Molecular Imaging to Identify Tumor Margins

描述(申请人提供)：2012年，美国将有超过23万名女性因乳腺癌接受手术。在这些人中，大约75%的人将成为候选人并选择保乳手术(BCS)。BCS在美观上优于另一种方法(乳房切除术)，且长期存活率相同。但BCS有可能要贵得多。在接受BCS的175,000名女性中，25%-40%将被召回医院进行额外的手术，以移除在第一次手术中未被发现和移除的活跃的癌症组织。除了对患者的负面影响，这是临床医生主要关注的问题，二次手术对总体医疗成本和个别医疗机构都有重大的经济影响。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，石蜡包埋)组织病理学。在患者出院后，外科医生切除的组织会被评估是否有活跃的肿瘤边缘，结果可能需要长达两周的时间。由于它不是在术中进行的，FFPE几乎保证了当检测到活跃的切缘时会有第二次手术。更重要的是，FFPE不检查整个切除的肿瘤，而只检查一些冰冻切片。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%被宣布为边缘“干净”的患者在一年内局部复发，这表明病理可能由于采样不足而遗漏了边缘疾病。最近，《纽约时报》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，即由于肿瘤边缘未检测到/未切除的癌细胞而导致的二次手术减少(“乳腺癌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，在351名做出回应的美国外科医生中，只有48%的人会在手术中与病理学家一起粗略检查切缘，更少的人会在手术中使用任何技术来确定他们是否已经切除了乳房的所有癌症组织。在所有参与的外科医生中，28%的人认为1 mm的边缘没有癌症，50%的人认为2 mm的边缘，12%的人认为5 mm的边缘，3%的人认为10 mm的边缘。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，它试图通过根据差异对细胞进行成像来识别细胞 而不是试图解决在典型的X光或乳房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猝灭的分子成像探针和应用技术来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首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。利用乳腺癌边缘增加的蛋白水解酶表达，这项建议引入了体外局部给药猝灭分子成像探针来识别癌症的新概念。应用几分钟后，探头在肿块切除标本中的有限扩散确定了边缘，并允许识别浸润性癌细胞，而不需要血管形成。这种方法能够在全球范围内快速识别手术中切除标本的表面和边缘是否存在癌症，所有这些都是这项技术所独有的。如果成功，这项技术可以将再次切除的次数减少高达60%。此外，IF将减少再次切除和在组织病理学分析中因采样不足而导致的假阴性率。这里提出的研究将首先为这一过程优化探针混合物，然后将测试 50例女性肿块切除标本中的技术。这项研究的结果将对这项技术进行统计检验。由于所有的手术都发生在体外，因此将这项技术迅速送到外科医生手中的监管障碍微乎其微。

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.