Novel Biomarkers for the Clinical Management of Bladder Cancer

摘要：目前的临床实践中，侵入性诊断检查，膀胱癌后复发频繁 肿瘤切除术和肌层浸润性膀胱癌（MIBCa）转移的高倾向，有助于 与膀胱癌（BCa）相关的显著发病率和死亡率; 临床管理无痛性血尿是膀胱癌患者常见的临床表现。但只有 15-25%的可见血尿患者和约10%的镜下血尿患者实际上 有BCa。血尿患者接受泌尿系统检查，包括膀胱镜检查和CT检查。 尿路造影膀胱镜检查是侵入性的和不舒服的，这两种程序都与相当大的风险， 发病率高，成本高。频繁的BCa复发需要每3至6个月通过膀胱镜检查进行监测。 非侵入性生物标志物，包括尿细胞学检查，可以减少患者的侵入性和昂贵的检查 血尿患者或接受BCa复发监测的患者。然而，现有的生物标志物 由于其次优疗效和/或高假阳性率而未用于临床。此外，生物标志物不是 用于预测膀胱切除手术后转移或治疗反应方面的临床结果。 在试点研究中，两种新的非侵入性测试基于糖胺聚糖家族的新成员， 显示出高准确性检测BCa，用于无创评估其等级和早期检测BCa 复发BCa组织中的生物标志物水平与临床结局相关。该项目旨在评估 假设这两种尿检可以准确诊断BCa，并在 需要对血尿进行泌尿系统检查或监测BCa复发的患者。此外，基于组织的 生物标志物可准确预测临床结果。 将评价两种尿液检查的有效性，以用于BCa诊断和评价其在以下人群中的分级： 因血尿而接受泌尿科检查的患者（目的1）。这些尿液检查的有效性将与 膀胱镜检查结果在监测BCa复发的监测患者。测试结果也将 评估以预测未来复发（目标2）。将检查BCa组织中生物标志物的表达 用于预测MIBCa的发展、转移和总体临床结果（Aim 3）。 影响：该研究可能导致两种经验证的尿液检测，用于非侵入性和准确地检测BCa， 评分作为一个额外的好处。这可以大大减少患者的数量， 血尿的泌尿系统检查或膀胱镜检查以监测BCa复发。组织生物标志物， 如果发现是准确的指示剂，可以减少MIBCa不必要的侵入性膀胱再切除术， 并有助于晚期BCa患者的早期干预和个体化治疗。总的来说，如果有效， 这些生物标志物可以降低与BCa相关的发病率和成本，同时通过早期干预改善临床结果。 预测。

ABSTRACT: The current clinical practice of invasive diagnostic workup, frequent recurrence following bladder tumor resection, and high propensity of muscle invasive bladder cancer (MIBCa) for metastasis, contribute to the significant morbidity and mortality associated with bladder cancer (BCa); one of the costliest cancer to manage clinically. Painless hematuria is the common presenting symptom among BCa patients. However, only 15-25% of patients with visible hematuria and about 10% of the patients with microscopic hematuria actually have BCa. Patients presenting with hematuria undergo urological workup that involves cystoscopy and CT- urography. Cystoscopy is invasive and uncomfortable and both procedures associate with considerable risk for morbidity and are costly. Frequent BCa recurrence requires surveillance by cystoscopy every 3 to 6 months. Non-invasive biomarkers, including urine cytology, can reduce the invasive and costly workup among patients with hematuria or for those under surveillance for monitoring BCa recurrence. However, existing biomarkers are not used in clinic due to their sub-optimal efficacy and/or high false-positive rate. Further, biomarkers are not used for predicting clinical outcome in terms of metastasis or treatment response after a bladder removal surgery. In pilot studies, two new non-invasive tests based on a novel member of a glycosaminoglycan family, showed high accuracy to detect BCa, for non-invasively evaluating its grade and for early detection of BCa recurrence. Biomarker levels in BCa tissues correlated with clinical outcome. This project is designed to evaluate a hypothesis that this two urine tests can accurately diagnose BCa and non-invasively evaluate its grade among patients needing urological workup for hematuria, or to monitor BCa recurrence. Furthermore the tissue-based biomarkers accurately predict clinical outcome. The efficacy of both urine tests will be evaluated for BCa diagnosis and for evaluation of its grade among patients undergoing urological workup for hematuria (Aim 1). Efficacy of these urine tests will be compared to cystoscopy findings in patients under surveillance for monitoring BCa recurrence. The tests’ findings will also be evaluated for predicting future recurrence (Aim 2). The biomarkers’ expression in BCa tissues will be examined for predicting the development of MIBCa, metastasis and overall clinical outcome (Aim3). Impact: The study may result in two validated urine tests for non-invasively and accurately detecting BCa with grade evaluation as an added benefit. This could substantially reduce the number of patients undergoing urological workup for hematuria or surveillance cystoscopies for monitoring BCa recurrence. Tissue biomarkers, if found to be accurate prognosticators, could reduce unnecessary invasive bladder re-resections for MIBCa, and aid in early intervention and individualized treatment for patients with advanced BCa. Overall, if efficacious, these biomarkers could reduce BCa-related morbidity, and costs, while improving clinical outcome by early predictions.