High resolution imaging & HPV oncoprotein detection for global prevention of cerv

描述（由申请人提供）：宫颈癌仍然是低收入和中等收入国家妇女癌症死亡的第一或第二大原因。在美国，低社会经济地位（SES）与宫颈癌生存率低密切相关。在美国和国外资源有限的环境中，非常需要新的床旁护理 诊断，使联合检测和治疗宫颈癌前病变在一个单一的访问。到目前为止，全球尝试实施“看和治疗”协议受到了限制，因为可以在护理点使用的三种现有诊断方法的特异性极低。基于成像（阴道镜检查或醋酸目视检查（VIA））或生物标志物检测（HPV DNA检测）的“看和治疗”方案导致过度治疗率很高，使患者接受不必要的程序并浪费医疗资源。我们假设，成像和生物标志物检测的组合可以降低目前宫颈筛查工具的高假阳性率。增加的核质（N/C）比是宫颈癌前病变最著名的表型生物标志物之一，但目前只能从细胞学或活检评估。我们开发了一种研究性的成像方法，高分辨率显微内窥镜（HRME），以识别N/C比值增加的宫颈原位病变。在目标1中，我们将调整HRME到一个移动的平台，该平台包含一个手机来捕获、显示、分析和传输图像。然后，我们将评估移动的HRME（mHRME）与现有生物标志物（HPV DNA检测）和研究生物标志物（HPV E7癌蛋白）的性能。在目标2中，我们将在两个全球相关背景下评估mHRME的性能：（A）在美国429名女性的临床评估中，我们将评估增加mHRME成像是否提高了阴道镜检查的特异性，而不显著降低灵敏度;（B）在对萨尔瓦多的4，592名妇女的临床评价中，我们将评估mHRME成像是否提高了单独通过VIA、单独通过HPV DNA检测或通过HPV DNA检测随后通过VIA进行筛查的特异性。HPVE 7癌蛋白的过表达是宫颈癌前病变的一个重要分子标志物。为了进一步提高分子检测的特异性，在目标3中，我们将开发一种快速、低成本、侧流检测来检测E7。我们将使用宫颈标本在270例参与目标2的宫颈癌前病变和非宫颈癌前病变患者的巢式病例对照中评估检测性能。这项工作将为美国和全球的临床医生提供强大的，负担得起的，集成的， 直接成像表型变化和检测与宫颈癌前病变的发展和进展相关的分子标志物的护理工具，解决了当前方法的特异性差的问题。总之，这些工具将提高宫颈癌前病变早期检测的有效性和成本效益，允许在一次就诊中进行诊断和治疗，以预防浸润性宫颈癌的发展。

DESCRIPTION (provided by applicant): Cervical cancer continues to be the 1st or 2nd leading cause of cancer death among women in low- and middle- income countries. In the U.S., low socioeconomic status (SES) is strongly correlated with poor cervical cancer survival. In resource-limited settings in the U.S. and abroad, there is a significant need for new point-of-care diagnostics that enable combined detection and treatment of cervical precancer in a single visit. To date, global attempts to implement "see & treat" protocols have been limited by the extremely low specificity of the three existing diagnostic approaches that can be used at the point-of-care. "See & treat" protocols based on imaging (colposcopy or visual inspection with acetic acid (VIA)) or biomarker detection (HPV DNA testing) result in high rates of overtreatment, subjecting patients to unnecessary procedures and wasting healthcare resources. We hypothesize that a combination of imaging and biomarker detection can reduce the high false positive rate of current cervical screening tools. Increased nuclear-to-cytoplasmic (N/C) ratio is one of the best known phenotypic biomarkers of cervical precancer, but can currently only be assessed from cytology or biopsy. We have developed an investigational imaging method, high-resolution microendoscopy (HRME), to identify cervical lesions in situ with increased N/C ratio. In Aim 1, we will adapt the HRME to a mobile platform which incorporates a cell phone to capture, display, analyze, and transmit images. We will then evaluate the performance of the mobile HRME (mHRME) with an existing biomarker (HPV DNA testing) and an investigational biomarker (HPV E7 oncoprotein). In Aim 2, we will evaluate performance of the mHRME in two globally relevant contexts: (A) in a clinical evaluation of 429 women in the U.S., we will assess whether addition of mHRME imaging improves specificity of colposcopy, without significantly reducing sensitivity; (B) in a clinical evaluation of 4,592 women in El Salvador, we will assess whether mHRME imaging improves the specificity of screening by VIA alone, HPV DNA testing alone, or with HPV DNA testing followed by VIA. Overexpression of HPV E7 oncoprotein is one of the best known molecular biomarkers of cervical precancer. To further improve specificity of molecular testing, in Aim 3 we will develop a rapid, low-cost, laterl flow test to detect E7. We will assess test performance using cervical specimens in a nested case-control of 270 patients with and without cervical precancer who participated in Aim 2. This work will provide clinicians in the U.S. and globally with robust, affordable, integrated, point-of care tools to directly image phenotypic changes and detect molecular markers associated with the development and progression of cervical precancer, addressing the poor specificity of current methods. Together, these tools will improve the efficacy and cost-effectiveness of early detection of cervical precancer, allowing diagnosis and treatment in a single visit to prevent the development of invasive cervical cancer.