Nano-architecture Based Biomarkers for Cervical Cancer Screening

基于纳米结构的宫颈癌筛查生物标志物

• 批准号: 8384997
• 负责人: Yang Liu
• 金额: $ 19.62万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384997
• 关键词: Anxiety; Architecture; Archives; Atypical Squamous Cell; Biological Markers; Biopsy; Cancer Detection; Cancerous; Cell Nucleus; Cells; Cervical Cancer Screening; Cervical Intraepithelial Neoplasia; Characteristics; Clinical; Collection; Colposcopy; Communities; Cytology; Cytology Histology; Data; Data Analyses; Detection; Diagnosis; Exhibits; Goals; Graph; Guidelines; HPV-High Risk; Health Care Costs; Histologic; Human Papillomavirus; Human papilloma virus infection; Incidence; Label; Lead; Liquid substance; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Manuals; Methods; Microscopy; Modification; Nuclear; Operative Surgical Procedures; Optics; Pap smear; Pathologist; Patients; Performance; Phase; Procedures; Process; Protocols documentation; Public Health; Reproducibility; Resources; Risk Assessment; Screening procedure; Slide; Specificity; Specimen; Speed; Squamous Cell; System; Techniques; Testing; Training; Validation; Woman; base; cancer type; carcinogenesis; clinically significant; cohort; cost effective; cost effectiveness; design; follow-up; high risk; improved; mortality; nano; nanoscale; novel; prevent; prospective; tool

DESCRIPTION (provided by applicant): Cervical cancer is the second most common cancer in women worldwide. Papanicolaou (Pap) cytology is an established screening technique that has led to a significant reduction of incidence and mortality in cervical cancer. It is important t detect the clinically significant high-grade cervical intraepithelial neoplasia (HGCIN) that requires further extensive and invasive examination and treatment. However, about 3 million Pap smears in US annually receive a diagnosis of "atypical squamous cells of undetermined significance (ASC-US)", but HGCIN is confirmed on a subsequent follow-up colposcopy biopsy for only less than 5% of patients receiving this diagnosis. While the emergence of human papillomavirus (HPV) testing has enhanced cervical cancer detection, but only a very small number of HPV-infected patients harbor HGCIN. Due to the low specificity of Pap cytology and HPV testing, substantial unnecessary expenses and efforts have been made to identify these HGCIN patients and over-treatment. Novel biomarkers are crucially necessary to enhance the detection of true high-risk patients, especially in HPV-infected patients and allow more effective cervical cancer screening. The main objective of this application is to identify novel biomarkers to improve the accurate detection of HGCIN and malignancy in patients with ASC-US cytology and/or HPV infection. Our primary aim is to identify novel and clinically applicable optical "biomarkers" for detecting HGCIN and malignancy based on the analysis of nanoscale structural characteristics. Our recently developed Spatial-domain Low-coherence Quantitative Phase Microscopy (SL-QPM) can detect, with nanoscale sensitivity, sub-cellular structural changes (0.9 nm) in standard cytology and histology slides without any additional modification. We have demonstrated that SL-QPM-derived nuclear nano-architecture "biomarkers" can unambiguously detect several types of cancer even in cells labeled as "normal" or "indeterminate" by expert pathologists that were confirmed at surgery to be cancerous. We have also validated the analytical reproducibility and developed a standard operating protocol for SL-QPM analysis. We hypothesize that atypical and cytologically normal squamous cells from patients with HGCIN will exhibit subtle nano-architectural changes in the cell nuclei that appear invisible to conventional cytology, but can be distinguished using SL-QPM-derived biomarkers. In this project, we will improve the throughput of this technique for routine clinical use and further refine and validate these novel optical biomarkers to detect HGCIN in routine cytology slides from women with ASC-US cytology. Further, a proof-of-concept study will be performed to confirm the accuracy of SL-QPM markers when implemented in a real clinical setting in patients with ASC-US cytology and positive HPV test. Given the cost-effectiveness of SL-QPM and the ease with which it can be integrated into the current clinical workflow (including in community and resource-limited settings), our technique has the potential to significantly prevent the overtreatment of women with such diagnoses, reducing anxiety, invasive procedures, and associated healthcare costs in the process. PUBLIC HEALTH RELEVANCE: This project is significant to the public health since it aims to develop and validate novel nano-architecture based biomarkers for identifying high-risk patients from those infected with human papillomavirus and equivocal cytology diagnosis. It could allow for more effective cervical cancer screening and save unnecessary workup and over-treatment.

描述（由申请人提供）：宫颈癌是全球女性第二常见的癌症。巴氏细胞学检查是一种成熟的筛查技术，已导致宫颈癌的发病率和死亡率显着降低。重要的是要发现临床上显著的高级别宫颈上皮内瘤变（HGCIN），需要进一步广泛和侵入性的检查和治疗。然而，美国每年约有300万例巴氏涂片检查被诊断为“意义不明的非典型鳞状细胞（ASC-US）”，但只有不到5%的患者在随后的随访阴道镜活检中确诊HGCIN。虽然人乳头瘤病毒（HPV）检测的出现提高了宫颈癌的检出率，但只有极少数HPV感染患者携带HGCIN。由于巴氏细胞学和HPV检测的低特异性，大量不必要的费用和努力已经确定这些HGCIN患者和过度治疗。新的生物标志物对于提高真正高危患者的检测至关重要，特别是在HPV感染患者中，并允许更有效的宫颈癌筛查。本申请的主要目的是鉴定新的生物标志物，以提高ASC-US细胞学和/或HPV感染患者中HGCIN和恶性肿瘤的准确检测。我们的主要目的是确定新的和临床上适用的光学“生物标志物”检测HGCIN和恶性肿瘤的基础上分析的纳米结构特征。我们最近开发的空间域低相干定量相位显微镜（SL-QPM）可以检测，与纳米级的灵敏度，亚细胞结构的变化（0.9 nm）在标准细胞学和组织学切片没有任何额外的修改。我们已经证明，SL-QPM衍生的核纳米结构“生物标志物”可以明确地检测几种类型的癌症，即使是在手术中被专家病理学家确认为癌性的标记为“正常”或“不确定”的细胞中。我们还验证了分析的重现性，并制定了一个标准的操作方案SL-QPM分析。我们假设HGCIN患者的非典型和细胞学正常鳞状细胞将在细胞核中表现出微妙的纳米结构变化，这些变化在常规细胞学中是不可见的，但可以使用SL-QPM衍生的生物标志物进行区分。在这个项目中，我们将提高该技术的常规临床使用的吞吐量，并进一步完善和验证这些新的光学生物标志物，以检测ASC-US细胞学女性的常规细胞学切片中的HGCIN。此外，将进行概念验证研究，以确认SL-QPM标志物在ASC-US细胞学检查和HPV检测阳性患者中真实的临床环境中实施时的准确性。考虑到SL-QPM的成本效益以及它可以轻松集成到当前的临床工作流程中（包括在社区和资源有限的环境中），我们的技术有可能显着防止过度治疗患有此类诊断的女性，减少焦虑，侵入性程序和相关的医疗保健费用。 公共卫生相关性：该项目对公共卫生具有重要意义，因为它旨在开发和验证基于纳米结构的新型生物标志物，用于从感染人乳头瘤病毒和可疑细胞学诊断的患者中识别高危患者。它可以允许更有效的宫颈癌筛查，并节省不必要的检查和过度治疗。