Intraoperative assessment of non-melanoma skin cancer margins using NIRF probes.

描述(申请人提供)：在美国，皮肤癌的发病率正在迅速增加。1994年，每年约有100万例非黑色素瘤皮肤癌病例；到2011年，这一数字增长到400多万例。其中许多肿瘤出现在身体暴露在阳光下的区域(面部、手等)，在这些区域，出于美容考虑，需要最大限度地切除正常组织。然而，更广泛地说，成功的皮肤手术需要完全切除病变组织，同时最大限度地减少健康组织的切除。虽然标准手术方法可能会切除更多的健康组织或无法切除所有癌症组织，但与标准手术方法相比，Mohs显微外科手术(MMS)可以达到上述要求，提供更好的结果、更低的疾病复发机会、更好的美容效果和最少的健康组织切除。然而，MMS耗时长，专利吞吐量低，需要专门的临床培训和现场实验室设施。此外，建议MMS仅用于符合特定特征的皮肤癌的一小部分[35]。MMS和标准手术方法缺乏经济有效、易于使用的替代品，这是一个尚未得到满足的重大临床需求。在这份第一阶段的意见书中，我们建议开发一种简单、廉价和快速的成像技术来在手术过程中识别切除组织中的癌症。这种技术将为许多非黑色素瘤皮肤癌切除带来MMS手术的优势，同时减轻或消除MMS的缺点。我们建议的方法是在体外将一种专有的、智能的、蛋白酶结合的近红外荧光(NIRF)探针应用于切除的皮肤肿瘤组织。由于许多形式的癌症依赖于特定的蛋白酶(称为组织蛋白酶B或L)来侵袭周围的正常组织，因此该探测器被设计为在遇到活性酶时在近红外光下发出荧光。由于它的激活速度很快，结果几乎可以立即为临床决策提供信息。这项拟议的技术可能会对公众健康产生重大影响。将这一程序应用于患者护理可以非常迅速地进行，并有可能从根本上改进非黑色素瘤皮肤癌的治疗，降低成本，改善结果，并减少许多患者的并发症。第一阶段的工作包括：测量皮肤活检组织中活性蛋白水解酶对局部给药探针的激活。我们将与莫斯大学培训的皮肤科医生合作，获取被丢弃的肿瘤组织样本。我们将对它们应用探测器并对其进行成像。探针激活与癌细胞和活性组织蛋白的相关性。统计分析，以确定测试的准确性(敏感度和特异度)，以确定是否 作为一种有用的术中临床工具来评估皮肤癌切除。

DESCRIPTION (provided by applicant): The incidence of skin cancer is increasing rapidly in the US. In 1994, there were around 1 million cases of non-melanoma skin cancer per year; this number had grown to more than 4 million by 2011. Many of these tumors appear in areas of the body that are exposed to sunlight (face, hands, etc.), where cosmetic considerations require minimizing resection of normal tissue. More generally, however, successful skin surgery requires the complete removal of diseased tissue while minimizing removal of healthy tissues. While standard surgical approaches may remove more healthy tissue than necessary or fail to remove all cancerous tissue, Mohs Micrographic Surgery (MMS) can achieve the above requirements, offering improved outcomes, lower chances of disease recurrence, better cosmetic results and minimal removal of healthy tissue compared to standard surgical approaches. However, MMS is time-consuming, has low patent throughput, requires specialized clinical training and on-site laboratory facilities. Moreover, it has been recommended that MMS only be used on a small subset of skin cancers conforming to specific characteristics [35]. The lack of a cost-effective, easy-to-use alternative to MMS and standard surgical approaches represents a significant, unmet clinical need that has yet to be addressed. In this Phase I submission, we propose to develop a simple, inexpensive and rapid imaging technology to identify cancer in resected tissues during surgery. Such a technology would bring the advantages of MMS surgery to many non-melanoma skin cancer resections while mitigating or eliminating the disadvantages of MMS. Our proposed approach is to topically apply a proprietary, smart, protease binding near- infrared fluorescent (NIRF) probe ex vivo to excised skin tumor tissue. Because many forms of cancer rely on specific proteases (known as cathepsins B or L) in order to invade surrounding normal tissue, the probe is designed to fluoresce under near-infrared light when it encounters active enzyme. Because it activates quickly, results can inform clinical decision-making almost immediately. The proposed technology can have a significant public health impact. Adaptation of this procedure into patient care can happen very rapidly and has the potential to radically improve the treatment of non-melanoma skin cancers, reducing costs, improving outcomes, and reducing complications for many patients. Phase I work involves: Studies to measure the activation of topically-administered probe by active proteases in skin biopsies. We will work with a Mohs-trained dermatologist to obtain discarded tumor tissue samples. We will apply probe to them and image them. Correlation of probe activation with cancer cells and active cathepsins. Statistical analysis to determine the accuracy (sensitivity and specificity) of the test to determine if it is useful as an intraoperative clinical tool to assess skin cancer resections.