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。其中，约75%将 选择保乳手术（BCS）。BCS比替代方案（乳房切除术）更可取 和长期存活率是相当的。但BCS有可能要贵得多。在175，000人中 接受BCS的女性，25%-40%将被召回医院接受额外手术以切除活动性癌细胞 在第一次手术中未检测到并移除的组织。除了对病人的负面影响， 作为临床医生的主要关注点，第二次手术通常对医疗保健成本具有重大的经济影响， 以及个别供应商机构。 目前用于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。手术后，对外科医生切除的组织进行活性肿瘤边缘评估。 患者出院，结果可能需要两周。因为它不是在术中进行的，所以FFPE实际上 保证在检测到活动边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，但只有一些冷冻切片。不可避免的采样误差可能会错过活性肿瘤“尖峰”。 数据表明，大约15%的宣称具有“干净”切缘的患者在一年内局部复发。 这表明病理学在边缘遗漏了疾病，可能是由于采样不足。最近，纽约 《泰晤士报》对美国乳腺癌手术治疗的报道进一步强调， 由于肿瘤边缘未检测到/未切除的癌细胞，明显存在第二次手术的减少（“乳腺癌 Surgery Rules Are Called Unclear”，NY Times，第A1页，2012年2月1日）。最近的一项调查显示，只有48%的 351名美国外科医生在手术中与病理学家一起对切缘进行了大体检查， 在手术过程中使用任何技术来确定他们是否已经从乳房上切除了所有的癌组织。脱离一切 在参与的外科医生中，28%的人认为1 mm的无癌边缘为阴性，50%的人认为2 mm的无癌边缘为阴性，12%的人认为5 mm的无癌边缘为阴性， 10 mm边缘的占3%。显然，这些缺点定义了BCS的未满足的临床需求。 解决未满足的需求。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 而不是试图解决细微的解剖学差异， 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 使用淬灭的分子成像探针和应用技术来快速识别癌细胞的可能性 身体最近，我们开发了新的技术，将分子探针局部应用于组织， 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开创的这项新技术， 开发一种标准化的方法，以减少BCS患者的再次切除和假阴性。 利用乳腺癌边缘蛋白酶表达的增加，该提案引入了表达蛋白酶的新概念。 体内局部施用淬灭的分子成像探针以鉴定癌症。应用后分钟，有限 探针扩散到肿块切除标本中限定了边缘，并允许识别浸润的癌细胞 而不需要血管化。这种方法能够快速和全面地识别癌症的存在， 在手术过程中切除标本的表面和边缘，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减少60%的再切除次数。此外，如果将减少再切除 以及在组织病理学分析期间由于采样不足而导致的假阴性率。这里提出的研究 将首先优化该手术的探针混合物，然后将在乳房肿瘤切除术标本中测试该技术， 50个女人这项研究的结果将在统计上测试这项技术。因为所有的手术都是在 在身体上，有最小的监管障碍，以推动这项技术迅速进入外科医生手中。