Ultrasound Monitoring of Rat Metastatic Uveal Melanoma

描述(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，确诊后的中位生存期为4至7个月。目前还没有标准的治疗方法，需要更好的治疗方法来提高患者的存活率。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，这些原发和转移性葡萄膜黑色素瘤模型应该允许随着时间的推移测量肿瘤大小。这将允许从标准的肿瘤大小开始治疗，并允许在治疗期间监测肿瘤的生长。在目前的人葡萄膜原位黑色素瘤模型中，不可能连续监测肿瘤的生长，因为免疫受损的动物不能轻易地转移到标准的成像设备上。手持式、高分辨率、高频超声(HF-US)系统的发展使尝试对裸鼠眼睛和肝脏中的肿瘤生长进行成像成为可能。在这项研究中，将检验以下总体假设：使用高频超声和一种新的原发脉络膜黑色素瘤模型， 肿瘤进展的差异可能与原发肿瘤中存在过碘酸-席夫碱(PAS)阳性环有关。它将在两个特定的目标(SA)中解决，这两个假设：1)高频超声成像可以重复用于监测原发和转移性人脉络膜黑色素瘤裸鼠模型中的原发肿瘤生长和转移疾病的程度；2)裸鼠存活率、血浆肿瘤标志物水平和转移灶数量将与去核时原发人脉络膜黑色素瘤中PAS阳性环、网络和交叉连接的平行通道的存在有关。在SA1中，HF-US将被创新地用于对人葡萄膜黑色素瘤原发和转移性黑色素瘤裸鼠模型的原发肿瘤生长和肝转移疾病进行无创成像。在SA2中，HF-US系统将用于对裸鼠的原发性黑色素瘤进行成像，从而可靠地再现与患者生存相关的PAS阳性血管模式。在肿瘤眼被摘除后，将获得每两周一次的肝脏高频超声图像，以跟踪转移进展。如果显示PAS阳性环路的原发肿瘤的大鼠有更高的肝脏转移负荷，如HF-US所确定的，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。总而言之，该项目应该揭示出强大的新技术在模拟人类疾病的模型中研究原发和转移性葡萄膜黑色素瘤的生长和治疗反应的适用性。

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.