Multi-probe fluorescence imaging for rapid intra-operative tumor margin assessment

多探针荧光成像用于快速术中肿瘤边缘评估

• 批准号: 9105786
• 负责人: Scott C Davis
• 金额: $ 60.5万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9105786
• 关键词: Accounting; Address; Adipose tissue; Affinity; Area; Biological Markers; Biopsy; Breast; Breast Cancer Model; Breast biopsy; Breast-Conserving Surgery; Cell Line; Characteristics; Clinic; Clinical; Clinical Trials; Communities; Contrast Media; Diagnosis; Diagnostic; Diagnostic Imaging; Diffusion; Ensure; Epidermal Growth Factor Receptor; Excision; Feasibility Studies; Fluorescent Probes; Fresh Tissue; Future; Goals; Healthcare Systems; Histocompatibility Testing; Human; Image; Imagery; Imaging Techniques; Light; Lighting; Malignant Neoplasms; Molecular; Molecular Diagnosis; Morbidity - disease rate; Normal tissue morphology; Operating Rooms; Operative Surgical Procedures; Outcome; Palpation; Patients; Performance; Physiologic pulse; Pilot Projects; Postoperative Period; Prevalence; Procedures; Prognostic Marker; Property; Protocols documentation; Psyche structure; Recurrence; Repeat Surgery; Reporting; Research; Risk; S Phase; Safety; Solid; Specimen; Staining method; Stains; Stress; Structure; Surface; Surgeon; System; Techniques; Technology; Testing; Tissues; Topical application; Tracer; Translations; Tumor Markers; Visual; Work; base; breast lumpectomy; cancer biomarkers; cancer cell; cancer surgery; chemical synthesis; combinatorial; cost; design; diagnostic accuracy; falls; fluorescence imaging; fluorophore; follow-up; human tissue; image guided; imaging agent; imaging system; improved; in vivo; malignant breast neoplasm; molecular imaging; neoplastic cell; novel; novel diagnostics; novel therapeutics; optical imaging; patient safety; public health relevance; receptor; receptor density; receptor expression; small molecule; specific biomarkers; tissue processing; triple-negative invasive breast carcinoma; tumor; tumor xenograft; uptake

 DESCRIPTION (provided by applicant): The extent to which cancer tissue is completely removed during primary surgery is a critical prognostic indicator of local recurrence and overall patient survival. However, current techniques deployed to identify and remove cancer cells during surgery are terribly inadequate, often relying on a combination of visual inspection, palpation, and co-registered pre-operative imaging. Incomplete resection during breast conserving surgery has emerged as a particularly prevalent problem, with some studies reporting repeat surgery rates over 50%, representing an enormous mental and physical cost for patients and the health care system. This project aims to dramatically reduce this rate by advancing a novel optical imaging strategy to rapidly identify incomplete tumor resection during surgery. Significant effort has been directed towards developing fluorescent imaging agents targeted to abnormal molecular features characteristic of tumor cells, such as receptor expression. However, administering these agents in humans is a significant regulatory challenge. Topical application of targeted probes to excised fresh tissue during surgery is an attractive alternative which precludes administering diagnostic contrast agents to humans. While conceptually simple, the practical challenges involved in implementing this approach, especially the prevalence of non-specific uptake in normal tissues, constitute a nearly intractable problem. To address this problem, we have developed a dual-probe difference specimen imaging (DDSI) strategy which deploys a non-targeted counterpart probe to account for non-specific uptake in normal tissue. Applying this technique in breast tumor models increased tumor-to-normal contrast by between 5 and 340-fold, depending on the normal tissue type considered, over approaches which use a single targeted probe. These extremely promising results motivate this project, dedicated to advancing and validating DDSI on multiple fronts. Specifically, we will develop and evaluate a multi-channel wide-field fluorescence imaging system dedicated to biomarker-specific DDSI in the operating room (OR). This system will incorporate depth-sensitive capabilities and a novel diagnostic projection technology for intuitive integration in th OR. We will also apply small-molecule chemical synthesis to develop and test novel fluorescent probes with properties favorable to DDSI. We will deploy these technologies to establish the diagnostic performance of DDSI against a single breast cancer biomarker, and show that DDSI against multiple biomarkers simultaneously, i.e. truly personalized imaging based on pre-surgical biopsy information, provides even higher diagnostic performance. Finally, we will complete a clinical pilot study to evaluate the feasibility of clinical translation and confirm tha multi-target DDSI provides higher tumor contrast than single-target DDSI in lumpectomy specimens. This clinical pilot study will establish the groundwork for a future clinical trial.

 描述（由申请人提供）：初次手术期间癌组织被完全切除的程度是局部复发和患者总体生存的关键预后指标。然而，目前用于在手术期间识别和去除癌细胞的技术非常不足，通常依赖于视觉检查，触诊和共同配准的术前成像的组合。保乳手术中的不完全切除已经成为一个特别普遍的问题，一些研究报告重复手术率超过50%，这对患者和医疗保健系统来说是巨大的精神和身体成本。该项目旨在通过推进一种新型光学成像策略来快速识别手术期间不完整的肿瘤切除，从而大幅降低这一比例。已经针对开发靶向肿瘤细胞的异常分子特征（例如受体表达）的荧光成像剂进行了大量努力。然而，在人类中施用这些药剂是一个重大的监管挑战。在手术期间将靶向探针局部应用于切除的新鲜组织是一种有吸引力的替代方案，其排除了对人类施用诊断造影剂。虽然概念上很简单，但实施这种方法所涉及的实际挑战，特别是正常组织中非特异性摄取的普遍性，构成了一个几乎难以解决的问题。为了解决这个问题，我们已经开发了一种双探头差异样本成像（DDSI）的战略，部署了非靶向对应的探针，以说明在正常组织中的非特异性吸收。在乳腺肿瘤模型中应用这种技术，与使用单一靶向探针的方法相比，肿瘤与正常组织的对比度增加了5至340倍，这取决于所考虑的正常组织类型。这些非常有前途的结果激励了这个项目，致力于在多个方面推进和验证DDSI。具体来说，我们将开发和评估一种多通道宽视场荧光成像系统，专用于手术室（OR）中的生物标志物特异性DDSI。该系统将结合深度敏感功能和一种新的诊断投影技术，用于直观地集成在手术室中。我们还将应用小分子化学合成来开发和测试具有有利于DDSI特性的新型荧光探针。我们将部署这些技术来建立DDSI对单一乳腺癌生物标志物的诊断性能，并证明DDSI同时对多种生物标志物的诊断性能，即基于术前活检信息的真正个性化成像，提供更高的诊断性能。最后，我们将完成一项临床初步研究，以评估临床转化的可行性，并证实多靶点DDSI在肿块切除术标本中提供比单靶点DDSI更高的肿瘤对比度。这项临床初步研究将为未来的临床试验奠定基础。