Increasing nerve-sparing radical prostatectomy rates using intraoperative nonlinear microscopy

前列腺癌是美国男性人群中最常见的癌症，估计有16万新发病例 2018年根治性前列腺切除术（RP），完全手术切除前列腺，导致 有利的肿瘤学结局和长期生存获益。如果癌症不支持神经保留RP， 涉及神经血管束，因为患者有更好的恢复性功能和勃起功能， 决定术后生活质量的因素。然而，目前的术前方法不能准确识别 可采用保留神经RP治疗的患者。NeuroSAFE研究，Schlomm等人，2012年展示 对神经血管束附近的边缘进行全面的术中冷冻切片分析（FSA）， 增加了保留神经的RP的比率。然而，全面的术中FSA需要大量时间 这对大多数医院来说是不切实际的。非线性显微镜（NLM）可以生成 新鲜切除的组织类似于H&E组织学，无需冷冻或切片，减少了时间和劳动力 病理学评价所需。我们开发了定制的NLM技术和标本处理/染色 用于快速、高通量评估子宫切除术标本的方案。我们的初步数据显示 与福尔马林固定石蜡相比，NLM检测前列腺癌的灵敏度为97%，特异性为100%， 包埋（FFPE）H&E在来自40名患者的122份RP标本的研究中进行了三次盲法阅读， 病理学家NLM承诺通过简化的工作流程实现RP标本的术中评价， 对于广泛的临床应用是实用的。我们的假设是：NLM可用于快速评估前列腺 手术标本和增加神经保留RP率，而不增加阳性边缘率。这是一 与马萨诸塞州理工学院的研究人员合作的多学科项目， 以色列女执事医疗中心（BIDMC），哈佛医学院。Aim 1将开发下一代NLM 用于RP中前列腺标本快速、全面评价的技术和临床工作流程。这些 先进的技术将使一个两人小组（组织技术/居民和病理学家）进行全面的NLM， RP切缘邻近神经血管束，比NeuroSAFE更快，人员更少。 Aim 2将对接受机器人RP的患者进行随机对照试验。主要终点将 保留神经的RP率和神经血管附近区域的手术切缘阳性率 接受术中NLM切缘评估和术后标准护理的研究组中的束 FFPE组织学与接受标准治疗FFPE术后组织学的对照组。次级 终点将是研究组术中NLM与术后组织学之间的一致性， Aim 3将开发NLM技术和工作流程， 远程NLM评估，这将增加对具有亚专业知识的病理学家的访问，简化 病理学家的工作流程，并促进采用术中边缘评估RP。

Prostate cancer is the most common cancer in the US male population, with an estimated 160,000 new cases in 2018. Treatment with radical prostatectomy (RP), complete surgical excision of the prostate, results in favorable oncologic outcomes with long-term survival benefits. Nerve-sparing RP is favored if cancer does not involve the neurovascular bundles since patients have better recovery of sexual function and continence, major factors determining postoperative quality of life. However current preoperative methods do not accurately identify patients who could be treated by nerve-sparing RP. The NeuroSAFE study, Schlomm, et al., 2012 demonstrated that comprehensive intraoperative frozen section analysis (FSA) of margins near the neurovascular bundles increased the rate of nerve-sparing RPs. However comprehensive intraoperative FSA required extensive time and personnel, which is impractical for most hospitals. Nonlinear microscopy (NLM) can generate images of freshly excised tissue resembling H&E histology, without freezing or microtoming, reducing the time and labor required for pathology evaluation. We developed custom NLM technology and specimen handing/staining protocols for rapid, high-throughput evaluation of prostatectomy specimens. Our preliminary data demonstrates that NLM detects prostate cancer with 97% sensitivity and 100% specificity compared to formalin fixed paraffin embedded (FFPE) H&E in a study of 122 RP specimens from 40 patients with blinded reading by three pathologists. NLM promises to enable intraoperative evaluation of RP specimens with a simplified workflow that is practical for widespread clinical adoption. Our hypothesis is: NLM can be used to rapidly assess prostate surgical specimens and increase nerve-sparing RP rates without increasing positive margin rates. This is a collaborative, multidisciplinary program with investigators at the Massachusetts Institute of Technology and Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School. Aim 1 will develop next generation NLM technology and clinical workflow for rapid, comprehensive evaluation of prostate specimens in RP. These advances will enable a two person team (histotech/resident and pathologist) to perform comprehensive NLM of RP margins adjacent to the neurovascular bundles, faster and with much fewer personnel than NeuroSAFE. Aim 2 will perform a randomized controlled trial with patients undergoing robotic RP. The primary endpoints will be the rate of nerve-sparing RPs and rate of positive surgical margins in areas adjacent to the neurovascular bundles in a study group receiving intraoperative NLM margin assessment and standard-of-care postoperative FFPE histology versus a control group receiving standard-of-care FFPE postoperative histology. The secondary endpoints will be agreement between intraoperative NLM versus postoperative histology in the study arm and surgical times in the study arm versus control arm. Aim 3 will develop NLM technology and workflows that enable remote NLM evaluation which would increase access to pathologists with subspecialty expertise, streamline pathologist workflow, and facilitate adoption of intraoperative margin assessment in RP.