Ultrasound Monitoring of Rat Metastatic Uveal Melanoma

描述（由申请人提供）：约30%的葡萄膜黑色素瘤患者在5年内死于转移性疾病。转移的主要目标是肝脏，诊断后的中位生存期为4至7个月。目前没有标准的治疗方法，需要更好的治疗方法来提高患者的生存率。有必要在模拟人类疾病的临床相关动物模型中严格测试新的治疗方法。理想情况下，这些原发性和转移性葡萄膜黑色素瘤模型应允许随时间测量肿瘤大小。这将允许治疗开始于标准肿瘤大小，并允许在治疗期间监测肿瘤生长。在目前的原位人葡萄膜黑色素瘤模型中，不可能连续监测肿瘤生长，因为免疫功能低下的动物不能容易地移动到标准成像设备。一个手持的，高分辨率，高频超声（HF-US）系统的发展，使它成为可能，试图成像肿瘤生长在裸鼠的眼睛和肝脏。在本研究中，将检验以下总体假设：使用HF-US和原发性脉络膜黑色素瘤的新模型， 肿瘤进展的差异可能与原发性肿瘤中高碘酸-希夫碱（PAS）阳性环的存在相关。这将在2个具体目标（SA）中解决，其中假设：1）HF-US成像可重复用于监测原发性和转移性人脉络膜黑色素瘤的裸大鼠模型中的原发性肿瘤生长和转移性疾病的程度，和2）裸大鼠存活、血浆肿瘤标志物的水平和转移性病变的数量将与PAS阳性环、网络、和交联的平行通道在原发性人脉络膜黑色素瘤中在眼球摘除时。在SA 1中，HF-US将创新性地用于在原发性和转移性人葡萄膜黑色素瘤的裸大鼠模型中对原发性肿瘤生长和肝转移性疾病进行非侵入性成像。在SA 2中，HF-US系统将用于裸大鼠原发性黑色素瘤成像，其可靠地再现与患者生存相关的PAS阳性血管模式。摘除患眼肿瘤后，每两周进行一次肝脏高频超声成像，以跟踪转移进展。如果具有显示PAS阳性环的原发性肿瘤的大鼠具有较高的肝转移负荷，如通过HF-US所确定的，则该模型可用于研究这些模式在肿瘤生长和治疗反应中的重要性。总之，这个项目应该揭示强大的新技术的适用性，以研究在模拟人类疾病的模型中原发性和转移性葡萄膜黑色素瘤的生长和治疗反应。

DESCRIPTION (provided by applicant): About 30% of uveal melanoma patients die from metastatic disease within 5 years. The primary target of metastasis is the liver, and the median survival after a diagnosis is 4 to 7 months. There is current no standard treatment, and better therapies are needed to improve patient survival. It will be necessary to rigorously test new treatments in clinically relevant animal models that mimic the human disease. Ideally these primary and metastatic uveal melanoma models should allow tumor size to be measured over time. This would permit treatment to begin at a standard tumor size and allow tumor growth to be monitored during therapy. In current models of orthotopic human uveal melanoma, it is not possible to continuously monitor tumor growth, because immunocompromised animals cannot be readily moved to standard imaging equipment. The development of a hand-held, high-resolution, high-frequency ultrasound (HF-US) system has made it feasible to attempt to image tumor growth in the eye and liver of nude rats. In this study, the following overall hypothesis will be tested: Using HF-US and a new model of primary choroidal melanoma, differences in tumor progression can be correlated to the presence of periodic acid-Schiff base (PAS)-positive loops in the primary tumor. It will be addressed in 2 specific aims (SA) which hypothesize that: 1) HF-US imaging can be repeatedly used to monitor primary tumor growth and the extent of metastatic disease in nude rat models of primary and metastatic human choroidal melanoma and 2) nude rat survival, levels of plasma tumor markers, and the number of metastatic lesions will be related to the presence of PAS-positive loops, networks, and cross-linked parallel channels in the primary human choroidal melanoma at the time of enucleation. In SA1 HF-US will be innovatively used to noninvasively image primary tumor growth and hepatic metastatic disease in nude rat models of primary and metastatic human uveal melanoma. In SA2 the HF-US system will be used to image primary melanomas in nude rats that reliably reproduce the PAS-positive vascular patterns associated with patient survival. After the tumor-bearing eyes have been enucleated, biweekly HF-US images of the liver will be obtained to track metastatic progression. If rats with primary tumors that show PAS-positive loops have a higher liver metastatic burden as determined by HF-US, this model could be used to study the importance of these patterns in tumor growth and in treatment response. In summary, this project should reveal the applicability of powerful new techniques to study the growth and treatment response of primary and metastatic uveal melanoma in models that mimic the human disease.