ORIGINAL ARTICLE: Clinical Endoscopy
Polyglycolic acid sheets and fibrin glue decrease the risk of bleeding after endoscopic submucosal dissection of gastric neoplasms (with video) Yosuke Tsuji, MD, PhD,1,2 Mitsuhiro Fujishiro, MD, PhD,1,2 Shinya Kodashima, MD, PhD,1 Satoshi Ono, MD, PhD,1 Keiko Niimi, MD, PhD,3 Satoshi Mochizuki, MD, PhD,1 Itsuko Asada-Hirayama, MD,1 Rie Matsuda, MD,1 Chihiro Minatsuki, MD,1 Chiemi Nakayama, MD,1 Yu Takahashi, MD,1 Yoshiki Sakaguchi, MD,1 Nobutake Yamamichi, MD, PhD,1 Kazuhiko Koike, MD, PhD1 Tokyo, Japan
Background: The prevention of bleeding after endoscopic submucosal dissection (ESD) for gastric neoplasms is still an important problem. Objective: To investigate the efficacy and safety of a shielding method that uses polyglycolic acid (PGA) sheets and fibrin glue to prevent post-ESD bleeding in high-risk patients. Design: A nonrandomized trial with historical control subjects. Setting: A single academic hospital in Japan. Patients: From July 2013 to February 2014, 45 ESD-induced ulcers in 41 patients with a high risk of bleeding were enrolled in a study group. Forty-one consecutive ESD-induced ulcers in 37 control subjects with a high risk of bleeding were treated in 2013 before the first enrollment. Interventions: We placed PGA sheets on the mucosal defect and fixed with fibrin glue in the study group. Main Outcome Measurements: The post-ESD bleeding rate. Results: The post-ESD bleeding occurred at a rate of 6.7% in the study group (3/45 lesions) and 22.0% in the historical control group (9/41 lesions). There was a significant difference in the post-ESD bleeding rate between the 2 groups (P Z .041). Limitations: A nonrandomized trial with historical control subjects; a single-center analysis; small sample size. Conclusions: The endoscopic tissue shielding method with PGA sheets and fibrin glue appears to be promising for the prevention of post-ESD bleeding. (Clinical trial registration number: UMIN000011058.) (Gastrointest Endosc 2015;81:906-12.) (footnotes appear on last page of article)
Endoscopic submucosal dissection (ESD) has been accepted as an excellent treatment for gastric neoplasms because a large tumor or lesion with an ulcer scar can be successfully resected in an en bloc fashion.1-4 ESD is minimally invasive and can be applied to elderly patients.5 Moreover, ESD is reported to be safe and effective,
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even for early gastric cancer in the altered anatomy, such as a remnant stomach or gastric tube, and locally recurrent early gastric cancer after endoscopic resection.6-8 According to guidelines from the Japanese Gastric Cancer Association,9 absolute guideline criteria for tumors indicated for ESD are differentiated-type mucosal adenocarcinoma % 2 cm without ulcerative findings. The indication criteria for endoscopic resection have been expanded based on the large case series treated by gastrectomy with lymph node dissection,10 and there have been some reports about the validity of the expanded criteria.1,11,12 The tumors categorized into expanded criteria were as follows: a differentiated-type mucosal adenocarcinoma O 2 cm without ulcerative
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findings, a differentiated-type mucosal adenocarcinoma % 3 cm with ulcerative findings, and undifferentiated-type mucosal adenocarcinoma % 2 cm without ulcerative findings.9 Although ESD has its advantages, it has a substantial risk of adverse events, such as post-ESD bleeding or perforation.2,3 In particular, post-ESD bleeding may lead to serious conditions, including massive bleeding and life-threatening hemorrhagic shock. Therefore, preventing post-ESD bleeding is desirable.13,14 To date, proton pump inhibitors or histamine-2 receptor antagonists have been used to prevent post-ESD bleeding.4,15-17 Moreover, Takizawa et al14 reported that preventive coagulation of visible vessels in the resection area after ESD might lead to a lower bleeding rate. However, previous studies revealed the rate of post-ESD bleeding is still approximately 5%, even with such preventive methods.12,13,18-20 Several reports revealed that antithrombotic drug usage and a large resection size (R40 mm) may be independent risk factors for postESD bleeding, but there is still a question regarding how to overcome post-ESD bleeding in high-risk patients.13,18,20-23 More recently, Takimoto et al24 reported a novel endoscopic tissue shielding method that uses polyglycolic acid (PGA) sheets (Neoveil; Gunze Co, Kyoto, Japan) and fibrin glue (Beriplast P Combi-Set; CSL Behring Pharma, Tokyo, Japan). PGA is an absorbent suture reinforcement material, and PGA sheets have been applied to videoassisted major lung resection, partial glossectomy, pancreaticoduodenectomy, and gastrectomy.25-28 As for the field of endoscopy, this method may be effective for the prevention of adverse events after colorectal ESD, such as bleeding or perforation.29 However, to our knowledge, there are no reports regarding the application of this technique for the prevention of bleeding after gastric ESD. Therefore, we prospectively enrolled patients with PGA sheets as a study group and evaluated the efficacy and safety of this novel method with the purpose of preventing post-ESD bleeding in high-risk patients, comparing the results with the historical control group of those without PGA sheets.
Use of PGA sheets and fibrin glue to prevent post-ESD bleeding
Patients Written informed consent for gastric ESD was obtained from all patients before performing ESD regardless of enrollment for clinical studies. The target lesions had to be within the expanded indication criteria of gastric ESD, and CT had to reveal no lymph node or other organ metastasis. We defined high-risk patients for post-ESD bleeding as follows: those who took antithrombotic drugs regularly, or those who were expected to undergo large mucosal resection (R40 mm). Aspirin, ticlopidine, clopidogrel, cilostazol, ethyl icosapentate, warfarin, and dabigatran were defined as antithrombotic drugs. The cessation and resumption of antithrombotic drugs were carried out according to the newest guideline by the Japan Gastroenterological Endoscopy Society.30
Study group We enrolled patients who were scheduled to undergo gastric ESD and had an above-mentioned high risk for post-ESD bleeding. Because the latter criterion could not be obtained preoperatively, we enrolled patients with a tumor R 20 mm in preoperative size or with an ulcer scar inside or close to a tumor, where the resection size would exceed 40 mm. The exclusion criteria were contraindications of PGA sheets or fibrin glue as follows: (1) those who have systemic adverse events (as to PGA sheets); (2) those who have a history of anaphylaxis to components of fibrin glue or drugs made of bovine lung, such as aprotinin; and (3) those who were treated with procoagulants (hemocoagulase made from snake venom), antifibrolytic agents, and aprotinin (as to fibrin glue).
Historical control group Between January and July 2013 before the first enrollment of a study patient, 126 gastric neoplasms in 101 consecutive patients were treated with ESD. Among them, 44 lesions in 37 patients were extracted as a highrisk group, fulfilling the definition of high-risk patients for post-ESD bleeding. In 2 patients, 2 or 3 adjacent neoplasms were resected as 1 piece to yield 1 ulcer, so 41 ESD-induced ulcers were finally enrolled as control subjects.
METHODS ESD procedure This nonrandomized trial with historical control subjects was undertaken at the University of Tokyo Hospital, Tokyo, Japan. The study protocol was approved by the research ethics committee of the University of Tokyo on June 24, 2013 and was registered in the University Hospital Medical Network Clinical Trial Registry (UMIN-CTR) on July 1, 2013 (UMIN000011058). The first study patient was enrolled after the study registration, and all study patients gave written informed consent for the intervention and for gastric ESD.
ESD was performed with the patient under intravenous sedation with diazepam and pentazocine using a video endoscope (GIF-Q260J; Olympus Medical, Tokyo, Japan) and an electrosurgical unit (VIO 300D; Erbe, Tübingen, Germany). The ESD procedure was performed as follows. First, circumferential markings were made by a dual knife (KD-650L; Olympus Medical). After submucosal injection using a mixture of .4% sodium hyaluronic acid solution (Mucoup; Johnson and Johnson K.K., Tokyo, Japan) and normal saline solution, a mucosal incision and submucosal
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Use of PGA sheets and fibrin glue to prevent post-ESD bleeding
dissection were performed by a dual knife or IT-Knife 2 (KD-611L; Olympus Medical). After resection of the lesion, all visible vessels on the ulcer floor were coagulated with hemostatic forceps (HDB-2422-W; Pentax, Tokyo, Japan; or M00515031; Boston Scientific Japan, Tokyo, Japan) using the soft coagulation mode.
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roni correction was performed for multiple comparisons in the subgroup analysis.
RESULTS
We set a post-ESD bleeding rate as the primary endpoint to compare both groups. Additionally, we made subgroup analyses by dividing into solely a large resection group and an antithrombotic therapy group. The latter was further divided into 2 groups: with and without heparin bridging therapy. The rates of other adverse events were noted as secondary endpoints. All statistical analyses were performed with JMP 10.0.2 (SAS Institute Inc, Cary, NC, USA). Categorical data were compared using a c2 test or the Fisher exact test, as appropriate. If each cell in a 2 2 cross-tabulation table had an expected value ! 5, we used the Fisher exact test. The differences in the means of continuous data were compared by a Student t test or Mann-Whitney U test. P ! .05 was considered significant, and all tests were 2-sided. Bonfer-
Between July 2013 and February 2014, 44 patients met the inclusion criteria for the study group. Three patients refused to participate in the study; therefore, 41 patients were enrolled in the study group. All ESD cases were completed without life-threatening events, and 45 ESDinduced ulcers were created in the 41 patients. The baseline characteristics of the patients and tumors in the study and control groups are listed in Table 1. No significant differences were found in resection size of antithrombotic drug users between the study group and the historical control group (36.7 9.7 mm and 37.1 14.3 mm, respectively; P Z .914). In the study group, the mean procedural time for applying PGA sheets and fibrin glue was 20.4 9.5 minutes. In all cases, we successfully covered the entire mucosal defect after ESD. Between July and December 2013, we placed PGA sheets as previously reported,24,29 with a mean procedural time of 21.4 11.0 minutes. After converting to the clip and pull method,31 the mean procedural time was 18.9 6.6 minutes. There was no significant difference between the 2 procedures (P Z .390). The post-ESD bleeding occurred at a rate of 6.7% in the study group (3/45 lesions) and 22.0% in the historical control group (9/41 lesions). There was a significant difference in the post-ESD bleeding rate between the 2 groups (P Z .041). The characteristics of ulcers that developed post-ESD bleeding are shown in Figure 2. In the study group, all bleeding events occurred in the patients under heparin bridging therapy. Between the study and control groups, there was no significant difference in the date of bleeding onset (P Z .918). In the study group, bleeding rates were not significantly different between ulcers with original application and with the clip and pull method (7.4% vs. 5.6%; P Z 1.000). Subgroup analyses are shown in Table 2. For large-sized resections, the ESD-induced ulcers shielded by PGA sheets tended to have a lower risk of post-ESD bleeding than those without PGA sheets (0% and 22.2%, respectively); however, the difference was not statistically significant (P Z .105). For antithrombotic therapy without heparin bridging, the post-ESD bleeding rate tended to be lower in the study group than in the historical control group (0% and 22.0%, respectively; P Z .043). In the study group, 7 lesions were under heparin bridging therapy, and 3 lesions were in the historical control group. The post-ESD bleeding rate was 42.9% in the study group and 33.3% in the historical control group (P Z 1.000). Other adverse events were as follows: 1 patient in the study group developed mild pancreatitis 8 days after
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PGA sheet application After completing the ESD procedure, PGA sheets were placed onto the mucosal defect and fixed with fibrin glue. The delivery method was at first based on the report of Takimoto et al,24 and the details were also described in our previous report.29 Taking account of the speed and ease, we adopted “the clip and pull method” from Ono et al31 (Fig. 1; Video 1, available online at www. giejournal.org). In this study we modified this method, as follows: (1) the PGA sheet was grasped with biopsy forceps and then (2) wrapped around the endoscope, (3) the endoscope was inserted orally to the site of the post-ESD defect, (4) the biopsy forceps was removed and the PGA sheet was anchored to the 1 side of the post-ESD mucosal defect using endoclips and (5) stretched so it could cover the whole post-ESD ulcer with several endoclips.
Follow-up after ESD Patients fasted on the morning of the ESD and were prohibited from eating and drinking until the next day of ESD. If laboratory findings and chest and abdominal radiographs proved to be unremarkable, patients were permitted to take oral soft foods.4 Patients took 10 mg oral rabeprazole daily 1 day before ESD. Based on the report by Niimi et al,16 the duration of the rabeprazole prescription was set for at least 14 days, depending on doctors in charge. A scheduled second-look endoscopy was not performed for any patient. When post-ESD bleeding occurred, we performed an urgent endoscopy and executed endoscopic hemostasis. Post-ESD bleeding was defined as hemorrhage resulting in overt hematemesis or melena or a hemoglobin decrease R2.0 g/dL.
Endpoints and statistical analysis
Use of PGA sheets and fibrin glue to prevent post-ESD bleeding
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TABLE 1. Baseline characteristics of patients and tumors based on the number of ESD-induced ulcers Study group (n [ 45)
Historical control group (n [ 41)
P value
73.6 7.5
74.8 7.0
.482
41/4
34/7
.256
Antithrombotic drug therapy
29 (64.4)
23 (56.1)
.429
Heparin bridge therapy
7 (15.6)
3 (7.3)
.319
Hypertension
33 (73.3)
32 (78.1)
.611
Hyperlipidemia
15 (33.3)
20 (48.8)
.145
4 (8.9)
8 (19.5)
.156
26 (57.8)
25 (61.0)
.763
Liver cirrhosis
2 (4.4)
1 (2.4)
1.000
Hemodialysis
0
1 (2.4)
.477
40.1 12.4
43.9 15.1
.206
1/44/0
2/36/3
.131
Tumor location (U/M/L)
11/17/17
6/20/15
.437
Tumor depth (no tumor/M/SM1/SM massive)
1/37/3/4
2/32/4/3
.870
En bloc resection
45 (100)
40 (97.6)
.477
Patient Mean age, y (SD) Sex: males/females
Diabetes mellitus Cardiovascular disease
Tumor Mean resection size, mm (SD) Tumor histology (no tumor/intestinal/diffuse)
Values are number of cases with percents in parentheses, unless otherwise noted. SD, Standard deviation; U/M/L, the upper/middle/lower third of the stomach; M, tumor confined to the mucosa; SM1, tumor invading the submucosa % 500 mm; SM massive, tumor invading the submucosa O 500 mm.
ESD, from which the patient recovered with conservative treatment. No other adverse events associated with PGA sheet application were observed.
In this nonrandomized trial with historical control subjects, we demonstrated that the endoscopic tissue shielding method with PGA sheets and fibrin glue decreased the risk of bleeding after gastric ESD. To date, there has been no medication to prevent post-ESD bleeding other than proton pump inhibitors or histamine-2 receptor antagonists.15,17 Takizawa et al14 found that preventive coagulation of visible vessels in the resection area after ESD might lead to a lower bleeding rate. However, the incidence of bleeding after ESD was still 3.1% after preventive coagulation. Therefore, additional measures are essential to prevent post-ESD bleeding. We previously reported the feasibility of the endoscopic tissue shielding method with PGA sheets and fibrin glue after colorectal ESD.29 As described in that report, the safety and efficacy of the tissue shielding method with PGA sheets and fibrin glue were described in several fields.25-28 In this study, 1
patient developed mild pancreatitis 8 days after ESD, but there was no increase in transaminase, alkaline phosphatase, or g-glutamyl transpeptidase. Therefore, it was not likely that fibrin glue or detached PGA sheets obstructed the pancreaticobiliary tract, and we concluded the cause most likely had no association with PGA sheets or fibrin glue. Regarding feasibility, the mean procedural time for delivering PGA sheets and fibrin glue was 20.4 minutes in this study, a duration comparable with a previously published result in the colorectum, 18.7 minutes.29 In this study, we identified the high-risk group for post-ESD bleeding as taking antithrombotic drugs and/or the necessity of a large-sized resection from previous reports.13,18,20,21,23 Although there is still controversy about the risk factors for post-ESD bleeding,3235 the rate of 22% in the historical control group revealed that we could successfully identify high-risk patients, considering the approximately 5% overall post-ESD bleeding rate.12,13,18-20 Moreover, we revealed that post-ESD bleeding rates in high-risk patients could be reduced to one third using PGA sheets and fibrin glue. Interestingly, this study showed that all 3 cases of postESD bleeding after application of PGA sheets and
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DISCUSSION
Use of PGA sheets and fibrin glue to prevent post-ESD bleeding
Tsuji et al
Figure 1. PGA sheet delivery and fixation (clip and pull method). A, An artificial ulcer after gastric ESD. B, Anchoring the PGA sheet to the distal side of the ulcer with a clip. C, Pulling the endoscope and deploying the PGA sheet. D, Stretching and anchoring the circumference of the PGA sheet with several clips. E, A fixed PGA sheet after spraying fibrin glue.
Figure 2. The date of bleeding onset after ESD and the status of antithrombotic drugs.
fibrin glue had heparin bridging therapy. Therefore, this technique might not be effective in cases of heparin bridging therapy but would be very effective and safe for patients with antithrombotic drugs, except for those with heparin bridging therapy.
There are some limitations to our study. First, this was a single-center analysis with a relatively small number of cases. Second, this was not a randomized controlled trial. To confirm our findings, a largescale randomized controlled trial is necessary in the
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TABLE 2. Post-ESD bleeding rates of the 2 groups Post-ESD bleeding, n (%) Study group (n [ 45) Overall
Historical control group (n [ 41)
P value
3 (6.7)
9 (22.0)
.041
Large-sized resection
0 (n Z 16)
4 (22.2) (n Z 18)
.105
Antithrombotic drug therapy without heparin bridging
0 (n Z 22)
4 (20.0) (n Z 20)
.043
Heparin bridge therapy
3 (42.9) (n Z 7)
1 (33.3) (n Z 3)
1.000
1. Isomoto H, Shikuwa S, Yamaguchi N, et al. Endoscopic submucosal dissection for early gastric cancer: a large-scale feasibility study. Gut 2009;58:331-6. 2. Oka S, Tanaka S, Kaneko I, et al. Advantage of endoscopic submucosal dissection compared with EMR for early gastric cancer. Gastrointest Endosc 2006;64:877-83. 3. Gotoda T, Yamamoto H, Soetikno RM. Endoscopic submucosal dissection of early gastric cancer. J Gastroenterol 2006;41:929-42. 4. Fujishiro M. Endoscopic submucosal dissection for stomach neoplasms. World J Gastroenterol 2006;12:5108-12. 5. Tokioka S, Umegaki E, Murano M, et al. Utility and problems of endoscopic submucosal dissection for early gastric cancer in elderly patients. J Gastroenterol Hepatol 2012;27(Suppl 3):63-9. 6. Nonaka S, Oda I, Sato C, et al. Endoscopic submucosal dissection for gastric tube cancer after esophagectomy. Gastrointest Endosc 2014;79:260-70. 7. Sekiguchi M, Suzuki H, Oda I, et al. Favorable long-term outcomes of endoscopic submucosal dissection for locally recurrent early gastric cancer after endoscopic resection. Endoscopy 2013;45:708-13. 8. Nonaka S, Oda I, Makazu M, et al. Endoscopic submucosal dissection for early gastric cancer in the remnant stomach after gastrectomy. Gastrointest Endosc 2013;78:63-72. 9. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2010 (version 3). Gastric Cancer 2011;14:113-23. 10. Gotoda T, Yanagisawa A, Sasako M, et al. Incidence of lymph node metastasis from early gastric cancer: estimation with a large number of cases at two large centers. Gastric Cancer 2000;3:219-25.
11. Hirasawa T, Gotoda T, Miyata S, et al. Incidence of lymph node metastasis and the feasibility of endoscopic resection for undifferentiatedtype early gastric cancer. Gastric Cancer 2009;12:148-52. 12. Goto O, Fujishiro M, Kodashima S, et al. Outcomes of endoscopic submucosal dissection for early gastric cancer with special reference to validation for curability criteria. Endoscopy 2009;41:118-22. 13. Tsuji Y, Ohata K, Ito T, et al. Risk factors for bleeding after endoscopic submucosal dissection for gastric lesions. World J Gastroenterol 2010;16:2913-7. 14. Takizawa K, Oda I, Gotoda T, et al. Routine coagulation of visible vessels may prevent delayed bleeding after endoscopic submucosal dissectiondan analysis of risk factors. Endoscopy 2008;40: 179-83. 15. Tomita T, Kim Y, Yamasaki T, et al. Prospective randomized controlled trial to compare the effects of omeprazole and famotidine in preventing delayed bleeding and promoting ulcer healing after endoscopic submucosal dissection. J Gastroenterol Hepatol 2012;27:1441-6. 16. Niimi K, Fujishiro M, Goto O, et al. Prospective single-arm trial of twoweek rabeprazole treatment for ulcer healing after gastric endoscopic submucosal dissection. Dig Endosc 2012;24:110-6. 17. Uedo N, Takeuchi Y, Yamada T, et al. Effect of a proton pump inhibitor or an H2-receptor antagonist on prevention of bleeding from ulcer after endoscopic submucosal dissection of early gastric cancer: a prospective randomized controlled trial. Am J Gastroenterol 2007;102:1610-6. 18. Koh R, Hirasawa K, Yahara S, et al. Antithrombotic drugs are risk factors for delayed postoperative bleeding after endoscopic submucosal dissection for gastric neoplasms. Gastrointest Endosc 2013;78:476-83. 19. Goto O, Fujishiro M, Oda I, et al. A multicenter survey of the management after gastric endoscopic submucosal dissection related to postoperative bleeding. Dig Dis Sci 2012;57:435-9. 20. Okada K, Yamamoto Y, Kasuga A, et al. Risk factors for delayed bleeding after endoscopic submucosal dissection for gastric neoplasm. Surg Endosc 2011;25:98-107. 21. Takeuchi T, Ota K, Harada S, et al. The postoperative bleeding rate and its risk factors in patients on antithrombotic therapy who undergo gastric endoscopic submucosal dissection. BMC Gastroenterol 2013;13:136. 22. Lim JH, Kim SG, Kim JW, et al. Do antiplatelets increase the risk of bleeding after endoscopic submucosal dissection of gastric neoplasms? Gastrointest Endosc 2012;75:719-27. 23. Cho SJ, Choi IJ, Kim CG, et al. Aspirin use and bleeding risk after endoscopic submucosal dissection in patients with gastric neoplasms. Endoscopy 2012;44:114-21. 24. Takimoto K, Toyonaga T, Matsuyama K. Endoscopic tissue shielding to prevent delayed perforation associated with endoscopic submucosal dissection for duodenal neoplasms. Endoscopy 2012;44(Suppl 2):E414-5. 25. Takeuchi J, Suzuki H, Murata M, et al. Clinical evaluation of application of polyglycolic acid sheet and fibrin glue spray for partial glossectomy. J Oral Maxillofac Surg 2013;71:e126-31.
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future. Third, in this study protocol we did not have independent observers for the classification and comparison of postoperative adverse events in the followup period. Finally, how to cover larger mucosal defects, such as those larger than 10 cm, has not yet been established. In this study we investigated the preventive effect of PGA sheet with fibrin glue on post-ESD bleeding, but this tissue shielding method has the potential to prevent delayed perforation.24,29 As for this point, further evaluation is needed. In conclusion, the present study demonstrated promising results of the tissue shielding method, which uses PGA sheets and fibrin glue, for the prevention of post-ESD bleeding in patients with a high risk of bleeding undergoing gastric ESD. REFERENCES
Use of PGA sheets and fibrin glue to prevent post-ESD bleeding 26. Hiura Y, Takiguchi S, Yamamoto K, et al. Use of fibrin glue sealant with polyglycolic acid sheets to prevent pancreatic fistula formation after laparoscopic-assisted gastrectomy. Surg Today 2013;43: 527-33. 27. Ueda K, Tanaka T, Hayashi M, et al. Mesh-based pneumostasis contributes to preserving gas exchange capacity and promoting rehabilitation after lung resection. J Surg Res 2011;167:e71-5. 28. Uemura K, Murakami Y, Hayashidani Y, et al. Combination of polyglycolic acid felt and fibrin glue for prevention of pancreatic fistula following pancreaticoduodenectomy. Hepatogastroenterology 2009;56:1538-41. 29. 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;79:151-5. 30. Fujimoto K, Fujishiro M, Kato M, et al. Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment. Dig Endosc 2014;26:1-14. 31. 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(Suppl 1): E44-5. 32. Choi CW, Kim HW, Kang DH, et al. Clinical outcomes of second-look endoscopy after gastric endoscopic submucosal dissection: predictive factors with high risks of bleeding. Surg Endosc 2014;28:2213-20. 33. Sanomura Y, Oka S, Tanaka S, et al. Continued use of low-dose aspirin does not increase the risk of bleeding during or after endoscopic submucosal dissection for early gastric cancer. Gastric Cancer 2014;17:489-96. 34. Mukai S, Cho S, Kotachi T, et al. Analysis of delayed bleeding after endoscopic submucosal dissection for gastric epithelial neoplasms. Gastroenterol Res Pract 2012;2012:875323. 35. Higashiyama M, Oka S, Tanaka S, et al. Risk factors for bleeding after endoscopic submucosal dissection of gastric epithelial neoplasm. Dig Endosc 2011;23:290-5.
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Abbreviations: ESD, endoscopic submucosal dissection; PGA, polyglycolic acid. DISCLOSURE: The following author disclosed financial relationships relevant to this publication: M. Fujishiro: Speaker for Olympus, BoehringerIngelheim, Otsuka Pharmaceutical, Astrazeneca Pharmaceutical, DaiichiSankyo Pharmaceutical, Eisai Corporation, Aska Pharmaceutical, Nihon Pharmaceutical, Pentax, Mitsubishi Tanabe Pharma Corporation, Amco Corporation, and Takeda Pharmaceutical; Unrestricted Research Grants from Astellas Pharmaceutical, Takeda Pharmaceutical, Zeria Pharmaceutical, Otsuka Pharmaceutical, Astrazeneca Pharmaceutical, Dainihon-Sumitomo Pharmaceutical, Taiho Pharmaceutical, Ajinomoto Pharmaceutical, and Eisai; Nonfinancial Support from HOYA Pentax, Olympus Medical Systems, and Fujifilm; and Honoraria from Olympus Medical Systems, HOYA Pentax, Eisai, MSD, Daiichi-Sankyo Pharmaceutical, Astrazeneca Pharmaceutical, Aska Pharmaceutical, Taisho-Toyama Pharmaceutical, Otsuka Pharmaceutical, Zeria Pharmaceutical, Takeda Pharmaceutical, Astellas Pharmaceutical, Seikagaku Corp, Johnson & Johnson, Ajinomoto Pharmaceutical, Amco, Novartis Pharmaceutical, Boston Scientific, and, Boehringer-Ingelheim. All other authors disclosed no financial relationships relevant to this publication. Copyright ª 2015 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2014.08.028 Received April 10, 2014. Accepted August 25, 2014. Current affiliations: Department of Gastroenterology (1), Department of Endoscopy and Endoscopic Surgery (2), Center for Epidemiology and Preventive Medicine (3), Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Reprint requests: Dr. Mitsuhiro Fujishiro, MD, PhD, Department of Gastroenterology and Department of Endoscopy and Endoscopic Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
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Polyglycolic acid sheets and fibrin glue decrease the risk of bleeding after endoscopic submucosal dissection of gastric neoplasms (with video) Yosuke Tsuji, MD, PhD,1,2 Mitsuhiro Fujishiro, MD, PhD,1,2 Shinya Kodashima, MD, PhD,1 Satoshi Ono, MD, PhD,1 Keiko Niimi, MD, PhD,3 Satoshi Mochizuki, MD, PhD,1 Itsuko Asada-Hirayama, MD,1 Rie Matsuda, MD,1 Chihiro Minatsuki, MD,1 Chiemi Nakayama, MD,1 Yu Takahashi, MD,1 Yoshiki Sakaguchi, MD,1 Nobutake Yamamichi, MD, PhD,1 Kazuhiko Koike, MD, PhD1 Tokyo, Japan
Background: The prevention of bleeding after endoscopic submucosal dissection (ESD) for gastric neoplasms is still an important problem. Objective: To investigate the efficacy and safety of a shielding method that uses polyglycolic acid (PGA) sheets and fibrin glue to prevent post-ESD bleeding in high-risk patients. Design: A nonrandomized trial with historical control subjects. Setting: A single academic hospital in Japan. Patients: From July 2013 to February 2014, 45 ESD-induced ulcers in 41 patients with a high risk of bleeding were enrolled in a study group. Forty-one consecutive ESD-induced ulcers in 37 control subjects with a high risk of bleeding were treated in 2013 before the first enrollment. Interventions: We placed PGA sheets on the mucosal defect and fixed with fibrin glue in the study group. Main Outcome Measurements: The post-ESD bleeding rate. Results: The post-ESD bleeding occurred at a rate of 6.7% in the study group (3/45 lesions) and 22.0% in the historical control group (9/41 lesions). There was a significant difference in the post-ESD bleeding rate between the 2 groups (P Z .041). Limitations: A nonrandomized trial with historical control subjects; a single-center analysis; small sample size. Conclusions: The endoscopic tissue shielding method with PGA sheets and fibrin glue appears to be promising for the prevention of post-ESD bleeding. (Clinical trial registration number: UMIN000011058.) (Gastrointest Endosc 2015;81:906-12.) (footnotes appear on last page of article)
Endoscopic submucosal dissection (ESD) has been accepted as an excellent treatment for gastric neoplasms because a large tumor or lesion with an ulcer scar can be successfully resected in an en bloc fashion.1-4 ESD is minimally invasive and can be applied to elderly patients.5 Moreover, ESD is reported to be safe and effective,
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even for early gastric cancer in the altered anatomy, such as a remnant stomach or gastric tube, and locally recurrent early gastric cancer after endoscopic resection.6-8 According to guidelines from the Japanese Gastric Cancer Association,9 absolute guideline criteria for tumors indicated for ESD are differentiated-type mucosal adenocarcinoma % 2 cm without ulcerative findings. The indication criteria for endoscopic resection have been expanded based on the large case series treated by gastrectomy with lymph node dissection,10 and there have been some reports about the validity of the expanded criteria.1,11,12 The tumors categorized into expanded criteria were as follows: a differentiated-type mucosal adenocarcinoma O 2 cm without ulcerative
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findings, a differentiated-type mucosal adenocarcinoma % 3 cm with ulcerative findings, and undifferentiated-type mucosal adenocarcinoma % 2 cm without ulcerative findings.9 Although ESD has its advantages, it has a substantial risk of adverse events, such as post-ESD bleeding or perforation.2,3 In particular, post-ESD bleeding may lead to serious conditions, including massive bleeding and life-threatening hemorrhagic shock. Therefore, preventing post-ESD bleeding is desirable.13,14 To date, proton pump inhibitors or histamine-2 receptor antagonists have been used to prevent post-ESD bleeding.4,15-17 Moreover, Takizawa et al14 reported that preventive coagulation of visible vessels in the resection area after ESD might lead to a lower bleeding rate. However, previous studies revealed the rate of post-ESD bleeding is still approximately 5%, even with such preventive methods.12,13,18-20 Several reports revealed that antithrombotic drug usage and a large resection size (R40 mm) may be independent risk factors for postESD bleeding, but there is still a question regarding how to overcome post-ESD bleeding in high-risk patients.13,18,20-23 More recently, Takimoto et al24 reported a novel endoscopic tissue shielding method that uses polyglycolic acid (PGA) sheets (Neoveil; Gunze Co, Kyoto, Japan) and fibrin glue (Beriplast P Combi-Set; CSL Behring Pharma, Tokyo, Japan). PGA is an absorbent suture reinforcement material, and PGA sheets have been applied to videoassisted major lung resection, partial glossectomy, pancreaticoduodenectomy, and gastrectomy.25-28 As for the field of endoscopy, this method may be effective for the prevention of adverse events after colorectal ESD, such as bleeding or perforation.29 However, to our knowledge, there are no reports regarding the application of this technique for the prevention of bleeding after gastric ESD. Therefore, we prospectively enrolled patients with PGA sheets as a study group and evaluated the efficacy and safety of this novel method with the purpose of preventing post-ESD bleeding in high-risk patients, comparing the results with the historical control group of those without PGA sheets.
Use of PGA sheets and fibrin glue to prevent post-ESD bleeding
Patients Written informed consent for gastric ESD was obtained from all patients before performing ESD regardless of enrollment for clinical studies. The target lesions had to be within the expanded indication criteria of gastric ESD, and CT had to reveal no lymph node or other organ metastasis. We defined high-risk patients for post-ESD bleeding as follows: those who took antithrombotic drugs regularly, or those who were expected to undergo large mucosal resection (R40 mm). Aspirin, ticlopidine, clopidogrel, cilostazol, ethyl icosapentate, warfarin, and dabigatran were defined as antithrombotic drugs. The cessation and resumption of antithrombotic drugs were carried out according to the newest guideline by the Japan Gastroenterological Endoscopy Society.30
Study group We enrolled patients who were scheduled to undergo gastric ESD and had an above-mentioned high risk for post-ESD bleeding. Because the latter criterion could not be obtained preoperatively, we enrolled patients with a tumor R 20 mm in preoperative size or with an ulcer scar inside or close to a tumor, where the resection size would exceed 40 mm. The exclusion criteria were contraindications of PGA sheets or fibrin glue as follows: (1) those who have systemic adverse events (as to PGA sheets); (2) those who have a history of anaphylaxis to components of fibrin glue or drugs made of bovine lung, such as aprotinin; and (3) those who were treated with procoagulants (hemocoagulase made from snake venom), antifibrolytic agents, and aprotinin (as to fibrin glue).
Historical control group Between January and July 2013 before the first enrollment of a study patient, 126 gastric neoplasms in 101 consecutive patients were treated with ESD. Among them, 44 lesions in 37 patients were extracted as a highrisk group, fulfilling the definition of high-risk patients for post-ESD bleeding. In 2 patients, 2 or 3 adjacent neoplasms were resected as 1 piece to yield 1 ulcer, so 41 ESD-induced ulcers were finally enrolled as control subjects.
METHODS ESD procedure This nonrandomized trial with historical control subjects was undertaken at the University of Tokyo Hospital, Tokyo, Japan. The study protocol was approved by the research ethics committee of the University of Tokyo on June 24, 2013 and was registered in the University Hospital Medical Network Clinical Trial Registry (UMIN-CTR) on July 1, 2013 (UMIN000011058). The first study patient was enrolled after the study registration, and all study patients gave written informed consent for the intervention and for gastric ESD.
ESD was performed with the patient under intravenous sedation with diazepam and pentazocine using a video endoscope (GIF-Q260J; Olympus Medical, Tokyo, Japan) and an electrosurgical unit (VIO 300D; Erbe, Tübingen, Germany). The ESD procedure was performed as follows. First, circumferential markings were made by a dual knife (KD-650L; Olympus Medical). After submucosal injection using a mixture of .4% sodium hyaluronic acid solution (Mucoup; Johnson and Johnson K.K., Tokyo, Japan) and normal saline solution, a mucosal incision and submucosal
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Use of PGA sheets and fibrin glue to prevent post-ESD bleeding
dissection were performed by a dual knife or IT-Knife 2 (KD-611L; Olympus Medical). After resection of the lesion, all visible vessels on the ulcer floor were coagulated with hemostatic forceps (HDB-2422-W; Pentax, Tokyo, Japan; or M00515031; Boston Scientific Japan, Tokyo, Japan) using the soft coagulation mode.
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roni correction was performed for multiple comparisons in the subgroup analysis.
RESULTS
We set a post-ESD bleeding rate as the primary endpoint to compare both groups. Additionally, we made subgroup analyses by dividing into solely a large resection group and an antithrombotic therapy group. The latter was further divided into 2 groups: with and without heparin bridging therapy. The rates of other adverse events were noted as secondary endpoints. All statistical analyses were performed with JMP 10.0.2 (SAS Institute Inc, Cary, NC, USA). Categorical data were compared using a c2 test or the Fisher exact test, as appropriate. If each cell in a 2 2 cross-tabulation table had an expected value ! 5, we used the Fisher exact test. The differences in the means of continuous data were compared by a Student t test or Mann-Whitney U test. P ! .05 was considered significant, and all tests were 2-sided. Bonfer-
Between July 2013 and February 2014, 44 patients met the inclusion criteria for the study group. Three patients refused to participate in the study; therefore, 41 patients were enrolled in the study group. All ESD cases were completed without life-threatening events, and 45 ESDinduced ulcers were created in the 41 patients. The baseline characteristics of the patients and tumors in the study and control groups are listed in Table 1. No significant differences were found in resection size of antithrombotic drug users between the study group and the historical control group (36.7 9.7 mm and 37.1 14.3 mm, respectively; P Z .914). In the study group, the mean procedural time for applying PGA sheets and fibrin glue was 20.4 9.5 minutes. In all cases, we successfully covered the entire mucosal defect after ESD. Between July and December 2013, we placed PGA sheets as previously reported,24,29 with a mean procedural time of 21.4 11.0 minutes. After converting to the clip and pull method,31 the mean procedural time was 18.9 6.6 minutes. There was no significant difference between the 2 procedures (P Z .390). The post-ESD bleeding occurred at a rate of 6.7% in the study group (3/45 lesions) and 22.0% in the historical control group (9/41 lesions). There was a significant difference in the post-ESD bleeding rate between the 2 groups (P Z .041). The characteristics of ulcers that developed post-ESD bleeding are shown in Figure 2. In the study group, all bleeding events occurred in the patients under heparin bridging therapy. Between the study and control groups, there was no significant difference in the date of bleeding onset (P Z .918). In the study group, bleeding rates were not significantly different between ulcers with original application and with the clip and pull method (7.4% vs. 5.6%; P Z 1.000). Subgroup analyses are shown in Table 2. For large-sized resections, the ESD-induced ulcers shielded by PGA sheets tended to have a lower risk of post-ESD bleeding than those without PGA sheets (0% and 22.2%, respectively); however, the difference was not statistically significant (P Z .105). For antithrombotic therapy without heparin bridging, the post-ESD bleeding rate tended to be lower in the study group than in the historical control group (0% and 22.0%, respectively; P Z .043). In the study group, 7 lesions were under heparin bridging therapy, and 3 lesions were in the historical control group. The post-ESD bleeding rate was 42.9% in the study group and 33.3% in the historical control group (P Z 1.000). Other adverse events were as follows: 1 patient in the study group developed mild pancreatitis 8 days after
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PGA sheet application After completing the ESD procedure, PGA sheets were placed onto the mucosal defect and fixed with fibrin glue. The delivery method was at first based on the report of Takimoto et al,24 and the details were also described in our previous report.29 Taking account of the speed and ease, we adopted “the clip and pull method” from Ono et al31 (Fig. 1; Video 1, available online at www. giejournal.org). In this study we modified this method, as follows: (1) the PGA sheet was grasped with biopsy forceps and then (2) wrapped around the endoscope, (3) the endoscope was inserted orally to the site of the post-ESD defect, (4) the biopsy forceps was removed and the PGA sheet was anchored to the 1 side of the post-ESD mucosal defect using endoclips and (5) stretched so it could cover the whole post-ESD ulcer with several endoclips.
Follow-up after ESD Patients fasted on the morning of the ESD and were prohibited from eating and drinking until the next day of ESD. If laboratory findings and chest and abdominal radiographs proved to be unremarkable, patients were permitted to take oral soft foods.4 Patients took 10 mg oral rabeprazole daily 1 day before ESD. Based on the report by Niimi et al,16 the duration of the rabeprazole prescription was set for at least 14 days, depending on doctors in charge. A scheduled second-look endoscopy was not performed for any patient. When post-ESD bleeding occurred, we performed an urgent endoscopy and executed endoscopic hemostasis. Post-ESD bleeding was defined as hemorrhage resulting in overt hematemesis or melena or a hemoglobin decrease R2.0 g/dL.
Endpoints and statistical analysis
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TABLE 1. Baseline characteristics of patients and tumors based on the number of ESD-induced ulcers Study group (n [ 45)
Historical control group (n [ 41)
P value
73.6 7.5
74.8 7.0
.482
41/4
34/7
.256
Antithrombotic drug therapy
29 (64.4)
23 (56.1)
.429
Heparin bridge therapy
7 (15.6)
3 (7.3)
.319
Hypertension
33 (73.3)
32 (78.1)
.611
Hyperlipidemia
15 (33.3)
20 (48.8)
.145
4 (8.9)
8 (19.5)
.156
26 (57.8)
25 (61.0)
.763
Liver cirrhosis
2 (4.4)
1 (2.4)
1.000
Hemodialysis
0
1 (2.4)
.477
40.1 12.4
43.9 15.1
.206
1/44/0
2/36/3
.131
Tumor location (U/M/L)
11/17/17
6/20/15
.437
Tumor depth (no tumor/M/SM1/SM massive)
1/37/3/4
2/32/4/3
.870
En bloc resection
45 (100)
40 (97.6)
.477
Patient Mean age, y (SD) Sex: males/females
Diabetes mellitus Cardiovascular disease
Tumor Mean resection size, mm (SD) Tumor histology (no tumor/intestinal/diffuse)
Values are number of cases with percents in parentheses, unless otherwise noted. SD, Standard deviation; U/M/L, the upper/middle/lower third of the stomach; M, tumor confined to the mucosa; SM1, tumor invading the submucosa % 500 mm; SM massive, tumor invading the submucosa O 500 mm.
ESD, from which the patient recovered with conservative treatment. No other adverse events associated with PGA sheet application were observed.
In this nonrandomized trial with historical control subjects, we demonstrated that the endoscopic tissue shielding method with PGA sheets and fibrin glue decreased the risk of bleeding after gastric ESD. To date, there has been no medication to prevent post-ESD bleeding other than proton pump inhibitors or histamine-2 receptor antagonists.15,17 Takizawa et al14 found that preventive coagulation of visible vessels in the resection area after ESD might lead to a lower bleeding rate. However, the incidence of bleeding after ESD was still 3.1% after preventive coagulation. Therefore, additional measures are essential to prevent post-ESD bleeding. We previously reported the feasibility of the endoscopic tissue shielding method with PGA sheets and fibrin glue after colorectal ESD.29 As described in that report, the safety and efficacy of the tissue shielding method with PGA sheets and fibrin glue were described in several fields.25-28 In this study, 1
patient developed mild pancreatitis 8 days after ESD, but there was no increase in transaminase, alkaline phosphatase, or g-glutamyl transpeptidase. Therefore, it was not likely that fibrin glue or detached PGA sheets obstructed the pancreaticobiliary tract, and we concluded the cause most likely had no association with PGA sheets or fibrin glue. Regarding feasibility, the mean procedural time for delivering PGA sheets and fibrin glue was 20.4 minutes in this study, a duration comparable with a previously published result in the colorectum, 18.7 minutes.29 In this study, we identified the high-risk group for post-ESD bleeding as taking antithrombotic drugs and/or the necessity of a large-sized resection from previous reports.13,18,20,21,23 Although there is still controversy about the risk factors for post-ESD bleeding,3235 the rate of 22% in the historical control group revealed that we could successfully identify high-risk patients, considering the approximately 5% overall post-ESD bleeding rate.12,13,18-20 Moreover, we revealed that post-ESD bleeding rates in high-risk patients could be reduced to one third using PGA sheets and fibrin glue. Interestingly, this study showed that all 3 cases of postESD bleeding after application of PGA sheets and
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DISCUSSION
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Tsuji et al
Figure 1. PGA sheet delivery and fixation (clip and pull method). A, An artificial ulcer after gastric ESD. B, Anchoring the PGA sheet to the distal side of the ulcer with a clip. C, Pulling the endoscope and deploying the PGA sheet. D, Stretching and anchoring the circumference of the PGA sheet with several clips. E, A fixed PGA sheet after spraying fibrin glue.
Figure 2. The date of bleeding onset after ESD and the status of antithrombotic drugs.
fibrin glue had heparin bridging therapy. Therefore, this technique might not be effective in cases of heparin bridging therapy but would be very effective and safe for patients with antithrombotic drugs, except for those with heparin bridging therapy.
There are some limitations to our study. First, this was a single-center analysis with a relatively small number of cases. Second, this was not a randomized controlled trial. To confirm our findings, a largescale randomized controlled trial is necessary in the
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TABLE 2. Post-ESD bleeding rates of the 2 groups Post-ESD bleeding, n (%) Study group (n [ 45) Overall
Historical control group (n [ 41)
P value
3 (6.7)
9 (22.0)
.041
Large-sized resection
0 (n Z 16)
4 (22.2) (n Z 18)
.105
Antithrombotic drug therapy without heparin bridging
0 (n Z 22)
4 (20.0) (n Z 20)
.043
Heparin bridge therapy
3 (42.9) (n Z 7)
1 (33.3) (n Z 3)
1.000
1. Isomoto H, Shikuwa S, Yamaguchi N, et al. Endoscopic submucosal dissection for early gastric cancer: a large-scale feasibility study. Gut 2009;58:331-6. 2. Oka S, Tanaka S, Kaneko I, et al. Advantage of endoscopic submucosal dissection compared with EMR for early gastric cancer. Gastrointest Endosc 2006;64:877-83. 3. Gotoda T, Yamamoto H, Soetikno RM. Endoscopic submucosal dissection of early gastric cancer. J Gastroenterol 2006;41:929-42. 4. Fujishiro M. Endoscopic submucosal dissection for stomach neoplasms. World J Gastroenterol 2006;12:5108-12. 5. Tokioka S, Umegaki E, Murano M, et al. Utility and problems of endoscopic submucosal dissection for early gastric cancer in elderly patients. J Gastroenterol Hepatol 2012;27(Suppl 3):63-9. 6. Nonaka S, Oda I, Sato C, et al. Endoscopic submucosal dissection for gastric tube cancer after esophagectomy. Gastrointest Endosc 2014;79:260-70. 7. Sekiguchi M, Suzuki H, Oda I, et al. Favorable long-term outcomes of endoscopic submucosal dissection for locally recurrent early gastric cancer after endoscopic resection. Endoscopy 2013;45:708-13. 8. Nonaka S, Oda I, Makazu M, et al. Endoscopic submucosal dissection for early gastric cancer in the remnant stomach after gastrectomy. Gastrointest Endosc 2013;78:63-72. 9. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2010 (version 3). Gastric Cancer 2011;14:113-23. 10. Gotoda T, Yanagisawa A, Sasako M, et al. Incidence of lymph node metastasis from early gastric cancer: estimation with a large number of cases at two large centers. Gastric Cancer 2000;3:219-25.
11. Hirasawa T, Gotoda T, Miyata S, et al. Incidence of lymph node metastasis and the feasibility of endoscopic resection for undifferentiatedtype early gastric cancer. Gastric Cancer 2009;12:148-52. 12. Goto O, Fujishiro M, Kodashima S, et al. Outcomes of endoscopic submucosal dissection for early gastric cancer with special reference to validation for curability criteria. Endoscopy 2009;41:118-22. 13. Tsuji Y, Ohata K, Ito T, et al. Risk factors for bleeding after endoscopic submucosal dissection for gastric lesions. World J Gastroenterol 2010;16:2913-7. 14. Takizawa K, Oda I, Gotoda T, et al. Routine coagulation of visible vessels may prevent delayed bleeding after endoscopic submucosal dissectiondan analysis of risk factors. Endoscopy 2008;40: 179-83. 15. Tomita T, Kim Y, Yamasaki T, et al. Prospective randomized controlled trial to compare the effects of omeprazole and famotidine in preventing delayed bleeding and promoting ulcer healing after endoscopic submucosal dissection. J Gastroenterol Hepatol 2012;27:1441-6. 16. Niimi K, Fujishiro M, Goto O, et al. Prospective single-arm trial of twoweek rabeprazole treatment for ulcer healing after gastric endoscopic submucosal dissection. Dig Endosc 2012;24:110-6. 17. Uedo N, Takeuchi Y, Yamada T, et al. Effect of a proton pump inhibitor or an H2-receptor antagonist on prevention of bleeding from ulcer after endoscopic submucosal dissection of early gastric cancer: a prospective randomized controlled trial. Am J Gastroenterol 2007;102:1610-6. 18. Koh R, Hirasawa K, Yahara S, et al. Antithrombotic drugs are risk factors for delayed postoperative bleeding after endoscopic submucosal dissection for gastric neoplasms. Gastrointest Endosc 2013;78:476-83. 19. Goto O, Fujishiro M, Oda I, et al. A multicenter survey of the management after gastric endoscopic submucosal dissection related to postoperative bleeding. Dig Dis Sci 2012;57:435-9. 20. Okada K, Yamamoto Y, Kasuga A, et al. Risk factors for delayed bleeding after endoscopic submucosal dissection for gastric neoplasm. Surg Endosc 2011;25:98-107. 21. Takeuchi T, Ota K, Harada S, et al. The postoperative bleeding rate and its risk factors in patients on antithrombotic therapy who undergo gastric endoscopic submucosal dissection. BMC Gastroenterol 2013;13:136. 22. Lim JH, Kim SG, Kim JW, et al. Do antiplatelets increase the risk of bleeding after endoscopic submucosal dissection of gastric neoplasms? Gastrointest Endosc 2012;75:719-27. 23. Cho SJ, Choi IJ, Kim CG, et al. Aspirin use and bleeding risk after endoscopic submucosal dissection in patients with gastric neoplasms. Endoscopy 2012;44:114-21. 24. Takimoto K, Toyonaga T, Matsuyama K. Endoscopic tissue shielding to prevent delayed perforation associated with endoscopic submucosal dissection for duodenal neoplasms. Endoscopy 2012;44(Suppl 2):E414-5. 25. Takeuchi J, Suzuki H, Murata M, et al. Clinical evaluation of application of polyglycolic acid sheet and fibrin glue spray for partial glossectomy. J Oral Maxillofac Surg 2013;71:e126-31.
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future. Third, in this study protocol we did not have independent observers for the classification and comparison of postoperative adverse events in the followup period. Finally, how to cover larger mucosal defects, such as those larger than 10 cm, has not yet been established. In this study we investigated the preventive effect of PGA sheet with fibrin glue on post-ESD bleeding, but this tissue shielding method has the potential to prevent delayed perforation.24,29 As for this point, further evaluation is needed. In conclusion, the present study demonstrated promising results of the tissue shielding method, which uses PGA sheets and fibrin glue, for the prevention of post-ESD bleeding in patients with a high risk of bleeding undergoing gastric ESD. REFERENCES
Use of PGA sheets and fibrin glue to prevent post-ESD bleeding 26. Hiura Y, Takiguchi S, Yamamoto K, et al. Use of fibrin glue sealant with polyglycolic acid sheets to prevent pancreatic fistula formation after laparoscopic-assisted gastrectomy. Surg Today 2013;43: 527-33. 27. Ueda K, Tanaka T, Hayashi M, et al. Mesh-based pneumostasis contributes to preserving gas exchange capacity and promoting rehabilitation after lung resection. J Surg Res 2011;167:e71-5. 28. Uemura K, Murakami Y, Hayashidani Y, et al. Combination of polyglycolic acid felt and fibrin glue for prevention of pancreatic fistula following pancreaticoduodenectomy. Hepatogastroenterology 2009;56:1538-41. 29. 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;79:151-5. 30. Fujimoto K, Fujishiro M, Kato M, et al. Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment. Dig Endosc 2014;26:1-14. 31. 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(Suppl 1): E44-5. 32. Choi CW, Kim HW, Kang DH, et al. Clinical outcomes of second-look endoscopy after gastric endoscopic submucosal dissection: predictive factors with high risks of bleeding. Surg Endosc 2014;28:2213-20. 33. Sanomura Y, Oka S, Tanaka S, et al. Continued use of low-dose aspirin does not increase the risk of bleeding during or after endoscopic submucosal dissection for early gastric cancer. Gastric Cancer 2014;17:489-96. 34. Mukai S, Cho S, Kotachi T, et al. Analysis of delayed bleeding after endoscopic submucosal dissection for gastric epithelial neoplasms. Gastroenterol Res Pract 2012;2012:875323. 35. Higashiyama M, Oka S, Tanaka S, et al. Risk factors for bleeding after endoscopic submucosal dissection of gastric epithelial neoplasm. Dig Endosc 2011;23:290-5.
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Abbreviations: ESD, endoscopic submucosal dissection; PGA, polyglycolic acid. DISCLOSURE: The following author disclosed financial relationships relevant to this publication: M. Fujishiro: Speaker for Olympus, BoehringerIngelheim, Otsuka Pharmaceutical, Astrazeneca Pharmaceutical, DaiichiSankyo Pharmaceutical, Eisai Corporation, Aska Pharmaceutical, Nihon Pharmaceutical, Pentax, Mitsubishi Tanabe Pharma Corporation, Amco Corporation, and Takeda Pharmaceutical; Unrestricted Research Grants from Astellas Pharmaceutical, Takeda Pharmaceutical, Zeria Pharmaceutical, Otsuka Pharmaceutical, Astrazeneca Pharmaceutical, Dainihon-Sumitomo Pharmaceutical, Taiho Pharmaceutical, Ajinomoto Pharmaceutical, and Eisai; Nonfinancial Support from HOYA Pentax, Olympus Medical Systems, and Fujifilm; and Honoraria from Olympus Medical Systems, HOYA Pentax, Eisai, MSD, Daiichi-Sankyo Pharmaceutical, Astrazeneca Pharmaceutical, Aska Pharmaceutical, Taisho-Toyama Pharmaceutical, Otsuka Pharmaceutical, Zeria Pharmaceutical, Takeda Pharmaceutical, Astellas Pharmaceutical, Seikagaku Corp, Johnson & Johnson, Ajinomoto Pharmaceutical, Amco, Novartis Pharmaceutical, Boston Scientific, and, Boehringer-Ingelheim. All other authors disclosed no financial relationships relevant to this publication. Copyright ª 2015 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2014.08.028 Received April 10, 2014. Accepted August 25, 2014. Current affiliations: Department of Gastroenterology (1), Department of Endoscopy and Endoscopic Surgery (2), Center for Epidemiology and Preventive Medicine (3), Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Reprint requests: Dr. Mitsuhiro Fujishiro, MD, PhD, Department of Gastroenterology and Department of Endoscopy and Endoscopic Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Registration of Clinical Trials Gastrointestinal Endoscopy follows the International Committee of Medical Journal Editors (ICMJE)’s Uniform Requirements for Manuscripts Submitted to Biomedical Journals. All clinical trials eventually submitted in GIE must have been registered through one of the registries approved by the ICMJE, and proof of that registration must be submitted to GIE along with the article. For further details and explanation of which trials need to be registered as well as a list of ICMJE-acceptable registries, please go to http://www.icmje.org.
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