Differential Effect of Sex on Outcomes after Radical Surgery for Upper Tract and Bladder Urothelial Carcinoma: A Systematic Review and Meta-Analysis.
- 作者列表："Mori K","Mostafaei H","Enikeev DV","Lysenko I","Quhal F","Kimura S","Karakiewicz PI","Egawa S","Shariat SF
PURPOSE:We assessed the prognostic value of sex differences in upper tract urothelial carcinoma and urothelial carcinoma of the bladder treated with radical surgery. MATERIALS AND METHODS:The PubMed®, Web of Science®, Cochrane Library and Scopus® databases were searched in July 2019 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Studies were deemed eligible if they compared overall, cancer specific, and recurrence-free survival in patients with upper tract urothelial carcinoma and urothelial carcinoma of the bladder. Formal meta-analyses were performed for these outcomes according to sex differences. RESULTS:Overall 66 studies with 100,389 patients with urothelial carcinoma of the bladder and 40 studies with 39,759 patients with upper tract urothelial carcinoma were eligible for review and meta-analysis. Female patients with urothelial carcinoma of the bladder were associated with worse cancer specific survival (pooled HR 1.20, 95% CI 1.10-1.31), overall survival (pooled HR 1.03, 95% CI 1.01-1.05) and recurrence-free survival (pooled HR 1.13, 95% CI 1.02-1.25). In contrast, those with upper tract urothelial carcinoma were not associated with cancer specific survival (pooled HR 0.94, 95% CI 0.89-1.00), overall survival (pooled HR 0.98, 95% CI 0.95-1.01) and recurrence-free survival (pooled HR 0.90, 95% CI 0.78-1.03). CONCLUSIONS:Sex is associated with cancer specific mortality, overall mortality and disease recurrence in urothelial carcinoma of the bladder but not in upper tract urothelial carcinoma. Given the genetic and social differences between the sexes, sex differences may represent a key factor in the clinical decision making process.
目的: 我们评估根治性手术治疗上尿路尿路上皮癌和膀胱尿路上皮癌的性别差异的预后价值。 材料和方法: PubMed®,Web of Science®、Cochrane图书馆和Scopus®根据系统评价和荟萃分析声明的首选报告项目，在2019年7月检索数据库。如果比较上尿路尿路上皮癌和膀胱尿路上皮癌患者的总体、癌症特异性和无复发生存期，则认为研究是合格的。根据性别差异对这些结果进行了正式的荟萃分析。 结果: 共有66项研究，包括100,389例膀胱尿路上皮癌患者和40项研究，包括39,759例上尿路尿路上皮癌患者，符合回顾和荟萃分析的标准。患有膀胱尿路上皮癌的女性患者与较差的癌症特异性生存期 (合并HR 1.20，95% CI 1.10-1.31)，总生存期 (合并HR 1.03，95% CI 1.01-1.05) 和无复发生存期 (合并HR 1.13，95% CI 1.02-1.25) 相关。相比之下，上尿路尿路上皮癌患者与癌症特异性生存期 (合并HR 0.94，95% CI 0.89-1.00)，总生存期 (合并HR 0.98，95% CI 0.95-1.01) 和无复发生存期 (合并HR 0.90，95% CI 0.78-1.03) 无关。 结论: 性别与膀胱尿路上皮癌的癌症特异性死亡率、总死亡率和疾病复发相关，而与上尿路尿路上皮癌无关。鉴于性别之间的遗传和社会差异，性别差异可能是临床决策过程中的一个关键因素。
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.
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.
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.