Innovations and brief communications
Polyglycolic acid sheets with fibrin glue can prevent esophageal stricture after endoscopic submucosal dissection
Authors
Yoshiki Sakaguchi1, Yosuke Tsuji1, 2, Satoshi Ono1, Itaru Saito1, Yosuke Kataoka1, Yu Takahashi1, Chiemi Nakayama1, Satoki Shichijo1, Rie Matsuda1, Chihiro Minatsuki1, Itsuko Asada-Hirayama1, Keiko Niimi1, 3, Shinya Kodashima1, Nobutake Yamamichi1, Mitsuhiro Fujishiro1, 2, Kazuhiko Koike1
Institutions
Institutions are listed at the end of article.
submitted 14. May 2014 accepted after revision 2. September 2014
Background and study aims: Suitable techniques for the prevention of stricture formation after esophageal endoscopic submucosal dissection (ESD) are still lacking. We investigated the efficacy of polyglycolic acid (PGA) sheets with fibrin glue to prevent post-ESD stricture. Patients and methods: We conducted a pilot study on a total of eight consecutive patients who underwent esophageal ESD that left a mucosal defect of more than three-quarters of the esophageal circumference. PGA sheets were attached to the defect with fibrin glue immediately after the completion of ESD. The primary endpoint was the incidence of post-ESD stricture. The secondary endpoints were the number of ses-
sions of endoscopic balloon dilation (EBD) required to resolve any stricture and the rate of complications. Results: There were no adverse events related to the use of PGA sheets and fibrin glue. Post-ESD stricture occurred in 37.5 % of the subjects and 0.8 ± 1.2 sessions of EBD were required. Conclusion: The use of PGA sheets and fibrin glue after esophageal ESD is a novel method that radically decreases the incidence of esophageal stricture and the number of EBD sessions subsequently required. University Hospital Medical Network Clinical Trial Registry (UMIN000011058).
Introduction
been reports of the efficacy of the application of PGA sheets with fibrin glue to post-ESD defects [10, 11], but there have been no reports to date concerning the prevention of stricture after esophageal ESD with this method. The aim of this study was to determine the efficacy of the application of PGA sheets and fibrin glue for the prevention of post-ESD esophageal stricture.
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1390787 Published online: 14.10.2014 Endoscopy 2015; 47: 336–340 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X Corresponding author Mitsuhiro Fujishiro, MD Department of Endoscopy and Endoscopic Surgery Graduate School of Medicine The University of Tokyo 7-3-1, Hongo, Bunkyo-ku Tokyo, 113-8655 Japan Fax: +81-3-58008806 [email protected]
!
Postoperative stricture frequently occurs after esophageal endoscopic submucosal dissection (ESD). The incidence of stricture is known to significantly increase in proportion to the overall size of the target lesion and the circumferential size of the post-ESD mucosal defect. Strictures have been reported to occur in 90 % of patients left with a post-ESD mucosal defect that covers more than three-quarters of the circumference of the esophagus [1]. Esophageal stricture often requires multiple sessions of endoscopic balloon dilation (EBD) over a period of several months [2]. Although there have been reports regarding the efficacy of postoperative corticosteroid administration [3 – 5], these methods are accompanied by a risk of severe adverse effects [6, 7]. The use of a polyglycolic acid (PGA) sheet, a biodegradable suture material, has demonstrated its potential as a method to reinforce the suture and minimize scar contracture in other medical fields [8]. PGA is a synthetic compound that is completely degraded into a nontoxic degradation product, glycolic acid, over a period of 4 – 6 months in physiological conditions [9]. Recently there have
Patients and methods !
This was a pilot study of patients treated with the application of PGA sheets and fibrin glue after esophageal ESD. The use of PGA sheets with fibrin glue after ESD was begun only after approval from the Research Ethics Committee of the Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, and appropriate trial registration in July 2013. We enrolled subjects into our study who were referred to our institute with a diagnosis of superficial esophageal cancer with single or multiple lesions covering over half the circumference of the esophagus, which might therefore cause a post-
Sakaguchi Yoshiki et al. PGA sheets with fibrin glue can prevent esophageal stricture after ESD … Endoscopy 2015; 47: 336–340
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
336
Innovations and brief communications
Endoscopic submucosal dissection (ESD) for esophageal squamous cell neoplasm performed between September 2013 and March 2014 (n = 23) Excluded Post-ESD mucosal defect < 3/4 of esophageal circumference (n = 14)
337
were excluded from this study because of contraindications. All the enrolled patients submitted written forms of informed consent for the application of PGA sheets with fibrin glue in addition to giving consent for esophageal ESD according to normal clinical practice.
Excluded Contraindications to further treatment (n = 0) Treated with application of a polyglycolic acid (PGA) sheet and fibrin glue immediately after ESD (n = 9) Excluded Steroids also used (n = 1)
Included in per protocol analysis (n = 8)
Fig. 1
Flow diagram of the study patients.
ESD mucosal defect of more than three-quarters of the circumfer" Fig. 1). Contraindications to the use of ence of the esophagus (● PGA sheets and fibrin glue are nearly non-existent: the use of PGA sheets is contraindicated in those who have systemic complications, while the contraindications for the use of fibrin glue are listed as a history of: (i) anaphylaxis to components of fibrin glue or drugs made of bovine lung; or (ii) treatment with procoagulants, antifibrolytic agents, or aprotinin. Therefore, no subjects
A single-channel upper gastrointestinal endoscope (GIF Q260J; Olympus Co.) with a high frequency generator VIO 300 D (ERBE Elektromedizin GmbH, Tübingen, Germany) was used. ESD was performed at the University of Tokyo Hospital as described in detail previously [12]. In brief, a representative sequence would be: close observation of the targeted esophageal lesion(s) using chro" Fig. 2 a), followed by markmoendoscopy with iodine staining (● ing of the margin of the lesion using the Dual Knife (KD-630L; Olympus Co.). The lesion was injected submucosally using a two-fold diluted solution of 0.4 % hyaluronic acid (Mucoup; Johnson and Johnson K.K., Tokyo, Japan) and was then incised and dis" Fig. 2 b). sected using the Dual Knife until ESD was completed (●
PGA sheet deployment with fibrin glue Immediately after ESD had been completed, a PGA sheet (Neoveil, " Fig. 2 c) was de100 × 50 × 0.15 mm; Gunze Co., Tokyo, Japan) (● ployed using a modified version of the clip-and-pull method pre" Fig. 3; ● " Video 1) [13]. After the PGA sheet viously described (● had been grasped with endoscopic forceps, it was wrapped around the endoscope, which was then inserted orally to the site of the post-ESD defect. The PGA sheet was anchored to the anal end of the post-ESD mucosal defect using endoscopic clips and was then deployed so as to cover the entire circumference " Fig. 2 d). After the oral end of the PGA sheet of the esophagus (●
Fig. 2 Images from the management of one of the study patients showing: a a widespread esophageal squamous cell carcinoma viewed using chromoendoscopy and iodine staining; b the mucosal defect immediately after endoscopic submucosal dissection (ESD) had been performed; c the soft elastic polyglycolic acid (PGA) sheet before insertion; d an endoscopic view of the PGA sheet positioned over the entire mucosal defect; e the endoscopic appearance 1 month after ESD showing no signs of a stricture; f the endoscopic appearance of the esophagus 2 months after ESD.
Sakaguchi Yoshiki et al. PGA sheets with fibrin glue can prevent esophageal stricture after ESD … Endoscopy 2015; 47: 336–340
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Endoscopic submucosal dissection procedure Post-ESD mucosal defect > 3/4 of esophageal circumference (n = 9)
Innovations and brief communications
had also been anchored using endoscopic clips, fibrin glue (Beriplast P 3 mL Combi-Set; Behring Pharma, Tokyo, Japan) was instilled along the entire length of the sheet, firmly fixing it to the post-ESD mucosal defect.
Perioperative management On the day before ESD, oral diet was discontinued after the evening meal, and patients were prohibited from eating thereafter until instructed. Oral administration of a daily dose of 10 mg rabeprazole was also begun on the day before ESD and was continued daily for a minimum of 28 days. On the day following ESD, laboratory investigations along with chest and abdominal radiographs were performed. Oral diet was resumed 2 days after ESD, and scheduled postoperative endoscopies were routinely per" Fig. 2 e, f). formed on day 7 and day 28 after ESD (●
Definition of postoperative stricture Postoperative stricture was defined as the presence of a stenosis of the esophageal lumen that had progressed to the point where a 9.8-mm diameter upper gastrointestinal endoscope (GIF Q240 or GIF H260; Olympus Co.) could not be passed through it. The day of stricture occurrence was defined as the day when the stricture was endoscopically confirmed. In addition to the scheduled endoscopies, endoscopy was also performed if the patient began to experience symptoms of dysphagia.
Endoscopic balloon dilation In patients who developed an esophageal stricture, the first session of EBD was performed using an esophageal balloon dilation catheter (CRE Fixed Wire 12 mm/15 mm/18 mm; Boston Scientific Co., Natick, Massachusetts, USA) immediately after the stricture had been endoscopically confirmed. EBD was repeated as required until the stenosis of the esophageal lumen widened and it was possible to pass the endoscope through the esophageal lumen. After the postoperative stricture had been resolved, endoscopic follow-up was continued for a minimum of 4 weeks. After this period, scheduled endoscopic follow-up was terminated if it was confirmed that the endoscope could be smoothly passed through the esophagus.
Follow-up endpoints The primary endpoint of this study was the incidence of postoperative stricture after esophageal ESD. The secondary endpoints were the number of sessions of EBD required to resolve any strictures and the rate of complications.
Results !
Fig. 3 Diagram of the modified clip-and-pull method. a The polyglycolic acid (PGA) sheet is grasped with endoscopic forceps. b The sheet and endoscope are inserted into the esophagus next to the mucosal defect left after endoscopic submucosal dissection (ESD). c The PGA sheet is released and anchored to the anal end of the defect using endoscopic clips. d The endoscope is pulled out leaving the PGA sheet in place. e The procedure results in total coverage of the mucosal defect and the adjacent esophageal mucosa.
gus. The size of the largest lesion was measured in those patients who had adjacent lesions resected in an en bloc fashion with several lesions being included in the same ESD sample.
Patients Between September 2013 and March 2014, nine patients underwent ESD that left a post-ESD defect of over three-quarters of the circumference of the esophagus and were treated by adhesion of a PGA sheet with fibrin glue. One patient was excluded from the analysis because of predetermined combined use of corticosteroids to further minimize the risk of esophageal stricture after dis" Fig. 1). Therefore, eight patients were cussion with the patient (● eligible for per protocol analysis. The baseline characteristics of " Table 1. the subjects are detailed in ● Although several patients presented with multiple esophageal lesions, all patients were left with only a single mucosal defect that covered over three-quarters of the circumference of the esopha-
Video 1
The modified clip-and-pull method of Online content including polyglycolic acid (PGA) sheet delivery video sequences viewable after endoscopic submucosal dissec- at: www.thieme-connect.de tion (ESD) in the esophagus.
Sakaguchi Yoshiki et al. PGA sheets with fibrin glue can prevent esophageal stricture after ESD … Endoscopy 2015; 47: 336–340
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338
Innovations and brief communications
Patient sex (men : women)
7:1
Patient age, mean ± SD, years
69.1 ± 9.0
Tumor location Cervical esophagus
0
Upper thoracic esophagus
2
Mid-thoracic esophagus
4
Lower thoracic esophagus
2
Table 2 Details of the endoscopic submucosal dissection (ESD) and polyglycolic acid (PGA) sheet application procedures, adverse events, and their subsequent management in the eight patients available for per protocol analysis. Procedure details Size of resected specimen, mean ± SD, mm
53.8 ± 8.8
Total dissection time, mean ± SD, minutes
120.0 ± 28.8
Application time for PGA sheet, mean ± SD, minutes Patients developing a stricture after ESD, n (%) Time to stricture occurrence, mean ± SD, day 1
Tumor depth
12.8 ± 5.5
Adverse events 3 (37.5 %) 28.0 ± 7.0
Confined to the epithelium
1
Sessions of EBD required, mean ± SD, n
0.8 ± 1.2
Confined to the lamina propria mucosae
5
Other complications, n (%)
0 (0.0)
Confined to the muscularis mucosae
0
sm1 (invading the submucosa ≤ 200 μm)
0
sm2 (invading the submucosa > 200 μm) Tumor size, mean ± SD, mm
SD, standard deviation; EBD, endoscopic balloon dilation. 1 Calculated only for the three patients who developed strictures.
2 37.9 ± 8.9
SD, standard deviation.
Technical success of procedures En bloc esophageal ESD with tumor-free vertical and lateral margins was successfully completed in all subjects. There were no intraoperative adverse events. The application of PGA sheets was also successful in all subjects, with 12.8 ± 5.5 minutes being re" Table 2). quired for this part of the procedure (●
Endpoint results The overall incidence of postoperative stricture was 37.5 % (3/8 patients). The number of EBD sessions required to treat strictures was 0.8 ± 1.2 sessions. There were no other postoperative adverse events.
Discussion !
This pilot study suggests that the use of PGA sheets and fibrin glue may significantly reduce the incidence of post-ESD esophageal stricture. Even in patients whose stricture cannot be completely prevented, the number of sessions of EBD required to relieve their post-ESD esophageal stricture can be radically reduced. Previous reports on methods of esophageal stricture prevention after ESD have mainly focused on the administration of corticosteroids [1, 3, 4], with both systemic oral administration and direct focal injections of corticosteroids shown to be effective. However, there is concern over the safety of these methods as there have been reports of severe adverse events: systemic infection with oral administration and postoperative perforation after focal injections [6]. Although the incidence rates of these complications are not high, they do carry a risk of mortality. In terms of the safety of the methods used in this study, both PGA sheets and fibrin glue have been used in the gastrointestinal tract for decades with few reports of adverse effects to date [14]. Although there are still only a few reports of the use of PGA sheets within the gastrointestinal lumen and long-term follow-up is necessary [10, 11], the risk of adverse events related to the use of PGA sheets and fibrin glue is minimal. In similar patients undergoing ESD procedures with a mucosal defect of more than three-quarters of the circumference of the esophagus, only focal corticosteroid injection has been reported to significantly decrease the incidence of post-ESD stricture [3, 5]. The mean number of EBD sessions required after esophageal
ESD was reported to be 1.7 after oral administration of corticosteroids [4] and 1.7 after focal corticosteroid injection [3]. Our results indicate that the effectiveness of using PGA sheets with fibrin glue is comparable to, or even better than, previous methods. Given also the safety concerns with the previous methods, our method should be considered as an alternative method for the prevention of post-ESD esophageal stricture. As for the technical aspects of the method used in this study, while a certain level of technical expertise was required, the procedure was successfully performed by several operators in our institute. In addition, the amount of time required for this method of PGA sheet deployment and instillation of fibrin glue (12.8 ± 5.5 minutes) seems acceptable considering the amount of time that can be required for multiple sessions of EBD. There were several limitations to our study. First, this was a single-center analysis involving only a limited number of patients. A randomized controlled study is required for confirmation of the results of this pilot study. Second, the mechanism through which the PGA sheet prevents stricture is as yet unclear. In conclusion, the use of PGA sheets and fibrin glue is a promising new method that may significantly decrease the incidence of esophageal stricture following ESD and may also radically decrease the number of sessions of EBD that are required in the event of stricture formation. Although there have recently been several methods suggested for the prevention for post-ESD stricture, including the use of tissue-engineered cell sheets [15], the efficacy and especially the safety of these methods still require careful assessment. Given the safety concerns relating to the previous methods of stricture prevention, this safe and simple method may be considered to be of immense clinical value. Competing interests: None Institutions 1 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 2 Department of Endoscopy and Endoscopic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 3 Center for Epidemiology and Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
References 1 Ono S, Fujishiro M, Niimi K et al. Predictors of postoperative stricture after esophageal endoscopic submucosal dissection for superficial squamous cell neoplasms. Endoscopy 2009; 41: 661 – 665 2 Ezoe Y, Muto M, Horimatsu T et al. Efficacy of preventive endoscopic balloon dilation for esophageal stricture after endoscopic resection. J Clin Gastroenterol 2011; 45: 222 – 227
Sakaguchi Yoshiki et al. PGA sheets with fibrin glue can prevent esophageal stricture after ESD … Endoscopy 2015; 47: 336–340
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Table 1 Baseline characteristics of the eight patients who were available for per protocol analysis and characteristics of the tumors that were treated by endoscopic submucosal dissection (ESD).
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Innovations and brief communications 3 Hashimoto S, Kobayashi M, Takeuchi M et al. The efficacy of endoscopic triamcinolone injection for the prevention of esophageal stricture after endoscopic submucosal dissection. Gastrointest Endosc 2011; 74: 1389 – 1393 4 Yamaguchi N, Isomoto H, Nakayama T et al. Usefulness of oral prednisolone in the treatment of esophageal stricture after endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma. Gastrointest Endosc 2011; 73: 1115 – 1121 5 Hanaoka N, Ishihara R, Takeuchi Y et al. Intralesional steroid injection to prevent stricture after endoscopic submucosal dissection for esophageal cancer: a controlled prospective study. Endoscopy 2012; 44: 1007 – 1011 6 Yamashina T, Uedo N, Fujii M et al. Delayed perforation after intralesional triamcinolone injection for esophageal stricture following endoscopic submucosal dissection. Endoscopy 2013; 45: 02E92 7 Ishida T, Morita Y, Hoshi N et al. Disseminated nocardiosis during systemic steroid therapy for the prevention of esophageal stricture after endoscopic submucosal dissection. Dig Endosc [Epub ahead of print 05 2014: DOI 2910.111/den.12317] 8 Shinozaki T, Hayashi R, Ebihara M et al. Mucosal defect repair with a polyglycolic acid sheet. Jpn J Clin Oncol 2013; 43: 33 – 36
9 Middleton JC, Tipton AJ. Synthetic biodegradable polymers as orthopedic devices. Biomaterials 2000; 21: 2335 – 2346 10 Tsuji Y, Ohata K, Gunji T et al. Endoscopic tissue shielding method with polyglycolic acid sheets and fibrin glue to cover wounds after colorectal endoscopic submucosal dissection (with video). Gastrointest Endosc 2014; 79: 151 – 155 11 Takimoto K, Toyonaga T, Matsuyama K. Endoscopic tissue shielding to prevent delayed perforation associated with endoscopic submucosal dissection for duodenal neoplasms. Endoscopy 2012; 44: E414 – E415 12 Ono S, Fujishiro M, Koike K. Endoscopic submucosal dissection for superficial esophageal neoplasms. World J Gastrointest Endosc 2012; 4: 162 – 166 13 Ono S, Tsuji Y, Fujishiro M et al. An effective technique for delivery of polyglycolic acid sheet after endoscopic submucosal dissection of the esophagus: the clip and pull method. Endoscopy 2014; 46: E44 – E45 14 Petersen B, Barkun A, Carpenter S et al. Tissue adhesives and fibrin glues. Gastrointest Endosc 2004; 60: 327 – 333 15 Ohki T, Yamato M, Okano T et al. Regenerative medicine: tissue-engineered cell sheet for the prevention of post-esophageal ESD stricture. Gastrointest Endosc Clin N Am 2014; 24: 273 – 281
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Polyglycolic acid sheets with fibrin glue can prevent esophageal stricture after endoscopic submucosal dissection
Authors
Yoshiki Sakaguchi1, Yosuke Tsuji1, 2, Satoshi Ono1, Itaru Saito1, Yosuke Kataoka1, Yu Takahashi1, Chiemi Nakayama1, Satoki Shichijo1, Rie Matsuda1, Chihiro Minatsuki1, Itsuko Asada-Hirayama1, Keiko Niimi1, 3, Shinya Kodashima1, Nobutake Yamamichi1, Mitsuhiro Fujishiro1, 2, Kazuhiko Koike1
Institutions
Institutions are listed at the end of article.
submitted 14. May 2014 accepted after revision 2. September 2014
Background and study aims: Suitable techniques for the prevention of stricture formation after esophageal endoscopic submucosal dissection (ESD) are still lacking. We investigated the efficacy of polyglycolic acid (PGA) sheets with fibrin glue to prevent post-ESD stricture. Patients and methods: We conducted a pilot study on a total of eight consecutive patients who underwent esophageal ESD that left a mucosal defect of more than three-quarters of the esophageal circumference. PGA sheets were attached to the defect with fibrin glue immediately after the completion of ESD. The primary endpoint was the incidence of post-ESD stricture. The secondary endpoints were the number of ses-
sions of endoscopic balloon dilation (EBD) required to resolve any stricture and the rate of complications. Results: There were no adverse events related to the use of PGA sheets and fibrin glue. Post-ESD stricture occurred in 37.5 % of the subjects and 0.8 ± 1.2 sessions of EBD were required. Conclusion: The use of PGA sheets and fibrin glue after esophageal ESD is a novel method that radically decreases the incidence of esophageal stricture and the number of EBD sessions subsequently required. University Hospital Medical Network Clinical Trial Registry (UMIN000011058).
Introduction
been reports of the efficacy of the application of PGA sheets with fibrin glue to post-ESD defects [10, 11], but there have been no reports to date concerning the prevention of stricture after esophageal ESD with this method. The aim of this study was to determine the efficacy of the application of PGA sheets and fibrin glue for the prevention of post-ESD esophageal stricture.
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1390787 Published online: 14.10.2014 Endoscopy 2015; 47: 336–340 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X Corresponding author Mitsuhiro Fujishiro, MD Department of Endoscopy and Endoscopic Surgery Graduate School of Medicine The University of Tokyo 7-3-1, Hongo, Bunkyo-ku Tokyo, 113-8655 Japan Fax: +81-3-58008806 [email protected]
!
Postoperative stricture frequently occurs after esophageal endoscopic submucosal dissection (ESD). The incidence of stricture is known to significantly increase in proportion to the overall size of the target lesion and the circumferential size of the post-ESD mucosal defect. Strictures have been reported to occur in 90 % of patients left with a post-ESD mucosal defect that covers more than three-quarters of the circumference of the esophagus [1]. Esophageal stricture often requires multiple sessions of endoscopic balloon dilation (EBD) over a period of several months [2]. Although there have been reports regarding the efficacy of postoperative corticosteroid administration [3 – 5], these methods are accompanied by a risk of severe adverse effects [6, 7]. The use of a polyglycolic acid (PGA) sheet, a biodegradable suture material, has demonstrated its potential as a method to reinforce the suture and minimize scar contracture in other medical fields [8]. PGA is a synthetic compound that is completely degraded into a nontoxic degradation product, glycolic acid, over a period of 4 – 6 months in physiological conditions [9]. Recently there have
Patients and methods !
This was a pilot study of patients treated with the application of PGA sheets and fibrin glue after esophageal ESD. The use of PGA sheets with fibrin glue after ESD was begun only after approval from the Research Ethics Committee of the Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, and appropriate trial registration in July 2013. We enrolled subjects into our study who were referred to our institute with a diagnosis of superficial esophageal cancer with single or multiple lesions covering over half the circumference of the esophagus, which might therefore cause a post-
Sakaguchi Yoshiki et al. PGA sheets with fibrin glue can prevent esophageal stricture after ESD … Endoscopy 2015; 47: 336–340
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
336
Innovations and brief communications
Endoscopic submucosal dissection (ESD) for esophageal squamous cell neoplasm performed between September 2013 and March 2014 (n = 23) Excluded Post-ESD mucosal defect < 3/4 of esophageal circumference (n = 14)
337
were excluded from this study because of contraindications. All the enrolled patients submitted written forms of informed consent for the application of PGA sheets with fibrin glue in addition to giving consent for esophageal ESD according to normal clinical practice.
Excluded Contraindications to further treatment (n = 0) Treated with application of a polyglycolic acid (PGA) sheet and fibrin glue immediately after ESD (n = 9) Excluded Steroids also used (n = 1)
Included in per protocol analysis (n = 8)
Fig. 1
Flow diagram of the study patients.
ESD mucosal defect of more than three-quarters of the circumfer" Fig. 1). Contraindications to the use of ence of the esophagus (● PGA sheets and fibrin glue are nearly non-existent: the use of PGA sheets is contraindicated in those who have systemic complications, while the contraindications for the use of fibrin glue are listed as a history of: (i) anaphylaxis to components of fibrin glue or drugs made of bovine lung; or (ii) treatment with procoagulants, antifibrolytic agents, or aprotinin. Therefore, no subjects
A single-channel upper gastrointestinal endoscope (GIF Q260J; Olympus Co.) with a high frequency generator VIO 300 D (ERBE Elektromedizin GmbH, Tübingen, Germany) was used. ESD was performed at the University of Tokyo Hospital as described in detail previously [12]. In brief, a representative sequence would be: close observation of the targeted esophageal lesion(s) using chro" Fig. 2 a), followed by markmoendoscopy with iodine staining (● ing of the margin of the lesion using the Dual Knife (KD-630L; Olympus Co.). The lesion was injected submucosally using a two-fold diluted solution of 0.4 % hyaluronic acid (Mucoup; Johnson and Johnson K.K., Tokyo, Japan) and was then incised and dis" Fig. 2 b). sected using the Dual Knife until ESD was completed (●
PGA sheet deployment with fibrin glue Immediately after ESD had been completed, a PGA sheet (Neoveil, " Fig. 2 c) was de100 × 50 × 0.15 mm; Gunze Co., Tokyo, Japan) (● ployed using a modified version of the clip-and-pull method pre" Fig. 3; ● " Video 1) [13]. After the PGA sheet viously described (● had been grasped with endoscopic forceps, it was wrapped around the endoscope, which was then inserted orally to the site of the post-ESD defect. The PGA sheet was anchored to the anal end of the post-ESD mucosal defect using endoscopic clips and was then deployed so as to cover the entire circumference " Fig. 2 d). After the oral end of the PGA sheet of the esophagus (●
Fig. 2 Images from the management of one of the study patients showing: a a widespread esophageal squamous cell carcinoma viewed using chromoendoscopy and iodine staining; b the mucosal defect immediately after endoscopic submucosal dissection (ESD) had been performed; c the soft elastic polyglycolic acid (PGA) sheet before insertion; d an endoscopic view of the PGA sheet positioned over the entire mucosal defect; e the endoscopic appearance 1 month after ESD showing no signs of a stricture; f the endoscopic appearance of the esophagus 2 months after ESD.
Sakaguchi Yoshiki et al. PGA sheets with fibrin glue can prevent esophageal stricture after ESD … Endoscopy 2015; 47: 336–340
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Endoscopic submucosal dissection procedure Post-ESD mucosal defect > 3/4 of esophageal circumference (n = 9)
Innovations and brief communications
had also been anchored using endoscopic clips, fibrin glue (Beriplast P 3 mL Combi-Set; Behring Pharma, Tokyo, Japan) was instilled along the entire length of the sheet, firmly fixing it to the post-ESD mucosal defect.
Perioperative management On the day before ESD, oral diet was discontinued after the evening meal, and patients were prohibited from eating thereafter until instructed. Oral administration of a daily dose of 10 mg rabeprazole was also begun on the day before ESD and was continued daily for a minimum of 28 days. On the day following ESD, laboratory investigations along with chest and abdominal radiographs were performed. Oral diet was resumed 2 days after ESD, and scheduled postoperative endoscopies were routinely per" Fig. 2 e, f). formed on day 7 and day 28 after ESD (●
Definition of postoperative stricture Postoperative stricture was defined as the presence of a stenosis of the esophageal lumen that had progressed to the point where a 9.8-mm diameter upper gastrointestinal endoscope (GIF Q240 or GIF H260; Olympus Co.) could not be passed through it. The day of stricture occurrence was defined as the day when the stricture was endoscopically confirmed. In addition to the scheduled endoscopies, endoscopy was also performed if the patient began to experience symptoms of dysphagia.
Endoscopic balloon dilation In patients who developed an esophageal stricture, the first session of EBD was performed using an esophageal balloon dilation catheter (CRE Fixed Wire 12 mm/15 mm/18 mm; Boston Scientific Co., Natick, Massachusetts, USA) immediately after the stricture had been endoscopically confirmed. EBD was repeated as required until the stenosis of the esophageal lumen widened and it was possible to pass the endoscope through the esophageal lumen. After the postoperative stricture had been resolved, endoscopic follow-up was continued for a minimum of 4 weeks. After this period, scheduled endoscopic follow-up was terminated if it was confirmed that the endoscope could be smoothly passed through the esophagus.
Follow-up endpoints The primary endpoint of this study was the incidence of postoperative stricture after esophageal ESD. The secondary endpoints were the number of sessions of EBD required to resolve any strictures and the rate of complications.
Results !
Fig. 3 Diagram of the modified clip-and-pull method. a The polyglycolic acid (PGA) sheet is grasped with endoscopic forceps. b The sheet and endoscope are inserted into the esophagus next to the mucosal defect left after endoscopic submucosal dissection (ESD). c The PGA sheet is released and anchored to the anal end of the defect using endoscopic clips. d The endoscope is pulled out leaving the PGA sheet in place. e The procedure results in total coverage of the mucosal defect and the adjacent esophageal mucosa.
gus. The size of the largest lesion was measured in those patients who had adjacent lesions resected in an en bloc fashion with several lesions being included in the same ESD sample.
Patients Between September 2013 and March 2014, nine patients underwent ESD that left a post-ESD defect of over three-quarters of the circumference of the esophagus and were treated by adhesion of a PGA sheet with fibrin glue. One patient was excluded from the analysis because of predetermined combined use of corticosteroids to further minimize the risk of esophageal stricture after dis" Fig. 1). Therefore, eight patients were cussion with the patient (● eligible for per protocol analysis. The baseline characteristics of " Table 1. the subjects are detailed in ● Although several patients presented with multiple esophageal lesions, all patients were left with only a single mucosal defect that covered over three-quarters of the circumference of the esopha-
Video 1
The modified clip-and-pull method of Online content including polyglycolic acid (PGA) sheet delivery video sequences viewable after endoscopic submucosal dissec- at: www.thieme-connect.de tion (ESD) in the esophagus.
Sakaguchi Yoshiki et al. PGA sheets with fibrin glue can prevent esophageal stricture after ESD … Endoscopy 2015; 47: 336–340
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338
Innovations and brief communications
Patient sex (men : women)
7:1
Patient age, mean ± SD, years
69.1 ± 9.0
Tumor location Cervical esophagus
0
Upper thoracic esophagus
2
Mid-thoracic esophagus
4
Lower thoracic esophagus
2
Table 2 Details of the endoscopic submucosal dissection (ESD) and polyglycolic acid (PGA) sheet application procedures, adverse events, and their subsequent management in the eight patients available for per protocol analysis. Procedure details Size of resected specimen, mean ± SD, mm
53.8 ± 8.8
Total dissection time, mean ± SD, minutes
120.0 ± 28.8
Application time for PGA sheet, mean ± SD, minutes Patients developing a stricture after ESD, n (%) Time to stricture occurrence, mean ± SD, day 1
Tumor depth
12.8 ± 5.5
Adverse events 3 (37.5 %) 28.0 ± 7.0
Confined to the epithelium
1
Sessions of EBD required, mean ± SD, n
0.8 ± 1.2
Confined to the lamina propria mucosae
5
Other complications, n (%)
0 (0.0)
Confined to the muscularis mucosae
0
sm1 (invading the submucosa ≤ 200 μm)
0
sm2 (invading the submucosa > 200 μm) Tumor size, mean ± SD, mm
SD, standard deviation; EBD, endoscopic balloon dilation. 1 Calculated only for the three patients who developed strictures.
2 37.9 ± 8.9
SD, standard deviation.
Technical success of procedures En bloc esophageal ESD with tumor-free vertical and lateral margins was successfully completed in all subjects. There were no intraoperative adverse events. The application of PGA sheets was also successful in all subjects, with 12.8 ± 5.5 minutes being re" Table 2). quired for this part of the procedure (●
Endpoint results The overall incidence of postoperative stricture was 37.5 % (3/8 patients). The number of EBD sessions required to treat strictures was 0.8 ± 1.2 sessions. There were no other postoperative adverse events.
Discussion !
This pilot study suggests that the use of PGA sheets and fibrin glue may significantly reduce the incidence of post-ESD esophageal stricture. Even in patients whose stricture cannot be completely prevented, the number of sessions of EBD required to relieve their post-ESD esophageal stricture can be radically reduced. Previous reports on methods of esophageal stricture prevention after ESD have mainly focused on the administration of corticosteroids [1, 3, 4], with both systemic oral administration and direct focal injections of corticosteroids shown to be effective. However, there is concern over the safety of these methods as there have been reports of severe adverse events: systemic infection with oral administration and postoperative perforation after focal injections [6]. Although the incidence rates of these complications are not high, they do carry a risk of mortality. In terms of the safety of the methods used in this study, both PGA sheets and fibrin glue have been used in the gastrointestinal tract for decades with few reports of adverse effects to date [14]. Although there are still only a few reports of the use of PGA sheets within the gastrointestinal lumen and long-term follow-up is necessary [10, 11], the risk of adverse events related to the use of PGA sheets and fibrin glue is minimal. In similar patients undergoing ESD procedures with a mucosal defect of more than three-quarters of the circumference of the esophagus, only focal corticosteroid injection has been reported to significantly decrease the incidence of post-ESD stricture [3, 5]. The mean number of EBD sessions required after esophageal
ESD was reported to be 1.7 after oral administration of corticosteroids [4] and 1.7 after focal corticosteroid injection [3]. Our results indicate that the effectiveness of using PGA sheets with fibrin glue is comparable to, or even better than, previous methods. Given also the safety concerns with the previous methods, our method should be considered as an alternative method for the prevention of post-ESD esophageal stricture. As for the technical aspects of the method used in this study, while a certain level of technical expertise was required, the procedure was successfully performed by several operators in our institute. In addition, the amount of time required for this method of PGA sheet deployment and instillation of fibrin glue (12.8 ± 5.5 minutes) seems acceptable considering the amount of time that can be required for multiple sessions of EBD. There were several limitations to our study. First, this was a single-center analysis involving only a limited number of patients. A randomized controlled study is required for confirmation of the results of this pilot study. Second, the mechanism through which the PGA sheet prevents stricture is as yet unclear. In conclusion, the use of PGA sheets and fibrin glue is a promising new method that may significantly decrease the incidence of esophageal stricture following ESD and may also radically decrease the number of sessions of EBD that are required in the event of stricture formation. Although there have recently been several methods suggested for the prevention for post-ESD stricture, including the use of tissue-engineered cell sheets [15], the efficacy and especially the safety of these methods still require careful assessment. Given the safety concerns relating to the previous methods of stricture prevention, this safe and simple method may be considered to be of immense clinical value. Competing interests: None Institutions 1 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 2 Department of Endoscopy and Endoscopic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 3 Center for Epidemiology and Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Sakaguchi Yoshiki et al. PGA sheets with fibrin glue can prevent esophageal stricture after ESD … Endoscopy 2015; 47: 336–340
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Table 1 Baseline characteristics of the eight patients who were available for per protocol analysis and characteristics of the tumors that were treated by endoscopic submucosal dissection (ESD).
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