A Fluorescence Histology System for In Vivo Breast Tumor Margin Assessment

描述(申请人提供)：2009年，估计有197,300名患有早期浸润性乳腺癌和/或原位癌(CIS)的妇女接受了保乳手术(BCS)。BCS包括切除周围有正常乳腺组织边缘的恶性组织。手术后在该切缘发现的残留癌是BCS术后肿瘤局部复发的重要预测指标。最近发现，在避免局部复发的情况下，每四名妇女中就有一人避免死亡。因此，彻底切除肿瘤是降低复发风险的关键。多达20%-70%的BCS患者必须接受再次切除手术，因为他们的癌细胞在第一次BCS手术中没有完全切除。这给患者带来了巨大的身体负担(增加了她发生手术并发症和/或最终癌症相关死亡的机会)，并给卫生保健系统带来了经济负担(实际上使这类患者的治疗费用翻了一番)。到2015年，预计美国接受BCS的患者数量将从每年约19.7万人增加到超过27万人，年增长率为5.5%。由于没有防止再次切除的行业标准，预计再次切除手术的数量将会随之增加。因此，有一个重要的未得到满足的临床需要，有效的术中评估乳腺肿瘤的边缘。这项应用的长期研究目标是开发一种临床可行的系统，用于BCS手术中肿瘤床的广域高分辨率显微镜检查，使用针对活体成像进行优化的广域光学切片扫描成像器，以及无毒的组织增强荧光造影剂。这将与自动图像分类算法相结合，使外科医生能够在术中自动决定是否应该从肿瘤床上切除更多的组织。这一开发阶段R21提案的目标是完成关键技术改进，并在临床前肿瘤边缘模型中进行验证。目前R21方案的具体目标是：1)开发一种实用的、非接触的、光学切片的广域荧光成像系统，用于体内肿瘤床评估；2)在转基因小鼠肿瘤边缘模型中，评估该成像系统用于体内肿瘤边缘评估。R21的成功完成将导致向临床可行的乳腺肿瘤边缘体内荧光组织学系统迈出关键的第一步。 公共卫生相关性：临床上可行的乳腺组织体内显微分析系统和方法的成功开发，对每年接受乳腺癌保乳手术的19.7万多名妇女具有巨大的影响。目前还没有广泛可用的术中工具来帮助外科医生确定手术是否成功，因此这些女性中有20%-70%将接受多次手术来完全切除她们的癌症。开发一种能够对肿瘤床进行高分辨率显微测绘的系统，可以让外科医生在第一次手术时捕捉到患者体内残留的肿瘤片段，从而避免了多次手术的需要，降低了患者发生手术并发症和肿瘤复发的机会，并大幅降低了这一不断增长的患者群体的医疗成本。

DESCRIPTION (provided by applicant): In 2009, an estimated 197,300 women with early stage invasive breast cancer and/or carcinoma in situ (CIS) received breast conserving surgery (BCS). BCS involves removal of malignant tissue with a surrounding margin of normal breast tissue. Residual cancer found in this margin after surgery is an important predictor of local recurrence of cancer after BCS. Recently, it was found that one death was averted for every four women in which a local recurrence is avoided. Thus, complete tumor excision is essential to reduce the risk of recurrence. As many as 20-70% of BCS patients must undergo re-excision surgery, because their cancer was incompletely removed during the first BCS procedure. This represents an enormous physical burden to the patient (increasing her chances for surgical complications and/or eventual cancer-related mortality) and financial burden to the health care system (effectively doubling the cost of treatment for this group of patients). By 2015, it is expected that the number of patients undergoing BCS will rise from approximately 197,000 to more than 270,000 per year in the U.S., at an annual growth rate of 5.5%. With no industry standard to prevent re-excision, it is expected that there will be a concomitant rise in the number of re-excision surgeries. Thus, there is a significant unmet clinical need for effective intra-operative assessment of breast tumor margins. The long-term research objective of this application is to develop a clinically-viable system for wide-field high-resolution microscopy of the tumor bed in BCS procedures, using a wide-field optically-sectioned scanning imager optimized for in vivo imaging, and non-toxic tissue-enhancing fluorescent contrast agents. This would be combined with automated image classification algorithms, which confer an automatic decision to the surgeon intra-operatively, whether or not additional tissue should be resected from the tumor bed. The objective of this development-phase R21 proposal is to complete a critical technology refinement, and to validate it in a pre-clinical tumor margin model. The specific aims of the current R21 proposal are 1) To develop a practical, non-contact, optically-sectioned wide-field fluorescence imaging system for in vivo tumor bed assessment, and 2) To evaluate the imaging system for in vivo tumor margin assessment in a transgenic murine tumor margin model. Successful completion of the R21 will result in a critical first step towards a clinically-viable system for in vivo fluorescence histology of breast tumor margins. PUBLIC HEALTH RELEVANCE: The successful development of a clinically-viable system and methodology for in vivo microscopic analysis of breast tissue has tremendous implications for the more than 197,000 women who annually undergo breast conserving cancer surgery. There is currently no widely available intra-operative tool to aid surgeons in determining whether surgery has been successful, therefore 20-70% of these women will undergo multiple surgeries to have their cancer fully removed. The development of a system which allows high-resolution microscopic mapping of the tumor bed could allow surgeons to catch bits of tumor left behind in the patient during the first surgery, thereby preventing the need for multiple surgeries, decreasing the patients' chances for surgical complications and tumor recurrence, and drastically reducing the healthcare costs for this growing patient population.