Fast, large area, multiphoton exoscope (FLAME) for improving early detection of melanoma

项目摘要 早期发现黑色素瘤是提高患者生存率和减少治疗的关键因素 成本皮肤镜检查是诊断黑色素细胞病变的标准治疗方法， 据报道，这是高度可变的，范围在68- 96%之间，这取决于医生和医生的熟练程度。 病变的阶段。低敏感性反映了高假阴性率，这会延误诊断， 治疗因此，医生必须谨慎行事，这会导致过多的不必要的活检， 增加了医疗费用。皮肤黑色素瘤与良性黑色素细胞痣的高准确性鉴别 即使在专家临床医生手中， 只能提供病变表面结构的二维图像。最终，活检是必要的， 皮肤病理学家的明确诊断，但这也可能受到观察者间差异的影响， 导致不一致的结论。加州大学旧金山分校的黑色素瘤中心进行的一项研究估计， 在美国，214，500至643，500例黑色素细胞肿瘤将被不同地诊断， 另一位皮肤病理学家，每年一次，这对患者有重大影响，无论 病变的性质。我们建议开发一种快速、大面积多光子内窥镜并进行临床评估 （FLAME）作为黑色素瘤的非侵入性成像和早期检测的工具，以减少假阳性 以及皮肤镜检查和组织病理学的假阴性。多光子显微术（MPM）是一种非线性光学技术。 一种光学成像技术，基于内源性信号提供独特的结构和分子对比度 如胶原的二次谐波产生和NAD（P）H/FAD+的双光子激发荧光， 角蛋白、黑色素和弹性蛋白纤维。在初步研究中，我们证明了皮肤的宏观区域 (cm2规模）可以映射出与显微镜分辨率在2分钟内，通过结合光学和 机械扫描机制与深度学习图像恢复。根据PAR-20-155的要求， 学术界和工业界的合作将为临床医生提供一个强大的MPM成像工具，用于非侵入性、真实的 在床边进行定量评估，不需要专门的培训。我们提出的 应用是为了黑色素瘤的早期诊断，但该方法将具有更广泛的影响， 表征患者的细胞形态学和代谢成像终点。我们的具体目标是： (1)开发FLAME，一种紧凑的便携式MPM原型系统，用于快速，深度分辨的体内成像， 皮肤，在宏观区域（cm 2尺度）上，具有微观分辨率和增强的分子对比度;（2） 实施安全功能并证明技术可行性;（3）通过以下方式测试FLAME的性能： 评价其提供具有足够高预测能力的体内定量光学终点的能力， 可靠地区分良性和早期黑色素瘤病变。我们是一个多学科的调查团队， 加州大学欧文分校，Vidrio Technologies，LLC和塔夫茨大学有3到8年的合作记录。

Project Summary Early detection of melanoma is a key factor in improving patient survival and decreasing treatment costs. The sensitivity of dermoscopy, the standard of care in the diagnosis of melanocytic lesions, was reported to be highly variable, ranging between 68-96%, depending on the proficiency of the physician and the stage of the lesion. Low sensitivity reflects high rates of false-negative findings, which delay diagnosis and treatment. Thus doctors must err on the side of caution, which leads to an excess of unnecessary biopsies and increased medical costs. Distinguishing cutaneous melanoma from benign melanocytic nevi with high accuracy based on dermoscopy remains a challenge even when in the hands of expert clinicians since this approach only offers a two-dimensional image of the lesion's superficial structure. Ultimately, a biopsy is necessary for definitive diagnosis by the dermatopathologist, but this too may be affected by inter-observer variability, resulting in discordant conclusions. A study performed at the Melanoma Center, at UCSF estimated that 214,500 to 643,500 cases of melanocytic neoplasms in the United States would be diagnosed differently by another dermatopathologist, annually, which has significant consequences for the patient regardless of the nature of the lesion. We propose to develop and clinically evaluate a fast, large area multiphoton exoscope (FLAME) as a tool for non-invasive imaging and early detection of melanoma in order to reduce false positives and false negatives in both dermoscopy and histopathology. Multiphoton microscopy (MPM) is a nonlinear optical imaging technique that provides unique structural and molecular contrast based on endogenous signals such as second harmonic generation from collagen and two-photon excited fluorescence from NAD(P)H/FAD+, keratin, melanin and elastin fibers. In preliminary studies, we demonstrated that macroscopic areas of skin (cm2 scale) could be mapped out with microscopic resolution within ~2 minutes by combining optical and mechanical scanning mechanisms with deep learning image restoration. As required by PAR-20-155 our academic-industrial partnership will deliver a powerful MPM imaging tool to clinicians for non-invasive, real- time quantitative assessment at the bedside that would not require specialized training. Our proposed application is for early diagnosis of melanoma, but the approach will have wider impact, for rapid, in vivo characterization of cellular morphologic and metabolic imaging endpoints in patients. Our specifics aims are: (1) to develop FLAME, a compact, portable MPM prototype system for rapid, depth-resolved in vivo imaging of skin, over macroscopic areas (cm2-scale) with microscopic resolution and enhanced molecular contrast; (2) to implement safety features and demonstrate the technical feasibility; (3) to test the performance of FLAME by evaluating its ability to provide in vivo quantitative optical endpoints with sufficiently high predictive power to reliably distinguish benign from early melanoma lesions. We are a multi-disciplinary team of investigators from UC Irvine, Vidrio Technologies, LLC and Tufts University with 3 to 8 years record of collaboration.