Molecular Imaging to Identify Tumor Margins

分子成像识别肿瘤边缘

• 批准号: 8648183
• 负责人: James Peter Basilion
• 金额: $ 17.24万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8648183
• 关键词: Address; American; Biochemistry; Breast Cancer Treatment; Breast-Conserving Surgery; Cancerous; Cessation of life; Clinical; Clinical Protocols; Cosmetics; Cytology; Data; Detection; Diffusion; Disease; Distant; Drug Formulations; Emotional; Excision; Formalin; Frozen Sections; Goals; Gold; Hand; Health Care Costs; Home environment; Hospitals; Image; Imaging Techniques; Imaging technology; Individual; Infiltration; Institution; Institutional Review Boards; Laboratories; Malignant Neoplasms; Mammaplasty; Mammary Gland Parenchyma; Mammography; Mastectomy; Methods; Molecular Probes; New York; Normal tissue morphology; Operative Surgical Procedures; Paraffin Embedding; Pathologist; Pathology; Patients; Penetration; Peptide Hydrolases; Procedures; Protocols documentation; Provider; Recurrence; Repeat Surgery; Reporting; Research; Resected; Roentgen Rays; Sampling; Sampling Errors; Solutions; Specimen; Surface; Surgeon; Surveys; Survival Rate; Techniques; Technology; Testing; Time; Tissues; Topical application; Translations; Tumor Tissue; Validation; Vascularization; Woman; Work; base; breast lumpectomy; cancer cell; cancer surgery; cellular imaging; cost; design; economic impact; human tissue; imaging probe; improved; malignant breast neoplasm; molecular imaging; new technology; novel; optical imaging; overexpression; prevent; public health relevance; research study; screening; standard of care; statistics; success; tumor

Abstract More than 230,000 women will undergo surgery for breast cancer in 2012 in the US. Of these, around 75% will be candidates and choose breast conserving surgery (BCS). BCS is cosmetically preferable to the alternative (mastectomy) and long-term survival rates are equivalent. But BCS has the potential to be significantly more expensive. Of the 175,000 women who undergo BCS, 25%-40% will be recalled to the hospital for additional surgery to remove active cancerous tissue that was not detected and removed during the first procedure. Apart from the negative impact on patients, which is the primary concern of clinicians, second surgeries have a significant economic impact on healthcare costs in general as well as on individual provider institutions. The current "gold standard" for the detection of active tumor margins after tumor excision is FFPE (Formalin-Fixed, Paraffin-Embedded) tissue pathology. Tissue removed by the surgeon is evaluated for active tumor margins after the patient is discharged and results may take up to two weeks. Because it is not performed intra-operatively, FFPE virtually guarantees there will be second surgeries when active margins are detected. More importantly, FFPE does not examine the entire excised tumor, but only a number of frozen sections. The inevitable sampling errors may miss active tumor "spikes". Data suggests that approximately 15% of patients that are declared to have "clean" margins have local recurrence within a year indicating that pathology missed disease in the margins, likely due to undersampling. Recently, The New York Times reported on surgical breast cancer treatments in the USA further underscoring that an unmet public need, the reduction in second surgeries due to undetected/unexcised cancer cells in tumor margins, clearly exists ("Breast Cancer Surgery Rules Are Called Unclear", NY Times, page A1, February 1, 2012). A recent survey revealed that only 48% of the 351 American surgeons who responded grossly examine margins intraoperatively with a pathologist and even fewer used any techniques during the surgery to determine if they had removed all the cancer tissue from the breast. Out of all the participating surgeons, 28% would consider a 1-mm margin free of cancer as negative, 50% a 2-mm margin, 12% a 5- mm margin and 3% a 10-mm margin. Clearly, these shortcoming define an unmet clinical need for BCS. Solution to the Unmet Need. Molecular imaging is a relatively new field that tries to identify cells by imaging them based on differences in their biochemistry rather than trying to resolve subtle anatomical differences that are used to identify cancer in typical X-ray or mammography exams. For a number of years our laboratory has been looking into the possibility of using quenched molecular imaging probes and application technologies to rapidly identify cancer cells in the body. Recently, we have developed novel techniques to apply molecular probes topically to tissues and very rapidly differentiate cancer cells from normal tissues. Our idea is to utilize this novel technology pioneered in our laboratories to develop a standardized method to reduce re-excisions and false negatives for BCS patients. Exploiting increased protease expression at the edge of breast cancers this proposal introduces the novel concept of ex vivo topical administration of quenched molecular imaging probes to identify cancer. Minutes after application, limited diffusion of the probe into lumpectomy specimens defines a margin and allows identification of infiltrating cancer cells without a requirement for vascularization. This approach enables rapid and global identification of cancer presence both on the surface and in the margins of resected specimens during surgery, all of which is unique to this technology. If successful this technology could reduce the number of re-excisions by up to 60%. Moreover, if will reduce re-excisions and the false negative rate that results from undersampling during histopathological analysis. The research proposed here will first optimize the probe mixtures for this procedure and then will test the technology in the lumpectomy specimens of 50 women. The results of this study will statistically test this technology. Since all of the procedures happen outside of the body, there are minimal regulatory hurdles to drive this technology rapidly into the hands of surgeons.

抽象的 2012 年，美国将有超过 230,000 名女性接受乳腺癌手术。其中，大约 75% 将是 候选人并选择保乳手术（BCS）。 BCS 在美容上优于替代方案（乳房切除术） 和长期生存率相当。但 BCS 的成本可能要高得多。在这 175,000 人中 接受 BCS 的女性中，25%-40% 将被召回医院进行额外手术以去除活动性癌组织 在第一次手术中未检测到并去除的组织。除了对患者造成的负面影响外， 作为临床医生最关心的问题，二次手术通常会对医疗费用产生重大的经济影响，因为 以及个别提供机构。 目前检测肿瘤切除后活动性肿瘤边缘的“金标准”是FFPE（福尔马林固定， 石蜡包埋）组织病理学。外科医生切除的组织在手术后评估活跃的肿瘤边缘 患者出院，结果可能需要两周时间。由于 FFPE 不是在术中进行，因此实际上 保证在检测到活跃切缘时进行第二次手术。更重要的是，FFPE 不检查 整个切除的肿瘤，但只有一些冰冻切片。不可避免的采样错误可能会错过活跃的肿瘤“尖峰”。 数据表明，大约 15% 被宣称具有“干净”边缘的患者在一段时间内出现局部复发。 这一年表明病理学遗漏了边缘疾病，可能是由于采样不足。近日，纽约 《泰晤士报》报道了美国乳腺癌手术治疗，进一步强调了公众需求未得到满足， 由于肿瘤边缘未检测到/未切除的癌细胞，第二次手术的减少显然存在（“乳腺癌 手术规则被称为不清楚”，《纽约时报》，A1 页，2012 年 2 月 1 日）。最近的一项调查显示，只有 48% 351 名美国外科医生做出回应，在术中与病理学家一起粗略地检查了边缘，甚至更少 在手术过程中使用任何技术来确定他们是否已从乳房中切除了所有癌症组织。全部中 在参与的外科医生中，28% 认为 1 毫米边缘无癌症为阴性，50% 认为 2 毫米边缘，12% 认为 5 毫米边缘无癌症。 毫米边距和 3% 10 毫米边距。显然，这些缺点表明 BCS 的临床需求尚未得到满足。 解决未满足的需求。分子成像是一个相对较新的领域，试图通过成像来识别细胞 基于生物化学的差异，而不是试图解决习惯上的微妙的解剖学差异 通过典型的 X 射线或乳房 X 光检查来识别癌症。多年来，我们的实验室一直致力于研究 使用淬灭分子成像探针和应用技术快速识别肿瘤细胞的可能性 身体。最近，我们开发了新技术，可以将分子探针局部应用到组织上，并且非常快速 将癌细胞与正常组织区分开来。我们的想法是利用我们实验室首创的这项新技术 开发一种标准化方法来减少 BCS 患者的再次切除和假阴性。 该提案利用乳腺癌边缘增加的蛋白酶表达引入了 ex 的新概念 体内局部施用淬灭分子成像探针来识别癌症。申请后几分钟，有限 探针扩散到肿瘤切除标本中定义了边缘并允许识别浸润的癌细胞 无需血管化。这种方法能够快速、全面地识别癌症的存在 在手术过程中，在切除标本的表面和边缘，所有这些都是该技术所独有的。如果 这项技术的成功可以将再次切除的次数减少高达 60%。此外，如果会减少重新切除 以及组织病理学分析过程中采样不足导致的假阴性率。这里提出的研究 将首先优化该手术的探针混合物，然后在肿瘤切除标本中测试该技术 50 名女性。这项研究的结果将对这项技术进行统计测试。由于所有程序都发生在外部 在身体上，几乎没有什么监管障碍可以将这项技术迅速推向外科医生手中。