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Clinical Parameters Outperform Molecular Subtypes for Predicting Outcome in Bladder Cancer: Results from Multiple Cohorts, Including TCGA.

临床参数优于预测膀胱癌结局的分子亚型: 来自多个队列的结果,包括TCGA。

  • 影响因子:1.46
  • DOI:10.1097/JU.0000000000000351
  • 作者列表:"Morera DS","Hasanali SL","Belew D","Ghosh S","Klaassen Z","Jordan AR","Wang J","Terris MK","Bollag RJ","Merseburger AS","Stenzl A","Soloway MS","Lokeshwar VB
  • 发表时间:2020-01-01
Abstract

PURPOSE:Studies indicate that molecular subtypes in muscle invasive bladder cancer predict the clinical outcome. We evaluated whether subtyping by a simplified method and established classifications could predict the clinical outcome. MATERIALS AND METHODS:We subtyped institutional cohort 1 of 52 patients, including 39 with muscle invasive bladder cancer, an Oncomine™ data set of 151 with muscle invasive bladder cancer and TCGA (The Cancer Genome Atlas) data set of 402 with muscle invasive bladder cancer. Subtyping was done using simplified panels (MCG-1 and MCG-Ext) which included only transcripts common in published studies and were analyzed for predicting metastasis, and cancer specific, overall and recurrence-free survival. TCGA data set was further analyzed using the Lund taxonomy, the Bladder Cancer Molecular Taxonomy Group Consensus and TCGA 2017 mRNA subtype classifications. RESULTS:Muscle invasive bladder cancer specimens from cohort 1 and the Oncomine data set showed intratumor heterogeneity for transcript and protein expression. MCG-1 subtypes did not predict the outcome on univariate or Kaplan-Meier analysis. On multivariate analysis N stage (p ≤0.007), T stage (p ≤0.04), M stage (p=0.007) and/or patient age (p=0.01) predicted metastasis, cancer specific and overall survival, and/or the cisplatin based adjuvant chemotherapy response. In TCGA data set publications showed that subtypes risk stratified patients for overall survival. Consistently the MCG-1 and MCG-Ext subtypes were associated with overall but not recurrence-free survival on univariate and Kaplan-Meier analyses. TCGA data set included 21 low grade specimens of the total of 402 and subtypes associated with tumor grade (p=0.005). However, less than 1% of muscle invasive bladder cancer cases are low grade. In only high grade specimens the MCG-1 and MCG-Ext subtypes could not predict overall survival. On univariate analysis subtypes according to the Bladder Cancer Molecular Taxonomy Group Consensus, TCGA 2017 and the Lund taxonomy were associated with tumor grade (p <0.0001) and overall survival (p=0.01 to <0.0001). Regardless of classification, subtypes had about 50% to 60% sensitivity and specificity to predict overall and recurrence-free survival. On multivariate analyses N stage and lymphovascular invasion consistently predicted recurrence-free and overall survival (p=0.039 and 0.003, respectively). CONCLUSIONS:Molecular subtypes reflect bladder tumor heterogeneity and are associated with tumor grade. In multiple cohorts and subtyping classifications the clinical parameters outperformed subtypes for predicting the outcome.

摘要

目的: 研究表明肌层浸润性膀胱癌的分子亚型可预测临床结局。我们通过简化的方法和建立的分类评价了亚型是否可以预测临床结果。 材料和方法: 我们对 52 例患者的机构队列 1 进行了亚分型,包括 39 例肌层浸润性膀胱癌,一种Oncomine™151 例肌层浸润性膀胱癌数据集,402 例肌层浸润性膀胱癌TCGA (The cancer Genome Atlas) 数据集。使用简化的panel (MCG-1 和MCG-Ext) 进行亚分型,仅包括已发表研究中常见的转录本,并分析其预测转移、癌症特异性、总体和无复发生存率。使用Lund分类学、膀胱癌分子分类学组共识和TCGA 2017 mRNA亚型分类进一步分析TCGA数据集。 结果: 来自队列 1 和Oncomine数据集的肌层浸润性膀胱癌标本显示转录本和蛋白表达的瘤内异质性。单变量或Kaplan-Meier分析MCG-1 亚型不能预测预后。在多变量分析上N分期 (p ≤ 0.007) 、T分期 (p ≤ 0.04) 、M分期 (p = 0.007) 和/或患者年龄 (p = 0.01) 预测转移,癌症特异性和总生存率,和/或基于顺铂的辅助化疗反应。在TCGA数据集的出版物显示,亚型风险分层患者的总生存期。一致地,在单变量和Kaplan-Meier分析中,MCG-1 和MCG-Ext亚型与总体生存率相关,但与无复发生存率无关。TCGA数据集包括 21 个低级别标本,共 402 个与肿瘤分级相关的亚型 (p = 0.005)。然而,只有不到 1% 的肌层浸润性膀胱癌病例是低度恶性的。仅在高级别标本中,MCG-1 和MCG-Ext亚型不能预测总生存期。在单因素分析中,根据膀胱癌分子分类组共识,TCGA 2017 和Lund分类与肿瘤分级相关 (p <0.0001) 和总生存期 (p = 0.01 至 <0.0001)。无论分类如何,亚型预测总体和无复发生存期的敏感性和特异性约为 50%-60%。在多变量分析中,N分期和淋巴管浸润一致预测无复发和总生存率 (p分别为 0.039 和 0.003)。 结论: 分子亚型反映膀胱肿瘤异质性,并与肿瘤分级相关。在多个队列和分型分类中,临床参数优于预测结局的亚型。

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影响因子:1.46
发表时间:2020-01-01
来源期刊:The Journal of urology
DOI:10.1097/JU.0000000000000351
作者列表:["Morera DS","Hasanali SL","Belew D","Ghosh S","Klaassen Z","Jordan AR","Wang J","Terris MK","Bollag RJ","Merseburger AS","Stenzl A","Soloway MS","Lokeshwar VB"]

METHODS:PURPOSE:Studies indicate that molecular subtypes in muscle invasive bladder cancer predict the clinical outcome. We evaluated whether subtyping by a simplified method and established classifications could predict the clinical outcome. MATERIALS AND METHODS:We subtyped institutional cohort 1 of 52 patients, including 39 with muscle invasive bladder cancer, an Oncomine™ data set of 151 with muscle invasive bladder cancer and TCGA (The Cancer Genome Atlas) data set of 402 with muscle invasive bladder cancer. Subtyping was done using simplified panels (MCG-1 and MCG-Ext) which included only transcripts common in published studies and were analyzed for predicting metastasis, and cancer specific, overall and recurrence-free survival. TCGA data set was further analyzed using the Lund taxonomy, the Bladder Cancer Molecular Taxonomy Group Consensus and TCGA 2017 mRNA subtype classifications. RESULTS:Muscle invasive bladder cancer specimens from cohort 1 and the Oncomine data set showed intratumor heterogeneity for transcript and protein expression. MCG-1 subtypes did not predict the outcome on univariate or Kaplan-Meier analysis. On multivariate analysis N stage (p ≤0.007), T stage (p ≤0.04), M stage (p=0.007) and/or patient age (p=0.01) predicted metastasis, cancer specific and overall survival, and/or the cisplatin based adjuvant chemotherapy response. In TCGA data set publications showed that subtypes risk stratified patients for overall survival. Consistently the MCG-1 and MCG-Ext subtypes were associated with overall but not recurrence-free survival on univariate and Kaplan-Meier analyses. TCGA data set included 21 low grade specimens of the total of 402 and subtypes associated with tumor grade (p=0.005). However, less than 1% of muscle invasive bladder cancer cases are low grade. In only high grade specimens the MCG-1 and MCG-Ext subtypes could not predict overall survival. On univariate analysis subtypes according to the Bladder Cancer Molecular Taxonomy Group Consensus, TCGA 2017 and the Lund taxonomy were associated with tumor grade (p <0.0001) and overall survival (p=0.01 to <0.0001). Regardless of classification, subtypes had about 50% to 60% sensitivity and specificity to predict overall and recurrence-free survival. On multivariate analyses N stage and lymphovascular invasion consistently predicted recurrence-free and overall survival (p=0.039 and 0.003, respectively). CONCLUSIONS:Molecular subtypes reflect bladder tumor heterogeneity and are associated with tumor grade. In multiple cohorts and subtyping classifications the clinical parameters outperformed subtypes for predicting the outcome.

翻译标题与摘要 下载文献
影响因子:6.93
发表时间:2020-02-15
DOI:10.1002/ijc.32505
作者列表:["Namekawa T","Ikeda K","Horie-Inoue K","Suzuki T","Okamoto K","Ichikawa T","Yano A","Kawakami S","Inoue S"]

METHODS::Acquired chemoresistance is a critical issue for advanced bladder cancer patients during long-term treatment. Recent studies reveal that a fraction of tumor cells with enhanced tumor-initiating potential, or cancer stem-like cells (CSCs), may particularly contribute to acquired chemoresistance and recurrence. Thus, CSC characterization will be the first step towards understanding the mechanisms underlying advanced disease. Here we generated long-term patient-derived cancer cells (PDCs) from bladder cancer patient specimens in spheroid culture, which is favorable for CSC enrichment. Pathological features of bladder cancer PDCs and PDC-dependent patient-derived xenografts (PDXs) were basically similar to those of their corresponding patients' specimens. Notably, CSC marker aldehyde dehydrogenase 1A1 (ALDH1A1), a critical enzyme that synthesizes retinoic acid (RA), was abundantly expressed in PDCs. ALDH1A1 inhibitors and shRNAs repressed both PDC proliferation and spheroid formation, whereas all-trans RA could rescue ALDH1A1 shRNA-suppressed spheroid formation. ALDH inhibitor also reduced the in vivo growth of PDC-derived xenografts. ALDH1A1 knockdown study showed that tubulin beta III (TUBB3) was one of the downregulated genes in PDCs. We identified functional RA response elements in TUBB3 promoter, whose transcriptional activities were substantially activated by RA. Clinical survival database reveals that TUBB3 expression may associate with poor prognosis in bladder cancer patients. Moreover, TUBB3 knockdown was sufficient to suppress PDC proliferation and spheroid formation. Taken together, our results indicate that ALDH1A1 and its putative downstream target TUBB3 are overexpressed in bladder cancer, and those molecules could be applied to alternative diagnostic and therapeutic options for advanced disease.

翻译标题与摘要 下载文献
影响因子:3.27
发表时间:2020-02-01
来源期刊:BJU international
DOI:10.1111/bju.14850
作者列表:["Saad M","Moschini M","Stabile A","Macek P","Lanz C","Prapotnich D","Rozet F","Cathala N","Mombet A","Sanchez-Salas R","Cathelineau X"]

METHODS:OBJECTIVES:To evaluate the technical feasibility, oncological and functional outcomes of nerve sparing cystoprostatectomy (NSCP) and prostate capsule-sparing cystectomy (PCSC) for the treatment of organ-confined bladder cancer at a single referral centre. PATIENTS AND METHODS:From April 2001 to June 2012, 60 patients underwent PCSC and 47 were treated with NSCP. Inclusion criteria for PCSC were: fully informed consent for the well-motivated patient; negative transurethral resection of the bladder neck; normal prostatic specific antigen (PSA) level (defined as <4 ng/dL during the first year of the study, which was later lowered to 2.5 ng/dL); and normal transrectal ultrasonography, with biopsy for any suspicious nodule. Patients received a complete oncological and functional follow-up. The Kaplan-Meier method was used to depict survival outcomes after surgery. RESULTS:After a median follow-up of 73 and 62 months for PCSC and NSCP, respectively, the 5-year cancer-specific survival was 90% for the PCSC group and 78% for the NSCP group (P = 0.055). Considering complications within 30 days after surgery, 13% and 21% patients had Clavien ≥III complications in the PCSC and NSCP groups, respectively (P = 0.2). For functional outcomes, at 3 months after surgery, 54 (90%) and 24 (51%) patients reported full recovery of daytime urinary continence in the PCSC and NSCP groups, respectively (P < 0.001); and for erectile function recovery, 32 (53%) and four (9%) patients in the PCSC group and in the NSCP group were respectively potent without any treatment (P < 0.001). CONCLUSIONS:NSCP and PCSC are appropriate for a subset of patients with bladder cancer, with excellent oncological and functional results. These surgical procedures should be proposed to well-motivated patients.

膀胱疾病方向

包括膀胱炎、膀胱结石、膀胱瘘、膀胱肿瘤等疾病。

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