Virtual Histology of the Bladder Wall for Bladder Cancer Staging

膀胱癌（BCa）是世界范围内五种最常见的恶性肿瘤之一，其由膀胱癌分期系统（BCA）分期。 膀胱肿瘤穿透膀胱壁的不同层，以获得最佳治疗。目前，一个昂贵的方案 常规膀胱镜检查，经尿道肿瘤切除术（TURBT）和影像学监测的建议 以对抗高达80%的乳腺癌复发率。虽然根治性膀胱癌是分期的金标准 准确性，这是不实际的指导治疗。由于TURBT和可用的成像方式受到 检测肌肉浸润的失败率约为50%，但对安全的放射学措施的需求尚未得到满足， 区分惰性和侵袭性BCa进行监测，以选择适当的膀胱治疗方案的患者 节省新辅助治疗，并最大限度地减少侵袭性BCa的治愈周期延迟。虽然 静脉注射钆后动态增强磁共振成像（DCE-MRI）， 基于造影剂（GBCA）的BCa肿瘤分期明显优于计算机断层扫描， MRI发展相对落后，在MRI用于BCa诊断方面仍存在主要障碍， 预后此外，注射GBCA具有过敏反应，健康风险和增加医疗保健的风险 成本这项探索性研究的科学前提是基于我们最近的高分辨率MRI报告， 直接膀胱滴注（通过尿道导管）新型造影剂后的啮齿动物和人膀胱壁 由钆布醇（GBCA）和Ferumoxytol在无菌水中组成的混合物（NCM），用于 膀胱壁通过扩散GBCA，同时膀胱腔内通过保留 Ferumoxytol（分子大小为GBCA的10倍）。因此，NCM增强的T1加权MRI可以利用 膀胱壁中癌细胞和正常细胞的不同GBCA渗透性， (3D)膀胱壁成像用于改进肿瘤检测和非手术BCa分期。根据具体目标 旨在确定NCM-MRI用于BCa分期的技术和科学价值，然后再进行 未来的随机临床试验，目标是制作高分辨率3D MRI，作为BCa的临床标准 诊断和治疗。目的1将评价间的一致性组织病理学分期的 21例前列腺增生症患者TURBT标本及简化NCM-MRI对BCa术前临床分期的研究 至少有一个膀胱镜检查证实的乳头状膀胱肿瘤。目标2将评估多式联运协议 术前NCM-MRI BCa分期与整体病理检查的金标准之间 21例经组织学证实的肌肉浸润性BCa患者的细胞标本。多式联运的优势 NCM-MRI和组织病理学之间的一致性将通过Kappa（κ）统计和相对 配对t检验两种技术的差异。基于MRI的主动监测已经改变了 前列腺癌，这项探索性研究旨在通过像素方式实现虚拟组织学的目标。 T1标测以证明NCM增强MRI作为BCa分期微创工具的潜力。

Bladder cancer (BCa) is one the five most common malignancies worldwide, which is staged by the penetration of bladder tumor in different layers of bladder wall for optimal treatment. Currently, a costly regimen of routine cystoscopy, transurethral resection of the tumor (TURBT) and imaging surveillance is recommended to counter the high BCa recurrence rate of 80%. Although radical cystectomy is the gold standard for staging accuracy, it is not practical for directing treatment. Since TURBT and available imaging modalities suffer from a ~50% failure rate in detecting muscle invasion, there is an unmet need for safe, radiologic measures to distinguish indolent from aggressive BCa for surveillance, to select patients for appropriate regimens of bladder sparing neoadjuvant therapy and to minimize the delay in curative cystectomy of aggressive BCa. Although dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) after intravenous injection of gadolinium- based contrast agent (GBCA) was dramatically superior to computed tomography for tumor staging of BCa, MRI is relatively poorly developed and major barriers still exist in the adaption of MRI for BCa diagnosis and prognosis. Besides, injected GBCA carries the risk of allergic reaction, health risk and increased healthcare cost. The scientific premise of this exploratory study is based on our recent report of high-resolution MRI of rodent and human bladder wall following direct bladder instillation (via urethral catheter) of a novel contrast mixture (NCM) composed of Gadobutrol (GBCA) and Ferumoxytol in sterile water for positive contrast in bladder wall via diffusion of GBCA and simultaneous negative contrast in bladder lumen via retention of Ferumoxytol (molecular size 10 fold of GBCA). Thus, NCM enhanced T1 weighted MRI can leverage the differential GBCA permeability of cancerous and normal cells in bladder wall to accomplish three-dimensional (3D) bladder wall imaging for improved tumor detection and non-surgical BCa staging. Following specific aims are designed to establish the technical and scientific merit of NCM-MRI for BCa staging, before pursuing a future randomized clinical trial towards the goal of making high resolution 3D MRI, a clinical standard in BCa diagnosis and treatment. Aim 1 will evaluate the intermodality agreement between histopathologic staging of TURBT specimens and the pre-operative clinical staging of BCa by abbreviated NCM-MRI in 21 patients with at least one cystoscopically confirmed papillary bladder tumor. Aim 2 will evaluate the intermodality agreement between preoperative NCM-MRI for BCa staging with the gold standard of whole-mount pathologic review of cystectomy specimen in 21 histologically proven muscle invasive BCa patients. The strength of intermodality agreement between NCM-MRI and the histopathology will be assessed by Kappa (κ) statistics and the relative differences of two techniques by paired t test. MRI based active surveillance has transformed the care of prostate cancer and this exploratory study seeks to accomplish the goal of virtual histology through pixel-wise T1 mapping to demonstrate the potential of NCM enhanced MRI as minimally invasive tool for BCa staging.