| Part I:Prediction of response to dopamine agonists in the treatment of prolactinomaObjectiveTo explore the clinical significance of bromocriptine test,and to build prediction models of prolactinomas resistant to dopamine agonists(DAs).MethodsClinical data of 21 prolactinoma patients resistant to DAs and 63 prolactinoma patients sensitive to DAs were collected from patients who underwent bromocriptine test from May,2013 to March,2021 in Peking Union Medical College Hospital.ROC analysis was used to compare the efficacy of parameters in the bromocriptine test.Prediction models were built by logistic regression based on baseline characteristics and other parameters.ResultsCompared with patients sensitive to DAs,resistant patients had higher prolactin level and larger tumor size,and the proportion of invasive tumors was higher.The area under curve(AUC)of nadir prolactin in the bromocriptine test to predict resistance was 0.850,which was significantly higher than that of nadir suppression rate.The best cutoff for nadir prolactin was 28.3ng/ml,under which the sensitivity was 0.952 and the specificity was 0.651.The prediction model based on baseline prolactin and invasiveness had an AUC of 0.878,sensitivity of 0.895,and specificity of 0.833.The prediction model based on nadir prolactin and maximum diameter of tumor had an AUC of 0.872,sensitivity of 0.737,and specificity of 0.889.The mean error of the predicted probability of resistance was 0.124 for the former model,and 0.063 for the latter model.When the nadir prolactin in the bromocriptine test and the maximum diameter of tumor were used in tandem to predict drug resistance,the sensitivity was 0.571 and the specificity was 0.905.Moreover,a higher dose of bromocriptine and longer time were needed to normalize the prolactin among the patients sensitive to DAs whose prolactin was not suppressed during the bromocriptine test compared with those with suppressed prolactin during the test.ConclusionNadir prolactin had a higher efficacy to predict drug response than nadir suppression rate in the bromocriptine test,but the clinical effectiveness was limited when used alone.The prediction model that combined the maximum diameter of tumor and the nadir prolactin in the bromocriptine test could accurately predict drug resistance,so it had a certain amount of clinical value.Part Ⅱ:Dopamine agonists resistance mechanisms of prolactinomaObjectiveTo find the proteins and pathways related to DAs resistance by studying the protein profile of prolactinomas,and to explore the mechanisms of resistance.MethodsThe proteomics of 4 prolactinomas resistant to DAs and 5 prolactinomas sensitive to DAs were measured by label-free LC-MS/MS.Bioinformatic analyses including GSEA,GO enrichment and pathway enrichment for differentially expressed proteins(DEPs),and protein-protein interaction analysis were conducted.Masson staining was used to confirm the fibrosis status,and immunohistochemical staining to confirm the expression of fibrinogen.ResultsA total of 4544 proteins were detected in the tissue of prolactinomas.GSEA showed that coagulation pathway,ribosomal proteins,and extracellular matrix were up-regulated in resistant prolactinomas.Among the DEPs,95 were up-regulated while 91 were downregulated.Prostaglandin synthesis pathway,coagulation pathway,and ribosomal proteins were enriched in up-regulated DEPs.In the interaction analysis,up-regulated DEPs formed two sub-networks,including ribosomal proteins and proteins related to blood coagulation,and down-regulated DEPs formed a network related to catabolism.Among resistant prolactinomas,proteins in the coagulation pathways and in the ribosome were generally up-regulated,and proteins of the annexin family in the prostaglandin synthesis pathway were up-regulated.Masson staining showed that some of the resistant prolactinomas had a high extent of fibrosis.Immunohistochemical staining confirmed that the expression of fibrinogen was significantly higher among resistant prolactinomas than among sensitive prolactinomas.ConclusionExtracellular matrix such as collagens and coagulation pathway were up-regulated among the tissue of DAs resistant prolactinomas,which might be related to the mechanisms of DAs resistance. |
PDF Full Text Request