Real time fine needle assessment of architectural heterogeneity in prostate cancer

摘要 在过去的二十年中，前列腺癌（PCa）已成为最常见的诊断癌症， 是美国男性癌症死亡的第二大原因。前列腺活检是标准的 用于评估PCa的存在和侵袭性的程序。经直肠超声（TRUS）引导 和术前磁共振成像（MRI），从前列腺中取出小块组织。 建筑异质性被分配一个格里森分数作为定量描述的 侵略性然而，TRUS对PCa的敏感性较低。MRI的可用性有限，并且空间 当将术前MRI与实时TRUS共配准时，可能会发生不匹配。因此，标准 TRUS引导活检，无论是否有额外的MRI，在临床上都存在缺失或采样不足的问题 显著的肿瘤，导致PCa分级过低。血液生物标志物升高的高危患者 进行重复和饱和的活检，导致额外的诊断成本和时间以及焦虑和疼痛。 我们建议通过引入针光声技术来解决PCa诊断中的这一长期存在的技术差距。 (PA)探头用于TRUS活检的在线引导。正如我们对两种动物模型的初步研究所证实的那样 和人体组织，定量多光谱PA信号分析具有客观的独特能力， 表征前列腺组织中的结构异质性并在体内对PCa进行分级。我们的针PA 探头具有全光学设计，允许较小的探头尺寸，以避免造成额外的侵入， 目前的活检程序。利用光学穿透，针PA探头可以评估 组织体积中的组织病理学信息比没有组织的标准活检芯的组织体积大得多 的拔除.因此，与TRUS穿刺活检一起进行的PA活检前测量可以提供 非常有价值的诊断信息覆盖整个前列腺。核心提取可以集中在 可疑的癌性区域。这项研究的中心假设是， PA前列腺预活检可指导前列腺穿刺活检，提高穿刺率，降低假阴性率。 本研究的目的是验证PA测量和PCa分级之间的相关性 通过一项观察性的人类研究。具体目标包括调查 使用1）活检组织芯; 2）获得的离体人前列腺样本， 通过直肠切除术，以及3）人类受试者。我们将利用研究团队在以下方面的广泛专业知识： PCa诊断、病理及PA技术的临床应用。拟议的活检前程序 是在当前临床实践的框架内设计的，因此是高度转化的。的 本研究中获得的知识将为我们将来进行拟议诊断的临床试验做好准备。 检测PCa的程序。一旦成功测试，PA活检前将通过以下方式使PCa患者受益： 有助于准确靶向的针活检，以早期检测临床上显著的PCa。

ABSTRACT During the past two decades, prostate cancer (PCa) has become the most commonly diagnosed cancer and ranks as the second leading cause of cancer deaths for American men. Prostate biopsy is the standard procedure for evaluating the presence and aggressiveness of PCa. Guided by transrectal ultrasound (TRUS) and preprocedure magnetic resonance imaging (MRI), small pieces of tissues are removed from the prostate. The architectural heterogeneities are assigned a Gleason score as a quantitative description of the aggressiveness. However, TRUS has low sensitivity to PCa. MRI has limited availability, and a spatial mismatch can occur when co-registering the preprocedure MRI with the real-time TRUS. Therefore, standard TRUS-guided biopsy, either with or without additional MRI, suffers from missing or under-sampling clinically significant tumors, leading to under-grading of PCa. At-risk patients with rising blood-based biomarkers undergo repeated and saturated biopsies, causing extra diagnostic costs and time as well as anxiety and pain. We propose to solve this long-standing technical gap in PCa diagnosis by introducing a needle photoacoustic (PA) probe for online guidance of TRUS biopsy. As validated in our preliminary studies on both animal models and human tissues, quantitative multispectral PA signal analysis possesses the unique capability of objectively characterizing the architectural heterogeneities in prostate tissues and grading PCa in vivo. Our needle PA probe has an all-optical design that allows a small probe dimension to avoid causing additional invasiveness to the current biopsy procedure. Taking advantage of the optical penetration, the needle PA probe can assess the histopathological information in a tissue volume much larger than that of a standard biopsy core without tissue removal. Hence, PA pre-biopsy measurements, performed together with the TRUS needle biopsy, can provide highly valuable diagnostic information covering the whole prostate. Core extractions can then be focused within the suspicious cancerous region(s). The central hypothesis of this research is that a fine needle probe-based PA prostate pre-biopsy can guide prostate biopsy, improve the core yield, and decrease false negative rates. The objective of this study is to validate the correlation between the PA measurements and the PCa grading through an observational human subjects study. The specific aims include investigating the performance of the needle PA probe in accessing PCa using 1) biopsy tissue cores; 2) ex vivo human prostate samples procured through prostatectomy, and 3) human subjects. We will leverage the research team's extensive expertise in the clinical practice of PCa diagnosis and pathology as well as PA technology. The proposed pre-biopsy procedure is designed within the framework of current clinical practice and is, therefore, highly translational. The knowledge gained in this study will prepare us to conduct a future clinical trial of the proposed diagnostic procedure in detecting PCa. Once successfully tested, the PA pre-biopsy will benefit PCa patients by facilitating accurately targeted needle biopsies for the early detection of clinically significant PCa.