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）：初次手术期间癌症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切除癌细胞的技术通常严重不足。依靠目视检查、触诊和联合配准的术前成像相结合，保乳手术期间的不完全切除已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%，这对精神和身体造成了巨大的影响。成本为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，从而显着降低这一比率，并致力于开发针对肿瘤细胞异常分子特征特征的荧光成像剂。然而，在手术期间对切除的新鲜组织进行局部应用这些试剂是一个重大的监管挑战，这排除了对人类使用诊断造影剂的可能性。参与实施该方法，特别是正常组织中非特异性摄取的普遍存在，构成了一个几乎棘手的问题。为了解决这个问题，我们开发了一种双探针差异样本成像（DDSI）策略，该策略部署非靶向对应探针来解释非特异性摄取。与使用单一靶向探针的方法相比，在乳腺肿瘤模型中应用该技术可将肿瘤与正常组织的对比度提高 5 至 340 倍，具体取决于所考虑的正常组织类型。这个项目，致力于具体来说，我们将开发和评估专用于手术室 (OR) 中生物标记物特异性 DDSI 的多通道宽视场荧光成像系统。我们还将应用小分子化学合成来开发和测试具有利于 DDSI 特性的新型荧光探针，以建立 DDSI 针对单一乳腺癌生物标志物的诊断性能。 ，并证明同时针对多个生物标志物的DDSI，即基于术前活检信息的真正个性化成像，可提供更高的诊断性能。最后，我们将完成一项临床试点研究，以评估临床转化的可行性，并确认多靶点DDSI可提供更高的肿瘤诊断效果。与肿瘤切除标本中的单靶点 DDSI 相比，这项临床试点研究将为未来的临床试验奠定基础。