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

描述（由申请人提供）：皮肤癌的发病率在美国迅速上升。1994年，每年约有100万例非黑色素瘤皮肤癌病例；到2011年，这一数字已增长到400多万。这些肿瘤大多出现在身体暴露在阳光下的部位（面部、手部等），出于美观考虑，这些部位需要尽量减少正常组织的切除。然而，更普遍的是，成功的皮肤手术需要完全切除病变组织，同时尽量减少健康组织的切除。虽然标准手术方法可能会切除比必要的更多的健康组织或不能切除所有的癌组织，但莫氏显微手术（Mohs Micrographic Surgery， MMS）可以达到上述要求，与标准手术方法相比，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小的健康组织切除。然而，MMS耗时，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，有人建议MMS仅用于符合特定特征的一小部分皮肤癌。缺乏一种成本效益高、易于使用的MMS和标准手术入路的替代方法，这是一个尚未得到满足的重大临床需求。在这个I期申请中，我们建议开发一种简单、廉价和快速的成像技术来识别手术中切除组织中的癌症。这种技术将在减轻或消除MMS的缺点的同时，为许多非黑色素瘤皮肤癌切除带来MMS手术的优点。我们提出的方法是局部应用专有的，智能的，蛋白酶结合的近红外荧光（NIRF）探针在体外切除的皮肤肿瘤组织。因为许多形式的癌症依赖于特定的蛋白酶（被称为组织蛋白酶B或L）来侵入周围的正常组织，所以当探针遇到活性酶时，它被设计成在近红外光下发出荧光。因为它能迅速激活，结果几乎可以立即为临床决策提供信息。拟议的技术可对公共卫生产生重大影响。将这种方法应用到患者护理中可以非常迅速地发生，并且有可能从根本上改善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：研究通过皮肤活检中的活性蛋白酶来测量局部给药探针的激活。我们将与一位经过mohs培训的皮肤科医生合作，获取丢弃的肿瘤组织样本。我们将对它们进行探测并成像。探针活化与癌细胞和活性组织蛋白酶的关系。统计分析，以确定准确性（敏感性和特异性）的测试，以确定它是否

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.