Multi-modality optical molecular imaging for melanoma tumor margin assessment

用于黑色素瘤肿瘤边缘评估的多模态光学分子成像

• 批准号: 8874744
• 负责人: Francisco E Robles
• 金额: $ 5.6万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874744
• 关键词: Algorithms; Animal Model; Architecture; Automobile Driving; Back; Benign; Biological Markers; Cadaver; Caliber; Cell Line; Cell Nucleus; Clinical; Collaborations; Computing Methodologies; Custom; Cutaneous; Data; Dermal; Dermatopathology; Diagnosis; Disease; Disease Progression; Ensure; Environment; Excision; Feedback; Generations; Growth; Health; Healthcare; Histopathology; Human; Human Development; Image; Imaging Techniques; Incidence; Laboratories; Lesion; Light; Malignant - descriptor; Melanins; Methods; Microsatellite Repeats; Microscope; Microscopy; Modality; Modeling; Molecular; Mus; Neoplasm Metastasis; Nuclear; Operative Surgical Procedures; Optical Methods; Optics; Pathology; Patients; Phase; Pigments; Play; Postoperative Period; Primary Lesion; Property; Pump; Punch Biopsy; Radial; Resolution; Role; Sampling; Side; Skin graft; Source; Specimen; Spectrum Analysis; Staging; Surgical Oncology; Surgical margins; System; Testing; Thick; Time; Tissues; Tube; Viscosity; Visual; Width; Work; absorption; aqueous; base; cancer type; cost; eumelanin; imaging modality; imaging system; improved; instrument; instrumentation; light scattering; melanocyte; melanoma; molecular imaging; mortality; mouse model; multi-photon; novel; optical imaging; phase change; second harmonic; success; tool; transmission process; tumor

DESCRIPTION (provided by applicant): Melanoma has the fastest growing incidence and mortality rates compared to any other type of cancer (5, 6). Current treatment for all stages of melanoma includes surgery with margins of the primary lesions assessed via visual inspection and post-operative histopathology. However, controversy still exists on the width of the surgical margins needed to eliminate local reoccurrence and/or in-transit metastases (3, 12, 13), conditions that have severe consequences for patients. In addition, post-operative assessment of tumor-free margins, achieved via histopathology, has significant limitations, including 1. It is subjective, 2. Surveillance of the margins is performed on just a small portion of the excision, and 3. The time between surgery and feedback on its success (i.e., confirmation of negative margins) can take days. Optical high-resolution, 3D, molecular imaging provides a means by which margins can be assessed quantitatively, non-invasively, and in real time. To this end, this proposal focuses on a multi-modality optical approach to assess melanoma tumor margins based on quantitative molecular and structural surrogate biomarkers. Two molecular imaging methods will be used. The first is pump-probe microscopy, a nonlinear optical method that achieves quantitative molecular contrast of pigments, including eumelanin and phoemelanin (12). This method is uniquely suited for diagnosing melanoma since eu- and pheo-melanin play an important role in the malignant progression of this disease (12). The second method, pump-probe nonlinear phase dispersion spectroscopy (PP-NLDS), yields complementary information by probing phase changes resulting from cross phase modulation, a ubiquitous effect that provides structural information (35, 36), and molecular reorientation effects (i.e., optical Kerr effect), which provides sensitivity to the diffusive properties of aqueous environments (20, 32). Additional structural information will be obtained from multiphoton autofluorescence, second harmonic generation, and optical coherence microscopy (OCM). The first aim of the proposal is to develop a combined, multi-modality system. The strategy is to modify an existing custom-built microscope to incorporate PP-NLDS and OCM, both detected with the same instrumentation. Aim 2 will focus on developing proper criteria for margin assessment using a human grafted skin mouse model. We expect that lesions with positive margins will contain a combination of markers including a shift toward eumlanic pigment, dermal microsatellite, disorganized tissue architecture, differences in intracellular environments, and enlarged cell nuclei. Aim 3 will validate the approach using human specimens from cadavers and patients undergoing surgery. All imaging results will be correlated with histopathology to validate the approach. Successful completion of this work will pave the way for an instrument that provides quantitative biomarkers to assess melanoma tumor margins, thereby improving the chances of surgical success in the first excision and in a timely manner, without altering accepted clinical paradigms.

描述（由申请人提供）：与任何其他类型的癌症相比，黑色素瘤的发病率和死亡率增长最快 (5, 6)。目前对黑色素瘤所有阶段的治疗包括手术，通过目视检查和术后组织病理学评估原发病变的边缘。然而，对于消除局部复发和/或途中转移所需的手术切缘宽度仍然存在争议(3,12,13)​​，这些情况会对患者造成严重后果。此外，通过组织病理学实现的无肿瘤边缘的术后评估具有显着的局限性，包括 1. 它是 主观，2. 仅对切除的一小部分进行边缘监测，并且 3. 手术和成功反馈（即确认负边缘）之间的时间可能需要数天。光学高分辨率 3D 分子成像提供了一种可以定量、非侵入性、实时评估边缘的方法。为此，该提案重点关注基于定量分子和结构替代生物标志物的多模态光学方法来评估黑色素瘤肿瘤边缘。将使用两种分子成像方法。第一种是泵浦探针显微镜，这是一种非线性光学方法，可实现色素（包括真黑色素和褐黑色素）的定量分子对比度 (12)。该方法特别适合诊断黑色素瘤，因为 eu- 和 pheo-melanin 在这种疾病的恶性进展中发挥着重要作用 (12)。第二种方法是泵浦探针非线性相位色散光谱 (PP-NLDS)，通过探测交叉相位调制产生的相位变化来产生补充信息，交叉相位调制是一种普遍存在的提供结构信息的效应 (35, 36) 和分子重定向效应（即，光学克尔效应），它提供了对水环境扩散特性的敏感性 (20, 32)。额外的结构信息将从多光子自发荧光、二次谐波产生和光学相干显微镜（OCM）中获得。该提案的首要目标是开发一个组合的多模态系统。该策略是修改现有的定制显微镜，以纳入 PP-NLDS 和 OCM，两者均使用相同的仪器进行检测。目标 2 将侧重于使用人类移植皮肤小鼠模型制定适当的边缘评估标准。我们预计边缘阳性的病变将包含多种标志物的组合，包括向真色素、真皮微卫星、组织结构紊乱、细胞内环境差异和细胞核增大的转变。目标 3 将使用来自尸体和接受手术的患者的人体样本来验证该方法。所有成像结果将与组织病理学相关以验证该方法。这项工作的成功完成将为提供定量生物标志物来评估黑色素瘤肿瘤边缘的仪器铺平道路，从而在不改变公认的临床范例的情况下及时提高首次切除手术成功的机会。