Multi-modality optical molecular imaging for melanoma tumor margin assessment

描述（由申请人提供）：与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）。目前对所有阶段黑色素瘤的治疗包括手术，通过目视检查和术后组织病理学评估原发病灶的边缘。然而，对于消除局部复发和/或转移转移所需的手术切界宽度仍然存在争议（3,12,13），这些情况对患者造成严重后果。此外，通过组织病理学获得的术后无肿瘤边缘评估有明显的局限性，包括1。它是

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.