Background: Endoscopic submucosal dissection (ESD) is widely used in the treatment of early esophageal cancer. However, the incidence of postoperative esophageal stricture is relatively high, especially after full circumferential ESD. Previous studies have shown that thymosin β4 (Tβ4) has anti-fibrotic activity and prevents scar formation. In this study, we investigated the safety and therapeutic effect of Tβ4 injection in preventing esophageal stricture after circumferential ESD in a porcine model. Methods: A total of 8 Bama pigs underwent esophageal circumferential ESD under anesthesia (n = 4 for experimental and control group). Local injection of Tβ4 gel was administered in the experimental group. Follow-up endoscopy was conducted, and balloon dilation (EBD) was performed to prevent the occurrence of esophageal stricture. Results: Esophageal stricture developed after circumferential ESD in all pigs. Local Tβ4 gel injection has shortened resolution of the stricture (p = 0.012) and was associated with a lesser number of EBD sessions (p = 0.002). The severity of esophageal stricture was milder in the experimental group (p = 0.046 vs. control group). No adverse events occurred in the study. Conclusions: Local Tβ4 gel injection appeared to be safe and effective for the prevention of esophageal stricture after circumferential ESD in a porcine model.

Keywords:
Thymosin β4, Endoscopic submucosal dissection, Esophageal stricture
1.
Isomoto H, Shikuwa S, Yamaguchi N, Fukuda E, Ikeda K, Nishiyama H, Ohnita K, Mizuta Y, Shiozawa J, Kohno S: Endoscopic submucosal dissection for early gastric cancer: a large-scale feasibility study. Gut 2009; 58: 331–336.
2.
Ono S, Fujishiro M, Niimi K, Goto O, Kodashima S, Yamamichi N, Omata M: Predictors of postoperative stricture after esophageal endoscopic submucosal dissection for superficial squamous cell neoplasms. Endoscopy 2009; 41: 661–665.
3.
Jain D, Singhal S: Esophageal stricture prevention after endoscopic submucosal dissection. Clin Endosc 2016; 49: 241–256.
4.
Isomoto H, Yamaguchi N, Nakayama T, Hayashi T, Nishiyama H, Ohnita K, Takeshima F, Shikuwa S, Kohno S, Nakao K: Management of esophageal stricture after complete circular endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma. BMC Gastroenterol 2011; 11: 46.
5.
Uno K, Iijima K, Koike T, Shimosegawa T: Useful strategies to prevent severe stricture after endoscopic submucosal dissection for superficial esophageal neoplasm. World J Gastroenterol 2015; 21: 7120–7133.
6.
Hannappel E: Thymosin beta4 and its posttranslational modifications. Ann N Y Acad Sci 2010; 1194: 27–35.
7.
Goldstein AL, Hannappel E, Sosne G, Kleinman HK: Thymosin beta4:a multi-functional regenerative peptide. Basic properties and clinical applications. Expert Opin Biol Ther 2012; 12: 37–51.
8.
Mizutani T, Tanaka M, Eba J, Mizusawa J, Fukuda H, Hanaoka N, Takeuchi M, Aoyama I, Kojima T, Takizawa K, Ono H, Muto M; Gastrointestinal Endoscopy Study Group of the Japan Clinical Oncology Group: A Phase III study of oral steroid administration versus local steroid injection therapy for the prevention of esophageal stricture after endoscopic submucosal dissection (JCOG1217, Steroid EESD P3). Jpn J Clin Oncol 2015; 45: 1087–1090.
9.
Yamashina T, Uedo N, Fujii M, Ishihara R, Mikamori M, Motoori M, Yano M, Iishi H: Delayed perforation after intralesional triamcinolone injection for esophageal stricture following endoscopic submucosal dissection. Endoscopy 2013; 45(suppl 2) UCTN: E92.
10.
Wen J, Lu Z, Yang Y, Liu Q, Yang J, Wang S, Wang X, Du H, Meng J, Wang H, Linghu E: Preventing stricture formation by covered esophageal stent placement after endoscopic submucosal dissection for early esophageal cancer. Dig Dis Sci 2014; 59: 658–663.
11.
Ohki T, Yamato M, Ota M, Takagi R, Kondo M, Kanai N, Okano T, Yamamoto M: Application of regenerative medical technology using tissue-engineered cell sheets for endoscopic submucosal dissection of esophageal neoplasms. Dig Endosc 2015; 27: 182–188.
12.
Beye B, Barret M, Alatawi A, Beuvon F, Nicco C, Pratico CA, Chereau C, Chaussade S, Batteux F, Prat F: Topical hemostatic powder promotes reepithelialization and reduces scar formation after extensive esophageal mucosal resection. Dis Esophagus 2016; 29: 520–527.
13.
Iizuka T, Kikuchi D, Yamada A, Hoteya S, Kajiyama Y, Kaise M: Polyglycolic acid sheet application to prevent esophageal stricture after endoscopic submucosal dissection for esophageal squamous cell carcinoma. Endoscopy 2015; 47: 341–344.
14.
Lua GW, Tang J, Liu F, Li ZS: Prevention of esophageal strictures after endoscopic submucosal dissection: a promising therapy using carboxymethyl cellulose sheets. Dig Dis Sci 2016; 61: 1763–1769.
15.
Badamchian M, Fagarasan MO, Danner RL, Suffredini AF, Damavandy H, Goldstein AL: Thymosin beta(4) reduces lethality and down-regulates inflammatory mediators in endotoxin-induced septic shock. Int Immunopharmacol 2003; 3: 1225–1233.
16.
Sosne G, Qiu P, Christopherson PL, Wheater MK: Thymosin beta 4 suppression of corneal NFkappaB: a potential anti-inflammatory pathway. Exp Eye Res 2007; 84: 663–669.
17.
Tang YQ, Yeaman MR, Selsted ME: Antimicrobial peptides from human platelets. Infect Immun 2002; 70: 6524–6533.
18.
Malinda KM, Goldstein AL, Kleinman HK: Thymosin beta 4 stimulates directional migration of human umbilical vein endothelial cells. FASEB J 1997; 11: 474–481.
19.
Cha HJ, Jeong MJ, Kleinman HK: Role of thymosin beta4 in tumor metastasis and angiogenesis. J Natl Cancer Inst 2003; 95: 1674–1680.
20.
Philp D, Huff T, Gho YS, Hannappel E, Kleinman HK: The actin binding site on thymosin beta4 promotes angiogenesis. FASEB J 2003; 17: 2103–2105.
21.
Sosne G, Xu L, Prach L, Mrock LK, Kleinman HK, Letterio JJ, Hazlett LD, Kurpakus-Wheater M: Thymosin beta 4 stimulates laminin-5 production independent of TGF-beta. Exp Cell Res 2004; 293: 175–183.
22.
Qiu P, Kurpakus-Wheater M, Sosne G: Matrix metalloproteinase activity is necessary for thymosin beta 4 promotion of epithelial cell migration. J Cell Physiol 2007; 212: 165–173.
23.
Cavasin MA, Liao TD, Yang XP, Yang JJ, Carretero OA: Decreased endogenous levels of Ac-SDKP promote organ fibrosis. Hypertension 2007; 50: 130–136.
24.
Werner S, Grose R: Regulation of wound healing by growth factors and cytokines. Physiol Rev 2003; 83: 835–870.
25.
Honda M, Nakamura T, Hori Y, Shionoya Y, Nakada A, Sato T, Yamamoto K, Kobayashi T, Shimada H, Kida N, Hashimoto A, Hashimoto Y: Process of healing of mucosal defects in the esophagus after endoscopic mucosal resection: histological evaluation in a dog model. Endoscopy 2010; 42: 1092–1095.
26.
Crockford D, Turjman N, Allan C, Angel J: Thymosin beta4: structure, function, and biological properties supporting current and future clinical applications. Ann N Y Acad Sci 2010; 1194: 179–189.
27.
Ruff D, Crockford D, Girardi G, Zhang Y: A randomized, placebo-controlled, single and multiple dose study of intravenous thymosin beta4 in healthy volunteers. Ann N Y Acad Sci 2010; 1194: 223–229.
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2018
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