Patients
This was a retrospective cohort study consecutively collected 361 cases completed ESD for early esophageal cancer from 1st January 2014 to 30th October 2020 at Beijing Friendship Hospital, Capital Medical University in China. Exclusion criteria included: (1) not high-grade intraepithelial neoplasia (HGIN)/squamous cell carcinoma (SCC) confirmed by histopathology; (2) additional treatment due to positively cutting edge of resected specimen, such as surgery treatment, radiotherapy and chemotherapy; (3) missing the gastroscopy review or other essential information.
Information and materials
Information of patient characteristics (age, sex, drinking history, smoking history, body mass index (BMI), family history), lesion characteristics (infiltration depth) and treatment process (operation time, hospital stay, glucocorticoid prevention, postoperative fever, blood test) was collected from medical record. Endoscopic images of lesions (lesion location, longitudinal lesion length, proportion of esophageal circumference, number of clips, postoperative stricture) was collected from picture archiving and communication system (Qingdao Medicon Digital Engineering Co., Ltd., Medicare I-EndoCenter, Qingdao, China).
Esophageal stricture was defined as an esophageal diameter <11 mm, rather than the inability to pass the gastroscope (which had a diameter of 9.8-11.0 mm)[8]. Classify dysphagia severity into the following four grades: score 0=able to eat a conventional diet; score 1 (mild)=able to eat some solid meals; score 2 (moderate)=able to eat semisolid but not solid foods; score 3 (severe) =able to consume liquids only; score 4=aphagia[9]. Score 2 and above was defined as both dysphagia and esophageal stricture.
The upper segment of esophagus was defined as the cervical and upper thoracic segments, 15-25cm away from the incisors; the middle segment of the esophagus was defined as mid-thoracic esophagus, 25-30cm away from the incisors; the lower segment of esophagus was defined as the lower thoracic esophagus and the abdomen, below 30cm from the incisors[10]. Operation time was defined as duration of anesthesia. Postoperative fever was defined as axillary body temperature exceeding 37.3°C within 48 hours after ESD. White blood cell (WBC) was tested on the second day after ESD. Deep muscle layer injury, subcutaneous emphysema, mediastinal emphysema, and esophageal fistula were defined as perforation. Some patients with large resected area were prescribed to oral glucocorticoid (Tianjin Lisheng Pharmaceutical Co., Ltd., Prednisone acetate, Tianjin, China) to prevent stricture, with a dose of 30 mg/day on the third day after ESD, tapered gradually (30, 30, 25, 25, 20, 15, 10, and 5 mg for 7 days each) and then discontinued 8 weeks later[11].
Esophageal ESD
A complete description of the ESD (Olympus, Co., Ltd., GIF-Q260J/GIF-Q180, Tokyo, Japan) procedure has been reported[12]. Mark margin of the lesion with dual knife, inject Meilan hyaluronate sodium saline into submucosa, cut the periphery, gradually peel off the lesion along the submucosa, and intermittently give hemostatic forceps to stop bleeding. Careful observation of no active bleeding on the wound, indwelling gastric tube after operation.
Study endpoints
Endoscopic review was performed 3th month and 9th month after ESD and once a year thereafter or when a patient complained of dysphagia associated with semisolid foods. The primary endpoint was esophageal diameter <11 mm or dysphagia confirmed. The second endpoint was scarring confirmed or the last gastroscopy review.
Statistical analysis
The student t test was used to compare the differences between continuous variables with normal or approximate normal distribution, which were presented as the mean and standard deviations (SD). Other continuous variables were presented as the median and quartile, and the categorical variables were presented as counts and percentages. Chi-square (c2) test was for unordered categorical variables. The Mann-Whitney test were used to compare ordinal categorical variables or continuous variables that not meet Student’s test. Univariate Cox regression analysis was used to evaluate the effects of clinically significant variables. Statistically significant factors obtained from the univariate Cox regression analysis were then entered into a forward LR multivariate Cox proportional hazard regression to identify independent risk factors after adjusting for other covariates. The risk factors for stricture formation were estimated by calculating the hazard ratios (HR) and the 95% confidence intervals (95%CI). The statistical tests above were evaluated by SPSS software version 22.0.
Kaplan-Meier cumulative incidence plots were created by Graphpad Prism (v.9.1.1.225). Package “rms” “survivalROC” in R Software 4.0.5 (www.r-project.org) was used for nomogram building based on multivariate Cox proportional hazard regression model. Receiver operating characteristic curves (ROC) were used to present the predictive accuracy of nomograms graphically. We performed calibration for established nomograms and applied 1,000 repetitions by 4 groups (n=55) of bootstrap sample corrections to internally validate the nomograms. The area under the curve (AUC) for validation was applied to evaluate the accuracy of the nomogram. Two-sided and a value of P<0.05 was considered statistically significant all above.