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Perspective on cytoreduction and metastasis-directed therapy in node positive and metastatic urothelial carcinoma of the bladder.

ABSTRACT: The outcome of node positive or metastatic urothelial carcinoma of the bladder (mUCB) is poor and palliative chemotherapy has long been considered the only treatment option for this patient group. Cytoreduction and metastasis-directed therapy, either by surgery or radiotherapy, has been successfully applied in other metastatic solid tumors in order to increase survival. In this article, we explore the literature supporting cytoreduction and metastasis-directed therapy in node positive and mUCB and try to define a patient cohort that could benefit from these treatments. From these data, it is clear that a selected group of patients survive a long time or could even be cured, however the data are scarce and the level of evidence is low. The criteria of a randomized clinical trial, to deliver the necessary evidence, are proposed.

SUBMITTER: Decaestecker K

PROVIDER: S-EPMC5760372 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Perspective on cytoreduction and metastasis-directed therapy in node positive and metastatic urothelial carcinoma of the bladder.

Decaestecker Karel K Fonteyne Valérie V Oosterlinck Willem W

Translational andrology and urology 20171201 6

The outcome of node positive or metastatic urothelial carcinoma of the bladder (mUCB) is poor and palliative chemotherapy has long been considered the only treatment option for this patient group. Cytoreduction and metastasis-directed therapy, either by surgery or radiotherapy, has been successfully applied in other metastatic solid tumors in order to increase survival. In this article, we explore the literature supporting cytoreduction and metastasis-directed therapy in node positive and mUCB a ...[more]

PMID: 29354498

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Project description:The status of lymph node (LN) metastases plays a decisive role in the selection of surgical procedures and post-operative treatment. Several histopathologic features, known as predictors of LN metastasis, are commonly available post-operatively. Medical imaging improved pre-operative diagnosis, but the results are not fully satisfactory due to substantial false positives. Thus, a reliable and robust method for pre-operative assessment of LN status is urgently required. We developed a prediction model in a training set from the TCGA-BLCA cohort including 196 bladder urothelial carcinoma samples with confirmed LN metastasis status. Least absolute shrinkage and selection operator (LASSO) regression was harnessed for dimension reduction, feature selection, and LNM signature building. Multivariable logistic regression was used to develop the prognostic model, incorporating the LNM signature, and a genomic mutation of MLL2, and was presented with a LNM nomogram. The performance of the nomogram was assessed with respect to its calibration, discrimination, and clinical usefulness. Internal validation was evaluated by the testing set from the TCGA cohort and independent validation was assessed by two independent cohorts. The LNM signature, which consisted of 48 selected features, was significantly associated with LN status (p < 0.005 for both the training and testing sets of the TCGA cohort). Predictors contained in the individualized prediction nomogram included the LNM signature and MLL2 mutation status. The model demonstrated good discrimination, with an area under the curve (AUC) of 98.7% (85.3% for testing set) and good calibration with p = 0.973 (0.485 for testing set) in the Hosmer-Lemeshow goodness of fit test. Decision curve analysis demonstrated that the LNM nomogram was clinically useful. This study presents a pre-operative nomogram incorporating a LNM signature and a genomic mutation, which can be conveniently utilized to facilitate pre-operative individualized prediction of LN metastasis in patients with bladder urothelial carcinoma.

Project description:BackgroundBladder urothelial carcinoma (BLCA) is a malignant tumor of the urinary system. This study aimed to explore the potential role of lymph node metastasis-associated aberrant methylation differentially expressed genes (DEGs) in BLCA.MethodsCHAMP and limma packages were used to identify lymph node metastasis-associated aberrant methylation DEGs. Univariate Cox analysis and Lasso analysis were performed to identify the signature genes, and multivariate Cox analysis was used to construct the risk score. Subsequently, the molecular characteristics of the signature genes and the relationship between risk score and prognosis, clinical characteristics and immune cell infiltration were analyzed. The signature gene AKAP7 was selected for functional verification.ResultsA novel risk score model was constructed based on 12 signature genes. The risk score had a good ability to predict overall survival (OS). The nomogram constructed based on age, N stage and risk score had a higher value in predicting the prognosis of patients. It was also found that stromal activation in TIME may inhibit the antitumor effects of immune cells. Functional enrichment analysis revealed that ECM receptor interaction and focal adhesion were two important pathways involved in the regulation of BLCA. Immunohistochemistry showed that AKAP7 may be associated with the occurrence, clinical stages and grades, and lymph node metastasis of BLCA. In vitro cell experiments showed that the migration and invasion ability of EJ cells was significantly inhibited after AKAP7 overexpression, while the migration and invasion ability of T24 cells was significantly promoted after AKAP7 knockdown.ConclusionThe risk score model based on lymph node metastasis-associated aberrant methylation DEGs has a good ability to predict OS and is an independent prognostic factor for BLCA. It was also found that stromal activation in TIME may inhibit the antitumor effects of immune cells. This implicates aberrant methylation modifications as an important factor contributing to the heterogeneity and complexity of individual tumor microenvironments. Functional enrichment analysis revealed that ECM receptor interaction and focal adhesion were two important pathways involved in the regulation of BLCA, which contributed to the exploration of the pathological mechanism of BLCA. In addition, immunohistochemistry showed that AKAP7 may be associated with the occurrence, progression and lymph node metastasis of BLCA. In vitro cell experiments showed that AKAP7 could also inhibit the migration and invasion of cancer cells.

Dataset Information

Perspective on cytoreduction and metastasis-directed therapy in node positive and metastatic urothelial carcinoma of the bladder.

Publications

Perspective on cytoreduction and metastasis-directed therapy in node positive and metastatic urothelial carcinoma of the bladder.

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