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

描述(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)与低宫颈癌存活率密切相关。在美国和国外的资源有限的情况下，非常需要新的护理点 能够在一次就诊中联合检测和治疗宫颈癌前病变的诊断。到目前为止，由于现有的三种诊断方法的特异度极低，全球实施“查看和治疗”方案的努力一直受到限制，这三种诊断方法可以在护理地点使用。基于成像(阴道镜检查或醋酸目视检查(VIA))或生物标记物检测(HPV DNA检测)的“查看和治疗”方案会导致高比率的过度治疗，使患者接受不必要的程序，并浪费医疗资源。我们假设，结合影像和生物标记物检测可以降低目前宫颈筛查工具的高假阳性率。核浆比(N/C)升高是宫颈癌前病变最著名的表型生物标志物之一，但目前只能通过细胞学或活检来评估。我们开发了一种探索性的成像方法，高分辨率显微内窥镜(HRME)，可以在N/C比增加的情况下原位识别宫颈病变。在目标1中，我们将使HRME适应于一个结合了手机来捕获、显示、分析和传输图像的移动平台。然后，我们将使用现有的生物标记物(HPV DNA检测)和研究中的生物标记物(HPVE7癌蛋白)来评估移动HRME(MHRME)的性能。在目标2中，我们将评估mHRME在两个全球相关背景下的表现：(A)在对美国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，而不会显著降低敏感性；(B)在萨尔瓦多对4592名女性的临床评估中，我们将评估mHRME成像是通过单独VIA、单独检测HPV DNA还是结合HPV DNA检测和VIA来提高筛查的特异性。HPVE7蛋白的过表达是宫颈癌前病变最常见的分子生物学标志之一。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、低成本的后期流动检测方法来检测E7。我们将在参加AIM 2的270名患有和不患有宫颈癌前病变的患者的嵌套病例对照中使用宫颈样本来评估检测性能。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、综合的、 CARE工具可直接成像表型变化并检测与宫颈癌前病变的发展和进展相关的分子标记，解决了当前方法特异性差的问题。这些工具结合在一起，将提高宫颈癌前病变早期检测的效率和成本效益，使诊断和治疗可以在一次访问中进行，以防止侵袭性宫颈癌的发展。

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.