Radiation Force Imaging of Prostate Cancer and Guidance of Biopsy Procedures

描述（由申请人提供）：前列腺癌（PCa）是美国男性中最常见的非皮肤癌症，每年有超过185,000例新诊断病例，超过28,000例死亡[1,2]。筛查方法目前在美国和欧洲广泛用于检测前列腺癌，其中包括直肠指检（DRE）和前列腺特异性抗原（PSA）分析。当通过这些筛查机制产生怀疑时，进行前列腺活检诊断前列腺癌，这取决于活检芯中是否存在腺癌，临床意义取决于3个或更多活检芯中存在50%或以上的前列腺癌肿瘤组织，Gleason sum （GS，组织学分析）大于6，PSA密度（PSA除以超声所得的前列腺体积）大于0.15[3]。前列腺活检的临床标准是超声引导下，经直肠，横向定向18G针芯，针芯数量为6-12个，系统地采样前列腺不同区域。本标准不涉及将针瞄准可疑区域，因为前列腺癌没有独特的b超图像特征，无法从正常结构和前列腺良性病理（如良性前列腺增生（BPH）和炎症）中区分病变。目前的护理标准的敏感性很低（在一组根治性前列腺切除术标本中，既往诊断有临床意义的疾病[5]，使用八区系统活检仅53%），主要是因为采样网格仅随机交叉病理组织。在美国，每年进行超过100万例前列腺活检，前列腺癌的检出率很低（25-36%）。重复活检（首次活检阴性的病例）的PCa检出率为10-35%[7,8]。这些比率相同的事实表明，在一次系统活检中，检测到的癌症与遗漏的癌症一样多。此外，用这种方法检测到的许多癌症在临床上并不明显。弹性成像方法显示了前列腺癌可视化和前列腺活检指导的希望，基于正常和病理组织之间的刚度差异[9]。然而，弹性成像方法由于不能使用手持式经直肠超声换能器对前列腺施加均匀的压缩（应力）而受到限制。声辐射力脉冲成像（ARFI）是我们在杜克大学开发的一种弹性成像方法，通过使用聚焦声束施加应力来克服这些挑战。我们已经获得了初步的体外和体内结果，其中正常前列腺结构和局灶性前列腺癌病变在ARFI图像中清晰可见，而在匹配的b型图像中无法显示。活体数据表明，在前列腺癌可视化方面，ARFI成像比传统弹性成像有明显的优势，因为声能直接耦合到前列腺。我们建议开发和优化专用的2D和3D经直肠体内ARFI成像方法，以实现前列腺癌的可视化和前列腺癌与前列腺良性病变的区分；评估ARFI图像中可疑区域与组织组织学的相关性，探讨局部PCa Gleason模式（衡量组织侵袭性）与ARFI图像中PCa可见性的相关性，评估ARFI图像指导下临床意义显著的PCa活检检出率的潜在提高。如果成功，本研究有可能在第一次活检中大大提高临床显著级PCa（即gs7或以上）的癌症检出率，减少活检过程中活检芯的数量，促进原位治疗后PCa生长或复发的纵向监测，并为局灶性PCa治疗提供图像指导。

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the most common non-cutaneous cancer in men in the United States, with over 185,000 cases newly diagnosed, and over 28,000 deaths annually [1, 2]. Screening methods are now widely used in the United States and Europe to detect PCa, which include digital rectal examination (DRE), and prostate-specific antigen (PSA) analysis. When suspicion is raised through these screening mechanisms, prostate biopsies are performed to diagnose PCa, which depends upon the presence of adenocarcinoma in biopsy cores, with clinical significance being determined by the presence of 50% or more PCa tumor tissue in 3 or more biopsy cores, a Gleason sum (GS, histologic analysis) greater than 6, and a PSA density (PSA divided by ultrasound derived volume of prostate) more than 0.15[3]. The clinical standard for performing prostate biopsy is ultrasound-guided, transrectal, laterally directed 18G needle cores, with the number of cores ranging from 6-12, systematically sampling different regions of the prostate[4]. This standard does not involve targeting needles to suspicious regions since PCa does not have unique B-mode ultrasound image characteristics that can delineate diseased from normal structures and benign pathologies of the prostate (e.g., benign prostatic hyperplasia (BPH) and inflammation). The current standard of care has a dismal sensitivity (only 53% using octant systematic biopsy in a cohort of radical prostatectomy specimens with previously diagnosed, clinically significant disease, [5]), mainly because the sampling grid only randomly intersects the pathologic tissues. Over 1,000,000 prostate biopsies are performed annually in the United States[6], with PCa detection rates being low (25-36%)[6]. PCa detection rates on repeat biopsies (cases with negative first biopsies) are again 10-35% [7, 8]. The fact that these rates are identical suggests that as many cancers are detected as are missed during a single systematic biopsy session. In addition, many of the cancers that are detected with this approach are clinically insignificant[3]. Elastography imaging methods have shown promise for PCa visualization and prostate biopsy guidance based upon stiffness differences between normal and pathologic tissues[9]. However, elastography methods can be limited by an inability to apply uniform compression (stress) to the prostate using a hand-held transrectal ultrasonic transducer. Acoustic Radiation Force Impulse (ARFI) imaging is an elastography imaging method that we have developed at Duke University that overcomes these challenges through the use of focused acoustic beams for the application of stress. We have obtained promising initial ex vivo and in vivo results, in which normal prostatic structures and focal PCa lesions are clearly visualized in ARFI images that are not visualized in matched B-mode images. The in vivo data demonstrate a clear advantage of ARFI imaging over conventional elastography for PCa visualization, in that the acoustic energy is coupled directly into the prostate. We propose to develop and optimize dedicated 2D and 3D transrectal in vivo ARFI imaging methods for the purpose of visualizing PCa and differentiating PCa from benign processes in the prostate; to evaluate the correlation between suspicious regions in ARFI images and tissue histology, to investigate the correlation between local PCa Gleason pattern (measure of histologic aggressiveness) and PCa visibility in ARFI images, and to evaluate the potential increase in biopsy detection rate of clinically significant PCa under ARFI image guidance. If successful, this research has the potential to greatly improve cancer detection rates for clinically significant grade PCa (i.e. GS 7 or more) during first time biopsies, to reduce the number of biopsy cores taken during biopsy, to facilitate longitudinal monitoring of PCa growth or recurrence after in situ therapies, and to provide image guidance for focal PCa therapies.