- 作者列表："van Kessel KEM","de Jong JJ","Ziel-van der Made ACJ","Roshani H","Haensel SM","Wolterbeek JH","Boevé ER","Oomens EHGM","van Casteren NJ","Krispin M","Boormans JL","Steyerberg EW","van Criekinge W","Zwarthoff EC
PURPOSE:Current clinical guidelines recommend cystoscopy in patients who present with hematuria to rule out a bladder tumor. We evaluated whether our previously developed urine assay was able to triage patients with hematuria for cystoscopy in a large prospective cohort. MATERIALS AND METHODS:A urine sample was collected before cystoscopy and mutation/methylation status of 6 genes was determined on cellular DNA. The existing diagnostic model was validated on this cohort. Logistic regression was applied to investigate other potential variables. The primary end point was the model performance as indicated by the AUC. Secondary end points were sensitivity, specificity and negative predictive value. Clinical usefulness was determined by the net benefit approach. RESULTS:In 838 patients biomarker status could be determined for all genes. Urothelial cancer was observed in 112 patients (98 of 457 in the gross and 14 of 381 in the microscopic hematuria group). Validation of the existing model resulted in an AUC of 0.93. Logistic regression analysis identified type of hematuria as a significant additional variable. Adding type of hematuria resulted in an AUC of 0.95 (96% sensitivity, 73% specificity, 99% negative predictive value). The assay identified all upper tract tumors not visible by cystoscopy (in 6). Net benefit analysis showed that the urine assay should be preferred over current clinical practice. Implementing the urine assay as a triage tool could lead to a 53% reduction in cystoscopies. CONCLUSIONS:The urine assay detected urothelial cancer with a very high accuracy and can be used to triage patients presenting with hematuria for cystoscopy.
目的: 目前的临床指南建议对血尿患者进行膀胱镜检查以排除膀胱肿瘤。我们评估了我们以前开发的尿液测定是否能够在大型前瞻性队列中对血尿患者进行膀胱镜检查。 材料和方法: 在膀胱镜检查之前收集尿样，并在细胞DNA上确定6个基因的突变/甲基化状态。现有的诊断模型在该队列中得到验证。应用Logistic回归研究其他潜在变量。主要终点是由AUC指示的模型性能。次要终点为敏感性、特异性和阴性预测值。通过净获益方法确定临床有用性。 结果: 在838例患者中，可以确定所有基因的生物标志物状态。在112例患者中观察到尿路上皮癌 (肉眼血尿组457例中的98例和镜下血尿组381例中的14例)。现有模型的验证导致0.93的AUC。Logistic回归分析确定血尿类型是一个显著的附加变量。加入血尿类型导致0.95的AUC (96% 灵敏度，73% 特异性，99% 阴性预测值)。该测定鉴定了通过膀胱镜检查不可见的所有上尿路肿瘤 (在6中)。净效益分析表明，尿液测定应优先于目前的临床实践。将尿液测定作为分诊工具实施可导致膀胱镜检查减少53%。 结论: 尿液检测尿路上皮癌具有很高的准确性，可用于对血尿患者进行膀胱镜检查。
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.