Prophylaxis And Treatment Of Esophageal Strictures After Endoscopic Submucosal Dissection By Endoscopic Injection Of Botulinum Toxin Type A

Aims: To investigate the efficacy and mechanism of endoscopic injection of BTX-Afor preventing esophageal strictures after endoscopic submucosal dissection (ESD).Methods: In this research, two parts of study were conducted, including therandomized clinical trial and the experimental study. In the clinical trial, sixty-threeearly esophageal cancer or precancerous lesions patients with a mucosal defects thatexceeded50%of the circumference of the esophagus after ESD treatment, from June2012to February2014in Chinese PLA General Hospital, were enrolled and randomlydivided into two groups (group A, n=32; group B, n=31). Patients in group A (BTX-Agroup) were immediately injected of BTX-A after ESD, while patients in group B(control group) received ESD only, without injection of BTX-A. Endoscopy and biopsywere performed at6weeks after operation for the evaluation of ESD complications andhistopathologic changes. Endoscopy and esophagography was performed at12weeks.The grading of dysphagia was recorded. Patients experienced post-ESD esophagealstricture in both groups received bougie dilation. The rates of post-ESD esophagealstrictures and the times of bougie dilation procedures for each stricture patient werecompared between group A and group B. In the experimental study, histopathologicchanges of the esophageal specimens at6weeks after operation were assessed byMasson’s staining. Expression of transforming growth factor-beta1(TGF-β1) mRNAand a-smooth muscle actins (a-SMA) mRNA were investigated by Real-time PCR. Theprotein levels of TGF-β1and a-SMA were investigated by Western blot.Results:1. No patient with mucosal defect covered from1/2to2/3of the esophagealcircumference developed esophageal stricture. Only three patients in group B withmucosal defect covered from2/3to3/4of the esophageal circumference developedesophageal stricture (3/8,37.5%). Two patients in group A and four patients in group Bwith mucosal defect more than three-quarters of the circumference developedesophageal stricture (2/6,33.3%vs4/5,80%). Only two patients in group B with full ornearly full circumferential mucosal defect developed stents placement and esophagealstricture (2/4,50%), while no patient developed stents placement and esophageal stricture in group A (0/2,0%).2. Compared with control group, the decrease ofAtkinson grading of dysphagia, quality of life questionnaire（EORTC QLQ-OES18),incidence of stenosis and times of bougie dilation procedures and increase of esophagealdiameter in group A were significant. There are significantly differences of above databetween group A and group B (P＜0.05).3. The multivariate logistic regressionanalysis revealed that sex, age, location and the depth of invasion were not associatedwith post-ESD strictures. The maximum diameter of the resected specimens(OR=3.67,95%CI:0.99~13.61, P=0.05) and the proportion of extension to the whole circumferenceof the lumen(OR=6.52,95%CI:1.33~31.91, P=0.02) were the risk factors for post-ESDstrictures. However, stent placement (OR=0.00,95%CI:0.00~0.07, P=0.00) andinjection of BTX-A (OR=0.03，95%CI：0.004~0.23，P=0.00) were the preventive factorsof post-ESD strictures.4. Esophageal tissue Masson’ staining showed that comparedwith the BTX-A group the control group presented disordered structure, more bluecollagen deposition and more inflammatory cells infiltration.5. The result of Realtime-PCR showed that the TGF-β1mRNA and a-SMA mRNA expression weresignificantly lower in the BTX-A groups than that in control group.6. The result ofWestern blot showed that the TGF-β1and a-SMA protein levels were significantlylower in the BTX-A groups than that in control group.Conclusions:①The risk of post-ESD esophageal stricture was associated with thecircumferential extension of the mucosal defect. Patients with mucosal defect more thanthree-quarters of the circumference were associated with a high risk of post-ESDesophageal stricture.②Endoscopic injection of BTX-A was effective in preventingpost-ESD esophageal stricture and decreasing the times of bougie dilation procedures.③Endoscopic injection of BTX-A combined with stents placement was effective inreducing the incidence of stents displacement and esophageal stricture.④Endoscopic injection of BTX-A could alleviate the histopathologic changes inesophageal tissue after ESD, reduce the expression of TGF-β1and a-SMA mRNA, andinhibit the synthesis of TGF-β1and a-SMA protein.