| Ovarian malignancy is one of the common malignancies in female reproductive system,with higher malignancy,higher mortality rate,rapid disease progression and poor prognosis.Since ovarian cancers have no specific symptoms at the early stage,most of ovarian cancer patients have been already at the advanced stage when diagnosed,the surgical efficacy is poor.Therefore,good early screening and auxiliary diagnosis methods of ovarian cancer may play an important role in improving the prognosis of ovarian cancer patients.A good screening or auxiliary diagnosis method should have the characteristics of easy access to materials,simple detection methods,rapid results,and low price.Pathological diagnosis is the gold standard for the diagnosis of ovarian cancer,and it can be used in staging and evaluation of prognosis.Magnetic resonance imaging,proteomics and gene chip are good complementary examination.Because of invasiveness or expense,these examination cannot be used as the screening method.The clinical screening methods such as serum carbohydrate antigen 125(CA125)and vaginal ultrasound have a certain detection rate of ovarian cancer among high-risk groups,and the methods are relatively simple,but the screening efficacy is not satisfactory.Intestinal microbial community balance plays a crucial role in maintaining human health.Intestinal microbial community disorders can promote cancer by regulating inflammatory immune responses,affecting the genomic stability of the host cell,destroying the intestinal mucosa barrier,producing internal toxins.Intestinal microbial community disorders may increase the level of estrogen in the body,and estrogen can regulate the gene transcriptional activity of ovarian epithelial cells and promote the mitosis of ovarian epithelial cells,which is advantageous for the canceration of ovarian epithelial cells;estrogen can promote infiltration and metastasis of ovarian cancer,by enhancing cell adhesion and migration.In addition,intestinal microbial community disorders may also participate the occurrence and develop of ovarian cancer by activating immune response and inducing gene mutation.Intestinal inflammation can induce the cell canceration by activating immunocytes,inducing peroxidation damage,promoting inflammatory cytokine secretion,inducing gene mutation or abnormal methylation,inducing cell autophagy function.The inflammation origin hypothesis of malignant tumors proposes that the occurrence and development of colorectal cancer,gastric cancer,liver cancer are related to intestinal inflammatory response,and may be the key factors.Intestinal inflammation and intestinal microbial community disorders influences and activates each other.Sustained infection and inflammatory reaction increase the intestinal permeability,the harmful substances,such as intestinal pathogenic bacteria and endotoxin,enter the internal circulation through the intestinal skin barrier,and induce the cell canceration.Some studies have been studied that intestinal inflammation has appeared in the early cervical cancer or endometrial cancer,intestinal inflammation may be have occurred before cancer.Due to cluster and uterine are closer to intestine,so inflammatory cytokines or endotoxins may enter into the cervix or uterus through intestinal epithelial barriers damaged by intestinal inflammation,and promote cell canceration.This may be the potential relationship between intestinal inflammation and gynecological tumors.However,the related study of intestinal inflammation or intestinal inflammation and ovarian cancer has not been reported.In order to explore the correlation between ovarian cancer and intestinal inflammation,and to analyze the application value of fecal markers in the early diagnosis and treatment of ovarian cancer.This study is carried out from the following aspects:The gastrointestinal function of all the subjects are evaluated and compared by using gastrointestinal symptom assessment scale(GSRS),the irritable bowel syndrome symptom severity scale(IBS-SSS)and the Rome In.diagnostic criteria for constipation between the epithelial ovarian cancer(EOC)group and the normal control(NC)group;the intestinal inflammation occurrence are observed and compared by hematoxylin-eosin(HE)staining between the two groups;the expression and position of intestinal tight linked protein closing protein(OCLN)and latching ligation protein-1(ZO-1)are observed and compared by immunohistochemical staining and immunofluorescence staining between the two group;the levels of intestinal inflammation related fecal markers[fecal calprotectin(FCP)and fecal lactoferrin(FLF)]and the intestinal mucosal permeability related fecal markers[fecal alpha-1-antitrypsin(FATT)and fecal protein(FZ)]were detected and compared between the two groups.Materials and Methods1.Collection of clinical pathological data of EOC patientsThe basic data of EOC patients(the EOC group)and healthy subjects(the NC group)from November 2018 to May 2020 in the Second Affiliated Hospital of Zhengzhou University were collect and analyzed,who had been diagnosed by clinical pathology and met the enrollment conditions,the age,pathological type,degree of differentiation,lymph node metastasis,American Obstetrics and Gynecology Association(FIGO)staging,and serum CA125 levels were analyzed in the EOC group,and the age of the subjects were analyzed in the NC group.2.Assessment of gastrointestinal function of the EOC patientsThe GSRS scale,the IBS-SSS scale and the Rome Ⅲ diagnostic criteria for constipation were used to compare the gastrointestinal function of the subjects in the EOC group and the NC group,and to compare the gastrointestinal symptoms.The relationship between the occurrence of gastrointestinal symptoms of EOC patients and their FIGO staging.3.Detection of intestinal inflammation related indicators in the EOC patientsThe intestinal mucosal biopsy tissues were collected,the epithelial morphology and the number of inflammatory cells in the colonic mucosa samples were detected by HE staining,and were compared between the EOC group and the NC group.The fresh stool specimens were collected,ELISA was used to detect and compared the FCP and FLF levels in the two groups,and their relationship with FIGO staging of EOC patients were analyzed too.4.Detection of intestinal inflammation related indicators in the EOC patientsThe intestinal mucosal biopsy tissues were collected,the expression and distribution of OCLN and ZO-1 in the colonic mucosa samples were detected by using by immunohistochemical staining and immunofluorescence staining,and were compared between the EOC group and the NC group.The fresh stool specimens were collected,ELISA was used to detect and compared the FAAT and FZ levels in the two groups,and their relationship with FIGO staging of EOC patients were analyzed too.5.Statistical analysisGraphPad Prism 8.3.0 and SPSS 23.0 were used to process data;the measurement data were recorded by using x±s,Mann-Whitney U test was used to compare and analyze the differences between the two groups,and the Spearman rank correlation test was used to analyze its correlation with the FIGO staging of EOC patients;the count data were recorded by using percentages,and χ2 test was used to analyze the differences between the two groups;ROC curve was drawn to evaluate the diagnostic value of FCP,FLF,FAAT and FZ levels for EOC;the inspection level a=0.05.Results1.Analysis results of clinical data of the EOC patientsAccording to the inclusion and exclusion criteria,35 EOC patients(the EOC group)and 20 healthy subjects(the NC group)were finally included in the study.The age of patients was(57.51±15.19)years old in the EOC group,and was(56.60±10.96)years old in the NC group,the difference was not statistically significant(U=330.0000,Z=0.3502,P=0.7262).Among the 35 EOC patients,19 patients were serous cystadenocarcinoma,7 patients were clear cell carcinoma,5 patients were mucinous cystadenocarcinoma,4 patients were endometrioid adenocarcinoma;21 patients were poorly differentiated,8 patients were moderately differentiated,and 6 patients were well differentiated;there were 13 patients with lymph node metastasis,22 patients without lymph node metastasis;FIGO staging:9 patients in the stage Ⅰ,11 patients in the stage Ⅱ,11 patients in the stage Ⅲ,and 4 patients in stage Ⅳ,20 patients in the stage Ⅰ or Ⅱ were included in the early EOC group,15 patients in the stage Ⅲ or Ⅳ were included in the advanced EOC group.Serum CA125 levels of the 35 EOC patients were(411.39±377.49)U/mL;Serum CA125 levels of the patients with advanced EOC were higher than those of the patients with early EOC[(698.80±416.11)and(195.84±115.26)U/mL;U=30.0000,Z=4.0003,P=0.0001]。2.Evaluation results of gastrointestinal function in the EOC patientsThe GSRS scores and IBS-SSS scores of the EOC group were(20.69±7.65)and(212.57±68.96)scores,respectively,which were higher than those of the NC group[(13.25±4.84)and(147.00±29.22)scores;U=149.0000,Z=3.5231,P=0.0004;U=159.5000,Z=3.3533,P=0.0008].The incidence of constipation in the EOC group was 54.29%,which was higher than 25.00%in the NC group(χ2=4.4381,P=0.0351).The GSRS scores and IBS-SSS scores of the patients with advanced EOC were(24.47±8.58)and(252.00±64.50)scores,respectively,which were higher than those of the patients with early EOC[(17.85±5.55)and(183.00±57.41)scores;U=79.0000,Z=2.3713,P=0.0177;U=65.0000,Z=2.8463,P=0.0044].The GSRS scores and IBS-SSS scores of the EOC patients were positively correlated with FIGO staging(r=0.4436,P=0.0076;r=0.5816,P=0.0002).The GSRS and IBS-SSS scores of the EOC patients had the positive correlation with their serum CA125 levels(r=0.4346,P=0.0091;r=0.4976,P=0.0024).The area under the ROC curve of GSRS score for EOC diagnosis was 0.79.When the cut-off value was 15.50,the sensitivity was 70.00%and the specificity was 71.43%.3.Test results of intestinal inflammation related indicators in the EOC patientsHE staining results of intestinal mucosal biopsy:In the NC group,colon tissue samples showed no obvious pathological abnormalities;in the EOC group,colon tissue samples showed intestinal epithelial damage and non-specific inflammation,and there was a large number of inflammatory cell infiltration in the lamina propria of the mucosa,and was dominated by mononucleus cells.Test results of stool markers related to intestinal inflammation:The FCP and FLF levels in the stool of the EOC group were(277.84±130.05)and(195.62±83.31)ng/mL,which were significantly higher than those in the NC group[(204.84±61.20)and(140.49±66.87)ng/mL;U=238.0000,Z=1.9607,P=0.0499;U=223.0000,Z=2.2226,P=0.0262];the FCP and FLF levels in the patients with advanced EOC were(348.45±143.27)and(227.30±75.04)ng/mL,which were higher than those the patients with early EOC[(224.88±90.84)and(171.86±82.96)ng/mL;U=73.5000,Z=2.5520,P=0.0107;U=87.5000,Z=2.0844,P=0.0371].The FCP and FLF levels of the EOC patients had the positive correlation with their FIGO staging(r=0.3792,P=0.0246;r=0.3642,P=0.0416).The FCP and FLF levels of the EOC patients had the positive correlation with their serum CA125 levels(r=0.3856,P=0.0222;r=0.4605,P=0.0054).The FCP and FLF levels of the EOC patients had the positive correlation with their GSRS scores(r=0.4471,P=0.0071;r=0.5096,P=0.0018).The area under the ROC curve of FCP for EOC diagnosis was 0.66.When the cut-off value was 267.30 ng/mL,the sensitivity was 42.86%and the specificity was 90.00%.The area under the ROC curve of FLF for EOC diagnosis was 0.68.When the cut-off value was 98.00 ng/mL,the sensitivity was 91.43%and the specificity was 45.00%.4.Test results of intestinal permeability related indexes in the EOC patientsAccording to the results of immunohistochemical staining,the relative expressions of OCLN and ZO-1 in the colonic mucosal epithelial tissue of the EOC group were 18.06±2.34 and 25.70±1.35,.respectively,which were significantly lower than those of the NC group(24.35±2.54 and 27.76±1.71;U=1.0000,Z=3.2557,P=0.0011;U=10.0000,Z=2.3105,P=0.0209).According to immunofluorescence staining results,the tight junction proteins OCLN and ZO-1 in the colon mucosal tissue samples of the NC group had no obvious abnormal distribution;in the intestinal mucosal samples of the EOC group,OCLN and ZO-1 were abnormally distributed,lost their characteristic network structure,and became irregular connections.According to ELISA results,the fecal levels of FAAT and FZ in the EOC group were(711.11±323.78)and(2.02±0.61)ng/mL,respectively,which were significantly higher than those in the control group[(503.02±317.00)and(1.60±0.58)ng/mL,U=227.5000,Z=2.1438,P=0.0321;U=237.0000,Z=1.9777,P=0.0480];the fecal levels of FAAT and FZ of the patients with advanced EOC were(828.53±220.46)and(2.27±0.54)ng/mL,which were higher than those of the patients with early EOC[(630.54±368.57)and(1.83±0.61)ng/mL;U=80.0000,Z=2.3348,P=0.0196;U=84.5000,Z=2.1841,P=0.0290].The fecal levels of FAAT and FZ in the EOC patients were positively correlated with their FIGO staging(r=0.4460,P=0.0073;r=0.3982,P=0.0178).The FAAT and FZ levels of the EOC patients had the positive correlation with their serum CA125 levels(r=0.3385,P=0.0467;r=0.4077,P=0.0150).The FZ levels of the EOC patients had the positive correlation with their GSRS scores(r=0.3696,P=0.0289);the FAAT levels of the EOC patients had the positive correlation with their IBS-SSS scores(r=0.6206,P=0.0001).The area under the ROC curve of FAAT for EOC diagnosis was 0.68.When the cut-off value was 714.00 ng/mL,the sensitivity was 51.43%and the specificity was 80.00%.The area under the ROC curve of FZ for EOC diagnosis was 0.6614.When the cut-off value was 1.78 ng/mL,the sensitivity was 68.57%and the specificity was 65.00%.Conclusions1.Gastrointestinal symptoms may be one of the early manifestations of EOC patients,and the gastrointestinal symptoms aggravate gradually with the progression of EOC.2.EOC patients have intestinal inflammation,the intestinal permeability of EOC patients is increased,and the inflammation aggravates gradually and the permeability increases gradually with the progression of EOC.3.Fecal markers such as FCP,FLF,FAAT,FZ have potential diagnostic value for the screening,diagnosis and prognostic evaluation of ovarian cancer. |
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