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; 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）。当前对黑色素瘤所有阶段的治疗方法包括通过视觉检查和术后组织病理学评估的主要病变的手术。然而，争议仍然存在于消除局部重新发生和/或跨传输转移所需的手术边缘的宽度上（3，12，13），这些疾病对患者产生了严重后果。此外，通过组织病理学实现的无肿瘤边缘的术后评估具有重大局限性，包括1。 主观，2。边缘的监视仅在切除的一小部分和3中进行。光学高分辨率3D，分子成像提供了一种可以在定量，非侵入性和实时评估边缘的手段。为此，该提案的重点是基于定量分子和结构替代生物标志物评估黑色素瘤肿瘤边缘的多模式光学方法。将使用两种分子成像方法。首先是泵探针显微镜，这是一种非线性光学方法，可实现色素的定量分子对比，包括依美酸酯和苯丙酰胺（12）。这种方法非常适合诊断黑色素瘤，因为EU-黑兰娜蛋白在该疾病的恶性发展中起着重要作用（12）。第二种方法，即泵探针非线性相位分散光谱（PP-NLDS），通过探测跨相调制引起的相变量，一种无处不在的效应（35、36）和分子重新定位效应（即，光学的KERR效应）（即提供了差异性的特性），从而产生了互补信息。其他结构信息将从多光子自动荧光，第二个谐波生成和光学相干显微镜（OCM）获得。该提案的第一个目的是开发一个组合的多模式系统。该策略是修改现有的定制显微镜，以合并PP-NLD和OCM，均通过相同的仪器检测到。 AIM 2将专注于使用人移植的皮肤小鼠模型制定适当的标准来评估边缘评估。我们预计，阳性缘的病变将包含标记的组合，包括向Eumlanic色素，真皮微卫星，杂乱无章的组织结构，细胞内环境的差异和扩大细胞核的差异。 AIM 3将使用尸体和接受手术的患者的人类标本来验证该方法。所有成像结果都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评估黑色素瘤肿瘤边缘的仪器铺平道路，从而提高第一次切除和及时的手术成功的机会，而无需改善所接受的临床范式。