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Molecular Imaging to Identify Tumor Margins

分子成像识别肿瘤边缘

基本信息

批准号：
8787724
负责人：
James Peter Basilion
金额：
$ 20.68万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8787724
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 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 image guided imaging agent imaging probe improved malignant breast neoplasm molecular imaging new technology novel optical imaging overexpression prevent research study screening standard of care statistics success tumor

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（申请人提供）：2012年，美国将有超过23万名女性接受乳腺癌手术。其中，约75%的人将成为候选人并选择保乳手术（BCS）。BCS比替代方案（乳房切除术）更可取，长期生存率相当。但BCS有可能要贵得多。在接受BCS的175，000名妇女中，25%-40%将被召回医院进行额外的手术，以去除在第一次手术中未检测到并去除的活性癌组织。除了对患者的负面影响外，这是临床医生的主要关注点，二次手术对一般医疗保健成本以及个别提供机构都有重大的经济影响。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。由外科医生切除的组织在患者出院后评估活动性肿瘤边缘，结果可能需要长达两周的时间。由于FFPE不是在术中进行，因此实际上可以保证在检测到活动边缘时会进行第二次手术。更重要的是，FFPE并不检查整个切除的肿瘤，而只是一些冷冻切片。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%的被宣布为具有“干净”切缘的患者在一年内局部复发，这表明病理学遗漏了切缘中的疾病，这可能是由于采样不足。最近，《纽约时报》报道了美国的乳腺癌手术治疗，进一步强调了未满足的公众需求，即由于肿瘤边缘中未检测到/未切除的癌细胞而导致的二次手术的减少，显然存在（“Breast Cancer Surgery Rules Are Called Unclear”，NY Times，page A1，February 1，2012）。最近的一项调查显示，在351名美国外科医生中，只有48%的人在手术中与病理学家一起仔细检查了边缘，甚至更少的人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。在所有参与的外科医生中，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，12%的人认为5 mm的无癌边缘，3%的人认为10 mm的无癌边缘。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，它试图通过基于差异的成像来识别细胞而不是试图解决在典型的X射线或乳房X光检查中用于识别癌症的细微解剖差异。多年来，我们的实验室一直在研究使用淬灭分子成像探针和应用技术快速识别体内癌细胞的可能性。最近，我们开发了新的技术，将分子探针局部应用于组织，并非常迅速地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来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，该提议引入了离体局部施用淬灭的分子成像探针以识别癌症的新概念。应用后几分钟，探针进入肿瘤切除术标本的有限扩散限定了边缘，并允许识别浸润癌细胞，而无需血管形成。这种方法能够在手术过程中快速和全面地识别切除标本表面和边缘的癌症存在，所有这些都是这项技术所独有的。如果成功，这项技术可以减少高达60%的再次切除次数。此外，如果将减少再切除和假阴性率，导致在组织病理学分析的采样不足。这里提出的研究将首先优化该程序的探针混合物，然后进行测试在50名妇女的乳房肿瘤切除术标本中的技术。这项研究的结果将在统计上测试这项技术。由于所有的手术都发生在体外，因此将这项技术迅速推向外科医生手中的监管障碍很小。