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.

摘要 2012年，美国将有超过23万名女性接受乳腺癌手术。在这些人中，大约75%将是 并选择保乳手术(BCS)。BCS在美观上优于替代方案(乳房切除术) 长期存活率是相等的。但BCS有可能要贵得多。在175,000人中 接受BCS的女性，25%-40%将被召回医院进行额外的手术，以移除活动性癌症 在第一次手术中没有检测到并被移除的组织。除了对患者的负面影响外， 临床医生的主要关注点是，二次手术对总体医疗成本有重大的经济影响，因为 以及个别提供服务的机构。 目前检测肿瘤切除后活跃的肿瘤边缘的“金标准”是FFPE(福尔马林固定的， 石蜡包埋)组织病理学。外科医生切除的组织在术后对活跃的肿瘤边缘进行评估 患者出院了，结果可能需要长达两周的时间。因为它不是在手术中进行的，所以FFPE实际上 当检测到活跃的利润率时，保证会有第二次手术。更重要的是，FFPE不会检查 整个切除的肿瘤，但只有一些冰冻切片。不可避免的抽样误差可能会遗漏活跃的肿瘤“尖峰”。 数据显示，大约15%被宣布边缘干净的患者在一年内局部复发。 一年表明病理漏掉了边缘的疾病，可能是由于采样不足。最近，《纽约时报》 《泰晤士报》报道了美国的乳腺癌外科治疗，进一步强调了一个未得到满足的公众需求， 由于肿瘤边缘未检测到/未切除的癌细胞而导致的第二次手术的减少是明显存在的 手术规则被称为不明确“，《纽约时报》，2012年2月1日A1页)。最近的一项调查显示，只有48%的 351名美国外科医生回答说，他们粗略地检查了手术中的切缘，病理学家的人数甚至更少。 在手术过程中使用了任何技术来确定他们是否已经从乳房移除了所有的癌症组织。最重要的是 参与调查的外科医生中，28%的人认为无癌边缘1 mm为阴性，50%认为2 mm边缘为阴性，12%认为5 mm边缘为阴性。 Mm边距和3%的10 mm边距。显然，这些缺陷定义了BCS未得到满足的临床需求。 解决未得到满足的需求。分子成像是一个相对较新的领域，它试图通过成像来识别细胞 基于它们的生物化学差异，而不是试图解决细微的解剖差异，这些差异被用来 在典型的X光或乳房X光检查中识别癌症。多年来，我们的实验室一直在研究 使用猝灭的分子成像探针和应用技术快速识别肿瘤细胞的可能性 尸体。最近，我们开发了新的技术，将分子探针局部应用到组织中，并非常迅速 区分癌细胞和正常组织。我们的想法是利用我们实验室首创的这项新技术来 开发一种标准化的方法来减少BCS患者的再次切除和假阴性。 利用乳腺癌边缘组织中增加的蛋白水解酶的表达，该方案引入了EX的新概念 活体局部注射猝灭的分子成像探针以识别癌症。申请后数分钟，有限 探针在肿块切除标本中的扩散界定了边缘，并允许识别浸润性癌细胞 而不需要血管形成。这种方法使快速和全球识别癌症的存在成为可能 在手术过程中切除的标本的表面和边缘，所有这些都是这项技术所独有的。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，IF将减少再次切除 以及组织病理学分析过程中采样不足所导致的假阴性率。在这里提出的这项研究 将首先为这一过程优化探针混合物，然后将在肿块切除标本中测试该技术 50个女人。这项研究的结果将对这项技术进行统计检验。因为所有的程序都发生在 在人体内，将这项技术迅速送到外科医生手中的监管障碍微乎其微。