Research On Risk Factors And Animal Models Related To Hypothalamic Obesity After Craniopharyngioma Surgery

Background and objectiveCraniopharyngioma(CP)is a rare benign brain tumor that occurs in the suprasellar region and/or parasellar region,and originates from epithelial cells of the craniopharyngeal canal remnant(Rathke’s pounch).Hypothalamic involvement and/or treatment of CP often cause hypothalamic structural damage,resulting in weight gain and even obesity.Identifying risk factors related to obesity after CP resection is pivotal to the prediction and prevention of postoperative obesity.Although multiple elegant studies have investigated this issue,studies focusing on Asian pediatric patients in are missing.In addition,although clinical studies such as radiological imaging,intraoperative video and nuclear atlas have observed that tumor attached hypothalamic tissue involves the hypothalamic nucleus,but there is still a lack of histological evidence to support it.This study first reviewed the clinical data of CP patients in our center to explore the risk factors related to obesity after CP surgery.Based on the conclusions of clinical research,further pathohistological analysis was performed on tumor specimens of hypothalamic tissue attached to CP,and an animal model of hypothalamic nucleus lesion was constructed to confirm it.The purpose is to provide ideas for reducing the incidence of obesity after CP surgery,as well as theoretical basis for selecting surgical strategies for CP surgery.Methods1.The clinical data of 53 children with CP who met the inclusion criteria from July 2011 to August 2020 in our center were collected for retrospective analysis.Univariate and multivariate logistic retrospective analysis were used to identify the independent risk factors contributing to postoperative obesity.A review of the available literature reporting the risk factors associated with obesity after CP surgery over the past two decades was performed for comparison.2.Collect tumor samples from hypothalamic tissue attached to CP,and conduct staining and analysis on hypothalamic tissue attached to CP using histopathological methods such as hematoxylin eosin staining,immunohistochemistry,and fluorescence in situ hybridization.Fourteen adult male Sprague-Dawley(SD)rats were randomly divided into hypothalamic nucleus lesion group and sham operation group by numerical method.Electrolytic lesion was performed according to the localization coordinates of the rat brain atlas under a stereotactic apparatus.The sham surgery group did not receive electricity,and the remaining operations were the same.The body weight,food intake,and water consumption of the two groups of rats were monitored daily.Results1.The median age at diagnosis of this cohort was 11.0 years old(IQR 8-15.5),and the median follow-up time was 44.0 months(range 8-119 months).18 cases(34.0%)developed obesity at the last follow-up.Univariate analysis showed significant differences(p<0.05)in preoperative body mass index standard deviation score(BMI SDS),age at diagnosis,and preoperative hypothalamic involvement.To further identing the independent risk factors,they were included in a multivariate analysis.Multivariate logistic regression analysis showed that preoperative BMI SDS(odds ratio [OR],1.71;95% confidence interval [CI]: 1.01-2.90;P=0.046),preoperative hypothalamic involvement(OR,29.38;95% CI: 1.76-490.66;P=0.019),age at diagnosis(OR,0.76;95% CI: 0.61-0.95;P=0.016)were independent risk factors for obesity after CP resection in children.2.According to hematoxylin eosin staining of the junction area between the tumor and the hypothalamus,it was found that the tumor protruded into the brain tissue with a fingerlike protrusion structure;Then,GFAP immunohistochemical staining was positive,indicating that the invaded brain tissue was the hypothalamus,and multiple fluorescence in situ hybridization of hypothalamic nuclear markers suggested positive results,indicating the presence of hypothalamic nuclei in the CP attachment tissue.Animal model studies suggest that,compared with the sham operated group,the weight(349.0±5.3g vs 294.6±3.0g,P<0.001),the Lee’s index(0.368±0.040 vs 0.323±0.027,P<0.05),and the food intake(39.5±8.8g vs 27.8±3.5g,P<0.01)of the hypothalamic nucleus injury group were significantly higher,but there was no statistically significant difference in water consumption.Conclusion1.Our results combined with previous literature support that preoperative BMI SDS,preoperative hypothalamic involvement and age at diagnosis are the independent risk factors associated with obesity after childhood-onset CP resection.2.Combined with the clinical study in Chapter 1,the conclusion that hypothalamic injury is an independent risk factor for obesity after CP surgery has not only been confirmed from the histopathological level,but also led to increased food intake and obesity after simulating hypothalamic injury through animal models.It can be seen that preoperative hypothalamic injury can predict postoperative obesity,and avoiding hypothalamic injury can reduce the incidence of obesity after CP surgery.