Prostate Cancer Imaging

背景：前列腺癌是男性癌症死亡的第二大原因。由于血清前列腺特异性抗原（PSA）筛查的结果，被诊断患有前列腺癌的男性人数急剧增加，每年约有22万例新诊断。诊断是在一个更年轻的年龄，但发病率的标准治疗；手术和放疗，保持不变。因此，诊断为前列腺癌的男性很可能因其疾病而被过度治疗，并将在这种治疗的后果中生活多年，这极大地影响了生活质量年（QALY）。这一困境的最终答案是血清生物标志物，它可以识别致命的癌症，而不是偶然的癌症，但这不太可能很快发生。与此同时，前列腺癌的定位和微创治疗方法将大大减少前列腺癌广泛筛查和过度诊断相关的发病率。各种成像方法已经发展起来，我们正在探索它们在早期前列腺癌定位中的作用(1)。泌尿外科肿瘤科正在与MIP合作开发新的成像方法，与他们的微创治疗方法相结合，包括射频消融、冷冻治疗和酒精消融。临床前研究MIP一直在与病理学实验室的Mike Buck一起研究各种靶点。我们已经在前列腺癌动物模型中评估了一种针对PSMA （3TC）的抗体，虽然该药物成功靶向LnCAP和PC3肿瘤系，但在临床开发中，该药物与许多类似的药物竞争。Buck实验室发现了一种新的前列腺癌标志物上皮细胞粘附分子（epithelial cell adhesion molecule, EpCAM）作为基质靶点。与传统的前列腺癌靶点不同，这个靶点位于与癌症相关的基质中。因此，它可能比位于基底膜后面的腺泡内的前列腺癌细胞标记物更容易接近（尽管前列腺癌的基底膜经常被破坏）。基质是包括血管和淋巴管在内的微环境的一部分，因此可能更具“针对性”。一种抗EpCAM的人抗体已经开发出来，并正在临床试验中。这种放射性标记抗体已经在人体组织中进行了测试。在犬类前列腺癌模型中也发现了类似的标记物，目前正在设计犬类试验。临床试验MIP自成立以来一直在研究人类前列腺癌成像。我们在3T时进行直肠内线圈MRI，包括DCE-MRI， MR光谱和扩散加权成像。我们与飞利浦医疗系统的CRADA一起开发了这三种技术的分析工具。我们已经证明DCE-MRI提高了3T MRI对前列腺癌的特异性。然而，3T MRI的敏感性和特异性仍然存在明显的局限性。在患者接受前列腺切除术后，他们的标本可用于复查，很明显，不到40%的患者可以接受局灶治疗，这是基于MRI上可见的单一的、界限明确的病变。我们与约翰霍普金斯大学生物工程学院合作设计了MR引导活检设备，但结论是该设备对于临床使用过于复杂且耗时（2-5）。该装置用于确定高剂量率近距离放射治疗的治疗场，然而，它被证明有些麻烦。因此，我们与飞利浦医疗系统公司合作，设计了一种US-MR融合系统，该系统将3T MRI的数据融合到实时超声图像中(6)。活检和介入手术可以在超声的“MR指导”下进行。该装置已成功应用于25名患者。我们不久将在狗身上进行一项研究，以证实针头放置的准确性。我们认为MRI在鉴别前列腺内疾病方面是有限的。我们正在使用11C-Acetate进行PET研究，以研究该药物在识别前列腺内病变中的价值(1)。患者还将接受3T MRI， PET图像将与MRI融合。我们计划研究18F-ACBC，这是一种与氨基酸运输相关的药物，在前列腺癌的定位中显示出益处。最终我们希望结合PET-MR研究并在US融合后进行微创治疗。1. Hricak， H., Choyke， P. L., Eberhardt， S. C., Leibel， S. A.和Scardino， P. T.前列腺癌成像：多学科视角。中华放射学杂志，2003,24(3):344 - 344。2. Susil， R. C, Menard， C, Krieger， A, Coleman， J. A, Camphausen， K., Choyke， P., Fichtinger， G., Whitcomb， L. L., Coleman， C. N.和Atalar， E.经直肠前列腺活检和标准1.5T磁共振成像扫描仪中的基准标记物放置。中国生物医学工程学报，2004,31(2):393 - 398。3. Menard， C, Susil， R. C, Choyke， P., Coleman， J., Grubb， R., Gharib， A., Krieger， A., Guion， P., Thomasson， D., Ullman， K., Gupta， S., Espina， V., Liotta， L., Petricoin， E., Fitchtinger， G., Whitcomb， L., Atalar， E., Coleman， C. N.和Camphausen， K.一种用于前列腺内动态对比增强分子表征的介入磁共振成像技术。中国生物医学工程学报，2004,31(4):663 - 666。4. Susil， R. C, Camphausen， K., Choyke， P., McVeigh， E. R., Gustafson， G. S., Ning， H., Miller， R. W., Atalar， E., Coleman， C. N.和Menard， C.在标准的1.5 T MRI扫描仪中用于前列腺近距离治疗和活检的系统。中华医学杂志，32(2):683-687,2004。5. Menard， C, Susil， R. C, Choyke， P., Gustafson， G. S, Kammerer， W., Ning， H., Miller， R. W., Ullman， K. L., Sears Crouse， N., Smith， S., Lessard， E., Pouliot， J., Wright， V., McVeigh， E., Coleman， C. N., Camphausen， K.， mri引导的HDR前列腺近距离治疗标准1.5T扫描仪。中国生物医学工程学报，32(2):444 - 444,2004。6. Lattouf， J. B., Grubb， R. L., 3, Lee， S. J, Bjurlin， M. A., Albert， P., Singh， A. K., Ocak， I., Choyke， P., Coleman， J. A.磁共振成像引导下经直肠超声活检在前列腺癌患者中的应用。中国生物医学工程学报，2009,31(2):441 - 446。

Molecular Imaging of Prostate Cancer Background: Prostate cancer is the 2nd leading cause of cancer death in males. As a result of screening with serum prostate specific antigen (PSA) there has been a dramatic increase in the number of men diagnosed with prostate cancer, about 220,000 new diagnoses annually. The diagnosis is being made at a younger age yet the morbidity of the standard treatments; surgery and radiation---remain unchanged. Thus, men with the diagnosis of prostate cancer are likely being overtreated for their disease and will live with the consequences of this treatment for many years greatly affecting the Quality of Life Years (QALY). The ultimate answer to this dilemma is serum biomarkers that identify lethal cancers but not incidental cancers but this is unlikely to occur soon. In the meantime, methods of localizing prostate cancer and treating them with minimally invasive therapy would dramatically lessen the morbidity associated with widespread screening and the overdiagnosis of prostate cancer. A variety of imaging methods have been developed and we are exploring their role in localizing early prostate cancer(1). The Urologic Oncology Branch is partnering with the MIP to develop new imaging methods to be coupled with their minimally invasive treatment methods which include RF ablation, cryotherapy and alcohol ablation. Pre-Clinical Research The MIP has been investigating a variety of targets in conjunction with Mike Buck in the Laboratory of Pathology. We have evaluated an antibody against PSMA (3TC) in animal models of prostate cancer and while this agent was successful in targeting LnCAP and PC3 tumor lines, the agent competes against many similar agents further along in clinical development. A novel marker of prostate cancer, epithelial cell adhesion molecule (EpCAM) has been identified as a stromal target by the Buck lab. Unlike conventional prostate cancer targets, this target is located in the stroma associated with cancers. As a result it may be more accessible than prostate cancer cell markers that are within acini and located behind the basement membrane (although the basement membrane is often disrupted in prostate cancer). Stroma is part of the microvenvironment that includes vessels and lymphatics and therefore may be more "targetable" . A human antibody against EpCAM has been developed and is in clinical trials. The radiolabeled antibody has been tested in human tissue. Analagous markers have been found in the canine model of prostate cancer and trials in dogs are being designed. Clinical Trials The MIP has been studying prostate cancer imaging in humans since its inception. We perform endorectal coil MRI at 3T which includes DCE-MRI, MR Spectroscopy and Diffusion Weighted Imaging. We have developed analytic tools for all three techniques in conjunction with a CRADA with the Philips Medical Systems. We have demonstrated that DCE-MRI improves the specificity of 3T MRI for prostate cancer. However, there remain significant limitations in the sensitivity and specificity of 3T MRI. After patients undergo prostatectomy and their specimens are available for review it is clear that less than 40% would be amenable for focal therapy based on being single, well circumscribed lesions that are visible on MRI. We have designed MR guided biopsy devices in conjunction with Johns Hopkins University School of Bioengineering but concluded that this device was too complex and time consuming for clinical use(2-5). This device was used to define treatment fields for High Dose Rate Brachytherapy, however, it proved somewhat cumbersome. Therefore, working with Philips Medical Systems we have designed an US-MR fusion system that takes the data from the 3T MRI and fuses it to the real time ultrasound image(6). Biopsy and interventional procedures can then be performed under "MR guidance" using the ultrasound. This device has been used successfully in 25 patients. We will shortly perform a study in dogs in which the accuracy of needle placement is confirmed. We believe that MRI is fundamentally limited in identifying intraprostatic disease. We are conducting a PET study using 11C-Acetate to study the value of this agent in identifying intraprostatic lesions(1). Patients will also undergo 3T MRI and the PET image will be fused to the MRI. We have plans to study 18F-ACBC an agent associated with amino acid transport which has shown benefit in localizing prostate cancer. Ultimately we wish to combine PET-MR studies and conduct minimally invasive therapies after US fusion. 1. Hricak, H., Choyke, P. L., Eberhardt, S. C., Leibel, S. A., and Scardino, P. T. Imaging prostate cancer: a multidisciplinary perspective. Radiology, 243: 28-53, 2007. 2. Susil, R. C., Menard, C., Krieger, A., Coleman, J. A., Camphausen, K., Choyke, P., Fichtinger, G., Whitcomb, L. L., Coleman, C. N., and Atalar, E. Transrectal prostate biopsy and fiducial marker placement in a standard 1.5T magnetic resonance imaging scanner. J Urol, 175: 113-120, 2006. 3. Menard, C., Susil, R. C., Choyke, P., Coleman, J., Grubb, R., Gharib, A., Krieger, A., Guion, P., Thomasson, D., Ullman, K., Gupta, S., Espina, V., Liotta, L., Petricoin, E., Fitchtinger, G., Whitcomb, L. L., Atalar, E., Coleman, C. N., and Camphausen, K. An interventional magnetic resonance imaging technique for the molecular characterization of intraprostatic dynamic contrast enhancement. Mol Imaging, 4: 63-66, 2005. 4. Susil, R. C., Camphausen, K., Choyke, P., McVeigh, E. R., Gustafson, G. S., Ning, H., Miller, R. W., Atalar, E., Coleman, C. N., and Menard, C. System for prostate brachytherapy and biopsy in a standard 1.5 T MRI scanner. Magn Reson Med, 52: 683-687, 2004. 5. Menard, C., Susil, R. C., Choyke, P., Gustafson, G. S., Kammerer, W., Ning, H., Miller, R. W., Ullman, K. L., Sears Crouse, N., Smith, S., Lessard, E., Pouliot, J., Wright, V., McVeigh, E., Coleman, C. N., and Camphausen, K. MRI-guided HDR prostate brachytherapy in standard 1.5T scanner. Int J Radiat Oncol Biol Phys, 59: 1414-1423, 2004. 6. Lattouf, J. B., Grubb, R. L., 3rd, Lee, S. J., Bjurlin, M. A., Albert, P., Singh, A. K., Ocak, I., Choyke, P., and Coleman, J. A. Magnetic resonance imaging-directed transrectal ultrasonography-guided biopsies in patients at risk of prostate cancer. BJU Int, 99: 1041-1046, 2007.