Validation of Mesoscopic Imaging to Predict Cutaneous Carcinogenesis and its Therapeutic Response

项目总结 光化性肿瘤(癌前光化性角化病和非黑色素瘤皮肤癌)是最常见的类型 人类肿瘤，是退伍军人皮肤科临床上最常见的诊断。我们和其他团体有 描述了衰老和紫外线B辐射(UVB)促进光化性肿瘤形成的机制。 特别是，高风险光化性肿瘤的人类皮肤表现出生化特征，包括减少 角质形成细胞表达DNA修复酶，衰老成纤维细胞数量增加，水平较低 成纤维细胞IGF-1水平升高，成纤维细胞细胞因子IL-6、IL-8和肿瘤坏死因子水平升高。此外，处于风险中的皮肤 对UVB的反应是在仍有DNA突变的情况下产生基底层角质形成细胞增殖。这 修改后的VA Merit应用程序将利用我们最近的发现，即非侵入性、多光谱、中观 成像平台可以潜在地识别临床上看起来正常的皮肤有患光化性肿瘤的风险。这 该建议还提供了证据，证明介观成像可以用于量化现场癌症的发生。至 最终，两个特定的目标将检验这一假设，即中观成像将能够通过 光化性肿瘤高危组织的生化和功能特征。第一个目标包括 有两个部分。在第一部分中，介观成像将用于预测高危皮肤与正常皮肤的区域，这将 通过活检和非侵入性转录组分析进行检测，以比较基于成像参数的 与光化性皮肤高危相关的生化、组织学和功能特征的预测 肿瘤。在目标1的第二部分，我们将利用我们最近的发现，照片中的伤人- 分次激光表面处理受损的老年皮肤使光化性肿瘤正常化 生化/组织学改变。我们将通过对激光进行介观成像来利用这些发现- 光损伤皮肤的老年受试者中受伤皮肤与未受伤皮肤的比较。第二个目标是测试 以量化局部光动力疗法(PDT)的有效性或 化疗药物5-氟尿嘧啶乳膏用于需要现场治疗的多发性光化性角化病患者。 此外，未经现场治疗的光化性肿瘤高危人群将受到监测。 通过连续介观成像在临床上纵向应用。Aim 2中的这三种策略将测试这种非侵入性 成像可以预测光化性角化病的发生地点，并评估中观成像是否在临床上应用于 量化光化性肿瘤和光化性角化病的风险皮肤。总体目标是建立一个快速、广泛的- 野外多光谱成像系统，可为监测人体皮肤提供定量成像参数 非侵入性的。如果成功，这些研究将验证一种有价值的临床工具，可以对光化风险进行分层 即使在临床上皮肤看起来正常的情况下也会发生肿瘤。此外，这种基于图像的非侵入性对比度 标测方法可以推动以皮肤为模型系统的野外癌变研究，该系统 可以适应其他器官系统，如结肠癌、食道癌和肺癌。这些研究将 改善我们皮肤科诊所服务的退伍军人的护理。这项建议还将提供宝贵的工具 对美国退伍军人中发现的许多癌症类型的研究和监测。

PROJECT SUMMARY Actinic neoplasia (precancerous actinic keratosis and non-melanoma skin cancer) is the most common type of human neoplasia, and the most common diagnosis in VA dermatology clinics. We and other groups have characterized the mechanisms by which aging and ultraviolet B radiation (UVB) contribute to actinic neoplasia. In particular, human skin at high risk for actinic neoplasia exhibits biochemical features, including decreased keratinocyte expression of DNA repair enzymes, increased numbers of senescent fibroblasts with lower levels of fibroblast IGF-1, and increased fibroblast cytokines including IL-6, IL-8 and TNF. Moreover, at risk skin responds to UVB by generating basal keratinocytes proliferating while still harboring DNA mutations. This revised VA Merit application will leverage our recent findings that a noninvasive, multi-spectral, mesoscopic imaging platform could potentially identify clinically normal-appearing skin at risk for actinic neoplasia. This proposal also provides evidence that mesoscopic imaging could have use in quantifying field carcinogenesis. To that end, two specific aims will test the hypothesis that mesoscopic imaging will be able to discern skin with biochemical and functional characteristics of tissue at high risk for actinic neoplasia. The first aim consists of two parts. In the first part, mesoscopic imaging will be used to predict areas of at-risk vs. normal skin, which will be tested with biopsies and non-invasive transcriptome analysis to compare imaging parameter-based predictions against biochemical, histological and functional features associated with skin at high risk for actinic neoplasia. In the second part of Aim 1 we will take advantage of our recent findings that wounding of photo- damaged geriatric skin with fractionated laser resurfacing normalizes the actinic neoplastic biochemical/histological changes. We will leverage these findings by conducting mesoscopic imaging of laser- wounded vs unwounded skin in geriatric subjects with photo-damaged skin. The second aim will test the ability of mesoscopic imaging to quantify the effectiveness of topical photodynamic therapy (PDT) performed or chemotherapy agent 5-fluorouracil cream on subjects with multiple actinic keratosis requiring field therapy. Additionally, subjects at high risk for actinic neoplasia not treated with field therapy will be monitored longitudinally in clinics by serial mesoscopic imaging. These three strategies in Aim 2 will test if this noninvasive imaging can predict where actinic keratosis will arise and assess if mesoscopic imaging has use in the clinic for quantifying skin at-risk for actinic neoplasia and actinic keratosis. The overall goal is to establish a fast, wide- field, multi-spectral imaging system that can provide quantitative imaging parameters for monitoring human skin non-invasively. If successful, these studies will validate a valuable clinical tool that can stratify risk of actinic neoplasia even when skin appears clinically normal. Moreover, this non-invasive, image-based contrast mapping approach could serve to propel research in field cancerization using skin as a model system, which could be adapted to other organ systems such as colon, esophagus and lung cancers. These studies will improve the care of veterans served in our dermatology clinics. This proposal will also provide valuable tools for both the study and monitoring of many cancer types found in US Veterans.