A Preliminary Study On The Clinical And Pathogenesis Of Ureteral Dysfunction After Radical Hysterectomy

Radical hysterectomy combined with bilateral pelvic lymph node dissection is the standard treatment for early cervical cancer[1].Intraoperative bladder and ureteral injuries as well as post-operative vesicovaginal fistula and ureterovaginal fistula are important urinary complications of radical hysterectomy[2].Compared with other gynecological operations,the incidence of perioperative urinary complications in radical hysterectomy was higher than other gynecological operations.Gynecological surgery may account for 52% of iatrogenic ureteral injuries[3-5].The incidence of ureteral injury after radical hysterectomy is difficult to estimate,ranging from 0.7% to 30%.The female urinary system is anatomically adjacent to the reproductive system,and the two are embryologically related.Therefore,complications of urinary tract injury are common in gynecological surgery.At the same time,the opening of the ureteral tunnel and the extensive dissection of the ureteral and peribladder tissues during radical hysterectomy are also associated with increased perioperative urinary complications.Clinically,bladder injury can be easily recognized and repaired immediately,whereas ureteral injury is more important because it is often not recognized.Radical hysterectomy of ureteral injury during the occurrence of the most typical parts in ureter the lower ureteral segment,the possible reasons including thermal damage,ureteral ischemia,stripped of ureteral surrounding tissues,such as excessively causing tiny damage,not easy to be identified,in turn,lead to ureteral stricture and dysfunction,and even a potential loss of renal function and reduced patients quality of life,affect the patient’s follow-up treatment [6-7].At present,domestic and foreign studies on ureteral-related complications after radical hysterectomy are single-center studies with small sample size,and only focus on perioperative related diseases,and there are few reports on delayed postoperative ureteral dysfunction.In addition,the relevant studies are all foreign reports,and there are few domestic research data.There are few reports on the incidence and related risk factors of ureteral dysfunction after radical hysterectomy,especially on the related pathogenesis.Therefore,this study retrospectively analyzed the clinical treatment of gynecological tumor patients in our hospital to explore the related risk factors affecting ureteral dysfunction after radical hysterectomy.Bioinformatics method was used to retrieve the relevant gene chip data of ureteral fibrosis and screen the transcriptional factors potentially related to ureteral fibrosis and stenosis.By constructing an animal model of ureteral dysfunction after ureteral injury in New Zealand rabbits,and observing its pathological characteristics,the possible pathogenesis of ureteral dysfunction after radical hysterectomy was analyzed.At the same time,we attempted to use paclitaxel as an intervention in an animal model to evaluate its potential clinical efficacy in reducing ureteral dysfunction after ureteral injury.In addition,we have also explored and improved the surgical treatment methods,which have certain theoretical and practical application value for the prevention of ureteral dysfunction after radical hysterectomy.CHARPTER 1 Analysis Of Risk Factors For Ureteral Dysfunction After Radical HysterectomyObjective: To investigate the risk factors of postoperative persistent ureteral stricture and hydronephrosis by collecting and analyzing the clinical pathological data of patients after radical hysterectomy,so as to guide the clinical prevention and treatment of postoperative ureteral stricture.Methods: a retrospective analysis on December 31,2013 solstice December31,2018 in guangxi medical university affiliated tumor hospital diagnosed with cervical cancer,endometrial carcinoma undergoing radical hysterectomy clinical pathological data of 1303 patients,and carries on the telephone follow-up for all patients,postoperative persistent ureteral stricture,statistical methods analysis the incidence of hydronephrosis and associated risk factors.Results: a total of 1068 patients included in the final study,194 patients in the radical hysterectomy in postoperative persistent ureteral stricture,hydronephrosis,the overall rate of 18.1%,the incidence of cervical cancer was18.7%,the incidence of endometrial carcinoma was 16.4%.There was no significant difference in the incidence of postoperative continuous hydronephrosis between the two types of tumors(P>0.05).FIgo stage,postoperative adjuvant chemotherapy,Q-M classification,LVSI,lymph node metastasis,postoperative adjuvant radiotherapy,postoperative ureteral fistula,postoperative lymphatic cyst are risk factors for postoperative persistent ureteral stricture and hydronephrosis(P<0.05).Only adjuvant postoperative radiotherapy,postoperative adjuvant chemotherapy,postoperative ureteral fistula and postoperative lymphatic cyst were independent risk factors(P<0.05).They could predict the occurrence of postoperative persistent ureteral stricture and hydronephrosis.The ROC curve area was 0.768(P=0.00),the sensitivity was 83.3%,and the specificity was 56.2%.Postoperative persistent ureteral stricture and hydronephrosis can affect the prognosis of patients.Compared with the survival rate of patients with persistent hydronephrosis without continuous hydronephrosis,the difference in prognosis is statistically significant(P=0.00).Conclusion: The incidence of persistent ureteral stricture and hydronephrosis in patients with cervical cancer and endometrial cancer after radical hysterectomy was 18.1%.Postoperative ureteral fistula,postoperative adjuvant radiotherapy,postoperative adjuvant chemotherapy and lymphatic cyst may be independent risk factors.Persistent ureteral stricture and hydronephrosis after surgery may affect the prognosis of patients.CHARPTER 2 Bioinformatics Analysis Of Genes Related To Ureteral FibrosisObjective: To explore the differentially expressed genes involved in the activation of myofibroblasts by TGF-β using microarray data and bioinformatics methods,and to screen the transcriptional factors potentially related to the mining of ureteral fibrosis stenosis.Methods: From GEO database retrieval and download the TGF-beta and common muscle fibrosis disease fibroblast activation related GSE152250.Highthroughput data sets,select three groups of data sets,difference analysis,to filter out common gene expression differences of gene ontology(GO)and the Kyoto encyclopedia of gene and genome(KEGG)signaling pathway enrichment analysis,and constructing PPI network,filter core gene.Results: The GO analysis of 62 up-regulated and 46 down-regulated differentially expressed genes based on this dataset showed that the biological processes of co-expressed differentially expressed genes mainly included the formation of interstitial connective tissue and the formation of extracellular matrix,interstitial generation,etc.The molecular function mainly includes the structural composition of cytokine binding collagen binding extracellular matrix and so on.The cell composition mainly includes the extracellular matrix collagen fiber endoplasmic reticulum Golgi apparatus,etc.Through KEGG signal pathway enrichment analysis,the main relevant signal pathways screened out include the TGF-β signal pathway adhesion plaque extracellular matrix receptor interaction protein digestion and absorption regulation of stem cell pluripotent signaling pathway cell decline PPI network was constructed by HIPPO signaling pathway,atherosclerosis HIF-1 signaling pathway,and 20 protein factors were screened.COL1A1 was the core protein with the highest node number.Conclusion: Totally 20 differentially expressed genes and 10 signaling pathways related to fibrosis were screened out,which may provide new research directions and ideas for the research on the mechanism of the occurrence and development of fibrosis,including ureteral fibrosis.CHARPTER 3: A Preliminary Study On The Mechanism Of Ureteral Dysfunction After Radical HysterectomySection 1 Establishment of animal model of ureteral injury and detection and expression significance of related proteinsObjective: To analyze the possible mechanism of dysfunction after ureteral injury by constructing an animal model of ureteral injury and studying the pathophysiological changes after ureteral injury.Methods: Adult female New Zealand rabbits were used as experimental subjects to construct animal models of ureteral stricture after ureteral heat injury,mesangial peeling injury and ischemia injury.The injured side of the ureter was used as the experimental group and the contralateral normal ureter was used as the control group.Three weeks after modeling,the changes of ureteral peristaltic function in the experimental group and the control group were observed.The degree of ureteral fibrosis after injury was observed by HE staining.The MOD value of collagen fiber was detected by Masson staining and image analysis system.TGF-β1,IL33,and COL1A1 expressions were detected by immunohistochemical technique,and the expression intensity was evaluated by calculating the H-score value using image analysis system.S100 pairs of nerve fibers were used to mark the ureteral nerve fiber density after injury.Results: The animal models of ureteral heat injury,peeling mesangial injury and ischemia injury in New Zealand rabbits were successfully established.At 3 weeks after injury,the number of ureter peristalsis in the three experimental groups was significantly decreased compared with the normal ureter in the control group,with statistical significance(P<0.05).He staining could observe the proliferation of fibrous scar tissue in the ureter of the injured side in the three groups.After Masson staining,MOD values of collagen fibers in three groups were significantly higher than those in the control group(P<0.05).Immunohistochemical analysis showed that the expression of TGF-β1,IL33 and COL1A1 in the ureteral tissues of the three groups was significantly higher than that of the control group,with statistical significance(P<0.05).The density of nerve fibers labeled with S100 in the ureteral tissues of the three groups was significantly lower than that of the control group,and the difference was statistically significant(P<0.05).Conclusion: Heat injury,peeling mesangial injury and ischemic injury are the injury factors leading to ureteral stricture.Fibrosis is the main pathological change of ureteral stricture after ureteral injury.The increased expression of TGF-β1,IL33 and COL1A1 in the ureteral tissue after injury may play an important role in the occurrence and development of ureteral stricture after injury.Section 2: Preliminary Study On The Intervention Effect Of Low Dose Paclitaxel On Fibrous Scar After Ureteral InjuryObjective: To investigate the effect of low dose paclitaxel on the prevention of ureteral fibrosis after ureteral injury by constructing an animal model of ureteral injury.Methods: Adult female New Zealand rabbits were used as experimental subjects to construct the animal models of ureteral stenosis after ureteral heat injury,mesangial peeling injury and ischemia injury.The intervention group and the control group were set up.The intervention group was given 0.3g/kg paclitaxel intraperitoneal injection,while the control group was given normal saline intraperitoneal injection,twice a week.Three weeks after modeling,the degree of ureteral fibrosis after injury was observed by HE staining,and the MOD value of collagen fiber was detected by Masson staining and image analysis system.TGF-β1,IL33,and COL1A1 expressions were detected by immunohistochemical technique,and the expression intensity was evaluated by calculating the H-score value using image analysis system.Results: Three weeks after modeling,HE staining could observe the proliferation of fibrous scar tissue in the ureter of the injured side in both the intervention group and the control group.After Masson staining,the MOD values of collagen fibers in the intervention group and the control group were significantly decreased(P<0.05).Immunohistochemical analysis showed that the expression of TGF-β1 and COL1A1 in the ureteral tissues of the intervention group was significantly higher than that of the control group,with statistical significance(P<0.05).The expression of IL-33 in the ureteral tissues of the intervention group was higher than that of the control group,but the difference was not statistically significant(P>0.05).Conclusions: Paclitaxel can partially block the progression of ureteral fibrosis after ureteral injury,reduce the expression of TGF-β1 and COL1A1 protein,but has no significant inhibitory effect on the expression of IL-33 protein.CHARPTER 4: Clinical Study Of Modified Radical Hysterectomy for Ureteral ProtectionSection 1: Effect of radical hysterectomy with sparing uterine artery branches under ICG angiography on ureteral functionObjective: To investigate the safety and effectiveness of preserving uterine artery and ureteral branch in radical hysterectomy.Methods: Clinical data of patients with cervical cancer who received laparoscopic radical hysterectomy in the Affiliated Cancer Hospital of Guangxi Medical University from September 2016 to June 2020 were collected.Thirtytwo patients who received branch sparing uterine artery radical hysterectomy under ICG angiography were selected as the study group,and patients who received conventional laparoscopic radical hysterectomy during the same period were selected as the control group.The general clinical characteristics,pathological characteristics,surgical indicators and postoperative follow-up information of the patients between the two groups were compared.In the study group,3D-CTA technique and intraoperative ICG angiography were used to observe the blood supply of the lower segment of the ureter.Results: The clinical characteristics,pathological conditions,surgical conditions and postoperative complications of the study group and the control group were compared and analyzed.There was no statistical significance in the clinical characteristics,pathological conditions and surgical conditions of the patients(P>0.05).Follow-up of postoperative complications showed that the incidence of urinary complications in the study group and the control group was6.25% and 14.6%,respectively,the difference was statistically significant(P<0.05).In the study group of 5 patients,preoperative 3D-CTA technique was used to observe the ureteral blood supply,and the uterine artery could be reconstructed,but the ureteral branch of the uterine artery could not be reconstructed.The blood supply of the lower segment of the ureter was observed by ICG angiography in 32 patients in the study group during radical hysterectomy with sparing uterine artery branches,and the lower segment of the ureter and the uterine artery branches could be clearly observed,showing good blood supply.Conclusion: Preserving the ureteral branch of the uterine artery can protect the blood flow of the lower ureteral segment after surgery.Intraoperative ICG angiography can be used to effectively evaluate the lower segment of ureteral blood flow.Section 2: Application of membrane anatomy for ureteral protection in total mesometrial resection under ICG imagingObjective: To investigate the safety and effectiveness of total mesometrial resection under ICG imaging.Methods: Clinical data of patients with cervical cancer who underwent laparoscopic radical hysterectomy in the Affiliated Cancer Hospital of Guangxi Medical University from June 2019 to December 2019 were collected.A total of18 patients who received total mesometrial resection under ICG imaging were selected as the study group,and 30 patients who received conventional laparoscopic radical hysterectomy during the same period were selected as the control group.The general clinical characteristics,pathological characteristics,surgical related indicators and postoperative follow-up information of the patients between the two groups were compared.Results: All of the 18 patients in the study group received lympho-network angiography(ICG)in the total mesoscopic hysterectomy,and the total mesometrial resection under ICG imaging was successfully completed.The clinical characteristics,pathological conditions,surgical conditions and postoperative complications of the study group and the control group were compared and analyzed,and there was no statistical significance in the clinical characteristics,pathological conditions and other conditions of the patients(P>0.05).Among the operation-related conditions of patients,the operation time in the study group was longer than that in the control group,with statistical significance(P<0.05).Follow-up of postoperative complications showed that the incidence of urinary complications in the study group and the control group was5.6% and 13.3%,respectively,with no statistical significance(P>0.05).Conclusion: Total mesometrial resection is safe and feasible in the treatment of early cervical cancer,and has certain value in reducing postoperative complications related to urinary system.