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: 10041690
• 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/10041690
• 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; base; 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 stratification; senescence; skin damage; 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.

项目摘要 活化性肿瘤（癌性活化性角化病和非黑色素瘤皮肤癌）是最常见的类型 人类肿瘤和VA皮肤病学诊所中最常见的诊断。我们和其他团体有 表征了衰老和紫外线B辐射（UVB）有助于阳光肿瘤的机制。 特别是，活化性肿瘤高风险的人皮表现出生化特征，包括降低 DNA修复酶的角质形成细胞表达，衰老成纤维细胞的数量较低 成纤维细胞IGF-1，以及包括IL-6，IL-8和TNF在内的成纤维细胞因子的增加。而且，处于风险的皮肤 通过产生基础角质形成细胞增殖，同时仍含有DNA突变，从而对UVB做出反应。这 修订后的VA绩效应用将利用我们最近的发现，即无创，多光谱的介观 成像平台可以潜在地识别出临床正常表现的皮肤，处于光化性肿瘤的风险中。这 提案还提供了证据，表明介质成像可以用于量化现场致癌作用。到 那一端，两个具体的目标将检验以下假设：介观像将能够辨别皮肤 活化性肿瘤高风险的组织的生化和功能特征。第一个目标包括 两个部分。在第一部分中，介质成像将用于预测处于危险和正常皮肤的区域，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 针对与皮肤高风险相关的生化，组织学和功能特征的预测 肿瘤。在AIM 1的第二部分中，我们将利用我们最近的发现，即照片受伤 - 损坏的老年皮肤和分离激光重外面的肿瘤使光活化肿瘤归一化 生化/组织学变化。我们将通过对激光进行介绍成像来利用这些发现。 受伤的皮肤受伤的皮肤，带有照相损坏的皮肤。第二个目标将测试能力 介观成像以量化进行或 化学疗法剂5-氟尿嘧啶乳膏对具有现场疗法的多个光整性角化病的受试者。 此外，将监测未接受现场疗法治疗的活化性肿瘤风险的受试者 通过串行介绍成像在诊所进行纵向。 AIM 2中的这三种策略将测试这种无创的 成像可以预测出现光化性角化病的位置，并评估诊所中是否使用过介绍成像的 量化皮肤危险性肿瘤和放光性角化病的皮肤。总体目标是建立一个快速，广泛的目标 字段，多光谱成像系统，可以提供定量成像参数以监测人体皮肤 非侵入性。如果成功，这些研究将验证一个有价值的临床工具，该工具可以分层阳光的风险 即使皮肤在临床上显得正常，肿瘤也是如此。此外，这种非侵入性的，基于图像的对比 映射方法可以用来推动使用皮肤作为模型系统进行现场癌化的研究， 可以适应其他器官系统，例如结肠，食道和肺癌。这些研究会 改善在我们的皮肤病学诊所服务的退伍军人的护理。该建议还将为 在美国退伍军人中发现的许多癌症类型的研究和监测。