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

验证细观成像预测皮肤癌发生及其治疗反应

• 批准号: 10595503
• 负责人: Jeffrey B. Travers
• 金额: --
• 依托单位: DAYTON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10595503
• 关键词: Actinic keratosis; Acute; Age; Aging; Area; Biochemical; Biological Models; Biopsy; Blood Vessels; Blood Volume; Caring; Cause of Death; Characteristics; Chronic; Clinic; Clinical; Clinical Treatment; Colon Carcinoma; Cream; Cutaneous; DNA Repair Enzymes; DNA Sequence Alteration; Dermabrasion; Dermal; Dermatology; Diagnosis; Diagnostic; Effectiveness; Elderly; Exhibits; Fibroblasts; Financial Hardship; Fluorouracil; General Population; Goals; Healthcare Systems; Hemoglobin; Histologic; Histology; Hot Spot; Human; IL8 gene; Image; Incidence; Insulin-Like Growth Factor I; Interleukin-6; Intervention; Lasers; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of lung; Maps; Measurement; Methodology; Modeling; Monitor; Morbidity - disease rate; Mutation; Neoplasms; Optics; Organ Transplantation; Organ failure; PUVA Photochemotherapy; Patients; Phenotype; Physiological; Pilot Projects; Prediction of Response to Therapy; Prevention; Proliferating; Reporting; Research; Research Personnel; Risk; Risk Factors; Site; Skin; Skin Cancer; Skin Carcinoma; Solid; Source; Spatial Frequency Domain Imaging; Spottings; Stains; Sun Exposure; TNF gene; TP53 gene; Testing; Thymidine; Time; Tissues; Transplant Recipients; UV Radiation Exposure; Ultraviolet B Radiation; Validation; Veterans; body system; cancer type; carcinogenesis; chemotherapy; cohort; cytokine; dimer; early detection biomarkers; experience; high risk; high risk population; imaging platform; imaging system; improved; insight; keratinocyte; mortality; mutant; neoplastic; non-invasive imaging; novel; patient response; preclinical study; predicting response; premalignant; quantitative imaging; radiation response; risk prediction; risk stratification; senescence; skin photodamage; spectrograph; tool; transcriptome; treatment response; wound

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.

项目概要 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，也是 VA 皮肤科诊所最常见的诊断。我们和其他团体有 表征了衰老和紫外线 B 辐射 (UVB) 导致光化性肿瘤的机制。 特别是，处于光化性肿瘤高风险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但水平较低 成纤维细胞 IGF-1 的减少，以及成纤维细胞细胞因子（包括 IL-6、IL-8 和 TNF）的增加。此外，高危皮肤 通过产生增殖的基底角质形成细胞（同时仍含有 DNA 突变）来响应 UVB。这 修订后的 VA Merit 申请将利用我们最近的发现，即无创、多光谱、介观 成像平台有可能识别临床上表现正常的皮肤，有患光化性肿瘤的风险。这 该提案还提供了介观成像可用于量化现场致癌作用的证据。到 为此，两个具体目标将检验介观成像能够识别皮肤的假设 光化性肿瘤高危组织的生化和功能特征。第一个目标包括 两部分。在第一部分中，细观成像将用于预测有风险的皮肤区域与正常皮肤的区域，这将 通过活检和非侵入性转录组分析进行测试，以比较基于成像参数的 针对与光化性高风险皮肤相关的生化、组织学和功能特征进行预测 瘤形成。在目标 1 的第二部分中，我们将利用我们最近的发现，即照片受伤- 受损的老年皮肤通过分次激光换肤使光化性肿瘤正常化 生化/组织学变化。我们将通过对激光进行细观成像来利用这些发现 皮肤受光损伤的老年受试者的受伤皮肤与未受伤皮肤。第二个目标考验能力 介观成像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，将对未接受现场治疗的光化性肿瘤高危受试者进行监测 通过连续细观成像在临床上进行纵向研究。目标 2 中的这三种策略将测试这种非侵入性方法是否有效 成像可以预测光化性角化病发生的位置，并评估细观成像是否可用于临床 量化有光化性肿瘤和光化性角化病风险的皮肤。总体目标是建立一个快速、广泛的 现场多光谱成像系统，可为监测人体皮肤提供定量成像参数 非侵入性。如果成功，这些研究将验证一种有价值的临床工具，可以对光化性风险进行分层 即使皮肤临床表现正常，也会出现肿瘤。此外，这种非侵入性、基于图像的对比 绘图方法可以利用皮肤作为模型系统来推动现场癌化研究， 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。该提案还将提供宝贵的工具 对美国退伍军人中发现的多种癌症类型的研究和监测。