including safe and reliable closure of the generated defects.
MATERIAL AND METHODS Animals and preoperative preparation The study was conducted at the animal facility in Beichlingen, Thüringen, Germany, after approval of the
von Renteln et al
Take-home Message ●
This study showed the grasp-and-snare technique to be feasible for endoscopic full-thickness resection (eFTR) of colonic specimens up to 5.5 cm in diameter. eFTR defects of up to 2.7 cm can be adequately closed in the majority of cases by using an over-the-scope clip. The concept of applying a closure mechanism before eFTR reduces complication rates, results in leak proof closures, and should be the foundation for future research.
Animal Care and Use Committee. Fourteen female domestic pigs with a mean weight of 28.1 kg (range 20-36 kg, SD 5.0) were used. The animals were fasted from solid food for 48 hours before surgery, but were allowed full access to water and milk. Preanesthesia sedation consisted of ketamine 2 mg/kg and xylazine 2 mg/kg. General anesthesia was achieved using isoflurane, nitrous oxide (N2O), and O2 after endotracheal intubation. Continuous pulse oximetry and electrocardiography were monitored throughout the procedure. All procedures were performed with the animals in the supine position. With the animal under general anesthesia, an extensive colonic lavage was performed with tap water using an endoscopic waterjet pump (AFU-100; Olympus, Hamburg, Germany).
Figure 1. The tissue anchor is (A) passed through an electrocautery snare and (B) deployed into tissue. (C) The tissue anchor is withdrawn and the snare closed, creating a pseudopedunculated lesion.
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Colonic endoscopic full-thickness resection and defect closure
Endoscopic procedures All procedures were performed using a 2T160 double-channel upper endoscope (Olympus, Hamburg, Germany). A novel tissue anchor (Ovesco Endoscopy, Tübingen, Germany) that deploys 3 needle pins at its tip was used for tissue anchoring and manipulation (Fig. 1). The tissue anchor was used through the left channel, and a 2.5 cm oval-shaped monofilament snare (SD-990; Olympus) was used through the right channel. The tissue anchor was deployed transmurally into the colonic wall and then partially retracted into the endoscope to lift the pseudopedunculated lesion into the snare. The snare was then secured around the created pseudopolyp. The eFTR resection of the pseudopedunculated lesion was completed using blended electrosurgical current. Twenty eFTRs were performed in 10 animals with defect closure subsequent to resection, and 8 eFTRs were performed in 4 animals after ligating the base of the pseudopedunculated lesion with an endoloop (HX-400U-30; Olympus) before resection (Figs. 2-4). Time to perform eFTR was defined as time of insertion of the needle pins into the colonic wall until complete resection of the specimen. For defect closure, the second-generation atraumatic over-thescope clip (OTSC; Ovesco Endoscopy, Tübingen, Germany), loaded onto a transparent 14 mm applicator cap in combination with the twin grasper (Ovesco Endoscopy) was used (Fig. 4). The twin grasper technique was used as described previously.24,25 Time to perform OTSC closure was defined as time from initial insertion of the twin grasper into the working channel (with the endoscope being at the eFTR defect) until release of the final clip.
Postresection evaluation The animals were killed after the procedures using intravenous pentobarbital, and laparotomies were performed to evaluate eFTR-related complications, including bleeding and injury to adjacent structures. The specimens were examined for size. All colons were harvested to assess the complete closure of the eFTR sites and lumen obstruction. Closures were considered to be adequate and complete if they could be fully extended by air insufflation even if the defect was not completely centered within the OTSC. Acceptable closures had no obvious gaps, with well approximated wound edges, and no more than 5 mm of the defect beyond the OTSC. Lumen obstruction was documented if the endoscope could not be passed beyond the OTSC. The colons were subsequently cannulated to permit air insufflation and then sealed at both ends. While recording intracolonic pressures, the specimens were gradually inflated using a sphygmomanometer to maximum capacity while being submerged in water. The point of www.giejournal.org
Figure 2. Schematic illustration of the endoloop eFTR technique. a and b, The tissue anchor is passed through the snare and deployed into the colonic wall. c, The tissue anchor is partially withdrawn into the endoscope and the monofilament snare closed. d, The endoloop is placed over the pseudopedunculated lesion and deployed. e, The snare is subsequently opened and placed above the endoloop, and the specimen is resected. f, An over-the-scope clip is placed to finally seal the resection site. (Image courtesy of Ovesco Endoscopy; reprinted with kind permission.)
failure was defined as the pressure at which the first sign of air was seen bubbling from the serosal surface. Pressures were recorded in mm Hg. The Mann-Whitney U test for 2 independent samples was used to estimate differences of both groups (SPSS 14.0; SPSS, Chicago, Ill). A P value of ⬍.05 was considered to be significant. Volume 71, No. 7 : 2010 GASTROINTESTINAL ENDOSCOPY
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Figure 3. Endoscopic view of the endoloop endoscopic full-thickness resection (eFTR) technique. A, The tissue anchor is passed through the snare and deployed into the colonic wall. B, The tissue anchor is partially withdrawn into the endoscope, and C, the monofilament snare is closed. D and E, An endoloop is passed over the snare to ligate the pseudopedunculated lesion. F, The snare is opened and repositioned above the endoloop, and using electrocautery the eFTR specimen is obtained. G, The resection base remains closed by the endoloop. H and I, a 14 mm over-the-scope clip is finally released on the eFTR defect reinforcing the closure mechanism.
RESULTS Results for eFTR with secondary OTSC closure Twenty eFTRs were performed in 10 animals without prior placement of an endoloop. Outcomes are provided in Table 1. The eFTRs produced complete colonic wall defects in all cases. Adequate closure of eFTR defects (size 2.4-5.5 cm) was successful in 9 out of 20 cases (45%). Defects ranging from 2.4 to 2.7 cm were successfully repaired in 5 out of 6 cases (83%), and the largest resections that left defects ranging from 2.9 to 5.5 cm were adequately closed in 4 out of 14 cases (29%). In 5 cases (eFTR defects size ranging from 3.4 to 5.5 cm), closure was attempted using 2 serially placed OTSCs. Closure using 1270 GASTROINTESTINAL ENDOSCOPY
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2 OTSCs was successful in 3 (60%) of those 5 cases, with lumen obstruction due to the closure in 2 (40%) of those 5 cases. Lumen obstruction was seen in 1 additional case of closure using a single OTSC. Incomplete closures demonstrated air leakage at the slightest attempt to insufflate air with the sphygmomanometer (2-10 mm Hg), and the colonic specimens could not be fully extended by air insufflation. Burst pressures for complete closures were in the range of 24 to 90 mm Hg. In 1 case, the anchor pins were placed through the colon wall into adjacent small-bowel wall, resulting in accidental small bowel perforation. In 2 cases, OTSC closure was associated with incorporation of adjacent small bowel into the clip, resulting in lumen obstruction of the adjacent small bowel loop. Overall, 6 serious complicawww.giejournal.org
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Colonic endoscopic full-thickness resection and defect closure
TABLE 1. Outcome of eFTR group with secondary closure Mean Range Time for eFTR (min) Time for OTSC closure (min) eFTR specimen resection size (cm) Burst pressure of the closure (mm Hg)
SD
4
2-10
2.38
10.8
5-26
5.85
3.32 2.4-5.5 29.2
2-90
0.84 29.92
eFTR, endoscopic full-thickness resection; OTSC, over-the-scope clip.
TABLE 2. Outcome of endoloop eFTR group Mean Range Time for eFTR (min)
SD
27.9
19-36
5.54
Time for OTSC closure (min)
3.6
2-6
1.19
eFTR specimen resection size (cm)
1.8
Burst pressure of the closure (mm Hg)
76.6
1.2-2.2 0.39 35-120
31
eFTR, endoscopic full-thickness resection; OTSC, over-the-scope clip.
The eFTRs produced complete colonic wall defects in all cases. In 1 case, the endoloop was cut open by electrocautery application during resection and the OTSC was used to close the open eFTR defect. In all other cases, the OTSC was applied on top of the endoloop to reinforce the endoloop closure. Lumen obstruction due to the OTSC closure occurred in 1 case. No organ injury or other complication occurred in the endoloop eFTR group. Table 3 shows comparative outcomes of both eFTR methods.
DISCUSSION Figure 4. Laparoscopic view of tissue-anchor endoscopic full-thickness resection and subsequent over-the-scope clip (OTSC) closure. A, The tissue anchor is passed through the snare and deployed into the colonic wall. B and C, The tissue anchor is partially withdrawn into the endoscope and the snare closed. D, Electrocautery is applied and (E) a full-thickness resection defect remains. F, The twin grasper is used for lesion border apposition, and (G) the defect is drawn into the 14 mm applicator cap before (H) the OTSC is released.
tions occurred (30%). One complication was related to the eFTR technique and 5 were associated with OTSC closure.
Results for eFTR with an endoloop ligating the resection base Eight eFTRs were performed in 4 pigs using an endoloop to secure the eFTR site before resection. Results are presented in Table 2. www.giejournal.org
This pilot study demonstrates several strengths and weaknesses of eFTR in combination with OTSC closure. The grasp-and-snare technique is very straightforward and resulted in specimens up to 5.5 cm in size. These results are in accordance with an earlier report using a similar technique for gastric eFTR.22 The tissue anchor can be easily deployed in the middle of any targeted resection area and allows for reliable tissue anchoring, pseudopolyp creation, and full-thickness resection. The most important complication we encountered in the first group appeared to be injury to adjacent structures. Eversion of the colonic wall into the lumen before resection should theoretically minimize the risk of injury to adjacent structures. Nevertheless, transmural placement of the anchoring pins resulted in inadvertent small-bowel perforation in 1 case. Because the colonic wall is thinner than gastric tissue, Volume 71, No. 7 : 2010 GASTROINTESTINAL ENDOSCOPY
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TABLE 3. Comparative values of both eFTR groups eFTR without endoloop
eFTR with endoloop
P value*
4
27.9
⬍.01*
10.8
3.6
⬍.01*
1.8
⬍.01*
76.6
⬍.01*
Mean time for eFTR (min) Mean time for OTSC closure (min) Mean eFTR specimen resection size (cm) Mean burst pressure after closure (mm Hg)
3.32 29.2
eFTR, endoscopic full-thickness resection; OTSC, over-the-scope clip. *P value obtained from a Mann-Whitney U test for 2 independent samples.
specifically designed anchoring pins or submucosal infiltration before anchor deployment might avoid these complications. Further research should evaluate different needle pins with optimized penetration depth for gastric and colonic eFTR. As seen in another study, OTSC closure can result in incorporation of adjacent bowel loops.25 This complication might result in mechanical bowel obstruction or delayed perforation, and meticulous caution must be exercised when applying suction during closure. As described in previous studies, the twin grasper was essential in the first group to approximate defect borders into the OTSC.24,25 In the second group, defect borders remained approximated by the endoloop ligation and OTSCs could be applied without the twin grasper. This study provides some important data regarding the defect size that can be created and subsequently closed using 14 mm OTSCs. We aimed to generate defects ranging from about 2 cm up to the maximum capacity. Using the grasp-and-snare technique, we found that the resection can be easily extended to about 5 to 6 cm in diameter without extensive traction on the anchoring device or tissue. In the present animal population, a 4 to 5.5 cm eFTR defect translates into resection of approximately one-third to one-half of the colonic circumference. These very extensive resection areas also allowed us to investigate possible limitations of the OTSC system. Earlier studies evaluated OTSC for closure of defects only up to 18 mm.24,25 These 18 mm openings were created using balloon dilatation, rendering tissue approximation much easier compared with eFTR defects. Study outcomes demonstrate that eFTR defects up to 2.7 cm can be adequately closed using OTSCs in the majority of cases. For defects larger than 2.7 cm, OTSC does not suffice. For some colonic defects ⬎2.7 cm, serial OTSC placement can be used with success, but closure may be associated with lumen obstruction, depending on the location and configuration of the initial resection. Furthermore, large eFTR defects induce a distinct luminal collapse, rendering endoscopic closure very difficult. To overcome these limitations we developed the endoloop technique to secure the base of the eFTR site before tissue resection (Fig. 3). Commercially available endoloops are too floppy to be 1272 GASTROINTESTINAL ENDOSCOPY
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placed directly over the tissue anchor. Therefore, we secured the pseudopedunculated lesion first with a monofilament snare, and then placed the loop above the snare (Fig. 3). This led to significantly longer procedure times in the endoloop eFTR group. An optimized and more rigid endoloop might improve this cumbersome and time-consuming part of the procedure. A specifically designed endoloop might even suffice as sole closure mechanism without OTSC reinforcement. This might have also prevented the lumen obstruction that was seen in 1 case of combined endoloop/OTSC closure. Recent studies report successful closure of GI defects using standard endoloops, endoclips, OTSC, T-tags, and suturing devices.26-32 Nevertheless, comparative trials suggest that the novel endoscopic closure devices such as OTSC or T-tags are superior because of a higher rate of full-thickness closures.25,26,33,34 The study was designed to develop a model for eFTR and not as a controlled trial. Therefore, comparative outcomes for both groups are affected by study design and should be interpreted with caution. The higher burst pressures of endoloop eFTR closures show these closures to be completely sealed and leak proof, but the absolute values might also be affected by differences in the resection size of each group. Although the method and devices used in this study are not yet ready for clinical application, we strongly feel that the concept of applying a closure mechanism before resection is of fundamental importance for further studies. The endoloops used for this technique can be cut open using electrocautery. Therefore, snare resection had to be performed with a safety margin toward the loop. This resulted in much smaller resection specimens in the endoloop eFTR group. Modified endoloops or application of an OTSC before eFTR might provide a potential solution. Based on these pilot data, a novel prototype eFTR device has been developed. The new eFTR prototype allows creation of a pseudopolyp inside an enlarged transparent cap. The OTSC can be applied at the resection base, and subsequent snare resection can be performed above the OTSC. This device is currently under investigation in ex vivo animal trials. In summary, grasp-and-snare eFTR using a tissue anchor is feasible and can achieve full-thickness colonic www.giejournal.org
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resections up to 5.5 cm in size. OTSC results in adequate closure of most eFTR defects up to 2.7 cm in diameter, but does not suffice for larger lesions. The concept of applying a closure mechanism before eFTR should be considered as the basis for future research. REFERENCES 1. Deyhle PFL, Jenny S, Fumagalli I. A method for endoscopic electroresection of sessile colonic polyps. Endoscopy 1973;5:38-40. 2. Wolff WI, Shinya H. A new approach to the management of colonic polyps. Adv Surg 1973;7:45-67. 3. Deyhle PSH, Säuberli H. Endoscopic snare ectomy of an early gastric cancer—a therapeutical method? Endoscopy 1974;6:195-8. 4. Deyhle P. Results of endoscopic polypectomy in the gastrointestinal tract. Endoscopy 1980;(Suppl):35-46. 5. Rosch W, Fruhmorgen P. Endoscopic treatment of precanceroses and early gastric carcinoma. Endoscopy 1980;12:109-13. 6. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin 2009;59:225-49. 7. Winawer S, Fletcher R, Rex D, et al. Colorectal cancer screening and surveillance: clinical guidelines and rationale— update based on new evidence. Gastroenterology 2003;124:544-60. 8. Rex DK, Johnson DA, Lieberman DA, et al. American College of Gastroenterology. Colorectal cancer prevention 2000: screening recommendations of the American College of Gastroenterology. Am J Gastroenterol 2000;868-77. 9. Winawer SJ, Zauber AG, Ho MN, et al, National Polyp Study Workgroup. Prevention of colorectal cancer by colonoscopic polypectomy. N Engl J Med 1993;329:1977-81. 10. Abe N, Mori T, Takeuchi H, et al. Successful treatment of early stage gastric cancer by laparoscopy-assisted endoscopic full-thickness resection with lymphadenectomy. Gastrointest Endosc 2008;68:1220-4. 11. Abe N, Takeuchi H, Yanagida O, et al. Endoscopic full-thickness resection with laparoscopic assistance as hybrid NOTES for gastric submucosal tumor. Surg Endosc2009;23:1908-13. 12. Cahill RA, Asakuma M, Perretta S, et al. Supplementation of endoscopic submucosal dissection with sentinel node biopsy performed by natural orifice transluminal endoscopic surgery (NOTES) (with video). Gastrointest Endosc 2009;69:1152-60. 13. Tsujimoto H, Ichikura T, Nagao S, et al. Minimally invasive surgery for resection of duodenal carcinoid tumors: endoscopic full-thickness resection under laparoscopic observation. Surg Endosc 2010;24:471-5. 14. Suzuki H, Ikeda K. Endoscopic mucosal resection and full thickness resection with complete defect closure for early gastrointestinal malignancies. Endoscopy 2001;33:437-9. 15. Ikeda K, Fritscher-Ravens A, Mosse CA, et al. Endoscopic full-thickness resection with sutured closure in a porcine model. Gastrointest Endosc 2005;62:122-9. 16. Ikeda K, Mosse CA, Park PO, et al. Endoscopic full-thickness resection: circumferential cutting method. Gastrointest Endosc 2006;64:82-9. 17. Kaehler G, Grobholz R, Langner C, et al. A new technique of endoscopic full-thickness resection using a flexible stapler. Endoscopy 2006;38: 86-9.
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Colonic endoscopic full-thickness resection and defect closure 18. Kaehler GF, Langner C, Suchan KL, et al. Endoscopic full-thickness resection of the stomach: an experimental approach. Surg Endosc 2006;20: 519-21. 19. Kantsevoy SV. Endoscopic full-thickness resection: new minimally invasive therapeutic alternative for GI-tract lesions. Gastrointest Endosc 2006;64:90-1. 20. Kahler GF, Collet PH, Grobholz R, et al. Endoscopic full-thickness gastric resection using a flexible stapler device. Surg Technol Int 2007;16:61-5. 21. Sumiyama K, Gostout CJ. Novel techniques and instrumentation for EMR, ESD, and full-thickness endoscopic luminal resection. Gastrointest Endosc Clin North Am 2007;17:471-85. 22. Elmunzer BJ, Trunzo JA, Marks JM, et al. Endoscopic full-thickness resection of gastric tumors using a novel grasp-and-snare technique: feasibility in ex vivo and in vivo porcine models. Endoscopy 2008;40:931-5. 23. Fritscher-Ravens A, Cuming T, Jacobsen B, et al. Feasibility and safety of endoscopic full-thickness esophageal wall resection and defect closure: a prospective long-term survival animal study. Gastrointest Endosc 2009;69:1314-20. 24. von Renteln D, Schmidt A, Vassiliou MC, et al. Natural orifice transluminal endoscopic surgery gastrotomy closure with an over-theendoscope clip: a randomized, controlled porcine study (with videos). Gastrointest Endosc 2009;70:732-9. 25. von Renteln D, Schmidt A, Vassiliou MC, et al. Endoscopic closure of large colonic perforations using an over-the-scope clip: a randomized controlled porcine study. Endoscopy 2009;41:481-6. 26. Raju GS, Shibukawa G, Ahmed I, et al. Endoluminal suturing may overcome the limitations of clip closure of a gaping wide colon perforation (with videos). Gastrointest Endosc 2007;65:906-11. 27. Raju GS, Ahmed I, Shibukawa G, et al. Endoluminal clip closure of a circular full-thickness colon resection in a porcine model (with videos). Gastrointest Endosc 2007;65:503-9. 28. Raju GS, Ahmed I, Xiao SY, et al. Controlled trial of immediate endoluminal closure of colon perforations in a porcine model by use of a novel clip device (with videos). Gastrointest Endosc 2006;64:989-97. 29. Raju GS, Fritscher-Ravens A, Rothstein RI, et al. Endoscopic closure of colon perforation compared to surgery in a porcine model: a randomized controlled trial (with videos). Gastrointest Endosc 2008;68:324-32. 30. von Renteln D, Schmidt A, Riecken B, et al. Gastric full-thickness suturing during EMR and for treatment of gastric-wall defects (with video). Gastrointest Endosc 2008;67:738-44. 31. Hookey LC, Bielawska B, Samis A, et al. A reliable and safe gastrotomy closure technique assessed in a porcine survival model pilot study: success of the Queen’s closure. Endoscopy 2009;41:493-7. 32. Hookey LC, Khokhotva V, Bielawska B, et al. The Queen’s closure: a novel technique for closure of endoscopic gastrotomy for natural-orifice transluminal endoscopic surgery. Endoscopy 2009;41:149-53. 33. von Renteln D, Vassiliou MC, Rothstein RI. Randomized controlled trial comparing endoscopic clips and over-the-scope clips for closure of natural orifice transluminal endoscopic surgery gastrotomies. Endoscopy 2009;41:1056-61. 34. Voermans RP, van Berge Henegouwen MI, Bemelman WA, et al. Novel over-the-scope-clip system for gastrotomy closure in natural orifice transluminal endoscopic surgery (NOTES): an ex vivo comparison study. Endoscopy 2009;41:1052-5.
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Endoscopic full-thickness resection and defect closure in the colon Daniel von Renteln, MD, Arthur Schmidt, MD, Melina C. Vassiliou, MD, MEd, Hans-Ulrich Rudolph, MD, Karel Caca, MD Mannheim, Germany; Montreal, Canada
Background: Endoscopic full-thickness resection (eFTR) is a minimally invasive method for en bloc resection of GI lesions. Objective: The aim of this pilot study was to evaluate the feasibility of a grasp-and-snare technique for eFTR combined with an over-the-scope clip (OTSC) for defect closure. Design: Nonsurvival animal study. Setting: Animal laboratory. Animals: Fourteen female domestic pigs. Interventions: The eFTR was performed in porcine colons using a novel tissue anchor in combination with a standard monofilament snare and 14 mm OTSC. In the first group (n ⫽ 20), closure of the colonic defects with OTSC was attempted after the resection. In the second group (n ⫽ 8), an endoloop was used to secure the resection base before eFTR was performed. Results: In the first group (n ⫽ 20), eFTR specimens ranged from 2.4 to 5.5 cm in diameter. Successful closure was achieved in 9 out of 20 cases. Mean burst pressure for OTSC closure was 29.2 mm Hg (range, 2-90; SD, 29.92). Injury to adjacent organs occurred in 3 cases. Lumen obstruction due to the OTSC closure occurred in 3 cases. In the second group (n ⫽ 8), the diameter of specimens ranged from 1.2 to 2.2 cm. Complete closure was achieved in all cases, with a mean burst pressure of 76.6 mm Hg (range, 35-120; SD, 31). Lumen obstruction due to the endoloop closure occurred in one case. No other complications or injuries were observed in the second group. Limitations: Nonsurvival setting. Conclusions: Colonic eFTR using the grasp-and-snare technique is feasible in an animal model. Ligation of the resection base with an endoloop before eFTR seems to reduce complication rates and improve closure success and leak test results despite yielding smaller specimens. (Gastrointest Endosc 2010;71:1267-73.)
The technique of endoscopic removal of adenomas and early (T1) cancers of the GI tract has evolved substantially since its introduction in the 1970s.1-5 Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have now become widely accepted methods for treatment of premalignant lesions and superficial GI carcinomas. These methods aim to maintain the integrity of the organ wall while achieving complete resection of the
lesions through mucosal resection or submucosal dissection. The colorectum is the portion of the GI tract most frequently affected by tumors, with colorectal adenocarcinoma being the third most common cancer and cause of cancer deaths in the United States.6 Research suggests that the decline of colorectal carcinoma incidence of about 1.5% annually since the 1980s is associated with endoscopic screening and polyp removal.6-9 Endoscopic full-
Abbreviations: eFTR, endoscopic full-thickness resection; EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection; OTSC, over-the-scope clip.
Current affiliations: Department of Gastroenterology, Medizinische Klinik I, Klinikum Ludwigsburg, Ludwigsburg (D.v.R., A.S., K.C.), University Hospital Mannheim, University of Heidelberg, Mannheim (H.-U.R.), Germany; Department of Surgery, Montreal General Hospital, McGill University, Montreal, Quebec, Canada (M.C.V.).
DISCLOSURE: All authors disclosed no financial relationships relevant to this publication. (Research support for this study was provided by Ovesco Endoscopy and Olympus Germany.) Copyright © 2010 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2009.12.056 Received September 20, 2009. Accepted December 17, 2009.
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Reprint requests: Daniel von Renteln, MD, Department of Gastroenterology, Hepatology and Oncology, Klinikum Ludwigsburg, 71640 Ludwigsburg, Germany. If you want to chat with an author of this article, you may contact Dr. von Renteln at [email protected]
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thickness resection (eFTR) may provide a less-invasive alternative to surgery for en bloc resection and may improve the accuracy of histologic assessment compared with ESD. In combination with translumenal lymph node staging, eFTR might be particularly useful in the management of T1sm cancers, with colorectal lesions being the most important clinical target.10-13 Recent animal studies have evaluated eFTR in various areas of the GI tract.10,11,13-23 Most techniques are limited regarding safety and reproducibility, are technically challenging, and require complex or specialized equipment.15,16,19-21 Moreover, a secure and reliable closure technique is of fundamental importance before these procedures can be introduced into the clinical arena. An earlier study demonstrated a “grasp and snare” technique for gastric eFTR to be feasible and efficient, but it did not aim to close the generated defects.22 The purpose of the present study was to evaluate colonic eFTR when using a novel endoscopic anchoring device and to develop a model including safe and reliable closure of the generated defects.
MATERIAL AND METHODS Animals and preoperative preparation The study was conducted at the animal facility in Beichlingen, Thüringen, Germany, after approval of the
von Renteln et al
Take-home Message ●
This study showed the grasp-and-snare technique to be feasible for endoscopic full-thickness resection (eFTR) of colonic specimens up to 5.5 cm in diameter. eFTR defects of up to 2.7 cm can be adequately closed in the majority of cases by using an over-the-scope clip. The concept of applying a closure mechanism before eFTR reduces complication rates, results in leak proof closures, and should be the foundation for future research.
Animal Care and Use Committee. Fourteen female domestic pigs with a mean weight of 28.1 kg (range 20-36 kg, SD 5.0) were used. The animals were fasted from solid food for 48 hours before surgery, but were allowed full access to water and milk. Preanesthesia sedation consisted of ketamine 2 mg/kg and xylazine 2 mg/kg. General anesthesia was achieved using isoflurane, nitrous oxide (N2O), and O2 after endotracheal intubation. Continuous pulse oximetry and electrocardiography were monitored throughout the procedure. All procedures were performed with the animals in the supine position. With the animal under general anesthesia, an extensive colonic lavage was performed with tap water using an endoscopic waterjet pump (AFU-100; Olympus, Hamburg, Germany).
Figure 1. The tissue anchor is (A) passed through an electrocautery snare and (B) deployed into tissue. (C) The tissue anchor is withdrawn and the snare closed, creating a pseudopedunculated lesion.
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Colonic endoscopic full-thickness resection and defect closure
Endoscopic procedures All procedures were performed using a 2T160 double-channel upper endoscope (Olympus, Hamburg, Germany). A novel tissue anchor (Ovesco Endoscopy, Tübingen, Germany) that deploys 3 needle pins at its tip was used for tissue anchoring and manipulation (Fig. 1). The tissue anchor was used through the left channel, and a 2.5 cm oval-shaped monofilament snare (SD-990; Olympus) was used through the right channel. The tissue anchor was deployed transmurally into the colonic wall and then partially retracted into the endoscope to lift the pseudopedunculated lesion into the snare. The snare was then secured around the created pseudopolyp. The eFTR resection of the pseudopedunculated lesion was completed using blended electrosurgical current. Twenty eFTRs were performed in 10 animals with defect closure subsequent to resection, and 8 eFTRs were performed in 4 animals after ligating the base of the pseudopedunculated lesion with an endoloop (HX-400U-30; Olympus) before resection (Figs. 2-4). Time to perform eFTR was defined as time of insertion of the needle pins into the colonic wall until complete resection of the specimen. For defect closure, the second-generation atraumatic over-thescope clip (OTSC; Ovesco Endoscopy, Tübingen, Germany), loaded onto a transparent 14 mm applicator cap in combination with the twin grasper (Ovesco Endoscopy) was used (Fig. 4). The twin grasper technique was used as described previously.24,25 Time to perform OTSC closure was defined as time from initial insertion of the twin grasper into the working channel (with the endoscope being at the eFTR defect) until release of the final clip.
Postresection evaluation The animals were killed after the procedures using intravenous pentobarbital, and laparotomies were performed to evaluate eFTR-related complications, including bleeding and injury to adjacent structures. The specimens were examined for size. All colons were harvested to assess the complete closure of the eFTR sites and lumen obstruction. Closures were considered to be adequate and complete if they could be fully extended by air insufflation even if the defect was not completely centered within the OTSC. Acceptable closures had no obvious gaps, with well approximated wound edges, and no more than 5 mm of the defect beyond the OTSC. Lumen obstruction was documented if the endoscope could not be passed beyond the OTSC. The colons were subsequently cannulated to permit air insufflation and then sealed at both ends. While recording intracolonic pressures, the specimens were gradually inflated using a sphygmomanometer to maximum capacity while being submerged in water. The point of www.giejournal.org
Figure 2. Schematic illustration of the endoloop eFTR technique. a and b, The tissue anchor is passed through the snare and deployed into the colonic wall. c, The tissue anchor is partially withdrawn into the endoscope and the monofilament snare closed. d, The endoloop is placed over the pseudopedunculated lesion and deployed. e, The snare is subsequently opened and placed above the endoloop, and the specimen is resected. f, An over-the-scope clip is placed to finally seal the resection site. (Image courtesy of Ovesco Endoscopy; reprinted with kind permission.)
failure was defined as the pressure at which the first sign of air was seen bubbling from the serosal surface. Pressures were recorded in mm Hg. The Mann-Whitney U test for 2 independent samples was used to estimate differences of both groups (SPSS 14.0; SPSS, Chicago, Ill). A P value of ⬍.05 was considered to be significant. Volume 71, No. 7 : 2010 GASTROINTESTINAL ENDOSCOPY
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Figure 3. Endoscopic view of the endoloop endoscopic full-thickness resection (eFTR) technique. A, The tissue anchor is passed through the snare and deployed into the colonic wall. B, The tissue anchor is partially withdrawn into the endoscope, and C, the monofilament snare is closed. D and E, An endoloop is passed over the snare to ligate the pseudopedunculated lesion. F, The snare is opened and repositioned above the endoloop, and using electrocautery the eFTR specimen is obtained. G, The resection base remains closed by the endoloop. H and I, a 14 mm over-the-scope clip is finally released on the eFTR defect reinforcing the closure mechanism.
RESULTS Results for eFTR with secondary OTSC closure Twenty eFTRs were performed in 10 animals without prior placement of an endoloop. Outcomes are provided in Table 1. The eFTRs produced complete colonic wall defects in all cases. Adequate closure of eFTR defects (size 2.4-5.5 cm) was successful in 9 out of 20 cases (45%). Defects ranging from 2.4 to 2.7 cm were successfully repaired in 5 out of 6 cases (83%), and the largest resections that left defects ranging from 2.9 to 5.5 cm were adequately closed in 4 out of 14 cases (29%). In 5 cases (eFTR defects size ranging from 3.4 to 5.5 cm), closure was attempted using 2 serially placed OTSCs. Closure using 1270 GASTROINTESTINAL ENDOSCOPY
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2 OTSCs was successful in 3 (60%) of those 5 cases, with lumen obstruction due to the closure in 2 (40%) of those 5 cases. Lumen obstruction was seen in 1 additional case of closure using a single OTSC. Incomplete closures demonstrated air leakage at the slightest attempt to insufflate air with the sphygmomanometer (2-10 mm Hg), and the colonic specimens could not be fully extended by air insufflation. Burst pressures for complete closures were in the range of 24 to 90 mm Hg. In 1 case, the anchor pins were placed through the colon wall into adjacent small-bowel wall, resulting in accidental small bowel perforation. In 2 cases, OTSC closure was associated with incorporation of adjacent small bowel into the clip, resulting in lumen obstruction of the adjacent small bowel loop. Overall, 6 serious complicawww.giejournal.org
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Colonic endoscopic full-thickness resection and defect closure
TABLE 1. Outcome of eFTR group with secondary closure Mean Range Time for eFTR (min) Time for OTSC closure (min) eFTR specimen resection size (cm) Burst pressure of the closure (mm Hg)
SD
4
2-10
2.38
10.8
5-26
5.85
3.32 2.4-5.5 29.2
2-90
0.84 29.92
eFTR, endoscopic full-thickness resection; OTSC, over-the-scope clip.
TABLE 2. Outcome of endoloop eFTR group Mean Range Time for eFTR (min)
SD
27.9
19-36
5.54
Time for OTSC closure (min)
3.6
2-6
1.19
eFTR specimen resection size (cm)
1.8
Burst pressure of the closure (mm Hg)
76.6
1.2-2.2 0.39 35-120
31
eFTR, endoscopic full-thickness resection; OTSC, over-the-scope clip.
The eFTRs produced complete colonic wall defects in all cases. In 1 case, the endoloop was cut open by electrocautery application during resection and the OTSC was used to close the open eFTR defect. In all other cases, the OTSC was applied on top of the endoloop to reinforce the endoloop closure. Lumen obstruction due to the OTSC closure occurred in 1 case. No organ injury or other complication occurred in the endoloop eFTR group. Table 3 shows comparative outcomes of both eFTR methods.
DISCUSSION Figure 4. Laparoscopic view of tissue-anchor endoscopic full-thickness resection and subsequent over-the-scope clip (OTSC) closure. A, The tissue anchor is passed through the snare and deployed into the colonic wall. B and C, The tissue anchor is partially withdrawn into the endoscope and the snare closed. D, Electrocautery is applied and (E) a full-thickness resection defect remains. F, The twin grasper is used for lesion border apposition, and (G) the defect is drawn into the 14 mm applicator cap before (H) the OTSC is released.
tions occurred (30%). One complication was related to the eFTR technique and 5 were associated with OTSC closure.
Results for eFTR with an endoloop ligating the resection base Eight eFTRs were performed in 4 pigs using an endoloop to secure the eFTR site before resection. Results are presented in Table 2. www.giejournal.org
This pilot study demonstrates several strengths and weaknesses of eFTR in combination with OTSC closure. The grasp-and-snare technique is very straightforward and resulted in specimens up to 5.5 cm in size. These results are in accordance with an earlier report using a similar technique for gastric eFTR.22 The tissue anchor can be easily deployed in the middle of any targeted resection area and allows for reliable tissue anchoring, pseudopolyp creation, and full-thickness resection. The most important complication we encountered in the first group appeared to be injury to adjacent structures. Eversion of the colonic wall into the lumen before resection should theoretically minimize the risk of injury to adjacent structures. Nevertheless, transmural placement of the anchoring pins resulted in inadvertent small-bowel perforation in 1 case. Because the colonic wall is thinner than gastric tissue, Volume 71, No. 7 : 2010 GASTROINTESTINAL ENDOSCOPY
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TABLE 3. Comparative values of both eFTR groups eFTR without endoloop
eFTR with endoloop
P value*
4
27.9
⬍.01*
10.8
3.6
⬍.01*
1.8
⬍.01*
76.6
⬍.01*
Mean time for eFTR (min) Mean time for OTSC closure (min) Mean eFTR specimen resection size (cm) Mean burst pressure after closure (mm Hg)
3.32 29.2
eFTR, endoscopic full-thickness resection; OTSC, over-the-scope clip. *P value obtained from a Mann-Whitney U test for 2 independent samples.
specifically designed anchoring pins or submucosal infiltration before anchor deployment might avoid these complications. Further research should evaluate different needle pins with optimized penetration depth for gastric and colonic eFTR. As seen in another study, OTSC closure can result in incorporation of adjacent bowel loops.25 This complication might result in mechanical bowel obstruction or delayed perforation, and meticulous caution must be exercised when applying suction during closure. As described in previous studies, the twin grasper was essential in the first group to approximate defect borders into the OTSC.24,25 In the second group, defect borders remained approximated by the endoloop ligation and OTSCs could be applied without the twin grasper. This study provides some important data regarding the defect size that can be created and subsequently closed using 14 mm OTSCs. We aimed to generate defects ranging from about 2 cm up to the maximum capacity. Using the grasp-and-snare technique, we found that the resection can be easily extended to about 5 to 6 cm in diameter without extensive traction on the anchoring device or tissue. In the present animal population, a 4 to 5.5 cm eFTR defect translates into resection of approximately one-third to one-half of the colonic circumference. These very extensive resection areas also allowed us to investigate possible limitations of the OTSC system. Earlier studies evaluated OTSC for closure of defects only up to 18 mm.24,25 These 18 mm openings were created using balloon dilatation, rendering tissue approximation much easier compared with eFTR defects. Study outcomes demonstrate that eFTR defects up to 2.7 cm can be adequately closed using OTSCs in the majority of cases. For defects larger than 2.7 cm, OTSC does not suffice. For some colonic defects ⬎2.7 cm, serial OTSC placement can be used with success, but closure may be associated with lumen obstruction, depending on the location and configuration of the initial resection. Furthermore, large eFTR defects induce a distinct luminal collapse, rendering endoscopic closure very difficult. To overcome these limitations we developed the endoloop technique to secure the base of the eFTR site before tissue resection (Fig. 3). Commercially available endoloops are too floppy to be 1272 GASTROINTESTINAL ENDOSCOPY
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placed directly over the tissue anchor. Therefore, we secured the pseudopedunculated lesion first with a monofilament snare, and then placed the loop above the snare (Fig. 3). This led to significantly longer procedure times in the endoloop eFTR group. An optimized and more rigid endoloop might improve this cumbersome and time-consuming part of the procedure. A specifically designed endoloop might even suffice as sole closure mechanism without OTSC reinforcement. This might have also prevented the lumen obstruction that was seen in 1 case of combined endoloop/OTSC closure. Recent studies report successful closure of GI defects using standard endoloops, endoclips, OTSC, T-tags, and suturing devices.26-32 Nevertheless, comparative trials suggest that the novel endoscopic closure devices such as OTSC or T-tags are superior because of a higher rate of full-thickness closures.25,26,33,34 The study was designed to develop a model for eFTR and not as a controlled trial. Therefore, comparative outcomes for both groups are affected by study design and should be interpreted with caution. The higher burst pressures of endoloop eFTR closures show these closures to be completely sealed and leak proof, but the absolute values might also be affected by differences in the resection size of each group. Although the method and devices used in this study are not yet ready for clinical application, we strongly feel that the concept of applying a closure mechanism before resection is of fundamental importance for further studies. The endoloops used for this technique can be cut open using electrocautery. Therefore, snare resection had to be performed with a safety margin toward the loop. This resulted in much smaller resection specimens in the endoloop eFTR group. Modified endoloops or application of an OTSC before eFTR might provide a potential solution. Based on these pilot data, a novel prototype eFTR device has been developed. The new eFTR prototype allows creation of a pseudopolyp inside an enlarged transparent cap. The OTSC can be applied at the resection base, and subsequent snare resection can be performed above the OTSC. This device is currently under investigation in ex vivo animal trials. In summary, grasp-and-snare eFTR using a tissue anchor is feasible and can achieve full-thickness colonic www.giejournal.org
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resections up to 5.5 cm in size. OTSC results in adequate closure of most eFTR defects up to 2.7 cm in diameter, but does not suffice for larger lesions. The concept of applying a closure mechanism before eFTR should be considered as the basis for future research. REFERENCES 1. Deyhle PFL, Jenny S, Fumagalli I. A method for endoscopic electroresection of sessile colonic polyps. Endoscopy 1973;5:38-40. 2. Wolff WI, Shinya H. A new approach to the management of colonic polyps. Adv Surg 1973;7:45-67. 3. Deyhle PSH, Säuberli H. Endoscopic snare ectomy of an early gastric cancer—a therapeutical method? Endoscopy 1974;6:195-8. 4. Deyhle P. Results of endoscopic polypectomy in the gastrointestinal tract. Endoscopy 1980;(Suppl):35-46. 5. Rosch W, Fruhmorgen P. Endoscopic treatment of precanceroses and early gastric carcinoma. Endoscopy 1980;12:109-13. 6. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin 2009;59:225-49. 7. Winawer S, Fletcher R, Rex D, et al. Colorectal cancer screening and surveillance: clinical guidelines and rationale— update based on new evidence. Gastroenterology 2003;124:544-60. 8. Rex DK, Johnson DA, Lieberman DA, et al. American College of Gastroenterology. Colorectal cancer prevention 2000: screening recommendations of the American College of Gastroenterology. Am J Gastroenterol 2000;868-77. 9. Winawer SJ, Zauber AG, Ho MN, et al, National Polyp Study Workgroup. Prevention of colorectal cancer by colonoscopic polypectomy. N Engl J Med 1993;329:1977-81. 10. Abe N, Mori T, Takeuchi H, et al. Successful treatment of early stage gastric cancer by laparoscopy-assisted endoscopic full-thickness resection with lymphadenectomy. Gastrointest Endosc 2008;68:1220-4. 11. Abe N, Takeuchi H, Yanagida O, et al. Endoscopic full-thickness resection with laparoscopic assistance as hybrid NOTES for gastric submucosal tumor. Surg Endosc2009;23:1908-13. 12. Cahill RA, Asakuma M, Perretta S, et al. Supplementation of endoscopic submucosal dissection with sentinel node biopsy performed by natural orifice transluminal endoscopic surgery (NOTES) (with video). Gastrointest Endosc 2009;69:1152-60. 13. Tsujimoto H, Ichikura T, Nagao S, et al. Minimally invasive surgery for resection of duodenal carcinoid tumors: endoscopic full-thickness resection under laparoscopic observation. Surg Endosc 2010;24:471-5. 14. Suzuki H, Ikeda K. Endoscopic mucosal resection and full thickness resection with complete defect closure for early gastrointestinal malignancies. Endoscopy 2001;33:437-9. 15. Ikeda K, Fritscher-Ravens A, Mosse CA, et al. Endoscopic full-thickness resection with sutured closure in a porcine model. Gastrointest Endosc 2005;62:122-9. 16. Ikeda K, Mosse CA, Park PO, et al. Endoscopic full-thickness resection: circumferential cutting method. Gastrointest Endosc 2006;64:82-9. 17. Kaehler G, Grobholz R, Langner C, et al. A new technique of endoscopic full-thickness resection using a flexible stapler. Endoscopy 2006;38: 86-9.
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